Methods for isotopic modification of polyunsaturated fatty acids and their derivatives

Abstract

Disclosed herein are methods for preparing isotopically modified polyunsaturated lipids containing 1,4-diene systems, comprising selective isotopic modification of one or more bis-allylic positions of the polyunsaturated lipid in the presence of a transition metal catalyst.

Description

[Technical Field]

[0001] (Reference to related applications) This application claims priority to U.S. Provisional Application No. 62 / 979,627, filed on 21 February 2020, which is incorporated herein by reference in its entirety for all purposes.

[0002] (Technical field) The present invention provides isotopic-modified polyunsaturated lipids, mixtures of isotopic-modified polyunsaturated lipids, methods for producing such compounds or mixtures thereof, pharmaceutical compositions and pharmaceuticals comprising such compounds or mixtures, and the use of such compounds or mixtures for treating, preventing or alleviating various diseases, disorders, or conditions related to lipid peroxidation. [Background technology]

[0003] (Explanation of related technologies) Oxidative damage is involved in a wide variety of diseases, including, but not limited to, mitochondrial diseases, neurodegenerative diseases, neurodegenerative muscle diseases, retinal diseases, energy processing disorders, kidney diseases, liver diseases, dyslipidemia, heart diseases, inflammation, and genetic disorders.

[0004] While the number of diseases associated with oxidative stress is numerous and diverse, it is well established that oxidative stress is caused by a disruption of the normal redox state within cells. An imbalance between the routine generation and detoxification of reactive oxygen species ("ROS"), such as peroxides and free radicals, can lead to oxidative damage to cellular structures and mechanisms. Under normal conditions, a potentially important source of ROS in aerobic organisms is the leakage of reactive oxygen species from mitochondria during normal oxidative respiration. Furthermore, macrophages and enzymatic reactions are also known to contribute to the generation of ROS within cells. Since cells and their internal organelles are enclosed by lipid membranes, ROS can easily come into contact with membrane components and induce lipid oxidation. Ultimately, such oxidative damage can be relayed to other biomolecules within the membrane and cells, such as proteins and DNA, through direct and indirect contact with reactive oxygen species, oxidized membrane components, or other oxidized cellular components. Therefore, it is easy to imagine how oxidative damage propagates throughout the cell, giving rise to the mobility of internal components and the interconnectivity of cellular pathways.

[0005] Lipid-forming fatty acids are well known as one of the major components of living cells. Therefore, they are involved in many metabolic pathways and play an important role in various pathological conditions. Polyunsaturated fatty acids ("PUFAs") are an important subclass of fatty acids. Essential nutrients are food components that perform essential biological functions directly or through conversion and are not produced endogenously or in sufficient quantities to meet the requirements. For warm-blooded animals, the two strictly essential PUFAs are linoleic acid (cis,cis-9,12-octadecadienoic acid; (9Z,12Z)-9,12-octadecadienoic acid; "LA"; 18; cis,cis-9,12,15-octadecatrienoic acid; (9Z,12Z,15Z)-9,12,15-octadecatrienoic acid; "ALA"; 18:3; n-3), osapentaenoic acid (EPA; 20:5; n-3), and docosahexaenoic acid (DHA; 22:6; n-3), osapentaenoic acid (EPA; 20:5; n-3), and docosahexaenoic acid (DHA; 22:6; n-3). Due to the essential nature of certain PUFAs or PUFA precursors, there are many known examples of their deficiencies, which are often associated with medical conditions. Furthermore, many PUFA supplements are available in stores and have been proven effective against certain diseases.

[0006] PUFAs impart the appropriate fluidity necessary for optimal oxidative phosphorylation performance to mitochondrial membranes. PUFAs also play a crucial role in the initiation and propagation of oxidative stress. PUFAs react with ROS via a chain reaction that amplifies the original event (Sun M, Salomon RG, J.Am.Chem.Soc.2004;126:5699-5708). However, the non-enzymatic formation of high levels of lipid hydroperoxides is known to lead to several detrimental changes. In fact, coenzyme Q10 has been linked to increased PUFA toxicity through PUFA peroxidation and the toxicity of the resulting products (Do TQ et al., PNAS USA 1996;93:7534-7539). Such oxidation products adversely affect membrane fluidity and permeability, leading to oxidation of membrane proteins and conversion to numerous highly reactive carbonyl compounds. The latter includes reactants such as acrolein, dialdehyde malonate, glyoxal, and methylglyoxal (Negre-Salvayre A et al., Brit. J. Pharmacol. 2008; 153: 6-20).

[0007] Site-selective isotope enhancement of polyunsaturated fatty acids at the bis-allyl moiety has been identified as a unique approach to prevent oxidative damage in these molecules associated with neurological and retinal diseases, atherosclerosis, and aging. Typical methods for preparing site-selectively deuterated PUFAs are quite lengthy, laborious, and expensive, sometimes generating undesirable byproducts. (See Smarun et al., J.Chem. 2017, 82, 13115-13120.) There is a need to develop efficient catalytic processes for site-specific deuteration of PUFAs and similar polyalkenes. [Overview of the project]

[0008] Some embodiments of this disclosure are A method for isotopic modification of polyunsaturated lipids, A process of reacting a polyunsaturated lipid with an isotope-containing agent in the presence of a transition metal catalyst to obtain an isotope-modified polyunsaturated lipid having an isotope at one or more bis-allylic positions, wherein the isotope-containing agent contains at least one isotope selected from the group consisting of deuterium, tritium, and combinations thereof, and the transition metal catalyst has a structure of formula (I) or (II); [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-C 10 aryl, 5-10 member heteroaryl, or 3-10 member heterocyclyl, where L 1 is optionally substituted with one or more R A , in which case L 1 is substituted with 1-10 members, each L 2 is independently imine, carbene, carbonyl, alkene, alkyne, nitrile, isonitrile, acetonitrile, ether, thioether, phosphine, pyridine, optionally substituted C3-C 10 cycloalkenyl, optionally substituted C4-C 10 cycloalkynyl, optionally substituted C6-C 10 ​​Selected from the group consisting of aryls, optionally substituted 5-membered to 10-membered heterocycles, or optionally substituted 3-membered to 10-membered heterocyclines, Each L 3 These are independently C1-C6 alkyl, NR 1 R 2 Or it is a C1-C6 alkoxy, Each R 1 and R 2 These are independently H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C4-C 10 Cycloalkynyl, optionally substituted C6-C 10 The aryl, optionally substituted 5- to 10-membered heteroallyls, or optionally substituted 3- to 10-membered heterocyclines, each R 2 and R 2 It is independently, C2-C 10 Alkyl, optionally substituted C2-C6 aryl or optionally substituted C2-C7 aryl or optionally substituted C2-C 10 Showing heterocycline Each R A These are independently hydroxyl, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or optionally substituted amino; L is a C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkylylene linker. m, ml, 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 one of 0, 1, or 2. Methods for isotopic modification of polyunsaturated lipids.

[0009] In some embodiments of this method, M is ruthenium. In some embodiments, the polyunsaturated lipid is a phospholipid containing a fatty acid (PUFA), fatty acid ester, fatty acid thioester, fatty acid amide, or fatty acid moiety.

[0010] Some embodiments of this disclosure relate to compositions comprising one or more isotopically modified polyunsaturated lipids having isotopes at one or more bis-allylic positions, wherein the isotopically modified polyunsaturated lipids are prepared by the methods described herein. Detailed description

[0011] Embodiments of this disclosure relate to a process for preparing isotopic polyunsaturated lipids using transition metal-catalyzed reactions. Polyunsaturated lipids may be fatty acids (PUFAs), fatty acid esters, fatty acid thioesters, fatty acid amides, or phospholipids containing fatty acid moieties. In some embodiments, the method provides deuterated polyunsaturated lipids or mixtures of deuterated polyunsaturated lipids. In some embodiments, the method described herein results in site-specific deuteration of polyunsaturated lipids, where deuteration occurs at both the bis-allylic and mono-allylic positions. In some further embodiments, the method may result in site-specific deuteration occurring primarily and exclusively at the bis-allylic position.

[0012] (definition) The headings used herein are for structural purposes only and should not be interpreted as limiting the subject matter described.

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art. The term “including” is not limited, as is the use of other forms such as “include,” “includes,” and “included.” The term “having” is not limited, as is the use of other forms such as “have,” “has,” and “have.” Where used herein, whether in a transitional clause or in the body of a claim, the terms “comprise” and “comprising” should be interpreted as having an open-ended meaning; that is, the above terms should be interpreted as synonymous with the phrases “at least have” or “at least include.” For example, where used in the context of a process, the term “comprise” means that the process includes at least the listed steps, but may include additional steps. When used in the context of compounds, compositions, formulations, or devices, the term “including” means that the compound, composition, formulation, or device includes at least the listed features or components, but may also include additional features or components.

[0014] As used herein, the term “about” means a quantity, value, number, percentage, amount, or weight that is changed from a reference quantity, value, number, percentage, amount, or weight by a change that would be considered acceptable to a person skilled in the art with respect to that type of quantity, value, number, percentage, amount, or weight. In various embodiments, the term “about” means a change of 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% relative to the reference quantity, value, number, percentage, amount, or weight.

[0015] As used herein, the “bis-allyl” position refers to the methylene group of the 1,4-diene system of the polyunsaturated lipids described herein (e.g., the Y substitution position of the polyunsaturated lipid of chemical formula (I)). As used herein, the “mono-allyl” position refers to the methylene group adjacent to only one double bond, but not the bis-allyl position (e.g., the X substitution position of the polyunsaturated lipid of chemical formula (I)). Further examples are given in the following structures: [ka]

[0016] As used herein, the term "polyunsaturated lipid" refers to a lipid that contains two or more unsaturated bonds, such as double or triple bonds, in its hydrocarbon chain. Here, polyunsaturated lipids may be polyunsaturated fatty acids, polyunsaturated fatty acid esters, polyunsaturated fatty acid thioesters, polyunsaturated fatty acid amides, polyunsaturated fatty acid phosphates, or phospholipids containing polyunsaturated fatty acid residues.

[0017] In some embodiments, an isotope-modified PUFA molecule may contain one deuterium atom, such as when one of the two hydrogen atoms in the methylene group is substituted with deuterium, and may therefore be called a "D1" PUFA. Similarly, an isotope-modified PUFA molecule may contain two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen deuterium atoms, which may be referred to as "D2," "D3," "D4," "D5," "D6," "D7," "D8," "D9," "D10," "D11," "D12," "D13," or "D14" PUFAs, respectively.

[0018] As used herein, C where "a" and "b" are integers. b To "C a"C1-C4 alkyl" refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a cycloalkyl, aryl, heteroaryl, or heterocyclyl ring. That is, a cycloalkyl alkyl, alkenyl, alkynyl, ring, aryl ring, heteroaryl ring, or heterocyclyl ring can contain "a"-"b" (including both ends) carbon atoms. Therefore, for example, a "C1-C4 alkyl" group refers to all alkyl groups having 1 to 4 carbon atoms.

[0019] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain containing a fully saturated (non-double or triple bonded) hydrocarbon group of 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.

[0020] As used herein, “alkenyl” refers to an alkyl group containing one or more double bonds in a linear or branched hydrocarbon chain. An alkenyl group may have 2 to 20 carbon atoms or 8 to 18 carbon atoms.

[0021] As used herein, cycloalkylyl refers to a hydrocarbon ring system having 6 to 20 carbon atoms, or 8 to 20 carbon atoms, and containing 1 to 3 alkynyl groups within the ring system.

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

[0023] As used herein, "cycloalkyl" refers to a completely saturated (without double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. If composed of two or more rings, the rings may be bonded together in a condensation manner. A cycloalkyl group may contain 3 to 10 atoms or 3 to 8 atoms in the ring. Cycloalkyl groups may be unsubstituted or optionally substituted. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0024] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system of 6 to 14 ring atoms (e.g., a condensed, bridging, or spirocyclic system in which two carbocyclic rings share a chemical bond, including one or more aryl rings having one or more aryl or nonaryl rings). The number of carbon atoms in an aryl group can vary. For example, an aryl group is C6-C 14 Aryl group, C6-C 10 The group may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0025] As used herein, “heteroaryl” means one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms), i.e., monocyclic or polycyclic aromatic ring systems (ring systems having a completely delocalized π-electron system) containing elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. The number of atoms in the ring of a heteroaryl group can vary. For example, a heteroaryl group may contain 5 to 10 atoms or 6 to 10 atoms in the ring. Examples of heteroaryl rings, but not limited to, where the heteroaryl group may be substituted or unsubstituted, include furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, and isoxazole. This includes triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinolin, and triazine A.

[0026] As used herein, “heterocyclyl” refers to monocyclic, bicyclic, and tricyclic ring systems of 3, 4, 5, 6, 7, 8, 9, and 10 members, where a carbon atom, together with 1 to 5 heteroatoms, constitutes the ring system. A heterocycle may optionally contain one or more unsaturated bonds, provided the system is not aromatic. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur, and nitrogen. Heterocyclyl groups may be unsubstituted or optionally substituted. Examples of such "heterocyclyl" groups include aziridine, oxirane, thiirane, azetidine, oxetane, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxathiane, te Trahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidinone, morpholine, oxirane, piperidine These include N-oxides, piperidines, piperazines, pyrrolidines, azepanes, pyrrolidones, pyrrolidiones, 4-piperidones, pyrazolins, pyrazolidines, 2-oxopyrrolidines, tetrahydropyrans, 4Hpyrans, tetrahydrothiopyrans, thymorpholins, thymorpholin sulfoxides, thymorpholin sulfones, and their benzo-condensed analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and / or 3,4-methylenedioxyphenyl). Examples of spiroheterocyclyl groups include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.]heptane, 2-oxaspiro[3.4]octane, and 2-azaspiro[3.4]octane.

[0027] As used herein, substituents are derived from an unsubstituted parent group in which one or more hydrogen atoms are exchanged with another atom or group. Unless otherwise specified, when a group is considered "substituted", that group is a C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocykyl (halo, C1-C6 alkyl, C1-C6 alkoxy, v Optionally substituted with haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclylcurk C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl), 5-10 member heterocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 member heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), and 5 member halocyclyl-(optionally substituted with halo, 5 member halocyclyl, and haloalkyl, C1-C6 alkyl, and haloalkoxy).(and optionally substituted with C1-C6 haloalkoxy), aryl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and optionally substituted with C1-C6 haloalkoxy), aryl(C1-C6)alkyl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and optionally substituted with C1-C6 haloalkoxy), 5-10 member heteroaryl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and optionally substituted with C1-C6 haloalkoxy), 5-10 member heteroaryl(C1-C6)alkyl (halo, C1-C6 alkyl, C1-C6 alkoxy, and optionally substituted with C1-C6 haloalkyl), halo, cyano, hydroxy, C1 -This means that the group is substituted with one or more substituents independently selected from 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., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6) alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, oxo (=O), etc. If a group is described as "substituted," that group may be substituted with any of the substituents listed above. In some embodiments, the substituent(s) are substituted with one or more substituents individually and independently selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, amino, hydroxy, and halogen.

[0028] As used herein, the term "thioester" refers to a structure in which carboxylic acid and thiol groups are linked by an ester bond, or where the carbonyl carbon is a sulfur atom -C(=O)SR A This refers to a structure that forms a covalent bond with R. A is hydrogen, optionally substituted C1-30 Alkyl (branched or linear), optionally substituted C 2-30 Alkenyl (branched or linear), optionally substituted C 2-30 Alkynnyl (branched or linear), or optionally substituted ring structures, e.g., C 6-10 It may contain aryl, heteroaryl, carbocykryl, cycloalkyl, or heterocyclyl. "Polyunsaturated fatty acid thioester" is PC(=O)SR A This refers to a polyunsaturated fatty acid as described herein.

[0029] As used herein, the term "amide" refers to the structure C(O)NR A R B and R A and R B Refers to a compound or part of, independently of hydrogen, optionally substituted with C 1-30 Alkyl (branched or linear), optionally substituted C 2-30 Alkenyl (branched or linear), optionally substituted C 2-30 Alkynnyl (branched or linear), or optionally substituted ring structures, e.g., C 6-10 It may be an aryl, heteroaryl, carbocykryl, cycloalkyl, or heterocyclyl. "Polyunsaturated fatty acid amide" is PC(=O)NR A R B This refers to the structure, where P is a polyunsaturated fatty acid as described herein.

[0030] As used herein, the term "salt" is a broad term, and its ordinary, customary meaning should be given to those skilled in the art (and not limited to any special or customized meaning).

[0031] It should be understood that certain radical naming conventions can include either mono-radicals or di-radicals, depending on the context. For example, a substituent is understood to be a diradical if it requires two bonding sites to the rest of the molecule. Examples of substituents identified as alkyls that require two bonding sites include diradicals such as -CH2-, -CH2CH2-, and -CH2CH(CH3)CH2. Other radical naming conventions clearly indicate that a radical is a diradical, such as an "alkylene" or "alkenylene."

[0032] In any compound described herein having one or more chiral centers, where absolute stereochemistry is not explicitly indicated, it is understood that each center may independently be in an R configuration, an S configuration, or a mixture thereof. Therefore, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, or a mixture of stereoisomers, encompassing all diastereomer and enantiomer forms. Furthermore, in any compound described herein having one or more double bonds that produce geometric isomers that can be defined as E or Z, it is understood that each double bond may independently be a mixture of E or Z. Stereoisomers may be obtained, if necessary, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography column.

[0033] Similarly, it is understood that all tautomers are intended to be included for any compound described.

[0034] As used herein, “primarily” means about 50% or more. In one embodiment, “primarily” means about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more than 100%.

[0035] Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," that position is understood to contain hydrogen in its naturally occurring isotopic composition. Unless otherwise specified, when a position is specifically designated as "D" or "deuterium," that position contains deuterium in an abundance of 0.0156% (i.e., at least 50% deuterium incorporation), which is at least 3206 times the naturally occurring abundance of deuterium. More specifically, it may contain an amount of deuterium at a position corresponding to at least 3500 times (54.6% deuterium uptake), 4000 times (62.4% deuterium uptake), 4500 times (70.2% deuterium uptake), 5000 times (78% 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) of the naturally occurring deuterium abundance.

[0036] As used herein, the term “isotope-containing agent” refers to a compound containing deuterium or tritium atoms in an abundance significantly higher than the natural abundance of each atom. In the case of a deuterium-containing agent, it contains at least 3206 times the natural abundance of deuterium (i.e., at least 50% deuterium incorporation). In some further embodiments, the isotope-containing agent has at least 4000, 4500, 5000, 5500, 6000, 6090, 6250, 6346, or 6378 times the natural abundance of deuterium.

[0037] As used herein, the term "isotope purity" in relation to isotope-containing agents refers to the percentage of molecules containing heavy atoms (e.g., D or T) relative to the total number of molecules containing molecules without heavy atoms. For example, if an isotope-containing agent is heavy water (i.e., D2O) with an isotope purity of 95%, then for every 100 water molecules, there will be 95 D2O molecules and 5 H2O molecules. In some examples, the isotope purity of an isotope-containing agent may be at least 50%, 65%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[0038] (Methods for site-directed isotope modification) Conventional deuteration of molecules containing a single alkene using a transition metal catalyst often presents problems, primarily involving the selective deuteration of the vinyl position (hydrogen atoms linked to the double bond carbon atom). Many alkenes contain double bonds with restricted movement. Limited examples of linear (unrestricted movement) alkenes yield positional isomers, and cis-trans isomerization always involves a deuteration process, with no reports of H / D exchange involving polyunsaturated alkenes.

[0039] Ru-based complexes (e.g., [Ru(Cp)(ACN)3]±PF6) using a deuterium source D2O. - The selective and efficient deuteration of various polyalkenes (including PUFAs) at the bis-allyl moiety using Ru catalyst (Cp = cyclopentadiene; CAN = acetonitrile) is described in U.S. International Publication No. 2017 / 091279. This Ru catalyst was able to perform H / D exchange (deuteration) at the bis-allyl position of linolenic acid (LNN), arachidonic acid (ARA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) or their esters with a deuteration efficiency of at least 95%. Furthermore, deuteration of less than approximately 30% occurred at the mono-allyl position of these polyunsaturated fatty acids or their esters. However, when linoleic acid (LIN) or alkyl esters (e.g., ethyl esters) were subjected to the catalytic procedure using this Ru catalyst, only the mono-allyl moiety was deuterated to an efficiency of approximately 95%.

[0040] While not bound by any theory, the reason for LIN's exception to deuteration selectivity is thought to lie in the proposed mechanism in which the PUFA binds to a ruthenium center with two double bonds, and a D2O molecule occupies the remaining coordination site (Structure A, Scheme 1). This structure is thought to activate both the mono- and bis-allyl moieties of the bound PUFA with the heavy water molecule (making it more acidic). In the next step, an H / D exchange occurs with the help of one or more additional D2O molecules (B in Scheme 1), but at the CH2 site closer to the bound D2O molecule. This CH2 site can be either mono- or bis-allyl for LNN, ARA, EPA, and DHA, but the bis-allyl site appears to be preferred over the mono-allyl site for the deuteration process of these PUFAs. Nevertheless, in the case of LIN, there is only one bis-allyl site that is spatially far from the bound D2O molecule (Structure A, Scheme 1). Therefore, this site may not be involved in the overall deuteration process. Since only the mono-allyl moieties of LIN are spatially adjacent to the bonded D2O, these mono-allyl moieties are actually deuterated. Scheme 1. Proposed mechanism for H / D exchange process using Ru catalyst containing PUFA [ka]

[0041] Based on this proposed mechanism, the following factors are considered important for the deuteration of LIN primarily and exclusively at the bis-allyl position: (1) LIN needs to coordinate to a transition metal (e.g., ruthenium) in a manner similar to that shown in Figure 1A, B, or C; (2) the isotopic agent (e.g., D2O) binding site to ruthenium needs to be occupied / blocked by another molecule to avoid monoallyl deuteration; and (3) the D2O present in solution may need to be acidified. It should also be noted that the presence of a cyclopentadienyl ligand (Cp), or possibly several other cyclic ligands (e.g., benzene), may be important for the overall deuteration. Therefore, several different approaches are proposed to achieve optimal results, as detailed below.

[0042] Some embodiments of this disclosure are A method for isotopic modification of polyunsaturated lipids, A step of reacting a polyunsaturated lipid with an isotope-containing agent in the presence of a transition metal catalyst to obtain an isotopically modified polyunsaturated lipid having isotopes at one or more bis-allylic positions, The isotope-containing agent comprises at least one isotope selected from the group consisting of deuterium, tritium, and combinations thereof, and the transition metal catalyst has the structure of formula (I) or (II); [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) Here M is rhodium, iridium, or ruthenium, L 1 is C3-C 10 cycloalkenyl, C4-C 10 cycloalkynyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, where L 1 is optionally substituted with one or more R A and in this case, L 1 is substituted with 1-10 members, each L 2 is independently selected from the group consisting of imine, carbene, carbonyl, alkene, alkyne, nitrile, isonitrile, acetonitrile, ether, thioether, phosphine, pyridine, optionally substituted C3-C 10 cycloalkenyl, optionally substituted C4-C 10 cycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5-membered - 10-membered heterocycle, or optionally substituted 3-membered - 10-membered heterocyclyl, each L 3 is independently C1-C6 alkyl, NR 1 R 2 or C1-C6 alkoxy, each R 1 and R 2 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C3-C 10 cycloalkenyl, optionally substituted C4-C 10 cycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroallyl or optionally substituted 3- to 10-membered heterocyclyl, each R 2 and R 2 are independently C2-C 10 alkyl, optionally substituted C2-C6 aryl or optionally substituted C2-C7 aryl or optionally substituted C2-C 10 heterocyclyl, each R AThese are independently hydroxyl, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or optionally substituted amino; L is a C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkylylene linker. m, ml, 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 one of 0, 1, or 2. Methods for isotopic modification of polyunsaturated lipids.

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

[0044] In some embodiments, blocking of the coordination site of an isotope-containing agent (e.g., D2O) can be achieved by using a ligand that (a) is sterically small and therefore does not interfere with polyunsaturated lipid (e.g., PUFA) bonding, and (b) is strongly bonded to a transition metal (e.g., ruthenium) so as not to be substituted by PUFA bonding. To achieve these objectives, ligands such as alkyl, amino, or alkoxy groups can be used. Embodiments for preparing such catalysts are illustrated in Scheme 2 below. Scheme 2. Proposal for the synthesis of catalyst D and the generation of the active species (D'). [ka]

[0045] When LIN is added, catalyst D blocks deuteration at the monoallylic position (i.e., formation of D') and simultaneously activates the bis-allylic position, preparing for deuteration if the acidity of the medium is appropriate. However, compounds D and D' are neutral compounds. Such neutral forms may affect their solubility and / or catalytic activity in the overall reaction medium.

[0046] If a neutral transition metal catalyst (e.g., catalyst D) is incompatible with the reaction mixture and / or is insufficiently catalytic, a cationic analog of the catalyst can be used. In some embodiments, a benzene ligand may be used to replace cyclopentadiene (Cp) because this ligand switch keeps the overall charge of the complex positive. Embodiments of the synthesis of such catalysts are illustrated in Scheme 3 below. Scheme 3. Proposed synthesis of cationic Ru catalyst [ka]

[0047] In some embodiments, the reaction efficiency can be improved by changing the acidity of the catalyst. In some such embodiments, a Lewis acid can be used to tether a portion of the catalyst (e.g., to a ligand of the catalyst). The tethering process can potentially reduce the amount of Lewis acid required to acidify the solution because this tethered fragment is positioned very close to the activated (i.e., Ru-bonded) LIN. Embodiments of such catalysts (catalysts F and F') are illustrated below. [ka]

[0048] Alternatively, a dinuclear catalyst system of chemical formula (II) may also be used in the methods described herein. An embodiment of the deuteration of linoleic acid in the presence of heavy water using a dinuclear Ru catalyst is shown in Scheme 4. In this embodiment, one side of the Ru center (left) has two sites blocked by ligands (i.e., ERn) that allow only D2O to be bonded, while the other side (right) has only one site blocked that allows LIN to be bonded. Scheme 4. Dinuclear Ru-catalyzed deuterization of LIN [ka]

[0049] In some embodiments of transition metal catalysts of chemical formula (I) or (II), L 1 C3-C 10 Cycloalkenyl or C6-C 10 It is an aryl, and each has 1 or more R A It was optionally replaced with. In one embodiment, L 1 is an unsubstituted cyclopentadienyl (Cp). In another embodiment, L 1 This is one R A It is a substituted cyclopentadienyl having L 1 L is an unsubstituted benzene. In another embodiment, L 1 This is one R A It is a substituted benzene having L 1 C3-C 10 Cycloalkenyl or C6-C 10 Each is an aryl, with one or more R A It is replaced by R A is a C1-C6 alkyl substituted with a Lewis acid. In some further embodiments, R A It is a C1-C6 alkyl group, and B(R 3 ) is substituted with 2, and each R 3 These are independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C6-C10 It is an arrow. In some further embodiments, R A This is C1-C6 substituted with B(C6H5)2.

[0050] In some embodiments of transition metal catalysts of chemical formula (I) or (II), each L 2 L is independently a nitrile, isonitrile, acetonitrile, or phosphine. In some embodiments, each L 2 is acetonitrile (CH3CN). In some embodiments, at least one L 2 is P(R 4 )3 is a phosphine, where each R 4 These are independently and arbitrarily substituted, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heteroaryl, C 6-10 It is an arrow. In some further embodiments, P(R 4 )3 is P(t-Bu)2(C6H5). In some embodiments, P(R 4 )3 is 4-(tert-butyl)-2-(diisopropylphosphan 1)-1H-imidazole. In some embodiments, each L 2 This is independently acetonitrile or optionally substituted cyclopentadienyl.

[0051] In some embodiments of transition metal catalysts of chemical formula (I) or (II), L 3 This is N(CH3)2.

[0052] In some embodiments of the transition metal catalyst of chemical 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 chemical formula (II), each of m1 and m2 is 1 or 2. In some embodiments, each of n1 and n2 is 2 or 1. In some further embodiments, ml + n1 = 3 and / or m2 + n2 = 3.

[0053] In some embodiments of the transition metal catalyst of chemical 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 Allyl) 4 - Al(PF6) - Allyl) - F - , I - , Br - NO3 - or an anion having a single negative charge, such as a carborane anion. In one embodiment, Q is PF6 - In such embodiments, p and / or q are 1. In some other embodiments, Q is a double negatively charged anion, for example, SO4. 2- In this embodiment, p or q is 2.

[0054] Further ligands that may be used in the transition metal catalysts described herein include amine ligands. Amine ligands may be monodentate or polydentate and may include monoamines, diamines, and triamine moieties. Monoamines may have the chemical formula N(Rb)2, and exemplary monoamines include, but are not limited to, dialkylmonoamines (e.g., di-ra-butylamine, or DBA) and trialkylmonoamines (e.g., N,N-dimethylbutylamine, or DMBA). Suitable dialkylmonoamines include 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)phenylethanolamine, N-(2,6-dimethyl)phenylethanolamine, N-(p-chloro)phenylethanolamine, N-ethylaniline, N-butylaniline, N-methyl-2-methylaniline, N-methyl-2,6-dimethylaniline, diphenylamine, and combinations thereof. Suitable trialkylmonoamines include trimethylamine, triethylamine, tripropylamine, tributylamine, butyldimethylamine, phenyldiethylamine, and combinations thereof. Diamines are defined by the chemical formula (R b )2N-R a -N(R b )2 may have, and exemplary diamines may include alkylenediamines such as N,N'-di-ethylbutylethylenediamine or DBEDA. Triamines refer to organic molecules having three amine moieties, and include, but are not limited to, diethylenetriamine (DETA), guanidine HCl, and tetramethylguanidine. For both monoamines and diamines, R a These are substituted or unsubstituted divalent residues; each R b These independently contain hydrogen, C1-C8 alkyl, or C 6-10It is aryl. In some examples of the above chemical formula, two or three aliphatic carbon atoms form the closest bond between two diamine nitrogen atoms. Specific alkylenediamine ligands include R a Examples include those in which the compound is dimethylene (-CH2CH2-) or trimethylene (-CH2CH2CH2-). b This can independently be hydrogen, methyl, propyl, isopropyl, butyl, or a C4-C8 α-tertiary alkyl group. In some embodiments, the diamine may be an ethylenediamine. In some embodiments, the triamine may be a diethylenetriamine.

[0055] Alkylenediamine ligands can be monodentate or polydentate, examples of which include N,N',N'-tetramethylethylenediamine (TMED), N,N'-di-tert-butylethylenediamine (DBEDA), N,N',N'-tetramethyl-1-1,3-diaminopropane (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 1,4-diaminobutane, N,N,N'-trimethyl-1,4-diaminobutane, N,N'-tetramethyl 1,4-diaminobutane, N,N,N'-tetramethyl 1-1,4,4-diaminobutane, N,N,N',N'-tetramethyl 1-1,5-diaminopentane, and combinations thereof. In some embodiments, the amine ligand is selected from di-la-butylamine (DBA), N,N-dimethylbutylamine (DMBA), N,N'-di-tert-butylethylenediamine (DBEDA), and combinations thereof.

[0056] Examples of additional ligands used in the transition metal catalysts described herein include alkene ligands and amines. The alkene ligands described herein are monodentate or polydentate and comprise molecules having at least one non-aromatic carbon-carbon double bond, and may include, but are not limited to, monoalkenes and dialkenes. Examples of alkene ligands include ethylene, propylene, butene, hexene, decene, and butadiene.

[0057] The isonitrile ligands described herein, also known as isocyanides, refer to molecules having at least one -NC moiety, which may be monodentate or polydentate, and include, but are not limited to, monoisonitrile and diisonitrile ligands. Examples of monoisonitrile and diisonitrile include C 1-10 Examples include alkyl-NC and CN-R-NC, but are not limited to these, where R is C 1-10 These include 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, and PhP(O)(OCH2CH(CH3)NC)2. Further isonitrile ligands are described in Naik et al., Chem.Commun., 2010, 46, 4475-4477, which are incorporated herein by reference in their entirety.

[0058] The nitrile ligands described herein refer to molecules having at least one -CN moiety, which may be monodentate or polydentate, and include, but are not limited to, monoisonitrile and diisonitrile ligands. Examples of monoisonitrile and diisonitrile include C 1-10 Examples include alkyl-CN and CN-R-CN, but are not limited to these examples, where R is C 1-10These include alkylene, acetonitrile, 1,3,5-cyclohexanetricarbonitride, propionitrile, butyronitrile, glutaronitrile, pivalonitrile, capronitrile, (CH2)3CN, (CH2)4CN, and (CH2)5CN. Further nitrile ligands can be found in Lee et al., Inorganic and Nuclear Chemistry Letters, v10, 10 (Oct1974), pp. 895-898, which is incorporated herein by reference in its entirety.

[0059] The ether ligands described herein refer to molecules having at least one ROR moiety, where each R is independently an alkyl or aryl group and can be monodentate or polydentate, and include monoethers, diethers, and triether ligands. Examples of monoethers, diethers, triethers, and other suitable ethers include, but are not limited to, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, polyethylene glycol, and anisole.

[0060] The thioether ligands described herein refer to molecules having at least one RSR moiety, where each R is independently an alkyl or aryl group, and can be monodentate or polydentate, and include monothioethers, dithioethers, and trithioether ligands. Examples of monothioethers, dithioethers, and trithioethers include, but are not limited to, dimethyl sulfide and methylphenyl sulfide.

[0061] The imine ligands described herein refer to molecules having at least one carbon-nitrogen double bond moiety, which may be monodentate or polydentate, and include monoimines, diimines, and triimines. Examples of imine ligands, but not limited to, include 1,2-ethanediimine, imidazoline-2-imine, 1,2-dikethymine, dimethylglyoxime, o-phenylenediamine, 1,3-dikethymine, and glyox al-bi s (mesitylimine).

[0062] The carbene ligands described herein refer to compounds having at least one divalent carbon atom that, when not coordinated to a metal, has only six electrons in its valence shell. This definition is not limited to metal-carbene complexes synthesized from carbenes, but rather is intended to address the orbital structure and electron distribution associated with the carbon atom bonded to the metal. This definition recognizes that a “carbene” may not be technically divalent when bonded to a metal, but is divalent when detached from the metal. Many such compounds are synthesized by first synthesizing a carbene and then bonding it to a metal, but this definition is intended to encompass compounds synthesized by other methods having similar orbital structures and electron configurations. Lowry & Richardson, Mechanism and Theory in Organic Chemistry 256 (Harper & Row, 1976) defines “carbene” in a manner consistent with how the term is used herein. The carbene ligands described herein may be monocarbenes, dicarbenes, and tricarbenes. Examples of carbene ligands include 1,10-dimethyl-3,30-methylenediimidazoline-2,20-diylidene, 1,10-dimethyl-3,30-ethylenediimidazoline-2,20-diylidene, 1,10-dimethyl-3,30-propylenediimidazoline-2,20-diylidene, 1,10-dimethyl-1-3,30-methylenediimidazoline-2,20-diylidene, 1,10-dimethyl-1-3,30-ethylenediimidazoline-2,20-diylidene, [ka] And n is 1, 2, or 3, and [ka] Additional carbene ligands can be found in Huynh et al., Journal of Organometallic Chemistry, v696, 21, (October 2011), pp. 3369-33'75, and Malty et al., Chem.Commun., 2013, 49, 101-101, which are incorporated herein by reference in their entirety.

[0063] The pyridine ligands described herein refer to molecules having at least one pyridine ring moiety and may include monopyridine, dipyridine, and tripyridine ligands. Examples of pyridine ligands include, but are not limited to, 2,2'-bipyridine and 2,6-di(2pyridyl)pyridine.

[0064] The phosphine ligands described herein contain at least one P(R) 4 ) refers to molecules that have 3, and each R 4 is hydrogen, optionally substituted C 1-15 Alkyl, optionally substituted C 3-8 The phosphine ligand is independently selected from the group consisting of cycloalkyls, optionally substituted C6-15 aryls, and optionally substituted 4- to 10-membered heteroaryls. The phosphine ligand may include monophosphines, bisphosphines, and trisphosphines. Suitable phosphine ligands include, but are not limited to, PH3, trimethylphosphine, triphenylphosphine, methyldiphenylphosphine, trifluorophosphine, trimethylphosphine, triphenylphosphine, tricyclohexylphosphine, dimethylphosphinomethane (dmpm), dimethylphosphinoethane (dmpe), PROPHOS, PAMP, DIPAMP, DIOP, DuPHOS, P(tBu)2Ph, 1,2-B is (diphenylphosphino)ethane (dppe), 1,1'-B is (diphenylphosphino)ferrocene (dppf), 4-(tert-butyl)-2-(diisopropylphosphan y1)-1H-imidazole, and P(t-Bu)2(C6H5).

[0065] In some embodiments of the methods described herein, the isotope-containing agent is D2O, DO(C1-C 12 Alkyl) (e.g., DOCH3 or DOCD3), T2O, 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, the reaction of polyunsaturated lipids with isotope-containing agents is carried out in an acidic reaction medium, such as an acidic aqueous solution, an acidic solvent, or a mixture of acidic solvents, or a combination thereof. In some embodiments, the reaction medium may include one or more solvents selected from the group consisting of acetone, methanol, ethanol, 1-propanol, isopropanol, 2-butanol, 1,4-dioxane, acetonitrile, dichloromethane (DCM), toluene, dimethyl sulfoxide (DMSO), acetic acid, dimethyl carbonate, ethyl acetate, ether, ethylene glycol, or N-methyl-2-pyrrolidone (NMP), and combinations thereof. In some such embodiments, the reaction medium includes heavy water (D2O). In some such embodiments, the acidic reaction medium includes one or more pH adjusters selected from the group consisting of organic acids, inorganic acids, Lewis acids, and combinations thereof. For example, acidification of heavy water can be carried out by introducing either a Lewis acid or a certain amount of DCl (deuterium chloride) into the entire reaction solution. The level of acidity must strike a balance between the system's ability to perform deuteration and the stability of the catalyst in this acidified solution. The presence of C1 can potentially interfere with catalytic function because it may bind to transition metals such as ruthenium. In such cases, the use of a Lewis acid (e.g., B(C6F5)3) may be more attractive because it is far less likely to interfere with catalytic function.

[0067] (Polyunsaturated lipids) In some embodiments, the polyunsaturated lipid includes fatty acids, fatty acid esters, fatty acid thioesters, fatty acid amides, fatty acid phosphates, or phospholipid derivatives of fatty acids, or combinations thereof. In some further embodiments, the phospholipid contains a polyunsaturated fatty acid residue after an esterification or amidation reaction between the carboxyl group of the fatty acid and the hydroxyl or amino group of the phospholipid. In some such embodiments, the polyunsaturated lipid may have two or more carbon-carbon double bonds (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon-carbon double bonds). In some further embodiments, the polyunsaturated lipid is an ω-3 fatty acid, an ω-6 fatty acid, or an ω-9 fatty acid, or an ester, amide, thioester, phosphate, or phospholipid derivative thereof. In some embodiments, the polyunsaturated lipid is linoleic acid, linolenic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, or esters thereof. In some further embodiments, the polyunsaturated fatty acid ester is an alkyl ester, triglyceride, diglyceride, or monoglyceride.

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

[0069] In some embodiments, polyunsaturated lipids are chemically defined as (III): [ka] Each R 5 These are, independently, H, and the optionally substituted C1-C 21 Alkyl, optionally substituted C2-C 21 Alkenyl, optionally substituted C2-C 21 Alkinyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 These are aryls, optionally substituted 4- to 10-membered heteroaryls, optionally substituted 3- to 10-membered heterocyclines, monosaccharides, disaccharides, or oligosaccharides; R 6a and R 6b Each of these is independently H, and the arbitrarily substituted -C(=O)C1-C 21 Alkyl, arbitrarily substituted -C(=O)C2-C 21 Alkenyl, or optionally substituted -C(=O)C2-C 21 It is alkinyl; R 7 and R 8 Each of these is independently H, and C1-C which are arbitrarily substituted. 21 Alkyl, optionally substituted C2-C 21 Alkenyl, optionally substituted C2-C 21 Alkinyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 Aryl, optionally substituted 4- to 10-membered heteroaryl, or optionally substituted 3- to 10-membered heterocyclyl; or R 7 and R 8 These, along with the nitrogen atoms to which they are bonded, form optionally substituted 3- to 10-membered heterocyclines; Each R 9 These are independently and arbitrarily substituted C1-C 21 Alkinyl, optionally substituted C2-C 21 Alkinyl, optionally substituted C2-C 21 It is alkinyl; Each R 10 H, independently [ka] -CH2CH2NH2,-CH2CH2NH3 + ,-CH2CH(NH2)C(=O)O - -CH2CH(OH)CH2OH is a monosaccharide, disaccharide, or oligosaccharide; R 11 This is an arbitrarily substituted C8-C 21 Alkinyl, optionally substituted C8-C 21 Alkynyl, or optionally substituted C8-C 21 It is alkinyl; R 12 H, [ka] It is a monosaccharide, disaccharide, or oligosaccharide. p and q are independently integers of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

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

[0071] In some embodiments, this method yields deuterated linoleic acid of chemical formula (IIIa) (wherein R is n-butyl, p=1, and q=6) or a derivative thereof: [ka] In some such embodiments, one or both of Y are D. In some further embodiments, X are H, respectively. In other embodiments, at least one of X is D. In some such embodiments, R' is -OR 5 And here, R 5 H or C1-C which are substituted by any choice. 21 In one embodiment, R 5is ethyl. In such one embodiment, the deuterated polyunsaturated lipid is 11,11-D2-linoleic acid (D2-Lin), a pharmaceutically acceptable salt thereof, or its ethyl ester.

[0072] In some embodiments, this method yields deuterated linoleic acid of chemical formula (IIIb) (wherein R is methyl, p=2, and q=6) 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 X is D. In some such embodiments, R' is -OR 5 Here, R5 is replaced by H or C1-C of any choice. 21 In one embodiment, R 5 is ethyl. In such one embodiment, the deuterated polyunsaturated lipid is 11,11,14,14-D4-linolenic acid, a pharmaceutically acceptable salt thereof, or its ethyl ester.

[0073] In some embodiments, this method yields deuterated arachidonic acid of chemical formula (IIIc) (wherein R is n-butyl, p=3, and q=2) 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 X is D. In some such embodiments, R' is -OR 5 And here, R 5 C1-C is replaced by H or of any choice. 21 In one embodiment, R 5is ethyl. In such one embodiment, the deuterated polyunsaturated lipid is 7,7,10,10,13,13-D6-arachidonic acid, a pharmaceutically acceptable salt thereof, or its ethyl ester.

[0074] In some embodiments, the method yields deuterated eicosapentaenoic acid or a derivative thereof of chemical formula (IIId) (wherein R is methyl, p=4, and q=2): [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 X is D. In some such embodiments, R' is -OR 5 And here, R 5 C1-C is replaced by H or of any choice. 21 In one embodiment, R 5 is ethyl. In such one embodiment, the deuterated polyunsaturated lipid is 7,7,10,10,13,13,16,16-D8-eicosapentaenoic acid, a pharmaceutically acceptable salt thereof, or its ethyl ester.

[0075] In some embodiments, the method yields deuterated docosahexaenoic acid or a derivative thereof of chemical formula (IIIe) (wherein R is methyl, p=5, and q=1): [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 X is D. In some such embodiments, R' is -OR 5 And here, R 5 C1-C is replaced by H or of any choice. 21In one embodiment, R 5 is ethyl. In such one embodiment, the deuterated polyunsaturated lipid is 6,6,9,9,12,12,15,15,18,18-D10-docosahexaenoic acid, a pharmaceutically acceptable salt thereof, or its ethyl ester.

[0076] In other embodiments of the polyunsaturated lipid of chemical formula (III), the polyunsaturated lipid is in the form of a glyceride ester, where R'=-O(CH2)CH(OR 6a )CH 2 (OR 6b ) is R 6a and R 6b If each of them is H, then such an ester is a monoglyceride, and R 6a and R 6b If only one of the atoms is H, then such an ester is a diglyceride. 6a R 6b If it is not H, then such an ester is a triglyceride.

[0077] (A mixture of deuterated polyunsaturated lipids) In some embodiments, the catalytic method described herein produces a mixture of polyunsaturated lipids described herein. In some such embodiments, at least one polyunsaturated lipid in the mixture is deuterated at all bis-allylic positions. In some further embodiments, one or more polyunsaturated lipids in the mixture are further deuterated at one or more monoallylic positions. In other embodiments, none of the polyunsaturated lipids in the mixture are deuterated at one or more monoallylic positions. In some such embodiments, the mixture of polyunsaturated lipids comprises two or more species of the same fatty acid or its derivatives described herein, the only difference between the different species being the number of deuterium atoms at the bis-allylic and / or monoallylic positions. For example, if the mixture contains deuterated linolenic acid, it can include various species of linolenic acid containing 1 to 4 deuterium atoms at the bis-allylic positions, such as: [ka]

[0078] Similarly, if the mixture contains a species of deuterated linoleic acid or its derivatives, the mixture may contain a combination of various species of linoleic acid containing one or two deuterium atoms at the bis-allyl position, or one of any 1 to 6 deuterium atoms at various bis-allyl and mono-allyl positions. If the mixture contains a species of deuterated arachidonic acid or its derivatives, the mixture may contain a combination of various species of arachidonic acid containing one to 6 deuterium atoms at the bis-allyl position, or one of any 1 to 10 deuterium atoms at various bis-allyl and mono-allyl positions. If the mixture contains a species of deuterated eicosapentaenoic acid or its derivatives, the mixture may contain a combination of various species of eicosapentaenoic acid containing one to 8 deuterium atoms at the bis-allyl position, or one of any 1 to 12 deuterium atoms at various bis-allyl and mono-allyl positions. If the mixture contains a species of deuterated docosahexaenoic acid or its derivatives, the mixture may contain a combination of various species of docosahexaenoic acid containing 1 to 10 deuterium atoms at the bis-allyl position, or any one of 1 to 14 deuterium atoms at various bis-allyl and mono-allyl positions. In some further embodiments, the method produces a deuterated product mainly at the bis-allyl position. In some such embodiments, the method produces a deuterated product having a degree of deuteration of less than 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or less than 0.1% at the monoallyl position.

[0079] In some embodiments of the polyunsaturated lipid mixtures described herein, the method produces a mixture having a degree of deuteration of at least 50%, for example, at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% at the bis-allylic position after the reaction is complete. In some further embodiments, the degree of deuteration is at least 70% at the bis-allylic position. As used herein, the terms “degree of deuteration” and “degree of deuteration” refer to the percentage of deuterium atoms at the bis-allylic and / or mono-allylic positions of a compound compared to the same compound without deuteration. It may be calculated as follows: Degree of deuteration at the bis-allylic position (%) = Number of deuterium atoms at the bis-allylic position of the compound / Total number of hydrogen and deuterium atoms at the bis-allylic position of the compound

[0080] For a mixture containing deuterated compounds with varying degrees of deuteration (for example, a mixture containing equal amounts of compound A and B, each with degrees of deuteration of 33.3% and 66.7%, respectively), the total degree of deuteration of the mixture can be calculated as follows: Compound A * Deuterated degree molar percentage + compound B * Mole percentage of deuterated degree

[0081] For example, if the product mixture contains equimolar amounts of the following three compounds: [ka] The degree of deuteration at the bis-allyl position is 66.7%. A more practical method for determining the total percentage of deuteration is proton-carbon 13 NMR bis-allyl peak integration measurement (proton-carbon 13 This relies on NMR bis-allylic peak integration measurements and mass spectrometry.

[0082] (composition) Some embodiments relate to compositions comprising one or more isotopically modified polyunsaturated lipids having isotopes primarily at one or more bis-allylic positions, wherein the isotopically modified polyunsaturated lipids are prepared by the method described in any one of the claims. In some embodiments, the isotope is deuterium. In some embodiments, the isotope is tritium.

[0083] In some embodiments, the isotope-modified polyunsaturated lipids in the compositions described herein are deuterated primarily at the bis-allyl moiety. In some embodiments, the compositions described herein contain polyunsaturated lipids having two or more carbon-carbon double bonds. In some embodiments, the compositions described herein contain polyunsaturated lipids having three or more carbon-carbon double bonds.

[0084] It is readily apparent that when one of the two hydrogen atoms of a methylene group is replaced by a deuterium atom, the resulting compound may have a stereocenter. In some embodiments, it may be desirable to use racemic compounds. In other embodiments, it may be desirable to use enantiomerically pure compounds. In further embodiments, it may be desirable to use diastereomerically pure compounds. In some embodiments, it may be desirable to use mixtures of compounds having enantiomeric and / or diastereomer excesses of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 65%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or a range bounded by any two of the aforementioned percentages. In some embodiments, it may be preferable to utilize the stereochemically pure enantiomers and / or diastereomers of the embodiments, for example, when enzymatic 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 targeted to attenuate oxidative damage. In such situations, embodiments may be used without regard to their stereochemical purity. Furthermore, in some embodiments, mixtures of enantiomers and diastereomers may be used even when the compounds target enzymatic reactions and / or chiral molecules to attenuate oxidative damage.

[0085] In some embodiments, isotope-modified compounds confer a certain amount of heavy atoms to a particular tissue upon administration. Thus, in some embodiments, the amount of heavy molecules is a specific percentage of the same type of molecule in the tissue. For example, the percentage of heavy molecules may be at least about 0.001%, 0.005%, 0.1%, 1%, 10%, 20%, 30%, 40%, or 50% of the same type of molecule in the tissue (i.e., naturally occurring as opposed to isotope-modified).

[0086] Treatment methods Some embodiments provide methods for treating, improving, or preventing diseases or conditions related to lipid peroxidation or lipid autooxidation in a subject requiring such treatment, comprising administering an effective amount of one or more isotopically modified polyunsaturated lipids or pharmaceutically acceptable salts thereof to the subject. In some embodiments, the administered isotopically modified polyunsaturated lipid comprises about 1% to about 99%, about 1% to about 10%, or about 1% to about 5% of the total amount of fats, fatty acids, and fatty acid esters administered to or ingested by the subject. In some further embodiments, one or more isotopically modified polyunsaturated lipids or pharmaceutically acceptable salts thereof constitute less than about 5%, less than about 2%, or less than 1% of the total amount of fats, fatty acids, and fatty acid esters administered to or ingested by the subject.

[0087] In some embodiments described herein, the disease or condition is a neurological condition or neurodegenerative condition. In some further embodiments, the neurological condition is Alzheimer's disease, Parkinson's disease, mild cognitive impairment, frontal lobar degeneration, amyotrophic lateral sclerosis, ataxia (such as Friedreich's ataxia), Down syndrome, epilepsy, Huntington's disease, infantile axonal dystrophy (INAD), Alpers disease, schizophrenia, Wilson's disease, cerebral iron-storing neurodegeneration (NBIA), progressive supranuclear palsy (PSP), multiple sclerosis, Creutzfeldt-Jakob disease, Duchenne muscular dystrophy, Smith-Lemle-Oppitz syndrome (SLOS), Rett syndrome, Gaucher type II, or Angelman syndrome. In some other embodiments, tauopathy is associated with neurodegenerative diseases or conditions, such as argyurophilic-Greun disease (AGD), chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), chromosome 17-associated frontotemporal dementia and parkinsonism (FTDP-17), gangliomas, gangliocytomas, lipofuscinosis, Ritkobodigg disease, meningeal hemangioma, pantothenate kinase-associated neurodegeneration (PKAN), Pick's disease, hindbrain parkinsonism, primary senescent tau degeneration (PART), Steele-Richardson-Olsewski syndrome (SROS), 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 disorder is Batten disease, Nieman-Pick disease, Tay-Sachs disease, Sandhoff disease, or ataxia with vitamin E deficiency (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, cataract, diabetic retinopathy, Leber hereditary optic neuropathy (LHON), Leber congenital amaurosis, macular telangiectasia, Stargardt disease, glaucoma, optic neuropathy, or oculopalsy.

[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 thermal allodynia (pain resulting from stimuli that are not normally painful); or increased response to painful stimuli (such as hyperalgesia, fibromyalgia, and activation of the TRPA1 receptor).

[0091] In some embodiments described herein, the disease or condition is a sleep disorder. Non-exclusive examples of sleep disorders include lifestyle-related sleep deprivation; alcohol-related sleep deprivation; idiopathic hypersomnia; narcolepsy; various sleep apnea disorders; various parasomnias; restless limb syndromes; sleep state misidentification; mood disorders such as depression; anxiety disorders; panic attacks; psychoses such as schizophrenia; and circadian rhythm-related sleep disorders, including jet lag-related disorders and night shift-related conditions.

[0092] In some embodiments described herein, the disease or condition is an energy processing disorder or mitochondrial deficiency, such as: coenzyme Q deficiency, mitochondrial complex IV deficiency; diabetes mellitus and hearing loss (DAD); maternal inherited diabetes mellitus and hearing loss (MIDD); Barth syndrome; Leigh syndrome; Kearns-Sayre syndrome (KSS); mitochondrial myopathy; mitochondrial encephalopathy, lactic acidosis; stroke-like episode (MELAS); mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); myoclonus epilepsy (MERRF) syndrome, myoneurogenic gastroenteropathy (MNGIE) and neuropathy, Wolff-Parkinson-White syndrome and other cardiomyopathy, X-linked adrenoleukodystrophy (X-ALD), musculoskeletal disorders (lipid myopathy, chronic fatigue, fibromyalgia), kidney (Fanconi syndrome, glomerulonephropathy), blood (Pearson syndrome, sideroblastic anemia), and brain (migraine, seizure, cerebral infarction).

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

[0094] In some embodiments described herein, the disease or condition is a dyslipidemia or a cardiac-related condition, such as lipodystrophy, lipotoxicity, ischemic heart disease, hypertension, atrial fibrillation, left ventricular hypertrophy, coronary artery disease, or atherosclerosis.

[0095] In some further embodiments, at least a certain amount of isotopically modified polyunsaturated lipids are incorporated into the patient's body after administration so that the incorporated compound is sufficient to reduce or prevent lipid autooxidation of natural (undeuterated) polyunsaturated fatty acids or esters in the subject's body. In some embodiments, the method also reduces ferroptosis.

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

[0097] It is also considered that formulating polyunsaturated lipids in salt form may be useful. For example, the use of salt formation as a means of modifying the properties of pharmaceutical compounds is well known. See Stahl et al., Handbook of pharmaceutical salts: Properties, selection and use (2002) Weinheim / Zurich: Wiley-VCH / VHCA; Gould, Salt selection for basic drugs, Int. J. Pharm (1986), 33:201-217. Salt formation can be used to increase or decrease solubility, to improve stability or toxicity, and to reduce the hygroscopicity of formulations.

[0098] Preparations of polyunsaturated lipids as salts include, but are not limited to, the use of basic inorganic salt-forming agents, basic organic salt-forming agents, and salt-forming agents containing both acidic and basic functional groups. A variety of useful inorganic bases for salt formation include, but are not limited to, alkali metal salts such as lithium, sodium, potassium rubidium, cesium, and francium salts, as well as alkaline earth metal salts such as beryllium, magnesium, calcium, strontium, barium, and radium, and metals such as aluminum. These inorganic bases may also be counterions, such as carbonates, bicarbonates, sulfates, bisulfites, sulfites, bisulfites, phosphates, hydrogen phosphates, dihydrogen phosphates, phosphates, hydrogen phosphites, hydroxides, oxides, sulfides, alkoxides, such as methoxides, ethoxides, and t-butoxides. Various useful organic bases for salt formation include, but are not limited to, amino acids, basic amino acids such as arginine, lysine, and ornithine; ammonia, alkylamines such as methylamine, dimethylamine, diethylamine, diethylamine, trimethylamine, and triethylamine; heterocyclic amines such as pyridine and picoline; alkanolamines such as ethanolamine, diethanolamine, and triethanolamine; diethylaminoethanol, dimethylaminoethanol, N-methylglucamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, ethylenediamine, piperazine, choline, trolamine, imidazole, diolamine, betaine, tromethamine, meglumine, and chloroprocaine.

[0099] Pharmacokinetically acceptable salts are well known in the art and include many of the inorganic and organic bases mentioned above. Pharmacokinetically acceptable salts further include salts and salt-forming agents found in drugs approved by the Food and Drug Administration and foreign regulatory authorities. Examples of pharmaceutically acceptable organic cations for incorporation include, but are not limited to, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, benetamine, cremisole, diethylamine, piperazine, and tromethamine. Examples of pharmaceutically acceptable metal cations for incorporation include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, barium, and bismuth. Further salt-forming agents include, but are not limited to, arginine, betaine, carnitine, diethylamine, L-glutamine, 2-(4-imidazolyl)ethylamine, isobutanolamine, lysine, N-methylpiperazine, morpholine, and theobromine.

[0100] In addition to the useful selected compounds described above, some embodiments include compositions containing pharmaceutically acceptable carriers. As used herein, “pharmaceutically acceptable carrier” means one or more compatible solid or liquid fillers, diluents, or encapsulants suitable for administration to mammals. As used herein, “compatible” means that the components of the composition can be mixed with and with the subject compound in such a way that there are no interactions that substantially reduce the pharmaceutically effectiveness of the composition under normal use conditions. The pharmaceutically acceptable carrier must, of course, be sufficiently high in purity and sufficiently low in toxicity to be suitable for administration to the animals being treated, preferably mammals.

[0101] Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. Some examples of substances that serve as pharmaceutically acceptable carriers or components thereof are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils (such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and bobroma oil); polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; emulsifiers such as alginic acid and TWEENS; humectants such as sodium lauryl sulfate; colorants; fragrances; tablets; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic salines; and phosphate buffers.

[0102] Any pharmaceutically active material that does not substantially interfere with the inhibitory activity of the compound may be included. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of the substance for administration per unit dose of the compound. The techniques and compositions for producing formulations useful for the methods described herein are all included in the following references: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); Ansel, Introduction to Pharmaceutical Dosage Forms, 8th edition (2004).

[0103] Various oral administration forms are available, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets include compressed, wet tablets, enteric-coated, sugar-coated, film-coated, or multi-compressed tablets, and contain suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow inducers, and melting agents. Liquid oral administration forms include aqueous solutions; emulsions, suspensions, solutions and / or suspensions reconstituted from non-foaming granules, and effervescent preparations reconstituted from effervescent granules, and contain suitable solvents, preservatives, emulsifiers, dispersants, diluents, sweeteners, melting agents, colorants, and flavorings.

[0104] Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Tablets typically contain inert diluents, e.g., calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders, e.g., starch, gelatin, and sucrose; disintegrants, e.g., starch, alginic acid, and croscarmellose; lubricants, e.g., magnesium stearate, stearic acid, and talc. Flow enhancers, such as silicon dioxide, can be used to improve the flow properties of powder mixtures. Colorants, such as FD&C dyes, can be added for appearance. Sweeteners and flavorings, e.g., aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically contain one or more of the solid diluents disclosed above. The selection of carrier components depends on secondary considerations such as taste, cost, and storage stability, which are not critical and can be easily done by those skilled in the art.

[0105] Oral compositions also include liquid solutions, emulsions, suspensions, and the like. pharmaceutically acceptable carriers suitable for the preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more components such as sweeteners, flavorings, and colorants disclosed above.

[0106] Such compositions may also be coated by conventional methods, typically using pH or time-dependent coatings, at various time points so that the compound of the subject is released into the gastrointestinal tract near the desired topical application, or to extend the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, eudragit coating, wax, and shellac.

[0107] The compositions described herein may optionally contain other pharmacoactive substances or supplements. For example, the pharmaceutical composition is administered simultaneously with one or more antioxidants. In some embodiments, the antioxidant is selected from the group consisting of coenzyme Q, idebenone, mitokinone, mitokinol, vitamin E, and vitamin C, and combinations thereof. In some such embodiments, at least one antioxidant may be taken simultaneously with, before, or after the administration of 11,11-D2-linoleic acid or its esters. In some embodiments, the antioxidant and 11,11-D2-linoleic acid or its esters may be in single dosage forms. In some embodiments, the single dosage form is selected from the group consisting of pills, tablets, and capsules.

[0108] Those skilled in the art will understand that numerous modifications can be made without departing from the spirit of the invention. Therefore, it should be clearly understood that the embodiments of the invention disclosed herein are illustrative and not intended to limit the scope of the invention. Any references mentioned herein are incorporated herein by reference to the material discussed herein and in whole.

[0109] (Joint administration) In some embodiments, the polyunsaturated lipids disclosed herein are administered in combination with one or more antioxidants.

[0110] While antioxidants cannot counteract the negative effects of PUFA peroxidation due to the stochastic nature of the process and the stability of PUFA peroxidation products (reactive carbonyls) against antioxidant treatment, the co-administration of antioxidants with oxidation-resistant compositions, such as those described herein, may prove beneficial for treating oxidative stress-related disorders.

[0111] Specific antioxidants considered useful for co-administration include: vitamins such as vitamin C and vitamin E; glutathione, lipoic acid, uric acid, carotene, lycopene, lutein, anthocyanins, oxalic acid, phytic acid, tannins, coenzyme Q, melatonin, polyphenols including tocopherol, tocotrienol, and resveratrol, flavonoids, selenium, eugenol, idebenone, mitokinone, ubiquinone, Szeto-S cooling peptide, and mitochondrial-targeted antioxidants. Unless explicitly mentioned, quinone derivatives of the aforementioned antioxidants are also considered useful for co-administration.

[0112] (kit) Some additional embodiments of this disclosure relate to a kit comprising a pharmaceutical composition, formulation information, and a container, wherein the pharmaceutical composition comprises a therapeutically effective amount of one or more isotopically modified polyunsaturated lipids described herein. In some embodiments, the isotopically modified polyunsaturated lipid is a deuterated polyunsaturated acid (PUFA), or its ester, thioester, amide, phosphate, or other prodrug (such as a phospholipid derivative). In some further embodiments, 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-linoleic acid ethyl ester. In some embodiments, the formulation information advises the subject to take the pharmaceutical composition with food or between meals. The kit may comprise one or more unit dosage forms comprising 11,11-D2-linoleic acid or its esters. The unit dosage forms may be oral formulations. For example, the unit dosage forms may comprise pills, tablets, or capsules. The kit may contain multiple unit dosage forms. In some embodiments, the unit dosage forms are in a container. In some embodiments, the dosage form is a single oral dosage form containing 11,11-D2-linoleic acid or its ester, such as an ethyl ester.

[0113] The methods, compositions, and kits disclosed herein may include information. This information may be in a format prescribed by a government agency that regulates the manufacture, use, or sale of a medicinal product, and this notice reflects the agency's approval of a format for a medicinal product for human or veterinary administration. Such information may be, for example, a label or product insert approved by the U.S. Food and Drug Administration for a prescription drug. The information may include dosage and formulation, administration schedule and route, adverse events, contraindications, warnings and precautions, drug interactions, and necessary information regarding use in a particular population (see, for example, 21 CFR §201.57, which is incorporated herein by reference in its entirety), and in some embodiments, it is required to be present on or associated with the drug for the purpose of selling the drug. In some embodiments, the kit is for the sale of a prescription drug that requires and complies with regulatory approval from a government agency such as the U.S. Food and Drug Administration. In some embodiments, the kit includes a label or product insert required by an agency such as the FDA for the sale of the kit to consumers, for example, in the United States. In a preferred embodiment, the information instructs the individual to take 11,11-D2-linoleic acid or its esters during or with meals in order to reduce possible adverse events, such as gastrointestinal adverse events.

[0114] Instructions and / or information may exist in various forms, including printed information on a suitable medium or substrate (e.g., a piece of paper on which the information is printed), a computer-readable medium (e.g., a diskette or CD on which the information is recorded), or a website address accessible via the Internet. Printed information may be provided to the patient separately from the medicine, for example, on a label related to the medicine, on the medicine container, packaged with the medicine, or made available to the patient independently (e.g., a website). Printed information may also be provided to healthcare providers involved in the patient's treatment. In some embodiments, the information is provided orally.

[0115] Some embodiments include therapeutic packaging suitable for commercial sale. Some embodiments include containers. Containers may be any conventional shape or form known in the art, made from pharmaceutically acceptable materials, e.g., paper or cardboard boxes, glass or plastic bottles or jars, resealable bags (e.g., for holding "refills" of tablets for placement in different containers), or blister packs having individual doses for dispensing from the pack according to a therapeutic schedule. The container used may depend on the exact dosage form it contains; for example, conventional cardboard boxes are generally not used to hold liquid suspensions. It is possible to use two or more containers together in a single package for selling a single dosage form. For example, tablets may be contained in bottles housed in a box.

[0116] Information can be associated with a container in the following ways, for example: on a label (e.g., a prescription label or a separate label) affixed to the bottle containing the dosage form described herein; included inside the container as an accompanying document, such as inside the box containing the unit dose packet; affixed directly to the container, such as printed on the wall of the box; or affixed by being tied or taped, for example, as an instruction card attached to the neck of the bottle via a string, cord or other line, lanyard, or tether-type device. Information may also be printed directly on the unit dose pack, blister pack, or blister card.

Claims

1. A method for isotopic modification of polyunsaturated lipids, A step of reacting a polyunsaturated lipid with an isotope-containing agent in the presence of a transition metal catalyst to obtain an isotope-modified polyunsaturated lipid having isotopes at one or more bis-allylic positions, The isotope-containing agent comprises at least one isotope selected from the group consisting of deuterium, tritium, and combinations thereof, and the transition metal catalyst has the structure of formula (I); [ML １ (L ２ ) ｍ (L ３ ) ｎ ] ｐ Q ｋ (I) Here M is rhodium, iridium, or ruthenium. Each L １ These are independently cyclopentadienyl or benzene, Each L ２ is acetonitrile, Each L ３ is -CH3, -NCH3, or -OCH3, m is 2, n is 1, p is an integer of 1, 2, 3, or 4. Q is an anion; and k is one of 0, 1, or 2. Methods for isotopic modification of polyunsaturated lipids.

2. The method according to claim 1, wherein p is independently 1.

3. The method according to claim 1 or 2, wherein k is 0.

4. The method according to claim 1 or 2, wherein k is 1 and Q is a single negatively charged anion.

5. Q is PF ６ － , Cl － F － , I － , Br － NO ３ － CIO ４ － BF ４ － , B (C １ -C ４ Alkyl 1) ４ － Al(C) １ -C ４ Alkyl 1) ４ － , B (C ６ -C １０ Aryl 1) ４ － Al(C) ６ -C １０ Aryl 1) ４ － The method according to claim 4, wherein the method is a carborane anion.

6. The method according to any one of claims 1 to 5, wherein the isotope-containing agent contains deuterium.

7. The isotope-containing agent is D ２ O, DO(C １ -C １２ Alkyl), T ２ O, or TO (C １ -C １２ The method according to any one of claims 1 to 5, wherein the alkyl group is, or a combination thereof.

8. The isotope-containing agent is D ２ O, DO(C １ -C １２ The method according to any one of claims 1 to 7, wherein the alkyl group is, or a combination thereof.

9. The method according to any one of claims 1 to 8, wherein the reaction between the polyunsaturated lipid and the isotope-containing agent is carried out in an acidic reaction medium comprising an acidic aqueous solution, an acidic solvent, a mixture of acidic solvents, or a combination thereof.

10. The method according to claim 9, wherein the acidic reaction medium comprises one or more pH adjusting agents selected from the group consisting of organic acids, inorganic acids, Lewis acids, and combinations thereof.

11. The method according to any one of claims 1 to 10, wherein the polyunsaturated lipid is selected from the group consisting of fatty acids, fatty acid esters, fatty acid thioesters, fatty acid amides, and phospholipids.

12. The method according to claim 11, wherein the polyunsaturated lipid has two or more carbon-carbon double bonds.

13. The polyunsaturated lipid has the structure of formula (III), according to any one of claims 1 to 12. 【Chemistry 1】 Here, R is H or C １ -C １０ It is alkyl, R’は、-OR ５ 、-SR ５ 、-O(CH ２ )CH(OR ６ａ )CH ２ (OR ６ｂ )、-NR ７ R ８ 、 【Chemistry 2】 can be, R ５ H, and C as arbitrarily substituted. １ -C ２１ Alkyl, optionally substituted C ２ -C ２１ Alkenyl, optionally substituted C ２ -C ２１ Alkinyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ６ -C １０ These are aryls, optionally substituted 4-10 membered heteroaryls, optionally substituted 3-10 membered heterocyclines, monosaccharides, disaccharides, or oligosaccharides. R ６ａ and R ６ｂ These are independently H, and arbitrarily substituted -C (=O)C. １ -C ２１ Alkyl, optionally substituted -C(=O)C ２ -C ２１ Alkenyl, or optionally substituted -C(=O)C ２ -C ２１ It is alkinyl, R ７ and R ８ are, independently, H, optionally substituted C １ -C ２１ alkyl, optionally substituted C ２ -C ２１ alkenyl, optionally substituted C ２ -C ２１ alkynyl, optionally substituted C ３ -C １０ cycloalkyl, optionally substituted C ６ -C １０ aryl, optionally substituted 4- to 10-membered heteroaryl, or optionally substituted 3- to 10-membered heterocyclyl, or R ７ and R ８ are, together with the nitrogen atom to which they are attached, form an optionally substituted 3- to 10-membered heterocyclyl, R ９ is optionally substituted C １ -C ２１ -alkyl, optionally substituted C ２ -C ２１ -alkenyl, optionally substituted C ２ -C ２１ -alkynyl, and R １０ H, -CH ２ CH ２ N(CH ３ ) ３ ＋ ien-CH ２ CH ２ NH ２ ien-CH ２ CH ２ NH ３ ＋ ien-CH ２ CH(NH ２ )C(=O)O － ien-CH ２ CH(OH)CH ２ OH, monosaccharide, disaccharide, or oligosaccharide, R １１ is an arbitrarily substituted C ８ -C ２１ Alkinyl, optionally substituted C ８ -C ２１ Alkynyl, or optionally substituted C ８ -C ２１ It is alkinyl, R １２ H, 【Transformation 3】 It is a monosaccharide, disaccharide, or oligosaccharide. p and q are independently integers of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

14. The method according to any one of claims 1 to 13, wherein the polyunsaturated lipid is an omega-3 fatty acid, an omega-6 fatty acid, or an omega-9 fatty acid, or an ester thereof.

15. The method according to claim 14, wherein the polyunsaturated lipid is linoleic acid, linolenic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, or esters thereof.

16. The method according to claim 14 or 15, wherein the polyunsaturated fatty acid ester is an alkyl ester, a triglyceride, a diglyceride, or a monoglyceride.

17. The method according to claim 16, wherein the fatty acid ester is an ethyl ester.

18. The method according to any one of claims 1 to 17, wherein the isotope-modified polyunsaturated lipid is deuterated at one or more bis-allyl positions.

19. The method according to claim 18, wherein the isotope-modified polyunsaturated lipid is deuterated at all bis-allylic positions after the reaction product.

20. The method according to claim 18 or 19, wherein the polyunsaturated lipid has a degree of deuteration of at least 50% at the bis-allyl position after the reaction.

21. The method according to claim 20, wherein the polyunsaturated lipid has a degree of deuteration of more than 80% at the bis-allyl position after the reaction.

22. The method according to any one of claims 1 to 21, wherein the isotope-modified polyunsaturated lipid is further deuterated at one or more monoallylic positions.

23. The method according to claim 22, wherein the polyunsaturated lipid has a degree of deuteration of less than 30% at the monoallylic position after the reaction.

24. The method according to any one of claims 1 to 23, for producing a mixture of isotopically modified polyunsaturated lipids having a variety of isotopic atoms.

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