HK1170722B - Polyunsaturated fatty acids for the treatment of diseases related to cardiovascular, metabolic and inflammatory disease areas - Google Patents

Description

Polyunsaturated fatty acids for the treatment of diseases related to the cardiovascular, metabolic and inflammatory disease fields

Priority

This application claims priority from U.S. provisional patent application 61/176,503 filed on 8.5.2009, the contents of which are incorporated by reference.

Technical Field

The present disclosure relates to lipid compounds of general formula (I) or pharmaceutically acceptable salts, solvates of such salts, or prodrugs thereof:

wherein

●R₁Is C₁₀-C₂₂Alkyl, C having 1-6 double bonds₁₀-C₂₂Alkenyl, or C having 1-6 triple bonds₁₀-C₂₂An alkynyl group;

●R₂and R₃Identical or different and can be chosen from hydrogen atoms, hydroxyl groups, alkyl groups, halogen atoms, alkoxy groups, acyloxy groups, acyl groups, alkenyl groups, alkynyl groups, aryl groups, alkylthio groups, alkoxycarbonyl groups, carboxyl groups, alkylsulfinyl groups, alkylsulfonyl groups, amino groups and alkylamino groups, with the proviso that R is a hydrogen atom, a hydroxyl group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group₂And R₃Cannot all be hydrogen atoms; or

●R₂And R₃Together form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane;

● X is a carboxylic acid group or derivative thereof, such as a carboxylic acid ester, carboxylic acid anhydride, carboxamide, phospholipid, monoglyceride, diglyceride, or triglyceride.

In which R is₂And R₃In various embodiments, the compounds of formula (I) may exist in stereoisomeric forms. It is to be understood that the present invention encompasses all optical isomers of the compounds of formula (I) and mixtures thereof.

The present disclosure also relates to pharmaceutical and lipid compositions comprising at least one compound of formula (I). Furthermore, the disclosure includes the use of the compounds of formula (I) as medicaments or in therapy, for example for the treatment of diseases related to the cardiovascular, metabolic and inflammatory disease areas.

Background

Dietary polyunsaturated fatty acids (PUFAs) have an impact on a variety of physiological processes affecting normal health and chronic diseases, such as modulation of blood lipid levels, cardiovascular and immune function, insulin action, neuronal development and visual function.

Because of their limited stability in vivo and their lack of biospecificity, PUFAs have not achieved widespread use as therapeutic agents. Several groups have performed chemical modifications of n-3 polyunsaturated fatty acids to alter or enhance their effect.

For example, the hypolipidemic effect of (4Z,7Z,10Z,13Z,16Z,19Z) -docosahexenoic acid (DHA) is potentiated by introducing a substituent at the alpha position of (4Z,7Z,10Z,13Z,16Z,19Z) -docosahexenoic acid ethyl ester (dheae) (WO 2006/117664). Treatment of high fat bred obese mice with alpha substituted DHA derivatives is reported to prevent and reverse obesity and glucose intolerance (Rossmeisl, m., et al, obecity (silver spring)2009, 1 month and 15 days).

Several groups have produced unsaturated fatty acids that introduce oxygen at the beta position (Flock, S. et al, Acta ChemicaScandinavica, (1999) 53: 436 and Pitt, MJ, et al, Synthesis, (1997) 1240-42).

A new group of fatty acid derivatives represented by general formula (I) in which oxygen is introduced at the β -position and which have an α -substituent has been developed. These novel fatty acids reduce blood lipid levels in mouse models of dyslipidemia to a greater extent than natural polyunsaturated fatty acids.

Drawings

FIG. 1: in administration of one embodiment of the present application and Omacor^TMThereafter, cholesterol and triglyceride levels in APOE x 3 retton mice.

FIG. 2: cholesterol and triglyceride levels in APOE x 3 leton CETP mice following administration of one embodiment of the present application and fenofibrate.

FIG. 3: HDL levels in APOE x 3 leton CETP mice following administration of one embodiment of the present application and fenofibrate.

Disclosure of Invention

It is an object of the present disclosure to provide lipid compounds having improved biological activity compared to natural polyunsaturated fatty acids. This object is achieved by a lipid compound of the formula (I),

for example, the present disclosure relates to compounds of formula (I) or a pharmaceutically acceptable salt, solvate of such a salt, or prodrug thereof, wherein:

●R₁is C₁₀-C₂₂Alkyl, C having 1-6 double bonds₁₀-C₂₂Alkenyl, or C having 1-6 triple bonds₁₀-C₂₂An alkynyl group;

●R₂and R₃Identical or different and can be chosen from hydrogen atoms, hydroxyl groups, alkyl groups, halogen atoms, alkoxy groups, acyloxy groups, acyl groups, alkenyl groups, alkynyl groups, aryl groups, alkylthio groups, alkoxycarbonyl groups, carboxyl groups, alkylsulfinyl groups, alkylsulfonyl groups, amino groups and alkylamino groups,provided that R is₂And R₃Cannot all be hydrogen atoms; or

●R₂And R₃Together form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane;

● X is a carboxylic acid group or derivative thereof, such as a carboxylate, carboxylic anhydride, carboxamide, phospholipid or triglyceride group.

In at least one embodiment, the alkyl group may be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and n-hexyl. The alkenyl group may be selected from allyl, 2-butenyl, and 3-hexenyl. The alkynyl group may be selected from propargyl, 2-butynyl and 3-hexynyl. The halogen atom may be selected from fluorine, chlorine, bromine and iodine. Said alkoxy group is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, sec-butoxy, phenoxy, benzyloxy, OCH₂CF₃And OCH₂CH₂OCH₃. The acyloxy group may be selected from acetoxy, propionyloxy and butyryloxy. The aryl group is phenyl. The alkylthio group may be selected from methylthio, ethylthio, isopropylthio and phenylthio. The alkoxycarbonyl group may be selected from methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl. The alkylsulfinyl group may be selected from the group consisting of methanesulfinyl, ethanesulfinyl and isopropylsulfinyl. The alkylsulfonyl group may be selected from methylsulfonyl, ethylsulfonyl and isopropylsulfonyl. The alkylamino group may be selected from methylamino, dimethylamino, ethylamino, and diethylamino. The carboxylate group may be selected from the group consisting of ethyl carboxylate, methyl carboxylate, n-propyl carboxylate, isopropyl carboxylate, n-butyl carboxylate, sec-butyl carboxylate, and n-hexyl carboxylate. The carboxamide group may be selected from amide groups such as N-methylcarboxamide, N-dimethylcarboxamide, N-ethylcarboxamide and N, N-diethylcarboxamide groups.

In at least one embodiment of the invention, the substituent R of the compound of formula (I)₂And R₃One of them is hydrogen and the other is selected from the group consisting of a hydroxyl group, an alkyl group, a halogen atom, an alkoxy group, a,Acyloxy, acyl, alkenyl, alkynyl, aryl, alkylthio, alkoxycarbonyl, carboxy, alkylsulfinyl, alkylsulfonyl, amino and alkylamino.

In another embodiment of the invention, the substituent R of the compounds of the formula (I)₂And R₃Identical or different and can be chosen from hydroxyl, alkyl, halogen atoms, alkoxy, acyloxy, acyl, alkenyl, alkynyl, aryl, alkylthio, alkoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl, amino. For example, R₂And R₃Can be selected from methyl, ethyl, n-propyl or isopropyl.

When the compound of formula (I) is derived from or prepared from a polyunsaturated fatty acid, R₁Typically a C having 3-6 double bonds (e.g., 3-6 methylene interrupted Z-type double bonds)₁₀-C₂₂An alkenyl group. For example, R₁Can be selected from:

● C with 4 methylene interrupted double bonds of the Z type₁₅An alkenyl group, which is a radical of an alkenyl group,

● C with 3-5 double bonds₁₈Alkenyl, e.g. C with 5 methylene interrupted double bonds of the Z type₁₈An alkenyl group, which is a radical of an alkenyl group,

● C with 5 methylene interrupted double bonds of the Z type₂₀Alkenyl, or

● C with 6 methylene interrupted double bonds of the Z type₂₂An alkenyl group.

Furthermore, R₁May be C₁₀-C₂₂Alkynyl, e.g. C having 1-6 triple bonds₁₆-C₂₂Alkynyl.

The disclosure also relates to salts of the compounds of formula (I). The salt may be represented by the formula:

wherein X is COO^-And Z is⁺May be NH₄ ⁺Metal ions (e.g. Li)⁺、Na⁺Or K⁺) Protonated primary amines (e.g., t-butylammonium, (3s, 5s, 7s) -adamantan-1-ammonium, 1, 3-dihydroxy-2- (hydroxymethyl) propan-2-ammonium), protonated aminopyridines (e.g., pyridin-2-ammonium), protonated secondary amines (e.g., diethylammonium, 2,3, 4, 5, 6-pentahydroxy-N-methylhexan-1-ammonium, N-ethylnaphthalen-1-ammonium), protonated tertiary amines (e.g., 4-methylmorpholin-4-) Protonated guanidines (e.g. amino ((4-amino-4-carboxybutyl) amino) methylimino)) Or protonated heterocycles (e.g. 1H-imidazole-3-)，

Alternatively, it is represented by the following formula:

wherein X ═ COO^-And Z is²⁺May be Mg²⁺Or Ca²⁺Or a di-protonated diamine (e.g. ethylene-1, 2-diammonium or piperazine-1, 4-di)。

Another representative salt is

Wherein X is COO^-And Z isⁿ⁺Is a protonated chitosan:

furthermore, the present disclosure relates to compounds of formula (I) wherein X is a carboxylic acid group, said carboxylic acid group being in phospholipid form. The compound may be represented by the following formula (II-IV),

wherein W is:

wherein W is:

wherein W is:

compounds of formula (I) wherein X is a carboxylic acid group in the form of a triglyceride, a 1, 2-diglyceride, a 1, 3-diglyceride, a 1-monoglyceride and a 2-monoglyceride are also included in the present disclosure. These are hereinafter represented by the formulae (V), (VI), (VII), (VIII) and (IX), respectively.

The compounds of formula (I) can exist in stereoisomeric forms. It is to be understood that the present invention encompasses all optical isomers of the compounds of formula (I) and mixtures thereof. Thus, compounds of formula (I) that exist as diastereomers, racemates and enantiomers are included within the scope of the present disclosure.

The present disclosure also relates to at least one lipid compound of formula (I) for use as a medicament.

In another embodiment, the present disclosure provides a food supplement, food additive or nutritional formulation comprising the lipid compound of formula (I).

The food supplement may be formulated for administration by any route of administration. For example, the food supplement may be administered as a liquid nutritional agent or as a beverage.

The food supplement may be in the form of a capsule (e.g., a gelatin capsule), and the capsule may be flavored.

In another embodiment, the present disclosure provides a pharmaceutical composition comprising at least one compound of formula (I) and optionally one or more pharmaceutically acceptable carriers or excipients.

The novel lipid compounds and compositions disclosed herein may be formulated into conventional oral dosage forms such as tablets, coated tablets, capsules, powders, granules, solutions, dispersions, suspensions, syrups, emulsions and sprays, using conventional excipients such as solvents, diluents, binders, sweeteners, flavorants, pH regulators, viscosity regulators, antioxidants, corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, ethanol, glycerol, sorbitol, polyethylene glycol, propylene glycol, cetostearyl alcohol, carboxymethylcellulose, or fatty substances (e.g., hard fat), or suitable mixtures thereof. Conventional formulation techniques well known in the art may be used to formulate the lipid compounds disclosed herein.

The compositions may be administered by conventional routes of administration (e.g., orally). The use of orally-administrable compositions (e.g., tablets, coated tablets, capsules, or syrups) is included within the scope of the present disclosure. For example, in some embodiments, the composition may be in the form of a gelatin capsule, tablet, or sachet.

A suitable daily dose of the at least one compound according to formula (I) may be from about 1mg to about 3 g. For example, in some embodiments, the daily dose is from about 1mg to about 10g, from about 50mg to about 1g, from about 10mg to about 2g, from about 50mg to about 500mg, from about 50mg to about 200mg, from about 100mg to about 1g, from about 100mg to about 500mg, or from about 100mg to about 250 mg.

The pharmaceutical compositions disclosed herein may be used as medicaments.

The present disclosure also relates to lipid compositions comprising at least one lipid compound according to formula (I). Suitably, the lipid composition may comprise at least 60 wt.%, or at least 80 wt.% of at least one compound of formula (I).

The lipid composition may further comprise a pharmaceutically acceptable antioxidant, such as tocopherol or 3-BHA.

Furthermore, the disclosure also relates to the lipid composition for use as a medicament.

Furthermore, the present disclosure also relates to the use of a lipid compound of formula (I) in:

● activates or modulates at least one of the human peroxisome proliferator-activated receptor (PPAR) subtypes alpha, gamma, or vice versa, wherein the compound is, for example, a pan-agonist (pan-angonist) or a modulator,

● the prevention or treatment of inflammation is provided,

● can be used for the prevention or treatment of rheumatoid arthritis,

● for the prevention or treatment of inflammatory bowel disease,

● can be used for the prevention or treatment of metabolic syndrome,

● prevent and/or treat dyslipidemia, such as Hypertriglyceridemia (HTG),

● prevent and/or treat elevated triglyceride levels, LDL cholesterol levels and/or VLDL cholesterol levels,

● for the treatment and/or prevention of obesity or overweight,

● reducing body weight and/or preventing weight gain,

● for the treatment and/or prevention of fatty liver disease, such as non-alcoholic fatty liver disease (NAFLD),

● for the treatment and/or prevention of inflammatory diseases or conditions,

● for the treatment and/or prevention of atherosclerosis,

● for the treatment and/or prevention of peripheral insulin resistance (peripheral insulin resistance) and/or diabetes,

● for the treatment and/or prevention of type II diabetes, or

● reduce plasma insulin, blood glucose and/or serum triglycerides.

The present disclosure also relates to lipid compounds of formula (I) for use in treating the above-mentioned conditions, and methods of treating and/or preventing the above-mentioned conditions comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I).

Furthermore, the present disclosure encompasses methods of making the lipid compounds of formula (I). The feedstock may, for example, be derived from plants, microorganisms and/or animals, such as marine fish oil. In at least one embodiment, a marine oil or krill oil is used.

Detailed Description

The present inventors have found that the compounds of formula (I) have quite good pharmaceutical activity.

The term "lipid compound" as used herein refers to fatty acid analogues derived from, for example, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, and lipids having 1-6 triple bonds. It is understood that "derived from" includes the preparation of compounds of formula (I) from fatty acids (e.g., saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids) and lipids having 1-6 triple bonds. The fatty acids may be natural or synthetic.

"pharmaceutically effective amount" refers to an amount that will result in the desired pharmacological and/or therapeutic effect, i.e., an amount of a product disclosed herein that is effective to achieve its intended purpose. Although individual patient needs may vary, it is within the skill of the art to determine the optimal range for an effective amount of the product disclosed herein. In general, the dosing regimen for treating a condition with the products disclosed herein is selected according to a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient.

By "pharmaceutical composition" is meant a lipid compound of the present application in any form suitable for medical purposes.

"treatment" includes any therapeutic application that can benefit a human or non-human mammal. Both human and veterinary treatment are within the scope of the present disclosure. Treatment may be for an existing condition, or it may be prophylactic, e.g., disease-preventing.

Fatty acids are straight chain hydrocarbons having a carboxyl group (COOH) at one end (α) and a methyl group (typically) at the other end (ω). Chemically, the numbering of the carbon atoms starts at the alpha terminus.

Alpha carbon refers to the first carbon after the carbon to which the functional group is attached, and the second carbon is beta carbon.

The expression "methylene interrupted double bond" as used herein refers to a methylene group (-CH) in the carbon chain of a lipid compound₂-) is located between two double bonds.

More specifically, the present inventors have unexpectedly found that the following lipid compound classes a-D are particularly preferred.

Class A

● derived from saturated fatty acids

●R₁Is C₁₀-C₂₂Alkyl radical

Example i:

R₁＝C₁₄

class B

● derived from monounsaturated fatty acids

●R₁Is C having 1 double bond₁₀-C₂₂Alkenyl radical

Example ii:

R₁＝C₁₈

example iii:

R₁＝C₁₄

class C:

● derived from polyunsaturated fatty acids

●R₁Is C having 5 double bonds₂₀Alkenyl radical

Example iv:

R₁C-Z-type double bond with 5 methylene interruptions₂₀

Class D:

● derived from polyunsaturated fatty acids

●R₁Is C having 6 double bonds₂₂Alkenyl radical

Example v:

R₁C-Z-type double bond with 6 methylene interruptions₂₂

Class E:

● derived from polyunsaturated fatty acids

●R₁Is C having 3 double bonds₁₈Alkenyl radical

Example vi:

R₁C-Z-type double bond with 3 methylene interruptions₁₈

Class F:

● derived from polyunsaturated fatty acids

●R₁Is C having 4 double bonds₁₅Alkenyl radical

Example vii:

R₁C-Z-type double bond with 4 methylene interruptions₁₅

Category G:

● derived from polyunsaturated fatty acids

●R₁Is C having 5 double bonds₁₈Alkenyl radical

Example viii:

R₁C-Z-type double bond with 5 methylene interruptions₁₈

Class H:

● X is a carboxylic acid group in the form of a triglyceride, diglyceride, monoglyceride, or phospholipid

Example ix:

x ═ carboxylic acid groups in the form of triglycerides

Example x:

x ═ carboxylic acid group, in the form of 2-monoglycerides

Class I

● X is a carboxylate

Example xi:

● n is 1 or 2

Class J

● derived from lipids having 1-6 triple bonds

●R₁Is C₁₀-C₂₂Alkynyl radical

Example xii:

R₁c with 1 triple bond₁₄

Wherein R is₂And R₃The different above mentioned compounds of classes a-J can exist in stereoisomeric forms, i.e. the application covers all optical isomers of said compounds as well as mixtures thereof. Thus, the compounds may exist as diastereomers, racemates and enantiomers.

Specific examples of preferred lipid compounds of the present application include:

class A:

2- (tetradecyloxy) butyric acid (1)

R₁＝C₁₄H₂₉，R₂Ethyl, R₃H and X COOH

2-Ethyl-2- (tetradecyloxy) butanoic acid (2)

R₁＝C₁₄H₂₉，R₂＝R₃Ethyl and X-COOH

2- (tetradecyloxy) propionic acid (3)

R₁＝C₁₄H₂₉，R₂Methyl, R₃H and X COOH

2-methyl-2- (tetradecyloxy) propionic acid (4)

R₁＝C₁₄H₂₉，R₂＝R₃Methyl and X-COOH

2-methoxy-2- (tetradecyloxy) acetic acid (5)

R₁＝C₁₄H₂₉，R₂Methoxy radical, R₃H and X COOH

2-ethoxy-2- (tetradecyloxy) acetic acid (6)

R₁＝C₁₄H₂₉，R₂Ethoxy, R₃H and X COOH

Class B:

(Z) -2- (tetradec-6-en-1-yloxy) butanoic acid (7)

R₁＝C₁₄H₂₇，R₂Ethyl, R₃H and X COOH

(Z) -2-Ethyl-2- (tetradec-6-en-1-yloxy) butanoic acid (8)

R₁＝C₁₄H₂₇，R₂＝R₃Ethyl and X-COOH

(Z) -2- (tetradec-6-en-1-yloxy) propionic acid (9)

R₁＝C₁₄H₂₇，R₂Methyl, R₃H and X COOH

(Z) -2-methyl-2- (tetradec-6-en-1-yloxy) propionic acid (10)

R₁＝C₁₄H₂₇，R₂＝R₃Methyl and X-COOH

(Z) -2-methoxy-2- (tetradec-6-en-1-yloxy) acetic acid (11)

R₁＝C₁₄H₂₇，R₂Methoxy radical, R₃H and X COOH

(Z) -2-ethoxy-2- (tetradec-6-en-1-yloxy) acetic acid (12)

R₁＝C₁₄H₂₇，R₂Ethoxy, R₃H and X COOH

Class C:

2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-penten-1-yloxy) butanoic acid (13)

R₁＝C₂₀H₃₁，R₂Ethyl, R₃H and X COOH

2-Ethyl-2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-penten-1-yloxy) butanoic acid (14)

R₁＝C₂₀H₃₁，R₂＝R₃Ethyl and X-COOH

2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-penten-1-yloxy) propanoic acid (15)

R₁＝C₂₀H₃₁，R₂Methyl, R₃H and X COOH

2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-penten-1-yloxy) -2-methylpropanoic acid (16)

R₁＝C₂₀H₃₁，R₂＝R₃Methyl and X-COOH

2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-penten-1-yloxy) -2-methoxyacetic acid (17)

R₁＝C₂₀H₃₁，R₂Methoxy radical, R₃H and X COOH

2-ethoxy-2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-penten-1-yloxy) acetic acid (18)

R₁＝C₂₀H₃₁，R₂Ethoxy, R₃H and X COOH

Class D:

2- ((4Z,7Z,10Z,13Z,16Z,19Z) -docosae-4, 7,10,13,16, 19-hexaen-1-yloxy) butanoic acid (19)

R₁＝C₂₂H₃₃，R₂Ethyl, R₃H and X COOH

2- ((4Z,7Z,10Z,13Z,16Z,19Z) -docosae-4, 7,10,13,16, 19-hexaen-1-yloxy) -2-ethylbutanoic acid (20)

R₁＝C₂₂H₃₃，R₂＝R₃Ethyl and X-COOH

2- ((4Z,7Z,10Z,13Z,16Z,19Z) -docodeca-4, 7,10,13,16, 19-hexaen-1-yloxy) propanoic acid (21)

R₁＝C₂₂H₃₃，R₂Methyl, R₃H and X COOH

2- ((4Z,7Z,10Z,13Z,16Z,19Z) -docosae-4, 7,10,13,16, 19-hexaen-1-yloxy) -2-methylpropanoic acid (22)

R₁＝C₂₂H₃₃，R₂＝R₃Methyl and X-COOH

2- ((4Z,7Z,10Z,13Z,16Z,19Z) -docosae-4, 7,10,13,16, 19-hexaen-1-yloxy) -2-methoxyacetic acid (23)

R₁＝C₂₂H₃₃，R₂Methoxy radical, R₃H and X COOH

2- ((4Z,7Z,10Z,13Z,16Z,19Z) -docosae-4, 7,10,13,16, 19-hexaen-1-yloxy) -2-ethoxyacetic acid (24)

R₁＝C₂₂H₃₃，R₂Ethoxy, R₃H and X COOH

Class E:

2- ((9Z,12Z,15Z) -octadeca-9, 12, 15-trien-1-yloxy) butanoic acid (25)

R₁＝C₁₈H₃₁，R₂Ethyl, R₃H and X COOH

2-Ethyl-2- ((9Z,12Z,15Z) -octadeca-9, 12, 15-trien-1-yloxy) butanoic acid (26)

R₁＝C₁₈H₃₁，R₂＝R₃Ethyl and X-COOH

2- ((9Z,12Z,15Z) -octadeca-9, 12, 15-trien-1-yloxy) propanoic acid (27)

R₁＝C₁₈H₃₁，R₂Methyl, R₃H and X COOH

2-methyl-2- ((9Z,12Z,15Z) -octadeca-9, 12, 15-trien-1-yloxy) propanoic acid (28)

R₁＝C₁₈H₃₁，R₂＝R₃Methyl and X-COOH

2-methoxy-2- ((9Z,12Z,15Z) -octadeca-9, 12, 15-trien-1-yloxy) acetic acid (29)

R₁＝C₁₈H₃₁，R₂Methoxy radical, R₃H and X COOH

2-ethoxy-2- ((9Z,12Z,15Z) -octadeca-9, 12, 15-trien-1-yloxy) acetic acid (30)

R₁＝C₁₈H₃₁，R₂Ethoxy, R₃H and X COOH

Class F:

2- ((3Z,6Z,9Z,12Z) -pentadecan-3, 6,9, 12-tetraen-1-yloxy) butyric acid (31)

R₁＝C₁₅H₂₃，R₂Ethyl, R₃H and X COOH

2-Ethyl-2- ((3Z,6Z,9Z,12Z) -pentadecane-3, 6,9, 12-tetraen-1-yloxy) butanoic acid (32)

R₁＝C₁₅H₂₃，R₂＝R₃Ethyl and X-COOH

2- ((3Z,6Z,9Z,12Z) -pentadecane-3, 6,9, 12-tetraen-1-yloxy) propionic acid (33)

R₁＝C₁₅H₂₃，R₂Methyl, R₃H and X COOH

2-methyl-2- ((3Z,6Z,9Z,12Z) -pentadecane-3, 6,9, 12-tetraen-1-yloxy) propionic acid (34)

R₁＝C₁₅H₂₃，R₂＝R₃Methyl and X-COOH

2-methoxy-2- ((3Z,6Z,9Z,12Z) -pentadecane-3, 6,9, 12-tetraen-1-yloxy) acetic acid (35)

R₁＝C₁₅H₂₃，R₂Methoxy radical, R₃H and X COOH

2-ethoxy-2- ((3Z,6Z,9Z,12Z) -pentadecane-3, 6,9, 12-tetraen-1-yloxy) acetic acid (36)

R₁＝C₁₅H₂₃，R₂Ethoxy, R₃H and X COOH

Category G:

2- ((3Z,6Z,9Z,12Z,15Z) -octadeca-3, 6,9,12, 15-pent-1-yloxy) butanoic acid (37)

R₁＝C₁₈H₂₇，R₂Ethyl, R₃H and X COOH

2-Ethyl-2- ((3Z,6Z,9Z,12Z,15Z) -octadeca-3, 6,9,12, 15-penten-1-yloxy) butanoic acid (38)

R₁＝C₁₈H₂₇，R₂＝R₃Ethyl and X-COOH

2- ((3Z,6Z,9Z,12Z,15Z) -octadeca-3, 6,9,12, 15-pent-1-yloxy) propanoic acid (39)

R₁＝C₁₈H₂₇，R₂Methyl, R₃H and X COOH

2-methyl-2- ((3Z,6Z,9Z,12Z,15Z) -octadeca-3, 6,9,12, 15-pent-1-yloxy) propanoic acid (40)

R₁＝C₁₈H₂₇，R₂＝R₃Methyl groupAnd X ═ COOH

2-methoxy-2- ((3Z,6Z,9Z,12Z,15Z) -octadeca-3, 6,9,12, 15-penten-1-yloxy) acetic acid (41)

R₁＝C₁₈H₂₇，R₂Methoxy radical, R₃H and X COOH

2-ethoxy-2- ((3Z,6Z,9Z,12Z,15Z) -octadeca-3, 6,9,12, 15-pent-1-yloxy) acetic acid (42)

R₁=C₁₈H₂₇，R₂= ethoxy, R₃= H and X = COOH

Class H:

tris (2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-penten-1-yloxy) butanoic acid) propane-1, 2, 3-triester (43)

R₁=C₂₀H₃₁，R₂= ethyl, R₃= H and X = carboxylic acid group, in the form of a triglyceride

2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-penten-1-yloxy) butanoic acid 1, 3-dihydroxypropan-2-yl ester (44)

R₁=C₂₀H₃₁，R₂= ethyl, R₃= H and X = carboxylic acid group, in the form of 2-monoglyceride

Class I:

sodium 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-penten-1-yloxy) butanoate (45)

R₁=C₂₀H₃₁，R₂= ethyl, R₃=H，X=COO^-And Z is⁺Is Na⁺。

Potassium 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaen-1-yloxy) butanoate (46).

R₁=C₂₀H₃₁，R₂= ethyl, R₃=H，X=COO^-And Z is⁺Is K⁺。

Ammonium 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-penten-1-yloxy) butanoate (47)

R₁=C₂₀H₃₁，R₂= ethyl, R₃=H，X=COO^-And Z is⁺Is NH₄ ⁺。

Tert-butylammonium 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-penten-1-yloxy) butyrate (48)

R₁=C₂₀H₃₁，R₂= ethyl, R₃=H，X=COO^-And Z is⁺Is tert-butylammonium.

((2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-penten-1-yloxy) butanoic acid 1, 3-dihydroxy-2- (hydroxymethyl) propan-2-ammonium (49)

R₁=C₂₀H₃₁，R₂= ethyl, R₃=H，X=COO^-And Z is⁺Is 1, 3-dihydroxy-2- (hydroxymethyl) propan-2-ammonium.

Magnesium 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-penten-1-yloxy) butyrate (50)

R₁=C₂₀H₃₁，R₂= ethyl, R₃=H，X=COO^-And Z is²⁺Is Mg²⁺。

Calcium 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-penten-1-yloxy) butyrate (51)

R₁=C₂₀H₃₁，R₂= ethyl, R₃=H，X=COO^-And Z is²⁺Is Ca²⁺。

Class J:

2- (tetradec-12-ynyloxy) butyric acid (52)

R₁=C₁₄H₂₅，R₂= ethyl, R₃= H and X = COOH

2-Ethyl-2- (tetradec-12-yn-1-yloxy) butanoic acid (53)

R₁=C₁₄H₂₅，R₂=R₃= ethyl and X = COOH

2- (tetradec-12-yn-1-yloxy) propionic acid (54)

R₁=C₁₄H₂₅，R₂= methyl, R₃= H and X = COOH

2-methyl-2- (tetradec-12-yn-1-yloxy) propionic acid (55)

R₁=C₁₄H₂₅，R₂=R₃= methyl and X = COOH

2-methoxy-2- (tetradec-12-ynyloxy) acetic acid (56)

R₁＝C₁₄H₂₅，R₂Methoxy radical, R₃H and X COOH

2-ethoxy-2- (tetradec-12-yn-1-yloxy) acetic acid (57)

R₁＝C₁₄H₂₅，R₂Ethoxy, R₃H and X COOH

Specific embodiments of the compounds of the present application include the following.

General synthetic methods for the Compounds described herein

The compounds of formula (I) can be prepared by the following general procedure:

the method I comprises the following steps:

method II:

method III:

the alcohols of formula (X) described in methods I, II and III can be prepared directly from, for example, carboxylic esters of natural fatty acids such as alpha-linolenic acid, conjugated linoleic acid or eicosapentaenoic acid (EPA) by reduction with reducing agents such as Lithium Aluminum Hydride (LAH) or diisobutylaluminum hydride (DIBAL-H) at-10 ℃ to 0 ℃. The alcohols can also be prepared by degradation of polyunsaturated fatty acids (e.g., EPA and DHA), as described by Holmeide et al (j. chem. soc., Perkin trans.1(2000) 2271). In this case, the person skilled in the art can start from purified EPA or DHA, but also from fish oils comprising EPA and DHA.

The compounds of formula (XI) and (XII) are commercially available, or they are known in the literature, or they are prepared by standard methods known in the art. The Leaving Group (LG) present in the compound of formula (XI) may for example be mesylate, tosylate, or a suitable halogen such as bromine. Other leaving groups will be apparent to those skilled in the art.

Using method I, an alcohol of formula (X) can be reacted with a compound of formula (XI) in a substitution reaction in the presence of a base, such as an alkali metal hydroxide (e.g., NaOH), in a suitable solvent system. Suitable solvent systems include a two-phase mixture of toluene and water. In those cases where R2 and/or R3 present in the compound of formula (XI) are hydrogen, an alkylation step may be added to the sequence (step II) to replace one or both of the hydrogens with an alkyl group. The alkylation may be carried out by treating the product from step I with an alkyl group containing a suitable leaving group, for example a halogen such as bromine or iodine, or other leaving groups as will be appreciated by those of ordinary skill in the art, in the presence of a base (e.g. LDA) in a suitable solvent system.

Using method II, alcohols of formula (X) can be converted by methods familiar to the skilled worker by means of functional group interconversion to compounds in which the terminal hydroxyl group has been converted to a suitable Leaving Group (LG). Suitable leaving groups include bromine, mesylate and tosylate, or other leaving groups as will be apparent to those of ordinary skill in the art. These compounds can be further reacted in a substitution reaction with an appropriately substituted glycolic acid derivative (compound of formula XII) in the presence of a base in an appropriate solvent system (step IV).

Using method III, the alcohol of formula (X) can be reacted with an appropriately substituted glycolic acid derivative (compound of formula XII) using methods familiar to those skilled in the art under classical or non-classical Mitsunobu conditions.

If the acid derivative used is a carboxylic acid ester, hydrolysis may be carried out to give the free fatty acid. The esterified groups (e.g., methyl and ethyl) can be removed by basic hydrolysis, for example, with a base (e.g., an alkali metal hydroxide such as LiOH, NaOH, or KOH) or with an organic base (e.g., Et₃N)) and inorganic salts (e.g., LiCl) in a suitable solvent system. The tert-butyl group can be removed, for example, by treatment with an acid, such as an organic acid (e.g., trifluoroacetic acid or formic acid), in a suitable solvent system. Suitable solvent systems include dichloromethane. The arylmethylene group (e.g., benzyl) can be removed, for example, by hydrogenation over a catalyst (e.g., palladium on charcoal) in a suitable solvent system.

The salification of the carboxylic acid of formula (I) can be carried out by treatment with a suitable base in a suitable solvent system. Removal of the solvent will yield the salt formed.

Preparation of the compound of formula (I) according to method I, II or III gives a mixture of stereoisomers. If desired, these isomers can be separated by means of chiral resolving agents and/or by means of chiral column chromatography by methods known to the person skilled in the art.

Method IV

The compounds of formula (I) wherein X is a carboxylic acid derivative in phospholipid form may be prepared by the following procedure.

Acylation of sn-glycerol-3-phosphocholine (GPC) with an activated fatty acid, such as the fatty acid imidazolium (imidazolide), is a standard procedure in phospholecithin synthesis. This is usually carried out in DMSO as a solvent in the presence of DMSO anions (Hermetter; Chemistry and Physics of lipids, (1981)28, 111.). Sn-glycerol-3-phosphocholine (as cadmium (II) adduct) can also be reacted with fatty acids activated with imidazole anions in the presence of DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene) to prepare lecithin phosphates of the respective fatty acids (International application No. PCT/GB 2003/002582). Enzymatic transphosphatidylation can effect the conversion of phosphatidylcholine to phosphatidylethanolamine (Wang et al, j.am.chem.soc., (1993)115, 10487.).

Phospholipids can also be prepared by enzymatic esterification and transesterification of phospholipids or enzymatic transphosphatidylation of phospholipids (Hosokawa, J.Am.oil chem.Soc.1995, 1287, Lilja-Hallberg, Biocatalysis, (1994) 195.).

Method V

The compounds of formula (I) wherein X is a carboxylic acid derivative in triglyceride form can be prepared by the following procedure. The excess fatty acid can be obtained by using Dimethylaminopyridine (DMAP) and 2- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethylureaHexafluorophosphate (HBTU) was coupled to glycerol.

Method VI

Compounds of formula (I) wherein X is a carboxylic acid derivative in the form of a diglyceride can be prepared by reacting a fatty acid (2 equivalents) with glycerol (1 equivalent) in the presence of 1, 3-Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP).

Process VII

The compounds of formula (I) wherein X is a carboxylic acid derivative in the form of a monoglyceride can be prepared by the following method.

1, 2-O-isopropylidene-sn-glycerol was acylated with a fatty acid using DCC and DMAP in chloroform to give mono dienoyl glycerol (monodienoylglycerol). Deprotection of the isopropylidene group can be accomplished by treating the protected glycerol with an acid (HCl, acetic acid, etc.) (O' Brian, j.org.chem., (1996) 5914.).

There are several synthetic methods for preparing monoglycerides with fatty acids in the 2-position. One method utilizes esterification of fatty acids with glycidol in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 4-Dimethylaminopyridine (DMAP) to produce glycidyl derivatives. Treatment of the glycidyl derivative with trifluoroacetic anhydride (TFAA) followed by transesterification yields the monoglyceride (Parkkari et al, bioorg.Med.chem.Lett. (2006) 2437.).

Other processes for the preparation of mono-, di-and triglycerides of fatty acid derivatives are described in international application PCT/FR 02/02831.

Enzymatic processes (lipase reactions) can also be used to convert the fatty acids into mono-, di-, and triglycerides. 1, 3-regiospecific lipases from the fungus Mucor miehei can be used for the preparation of triglycerides or diglycerides from polyunsaturated fatty acids and glycerol. Another lipase, the non-regiospecific yeast lipase from Candida antartica, is highly efficient in the production of triglycerides from polyunsaturated fatty acids (Haraldsson, Pharmazie, (2000) 3.).

Preparation, characterization and biological testing of particular fatty acid derivatives of formula (I)

Examples

The present application is now further described by the following non-limiting examples, where standard techniques known to skilled chemists and techniques similar to those described in these examples may be used as appropriate. Unless otherwise stated:

● Evaporation was performed by vacuum rotary evaporation;

● all reactions were carried out at room temperature (typically 18-25 ℃) using HPLC grade solvents under anhydrous conditions;

● column chromatography is carried out by rapid methods on silica gel 40-63 μm (Merck), or by Armen Spotflash with pre-filled silica gel columns "MiniVarioFlash", "SuperVarioFlash", "SuperVarioPrep" or "EasyVarioPrep" (Merck);

● yields are given for illustrative purposes only and are not necessarily the highest obtainable yields;

● Nuclear Magnetic Resonance (NMR) shift values were recorded on a Bruker Avance DPX 200 or 300 instrument, with peak multiplicities as shown below: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; q, quartet; p, quintuple peak; m, multiplet; br, broad peak;

● Mass spectra were recorded using an LC/MS spectrometer. The separation was performed by gradient elution using an Agilent 1100 series module on an Eclipse XDB-C182.1X 150mm column. A gradient of 5-95% acetonitrile in a buffer containing 0.01% trifluoroacetic acid or 0.005% sodium formate was used as eluent. Mass spectra were recorded on a G1956A mass spectrometer (electrospray, 3000V) in positive and negative ionization switching mode.

Example 1.

Preparation of tert-butyl 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaen-1-yloxy) butyrate:

tetrabutylammonium chloride (0.55g, 1.98mmol) was added to a solution of (5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaen-1-ol (3.50g, 12.1mmol) in toluene (35mL) at ambient temperature under nitrogen. At room temperatureAqueous sodium hydroxide (50% (w/w), 11.7mL) was added with vigorous stirring, followed by tert-butyl 2-bromobutyrate (5.41g, 24.3 mmol). The resulting mixture was heated to 50 ℃ and additional tert-butyl 2-bromobutyrate was added after the following times: 1.5 hours (2.70g, 12.1mmol), 3.5 hours (2.70g, 12.1mmol) and 4.5 hours (2.70g, 12.1mmol) and stirring was carried out for a total of 12 hours. After cooling to room temperature, ice water (25mL) was added and the resulting two phases were separated. The organic phase was washed with a mixture of NaOH (5%) and brine, dried (MgSO)₄) Filtered and concentrated. The residue was purified by flash chromatography on silica gel using a mixture of heptane and ethyl acetate of increasing polarity (100: 0 → 95: 5) as eluent. Concentration of the appropriate fractions gave 1.87g (36% yield) of the title compound as an oil.¹H NMR(300MHz，CDCl₃)：0.85-1.10(m，6H)，1.35-1.54(m，11H)，1.53-1.87(m，4H)，1.96-2.26(m，4H)，2.70-3.02(m，8H)，3.31(dt，1H)，3.51-3.67(m，2H)，5.10-5.58(m，10H)。

Example 2:

preparation of 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) butanoic acid:

tert-butyl 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-penten-1-yloxy) butyrate (19.6g, 45.5mmol) was dissolved in dichloromethane (200mL) and placed under nitrogen. Trifluoroacetic acid (50mL) was added and the reaction mixture was stirred at room temperature for 1 hour. Water was added and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine and dried (Na)₂SO₄) Filtered and concentrated. The residue is purified by flash chromatography on silica gel using an increasingly polar mixture (90: 10: 1 → 80: 20: 1) of heptane, ethyl acetate and formic acid as eluent. Concentrating the appropriate fractions12.1g (71% yield) of the title compound are obtained as an oil.¹H-NMR(300MHz，CDCl₃): 0.90-1.00(m, 6H), 1.50(m, 2H), 1.70(m, 2H), 1.80(m, 2H), 2.10(m, 4H), 2.80-2.90(m, 8H), 3.50(m, 1H), 3.60(m, 1H), 3.75(t, 1H), 5.30-5.50(m, 10H); MS (electrospray): 373.2[ M-H]^-。

Example 3:

(4S, 5R) -3- ((S) -2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) butyryl) -4-methyl-5-phenylOxazolidin-2-one and (4S, 5R) -3- ((R) -2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaalkenyloxy) butyryl) -4-methyl-5-phenylPreparation of oxazolidin-2-one:

DMAP (1.10g, 8.90mmol) and DCC (1.90g, 9.30mmol) were added under nitrogen to a mixture of 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) butyric acid (3.20g, 8.50mmol) in dry dichloromethane (100mL) maintained at 0 ℃. The resulting mixture was stirred at 0 ℃ for 20 minutes. Adding (4S, 5R) -4-methyl-5-phenylOxazolidin-2-one (1.50g, 8.50mmol), and the resulting cloudy mixture was stirred at ambient temperature for 5 days. The mixture was filtered and concentrated under reduced pressure to give the crude product with the desired product as a mixture of two diastereomers. The residue was purified by flash chromatography on silica gel with 15% ethyl acetate in heptaneThe solution in (1) serves as an eluent. The two diastereomers were separated and the appropriate fractions were concentrated. (4S, 5R) -3- ((S) -2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaalkenyloxy) butyryl) -4-methyl-5-phenylOxazolidin-2-one to give 1.1g (40% yield) as an oil. To give (4S, 5R) -3- ((R) -2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaalkenyloxy) butyryl) -4-methyl-5-phenylOxazolidin-2-one 0.95g (34% yield) as an oil.

(4S, 5R) -3- ((S) -2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) butyryl) -4-methyl-5-phenylOxazolidin-2-one (E1):

¹H-NMR(300MHz，CDCl₃)：0.90(d，3H)，1.00(t，3H)，1.07(t，3H)，1.45-1.57(m，2H)，1.62-1.76(m，3H)，1.85-1.95(m，1H)，2.05-2.15(m，4H)，2.87(m，8H)，3.39(m，1H)，3.57(m，1H)，4.85-4.92(m，2H)，5.30-5.45(m，10H)，5.75(d，1H)，7.32(m，2H)，7.43(m，3H)。

(4S, 5R) -3- ((R) -2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) butyryl) -4-methyl-5-phenylOxazolidin-2-one (E2):

¹H-NMR(300MHz，CDCl₃): 0.98(d, 3H), 0.99(t, 3H), 1.08(t, 3H), 1.40-1.52(m, 2H), 1.55-1.75(m, 3H), 1.80-1.90(m, 1H), 2.05-2.15(m, 4H), 2.84(m, 8H), 3.39(m, 1H), 3.56(m, 1H), 4.79 (quintuple, 1H), 4.97(dd,1H)，5.30-5.45(m，10H)，5.71(d，1H)，7.33(m，2H)，7.43(m，3H)。

example 4:

preparation of (S) -2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) butanoic acid:

hydrogen peroxide (35% aqueous solution, 0.75mL, 8.54mmol) and lithium hydroxide monohydrate (0.18g, 4.27mmol) were added to (4S, 5R) -3- ((S) -2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaalkenyloxy) butyryl) -4-methyl-5-phenyl maintained at 0 ℃ under nitrogenA solution of oxazolidin-2-one (1.10g, 2.13mmol) in tetrahydrofuran (12mL) and water (4 mL). The reaction mixture was stirred at 0 ℃ for 30 minutes. Adding 10% Na₂SO₃Aqueous (30mL), pH adjusted to about 2 with 2MHCl and the mixture extracted twice with heptane (30 mL). The combined organic extracts were dried (Na)₂SO₄) Filtering and concentrating. The residue was purified by flash chromatography on silica gel using a polar-increasing mixture of heptane and ethyl acetate (98: 8 → 1: 1) as eluent. Concentration of the appropriate fractions gave 0.48g (60% yield) of the title compound as an oil.¹H-NMR(300MHz，CDCl₃): 0.90-1.00(m, 6H), 1.48(m, 2H), 1.65(m, 2H), 1.85(m, 2H), 2.10(m, 4H), 2.80-2.90(m, 8H), 3.55(m, 1H), 3.60(m, 1H), 3.88(t, 1H), 5.35-5.45(m, 10H); MS (electrospray): 373.3[ M-H]^-；[α]_D+37 ° (c ═ 0.104, ethanol)

Example 5:

preparation of (R) -2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) butanoic acid:

hydrogen peroxide (35% aqueous solution, 0.65mL, 7.37mmol) and lithium hydroxide monohydrate (0.15g, 3.69mmol) were added to (4S, 5R) -3- ((R) -2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaalkenyloxy) butyryl) -4-methyl-5-phenyl maintained at 0 ℃ under nitrogenA solution of oxazolidin-2-one (0.95g, 1.84mmol) in tetrahydrofuran (12mL) and water (4 mL). The reaction mixture was stirred at 0 ℃ for 30 minutes. Adding 10% Na₂SO₃Aqueous (30mL), pH adjusted to about 2 with 2MHCl and the mixture extracted twice with heptane (30 mL). The combined organic extracts were dried (Na)₂SO₄) Filtering and concentrating. The residue was purified by flash chromatography on silica gel using a polar-increasing mixture of heptane and ethyl acetate (98: 8 → 50: 50) as eluent. Concentration of the appropriate fractions gave 0.19g (29% yield) of the title compound as an oil.¹H-NMR(300MHz，CDCl₃): 0.90-1.00(m, 6H), 1.48(m, 2H), 1.65(m, 2H), 1.85(m, 2H), 2.10(m, 4H), 2.80-2.90(m, 8H), 3.55(m, 1H), 3.60(m, 1H), 3.88(t, 1H), 5.35-5.45(m, 10H); MS (electrospray): 373.3[ M-H]^-；[α]_D-31 ° (c ═ 0.088, ethanol).

Example 6:

preparation of tert-butyl 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) propionate:

a mixture of (5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaen-1-ol (1.00g, 3.47mmol), tetrabutylammonium chloride (0.24g, 0.87mmol) and t-butyl α -bromopropionate (3.62g, 17.3mmol) was dissolved in toluene (36mL) and placed under nitrogen and aqueous sodium hydroxide solution (50%, 8mL) was added slowly with vigorous stirring, the resulting mixture was stirred at ambient temperature for 20 hours, water was added, the mixture was extracted 3 times with diethyl ether, the combined organic extracts were washed with brine, dried (Na)₂SO₄) Filtered and concentrated. The residue was purified by flash chromatography on silica gel with 2% ethyl acetate in heptane as eluent. Concentration of the appropriate fractions gave 1.40g (90% yield) of the title compound as an oil.¹H-NMR(300MHz，CDCl₃)：0.95(t，3H)，1.41(d，3H)，1.48(s，9H)，1.48-1.66(m，4H)，2.05(m，4H)，2.83(m，8H)，3.35(m，1H)，3.55(m，1H)，3.79(q，1H)，5.32-5.44(m，10H)。

Example 7:

preparation of 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) propionic acid:

trifluoroacetic acid (2mL) was added to a solution of tert-butyl 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) propionate (1.40g, 3.36mmol) in dichloromethane (10mL) maintained under nitrogen and the reaction mixture was stirred at room temperature for 3 hours. Ether (50mL) was added and the organic phase was washed with water (30mL) and dried (Na)₂SO₄) And concentrated. The residue is purified by flash chromatography on silica gel using an increasing polarity mixture of heptane, ethyl acetate and formic acid (95: 5: 0.25 → 80: 20: 1) as a washAnd (4) removing the agent. Concentration of the appropriate fractions gave 0.67g of slightly impure product. This material was dissolved in heptane (15mL), washed 3 times with water (5mL), and dried (Na)₂SO₄) Filtered and concentrated to give 0.50g (41% yield) of the title compound as an oil.¹H-NMR(300MHz，CDCl₃): 0.99(t, 3H), 1.40-1.48(m, 5H), 1.67(m, 2H), 2.09(m, 4H), 2.80-2.60(m, 8H), 3.53(m, 2H), 4.01(q, 1H), 5.31-5.47(m, 10H); MS (electrospray): 359.2[ M-H]^-。

Example 8:

preparation of tert-butyl 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) -2-methylpropionate:

a mixture of (5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaen-1-ol (0.83g, 3.14mmol), tetrabutylammonium chloride (0.24g, 0.85mmol) and α -bromoisobutyric acid tert-butyl ester (3.50g, 15.7mmol) was dissolved in toluene (15mL) and placed under nitrogen, aqueous sodium hydroxide solution (50%, 5mL) was slowly added at room temperature with vigorous stirring, the resulting mixture was heated to 60 ℃ and stirred for 6 hours, the mixture was cooled, water was added, extracted 3 times with ether, the combined organic extracts were washed with brine, and dried (Na) (0.83g, 3.14mmol)₂SO₄) Filtered and concentrated. The residue was purified by flash chromatography on silica gel with a gradient of 5-10% ethyl acetate in heptane as eluent. Concentration of the appropriate fractions gave 0.60g (44% yield) of the title compound as an oil. MS (electrospray): 453.3[ M + Na ]]⁺。

Example 9:

preparation of 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) -2-methylpropanoic acid:

to a solution of tert-butyl 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) -2-methylpropionate (600mg, 1.39mmol) in dichloromethane (20mL) was added trifluoroacetic acid (5mL) under nitrogen and the reaction mixture was stirred at room temperature for 2 hours. Water was added and the aqueous phase was extracted 2 times with dichloromethane. The combined organic extracts were washed with brine and dried (Na)₂SO₄) Filtered and concentrated. The residue was purified by flash chromatography on silica gel using a mixture of heptane, ethyl acetate and formic acid (80: 20: 1) as eluent. The appropriate fractions were concentrated and the residue (135mg) was purified by flash chromatography on silica gel using a gradient of 5-10% ethyl acetate and formic acid (95: 5) in heptane as eluent. Concentration of the appropriate fractions gave 80mg of slightly impure product. This material was dissolved in heptane (5mL), washed twice with water (5mL) and dried (Na)₂SO₄) Filtration and concentration gave 40mg (8% yield) of the title compound as an oil.¹H-NMR(300MHz，CDCl₃): 0.99(t, 3H), 1.47(s, 6H), 1.64(m, 2H), 2.07(m, 4H), 2.81-2.88(m, 8H), 3.46(t, 2H), 5.29-5.44(m, 10H); MS (electrospray): 373.3[ M-H]^-

Example 10:

preparation of 2- ((3Z,6Z,9Z,12Z) -pentadecano-3, 6,9, 12-tetraalkenyloxy) butanoic acid:

mixing (3Z,6Z,9Z,12Z) -pentadecan-3, 6,9, 12-tetraen-1-ol (S.Flock, Acta ChemicaScadi)A mixture of navica, (1999)53, 436-. Aqueous sodium hydroxide (50%, 4ml) was added slowly at room temperature with vigorous stirring. The resulting mixture was heated to 50 ℃ and stirred for 2 hours, then at ambient temperature overnight. After cooling to room temperature, water was added and the aqueous phase was extracted 3 times with ether. The combined organic extracts were washed with water and then brine and dried (Na)₂SO₄) Filtered and concentrated. The residue was purified by flash chromatography on silica gel with 5% ethyl acetate in heptane as eluent. Concentration of the appropriate fractions gave 0.30g of tert-butyl ester as an oil. The residue was dissolved in dichloromethane (10mL) and placed under nitrogen. Trifluoroacetic acid (2mL) was added and the reaction mixture was stirred at room temperature for 1 hour. Water was added and the aqueous phase was extracted 2 times with dichloromethane. The combined organic extracts were washed with brine and dried (Na)₂SO₄) Filtered and concentrated. The residue was purified by flash chromatography on silica gel using a mixture of heptane, ethyl acetate and formic acid (80: 20: 1) as eluent. Concentration of the appropriate fractions gave 0.18g (59% yield) of the desired product as an oil.¹H-NMR(300MHz，CDCl₃)：0.90-1.05(m，6H)，1.75-1.90(m，2H)，2.05-2.15(m，2H)，2.30-2.50(m，2H)，2.85(m，6H)，3.60(m，2H)，3.85(t，1H)，5.25-5.60(m，8H)。

Example 11:

preparation of 2- ((9Z,12Z,15Z) -octadec-9, 12, 15-trienoyloxy) butanoic acid:

a mixture of (9Z,12Z,15Z) -octadeca-9, 12, 15-trien-1-ol (1.26g, 4.76mmol), tetrabutylammonium chloride (0.36g, 1.28mmol) and tert-butyl 2-bromobutyrate (2.86g, 12.82mol) was preparedThe compound was dissolved in toluene (15mL) and placed under nitrogen. Aqueous sodium hydroxide (50%, 6mL) was added slowly at room temperature with vigorous stirring. The resulting mixture was heated to 60 ℃ and stirred for 5 hours. After cooling to room temperature, water was added and the aqueous phase was extracted 3 times with diethyl ether. The combined organic extracts were washed with water and then brine and dried (Na)₂SO₄) Filtered and concentrated. The residue was purified by flash chromatography on silica gel with a gradient of 2.5-5% ethyl acetate in heptane as eluent. Concentration of the appropriate fractions gave 1.36g of tert-butyl ester as an oil. The residue was dissolved in dichloromethane (20mL) and placed under nitrogen. Trifluoroacetic acid (5mL) was added and the reaction mixture was stirred at room temperature for 1 hour. Water was added and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine and dried (Na)₂SO₄) Filtered and concentrated. The residue was purified by flash chromatography on silica gel using a mixture of heptane, ethyl acetate and formic acid (80: 20: 1) as eluent. Concentration of the appropriate fractions gave 0.38g (23% yield) of the desired product as an oil.¹H-NMR(300MHz，CDCl₃): 0.95-1.00(m, 6H), 1.30-1.45(m, 10H), 1.65(m, 2H), 1.80(m, 2H), 2.10(m, 4H), 2.80(m, 4H), 3.50(m, 1H), 3.60(m, 1H), 3.85(t, 1H), 5.30-5.50(m, 6H); MS (electrospray): 349.2[ M-H]^-。

Example 12:

preparation of tert-butyl 2-ethyl-2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaen-1-yloxy) butyrate:

under nitrogen, tert-butyl 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaen-1-yloxy) butanoate (480mg, 1.11mmol) was added dropwise over 30 minutes to Lithium Diisopropylamide (LDA) (2) maintained at-70 ℃.0M, 750. mu.L, 1.50mmol) in anhydrous tetrahydrofuran (10 mL). The reaction mixture was stirred for 30 minutes. Iodotethane (312mg, 2.00mmol) was added in one portion and the resulting mixture was warmed to ambient temperature over 1 hour. The reaction mixture was stirred at ambient temperature for 17 hours. The mixture was poured into saturated NH₄Aqueous Cl (50mL), extracted with heptane (2 × 50 mL.) the combined organic phases were washed with brine (50mL), 0.25M HCl (50mL) and brine (50mL) and dried (MgSO)₄) Filtered and concentrated. The residue was purified by flash chromatography on silica gel using a polar-increasing mixture of heptane and ethyl acetate (100: 0 → 95: 5) as eluent. Concentration of the appropriate fractions gave 343mg (67% yield) of the title compound as an oil.¹H NMR(300MHz，CDCl₃): 0.84(t, 6H), 0.99(td, 3H), 1.35-1.55(m, 11H), 1.54-1.69(m, 2H), 1.68-1.87(m, 4H), 1.99-2.24(m, 4H), 2.74-2.99(m, 8H), 3.31(t, 2H), 5.23-5.52(m, 10H); MS (electrospray): 401.3[ M-1 ]]^-。

Example 13:

preparation of 2-ethyl-2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaen-1-yloxy) butanoic acid:

a mixture of formic acid (5ml) and tert-butyl 2-ethyl-2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaen-1-yloxy) butyrate (250mg, 0.55mmol) was stirred vigorously under nitrogen at room temperature for 4.5 hours. Formic acid was removed in vacuo. The residue was purified by flash chromatography on silica gel using a polar-increasing mixture of heptane and ethyl acetate (100: 0 → 80: 20) as eluent. Concentration of the appropriate fractions gave 163mg (74% yield) of the title compound as an oil.¹H NMR(300MHz，CDCl₃)：0.86(t，6H)，0.99(t，3H)，1.36-1.57(m，2H)，1.68(dd, 2H), 1.73-1.98(m, 4H), 2.11(tt, 4H), 2.70-3.01(m, 8H), 3.39(t, 2H), 5.20-5.56(m, 10H). MS (electrospray): 481.4[ M + Na ]]⁺。

Example 14:

preparation of tert-butyl 2- ((4Z,7Z,10Z,13Z,16Z,19Z) -docosal-4, 7,10,13,16, 19-hexaen-1-yloxy) butyrate:

aqueous sodium hydroxide (50% (w/w), 6ml) was added portionwise to a mixture of (5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaen-1-ol (2.01g, 6.39mmol), tert-butyl 2-bromobutyrate (2.85g, 12.8mmol) and tetrabutylammonium hydrogen sulfate (0.65g, 1.91mmol) in toluene (12 ml). In N₂The reaction mixture was stirred vigorously under an atmosphere and warmed to 50 ℃. The reaction mixture was stirred at 50 ℃ for a total of 22 hours. Additional tert-butyl 2-bromobutyrate (1.43g, 6.39mmol) and (1.44g, 6.44mmol) were added after 1.5 hours and 3 hours, respectively. The mixture was cooled, ice water (about 50ml) and heptane (50ml) were added, the phases were separated and the organic phase was concentrated under reduced pressure. Flash chromatography on silica gel (30g) eluting with heptane-heptane/EtOAc (99: 1) afforded 2.12g of the title compound as a liquid.¹H NMR(300MHz，CDCl₃)0.94-1.04(m，6H)，1.47(s，9H)，1.68-1.85(m，4H)，1.93-2.20(m，4H)，2.80-2.86(m，10H)，3.28-3.36(m，1H)，3.55-3.63(m，2H)，5.27-5.43(m，12H)。

Example 15:

preparation of 2- ((4Z,7Z,10Z,13Z,16Z,19Z) -docosac-4, 7,10,13,16, 19-hexaen-1-yloxy) butanoic acid:

a mixture of tert-butyl 2- ((4Z,7Z,10Z,13Z,16Z,19Z) -docodeca-4, 7,10,13,16, 19-hexaen-1-yloxy) propionate (2.09g, 4.58mmol) in HCOOH (9ml) was stirred at 40 ℃ for 6 hours under a nitrogen atmosphere. The reaction mixture was diluted with ether (100mL), washed with water (30mL), and dried (MgSO)₄) Filtered and evaporated under reduced pressure. Purification by dry column flash chromatography on silica gel (50g), eluting with toluene-toluene (85: 15) afforded 1.44g of the crude title compound. Flash chromatography on silica gel (30g) eluting with heptane-heptane/(EtOAc containing 5% HCOOH) 98: 2-95: 5-80: 20 afforded 1.07g (58% yield) of the title compound as a liquid.¹H NMR(200MHz，CDCl₃)0.97(t, 3H), 0.99(t, 3H), 1.64-1.91(m, 4H), 2.00-2.23(m, 4H), 2.78-2.87(m, 10H), 3.42-3.66(m, 2H), 3.85(dd, 1H), 5.26-5.46(m, 12H). MS (electrospray) (negative): 399(M-H)^-。

Example 16:

preparation of tert-butyl 2- ((3Z,6Z,9Z,12Z,15Z) -octadeca-3, 6,9,12, 15-penten-1-yloxy) butyrate:

aqueous sodium hydroxide (50% (w/w), 6mL) was added portionwise to a mixture of (3Z,6Z,9Z,12Z,15Z) -octadeca-3, 6,9,12, 15-penten-1-ol (1.66g, 6.37mmol), tert-butyl 2-bromobutyrate (2.86g, 12.8mmol) and tetrabutylammonium hydrogen sulfate (0.65g, 1.91mmol) in toluene (12 mL). In N₂The reaction mixture was stirred vigorously under an atmosphere and warmed to 50 ℃. The reaction mixture was stirred at 50 ℃ for a total of 25 hours. Additional tert-butyl 2-bromobutyrate (1.43g, 6.41mmol) and (1.42g, 6) were added after 1.5 hours and 3 hours, respectively38 mmol). The mixture was cooled to room temperature, water (30mL) and heptane (50mL) were added, the resulting two phases were separated, and the organic phase was dried (Na)₂SO₄) Filtering and evaporating under reduced pressure. Flash chromatography on silica gel (30g) eluting with heptane-heptane/EtOAc (99: 1) afforded 1.55g of the title compound as a liquid.¹H NMR(300MHz，CDCl₃)0.96(t，3H)，0.97(t，3H)，1.48(s，9H)，1.64-1.86(m，2H)，2.03-2.12(m，2H)，2.39(dd，J＝12.1，6.7Hz，2H)，2.79-2.86(m，8H)，3.29-3.37(m，1H)，3.57-3.66(m，2H)，5.27-5.49(m，10H)。

Example 17:

preparation of 2- ((3Z,6Z,9Z,12Z,15Z) -octadeca-3, 6,9,12, 15-penten-1-yloxy) butanoic acid:

a mixture of tert-butyl 2- ((3Z,6Z,9Z,12Z,15Z) -octadec-3, 6,9,12, 15-pentaen-1-yloxy) butanoate (2.09g, 4.58mmol) in HCOOH (9ml) was stirred at 40 ℃ for 6 hours under a nitrogen atmosphere. The reaction mixture was diluted with ether (100mL), washed with water (30mL), and dried (MgSO)₄) Filtered and evaporated under reduced pressure. Purification by dry column flash chromatography on silica gel (50g) eluting with toluene-toluene/EtOAc (85: 15) afforded 1.44g of the crude title compound. Flash chromatography on silica gel (30g) eluting with heptane-heptane/(EtOAc containing 5% HCOOH) 98: 2-95: 5-80: 20 afforded 1.07g (58% yield) of the title compound as a liquid.¹H NMR(200MHz，CDCl₃)0.97(t, 3H), 0.99(t, 3H), 1.75-1.91(m, 2H), 2.00-2.15(m, 2H), 2.35-2.48(m, 2H), 2.78-2.87(m, 8H), 3.47-3.62(m, 2H), 3.86(dd, 1H), 5.25-5.55(m, 10H). MS (electrospray) (negative): 345(M-H)^-。

Biological assay

Example 18:

in vitro evaluation of PPAR activation

The assay was performed in vitro using a mammalian-1-hybrid assay (M1H) comprising the GAL4-DNA binding domain-PPAR-LBD fusion construct in transiently transfected HEK293 cells together with a 5XGAL 4-site driven North American firefly (Photinus pyralis) luciferase reporter construct.

Cells were transfected for 4-6 hours, grown overnight, and then compound was added. The compound was incubated for 16-20 hours.

Renilla luciferase (Renilla reniformis luciferase) driven by a constitutive promoter was included as an internal control to improve experimental accuracy.

Compounds (a-C) and positive controls were tested in duplicate at 6 different concentrations. Positive controls were GW7647(PPAR α), GW501516(PPAR), and rosiglitazone (rosiglitazone) (PPAR γ). The efficacy of the control was set at 100%.

The results are shown in Table 1.

Table 1: in vitro PPAR activation

Example 19:

evaluation of the Effect on in vivo lipid metabolism in a mouse model of dyslipidemia (APOE. multidot.3Leton transgenic mice)

This animal model has been shown to represent a human situation in terms of plasma lipoprotein levels and their response to hypolipidemic drugs, such as statins and fibrates, as well as nutritional interventions. Furthermore, depending on plasma cholesterol levels, APOE x 3 retton mice developed atherosclerotic lesions in the aorta that were similar in cellular composition as well as morphological and immunohistochemical properties to those found in humans.

Semi-synthetic western diet (WTD, 15% cocoa butter, 40% sucrose and 0.25% cholesterol; all by weight) was administered to female APOE 3 leiton mice. At this diet, plasma cholesterol levels gently reached elevated levels of about 12-15 mmol/l. After this diet period of 4 weeks, the mice were subdivided into several groups of 10 mice each, and plasma cholesterol, triglycerides and body weight were compared (t ═ 0).

A mixture of test substance and the western style diet is administered orally. To facilitate the mixing of the compounds, sunflower oil was added, with a total oil volume of 10mL/kg diet.

Blood samples were taken after a 4 hour fast at t-0 and 4 weeks for plasma cholesterol and triglycerides.

The test substance (A) was tested at 0.3mmol/kg body weight/day. Reference (omega-3 ethyl ester, Omacor)^TM、Lovaza^TM) The test was carried out at 3.3mmol/kg body weight/day.

The results are shown in FIG. 1.

Example 20：

Evaluation of the Effect on in vivo lipid metabolism in a mouse model of dyslipidemia (APOE. multidot.3Ledun CETP transgenic mice)

APOE x 3 retton CETP transgenic mice are a model for the introduction of human cholesterol ester transfer protein into APOE x 3 retton transgenic mice. This results in a lipoprotein profile that is more similar to that of humans. This model is very well suited for testing the effect of drugs on plasma HDL and triglyceride levels.

Semi-synthetic modified western diet (0.15% cholesterol and 15% saturated fat, both by weight) was administered to female APOE x 3 retp CETP mice. At this diet, plasma cholesterol levels gently reached elevated levels of about 13-15mmol/l and triglyceride levels of about 3 mmol/l. After this meal period of 4 weeks, the mice were subdivided into several groups of 6 mice each, mainly comparing plasma cholesterol, triglycerides and body weight, and secondly comparing HDL-cholesterol (t ═ 0).

A mixture of test substance and the western style diet is administered orally.

At t 0 and 4 weeks, blood samples were taken after a 4 hour fast for measurement of plasma cholesterol, HDL-cholesterol, and triglycerides.

The test substance (A) was tested at 0.18mmol/kg body weight/day. The reference (fenofibrate) was tested at 10mg/kg body weight/day.

The results are shown in FIGS. 2 and 3.

Example 21:

evaluation of the Effect on the development of atherosclerosis in vivo in a mouse model (APOE 3 Lepton CETP transgenic mice)

This animal model has been shown to represent a human situation in terms of plasma lipoprotein levels and their response to hypolipidemic drugs (e.g., statins and fibrates, etc.) as well as nutritional intervention. APOE x 3 reton CETP mice developed atherosclerotic lesions in the aorta that were similar in cellular composition as well as morphological and immunohistochemical properties to those found in humans.

Administering to female APOE x 3 retn CETP mice a western-style diet (WTD) containing 0.15% cholesterol and 15% saturated fat; resulting in plasma cholesterol levels of about 13-15 mM. After this western diet period of 3 weeks, the mice were subdivided into 4 groups of 15 mice: control (no treatment), compound a, fenofibrate and a low cholesterol diet. The groups were compared for body weight, total plasma cholesterol (TC), HDL cholesterol (HDL-C) and Triglycerides (TG) after a 4 hour fast (t ═ 0).

A mixture of test substance and the western style diet is administered orally. To facilitate the mixing of the compounds, sunflower oil was added, with a total oil volume of 10mL/kg diet. Test compound (A) was initially tested at 0.1mmol/kg body weight/day, decreasing to 0.04mmol/kg body weight/day at week 4. Initial doses were based on prior dose-finding studies to establish the required dose that would reduce VLDL/LDL cholesterol by 25-30%.

The fenofibrate dose was initially 10mg/kg body weight/day and then decreased to 4.2mg/kg body weight/day (in proportion to the VLDL/LDL decrease caused by compound a).

At t-0, 4, 8, 12 and 14 weeks, blood samples were taken after a 4 hour fast to measure the distribution of food intake, total plasma cholesterol, HDL cholesterol and triglycerides and lipoproteins. The development of atherosclerosis (number of lesions, total lesion area and lesion severity) at the aortic root was assessed at the end of the study.

The invention should not be limited to the embodiments and examples shown above.

Claims (72)

1. A lipid compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein R is₁Is C having 3-6 double bonds₁₀-C₂₂An alkenyl group;

wherein R is₂And R₃Independently selected from a hydrogen atom and an alkane selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and n-hexylProvided that R is₂And R₃Not being hydrogen atoms at the same time; and

x is a carboxylic acid group, a carboxylic ester, or a carboxamide.

2. A lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the double bond is a methylene interrupted Z-type double bond.

3. A lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₁Is C₁₄-C₂₂An alkenyl group having at least one double bond in the Z form and having a first double bond at the 3 rd carbon bond counted from the ω -terminus of the carbon chain.

4. A lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₁Selected from C having 3, 4, 5 or 6 double bonds₁₈、C₂₀Or C₂₂An alkenyl group.

5. A lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the formula:

6. a lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the formula:

7. a lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₂Is hydrogen, R₃Is an alkyl group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and n-hexyl, and X is a carboxylic acid group.

8. A lipid compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein the alkyl group is ethyl.

9. A lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the formula:

10. a lipid compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein the compound is present in the form of its R enantiomer.

11. A lipid compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein the compound is present in the form of its S enantiomer.

12. A lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the formula:

13. a lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the formula:

14. a lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the formula:

15. a lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the formula:

16. a lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the salt of the compound of formula (I) is selected from

Wherein X is COO^-And Z is⁺Selected from Li⁺、Na⁺、K⁺、NH₄ ⁺A protonated primary amine, a protonated aminopyridine, a protonated secondary amine, a protonated tertiary amine, a protonated guanidine, or a protonated heterocycle; or

Wherein X is COO^-And Z is²⁺Selected from Mg²⁺、Ca²⁺Or a di-protonated diamine; or

Wherein X is COO^-And Z isⁿ⁺Is a protonated chitosan:

17. a lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the alkyl group is methyl, ethyl or propyl.

18. A lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₂And R₃Is a hydrogen atom, and R₂And R₃And the other is an alkyl group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and n-hexyl.

19. A lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₂And R₃Identical or different and are alkyl radicals selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and n-hexyl.

20. A lipid compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein R₂Is methyl, and R₃Is ethyl.

21. A lipid compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein R₂And R₃Identical and selected from methyl or ethyl.

22. A lipid compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein R₁Is C having at least one Z-type double bond and having a first double bond at the 3 rd carbon-carbon bond counted from the omega end of the carbon chain₁₄-C₂₂An alkenyl group.

23. A lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is a carboxylic acid group or a carboxylic acid ester.

24. A lipid compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein X is ethyl carboxylate.

25. A lipid compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein R₂And R₃Is an ethyl group and a hydrogen atom, and X is a carboxylic acid 2-monoglyceride.

26. A lipid compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein X is a carboxylic acid group.

27. The lipid compound of claim 1, or a pharmaceutically acceptable salt thereof, in a mixture of diastereoisomers, enantiomers, or racemic forms.

28. A lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

(A) a lipid compound derived from a polyunsaturated fatty acid, wherein R₁Is C having 5 double bonds₂₀An alkenyl group;

(B) a lipid compound derived from a polyunsaturated fatty acid, wherein R₁Is C having 6 double bonds₂₂An alkenyl group;

(C) a lipid compound derived from a polyunsaturated fatty acid, wherein R₁Is C having 3 double bonds₁₈An alkenyl group;

(D) a lipid compound derived from a polyunsaturated fatty acid, wherein R₁Is C having 4 double bonds₁₅An alkenyl group;

(E) a lipid compound derived from a polyunsaturated fatty acid, wherein R₁Is C having 5 double bonds₁₈An alkenyl group;

(F) wherein X is a lipid compound of a carboxylic acid triglyceride; or

(G) A lipid compound wherein X is a carboxylate.

29. A lipid compound according to claim 23, OR a pharmaceutically acceptable salt thereof, wherein the compound is in combination with-OR₁、R₂、R₃The carbon to which X is attached is in the form of its R enantiomer.

30. A lipid compound according to claim 23, OR a pharmaceutically acceptable salt thereof, wherein the compound is in combination with-OR₁、R₂、R₃The carbon to which X is attached is in its S enantiomerIn the form of a body.

31. A lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:

2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) butanoic acid;

(R) -2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) butanoic acid;

(S) -2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) butanoic acid;

2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) -2-methylpropanoic acid;

2- ((3Z,6Z,9Z,12Z) -pentadecano-3, 6,9, 12-tetraalkenyloxy) butanoic acid;

2- ((9Z,12Z,15Z) -octadec-9, 12, 15-trienoyloxy) butanoic acid;

2-ethyl-2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) butanoic acid; or

2-ethyl-2- ((4Z,7Z,10Z,13Z,16Z,19Z) -docosa-4, 7,10,13,16, 19-hexaenyloxy) butanoic acid.

32. A pharmaceutical composition comprising a lipid compound of formula (I) or a pharmaceutically acceptable salt thereof

Wherein R is₁Is C having 3-6 double bonds₁₀-C₂₂An alkenyl group;

R₂and R₃Independently selected from a hydrogen atom and an alkyl group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and n-hexyl, with the proviso that R is₂And R₃Not being hydrogen atoms at the same time; and

x is a carboxylic acid group, a carboxylic ester, or a carboxamide.

33. The pharmaceutical composition of claim 32, further comprising a pharmaceutically acceptable carrier, excipient, or diluent, or any combination thereof.

34. The pharmaceutical composition of claim 32 or 33, further comprising a pharmaceutically acceptable antioxidant.

35. The pharmaceutical composition of claim 32, formulated for oral administration.

36. The pharmaceutical composition of claim 32 in the form of a tablet or sachet.

37. A lipid composition comprising at least one lipid compound of formula (I) or a pharmaceutically acceptable salt thereof

Wherein R is₁Is C having 3-6 double bonds₁₀-C₂₂An alkenyl group;

R₂and R₃Independently selected from a hydrogen atom and an alkyl group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and n-hexyl, with the proviso that R is₂And R₃Not being hydrogen atoms at the same time; and

x is a carboxylic acid group, a carboxylic ester, or a carboxamide.

38. Use of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of inflammation.

39. Use of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of rheumatoid arthritis.

40. Use of a compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of Inflammatory Bowel Disease (IBD).

41. Use of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of atherosclerosis.

42. Use of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of diabetes.

43. The use of claim 42, wherein the diabetes is type II diabetes.

44. Use of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of peripheral insulin resistance.

45. Use of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of dyslipidemia or mixed dyslipidemia.

46. The use of claim 45, wherein the dyslipidemia is hypertriglyceridemia.

47. Use of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of metabolic syndrome.

48. Use of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for lowering cholesterol.

49. The use of claim 48, wherein the cholesterol is non-HDL cholesterol.

50. The use of claim 48, wherein the cholesterol is LDL and/or VLDL cholesterol.

51. The use of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for raising HDL cholesterol.

52. A process for preparing a lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, comprising:

a) make R₁-OH withA reaction wherein LG is a leaving group; and

b) isolating the lipid compound.

53. The method of claim 52, wherein said leaving group is selected from the group consisting of a mesylate group, a tosylate group, a hydroxyl group, or a halogen atom.

54. The method of claim 52, further comprising protecting and deprotecting steps.

55. The process of claim 52, wherein step a) is carried out in the presence of a base.

56. The method of claim 55, wherein the base is sodium hydroxide.

57. The method of claim 52, wherein step a) is performed under Mitsunobu conditions.

58. A method of preparing 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) butanoic acid, comprising:

a) reacting (5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaen-1-ol with tert-butyl 2-bromobutyrate;

b) converting the ester obtained from step a) into a carboxylic acid; and

c) isolating the 2- ((5Z,8Z,11Z,14Z,17Z) -eicosa-5, 8,11,14, 17-pentaenyloxy) butanoic acid.

59. A lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is a carboxamide.

60. A lipid compound or pharmaceutically acceptable salt thereof according to claim 59, wherein the carboxamide is selected from the group consisting of N-methylcarboxamide, N-dimethylcarboxamide, N-ethylcarboxamide and N, N-diethylcarboxamide.

61. A lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is a carboxylate selected from: ethyl carboxylate, methyl carboxylate, n-propyl carboxylate, isopropyl carboxylate, n-butyl carboxylate, sec-butyl carboxylate, and n-hexyl carboxylate.

62. A lipid compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:

wherein

R₂And R₃Identical or different and selected from the group consisting of a hydrogen atom, a methyl group and an ethyl group, with the proviso that R₂And R₃Not being hydrogen atoms at the same time; and is

X is carboxylic acid amine.

63. A lipid compound according to claim 62, or a pharmaceutically acceptable salt thereof, wherein the carboxamide is selected from the group consisting of N-methylcarboxamide, N-dimethylcarboxamide, N-ethylcarboxamide and N, N-diethylcarboxamide.

64. Use of a compound according to at least one of claims 1 to 31 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prophylaxis of fatty liver diseases.

65. The use of claim 64, wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD).

66. Use of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for weight loss and/or prevention of weight gain.

67. Use of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of obesity or an overweight condition.

68. A lipid compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein the compound is present as a racemate.

69. The pharmaceutical composition of claim 34, wherein the antioxidant is tocopherol or 3-tert-butyl-4-hydroxyanisole.

70. The pharmaceutical composition of claim 32, in the form of a gelatin capsule.

71. A lipid compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein the carboxylic acid ester is selected from a mono-, di-, tri-, or phospholipid of a carboxylic acid.

72. A lipid compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein the carboxylic acid ester is selected from 2-monoglycerides of carboxylic acids.