Cardioprotective lipids and methods of use

Abstract

The present invention includes a method for reducing or eliminating the cardiotoxic or cardiac effects of one or more active agents, comprising: administering to a subject in need an effective amount of one or more lipids that reduce or eliminate the cardiotoxic effects of said one or more active agents.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480069256.X (22) Application Date 2024.08.07 (30) Priority Data 18 / 457037 2023.08.28 US (85) PCT International Application Entering National Phase Date 2026.04.28 (86) PCT International Application Application Data PCT / US2024 / 041253 2024.08.07 (87) PCT International Application Publication Data WO2025 / 049064 EN 2025.03.06 (71) Applicant: Saenpass Pharmaceuticals, Inc. Address: Utah, USA (72) Inventor: D.E. Revey (74) Patent Agency: Beijing Panhua Weiye Intellectual Property Agency Co., Ltd. 11280 Patent Attorney Guo Guangxun (51) Int.Cl. C07F 9 / 09 (2006.01) A61K 31 / 6615 (2006.01) A61K 47 / 24 (2006.01) A61P 9 / 06 (2006.01) (54) Invention Title Cardioprotective Lipids and Method of Use (57) Abstract This invention includes a method for reducing or eliminating the cardiotoxic or cardiac effects of one or more active agents, comprising: administering to a subject in need an effective amount of one or more lipids that reduce or eliminate the cardiotoxic effects of said one or more active agents. Claims 22 pages, Description 128 pages, Drawings 17 pages, CN 122094963 A 2026.05.26 CN 1 22 09 49 63 A 1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein, R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R3 is; R4 is H or a pharmaceutically acceptable cation, wherein the introduction of said pharmaceutically acceptable cation forms a salt; R5 is optionally separated by one or more of OH, OAc, OMe, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl, Br and I. R6 is a C1-C10 branched or unbranched hydrocarbon substituted with a group; R7 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R8)2, SH, CN, COOH, CONH2, Cl, Br and I; each R7 is independently H or C1-C6 branched or unbranched alkyl; each R8 is independently H or C1-C6 branched or unbranched alkyl.X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and each stereocenter is independently R, S, or racemic. 2. The compound of claim 1, represented by a compound of formula IA or a pharmaceutically acceptable salt thereof, wherein R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R3 is; R4 is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt; R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, N(R7)2, and COOH; R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, N(R8)2, and COOH. Each R7 is independently H or C1-C6 branched or unbranched alkyl; each R8 is independently H or C1-C6 branched or unbranched alkyl; X is a direct bond; Y is a direct bond; and, each stereocenter is independently R, S or racemic, and optionally, R4 is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium. 3. The compound of claim 1, wherein the compound is selected from at least one of the following: (Claims 2 / 22, Page 3, CN 122094963 A) 4. The compound of claim 1, wherein any oxyanion O− of any compound is paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH of any compound is optionally in the form of a pharmaceutically acceptable salt, wherein the compound is a single entity, a solvate, a hydrate, a crystal, an amorphous solid, a liquid or an oil. 5. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, wherein, R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R3 is; R4 is H or a pharmaceutically acceptable cation, wherein the introduction of said pharmaceutically acceptable cation forms a salt;R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl, Br, and I; R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R8)2, SH, CN, COOH, CONH2, Cl, Br, and I; each R7 is independently H or C1-C6 branched or unbranched alkyl; each R8 is independently H or C1-C6 branched or unbranched alkyl; X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and, each stereocenter is independently R, S, or racemic; the method comprises the step of: converting the hydroxyl group of the compound of formula II to an ester, carbonate, or carbamate, wherein all substitutions are defined as described above. Optionally, the phosphorus-bound OH group is converted to O-R4, wherein R4 is not H; and, optionally, one or more protecting groups are removed; or the method comprises the step of: linking a compound of formula III to a compound of formula IV by generating a phosphodiester bridge, wherein R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; each R7 is independently H or a C1-C6 branched or unbranched alkyl group; each R8 is independently H or a C1-C6 branched or unbranched alkyl group; R9 is a C1-C10 branched or unbranched hydrocarbon substituted with one or more groups independently selected from OR11, N(R7)R12, N(R7)2, SR13, CN, COOR14, CONH2, Cl, Br, and I; R10 is a C1-C10 branched or unbranched hydrocarbon substituted with one or more groups independently selected from OR11, N(R8)R12, N(R8)2, SR13, CN, COOR14, CONH2, Cl, Br, and I; each R11 is independently H, Ac, Me, tert-butyl, benzyl, triphenylmethyl, benzoyl, p-nitrobenzoyl, MOM, BOM, or Si constituting the core of a silyl ether; each R12 is independently H, Me, Boc, Cbz, Fmoc, benzyl, 4-methoxybenzyl, tert-butyl, or triphenylmethyl; Each R13 is independently H, Ac, benzoyl, p-nitrobenzoyl, or triphenylmethyl; each R14 is independently H, C1-C6 branched or unbranched alkyl, benzyl, or 4-methoxybenzyl; X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and,Each stereocenter is independently R, S, or racemic; optionally, the phosphorus-bound OH group is converted to O-R4, wherein R4 is not H; and optionally, each OR11, N(R7)R12, N(R8)R12, SR13, or COOR14 is converted to OH, NHR7, NHR8, SH, or COOH, respectively. 6. The method of claim 5, wherein the method is used to prepare a compound of formula IA or a pharmaceutically acceptable salt thereof, wherein R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R3 is; R4 is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt; R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, N(R7)2, and COOH; R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, N(R8)2, and COOH. Each R7 is independently H or C1-C6 branched or unbranched alkyl; each R8 is independently H or C1-C6 branched or unbranched alkyl; X is a direct bond; Y is a direct bond; and, each stereocenter is independently R, S or racemic; the method comprises the steps of: converting the hydroxyl group of the compound of formula II to an ester, carbonate or carbamate, II wherein all substitutions are defined as described above; optionally, converting the phosphorus-bound OH group to O-R4, wherein R4 is not H; and, optionally, removing one or more protecting groups; or the method comprises the steps of: linking the compound of formula III to the compound of formula IV by generating a phosphodiester bridge, III IV wherein, claims 6 / 22 page 7 CN 122094963 A R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds or a combination of 0-10 double bonds and triple bonds; R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; each R7 is independently H or a C1-C6 branched or unbranched alkyl group; each R8 is independently H or a C1-C6 branched or unbranched alkyl group; R9 is a C1-C10 branched or unbranched hydrocarbon substituted with one or more groups independently selected from OR11, N(R7)R12, N(R7)2, and COOR14.R10 is a C1-C10 branched or unbranched hydrocarbon substituted with one or more groups independently selected from OR11, N(R8)R12, N(R8)2, and COOR14; each R11 is independently H, Ac, Me, tert-butyl, benzyl, triphenylmethyl, benzoyl, p-nitrobenzoyl, MOM, BOM, or Si constituting the core of a silyl ether; each R12 is independently H, Me, Boc, Cbz, Fmoc, benzyl, 4-methoxybenzyl, tert-butyl, or triphenylmethyl; each R14 is independently H, C1-C6 branched or unbranched alkyl, benzyl, or 4-methoxybenzyl; X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and each stereocenter is independently R, S, or racemic; optionally, the phosphorus-bonded OH group is converted to O-R4, wherein R4 is not H; and, Optionally, each OR11, N(R7)R12, N(R8)R12, or COOR14 is converted to OH, NHR7, NHR8, or COOH, respectively. 7. The method of claim 5, wherein the method comprises the steps of: converting the hydroxyl group of the compound of formula II to an ester, carbonate, or carbamate, wherein all substitutions are defined as described above; optionally, converting the phosphorus-bound OH group to O-R4, wherein R4 is not H; and optionally, removing one or more protecting groups. 8. The method of claim 5, wherein the method comprises the step of: linking a compound of formula III to a compound of formula IV by generating a phosphodiester bridge, wherein, R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; each R7 is independently H or a C1-C6 branched or unbranched alkyl group; each R8 is independently H or a C1-C6 branched or unbranched alkyl group; R9 is a compound independently selected from OR11, N(R7)R12, N(R7)2, SR 13. A C1-C10 branched or unbranched hydrocarbon substituted with groups of CN, COOR14, CONH2, Cl, Br, and I; R10 is a C1-C10 branched or unbranched hydrocarbon substituted with one or more groups independently selected from OR11, N(R8)R12, N(R8)2, SR13, CN, COOR14, CONH2, Cl, Br, and I; Each R11 is independently H, Ac, Me, tert-butyl, benzyl, triphenylmethyl, benzoyl, p-nitrobenzoyl, MOM, BOM, or Si constituting the core of a silyl ether;Each R12 is independently H, Me, Boc, Cbz, Fmoc, benzyl, 4-methoxybenzyl, tert-butyl, or triphenylmethyl; each R13 is independently H, Ac, benzoyl, p-nitrobenzoyl, or triphenylmethyl; each R14 is independently H, C1-C6 branched or unbranched alkyl, benzyl, or 4-methoxybenzyl; X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and each stereocenter is independently R, S, or racemic; optionally, the phosphorus-bonded OH group is converted to O-R4, wherein R4 is not H; and optionally, each OR11, N(R7)R12, N(R8)R12, SR13, or COOR14 is converted to OH, NHR7, NHR8, SH, or COOH, respectively, and optionally R4 is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium. 9. The method of claim 5, wherein the compound is selected from at least one of the following: (Claims 8 / 22, page 9, CN 122094963 A), (Claims 9 / 22, page 10, CN 122094963 A). 10. The method of claim 5, wherein any oxyanion O− of any compound is paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium; and wherein any NH2 or COOH of any compound is optionally in the form of a pharmaceutically acceptable salt, and optionally, the method prepares the compound as a single entity, solvate, hydrate, crystal, amorphous solid, liquid, or oil. 11. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier, wherein R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R3 is; R4 is H or a pharmaceutically acceptable cation, wherein the introduction of said pharmaceutically acceptable cation forms a salt; R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl, Br, and I; R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R8)2, SH, CN, COOH, CONH2, Cl, Br and I; each R7 is independently H or C1-C6 branched or unbranched alkyl.Each R8 is independently H or C1-C6 branched or unbranched alkyl; X is a direct bond, O or NH; Y is a direct bond, O or NH; and, each stereocenter is independently R, S or racemic, and, optionally, R4 of the compound of formula I is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium. Claims 10 / 22 pages 11 CN 122094963 A 12. The pharmaceutical composition of claim 11, wherein the compound of formula I is selected from one or more of the following: , ... 13. The pharmaceutical composition of claim 11, wherein any oxyanion O− of any compound is paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium; and wherein any NH2 or COOH of any compound is optionally in the form of a pharmaceutically acceptable salt, and optionally, the compound of formula I exists as a single entity, solvate, hydrate, crystal, amorphous solid, liquid, or oil. 14. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition further comprises one or more agents that induce cardiac disease as a side effect. 15. The pharmaceutical composition of claim 14, wherein one or more agents inducing cardiac events as a side effect are selected from at least one of the following: adrenaline, salbutamol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, afortrol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, benprodil, bortezomib, bosutinib, bromhexine, buprenorphine, capecitabine, chloral hydrate, clomipramine, chloroquine, chlorpromazine, ciprofloxacin, cisapride, Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine, Crizotinib, Curcumin, Cyclobenzaline, Cyclosporine, Darafenib, Dasatinib, Degarelix, Desipramine, Desvenlafaxine, Dexmedetomidine, Methylphenidate, Dextromethorphan, Dihydroartemisinin and Piperaquine, Diphenhydramine, Disopyramide, Dobutamine, Dofetilide, Dolastron, Domperidone, Donepezil, Dopamine, Doxepin, Dronedarone, Fluperidone, Ephedrine, Epinephrine, Erebulin, Erythromycin, Edeprom, Famotidine, Femimetabolic Acid, Fenfluramine, Fingolimod, Flucainide, Fluconazole, Fluoxetine, Formoterol Phosphoric acid, fosphenytoin, furosemide, galantamine, gatifloxacin, gemcitabineStar, Granisetron, Halofantrolin, Haloperidol, Hydrochlorothiazide, Hydroxychloroquine, Hydroxyzine, Ibutilide, Ipraridone, Imipramine, Indapamide, Isoproterenol, Iradipine, Itraconazole, Ivabradine, Ketoconazole, Lapatinib, Leuprorelin, Levosalbutamol, Levofloxacin, Levomethasone, Levomethadone, Lysine Mesylate, Lithium, Loperamide, Maprotiline, Mefloquine, Melipramine, Mesordazine, Osinaline, Methadone, Methamphetamine Methylphenidate, Metoclopramide, Mexiletine, Midodrine, Mifepristone, Mirabelon, Mirtazapine, Moxipril / HCTZ, Moxifloxacin, Neferunavir, Nicardipine, Nilotinib, Norepinephrine, Norfloxacin, Nortriptyline, Octreotide, Ofloxacin, Olanzapine, Ondansetron, Ophenadrine, Oxaliplatin, Oxycodone, Oxytocin, Palapivene, Papaverine Hydrochloride, Paroxetine, Parretide, Pazopanib, Pazopanib, Pentamidine, Perfluoropropane Lipospheres, Perphenazine, Phenylephrine, Phenylephrine Phenylacetolamine, pimozide, posaconazole, probucol, procainamide, promethazine, propafenone, propofol, dextropropoxyfen, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, ritonavir and lopinavir, roxithromycin, salbutamol, salmeterol, saquinavir, serindole, claims 12 / 22 pages 13 CN 122094963 A Sertraline, sevoflurane, sibutramine, sofenacin, sorafenib, sotalol, sparfloxacin, spiramycin, sulpiride, sunitinib, tacrolimus, tamoxifen, terabhivir, terbinafine, terfenadine, tetrabenzylquinazine, thioridazine, tevothixol, tizanidine, tizanidinev, tolterodine, toremifene, torasemide, trazodone, trimethoprim and sulfamethoxazole, sulfamethoxazole, trimethoprim, trimethoprim, vandetanil, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, ziprasidone or ziprasidone. 16. The pharmaceutical composition of claim 11, wherein the compound of formula I is at least one of the following: existing as a single entity, solvate, hydrate, crystal, amorphous solid, liquid, or oil; reducing or eliminating one or more of cardiac ion channelopathies caused by the active agent used to treat a disease or symptoms caused by irregularities or alterations in cardiac rhythm; administered in an amount per unit dose between about 1 mg and about 1 g; or formulated for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, skin, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration, and optionally, the compound of formula I is formulated as tablets, capsules, pouches, pills, powders, lozenges, syrups, or liquids.Solutions, suspensions, emulsions, elixirs, or oral films (OTFs), solid forms, solutions, suspensions, or soft gels are intended for oral administration; or optionally, the solid form further comprises one or more excipients, binders, anti-adhesion agents, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, gliding agents, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, or combinations thereof. 17. A method for reducing or eliminating one or more of cardiac ion channelopathies, myocardial injury, or symptoms caused by irregularities or alterations in cardiac rhythm in a human or animal subject, comprising administering to a human or animal subject one or more of compounds of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R3 is; R4 is H or a pharmaceutically acceptable cation, wherein the introduction of said pharmaceutically acceptable cation forms a salt; R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl, Br, and I; R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R8)2, SH, CN, COOH, CONH2, Cl, Br, and I; Each R7 is independently H or C1-C6 branched or unbranched alkyl; Each R8 is independently H or C1-C6 branched or unbranched alkyl; X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and, each stereocenter is independently R, S, or racemic, and; Optionally, R4 of the compound of formula I is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium. 18. The method of claim 17, wherein the compound of formula I is at least one of the following: existing as a single entity, solvate, hydrate, crystal, amorphous solid, liquid, or oil; reducing or eliminating one or more of cardiac ion channelopathies or symptoms caused by irregularities or alterations in cardiac rhythm due to the active agent used to treat a disease; administered in an amount per unit dose between about 1 mg and about 1 g; or formulated for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, skin, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration, and optionally, the compound of formula I is formulated as tablets, capsules, pouches, pills, powders, lozenges, slurries, liquid solutions, or suspensions.The compound is intended for oral administration in the form of a preparation, emulsion, elixir, or oral film (OTF), solid form, solution, suspension, or soft gel; or optionally, the solid form further comprises one or more excipients, binders, anti-adhesion agents, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, flow aids, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, or combinations thereof. 19. The method of claim 17, wherein the compound of formula I is co-administered with one or more agents that induce cardiac events as a side effect. 20. The method of claim 19, wherein one or more active agents that induce cardiac events as a side effect are selected from at least one of the following: adrenaline, salbutamol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, afortrol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, benprodil, bortezomib, bosutinib. bromide, benzylamine, buprenorphine, capecitabine, chloral hydrate, clomipramine, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, crizotinib, curcumin, cyclobenzaline, cyclosporine, dabrafenib, dasatinib, degarelix, desipramine, desvenlafaxine, dexmedetomidine, dextromethorphan, dextromethorphan, dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, donepezil Dopamine, Doxepin, Dronedarone, Fluperidone, Ephedrine, Epinephrine, Erebulin, Erythromycin, Ediprom, Famotidine, Femimetabolic Acid, Fenfluramine, Fingolimod, Flucainide, Fluconazole, Fluoxetine, Formoterol, Foscarboxylic Acid, Phosphotoin, Frusemide, Galantamine, Gatifloxacin, Gemimifloxacin Granisetron, Halofantrolin, Haloperidol, Hydrochlorothiazide, Hydroxychloroquine, Hydroxyzine, Ibutilide, Ipraridone, Imipramine, Indapamide, Isoproterenol, Iradipine, Itraconazole, Ivabradine, Ketoconazole, Lapatinib, Leuprorelin, Levosalbutamol, Levofloxacin, Levomethasone, Levomethadone, Lysine Mesylate, Lithium, Loperamide, Maprotiline, Mefloquine, Mepratrimine, Mesodexazine, Osinaline Methadone, methamphetamine, methylphenidate, metoclopramide, mexiletine, midodrine, mifepristone, mirabezoni, mirtazapine, moxipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, octreotide, ofloxacin, olanzapine, ondansetron, oxaliplatin, oxytocin, palapirone, papaverine hydrochloride, paroxetine, parretoxin, pazopatamineNi, Pazopanib, Pentamidine, Perfluoropropane lipid microspheres, Perphenazine, Phenylephrine, Phenylephrine, Phenylephrine, Pimozide, Posaconazole, Probucol, Procainamide, Promethazine, Propafenone, Propofol, Dextropropoxyfen, Protriptyline, Pseudoephedrine, Quetiapine, Quinidine, Quinine, Quinine Sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir, Ritonavir and Lopinavir, Roxithromycin, Salbutamol, Salmeterol, Saquinavir, Sertraline, Sevoflurane, West African swine fever, Butyrine, Sofenac, Sorafenib, Sotalol, Sparfloxacin, Spiramycin, Sulpiride, Sunitinib, Tacrolimus Tamoxifen, terabhivir, terabinin, telithromycin, terbutaline, terfenadine, tetrabenzidine, thioridazine, tevothixol, tizanidine, tizanidinev, tolterodine, toremifene, torasemide, trazodone, trimethoprim and sulfamethoxazole, sulfamethoxazole, trimethoprim, trimethoprim, vandetanil, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, ziprasidone or ziprasidone. 21. The method of claim 17, wherein the compound of formula I reduces or eliminates drug-induced or disease- or condition-related cardiac events, such as QT interval prolongation, myocardial damage, or AV block. 22. The method of claim 17, wherein the compound is: [a, b], [a, c], [a, b ... 24. A method for reducing or eliminating the cardiotoxic or cardiac effects of one or more active agents, comprising: administering one or more cardiotoxic active agents to a subject requiring treatment of a disease or disorder; and providing a combination therapy with an effective amount of one or more lipids, said one or more lipids reducing or eliminating the cardiotoxic effects of said one or more active agents, wherein said lipids have the following formula or are pharmaceutically acceptable salts thereof: I Wherein, R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; ClaimsRequesting book 16 / 22, page 17, CN 122094963 A. R3 is; R4 is H or a pharmaceutically acceptable cation, wherein the introduction of said pharmaceutically acceptable cation forms a salt; R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl, Br, and I; R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R8)2, SH, CN, COOH, CONH2, Cl, Br, and I; Each R7 is independently H or a C1-C6 branched or unbranched alkyl group; Each R8 is independently H or a C1-C6 branched or unbranched alkyl group; X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and, Each stereocenter is independently R, S, or racemic, and; wherein cardiotoxicity is reduced by at least 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, or 100% compared to treatment without said lipid, and optionally, wherein R4 is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium. 25. The method of claim 24, wherein said cardiotoxicity or cardiac lesion is selected from at least one of: minimal left ventricular dilatation, systolic dysfunction, moderate valvular regurgitation, decreased left ventricular ejection fraction (LVEF), cardiac hypertrophy, decreased cardiac contractility, decreased cardiac output, pressure and volume overload hypertrophy, myocardial dysfunction, cardiac remodeling, post-myocardial infarction heart failure, or cardiac disease. 26. The method of claim 24, wherein the one or more active agents and the lipids are administered simultaneously, or the one or more active agents and the lipids are formulated for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, skin, subcutaneous, local, pulmonary, rectal, vaginal, or intramuscular administration, or wherein the one or more lipids, the one or more active agents, or both are infused over 3 hours. 27. The method of claim 24, wherein one or more agents inducing cardiotoxicity or cardiac lesions are selected from at least one of the following: adrenaline, salbutamol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, afortrol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, benprodil, bortezomib, bosutinib, bromoxynil, buprenorphine, capecitabine, chloral hydrate, clomipramine, chloroquine, chlorpromazine, ciprofloxacin, cisapride, cetirizine.Pramiprine, Clarithromycin, Clomipramine, Clozapine, Cocaine, Crizotinib, Curcumin, Cyclobenzaline, Cyclosporine, Dasatinib, Degarelix, Desipramine, Desvenlafaxine, Dexmedetomidine, Methylphenidate, Dextromethorphan, Dihydroartemisinin and Piperaquine, Diphenhydramine, Disopyramide, Dobutamine, Dofetilide, Dolastron, Domperidone, Donepezil, Dopamine, Doxepin, Dronedarone, Fluperidone, Ephedrine, Epinephrine, Erebulin, Erythromycin Ideprom, Famotidine, Femaminophen, Fenfluramine, Fingolimod, Flucainide, Fluconazole, Fluoxetine, Formoterol, Foscarboxylic Acid, Phosphotoin, Frusemide, Furosemide, Galantamine, Gatifloxacin, Gemimifloxacin, Granisetron, Haloperidol, Hydrochlorothiazide, Hydroxychloroquine, Hydroxyzine, Ibutilide, Ipraridone, Imipramine, Indapamide, Isoproterenol, Iradipine, Itraconazole, Ivabradine, Ketoconazole, Lapatinib, Leuprorelin, Levosalbutamol, Levofloxacin, Levomethasone, Levomethadone, Lysine Mesylate, Amphetamine, Lithium, Loperamide, Max Planck Claims 17 / 22 Pages 18 CN 122094963 A Triptylamine, Mefloxacin, Melipramine, Mesordazine, Osinaline, Methadone, Methamphetamine, Methylphenidate, Metoclopramide, Mexiletine, Midodrine, Mifepristone, Mirabelon, Mirtazapine, Moxifloxacin / HCTZ, Moxifloxacin, Nefernavir, Nicardipine, Nilotinib, Norepinephrine, Norfloxacin, Nortriptyline, Octreotide, Ofloxacin, Olanzapine, Ondansetron, Ophenadrine, Oxaliplatin, Oxycodone, Oxytocin, Palpanidone, Papaverine Hydrochloride, Paroxetine, Parretide, Pazopanib, Pazopanib, Pentamidine, Perfluoropropane Lipospheres Perphenazine, phenylbutazone, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, propafenone, propofol, dextropropoxyfen, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, ritonavir and lopinavir, roxithromycin, salbutamol, salmeterol, saquinavir, sertraline, sevoflurane, sibutramine, sofenac, sorafenib, sotalol, sparfloxacin, spiramycin, sulpiride, sunitinib, tacrolimus Tamoxifen, terabhivir, terabinin, telithromycin, terbutaline, terfenadine, tetrabenzylquinazine, thioridazine, tevothixeol, tizanidine, tizanidinev, tolterodine, toremifene, torasemide, trazodone, trimethoprim and sulfamethoxazole, sulfamethoxazole, trimethoprim, trimethoprim, vandetanil, vardenafil, vemurafenib, and other similar drugs.Lafaxine, voriconazole, vorinostat, ziprasidone, or ziprasidone. 28. The method of claim 27, wherein the pharmaceutical composition comprises at least one of the following: the one or more lipids further comprise one or more excipients, binders, anti-adhesion agents, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, flow aids, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, or combinations thereof; a compound of formula I, wherein the amount per unit dose is about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 24, 30, 40, 50, 60, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, per unit dose. Preparations for oral, sublingual, transdermal, suppository, intrathecal, enteric, parenteral, intravenous, intraperitoneal, skin, subcutaneous, local, pulmonary, rectal, vaginal, or intramuscular administration of 375, 400, 450, 500, 550, 600, 700, 8000, 9000, or 10000 mg; Preparations for oral administration in the form of tablets, capsules, pouches, pills, powders, lozenges, syrups, liquid solutions, suspensions, emulsions, elixirs, or oral films (OTF); or preparations in solid, solution, suspension, or soft gel form. 29. The method of claim 24, wherein the compound of formula I is selected from one or more of the following: (Claims 18 / 22, page 19, CN 122094963 A) or . 30. The method of claim 24, wherein any oxyanion O− of any compound is paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium; and wherein any NH2 or COOH of any compound is optionally in the form of a pharmaceutically acceptable salt, wherein the compound is a single entity, a solvate, a hydrate, a crystal, an amorphous solid, a liquid, or an oil. 31. A method for reducing or eliminating the cardiotoxic effects of one or more antiproliferative agents, comprising: administering one or more cardiotoxic antiproliferative agents to a subject requiring treatment for proliferative disorders; and providing a combination therapy with an effective amount of one or more lipids, said one or more lipids reducing or eliminating the cardiotoxic effects of the one or more antiproliferative agents, wherein the lipids have the following formula or are pharmaceutically acceptable salts thereof: I wherein,R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; R3 is; R4 is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt; R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl, Br, and I; R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R8)2, SH, CN, COOH, CONH2, Cl, Br, and I. Each R7 is independently H or C1-C6 branched or unbranched alkyl; each R8 is independently H or C1-C6 branched or unbranched alkyl; X is a direct bond, O or NH; Y is a direct bond, O or NH; and, each stereocenter is independently R, S or racemic, and optionally, R4 is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein, compared with treatment without the lipids, cardiotoxicity is reduced by at least 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95% or 100%. 32. The method of claim 31, wherein the cardiotoxicity is selected from at least one of the following: minimal left ventricular dilatation, systolic dysfunction, moderate valvular regurgitation, decreased left ventricular ejection fraction (LVEF), cardiac hypertrophy, decreased cardiac contractility, decreased cardiac output, pressure and volume overload hypertrophy, myocardial dysfunction, cardiac remodeling, post-myocardial infarction heart failure, or heart disease; concurrent administration of the one or more antiproliferative agents and the lipids; oral or intravenous administration of the one or more antiproliferative agents and the lipids; infusion of the one or more lipids, the one or more antiproliferative agents, or both, over 3 hours; the one or more antiproliferative agents that induce heart disease as a side effect are selected from at least one of the following: bosutinib, crizotinib, dabrafenib, dasatinib, doxorubicin, lapatinib, nilotinib, sorafenib, sunitinib, vandetanib, or vemurafenib. 33. The method of claim 31, wherein the compound of formula I is selected from one or more of the following: (Claims 20 / 22, page 21, CN 122094963 A) or... (Claims 21 / 22, page 22, CN 122094963 A)34. The method of claim 31, wherein any oxyanion O− of any compound is paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium; and wherein any NH2 or COOH of any compound is optionally in the form of a pharmaceutically acceptable salt, wherein said compound is a single entity, a solvate, a hydrate, a crystal, an amorphous solid, a liquid, or an oil. Claims 22 / 22 Page 23 CN 122094963 A Cardioprotective lipids and methods of use

[0001] Cross-reference to related applications

[0002] This application is a continuation-in-part of U.S. Patent Application No. 17 / 950,898, filed September 9, 2022, and claims priority thereto; U.S. Patent Application No. 17 / 950,898 is a continuation-in-part of U.S. Application No. 17 / 520,287, filed November 5, 2021 (now U.S. Patent No. 11,746,119, granted September 5, 2023), and claims priority thereto; U.S. Application No. 17 / 520,287 is a continuation-in-part of U.S. Patent Application No. 17 / 191,214, filed March 3, 2021 (now U.S. Patent No. 11,643,424, granted May 9, 2023), and claims priority thereto; 17 / U.S. Patent Application No. 191,214 is a continuation-into-priority application of U.S. Patent Application No. 16 / 452,858, filed June 26, 2019 (now U.S. Patent No. 10,975,111, granted April 13, 2021); and claims priority to U.S. Patent Application No. 16 / 452,858, which claims priority to U.S. Provisional Patent Application No. 62 / 690,196, filed June 26, 2018, the contents of each of which are incorporated herein by reference in their entirety.

[0003] Statement of Federally Funded Research

[0004] None.

[0005] Field of Invention

[0006] This invention generally relates to the field of novel lipids for reducing or eliminating drug-induced or disease- or condition-related heart disease, such as QT prolongation, myocardial damage, or AV blockade.

[0007] Background of the Invention

[0008] The background of this invention is described in relation to drug-induced QT prolongation and other cardiac and cardiotoxic effects without limiting the scope of the invention.

[0009] Many pharmaceutical agents designed to treat a variety of diseases are commonly prescribed despite being known or suspected to have adverse effects on the patient's heart. In addition to arrhythmias including QT prolongation, supraventricular tachycardia (SVT), and atrial fibrillation (AF), many other cardiotoxic effects as side effects of these pharmaceutical agents occur, including myocardial damage, cardiomyopathy, congestive heart failure, and left ventricular hypertrophy (LVH).

[0010] The cardiotoxicity of these agents can lead to serious complications that can affect patients receiving treatment for various diseases, such as proliferative malignancies. The severity of such toxicity depends on many factors, such as immediate and cumulative doses, method of administration, the presence of any underlying cardiac conditions, and various congenital or acquired cardiac risk factors specific to the patient. Furthermore, toxicity may be influenced by current or previous treatment with other agents. Cardiotoxic effects may occur immediately during drug administration or may not manifest until months or years after the patient has been treated.

[0011] High-dose chemotherapy remains the preferred treatment for aggressive malignancies. Numerous clinical studies have shown that high-dose chemotherapy can significantly prolong patient survival; however, its use and effectiveness are limited by significant side effects, particularly cardiotoxicity. In mid-to-late-stage cardiotoxicity, heart failure can occur years after chemotherapy has ended. Treatment with chemotherapeutic agents is known to cause pericardial and endocardial myocardial fibrosis, heart failure, myocarditis, or pericarditis. Chemotherapy is also associated with hemorrhagic myocardial necrosis and cardiomyopathy.

[0012] In addition, antitumor monoclonal antibodies are also associated with cardiotoxicity. Infusion-related cardiotoxicity may occur, such as left ventricular dysfunction, congestive heart failure, and other heart failures. The risk of such complications is increased if the patient has a pre-existing heart condition, is elderly, has received previous cardiotoxic treatments, or has received radiation therapy to the chest.

[0013] Tyrosine kinase inhibitors (TKIs) have well-known cardiotoxic effects. Anthracyclines, trastuzumab, imatinib mesylate, dasatinib, nilotinib, sunitinib, sorafenib, vandetanib, and lapatinib are all associated with a range of mechanical and electrical dysfunctions.

[0014] TKI-related toxicities include QT prolongation, sudden cardiac death (both considered rhythmic dysfunctions), and contractile problems such as decreased left ventricular ejection fraction (LVEF), congestive heart failure (CHF), acute coronary artery disease, hypertension, and myocardial infarction (MI). Given the therapeutic potential of drugs such as tyrosine kinase inhibitors, various strategies have been used to attempt to mitigate cardiotoxicity from cancer treatments. A primary approach to preventing cardiotoxicity is limiting the dosage of cardiotoxic drugs. There is also evidence that some administration methods may affect the risk of cardiotoxicity. Rapid administration of cardiotoxic agents results in high blood levels, which may cause more cardiac damage than administering the same amount of drug over a longer period. Administering smaller doses more frequently can also reduce toxicity compared to administering larger doses at longer intervals.

[0015] The risk of cardiotoxicity due to these drugs has been reduced by encapsulating certain chemotherapeutic agents in liposomes.Risk. For example, studies have shown that cardiotoxicity with liposomal doxorubicin formulations is much lower than with conventional doxorubicin.

[0016] Dexrazoxane, an amino polycarboxylic acid, has been shown to prevent or reduce the severity of cardiac damage caused by doxorubicin. Dexrazoxane is thought to protect the myocardium by preventing the formation of oxygen free radicals. One way radiation and chemotherapy drugs damage cells is by forming free radicals. Free radicals are unstable molecules that form during many normal cellular processes involving oxygen, such as burning fuel to obtain energy. They are also formed by exposure to environmental factors such as tobacco smoke, radiation, and chemotherapy drugs.

[0017] However, there remains a need for new compositions and methods for reducing drug-induced or disease- or condition-related cardiac events.

[0018] Summary of the Invention

[0019] As embodied and broadly described herein, one aspect of this disclosure relates to compounds of formula I or pharmaceutically acceptable salts thereof,

[0020]

[0021] I

[0022] wherein,

[0023] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0024] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0025] R3 is;

[0026] R4 is H or a pharmaceutically acceptable cation, wherein the introduction of said pharmaceutically acceptable cation results in a salt as described on page 2 / 128 of this specification, CN 122094963 A;

[0027] R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl, Br, and I;

[0028] R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R8)2, SH, CN, COOH, CONH2, Cl, Br, and I;

[0029] Each R7 is independently H or C1-C6 branched or unbranched alkyl;

[0030] Each R8 is independently H or C1-C6 branched or unbranched alkyl;

[0031] X is a direct bond, O, or NH;

[0032] Y is a direct bond, O, or NH; and,

[0033] Each stereocenter is independently R, S, or racemic.

[0034] On one hand, the compound has formula IA or its pharmaceutically acceptable salt,

[0035]

[0036] IA

[0037] wherein,

[0038] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds or a combination of 0-10 double and triple bonds;

[0039] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0040] R3 is;

[0041] R4 is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt;

[0042] R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, N(R7)2, and COOH;

[0043] R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, N(R8)2, and COOH;

[0044] Each R7 is independently H or a C1-C6 branched or unbranched alkyl;

[0045] Each R8 is independently H or a C1-C6 branched or unbranched alkyl;

[0046] X is a direct bond;

[0047] Y is a direct bond; and,

[0048] each stereocenter is independently R, S or racemic.

[0049] On the other hand, R4 is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium. Specification 3 / 128 page 26 CN 122094963 A

[0050] On the other hand, the compounds of formula I are selected from at least one of the following:

[0051] , , , , , , , , , , , , , , , , Specification 4 / 128 page 27 CN 122094963 A, , , , and; wherein any oxyanion O- of any compound is paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH of any compound is optionally in the form of a pharmaceutically acceptable salt. On the other hand, the compound is a single entity, a solvate, a hydrate, a crystal, an amorphous solid, a liquid, or an oil. On the other hand, the compound is selected from one or more compounds of formula 31 to 51.

[0052] On the other hand, the compound of formula I is:

[0053] ,

[0054] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium.

[0055] On the other hand, the compound of formula I is:

[0056] ,

[0057] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0058] On the other hand, the compound of formula I is: Specification 5 / 128 pages 28 CN 122094963 A

[0059] ,

[0060] The oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0061] On the other hand, the compound of formula I is:

[0062] ,

[0063] wherein the oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium.

[0064] On the other hand, the compound of formula I is:

[0065] ,

[0066] wherein the oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0067] On the other hand, the compound of Formula I is:

[0068] ,

[0069] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0070] On the other hand, the compound of Formula I is: Specification 6 / 128 page 29 CN 122094963 A

[0071] ,

[0072] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

[0073] On the other hand, the compound of Formula I is:

[0074] ,

[0075] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0076] On the other hand, the compound of Formula I is:

[0077] ,

[0078] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH is optionally in the form of a pharmaceutically acceptable salt.

[0079] On the other hand, the compound of Formula I is:

[0080] ,

[0081] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any COOH is optionally in the form of a pharmaceutically acceptable salt.

[0082] On the other hand, the compound of formula I is: Specification 7 / 128 page 30 CN 122094963 A

[0083] ,

[0084] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any COOH is optionally in the form of a pharmaceutically acceptable salt.

[0085] On the other hand, the compound of Formula I is:

[0086] ,

[0087] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH is optionally in the form of a pharmaceutically acceptable salt.

[0088] On the other hand, the compound of Formula I is:

[0089] ,

[0090] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0091] On the other hand, the compound of Formula I is:

[0092] ,

[0093] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0094] On the other hand, the compound of Formula I is: Specification 8 / 128 page 31 CN 122094963 A

[0095] ,

[0096] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0097] On the other hand, the compound of Formula I is:

[0098] ,

[0099] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0100] On the other hand, the compound of Formula I is:

[0101] ,

[0102] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0103] On the other hand, the compound of Formula I is:

[0104] ,

[0105] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0106] On the other hand, the compound of Formula I is: Specification 9 / 128 page 32 CN 122094963 A

[0107] ,

[0108] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0109] On the other hand, the compound of Formula I is:

[0110] ,

[0111] The oxygen anion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0112] On the other hand, the compound of formula I is:

[0113] ,

[0114] wherein the oxygen anion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0115] As embodied and broadly described herein, one aspect of this disclosure relates to a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof,

[0116]

[0117] I

[0118] wherein,

[0119] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0120] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0121] R3 is;

[0122] R4 is H or a pharmaceutically acceptable cation, wherein the introduction of said pharmaceutically acceptable cation forms a salt;

[0123] R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl, Br, and I;

[0124] R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R8)2, SH, CN, COOH, CONH2, Cl, Br, and I;

[0125] Each R7 is independently H or C1-C6 branched or unbranched alkyl;

[0126] Each R8 is independently H or C1-C6 branched or unbranched alkyl;

[0127] X is a direct bond, O, or NH;

[0128] Y is a direct bond, O, or NH; and,

[0129] Each stereocenter is independently R, S, or racemic;

[0130] The method includes the following steps:

[0131] The hydroxyl group of the compound of formula II is converted to an ester, carbonate, or carbamate,

[0132]

[0133] II

[0134] wherein all substitutions are defined as described above;

[0135] Optionally, the phosphorus-bound OH group is converted to O-R4, wherein R4 is not H; and,

[0136] Optionally, one or more protecting groups are removed; or

[0137] the method comprises the following steps:

[0138] The compound of formula III is connected to the compound of formula IV by forming a phosphodiester bridge,

[0139]

[0140] III Specification 11 / 128 pages 34 CN 122094963 A

[0141]

[0142] IV

[0143] Wherein,

[0144] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double bonds and triple bonds;

[0145] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double bonds and triple bonds;

[0146] Each R7 is independently H or C1-C6 branched or unbranched alkyl;

[0147] Each R8 is independently H or C1-C6 branched or unbranched alkyl;

[0148] R9 is a C1-C10 branched or unbranched hydrocarbon substituted with one or more groups independently selected from OR11, N(R7)R12, N(R7)2, SR13, CN, COOR14, CONH2, Cl, Br, and I;

[0149] R10 is a C1-C10 branched or unbranched hydrocarbon substituted with one or more groups independently selected from OR11, N(R8)R12, N(R8)2, SR13, CN, COOR14, CONH2, Cl, Br, and I;

[0150] Each R11 is independently H, Ac, Me, tert-butyl, benzyl, triphenylmethyl, benzoyl, p-nitrobenzoyl, MOM, BOM, or Si constituting the core of a silyl ether;

[0151] Each R12 is independently H, Me, Boc, Cbz, Fmoc, benzyl, 4-methoxybenzyl, tert-butyl, or triphenylmethyl;

[0152] Each R13 is independently H, Ac, benzoyl, p-nitrobenzoyl, or triphenylmethyl;

[0153] Each R14 is independently H, C1-C6 branched or unbranched alkyl, benzyl, or 4-methoxybenzyl;

[0154] X is a direct bond, O, or NH;

[0155] Y is a direct bond, O, or NH; and,

[0156] Each stereocenter is independently R, S, or racemic;

[0157] Optionally, the phosphorus-bonded OH group is converted to O-R4, wherein R4 is not H; and,

[0158] Optionally, each OR11, N(R7)R12, N(R8)R12, SR13, or COOR14 is converted to OH, NHR7, NHR8, SH, or COOH, respectively.

[0159] In one aspect, the method is used to prepare a compound of formula IA or a pharmaceutically acceptable salt thereof,

[0160]

[0161] IA

[0162] wherein,

[0163] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0164] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0165] R3 is;

[0166] R4 is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt;

[0167] R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, N(R7)2, and COOH;

[0168] R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, N(R8)2, and COOH;

[0169] Each R7 is independently H or a C1-C6 branched or unbranched alkyl group;

[0170] Each R8 is independently H or C1-C6 branched or unbranched alkyl;

[0171] X is a direct bond;

[0172] Y is a direct bond; and,

[0173] each stereocenter is independently R, S or racemic;

[0174] the method comprises the following steps:

[0175] converting the hydroxyl group of the compound of formula II to an ester, carbonate or carbamate,

[0176]

[0177] II

[0178] wherein all substitutions are defined as described above;

[0179] optionally, converting the phosphorus-bound OH group to O-R4, wherein R4 is not H; and,

[0180] optionally, removing one or more protecting groups; or

[0181] the method comprises the following steps:

[0182] linking the compound of formula III to the compound of formula IV by generating a phosphodiester bridge,

[0183]

[0184] III Specification 13 / 128 pages 36 CN 122094963 A

[0185]

[0186] IV

[0187] Wherein,

[0188] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0189] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0190] Each R7 is independently H or a C1-C6 branched or unbranched alkyl group;

[0191] Each R8 is independently H or a C1-C6 branched or unbranched alkyl group;

[0192] R9 is a C1-C10 branched or unbranched hydrocarbon substituted with one or more groups independently selected from OR11, N(R7)R12, N(R7)2, and COOR14;

[0193] R10 is a C1-C10 group substituted with one or more groups independently selected from OR11, N(R8)R12, N(R8)2, and COOR14.Branched or unbranched hydrocarbons;

[0194] Each R11 is independently H, Ac, Me, tert-butyl, benzyl, triphenylmethyl, benzoyl, p-nitrobenzoyl, MOM, BOM, or Si constituting the core of a silyl ether;

[0195] Each R12 is independently H, Me, Boc, Cbz, Fmoc, benzyl, 4-methoxybenzyl, tert-butyl, or triphenylmethyl;

[0196] Each R14 is independently H, C1-C6 branched or unbranched alkyl, benzyl, or 4-methoxybenzyl;

[0197] X is a direct bond, O, or NH;

[0198] Y is a direct bond, O, or NH; and,

[0199] Each stereocenter is independently R, S, or racemic;

[0200] Optionally, the phosphorus-bonded OH group is converted to O-R4, wherein R4 is not H; and,

[0201] Optionally, each OR11, N(R7)R12, N(R8)R12 or COOR14 can be converted to OH, NHR7, NHR8 or COOH, respectively.

[0202] On the other hand, the method includes the following steps:

[0203] converting the hydroxyl group of the compound of formula II into an ester, carbonate, or carbamate,

[0204]

[0205] II

[0206] wherein all substitutions are defined as described above;

[0207] optionally, converting the phosphorus-bound OH group into O-R4, wherein R4 is not H; and,

[0208] optionally, removing one or more protecting groups; or specification 14 / 128 pages 37 CN 122094963 A

[0209] The method includes the following steps:

[0210] linking the compound of formula III to the compound of formula IV by generating a phosphodiester bridge,

[0211]

[0212] III

[0213]

[0214] IV

[0215] wherein,

[0216] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0217] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0218] Each R7 is independently H or a C1-C6 branched or unbranched alkyl group;

[0219] Each R8 is independently H or a C1-C6 branched or unbranched alkyl group;

[0220] R9 is a C1-C10 branched or unbranched hydrocarbon substituted with one or more groups independently selected from OR11, N(R7)R12, N(R7)2, SR13, CN, COOR14, CONH2, Cl, Br, and I;

[0221] R10 is a number independently selected from one or more of the following: OR11, N(R8)R12, N(R8)2, SR13, CN, COOR14, CONH2, Cl, Br.C1-C10 branched or unbranched hydrocarbons substituted with groups of I;

[0222] Each R11 is independently H, Ac, Me, tert-butyl, benzyl, triphenylmethyl, benzoyl, p-nitrobenzoyl, MOM, BOM or Si constituting the core of a silyl ether;

[0223] Each R12 is independently H, Me, Boc, Cbz, Fmoc, benzyl, 4-methoxybenzyl, tert-butyl or triphenylmethyl;

[0224] Each R13 is independently H, Ac, benzoyl, p-nitrobenzoyl or triphenylmethyl;

[0225] Each R14 is independently H, C1-C6 branched or unbranched alkyl, benzyl or 4-methoxybenzyl;

[0226] X is a direct bond, O or NH;

[0227] Y is a direct bond, O or NH; and,

[0228] Each stereocenter is independently R, S, or racemic;

[0229] optionally, the phosphorus-bound OH group is converted to O-R4, wherein R4 is not H; and,

[0230] optionally, each OR11, N(R7)R12, N(R8)R12, SR13, or COOR14 is converted to OH, NHR7, NHR8, SH, or COOH, respectively. On the other hand, R4 is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium.

[0231] On the other hand, the compound of formula I is selected from at least one of the following:

[0232] , ...

[0233] On the other hand, the compound of Formula I is:

[0234] ,

[0235] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

[0236] On the other hand, the compound of Formula I is:

[0237] ,

[0238] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0239] On the other hand, the compound of Formula I is:

[0240] ,

[0241] The oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0242] On the other hand, the compound of formula I is: Specification 17 / 128 pages 40 CN 122094963 A

[0243] ,

[0244] The oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

[0245] On the other hand, the compound of formula I is:

[0246] ,

[0247] The oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0248] On the other hand, the compound of Formula I is:

[0249] ,

[0250] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0251] On the other hand, the compound of Formula I is:

[0252] ,

[0253] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

[0254] On the other hand, the compound of Formula I is: Specification 18 / 128 pages 41 CN 122094963 A

[0255] ,

[0256] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0257] On the other hand, the compound of Formula I is:

[0258] ,

[0259] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH is optionally in the form of a pharmaceutically acceptable salt.

[0260] On the other hand, the compound of Formula I is:

[0261] ,

[0262] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any COOH is optionally in the form of a pharmaceutically acceptable salt.

[0263] On the other hand, the compound of Formula I is:

[0264] ,

[0265] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any COOH is optionally in the form of a pharmaceutically acceptable salt.

[0266] On the other hand, the compound of formula I is: Specification 19 / 128 page 42 CN 122094963 A

[0267] ,

[0268] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH is optionally in the form of a pharmaceutically acceptable salt.

[0269] On the other hand, the compound of formula I is:

[0270] ,

[0271] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0272] On the other hand, the compound of Formula I is:

[0273] ,

[0274] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0275] On the other hand, the compound of Formula I is:

[0276] ,

[0277] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0278] On the other hand, the compound of Formula I is: Specification 20 / 128 page 43 CN 122094963 A

[0279] ,

[0280] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0281] On the other hand, the compound of Formula I is:

[0282] ,

[0283] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0284] On the other hand, the compound of Formula I is:

[0285] ,

[0286] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0287] On the other hand, the compound of Formula I is:

[0288] ,

[0289] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0290] On the other hand, the compound of Formula I is: Specification 21 / 128 pages 44 CN122094963 A

[0291] ,

[0292] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0293] On the other hand, the compound of formula I is:

[0294] ,

[0295] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0296] As embodied and broadly described herein, one aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier:

[0297]

[0298] I

[0299] wherein,

[0300] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0301] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0302] R3 is;

[0303] R4 is H or a pharmaceutically acceptable cation, wherein the introduction of said pharmaceutically acceptable cation forms a salt; Specification 22 / 128 pages 45 CN 122094963 A

[0304] R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, Oac, Ome, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl, Br, and I;

[0305] R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, Oac, Ome, NHAc, N(R8)2, SH, CN, COOH, CONH2, Cl, Br, and I;

[0306] Each R7 is independently H or C1-C6 branched or unbranched alkyl;

[0307] Each R8 is independently H or C1-C6 branched or unbranched alkyl; X is a direct bond, O, or NH;

[0308] Y is a direct bond, O, or NH; and,

[0309] Each stereocenter is independently R, S, or racemic;

[0310] On the one hand, R4 of the compound of formula I is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium.

[0311] On the other hand, the compound of formula I is selected from at least one of the following:

[0312] , , , , , , , , , , , , , , , , , Specification 23 / 128 Page 46 CN 122094963 A , , , , , , and;

[0313] Any oxyanion O- of any compound is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium; and any NH2 or COOH of any compound is optionally in the form of a pharmaceutically acceptable salt. Alternatively, the compounds of Formula I exist as a single entity, solvate, hydrate, crystal, amorphous solid, liquid, or oil. Furthermore, the pharmaceutical composition further comprises one or more agents that induce cardiac events as a side effect. On the other hand, one or more drugs that induce heart disease as a side effect are selected from at least one of the following: adrenaline, salbutamol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, afortrol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, benprodil, bortezomib, bosutinib, bromhexine, buprenorphine, capecitabine, chloral hydrate, clomipramine, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, crizotinib, curcumin, cyclobenzaline, cyclosporine, and dextrin. Rafenib, Dasatinib, Degarelix, Desipramine, Desvenlafaxine, Dexmedetomidine, Dextromethorphan, Dextromethorphan, Dihydroartemisinin and Piperaquine, Diphenhydramine, Disopyramide, Dobutamine, Dofetilide, Dolastron, Domperidone, Donepezil, Dopamine, Doxepin, Dronedarone, Fluperidone, Ephedrine, Epinephrine, Erebulin, Erythromycin, Ediprid, Famotidine, Femimetazidine, Fenfluramine, Fingolimod, Flucainide, Fluconazole, Fluoxetine, Formoterol, Foscarboxylic Acid, Phosphotoin, Frusemide, Furosemide, Galantamine, Gatifloxacin, Gemimifloxacin, Granisetron, Halofantrone Haloperidol, hydrochlorothiazide, hydroxychloroquine, hydroxyzine, ibutilide, ipraridone, imipramine, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, leuprorelin, levosalbutamol, levofloxacin, levomethazine, levomethadone, lysine mesylate, lithium, loperamide, maprotiline, mefloquine, melipramine, mesoridazine, orsinil, methadone, methamphetamine, methylphenidate, metoclopramide Mexiletine, Midodrine, Mifepristone, Mirabelon, Mirtazapine, Moxifloxacin / HCTZ, Moxifloxacin, Nefernavir, Nicardipine, Nilotinib, Norepinephrine, Norfloxacin, Nortriptyline, Octreotide, Ofloxacin, Olanzapine, Ondansetron, Instructions for Use 24 / 128 pages 47 CN 122094963 AFennaldine, oxaliplatin, oxycodone, oxytocin, palapirone, papaverine hydrochloride, paroxetine, parreptide, pazopanib, pazopanib, pentamivir, perfluoropropane lipid microspheres, perphenazine, phenylbutazone, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, propafenone, propofol, dextropropoxyphene, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine, quinine sulfate, ranolazine. Rilpivirine, Risperidone, Ritodrine, Ritonavir, Ritonavir and Lopinavir, Roxithromycin, Salbutamol, Salmeterol, Saquinavir, Serindole, Sertraline, Sevoflurane, Sibutramine, Sofenac, Sorafenib, Sotalol, Sparfloxacin, Spiramycin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen, Terabixin, Terbutaline, Terfenadine, Tetrabenzidazine, Thioridazine, Tevothiazide Tizanidine, Tizanidinev, tolterodine, toremifene, torasemide, trazodone, trimethoprim, sulfamethoxazole, sulfamethoxazole, trimethoprim, trimethoprim, vandetanil, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, ziprasidone, or ziprasidone. On the other hand, the pharmaceutical composition further comprises one or more excipients, binders, anti-adhesion agents, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, flow aids, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, or combinations thereof. On the other hand, the binder is selected from hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic acid and methacrylic acid copolymers, pharmaceutical glazes, gums, and emulsion derivatives. On the other hand, the pharmaceutical composition comprises a compound of formula I in an amount from about 1 mg to about 1 g per unit dose. On the other hand, the pharmaceutical composition is a preparation for oral, sublingual, transdermal, suppository, intrathecal, enteric, parenteral, intravenous, intraperitoneal, skin, subcutaneous, local, pulmonary, rectal, vaginal, or intramuscular administration. On the other hand, the preparation for oral administration is a tablet, capsule, sac, pill, powder, lozenge, syrup, liquid solution, suspension, emulsion, elixir, or oral film (OTF). On the other hand, the preparation is in solid form, solution, suspension, or soft gel form. On the other hand, the compound is selected from one or more compounds of formula 31 to 51.

[0314] As embodied and broadly described herein, one aspect of this disclosure relates to a method for reducing or eliminating one or more of cardiac ion channelopathy, myocardial injury, or symptoms caused by irregularities or alterations in cardiac rhythm in human or animal subjects, comprising the step of administering one or more compounds of formula I or a pharmaceutically acceptable salt thereof to a human or animal subject,

[0315]

[0316] I

[0317] Wherein,

[0318] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0319] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; Specification 25 / 128 pages 48 CN 122094963 A

[0320] R3 is;

[0321] R4 is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt;

[0322] R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, Oac, Ome, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl, Br and I;

[0323] R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, Oac, Ome, NHAc, N(R8)2, SH, CN, COOH, CONH2, Cl, Br, and I;

[0324] Each R7 is independently H or C1-C6 branched or unbranched alkyl;

[0325] Each R8 is independently H or C1-C6 branched or unbranched alkyl;

[0326] X is a direct bond, O, or NH;

[0327] Y is a direct bond, O, or NH; and,

[0328] Each stereocenter is independently R, S, or racemic;

[0329] On the one hand, R4 of the compound of formula I is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium. On the other hand, the compound of formula I exists as a single entity, solvate, hydrate, crystal, amorphous solid, liquid, or oil. On the other hand, compounds of Formula I reduce or eliminate one or more of the following conditions: cardiac ion channelopathies caused by active agents used to treat diseases, or conditions caused by irregularities or alterations in heart rhythm. On the other hand, compounds of Formula I are administered in doses of about 1 mg to about 1 g per unit dose. On the other hand, compounds of Formula I are formulated for oral, sublingual, transdermal, suppository, intrathecal, enteric, parenteral, intravenous, intraperitoneal, skin, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration. On the other hand, compounds of Formula I are formulated as tablets, capsules, pouches, pills, powders, lozenges, syrups, liquid solutions, suspensions, emulsions, elixirs, or oral films (OTF) for oral administration. On the other hand, compounds of Formula I are formulated as solid forms, solutions, suspensions, or soft gels. On the other hand, the solid form further comprises one or more excipients, binders, anti-adhesion agents, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, flow aids, lubricants, preservatives, adsorbents, and sweeteners.Agents, their derivatives, or combinations thereof. On the other hand, the compound of formula I is co-administered with one or more agents that induce cardiac symptoms as a side effect. On the other hand, the one or more active agents that induce cardiac symptoms as a side effect are selected from at least one of the following: adrenaline, salbutamol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, afortrol, aripiprazole, arsenic trioxide, astemizole, Atazanavir, atomoxetine, azithromycin, bedaquiline, benprodil, bortezomib, bosutinib, bromhexine, buprenorphine, capecitabine, chloral hydrate, clomipramine, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, crizotinib, curcumin, cyclobenzaline, cyclosporine, dabrafenib, dasatinib, degarelix, desipramine, desvenlafaxine, dexmedetomidine, dextromethorphan, dextromethorphan, dihydroartemisinin and piperaquine, diphenhydramine, propiconazole Amine, Dobutamine, Dofetilide, Dolastron, Domperidone, Donepezil, Dopamine, Doxepin, Dronedarone, Fluperidone, Ephedrine, Epinephrine, Erebulin, Erythromycin, Ediprid, Famotidine, Femimetabolic Acid, Fenfluramine, Fingolimod, Flucainide, Fluconazole, Fluoxetine, Formoterol, Foscarboxylic Acid, Phosphotoin, Furosemide, Galantamine, Gatifloxacin, Gemimifloxacin, Granisetron Halofantrolin, Haloperidol, Hydrochlorothiazide, Hydroxychloroquine, Hydroxyzine, Ibutilide, Ipraridone, Imipramine, Indapamide, Isopropylbasil, Instructions for Use, Page 26 / 128, 49, CN 122094963 A, Epinephrine, Iradipine, Itraconazole, Ivabradine, Ketoconazole, Lapatinib, Leuprorelin, Levosalbutamol, Levofloxacin, Levomethasone, Levomethadone, Lysine Mesylate, Lithium, Loperamide, Maprotiline, Mefloquine, Melipramine, Mesordazine, Osinaline, Methadone, Methamphetamine, Methylphenidate, Metoclopramide, Mexiletine Midodrine, Mifepristone, Mirabelon, Mirtazapine, Moxifloxacin / HCTZ, Moxifloxacin, Nefernavir, Nicardipine, Nilotinib, Norepinephrine, Norfloxacin, Nortriptyline, Octreotide, Ofloxacin, Olanzapine, Ondansetron, Ophenazine, Oxaliplatin, Oxycodone, Oxytocin, Palpanidone, Papaverine Hydrochloride, Paroxetine, Parretide, Pazopanib, Pazopanib, Pentamidine, Perfluoropropane Lipospheres, Perphenazine, Phenylephrine, Phenylephrine, Phenylephrine, Pimozide, Posaconazole, Probucol, Procainamide, Promethazine, Propafenone, Propofol, Dextropropoxyfen, Protriptyline, Pseudoephedrine, QuinalidoneQuinidine, Quinine, Quinine Sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir, Ritonavir and Lopinavir, Roxithromycin, Salbutamol, Salmeterol, Saquinavir, Sertraline, Sevoflurane, Sibutramine, Sofenac, Sorafenib, Sotalol, Sparfloxacin, Spiramycin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen, Telavirancin, Telimycin Terbutaline, terfenadine, tetrabenzylquinazine, thioridazine, tevothixeol, tizanidine, tizanidinev, tolterodine, toremifene, torasemide, trazodone, trimethoprim, sulfamethoxazole, sulfamethoxazole, trimethoprim, trimethoprim, vandetanil, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, ziprasidone, or ziprasidone. On the other hand, compounds of formula I reduce or eliminate drug-induced or disease- or condition-related cardiac events, such as QT interval prolongation, myocardial damage, or AV block. On the other hand, said compounds are selected from one or more compounds of formulas 31 to 51.

[0330] On the other hand, the compounds of Formula I are selected from at least one of the following:

[0331] , , , , , , , , , Specification 27 / 128 pages 50 CN 122094963 A , , , , , , , , , , , and;

[0332] wherein any oxyanion O- of any compound is paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH of any compound is optionally in the form of a pharmaceutically acceptable salt.

[0333] On the other hand, the compounds of Formula I are:

[0334] ,

[0335] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium. Specification 28 / 128 pages 51 CN 122094963 A

[0336] On the other hand, the compound of formula I is:

[0337] ,

[0338] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0339] On the other hand, the compound of formula I is:

[0340] ,

[0341] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0342] On the other hand, the compound of formula I is:

[0343] ,

[0344] The oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

[0345] On the other hand, the compound of formula I is:

[0346] ,

[0347] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0348] On the other hand, the compound of formula I is: Specification 29 / 128 pages 52 CN 122094963 A

[0349] ,

[0350] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0351] On the other hand, the compound of Formula I is:

[0352] ,

[0353] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

[0354] On the other hand, the compound of Formula I is:

[0355] ,

[0356] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0357] On the other hand, the compound of Formula I is:

[0358] ,

[0359] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH is optionally in the form of a pharmaceutically acceptable salt.

[0360] On the other hand, the compound of Formula I is: Specification 30 / 128 pages 53 CN 122094963 A

[0361] ,

[0362] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any COOH is optionally in the form of a pharmaceutically acceptable salt.

[0363] On the other hand, the compound of Formula I is:

[0364] ,

[0365] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any COOH is optionally in the form of a pharmaceutically acceptable salt.

[0366] On the other hand, the compound of formula I is:

[0367] ,

[0368] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH is optionally in the form of a pharmaceutically acceptable salt.

[0369] On the other hand, the compound of formula I is:

[0370] ,

[0371] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0372] On the other hand, the compound of formula I is: Specification 31 / 128 pages 54 CN 122094963 A

[0373] ,

[0374] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0375] On the other hand, the compound of Formula I is:

[0376] ,

[0377] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0378] On the other hand, the compound of Formula I is:

[0379] ,

[0380] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0381] On the other hand, the compound of Formula I is:

[0382] ,

[0383] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0384] On the other hand, the compound of formula I is: Specification 32 / 128 pages 55 CN 122094963 A

[0385] ,

[0386] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0387] On the other hand, the compound of formula I is:

[0388] ,

[0389] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0390] On the other hand, the compound of Formula I is:

[0391] ,

[0392] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0393] On the other hand, the compound of Formula I is:

[0394] ,

[0395] The oxygen anion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt. Specification 33 / 128 pages 56 CN 122094963 A

[0396] As embodied and broadly described herein, one aspect of this disclosure relates to a method for reducing or eliminating the cardiotoxic or cardiac effects of one or more active agents, comprising: administering one or more cardiotoxic active agents to a subject requiring treatment of a disease or disorder; and providing a combination therapy with an effective amount of one or more lipids, said one or more lipids reducing or eliminating the cardiotoxic effects of said one or more active agents, wherein said lipids have the following formula or are pharmaceutically acceptable salts thereof:

[0397]

[0398] I

[0399] wherein,

[0400] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double bonds and triple bonds;

[0401] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double bonds and triple bonds;

[0402] R3 is;

[0403] R4 is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt;

[0404] R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, Oac, Ome, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl, Br and I;

[0405] R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, Oac, Ome, NHAc, N(R8)2, SH, CN, COOH, CONH2, Cl, Br and I;

[0406] Each R7 is independently H or a C1-C6 branched or unbranched alkyl;

[0407] Each R8 is independently H or a C1-C6 branched or unbranched alkyl;

[0408] X is a direct bond, O or NH;

[0409] Y is a direct bond, O, or NH; and,

[0410] each stereocenter is independently R, S, or racemic, and;

[0411] wherein cardiotoxicity is reduced by at least 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, or 100% compared to treatment without the lipids, and optionally, wherein R4 is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium. In one aspect, the cardiotoxicity or cardiac lesions are selected from at least one of the following: minimal left ventricular dilation, systolic function.This medication is indicated for conditions such as valvular obstruction, moderate valvular regurgitation, decreased left ventricular ejection fraction (LVEF), cardiac hypertrophy, decreased cardiac contractility, decreased cardiac output, pressure and volume overload hypertrophy, myocardial dysfunction, cardiac remodeling, post-myocardial infarction heart failure, or other heart diseases. Alternatively, the one or more active agents are selected from doxorubicin, trastuzumab, or both. Alternatively, the one or more active agents and the lipid are administered simultaneously. Alternatively, the one or more active agents and the lipid are formulated as per the instructions for use (page 34 / 128, 57 CN 122094963 A) for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, skin, subcutaneous, local, pulmonary, rectal, vaginal, or intramuscular administration. Alternatively, the one or more lipids, the one or more active agents, or both, are infused over 3 hours.

[0412] On the other hand, the compounds of Formula I are selected from at least one of the following:

[0413] , , , , , , , , , , , , , , , , , , , Specification 35 / 128 pages 58 CN 122094963 A , , , and;

[0414] wherein any oxyanion O- of any compound is paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH of any compound is optionally in the form of a pharmaceutically acceptable salt.

[0415] On the other hand, the compounds of Formula I are:

[0416] ,

[0417] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

[0418] On the other hand, the compound of Formula I is:

[0419] ,

[0420] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0421] On the other hand, the compound of Formula I is:

[0422] , Specification 36 / 128 pages 59 CN 122094963 A

[0423] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0424] On the other hand, the compound of Formula I is:

[0425] ,

[0426] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

[0427] On the other hand, the compound of Formula I is:

[0428] ,

[0429] The oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0430] On the other hand, the compound of formula I is:

[0431] ,

[0432] wherein the oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0433] On the other hand, the compound of formula I is:

[0434] , Specification 37 / 128 pages 60 CN 122094963 A

[0435] wherein the oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

[0436] On the other hand, the compound of Formula I is:

[0437] ,

[0438] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0439] On the other hand, the compound of Formula I is:

[0440] ,

[0441] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH is optionally in the form of a pharmaceutically acceptable salt.

[0442] On the other hand, the compound of Formula I is:

[0443] ,

[0444] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any COOH is optionally in the form of a pharmaceutically acceptable salt.

[0445] On the other hand, the compound of Formula I is:

[0446] ,

[0447] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any COOH is optionally in the form of a pharmaceutically acceptable salt.

[0448] On the other hand, the compound of Formula I is:

[0449] ,

[0450] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH is optionally in the form of a pharmaceutically acceptable salt.

[0451] On the other hand, the compound of Formula I is:

[0452] ,

[0453] wherein the oxygen anion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; andAny nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0454] On the other hand, the compound of formula I is:

[0455] ,

[0456] wherein the oxy anion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0457] On the other hand, the compound of formula I is:

[0458] ,

[0459] wherein the oxy anion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0460] On the other hand, the compound of Formula I is:

[0461] ,

[0462] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0463] On the other hand, the compound of Formula I is:

[0464] ,

[0465] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0466] On the other hand, the compound of Formula I is:

[0467] ,

[0468] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0469] On the other hand, the compound of Formula I is:

[0470] , Specification 40 / 128 pages 63 CN 122094963 A

[0471] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0472] On the other hand, the compound of Formula I is:

[0473] ,

[0474] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0475] On the other hand, the compound of formula I is:

[0476] ,

[0477] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0478] On the other hand, one or more agents that induce cardiotoxicity or cardiac effects are selected from at least one of the following: adrenaline, salbutamol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, afortrol, aripiprazole, arsenic trioxide, astemizole. Atazanavir, atomoxetine, azithromycin, bedaquiline, benprodil, bortezomib, bosutinib, bromhexine, buprenorphine, capecitabine, chloral hydrate, clomipramine, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, crizotinib, curcumin, cyclobenzaline, cyclosporine, dabrafenib, dasatinib, degarelix, desipramine, desvenlafaxine, dexmedetomidine, dextromethorphan, dextromethorphan, dihydroartemisinin and piperaquine, diphenhydramine, propiconazole Amine, Dobutamine, Dofetilide, Dolastron, Domperidone, Donepezil, Dopamine, Doxepin, Dronedarone, Fluperidone, Ephedrine, Epinephrine, Erebulin, Erythromycin, Ediprid, Famotidine, Femimetabolic Acid, Fenfluramine, Fingolimod, Flucainide, Fluconazole, Fluoxetine, Formoterol, Foscarboxylic Acid, Phosphotoin, Furosemide, Galantamine, Gatifloxacin, Gemimifloxacin, Granisetron Halofantrolin, Haloperidol, Hydrochlorothiazide, Hydroxychloroquine, Hydroxyzine, Ibutilide, Ipraridone, Imipramine, Indapamide, Isoproterenol, Iradipine, Itraconazole, Ivabradine, Ketoconazole, Lapatinib, Leuprorelin, Levosalbutamol, Levofloxacin, Levomethadone, Levomethadone, Lysine Mesylate, Lithium, Loperamide, Maprotiline, Mefloquine, Melipramine, Mesodrine, Osinaline, Methadone, Methamphetamine, Methylphenidate, Metoclopramide, Mexiletine, Midodrine, Mifepristone, Mirabelon, Mirtazapine, Moxifloxacin / HCTZ, Moxifloxacin, Nefernavir, Nicardipine, Niloxacin. Instructions for Use 41 / 128 pages 64 CN 122094963 A Tinidone, Norepinephrine, Norfloxacin, Nortriptyline, Octreotide, Ofloxacin, Olanzapine, Ondansetron, Ophenadrine, Oxaliplatin, Oxycodone, Oxytocin, Palpanidone, Papaverine Hydrochloride, Paroxetine, Parretide, Pazopanib, Pazopanib, Pentamidine, Perfluoropropane Lipospheres, Perphenazine, Phenylephrine, Phenylephrine, Phenylephrine, Pimozide, Posaconazole, Probucol, Procainamide, Promethazine, Propafenone, Propofol, Dextropropoxyfen, Protriptyline, Pseudoephedrine, Quetiapine, Quinidine, Quinine, Quinine Sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir, Ritonavir and LopivirNavir, Roxithromycin, Salbutamol, Salmeterol, Saquinavir, Serindole, Sertraline, Sevoflurane, Sibutramine, Sofenac, Sorafenib, Sotalol, Sparfloxacin, Spiramycin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen, Telavirvir, Telavancin, Telithromycin, Terbutaline, Terfenadine, Tetrabenzidazine, Thioridazine, Tevothiazide, Tizanidine, Tizanidinev, Tolterodine, Toremifene, Torasemide, Trazodone, Trimethoprim and Sulfamethoxazole, Sulfamethoxazole, Trimipramine, Vandetanil, Vardenafil, Vemurafenib, Venlafaxine, Voriconazole, Vorinostat, Ziprasidone or Ziprasidone. On the other hand, a pharmaceutical composition comprising one or more of the lipids further comprises one or more excipients, binders, anti-adhesion agents, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, flow aids, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, or combinations thereof. On the other hand, the pharmaceutical composition comprises a compound of formula I, wherein the amount per unit dose is about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 24, 30, 40, 50, 60, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, or 10000 mg. On the other hand, the pharmaceutical composition is a formulation for oral, sublingual, transdermal, suppository, intrathecal, enteric, parenteral, intravenous, intraperitoneal, skin, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration. Alternatively, the composition is formulated as tablets, capsules, pouches, pills, powders, lozenges, syrups, liquid solutions, suspensions, emulsions, elixirs, or oral films (OTF) for oral administration. Furthermore, the formulation is in solid, solution, suspension, or soft gel form. On the other hand, the compounds of Formula I are selected from at least one of the following:

[0479] , , , , , , , , , Specification 42 / 128 pages 65 CN 122094963 A , , , , , , , , , , , , and; wherein any oxyanion O- of any compound is paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH of any compound is optionally in the form of a pharmaceutically acceptable salt.

[0480] On the other hand, the compounds of Formula I are:

[0481] ,

[0482] The oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium. Specification 43 / 128 pages 66 CN 122094963 A

[0483] On the other hand, the compound of formula I is:

[0484] ,

[0485] wherein the oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0486] On the other hand, the compound of formula I is:

[0487] ,

[0488] wherein the oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0489] On the other hand, the compound of Formula I is:

[0490] ,

[0491] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

[0492] On the other hand, the compound of Formula I is:

[0493] ,

[0494] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0495] On the other hand, the compound of Formula I is: Specification 44 / 128 pages 67 CN 122094963 A

[0496] ,

[0497] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0498] On the other hand, the compound of Formula I is:

[0499] ,

[0500] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

[0501] On the other hand, the compound of Formula I is:

[0502] ,

[0503] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0504] On the other hand, the compound of Formula I is:

[0505] ,

[0506] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH is optionally in the form of a pharmaceutically acceptable salt.

[0507] On the other hand, the compound of Formula I is: (Specification 45 / 128 pages, 68 CN)122094963 A

[0508] ,

[0509] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any COOH is optionally in the form of a pharmaceutically acceptable salt.

[0510] On the other hand, the compound of formula I is:

[0511] ,

[0512] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any COOH is optionally in the form of a pharmaceutically acceptable salt.

[0513] On the other hand, the compound of formula I is:

[0514] ,

[0515] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH is optionally in the form of a pharmaceutically acceptable salt.

[0516] On the other hand, the compound of Formula I is:

[0517] ,

[0518] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0519] On the other hand, the compound of Formula I is: Specification 46 / 128 pages 69 CN 122094963 A

[0520] ,

[0521] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0522] On the other hand, the compound of Formula I is:

[0523] ,

[0524] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0525] On the other hand, the compound of Formula I is:

[0526] ,

[0527] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0528] On the other hand, the compound of Formula I is:

[0529] ,

[0530] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0531] On the other hand, the compound of formula I is: Specification page 47 / 128 70 CN 122094963 A

[0532] ,

[0533] The oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0534] On the other hand, the compound of formula I is:

[0535] ,

[0536] wherein the oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0537] On the other hand, the compound of formula I is:

[0538] ,

[0539] wherein the oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0540] On the other hand, the compound of Formula I is:

[0541] ,

[0542] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0543] As embodied and broadly described herein, one aspect of this disclosure relates to a method for reducing or eliminating the cardiotoxic effects of one or more antiproliferative agents, comprising: administering one or more cardiotoxic antiproliferative agents to a subject requiring treatment for proliferative disorders; and providing a combination therapy with an effective amount of one or more lipids, said one or more lipids reducing or eliminating the cardiotoxic effects of one or more antiproliferative agents, wherein said lipids have the following formula or are pharmaceutically acceptable salts thereof:

[0544]

[0545] I

[0546] wherein,

[0547] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double bonds and triple bonds;

[0548] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double bonds and triple bonds;

[0549] R3 is;

[0550] R4 is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt;

[0551] R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, Oac, Ome, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl, Br and I;

[0552] R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, Oac, Ome, NHAc, N(R8)2, SH, CN, COOH, CONH2, Cl, Br and I;

[0553] Each R7 is independently H or C1-C6 branched or unbranched alkyl;

[0554] Each R8 is independently H or C1-C6 branched or unbranched alkyl;

[0555] X is a direct bond, O or NH;

[0556] Y is a direct bond, O or NH; and,

[0557] Each stereocenter is independently R, S or racemic, and optionally, wherein

[0558] R4 is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and

[0559] wherein cardiotoxicity is reduced by at least 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95% or 100% compared to treatment without the lipids. On the one hand, the cardiotoxicity is selected from at least one of the following: minimal left ventricular dilatation, systolic dysfunction, moderate valvular regurgitation, decreased left ventricular ejection fraction (LVEF), cardiac hypertrophy, decreased cardiac contractility, decreased cardiac output, pressure and volume overload hypertrophy, myocardial dysfunction, cardiac remodeling, post-myocardial infarction heart failure, or heart disease. On the other hand, the one or more antiproliferative agents are selected from doxorubicin, trastuzumab, or both. On the other hand, the one or more antiproliferative agents and the lipid are administered simultaneously. On the other hand, the one or more antiproliferative agents and the lipid are administered orally or intravenously. On the other hand, the one or more lipids, the one or more antiproliferative agents, or both are infused over 3 hours. On the other hand, the one or more antiproliferative agents that induce heart disease as a side effect are selected from at least one of the following: bosutinib, crizotinib, dabrafenib, dasatinib, doxorubicin, lapatinib, nilotinib, sorafenib, sunitinib, vandetanib, or vemurafenib.

[0560] On the other hand, the compounds of Formula I are selected from at least one of the following:

[0561] , , , , , , , , , , , , , , , , , , Specification 50 / 128 pages 73 CN 122094963 A , , , and;

[0562] wherein any oxyanion O- of any compound is paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH of any compound is optionally in the form of a pharmaceutically acceptable salt.

[0563] On the other hand, the compounds of Formula I are:

[0564] ,

[0565] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

[0566] On the other hand, the compounds of Formula I are:

[0567] ,

[0568] The oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0569] On the other hand, the compound of formula I is:

[0570] , Specification 51 / 128 pages 74 CN 122094963 A

[0571] The oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0572] On the other hand, the compound of formula I is:

[0573] ,

[0574] The oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

[0575] On the other hand, the compound of Formula I is:

[0576] ,

[0577] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0578] On the other hand, the compound of Formula I is:

[0579] ,

[0580] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0581] On the other hand, the compound of Formula I is:

[0582] ,

[0583] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

[0584] On the other hand, the compound of Formula I is: Specification 52 / 128 pages 75 CN 122094963 A

[0585] ,

[0586] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0587] On the other hand, the compound of Formula I is:

[0588] ,

[0589] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH is optionally in the form of a pharmaceutically acceptable salt.

[0590] On the other hand, the compound of formula I is:

[0591] ,

[0592] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any COOH is optionally in the form of a pharmaceutically acceptable salt.

[0593] On the other hand, the compound of formula I is:

[0594] ,

[0595] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any COOH is optionally in the form of a pharmaceutically acceptable salt.

[0596] On the other hand, the compound of formula I is: Specification 53 / 128 pages 76 CN 122094963 A

[0597] ,

[0598] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any NH2 or COOH is optionally in the form of a pharmaceutically acceptable salt.

[0599] On the other hand, the compound of Formula I is:

[0600] ,

[0601] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0602] On the other hand, the compound of Formula I is:

[0603] ,

[0604] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0605] On the other hand, the compound of Formula I is:

[0606] ,

[0607] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0608] On the other hand, the compound of Formula I is: Specification 54 / 128 pages 77 CN 122094963 A

[0609] ,

[0610] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0611] On the other hand, the compound of Formula I is:

[0612] ,

[0613] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0614] On the other hand, the compound of Formula I is:

[0615] ,

[0616] wherein the oxyanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and wherein any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0617] On the other hand, the compound of Formula I is:

[0618] ,

[0619] The oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0620] On the other hand, the compound of formula I is: Specification 55 / 128 pages 78 CN 122094963 A

[0621] ,

[0622] The oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0623] On the other hand, the compound of formula I is:

[0624] ,

[0625] The oxoanion O- is optionally paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and any nitrogen atom is optionally in the form of a pharmaceutically acceptable salt.

[0626] Brief Description of the Drawings

[0627] To more fully understand the features and advantages of the present invention, reference is now made to the detailed description of the invention and the accompanying drawings, in which:

[0628] Figure 1 is a graph showing a comparison of the effects of a single oral dose of moxifloxacin (20 mg / kg) and simultaneous administration of the same single oral dose of moxifloxacin and a single oral dose of compound 31 on the QTc interval in guinea pigs.

[0629] Figure 2 is a graph showing a comparison of the effects of a single oral dose of moxifloxacin (20 mg / kg) and simultaneous administration of the same single oral dose of moxifloxacin and a single oral dose of compound 36 on the QTc interval in guinea pigs.

[0630] Figure 3 is a graph showing a comparison of the effects of a single oral dose of moxifloxacin (20 mg / kg) and simultaneous administration of the same single oral dose of moxifloxacin and a single oral dose of compound 34 on the QTc interval in guinea pigs.

[0631] Figure 4 is a graph comparing the effects of a single oral dose of moxifloxacin (20 mg / kg) with the same single oral dose of moxifloxacin concurrently with a single oral dose of compound 32 on the QTc interval in guinea pigs.

[0632] Figure 5 is a graph comparing the effects of a single oral dose of moxifloxacin (20 mg / kg) with the same single oral dose of moxifloxacin concurrently with a single oral dose of compound 35 on the QTc interval in guinea pigs.

[0633] Figures 6A and 6B are composite graphs comparing the effects of a single oral dose of moxifloxacin (20 mg / kg) with the same single oral dose of moxifloxacin concurrently with single oral doses of compounds 40, 41, 32, 34, 35, 36, 37, 38, 39, 40, 41, 44, 45, 47, and 51 on the QTc interval in guinea pigs.

[0634] Figure 7 is a schematic diagram of an example chemical structure as an embodiment of the present invention.

[0635] Figure 8 shows the outline of a 9-week study used to determine the cardioprotective effects of lipids.

[0636] Figure 9 shows M-mode echocardiography images comparing the effects of sham treatment, treatment with doxorubicin and trastuzumab, and treatment with doxorubicin and trastuzumab plus lipid compound 35.

[0637] Figure 10 shows left ventricular pressure recordings comparing sham treatment, treatment with doxorubicin and trastuzumab, and treatment with doxorubicin and trastuzumab plus two concentrations (10 mg / kg and 50 mg / kg) of lipid compound 35.

[0638] Figures 11A to 11I are graphs showing left ventricular systolic pressure (Figure 11A), heart rate (Figure 11B), stroke volume (Figure 11C), left ventricular ejection fraction (Figure 11D), fractional shortening (Figure 11E), N-terminal (NT)-proBNP on day 49 (Figure 11F), end-diastolic anterior wall thickness (AWT-ED) (mm) (Figure 11G), end-systolic anterior wall thickness (AWT-ES) mm (Figure 11H), and left ventricular mass (echo) (Figure 11I).

[0639] Detailed Description of the Invention

[0640] Although various embodiments of the invention are discussed in detail below, it should be understood that the invention provides many applicable inventive concepts that can be embodied in many specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways of forming and using the invention and do not limit the scope of the invention.

[0641] The compounds of the present invention include those outlined above, and are further described by the categories, subcategories and species disclosed herein. As used herein, unless otherwise indicated, the following definitions will apply. In at least some embodiments, chemical elements are determined according to the CAS edition of the periodic table, Handbook of Chemistry and Physics, 75th edition. Additionally, the general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5th edition, edited by Smith, MB and March J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0642] For ease of understanding of the invention, several terms are defined below. The terms defined herein have the meanings commonly understood by one of ordinary skill in the art related to the invention.

[0643] Terms such as “a”, “an”, and “the” are not intended to refer to a single entity, but rather to include broad classes that can be illustrated with specific examples. The terminology used herein is to describe specific embodiments of the invention, but its use does not limit the invention unless set forth in the claims. Specifically, the use of the words “a” or “an” in conjunction with the term “comprising” in the claims and / or specification may refer to “a”, but it also encompasses the meanings of “a or more,” “at least one,” and “a or more than one.” The term “or” used in the claims is intended to refer to “and / or” unless explicitly stated to refer only to alternatives or to mutually exclusive alternatives, but this disclosure supports the definition of “and / or” referring only to alternatives. Throughout this application, the term “about” is used to indicate that a value includes inherent variations in the measuring device, the error of the method used to determine the value, or variations present in the object of study.

[0644] General description of compounds in at least some embodiments of the invention. At least one embodiment of the present invention provides a structure of Formula I or a pharmaceutically acceptable salt thereof:

[0645]

[0646] I

[0647] wherein,

[0648] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; Specification 57 / 128 pages 80 CN 122094963 A

[0649] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0650] R3 is;

[0651] R4 is H or a pharmaceutically acceptable cation, wherein the introduction of said pharmaceutically acceptable cation forms a salt;

[0652] R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl, Br, and I;

[0653] R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R8)2, SH, CN, COOH, CONH2, Cl, Br, and I;

[0654] Each R7 is independently H or C1-C6 branched or unbranched alkyl;

[0655] Each R8 is independently H or C1-C6 branched or unbranched alkyl;

[0656] X is a direct bond, O, or NH;

[0657] Y is a direct bond, O, or NH; and,

[0658] each stereocenter is independently R, S, or racemic;

[0659] Compounds and definitions:

[0660] In one embodiment, an "alkyl" group refers to a saturated aliphatic hydrocarbon, including straight-chain, branched, and cyclic alkyl groups. In one embodiment, the alkyl group has 1-20 carbons. In another embodiment, the alkyl group has 1-15 carbons. In another embodiment, the alkyl group has 1-10 carbons. In another embodiment, the alkyl group has 11-20 carbons. In another embodiment, the alkyl group has 5-15 carbons. In yet another embodiment, the alkyl group has 1-5 carbons. The alkyl group may be unsubstituted or substituted with one or more groups selected from: halogen, hydroxyl, alkoxy, carboxylic acid, aldehyde, carbonyl, amide, cyano, alkylamide, dialkylamide, nitro, amino, alkylamino, dialkylamino, carboxyl, thio, and thioalkyl.

[0661] In one embodiment, an "alkenyl" group refers to an unsaturated hydrocarbon having one or more double bonds, including straight-chain, branched, and cyclic groups having one or more double bonds. The alkenyl group may have one double bond, two double bonds, three double bonds, etc. In another embodiment, the alkenyl group has 2-20 carbons. In another embodiment, the alkenyl group has 11-20 carbons. In another embodiment, the alkenyl group has 5-15 carbons. In another embodiment, the alkenyl group has 2-5 carbons. In another embodiment, the alkenyl group has 2-10 carbons. In another embodiment, the alkenyl group is vinyl (-CH=CH2). Examples of alkenyl groups that may be included are vinyl, propenyl, butenyl, cyclohexenyl, etc. The alkenyl group may be unsubstituted or substituted with halogen, hydroxyl, alkoxycarbonyl, amide, alkylamide, dialkylamide, nitro, cyano, amino, alkylamino, dialkylamino, carboxyl, thio and / or thioalkyl.

[0662] In one embodiment, an "alkynyl" group refers to an unsaturated hydrocarbon having one or more triple bonds, including straight-chain, branched and cyclic groups having one or more triple bonds. The alkynyl group may have one triple bond, two triple bonds, three triple bonds, etc. In another embodiment, the alkynyl group has 2-20 carbons. In another embodiment, the alkynyl group has 11-20 carbons. In another embodiment, the alkynyl group has 5-15 carbons. In another embodiment, the alkynyl group has 2-15 carbons. In another embodiment, the alkynyl group has 2-10 carbons. In another embodiment, the alkynyl group is ethynyl. Examples of alkynyl groups are ethynyl, propynyl, butynyl, cyclohexynyl, etc. The alkynyl group may be unsubstituted or substituted with halogen, hydroxyl, alkoxycarbonyl, cyano, amide, alkylamide, dialkylamide, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and / or thioalkyl.

[0663] In one embodiment, the term "halogen" refers to F in one embodiment, Cl in another embodiment, Br in another embodiment, and I in yet another embodiment.

[0664] "Pharmaceutically acceptable cation" in one embodiment refers to those organic or inorganic cations that are pharmaceutically acceptable for use in mammals and are well known in the art. For example, inorganic or organic cations include, but are not limited to, lithium, sodium, potassium, magnesium, calcium, barium, zinc, aluminum, cesium, and amine cations. Amine cations include, but are not limited to, cations derived from ammonia, triethylamine, tromethamine (TRIS), triethanolamine, ethylenediamine, glucosamine, N-methylglucosamine, glycine, lysine, ornithine, arginine, ethanolamine, choline, etc. In one embodiment, an amine cation is a cation in which X+ has the formula YH+, where Y is ammonia, triethylamine, trimethylamine (TRIS), triethanolamine, ethylenediamine, glucosamine, N-methylglucosamine, glycine, lysine, ornithine, arginine, ethanolamine, choline, etc. In one embodiment, a suitable cationic organic or inorganic salt may be used comprising a cationic moiety that can form an ion association with the O moiety on the compound and does not significantly adversely affect the desired properties of the compound for the purposes of this invention, such as increased solubility, improved stability, etc. Those skilled in the art will understand that compounds of formula I, wherein R4 is an organic or inorganic cation, can be converted into compounds of formula I comprising one or more different organic or inorganic cations.

[0665] Unless otherwise stated, the structures described herein are also intended to include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers) of the structures; for example, R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric isomers (or conformational isomers), are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention. Additionally, unless otherwise stated, the structures described herein are also intended to include compounds distinguished only by the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the invention, including those with hydrogen replaced by deuterium or tritium, or carbon replaced by carbon enriched in 13C or 14C, are within the scope of the invention. Such compounds can be used, for example, as analytical tools, as probes in biological analysis, or as therapeutic agents according to the invention.

[0666] As used herein, the term “in vivo” means inside the body. The term “in vitro” as used in this application should be understood to mean an operation performed in a non-living system.

[0667] As used herein, the term “treatment” refers to the treatment of the conditions mentioned herein, particularly the treatment of conditions in patients exhibiting symptoms of disease or disorder.

[0668] As used herein, the terms “treatment” or “treating” mean any administration of the compounds of the present invention and include (i) inhibiting the disease of an animal experiencing or exhibiting the pathology or symptoms of the disease (i.e., preventing further development of the pathology and / or symptoms); or (ii) alleviating the disease of an animal experiencing or exhibiting the pathology or symptoms of the disease (i.e., reversing the pathology and / or symptoms). The term “control” includes prevention, treatment, eradication, mitigation, or otherwise reducing the severity of the controlled condition.

[0669] As used herein, the terms “effective amount” or “therapeutic effective amount” mean the amount of the target compound that will elicit a biological or medical response in a tissue, system, animal, or human sought by an investigator, veterinarian, physician, or other clinician.

[0670] As used herein, the terms “administration” or “administering” as used herein with respect to a compound shall be understood to mean providing the compound of the invention to an individual in need of treatment in such a form that it may be introduced into the individual in a therapeutically useful form and in a therapeutically useful amount, including, but not limited to, oral dosage forms such as tablets, capsules, syrups, suspensions, etc.; injectable dosage forms such as IV, IM, or IP, etc.; transdermal dosage forms, including creams, gels, powders, or patches; buccal dosage forms; inhaled powders, sprays, suspensions, etc.; and rectal suppositories.

[0671] As used herein, the term “intravenous administration” includes injection and other methods of intravenous administration.

[0672] As used herein, the term “pharmaceuticalally acceptable” used herein to describe a carrier, diluent, or excipient must be compatible with other components of the formulation and harmless to the recipient.

[0673] Description of exemplary embodiments. In one embodiment, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof:

[0674]

[0675] I

[0676] wherein,

[0677] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0678] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0679] R3 is;

[0680] R4 is H or a pharmaceutically acceptable cation, wherein the introduction of said pharmaceutically acceptable cation forms a salt;

[0681] R5 is optionally separated by one or more compounds selected from OH, OAc, OMe, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl,

[0682] R6 is a C1-C10 branched or unbranched hydrocarbon substituted with Br and I groups;

[0683] R7 is independently H or C1-C6 branched or unbranched alkyl;

[0684] R8 is independently H or C1-C6 branched or unbranched alkyl;

[0685] X is a direct bond, O or NH;

[0686] Y is a direct bond, O or NH; and,

[0687] each stereocenter is independently R, S or racemic.

[0688] In one embodiment, the present invention relates to a compound of formula IA or a pharmaceutically acceptable salt thereof: Specification 60 / 128 pages 83 CN 122094963 A

[0689]

[0690] IA

[0691] wherein,

[0692] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0693] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0694] R3 is;

[0695] R4 is H or a pharmaceutically acceptable cation, wherein the introduction of said pharmaceutically acceptable cation forms a salt;

[0696] R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, N(R7)2 and COOH;

[0697] R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, N(R8)2 and COOH;

[0698] Each R7 is independently H or C1-C6 branched or unbranched alkyl;

[0699] Each R8 is independently H or C1-C6 branched or unbranched alkyl;

[0700] X is a direct bond;

[0701] Y is a direct bond; and,

[0702] each stereocenter is independently R, S or racemic.

[0703] In one embodiment, the present invention relates to a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof,

[0704]

[0705] I

[0706] wherein,

[0707] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds or a combination of 0-10 double bonds and triple bonds;

[0708] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds or a combination of 0-10 double bonds and triple bonds;

[0709] R3 is;

[0710] R4 is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt;

[0711] R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl, Br, and I;

[0712] R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R8)2, SH, CN, COOH, CONH2, Cl, Br, and I;

[0713] Each R7 is independently H or a C1-C6 branched or unbranched alkyl group;

[0714] Each R8 is independently H or a C1-C6 branched or unbranched alkyl group;

[0715] X is a direct bond, O, or NH;

[0716] Y is a direct bond, O, or NH; and,

[0717] each stereocenter is independently R, S, or racemic;

[0718] the method comprises the following steps:

[0719] converting the hydroxyl group of the compound of formula II to an ester, carbonate, or carbamate

[0720]

[0721] II

[0722] wherein all substitutions are defined as described above;

[0723] optionally, converting the phosphorus-bound OH group to O-R4, wherein R4 is not H; and,

[0724] optionally, removing one or more protecting groups; or

[0725] the method comprises the following steps:

[0726] linking the compound of formula III to the compound of formula IV by generating a phosphodiester bridge

[0727]

[0728] III Specification 62 / 128 pages 85 CN 122094963 A

[0729]

[0730] IV

[0731] wherein,

[0732] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0733] ​​R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0734] Each R7 is independently H or a C1-C6 branched or unbranched alkyl group;

[0735] Each R8 is independently H or a C1-C6 branched or unbranched alkyl group;

[0736] R9 is a C1-C10 branched or unbranched hydrocarbon substituted with one or more groups independently selected from OR11, N(R7)R12, N(R7)2, SR13, CN, COOR14, CONH2, Cl, Br, and I;

[0737] R10 is a number independently selected from one or more of the following: OR11, N(R8)R12, N(R8)2, SR13, CN, COOR14, CONH2, Cl, Br.C1-C10 branched or unbranched hydrocarbons substituted with groups of I;

[0738] Each R11 is independently H, Ac, Me, tert-butyl, benzyl, triphenylmethyl, benzoyl, p-nitrobenzoyl, MOM, BOM or Si constituting the core of a silyl ether;

[0739] Each R12 is independently H, Me, Boc, Cbz, Fmoc, benzyl, 4-methoxybenzyl, tert-butyl or triphenylmethyl;

[0740] Each R13 is independently H, Ac, benzoyl, p-nitrobenzoyl or triphenylmethyl;

[0741] Each R14 is independently H, C1-C6 branched or unbranched alkyl, benzyl or 4-methoxybenzyl;

[0742] X is a direct bond, O or NH;

[0743] Y is a direct bond, O or NH; and,

[0744] Each stereocenter is independently R, S or racemic;

[0745] Optionally, the phosphorus-bound OH group is converted to O-R4, wherein R4 is not H; and,

[0746] Optionally, each OR11, N(R7)R12, N(R8)R12, SR13 or COOR14 is converted to OH, NHR7, NHR8, SH or COOH, respectively.

[0747] In another embodiment, the present invention relates to a method for preparing a compound of formula IA or a pharmaceutically acceptable salt thereof.

[0748]

[0749] IA

[0750] wherein,

[0751] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds; Specification 63 / 128 pages 86 CN 122094963 A

[0752] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0753] R3 is;

[0754] R4 is H or a pharmaceutically acceptable cation, wherein the introduction of said pharmaceutically acceptable cation forms a salt;

[0755] R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, N(R7)2, and COOH;

[0756] R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, N(R8)2, and COOH;

[0757] Each R7 is independently H or C1-C6 branched or unbranched alkyl;

[0758] Each R8 is independently H or C1-C6 branched or unbranched alkyl;

[0759] X is a direct bond;

[0760] Y is a direct bond; and,

[0761] each stereocenter is independently R, S, or racemic;

[0762] The method comprises the following steps:

[0763] converting the hydroxyl group of the compound of formula II into an ester, carbonate, or carbamate

[0764]

[0765] II

[0766] Wherein, all substitutions are defined as described above;

[0767] Optionally, the phosphorus-bound OH group is converted to O-R4, wherein R4 is not H; and,

[0768] Optionally, one or more protecting groups are removed; or

[0769] The method comprises the following steps:

[0770] Connecting the compound of formula III to the compound of formula IV by generating a phosphodiester bridge

[0771]

[0772] III Specification 64 / 128 pages 87 CN 122094963 A

[0773]

[0774] IV

[0775] Wherein,

[0776] R1 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0777] R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds;

[0778] Each R7 is independently H or a C1-C6 branched or unbranched alkyl group;

[0779] Each R8 is independently H or a C1-C6 branched or unbranched alkyl group;

[0780] R9 is a C1-C10 branched or unbranched hydrocarbon substituted with one or more groups independently selected from OR11, N(R7)R12, N(R7)2, and COOR14;

[0781] R10 is a C1-C10 branched or unbranched hydrocarbon substituted with one or more groups independently selected from OR11, N(R8)R12, N(R8)2, and COOR14;

[0782] Each R11 is independently H, Ac, Me, tert-butyl, benzyl, triphenylmethyl, benzoyl, p-nitrobenzoyl, MOM, BOM, or Si constituting the core of a silyl ether;

[0783] Each R12 is independently H, Me, Boc, Cbz, Fmoc, benzyl, 4-methoxybenzyl, tert-butyl, or triphenylmethyl;

[0784] Each R14 is independently H, C1-C6 branched or unbranched alkyl, benzyl, or 4-methoxybenzyl;

[0785] X is a direct bond, O, or NH;

[0786] Y is a direct bond, O, or NH; and,

[0787] Each stereocenter is independently R, S, or racemic;

[0788] Optionally, the phosphorus-bonded OH group is converted to O-R4, wherein R4 is not H; and,

[0789] Optionally, each OR11, N(R7)R12, N(R8)R12, or COOR14 is converted to OH, NHR7, NHR8, or COOH, respectively.

[0790] As defined above, R1 has 0-10 double bonds, 0-10 triple bonds, or 0-10 double and triple bonds.The R1 is a combination of C1-C20 branched or unbranched hydrocarbons. In some embodiments, R1 is a C1-C15 branched or unbranched hydrocarbon having 0-7 double bonds, 0-7 triple bonds, or a combination of 0-7 double and triple bonds. In some embodiments, R1 is a C1-C10 branched or unbranched hydrocarbon having 0-5 double bonds, 0-5 triple bonds, or a combination of 0-5 double and triple bonds. In some embodiments, R1 is a C11-C20 branched or unbranched hydrocarbon having 0-5 double bonds, 0-5 triple bonds, or a combination of 0-5 double and triple bonds. In some embodiments, R1 is a C5-C15 branched or unbranched hydrocarbon having 0-5 double bonds, 0-5 triple bonds, or a combination of 0-5 double and triple bonds. In some embodiments, R1 is a C1-C5 branched or unbranched hydrocarbon having 0-2 double bonds, 0-2 triple bonds, or a combination of 0-2 double and triple bonds. In some embodiments, R1 is a C10-C15 branched or unbranched hydrocarbon.

[0791] As generally defined above, R2 is a C1-C20 branched or unbranched hydrocarbon having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. In some embodiments, R2 is a C1-C15 branched or unbranched hydrocarbon having 0-7 double bonds, 0-7 triple bonds, or a combination of 0-7 double and triple bonds. In some embodiments, R2 is a C1-C10 branched or unbranched hydrocarbon having 0-5 double bonds, 0-5 triple bonds, or a combination of 0-5 double and triple bonds. In some embodiments, R2 is a C11-C20 branched or unbranched hydrocarbon having 0-5 double bonds, 0-5 triple bonds, or a combination of 0-5 double and triple bonds, as described in specification 65 / 128, page 88, CN 122094963 A. In some embodiments, R2 is a C5-C15 branched or unbranched hydrocarbon having 0-5 double bonds, 0-5 triple bonds, or a combination of 0-5 double and triple bonds. In some embodiments, R2 is a C1-C5 branched or unbranched hydrocarbon having 0-2 double bonds, 0-2 triple bonds, or a combination of 0-2 double and triple bonds. In some embodiments, R2 is a C10-C15 branched or unbranched hydrocarbon.

[0792] As generally defined above, R1 and R2 have the same definition. In some embodiments, R1 and R2 are the same. In some embodiments, R1 and R2 are different.

[0793] As generally defined above, R3 is...

[0794] As generally defined above, R4 is H or a pharmaceutically acceptable cation, wherein the introduction of said pharmaceutically acceptable cation forms a salt, for example, a monomeric salt, a dimeric salt, a trimeric salt, or even a polymeric salt. In a preferred embodiment, R4 is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium. In some embodiments, R4 is H. In some embodiments...In the scheme, R4 is Li. In some embodiments, R4 is Na. In some embodiments, R4 is K. In some embodiments, R4 is Mg. In some embodiments, R4 is Ca. In some embodiments, R4 is Zn. In some embodiments, R4 is Cs. In some embodiments, R4 is ammonium. In some embodiments, R4 is tetraalkylammonium.

[0795] As generally defined above, R5 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R7)2, SH, CN, COOH, CONH2, Cl, Br, and I.

[0796] As generally defined above, R6 is a C1-C10 branched or unbranched hydrocarbon optionally substituted with one or more groups selected from OH, OAc, OMe, NHAc, N(R8)2, SH, CN, COOH, CONH2, Cl, Br, and I.

[0797] As generally defined above, R5 and R6 have the same definition. In some embodiments, R5 and R6 are the same. In some embodiments, R5 and R6 are different.

[0798] As generally defined above, each R7 is independently H or C1-C6 branched or unbranched alkyl. In some embodiments, each R7 is H. In some embodiments, each R7 is C1-C6 branched or unbranched alkyl. In some embodiments, at least one of R7 is H. In some embodiments, at least one of R7 is C1-C6 branched or unbranched alkyl.

[0799] As generally defined above, each R8 is independently H or C1-C6 branched or unbranched alkyl. In some embodiments, each R8 is H. In some embodiments, each R8 is C1-C6 branched or unbranched alkyl. In some embodiments, at least one of R8 is H. In some embodiments, at least one of R8 is C1-C6 branched or unbranched alkyl.

[0800] As generally defined above, R7 and R8 are similar. In some embodiments, R7 and R8 are the same. In some embodiments, R7 and R8 are different.

[0801] As generally defined above, R9 is a C1-C10 branched or unbranched hydrocarbon substituted with one or more groups independently selected from OR11, N(R7)R12, N(R7)2, SR13, CN, COOR14, CONH2, Cl, Br, and I.

[0802] As generally defined above, R10 is a C1-C10 branched or unbranched hydrocarbon substituted with one or more groups independently selected from OR11, N(R8)R12, N(R8)2, SR13, CN, COOR14, CONH2, Cl, Br, and I.

[0803] As generally defined above, each R11 is independently H, Ac, Me, tert-butyl, benzyl, triphenylmethyl, benzoyl,p-Nitrobenzoyl, MOM, BOM, or Si constituting the core of the silyl ether; in some embodiments, each R11 is H. In some embodiments, each R11 is Ac. In some embodiments, each R11 is Me. In some embodiments, each R11 is tert-butyl. In some embodiments, each R11 is benzyl. In some embodiments, each R11 is tribenzoyl. In some embodiments, each R11 is benzoyl. In some embodiments, each R11 is p-nitrobenzoyl. In some embodiments, each R11 is MOM. In some embodiments, each R11 is BOM. In some embodiments, each R11 is Si constituting the core of the silyl ether. In some embodiments, each R11 is the same. In some embodiments, each R11 is different.

[0804] As generally defined above, each R12 is independently H, Me, Boc, Cbz, Fmoc, benzyl, 4-methoxybenzyl, tert-butyl, or triphenylmethyl. In some embodiments, each R12 is H. In some embodiments, each R12 is Me. In some embodiments, each R12 is Boc. In some embodiments, each R12 is Cbz. In some embodiments, each R12 is Fmoc. In some embodiments, each R12 is benzyl. In some embodiments, each R12 is 4-methoxybenzyl. In some embodiments, each R12 is tert-butyl. In some embodiments, each R12 is triphenylmethyl. In some embodiments, each R12 is the same. In some embodiments, each R12 is different.

[0805] As generally defined above, each R13 is independently H, Ac, benzoyl, p-nitrobenzoyl, or triphenylmethyl. In some embodiments, each R13 is H. In some embodiments, each R13 is Ac. In some embodiments, each R13 is benzoyl. In some embodiments, each R13 is p-nitrobenzoyl. In some embodiments, each R13 is triphenylmethyl. In some embodiments, each R13 is the same. In some embodiments, each R13 is different.

[0806] As generally defined above, each R14 is independently H, C1-C6 branched or unbranched alkyl, benzyl, or 4-methoxybenzyl. In some embodiments, each R14 is H. In some embodiments, each R14 is C1-C6 branched or unbranched alkyl. In some embodiments, each R14 is benzyl. In some embodiments, each R14 is 4-methoxybenzyl. In some embodiments, each R14 is the same. In some embodiments, each R14 is different.

[0807] As generally defined above, X is a direct bond, O, or NH. In some embodiments, X is a direct bond. In some embodiments, X is O. In some embodiments, X is NH.

[0808] As generally defined above, Y is a direct bond, O, or NH. In some embodiments, Y is a direct bond. In some embodiments, Y is O. In some embodiments, Y is NH.

[0809] As generally defined above, X and Y have the same definition. In some embodiments, X and Y are the same. In some embodiments, X and Y are different.

[0810] As generally defined above, each stereocenter is independently R, S, or racemic.

[0811] In different embodiments, the present invention has the structure of compounds 1-51.

[0812] Specification page 67 / 128, page 90, CN 122094963 A

[0813] Specification page 68 / 128, page 91, CN 122094963 A

[0814] Specification page 69 / 128, page 92, CN 122094963 A

[0815] Specification page 70 / 128, page 93, CN 122094963 A

[0816]

[0817] Or,

[0818] Specification page 71 / 128, page 94, CN 122094963 A

[0819] Specification page 72 / 128, page 95, CN 122094963 A

[0820] And;

[0821] Any oxyanion O− of any compound is paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium; and any NH2 or COOH of any compound is optionally in the form of a pharmaceutically acceptable salt.

[0822] One embodiment of the invention relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable diluent or carrier. In one embodiment, the pharmaceutical composition comprises a compound of formula I in an amount of about 1 mg to about 1 g per unit dose. In some embodiments, the amount of each unit dose is about 1 mg to about 500 mg. In some embodiments, the amount of each unit dose is about 500 mg to about 1 g. In some embodiments, the amount of each unit dose is about 250 mg to about 750 mg. In some embodiments, the amount of each unit dose is about 50 mg to about 450 mg. In some embodiments, the amount of each unit dose is about 100 mg to about 300 mg.

[0823] Another embodiment of the invention relates to a pharmaceutical composition comprising a compound of formula IA and a pharmaceutically acceptable diluent or carrier. In one embodiment, the pharmaceutical composition comprises a compound of formula IA, wherein each unit dose is about 1 mg to about 1 mg.g. In some embodiments, the amount per unit dose is about 1 mg to about 500 mg. In some embodiments, the amount per unit dose is about 500 mg to about 1 g. In some embodiments, the amount per unit dose is about 250 mg to about 750 mg. In some embodiments, the amount per unit dose is about 50 mg to about 450 mg. In some embodiments, the amount per unit dose is about 100 mg to about 300 mg.

[0824] In some embodiments, the pharmaceutical composition further comprises one or more agents that induce heart disease as a side effect, and wherein a compound of formula I or a compound of formula IA alleviates or eliminates heart disease. In some embodiments, One or more drugs that induce heart disease as a side effect are selected from at least one of the following: adrenaline, salbutamol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, afortrol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, benprodil, bortezomib, bosutinib, bromoxynil, buprenorphine, capecitabine, chloral hydrate, chloramphenicol. Parmethazine, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine, Crizotinib, Curcumin, Cyclobenzaline, Cyclosporine, Dasafinib, Degarelix, Desipramine, Desvenlafaxine, Dexmedetomidine, Dextromethorphan, Dextromethorphan, Dihydroartemisinin and Piperaquine, Diphenhydramine, Disopyramide, Dobutamine, Dofetilide, Dolastron, Domperidone, Donepezil, Dopamine, Doxepin, Dronedarone, Fluphenazine (Instructions for Use 73 / 128) Page 96 CN 122094963 A Lidocaine, Ephedrine, Epinephrine, Erebulin, Erythromycin, Ediprom, Famotidine, Femimetabolic Acid, Fenfluramine, Fingolimod, Flucainide, Fluconazole, Fluoxetine, Formoterol, Phosphocarboxylic Acid, Phosphotoin, Frusemide, Furosemide, Galantamine, Gatifloxacin, Gemimifloxacin, Granisetron, Haloperidol, Hydrochlorothiazide, Hydroxychloroquine, Hydroxyzine, Ibutilide, Ipraridone, Imipramine, Indapamide, Isoproterenol Iradipine, itraconazole, ivabradine, ketoconazole, lapatinib, leuprorelin, levosalbutamol, levofloxacin, levomethasone, levomethadone, lysine mesylate, lithium, loperamide, maprotiline, mefloquine, melipramine, mesoridazine, orsinil, methadone, methamphetamine, methylphenidate, metoclopramide, mexiletine, midodrine, mifepristone, mirabezonone, mirtazapine, moxipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, and other medications.Norepinephrine, norfloxacin, nortriptyline, octreotide, ofloxacin, olanzapine, ondansetron, oxaliplatin, oxycodone, oxytocin, palapirone, papaverine hydrochloride, paroxetine, parretoxin, pazopanib, pazopanib, pentamivir, perfluoropropane lipospheres, perphenazine, phenbutazone, phenylephrine, phenylephrine, pimozide, posaconazole, probucol, procainamide, promethazine, propafenone, propofol, dextropropoxyfen, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, ritonavir and lopinavir. Roxithromycin, salbutamol, salmeterol, saquinavir, serindole, sertraline, sevoflurane, sibutramine, sofenacin, sorafenib, sotalol, sparfloxacin, spiramycin, sulpiride, sunitinib, tacrolimus, tamoxifen, terabixin, terbutaline, tetrabenzidine, thioridazine, tevothixone, tizanidine, tizanidinev, tolterodine, toremifene, torasemide, trazodone, trimethoprim and sulfamethoxazole, sulfamethoxazole, trimethoprim, trimethoprim, vandetanil, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, ziprasidone or ziprasidone. Those skilled in the art will recognize that other agents that induce heart disease exist, and it may be beneficial to include such agents in the formulations of the present invention.

[0825] In some embodiments, the present invention includes a composition comprising an active agent that induces heart disease and one or more compounds of formula I or formula IA described above, such as compounds of formula I or formula IA represented by compounds 1 to 42.

[0826] One embodiment of the present invention provides a pharmaceutical composition comprising a structure of formula I or formula IA, such as compounds 1 to 42, which is formulated as described above for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, skin, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration. In some embodiments, the composition formulated for oral administration is a tablet, capsule, pouch, pill, powder, lozenge, syrup, liquid solution, suspension, emulsion, elixir, or oral film (OTF). In some embodiments, the composition is in solid form, solution, suspension, or soft gel form.

[0827] One embodiment of the present invention provides a pharmaceutical composition comprising an active agent that causes cardiac disease as a side effect and a compound of formula I or formula IA as described above, such as compounds 1 to 42.

[0828] One embodiment of the present invention provides a method to reduce or eliminate cardiac ion channelopathies, myocardial damage, or symptoms caused by irregularities or alterations in cardiac rhythm in human or animal subjects caused by an active agent used to treat a disease.One or more methods comprising the step of administering to a human or animal subject a pharmaceutical composition comprising a compound of formula I or formula IA as described above, such as compounds 1 to 42.

[0829] In some embodiments, the pharmaceutical composition further comprises one or more excipients, binders, anti-adhesion agents, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, flow aids, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, or combinations thereof. In some embodiments, the binder is selected from hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic acid and methacrylic acid copolymers, pharmaceutical coating enamels, gums and emulsion derivatives. Specification 74 / 128 pages 97 CN 122094963 A

[0830] In one embodiment, the pharmaceutical composition comprises a compound of formula I or formula IA in an amount of about 1 mg to about 1 g per unit dose. In some embodiments, the amount of each unit dose is about 1 mg to about 500 mg. In some embodiments, the amount of each unit dose is about 500 mg to about 1 g. In some embodiments, the amount per unit dose is from about 250 mg to about 750 mg. In some embodiments, the amount per unit dose is from about 50 mg to about 450 mg. In some embodiments, the amount per unit dose is from about 100 mg to about 300 mg.

[0831] In some embodiments, the pharmaceutical composition further comprises one or more excipients, binders, anti-adhesion agents, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, flow aids, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, or combinations thereof. In some embodiments, the binder is selected from hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic acid and methacrylic acid copolymers, pharmaceutical coating enamels, gums and emulsion derivatives.

[0832] In one embodiment, the present invention includes a composition, a pharmaceutical composition, and a method, wherein the active agent causing cardiac disease as a side effect is selected from at least one of the following: adrenaline, salbutamol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, afortrol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, benprodil, and acetaminophen. Bortezomib, Bosutinib, Bromoxynil, Buprenorphine, Capecitabine, Chloral Hydrate, Clomipramine, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine, Crizotinib, Curcumin, Cyclobenzaline, Cyclosporine, Dasatinib, Degarelix, Desipramine, Desvenlafaxine, Dexmedetomidine, DextromethorphanMethyl ester, dextromethorphan, dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, donepezil, dopamine, doxepin, dronedarone, fluperidone, ephedrine, epinephrine, erythromycin, edepramine, famotidine, femoxanil, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, phosphonocarboxylic acid, fosphenytoin, furosemide, furosemide, galantamine, gatifloxacin, gemimifloxacin, granisetron, halofantrolin, haloperidol, hydrochlorothiazide, hydroxychloroquine, hydroxyzine, ibutilide, ipraprazole, imipramine, indapamide, isoproterenol, isradipine, itraconazole Ivabradine, ketoconazole, lapatinib, leuprorelin, levosalbutamol, levofloxacin, levomethazine, levomethadone, lysine mesylate, lithium, loperamide, maprotiline, mefloquine, melipramine, mesoridazine, orsinil, methadone, methamphetamine, methylphenidate, metoclopramide, mexiletine, midodrine, mifepristone, mirabezonone, mirtazapine, moxipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin Nortriptyline, Octreotide, Ofloxacin, Olanzapine, Ondansetron, Ophenadrine, Oxaliplatin, Oxycodone, Oxytocin, Palpanidone, Papaverine Hydrochloride, Paroxetine, Parretoline, Pazopanib, Pazopanib, Pentamidine, Perfluoropropane Lipospheres, Perphenazine, Phenylephrine, Phenylephrine, Phenylephrine, Pimozide, Posaconazole, Probucol, Procainamide, Promethazine, Propafenone, Propofol, Dextropropoxyfen, Protriptyline, Pseudoephedrine, Quetiapine, Quinidine, Quinine, Quinine Sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir, Ritonavir and Lopinavir, Roxithromycin, Salbutamol, Salmeterol, Saquina Viagra, sertraline, sevoflurane, sibutramine, sofenacin, sorafenib, sotalol, sparfloxacin, spiramycin, sulpiride, sunitinib, tacrolimus, tamoxifen, terbutaline, terfenadine, tetrabenzamine, thioridazine, tevothixol, tizanidine, tizanidinev, tolterodine, toremifene, torasemide, trazodone, trimethoprim and sulfamethoxazole, sulfamethoxazole, trimethoprim, tramipramin, vandetanil, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, ziprasidone or ziprasidone. Those skilled in the art will recognize that other agents that induce cardiac symptoms exist, and that it may be beneficial to include said agents in the formulations of the present invention.

[0833] In some embodiments, the pharmaceutical composition is formulated for oral, sublingual, transdermal, suppository, intrathecal, enteric, parenteral, intravenous, intraperitoneal, skin, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration. In some embodiments, the pharmaceutical composition formulated for oral administration is a tablet, capsule, pouch, pill, powder, lozenge, syrup, liquid solution, suspension, emulsion, elixir, or oral film (OTF). In some embodiments, the composition is in solid form, solution, suspension, or soft gel form. In some embodiments, the solid form further comprises one or more excipients, binders, anti-adhesion agents, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, flow aids, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, or combinations thereof. In some embodiments, the adhesive is selected from hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic acid and methacrylic acid copolymers, pharmaceutical coating enamels, gums, and emulsion derivatives.

[0834] In one embodiment, the pharmaceutical composition provided by the method comprises a compound of formula I or a compound of formula IA, wherein the amount per unit dose is from about 1 mg to about 1 g. In some embodiments, the amount per unit dose is from about 1 mg to about 500 mg. In some embodiments, the amount per unit dose is from about 500 mg to about 1 g. In some embodiments, the amount per unit dose is from about 250 mg to about 750 mg. In some embodiments, the amount per unit dose is from about 50 mg to about 450 mg. In some embodiments, the amount per unit dose is from about 100 mg to about 300 mg.

[0835] In one embodiment, the method provides a pharmaceutical composition formulated for oral, sublingual, transdermal, suppository, intrathecal, enteric, parenteral, intravenous, intraperitoneal, skin, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration. In some embodiments, the pharmaceutical composition formulated for oral administration is a tablet, capsule, pouch, pill, powder, lozenge, syrup, liquid solution, suspension, emulsion, elixir, or oral film (OTF). In some embodiments, the composition is in solid form, solution, suspension, or soft gel form. In some embodiments, the solid form further comprises one or more excipients, binders, anti-adhesion agents, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, flow aids, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, or combinations thereof. In some embodiments, the adhesive is selected from hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic acid and methacrylic acid copolymers, pharmaceutical coating enamels, gums, and emulsion derivatives.

[0836] In one embodiment, the method provides a pharmaceutical composition. One embodiment of the invention provides administration of a compound of formula I or formula IA, wherein the compound is a lipid that reduces or eliminates drug-induced or disease- or condition-related cardiac events such as QT prolongation, myocardial damage, or AV blockade.

[0837] The single most common reason for the withdrawal or restriction of commercially available drugs has consistently been QT interval prolongation associated with polymorphic ventricular tachycardia or the potentially fatal condition—torsius point ventricular tachycardia.

[0838] 5-HT3 antagonists block serotonin binding. Aloxi (or palonasitron hydrochloride HCl) is an antiemetic used for chemotherapy-induced nausea and vomiting, a 5-HT3 antagonist that blocks serotonin binding to 5-HT3. In one study, no significant difference in QTc interval was observed during the perioperative period when 0.075 mg of palonasitron was administered before or after sevoflurane anesthesia. Palonosetron may be safe in terms of QTc interval during sevoflurane anesthesia.

[0839] 5-HT4 receptor agonists. Cisapride is a gastrointestinal motility agent, a drug that increases upper gastrointestinal motility. It is used directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic agent. Cisapride prolongs the QT interval in a dose-dependent manner. When 33 patients were monitored during the higher dose phase, neither torsades de pointes nor ventricular tachycardia were recorded.

[0840] Histamine antagonists. Antihistamines used to treat allergies act by competing with histamine for H1 receptor sites on effector cells. Therefore, they prevent but do not reverse responses mediated solely by histamine.

[0841] Relief of pain and premenstrual symptoms. H1 antagonists are most useful in acute exudative allergies presenting with symptoms of rhinitis, urticaria, and conjunctivitis. However, their effects are purely mild and limited to suppressing symptoms attributable to histamine-antibody reactions (pages 76 / 128, CN 122094963 A).

[0842] Piramine is a first-generation histamine H1 antagonist for diuresis. There have been cases of QT interval prolongation following pyramine overdose in adolescents. Deaths due to ventricular tachyarrhythmias have been reported.

[0843] Tefenidine is an antihistamine used to treat allergies, hives (urticaria), and other allergic inflammatory conditions. The Seldane brand has been discontinued in the United States. Rare reports of serious cardiovascular adverse reactions have been received, including ventricular tachyarrhythmias (torsades de pointes, ventricular tachycardia, ventricular fibrillation, and cardiac arrest), hypotension, palpitations, or syncope.

[0844] Loratidine is a first-line antihistamine and a second-generation peripheral histamine H1 receptor blocker. In the striatum...Structurally, it is closely associated with tricyclic antidepressants such as imipramine and far associated with atypical antipsychotics such as quetiapine. Some antihistamines, such as mizolastine and ebastine, can prolong the QT interval and cause serious arrhythmias. As of mid-2009, very little clinical data had been published regarding the risk of QT prolongation with loratadine. Very rare cases of torsades de pointes ventricular tachycardia associated with loratadine appear to involve drug interactions, particularly with amiodarone and enzyme inhibitors. There are no reports of QT prolongation attributable to desloratadine, the major metabolite of loratadine. Patients with risk factors for torsades de pointes ventricular tachycardia or who are taking certain enzyme inhibitors should avoid using loratadine.

[0845] Astemizole is a long-acting and highly selective H1 antagonist that acts on histamine H-1 and H-3 receptors. It has antipruritic and anticholinergic effects. It is also a loss-of-function inhibitor of acid sphingomyelinase. Excessive astemizole can make the myocardium susceptible to ventricular arrhythmias, including torsades de pointes. However, arrhythmias only occur in patients with a corrected QT interval greater than 500 ms.

[0846] Calcium channel blockers. Preniramine is an amphetamine chemical calcium channel blocker used as a vasodilator in the treatment of angina. Resting ECGs of 29 patients with angina were recorded before, during, and after daily treatment with 180 mg preniramine. A significant QT interval prolongation was observed after one week of treatment. The prolongation persisted for up to 6 months as long as treatment continued. The QT interval returned to normal within 2 weeks after discontinuation of treatment.

[0847] Lidofluzidine is a piperazine calcium channel blocker and a coronary vasodilator with some antiarrhythmic effects. As a tricyclic antihistamine, it is used as a selective inverse agonist of peripheral histamine H1 receptors. It carries a significant risk of QT interval prolongation and ventricular arrhythmias. Lidocorizine potently inhibits HERG currents (I(HERG)) recorded in HEK 293 cells stably expressing wild-type HERG (IC50 of approximately 16 nM). Under similar conditions of preferential inhibition of activated / open HERG channels, it is approximately 13 times more potent against HERG than verapamil. Lidocorizine exerts a high affinity blockade on the α subunit of the HERG channel by binding to aromatic amino acid residues within the channel pore, which likely represents the molecular mechanism by which the drug prolongs the QT interval.

[0848] Beppridil is an antihypertensive drug that disrupts the movement of calcium (Ca2+) through calcium channels. It also prolongs the QT interval. Beppridil prolongs QT and refractory periods, and a linear correlation can be demonstrated between the percentage change in QTc and the prolongation of the refractory period. In one patient, beppridil reduced the number of stimuli required to induce VT by one, but no spontaneous arrhythmias were recorded; it has antiarrhythmic properties with minimal proarrhythmic effects.

[0849] Antimalarial drugs. Chloroquine-chlorpheniramine (chloroquine plus chlorpheniramine) is a histamine H1 receptor blocker that reverses the chloroquine insensitivity of Plasmodium falciparum in vitro, and chloroquine / chlorpheniramine produces a higher cure rate than chloroquine alone. Short QT syndrome (SQTS) is a sporadic or autosomal dominant disease characterized by significantly accelerated cardiac repolarization, ventricular arrhythmias, and sudden cardiac death. To date, mutations in five different ion channel genes (KCNH2, KCNQ1, KCNJ2, CACNA1C, and CACNB2) have been identified as causing SQTS. In SQTS, the risk of ventricular arrhythmias and sudden death is very high, with cardiac arrest reported as the primary symptom in 31% of SQTS patients. Chloroquine blocks the mutated Kir2.1 channel that leads to short QT syndrome and normalizes repolarization properties on a computer.

[0850] Halofantrolin is an antimalarial agent with a substituted phenanthrene and is associated with the antimalarial drugs quinine and fluorenol. It may be associated with cardiotoxicity. The most dangerous side effect is arrhythmia: halofantrolin causes significant QT prolongation, and this effect is seen even at standard doses. Therefore, this drug should not be given to patients with cardiac conduction defects, and it should not be used in combination with mefloquine. The mechanism of action of halofantrolin is unknown.

[0851] Quinidine is an antimalarial drug that acts in the heart as a class I antiarrhythmic agent (Ia). It is a stereoisomer of quinine, an alkaloid that inhibits the excitability of cardiac and skeletal muscle by blocking sodium and potassium currents across the cell membrane. It prolongs cellular action potentials and reduces automaticity. Quinidine also blocks muscarinic and α-adrenergic neurotransmission. At the same serum concentration, quinidine causes greater QT prolongation in women than in men. This difference may contribute to the observed higher incidence of drug-induced torsades de pointes in women taking quinidine and is indicative of other cardiac and non-cardiac medications that prolong the QTc interval.

[0852] Antipsychotics. First-generation antipsychotics, known as typical antipsychotics, were discovered in the 1950s. Although the first atypical antipsychotic, clozapine, was discovered in the 1960s and introduced into clinical practice in the 1970s, most second-generation drugs, known as atypical antipsychotics, have only recently been developed. Both generations of drugs tend to block receptors in the brain's dopamine pathway, but atypical drugs also tend to act on serotonin receptors. QTc interval prolongation can occur with treatment using both conventional and novel antipsychotics and is of clinical concern due to its association with potentially fatal ventricular arrhythmias, torsades de pointes.

[0853] Pimozide is a diphenylbutylpiperidine antipsychotic that can induce QT interval prolongation. Pimozide is contraindicated in individuals with acquired, congenital, or family history of QT interval prolongation. It is also recommended that individuals with a personal or family history of arrhythmias or torsades de pointes be advised against its use as an antagonist of D2, D3, and D4 receptors, as well as 5-HT7 receptors. It is also an hERG blocker.

[0854] Serindole is an antipsychotic. Like other atypical antipsychotics, it is active on dopamine and serotonin receptors in the brain. Abbott Labs first applied for FDA approval of serindole in 1996, but withdrew the application in 1998 due to concerns about the increased risk of sudden death resulting from QTc prolongation. In a trial involving 2,000 patients taking serindole, 27 patients died unexpectedly, including 13 sudden deaths. The drug has not been approved for use in the United States by the FDA. In Europe, serindole was approved and marketed in 19 countries from 1996, but its marketing authorization was suspended by the European Medicines Agency in 1998, and the drug was withdrawn from the market. In 2002, based on new data, the EMA's CHMP recommended that serindole could be reintroduced for restricted use in clinical trials with strong protective measures, including broad contraindications and warnings for patients at risk of arrhythmias, and, with exceptions, a reduction in the maximum total dose from 24 mg to 20 mg, and extensive ECG monitoring before and during treatment.

[0855] Chlorpromazine, marketed as Thorazine and Largactil, is a typical antipsychotic. Its mechanism of action is not fully understood, but is believed to be related to its ability as a dopamine antagonist. It also has antiserotonergic and antihistamine properties. Chlorpromazine is a very potent antagonist of the D2 dopamine receptor and similar receptors such as D3 and D5. Unlike most other drugs in this class, it also has a high affinity for the D1 receptor. Only a small number of people taking chlorpromazine have reported prolonged QT intervals on electrocardiograms. In a study of 2,633 people who experienced side effects while taking chlorpromazine, from the FDA and social media, 5 people had prolonged QT intervals on electrocardiograms.

[0856] Thioridazine is a typical piperidine antipsychotic, belonging to the phenothiazine class. The branded product was withdrawn from the market globally in 2005 due to serious arrhythmias, but a generic version is available in the United States. The drug was voluntarily discontinued globally by its manufacturer, Novartis, because it caused serious arrhythmias.Atypical. Thioridazine prolongs the QTc interval in a dose-dependent manner. It is believed that the ratio of 5-HT2A binding to the D2 receptor determines whether most antipsychotics are atypical or typical. In the case of thioridazine, the ratio of 5-HT2A binding to the D2 receptor is lower than the level required to be considered atypical, although the likelihood of extrapyramidal side effects is relatively low in practice.

[0857] Haloperidol or Haloperidol. The typical antipsychotic that prolongs the QT interval is meperidine. It is the most commonly used typical antipsychotic on the WHO Model List of Essential Medicines, with special considerations: patients at particular risk of developing QT prolongation (hypokalemia), and those using other drugs that cause QT, such as amiodarone: QTc interval prolongation (a potentially dangerous change in heart rate).

[0858] Mesoridazone is a piperidine sedative belonging to the class of drugs called phenothiazines, used to treat schizophrenia. It is a metabolite of thioridazine. Mesoridazine was withdrawn from the U.S. market in 2004 due to dangerous side effects, namely irregular heartbeats and QT prolongation on electrocardiograms.

[0859] Selective serotonin reuptake inhibitors. Celexa (citalopram) is an antidepressant in a group known as selective serotonin reuptake inhibitors (SSRIs). Its chemical structure is a racemic bicyclic dihydroisobenzofuran (phthalane) derivative named (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-nitrile, which is unrelated to the chemical structure of other SSRIs or other available antidepressants. Citalopram may cause symptoms affecting heart rhythm (QT prolongation).

[0860] Antibiotics. Moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent. It works by inhibiting DNA gyrase, type II topoisomerase, and topoisomerase IV (enzymes necessary for the separation of bacterial DNA to inhibit cell replication), and may cause torsades de pointes ventricular tachycardia. Moxifloxacin should be avoided when co-administered with other drugs that also prolong the QT interval or induce bradycardia (such as beta-blockers, amiodarone). Caution should be exercised when using moxifloxacin in patients with cardiovascular disease, including those with conduction abnormalities. Drugs that prolong the QT interval may have an additional effect on QT prolongation and lead to an increased risk of ventricular arrhythmias.

[0861] Pentamidine is an antimicrobial drug given for the prevention and treatment of Pneumocystis pneumonia. The exact mechanism of its antiprotozoal action is unknown (although it may involve ubiquitin and mitochondrial function responses). Severe or fatal arrhythmias and heart...Energy failure is very frequent. Aromatic diamidine pentamidine works by inhibiting hERG channel transport. Pentamidine has no acute effect on the currents generated by hERG, KvLQT1 / mink, Kv4.3, or SCNA5. However, after overnight exposure, pentamidine reduces hERG currents and inhibits hERG transport and maturation, with IC50 values ​​of 5 to 8 μM, similar to therapeutic concentrations.

[0862] Clarithromycin is an antibiotic made from erythromycin, chemically known as 6-O-methylerythromycin. It belongs to the macrolide class and works by preventing certain bacteria from producing proteins. It causes QT prolongation or ventricular arrhythmias, including torsades de pointes.

[0863] Erythromycin is an antibiotic with common side effects, including serious side effects such as arrhythmias with QT prolongation, including torsades de pointes.

[0864] Grefloxacin is an oral broad-spectrum fluoroquinolone antibacterial drug used to treat bacterial infections. Grefloxacin was withdrawn from the global market in 1999 due to its side effect of prolonging the QT interval on an electrocardiogram, leading to cardiac events and sudden death.

[0865] Sparfloxacin is a fluoroquinolone broad-spectrum antibiotic used to treat bacterial infections. It has a controversial safety data sheet 79 / 128 pages 102 CN 122094963 A. Use of sparfloxacin is contraindicated in patients with known QTc prolongation and in patients receiving concurrent treatment with class IA or III antiarrhythmic drugs. In one study, the maximum plasma concentrations (Cmax) after doses of 1200 mg and 1600 mg were lower than would be expected for a linear dose-response relationship. The same was true for the mean increase in QTc interval and the mean maximum increase. The increase in QTc interval correlated well with Cmax but not with AUC0-infinite.

[0866] Curcumin (diferoylmethane) is a bright yellow chemical substance produced by some plants. It is the main curcumin compound of turmeric (Curcuma longa) and exhibits antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and antitumor activities. In whole-cell patch-clamp experiments, curcumin inhibited hERG K+ currents in HEK293 cells stably expressing hERG channels in a dose-dependent manner, with an IC50 value of 5.55 μM. Acute treatment with 10 μM curcumin significantly altered the deactivation, inactivation, and recovery time from inactivation of hERG channels.

[0867] Antiarrhythmic drugs. Antiarrhythmic drugs are used to suppress abnormal rhythms of the heart (arrhythmias), such as atrial fibrillation, ventricular tachycardia, and ventricular fibrillation. Procainamide belongs to the class of antiarrhythmic drugs used to treat arrhythmias. It is classified as Class Ia by the Vaughan Williams classification system and is used for supraventricular and ventricular arrhythmias.Both. Procainamide, an antiarrhythmic drug, was also detected interfering with pacemakers. This is because the toxicity of procainamide leads to decreased ventricular conduction velocity and increased ventricular refractory period. This results in interference with artificial membrane potential and leads to supraventricular tachycardia, which induces pacemaker failure and death. It induces rapid blockade of sodium channels activated by myocardial dart poison (BTX) and acts as an antagonist for long-gated closure. Procainamide belongs to the aminobenzamide class and has similar cardiac effects to quinidine, and it has the same toxicity characteristics as quinidine.

[0868] Propafenone is a class 1C antiarrhythmic drug that treats diseases associated with rapid heartbeat, such as atrial and ventricular arrhythmias, and works by slowing the influx of sodium ions into cardiomyocytes, resulting in decreased cellular excitability. Propafenone is more selective to cells at a high rate and also blocks normal cells more than classes Ia or Ib. Propafenone differs from its prototype Class Ic antiarrhythmic drugs in that it possesses the additional activity of a β-adrenergic blocker, which can induce bradycardia.

[0869] Mesylate aniline (E-4031) is an experimental Class III antiarrhythmic drug that blocks potassium channels of Class III antiarrhythmic drugs. E-4031 acts on a specific type of voltage-gated potassium channel, namely the hERG channel, which is mainly present in the heart. The hERG channel (Kv11.1) mediates the IKr current, which repolarizes cardiomyocytes. The hERG channel is encoded by the ether-a-go-go-related gene (hERG). E-4031 blocks the hERG type potassium channel by binding to the open channel. Its structural target within the hERG channel is unknown, but some other mesylate aniline Class III antiarrhythmic drugs are known to bind to the S6 domain or C-terminus of the hERG channel. Because E-4031 can prolong the QT interval, it can cause fatal arrhythmias. To date, one clinical trial has been conducted to test the effect of E-4031 on prolonging the QT interval.

[0870] Amiodarone is a class III antiarrhythmic drug used for ventricular fibrillation or tachycardia, prolonging phase 3 of the cardiac action potential. Amiodarone is an antiarrhythmic drug known to cause prolongation of the duration of the action potential, which is reflected on the electrocardiogram as QT prolongation. Amiodarone has multiple effects on myocardial depolarization and repolarization, making it an extremely effective antiarrhythmic drug. Its main action is to block potassium channels, but it can also block sodium and calcium channels as well as β and α adrenergic receptors. Amiodarone significantly prolongs the QT interval and QTc value.

[0871] Dronedarone is a benzofuran derivative associated with amiodarone and is a drug mainly used for arrhythmias (approved by the FDA in 2009). It is a "multi-channel blocker," however, it is unclear which channel(s) play a key role in its success.Key effects. The role of dronedarone at the cellular level is controversial. Most studies suggest it inhibits multiple outward potassium currents, including fast delayed rectification, slow delayed rectification, and ACh-activated inward rectification. It is also thought to reduce inward fast Na currents and L-type Ca channels. In some studies, the reduction in K currents has been shown to be due to inhibition of K-ACh channels or related GTP-binding proteins. A 69% reduction in K+ currents leads to increased AP duration and effective refractory period, demonstrating amiodarone-like class III antiarrhythmic activity in in vitro and clinical trials. This drug also appears to exhibit activity in each of the four Vaughan-Williams antiarrhythmic classes. Concomitant use of drugs or herbal products that prolong the QT interval and may induce torsades de pointes ventricular tachycardia with a QTc-Bazett interval ≥500 ms is prohibited, as is use with drugs or herbal supplements (Class I or III antiarrhythmics, phenothiazines, tricyclic antidepressants, certain oral macrolides, ephedra) that prolong the QT interval or increase the risk of torsades de pointes ventricular tachycardia.

[0872] Disopyramide is an antiarrhythmic drug used to treat ventricular tachycardia. It is a sodium channel blocker and is therefore classified as a Class 1a antiarrhythmic. Disopyramide's Class 1a activity is similar to that of quinidine because it targets sodium channels to inhibit conduction. During phase 0 of the cardiac action potential, disopyramide inhibits the increase in sodium permeability in cardiomyocytes, thereby reducing inward sodium currents. This results in an increased excitation threshold and a decreased depolarization rise rate. Disopyramide prolongs the PR interval by prolonging the duration of the QRS and P waves. Concerns about disopyramide have been about the hypothetical possibility of sudden death induced by its type 1 antiarrhythmic effects.

[0873] Dofetilide is a class III antiarrhythmic drug. Due to the arrhythmic potential of dofetilide, it is only available by prescription from a physician who has received specialized training on the risks of using dofetilide. Furthermore, it is only available by mail order or from a specially trained local pharmacy. Dofetilide works by selectively blocking the rapid component of the delayed rectified outward potassium current. There is a dose-dependent increase in both the QT interval and the corrected QT interval (QTc). Therefore, many practitioners will only initiate dofetilide treatment on individuals under telemetry monitoring or if continuous EKG measurements of QT and QTc are possible.

[0874] Sotalol is a non-selective competitive β-adrenergic receptor blocker that also exhibits class III antiarrhythmic properties. The U.S. Food and Drug Administration recommends sotalol for use only in serious arrhythmias because its QT interval prolongation carries a low risk of causing life-threatening torsades de pointes ventricular tachycardia. Sotalol also acts on potassium channels and can cause...Delayed ventricular diastole. By blocking these potassium channels, sotalol inhibits the outflow of K+ ions, which leads to an increased time before another electrical signal can be generated in the ventricular myocytes. This increase occurs during the time period before a new systolic signal.

[0875] Ibutilide is a class III antiarrhythmic drug indicated for acute cardioversion in atrial fibrillation and atrial flutter, and for prolonging the action potential and refractory period of cardiomyocytes. Due to its class III antiarrhythmic activity, it should not be administered concurrently with class Ia and class III drugs. Unlike most other class III antiarrhythmic drugs, ibutilide does not produce its action potential prolongation by blocking the delayed rectifier potassium current in the heart, nor does it possess the sodium-blocking, antiadrenergic, and calcium-blocking activities found in other class III drugs. Therefore, it is often referred to as a “pure” class III antiarrhythmic drug. Like other class III antiarrhythmic drugs, ibutilide blocks the delayed rectifier potassium current. It does act on slow sodium channels and promotes sodium inflow through these slow channels. Like other antiarrhythmic drugs, ibutilide can cause arrhythmias because it prolongs the QT interval, which can lead to a potentially fatal arrhythmia known as torsades de pointes. This drug is contraindicated in patients who may develop arrhythmias; especially those with a history of polymorphic ventricular tachycardia, long QT intervals, sick sinus syndrome, or recent myocardial infarction.

[0876] Dopamine receptor antagonists. Dopamine antagonists (antidopaminergics) are a class of drugs that block dopamine receptors through receptor antagonism. Most antipsychotic drugs are dopamine antagonists, and therefore they have been found to be useful in the treatment of schizophrenia, bipolar disorder, and stimulant psychosis. Several other dopamine antagonists are antiemetics used to treat nausea and vomiting.

[0877] Fluperidone is an antidopaminerhein used as an antiemetic and antipsychotic. It is a potent D2 (dopamine receptor) antagonist with some histamine and serotonin antagonist activity. There are concerns about QT prolongation and type A ventricular tachycardia (TVT) as described in the product information leaflet 81 / 128, page 104, CN 122094963. The evidence for this is controversial, with nine cases of torsades de pointes reported in the last 30 years, and all of these patients received doses exceeding 5 mg. QT prolongation is a dose-related effect, and it appears that fluperidone does not pose a significant risk at low doses; however, QT prolongation does lead to torsades de pointes.

[0878] Domperidone is a peripherally selective dopamine D2 receptor antagonist used for Parkinson's disease. Caution is required due to the cardiotoxic side effects of domperidone, especially when administered intravenously, in the elderly, and at high doses (>30 mg daily). The clinical sign of potential cardiotoxicity of domperidone is QT interval prolongation (part of the electrocardiogram).Domperidone use is likely associated with an increased risk of sudden cardiac death (70%) through its effects of prolonging the cardiac QT interval and ventricular arrhythmias. The cause is thought to be the blockade of hERG voltage-gated potassium channels. The risk is dose-dependent, and appears to be greatest with high / very high doses administered intravenously and in the elderly, as well as with drugs that interact with domperidone and increase its circulating concentration (i.e., CYP3A4 inhibitors). However, conflicting reports exist. QT prolongation in newborns and infants is controversial and inconclusive.

[0879] Anticancer agents. QTc prolongation, increased QT dispersion, and the development of late potentials in doxorubicin and anthracyclines are hallmarks of doxorubicin-induced aberrant ventricular depolarization and repolarization. Both QT dispersion and late potentials are known to be associated with an increased risk of serious ventricular arrhythmias and sudden death in various cardiac diseases.

[0880] Arsenic trioxide is an antileukemic drug that can prolong the QTc interval. Cardiac conduction abnormalities: Before initiating treatment, perform a 12-lead electrocardiogram, assess serum electrolytes and creatinine, correct any pre-existing electrolyte abnormalities, and consider discontinuing any medications known to prolong the QT interval. Arsenic trioxide can cause QT prolongation and complete atrioventricular block. QT prolongation can lead to torsades de pointes, which can be fatal. The risk of torsades de pointes is associated with the degree of QT prolongation, concomitant administration of QT-prolonging medications, a history of torsades de pointes, pre-existing QT prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions leading to hypokalemia or hypomagnesemia. One patient (also receiving amphotericin B) developed torsades de pointes during arsenic trioxide induction therapy for recurrent APL. Arsenic trioxide (As2O3) used to treat acute promyelocytic leukemia reduces the hERG / IKr current not by direct blockade, but by inhibiting the processing of hERG protein in the endoplasmic reticulum (ER), thereby reducing the surface expression of hERG.

[0881] Opioids. Levoacetylmethadol is a levorotatory isomer of α-methadyl acetatea, a synthetic opioid with a structure similar to methadone. It has a long duration of action due to its active metabolite. In 2001, levacetylmethadol was removed from the European market due to reports of life-threatening ventricular arrhythmias.

[0882] Methadone is an opioid used to treat pain and drug addiction. Serious risks include opioid abuse, and arrhythmias, including QT prolongation, may also occur. In 2011, 4,418 people died in the United States due to methadone poisoning, accounting for 26% of all opioid poisoning deaths.

[0883] Lipid-lowering drugs. Lovastatin is a cholesterol-lowering drug that is an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), the enzyme that catalyzes the conversion of HMG-CoA to mevalonate. Mevalonate is a necessary component for cholesterol biosynthesis, and lovastatin interferes with cholesterol production by acting as a reversible competitive inhibitor of HMG-CoA bound to HMG-CoA reductase. QTc prolongation associated with antipsychotic drugs occurs in a dose-dependent manner. The addition of lovastatin leads to an increase in plasma quetiapine levels through competitive inhibition of cytochrome P(450) (CYP) isoenzyme 3A4. This highlights the possibility that drug interactions between quetiapine and lovastatin may lead to QTc prolongation during the management of dyslipidemia in patients with schizophrenia. Instructions for Use, Pages 82 / 128, 105, CN 122094963 A

[0884] Probucol is an anti-hyperlipidemic drug originally developed for the treatment of coronary artery disease. Probucol is associated with QT interval prolongation. Probucol exacerbates long QT syndrome associated with a novel missense mutation M124T at the N-terminus of HERG.

[0885] Ion channelopathies. When the human ether-a-go-go gene is associated with a cardiac tetramer potassium channel mutation, it can make patients sensitive to more than 163 drugs that inhibit ion conduction and deregulate action potentials. Following action in potassium channels, action potentials are prolonged. Ion channel active drugs can directly increase the QTc interval and increase the risk of torsades de pointes and sudden cardiac death. The deterioration of cardiomyocyte potassium channel sensitivity to drugs may also be associated with metabolic disease states, including diabetes, or may be of idiopathic origin.

[0886] As used herein, the term "liposome" refers to a capsule whose wall or membrane is formed of one or more of the novel lipids of the present invention. The lipids of the present invention can be used alone or in combination with other known lipids. In a specific, non-limiting example, the novel lipids form liposomes or are used for liposomes, said liposomes being empty liposomes and can be formulated from a single type of phospholipid or a combination of phospholipids. Empty liposomes may further include one or more surface modifications, such as proteins, sugars, glycolipids or glycoproteins, or even nucleic acids such as aptamers, thiomodified nucleic acids, protein-nucleic acid mimics, protein mimics, stealthing agents, etc. In one embodiment, said novel liposome or novel liposome precursor comprises a novel lipid-monoglycerate-fatty acid cocrystal, such as a cocrystal comprising: a lysophosphatidyl compound, a monoglyceride and a free fatty acid, and in some respects, the composition is in the ratio of 1:4:2, 1:3:3, 2:4:2.Alternatively, a novel lipid: monoglyceride: free fatty acid ratio of 1:2:4 molar percentage. The composition may comprise a cocrystal mixture containing the novel lipid, myristoyl monoglyceride, and myristic acid. In a specific non-limiting example, the composition further comprises an active agent in or around the novel lipid liposome, which may be an empty liposome, and the composition has a phospholipid to active agent ratio of 3:1, 1:1, 0.3:1, and 0.1:1.

[0887] Previous work from some of the inventors has demonstrated that formulations of liposomes comprising the following components prevent inhibition of hERG channels by various QT elongators: 1,2-dimyristoyl-sn-glycerol-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycerol-3-phosphoglycerol (DMPG), DMPC / DMPG, 1-myristoyl-2-hydroxy-sn-glycerol-3-phosphocholine, 12-myristoyl-2-hydroxy-sn-glycerol-3-[phospho-racemic-(glycerol)] (12- Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)]), 1-myristoyl-2-hydroxy-sn-glycerol-3-phosphate-(1'-racemic-glycerol) (LysoPG) or 1-myristoyl-2-hydroxy-sn-glycerol-3-phosphate choline (LysoPC), lysophosphatidylcholine, lauroyl lysophosphatidylcholine, myristoyl lysophosphatidylcholine, palmitoyl lysophosphatidylcholine, stearoyl lysophosphatidylcholine, arachidoyl lysophosphatidylcholine, oleoyl lysophosphatidylcholine, linoleoyl lysophosphatidylcholine, linolenicoyl lysophosphatidylcholine or erucoyl lysophosphatidylcholine.

[0888] In various regulatory-validated preclinical models using the above-described lipids, QTc prolongation of more than 20 QTc prolonging drugs was eliminated.

[0889] The novel lipids of the present invention can be prepared in natural form or as salts, hydrates, or solvates thereof. By way of example only, salts also include lithium, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc. Examples

[0890] Although certain features of the invention have been illustrated and described herein, many modifications, substitutions, alterations, and equivalent features will now occur to those skilled in the art. Therefore, it should be understood that the appended claims are intended to cover all such modifications and alterations falling within the true spirit of the invention.

[0891] Although certain reactions are described in the following claims, it should be understood that differences in the final results are expected because the following examples are based on laboratory-scale reactions and not on manufacturing processes. In addition, it should be understood that in many cases,In many cases, the amount of product isolated is the amount isolated from multiple replicate batches of the reaction, rather than the amount isolated from a single reaction.

[0892] Example 1. Effects of various lipids.

[0893] This invention demonstrates the enhancing effect of reducing or eliminating QT prolongation in a guinea pig model system. The guinea pig model system used herein is the closest model system to human cardiac function and is widely accepted for testing QT prolonging agents. Briefly, guinea pigs are fitted with electrocardiogram leads and given an increased oral dose of moxifloxacin. In Europe and Canada, guinea pigs are the preferred species for QT prolongation testing because they possess a set of cardiac ion channels most similar to those in humans and are highly sensitive to arrhythmogenic drugs. In terms of medicine, moxifloxacin is the preferred positive control for QTc prolongation in comprehensive QT (TQT) clinical studies because it causes dose-dependent QTc prolongation in all species and exhibits very linear pharmacokinetics, making it easy to administer and relatively safe at subtoxic exposure levels.

[0894] Guinea pigs given moxifloxacin alone exhibited severe (+10 ms) and life-threatening (+30 ms) QTc prolongations. In contrast, animals that had received concomitant administrations, such as 14:0 hemolytic PG, showed no or very small QTc changes. The QTc dose-response of moxifloxacin showed a statistically significant right shift, effectively preventing QTc prolongation from becoming dose-limiting.

[0895] AV block represents an interesting puzzle in cardiology: unlike patients with disease-induced AV block, patients with drug-induced AV block are not treated with pacemaker implantation. However, evidence suggests that in 56% of cases, drug-induced atrioventricular block is irreversible after drug discontinuation (Zeltser D, Justo D, Halkin A, et al. Drug-induced atrioventricular block: prognosis after discontinuation of the culprit drug. J Am Coll Cardiol. 2004; 44(1):105-108). Current practice is to discontinue AV-blocking drugs immediately upon detection of their effects. This leads to the removal of useful and effective drugs from pharmacopoeias available to oncologists, and also directly impacts clinical medication use.

[0896] The ion channels involved in AV block and QTc prolongation are entirely different: sodium (Na+) and calcium (Ca2+) channel inhibition is the cause of AV block, while QTc prolongation is caused by repolarization delay due to potassium (K+) inhibition. However, the hypothetical mechanism of lipid-rescue K+ currents may also benefit Na+ and Ca2+ currents.

[0897] To test this hypothesis, guinea pigs were fitted with subcutaneous ECG leads and exposed to increased intravenous doses of fingolimod and / or verapamil, both in the absence of and with oral administration of 14:0 hemolytic PG. ECG signals were continuously recorded for 2 hours following administration of the AV-blocking agents fingolimod and verapamil. The PR interval was measured after fingolimod infusion. PR measurement ceased when the P wave disconnected from the QRS complex, indicating third-degree AV block.

[0898] Guinea pigs exposed to intravenous fingolimod alone progressed to first-degree AV block up to a dose of 15 μg / kg, rapidly developed to Mobitz-1 type, second-degree AV block at 20 μg / kg, and ultimately to third-degree AV block up to a dose of 23 μg / kg. The progression of AV block was rapid and irreversible: cessation of infusion did not prevent P-QRS dissociation.

[0899] Guinea pigs exposed to verapamil received an intravenous injection of 0.5 mg / kg, followed by an intravenous infusion of fingolimod 60 minutes later. Grade 1 AV blockade occurred at a dose of 7 μg / kg, changing to Mobitz-1 type 2 AV blockade at 10 μg / kg, and transitioning to 3rd-degree dissociation between the P wave and QRS complex at a dose cutoff of 45 μg / kg.

[0900] Animals in a third group received an initial oral gavage of 1.0 mg / kg 14:0 hemolyzed PG, followed by an intravenous administration of 0.5 mg / kg verapamil 60 minutes later. Fingolimod was infused into the animals 60 minutes after verapamil administration, as described above. At doses up to 200 μ / kg, the animals exhibited moderate changes in the PR interval, at which point Grade 1 AV blockade occurred. Mobitz type II AV blockade was observed in 2 out of 6 animals, with AP-QRS dissociation observed at a dose of 51 μg / kg (see page 84 / 128 of the product manual, CN 122094963). P-QRS dissociation was observed at 300 μg / kg in the remaining animals in the same group.

[0901] In human patients, fingolimod is contraindicated in patients presenting with Mobitz type II second- or third-degree AV blockade or a history of sick sinus syndrome. The drug has been shown to produce AV blockade from the first dose, and treatment with fingolimod and AV blockers is advised to be avoided (Fingolimod full prescribing information, Novartis: T2016-22, February 2016). Given the history of guinea pig cardiovascular data being translatable to other species, including humans, these results suggest that 14:0 hemolytic PG can reduce the risk of AV blockade associated with fingolimod use, thereby enhancing the safety of the drug and enabling treatment of patients who would otherwise be ineligible for fingolimod due to AV blockade issues.

[0902] Figure 1 shows a single oral dose of moxifloxacin (20Figure 2 is a graph comparing the effects of a single oral dose of moxifloxacin (20 mg / kg) on ​​the QTc interval of guinea pigs with the same single oral dose of moxifloxacin and the same single oral dose of compound 31.

[0903] Figure 3 is a graph comparing the effects of a single oral dose of moxifloxacin (20 mg / kg) on ​​the QTc interval of guinea pigs with the same single oral dose of moxifloxacin and the same single oral dose of compound 4.

[0905] Figure 4 is a graph comparing the effects of a single oral dose of moxifloxacin (20 mg / kg) on ​​the QTc interval of guinea pigs with the same single oral dose of moxifloxacin and the same single oral dose of compound 32.

[0906] Figure 5 is a graph showing the effect of a single oral dose of moxifloxacin (20 mg / kg) on ​​the QTc interval in guinea pigs compared to the effect of the same single oral dose of moxifloxacin concurrently with a single oral dose of compound 35.

[0907] Figures 6A and 6B are composite graphs showing the effect of a single oral dose of moxifloxacin (20 mg / kg) on ​​the QTc interval in guinea pigs compared to the effect of the same single oral dose of moxifloxacin concurrently with single oral doses of compounds 40, 41, 32, 34, 35, 36, 37, 38, 39, 40, 41, 44, 45, 47, and 51.

[0908] Example 2. Cardioprotection against cardiotoxic agents.

[0909] The highly active chemotherapeutic agent doxorubicin has been associated with acute but reversible cardiotoxicity and long-term dose-related cardiomyopathy. This cardiomyopathy is characterized by minimal left ventricular dilatation and overall systolic dysfunction, often accompanied by moderate valvular regurgitation (Keefe, 2001). More than half of all patients exposed to doxorubicin develop cardiac dysfunction within 10 to 20 years after chemotherapy, and 5% of them develop overt HF (Cardinale, 2010). The incidence of cardiomyopathy in patients treated with doxorubicin has led to its current use as an adjunct therapy in combination with safer but often less effective treatments. One such therapy is Herceptin® (trastuzumab), a blockbuster humanized monoclonal antibody that targets the extracellular domain of HER2 in patients with breast cancer. However, Herceptin treatment is also hampered by cardiotoxicity, with reported incidences of decreased left ventricular ejection fraction (LVEF) as high as 27% (Bouwer, 2020).

[0910] Clinical studies have shown that the combination of doxorubicin and Herceptin improves overall survival in patients with breast cancer by 24–33%.(Romond, 2005). Since doxorubicin-induced and Herceptin-induced cardiomyopathy are mostly irreversible and cumulative, a key strategy for continuing to use these very potent oncology tools in clinical practice is to find ways to minimize the combined cardiac side effects.

[0911] It has been reported that, like the iron chelator dexazosin, vitamin D provides some protection against anthracyclines (Lee, 2021). Although the protective mechanism is not fully understood, it may involve preventing oxidation within biomembranes. In this ongoing research project, rats and mice were used to evaluate the protection provided by the anti-inflammatory complex lipid (SPP05) that preferentially integrates into the cardiomyocyte membrane.

[0912] All experiments were conducted in accordance with the Canadian Council against Cruelty to Animals (CCAC) and the IACUC guidelines for the use of laboratory animals of IPST. IPST is AAALAC certified.

[0913] Testing System and Treatment: Adult female C57 / BL6 mice (n=10 mice / group) weighing 25 g at the start of the study were administered DOX intraperitoneally for 2 weeks. After a 1-week pause, HER was administered intraperitoneally for 2 weeks. Simultaneously, throughout the project, starting from day -10, one group of animals was administered anti-inflammatory lipids (SPP05) at 10 mg / kg / day, and the other group at 50 mg / kg.

[0914] Experimental Endpoints. Body weight was measured weekly.

[0915] Echocardiography was performed on days -10, 14, 42, and 49 using a Vivid 9 instrument and a linear 13 MHz probe. Blood was drawn on days -7, 0, 21, and 49. Invasive hemodynamics were measured by insertion into the left ventricle using a fluid-filled PE15 catheter connected to a Millar pressure sensor.

[0916] Troponin I, NT-Pro-BNP, and caspase-3 activities were measured by Q-ELISA.

[0917] The heart and liver were histologically examined after fixation in 10% NBF and staining with H&E and Picro Sirius Red.

[0918] The combination of doxorubicin and Herceptin was considered the standard treatment for HER-2-expressing breast cancer patients until the occurrence of drug-induced heart failure prompted a shift in clinical treatment. In this mouse model, Doxo+Herc-treated animals exhibited left ventricular systolic dysfunction, as demonstrated by losses in ejection fraction, stroke volume, fractional shortening, and pulse pressure. In addition, Doxo+Herc-treated animals also exhibited overall and end-systolic and end-diastolic left ventricular tissue damage.Loss. Finally, the HF biomarker NT-Pro-BNP level was higher in Doxo+Herc treated animals than in healthy (sham-treated) animals.

[0919] Using compound 35, a complex anti-inflammatory lipid with known membrane-altering properties, treatment of animals partially prevented damage caused by tumor therapy in female mice. Considering the toxic mechanism of Doxo+Herc, it is speculated that the protection provided by compound 35 is related to the prevention of sphingomyelinase activation by reactive oxygen species.

[0920] Figures 7A and 7C are depictions of example chemical structures as embodiments of the invention.

[0921] Figure 8 shows a 9-week study outline for determining the cardioprotective effects of the lipid.

[0922] Figure 9 shows M-mode echocardiography images comparing the effects of sham treatment, treatment with doxorubicin and trastuzumab, and treatment with doxorubicin and trastuzumab + lipid compound 35.

[0923] Figure 10 shows left ventricular pressure recordings comparing sham treatment, treatment with doxorubicin and trastuzumab, and treatment with doxorubicin and trastuzumab plus two concentrations (10 mg / kg and 50 mg / kg) of lipid compound 35.

[0924] Figures 11A to 11H are graphs showing left ventricular systolic pressure (Figure 11A), heart rate (Figure 11B), stroke volume (Figure 11C), left ventricular ejection fraction (Figure 11D), percentage shortening (Figure 11E), N-terminal (NT)-B-type natriuretic peptide precursor (NT-proBNP) on day 49 (Figure 11F), end-diastolic anterior wall thickness (AWT-ED) (mm) (Figure 11G), end-systolic anterior wall thickness (AWT-ES) mm (Figure 11H), and left ventricular mass (echo) (Figure 11I).

[0925] In at least some embodiments of the invention, compounds of formula I or formula IA are prepared according to the following scheme. For reference, all variable groups included in the following schemes are related to the corresponding variables defined above. Those skilled in the art will recognize that alternative reagents and reactants can be used to produce the same target compound and intermediates.

[0926] As shown in Scheme 1, the compound of Formula V is reacted with an acid anhydride, followed by the formation of a salt, to obtain the compound of Formula VI. Those skilled in the art will recognize that alternatives to the acid anhydride will produce similar results. Such alternatives include, but are not limited to, acyl chlorides, acyl imidazoles, acyl succinimides, etc. In addition, those skilled in the art will recognize that carboxylic acids will produce similar results in the presence of an activator. Suitable activators include, but are not limited to, DCC, EDC, HBTU, BOP, PyBOP, carbonyl diimidazole, disuccinimide carbonates, etc. Those skilled in the art will recognize that DOWEX Na, used to form the salt, is suitable for the formation of the salt.Resin substitutes are useful. Such substitutes include, but are not limited to, sodium bicarbonate, sodium carbonate, etc. Those skilled in the art will recognize that when R5 and / or R6 contain functional groups with protecting groups, an "optional deprotection" step is required. Those skilled in the art will understand that a protecting group is a chemical additive that prevents reactivity with a given functional group until the protecting group is removed or cleaved. Those skilled in the art will understand that protecting groups include, but are not limited to, Ac, tert-butyl, benzyl, triphenylmethyl, benzoyl, p-nitrobenzoyl, MOM, BOM, Si constituting the core of a silyl ether, Boc, Cbz, Fmoc, 4-methoxybenzyl, and ester forms of carboxylic acids, wherein said esters contain C1-C6 branched or unbranched alkyl groups. Those skilled in the art will recognize that compounds of formula VI include compounds 1, 7, 8, 9, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, and 51.

[0927] Scheme 1

[0928]

[0929] As shown in Scheme 2, a compound of formula V is reacted with a chloroformate, followed by the formation of a salt, to give a compound of formula VII. Those skilled in the art will recognize that substitutes for chloroformates will produce similar results. Such substitutes include, but are not limited to, pyrocarbonates, etc. Those skilled in the art will recognize that bases other than triethylamine can be used in carbonate formation reactions. Such bases include, but are not limited to, triisopropylamine, diisopropylethylamine, DBU, N-methylmorpholine, N-methylpyridine, N,N-dimethylpiperazine, etc. Those skilled in the art will recognize that acyl transfer catalysts other than DMAP can be used in carbonate formation reactions. Such acyl transfer catalysts include, but are not limited to, pyridine, 2-methylpyridine, etc. Furthermore, those skilled in the art will recognize that the introduction of Lewis acid catalysts can promote the formation of carbonates. Such Lewis acid catalysts include, but are not limited to, zinc chloride, zinc acetate, zinc bromide, aluminum trichloride, titanium trichloride, titanium isopropoxide, boron trifluoride, tin chloride, alumina, silica gel, etc. Those skilled in the art will recognize that alternatives to sodium bicarbonate for salt formation are useful. Such alternatives include, but are not limited to, DOWEX Na+ resin, sodium carbonate, etc. Those skilled in the art will recognize that compounds of formula VII include compounds 2 and 3.

[0930] Scheme 2

[0931] Specification 87 / 128 pages 110 CN 122094963 A

[0932] As shown in Scheme 3, the compound of formula V is reacted with an isocyanate, followed by the formation of a salt, to obtain the compound of formula VIII. Those skilled in the art will recognize that alternatives to the isocyanate produce similar results.Those skilled in the art will recognize that bases can promote the formation of carbamates. Such bases include, but are not limited to, triethylamine, triisopropylamine, diisopropylethylamine, DBU, N-methylmorpholine, N-methylpyridine, N,N-dimethylpiperazine, etc. Those skilled in the art will recognize that acyl transfer catalysts can promote the formation of carbamates. Such acyl transfer catalysts include, but are not limited to, DMAP, pyridine, 2-methylpyridine, etc. Furthermore, those skilled in the art will recognize that the introduction of Lewis acid catalysts can promote the formation of carbamates. Such Lewis acid catalysts include, but are not limited to, zinc chloride, zinc acetate, zinc bromide, aluminum trichloride, titanium trichloride, titanium isopropoxide, boron trifluoride, tin chloride, alumina, silica gel, etc. Those skilled in the art will recognize that alternatives to sodium bicarbonate for salt formation are useful. Such alternatives include, but are not limited to, DOWEX Na+ resin, sodium carbonate, etc.

[0933] Scheme 3

[0934]

[0935] As shown in Scheme 4, the compound of formula IX is reacted with a carboxylic acid, acyl halide, acid anhydride, chloroformate, or isocyanate, followed by cleavage of the benzyl ether protecting group to obtain the compound of formula X. The compound of formula X is coupled with the compound of formula XI using phospholipase D to generate the compound of formula XII. Those skilled in the art will recognize that substitutes for carboxylic acids, acyl halides, and acid anhydrides will produce similar results for the preparation of the compound of formula X. Such substitutes include, but are not limited to, acyl imidazoles, acyl succinimides, etc. Furthermore, those skilled in the art will recognize that an activator is required for the reaction with the carboxylic acid to prepare the compound of formula X. Suitable activators include, but are not limited to, DCC, EDC, HBTU, BOP, PyBOP, carbonyl diimidazole, disuccinimide carbonate, etc. Those skilled in the art will recognize that substitutes for chloroformates will produce similar results for the preparation of the compound of formula X. Such substitutes include, but are not limited to, pyrocarbonates, etc. Those skilled in the art will recognize that isocyanate substitutes produce similar results for the preparation of compounds of formula X. Those skilled in the art will recognize that bases can promote the formation of esters, carbonates, and carbamates. Such bases include, but are not limited to, triethylamine, triisopropylamine, diisopropylethylamine, DBU, N-methylmorpholine, N-methylpyridine, N,N-dimethylpiperazine, etc. Those skilled in the art will recognize that acyl transfer catalysts can promote the formation of esters, carbonates, and carbamates. Such acyl transfer catalysts include, but are not limited to, DMAP, pyridine, 2-methylpyridine, etc. Furthermore, those skilled in the art will recognize that the introduction of Lewis acid catalysts can promote the formation of esters, carbonates, and carbamates. Such Lewis acid catalysts include, but are not limited to, zinc chloride, zinc acetate, zinc bromide, aluminum trichloride, titanium trichloride, titanium isopropoxide, boron trifluoride, tin chloride, alumina, silicon, etc.Gum, etc. Those skilled in the art will recognize the usefulness of substitutes for the benzyl ether protecting group and the relevant reaction conditions for its cleavage. A wide variety of suitable alcohol protecting groups are described extensively in "Green's Protective Groups in Organic Synthesis". Such benzyl ether substitutes include, but are not limited to, trimethylsilyl ether, tert-butyldimethylsilyl ether, triisopropylsilyl ether, tert-butyldiphenylsilyl ether, acetate, benzoate, 4-nitrobenzoate, tert-butyl ether, 4-methoxybenzyl ether, etc. Those skilled in the art will recognize that alternative enzymes and alternative enzyme reaction conditions can be used for the enzymatic formation of phosphodiester. Those skilled in the art will recognize that for schemes 1-4, R5 and R6 can be replaced with R7 and R8, respectively. Furthermore, those skilled in the art will understand that when R5 and R6 are replaced with R7 and R8, cleavage of the protecting group may be necessary. Those skilled in the art will recognize that suitable protecting groups associated with R7 and R8 depend on the functional groups that may require such protecting groups. Such protecting groups may be selected from, but are not limited to, Ac, C1-C6 branched or unbranched alkyl, tert-butyl, benzyl, 4-methoxybenzyl, triphenylmethyl, benzoyl, p-nitrobenzoyl, MOM, BOM, Boc, Cbz, Fmoc, or Si forming the core of a silyl ether. Various suitable protecting groups are extensively described in “Green’s Protective Groups in Organic Synthesis”. Those skilled in the art will recognize that compounds of formula XII include compounds 1, 2, 3, 7, 8, 9, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, and 51.

[0936] Scheme 4

[0937]

[0938] Schemes 5, 6, 7 and 8 together illustrate the preparation of compounds of formula XXVII. As shown in Scheme 5, the compound of formula XIII is converted to a benzyl ether to give the compound of formula XIV. The ketal of the compound of formula XIV is then cleaved to give the compound of formula XV. Upon reaction with one or more carboxylic acids and a suitable activator, the compound of formula XV is converted to the compound of formula XVI. Subsequently, the benzyl ether of the compound of formula XVI is cleaved to give the compound of formula XVII. Those skilled in the art will recognize that alternative reagents and reaction conditions can be used for the formation of benzyl ethers. Those skilled in the art will also recognize that substitutes for the protecting groups of benzyl ethers and the relevant reaction conditions for their formation are useful. In "Green's Protective Groups in OrganicThe specification "Synthesis" provides a broad description of various suitable alcohol protecting groups (pages 89 / 128, CN 122094963 A). Such benzyl ether substitutes include, but are not limited to, trimethylsilyl ether, tert-butyldimethylsilyl ether, triisopropylsilyl ether, tert-butyldiphenylsilyl ether, acetates, benzoates, 4-nitrobenzene esters, tert-butyl ethers, 4-methoxybenzyl ethers, etc. Similarly, those skilled in the art will recognize that alternative reaction conditions can be used for the cleavage of acetals and ketals. In "Green's Protective Groups in Organic..." Such conditions are generally described in “Synthesis”, the online version of Wiley. Those skilled in the art will recognize that carboxylic acids and related activators can be used for ester formation. Those skilled in the art will recognize that DCC is a suitable activator for coupling alcohols and carboxylic acids to form esters. Those skilled in the art will recognize that alternative activators can also be used for coupling alcohols and carboxylic acids to form esters. Such alternative activators include, but are not limited to, EDC, HBTU, BOP, PyBOP, carbonyl diimidazole, disuccinimide carbonate, etc. Those skilled in the art will further recognize that substitutes for carboxylic acids and activators can be used to generate esters from alcohols. Such substitutes include functionalizing agents, including but not limited to acid anhydrides, acyl chlorides, acyl imidazoles, acyl succinimides, etc. Those skilled in the art will recognize that substitutes for benzyl ether protecting groups and related reaction conditions for their cleavage are useful. In “Green's Protective Groups in Organic”... Various suitable alcohol protecting groups are extensively described in "Synthesis". Such benzyl ether substitutes include, but are not limited to, trimethylsilyl ether, tert-butyldimethylsilyl ether, triisopropylsilyl ether, tert-butyldiphenylsilyl ether, acetate, benzoate, 4-nitrobenzene, tert-butyl ether, 4-methoxybenzyl ether, etc.

[0939] Scheme 5

[0940]

[0941] As shown in Scheme 8, the compound of formula XVIII is converted into a benzyl ether to obtain the compound of formula XIX. The ketal of the compound of formula XIX is then cleaved to obtain the compound of formula IX. Those skilled in the art will recognize that alternative reagents and reaction conditions can be used for the formation of benzyl ethers. Those skilled in the art will also recognize that substitutes for benzyl ether protecting groups and the relevant reaction conditions for their formation are useful. In "Green's Protective Groups in Organic The book "Synthesis" provides a broad description of various suitable alcohol protecting groups. Such benzyl ether substitutes include, but are not limited to, trimethylsilyl ether, tert-butyldimethylsilyl ether, triisopropylsilyl ether, tert-butyldiphenylsilyl ether, acetates, etc.Benzoate esters, 4-nitrobenzene esters, tert-butyl ethers, 4-methoxybenzyl ethers, etc. Similarly, those skilled in the art will recognize that alternative reaction conditions can be used for the cleavage of acetals and ketals. Such conditions are described in general in "Green's Protective Groups in Organic Synthesis".

[0942] Scheme 8 Specification 90 / 128 pages 113 CN 122094963 A

[0943]

[0944] As shown in Scheme 9, the compound of formula IX is converted into a compound of formula XX. The compound of formula XX is a dicarbonate, diester, or dicarboxylate. After hydrogenation, the benzyl ether of compound XX is cleaved to give a compound of formula XXI.

[0945] Those skilled in the art will recognize that the dicarbonate form of the compound of formula XX can be prepared by reacting the compound of formula IX with a functionalizing agent, including but not limited to chloroformate esters, pyrocarbonate esters, etc. Those skilled in the art will recognize that the formation of carbonates may include the use of bases, such as, but not limited to, triethylamine, triisopropylamine, diisopropylethylamine, DBU, N-methylmorpholine, N-methylpyridine, N,N-dimethylpiperazine, etc. Those skilled in the art will recognize that the formation of carbonates may include the use of acyl transfer catalysts, such as, but not limited to, DMAP, pyridine, 2-methylpyridine, etc. Those skilled in the art will recognize that the formation of carbonates may include the use of Lewis acid catalysts, such as, but not limited to, zinc chloride, zinc acetate, zinc bromide, aluminum trichloride, titanium trichloride, titanium isopropoxide, boron trifluoride, tin chloride, aluminum oxide, silica gel, etc.

[0946] Those skilled in the art will recognize that the diacetate form of compounds of formula XX can be prepared by reacting compounds of formula IX with functionalizing agents, including but not limited to acid anhydrides, acyl chlorides, acyl imidazoles, acyl succinimides, etc. Furthermore, those skilled in the art will recognize that carboxylic acids produce similar results in the presence of an activator. Suitable activators include, but are not limited to, DCC, EDC, HBTU, BOP, PyBOP, carbonyl diimidazole, disuccinimide carbonate, etc.

[0947] Those skilled in the art will recognize that the dicarboxylate form of compounds of formula XX can be prepared by reacting compounds of formula IX with functionalizing agents, including but not limited to isocyanates. Those skilled in the art will recognize that bases can promote the formation of carbamates. Such bases include, but are not limited to, triethylamine, triisopropylamine, diisopropylethylamine, DBU, N-methylmorpholine, N-methylpyridine, N,N-dimethylpiperazine, etc. Those skilled in the art will recognize that acyl transfer catalysts can promote the formation of carbamates. Such acyl transfer catalysts include, but are not limited to,Limited to DMAP, pyridine, 2-methylpyridine, etc. Furthermore, those skilled in the art will recognize that the introduction of Lewis acid catalysts can promote the formation of carbamates. Such Lewis acid catalysts include, but are not limited to, zinc chloride, zinc acetate, zinc bromide, aluminum trichloride, titanium trichloride, titanium isopropoxide, boron trifluoride, tin chloride, alumina, silica gel, etc.

[0948] Those skilled in the art will also recognize that substitutes for benzyl ether protecting groups and the relevant reaction conditions for their cleavage are useful. Various suitable alcohol protecting groups are extensively described in "Green's Protective Groups in Organic Synthesis". Such benzyl ether substitutes include, but are not limited to, trimethylsilyl ether, tert-butyldimethylsilyl ether, triisopropylsilyl ether, tert-butyldiphenylsilyl ether, acetate, benzoate, 4-nitrobenzoate, tert-butyl ether, 4-methoxybenzyl ether, etc.

[0949] Those skilled in the art will recognize that for scheme 7, R5 and R6 can be replaced by R7 and R8, respectively. Furthermore, those skilled in the art will understand that when R5 and R6 are replaced by R7 and R8, it may be necessary to cleave the protecting group. Those skilled in the art will recognize that suitable protecting groups associated with R7 and R8 depend on the functional groups that may require said protecting groups. Such protecting groups may be selected from, but are not limited to, Ac, C1-C6 branched or unbranched alkyl, tert-butyl, benzyl, 4-methoxybenzyl, triphenylmethyl, benzoyl, p-nitrobenzoyl, MOM, BOM, Boc, Cbz, Fmoc or Si constituting the core of a silyl ether. Various suitable protecting groups are extensively described in “Green’s Protective Groups in Organic Synthesis”, pages 91 / 128, 114 CN 122094963 A.

[0950] Scheme 7

[0951]

[0952] As shown in Scheme 8, the compound of formula XVII is coupled to the compound of formula XXI via a phosphodiester bond. Subsequently, optional cleavage of the protecting group and optional formation of a phosphate diester salt yield compounds of formula XXII. Those skilled in the art will recognize that compounds of formula CVII and formula XXI each contain a primary hydroxyl group. Those also skilled in the art will recognize that phosphate diesters can be formed between two different alcohols by using various phosphorus reagents and reaction conditions. Phosphorus reagents that can be used to generate phosphate diesters include, but are not limited to, POCl3, etc. In some cases, both alcohols are simultaneously combined with the phosphorus reagent. In some cases, the two hydroxyl groups react sequentially with the phosphorus reagent. In some cases, the formation of the phosphate diester requires additional steps, including but not limited to oxidation,Deprotection or a combination thereof, the steps are performed either as a single additional step or as multiple additional steps. Those skilled in the art will recognize that bases can promote reactions with phosphorus reagents used for phosphate diester formation. Such bases include, but are not limited to, triethylamine, triisopropylamine, diisopropylethylamine, DBU, N-methylmorpholine, N-methylpyridine, N,N-dimethylpiperazine, etc. Those skilled in the art will recognize that acyl transfer catalysts can promote reactions with phosphorus reagents used for phosphate diester formation. Such acyl transfer catalysts include, but are not limited to, DMAP, pyridine, 2-methylpyridine, etc. Those skilled in the art will recognize that useful reagents for phosphate diester salt formation include, but are not limited to, DOWEX Na+ resin, sodium bicarbonate, sodium carbonate, etc.

[0953] Those skilled in the art will recognize that for scheme 8, R5 and R6 can be replaced by R7 and R8, respectively. Furthermore, those skilled in the art will understand that when R5 and R6 are replaced by R7 and R8, cleavage of the protecting group may be necessary. Those skilled in the art will recognize that suitable protecting groups associated with R7 and R8 depend on the functional groups that may require such protecting groups. Such protecting groups may be selected from, but are not limited to, Ac, C1-C6 branched or unbranched alkyl groups, tert-butyl, benzyl, 4-methoxybenzyl, triphenylmethyl, benzoyl, p-nitrobenzoyl, MOM, BOM, Boc, Cbz, Fmoc, or Si forming the core of a silyl ether. A wide variety of suitable protecting groups are described extensively in “Green’s Protective Groups in Organic Synthesis”.

[0954] Those skilled in the art will recognize that the compounds of formula XXII include compounds 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14, 19, 20, 22, 23, 27, 28, 29, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, and 51.

[0955] Embodiment 8 Specification 92 / 128 pages 115 CN 122094963 A

[0956]

[0957] Referring to embodiments 1-8, those skilled in the art will recognize that, in general, the embodiments enable the preparation of various stereoisomers of compounds of formula I and Ia. Furthermore, those skilled in the art will recognize that the various forms of the compounds of the present invention include salt forms other than Na. Regarding different salt forms, compounds of formulas I and Ia, where R4, as generally defined, can be converted from the OH form or from a given salt form to an alternative salt form. Reagents used for such interconversion include, but are not limited to, magnesium chloride, calcium chloride, etc. Furthermore, those skilled in the art will recognize that, as R5 and R6...Some of the functional groups present may exist in the form of salts suitable for the properties of said functional groups. For example, when R5 and / or R6 contains a carboxylic acid unit, the carboxylic acid may exist in a pharmaceutically acceptable salt form, which includes, but is not limited to, salt counterions such as Li+, Na+, K+, Zn2+, Mg2+, Ca2+, Cs2+, ammonium ions, tetraalkylammonium ions, etc. Similarly, when R5 and / or R6 contains an amine unit, the amine may be in a pharmaceutically acceptable form, which includes pharmaceutically acceptable acids, including, but not limited to, HCl, HBr, AcOH, MsOH, fumaric acid, maleic acid, etc. Those skilled in the art will recognize that, including the R4 transformation, compounds of formula XXII include compounds 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14, 19, 20, 22, 23, 27, 28, 29, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, and 51.

[0958] It is contemplated that any embodiments discussed in this specification can be practiced with respect to any method, kit, reagent, or composition of the invention, and vice versa. Furthermore, the compositions of the invention can be used to implement the methods of the invention.

[0959] Although certain features of the invention have been described and illustrated herein, those skilled in the art will now contemplate many modifications, substitutions, alterations, and equivalent features. Therefore, it should be understood that the appended claims are intended to cover all such modifications and alterations falling within the true spirit of the invention.

[0960] Details relating to equipment and analytical procedures are described below when performing the exemplary synthetic schemes described below. HPLC analysis was performed using an XBridge C8 column (50 x 4.6 mm, 3.5 µ) as described below. Solvent A = 25% ammonia solution, B = acetonitrile; flow rate: 1 ml / min.

[0961] Example 3. Preparation of sodium (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-diacetoxypropyl)phosphate (compound 1).

[0962]

[0963] Acetic anhydride (3.5 ml, 36.3 mmol, 10 equivalents) was added to an anhydrous pyridine (50 ml, 20 times the volume) solution of sodium DMPG (2.5 g, 3.63 mmol) at room temperature (25 °C) under a nitrogen atmosphere. DMAP (88 mg, 0.725 mmol, 0.2 equivalents) was added to the mixture, and the mixture was heated to 100°C for 48 h. After the reaction was complete (as confirmed by TLC analysis, 20% MeOH in DCM solution, Rf ~0.6, identified by phosphomolybdic acid staining), the solvent was evaporated, and the crude product was passed through a container packed with medium-strength DCM solution.Column chromatography on silica gel (230-400 mesh) (Note: the silica gel was neutralized by washing with a 10% ammonia-methanol solution). The product was eluted with dichloromethane containing 10% methanol to give (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-diacetoxypropyl) phosphate as its ammonium salt. The resulting ammonium salt was exchanged for a sodium salt by passing it through a Dowex® 50WX8 Na+ resin pad in dichloromethane containing 10% methanol. The product fraction was collected and concentrated. The product was dissolved in a mixture of acetonitrile and water (5 mL: 15 mL) and lyophilized to give (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-diacetoxypropyl) phosphate sodium salt as a light brown solid. Yield: 1.2 g (44%). 1H‑NMR (400 MHz, DMSO‑d6): δH 4.99 –5.05 (m, 2H) , 4.20–4.29 (m, 2H) , 4.07 (m, 2H) , 3.67 (m, 4H) , 2.26 (t, J = 4.49 Hz, 4H) , 2.01 (s, 6H), 1.49 (m, 4H), 1.23 (m, 40H) and 0.85 (t, J = 4.04 Hz, 6H) ppm. 13C‑NMR (100 MHz, DMSO‑d6): δH 172.63, 172.45, 170.37, 170.08, 71.07, 70.99, 70.89, 63.85, 62.98, 62.81, 33.99, 33.83, 31.85, 29.68, 29.62, 29.56, 29.39, 29.35, 29.30, 29.07, 29.00 and 24.94 ppm. LCMS(ELSD):749.1 (M-23).

[0964] Example 4. Preparation of sodium (R)-2,3-bis(tetradecanoyloxy)propyl((2,2-dimethyl-1,3-dioxolane-4-yl)methyl)phosphate (compound 12).

[0965]

[0966] 2,2-dimethoxypropane (7.54 g, 72.5 mmol, 10 equivalents) and p-toluenesulfonic acid (72 mg, 0.378 mmol, 0.052 equivalents) were added to a toluene (200 ml, 40 times the volume) solution of sodium DMPG (5 g, 7.25 mmol). The mixture was heated to 140°C for 16 h. The solvent was evaporated, and the crude product (5.6 g) was used for the next step without further purification.

[0967] Example 5.Preparation of sodium (R)-2,3-bis(tetradecanoyloxy)propyl((2-heptadecyl-1,3-dioxolane-4-yl)methyl)phosphate (compound 4).

[0968]

[0969] At room temperature (25°C), octadecaldehyde (4.55 g, 16.97 mmol, 3 equivalents) was added to a solution of crude compound 12 (4 g, 5.65 mmol) in 1,2-dichloroethane (80 ml, 20 times the volume), followed by the addition of Amberlyst-15 (800 mg, 20 wt%). The mixture was stirred at 80°C for 48 hours. After the reaction was complete (as confirmed by TLC analysis, 15% MeOH in DCM solution, Rf ~0.4, identified by phosphomolybdic acid staining), the reaction mixture was filtered and washed with NaHCO3 aqueous solution (1 x 80 ml). The aqueous layer was extracted with DCM (3 × 50 ml), and the combined organic layers were dried over sodium sulfate. The organic layer was concentrated, and the crude product was passed through a column chromatograph packed with neutral silica gel (230-400 mesh) (Note: the silica gel was neutralized by washing with a 10% ammonia methanol solution). The product was eluted with dichloromethane containing 10-12% methanol to give (R)-2,3-bis(tetradecanoyloxy)propyl((2-heptadecyl-1,3-dioxolane-4-yl)methyl)phosphate (1.8 g) as its ammonium salt. (R)-2,3-bis(tetradecanoyloxy)propyl ((2-heptadecyl-1,3-dioxolane-4-yl)methyl)phosphate was further purified by grinding with a mixture of DCM: MeOH (9 ml: 90 ml). The resulting solid was filtered and washed with methanol (1 x 10 ml). The ammonium salt was exchanged for the sodium salt by passing it through a 10% methanol-dichloromethane solution using a Dowex® 50WX8 Na+ resin pad. The product fraction was collected and concentrated to give sodium (R)-2,3-bis(tetradecanoyloxy)propyl ((2-heptadecyl-1,3-dioxolane-4-yl)methyl)phosphate as a grayish-white solid. Yield: 1.168 g (24.6%, 2 steps). 1H‑NMR (400 MHz, DMSO‑d6): δH 5.27 (m, 1H) , 4.97–4.84 (m, 1H) , 4.40 – 4.35 (m, 3H) , 4.26 – 4.12 (m, 2H) , 4.07 (m, 1H) , 4.00‑ 3.96 (m, 1H) , 3.87 (m, 1H) , 3.68 (m, 1H) , 2.31 (t, J = 7.40 Hz, 4H) , 1.61 (m, 6H) , 1.26 (m,0.89 (t, J = 6.04 Hz, 9H) ppm. 13C‑NMR (100 MHz, CDCl3): δH 173.51, 173.40, 105.20, 104.61, 74.47, 70.55, 67.11, 66.52, 65.88, 63.94, 62.74, 34.27, 34.15, 34.08, 34.02, 31.94, 31.93, 29.83, 29.80, 29.77, 29.75, 29.73, 29.71, 29.68, 29.51, 29.46, 29.40, 29.37, 29.30, 29.29, 24.97, 24.88, 24.46, 24.10, 22.69, 14.16 and 14.15 ppm.

[0970] Example 6. Preparation of sodium (R)-2,3-bis(tetradecanoyloxy)propyl((2-pentadecanyl-1,3-dioxolane-4-yl)methyl)phosphate (compound 5).

[0971]

[0972] At room temperature (25°C), hexadecaldehyde (6.12 g, 25.4 mmol, 3 equivalents) was added to a solution of crude compound 12 (6 g, 8.42 mmol) in 1,2-dichloroethane (120 ml, 20 times the volume). Amberlyst-15 (1.2 g, 20 wt%) was added, and the mixture was stirred at 80°C for 48 hours. After the reaction was complete (as confirmed by TLC analysis, 15% MeOH in DCM solution, Rf ~0.4, identified by phosphomolybdic acid staining), the reaction mixture was filtered and washed with an aqueous sodium bicarbonate solution (1 x 100 ml). The aqueous layer was extracted with DCM (3 x 60 ml), and the combined organic layers were dried over anhydrous sodium sulfate. The organic layers were concentrated, and the crude product was passed through a neutral silica gel (230-400 mesh) bed (Note: the silica gel was neutralized by washing with a 10% ammonia-methanol solution). The product was eluted with dichloromethane containing 10% methanol to give (R)-2,3-bis(tetradecanoyloxy)propyl((2-pentadecanyl-1,3-dioxolane-4-yl)methyl)phosphate as its ammonium salt. The ammonium salt was exchanged for the sodium salt by passing it through a Dowex® 50WX8 Na+ resin pad using a 10% methanol-dichloromethane solution. The product fraction was collected and concentrated to give sodium (R)-2,3-bis(tetradecanoyloxy)propyl((2-pentadecanyl-1,3-dioxolane-4-yl)methyl)phosphate (1.30 g, 17.3% yield in two steps) as a grayish-white solid. ¹H-NMR (400 MHz, DMSO-d6): δH 5.24 (m, ¹H), 4.99– 4.81 (2 t, J = 4.4 Hz, 1H), 4.42 (m, 1H), 4.26 – 4.17 (m, 2H), 4.12 – 3.65 (m, 6H), 2.34 – 2.28 (m, 4H), 1.60 (m, 6H), 1.32 (m, 66H) and 0.90 (t, J = 7.2 Hz, 9H) ppm. (See specification 95 / 128 pages, 118 CN 122094963 A) 13C-NMR (100 MHz, CDCl3): δH 173.59, 105.19, 104.63, 74.6, 70.74, 67.22, 66.41, 65.71, 63.58, 62.83, 34.33, 34.16, 34.11, 34.05, 31.95, 29.81, 29.79, 29.72, 29.68, 29.51, 29.47, 29.41, 29.31, 24.98, 24.90, 24.49, 24.12, 22.70 and 14.09 ppm.

[0973] Example 7. Preparation of (R)-2,3-bis(tetradecanoyloxy)propyl((2-pentyl-1,3-dioxolane-4-yl)methyl)phosphate sodium (compound 6).

[0974]

[0975] At room temperature (25°C), hexanal (4.17 ml, 33.94 mmol, 6 equivalents) was added to a DCM solution of crude compound 12 (4 g, 5.65 mmol) (80 ml, 20 times the volume). Amberlyst-15 (800 mg, 20 wt%) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete (as confirmed by TLC analysis, 15% MeOH in DCM solution, Rf ~ 0.4, identified by phosphomolybdic acid staining), the reaction mixture was filtered and washed with an aqueous sodium bicarbonate solution (80 ml). The aqueous layer was extracted with DCM (3 x 50 ml), and the combined organic layers were dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the crude product was passed through a neutral silica short column (230–400 mesh) and eluted with dichloromethane containing 10% methanol to give (R)-2,3-bis(tetradecanoyloxy)propyl((2-pentyl-1,3-dioxolane-4-yl)methyl)phosphate as its ammonium salt. The obtained ammonium salt was exchanged for sodium salt by passing it through a Dowex® 50WX8 Na+ resin pad using a dichloromethane solution of 10% methanol. The product fraction was collected and concentrated to give (R)-2,3-bis(tetradecanoyloxy)propyl((2-pentyl-1,3-dioxolane-4-yl)methyl)phosphate as a light brown viscous solid.Sodium 3-dioxolane-4-yl)methyl)phosphate. Yield: 1.77 g (41.74%). In 10:1.5 / DMSO:MeOH, Rf = 0.4. ¹H-NMR (400 MHz, DMSO-d6): δH 5.08 (m, 1H), 4.85–4.77 (m, 1H), 4.28 (m, 1H), 4.09–4.00 (m, 2H), 3.78–3.62 (m, 3H), 3.58–3.48 (m, 2H), 2.26 (t, J = 5.24 Hz, 4H), 1.50 (m, 6H), 1.27 (m, 47H) and 0.85 (t, J = 0.85 Hz, 9H) ppm. 13C-NMR (100 MHz, CDCl3): δH 173.65, 173.57, 105.21, 104.61, 74.64, 74.57, 70.76, 70.69, 67.17, 67.07, 66.36, 65.61, 63.54, 62.84, 34.32, 34.11, 34.03, 33.91, 31.95, 31.87, 31.77, 29.78, 29.76, 29.71, 29.65, 29.49, 29.45, 29.40, 29.30 and 24.97 ppm.

[0976] Example 8. Preparation of sodium 2,3-bis(butyryloxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (compound 7). Specification 96 / 128 pages 119 CN 122094963 A

[0977]

[0978] At room temperature (25°C) and under a nitrogen atmosphere, butyric anhydride (8.96 g, 56.61 mmol, 13 equivalents) was added to an anhydrous pyridine (60 ml, 20 times the volume) solution of sodium DMPG (3.0 g, 4.35 mmol). DMAP (1.59 g, 13.07 mmol, 3.0 equivalents) was added in portions to the mixture and the mixture was stirred at room temperature for 20 hours. After the reaction was complete (as confirmed by TLC and LCMS analysis, 20% MeOH in DCM solution, Rf ~0.6, identified by phosphomolybdic acid staining), the solvent was evaporated, and the crude product was eluted with dichloromethane containing 10% methanol and passed through a short silica gel column (230-400 mesh) to obtain a viscous gel-like product. This was diluted with ethyl acetate (20 times volume) and washed with 1.5 N HCl (10 times volume), then...Wash with water. Then, stir the organic layer with an aqueous solution of NaHCO3 (3 equivalents in 5 volumes of water) at room temperature for 30 minutes. Separate the organic layer, dry it with Na2SO4, and concentrate it under vacuum to give sodium 2,3-bis(butyryloxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate as a viscous syrup (1.6 g, 44% yield). 1H‑NMR (400 MHz, CDCl3): δH 5.23‑5.25 (m, 2H) , 4.40 – 4.43 (m, 2H) , 4.18‑4.24 (m, 2H) , 3.93 (m, 4H) , 2.28‑2.33 (m, 8H) , 1.58‑1.68 (m, 8H), 1.27‑1.33 (m, 40H) and 0.95‑0.97 (m, 6H) ppm. 13C-NMR (100 MHz, CDCl3): δH 173.57, 173.45, 70.72, 63.51, 62.70, 36.08, 35.91, 34.29, 34.08, 31.94, 29.75, 29.69, 29.65, 29.62, 29.45, 29.42, 29.39, 29.26, 29.24, 24.94, 24.87, 22.69, 18.31, 18.28, 14.10, 13.62 and 13.57 ppm.

[0979] Example 9. Preparation of sodium 2,3-bis((3-methylbutyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (compound 8).

[0980]

[0981] At room temperature (25°C) and under a nitrogen atmosphere, isovaleric anhydride (10.55 g, 56.66 mmol, 13 equivalents) was added to an anhydrous pyridine (60 ml, 20 times the volume) solution of sodium DMPG (3.0 g, 4.35 mmol). DMAP (1.59 g, 13.07 mmol, 3.0 equivalents) was added in portions, and the mixture was stirred at room temperature for 20 h. After the reaction was complete (as confirmed by TLC and LCMS analysis, 20% MeOH in DCM solution, Rf ~0.6, identified by phosphomolybdic acid staining), the solvent was evaporated, and the crude product was eluted with dichloromethane containing 10% methanol and passed through a short silica gel column (230-400 mesh) to obtain a viscous gel-like product. This was diluted with ethyl acetate (20 times by volume), washed with 1.5N HCl (10 times by volume), and then washed with water. (See specification 97 / 128 pages, 120 CN 122094963 A)The organic layer was then stirred with an aqueous solution of NaHCO3 (3 equivalents in 5 volumes of water) at room temperature for 30 minutes. The organic layer was separated, dried with Na2SO4, and concentrated under vacuum to obtain sodium 2,3-bis((3-methylbutyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate, which was a viscous syrup (2.4 g, 64% yield). 1H‑NMR (400 MHz, CDCl3): δH 5.24‑5.29 (m, 2H) , 4.40 – 4.44 (m, 2H) , 4.18‑4.22 (m, 2H) , 3.95 (m, 4H) , 2 .19‑2 .34 (m , 8H) , 2 .06‑2 .12 (m , 2H) , 1 .58‑1 .61 (m , 4H) , , 1 .27‑1 .33 (m , 40H) , 0 .96 (d , J = 6 .8 Hz , 12H) and 0 .90 (t, J = 7 .2 Hz , 6H) ppm. 13C-NMR (100 MHz, CDCl3): δH 173.51, 173.38, 172.80, 172.71, 70.69, 70.62, 63.59, 62.72, 43.27, 43.07, 34.27, 34.07, 31.92, 29.73, 29.67, 29.63, 29.60, 29.44, 29.41, 29.36, 29.25, 29.24, 25.50, 24.93, 24.86, 22.67, 22.34, 22.30 and 14.07 ppm. LCMS (ELSD): 833.5 (M-23). ​​Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50x4.6) mm, 3.5 µm. Rt (min): 5.74; area % -98.84.

[0982] Example 10. Preparation of sodium 2,3-bis(isobutyryloxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (compound 9).

[0983]

[0984] At room temperature (25°C) and under a nitrogen atmosphere, isobutyric anhydride (10.55 g, 56.66 mmol, 13 equivalents) was added to a solution of anhydrous pyridine (60 ml, 20 times the volume) containing sodium DMPG (3.0 g, 4.35 mmol). DMAP (1.59 g, 13.07 mmol) was then added in portions to the mixture.The mixture was stirred at room temperature for 20 hours (mmol, 3.0 equivalents). After the reaction was complete (as confirmed by TLC and LCMS analysis, 20% MeOH in DCM solution, Rf ~0.6, identified by phosphomolybdic acid staining), the solvent was evaporated, and the crude product was eluted with dichloromethane containing 10% methanol and passed through a short silica gel column (230-400 mesh) to give a viscous gel-like product. It was diluted with ethyl acetate (20 times volume) and washed with 1.5 N HCl (10 times volume), followed by washing with water. The organic layer was then stirred with an aqueous solution of NaHCO3 (3 equivalents dissolved in 5 times volume of water) at room temperature for 30 minutes. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum to give sodium 2,3-bis(isobutyryloxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate as a viscous syrup (1.6 g, 44% yield). 1H‑NMR (400 MHz, CDCl3): δH 5.24‑5.27 (m, 2H) , 4.39 – 4.44 (m, 2H) , 4.17‑4.23 (m, 2H) , 3.94 (m, 4H) , 2.52‑2.60 (m, 2H) , 2.28‑2.33 (m, 4H), 1.58‑1.61 (m, 4H), 1.31‑1.33 (m, 40H), 1.32 (t, J = 6.8 Hz, 12H) and 0.89 (t, J = 7.2 Hz, 6H) ppm. 13C-NMR (100 MHz, CDCl3): δH 176.74, 173.53, 173.41, 70.72, 63.50, 62.73, 34.28, 34.07, 33.93, 33.85, 31.92, 29.73, 29.68, 29.62, 29.60, 29.43, 29.39, 29.37, 29.24, 29.22, 24.92, 24.86, 22.68, 18.97 and 14.10 ppm.

[0985] Example 11. Preparation of sodium 2,3-bis((ethoxycarbonyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (compound 2). Specification 98 / 128 pages 121 CN 122094963 A

[0986]

[0987] At room temperature and under nitrogen, diethyl pyrocarbonate (1176.5 g, 7.258 mol) was added to a suspension of DMPG-Na (500.0 g, 0.7258 mol, 1.0 equivalent) in toluene (15 times the volume).128.61 g (0.943 mol, 1.3 equivalents) of anhydrous ZnCl2 (128.61 g, 0.943 mol, 1.3 equivalents) was added. The mixture was stirred at 37–40 °C for 30 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered through a Celite® thin-bed filter. The filtrate was concentrated under vacuum, keeping the bath temperature below 40 °C. The viscous residue was dissolved in EtOAc (30 volumes) and washed with water (5 volumes x 2). The organic layer was dried over Na2SO4 and concentrated under vacuum, keeping the bath temperature below 45 °C to obtain the viscous residue. The crude product (680 g) was purified by silica gel column chromatography (230–400 mesh) using a gradient of 5–20% MeOH in dichloromethane. The product fraction was concentrated to give 385 g of pure product. It was dissolved in a mixture of EtOAc and water (15:3 volumes) and cooled to ~5 °C. Add HCl solution (0.5 N, 2 equivalents) and stir the mixture at ~5°C for 15–20 minutes. Separate the organic layer and wash with 0.5 N HCl (3 volumes x 1) and water (5 volumes x 1). Slowly alkalize the organic layer at room temperature with NaHCO3 solution (4 equivalents dissolved in 5 volumes of water). Stir the mixture for 2 hours, separate the organic layer, and dry and concentrate it with Na2SO4 to obtain sodium 2,3-bis((ethoxycarbonyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate as a viscous syrup (300.0 g, 49% yield). 1H‑NMR (400 MHz, CDCl3): δH 5.23‑5.25 (m, 1H) , 5.10‑5.11 (m, 1H) , 4.49– 4.36 (m, 2H) , 4.35 – 4.16 (m, 6H) , 4.03 – 3.91 (m, 4H) , 2.34‑2.28 (m, 4H) , 1.61‑1.57 (m, 4H) , 1.35‑1.27 (m, 46H) and 0.89 (t, J = 68 Hz, 6H) ppm. 13C‑ NMR (100 MHz, CDCl3): δH 173.56, 173.50 154.97, 154.77, 154.73, 74.51, 74.44, 70.71, 70.64, 65.88, 64.48, 64.41, 64.23, 63.55, 63.20, 62.74, 34.25, 34.04, 31.93, 29.76, 29.74, 29.70, 29.66, 29.62, 29.46, 29.42, 29.39, 29.26, 29.23, 24.93,24.86, 22.69 and 14.10 ppm.

[0988] Example 12. Preparation of 2,3-bis((ethoxycarbonyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)magnesium phosphate (compound 10).

[0989]

[0990] A solution of magnesium chloride (0.571 g, 6.00 mmol, 0.5 equivalents) in water (10 times the volume) was added to a solution of 2,3-bis((ethoxycarbonyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (10 g, 12.00 mmol, 1.0 equivalents) in ethanol (100 ml) and the mixture was stirred at room temperature for 14 hours. The mixture was diluted with water (200 ml), and the precipitate was filtered, washed with water (100 ml), and dried under vacuum to give 2,3-bis((ethoxycarbonyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)magnesium phosphate (8.0 g, 79% yield) as a grayish-white solid. ¹H-NMR (400 MHz, CDCl₃): δH 5.27 (m, 1H), 5.13 (m, 1H), 4.50–4.00 (m, 14H), 2.34–2.28 (m, 4H), 1.60–1.59 (m, 4H), 1.35 (m, 46H) and 0.89 (t, J = 6.4 Hz, 6H) ppm. 13C-NMR (100 MHz, CDCl3): δH 173.50, 173.31, 154.91, 154.60, 74.21, 70.31, 65.84, 64.35, 64.19, 63.96, 63.60, 62.70, 34.15, 34.00, 31.92, 29.75, 29.68, 29.66, 29.62, 29.48, 29.43, 29.37, 29.26, 29.22, 24.91, 22.67, 14.13 and 14.07 ppm.

[0991] Example 13. Preparation of 2,3-bis((ethoxycarbonyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)calcium phosphate (compound 11).

[0992]

[0993] A solution of calcium chloride (0.666 g, 6.00 mmol, 0.5 equivalents) in water (10 times the volume) was added to sodium 2,3-bis((ethoxycarbonyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (10 g, 12.00 mmol, 1.0 equivalents) in ethanol (100 mL) at room temperature.The mixture was stirred in a solution of 2,3-bis((ethoxycarbonyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (8.2 g, 83% yield) as an off-white solid. 1H‑NMR (400 MHz, CDCl3): δH 5.28 (m, 1H) , 5.19 (m, 1H) , 4.51 – 4.40 (m, 2H) , 4.36 – 4.14 (m , 6H) , 3.90 – 4.10 (m , 4H) , 2.34-2.28 (m, 4H), 1.59 (m, 4H), 1.33-1.27 (m, 46H) and 0.89 (t, J = 6.8 Hz, 6H) ppm. 13C-NMR: (100 MHz, CDCl3): δH 173.54, 154.99, 74.44, 70.59, 68.70, 65.95, 64.49, 64.26, 63.92, 62.71, 34.17, 34.00, 31.91, 29.74, 29.72, 29.67, 29.61, 29.46, 29.42, 29.37, 29.25, 29.20, 24.88, 24.80, 22.66, 14.11 and 14.05 ppm.

[0994] Example 14. Preparation of sodium 2,3-bis((4-hydroxybutyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (compound 31).

[0995]

[0996] Step 1: Sodium 2,3-bis((4-(benzyloxy)butyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate. Specification 100 / 128 pages 123 CN 122094963 A

[0997] At room temperature, dicyclohexylmethanediimide (3.59 g, 17.42 mmol, 3 equivalents) was added to a stirred solution of 4-(benzyloxy)butyric acid (3.38 g, 17.42 mmol, 3 equivalents) in DCM (100 mL), and the mixture was stirred for 30 minutes. N,N-dimethylpyridine-4-amine (0.355 g, 2.90 mmol, 0.5 equivalents) and sodium (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-dihydroxypropyl)phosphate (4.0 g, 5.81 mmol, 1 equivalent) were added at room temperature. The reaction mixture was stirred at room temperature.The reaction mixture was allowed to stand for 32 hours, monitored by LCMS. After completion, the reaction mixture was diluted with DCM (50 ml), stirred for 10 minutes, and filtered. The filtrate was washed with water (50 ml x 1), 0.5 N HCl (50 ml x 1), and 10% NaHCO3 (50 ml x 1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 6.4 g of crude product. The crude product (6.4 g) was purified by column chromatography using alkaline 230–400 mesh silica gel (pre-alkaline with ammonia). The product was eluted with DCM solution in 0–10% methanol. The pure fraction was collected and concentrated to obtain sodium 2,3-bis((4-(benzyloxy)butyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (3.5 g), which was a colorless syrup. This syrup was dissolved in DCM (100 ml) and washed with 0.5N HCl (50 ml x 1) and 10% NaHCO3 solution (50 ml x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain sodium 2,3-bis((4-(benzyloxy)butyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (3.1 g, 51% yield), which was a colorless syrup. H NMR (400 MHz, DMSO-d6) δ (ppm) = 7.36-7.26 (m, 10H), 5.09-5.03 (m, 2H), 4.43 (d, J = 1.5 Hz, 4H), 4.32-4.22 (m, 2H) , 4.07 (dd , J = 6.6, 11.9 Hz, 2H) , 3.76 ‑ 3.65 (m, 4H) , 3.43 ‑ 3.38 (m, 4H) , 2.41 ‑ 2.30 (m, 4H) , 2.29 ‑ 2.20 (m, 4H) , 1.84- 1.73 (m, 4H), 1.55–1.43 (m, 4H), 1.22 (s, 40H), 0.90–0.80 (m, 6H). LCMS: Molecular formula: C56H90NaO14P, Formula weight: 1041.29, Exact mass: 1018.61. Observed mass: 1017.7 [M⁻¹]⁻, RT = 3.70 min, Purity: 99.42%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50 x 4.6) mm, 3.5 µm.

[0999] Step 2: Sodium 2,3-bis((4-hydroxybutyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate.

[1000] Under a nitrogen atmosphere, dihydroxypalladium (1.2 g, 8.54 mmol) on a 20% dry basis was added to a stirred solution of sodium 2,3-bis((4-(benzyloxy)butyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (1.4 g, 1.344 mmol, 1 equivalent) in 30 ml of THF. The reaction was stirred at 60 psi H2 pressure for 16 h. The reaction progress was monitored by LCMS and TLC. After completion, the reaction mixture was filtered through a diatomaceous earth bed, washed with THF (60 ml), and the filtrate was concentrated under reduced pressure at room temperature to give 1 g of product. The crude product was dissolved in DCM (20 ml), and Amberlite IR120 Na resin (2 g) was added. The mixture was stirred for 1.5 h and then filtered. The filtrate was concentrated and further dried under vacuum to give sodium 2,3-bis((4-hydroxybutyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (720 mg, 63.1% yield) as a grayish-white solid.

[1001] 1H NMR (400 MHz, DMSO‑d6) δ (ppm) = 5.09‑5.01 (m, 2H), 4.68 (td, J = 5.3, 15.0 Hz, 2H), 4.32‑4.19 (m, 2H), 4.16‑4.03 (m, 2H), 3.79-3.64 (m, 4H), 3.41-3.36 (m, 4H), 2.38-2.21 (m, 8H), 1.76-1.56 (m, 4H), 1.55-1.46 (m, 4H), 1.24 (s, 40H) , 0.91 - 0.80 (m, 6H). LCMS: Molecular formula: C42H78NaO14P, Formula weight: 861.04, Exact mass: 838.52, Observed mass: 837.4 [M-1]-, RT=2.99 min, Purity: 99.28%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50x4.6) mm, 3.5µ. HPLC: RT=4.17 min; Purity: 99.54%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid).Section). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50x4.6) mm, 3.5 µ. Specification 101 / 128 pages 124 CN 122094963 A

[1002] Example 15. Preparation of (2R)-3-(((2,3-bis((4-aminobutyryl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-dimethylbistetradecanoate dihydrochloride (compound 32).

[1003]

[1004] Step 1: 2,3-bis((4-((tert-butoxycarbonyl)amino)butyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate sodium.

[1005] EDC.HCl (3.48 g, 18.15 mmol, 2.5 equivalents) and 1H-benzo[d[1,2,3]triazole-1-ol (2.452 g, 18.15 mmol, 2.5 equivalents) were added to a stirred chloroform (75 ml) solution of 4-((tert-butoxycarbonyl)amino)butyric acid (4.43 g, 21.78 mmol, 3 equivalents) at room temperature. The reaction mixture was stirred at room temperature for 30 min. Sodium (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-dihydroxypropyl)phosphate (5 g, 7.26 mmol, 1 equivalent) and N,N-dimethylpyridine-4-amine (2.217 g, 18.15 mmol, 2.5 equivalents) were added, and the reaction mixture was refluxed for 16 h. The reaction progress was monitored by LCMS. After completion, the reaction mixture was diluted with DCM (100 ml) and washed with water (50 ml x 2), cold 1.5 N HCl (50 ml x 2), and 10% NaHCO3 solution (50 ml x 1). The organic layer was dried over sodium sulfate, filtered, and concentrated to give 7.5 g of crude product. The crude product (7.5 g) was purified by column chromatography using 230-400 mesh silica gel. The product was eluted with DCM solution in 0-5% methanol. The pure fraction was collected and concentrated to give sodium 2,3-bis((4-((tert-butoxycarbonyl)amino)butyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (3.3 g, 42.2% yield) as a pale yellow viscous syrup.

[1006] 1H NMR (400 MHz, DMSO‑d6) δ (ppm) = 6.97‑6.73 (m, 2H), 5.15‑5.03 (m, 2H), 4.36‑4.18 (m, 2H), 3.92 (br d, J = 4.0 Hz, 4H), 2.98-2.89 (m, 4H), 2.36-2.20 (m, 6H), 1.67-1.57 (m, 4H), 1.57–1.45 (m, 4H), 1.37 (s, 18H), 1.24 (s, 40H), 0.89–0.82 (m, 6H). LCMS: Molecular formula: C52H96N2NaO16P, Formula weight: 1059.30, Exact mass: 1036.66, Observed mass: 1035.6 [M⁻¹]⁻, RT = 3.44 min, Purity: 99.14%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50 x 4.6) mm, 3.5 µm.

[1007] Step 2: (2R)-3-(((2,3-bis((4-aminobutyryl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-dimethylbistetradecanoate dihydrochloride.

[1008] Hydrogen chloride (4.0 M HCl in 1,4-dioxane solution, 7 ml, 28.0 mmol) was added to a stirred solution of sodium 2,3-bis((4-((tert-butoxycarbonyl)amino)butyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propylphosphate (0.7 g, 0.661 mmol) in 1,4-dioxane at 10 °C. The reaction mixture was stirred at 15–20 °C for 1 hour and 20 minutes. The reaction progress was monitored by LCMS. After completion, the reaction mixture was concentrated under reduced pressure at room temperature. The residue was co-evaporated with ethyl acetate (25 ml x 1) to give (2R)-3-(((2,3-bis((3-aminopropionyl)oxy)propoxy)(hydroxy)phosphoryl)oxy)-propane-1,2-diylbistetradecanoate dihydrochloride (360 mg, 76%) as a grayish-white solid.

[1009] 1H NMR (400 MHz, DMSO‑d6) δ (ppm) = 8.19‑7.87 (m, 6H), 5.17‑5.07 (m, 2H), 4.33‑4.24 (m, 2H), 4.20‑4.03 (m, 2H), 4.03‑ 3.93 (m, 2H) , 3.92 ‑ 3.84 (m, 2H) , 2.82 (br d, J = 6.3 Hz, 4H) , 2.38 ‑ 2.24 (m, 4H) , 1.92 ‑ 1.74 (m, 4H) , 1.64 ‑ 1.37 (m, 4H), 1.31- 1.01 (m, 40H), 0.86 (t, J = 6.7 Hz, 6H).Instructions for Use, Pages 102 / 128, CN 122094963 A. LCMS: Molecular Formula: C42H83Cl2N2O12P, Formula Weight: 910.00, Exact Mass: 836.55. Observed Mass: 837.5 [M+1]+, RT = 3.12 min, Purity: 96.97%. Method: Mobile Phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile Phase B: Acetonitrile. Flow Rate: 1.0 ml / min. Column: XBridge C8 (50x4.6) mm, 3.5 µm. HPLC: RT = 6.61 min; Purity: 95.49%. Methods: Column: Xbridge C8 (50 x 4.6) mm, 3.5 μm, mobile phase A: 0.1% aqueous solution of TFA, mobile phase B: acetonitrile, flow rate: 2.0 ml / min.

[1010] Example 16. (2R)-3-(((2,3-bis((L-leucyl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-dimethylbistetradecanoate dihydrochloride (compound 33).

[1011]

[1012] Step 1: 2,3-bis((((benzyloxy)carbonyl)-L-leucyl)oxy)propyl((R)-2,3-bis(tetradecanoyl)propyl)phosphate sodium.

[1013] TBTU (9.32 g, 29.0 mmol, 4 equivalents) was added to a stirred solution of ((benzyloxy)carbonyl)-L-leucine (4.81 g, 18.15 mmol, 2.5 equivalents) in DCM (125 ml) at room temperature, and the mixture was stirred for 30 min. Sodium (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-dihydroxypropyl)phosphate (5.0 g, 7.26 mmol, 1 equivalent) and N-ethyl-N-isopropylpropyl-2-amine (6.32 ml, 36.3 mmol, 5 equivalents) were added at 5 °C, and the reaction was stirred at room temperature for 18 h, monitored by LCMS. After completion, the reaction mixture was diluted with DCM (75 ml), washed with water (50 ml x 2), cold 1.5 N HCl (50 ml x 2), and NaHCO3 solution (50 ml x 1). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 7.8 g of product. The crude product was purified by column chromatography using alkaline 230-400 mesh silica gel (pre-alkalized with ammonia). The product was eluted with 0-10% methanol in ethyl acetate. The pure fraction was collected and concentrated to give 3.6 g of product. The product was dissolved in DCM (100 ml) and washed with 0.5N HCl (50 ml x 1) and 10% NaHCO3 solution (50 ml x 2).The combined organic layers were dried with sodium sulfate, filtered, and concentrated under reduced pressure to give sodium 2,3-bis((((benzyloxy)carbonyl)-L-leucyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (3.1 g, 35.8% yield), as a colorless, viscous syrup.

[1014] 1H NMR (400 MHz, DMSO‑d6) δ (ppm) = 7.81‑7.68 (m, 2H), 7.41‑7.28 (m, 10H), 5.11‑4.97 (m, 6H), 4.30 (br d, J = 11.8 Hz, 2H) , 4.15 ‑ 4.00 (m, 4H) , 3.82 ‑ 3.63 (m, 4H) , 2.33 ‑ 2.15 (m, 4H) , 1.75 ‑ 1.36 (m, 10H) , 1.30 ‑ 1.15 (m, 40H) , 0.92 - 0.79 (m, 18H). LCMS: Molecular formula: C62H100N2NaO16P, Formula weight: 1183.44, Exact mass: 1160.69, Observed mass: 1159.6[M-1]-, RT=3.88 min, Purity: 99.14%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50x4.6) mm, 3.5 µ.

[1015] Step 2: (2R)-3-(((2,3-bis((L-leucyl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-dimethylbistetradecanoate dihydrochloride.

[1016] Under a nitrogen atmosphere, dihydroxypalladium (0.250 g, 0.422 mmol, 1 equivalent) was added to a stirred solution of 2,3-bis((((benzyloxy)carbonyl)L-leucyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (0.500 g, 0.422 mmol, 1 equivalent) in DCM (20 ml). The reaction was stirred for 3 hours under hydrogen balloon pressure. The reaction progress was monitored by LCMS and TLC. After completion, the reaction mixture was filtered through a diatomaceous earth bed and washed with a mixture of THF (25 ml) and DCM (25 ml). A solution of 1,4-dioxane (3.5 equivalents) in 4M HCl was added to the reaction mixture (filtrate) at 0°C, and the mixture was stirred at 0°C for 10 minutes. The mixture was concentrated under reduced pressure and dried at room temperature to obtain (2R)-3-(((2,3-Bis((L-Leucyl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-dimethylbistetradecanoate dihydrochloride (0.260 g, 66.5% yield) is a gray solid.

[1017] 1H NMR (400 MHz, DMSO‑d6) δ (ppm) = 8.91‑8.26 (m, 6H), 5.21‑5.06 (m, 2H), 4.40 (br d, J = 4.2 Hz, 2H), 4.28 (br d, J = 11 .7 Hz, 1H) , 4.19 ‑ 3.77 (m, 8H) , 2.34 ‑ 2.18 (m, 4H) , 1.85 ‑ 1.60 (m, 6H) , 1.57 ‑ 1.44 (m, 4H) , 1.24 (s, 40H) , 0.97 ‑ 0.79 (m, 18H). LCMS: Molecular formula: C46H91Cl2N2O12P, Formula weight: 966.11, Exact mass: 892.62, Observed mass: 893.5 [M+1]+, RT=3.26 min, Purity: 97.46%. Method information: Column: X-BRIDGE C8 (50x4.6) 3.5 μm, Mobile phase A: 0.1% aqueous solution of TFA, B: 0.1% ACN solution of TFA, Flow rate: 1.5 ml / min. HPLC: RT=7.13 min; Purity: 98.95%. Method information: A: 0.1% aqueous solution of TFA, B: ACN, Flow rate: 1.5 ml / min. Column: XBridge C8 (50X4.6) mm, 3.5 μm.

[1018] Example 17. Sodium 2,3-bis((3-hydroxypropionyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (compound 34).

[1019]

[1020] Step 1: Sodium 2,3-bis((3-(benzyloxy)propionyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate.

[1021] At room temperature, dicyclohexylmethanediimide (4.49 g, 21.78 mmol, 3 equivalents) was added to a stirred solution of 3-(benzyloxy)propionic acid (3.92 g, 21.78 mmol, 3 equivalents) in DCM (100 ml) and stirred for 30 minutes. N,N-dimethylpyridine-4-amine (0.443 g, 3.63 mmol, 0.5 equivalents) and (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-dihydroxypropyl)phosphate sodium (5.0 g, 7.26 mmol, 1 equivalent) were added at room temperature. The reaction mixture was stirred at room temperature for 32 hours.The reaction mixture was monitored by LCMS. After completion, the reaction mixture was diluted with DCM (75 ml), stirred for 10 minutes, and filtered. The filtrate was washed with water (50 ml x 1), 0.5 N HCl (50 ml x 1), and 10% NaHCO3 (50 ml x 1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 7.4 g of crude product. The crude product (7.4 g) was purified by column chromatography using basic 230–400 mesh silica gel (pre-alkalized with ammonia). The product was eluted with a 0–10% methanol solution of DCM. The purified fraction was collected and concentrated to give 3.6 g of product as a colorless syrup. This product was dissolved in DCM (100 ml) and washed with 0.5 N HCl (50 ml x 1) and 10% NaHCO3 solution (50 ml x 2). The combined organic layers were dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain sodium 2,3-bis((3-(benzyloxy)propionyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (3 g, 40.65% yield), which was a colorless, viscous syrup.

[1022] 1H NMR (400 MHz, DMSO‑d6) δ (ppm) = 7.45‑7.20 (m, 10H), 5.12‑5.04 (m, 2H), 4.45 (d, J = 3.3 Hz, 4H), 4.33‑4.23 (m, 2H) , 4.19-4.03 (m, 2H), 3.79-3.68 (m, 4H), 3.68-3.56 (m, 4H), 2.56 (td, J = 6.3, 8.6 Hz, 4H), 2.27-2.20 (m, 4H) , 1.53–1.43 (m, 4H), 1.22 (br s, 40H), 0.93–0.78 (m, 6H). LCMS: Molecular formula: C54H86NaO14P, Formula weight: 1013.23, Exact mass: 990.58, Observed mass: 991.6 [M+ 1]+, RT=3.67 min, Purity: 99.76%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50x4.6) mm, 3.5 µ.

[1023] Step 2: Sodium 2,3-bis((3-hydroxypropionyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate.

[1024] Dihydroxypalladium, 20% dry basis (2 g, 2.85 mmol), was added to a stirred solution of sodium 2,3-bis((3-(benzyloxy)propionyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (2.8 g, 2.76 mmol, 1 equivalent) in 50 ml of THF at room temperature and under a nitrogen atmosphere. The reaction was stirred at 60 psi H2 pressure for 16 h. The reaction progress was monitored by LCMS and TLC. After completion, the reaction mixture was filtered through a diatomaceous earth bed and washed with THF (100 ml). The filtrate was concentrated under reduced pressure at room temperature to give 1.85 g of 2,3-bis((3-hydroxypropionyl)oxy)propyl)((R)-2,3-bis(tetradecanoyloxy)propyl) phosphate. The crude product was dissolved in DCM (20 ml), and Amberlite IR120 Na resin (3.6 g) was added. The mixture was stirred for 1.5 h and filtered. The filtrate was concentrated and further dried under vacuum to give sodium 2,3-bis((3-hydroxypropionyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl) phosphate (1.5 g, 65.2% yield) as a grayish-white solid.

[1025] 1H NMR (400 MHz, DMSO‑d6) δ (ppm) = 5.09‑4.96 (m, 2H), 4.30‑4.23 (m, 2H), 4.19‑4.13 (m, 4H), 3.81‑3.50 (m, 8H), 2.47-2.37 (m, 4H), 2.26 (br t, J = 6.5 Hz, 4H), 1.63-1.37 (m, 4H), 1.24 (s, 40H), 0.85 (br t, J = 6.5 Hz, 6H). LCMS: Molecular formula: C40H74NaO14P, Formula weight: 832.98, Exact mass: 810.49, Observed mass: 809.4 [M⁻¹]⁻, RT = 2.93 min, Purity: 99.65%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50 x 4.6) mm, 3.5 µm. HPLC: RT = 4.15 min, Purity: 99.59%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid).ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50 x 4.6) mm, 3.5 µ.

[1026] Example 18. (2R)-3-(((2,3-bis((3-aminopropionyl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl bis(tetradecanoyl)propyl)phosphate dihydrochloride (compound 35).

[1027]

[1028] Step 1: 2,3-bis((3-((tert-butoxycarbonyl)amino)propionyl)oxy)propyl((R)-2,3-bis(tetradecanoyl)propyl)phosphate sodium salt.

[1029] At room temperature, dicyclohexylmethanediimide (13.48 g, 65.3 mmol, 3 equivalents) was added to a stirred solution of 3-(tert-butoxycarbonyl)amino)propionic acid (10.30 g, 54.4 mmol, 2.5 equivalents) in DCM (325 ml), and the mixture was stirred for 30 min. N,N-dimethylpyridine-4-amine (1.330 g, 10.89 mmol, 0.5 equivalents) and sodium (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-dihydroxypropyl)phosphate (15.0 g, 21.78 mmol, 1 equivalent) were added at room temperature. The reaction mixture was stirred at room temperature for 16 h and monitored by LCMS. After completion, the reaction mixture was diluted with DCM (100 ml), stirred for 10 min, and filtered. The filtrate was washed with water (100 ml x 1), 0.5N HCl (50 ml x 1), and 10% NaHCO3 (50 ml x 1). The combined organic layers were dried over sodium sulfate (CN 122094963 A, page 105 / 128 of the instruction manual), filtered, and concentrated to give 24.2 g of crude product. The crude product was purified by column chromatography using alkaline 230-400 mesh silica gel (pre-alkalized with ammonia). The product was eluted with 0%-10% methanol in ethyl acetate. The pure fraction was collected and concentrated to give 11.8 gm of pure product. The 11.8 gm product was dissolved in DCM (200 ml) and washed with 0.5N HCl (50 ml x 2) and 10% NaHCO3 solution (50 ml x 2). The combined organic layers were dried with sodium sulfate, filtered, and concentrated under reduced pressure to give sodium 2,3-bis((3-((tert-butoxycarbonyl)amino)propionyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (10.66 g, 47.35% yield), as a pale yellow syrup.

[1030] ¹H NMR (400 MHz, DMSO-d6) δ (ppm) = 7.09–6.89 (m, 2H), 5.08–4.99 (m, 2H),4.32 ‑ 4.19 (m, 2H) , 4.09 (dt, J = 6.5, 12.8 Hz, 2H) , 3.74 (br dd, J = 6.0, 12.0 Hz, 4H) , 3.22 ‑ 3.08 (m, 4H) , 2.42 (br t, J = 6.8 Hz, 4H), 2.29-2.22 (m, 4H), 1.55-1.45 (m, 4H), 1.37 (s, 18H), 1.24 (s, 40H), 0.90-0.81 (m, 6H). LCMS: Molecular formula: C50H92N2NaO16P, Formula weight: 1031.25, Exact mass: 1008.63, Observed mass: 1009.7 [M+1]+, RT=3.49 min, Purity: 98.40%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50x4.6) mm, 3.5 µ.

[1031] Step 2: (2R)-3-(((2,3-bis((3-aminopropionyl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-dimethylbistetradecanoate hydrochloride.

[1032] At 0 °C, hydrogen chloride (4 M 1,4-dioxane solution, 30 ml, 120 mmol) was added to a stirred solution of sodium 2,3-bis((3-((tert-butoxycarbonyl)amino)propionyl)oxy)propyl((R)-2,3-bis(tetradecanoyl)propyl)phosphate (6 g, 5.82 mmol) in DCM (60 ml). The reaction mixture was stirred at 10–15 °C for 2.5 h and monitored by LCMS. After completion, the reaction mixture was concentrated under reduced pressure at room temperature. The residue was co-evaporated with ethyl acetate (75 ml) and dried to give (2R)-3-(((2,3-bis((3-aminopropionyl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl bistetradecanoate dihydrochloride (4.9 g, 99.62% yield) as a grayish-white solid.

[1033] 1H NMR (400 MHz, DMSO‑d6) δ (ppm) = 8.26‑8.02 (m, 6H), 5.18‑5.09 (m, 2H), 4.32‑4.26 (m, 2H), 4.18‑4.00 (m, 4H), 3.98 ‑ 3.93 (m, 2H) , 3.03 (br d , J = 5.8 Hz, 4H) ,2.74 (dt, J = 3.2, 6.5 Hz, 4H), 2.33–2.22 (m, 4H), 1.60–1.43 (m, 4H), 1.24 (s, 40H), 0.91–0.80 (m, 6H). LCMS: Molecular formula: C40H78ClN2O12P, Formula weight: 881.95, Exact mass: 808.52. Observed mass: 809.5 [M+1]+, RT = 2.96 min, Purity: 97.87%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50x4.6) mm, 3.5 µm. HPLC: RT = 6.60 min; purity: 99.98%. Column: Xbridge C8 (50x4.6) mm, 3.5 μm, mobile phase A: 0.1% aqueous solution of TFA, mobile phase B: acetonitrile, flow rate: 2.0 ml / min.

[1034] Example 19. (2R)-3-(((2,3-bis((L-valinel)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-dimethylbistetradecanoate dihydrochloride (compound 36).

[1035] Instructions for use, pages 106 / 128, 129, CN 122094963 A

[1036] Step 1: 2,3-bis((((benzyloxy)carbonyl)-L-valine)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate sodium.

[1037] At room temperature, EDC.HCl (4.17 g, 21.78 mmol, 3 equivalents) and 1H-benzo[d][1,2,3]triazole-1-ol (2.94 g, 21.78 mmol, 3 equivalents) were added to a stirred solution of ((benzyloxy)carbonyl)-L-valine (4.56 g, 18.15 mmol, 2.5 equivalents) in chloroform (125 ml), and stirred for 30 minutes. (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-dihydroxypropyl)phosphate sodium (5.0 g, 7.26 mmol, 1 equivalent) and N,N-dimethylpyridine-4-amine (2.66 g, 21.78 mmol, 3 equivalent) were added at room temperature. The reaction mixture was refluxed for 16 h and monitored by LCMS. After completion, the reaction mixture was diluted with DCM (75 ml), water (50 ml x 2), cold 1.5N HCl (50 ml x 2), and 10% NaHCO3 solution (50 ml).x1) Washing. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 8.1 g of crude product. The crude product was purified by reversed-phase chromatography (C-18 column) using methanol and water. The pure fraction was collected, concentrated, and further extracted with DCM. It was washed with 0.5N HCl (50 ml x 1) and 10% NaHCO3 solution (50 ml x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2,3-bis((((benzyloxy)carbonyl)-L-valine)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (3.6 g, 43.5% yield), as a colorless, viscous syrup.

[1038] ¹H NMR (400 MHz, DMSO-d6) δ (ppm) = 7.73–7.63 (m, 2H), 7.41–7.28 (m, 10H), 5.14–5.01 (m, 6H), 4.44–4.25 (m, 2H), 4.18–3.93 (m, 4H), 3.82–3.64 (m, 4H), 2.30–2.19 (m, 4H), 2.13–2.01 (m, 2H), 1.54–1.44 (m, 4H), 1.23 (s, 40H), 0.91–0.81 (m, 18H). LCMS: Molecular formula: C60H96N2NaO16P, Formula weight: 1155.39, Exact mass: 1132.66, Observed mass: 1133.7 [M+1]+, RT = 3.67 min, Purity: 97.85%. Method: Mobile phase A: 1 25% ammonia solution was dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50 x 4.6) mm, 3.5 µ.

[1039] Step 2: (2R)-3-(((2,3-bis((L-valine)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-dimethylbistetradecanoate dihydrochloride.

[1040] Under a nitrogen atmosphere, dihydroxypalladium was added to a stirred solution of 2,3-bis((((benzyloxy)carbonyl)-L-valine)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate sodium (0.500 g, 0.433 mmol, 1 equivalent) in DCM (20 ml). g, 0.356 mmol). The reaction was stirred for 3 hours at room temperature under hydrogen balloon pressure.The reaction progress was monitored by LCMS and TLC. After completion, the reaction mixture was filtered through a diatomaceous earth bed and washed with a mixture of THF (50 ml) and DCM (50 ml). A solution of 1,4-dioxane (3.5 equivalents) in 4M HCl was added to the reaction mixture (filtrate) at 0 °C, and the mixture was stirred at 0 °C for 10 min. The mixture was concentrated under reduced pressure and dried at room temperature to give (2R)-3-(((2,3-bis((L-valinel)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl ditetradecanoate dihydrochloride (0.330 g, 85% yield) as a gray solid.

[1041] 1H NMR (400 MHz, DMSO‑d6) δ(ppm) = 8.85‑8.59 (m, 6H), 5.29‑5.07 (m, 2H), 4.46‑4.38 (m, 2H), 4.32‑4.24 (m, 1H), 4.17-3.95 (m, 4H), 3.92-3.75 (m, 4H), 2.33-2.13 (m, 6H), 1.50 (br d, J = 6.5 Hz, 4H), 1.24 (s, 40H), 1.05- 0.92 (m, 12H) , 0.91 - 0.79 (m, 6H). LCMS: Molecular formula: C44H87Cl2N2O12P, Formula weight: 938.06, Exact mass: 864.58, Observed mass: 865.5 [M+1]+, RT=3.23 min, Purity: 99.19%. Method information: Column: X-BRIDGE C8 (50x4.6), 3.5 μm, Mobile phase A: 0.1% TFA aqueous solution, B: 0.1% TFA in ACN solution, Flow rate: 1.5 ml / min. HPLC: RT=7.04 min; Purity: 99.92%. Method information: A: 0.1% TFA aqueous solution, B: ACN, Flow rate: 1.5 ml / min. Column: XBridge C8 (50X4.6) mm, 3.5 μm.

[1042] Example 20. Sodium 2,3-bis((5-hydroxypentanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyl)propyl)phosphate (compound 37).

[1043]

[1044] Step 1: Sodium 2,3-bis((5-(benzyloxy)pentanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyl)propyl)phosphate.

[1045] At room temperature, 5-(benzyloxy)pentanoic acid (4.16) was stirred.Dicyclohexylmethanediimide (4.94 g, 23.95 mmol, 3 equivalents) was added to a DCM (150 ml) solution (19.96 g, 2.5 equivalents), and the mixture was stirred for 30 min. N,N-dimethylpyridine-4-amine (0.488 g, 3.99 mmol, 0.5 equivalents) and (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-dihydroxypropyl)phosphate sodium (5.5 g, 7.98 mmol, 1 equivalent) were added at room temperature. The reaction mixture was stirred at room temperature for 24 h and monitored by LCMS. After completion, the reaction mixture was diluted with DCM (75 ml), stirred for 10 min, and filtered. The filtrate was washed with water (50 ml x 1), 0.5 N HCl (50 ml x 1), and 10% NaHCO3 (50 ml x 1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 8.2 g of crude product. The crude product (8.2 g) was purified by column chromatography using alkaline 230-400 mesh silica gel (pre-alkalized with ammonia). The product was eluted with 0-10% methanol in ethyl acetate. The pure fraction was collected and concentrated to give 3.8 g of sodium 2,3-bis((5-(benzyloxy)pentanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate as a colorless syrup. This product was dissolved in DCM (100 ml) and washed with 0.5N HCl (50 ml x 1) and 10% NaHCO3 solution (50 ml x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give sodium 2,3-bis((5-(benzyloxy)pentanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (3.5 g, 40.0% yield) as a colorless, viscous syrup.

[1046] 1H NMR (400 MHz, DMSO‑d6) δ (ppm) = 7.37‑7.24 (m, 10H), 5.09‑5.02 (m, 2H), 4.42 (s, 4H), 4.33‑4.23 (m, 2H), 4.13‑ 4.02 (m, 2H) , 3.75 ‑ 3.62 (m, 4H) , 3.44 ‑ 3.36 (m, 4H) , 2.35 ‑ 2.19 (m, 8H) , 1.67‑ 1.40 (m, 12H) , 1.22 (s, 40H) , 0.90 - 0.80 (m, 6H). LCMS: Molecular formula: C58H94NaO14P, Formula weight: 1069.34, Exact mass: 1046.65, Observed mass: 1047.7 [M+1]+, RT=3.79min, purity: 99.73%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50x4.6) mm, 3.5 µm.

[1047] Step 2: 2,3-bis((5-hydroxypentanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyl)propyl)phosphate sodium.

[1048] Under a nitrogen atmosphere, dihydroxypalladium (1 g, 7.12 mmol) on a 20 ml THF solution of 2,3-bis((5-(benzyloxy)valerate)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (1 g, 0.935 mmol, 1 equivalent) was added. The reaction was stirred at 60 psi H2 pressure for 16 h. The reaction progress was monitored by LCMS and TLC. After completion, the reaction mixture was filtered through a diatomaceous earth bed and washed with THF (50 ml). The filtrate was concentrated under reduced pressure at room temperature to give 0.750 g of 2,3-bis((5-hydroxyvalerate)oxy)propyl)((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate. The product (0.750 g) was further dissolved in DCM (10 ml), and Amberlite IR120 Na resin (1.5 g) was added. The reaction was stirred for 1.5 h and filtered. The filtrate was concentrated and further dried under vacuum to give sodium 2,3-bis((5-hydroxypentanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyl)propyl)phosphate (0.660 g, CN 122094963 A, page 131, 108 / 128, yield 79.4%) as a grayish-white solid.

[1049] 1H NMR (400 MHz, DMSO‑d6) δ (ppm) = 5.05 (br s, 2H), 4.55 (br s, 2H), 4.33‑4.18 (m, 2H), 4.09 (br dd, J = 5.8, 11.8 Hz, 2H), 3.74-3.66 (m, 4H), 3.48-3.43 (m, 4H), 2.36-2.18 (m, 8H), 1.59-1.37 (m, 12H), 1.23 (s, 40H), 0.85 (br t, J = 6.5 Hz, 6H). LCMS: Molecular formula: C44H82NaO14P, Formula weight: 889.09, Exact mass: 866.55, Observed mass: 865.5[M-1]-, RT = 2.94 min, purity: 99.78%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50x4.6) mm, 3.5 µ. HPLC: RT = 3.39 min; purity: 96.4%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50x4.6) mm, 3.5 µ.

[1050] Example 21. (2R)-3-(((2,3-bis((5-aminopentanoyl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-dimethylbis(tetradecanoyl)propyl phosphate dihydrochloride (compound 38).

[1051]

[1052] Step 1: 2,3-bis((5-((tert-butoxycarbonyl)amino)pentanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyl)propyl)phosphate sodium salt.

[1053] At room temperature, dicyclohexylmethanediimide (4.19 g, 20.348 mmol, 3 equivalents), N,N-dimethylpyridine-4-amine (0.177 g, 1.452 mmol, 0.25 equivalents), and sodium (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-dihydroxypropyl)phosphate (4.0 g, 5.81 mmol, 1 equivalent) were added to a stirred solution of 5-((tert-butoxycarbonyl)amino)valerate (3.78 g, 17.42 mmol, 3 equivalents) in DCM (100 ml). The reaction mixture was stirred at room temperature for 24 hours and monitored by LCMS. After completion, the reaction mixture was diluted with DCM (50 ml), stirred for 10 minutes, and filtered. The filtrate was washed with water (50 ml x 1), 0.5 N HCl (50 ml x 1), and 10% NaHCO3 (50 ml x 1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 6.2 g of crude product. The crude product (6.2 g) was purified by column chromatography using silica gel (230-400 mesh silica gel) and eluted with 0-8% methanol in DCM solution. The pure fraction was collected and concentrated to give 2,3-bis((5-((tert-butoxycarbonyl)amino)pentanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (3.5 g, 56.4%) as a pale yellow viscous syrup.

[1054] 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 6.95-6.74 (m, 2H),5.08-4.99 (m, 2H), 4.33-4.16 (m, 2H), 4.13-4.05 (m, 2H), 3.80-3.64 (m, 4H), 2.90 (q, J = 6.4 Hz, 4H), 2.30 - 2.18 (m, 7H), 1.57 - 1.39 (m, 11H), 1.37 (s, 20H), 1.24 (s, 40H), 0.88 - 0.84 (m, 6H). LCMS: Molecular formula: C54H100N2NaO16P, Formula weight: 1087.36, Exact mass: 1064.69, Observed mass: 1063.7 [M-1]-, RT=3.51 min, Purity: 99.56%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50x4.6) mm, 3.5 µ.

[1055] Step 2: (2R)-3-(((2,3-bis((5-aminopentanoyl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-dimethylbistetradecanoate dihydrochloride. Instructions for Use, pages 109 / 128, 132, CN 122094963 A

[1056] : At 10°C, hydrogen chloride (11 ml of 1,4-dioxane solution in 4.0 M HCl, 11 ml, 44.0 mmol) was added to a stirred solution of 2,3-bis((5-((tert-butoxycarbonyl)amino)pentanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (1.1 g, 1.033 mmol, 1 equivalent). The reaction mixture was stirred at 15–20°C for 1 hour and 30 minutes. The reaction progress was monitored by LCMS. After completion, the reaction mixture was concentrated under reduced pressure at room temperature. The residue was co-evaporated with ethyl acetate (25 ml x 1) to give (2R)-3-(((2,3-bis((5-aminopentanoyl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-dimethylbistetradecanoate dihydrochloride (760 mg, 76%), as a grayish-white solid.

[1057] ¹H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.16–8.02 (m, 6H), 5.16–5.06 (m, 2H), 4.33–4.19 (m, 2H), 4.17–4.09 (m, 2H), 4.04–3.96 (m, 1H), 3.92–3.73 (m, 4H), 2.75 (br s, 4H), 2.41–2.18 (m, 8H), 1.64–1.46 (m, 12H), 1.24 (s, 40H), 0.93–0.78 (m, 6H). LCMS: Molecular formula: C44H87Cl2N2O12, Formula weight: 938.06, Exact mass: 864.58. Observed mass: 865.5 [M+1]+, RT = 3.15 min, Purity: 97.29%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50 x 4.6) mm, 3.5 µm. HPLC: RT = 6.71 min; purity: 94.83%. Method: Column: Xbridge C8 (50 x 4.6) mm, 3.5 μm, mobile phase A: 0.1% TFA aqueous solution, mobile phase B: acetonitrile, flow rate: 2.0 ml / min.

[1058] Example 22. (3S,3'S)-4,4'-((3-((((R)-2,3-bis(tetradecanoyloxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl)bis(oxy))bis(3-amino-4-oxobutyric acid) dihydrochloride (compound 39).

[1059]

[1060] Step 1: Sodium 2,3-bis(((S)-4-(benzyloxy)-2-(((benzyloxy)carbonyl)amino)-4-oxobutyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate.

[1061] At room temperature, TBTU (7.46 g, 23.23 mmol, 4 equivalents) was added to a stirred solution of (R)-4-(benzyloxy)-2-(((benzyloxy)carbonyl)amino)-4-oxobutyric acid (5.19 g, 14.52 mmol, 2.5 equivalents) in DCM (100 ml) and stirred for 30 minutes. (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-dihydroxypropyl)phosphate sodium (4 g, 5.81 mmol, 1 equivalent) and N-ethyl-N-isopropylpropyl-2-amine (5.06 ml, 29.0 mmol, 5 equivalent) were added at 5 °C and stirred at room temperature for 20 hours. The reaction progress was monitored by LCMS. After completion, the reaction mixture was diluted with DCM (75 ml) and washed with water (50 ml x 2), cold 1.5N HCl (50 ml x 2), and 10% NaHCO3 (50 ml x 1). The combined organic layers were rinsed with brine.Wash, dry with sodium sulfate, filter, and concentrate under reduced pressure to give 7.1 g of crude product. Purify the crude product by column chromatography using basic 230-400 mesh silica gel (pre-alkalized with ammonia). Elute the product with 0-10% methanol in ethyl acetate. Collect and concentrate the pure fraction to give 3.4 g of product. Dissolve it in DCM (100 ml) and wash with 0.5N HCl (50 ml x 1) and 10% NaHCO3 solution (50 ml x 2). Dry the combined organic layers with sodium sulfate, filter, and concentrate under reduced pressure to give 2,3-bis(((S)-4-(benzyloxy)-2-(((benzyloxy)carbonyl)amino)-4-oxobutyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate sodium (3.1 g, 38.8% yield) as a colorless, viscous syrup.

[1062] ¹H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.11–7.92 (m, 2H), 7.37–7.29 (m, 20H), 5.11–4.99 (m, 8H), 5.06 (br s, 2H), 4.63–4.44 (m, 2H), 4.34–4.01 (m, 4H), 3.71 (br dd, J = 5.0, 10.0 Hz, 4H), 3.02–2.66 (m, 4H), 2.23 (br t, J = 7.3 Hz, 4H), 1.47 (br s, 4H), 1.29–1.15 (m, 40H), 0.85 (t, J = 6.8 Hz, 6H). LCMS: Molecular formula: C72H100N2NaO20P, Formula weight: 1367.55, Exact mass: 1344.67, Observed mass: 1343.7 [M⁻¹]⁻, RT = 3.74 min, Purity: 99.70%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50 x 4.6) mm, 3.5 µm.

[1063] Step 2: (3S,3'S)-4,4'-((3-((((R)-2,3-bis(tetradecanoyloxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl)bis(oxy))bis(3-amino-4-oxobutyric acid) dihydrochloride.

[1064] Dihydroxypalladium, 20% dry basis (0.750 g, 1.068 mmol), was added to a stirred solution of 2,3-bis(((S)-4-(benzyloxy)-2-(((benzyloxy)carbonyl)amino)-4-oxobutyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (1.5 g, 1.097 mmol, 1 equivalent) in 30 ml of DCM at room temperature and under a nitrogen atmosphere. The reaction was stirred for 4 h at room temperature and under hydrogen balloon pressure and monitored by LCMS and TLC. After completion, the reaction mixture was filtered through a diatomaceous earth bed and washed with a mixture of THF (50 ml) and DCM (50 ml). The filtrate was concentrated under reduced pressure to give 1.0 g of product, which was ground together with MTBE (20 ml x 2) and stirred for 15 min, filtered and dried to give 720 mg of product. The product was dissolved in DCM (10 times its volume) at 0 °C, and a 1,4-dioxane solution of 4 M HCl (4 equivalents) was added. The mixture was stirred at 0 °C for 30 minutes. The mixture was concentrated under reduced pressure and dried at room temperature to give bis(tetradecanoyloxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl)bis(oxy))bis(3-amino-4-oxobutyric acid) dihydrochloride (0.450 g, 42.45% yield), as a gray solid.

[1065] 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 9.20-8.24 (m, 6H), 5.20-5.07 (m, 2H), 4.48-4.25 (m, 5H), 4.16-3.94 (m, 4H) , 3.86 (br d , J = 5.5 Hz, 4H) , 2.96 (br d , J = 5.5 Hz, 4H) , 2.36 ‑ 2.18 (m, 4H) , 1.55 ‑ 1.45 (m, 4H) , 1.24 (s, 40H) , 0.90 ‑ 0.81 (m, 6H). LCMS: Molecular formula: C42H79Cl2N2O16P, Formula weight: 969.97, Exact mass: 896.50, Observed mass: 897.4 [M+1]+, RT = 3.12 min, Purity: 98.80%. Method information: Column: X-BRIDGE C8 (50*4.6), 3.5 μm, Mobile phase A: 0.1% TFA aqueous solution, B: 0.1% TFA in ACN solution, Flow rate: 1.5 ml / min. HPLC: RT = 6.68 min; Purity: 99.92%. Method information: A: 0.1% TFA aqueous solution, B: ACN, Flow rate: 1.5 ml / min.ml / min. Column: XBridge C8 (50 x 4.6) mm, 3.5 μm.

[1066] Example 23. Sodium 2,3-bis((4-carboxybutyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (compound 40).

[1067]

[1068] Step 1: Sodium 2,3-bis((5-(benzyloxy)-5-oxopentanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate.

[1069] At room temperature, dicyclohexylmethanediimide (4.49 g, 21.78 mmol, 3 equivalents) was added to a stirred solution of 5-(benzyloxy)-5-oxovalerate (4.03 g, 18.15 mmol, 2.5 equivalents) in DCM (125 ml), and the mixture was stirred for 30 minutes. N,N-dimethylpyridine-4-amine (0.443 g, 3.63 mmol, 0.5 equivalents) and sodium (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-dihydroxypropyl)phosphate (5.0 g, 7.26 mmol, 1 equivalent) were added at room temperature, and the reaction mixture was stirred for 16 hours at room temperature. The reaction progress was monitored by LCMS. After completion, the reaction mixture was diluted with DCM (75 ml), stirred for 10 minutes, and filtered. The filtrate was washed with water (50 ml x 1), 0.5N HCl (50 ml x 1), and 10% NaHCO3 (50 ml x 1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 8.0 g of crude product. The crude product (8.0 g) was purified by column chromatography using alkaline 230–400 mesh silica gel (pre-alkalized with ammonia). The product was eluted with 0–10% methanol in ethyl acetate. The pure fraction was collected and concentrated to give 4.0 g of sodium 2,3-bis((5-(benzyloxy)-5-oxopentanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate as a colorless syrup. The product was dissolved in DCM (100 ml) and washed with 0.5N HCl (50 ml x 1) and 10% NaHCO3 solution (50 ml x 2). The combined organic layers were dried with sodium sulfate, filtered, and concentrated under reduced pressure to give sodium 2,3-bis((5-(benzyloxy)-5-oxopentanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (3.67 g, 45.9% yield), as a colorless, viscous syrup.

[1070] ¹H NMR (400 MHz, DMSO-d6) δ (ppm) = 7.38–7.29 (m, 10H), 5.08 (s, 6H), 4.29(br d, J = 11.8 Hz, 2H), 4.14–4.04 (m, 2H), 3.72 (br s, 4H), 2.42–2.18 (m, 12H), 1.83–1.72 (m, 4H), 1.54–1.43 (m, 4H), 1.22 (s, 40H), 0.92–0.77 (m, 6H). LCMS: Molecular formula: C58H90NaO16P, Formula weight: 1097.31, Exact mass: 1074.60, Observed mass: 1073.5 [M⁻¹]⁻, RT = 3.58 min, Purity: 99.68%. Methods: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50 x 4.6) mm, 3.5 µm.

[1071] Step 2: 2,3-bis((4-(((carboxybutyryl)oxy)propyl)((R)-2,3-bis(tetradecanoyloxy)propyl)sodium phosphate.

[1072] Dihydroxypalladium, 20% dry basis (0.600 g, 4.27 mmol), was added to a stirred solution of 2,3-bis((5-(benzyloxy)-5-oxopentanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)sodium phosphate (1.0 g, 0.911 mmol, 1 equivalent) in DCM (20 ml) at room temperature and under a nitrogen atmosphere. The reaction was stirred under hydrogen balloon pressure for 16 hours and monitored by LCMS and TLC. After completion, the reaction mixture was filtered through a diatomaceous earth bed and washed with THF (25 ml) and DCM (50 ml). The filtrate was concentrated under reduced pressure at room temperature to give 0.650 g of sodium phosphate. Sodium 2,3-bis((4-carboxybutyryl)oxy)propyl)((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate. The product was dissolved in DCM (10 ml), Amberlite IR120 Na resin (3.5 g) was added, stirred for 1.5 h and filtered. The filtrate was concentrated and further dried under vacuum to give sodium 2,3-bis((4-carboxybutyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (0.520 g, 62.2% yield) as a grayish-white solid.

[1073] 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 12.93 - 12.12 (m , 2H), 5.08 (br s, 2H), 4.34 - 4.18 (m, 2H) , 4.11 (br dd , J =6.5, 11.0 Hz, 2H), 3.85–3.70 (m, 4H), 2.40–2.18 (m, 12H), 1.87–1.60 (m, 4H), 1.56–1.43 (m, 4H), 1.23 (s, 40H), 0.85 (br t, J = 6.5 Hz, 6H). LCMS: Molecular formula: C44H78NaO16P, Formula weight: 917.06, Exact mass: 894.51, Observed mass: 917.5 [M+Na]+, RT = 3.57 min, Purity: 98.07%. Method information: Column: X-BRIDGE C8 (50*4.6), 3.5 μm. Mobile phase A: 0.1% TFA aqueous solution, B: 0.1% TFA in CAN solution, flow rate: 1.5 ml / min. HPLC: RT=7.77 min; purity: 98.14%. Method information: A: 0.1% TFA aqueous solution, B: ACN, flow rate: 1.5 ml / min. Column: XBridge C8 (50X4.6) mm, 3.5 μm.

[1074] Example 24. Sodium 2,3-bis((3-carboxypropionyl)oxy)propyl((R)-2,3-bis(tetradecanoyl)propyl)phosphate (compound 41). Instructions for Use, pages 112 / 128, 135, CN 122094963 A

[1075]

[1076] Step 1: Sodium 2,3-bis((4-(benzyloxy)-4-oxobutyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate.

[1077] At room temperature, dicyclohexylmethanediimide (4.49 g, 21.78 mmol, 3 equivalents) was added to a stirred solution of 4-(benzyloxy)-4-oxobutyric acid (3.78 g, 18.15 mmol, 2.5 equivalents) in DCM (125 ml), and the mixture was stirred for 30 minutes. N,N-dimethylpyridine-4-amine (0.443 g, 3.63 mmol, 0.5 equivalent) and (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-dihydroxypropyl)phosphate sodium (5.0 g, 7.26 mmol, 1 equivalent) were added at room temperature and stirred for 18 hours at room temperature. The reaction progress was monitored by LCMS. After completion, the reaction mixture was diluted with DCM (75 ml), stirred for 10 minutes, and filtered. The filtrate was washed with water (50 ml x 1), 0.5N HCl (50 ml x 1), and 10% NaHCO3 solution (50 ml x 1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 6.8 g of crude product. The crude product was then purified using alkaline 230-400 mesh silica gel (to make...).The crude product (pre-alkalized with ammonia) was purified by column chromatography. The product was eluted with ethyl acetate solution of 0-10% methanol. The pure fraction was collected and concentrated to give 3.4 g of sodium 2,3-bis((4-(benzyloxy)-4-oxobutyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate as a colorless syrup. The product was dissolved in DCM (100 ml) and washed with 0.5N HCl (50 ml x 1) and 10% NaHCO3 solution (50 ml x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give sodium 2,3-bis((4-(benzyloxy)-4-oxobutyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (3.1 g, 40.4% yield) as a colorless viscous syrup.

[1078] 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 7.41-7.26 (m, 10H), 5.08 (s, 6H), 4.31-4.19 (m, 2H), 4.17-4.05 (m, 2H), 3.79-3.66 (m, 4H), 2.64-2.54 (m, 8H), 2.29-2.18 (m, 4H), 1.53-1.44 (m, 4H), 1.22 (br s, 40H), 0.84 (br t , J = 6.8 Hz, 6H). LCMS: Molecular formula: C56H86NaO16P, Formula weight: 1069.25, Exact mass: 1046.57, Observed mass: 1045.5 [M-1]-, RT=3.61 min, Purity: 99.47%. Method: Mobile phase A: 1 ml of 25% ammonia solution dissolved in 1000 ml of MilliQ water (pH: 9, adjusted with acetic acid). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50x4.6) mm, 3.5 µ.

[1079] Step 2: Sodium 2,3-bis((3-carboxypropionyl)oxy)propyl((R)-2,3-bis(tetradecanoyl)propyl)phosphate.

[1080] Dihydroxypalladium (0.600 g, 0.854 mmol) on a 20 ml solution of 2,3-bis((4-(benzyloxy)-4-oxobutyryl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (1.0 g, 0.935 mmol, 1 equivalent) in DCM was added to a stirred solution on a dry basis at room temperature and under a nitrogen atmosphere. The reaction was stirred for 16 h under hydrogen balloon pressure.The reaction progress was monitored by LCMS and TLC. After completion, the reaction mixture was filtered through a diatomaceous earth bed and washed with THF (25 ml) and DCM (50 ml). The filtrate was concentrated under reduced pressure at room temperature to give 0.750 g of sodium 2,3-bis((3-carboxypropionyl)oxy)propyl)((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate. The product was dissolved in DCM (10 ml), and Amberlite IR120 Na resin (4.5 g) was added. The mixture was stirred for 1.5 h and filtered. The filtrate was concentrated and further dried under vacuum to give sodium 2,3-bis((3-carboxypropionyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (0.600 g, 72.2% yield) as a grayish-white solid. Instruction manual, pages 113 / 128, 136, CN 122094963 A

[1081] 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 12.95-11.04 (m, 2H), 5.12-4.97 (m, 2H), 4.33-4.05 (m, 4H), 3.76 (br s, 4H), 2.64-2.54 (m, 12H), 1.57-1.41 (m, 4H), 1.23 (br s, 40H), 0.91-0.78 (m, 6H). LCMS: Molecular formula: C42H74NaO16P, Formula weight: 889.00, Exact mass: 866.48, Observed mass: 889.4 [M+Na]+, RT = 3.60 min, Purity: 98.80%. Method: Column: X-BRIDGE C8 (50*4.6), 3.5 μm, Mobile phase A: 0.1% TFA aqueous solution, B: 0.1% TFA in ACN solution, Flow rate: 1.5 ml / min. HPLC: RT = 7.80 min; Purity: 98.46%. Method information: A: 0.1% TFA aqueous solution, B: ACN, Flow rate: 1.5 ml / min. Column: XBridge C8 (50X4.6) mm, 3.5 μm.

[1082] Example 25. (4S,4'S)-5,5'-((3-((((R)-2,3-bis(tetradecanoyloxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl)bis(oxy))bis(4-amino-5-oxopentanoic acid) dihydrochloride (compound 42).

[1083]

[1084] Step 1: 2,3-bis(((S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxySodium (S)-5-((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate.

[1085] EDC.HCl (3.48 g, 18.15 mmol, 2.5 equivalent) and 1H-benzo[d][1,2,3]triazole-1-ol (2.452 g, 18.15 mmol, 2.5 equivalent) were added to a stirred chloroform (75 ml) solution of (S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxovalerate (6.61 g, 21.78 mmol, 3.0 equivalent) at room temperature and stirred for 30 minutes. (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-dihydroxypropyl)phosphate sodium (5.0 g, 7.26 mmol, 1 equivalent) and N,N-dimethylpyridine-4-amine (2.217 g, 18.15 mmol, 2.5 equivalent) were added at room temperature, and the reaction mixture was refluxed for 16 hours. Then, EDC.HCl (3.48 g, 18.15 mmol, 2.5 equivalent), 1H-benzo[d][1,2,3]triazol-1-ol (2.452 g, 18.15 mmol, 2.5 equivalent), and N,N-dimethylpyridine-4-amine (2.217 g, 18.15 mmol, 2.5 equivalent) were added, and the reaction mixture was refluxed for 2 hours. The reaction progress was monitored by LCMS. After completion, the reaction mixture was diluted with DCM (75 ml) and washed with water (50 ml x 2), cold 1.5N HCl (50 ml x ...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, I in, R 1 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 2 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 3 for ; R 4 It is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt; R 5 To be optionally subjected to one or more of the following: OH, OAc, OMe, NHAc, N(R) 7 )2. C1-C groups substituted with SH, CN, COOH, CONH2, Cl, Br, and I. 10 Branched or unbranched hydrocarbons; R 6 To be optionally subjected to one or more of the following: OH, OAc, OMe, NHAc, N(R) 8 )2. C1-C groups substituted with SH, CN, COOH, CONH2, Cl, Br, and I. 10 Branched or unbranched hydrocarbons; Each R 7 Independently, it is an H or C1-C6 branched or unbranched alkyl group; Each R 8 Independently, it is an H or C1-C6 branched or unbranched alkyl group; X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and, Each solid center is independently R, S, or racemic.

2. The compound of claim 1, wherein the compound is represented by a compound of formula IA or a pharmaceutically acceptable salt thereof. IA in, R 1 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 2 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 3 for ; R 4 It is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt; R 5 To be optionally selected by one or more of OH, N(R) 7 C1-C substituents of )2 and COOH groups 10 Branched or unbranched hydrocarbons; R 6 To be optionally selected by one or more of OH, N(R) 8 C1-C substituents of )2 and COOH groups 10 Branched or unbranched hydrocarbons; Each R 7 Independently, it is an H or C1-C6 branched or unbranched alkyl group; Each R 8 Independently, it is an H or C1-C6 branched or unbranched alkyl group; X is a direct bond; Y represents a direct bond; and, Each solid center is independently R, S, or racemic, and Optional, R 4 It can be H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

3. The compound of claim 1, wherein the compound is selected from at least one of the following: , , , , , , , , , , , , , , , , , , , or .

4. The compound of claim 1, wherein any compound contains any oxygen anion O. - Pairs with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium; and wherein, Any NH2 or COOH of any compound may optionally be in the form of a pharmaceutically acceptable salt, wherein said compound is a single entity, a solvate, a hydrate, a crystal, an amorphous solid, a liquid, or an oil.

5. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, I， in, R 1 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 2 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 3 for ; R 4 It is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt; R 5 To be optionally subjected to one or more of the following: OH, OAc, OMe, NHAc, N(R) 7 )2. C1-C groups substituted with SH, CN, COOH, CONH2, Cl, Br, and I. 10 Branched or unbranched hydrocarbons; R 6 To be optionally subjected to one or more of the following: OH, OAc, OMe, NHAc, N(R) 8 )2. C1-C groups substituted with SH, CN, COOH, CONH2, Cl, Br, and I. 10 Branched or unbranched hydrocarbons; Each R 7 Independently, it is an H or C1-C6 branched or unbranched alkyl group; Each R 8 Independently, it is an H or C1-C6 branched or unbranched alkyl group; X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and, Each solid center is independently R, S, or racemic; The method includes the following steps: The hydroxyl groups of the compounds of formula II are converted into esters, carbonates, or carbamates. II All substitutions are defined as described above; Optionally, the phosphorus-bound OH group is converted to OR. 4 , where R 4 Not H; and, Optionally, one or more protecting groups are removed; or The method includes the following steps: Compounds of formula III are linked to compounds of formula IV by forming phosphodiester bridges. III IV in, R 1 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 2 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; Each R 7 Independently, it is an H or C1-C6 branched or unbranched alkyl group; Each R 8 Independently, it is an H or C1-C6 branched or unbranched alkyl group; R 9 For being independently selected from OR 11 、N(R 7 )R 12 、N(R 7 2. SR 13 CN, COOR 14 C1-C groups substituted with CONH2, Cl, Br and I 10 Branched or unbranched hydrocarbons; R 10 For being independently selected from OR 11 、N(R 8 )R 12 、N(R 8 2. SR 13 CN, COOR 14 C1-C groups substituted with CONH2, Cl, Br and I 10 Branched or unbranched hydrocarbons; Each R 11 Independently, it can be H, Ac, Me, tert-butyl, benzyl, triphenylmethyl, benzoyl, p-nitrobenzoyl, MOM, BOM, or Si forming the core of a silyl ether; Each R 12 Independently, it can be H, Me, Boc, Cbz, Fmoc, benzyl, 4-methoxybenzyl, tert-butyl, or triphenylmethyl; Each R 13 It can be independently H, Ac, benzoyl, p-nitrobenzoyl, or triphenylmethyl; Each R 14 Independently, it is H, C1-C6 branched or unbranched alkyl, benzyl or 4-methoxybenzyl; X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and, Each solid center is independently R, S, or racemic; Optionally, the phosphorus-bound OH group is converted to OR. 4 , where R 4 Not H; and, Optionally, each OR 11 、N(R 7 )R 12 、N(R 8 )R 12 SR 13 or COOR 14 They are converted to OH and NHR respectively. 7 NHR 8 , SH or COOH.

6. The method of claim 5, wherein, The method is used to prepare compounds of formula IA or pharmaceutically acceptable salts thereof. IA in, R 1 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 2 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 3 for ; R 4 It is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt; R 5 To be optionally selected by one or more of OH, N(R) 7 C1-C substituents of )2 and COOH groups 10 Branched or unbranched hydrocarbons; R 6 To be optionally selected by one or more of OH, N(R) 8 C1-C substituents of )2 and COOH groups 10 Branched or unbranched hydrocarbons; Each R 7 Independently, it is an H or C1-C6 branched or unbranched alkyl group; Each R 8 Independently, it is an H or C1-C6 branched or unbranched alkyl group; X is a direct bond; Y represents a direct bond; and, Each solid center is independently R, S, or racemic; The method includes the following steps: The hydroxyl groups of the compounds of formula II are converted into esters, carbonates, or carbamates. II All substitutions are defined as described above; Optionally, the phosphorus-bound OH group is converted to OR. 4 , where R 4 Not H; and, Optionally, one or more protecting groups are removed; or The method includes the following steps: Compounds of formula III are linked to compounds of formula IV by forming phosphodiester bridges. III IV in, R 1 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 2 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; Each R 7 Independently, it is an H or C1-C6 branched or unbranched alkyl group; Each R 8 Independently, it is an H or C1-C6 branched or unbranched alkyl group; R 9 For being independently selected from OR 11 、N(R 7 )R 12 、N(R 7 )2 and COOR 14 C1-C groups substituted 10 Branched or unbranched hydrocarbons; R 10 For being independently selected from OR 11 、N(R 8 )R 12 、N(R 8 )2 and COOR 14 C1-C groups substituted 10 Branched or unbranched hydrocarbons; Each R 11 Independently, it can be H, Ac, Me, tert-butyl, benzyl, triphenylmethyl, benzoyl, p-nitrobenzoyl, MOM, BOM, or Si forming the core of a silyl ether; Each R 12 Independently, it can be H, Me, Boc, Cbz, Fmoc, benzyl, 4-methoxybenzyl, tert-butyl, or triphenylmethyl; Each R 14 Independently, it is H, C1-C6 branched or unbranched alkyl, benzyl or 4-methoxybenzyl; X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and, Each solid center is independently R, S, or racemic; Optionally, the phosphorus-bound OH group is converted to OR. 4 , where R 4 Not H; and, Optionally, each OR 11 、N(R 7 )R 12 、N(R 8 )R 12 or COOR 14 They are converted to OH and NHR respectively. 7 NHR 8 Or COOH.

7. The method of claim 5, wherein, The method includes the following steps: The hydroxyl groups of the compounds of formula II are converted into esters, carbonates, or carbamates. II All substitutions are defined as described above; Optionally, the phosphorus-bound OH group is converted to OR. 4 , where R 4 Not H; and, Optionally, one or more protecting groups may be removed.

8. The method of claim 5, wherein, The method includes the following steps: Compounds of formula III are linked to compounds of formula IV by forming phosphodiester bridges. III IV in, R 1 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 2 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; Each R 7 Independently, it is an H or C1-C6 branched or unbranched alkyl group; Each R 8 Independently, it is an H or C1-C6 branched or unbranched alkyl group; R 9 For being independently selected from OR 11 、N(R 7 )R 12 、N(R 7 2. SR 13 CN, COOR 14 C1-C groups substituted with CONH2, Cl, Br and I 10 Branched or unbranched hydrocarbons; R 10 For being independently selected from OR 11 、N(R 8 )R 12 、N(R 8 2. SR 13 CN, COOR 14 C1-C groups substituted with CONH2, Cl, Br and I 10 Branched or unbranched hydrocarbons; Each R 11 Independently, it can be H, Ac, Me, tert-butyl, benzyl, triphenylmethyl, benzoyl, p-nitrobenzoyl, MOM, BOM, or Si forming the core of a silyl ether; Each R 12 Independently, it can be H, Me, Boc, Cbz, Fmoc, benzyl, 4-methoxybenzyl, tert-butyl, or triphenylmethyl; Each R 13 It can be independently H, Ac, benzoyl, p-nitrobenzoyl, or triphenylmethyl; Each R 14 Independently, it is H, C1-C6 branched or unbranched alkyl, benzyl or 4-methoxybenzyl; X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and, Each solid center is independently R, S, or racemic; Optionally, the phosphorus-bound OH group is converted to OR. 4 , where R 4 Not H; and, Optionally, each OR 11 、N(R 7 )R 12 、N(R 8 )R 12 SR 13 or COOR 14 They are converted to OH and NHR respectively. 7 NHR 8 SH or COOH, and optionally R 4 It can be H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

9. The method of claim 5, wherein, The compound is selected from at least one of the following: , , , , , , , , , , , , , , , , , , , or .

10. The method of claim 5, wherein any compound contains any oxygen anion O - Pairs with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium; and wherein, Any NH2 or COOH of any compound is optionally in the form of a pharmaceutically acceptable salt, and optionally, the method prepares the compound as a single entity, solvate, hydrate, crystal, amorphous solid, liquid, or oil.

11. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. I in, R 1 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 2 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 3 for ; R 4 It is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt; R 5 To be optionally subjected to one or more of the following: OH, OAc, OMe, NHAc, N(R) 7 )2. C1-C groups substituted with SH, CN, COOH, CONH2, Cl, Br, and I. 10 Branched or unbranched hydrocarbons; R 6 To be optionally subjected to one or more of the following: OH, OAc, OMe, NHAc, N(R) 8 )2. C1-C groups substituted with SH, CN, COOH, CONH2, Cl, Br, and I. 10 Branched or unbranched hydrocarbons; Each R 7 Independently, it is an H or C1-C6 branched or unbranched alkyl group; Each R 8 Independently, it is an H or C1-C6 branched or unbranched alkyl group; X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and, Each solid center is independently R, S, or racemic, and, Optionally, the R of the compound of formula I 4 It can be H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

12. The pharmaceutical composition of claim 11, wherein, The compound of Formula I is selected from one or more of the following: , , , , , , , , , , , , , , , , , , , or .

13. The pharmaceutical composition of claim 11, wherein any compound contains any oxygen anion O - Pairs with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium; and wherein, Any NH2 or COOH of any compound is optionally in the form of a pharmaceutically acceptable salt, and optionally, the compound of Formula I exists as a single entity, a solvate, a hydrate, a crystal, an amorphous solid, a liquid, or an oil.

14. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition further comprises one or more agents that induce heart disease as a side effect.

15. The pharmaceutical composition of claim 14, wherein one or more agents inducing cardiac events as a side effect are selected from at least one of the following: adrenaline, salbutamol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, afortrol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, benprodil, bortezomib, bosutinib, bromhexine, buprenorphine, capecitabine, chloral hydrate, clomipramine, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, crizotinib, curcumin, cyclobenzaline. Cyclosporine, dasatinib, degarelix, desipramine, desvenlafaxine, dexmedetomidine, dextromethorphan, dextromethorphan, dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, donepezil, dopamine, doxepin, dronedarone, fluperidone, ephedrine, epinephrine, erythromycin, edepram, famotidine, fenfluramine, fungomod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, furosemide, furosemide, galantamine, gatifloxacin, gemimifloxacin, granisetron, halofantrone, fluperidone Pyridoxine, hydrochlorothiazide, hydroxychloroquine, hydroxyzine, ibutilide, ipraridone, imipramine, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, leuprolide, levosalbutamol, levofloxacin, levomethazine, levomethadone, lysine mesylate, lithium, loperamide, maprotiline, mefloxacin, melipramine, mesordazine, orsinol, methadone, methamphetamine, methylphenidate, metoclopramide, mexiletine, midodrine, mifepristone, mirabezolone, mirtazapine, moxifloxacin / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, octreotide, ofloxacin Olanzapine, Ondansetron, Olfenadrine, Oxaliplatin, Oxycodone, Oxytocin, Palpanidone, Papaverine Hydrochloride, Paroxetine, Parreptide, Pazopanib, Pazopanib, Pentamidine, Perfluoropropane Lipospheres, Perphenazine, Phenylephrine, Phenylaloepine, Phenylephrine, Pimozide, Posaconazole, Probucol, Procainamide, Promethazine, Propafenone, Propofol Dextropropoxyphene, Protriptyline, Pseudoephedrine, Quetiapine, Quinidine, Quinine, Quinine Sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir, Ritonavir and Lopinavir, Roxithromycin, Salbutamol, Salmeterol, Saquinavir, Serindole, Sertraline, Sevoflurane, Sibutramine, Sofenac, Sorafenib, Sotalol, Sparfloxacin, Spiramycin,Sulpiride, sunitinib, tacrolimus, tamoxifen, terabhivir, terabinin, telithromycin, terbutaline, terfenadine, tetrabenzidine, thioridazine, tevothixeol, tizanidine, tizanidinev, tolterodine, toremifene, torasemide, trazodone, trimethoprim and sulfamethoxazole, sulfamethoxazole, trimethoprim, trimethoprim, vandetanil, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, ziprasidone or ziprasidone.

16. The pharmaceutical composition of claim 11, wherein, The compound of Formula I is at least one of the following: existing as a single entity, solvate, hydrate, crystal, amorphous solid, liquid, or oil; reducing or eliminating one or more of the following: cardiac ion channelopathies caused by active agents used to treat diseases or symptoms caused by irregularities or changes in heart rhythm; in doses of about 1 mg to about 1... Dosage in amounts between g per unit dose; or formulated for oral, sublingual, transdermal, suppository, intrathecal, enteric, parenteral, intravenous, intraperitoneal, skin, subcutaneous, local, pulmonary, rectal, vaginal, or intramuscular administration, and optionally, the compound of formula I is formulated as tablets, capsules, pouches, pills, powders, lozenges, syrups, liquid solutions, suspensions, emulsions, elixirs, or oral films (OTF), solid forms, solutions, suspensions, or soft gels for oral administration; or optionally, the solid form further comprises one or more excipients, binders, anti-adhesion agents, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, glidants, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, or combinations thereof.

17. A method for reducing or eliminating one or more of cardiac ion channelopathy, myocardial injury, or symptoms caused by irregularities or alterations in cardiac rhythm in a human or animal subject, comprising administering to the human or animal subject one or more of compounds of formula I or a pharmaceutically acceptable salt thereof. I in, R 1 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 2 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 3 for ; R 4 It is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt; R 5 To be optionally subjected to one or more of the following: OH, OAc, OMe, NHAc, N(R) 7 )2. C1-C groups substituted with SH, CN, COOH, CONH2, Cl, Br, and I. 10 Branched or unbranched hydrocarbons; R 6 To be optionally subjected to one or more of the following: OH, OAc, OMe, NHAc, N(R) 8 )2. C1-C groups substituted with SH, CN, COOH, CONH2, Cl, Br, and I. 10 Branched or unbranched hydrocarbons; Each R 7 Independently, it is an H or C1-C6 branched or unbranched alkyl group; Each R 8 Independently, it is an H or C1-C6 branched or unbranched alkyl group; X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and, Each solid center is independently R, S, or racemic, and; Optionally, the R of the compound of formula I 4 It can be H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

18. The method of claim 17, wherein, The compound of Formula I is at least one of the following: existing as a single entity, solvate, hydrate, crystal, amorphous solid, liquid, or oil; reducing or eliminating one or more of the following: cardiac ion channelopathies caused by active agents used to treat diseases or symptoms caused by irregularities or changes in heart rhythm; in doses of about 1 mg to about 1... Dosage in amounts between g per unit dose; or formulated for oral, sublingual, transdermal, suppository, intrathecal, enteric, parenteral, intravenous, intraperitoneal, skin, subcutaneous, local, pulmonary, rectal, vaginal, or intramuscular administration, and optionally, the compound of formula I is formulated as tablets, capsules, pouches, pills, powders, lozenges, syrups, liquid solutions, suspensions, emulsions, elixirs, or oral films (OTF), solid forms, solutions, suspensions, or soft gels for oral administration; or optionally, the solid form further comprises one or more excipients, binders, anti-adhesion agents, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, glidants, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, or combinations thereof.

19. The method of claim 17, wherein, The compound of Formula I is administered co-administered with one or more drugs that induce heart disease as a side effect.

20. The method of claim 19, wherein, One or more active agents that induce cardiac events as a side effect are selected from at least one of the following: adrenaline, salbutamol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, afortrol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, benprodil, bortezomib, bosutinib, bromhexine, buprenorphine, capecitabine, chloral hydrate, clomipramine, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, crizotinib, curcumin, cyclobenzaline, cyclosporine, dabrafenib, dasatinib, degarelix. Desipramine, desmenolafaxine, dexmedetomidine, dextromethorphan, dextromethorphan, dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, donepezil, dopamine, doxepin, dronedarone, fluperidone, ephedrine, epinephrine, erythromycin, edepramine, famotidine, femoxanil, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, furosemide, furosemide, galantamine, gatifloxacin, gemimifloxacin, granisetron, halofantroline, haloperidol, hydrochlorothiazide, hydroxychloroquine, hydroxyzine, ibutilide, Ipraridone, Imipramine, Indapamide, Isoproterenol, Iradipine, Itraconazole, Ivabradine, Ketoconazole, Lapatinib, Leuprorelin, Levosalbutamol, Levofloxacin, Levomethadone, Levomethadone, Lysine Mesylate, Lithium, Loperamide, Maprotiline, Mefloquine, Mepratrimine, Mesordazine, Osinaline, Methadone, Methylbenzene Amphetamine, methylphenidate, metoclopramide, mexiletine, midodrine, mifepristone, mirabezilone, mirtazapine, moxifloxacin / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, octreotide, ofloxacin, olanzapine, ondansetron, oxaliplatin, oxytocin, oxytocin, palmiriton, salt Papaverine, paroxetine, parretoxin, pazopanib, pazopanib, pentamivir, perfluoropropane lipid microspheres, perphenazine, phenylbutazone, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, propafenone, propofol, dextropropoxyfen, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, ritonavir and lopinavir, roxithromycin, salbutamol, salmeterol, saquinavir, serindole, sertraline, sevoflurane, sibutramine, sofenac, sorafenib, sotalol, sparfloxacin, spiramycin, sulpiride, sunitinib, tacrolimus, tamoxifen, terabixin, telithromycinTerbutaline, terfenadine, tetrabenzylquinazine, thioridazine, tevothixeol, tizanidine, tizanidinev, tolterodine, toremifene, torasemide, trazodone, trimethoprim and sulfamethoxazole, sulfamethoxazole, trimethoprim, trimethoprim, vandetanil, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, ziprasidone or ziprasidone.

21. The method of claim 17, wherein the compound of formula I reduces or eliminates heart disease induced by drugs or caused by disease or condition, such as QT interval prolongation, myocardial damage, or AV block.

22. The method of claim 17, wherein, The compound is: , , , , , , , , , , , , , , , , , , , or .

23. The method of claim 17, wherein any compound contains any oxygen anion O. - Pairs with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium; and wherein, Any NH2 or COOH of any compound may optionally be in the form of a pharmaceutically acceptable salt, wherein said compound is a single entity, a solvate, a hydrate, a crystal, an amorphous solid, a liquid, or an oil.

24. A method for reducing or eliminating the cardiotoxic or cardiac effects of one or more active agents, comprising: Administer one or more cardiotoxic active agents to subjects who require treatment for a disease or disorder; and A combination therapy is provided with an effective amount of one or more lipids, said one or more lipids reducing or eliminating the cardiotoxic effects of said one or more active agents, wherein said lipids have the following formula or are pharmaceutically acceptable salts thereof: I in, R 1 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 2 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 3 for ; R 4 It is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt; R 5 To be optionally subjected to one or more of the following: OH, OAc, OMe, NHAc, N(R) 7 )2. C1-C groups substituted with SH, CN, COOH, CONH2, Cl, Br, and I. 10 Branched or unbranched hydrocarbons; R 6 To be optionally subjected to one or more of the following: OH, OAc, OMe, NHAc, N(R) 8 )2. C1-C groups substituted with SH, CN, COOH, CONH2, Cl, Br, and I. 10 Branched or unbranched hydrocarbons; Each R 7 Independently, it is an H or C1-C6 branched or unbranched alkyl group; Each R 8 Independently, it is an H or C1-C6 branched or unbranched alkyl group; X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and, Each solid center is independently R, S, or racemic, and; Compared with treatments that do not use the lipids, cardiotoxicity is reduced by at least 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, or 100%, and optionally, R 4 It can be H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium.

25. The method of claim 24, wherein the cardiotoxicity or cardiac lesion is selected from at least one of the following: minimal left ventricular dilatation, systolic dysfunction, moderate valvular regurgitation, decreased left ventricular ejection fraction (LVEF), cardiac hypertrophy, decreased cardiac contractility, decreased cardiac output, pressure and volume overload hypertrophy, myocardial dysfunction, cardiac remodeling, post-myocardial infarction heart failure, or cardiac disease.

26. The method of claim 24, wherein the one or more active agents and the lipids are administered simultaneously, or the one or more active agents and the lipids are formulated for oral, sublingual, transdermal, suppository, intrathecal, enteric, parenteral, intravenous, intraperitoneal, skin, subcutaneous, local, pulmonary, rectal, vaginal, or intramuscular administration, or wherein the one or more lipids, the one or more active agents, or both are infused over 3 hours.

27. The method of claim 24, wherein one or more agents inducing cardiotoxicity or cardiac lesions are selected from at least one of the following: adrenaline, salbutamol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, afortrol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, benprodil, bortezomib, bosutinib, bromhexine, buprenorphine, capecitabine, chloral hydrate, clomipramine, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, crizotinib, curcumin, cyclobenzaline, Cyclosporine, dasatinib, degarelix, desipramine, desvenlafaxine, dexmedetomidine, dextromethorphan, dextromethorphan, dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, donepezil, dopamine, doxepin, dronedarone, fluperidone, ephedrine, epinephrine, elebulin, erythromycin, edepram, famotidine, femoxanil, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, furosemide, furosemide, galantamine, gatifloxacin, gemimifloxacin, granisetron, halofantrone, fluperidone Alcohol, hydrochlorothiazide, hydroxychloroquine, hydroxyzine, ibutilide, ipraprazole, imipramine, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, leuprorelin, levosalbutanol, levofloxacin, levomethazine, levomethadone, lysine mesylate, lithium, loperamide, maprotiline, mefloxacin, melipramine, mesoridazine, ocinaridine, methadone, methamphetamine, methylphenidate, metoclopramide, mexiletine, midodrine, mifepristone, mirabezolone, mirtazapine, moxipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, octreotide, ofloxacin, olanzapine, ondansetron, olphenadrine Oxaliplatin, oxycodone, oxytocin, palapirone, papaverine hydrochloride, paroxetine, parreptide, pazopanib, pazopanib, pentamivir, perfluoropropane lipid microspheres, perphenazine, phenylbutazone, phenylephrine, phenylephrine, pimozide, posaconazole, probucol, procainamide, promethazine, propafenone, propofol, dextropropoxyphene, protriptyline, pseudoephedrine Quetiapine, Quinidine, Quinine, Quinine Sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir, Ritonavir and Lopinavir, Roxithromycin, Salbutamol, Salmeterol, Saquinavir, Serindole, Sertraline, Sevoflurane, Sibutramine, Sofenac, Sorafenib, Sotalol, Sparfloxacin, Spiramycin, Sulpiride, Sunitinib, TacrolimusTamoxifen, terabhivir, terabinin, telithromycin, terbutaline, terfenadine, tetrabenzidine, thioridazine, tevothixeol, tizanidine, tizanidinev, tolterodine, toremifene, torasemide, trazodone, trimethoprim and sulfamethoxazole, sulfamethoxazole, trimethoprim, trimethoprim, vandetanil, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, ziprasidone or ziprasidone.

28. The method of claim 27, wherein, The pharmaceutical composition comprises at least one of the following: The one or more lipids further comprise one or more excipients, binders, anti-adhesion agents, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, flow aids, lubricants, preservatives, adsorbents, sweeteners, their derivatives, or combinations thereof; The compound of formula I is present in a unit dose of approximately 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 24, 30, 40, 50, 60, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, or 10000 mg. Preparations for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, skin, subcutaneous, local, pulmonary, rectal, vaginal, or intramuscular administration; Preparations intended for oral administration include tablets, capsules, pouches, pills, powders, lozenges, syrups, liquid solutions, suspensions, emulsions, elixirs, or oral films (OTF); or The formulation is in solid form, solution, suspension or soft gel form.

29. The method of claim 24, wherein, The compound of Formula I is selected from one or more of the following: , , , , , , , , , , , , , , , , , , , or .

30. The method of claim 24, wherein any compound contains any oxygen anion O - Pairs with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium; and wherein, Any NH2 or COOH of any compound may optionally be in the form of a pharmaceutically acceptable salt, wherein said compound is a single entity, a solvate, a hydrate, a crystal, an amorphous solid, a liquid, or an oil.

31. A method for reducing or eliminating the cardiotoxic effects of one or more antiproliferative agents, comprising: Administer one or more cardiotoxic antiproliferative agents to subjects requiring treatment for proliferative disorders; and providing a combination therapy with an effective amount of one or more lipids, said one or more lipids reducing or eliminating the cardiotoxic effects of one or more antiproliferative agents, said lipids having the following formula or being a pharmaceutically acceptable salt thereof: I in, R 1 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 2 C1-C having 0-10 double bonds, 0-10 triple bonds, or a combination of 0-10 double and triple bonds. 20 Branched or unbranched hydrocarbons; R 3 for ; R 4 It is H or a pharmaceutically acceptable cation, wherein the introduction of the pharmaceutically acceptable cation forms a salt; R 5 To be optionally subjected to one or more of the following: OH, OAc, OMe, NHAc, N(R) 7 )2. C1-C groups substituted with SH, CN, COOH, CONH2, Cl, Br, and I. 10 Branched or unbranched hydrocarbons; R 6 To be optionally subjected to one or more of the following: OH, OAc, OMe, NHAc, N(R) 8 )2. C1-C groups substituted with SH, CN, COOH, CONH2, Cl, Br, and I. 10 Branched or unbranched hydrocarbons; Each R 7 Independently, it is an H or C1-C6 branched or unbranched alkyl group; Each R 8 Independently, it is an H or C1-C6 branched or unbranched alkyl group; X is a direct bond, O, or NH; Y is a direct bond, O, or NH; and, Each solid center is independently R, S, or racemic, and optionally, R 4 The lipids are H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium; and the cardiotoxicity is reduced by at least 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95% or 100% compared with treatments that do not use the lipids.

32. The method of claim 31, wherein the cardiotoxicity is selected from at least one of the following: minimal left ventricular dilatation, systolic dysfunction, moderate valvular regurgitation, decreased left ventricular ejection fraction (LVEF), cardiac hypertrophy, decreased cardiac contractility, decreased cardiac output, pressure and volume overload hypertrophy, myocardial dysfunction, cardiac remodeling, post-myocardial infarction heart failure, or heart disease; concurrent administration of the one or more antiproliferative agents and the lipids; oral or intravenous administration of the one or more antiproliferative agents and the lipids; infusion of the one or more lipids, the one or more antiproliferative agents, or both, over 3 hours; the one or more antiproliferative agents that induce heart disease as a side effect are selected from at least one of the following: bosutinib, crizotinib, dabrafenib, dasatinib, doxorubicin, lapatinib, nilotinib, sorafenib, sunitinib, vandetanib, or vemurafenib.

33. The method of claim 31, wherein, The compound of Formula I is selected from one or more of the following: , , , , , , , , , , , , , , , , , , , , or .

34. The method of claim 31, wherein any compound contains any oxygen anion O. - Pairs with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium; and wherein, Any NH2 or COOH of any compound may optionally be in the form of a pharmaceutically acceptable salt, wherein said compound is a single entity, a solvate, a hydrate, a crystal, an amorphous solid, a liquid, or an oil.

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