Method for isotope modification of polyunsaturated fatty acids and derivatives thereof

Abstract

Isotopically modified polyunsaturated lipids containing a 1, 4-diene system are provided.SOLUTION: Wherein R and R ' comprise residues of linolenic, arachidonic, eicosapentaenoic, or docosahexaenoic acids, or esters thereof, wherein the esters, if present, are C1 - C21 alkyl esters, wherein the ruthenium complex further comprises a cyclopentadiene (Cp) ligand, and wherein the ruthenium in the ruthenium complex is in the + 1 oxidation state (Ru + 1).SELECTED DRAWING: None

Description

[Technical Field]

[0001] (Reference to Related Application) This application is a continuation of U.S. Provisional Application No. 62 / 979,627, filed February 21, 2020. Priority is claimed and is incorporated herein in its entirety for all purposes.

[0002] (Technical field) Isotopically modified polyunsaturated lipids, mixtures of isotopically modified polyunsaturated lipids, such compounds or methods for making such mixtures, pharmaceutical compositions and medicaments containing such compounds or mixtures, and for treating, preventing, or alleviating various diseases, disorders, or conditions associated with lipid peroxidation. The use of such compounds or mixtures for the treatment of rheumatoid arthritis is provided. [Background technology]

[0003] Description of Related Art Oxidative damage is a major cause of mitochondrial disease, neurodegenerative diseases, neuromuscular diseases, retinal diseases, and energy These include, but are not limited to, impaired glycemic control, kidney disease, liver disease, lipidemia, heart disease, inflammation, and genetic disorders. It is involved in a wide variety of diseases, including but not limited to:

[0004] Although the number of diseases associated with oxidative stress is numerous and diverse, oxidative stress is a major factor affecting normal cells. It is well established that the cause is a disturbance to the redox state of the peroxides. and the imbalance between the daily production and detoxification of reactive oxygen species ("ROS"), such as free radicals. Equilibrium can result in oxidative damage to cell structures and machinery. Under normal conditions, aerobic A potentially important source of ROS in living organisms is from mitochondria during normal oxidative respiration. In addition, macrophages and enzyme reactions also contribute to the release of activated oxygen. It is known that the lipid membranes of cells and their internal organelles contribute to the production of S. Therefore, ROS can easily come into contact with membrane components and cause lipid oxidation. In general, such oxidative damage occurs through direct interaction with reactive oxygen species, oxidized membrane components, or other oxidized cellular components. Through direct and indirect contact, they interact with other biomolecules in membranes and cells, such as proteins and DNA. A, thus facilitating how oxidative damage propagates throughout the cell. It can be imagined, providing mobility of internal components and interconnectivity of cellular pathways.

[0005] Lipid-forming fatty acids are well known as one of the major components of living cells. Polyunsaturated fatty acids are involved in many metabolic pathways and play an important role in various pathological conditions. ("PUFAs") are an important subclass of fatty acids. Essential nutrients are obtained directly or by modification. They perform essential biological functions through metabolism and are produced endogenously or sufficiently to cover the needs. For warm-blooded animals, there are two strictly essential PUFAs: Linoleic acid (cis,cis-9,12-octadecadienoic acid; (9Z,12Z)-9,12 -Octadecadienoic acid; "LA"; 18; cis,cis-9,12,15-octadecatri Enoic acid; (9Z,12Z,15Z)-9,12,15-octadecatrienoic acid; "ALA 18:3;n-3) acid, formerly known as vitamin F (Cunnan e SC.Progress in Lipid Research 2003;42: 544-568) osapentaenoic acid (EPA; 20:5; n-3) and docosahexaenoic acid Acid (DHA; 22:6; n-3). The essential properties of certain PUFAs or PUFA precursors Therefore, there are many known examples of these deficiencies, which often result in medical conditions. Additionally, many PUFA supplements are available over the counter and may be used to treat specific illnesses. Its effectiveness has been proven.

[0006] PUFAs provide the mitochondrial membrane with the proper fluidity required for optimal oxidative phosphorylation performance. PUFAs also play an important role in the initiation and propagation of oxidative stress. FAs react with ROS through a chain reaction that amplifies the original event (Sun M, Salo mon RG, J.Am.Chem.Soc.2004;126:5699-5708) However, high levels of non-enzymatic formation of lipid hydroperoxides can lead to several harmful effects. In fact, coenzyme Q10 is known to inhibit PUFA peroxidation. and has been associated with increased PUFA toxicity via the toxicity of the resulting products (Do T Q et al., PNAS USA 1996;93:7534-7539). The compounds adversely affect membrane fluidity and permeability, leading to the oxidation of membrane proteins and the formation of numerous It can be converted into highly reactive carbonyl compounds, including acrolein, malonic acid, Reactive species include dialdehydes, glyoxal, and methylglyoxal (Neg re-Salvayre A et al. Brit.J.Pharmacol.2008;153 :6-20).

[0007] Site-selective isotope enrichment of polyunsaturated fatty acids at bis-allylic sites has implications for neurological and retinal diseases. Oxidative damage to these molecules has been linked to disease, atherosclerosis, and aging. It has been identified as a unique approach to prevent damage. Typical methods for preparing PUFAs require lengthy, laborious, and expensive synthesis. This requires a large amount of cleavage and sometimes produces undesirable by-products. Smarun et al., J. Chem. 20 17, 82, 13115-13120. There is a need to develop an efficient catalytic process for site-specific deuteration. Summary of the Invention

[0008] Some embodiments of the present disclosure include: A method for isotopic modification of polyunsaturated lipids, comprising: Reacting a polyunsaturated lipid with an isotope-containing agent in the presence of a transition metal catalyst to produce one or more A step of obtaining an isotope-modified polyunsaturated lipid having an isotope at the bis-allylic position of The isotope-containing agent is selected from the group consisting of deuterium, tritium, and combinations thereof. and the transition metal catalyst is represented by formula (I) or (II): having structure; [ML 1 (L 2 ) m (L 3 ) n ] p Q k (I) [ML l (L 2 ) m1 (L 3 ) n1 ]-L-[ML 1 (L 2 ) m2 (L 3 ) n2 ] q Q k (II) where M is rhodium, iridium, or ruthenium; L 1 is C3-C 10 Cycloalkenyl, C4-C 10Cycloalkynyl, C6-C1 aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl, L 1 is an R of 1 or more A where L 1 is substituted with 1-10 members, Each L 2 are independently imine, carbene, carbonyl, alkene, alkyne, nitrile , isonitrile, acetonitrile, ether, thioether, phosphine, pyridine, C3-C arbitrarily substituted 10 Cycloalkenyl, optionally substituted C-C 10 Cycloa alkynyl, optionally substituted C6-C 10 Aryl, optionally substituted 5- to 10-membered heteroaryl and optionally substituted 3- to 10-membered heterocyclyl; Each L 3 are independently C1-C6 alkyl, NR 1 R 2 or C1-C6 alkoxy the law of nature, Each R 1 and R 2 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 cycloalkenyl, Optionally substituted C4-C 10 Cycloalkynyl, optionally substituted C-C 10 Ally optionally substituted 5- to 10-membered heteroaryl or optionally substituted 3- to 10-membered heteroaryl is cyclocyclyl, and each R 2 and R 2 independently, C2-C 10 Alkyl, optionally substituted C2-C6 aryl or optionally substituted C2-C7 aryl or optionally substituted C2-C 10 represents a heterocyclyl, Each R A are independently selected from hydroxyl, halogen, cyano, nitro, and optionally substituted C 1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 haloalkyl, C1-C6 haloalkoxy or optionally substituted amino can be; L is C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene. is a m, m1, m2, n, n1, and n2 are independently integers of 1, 2, or 3; p and q are independently integers of 1, 2, 3, or 4; Q is an anion; and k is 0, 1, or 2. Methods for isotopic modification of polyunsaturated lipids.

[0009] In some embodiments of this method, M is ruthenium. Polyunsaturated lipids are fatty acids (PUFAs), fatty acid esters, fatty acid thioesters, and fats. It is a phospholipid containing an acid amide and a fatty acid moiety.

[0010] Some embodiments of the present disclosure have isotopes predominantly at one or more bis-allylic positions. A composition comprising one or more isotopically modified polyunsaturated lipids, The substance is prepared by the methods described herein.

[0011] Embodiments of the present disclosure include processes for preparing isotopically polyunsaturated lipids using transition metal catalysis. Polyunsaturated lipids are fatty acids (PUFAs), fatty acid esters, fatty acid thiol It may be an ester, a fatty acid amide, or a phospholipid containing a fatty acid moiety. In an embodiment, the method provides a deuterated polyunsaturated lipid or a mixture of deuterated polyunsaturated lipids. In some embodiments, the methods described herein provide for deuteration by bis(2-hydroxybenzoyl)methylation. Site-specific deuteration of polyunsaturated lipids occurs at both the -allylic and mono-allylic positions. In some further embodiments, the method results in primarily or exclusively bis-a This can result in site-specific deuteration occurring at the aryl positions.

[0012] (definition) The section headings used herein are for organizational purposes only and do not limit the scope of the subject matter described. should not be construed as limiting.

[0013] Unless otherwise defined, all technical and scientific terms used herein are understood to be of ordinary skill in the art. The term "including" has the same meaning as commonly understood by those skilled in the art. )" is used to express "include", "includes", and "contained" The use of the term "included" is not limiting, as are other forms such as "included." "Having" is a synonym for "have," "has," and "having" As used herein, the use of other forms such as "have" is not limiting. If the term "comprises" is used, whether in a transitional phrase or in the body of a claim, "comprise" and "comprising" have an open-ended meaning That is, the above terms should be interpreted as "having at least" or " should be interpreted synonymously with the phrase "includes at least" in the context of a process. When used in this context, the term "comprising" means that the process includes at least the recited steps. The compound, composition, formulation, or device may include additional steps. When used in this context, the term "comprises" refers to a compound, composition, formulation, or device. includes at least the recited features or components, but may also include additional features or components. This is the means.

[0014] As used herein, the term "about" means to express an amount, value, number, number, percentage, quantity, or The amount, value, number, or weight of the reference may be varied by a person skilled in the art. Refers to a quantity, value, number, percentage, amount, or weight that varies from a percentage, amount, or weight. In embodiments, the term "about" refers to a range of values ​​relative to a reference amount, value, number, percentage, quantity, or weight. 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or , refers to a 1% change.

[0015] As used herein, a "bis-allyl" position refers to a polyunsaturated amino acid as described herein. The methylene groups of the 1,4-diene systems of unsaturated lipids (e.g., the Y-position of polyunsaturated lipids of formula (I)) As used herein, a "mono-allyl" position refers to a position where one double bond is bonded to the other. refers to methylene groups adjacent only to bis-allylic positions (e.g., polyvalent unsubstituted aryls of formula (I)). (X substitution position of saturated lipids). Further exemplified in the following structure: [ka]

[0016] The term "polyunsaturated lipid" as used herein refers to a lipid that does not contain double bonds in its hydrocarbon chain. Polyunsaturated fats refer to lipids containing two or more unsaturated bonds, such as a double or triple bond. The quality is polyunsaturated fatty acids, polyunsaturated fatty acid esters, polyunsaturated fatty acid thioesters, Polyunsaturated fatty acid amides, polyunsaturated fatty acid phosphates, or polyunsaturated fatty acid residue-containing The lipid may be a phospholipid.

[0017] In some embodiments, the isotopically modified PUFA molecule has two hydrogen atoms in the methylene group. may contain one deuterium atom, such as when one of them is replaced by deuterium, Therefore, they may be referred to as "D1" PUFAs. Children are 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 1 They may contain 3 or 14 deuterium atoms, respectively designated as "D2", "D3", "D4", and "D 5", "D6", "D7", "D8", "D9", "D10", "D11", "D12" , may be referred to as "D13" or "D14" PUFAs.

[0018] As used herein, C b to "C a " is Al the number of carbon atoms in the alkyl, alkenyl, or alkynyl group, or the cycloalkyl, aryl, It refers to the number of carbon atoms in the ring of a heteroaryl or heterocyclyl group. alkyl, alkenyl, alkynyl, ring, aryl ring, heteroaryl ring or The heterocyclyl ring can contain carbon atoms "a"-"b" (inclusive) Thus, for example, a "C1-C4 alkyl" group refers to any alkyl group having from 1 to 4 carbons. refers to the alkyl group.

[0019] As used herein, "alkyl" refers to an alkyl group having 1 to 20 carbon atoms, or 1 to 10 carbon atoms or 1-6 carbon atoms fully saturated (no double or triple bonds) ) refers to a straight or branched hydrocarbon chain containing a hydrocarbon group.

[0020] As used herein, "alkenyl" refers to a group consisting of one or more alkyl groups in a straight or branched hydrocarbon chain. refers to an alkyl group containing multiple double bonds. An alkenyl group is a group having 2 to 20 carbon atoms or It can have 8 to 18 carbons.

[0021] As used herein, cycloalkylnyl refers to alkyl groups having 6 to 20 carbon atoms, or 8 to 2 A hydrocarbon ring system having 0 carbon atoms and 1 to 3 alkynyl groups contained within the ring system Refers to...

[0022] As used herein, "alkynyl" refers to an alkyl group having 2 to 20 carbon atoms, 2 to 10 It refers to an alkynyl group of 1 carbon atom or 2 to 6 carbon atoms.

[0023] As used herein, "cycloalkyl" refers to a group that is fully saturated (having no double bonds or triple bonds). It refers to a monocyclic or polycyclic hydrocarbon ring system (containing no double bonds). When it consists of two or more rings The rings may be joined together in a fused fashion. The cycloalkyl group may have 3 to 10 rings. The cycloalkyl group can contain 3 to 8 atoms in the atom or ring. Exemplary cycloalkyl groups include cyclopropyl, ... butyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups include, but are not limited to, unsubstituted or optionally substituted. It was.

[0024] As used herein, "aryl" refers to a carbocyclic ring (all carbon) of 6 to 14 ring atoms. ) monocyclic or polycyclic aromatic ring systems (e.g., fused rings in which two carbocyclic rings share a chemical bond, Bridged or spiro ring systems, e.g., one or more aryl or non-aryl rings The number of carbon atoms in an aryl group can vary. For example, , the aryl group is C6-C 14 Aryl groups, C6-C 10 Aryl group, or C6 aryl Examples of aryl groups include benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted. good.

[0025] As used herein, "heteroaryl" refers to an alkyl group containing one or more heteroatoms (e.g., 1 , 2 or 3 heteroatoms), i.e., carbon atoms including, but not limited to, nitrogen, oxygen, and sulfur. Monocyclic or polycyclic aromatic ring systems (completely delocalized π-electron systems) containing elements other than The number of atoms in the ring of a heteroaryl group can vary. The aryl group can contain 5 to 10 atoms, or 6 to 10 atoms in the ring. Examples of heteroaryl rings include, but are not limited to, heteroaryl groups, which may be substituted or unsubstituted. furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazolone azole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole azole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzo thiazole, imidazole, benzimidazole, indole, indazole, pyrazo benzopyrazole, isoxazole, triazole, benzotriazole, thiazol Azole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, butyl Lysine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine Contains A.

[0026] As used herein, "heterocyclyl" refers to 3, 4, 5, 6, 7, 8, 9, and refers to 10-membered monocyclic, bicyclic and tricyclic ring systems in which the carbon atoms are substituted with 1 to 5 heteroatoms. Together with the rings, they constitute the ring system. The heterocyclic rings may be one or more, as long as the system is not aromatic. Heteroatoms include oxygen, sulfur, and nitrogen. The heterocyclyl group may be unsubstituted or Examples of such "heterocyclyl" groups are aziridine, oxy, Ran, thiirane, azetidine, oxetane, 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxane Lan, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1, 3-Dithiol, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4- Thiazines, 2H-1,2-oxazines, maleimides, succinimides, barbituric acids, Thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, triox San, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazine thiazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine , oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, azepine Pan, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-o Xopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thymorph Thymorpholine, thymorpholine sulfoxide, thymorpholine sulfone and their benzo-condensed derivatives analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and / or 3,4- Examples of spiroheterocyclyl groups include 2-aza-methylenedioxyphenyl. Zaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6- Azaspiro[3.3]heptane, 2,6-diazaspiro[3.]heptane, 2-oxaspiro[3.]heptane These include pyro[3.4]octane and 2-azaspiro[3.4]octane.

[0027] As used herein, a substituent refers to a group in which one or more hydrogen atoms are exchanged with another atom or group. Unless otherwise specified, a group is considered to be "substituted." When made, the group may be C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, quinyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (halo, C1-C6 alkoxy) alkyl, C1-C6 alkoxy, v haloalkyl, and C1-C6 haloalkoxy, optionally substituted with), C3-C7-carbocyclyl, C1-C6-alkyl (halo, C1-C6 optionally substituted with alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl ), 5-10 membered heterocyclyl (halo, C1-C6 alkyl, C1-C6 alkoxy, C 1-C6 haloalkyl, and C1-C6 haloalkoxy optionally substituted), 5-10 membered heterocyclic Isocyclyl-C1-C6-alkyl (halo, C1-C6 alkyl, C1-C6 alkoxy) , optionally substituted with C1-C6 haloalkyl, substituted with C1-C6 haloalkoxy ), and 5-membered halocyclyl-(5-membered halocyclyl optionally substituted with halo, and halo optionally substituted with alkyl, C1-C6 alkyl, and haloalkoxy and C1-C6 haloalkoxy optionally substituted), aryl (halo, C1-C6 alkyl alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy optionally substituted with aryl(C1-C6)alkyl (halo, C1-C6 alkyl , C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. optionally substituted), 5-10 membered heteroaryl (halo, C1-C6 alkyl, C1-C6 Optionally substituted with alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy ), 5-10 membered heteroaryl(C1-C6) alkyl (halo, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl optionally substituted), halo, sia No, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6) alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1 -C6) alkyl (e.g., -CF3), halo(C1-C6) alkoxy (e.g., -O CF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6) ar Kyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl Mil, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carbo Oxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato one or more independently selected from nato, sulfinyl, sulfonyl, oxo (=O), etc. It means that a group is substituted with a substituent. When a group is described as being "substituted," In some embodiments, the group may be substituted with the substituents described above. The substituent(s) may be C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkoxy, amino, hydroxy and halogen The group is substituted with one or more substituents selected from the following:

[0028] As used herein, the term "thioester" refers to a compound in which a carboxylic acid and a thiol group are bonded to an ester. Structures in which the carbonyl carbon is bonded by a tert-bond, or the carbonyl carbon is bonded to a sulfur atom -C(=O)SR A R A is hydrogen, optionally substituted C 1-30 Archi C 2-30 alkenyl (branched or straight chain), optionally Substituted C 2-30 Alkynyl (branched or straight chain), or optionally substituted ring structures, e.g. Ba, C 6-10 Aryl, heteroaryl, carbocyclyl, cycloalkyl or hetero "Polyunsaturated fatty acid thioester" can include cyclyl. PC(=O)SR A refers to , where P is a polyunsaturated fatty acid as described herein.

[0029] As used herein, the term "amide" refers to a group having the structure -C(O)NR A R B and R A Reach BiR B and independently hydrogen, optionally substituted C 1-30 Alkyl (branched or straight chain), optionally substituted C 2-30 Alkenyl (branched or straight chain), optionally substituted Replaced C 2-30Alkynyl (branched or straight chain), or optionally substituted ring structures, e.g. , C 6-10 Aryl, heteroaryl, carbocyclyl, cycloalkyl or heterocyclyl "Polyunsaturated fatty acid amide" can be PC(=O)NR A R B Refers to the structure of where P is a polyunsaturated fatty acid as described herein.

[0030] As used herein, the term "salt" is a broad term. , should be given their ordinary and accustomed meaning to one of ordinary skill in the art (including special or customized (The term should not be limited to its intended meaning.)

[0031] Certain radical naming conventions allow for either mono- or di-radicals depending on the context. It is understood that a substituent may include any of the following: When two points of attachment are required, the substituent is understood to be a diradical. For example, 2 Substituents identified as alkyl requiring two points of attachment include -CH2-, -CH Examples of diradicals include -2CH2- and -CH2CH(CH3)CH2. The naming convention is that the radical is a diradical such as "alkylene" or "alkenylene". This clearly shows that

[0032] In any compound described herein that has one or more chiral centers, the absolute stereochemistry Unless the chemistry is explicitly indicated, each center may independently be in the R or S configuration, or It is understood that the compounds provided herein may be mixtures thereof. can be enantiomerically pure, enantiomerically enriched, or a stereoisomeric mixture. It may be present in any diastereomeric and enantiomeric form, including E or Z isomers, which may be defined as In any compound described herein, each double bond may independently be a mixture of E or Z. It is understood that stereoisomers may be obtained, if desired, by stereoselective synthesis and / or This can be achieved by methods such as the separation of stereoisomers on chiral chromatographic columns.

[0033] Likewise, all tautomeric forms of any compounds described are intended to be included. It is understood that this will be the case.

[0034] As used herein, "predominantly" refers to about 50% or more. In one embodiment, predominantly , about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95 %, 96%, 97%, 98%, 99%, or greater than 100%.

[0035] Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen," The position is understood to have hydrogen at its natural abundance isotopic composition. Unless a position is specifically designated as "D" or "deuterium", that position is 0. 0156% (i.e., at least 50% deuterium incorporation) More specifically, the position has deuterium at an abundance that is at least 3206 times greater than the natural At least 3500 times (54.6% deuterium incorporation), 4000 times (6 2.4% deuterium uptake), 4500 times (70.2% deuterium uptake), 5000 times (7 8% deuterium uptake), 5500 times (85.8% deuterium uptake), 6000 times (93. 6% deuterium uptake), 6090 times (95% deuterium uptake), 6250 times (97.5% deuterium uptake), 6346 times (99% deuterium uptake), or 6378 times (99.5% deuterium uptake) deuterium uptake).

[0036] As used herein, the term "isotopically-containing agent" refers to an isotope containing a deuterium or tritium atom. This refers to a compound that contains each atom in an abundance significantly higher than its natural abundance. In this case, it contains at least 3206 times the natural abundance of deuterium (i.e., at least In some further embodiments, the isotope-containing agent is at least At least 4000, 4500, 5000, 5500, 6000, 6090, 6250, 6 It has 346, or 6378 times the natural abundance of deuterium.

[0037] As used herein, the term "isotopic purity" of an isotopically containing agent does not include heavy atoms. The percentage of molecules containing a heavy atom (e.g., D or T) relative to the total number of molecules containing the molecule For example, if the isotope-containing agent is heavy water (i.e., DO) with 95% isotopic purity, For every 100 water molecules, there are 95 D2O molecules and 5 H2O molecules. In some instances, the isotopic purity of the isotope-containing agent is at least 50%, 65% or less. %, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% could be.

[0038] (Method of site-specific isotope modification) Conventional deuteration of molecules containing one alkene using transition metals as catalysts has been shown to be In most cases, the vinyl position (hydrogen atom connected to the double bond carbon atom) is selectively deuterated. Many alkenes contain double bonds with restricted mobility. The limited number of unrestricted alkenes gives rise to positional isomers, and cis-trans isomerization Any reports on H / D exchange involving polyunsaturated alkenes always involve a deuteration process. There was also a lack of notice.

[0039] Ru-based complexes (e.g., [Ru(Cp)(ACN)]±PF) were synthesized using a deuterium source, DO. 6 - (Cp = cyclopentadiene; Cp = acetonitrile) Selective and efficient deuteration of various polyalkenes (including PUFAs) at 1000 kJ / kg has been reported by the US International This Ru catalyst is described in the pamphlet of Publication No. 2017 / 091279. With deuteration efficiency of at least 95%, linolenic acid (LNN), arachidonic acid (ARA), and acetylcholine Cosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) or their esters H / D exchange (deuteration) was achieved at the bis-allylic position. Deuteration occurs at the mono-allylic position of these polyunsaturated fatty acids or their esters. However, linoleic acid (LIN) or alkyl esters (e.g., ethyl esters) When subjected to catalytic procedures using this Ru catalyst, only the mono-allylic moiety was obtained with approximately 95% efficiency. It was deuterated with

[0040] Without being bound by any theory, the LI The reason for this is that PUFA binds to a ruthenium center with two double bonds, and the D2O molecule This is thought to be due to the proposed mechanism of occupying the remaining coordination site (structure A, This structure consists of a heavy water molecule (making it more acidic) and a bound PUFA mono- and di-form. The next step is thought to be the activation of one or both bis-allylic sites. This occurs with the help of multiple additional DO molecules (B in Scheme 1), but the DO molecules bound together This occurs at the closer CH2 site, which is the site for LNN, ARA, EPA, and DHA. The bis-allylic moiety can be either mono- or bis-allylic, but the bis-allylic moiety is It appears that the deuteration process for FA is more favorable than the mono-allylic site. However, in the case of LIN, one bis- Only the allylic moiety is present (Structure A, Scheme 1). Therefore, this moiety is It may not be involved in the deuteration process. are the only mono-allylic sites of LIN, so these mono-allylic sites are actually deuterium It will be transformed. Scheme 1. Proposed mechanism of Ru-catalyzed H / D exchange process with PUFA [ka]

[0041] Based on this proposed mechanism, LIN is predominantly and exclusively loaded at the bis-allylic position. The following factors are considered to be important for hydrogenation: (1) LIN is A in Scheme 1; It must coordinate to a transition metal (e.g., ruthenium) in a manner similar to that shown in B or C. (2) The binding site of the isotope-containing agent (e.g., DO) to ruthenium is a monoallylic complex. To avoid hydrogenation, it must be occupied / blocked by another molecule; and (3 ) The DO present in the solution may need to be acidified. The presence of the ligand (Cp), or possibly some other cyclic ligand (e.g., benzene) It should also be noted that, may be important for overall deuteration. To achieve this result, several different approaches are used, as detailed below: It is suggested.

[0042] Some embodiments of the present disclosure include: A method for isotopic modification of polyunsaturated lipids, comprising: Reacting a polyunsaturated lipid with an isotope-containing agent in the presence of a transition metal catalyst to produce one or more A step of obtaining an isotope-modified polyunsaturated lipid having an isotope at the bis-allylic position of The isotope-containing agent is selected from the group consisting of deuterium, tritium, and combinations thereof. and the transition metal catalyst is represented by formula (I) or (II): having structure; [ML 1 (L 2 ) m (L 3 ) n ] p Q k (I) [ML l (L 2 ) m1 (L 3 ) n1 ]-L-[ML 1 (L 2 ) m2 (L 3 ) n2 ] q Q k (II) where M is rhodium, iridium, or ruthenium; L 1 is C3-C 10 Cycloalkenyl, C4-C 10 Cycloalkynyl, C6-C1 aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl, L 1 is an R of 1 or more A where L 1 is substituted with 1-10 members, Each L 2 are independently imine, carbene, carbonyl, alkene, alkyne, nitrile , isonitrile, acetonitrile, ether, thioether, phosphine, pyridine, C3-C arbitrarily substituted 10 Cycloalkenyl, optionally substituted C-C 10 Cycloa alkynyl, optionally substituted C6-C 10 Aryl, optionally substituted 5- to 10-membered heteroaryl and optionally substituted 3- to 10-membered heterocyclyl; Each L 3 are independently C1-C6 alkyl, NR 1 R 2 or C1-C6 alkoxy the law of nature, Each R 1 and R 2 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 cycloalkenyl, Optionally substituted C4-C 10 Cycloalkynyl, optionally substituted C-C 10 Ally optionally substituted 5- to 10-membered heteroaryl or optionally substituted 3- to 10-membered heteroaryl is cyclocyclyl, and each R 2 and R 2 independently, C2-C 10 Alkyl, optionally substituted C2-C6 aryl or optionally substituted C2-C7 aryl or optionally substituted C2-C 10 represents a heterocyclyl, Each R Aare independently selected from hydroxyl, halogen, cyano, nitro, and optionally substituted C 1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 haloalkyl, C1-C6 haloalkoxy or optionally substituted amino can be; L is C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene. is a m, m1, m2, n, n1, and n2 are independently integers of 1, 2, or 3; p and q are independently integers of 1, 2, 3, or 4; Q is an anion; and k is 0, 1, or 2. Methods for isotopic modification of polyunsaturated lipids.

[0043] In some embodiments of the transition metal catalyst of Formula (I) or (II), the transition metal catalyst The catalyst is a ruthenium (Ru) catalyst.

[0044] In some embodiments, the blocking of the isotope-containing agent (e.g., DO) coordination site is achieved by (a) sterically small, and therefore does not interfere with polyunsaturated lipid (e.g., PUFA) binding, and (b) a transition metal (e.g., ruthenium) to prevent substitution by the PUFA bond. This can be achieved by using ligands that bind strongly to the To this end, ligands such as alkyl, amino or alkoxy groups can be used. An embodiment of preparing such a catalyst is illustrated in Scheme 2 below. Scheme 2. Proposed synthesis of catalyst D and generation of the active species (D') [ka]

[0045] Catalyst D blocks deuteration at the monoallylic position when LIN is added (i.e. , formation of D'), simultaneously activating the bis-allylic position, and if the acidity of the medium is appropriate, However, compounds D and D' are neutral compounds. The neutral form of the hydroxyl group affects their solubility and / or catalytic ability in the overall reaction medium. There is a possibility that this may occur.

[0046] The neutral transition metal catalyst (e.g., catalyst D) is incompatible with the reaction mixture and / or If the effect is insufficient, cationic analogs of the catalysts can be used. In embodiments, benzene ligands are used to replace cyclopentadiene (Cp). This ligand switch can be used to keep the overall charge of the complex positive. An embodiment of the synthesis of the catalyst is illustrated in Scheme 3 below. Scheme 3. Proposed synthesis of cationic Ru catalyst [ka]

[0047] In some embodiments, altering the acidity of the catalyst improves reaction efficiency. In some such embodiments, a Lewis acid can be used to remove a portion of the catalyst. The tethering process can be carried out in a solvent. This can potentially reduce the amount of Lewis acid required to acidify the solution, which The tethered fragment comes into close proximity to activated (i.e., Ru-bound) LIN. This is because the catalysts are arranged in such a manner. Examples of such catalysts (catalysts F and F') are shown below. do. [ka]

[0048] Alternatively, a binuclear catalyst system of formula (II) may also be used in the methods described herein. The embodiment of deuteration of linoleic acid in the presence of heavy water using a binuclear Ru catalyst can be described as follows: This is shown in Scheme 4. In this embodiment, one of the Ru centers (left side) is bound only to DO. The other (right) has two sites blocked by ligands (i.e., ERn) that allow Only one site is blocked, allowing LIN to bind. Scheme 4. Dinuclear Ru-catalyzed deuteration of LIN [ka]

[0049] In some embodiments of the transition metal catalyst of Formula (I) or (II), L 1 is C 3-C 10 Cycloalkenyl or C6-C 10 aryl, each of which is one or more R A In one embodiment, L 1 is unsubstituted cyclopentadienyl (C p). In another embodiment, L 1 is one R A Substituted cyclopentadienes having In another embodiment, L 1 is unsubstituted benzene. L 1 is one R A In some further embodiments, the substituted benzene has the formula: L 1 is C3-C 10 Cycloalkenyl or C6-C 10 aryl, and One or more R AIn some such embodiments, R A teeth , C1-C6 alkyl substituted with a Lewis acid. In some further embodiments, Te, R A is C1-C6 alkyl, and B(R 3 )2, and each R 3 are independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or any arbitrarily substituted C6-C 10 In some further embodiments, R A is C1-C6 substituted with B(C6H5)2.

[0050] In some embodiments of the transition metal catalyst of Formula (I) or (II), each L 2 is independently a nitrile, an isonitrile, an acetonitrile, or a phosphine. In some embodiments, each L 2 is acetonitrile (CH3CN). In some embodiments, at least one L 2 is P(R 4 )3 phosphine, So, each R 4 are independently optionally substituted, C 1-6 Alkyl, C 3-8 Shik alkyl, 4-10 membered heteroaryl, C 6-10 Some further In some embodiments, P(R 4 )3 is P(t-Bu)2(C6H5). In the embodiment of P(R 4 )3 is 4-(tert-butyl)-2-(diisopropyl) In some embodiments, each L 2are independently acetonitrile or optionally substituted cyclopentadienyl .

[0051] In some embodiments of the transition metal catalyst of Formula (I) or (II), L 3 is N (CH3)2.

[0052] In some embodiments of the transition metal catalyst of Formula (I), m is 1 or 2. In some embodiments, n is 2 or 1. In some further embodiments, , m+n=3. In some embodiments of the transition metal catalyst of Formula (II), m Each of 1 and m2 is 1 or 2. In some embodiments, n1 and n2 is 2 or 1. In some further embodiments, m1+n1=3 and / or m2+n2=3.

[0053] In some embodiments of the transition metal catalyst of Formula (I) or (II), k is 0. In some other embodiments, k is 1. In some such embodiments, Q is PF6 - , Cl - ,F - ,I - ,Br - , NO3 - , ClO4 - , BF4 - , B(C1-C4 alkyl)4 - , Al(C1-C4 alkyl)4 - , B(C6-C 10 a Lil)4 - , Al(PF6 - Allyl) - , F - , I - , Br - , NO3 - , or Carbora In one embodiment, Q is an anion having a single negative charge, such as PF6 - In such embodiments, p and / or q are 1. In this state, Q is an anion with a double negative charge, e.g., SO4 2- Such a reality In an embodiment, p or q is 2.

[0054] Additional ligands that may be used in the transition metal catalysts described herein include azathioprine, azides ... The amine ligands may be monodentate or polydentate and include monoamines, diamines, Monoamines can have the formula N(Rb)2. Exemplary monoamines include dialkyl monoamines (e.g., di-ra-butylamine). amines (e.g., N,N-dimethylbutylamine, or DBA) and trialkylmonoamines (e.g., N,N-dimethylbutylamine Suitable dialkyl monoamines include, but are not limited to, dialkyl amines such as dimethyl amine (DMBA), ... Di-ra-propylamine, di-ra-butylamine, di-sec-butylamine , di-tert-butylamine, dipentylamine, dihexylamine, diectylamine dibenzylamine, dibenzylamine, methylethylamine, methylbutylamine, Dicyclohexylamine, N-phenylethanolamine, N-(p-methyl)phenyl Ethanolamine, N-(2,6-dimethyl)phenylethanolamine, N-(p-chloroethanolamine) (Iro)phenylethanolamine, N-ethylaniline, N-butylaniline, N-methyl N-methyl-2,6-dimethylaniline, diphenylamine, etc. Suitable trialkylmonoamines include trialkylaminos, ... Trimethylamine, triethylamine, tripropylamine, tributylamine, butyldiamine methylamine, phenyldiethylamine, and the like, and combinations thereof. Amines have the chemical formula (R b )2N-R a -N(R b ) 2, and exemplary Zia The amine is an alkylene such as N,N'-di-yli-butylethylenediamine or DBEDA. Triamines refer to organic molecules with three amine moieties. Diethylenetriamine (DETA), guanidine HCl, tetramethylguanidine, etc. For both monoamines and diamines, R a is a substituted or unsubstituted divalent residue; each R b are independently hydrogen, C1-C 8 alkyl, or C 6-10 In some examples of the above formula, two or Three aliphatic carbon atoms form the closest bond between the two diamine nitrogen atoms. The alkylenediamine ligands include R a is dimethylene (-CH2CH2-) or trimethylene An example is ethylene (-CH2CH2CH2-). b are independently hydrogen, methyl, propyl, isopropyl, butyl, or C4-C8 α-tertiary alkyl group In some embodiments, the diamine can be ethylenediamine. In embodiments, the triamine may be diethylenetriamine.

[0055] The alkylenediamine ligands can be monodentate or polydentate, examples of which include N,N', N'-Tetramethylethylenediamine (TMED), N,N'-di-tert-butyl ether Diethylenediamine (DBEDA), N,N',N'-tetramethyl 1-1,3-diaminopropane propane (TMPDA), N-methyl-1,3-diaminopropane, N,N'-dimethyl- 1,3-Diaminopropane, N,N,N'-dimethyl 1-1,3-diaminopropane, N -Ethyl 1,3-diaminopropane, N-methyl 1,4-diaminobutane, N,N'-trimethyl Trimethyl 1,4-diaminobutane, N,N,N'-trimethyl-1,4-diaminobutane , N,N'-tetramethyl 1,4-diaminobutane is N,N,N',N'-tetramethyl 1-1,4,4-Diaminobutane, N,N,N',N'-tetramethyl 1-1,5-diamin In some embodiments, the amine ligand is a diamine, a methylamine, a methylpentane ... -tera-butylamine (DBA), N,N-dimethylbutylamine (DMBA), N,N' -di-tert-butylethylenediamine (DBEDA), and combinations thereof be selected.

[0056] Additional further ligands for use in the transition metal catalysts described herein include: Alkene ligands include amines. The alkene ligands described herein may be monodentate or polydentate. and includes molecules having at least one non-aromatic carbon-carbon double bond, Examples of alkene ligands include, but are not limited to, kenes and dialkenes. Examples of the olefins include ethylene, propylene, butene, hexene, decene, and butadiene. It is possible.

[0057] The isonitrile ligands described herein, also known as isocyanides, are at least one It refers to molecules having two -NC moieties, which can be monodentate or polydentate, and includes monoisonitriles and diisonitriles. Isonitrile ligands include, but are not limited to, monoisonitrile and diisonitrile. An example of a rule is C 1-10 alkyl-NC and CN-R-NC. Without being limited thereto, R is C 1-10 Alkylene, t-butyl-NC, methyl-NC, PhP( O)(OCH2CH(t-Bu)NC)2, PhP(O)(OCH2CH(Bn)NC) 2, PhP(O)(OCH2CH(i-Pr)NC)2, PhP(O)(OCH2CH( Further isonitrile ligands include those described by Naik et al., Chem. .Commun.,2010,46,4475-4477, which is referred to as and is hereby incorporated by reference in its entirety.

[0058] The nitrile ligands described herein are molecules having at least one -CN moiety. It refers to ligands which may be monodentate or polydentate and include monoisonitrile and diisonitrile ligands. Examples of monoisonitriles and diisonitriles include, but are not limited to, C 1-10 a Examples include, but are not limited to, alkyl-CN and CN-R-CN, where R is C 1-10 a alkylene, acetonitrile, 1,3,5-cyclohexanetricarbonitrile, propionyl Nitrile, butyronitrile, glutaronitrile, pivalonitrile, capronitrile, (C (H2)3CN, (CH2)4CN, (CH2)5CN. Further nitrile ligands are , Lee et al., Inorganic and Nuclear Chemistry le It can be found in tters, v10, 10 (Oct 1974) pp. 895-898, which is incorporated herein by reference in its entirety.

[0059] The ether ligands described herein are molecules having at least one ROR moiety. wherein each R is independently an alkyl or aryl group, and is monodentate or polydentate. The resulting ligands include monoether, diether, and triether ligands. Examples of ethers, triethers, and other suitable ethers include dimethyl ether, diethyl ether, ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, polyethylene glycol, and anisole, Not limited to.

[0060] The thioether ligands described herein have at least one RSR moiety. where each R is independently an alkyl or aryl group, and may be monodentate or polydentate. and include monothioether, dithioether, and trithioether ligands. Examples of thioethers, dithioethers, and trithioethers include dimethyl sulfide, Examples include, but are not limited to, methyl phenyl sulfide.

[0061] The imine ligands described herein have at least one carbon-nitrogen double bond moiety. It refers to molecules that contain mono- or polydentate ligands, including monoimine, diimine, and triimine ligands. Examples of imine ligands include, but are not limited to, 1,2-ethanediimine, Imidazolin-2-imine, 1,2-diketimine, dimethylglyoxime, o-phenylene diamine, 1,3-diketimine, and glyoxal-bis(mesitylimine ( me s itylimine)) is one example.

[0062] The carbene ligands described herein, when not coordinated to a metal, have in their valence shell This definition refers to a compound that has at least one divalent carbon atom with only six electrons. is not limited to metal-carbene complexes synthesized from carbenes, but rather to metal-bound This definition is intended to address the orbital structure and electron distribution associated with the carbon atom. Although the "carbene" does not technically have to be divalent if it is bonded to a metal, Many such compounds are initially classified as divalent. It is synthesized by synthesizing rubene and then bonding it to a metal, but this definition This includes compounds synthesized by other methods that have similar orbital structures and electron configurations. Lowry & Richardson, Mechanism and Th eory in Organic Chemistry 256(Harper&Row , 1976) defined "carbene" in a manner consistent with how the term is used herein. The carbene ligands described herein include monocarbenes, dicarbenes, and tricarbenes. Examples of carbene ligands include 1,10-dimethyl-3,30-methylenediamine. Midazoline-2,20-diylidene, 1,10-dimethyl-3,30-ethylenediimidazoline Zoline-2,20-diylidene, 1,10-dimethyl-3,30-propylenediimidazo Phosphorus-2,20-diylidene, 1,10-dimethyl-1-3,30-methylenediimidazol 1,10-dimethyl-1,3,30-ethylenediimidazoline -2,20-diylidene, 1,10-dimethyl-3,30-propylenediimidazoline- 2,20-diylidene, [ka] and n is 1, 2, or 3, and [ka] Additional carbene ligands are described by Huynh et al., Journal of Organome tallic chemistry,v696,21,(October 2011), p.3369-33'75, and Malty et al., Chem. Commun., 2013 ,49,101-101, which are incorporated herein by reference in their entireties. To be incorporated.

[0063] The pyridine ligands described herein are molecules having at least one pyridine ring moiety. It refers to a pyridine, and can include monopyridine, dipyridine, and tripyridine ligands. Examples of the aryl ligands include 2,2'-bipyridine and 2,6-di(2-pyridyl)pyridine. These include, but are not limited to:

[0064] The phosphine ligands described herein comprise at least one P(R 4 )3 Each R 4 is hydrogen, optionally substituted C 1-15 Alkyl, optionally substituted TaC 3-8 Cycloalkyl, optionally substituted C6-15 aryl, and optionally substituted The phosphine ligand is independently selected from the group consisting of: Suitable phosphines include monophosphines, bisphosphines, and trisphosphines. Sphine ligands include PH3, trimethylphosphine, triphenylphosphine, and methyl diphenylphosphine, trifluorophosphine, trimethyl phosphite, triphenyl Nyl phosphite, tricyclohexylphosphine, dimethylphosphinomethane (DMP m), dimethylphosphinoethane (dmpe), PROPHOS, PAMP, DIPAM P, DIOP, DuPHOS, P(tBu)2Ph, 1,2-B is (diphenylphosphine ethane (dppe), 1,1'-B is (diphenylphosphino)ferrocene (dpp f), 4-(tert-butyl)-2-(diisopropylphosphane y1)-1H-imino Examples include, but are not limited to, dazole, P(t-Bu)2(C6H5).

[0065] In some embodiments of the methods described herein, the isotope-containing agent is DO, DO(C 1-C 12 alkyl) (e.g., DOCH3 or DOCD3), TO, or TO(C1 -C 12 alkyl) (e.g., TOCH3 or TOCT3), or a combination thereof .

[0066] (reaction medium) In some embodiments of the methods described herein, a polyunsaturated lipid is combined with an isotope-containing agent. The reaction is carried out in an acidic reaction medium, such as an aqueous acidic solution, an acidic solvent, or an acidic solvent mixture, or In some embodiments, the reaction medium is acetone, Methanol, ethanol, 1-propanol, isopropanol, 2-butanol, 1, 4-Dioxane, acetonitrile, dichloromethane (DCM), toluene, dimethyl sulfone HCl, DMSO, acetic acid, dimethyl carbonate, ethyl acetate, ether, ethylene glycol, or N-methyl-2-pyrrolidone (NMP), and combinations thereof In some such embodiments, the solvent may include one or more solvents selected from the group consisting of: In embodiments, the reaction medium comprises deuterium oxide (DO). In some such embodiments, an acid the reactive medium is selected from the group consisting of organic acids, inorganic acids, Lewis acids, and combinations thereof; For example, acidification with heavy water may be performed to provide a Lewis acid to the entire reaction solution. This can be done by introducing either an acid or a certain amount of DCl (deuterium chloride). The level of acidity determines the ability of the system to perform deuteration and the stability of the catalyst in this acidified solution. The presence of C1 is a key factor in determining whether or not the cations are bonded to transition metals such as ruthenium. In such cases, Lewis acids may be present. (e.g., B(C6F5)3) is highly unlikely to interfere with catalytic function, It can be more attractive.

[0067] (polyunsaturated lipids) In some embodiments, the polyunsaturated lipid is a fatty acid, a fatty acid ester, a fatty acid thioester, or a hydroxyl group. esters, fatty acid amides, fatty acid phosphates, or phospholipid derivatives of fatty acids, or combinations thereof In some further embodiments, the phospholipid comprises a carboxyl group of a fatty acid. After esterification or amidation reaction of the hydroxyl or amino groups of the phospholipid with the polyunsaturated fatty acid, In some such embodiments, the polyunsaturated lipid contains saturated fatty acid residues. or more carbon-carbon double bonds (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 In some further embodiments, the polyunsaturated lipid may have a carbon-carbon double bond. , omega-3 fatty acids, omega-6 fatty acids, or omega-9 fatty acids, or their esters, amides, thioesters In some embodiments, the fatty acid is a polyunsaturated fatty acid, a ester, a phosphoric acid, or a phospholipid derivative. The quality is linoleic acid, linolenic acid, gamma-linolenic acid, dihomogamma-linolenic acid, arachidonic acid carboxylic acid, eicosapentaenoic acid, docosahexaenoic acid, or their esters. In some further embodiments, the polyunsaturated fatty acid ester is an alkyl ester, a triglyceride ester, or a hydroxyl ester. The glyceride may be a glyceride, a diglyceride, or a monoglyceride.

[0068] In some embodiments of the methods described herein, the polyunsaturated lipid is one or more In some such embodiments, the polyunsaturated The lipid is deuterated at all bis-allylic positions. Polyunsaturated lipids are further deuterated at one or more monoallylic positions. In embodiments, the deuterated polyunsaturated lipid is deuterated linoleic acid, deuterated linolenic acid, deuterated Hydrogenated arachidonic acid, deuterated eicosapentaenoic acid, deuterated docosahexaenoic acid, or are salts or esters thereof. In some further embodiments, the ester is an alkyl ester, a triglyceride, a diglyceride, or a monoglyceride. In a further embodiment, the ester is an ethyl ester.

[0069] In some embodiments, the polyunsaturated lipid has the formula (III): [ka] Each R 5 are independently H, optionally substituted C-C 21 Alkyl, optionally substituted Replaced C2-C 21 Alkenyl, optionally substituted C-C 21 Alkynyl, optionally substituted Replaced C3-C 10 Cycloalkyl, optionally substituted C-C10 aryl, optionally substituted 4- to 10-membered heteroaryl, optionally substituted 3- to 10-membered heterocyclyl, is a sugar, disaccharide, or oligosaccharide; R 6a and R 6b each independently represents H, an optionally substituted —C(═O)C— C 21 Alkyl, optionally substituted -C(=O)C-C 21 alkenyl, or optionally substituted Replaced -C(=O)C2-C 21 is alkynyl; R 7 and R 8 each independently represents H, optionally substituted C-C 21 Alkyl, Optionally substituted C2-C 21 Alkenyl, optionally substituted C-C 21 Alkynyl, Optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Aryl , optionally substituted 4- to 10-membered heteroaryl, or optionally substituted 3- to 10-membered heteroaryl Cyclyl; or R 7 and R 8 together with the nitrogen atom to which they are attached, forming a 3- to 10-membered heterocyclyl; Each R 9 are independently optionally substituted C-C 21 Alkynyl, optionally substituted C2-C 21 Alkynyl, optionally substituted C-C 21 is alkynyl; Each R 10 are independently H, [ka] -CH2CH2NH2,-CH2CH2NH3 +,-CH2CH(NH2)C(=O)O - , -CH2CH(OH)CH2OH, a monosaccharide, disaccharide, or oligosaccharide; R 11 is an optionally substituted C8-C 21 Alkynyl, optionally substituted C8-C 21 Alkynyl or optionally substituted C-C 21 is alkynyl; R 12 H, [ka] a monosaccharide, disaccharide, or oligosaccharide, p and q are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. is.

[0070] In some embodiments of the polyunsaturated lipid of formula (III), R is methyl, C In other embodiments, the alkyl group is C4 alkyl, or C7 alkyl, each of which is optionally substituted. wherein R is unsubstituted.

[0071] In some embodiments, the method comprises providing a compound represented by formula (IIIa), wherein R is n-bromo-3-methyl-2-methyl-1-propanol. , p=1, and q=6), resulting in deuterated linoleic acid or its derivative: [ka] In some such embodiments, one or both of the Y's is D. In some embodiments, each X is H. In other embodiments, at least one X is In some such embodiments, R' is -OR 5 where R 5 is H or optionally substituted C-C 21 In one embodiment, R 5teeth, In one such embodiment, the deuterated polyunsaturated lipid is 11,11-D ethyl. 2-Linoleic acid (D2-Lin), its pharmaceutically acceptable salts, or its ethyl esters is.

[0072] In some embodiments, the method comprises providing a compound represented by formula (IIIb), wherein R is methyl , p=2, and q=6), resulting in a deuterated linoleic acid or derivative thereof: [ka] In some such embodiments, at least one Y is D. In some further embodiments, each Y is D. In some further embodiments, each X is H. In other embodiments, at least one of X is D. In the form R' is -OR 5 wherein R5 is H or optionally substituted C1- C 21 In one embodiment, R 5 is ethyl. In one such embodiment, , deuterated polyunsaturated lipid 11,11,14,14-D4-linolenic acid, its pharmaceutical an acceptable salt, or its ethyl ester.

[0073] In some embodiments, the method comprises providing a compound represented by formula (IIIc), wherein R is n-bromo-3-methyl-2-methyl-1-propanol. , p=3, and q=2) to yield deuterated arachidonic acid or a derivative thereof: [ka] In some such embodiments, at least one Y is D. In some further embodiments, each Y is D. In some further embodiments, each X is H. In other embodiments, at least one of X is D. In the form R' is -OR 5 where R 5 is H or optionally substituted C1- C 21 In one embodiment, R 5 is ethyl. In one such embodiment, , deuterated polyunsaturated lipids include 7,7,10,10,13,13-D6-arachidonic acid, a pharmaceutically acceptable salt thereof, or an ethyl ester thereof.

[0074] In some embodiments, the method comprises administering to a subject a compound of formula (I) comprising deuterated eicosapentaenoic acid or a compound of formula (I) IId) (wherein R is methyl, p=4, and q=2) Result: [ka] In some such embodiments, at least one Y is D. In some further embodiments, each Y is D. In some further embodiments, each X is H. In other embodiments, at least one of X is D. In the form R' is -OR 5 where R 5 is H or optionally substituted C1- C 21 In one embodiment, R 5 is ethyl. In one such embodiment, The deuterated polyunsaturated lipids are 7,7,10,10,13,13,16,16-D8-enantiomers. Eicosapentaenoic acid, a pharmaceutically acceptable salt thereof, or an ethyl ester thereof.

[0075] In some embodiments, the method comprises providing deuterated docosahexaenoic acid or a compound of formula (I) IIe) (wherein R is methyl, p=5, and q=1) Result: [ka] In some such embodiments, at least one Y is D. In further embodiments, each Y is D. In some further embodiments, Each X is H. In other embodiments, at least one X is D. In such embodiments, R' is -OR 5 where R 5 is H or optionally Substituted C1-C 21 In one embodiment, R 5 is ethyl. In one embodiment, the deuterated polyunsaturated lipid is 6,6,9,9,12,12,15,1 5,18,18-D10-docosahexaenoic acid, its pharmaceutically acceptable salts, or its esters It is a methyl ester.

[0076] In another embodiment of the polyunsaturated lipid of formula (III), the polyunsaturated lipid is a glycerin. It is in the form of a diester, where R' = -O(CH2)CH(OR 6a )CH 2 (O R 6b ) R 6a and R 6b When each of is H, such an ester is Monoglyceride, R 6a and R 6b If only one of the two is H, then such an R is a diglyceride. 6a MoR 6b If neither of the groups is H, such an ester is It is a triglyceride.

[0077] (mixture of deuterated polyunsaturated lipids) In some embodiments, the catalytic methods described herein involve the use of the polyvalent non-ionic surfactants described herein. In some such embodiments, at least one of the saturated lipids in the mixture is Another polyunsaturated lipid is deuterated at all bis-allylic positions. In some embodiments, one or more polyunsaturated lipids in the mixture are one or more monounsaturated lipids. In another embodiment, the polyunsaturated lipids in the mixture are further deuterated at the aryl position. None of the compounds are deuterated at one or more monoallylic positions. In the present invention, the mixture of polyunsaturated lipids is the same fatty acid or its derivative as described herein. The only difference between the various species is the bis-allylic and / or mono- The number of deuterium atoms at the allylic positions. For example, if the mixture contains deuterated linolenic acid, It is a linolenic acid containing one to four deuterium atoms in the bis-allylic positions, such as the following species: Various species of acids can include: [ka]

[0078] Similarly, if the mixture contains species of deuterated linoleic acid or its derivatives, the mixture may be - containing one or two deuterium atoms in the allylic position, or various bis-allylic and mono- Various species of linoleic acid containing one of one to six deuterium atoms in the no-allylic position If the mixture contains a species of deuterated arachidonic acid or a derivative thereof, In this case, the mixture contains 1 to 6 deuterium atoms in the bis-allylic positions or various bis- Arachidonic acid containing one of 1 to 10 deuterium atoms at the allylic and mono-allylic positions The mixture may contain a combination of various species of eicosapentaenoic acid. or derivative species, the mixture contains 1 to 8 deuterium atoms in bis-allylic positions. or 1 to 12 deuterium atoms in various bis-allylic and mono-allylic positions. It may also contain a combination of various species of eicosapentaenoic acid containing any one of the When the mixture contains a species of deuterated docosahexaenoic acid or its derivative, the mixture is called a bis- containing 1 to 10 deuterium atoms in the allylic positions, or various bis-allylic and mono-allylic positions. Various docosahexaenoic acids containing one of 1 to 14 deuterium atoms at the aryl position In some further embodiments, the method may comprise a combination of species. In some such embodiments, a deuterated product is produced at the bis-allylic position. This method allows for the following: 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7% at the monoallylic position , 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or less than 0.1% deuteration This produces a deuterated product.

[0079] In some embodiments of the mixture of polyunsaturated lipids described herein, the method further comprises reacting is completed, at least 50%, e.g., at least 50%, 55% at the bis-allylic position , 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% weight In some further embodiments, a mixture having a degree of deuteration is produced. is at least 70% at the bis-allylic positions. "Degree of deuteration" refers to the bis-aryl of a compound compared to the same compound without deuteration. This refers to the percentage of deuterium atoms in the allylic and / or mono-allylic positions. may be calculated as: Degree of deuteration at bis-allylic positions (%) = Number of deuterium atoms at bis-allylic positions of compound / Compound The total number of hydrogen and deuterium atoms in the bis-allylic positions of the compound

[0080] A mixture containing deuterated compounds with various degrees of deuteration (e.g., 33. a mixture containing equal amounts of compounds A and B, with deuteration degrees of 3% and 66.7% Thus, the total or combined deuteration degree of the mixture can be calculated as follows: Compound A * Mole percentage of deuteration + Compound B * Mole percentage of deuteration

[0081] For example, if the product mixture contains the following three compounds in equimolar amounts: [ka] The degree of deuteration at the bis-allylic position is 66.7%. A more practical method is to use the proton-carbon 13 NMR bis-allylic peak integration Measurement (proton-carbon 13 NMR bis-allylic peak integration measurements) and reliance on mass spectrometry is.

[0082] (composition) Some embodiments include one or more bis-allylic isotopes having isotopes predominantly at one or more bis-allylic positions. A composition comprising a plurality of isotopically modified polyunsaturated lipids, wherein the isotopically modified polyunsaturated lipids are In some embodiments, the isotope is deuterium. In some embodiments, the isotope is tritium.

[0083] In some embodiments, the isotopically modified polyunsaturated lipid in the compositions described herein is It is deuterated primarily at the bis-allylic moiety. The composition contains polyunsaturated lipids having two or more carbon-carbon double bonds. In some embodiments, the compositions described herein have three or more carbon-carbon double bonds. Contains polyunsaturated lipids.

[0084] When one of the two hydrogens in a methylene group is replaced by a deuterium atom, the resulting compound It will be readily understood that compounds may have stereocenters. In some embodiments, it may be desirable to use a racemic compound. In a further embodiment, it may be desirable to use pure compounds. It may be desirable to use rheomerically pure compounds. is approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50 %, 65%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, if Mixtures of compounds with enantiomeric and / or diastereomeric excess of 100% or less or use a range bounded by any two of the aforementioned percentages. In some embodiments, the stereochemically pure enantiomers of the embodiments may be It may be preferable to utilize thiomers and / or diastereomers, e.g., This is where elementary reactions or contact with chiral molecules are targeted to attenuate oxidative damage. However, in many situations, non-enzymatic processes and / or non-chiral molecules are required to produce the acid In such situations, embodiments may be used to target these Furthermore, in some embodiments, Therefore, the mixture of enantiomers and diastereomers indicates that the compound attenuates oxidative damage. It can even be used to target enzymatic reactions and / or chiral molecules for

[0085] In some embodiments, the isotopically modified compounds attach a certain amount of heavy atoms to a particular tissue upon administration. Thus, in some embodiments, the amount of a heavy molecule is proportional to the amount of the same type of molecule in the tissue. For example, the percentage of heavy molecules is the percentage of the same type in the tissue. of molecules (i.e., natural as opposed to isotopically modified) at least about 0. 001%, 0.005%, 0.1%, 1%, 10%, 20%, 30%, 40%, or 50 % can be.

[0086] Use of the treatment method Some embodiments comprise one or more isotopically modified polyunsaturated lipids or The method comprises administering to a subject an effective amount of a pharmaceutically acceptable salt thereof. for treating, ameliorating, or preventing diseases or conditions associated with lipid peroxidation or lipid autooxidation in mammals In some embodiments, the administered isotopically modified polyunsaturated lipid is The total amount of fats, fatty acids, and fatty acid esters administered to or ingested by a subject Some further examples include about 1% to about 99%, about 1% to about 10%, or about 1% to about 5% of the amount. In some embodiments, one or more isotopically modified polyunsaturated lipids described herein or their Pharmaceutically acceptable salts may be used in conjunction with fats, fats, or fats administered to or ingested by a subject. Constitutes less than about 5%, less than about 2%, or less than about 1% of the total amount of acids and fatty acid esters.

[0087] In some embodiments described herein, the disease or condition is a neurological condition or In some further embodiments, the neurological condition is Alzheimer's disease. Parkinson's disease, mild cognitive impairment, frontal lobar degeneration, amyotrophic lateral sclerosis, ataxia ( Friedreich's ataxia, Down's syndrome, epilepsy, Huntington's disease, infantile neuroaxonal dystonia Roffey's disease (INAD), Alpers' disease, schizophrenia, Wilson's disease, cerebral iron accumulation neurodegeneration Neuropathy (NBIA), Progressive Supranuclear Palsy (PSP), Multiple Sclerosis, Creutzfeldt-Jakob Disease Buer's disease, Duchenne muscular dystrophy, Smith-Lemli-Opitz syndrome (SLOS) , Rett syndrome, Gaucher type 2, or Angelman syndrome. In embodiments, the present invention relates to a neurodegenerative disease or condition associated with a tauopathy, such as argyrophilia. Glehn-Guerin disease (AGD), chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD) D), Frontotemporal Dementia and Parkinsonism Related to Chromosome 17 (FTDP-17), God Gangliomas, ganglioneuromas, lipofuscinosis, lithovodig's disease, meningioangiomatosis, pantothenic acidosis Acid kinase-associated neurodegeneration (PKAN), Pick's disease, hindbrain parkinsonism, primary aging Patients with tauopathy (PART), Steele-Richardson-Olsewski syndrome (SR) OS), and subacute sclerosing panencephalitis (SSPE).

[0088] In some embodiments described herein, the disease or condition is a lysosomal storage disorder. In some further embodiments, the lysosomal storage disease is Batten disease, Ni Coeman-Pick disease, Tay-Sachs disease, Sandhoff disease, or vitamin E deficiency Ataxia with AVED.

[0089] In some embodiments described herein, the disease or condition is a retinal condition. In some further embodiments, the retinal condition is retinitis pigmentosa, age-related macular degeneration, or vitreous edema. Diabetic retinopathy, Leber's hereditary optic neuropathy (LHON), Leber's congenital amaurosis, yellow eye syndrome Macular telangiectasia, Stargardt's disease, glaucoma, optic neuropathy, or ophthalmoplegia.

[0090] In some embodiments described herein, the disease or condition is pain. In some further embodiments, the pain is acute pain; neurogenic inflammation; chronic pain; dynamic, mechanical or is thermal allodynia (pain resulting from a stimulus that is not normally painful); or a response to a painful stimulus Increased sensitivity to pain (hyperalgesia, fibromyalgia, and activation of TRPA1 receptors).

[0091] In some embodiments described herein, the disease or condition is a sleep disorder. Non-limiting examples of harm include lifestyle-related sleep deprivation; alcohol-related sleep deprivation; idiopathic sleep deprivation; Hypersomnia; narcolepsy; various sleep apnea disorders; various parasomnias; restlessness Lower limb syndrome; sleep state misperception; mood disorders such as depression; anxiety disorders; panic; schizophrenia any psychiatric illness; and circadian rhythm-related sleep disorders, including jet lag-related disorders and night shift-related conditions Harm may be mentioned.

[0092] In some embodiments described herein, the disease or condition is an energy processing disorder or Mitochondrial deficiencies, e.g., coenzyme Q deficiency, mitochondrial complex IV deficiency Diabetes and Deafness (DAD); Maternally Inherited Diabetes and Deafness (MIDD); Barth Syndrome; Kearns-Sayre syndrome (KSS); mitochondrial myopathy; mitochondrial Dorian encephalopathy, lactic acidosis; stroke-like episodes (MELAS); mitochondrial degeneration Transgastrointestinal encephalomyopathies (MNGIE); Myoclonic epilepsy (MERRF) syndrome, Myoneuropathies MNGIE and neuropathy, Wolff-Parkinson-White syndrome and other cardiomyopathy, X-linked adrenoleukodystrophy (X- ALD), musculoskeletal disorders (lipid myopathy, chronic fatigue, fibromyalgia), kidney (Funko Knee syndrome, glomerular nephropathy), blood (Pearson syndrome, sideroblastic anemia), brain (migraine, seizures) , cerebral infarction).

[0093] In some embodiments described herein, the disease or condition is liver damage. Non-limiting examples of harm include alcoholic fatty liver disease, non-alcoholic fatty liver disease, Liver disease, steatohepatitis, cirrhosis, hepatocellular carcinoma, obstructive jaundice, cholelithiasis, or biliary tract disease. do.

[0094] In some embodiments described herein, the disease or condition is hyperlipidemia or cardiopathy. Heart-related conditions, e.g., lipo-dysregulation, lipotoxicity, ischemic heart disease, hypertension, atrial fibrillation, left ventricular ventricular hypertrophy, coronary artery disease, or atherosclerosis.

[0095] In some further embodiments, at least some amount of the isotopically modified polyunsaturated lipid is The compound introduced into the subject's body is a natural (undeuterated) polyunsaturated fatty acid or sufficient to reduce or prevent lipid autoxidation of the ester in the subject's body after administration. In some embodiments, the method also reduces ferroptosis. .

[0096] (Pharmaceutical composition) Some embodiments include (a) an effective amount of one or more isotopically modified polynucleotides described herein. (b) a pharmaceutically acceptable carrier, diluent, or a pharmaceutically acceptable salt thereof; In some embodiments, the pharmaceutical composition includes a diluent, an excipient, or a combination thereof. In some embodiments, the polyunsaturated lipid is 11,11-D2-linoleic acid or its ester. In an embodiment, the polyunsaturated lipid is 11,11-D2-linoleic acid ethyl ester.

[0097] It is also contemplated that it may be useful to formulate polyunsaturated lipids as salt forms. For example, the use of salt formation as a means of adjusting the properties of pharmaceutical compounds is well known. l et al., Handbook of pharmaceutical salts:Prop erties, selection and use (2002)Weinheim / Zurich:Wiley-VCH / VHCA;Gould,Saltselectio n for basic drugs,Int.J.Pharm(1986),33:2 See 01-217. Salt formation may increase or decrease solubility and therefore improve stability or toxicity. It can be used to improve the hygroscopicity of the formulation and to reduce the hygroscopicity of the formulation.

[0098] Formulations of polyunsaturated lipids as salts include basic inorganic salt formers, basic organic salt formers, and and the use of salt forming agents containing both acidic and basic functional groups. Various useful inorganic bases for forming salts include, but are not limited to: , such as salts of lithium, sodium, potassium rubidium, cesium, and francium. Alkali metal salts, as well as beryllium, magnesium, calcium, strontium, Examples include alkaline earth metal salts such as ammonium and radium, and metals such as aluminum. These inorganic bases may further contain counter ions, such as carbonate, bicarbonate, sulfur, etc. Acid salts, hydrogen sulfates, sulfites, bisulfites, phosphates, hydrogen phosphates, dihydrogen phosphates , phosphates, hydrogen phosphites, hydroxides, oxides, sulfides, alkoxides, e.g., methoxides, oxide, ethoxide, and t-butoxide. Useful organic bases include basic amino acids such as arginine, lysine, and ornithine. Amino acid, ammonia, alkylamine, methylamine, dimethylamine, diethylamine alkylamines such as diethylamine, trimethylamine, and triethylamine; Heterocyclic amines such as ethanolamine, diethanolamine, triethanolamine, etc. Alkanolamines such as diethylaminoethanol, dimethylaminoethanol, N-methylglucamine, dicyclohexylamine, N,N'-dibenzylethyl Diamine, ethylenediamine, piperazine, choline, trolamine, imidazole, diamine Examples include thalamine, betaine, tromethamine, meglumine, and chloroprocaine. Not limited to these.

[0099] Pharmaceutically acceptable salts are well known in the art and include the inorganic and organic bases described above. Pharmaceutically acceptable salts are those approved by the Food and Drug Administration and foreign regulatory authorities. Pharmaceutically acceptable salts for incorporation further include salts and salt-forming agents found in approved drugs. The organic cations that are used include benzathine, chloroprocaine, choline, and diethanolamine. ethylenediamine, meglumine, procaine, benethamine, clemizole, diethyl These include, but are not limited to, amines, piperazines, and tromethamine. Pharmaceutically acceptable metal cations for inclusion include aluminum, calcium, lithium, Calcium, magnesium, potassium, sodium, zinc, barium, and bismuth Additional salt forming agents include, but are not limited to, arginine, betaine, carnitine, and the like. Chin, diethylamine, L-glutamine, 2-(4-imidazolyl)ethylamine, isopropyl alcohol These include butanolamine, lysine, N-methylpiperazine, morpholine, and theobromine. Examples include, but are not limited to:

[0100] In addition to the selected compounds useful as described above, some embodiments also include pharmaceutically acceptable salts of As used herein, the term "pharmaceutically acceptable carrier" includes compositions containing a pharmaceutically acceptable carrier. "Solution" means one or more compatible solid or liquid fillers, diluents or fillers suitable for administration to a mammal. As used herein, the term "compatible" means that the components of the composition are compatible with normal use. In a manner that does not result in any interactions that would substantially reduce the pharmaceutical efficacy of the composition under use conditions. Pharmaceutically acceptable carriers are those that can be mixed with the subject compounds and with each other. Of course, it is preferably suitable for administration to the animal, preferably a mammal, to be treated. The compound must be of sufficiently high purity and sufficiently low toxicity to be of a high quality.

[0101] Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, , surfactants, and encapsulating materials. Some examples of stand-alone substances are sugars such as lactose, glucose, and sucrose; cornstarch; potato Starches such as potato starch; sodium carboxymethylcellulose, ethyl cellulose cellulose and its derivatives such as cellulose, methylcellulose; powdered tragacanth; malt; gelatin tin; talc; stearic acid, magnesium stearate, and other solid lubricants; calcium sulfate Vegetable oils (peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, bobroma oil, etc.) Propylene glycol, glycerin, sorbitol, mannitol, polyethylene glycol Polyols such as cholesteryl alcohol, alginic acid, emulsifiers such as TWEENS, sodium lauryl sulfate Wetting agents such as sodium, coloring agents, flavoring agents; tablets, stabilizers, antioxidants, preservatives, pyrogens Free water, isotonic saline, and phosphate buffer.

[0102] Any pharmaceutically active material may be included that does not substantially interfere with the inhibitory activity of the compound. The amount of carrier used in conjunction with the compound is determined by the ratio of the amount of material to be administered per unit dose of the compound. It is sufficient to provide a practical amount of the compound to produce a formulation useful in the processes described herein. The techniques and compositions for this are fully contained in the following reference: Modern P Harmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rh odes, editors, 2002);Lieberman et al., Pharmaceut ical Dosage Forms:Tablets(1989);Ansel,In troduction to Pharmaceutical Dosage Form s 8th edition (2004).

[0103] A variety of oral dosage forms, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets can be compressed, wet, enteric coated, sugar coated, or film coated. and multiple compressed tablets, and may contain suitable binders, lubricants, diluents, disintegrants, colorants, and flavorings. Liquid oral dosage forms include aqueous solutions; emulsions; suspensions. , solutions and / or suspensions reconstituted from non-effervescent granules, and solutions and / or suspensions reconstituted from effervescent granules There are effervescent preparations containing suitable solvents, preservatives, emulsifiers, dispersants, diluents, sweeteners, melting agents, Contains coloring agents and flavoring agents.

[0104] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets are typically prepared with an inert diluent, such as calcium carbonate or sodium carbonate. , mannitol, lactose and cellulose; binders, such as starch, gelatin and sucrose; disintegrating agents such as starch, alginic acid and croscarmellose; lubricants, Examples include magnesium stearate, stearic acid, and talc. Silicon dioxide, etc. Glidants such as FD&C dyes can be used to improve the flow characteristics of powder mixtures. Coloring agents such as sorbitol, ... Luteme, saccharin, menthol, peppermint, and fruit flavors are available in chewable form. Capsules are typically used in the preparation of tablets as disclosed above. The selection of the carrier component is not critical and can be readily determined by one skilled in the art. The present invention is dependent on secondary considerations such as taste, cost, and shelf stability that may be made in the prior art.

[0105] Oral compositions also include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for the preparation of syrups, elixirs, etc. are well known in the art. Typical components of carriers for emulsions, emulsions and suspensions include ethanol, glycerol, ethanol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and In the case of suspensions, typical suspending agents include methylcellulose, carboxymethylcellulose, and water. Sodium dimethylcellulose, AVICEL RC-591, tragacanth and algin Typical wetting agents include lecithin and polysorbate 80. typical preservatives include methylparaben and sodium benzoate Oral liquid compositions may also contain one or more of the sweeteners, flavoring agents and coloring agents disclosed above. It may contain several components.

[0106] Such compositions also provide for the release of the subject compounds in the gastrointestinal tract in the vicinity of the desired topical application. or at various times to prolong the desired effect, typically in a pH or time dependent manner. Such dosage forms may be coated by conventional methods with a hydrophilic coating. , typically cellulose acetate phthalate, polyvinyl acetate phthalate, hydro Roxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit Coat The adhesives may include, but are not limited to, one or more of gum arabic, gum tragacanth, wax and shellac.

[0107] The compositions described herein may optionally include other drug actives or supplements. For example, the pharmaceutical composition is administered simultaneously with one or more antioxidants. In embodiments, the antioxidant is selected from the group consisting of coenzyme Q, idebenone, mitoquinone, mitoquinol, and bicarbonate. Vitamin E, and vitamin C, and combinations thereof. In some such embodiments, the at least one antioxidant is 11,11-D2- It may be taken simultaneously with, before, or after administration of linoleic acid or its esters. In some embodiments, the antioxidant and 11,11-D2-linoleic acid or ester thereof In some embodiments, the single dosage form may be a pill, tablet, or capsule. The cell agent is selected from the group consisting of:

[0108] Those skilled in the art will appreciate that numerous and varied modifications may be made without departing from the spirit of the invention. It will be understood that the embodiments of the invention disclosed herein may be It should be clearly understood that the embodiments are for illustrative purposes only and are not intended to limit the scope of the present invention. It is understood that any reference cited herein is a non-transitory resource for the material discussed herein. and is incorporated by reference in its entirety.

[0109] (co-administration) In some embodiments, the polyunsaturated lipids disclosed herein are one or more is administered in combination with an antioxidant.

[0110] Antioxidants affect the stochastic nature of the process and PUFA peroxidation production in response to antioxidant treatment. The stability of reactive carbonyls can offset the negative effects of PUFA peroxidation. However, co-administration of antioxidants with oxidation-resistant compositions such as those described herein may be beneficial. Administration of riboflavin may prove beneficial for treating oxidative stress-related disorders.

[0111] Specific antioxidants that may be useful for co-administration include the following: Vitamins such as Vitamin C and Vitamin E; glutathione, lipoic acid, uric acid, carotene, Copene, lutein, anthocyanin, oxalic acid, phytic acid, tannin, coenzyme Q Polyphenols including melatonin, tocopherols, tocotrienols, and resveratrol ol, flavonoids, selenium, eugenol, idebenone, mitoquinone, mitoquinone, eugenol Biquinone, Szeto-S cooling peptide, and mitochondria-targeted antioxidant. Unless otherwise mentioned, quinone derivatives of the aforementioned antioxidants are also believed to be useful for co-administration. can be done.

[0112] (kit) Some additional embodiments of the present disclosure include a kit comprising a pharmaceutical composition, prescribing information, and a container. For the purposes of the present invention, the pharmaceutical composition comprises a therapeutically effective amount of one or more isotopically modified polynucleotides described herein. In some embodiments, the isotopically modified polyunsaturated lipid comprises a deuterated polyunsaturated lipid. Polyunsaturated fatty acids (PUFAs), or their esters, thioesters, amides, phosphates, if or other prodrugs (such as phospholipid derivatives). The deuterated PUFA is 11,11-D2-linoleic acid and / or its esters. In one particular embodiment, the isotopically modified PUFA is 11,11-D2-ethyl linoleate. In some embodiments, the prescribing information instructs the subject to take the pharmaceutical composition with food. The kit is also recommended to be taken between meals. The dosage form may contain one or more unit dosage forms containing -D2-linoleic acid or an ester thereof. For example, the unit dosage form may include a pill, tablet, or capsule. The kit may include a plurality of unit dosage forms. In some embodiments, the unit dosage form is in the container. In some embodiments, the dosage form comprises 11,11-D2-linoleic acid. It is a single oral dosage form containing the acid or its ester, for example the ethyl ester.

[0113] The methods, compositions, and kits disclosed herein may include information. This notice may be in a form prescribed by a government agency that regulates the manufacture, use, or sale of reflects agency approval of a form of drug for human or veterinary administration. Such information may be found, for example, in labeling approved by the U.S. Food and Drug Administration for prescription drugs, or This may be the approved product insert. Information on dosage and dosage form, administration schedule and administration Routes, adverse events, contraindications, warnings and precautions, drug interactions, and use in specific populations (e.g., the entire contents of which are incorporated herein by reference) See 21 CFR §201.57, incorporated herein by reference), in some embodiments: It is required to be present on or associated with a drug in order for the drug to be sold. In some embodiments, the kits may require regulatory approval from a government agency, such as the U.S. Food and Drug Administration. and for sale by prescription thereafter. In some embodiments, the kit comprises: For example, in the United States, kits must be required by agencies such as the FDA for sale to consumers. In a preferred embodiment, the information includes any necessary labels or product inserts. 11,11-D2-linoleic acid or its analogs to reduce adverse events, such as gastrointestinal adverse events. Individuals are instructed to take the ester during or with meals.

[0114] The instructions and / or information may be provided on a suitable medium or substrate (e.g., a piece of paper or sheet of paper on which the information is printed). ), a computer-readable medium (e.g., a diskette, CD, etc. having information recorded thereon), or Various types of information, including printed information on website addresses that can be accessed via the Internet Printed information can be present in a variety of forms. For example, printed information can be on a label associated with a pharmaceutical product, may be packaged with the drug on the product container, or provided to the patient separately from the drug; or may be provided so that patients can obtain the information independently (e.g., a website). Printed information may also be provided to healthcare caregivers involved in the patient's care. In some embodiments, the information is provided to the person verbally.

[0115] Some embodiments include treatment packages suitable for commercial sale. The container may be made of a pharmaceutically acceptable material, such as a paper or cardboard box, glass or Plastic bottles or jars, resealable bags (e.g., to be placed inside different containers) to hold "refills" of tablets for the purpose of administering the drug) or from the pack according to the treatment schedule. A method of dispensing a blister pack containing individual doses for extrusion is well known in the art. The container used may be of any conventional shape or form known in the art. For example, conventional cardboard boxes are commonly used to hold liquid suspensions. Two or more containers may not be combined in a single package to market a single dosage form. For example, tablets may be contained in a bottle which is contained in a box. This may also be done.

[0116] Information can be associated with the container, for example, as follows: A label (e.g., a prescription label or a separate label) adhesively affixed to the bottle containing the dosage form to be as indicated on the package insert, such as inside the box containing the unit dose packet contained inside the container; affixed directly to the container, e.g., printed on the wall of the box; or via a string, cord, or other line, lanyard, or tether-type device It can be tied or taped as an instruction card attached to the neck of the turtle. The information was affixed to the unit dose pack or blister pack or blister card. may be printed directly on

Claims

1. Ruthenium complexes of formula I: 【Chemistry 1】 In the above formula, R and R' comprise residues of linolenic acid, arachidonic acid, eicosapentaenoic acid, or docosahexaenoic acid, or esters thereof; When an ester is present, C １ -C ２１ is an alkyl ester, The ruthenium complex further comprises a cyclopentadiene (Cp) ligand, and Ruthenium in ruthenium complexes is in the +1 oxidation state (Ru ＋１ ) complex.

2. 2. The complex of claim 1, wherein R and R' comprise the residue of linolenic acid.

3. 2. The complex of claim 1, wherein R and R' comprise the residue of arachidonic acid.

4. 2. The complex of claim 1, wherein R and R' comprise the residue of eicosapentaenoic acid.

5. 2. The complex of claim 1, wherein R and R' comprise the residue of docosahexaenoic acid.

6. R and R' are linolenic acid C １ -C ２１ 10. The complex of claim 1 comprising an alkyl ester residue.

7. R and R' are arachidonic acid C １ -C ２１ 10. The complex of claim 1 comprising an alkyl ester residue.

8. R and R' are eicosapentaenoic acid C １ -C ２１ 10. The complex of claim 1 comprising an alkyl ester residue.

9. R and R' are docosahexaenoic acid C １ -C ２１ 10. The complex of claim 1 comprising an alkyl ester residue.

10. 2. The complex of claim 1, wherein R and R' comprise the residue of linolenic acid ethyl ester.

11. 2. The complex of claim 1, wherein R and R' comprise the residue of arachidonic acid ethyl ester.

12. 2. The complex of claim 1, wherein R and R' comprise the residue of eicosapentaenoic acid ethyl ester.

13. 2. The complex of claim 1, wherein R and R' comprise the residue of docosahexaenoic acid ethyl ester.

Images