RU2507193C2 - Alpha-substituted omega-3 lipids, activators or modulators of peroxisome proliferator activated receptor (ppar) - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel omega-3 lipid compounds of general formula (I)

or to their pharmaceutically acceptable salt, where in formula (I): R₁ and R₂ are similar or different and can be selected from group of substitutes, consisting of hydrogen atom, hydroxy group, C₁-C₇alkyl group, halogen atom, C₁-C₇alkoxy group, C₁-C₇alkylthio group, C₁-C₇alkoxycarbonyl group, carboxy group, aminogroup and C₁-C₇alkylamino group; X represents carboxylic acid or its carbonate, selected from ethylcarboxylate, methylcarboxylate, n-propylcarboxylate, isopropylcarboxylate, n-butylcarboxylate, sec-butylcarboxylate or n-hexylcarboxylate, carboxylic acid in form of triglyceride, diglyceride, 1-monoglyceride or 2-monoglyceride, or carboxamide, selected from primary carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, N-ethylcarboxamide or N,N-diethylcarboxamide; and Y stands for C₁₆-C₂₂ alkene with two or more double bonds, which have E- and/or Z-configuration.

EFFECT: described are pharmaceutical and lipid compositions, which contain said compounds, for application as medications, in particular, for treatment and/or prevention of peripheral insulin resistance and/or condition of diabetes, for instance, type 2 diabetes, increased levels of triglycerides and/or levels of non-HDL cholesterol, LDL cholesterol and VLDL cholesterol, hyperlipidemic condition, for instance, hypertriglyceridemia (HTG), obesity or condition of excessive body weight, fatty liver disease, for instance, non-alcoholic fatty liver disease (NAFLD) or inflammatory disease or condition.

60 cl, 3 tbl, 65 ex

Description

Technical field

The present invention relates to omega-3 lipid compounds of the general formula (I):

The invention also relates to pharmaceutical compositions and lipid compositions containing such compounds, and to such compounds for use as medicaments, in particular for the treatment of cardiovascular and metabolic diseases.

BACKGROUND OF THE INVENTION

Food-grade polyunsaturated fatty acids (PUFAs) (PUFAs) affect a variety of physiological processes, affecting normal health and chronic diseases, such as the regulation of blood plasma lipids, cardiovascular and immune functions, the effects of insulin, and the development of neurons and visual function. The intake of PUFAs (usually in the form of esters, for example, in the form of glycerides or phospholipids) will lead to their distribution in almost every cell of the body, affecting the composition and function of the membrane, synthesis of eicosanoids, signal transmission in the cell and regulation of gene expression.

Fluctuations in the distribution of various fatty acids / lipids across different tissues, in addition to cell-specific lipid metabolism, as well as the expression of transcription factors regulated by fatty acids, probably play an important role in determining how cells respond to changes in the composition of PUFAs. (Benatti, P. et al, J. Am. Coll. Nutr. 2004, 23, 281).

PUFAs or their metabolites have been shown to modulate gene transcription by interacting with several nuclear receptors. Peroxisome proliferator activated receptors (PPARs), hepatic nuclear factor 4 (HNF-4), liver X receptor (LXR), and 9-cis retinoic acid receptor (retinoic X receptor, RXR) exist. PUFA treatment can also help regulate the relative amount of many nuclear transcription factors, including SREBP, NFkB, c / EBPβ and HIF-1α. These effects are not due to direct binding of the fatty acid to the transcription factor, but rather, mechanisms are included that affect the content of transcription factors in the nucleus.

The regulation of gene transcription by means of PUFAs has a strong effect on cellular and tissue metabolism and provides a possible explanation for the involvement of nutrient-gene interactions in the occurrence and prevention or amelioration of diseases such as obesity, diabetes, cardiovascular disorders, immune-inflammatory diseases and malignant diseases ( Wahle, J., et al., Proceedings of the Nutrition Society, 2003, 349).

It has been shown that fish oil, rich in omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduces the risk of cardiovascular disease, in part by lowering the concentration of triglycerides in the blood. The indicated beneficial effect is mainly the result of the combined action of lipogenesis inhibition by reducing SPEBP-1 and stimulating the oxidation of fatty acids by activating PPAR-α in the liver.

It has been shown that omega-3 PUFAs in fish oil improve the prognosis of certain chronic inflammatory diseases characterized by leukocyte accumulation and leukocyte-mediated tissue damage, including atherosclerosis, IgA nephropathy, inflammatory bowel disease, rheumatoid arthritis, psoriasis, etc. (Mishra, A., Arterioscler. Thromb. Vasc. Biol., 2004, 1621).

Due to their limited in vivo resistance and lack of their biological specificity, PUFAs have not been widely used as therapeutic agents. Chemical modifications of omega-3 polyunsaturated fatty acids have been carried out by several research groups to alter or increase their metabolic effects.

For example, the lipid-lowering effects of EPA were enhanced by introducing methyl or ethyl into the α-position of the EPA ethyl ester. (Vaagenes et al. Biochemical Pharm. 1999, 58, 1133).

In a recent paper published by L. Larsen (Larsen, L. et al., Lipids, 2005, 40, 49), the authors showed that α-methyl derivatives of EPA and DHA increased the activation of the PPARa nuclear receptor and, therefore, the expression of L- FABP compared to EPA / DHA. The authors suggest that the delayed catabolism of these α-methyl derivatives of PUFAs contributes to an increase in their effect.

Nuclear receptors (NRs) make up a large and highly conserved family of ligand-activated transcription factors that regulate various biological processes, such as development, metabolism, and reproduction. It is recognized that ligands for these receptors can be used in the treatment of common diseases such as atherosclerosis, diabetes, obesity and inflammatory diseases. As such, NRs have become important drug targets, and the identification of new NR ligands has been the subject of numerous studies.

The activity of many nuclear receptors is controlled by binding of small, lipophilic ligands, which include hormones, metabolites such as fatty acids, bile acids, cholesterol oxidation products, and xeno- and endobiotics. Nuclear receptors can bind as monomers, homodimers, or RXR heterodimers to DNA.

The transcription factor NF-kB is an inducible eukaryotic transcription factor of the Rel family. It is a major component in a stress reaction sequence that regulates the activation of early response genes involved in the expression of inflammatory cytokines, adhesion molecules, heat shock proteins, cyclooxygenases, lipoxygenases, and redox enzymes.

Zhao, G. et al (Biochemical and Biophysical Research Comm., 2005, 909) suggested that the anti-inflammatory effects of PUFAs in human THP-1 monocytes are mediated, in part, by inhibiting the activation of transcription factor NF-kB via PPAR-γ activation. Other researchers have suggested that the anti-inflammatory effect of PUFAs is mediated through inhibition of NF-kB activation dependent on PPAR-α.

In order to analyze and evaluate the results, an extensive study is currently underway in the field of PUFAs, and in particular omega-3 polyunsaturated fatty acids. However, their pharmaceutical potential is still not fully appreciated, and therefore there is still a need for further evaluation and development of such compounds to increase their applicability in medicine.

SUMMARY OF THE INVENTION

One objective of the present invention is the provision of omega-3 lipid compounds having pharmaceutical activity.

This goal is achieved by omega-3 lipid compound of the formula (I):

Where

- R ₁ and R ₂ are the same or different and can be selected from the group of substituents consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group groups, carboxy groups, alkylsulfinyl groups, alkylsulfonyl groups, amino groups and alkylamino groups;

- X represents a carboxylic acid or its derivative, carboxylate, carboxylic anhydride or carboxamide,

- Y is a C ₁₆ -C ₂₂ alkene with two or more double bonds having an E and / or Z configuration,

or any pharmaceutically acceptable complex, salt, solvate or prodrug thereof,

provided that:

- R ₁ and R ₂ are not simultaneously a hydrogen atom or a fluorine atom; and

- the compound of formula (I) is not:

- 2-substituted (all-Z) -4,7,10,13,16,19-docosahexaenoic acid in the form of a carboxylic acid, carboxylate, carboxylic anhydride or carboxamide;

- (all-Z) -2-methyl-5,8,11,14,17 eicosapentaenoic acid or its ethyl ester;

- (all-Z) -2-ethyl-5,8,11,14,17 eicosapentaenoic acid or its ethyl ester;

- (all-Z) -2,2-dimethyl-5,8,11,14,17 eicosapentaenoic acid or its ethyl ether;

- (all-Z) -2-benzyl-5,8,11,14,17 eicosapentaenoic acid or its ethyl ester;

or

- (all-Z) -2-hydroxy-9,12,15-octadecatrienoic acid or its ethyl ester;

- (all-Z) -2-carboxy-6,9,12,15,18,21-tetracosahexaenoic acid;

- ethyl (all-Z) -2-ethoxycarbonyl-6,9,12,15,18,21-tetracosasexaenoate.

In particular, the present invention relates to omega-3 lipid compounds of the formula (I), wherein:

Y is a C ₁₆ -C ₂₀ alkene with 2-6 double bonds;

Y is a C ₁₆ -C ₂₀ alkene with 2-6 double bonds interrupted by a methylene group in the Z configuration;

Y is a C ₁₆ -C ₂₀ alkene with 3-5 double bonds;

Y is a C ₁₆ -C ₂₀ alkene with 3-5 double bonds interrupted by a methylene group in the Z configuration;

Y is a C ₂₀ alkene with 5 double bonds in the Z configuration;

Y is a C ₂₀ alkene with 5 double bonds interrupted by a methylene group in the Z configuration;

Y is a C ₁₆ alkene with 3 double bonds in the Z configuration; or

Y is a C ₁₆ alkene with 3 double bonds interrupted by a methylene group in the Z configuration.

The invention also relates to salts of the compounds of formula (I). Such salts may be provided.

where X is COO ^- ,

Z is selected from the group consisting of Li ⁺ , Na ⁺ , K ⁺ , NH ₄ ⁺ ,

Meglumina,

Tris (hydroxymethyl) aminomethane,

Diethylamine

and

Arginine;

or compound

where X = COO ^- ,

Z ^{2+ is} selected from the group consisting of Mg ²⁺ , Ca ²⁺ ,

Ethylene diamine

and

Piperazine.

Another characteristic salt is

where X is COO ^- ,

Z ^{n +} is

Chitosan.

In addition, the present invention relates to compounds of formula (I), wherein X is a carboxylic acid in the form of a phospholipid. Such compounds can be represented by the following formulas,

Where

Z is

или

or

and

Where

Z is

или

or

or

Where

Z is

или

or

Compounds of formula (I) wherein X is a carboxylic acid in the form of triglyceride, 1-monoglyceride and 2-monoglyceride are also included in the present invention. These compounds are represented in the description by formulas (V), (VI) and (VII), respectively.

More specifically, the present invention relates to an omega-3 lipid compound selected from the group consisting of:

- (all-Z) -9,12,15-octadecatrienoic acid

- (all-Z) -6,9,12,15-octadecatetetraenoic acid

- (all-Z) -7,10,13,16,19-docosapentaenoic acid

- (all-Z) -11,14,17-eicosatrienoic acid

- (all-Z) -6,9,12,15,18,21-tetracosahexaenoic acid

- (4E, 8Z, 11Z, 14Z, 17Z) -4,8,11,14,17-eicosapentaenoic acid

- (5E, 8Z, 11Z, 14Z, 17Z) -5,8,11,14,17-eicosapentaenoic acid

- (all-Z) -8,11,14,17-eicosatetraenoic acid

- (4E, 7Z, 10Z, 13Z, 16Z, 19Z) -4,7,10,13,16,19-docosahexaenoic acid

in the form of a carboxylic acid or its derivative, carboxylate, carboxylic anhydride or carboxamide,

or any pharmaceutically acceptable complex, salt, solvate or prodrug thereof;

where the specified compound is substituted at carbon 2, counting from the functional group of the omega-3 lipid compound, at least one substituent selected from the group consisting of:

hydrogen atom, hydroxy group, alkyl group, halogen atom, alkoxy group, acyloxy group, acyl group, alkenyl group, alkynyl group, aryl group, alkylthio group, alkoxycarbonyl group, carboxy group, alkyl sulfinyl group, alkyl sulfonyl group, amino group and alkylamino group;

provided that the omega-3 lipid compound is not

- substituted by two hydrogen atoms

- (all-Z) -2-carboxy-6,9,12,15,18,21-tetracosahexaenoic acid

- ethyl (all-Z) -2-ethoxycarbonyl-6,9,12,15,18,21-tetracosahexaenoate

- (all-Z) -2-hydroxy-9,12,15-octadecatrienoic acid, or its ethyl ester.

Examples of salts of the above compounds include

meglumine salt (all-Z) -2-ethyl-11,14,17-eicosatrienoic acid,

magnesium salt (all-Z) -2-ethyl-9,12,15-octadecatrienoic acid,

tris (hydroxymethyl) aminomethane salt (all-Z) -2-ethyl-7,10,13,16,19-docosapentaenoic acid,

ammonium salt of (all-Z) -2-ethyl-7,10,13,16,19-docosapentaenoic acid.

In addition, the present invention relates to an omega-3 lipid compound, which is obtained from (all-Z) -5,8,11,14,17-eicosapentaenoic acid (EPA). Such a compound can be represented by the following formula

in the form of a carboxylic acid or its derivative, carboxylate, carboxylic anhydride or carboxamide represented by X

or any pharmaceutically acceptable complex, salt, solvate or prodrug thereof, wherein

- R ₁ and R ₂ are the same or different and can be selected from the group consisting of a hydrogen atom, a hydroxy group, a C ₃ -C ₇ alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an alkylthio group, alkoxycarbonyl group, carboxy group, alkyl sulfinyl group, alkyl sulfonyl group, amino group and alkylamino group, provided that R ₁ and R ₂ are not simultaneously a hydrogen atom. Typically, R ₁ and R ₂ are selected from a hydrogen atom, a C ₃ -C ₇ alkyl group, an alkoxy group, an alkylthio group, an amino group, an alkylamino group, an alkoxycarbonyl group, and a carboxy group. More specifically, R ₁ and R ₂ are selected from a hydrogen atom, a C ₃ -C ₇ alkyl group, preferably propyl, a C ₁ -C ₇ alkoxy group, preferably methoxy, epoxy or propoxy, a C ₁ -C ₇ alkylthio group, preferably methylthio, ethylthio or propylthio , amino groups, C ₁ -C ₇ alkylamino groups, preferably ethyl or diethylamino groups, C ₁ -C ₇ alkoxycarbonyl groups and carboxy groups.

- The compound is substituted on carbon 2, counting from the functional group of the omega-3 lipid compound, by two substituents represented by R ₁ and R ₂ selected from the group consisting of a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group , an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, a carboxy group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group and an alkylamino group, provided that the above compound is not 2,2, dime yl-5,8, 11,14,17-Eicosapentaenoic acid. Typically, R ₁ and R ₂ are selected from an alkyl group, an alkoxy group, an alkylthio group, an amino group, an alkylamino group, an alkoxycarbonyl group, and a carboxy group. More specifically, R ₁ and R ₂ are selected from a C ₁ -C ₇ alkyl group, preferably methyl, ethyl or propyl, a C ₁ -C ₇ alkoxy group, preferably methoxy, ethoxy or propoxy, a C ₁ -C ₇ alkylthio group, preferably methylthio, ethylthio or propylthio, amino groups, C ₁ -C ₇ alkylamino groups, preferably ethylamino or diethylamino, C ₁ -C ₇ alkoxycarbonyl groups and carboxy groups.

In the compounds of formulas (I) and (VIII), X is usually a carboxylate or carboxylic acid. However, X may be a carboxylic acid derivative in the form of a phospholipid or tri-, di- or monoglyceride.

In addition, the present compound relates to an omega-3 lipid compound, which is obtained from (all-Z) -5,8,11,14,17-eicosapentaenoic acid (EPA) represented by formula (VIII)

in the form of a phospholipid, tri-, di- or monoglyceride, carboxylate, carboxylic anhydride or carboxamide represented by X,

or any pharmaceutically acceptable complex, salt, solvate or prodrug thereof,

where R ₁ and R ₂ are the same or different and can be selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group , carboxy groups, alkylsulfinyl groups, alkylsulfonyl groups, amino groups and alkylamino groups, provided that R ₁ and R ₂ are not simultaneously a hydrogen atom. The compound of formula (VIII) is not any one of

- (all-Z) -2-methyl-5,8,11,14,17-eicosapentaenoic acid or its ethyl ester;

- (all-Z) -2-ethyl-5,8,11,14,17-eicosapentaenoic acid or its ethyl ester;

- (all-Z) -2,2-dimethyl-5,8,11,14,17-eicosapentaenoic acid or its ethyl ester.

Typically, R ₁ and R ₂ are the same or different and are selected from a hydrogen atom, an alkyl group, an alkoxy group, an alkylthio group, an amino group, an alkylamino group, an alkoxycarbonyl group and a carboxy group. More specifically, R ₁ and R ₂ are selected from a hydrogen atom, a C ₁ -C ₇ alkyl group, preferably methyl, ethyl or propyl, a C ₁ -C ₇ alkoxy group, preferably methoxy, ethoxy or propoxy, a C ₁ -C ₇ alkylthio group, preferably methylthio , ethylthio or propylthio, an amino group, a C ₁ -C ₇ alkylamino group, preferably ethylamino or diethylamino, a C ₁ -C ₇ alkoxycarbonyl group and a carboxy group.

In the compounds of formula (VIII) above, X may be a carboxylate or carboxylic acid. However, group X may be represented by a carboxylic acid as a phospholipid according to formulas (II), (III) and (IV) described above. Examples of such compounds include:

1,2-Di ((all-Z) -2-ethyl-5,8,11,14,17-eicosapentaenoyl) -sn-glycero-3-phosphocholine,

2- (all-Z) -2-ethyl-5,8,11,14,17-eicosapentaenoyl-sn-glycero-3-phosphoethanolamine

In addition, group X can also be represented by carboxylic acid as a triglyceride according to formula (V) above. An example of such a compound is

1,2,3-tris ((all-Z) -2-ethyl-5,8,11,14,17-eicosapentaenoyl) -sn-glycerol.

Group X may also be represented by carboxylic acid as a 2-monoglyceride of formula (VII). An example of such a compound is

2 - ((all-Z) -2-ethyl-5,8,11,14,17-eicosapentaenoyl) -sn-glycerol

In the compound according to the invention, the above alkyl group can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and n-hexyl; the above halogen atom may be fluorine; the above alkoxy group may be selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, sec-butoxy, phenoxy, benzyloxy, OCH ₂ CF ₃ and OCH ₂ CH ₂ OCH ₃ ; the above alkenyl group may be selected from the group consisting of allyl, 2-butenyl and 3-hexenyl; the above alkynyl group may be selected from the group consisting of propargyl, 2-butynyl and 3-hexynyl; the above aryl group may be selected from a benzyl group and a substituted benzyl group; the above alkylthio group may be selected from the group consisting of methylthio, ethylthio, isopropylthio and phenylthio; the above alkoxycarbonyl group may be selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl; the above alkylsulfinyl group may be selected from the group consisting of methanesulfinyl, ethanesulfinyl and isopropanesulfinyl; the above alkylsulfonyl group may be selected from the group consisting of methanesulfonyl, ethanesulfonyl and isopropanesulfonyl; and the above alkylamino group may be selected from the group consisting of methylamino, dimethylamino, ethylamino and diethylamino.

The carboxylic acid derivative may be a phospholipid or a tri-, di- or monoglyceride, i.e. the compound of the invention may exist as a phospholipid, tri-, di- or monoglyceride or as a free acid.

According to the present invention, the above 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, and the above carboxamide group may be selected from primary carboxamide, N-methylcarboxamide, N, N-dimethylcarboxamide, N-ethylcarboxamide and N, N-diethylcarboxamide.

Examples of compounds according to the invention are those compounds in which X is ethyl carboxylate and Y is a C ₁₆ alkene with 3 double bonds disrupted by a methylene group having a Z configuration at positions 9, 12 and 15, where:

one of the groups R ₁ and R ₂ is methyl, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is ethyl, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is propyl, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is methoxy, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is ethoxy, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is propoxy, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is thiomethyl, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is thioethyl, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is thiopropyl, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is ethylamino, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is diethylamino, and the other is a hydrogen atom; or

one of the groups R ₁ and R ₂ is amino, and the other is a hydrogen atom.

Other examples of compounds according to the invention are those compounds in which X is an ethyl carboxylate and Y is a C ₂₀ alkene with 5 double bonds disrupted by a methylene group having a Z configuration at positions 7, 10, 13, 16 and 19, where:

one of the groups R ₁ and R ₂ is methyl, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is ethyl, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is propyl, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is methoxy, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is ethoxy, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is propoxy, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is thiomethyl, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is thioethyl, and the other is a hydrogen atom;

one of the groups R ₁ and R ₂ is thiopropyl, and the other is a hydrogen atom.

In the omega-3 lipid compound of formula (I) according to the present invention, R ₁ and R ₂ may be the same or different. When these groups are different, the compounds of formula (I) may exist in stereoisomeric forms. It should be understood that the invention covers all optical isomers of the compounds of formula (I) and mixtures thereof, including racemates. Therefore, the present invention includes, when R ₁ is different from R ₂ , compounds of formula (I) that are racemic or enantiomerically pure, either as (S) - or as (R) -enantiomer.

The present invention also relates to an omega-3 compound of formula (I) for use as a medicine or for diagnostic purposes, for example, positron emission tomography (PET).

In addition, the present invention relates to a pharmaceutical composition comprising an omega-3 lipid compound of the formula (I). The pharmaceutical composition may contain a pharmaceutically acceptable carrier, excipient or diluent, or any combination thereof, and is suitably formulated for oral administration, for example, in the form of a capsule or sachet. A suitable daily dose of a compound of formula (I) is from 1 mg to 10 g of said compound; from 50 mg to 1 g of the indicated compound; or from 50 mg to 200 mg of the indicated compound.

The present invention also relates to a lipid composition comprising an omega-3 lipid compound of the formula (I). Suitable is when at least 60% of the mass. or at least 80% of the mass. the lipid composition constitutes said compound. The lipid composition may also include fatty acids selected from (all-Z) -5,8,11,14,17-eicosapentaenoic acid (EPA), (all-Z) -4,7,10,13,16,19- docosahexaenoic acid (DHA), (all-Z) -6,9,12,15,18-genecosapentaenoic acid (HPA) and / or (all-Z) -7,10,13,16,19-docosapentaenoic acid (DPA ) or their derivatives, i.e. represented in their alpha-substituted form, and / or a pharmaceutically acceptable antioxidant, for example, tocopherol.

In addition, the invention relates to the use of an omega-3 lipid compound of the formula (I) for the manufacture of a medicament for:

- activation or modulation of at least one of the isoforms of a human receptor (PPAR) activated by peroxisome proliferators, wherein said peroxisome proliferated activator receptor (PPAR) is a peroxisome proliferated activator receptor (PPAR) α and / or γ.

- treatment and / or prevention of peripheral insulin resistance and / or diabetes.

- reducing plasma insulin, blood glucose and / or serum triglycerides.

- treatment and / or prevention of type 2 diabetes.

- preventing and / or treating elevated levels of triglycerides and / or non-HDL cholesterol (non-HDL), LDL cholesterol (LDL) and VLDL cholesterol (VLDL).

- preventing and / or treating a hyperlipidemic condition, for example, hypertriglyceridemia (HTG).

- increased levels of HDL (HDL) in human serum.

- treating and / or preventing obesity or overweight.

- reducing body weight and / or preventing weight gain.

- treating and / or preventing the disease of fatty liver, for example, non-alcoholic liver (NAFLD).

- treatment of insulin resistance, hyperlipidemia and / or obesity or overweight.

- obtaining a medicinal product for the treatment and / or prevention of an inflammatory disease or condition.

The invention also relates to a compound of formula (I) for treating and / or preventing the conditions listed above, and to methods of treating and / or preventing the above conditions, comprising administering to a mammal in need thereof a pharmaceutically active amount of a compound of formula (I).

In addition, the present invention encompasses methods for producing omega-3 lipid compounds of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

In the research leading up to the present invention, it was surprisingly found that the omega-3 lipid compounds represented by general formula (I) have high affinity for nuclear receptors of the PPAR family.

PPARα is known to be the most heterogeneous of the PPAR receptors, interacting with saturated and unsaturated fatty acids. The PPARδ receptor interacts with saturated and unsaturated fatty acids, although it is less effective than PPARα. The PPARγ receptor has the most limited binding profile for fatty acids, interacting most efficiently with PUFAs and only weakly with monounsaturated fatty acids (Xu et al., Molecular Cell, 1999, 397-403).

The action of PUFAs on these nuclear receptors is due not only to the structure and affinity of fatty acids for the receptor. Factors affecting the levels of the constituents of intracellular non-esterified fatty acids (NEFA) (NEFA) are also important. The indicated NEFA pool is affected by the concentration of exogenous fatty acids entering the cell, and the amount of endogenous synthesized fatty acids, their removal through incorporation into lipids, and their oxidation pathways. (Pawar, A. & Jump, DB, Journal of Biological Chem., 2003, 278, 35931).

According to the invention, the introduction of at least one substituent at the α-position of various polyunsaturated fatty acids leads to the accumulation of fatty acid derivatives in the NEFA pool rather than the inclusion of these fatty acids in neutral lipids or oxidation. The omega-3 lipid compounds of the present invention accumulate in the intracellular pool of NEFA and trigger the mechanism of action of local nuclear receptors to a greater extent than unsubstituted fatty acids.

Various PUFA substituents according to the invention will lead to different affinities of derivatives for nuclear receptors and, in particular, for PPAR receptors. Changes in affinity for different receptors in addition to a different set of cofactors lead to changes in the biological activity of these α-substituted lipid derivatives of formula (I).

Since PUFAs accumulate differently in different tissues, the above modified PUFAs have the potential to act as tissue-specific nuclear receptor ligands. Since many of the nuclear receptors are distributed differently in different tissues, it seems important to develop ligands that can be directed in vivo to specific cells to bind and activate the target receptor.

In addition to the fact that the derivatives according to the invention are the best ligands for nuclear receptors, they are not easily degraded by α- and β-oxidation, like natural PUFAs, due to substitution at the α-position.

Nomenclature and terminology

Fatty acids are straight chain hydrocarbons having a carboxyl (COOH) group at one end of (α) and a (usually) methyl group at the other (ω) end. In physiology, fatty acids are called by the position of the first double bond from the ω-terminus. The term ω-3 (omega-3) means that the first double bond is present as the third carbon-carbon bond from the terminal CH ₃ group (ω) of the carbon chain. In chemistry, the numbering of carbon atoms starts from the α-end.

As used herein, the expression “double bonds interrupted by a methylene group” refers to the case where the methylene group is located between individual double bonds in the carbon chain of the omega-3 lipid compound.

As used herein, the terms “2-substituted”, substituted at position 2 and “substituted at carbon 2, starting from the functional group of the omega-3 lipid compound” refer to substitution at the carbon atom designated 2 in accordance with the above-mentioned carbon chain numbering. Alternatively, such a substitution may be called an “alpha substitution”.

As used herein, the term “omega-3 lipid compound” (corresponding to ω-3 or n-3) refers to a lipid compound having a first double bond at a third carbon-carbon bond from the ω-terminus of the carbon chain, as defined above.

The main idea of the present invention is an omega-3 lipid compound of the formula (I):

Where

- R ₁ and R ₂ are the same or different and can be selected from the group of substituents consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group groups, carboxy groups, alkylsulfinyl groups, alkylsulfonyl groups, amino groups and alkylamino groups;

- X represents a carboxylic acid or its derivative, carboxylate, carboxylic anhydride or carboxamide; and

- Y is a C ₁₆ -C ₂₂ alkene with two or more double bonds having an E and / or Z configuration.

The resulting compound is an alpha-substituted omega-3 lipid compound, i.e. an omega-3 lipid compound substituted at position 2 on the carbon atom of the carbon chain, counting from the carbonyl end. More specifically, the resulting compound is an alpha-substituted polyunsaturated omega-3 fatty acid, which can be represented as a carboxylic acid or its derivative, as a carboxylate, as a carboxylic anhydride or as a carboxamide. The inventors of the present invention surprisingly found that the following omega-3 fatty acids are particularly suitable as being substituted at the alpha position, as shown in formula (I):

- (all-Z) -9,12,15-octadecatrienoic acid

- (all-Z) -6,9,12,15-octadecatetetraenoic acid

- (all-Z) -7,10,13,16,19-docosapentaenoic acid

- (all-Z) -11,14,17-eicosatrienoic acid

- (all-Z) -6,9,12,15,18,21-tetracosahexaenoic acid

- (4E, 8Z, 11Z, 14Z, 17Z) -4,8,11,14,17-eicosapentaenoic acid

- (5E, 8Z, 11Z, 14Z, 17Z) -5,8,11,14,17-eicosapentaenoic acid

- (all-Z) -8,11,14,17-eicosatetraenoic acid

- (4E, 7Z, 10Z, 13Z, 16Z, 19Z) -4,7,10,13,16,19-docosahexaenoic acid.

Among the possible substituents listed above, lower alkyl groups, in particular methyl and ethyl groups, have proven extremely useful in achieving the desired pharmaceutical activity. Other extremely suitable substituents are lower alkylthio groups and lower alkylamino groups, for example having 1-3 carbon atoms. Substitution of either an R ₁ group or an R ₂ group with one of these suitable substituents, while the other group is hydrogen, is believed to provide the most effective result.

(all-Z) -5,8,11,14,17-Eicosapentaenoic acid (EPA) is another omega-3 fatty acid that has proven to be suitable for substitution at the alpha position of the acid, as proposed according to the present invention. For EPA, suitable substituents are lower alkylthio groups and lower alkylamino groups, for example having 1-3 carbon atoms. By analogy with the above, the substitution of either an R ₁ group or an R ₂ group with one of these substituents, while the other group is hydrogen, is believed to provide the most effective result. The case where both groups R ₁ and R ₂ are ethyl represents another suitable EPA substitution.

Preferred omega-3 lipid compounds according to the present invention are divided into the following categories A-F:

Category A - (all-Z) -9,12,15-octadecatrienoic acid (alpha-linolenic acid, ALA) in the form of a carboxylic acid or its derivative, carboxylate, carboxylic anhydride or carboxamide, substituted at position 2:

Y = C ₁₆ alkene with 3 double bonds in the Z configuration at positions 9, 12 and 15;

Category B - (all-Z) -7,10,13,16,19-docosapentaenoic acid (clupanodonic acid, DPA) in the form of a carboxylic acid or its derivative, carboxylate, carboxylic anhydride or carboxamide, substituted at position 2:

Y = C ₂₀ alkene with 5 double bonds in the Z configuration at positions 7, 10, 13, 16 and 19;

Category C - (all-Z) -11,14,17-eicosatrienoic acid in the form of a carboxylic acid or its derivative, carboxylate, carboxylic anhydride or carboxamide, substituted at position 2:

Y = C ₁₈ alkene with 3 double bonds in the Z configuration at positions 11, 14 and 17;

Category D - (4E, 8Z, 11Z, 14Z, 17Z) -ecosapentaenoic acid in the form of a carboxylic acid or its derivative, carboxylate, carboxylic anhydride or carboxamide, substituted at position 2:

Y = C ₁₈ alkene with 5 double bonds in positions 4, 8, 11, 14 and 17, where the double bonds in position 8, 11, 14 and 17 have a Z configuration and the double bond in position 4 has an E configuration;

Category E - (all-Z) -5,8,11,14,17-eicosapentaenoic acid (EPA) in the form of a carboxylic acid or its derivative, carboxylate, carboxylic anhydride or carboxamide, substituted in position 2:

Y = C ₁₈ alkene with 5 double bonds in the Z configuration at positions 5, 8, 11, 14 and 17;

Category F - (4E, 7Z, 10Z, 13Z, 16Z, 19Z) -docosahexaenoic acid (trans-DHA) in the form of a carboxylic acid or its derivative, carboxylate, carboxylic anhydride or carboxamide, substituted at position 2:

Y = C ₂₀ alkene with 6 double bonds in positions 4, 7, 10, 13, 16 and 19, where the double bonds in position 7, 10, 13, 16 and 19 have a Z configuration and the double bond in position 4 has E -configuration.

Specific examples of preferred omega-3 lipid compounds according to the invention are:

Category A - examples (1) - (12):

For all examples (1) - (12):

X = ethyl carboxylate

Y = C ₁₆ alkene with 3 double bonds in the Z configuration at positions 9, 12 and 15

Ethyl (all-Z) -2-methyl-9,12,15-octadecatrienoate (1)

R ₁ = methyl and R ₂ = hydrogen atom, or

R ₂ = methyl and R ₁ = hydrogen atom

Ethyl (all-Z) -2-ethyl-9,12,15-octadecatrienoate (2)

R ₁ = ethyl and R ₂ = a hydrogen atom, or

R ₂ = ethyl and R ₁ = hydrogen atom

Ethyl (all-Z) -2-propyl-9,12,15-octadecatrienoate (3)

R ₁ = propyl and R ₂ = hydrogen atom, or

R ₂ = propyl and R ₁ = hydrogen atom

Ethyl (all-Z) -2-methoxy-9,12,15-octadecatrienoate (4)

R ₁ = methoxy and R ₂ = a hydrogen atom, or

R ₂ = methoxy and R ₁ = hydrogen atom

Ethyl (all-Z) -2-ethoxy-9,12,15-octadecatrienoate (5)

R ₁ = ethoxy and R ₂ = hydrogen atom, or

R ₂ = ethoxy and R ₁ = hydrogen atom

Ethyl (all-Z) -2-propoxy-9,12,15-octadecatrienoate (6)

R ₁ = propoxy and R ₂ = hydrogen atom, or

R ₂ = propoxy and R ₁ = hydrogen atom

Ethyl (all-Z) -2-thiomethyl-9,12,15-octadecatrienoate (7)

R ₁ = methylthio and R ₂ = hydrogen atom, or

R ₂ = methylthio and R ₁ = hydrogen atom

Ethyl (all-Z) -2-thioethyl-9,12,15-octadecatrienoate (8)

R ₁ = ethylthio and R ₂ = hydrogen atom, or

R ₂ = ethylthio and R ₁ = hydrogen atom

Ethyl (all-Z) -2-thiopropyl-9,12,15-octadecatrienoate (9)

R ₁ = propylthio and R ₂ = hydrogen atom, or

R ₂ = propylthio and R ₁ = hydrogen atom

Ethyl (all-Z) -2-ethylamino-9,12,15-octadecatrienoate (10)

R ₁ = ethylamino and R ₂ = a hydrogen atom, or

R ₂ = ethylamino and R ₁ = hydrogen atom

Ethyl (all-Z) -2-diethylamino-9,12,15-octadecatrienoate (11)

R ₁ = diethylamino and R ₂ = hydrogen atom, or

R ₂ = diethylamino and R ₁ = hydrogen atom

Ethyl (all-Z) -2-amino-9,12,15-octadecatrienoate (12)

R ₁ = amino and R ₂ = hydrogen atom, or

R ₂ = amino and R ₁ = hydrogen atom

Category B - examples (13) - (21):

For all examples (13) - (21):

X = ethyl carboxylate

Y = C ₂₀ alkene with 5 double bonds in the Z configuration at positions 7, 10, 13, 16 and 19

Ethyl (all-Z) -2-methyl-7,10,13,16,19-docosapentaenoate (13)

R ₁ = methyl and R ₂ = hydrogen atom, or

R ₂ = methyl and R ₁ = hydrogen atom

Ethyl (all-Z) -2-ethyl-7,10,13,16,19-docosapentaenoate (14)

R ₁ = ethyl and R ₂ = a hydrogen atom, or

R ₂ = ethyl and R ₁ = hydrogen atom

Ethyl (all-Z) -2-propyl-7,10,13,16,19-docosapentaenoate (15)

R ₁ = propyl and R ₂ = hydrogen atom, or

R ₂ = propyl and R ₁ = hydrogen atom

Ethyl (all-Z) -2-methoxy-7,10,13,16,19-docosapentaenoate (16)

R ₁ = methoxy and R ₂ = a hydrogen atom, or

R ₂ = methoxy and R ₁ = hydrogen atom

Ethyl (all-Z) -2-ethoxy-7,10,13,16,19-docosapentaenoate (17)

R ₁ = ethoxy and R ₂ = hydrogen atom, or

R ₂ = ethoxy and R ₁ = hydrogen atom

Ethyl (all-Z) -2-propoxy-7,10,13,16,19-docosapentaenoate (18)

R ₁ = propoxy and R ₂ = hydrogen atom, or

R ₂ = propoxy and R ₁ = hydrogen atom

Ethyl (all-Z) -2-thiomethyl-7,10,13,16,19-docosapentaenoate (19)

R ₁ = methylthio and R ₂ = hydrogen atom, or

R ₂ = methylthio and R ₁ = hydrogen atom

Ethyl (all-Z) -2-thioethyl-7,10,13,16,19-docosapentaenoate (20)

R ₁ = ethylthio and R ₂ = hydrogen atom, or

R ₂ = ethylthio and R ₁ = hydrogen atom

Ethyl (all-Z) -2-thiopropyl-7,10,13,16,19-docosapentaenoate (21)

R ₁ = propylthio and R ₂ = hydrogen atom, or

R ₂ = propylthio and R ₁ = hydrogen atom

Category C - examples (23) - (24) and (27) - (35):

For all examples (23) - (24) and (27) - (35):

Y = C ₁₈ alkene with 3 double bonds in the Z configuration at positions 11, 14 and 17

Ethyl (all-Z) -2-ethyl, 2-ethoxycarbonyl-11,14,17-eicosatrienoate (23)

R ₁ = ethoxycarbonyl and R ₂ = ethyl, or

R ₂ = ethoxycarbonyl and R ₁ = ethyl

X = ethyl carboxylate

(all-Z) -2-ethyl, 2-carboxy-11,14,17-eicosatrienoic acid (24)

R ₁ = carboxy and R ₂ = ethyl, or

R ₂ = carboxy and R ₁ = ethyl

X = acetic acid

For all examples (27) - (35):

X = ethyl carboxylate

Ethyl (all-Z) -2-methyl-11,14,17-eicosatrienoate (27)

R ₁ = methyl and R ₂ = hydrogen atom, or

R ₂ = methyl and R ₁ = hydrogen atom

Ethyl (all-Z) -2-ethyl-11,14,17-eicosatrienoate (28)

R ₁ = ethyl and R ₂ = a hydrogen atom, or

R ₂ = ethyl and R ₁ = hydrogen atom

Ethyl (all-Z) -2-propyl-11,14,17-eicosatrienoate (29)

R ₁ = propyl and R ₂ = hydrogen atom, or

R ₂ = propyl and R ₁ = hydrogen atom

Ethyl (all-Z) -2-methoxy-11,14,17-eicosatrienoate (30)

R ₁ = methoxy and R ₂ = a hydrogen atom, or

R ₂ = methoxy and R ₁ = hydrogen atom

Ethyl (all-Z) -2-ethoxy-11,14,17-eicosatrienoate (31)

R ₁ = ethoxy and R ₂ = hydrogen atom, or

R ₂ = ethoxy and R ₁ = hydrogen atom

Ethyl (all-Z) -2-propoxy-11,14,17-eicosatrienoate (32)

R ₁ = propoxy and R ₂ = hydrogen atom, or

R ₂ = propoxy and R ₁ = hydrogen atom

Ethyl (all-Z) -2-thiomethyl-11,14,17-eicosatrienoate (33)

R ₁ = methylthio and R ₂ = hydrogen atom, or

R ₂ = methylthio and R ₁ = hydrogen atom

Ethyl (all-Z) -2-thioethyl-11,14,17-eicosatrienoate (34)

R ₁ = ethylthio and R ₂ = hydrogen atom, or

R ₂ = ethylthio and R ₁ = hydrogen atom

Ethyl (all-Z) -2-thiopropyl-11,14,17-eicosatrienoate (35)

R ₁ = propylthio and R ₂ = hydrogen atom, or

R ₂ = propylthio and R ₁ = hydrogen atom

Category D - Examples (36) - (44):

For all examples (36) - (44):

Y = C ₁₈ alkene with 5 double bonds in positions 4, 8, 11, 14 and 17, where the double bonds in positions 8, 11, 14 and 17 have a Z configuration and the double bond in position 4 has an E configuration

X = ethyl carboxylate

Ethyl (4E, 8Z, 11Z, 14Z, 17Z) -2-methyl-4,8,11,14,17-eicosapentaenoate (36)

R ₁ = methyl and R ₂ = hydrogen atom, or

R ₂ = methyl and R ₁ = hydrogen atom

Ethyl (4E, 8Z, 11Z, 14Z, 17Z) -2-ethyl-4,8,11,14,17-eicosapentaenoate (37)

R ₁ = ethyl and R ₂ = a hydrogen atom, or

R ₂ = ethyl and R ₁ = hydrogen atom

Ethyl (4E, 8Z, 11Z, 14Z, 17Z) -2-propyl-4,8,11,14,17-eicosapentaenoate (38)

R ₁ = propyl and R ₂ = hydrogen atom, or

R ₂ = propyl and R ₁ = hydrogen atom

Ethyl (4E, 8Z, 11Z, 14Z, 17Z) -2-methoxy-4,8,11,14,17-eicosapentaenoate (39)

R ₁ = methoxy and R ₂ = a hydrogen atom, or

R ₂ = methoxy and R ₁ = hydrogen atom

Ethyl (4E, 8Z, 11Z, 14Z, 17Z) -2-ethoxy-4,8,11,14,17-eicosapentaenoate (40)

R ₁ = ethoxy and R ₂ = hydrogen atom, or

R ₂ = ethoxy and R ₁ = hydrogen atom

Ethyl (4E, 8Z, 11Z, 14Z, 17Z) -2-propoxy-4,8,11,14,17-eicosapentaenoate (41)

R ₁ = propoxy and R ₂ = hydrogen atom, or

R ₂ = propoxy and R ₁ = hydrogen atom

Ethyl (4E, 8Z, 11Z, 14Z, 17Z) -2-thiomethyl-4,8,11,14,17-eicosapentaenoate (42)

R ₁ = methylthio and R ₂ = hydrogen atom, or

R ₂ = methylthio and R ₁ = hydrogen atom

Ethyl (4E, 8Z, 11Z, 14Z, 17Z) -2-thioethyl-4,8,11,14,17-eicosapentaenoate (43)

R ₁ = ethylthio and R ₂ = hydrogen atom, or

R ₂ = ethylthio and R ₁ = hydrogen atom

Ethyl (4E, 8Z, 11Z, 14Z, 17Z) -2-thiopropyl-4,8,11,14,17-eicosapentaenoate (44)

R ₁ = propylthio and R ₂ = hydrogen atom, or

R ₂ = propylthio and R ₁ = hydrogen atom

Category E - Examples (45) - (50):

For all examples (45) - (50):

X = ethyl carboxylate

Y = C ₁₈ alkene with 5 double bonds in the Z configuration at positions 5, 8, 11, 14 and 17

Ethyl (all-Z) -2-methoxy-5,8,11,14,17-eicosapentaenoate (45)

R ₁ = methoxy and R ₂ = a hydrogen atom, or

R ₂ = methoxy and R ₁ = hydrogen atom

Ethyl (all-Z) -2-ethoxy-5,8,11,14,17-eicosapentaenoate (46)

R ₁ = ethoxy and R ₂ = hydrogen atom, or

R ₂ = ethoxy and R ₁ = hydrogen atom

Ethyl (all-Z) -2-propoxy-5,8,11,14,17-eicosapentaenoate (47)

R ₁ = propoxy and R ₂ = hydrogen atom, or

R ₂ = propoxy and R ₁ = hydrogen atom

Ethyl (all-Z) -2-thiomethyl-5,8,11,14,17-eicosapentaenoate (48)

R ₁ = methylthio and R ₂ = hydrogen atom, or

R ₂ = methylthio and R ₁ = hydrogen atom

Ethyl (all-Z) -2-thioethyl-5,8,11,14,17-eicosapentaenoate (49)

R ₁ = ethylthio and R ₂ = hydrogen atom, or

R ₂ = ethylthio and R ₁ = hydrogen atom

Ethyl (all-Z) -2-thiopropyl-5,8,11,14,17-eicosapentaenoate (50)

R ₁ = propylthio and R ₂ = hydrogen atom, or

R ₂ = propylthio and R ₁ = hydrogen atom

Category F - Examples (51) - (59):

For all examples (51) - (59):

X = ethyl carboxylate

Y = C ₂₀ alkene with 6 double bonds in positions 4, 7, 10, 13, 16 and 19, where the double bonds in positions 7, 10, 13, 16 and 19 have a Z configuration and the double bond in position 4 has E -configuration

Ethyl (4E, 7Z, 10Z, 13Z, 16Z, 19Z) -2-methyl-4,7,10,13,16,19-docosahexaenoate (51)

R ₁ = methyl and R ₂ = hydrogen atom, or

R ₂ = methyl and R ₁ = hydrogen atom

Ethyl (4E, 7Z, 10Z, 13Z, 16Z, 19Z) -2-ethyl-4,7,10,13,16,19-docosahexaenoate (52)

R ₁ = ethyl and R ₂ = a hydrogen atom, or

R ₂ = ethyl and R ₁ = hydrogen atom

Ethyl (4E, 7Z, 10Z, 13Z, 16Z, 19Z) -2-propyl-4,7,10,13,16,19-docosahexaenoate (53)

R ₁ = propyl and R ₂ = hydrogen atom, or

R ₂ = propyl and R ₁ = hydrogen atom

Ethyl (4E, 7Z, 10Z, 13Z, 16Z, 19Z) -2-methoxy-4,7,10,13,16,19-docosahexaenoate (54)

R ₁ = methoxy and R ₂ = a hydrogen atom, or

R ₂ = methoxy and R ₁ = hydrogen atom

Ethyl (4E, 7Z, 10Z, 13Z, 16Z, 19Z) -2-ethoxy-4,7,10,13,16,19-docosahexaenoate (55)

R ₁ = ethoxy and R ₂ = hydrogen atom, or

R ₂ = ethoxy and R ₁ = hydrogen atom

Ethyl (4E, 7Z, 10Z, 13Z, 16Z, 19Z) -2-propoxy-4,7,10,13,16,19-docosahexaenoate (56)

R ₁ = propoxy and R ₂ = hydrogen atom, or

R ₂ = propoxy and R ₁ = hydrogen atom

Ethyl (4E, 7Z, 10Z, 13Z, 16Z, 19Z) -2-thiomethyl-4,7,10,13,16,19-docosahexaenoate (57)

R ₁ = methylthio and R ₂ = hydrogen atom, or

R ₂ = methylthio and R ₁ = hydrogen atom

Ethyl (4E, 7Z, 10Z, 13Z, 16Z, 19Z) -2-thioethyl-4,7,10,13,16,19-docosahexaenoate (58)

R ₁ = ethylthio and R ₂ = hydrogen atom, or

R ₂ = ethylthio and R ₁ = hydrogen atom

Ethyl (4E, 7Z, 10Z, 13Z, 16Z, 19Z) -2-thiopropyl-4,7,10,13,16,19-docosahexaenoate (59)

R ₁ = propylthio and R ₂ = hydrogen atom, or

R ₂ = propylthio and R ₁ = hydrogen atom

Other Examples of Compounds of the Invention

Further preferred compounds include the following compounds / intermediates:

Ethyl (all-Z) -2-hydroxy-7,10,13,16,19-docosapentaenoate (65)

Ethyl (all-Z) -2-hydroxy-9,12,15-octadecatrienoate (61)

Compounds according to categories A to F can be presented in the form of salts, in the form of tri-, di- and monoglycerides and phospholipids, as described previously.

It should be understood that the present invention covers all possible pharmaceutically acceptable complexes, solvates or prodrugs of omega-3 lipid compounds of the formula (I).

“Prodrugs” are substances that may or may not have pharmacological activity per se, but that can be administered (such as oral or parenteral) and, therefore, are bioactivated (eg, metabolized) in the body to form the agent of the present invention being pharmacologically active.

“Pharmaceutically active amount” refers to an amount that will lead to the desired pharmacological and / or therapeutic effects, i.e. the amount of omega-3 lipid compound that is effective to achieve the intended goal. Although individual patient requirements may vary, determining the optimal ranges of effective amounts of omega-3 lipid compounds is within the competence of a person skilled in the art. Typically, a dosage regimen for treating a condition with the compounds and / or compositions of this invention is selected in accordance with a number of factors, including the type, age, weight, gender, nutrition, and medical condition of the patient.

By “drug” is meant an omega-3 lipid compound of the formula (I) in any form suitable for medical use, for example, in the form of a medicine, pharmaceutical or product, dietary product, food product or food supplement.

“Treatment” includes any therapeutic use that can beneficially affect a human or non-human mammal. Treatment, both human and in the field of veterinary medicine, is included in the scope of the present invention. Treatment can be directed to an existing condition or to prevention.

Omega-3 lipid compounds of formula (I) can be used as such, but are usually administered as a pharmaceutical composition in which the compounds of formula (I) (active ingredient) are in association with a pharmaceutically acceptable carrier, excipient or diluent (including combinations thereof )

Suitable carriers, excipients and diluents for therapeutic use are well known in the pharmaceutical field and may be selected based on the intended route of administration and standard pharmaceutical practice. Examples include binders, lubricants, suspending agents, coating agents, solubilizing agents, preservatives, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, fragrances, buffers, suspending agents, stabilizing agents and / or salts.

The pharmaceutical composition according to the invention is preferably formulated for oral administration to a human or animal. The pharmaceutical composition can also be formulated for administration in any other way, where the active ingredients can be effectively absorbed and disposed of, for example, by intravenous, subcutaneous, intramuscular, intranasal, rectal, vaginal or topical route.

In a separate embodiment of the invention, the pharmaceutical composition is formed in the form of a capsule, which may also be a microcapsule forming a powder or sachet. The capsule may be flavored. This embodiment includes a capsule, wherein the capsule and the encapsulated composition of the invention are flavored. Thanks to aromatization, the capsule becomes more attractive to the user. As regards the aforementioned goals of therapeutic use, the dosage administered, of course, will vary depending on the compound used, the route of administration, the treatment desired and the disorder indicated.

The pharmaceutical composition may be formulated to provide a daily dosage, for example, from 5 mg to 10 g; 50 mg to 1 g; or 50 mg to 200 g of an omega-3 lipid compound. By daily dosage is meant a dosage for 24 hours.

The dosage administered, of course, will vary depending on the compound used, the route of administration, the treatment desired and the disorder indicated. Usually, the attending physician determines the actual dosage, which will be most suitable for the individual subject. The individual dose level and dosage frequency for any individual patient may vary and will depend on a number of factors, including the activity of the particular compound used, metabolic stability and duration of action of the compound, age, body weight, general health, gender, nutrition, method and time of administration, the rate of excretion, the combination of drugs, the severity of an individual condition, and the therapy that the individual undergoes. The omega-3 lipid compound and / or pharmaceutical composition according to the present invention can be administered in accordance with the regimen from 1 to 10 times a day, for example, once or twice a day. As for the oral and parenteral route of administration to humans, the daily dosage level of the agent may be in the form of a single dose or in divided doses.

A further aspect of the present invention relates to a lipid composition comprising omega-3 lipid compounds of the formula (I). The lipid composition may contain in the range from 60 to 100% of the mass. omega-3 lipid compounds of the formula (I), wherein all percentages are by weight. based on the total weight of the lipid composition. For example, at least 60%, at least 70%, at least 80%, or at least 95% of the mass. the lipid composition are omega-3 lipid compounds of the formula (I).

The lipid composition may also contain at least one of the (all-Z) -5,8,11,14,17-eicosapentaenoic acid (EPA), (all-Z) -4,7,10,13 fatty acids, 16,19-docosahexaenoic acid (DHA), (all-Z) -6,9,12,15,18-genecosapentaenoic acid (HPA), (all-Z) -7,10,13,16,19-docosapentaenoic acid (DPA, n-3), (all-Z) -8,11,14,17-eicosatetraenoic acid (ETA, n-3), (all-Z) -4,7,10,13,16-docosapentaenoic acid (DPA, n-6) and / or (all-Z) -5,8,11,14-eicosatetraenoic acid (ARA) or derivatives thereof, i.e. present as their alpha substituted compounds.

In certain embodiments, the lipid composition is a pharmaceutical composition, a food composition, or a dietary composition.

The lipid composition may also contain an effective amount of a pharmaceutically acceptable antioxidant, for example, tocopherol or a mixture of tocopherols, in an amount up to 4 mg per g, for example, from 0.05 to 0.4 mg per g of tocopherols, based on the total weight of the lipid composition.

Omega-3 compounds and compositions according to the invention are suitable for the treatment of a wide range of diseases and conditions, as will be described in more detail below.

There are two main types of diabetes. One type is type 1 diabetes, which is known as insulin-dependent diabetes mellitus (IDDM), and the other is type 2 diabetes, which is known as non-insulin-dependent diabetes mellitus (NIDDM). Type 2 diabetes is associated with obesity / overweight and lack of exercise, in many cases it is characterized by a gradual onset of the disease, usually in adults, and is caused by a decrease in tissue sensitivity to insulin, the so-called peripheral insulin resistance. This leads to a compensatory increase in insulin production. This stage before the development of fully formed type 2 diabetes is called metabolic syndrome, and it is characterized by hyperinsulinemia, insulin resistance, obesity, lack of glucose tolerance, hypertension, abnormal blood lipids, hypercoagulopathy, dyslipidemia and inflammation. Thus, the present invention relates to the use of an omega-3 lipid compound of the formula (I) for the manufacture of a medicament for the treatment and / or prevention of a multimetabolic syndrome called “metabolic syndrome” and the related conditions mentioned above. In a later period, when insulin production is inhibited, type 2 diabetes develops. In one embodiment of the invention, the compounds of formula (I) can be used to treat type 2 diabetes.

Omega-3 lipid compounds of formula (I) can also be used to treat other types of diabetes selected from the group consisting of secondary diabetes, such as pancreatic diabetes, extrapancreatic diabetes / diabetes induced by endocrine disorders or drugs, or from exceptional forms of diabetes such as lipoatrophic, myatonic or a disease caused by impaired insulin receptors.

Accordingly, omega-3 lipid compounds of formula (I), as defined in the description above, can activate nuclear receptors, preferably PPAR (peroxisome proliferator activated receptor) α and / or γ.

Omega-3 lipid compounds of formula (I) can also be used to treat and / or prevent obesity. Obesity is usually associated with increased insulin resistance, and obese people are at high risk for developing type 2 diabetes, which is a major risk factor for developing cardiovascular disease. Obesity is a chronic disease that affects an increasing part of the population in Western communities, and it is associated not only with a social problem, but also with a decrease in life expectancy and numerous problems, such as diabetes mellitus, insulin resistance and hypertension. The present invention thus contributes to satisfying the long-felt need for a drug that will reduce total body weight, or the amount of adipose tissue, preferably in obese people, leading to ideal body weight without significant adverse side effects.

In addition, non-alcoholic fatty liver infiltration is a common condition associated with metabolic syndrome. More specifically, fatty liver infiltration is initially associated with hyperinsulinemia and insulin resistance. In one embodiment of the invention, the omega-3 lipid compound of formula (I) can act as an insulin-sensitive agent and reduce fatty degeneration of the liver.

In addition, fatty liver infiltration occurs in two main forms - alcoholic and nonalcoholic. Both terms express the accumulation of fat in the liver with varying degrees of liver damage, inflammation and fibrosis. The range of fatty liver disease varies from simple steatosis (recognized as non-hazardous and non-progressive) to steatohepatitis (fatty degeneration of the liver with damage to liver cells and inflammation), to increasing fibrosis and cirrhosis of the liver. All of these conditions are included in the prevention and / or treatment of an omega-3 lipid compound of the formula (I) according to the invention.

In addition, omega-3 lipid compounds of formula (I), as defined herein, are extremely useful for the treatment and prophylaxis of a variety of risk factors known for cardiovascular diseases such as hypertension, hypertriglyceridemia and the high activity of the complex of coagulation factor VII and phospholipid . Omega-3 lipid compounds of formula (I) can be used to treat elevated levels of lipids in human blood, acting as lipid lowering drugs.

The present invention also relates to the use of an omega-3 lipid compound of formula (I) for the manufacture of a medicament for reducing the level of triglycerides in the blood of mammals and / or increasing the levels of HDL cholesterol (HDL) in the serum of a sick person.

In another aspect, the present invention relates to the use of an omega-3 lipid compound of formula (I) for the manufacture of a medicament or pharmaceutical agent for the treatment and / or prevention of at least one of atherosclerosis or IgA nephropathy, the prevention of a variety of cardiovascular risk factors diseases, heart failure, atrial fibrillation and / or post myocardial infarction, stroke, cerebral or transient ischemic disorders associated with atherosclerosis of certain arteries, treatment of FA or HIV (HIV) and HTG treatment in HIV patients.

In one embodiment, the present invention also relates to the use of an omega-3 lipid compound of formula (I) for the manufacture of a medicament or pharmaceutical agent for the treatment and / or prevention of psoriasis, multiple sclerosis and / or rheumatoid arthritis.

Omega-3 lipid compounds of formula (I) or compositions comprising omega-3 lipid compounds of formula (I) are at least one of the activators or modulators of the receptor (PPAR) α, γ and / or δ of a person activated by peroxisome proliferators . As previously known, the PPARα receptor is more “illegible” compared to PPARγ, which means that the PPARα receptor binds to a large number of fatty acids as ligands compared to PPARγ. However, since patients with metabolic syndrome or type 2 diabetes are usually obese or overweight and have abnormal lipids in their blood, mainly elevated triglycerides and low levels of high density cholesterol (HDL cholesterol), receptor activation PPARα seems important. Therefore, in a more specific embodiment of the invention, the compound of formula (I) is a selective activator or modulator of the receptor (PPAR) of a person activated by peroxisome proliferators. In addition, an ideal drug for treating metabolic syndrome or type 2 diabetes can act as a ligand for both of these receptors. Thus, the present invention relates to the use of a compound of formula (I) as a dual activator or modulator of a human peroxisome proliferator-activated receptor (PPAR), α / γ and / or α / δ, preferably PPAR α / γ activator or modulator. The present invention also includes the case where the compounds of formula (I) are pan-agonists of PPAR (i.e., alpha, beta and gamma receptor agonists).

Methods for preparing compounds of the invention

The omega-3 lipid compound of formula (I), where R ₁ (or R ₂ ) is hydrogen, can be prepared by the following methods (Scheme 1). The omega-3 lipid compounds represented by the general formula (I), wherein R ₁ is hydrogen and R ₂ is a C ₁ -C ₆ alkyl group, benzyl, halogen, alkenyl, alkynyl, are prepared by reacting a long chain polyunsaturated ester with a strong non-nucleophilic base like lithium diisopropylamine, potassium / sodium hexamethyldisilazide or KH / NaH in DMF, in a solvent such as tetrahydrofuran, diethyl ether at a temperature of from -60 to -78 ° C to obtain an enol ester (method 1).

Method I

Scheme 1: R ₃ = alkyl group (methyl, ethyl, propyl)

Said enolate ester reacts with an electrophilic reagent similar to alkyl halide represented by ethyl iodide, benzyl chloride, carboxylic acid halide represented by acetyl chloride, benzoyl bromide, carboxylic anhydride, acetic anhydride, or electrophilic N β-bromosuccinimide or iodine, etc., to obtain a substituted derivative (method 2). 2-Halogen-substituted derivatives can be reacted with a nucleophilic reagent, such as thiols, to give 2-alkylthio derivatives.

The ester is then hydrolyzed in a solvent like ethanol or methanol to a derivative of a carboxylic acid compound by adding a base like lithium / sodium / potassium hydroxide in water at temperatures between 15 ° C and reflux.

Kleisen condensation of a long chain polyunsaturated ester occurs during the treatment of the ether with a strong base. (The condensation product may have biological activity of interest. Thus, in one embodiment of the invention, the condensation product (intermediate) mentioned above, as well as the use of this product for the treatment and / or prevention of diseases according to the present invention are disclosed).

In addition, in another embodiment, the compounds represented by general formula (I) are synthesized by the following methods (Scheme 2).

Method II:

Scheme 2: R ₃ = alkyl group (methyl, ethyl, propyl)

Compounds represented by the general formula (I), wherein R ₁ is hydrogen and R ₂ is a hydroxy group, an alkoxy group, an acyloxy group, are prepared by reacting a long chain polyunsaturated ester with a strong non-nucleophilic base such as lithium diisopropylamine or sodium hexamethyldisilazide hydrochloride diethyl ether at temperatures from -60 to -78 ° C to obtain an enol ester (method 4). This enol ester reacts with an oxygen source like dimethyldioxirane, 2- (phenylsulfonyl) -3-phenyloxaziridine, molecular oxygen with various excipients like trimethylphosphite, or various catalysts like Ni (II) complex to produce alpha-hydroxy acid ester (method 5). When a secondary alcohol reacts with a base like sodium hydride in a solvent like THF or DMF, an alcoholate forms that reacts with various electrophilic reagents, such as alkyl iodide, methyl iodide, ethyl iodide; benzyl bromide or carboxylic acid halide, for example, acetyl chloride, benzoyl bromide (method 6). The ester is hydrolyzed in a solvent like ethanol or methanol to a carboxylic acid derivative by adding a base like lithium / sodium / potassium hydroxide in water at temperatures between 15 ° C and reflux temperature (method 7).

An alpha hydroxy acid ester is a suitable intermediate for introducing other functional groups into the α-position according to the invention. Hydroxyl function can be activated by conversion to halogen or tosylate before interacting with various nucleophiles, such as ammonia, amines, thiols, etc. The Mitsunobu reaction is also useful for converting a hydroxyl group to other functional groups. (Mitsunobu, O., Synthesis, 1981, 1).

Compounds represented by general formula (I), wherein R ₁ is hydrogen and R ₂ is alkyl, phenyl, hydroxymethyl, carboxyl, alkoxycarbonyl, hydroxy, alkoxy, acyloxy, can be prepared by reacting a long chain polyunsaturated tosylate, mesylate or halogen with a dialkyl malonate or substituted dialkyl malonates. Method III, Scheme 3. Diester hydrolysis and decarboxylation lead to alpha-substituted products.

Method III

Scheme 3

The long chain polyunsaturated tosylates used in method III can be obtained from the corresponding long chain polyunsaturated alcohol. Such alcohols can be obtained directly from carboxylic acid esters of natural unsaturated fatty acids: alpha-linolenic acid, conjugated linolenic acid, eicosapentaenoic acid, etc., by a reduction reaction using a reducing reagent such as lithium aluminum hydride or diisobutylaluminium hydride at a temperature of from -10 to 0 ° C. Using alcohol derived from ethyl (all-Z) -5,8,11,14,17-eicosapentaenoate in the reaction sequence described in method III, 2-substituted DPA derivatives can be obtained. Alcohols can also be obtained by degradation of the polyunsaturated fatty acids EPA and DHA, as described by Holmeide et al. (J. Chem. Soc., Perkin Trans. 1, 2000, 2271). In this case, the method can start with purified EPA or DHA, but it can also start with fish oil containing EPA and DHA in a mixture. The reason for this is that DHA reacts faster in the iodolactonization reaction than EPA, with the formation of iodine-δ-lactone (Corey et al., Proc. Natl. Acad. Sci. USA, 1983, 3581, Wright et al., J. Org. Chem., 1987, 4399, Kuklev et al., Phytochemistry, 1992, 2401). (all-Z) -3,6,9,12,15-Octadecapentaenol can be obtained from DHA by the method described in the above literature. Using the above alcohol as a reagent in methods III, 2-substituted EPA derivatives can be obtained.

By combining method III with method I, disubstituted derivatives can be obtained.

Method IV

The compounds of formula (I), where X is a carboxylic acid in the form of a phospholipid, can be obtained by the following methods.

Acylation of sn-glycero-3-phosphocholine (GPC) with an activated fatty acid, such as fatty acid imidazolides, is a standard procedure in the synthesis of phosphatidylcholine. Typically, the synthesis is carried out in the presence of a DMSO anion with DMSO as solvent (Hermetter; Chemistry and Physics of lipids, 1981, 28, 111). Sn-Glycero-3-phosphocholine, as a cadmium (II) adduct, can also interact with imidazolid activated fatty acid in the presence of DBU (1,8-diazabicyclo [5.4.0] undec-7-ene) to produce the corresponding fatty acid phosphatidylcholine ( international application number PCT / GB2003 / 002582). Enzymatic transphosphatidylation can lead to the transformation of phosphatidylcholine into phosphatidylethanolamine (Wang et al., J. Am. Chem. Soc., 1993, 115, 10487).

Polyunsaturated compounds containing phospholipids can be obtained in various ways, mainly by chemical synthesis of phospholipids, as described, by enzymatic esterification and transesterification of phospholipids or by enzymatic transphosphatidylation of phospholipids. (Hosokawa, J. Am. Oil Chem. Soc. 1995, 1287, Lilja-Hallberg, Biocatalysis, 1994, 195). If enzymes are used, a preferred embodiment of the invention is a compound of formula (I), wherein R ₁ or R ₂ is hydrogen.

The compounds of formula (I), where X is a triglyceride carboxylic acid, can be prepared by the following methods. An excess of new fatty acid can be combined with glycerol using dimethylaminopyridine (DMAP) and 2- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU).

Compounds of formula (I) wherein X is a diglyceride carboxylic acid 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).

The compounds of formula (I), where X is a carboxylic acid as a monoglyceride, can be prepared by the following methods. Acylation of 1,2-O-isopropylidene-sn-glycerol with fatty acid using DCC and DMAP in chloroform leads to monodienoyl glycerol. The removal of the isopropylidene protecting 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 common synthetic methods for producing monoglycerides with a fatty acid in the 2-position. In one method, esterification of a fatty acid with glycidol in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP) is used to produce a glycidyl derivative. Treatment of the glycidyl derivative with trifluoroacetic anhydride (TFAA) before transesterification yields monoglyceride (Parkkari et al, Bioorg. Med. Chem. Lett. 2006, 2437).

Other general methods for preparing mono-, di- and triglycerides of fatty acid derivatives are described in International Patent Application, PCT / FR02 / 02831.

It is also possible to use enzymatic methods (reactions with lipase) to convert fatty acids to mono-, di-, and triglycerides. Mucor miehei 1,3-regiospecific lipase can be used to produce triglycerides or diglycerides from polyunsaturated fatty acids and glycerol. Another lipase, non-regiospecific yeast Candida antartica is highly effective in the formation of triglycerides from polyunsaturated fatty acids (Haraldsson, pharmazie, 2000, 3). For this enzymatic reaction, a preferred embodiment of the invention is a compound of formula I, wherein R ₁ and R ₂ are hydrogen.

Synthesis protocols

The invention will be described in more detail through the following examples, which should not be construed as limiting the invention. In the following examples, the structures were confirmed by NMR and mass spectrometry (MS). NMR spectra were recorded in CDCl ₃ . The values of J are given in Hz.

Ethyl (all-Z) -2-ethyl-7,10,13,16,19-docosapentaenoate (14)

Butyllithium (0.96 ml, 1.54 mmol, 1.6 M in hexane) was added dropwise to a stirred solution of diisopropylamine (0.23 ml, 1.60 mmol) in dry THF (5 ml) under N ₂ at 0 ° C. The resulting solution was stirred at 0 ° C for 20 minutes, cooled to -78 ° C and stirred for an additional 10 minutes until ethyl (all-Z) -7,10,13,16,19-docosapentaenoate (0.50 g) was added dropwise. , 1.40 mmol) in dry THF (5 ml) for 10 min. The green solution was stirred at -78 ° C for 10 min before adding ethyl iodide (0.16 ml, 2.09 mmol). The resulting solution was allowed to reach ambient temperature for one hour, partitioned between water (10 ml) and heptane (10 ml). The aqueous layer was extracted with heptane (20 ml), and the combined organic layer was washed with 1 M HCl and dried (Na ₂ SO ₄ ). Concentration under reduced pressure and purification by flash chromatography (heptane: EtOAc 98: 2) afforded 0.37 g (68%) of the title compound 14 as a colorless oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.83-0.99 (m, 6H), 1.20-1.60 (m, 11H), 2.05 (m, 4H), 2.19 ( m, 1H), 2.81 (m, 8H), 4.11 (q, 2H), 5.35 (m, 10H);

¹³ C-NMR (50 MHz, CDCl ₃ ) δ 11.72, 14.18, 14.28, 20.47, 25.43, 25.45, 25.54, 26.99, 29.45, 30, 22, 31.91, 37.70, 47.19, 59.82, 85.73, 126.94, 127.72, 127.79, 127.85, 128.05, 128.09, 128.36, 128.44, 129.97, 176.17;

MS (electrospray): 409.3 [M + Na].

Ethyl (all-Z) -2-hydroxy-7, l0,13,16,19-docosapentaenoate (65)

A solution of KHMDS (533.9 mg, 2.68 mmol) in THF, 10 ml, was cooled to -78 ° C under N ₂ until a solution of (all-Z) -7,10,13,16,19- was added dropwise. docosapentaenoate (478.8 mg, 1.33 mmol) in THF, 2.5 ml. The mixture was stirred at −78 ° C. for 30 minutes until a solution of trans-2- (phenylsulfonyl) -3-phenyloxaziridine (Davis reagent) (525.3 mg, 2.01 mmol) in THF, 1.5 ml was added dropwise. The reaction mixture was stirred at -78 ° C for 1 hour 50 minutes until the reaction was quenched with saturated NH ₄ Cl solution, 20 ml, after warming to room temperature, the mixture was extracted with diethyl ether, 50 ml × 2, the organic phase was washed with brine, 20 ml , dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The resulting crude product was flash chromatographed on silica gel, eluting with heptane / EtOAc (100: 1) - (95: 5) to give 293 mg (59%) of product 65 as a colorless liquid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.95 (t, J = 7.5 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.38-1.46 (m, 4H), 1.49-1.81 (m, 2H), 2.02-2.13 (m, 4H), 2.76-2.85 (m, 9H), 4.12 (dd , J = 2.5, 6.9 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 5.32-5.41 (m, 10H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 14.1, 14.2, 20.4, 24.4, 25.5, 25.6, 27.0, 29.3, 34.3, 61.5 , 70.3, 127.0, 127.8, 127.87, 127.92, 128.08, 128.15, 128.4, 128.5, 129.9, 132.0, 175.3 (2 signal is invisible).

MS (electrospray): 397 [M + Na] ⁺ .

Ethyl (all-Z) -2-ethoxy-7,10,13,16,19-docosapentaenoate (17)

A suspension of 35% KH (92.4 mg, 0.806 mmol KH) in DMF, 3 ml, was cooled in an atmosphere of N ₂ to 0 ° C, and a solution of ethyl (all-Z) -2-hydroxy-7,10 was added dropwise. 13,16,19-docosapentaenoate (65) (101 mg, 0.27 mmol) in DMF, 2 ml. The mixture was stirred for 30 minutes at 0 ° C. until EtI (0.22 ml, 2.73 mmol) was added. Then, the mixture was allowed to slowly reach room temperature and was stirred for 4 hours. The reaction was quenched with saturated NH ₄ Cl solution, 20 ml, and extracted with diethyl ether, 50 ml × 2. The organic phase was washed with brine, 20 ml, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo and flash chromatographed on silica gel, eluting with heptane: EtOAc (100: 1) - (95: 5) to give 19.4 mg (18%) of product 17 as a colorless liquid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.95 (t, J = 7.5 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.31-1.47 (m, 5H), 1.66-1.72 (m, 2H), 2.03-2.11 (m, 5H), 2, 77-2.84 (m, 6H), 3.33-3.47 (m, 1H), 3.55-3.65 (m, 1H), 3.78 (t, J = 6.4 Hz, 1H), 4.14-4.22 (m, 2H), 5.27-5.39 (m, 10H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 14.3, 15.2, 20.6, 25.0, 25.5, 25.6 (2 signals), 27.0, 29.3, 32.9 , 60.6, 65.9, 79.0, 127.0, 127.9 (2 signals), 128.0, 128.1, 128.2, 128.4, 128.5, 130.0, 132 , 0, 173.2 (2 signals are invisible).

MS (electrospray): 425 [M + Na] ⁺ .

(all-Z) -2-ethoxy-7,10,13,16,19-docosapentaenoic acid (69)

To a solution of ethyl (all-Z) -2-ethoxy-7,10,13,16,19-docosapentaenoate (17) (66.1 mg, 0.164 mmol) in EtOH (5 ml) was added a solution of LiOH · H ₂ O ( 57.7 mg, 1.38 mmol) in water (5 ml). The reaction mixture was stirred in an atmosphere of N ₂ at 80 ° C for 19½ hours. After cooling, 1 M HCl was added (to pH ~ 1). The resulting mixture was extracted with diethyl ether (50 ml), dried (MgSO ₄ ) and evaporated in vacuo to give 55 mg (90%) of the title compound as a pale yellow oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.95 (t, J = 7.5 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H), 1.38-1.41 (m, 4H), 1.75-1.85 (m, 2H), 2.03-2.13 (m, 4H), 2.80-2.83 (m, 8H), 3.46-3 71 (m, 2H); 3.88 (t, J = 5.8 Hz, 1H); 5.23-5.44 (m, 10H).

MS (electrospray): 373 [M-H] ^- .

Ethyl (all-Z) -2-ethyl-9,12,15-octadecatrienoate (2)

To a solution of diisopropylamine (265 μl, 1.88 mmol) in dry THF, 5 ml, in an atmosphere of N ₂ at 0 ° C, 1.6 M BuLi in hexane (1.15 ml, 1.84 mmol) was added dropwise. The resulting mixture was stirred at -78 ° C for 20 minutes until a solution of ethyl (all-Z) -9,12,15-octadecatrienoate (502 mg, 1.64 mmol) in THF, 5 ml was added dropwise. The resulting reaction mixture was stirred for 30 minutes at −78 ° C. until EtI (0.20 ml, 2.48 mmol) was added dropwise. The cooling bath was set aside, the reaction mixture was stirred for 3 hours 45 minutes until the reaction was quenched with water, 25 ml, and extracted with diethyl ether, 50 ml × 2. The organic phase was washed with 1 M HCl (aq), 20 ml, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The resulting crude product was flash chromatographed on silica gel eluting with a heptane / EtOAc (100: 1) mixture to give 216 mg (39%) ethyl (all-Z) -2-ethyl-9,12,15-octadecatrienoate (2) in the form of a colorless liquid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.84 (t, J = 7.4 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H), 1.25 (m, 8H), 1.33-1.65 (m, 4H), 2.02 (q, J = 7.0 Hz, 4H), 2.13 -2.27 (m, 1H), 2.76 (t, J = 5.6 Hz, 4H), 4.10 (q, J = 7.1 Hz, 2H), 5.20-5.41 ( m, 6H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 11.7, 14.2, 14.3, 20.5, 25.4, 25.5, 27.1, 27.3, 29.0, 29.4 , 29.5, 32.0, 47.2, 59.8, 127.0, 127.6, 128.1, 130.1, 131.8, 176.2 (2 signals are invisible)

MS (electrospray): 357 [M + Na] ⁺ .

(all-Z) -2-Ethyl-9,12,15-octadecatrienoic acid (70)

To a solution of ethyl (all-Z) -2-ethyl-9,12,15-octadecatrienoate (2) (111 mg, 0.312 mmol) in EtOH (10 ml) was added a solution of LiOH · H ₂ O (108 mg, 2.57 mmol) in water (10 ml). The reaction mixture was stirred in an atmosphere of N ₂ at 80 ° C for 15 hours. After cooling, 1 M HCl was added (to pH ~ 2). The resulting mixture was extracted with diethyl ether (50 ml), dried (MgSO ₄ ) and evaporated in vacuo to give 81 mg (79%) of the title compound as a yellow oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.83-0.99 (m, 6H), 1.20-1.29 (m, 8H), 1.41-1.78 (m, 4H), 1.99-2.13 (m, 4H), 2.21-2.30 (m, 1H), 2.76-2.82 (m, 4H), 5.23-5.44 (m, 6H) )

MS (electrospray): 305 [M-H] ^- .

Ethyl (all-Z) -2-iodine-9,12,15-octadecatrienoate (60)

To a solution of diisopropylamine (322 μl, 2.28 mmol) in dry THF, 5 ml, in an atmosphere of N ₂ at 0 ° C, 1.6 M BuLi in hexane (1.25 ml, 2.0 mmol) was added dropwise. The resulting mixture was stirred at -78 ° C for 20 minutes until a solution of ethyl (all-Z) -9,12,15-octadecatrienoate (501 mg, 1.63 mmol) in THF, 5 ml was added dropwise. The resulting yellow reaction mixture was stirred for 35 minutes at −78 ° C. until a solution of I ₂ (704 mg, 2.77 mmol) in THF, 5 ml was added dropwise. The reaction mixture was stirred at −78 ° C. for 25 minutes until the reaction was quenched with 1 M HCl, 20 ml, and extracted with heptane, 50 ml. The organic phase was washed with 10% Na ₂ S ₂ O ₃ (aq), 25 ml, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The resulting crude product was flash chromatographed on silica gel, eluting with a heptane / EtOAc (100: 1) mixture to give 152 mg (22%) ethyl (all-Z) -2-iodo-9,12,15-octadecatrienoate (60) in the form of a colorless liquid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.95 (t, J = 7.5 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.30 (m, 8H ), 1.89-2.09 (m, 6H), 2.78 (t, J = 5.5 Hz, 4H), 4.13-4.28 (m, 3H), 5.25-5 ( m, 6H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 13.7, 14.2, 20.5, 21.4, 25.5, 25.6, 27.1, 28.5, 28.9, 26.3 , 29.4, 36.0, 61.6, 127.0, 127.8, 128.2, 128.3, 130.1, 131.9, 171.4.

MS (electrospray): 455 [M + Na] ⁺ .

Ethyl (all-Z) -2-thiomethyl-9,12,15-octadecatrienoate (7)

Ethyl (all-Z) -2-iodo-9,12,15-octadecatrienoate (60) (146 mg, 0.338 mmol) was dissolved in THF, 5 ml, and cooled to 0 ° C in an N ₂ atmosphere before MeSNa was added. The reaction mixture was stirred at 0 ° C for 1 hour until it was diluted with heptane, 50 ml, washed with water, 2 × 20 ml, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The resulting crude product was flash chromatographed on silica gel, eluting with a heptane / EtOAc (100: 1) - (95: 5) mixture to give 110 mg (92%) ethyl (all-Z) -2-thiomethyl-9.12, 15-octadecatrienoate (7) as a colorless liquid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.94 (t, J = 7.5 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H), 1.29 (m, 8H ), (m, 1H), (m, 1H), 2.09 (s, 3H), 1.97-2.13 (m, 8H), 2.77 (t, J = 5.6 Hz, 4H ), 3.12 (dd, J = 6.8, 8.3 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 5.26-5.37 (m, 6H) .

¹³ C NMR (50 MHz, CDCl ₃ ) δ 13.7, 14.2, 20.5, 25.5, 25.6, 27.1, 27.2, 28.97, 29.04, 29.4 , 30.6, 47.3, 60.9, 127.1, 127.7, 128.17, 128.23, 130.1, 131.9, 172.4 (1 signal is invisible).

MS (electrospray): 375 [M + Na] ⁺ .

Ethyl (all-Z) -2-hydroxy-9,12,15-octadecatrienoate (61)

A solution of KHMDS (5.24 g, 26.2 mmol) in THF, 100 ml, was cooled to −78 ° C. under N ₂ until a solution of ethyl (all-Z) -9,12,15-octadecatrienoate (4) was added dropwise. 01 g, 13.1 mmol) in THF, 25 ml. The mixture was stirred at −78 ° C. for 30 minutes until a solution of trans-2- (phenylsulfonyl) -3-phenyloxaziridine (Davis reagent) (5.13 g, 19.6 mmol) in THF, 15 ml was added dropwise. The reaction mixture was stirred at -78 ° C for 1½ hours until the reaction was quenched with saturated NH ₄ Cl solution, 30 ml, after warming to room temperature, the mixture was extracted with diethyl ether, 100 ml × 2, the organic phase was washed with brine, 30 ml, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The resulting crude product was flash chromatographed on silica gel, eluting with a heptane / EtOAc (100: 1) - (95: 5) mixture to obtain 2.67 g (63%) of ethyl (all-Z) -2-hydroxy-9. 12,15-octadecatrienoate (61) as a colorless liquid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.92 (t, J = 7.5 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.28 (m, 8H ), 1.53-1.75 (m, 2H), 1.96-2.10 (m, 4H), 2.76 (t, J = 5.6 Hz, 5H), 4.11 (dd, J = 4.0, 6.7 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 5.22-5.41 (m, 6H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 14.09, 14.14, 20.4, 24.6, 25.4, 25.5, 27.1, 29.0, 29.1, 29.4 , 34.3, 61.4, 70.3, 127.0, 127.7, 128.11, 128.14, 130.1, 131.8, 175.3.

MS (electrospray): 345 [M + Na] ⁺ .

Ethyl (all-Z) -2-ethoxy-9,12,15-octadecatrienoate (5)

A suspension of 35% KH (84.3 mg, 0.735 mmol KH) in DMF, 2 ml, was cooled in an atmosphere of N ₂ to 0 ° C, and a solution of ethyl (all-Z) -2-hydroxy-9,12,15-octadecatrienoate (61) (119.7 mg, 0.37 mmol) in DMF, 2 ml, was added dropwise. The mixture was stirred for 30 minutes at 0 ° C. until EtI (0.15 ml, 1.87 mmol) was added. Then, the mixture was allowed to slowly reach room temperature and was stirred overnight. The reaction was quenched with saturated NH ₄ Cl solution, 20 ml, and the reaction mixture was extracted with diethyl ether, 50 ml × 2. The organic phase was washed with brine, 20 ml, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo and flash chromatographed on silica gel eluting with heptane: EtOAc (100: 1) - (95: 5) to give 31 5 mg (24%) of product 5 as a colorless liquid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.95 (t, J = 7.5 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H), 1.22-1.30 (m, 11H), 1.63-1.71 (m, 2H), 1.98-2.12 (m, 4H), 2.78 (t, J = 5.5 Hz, 4H), 3, 33-3.45 (m, 1H), 3.52-3.64 (m, 1H), 3.78 (t, J = 6.4 Hz, 1H), 4.12-4.24 (m, 2H), 5.27-5.40 (m, 6H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 14.2, 15.1, 20.5, 25.2, 25.5, 25.6, 27.2, 29.0, 29.1, 29.2 , 29.5, 33.0, 60.6, 65.9, 79.0, 127.1, 127.7, 128.2 (2 signals), 130.2, 131.9, 173.3.

MS (electrospray): 373 [M + Na] ⁺ .

Ethyl (all-Z) -2-phthalimide-9,12,15-octadecatrienoate (62)

A solution of ethyl (all-Z) -2-hydroxy-9,12,15-octadecatrienoate (61) (176.8 mg, 0.548 mmol), phthalimide (97.6 mg, 0.663 mmol) and triphenylphosphine (178.3 mg, 0.680 mmol) in THF was cooled to 0 ° C under N ₂ until diisopropyl azodicarboxylate (DIAD) was added (128 μl, 0.660 mmol). The cooling bath was set aside and the mixture was stirred for 22 hours. The reaction was evaporated in vacuo and flash chromatographed on silica gel eluting with heptane: EtOAc (95: 5) - (4: 1) to give 153.8 mg (62%) ethyl (all-Z) -2-phthalimide -9,12,15-octadecatrienoate (62) as a colorless liquid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.92 (t, J = 7.5 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H), 1.29 (m, 8H ), 1.97-2.10 (m, 4H), 2.17-2.24 (m, 2H), 2.72-2, 79 (m, 4H), 4.17 (q, J = 7 , 1 Hz, 2H), 4.79 (dd, J = 9.6, 6.0 Hz, 1H), 5.24-5.35 (m, 6H), 7.68-7.74 (m, 2H), 7.79-7.85 (m, 2H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 14.0, 14.2, 20.4, 25.4, 25.5, 26.2, 27.0, 28.5, 28.8, 28.9 , 29.4, 52.3, 61.6, 123.4, 127.0, 127.6, 128.11, 128.16, 130.1, 131.7, 131.8, 134.0, 167 , 6, 169.3.

MS (electrospray): 474 [M + Na] ⁺ .

Ethyl (all-Z) -2-amino-9,12,15-octadecatrienoate (12)

To a solution of ethyl (all-Z) -2-phthalimide-9,12, l5-octadecatrienoate (62) (104.6 mg, 0.232 mmol) in EtOH, 4 ml, hydrazine hydrate (17 μl, 0.35 mmol) was added and the mixture was refluxed under N ₂ for 15 hours. The reaction mixture was cooled, evaporated in vacuo and flash chromatographed on silica gel, eluting with a mixture of CH ₂ C1 ₂ : 2M NH ₃ in MeOH (97.5: 2.5) to give 58.4 mg (78%) of ethyl (all -Z) -2-amino-9,12,15-octadecatrienoate (12) as a colorless liquid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.92 (t, J = 7.5 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H), 1.27 (m, 8H ), 1.37-1.69 (m, 4H), 1.95-2.09 (m, 4H), 2.74 (t, J = 5.6 Hz, 4H), 3.36 (br. s, 1H), 4.11 (q, J = 7.1 Hz, 2H), 5.22-5.37 (m, 6H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 14.1 (2 C), 20.4, 25.4, 25.45, 25.49, 27.1, 29.0, 29.2, 29.4 , 34.8, 54.3, 60.6, 127.0, 127.6, 128.11, 128.15, 130.1, 131.8, 176.1.

MS (electrospray): 322 [M + H] ⁺ , 344 [M + Na] ⁺ .

Ethyl (all-Z) -2-diethylamino-9,12,15-octadecatrienoate (10) and ethyl (all-Z) -2-diethylamino-9,12,15-octadecatrienoate (11)

To a mixture of ethyl (all-Z) -2-amino-9,12,15-octadecatrienoate (12) (551.7 mg, 1.72 mmol), LiOH · H ₂ O (144.6 mg, 3.45 mmol ) and 4Å molecular sieves (507 mg) in DMF, 4 ml, ethyl bromide (2.6 ml, 34.8 mmol) was added, and the resulting mixture was stirred at ambient temperature for 46 hours. The mixture was diluted with diethyl ether, 100 ml, and filtered. The organic phase was washed with 1 M NaOH, 20 ml, and brine, 20 ml, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo and flash chromatographed on silica gel, eluting with heptane: EtOAc (95: 5) - CH ₂ Cl ₂ : 2M NH ₃ in MeOH (98: 2) to give 357 mg (55%) of diethylamino derivative ester 10 as a colorless liquid and 161 mg (27%) of ethylamino derivative ester 11 as a liquid yellow color.

Ethyl (all-Z) -2-diethylamino-9,12,15-octadecatrienoate (10)

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.93 (t, J = 7.5 Hz, 3H), 0.99 (t, J = 7.1 Hz, 6H), 1.22 (t, J = 7.1 Hz, 3H), 1.27 (m, 8H), 1.51-1.70 (m, 2H), 1.96-2.11 (m, 4H), 2.43 (sextet, J = 6.8 Hz, 2H), 2.66 (q, J = 7.3 Hz, 2H), 2.71-2.79 (m, 4H), 3.28 (t, J = 7.4 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 5.22-5.38 (m, 6H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 13.9, 14.2, 14.4, 20.5, 25.4, 25.5, 26.3, 27.1, 29.1, 29.3 , 29.5, 29.9, 44.4, 59.7, 63.0, 127.0, 127.6, 128.2 (2C), 130.2, 131.8, 173.5.

MS (electrospray): 378 [M + H] ⁺ , 400 [M + Na] ⁺ .

Ethyl (all-Z) -2-ethylamino-9,12,15-octadecatrienoate (11)

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.91 (t, J = 7.5 Hz, 3H), 1.02 (t, J = 1.1 Hz, 3H), 1.24 (m, 11H ), 1.55 (m, 3H), 1.94-2.08 (m, 4H), 2.35-2.65 (m, 2H), 2.73 (t, J = 5.6 Hz, 4H), 3.14 (t, J = 6.6 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 5.17-5.38 (m, 6H).

¹³ C NMR (50 MHz, CDCl ₃ ) δ 14.1, 14.2, 15.2, 20.4, 25.4, 25.5, 25.6, 27.0, 28.9, 29.2 , 29.4, 33.5, 42.3, 60.3, 61.3, 127.0, 127.6, 128.09, 128.11, 130.1, 131.8, 175.5.

MS (electrospray): 350 [M + H] ⁺ , 372 [M + Na] ⁺ .

(all-Z) -4,7,10,13,16,19-docosahexaenol (63)

A solution of ethyl (all-Z) -4,7,10,13,16,19-docosahexaenoate (10.72 g, 30.0 mmol) in THF, 30 ml, was added dropwise to a suspension of LiAlH ₄ in THH, 140 ml in an atmosphere of N ₂ at 0 ° C. The resulting mixture was stirred at 0 ° C for 50 minutes until the reaction was quenched with water, 50 ml, 1 M HCl, 100 ml was added, and stirred at room temperature for 1 hour. The phases were separated and the aqueous phase was extracted with diethyl ether, 100 ml × 2. The organic phase was washed with 1M HCl, 50 ml, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo to give 8.56 g (91%) (all-Z) -4,7,10,13,16,19- docosahexaenol (63) as a colorless liquid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.00 (t, J = 7.5 Hz, 3H), 1.63-1.73 (m, 2H), 1.83 (broad s, 1H) , 2.04-2.24 (m, 4H), 2.88 (broad s, 10H), 3.67 (t, J = 6.4 Hz, 2H), 5.41 (broad s, 12H )

(all-Z) -4,7,10,13,16,19-docosahexaentosylate (64)

A solution of (all-Z) -4,7,10,13,16,19-docosahexaenol (63) (8.50 g, 27.0 mmol) and tosyl chloride (5.41 g, 28.4 mmol) in dry CH ₂ Cl ₂ , 30 ml, cooled to 0 ° C. until Et ₃ N (4.15 ml, 29.8 mmol) was added. The reaction mixture was refrigerated. After 17 hours, additional tosyl chloride (774 mg, 4.06 mmol) and Et ₃ N (565 μl, 4.06 mmol) were added, and the mixture was refrigerated for 21½ hours. The reaction mixture was poured into ice water and extracted with CH ₂ Cl ₂ , 50 ml × 2, and evaporated in vacuo. The residue was dissolved in heptane, 100 ml, washed with water, 30 ml, 1M HCl, 30 ml × 2, and brine, 30 ml, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. Pyridine, 1.6 ml, and water, 1.25 ml, were added to the residue, and stirred at room temperature for 1 hour. The mixture was diluted with heptane, 100 ml, and washed with water, 25 ml, 1 M HCl, 25 ml × 2, brine, 25 ml, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo to give 10.27 g ( 81%) of tosylate 64 as a colorless oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.94 (t, J = 7.5 Hz, 3H), 1.61-1.75 (m, 2H), 1.97-2.12 (m, 4H), 2.41 (s, 3H), 2.70-2.89 (m, 10H), 4.00 (t, J = 6.4 Hz, 2H), 5.27-5.38 (m , 12H); 7.31 (d, 2H); 7.76 (d, 2H).

MS (electrospray): 491 [M + Na] ⁺ .

(all-Z) -9,12,15-octadecatrienol (66)

To a stirred suspension of LAH (0.130 g, 3.43 mmol) in dry THF (10 ml), which was kept at 0 ° C in an inert atmosphere, was added dropwise a solution of ethyl (all-Z) -9,12,15-octadecatrienoate ( 1.0 g, 3.26 mmol) in dry THF (15 ml). The resulting solution was stirred at 0 ° C for one hour, 10% NH ₄ Cl solution (15 ml) was added and filtered through a short pad of celite. Celite was washed with water (10 ml) and heptane (20 ml), and the layers were separated. The aqueous layer was extracted with heptane (20 ml), and the combined organic layers were washed with brine (20 ml) and dried (MgSO ₄ ). The synthesis resulted in 0.78 g (91%) of (all-Z) -9,12,15-octadecatrienol (66) as a colorless oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.95 (t, 3H), 1.20-1.35 (m, 10H), 1.48-1.58 (m, 2H), 1.98- 2.09 (m, 4H), 2.76-2.82 (m, 4H), 5.23-5.44 (m, 6H);

MS (electrospray): 287.3 [M + Na] ⁺ .

(all-Z) -9,12,15-octadecatrientosylate (67)

To a stirred solution of (all-Z) -9,12,15-octadecatrienol (66) (0.78 g, 2.95 mmol) in dry CH ₂ Cl ₂ (15 ml), which was kept at 0 ° C in an inert atmosphere toluene-4-sulfonyl chloride (1.12 g, 5.90 mmol) and Et ₃ N (0.82 ml, 5.90 mmol) were added. The resulting solution was stirred at 0 ° C for five hours and then for 66 hours at ambient temperature. The mixture was poured into ice water (40 ml), and the layers were separated. The aqueous layer was extracted with CH ₂ Cl ₂ (20 ml), and the combined organic layer was concentrated. 2 ml of pyridine and 1.6 ml of water were added to the crude product, and the mixture was stirred at ambient temperature for 30 minutes. Heptane (70 ml) was added and the organic layer was washed with water (30 ml), 1M HCl (30 ml) and brine (30 ml). Drying (MgSO ₄ ) and concentration under reduced pressure afforded 0.68 g (55%) of tosylate 67 as a colorless oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.91 (t, 3H), 1.15-1.35 (m, 10H), 1.53-1.60 (m, 2H), 1.98- 2.12 (m, 4H), 2.43 (s, 3H), 2.70-2.80 (m, 4H), 5.22-5.40 (m, 6H), 7.31 (d, 2H), 7.76 (d, 2H);

MS (electrospray): 441.2 [M + Na].

Ethyl (all-Z) -2-ethyl-2-ethoxycarbonyl-ll, 14.17-eicosatrienoate (23)

To a stirred suspension of NaH (60%, 0.098 g, 2.44 mmol) in dry THF (15 ml) and dry DMF (3 ml), which was kept at 0 ° C in an inert atmosphere, diethyl ethyl malonate (0.61) was added dropwise. ml, 3.25 mmol). The resulting mixture was stirred at 0 ° C for ten minutes, the temperature was brought to ambient temperature and stirred for another 20 minutes. Tosylate 67 (0.68 g, 1.62 mmol) in dry THF (3 ml) was added, followed by NaI (0.098 g, 0.65 mmol). Then, the resulting solution was stirred at 70 ° C for four hours, cooled and partitioned between 10% NH ₄ Cl (30 ml) and heptane (30 ml). The aqueous layer was extracted with heptane (20 ml), and the combined organic layer was washed with brine (30 ml) and dried (Na ₂ SO ₄ ). This synthesis gave 0.70 g (quantitative yield) of the title compound 23 as a colorless oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.91 (t, 3H), 1.18-1.30 (m, 19H), 1.80-2.10 (m, 10H), 2.75- 2.81 (m, 4H); 4.16 (m, 4H); 5.28-5.38 (m, 6H);

MS (electrospray): 457.3 [M + Na].

(all-Z) -2-ethyl, 2-carboxy-ll, 14,17-eicosatrienoic acid (24)

Ethyl (all-Z) -2-ethyl, 2-ethoxycarbonyl-11,14,17-eicosatrienoate (23) (0.70 g, 1.61 mmol) was dissolved in 96% ethanol (20 ml) and 5M KOH ( 2.6 ml, 13 mmol). The resulting mixture was stirred at the boil under reflux for 19 hours, cooled and concentrated under reduced pressure. To the resulting crude product was added 1M HCl (20 ml) and extracted twice with diethyl ether (30 ml). The combined organic layer was washed with brine (30 ml) and dried (MgSO ₄ ). Concentration under reduced pressure resulted in 0.60 g (quantitative yield) of the title compound 24 as a light brown oil.

MS (electrospray): 377.2 [M-H].

(all-Z) -2-ethyl-ll, 14,17-eicosatrienoic acid (68)

Pure (all-Z) -2-ethyl, 2-carboxy-11,14,17-eicosatrienoic acid (24) (0.60 g, 1.59 mmol) in an inert atmosphere was heated at 160 ° C for two hours, cooled and purified by flash chromatography (heptane: EtOAc 9: 1, then 4: 1). This procedure resulted in 0.33 g (62%) of the title (all-Z) -2-ethyl-l1,14,17-eicosatrienoic acid (68) as a colorless oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.84-0.99 (m, 8H), 1.15-1.35 (m, 10H), 1.35-1.70 (m, 4H), 2.00-2.15 (m, 4H), 2.20-2.30 (m, 1H), 2.75-2.85 (m, 4H), 5.25-5.45 (m, 6H) );

MS (electrospray): 333.2 [M-H].

Ethyl (all-Z) -2-ethyl-ll, 14.17-eicosatrienoate (28)

(all-Z) -2-Ethyl-l1,14,17-eicosatrienoic acid (0.15 g, 0.45 mmol) was dissolved in absolute EtOH (5 ml), concentrated H ₂ SO _{4 was} added dropwise and stirred while boiling under reflux in an inert atmosphere for 18 hours. The mixture was cooled, concentrated and purified by flash chromatography (heptane: EtOAc 95: 5). This procedure resulted in 0.13 g (80%) of the title compound 28 as a colorless oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.85 (t, 3H), 0.94 (t, 3H), 1.18-1.34 (m, 13H), 1.45-1.59 ( m, 4H), 1.97-2.08 (m, 4H), 2.25 (m, 1H), 2.74-2.85 (m, 4H), 4.09 (q, 4H), 5 24-5.42 (m, 6H);

¹³ C NMR (50 MHz, CDCl ₃ ) δ 11.76, 14.21, 14.30, 20.49, 25.46, 25.56, 27.18, 27.37, 29.22, 29.41 , 29.42, 29.50, 29.59, 32.06, 47.29, 59.83, 127.06, 127.59, 128.18, 128.21, 130.27, 131.85, 176 , 33;

MS (electrospray): 385.3 [M + Na] ⁺ .

2 - ((all-Z) -2-Ethyl-5,8,11,14,17-eicosapentaenoyl) -sn-glycerol (71)

Stage 1: Glycidyl (all-Z) -2-ethyl-5,8,11,14,17-

eicosapentaenoate

Раствор (все-Z)-2-этил-5,8,11,14,17-эйкозапентаеновой кислоты (1,00 г, 3,03 ммоль), глицидола (167 мкл, 2,52 ммоль), хлоргидрата N-этил-N'-(3-диметиламинопропил)карбодиимида (585 мг, 3,05 ммоль) и DMAP (372 мг, 3,05 ммоль) в сухом CH₂Cl₂ (10 мл) перемешивали в течение 18 часов в атмосфере N₂ при комнатной температуре. Смесь упаривали в вакууме. Остаток очищали флэш-хроматографией на силикагеле, элюируя смесью гептан - гептан:EtOAc (95:5), с получением 647 мг (55%) указанного в заголовке продукта в виде слегка желтой жидкости.

Solution of (all-Z) -2-ethyl-5,8,11,14,17-eicosapentaenoic acid (1.00 g, 3.03 mmol), glycidol (167 μl, 2.52 mmol), N-ethyl hydrochloride -N '- (3-dimethylaminopropyl) carbodiimide (585 mg, 3.05 mmol) and DMAP (372 mg, 3.05 mmol) in dry CH ₂ Cl ₂ (10 ml) were stirred for 18 hours under N ₂ at room temperature. The mixture was evaporated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with a heptane-heptane: EtOAc (95: 5) mixture to give 647 mg (55%) of the title product as a slightly yellow liquid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.85-0.99 (m, 6H), 1.42-1.80 (m, 5H), 2.03-2.09 (m, 4H), 2.28-2.42 (m, 1H), 2.60-2.64 (m, 1H), 2.79-2.82 (m, 8H), 3.14-3.21 (m, 1H) ), 3.88-3.97 (m, 1H), 4.36-4.46 (m, 1H), 5.23-5.51 (m, 10H).

MS (electrospray): 409 [M + Na] ⁺

Stage 2: 1,3-di (trifluoroacetate) -2 - ((all-Z) -2-ethyl-5.8, 11,14,17-eicosapentaenoyl) -sn-glycerol

A solution of glycidyl (all-Z) -2-ethyl-5,8,11,14,17-eicosapentaenoate (641 mg, 1.66 mmol) in dry alcohol-free CH ₂ Cl ₂ (6.5 ml) was cooled to - 20 ° C in an atmosphere of N ₂ . A solution of trifluoroacetic anhydride (TFAA) (0.93 ml, 6.69 mmol) in dry CH ₂ Cl ₂ (6.5 ml) was added dropwise. The cooling bath was set aside and the mixture was stirred for 70 minutes. The solvent and unreacted TFAA were evaporated in vacuo (t <40 ° C), and the residue was dissolved in toluene (15 ml), and the solution was passed through a pad of silica gel (16.5 g), eluting with toluene (350 ml). This synthesis gave 607 mg (61%) of the crude title product as a yellow oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.83-0.99 (m, 6H), 1.54-1.67 (m, 4H), 1.99-2.13 (m, 4H), 2.27-2.38 (m, 1H), 2.63-2.82 (m, 8H), 4.44 (dd, J = 11.8 Hz, 5.7 Hz, 2H), 4.62 (dd, J = 11.9 Hz, 4.1 Hz, 2H), 5.20-5.45 (m, 11H).

Stage 3: 2 - ((all-Z) -2-ethyl-5,8,11,14,17-eicosapentaenoyl) -sn-glycerol

A solution of 1,3-di (trifluoroacetate) -2 - ((all-Z) -2-ethyl-5,8,11,14,17-eicosapentaenoyl) -sn-glycerol (607 mg, 1.02 mmol) in a mixture pentane / CH ₂ Cl ₂ (2: 1, 10 ml) was cooled to -20 ° C in an atmosphere of N ₂ . A solution of pyridine (0.83 ml, 10.3 mmol) and MeOH (0.62 ml, 15.3 mmol) in a mixture of pentane / CH ₂ Cl ₂ (2: 1, 9 ml) was added dropwise. The cooling bath was set aside and the mixture was stirred for 4 hours. The resulting mixture was evaporated in vacuo. Flash chromatography on silica gel, eluting with a heptane-heptane: EtOAC 1: 1 mixture, provided 352 mg (86%) of the title product as a slightly yellow oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.86-0.99 (m, 6H), 1.43-1.81 (m, 4H); 1.94 (br s, 2H), 2.02-2.13 (m, 4H), 2.29-2.43 (m, 1H), 2.79-2.83 (m, 8H), 3.81 (d, J = 4.8 Hz, 4H), 4.89-4.98 (m, 1H), 5.22-5.43 (m, 10H).

MS (electrospray): 427 [M + Na] ⁺

1,2,3-tris ((all-Z) -2-ethyl-5,8,11,14,17-eicosapentaenoyl) -sn-glycerol (72)

(all-Z) -2-Ethyl-5,8,11,14,17-eicosapentaenoic acid (501 mg, 1.52 mmol), DMAP (185 mg, 1.52 mmol), N-ethyl-N 'hydrochloride - (3-Dimethylaminopropyl) carbodiimide (295 mg, 1.54 mmol) and dry CH ₂ Cl ₂ (5 ml) were added to a solution of glycerol (31.6 mg, 0.343 mmol) in DMF (2 ml). The resulting mixture was stirred for 17½ hours under N ₂ at room temperature. Diethyl ether (50 ml) was added, and the resulting mixture was washed with 1M HCl (20 ml) and brine (20 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo. Repeated flash chromatography on silica gel, eluting with heptane-heptane: EtOAc (100: 1) - (95: 5), afforded 206 mg (58%) of the title product as a colorless oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.83-0.99 (m, 18H), 1.43-1.77 (m, 12H), 1.98-2.13 (m, 12H), 2.23-2.37 (m, 3H), 2.77-2.85 (m, 24H), 4.04-4.18 (m, 2H), 4.28-4.42 (m, 2H) ), 5.23-5.49 (m, 31H).

MS (electrospray): 1051 [M + Na] ⁺ .

The compounds listed in tables 1-3 can be obtained similarly to the examples described above:

The case where R ₁ and R ₂ are inverse is also included. ∗ cases where X is a carboxylic acid or its derivative, carboxylate, carboxylic anhydride or carboxamide.

The case where R ₁ and R ₂ are inverse is also included; ∗ cases where X is a carboxylic acid or its derivative, carboxylate, carboxylic anhydride or carboxamide; ∗∗ cases where X is carboxylic acid anhydride, carboxamide, mono-, di- or triglyceride or phospholipid.

The case where R ₁ and R ₂ are inverse is also included. ∗ cases where X is a carboxylic acid or its derivative, carboxylate, carboxylic anhydride or carboxamide.

The invention should not be limited to the presented embodiments of the invention and examples.

Claims (60)

1. Omega-3 lipid compound of the formula (I):

Where
- R ₁ and R ₂ are the same or different and can be selected from the group of substituents consisting of a hydrogen atom, a hydroxy group, a C ₁ -C ₇ alkyl group, a halogen atom, a C ₁ -C ₇ alkoxy group, a C ₁ -C ₇ alkylthio group, A C ₁ -C ₇ alkoxycarbonyl group, a carboxy group, an amino group and a C ₁ -C ₇ alkylamino group;
- X is a carboxylic acid or its carboxylate selected from ethyl carboxylate, methyl carboxylate, n-propyl carboxylate, isopropyl carboxylate, n-butyl carboxylate, sec-butyl carboxylate or n-hexyl carboxylate, carboxylic acid in the form of triglyceride, di-di-glyceride or a carboxamide selected from primary carboxamide, N-methylcarboxamide, N, N-dimethylcarboxamide, N-ethylcarboxamide or N, N-diethylcarboxamide; and
- Y is a C ₁₆ -C ₂₂ alkene with two or more double bonds,
having an E and / or Z configuration
or any pharmaceutically acceptable salt thereof,
provided that:
- R ₁ and R ₂ are not simultaneously a hydrogen atom or a fluorine atom;
and
- the compound of formula (I) is not:
- 2-substituted (4Z, 7Z, 10Z, 13Z, 16Z, 19Z) -dose-4,7,10,13,16,19-hexaenoic acid in the form of a carboxylic acid, carboxylate, diglyceride, triglyceride or carboxamide;
- (5Z, 8Z, 11Z, 14Z, 17Z) -2-methyleicose-5,8,11,14,17-pentaenoic acid, its ethyl ether or its 4- (tert-butyl) phenyl ether;
- (5Z, 8Z, 11Z, 14Z, 17Z) -2-ethyleicose-5,8,11,14,17-pentaenoic acid, its ethyl ether or its mesityl ether;
- (5Z, 8Z, 11Z, 14Z, 17Z) -2,2-dimethyleukose-5,8,11,14,17-pentaenoic acid, its ethyl ether or its 4- (tert-butyl) phenyl ether;
- (5Z, 8Z, 11Z, 14Z, 17Z) -methyl-2,2-diethylaicose-5,8,11,14,17-pentaenoate;
- (5Z, 8Z, 11Z, 14Z, 17Z) -2-benzyl-leukemia-5,8,11,14,17-pentaenoic acid or its ethyl ester;
- (9Z, 12Z, 15Z) -2-hydroxyoctadec-9,12,15-trienoic acid, its methyl ether or its ethyl ether;
- diethyl 2 - ((3Z, 6Z, 9Z, 12Z, 15Z)-octadec-3,6,9,12,15-pentaen-1-yl) malonate;
- diethyl 2 - ((5Z, 9Z, 12Z) octadec-5,9,12-trien-1-yl) malonate;
- diethyl 2 - ((6Z, 9Z, 12Z, 15Z) octadec-6,9,12,15-tetraen-1-yl) malonate;
- diethyl 2 - ((5Z, 8Z, 11Z, 14Z) -eicose-5,8,11,14-tetraen-1-yl) malonate;
- diethyl 2 - ((5Z, 8Z, 11Z, 14Z, 15Z) -eicose-5,8,11,14,15-pentaen-1-yl) malonate;
- ethyl (4Z, 7Z, 10Z, 13Z, 16Z, 19Z) -2,2-diethyl docosa-4,7,10,13,16,19-hexaenoate. 2. The compound according to claim 1, where Y is a C ₁₆ -C ₂₀ alkene with 2-6 double bonds, for example 2-6 double bonds interrupted by a methylene group, in the Z-configuration. 3. The compound according to claim 1, where Y is a C ₁₆ -C ₂₀ alkene with 3-5 double bonds, for example, 3-5 double bonds interrupted by a methylene group, in the Z-configuration. 4. The compound according to claim 1, where Y is a C ₂₀ alkene with 5 double bonds in the Z configuration, for example, 5 double bonds interrupted by a methylene group in the Z configuration. 5. The compound according to claim 1, where Y is a C ₁₆ alkene with 3 double bonds in the Z configuration, for example, 3 double bonds interrupted by a methylene group in the Z configuration. 6. The compound according to claim 1, selected from the following categories:
Category A - (all-Z) -9,12,15-octadecatrienoic acid (alpha-linolenic acid, ALA)

Y = C ₁₆ alkene with 3 double bonds in the Z-configuration at positions 9, 12 and 15;
Category B - (all-Z) -7,10,13,16,19-docosapentaenoic acid (clupanodonic acid, DPA)

Y = C ₂₀ alkene with 5 double bonds in the Z configuration at positions 7, 10, 13, 16 and 19;
Category C - (all-Z) -11,14,17-eicosatrienic acid

Y = C ₁₈ alkene with 3 double bonds in the Z configuration at positions 11, 14 and 17;
Category D - (4E, 8Z, 11Z, 14Z, 17Z) -ecosapentaenoic acid

Y = C ₁₈ alkene with 5 double bonds in positions 4, 8, 11, 14 and 17, where the double bonds in position 8, 11, 14 and 17 are in the Z-configuration, and the double bond in position 4 is in the E-configuration ;
Category E - (all-Z) -5,8,11,14,17-eicosapentaenoic acid (EPA)

Y = C ₁₈ alkene with 5 double bonds in the Z configuration at positions 5, 8, 11, 14 and 17;
Category F - (4E, 7Z, 10Z, 13Z, 16Z, 19Z) -docosahexaenoic acid (trans-DHA)

Y = C ₂₀ alkene with 6 double bonds in positions 4, 7, 10, 13, 16 and 19, where the double bonds in position 7, 10, 13, 16 and 19 are in the Z-configuration, and the double bond in position 4 is in the E-configuration. 7. The compound according to any one of claims 1 to 6 in the form of a salt

where X is COO ^- ,
Z is selected from the group consisting of Li ⁺ , Na ⁺ , K ⁺ , NH ₄ ⁺ ,

Meglumina,

Tris (hydroxymethyl) aminomethane,

Diethylamine, and

Arginine; or

where X = COO ^- ,
Z ^{2+ is} selected from the group consisting of Mg ²⁺ , Ca ²⁺ ,

Ethylene diamine, and

Piperazine; or

where X is COO ^- ,
Z ^{n +} is

Chitosan. 8. The compound according to claim 7, where the above compound is selected from: meglumine salt (all-Z) -2-ethyl-11,14,17-eicosatrienoic acid

magnesium salt (all-Z) -2-ethyl-11,14,17-octadecatrienoic acid

(all-Z) -2-ethyl-7,10,13,16,19-docosapentaenoic acid tris (hydroxymethyl) aminomethane salt

(all-Z) -2-ethyl-7,10,13,16,19-docosapentaenoic acid ammonium salt

9. The compound according to any one of claims 1 to 6, wherein said carboxylic acid derivative is a tri-, di- or monoglyceride. 10. The compound according to claim 9, where X is a carboxylic acid in the form of a triglyceride represented by formula (V):

or, where X is a carboxylic acid in the form of a 1-monoglyceride represented by formula (VI)

or, where X is a carboxylic acid in the form of a 2-monoglyceride represented by formula (VII)

11. Omega-3 lipid compound selected from the group consisting of:
- (all-Z) -6,9,12,15-octadecatetetraenoic acid
- (all-Z) -6,9,12,15,18,21-tetracosahexaenoic acid
- (all-Z) -8,11,14,17-eicosatetraenoic acid
in the form of a carboxylic acid or its carboxylate selected from ethyl carboxylate, methyl carboxylate, n-propyl carboxylate, isopropyl carboxylate, n-butyl carboxylate, sec-butyl carboxylate or n-hexyl carboxylate, carboxylic acid in the form of a triglyceride, diglyceride, monideamide or selected from primary carboxamide, N-methylcarboxamide, N, N-dimethylcarboxamide, N-ethylcarboxamide or N, N-diethylcarboxamide;
or any pharmaceutically acceptable salt thereof;
where the above compound is substituted on carbon 2, counting from the functional group of the omega-3 lipid compound, at least one substituent selected from the group consisting of:
a hydrogen atom, a hydroxy group, a C ₁ -C ₇ alkyl group, a halogen atom, a C ₁ -C ₇ alkoxy group, a C ₁ -C ₇ alkylthio group, a C ₁ -C ₇ alkoxycarbonyl group, a carboxy group, an amino group and a C ₁ -C ₇ alkylamino group;
provided that the omega-3 lipid compound is not:
- substituted by two hydrogen atoms
- (all-Z) -2-carboxy-6,9,12,15,18,21-tetracosahexaenoic acid
- ethyl (all-Z) -2-ethoxycarbonyl-6,9,12,15,18,21-tetracosahexaenoate
- diethyl 2 - ((6Z, 9Z, 12Z, 15Z) octadec-6,9,12,15-tetraen-1-yl) malonate. 12. Omega-3 lipid compound, which is selected from:
(all-Z) -5,8,11,14,17-eicosapentaenoic acid (EPA) represented by formula (VIII)

in the form of a carboxylic acid or its carboxylate selected from ethyl carboxylate, methyl carboxylate, n-propyl carboxylate, isopropyl carboxylate, n-butyl carboxylate, sec-butyl carboxylate or n-hexyl carboxylate, carboxylic acid in the form of a triglyceride, diglyceride, monideamide or selected from primary carboxamide, N-methylcarboxamide, N, N-dimethylcarboxamide, N-ethyl carboxamide or N, N-diethylcarboxamido represented by X, or a pharmaceutically acceptable salt thereof, wherein R ₁ and R ₂ are identical and or different and may be selected from the group of substituents consisting of hydrogen, C ₃ -C ₇ alkyl group, C ₁ -C ₇ alkoxy, C ₁ -C ₇ alkylthio, C ₁ -C ₇ alkoxycarbonyl group, carboxyl group, amino group and C ₁ -C ₇ alkylamino groups,
provided that R ₁ and R ₂ are not simultaneously a hydrogen atom; and the lipid compound is not diethyl 2 - ((3Z, 6Z, 9Z, 12Z, 15Z) octadec-3,6,9,12,15-pentaen-1-yl) malonate. 13. The compound of claim 12, wherein R ₁ and R ₂ are selected from the group consisting of a hydrogen atom, a C ₃ -C ₇ alkyl group, for example, propyl, a C ₁ -C ₇ alkoxy group, for example, methoxy, ethoxy or propoxy, C ₁ -C ₇ alkylthio groups, for example, methylthio, ethylthio or propylthio, amino groups, C ₁ -C ₇ alkylamino groups, for example, ethylamino or diethylamino, a C ₁ -C ₇ alkoxycarbonyl group and a carboxy group. 14. Omega-3 lipid compound, which is selected from:
(all-Z) -5,8,11,14,17-eicosapentaenoic acid (EPA) represented by formula (VIII)

in the form of a carboxylic acid or its carboxylate selected from ethyl carboxylate, methyl carboxylate, n-propyl carboxylate, isopropyl carboxylate, n-butyl carboxylate, sec-butyl carboxylate or n-hexyl carboxylate, carboxylic acid in the form of a triglyceride, diglyceride, monideamide or selected from primary carboxamide, N-methylcarboxamide, N, N-dimethylcarboxamide, N-ethylcarboxamide or N, N-diethylcarboxamide represented by X,
or a pharmaceutically acceptable salt thereof,
where the above compound is substituted at carbon 2, counting from the functional group of the omega-3 lipid compound, by two substituents represented by R ₁ and R ₂ selected from a C ₁ -C ₇ alkyl group,
with the proviso that the above compound is not 2,2-dimethyl-5,8,11,14,17-eicosapentaenoic acid, its ethyl ester or its 4- (tert-butyl) phenyl ether; or (all-Z) -mesityl 2,2-diethyl-5,8,11,14,17-eicosapentaenoate. 15. The compound of claim 14, wherein R ₁ and R ₂ are selected from the group consisting of a C ₁ -C ₇ alkyl group, for example, methyl, ethyl, or propyl. 16. The omega-3 lipid compound according to any one of claims 11-15, wherein said carboxylic acid derivative is a tri-, di- or monoglyceride. 17. Omega-3 lipid compound, which is a tri- or monoglyceride
(all-Z) -5,8,11,14,17-eicosapentaenoic acid (EPA) represented by the formula (VIII)

where the tri- or monoglyceride is represented by X,
or any pharmaceutically acceptable salt thereof,
where R ₁ and R ₂ are the same or different and can be selected from the group consisting of a hydrogen atom, a C ₁ -C ₇ alkyl group, provided that
- R ₁ and R ₂ are not simultaneously a hydrogen atom. 18. The compound according to 17, where R ₁ and R ₂ are selected from the group consisting of a hydrogen atom, a C ₁ -C ₇ alkyl group, for example, methyl, ethyl or propyl. 19. The compound of claim 17, wherein said compound is selected from 1,2,3-tris ((all-Z) -2-ethyl-5,8,11,14,17-eicosapentaenoyl) -sn-glycerol

2 - ((all-Z) -2-ethyl-5,8,11,14,17-eicosapentaenoyl) -sn-glycerol

20. The compound according to any one of claims 1, 11, 12 or 14, wherein said carboxylate group is 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. 21. The compound according to any one of claims 1, 11, 12 or 14, where X is ethylcarboxylate. 22. The compound according to any one of claims 1, 11, 14 or 17, wherein said alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and n-hexyl. 23. The compound of claim 12, wherein said alkyl group is selected from the group consisting of n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and n-hexyl. 24. The compound according to any one of claims 1 or 11, wherein said halogen atom is fluorine. 25. The compound according to any one of claims 1, 11 or 12, wherein the above alkoxy group is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, sec-butoxy, OCH ₂ CF ₃ and OCH ₂ CH ₂ OCH ₃ . 26. The compound according to any one of claims 1, 11 or 12, wherein said alkylthio group is selected from the group consisting of methylthio, ethylthio and isopropylthio. 27. The compound according to any one of claims 1, 11, 12 or 14, wherein the above carboxamide group is selected from the group consisting of primary carboxamide, N-methylcarboxamide, N, N-dimethylcarboxamide, N-ethylcarboxamide and N, N-dimethylcarboxamide. 28. The compound according to claim 1, where Y is a C ₁₆ alkene with 3 double bonds interrupted by a methylene group in the Z configuration, one of the groups R ₁ and R ₂ is methyl, ethyl or propyl, and the other is a hydrogen atom. 29. The compound according to claim 1, where Y is a C ₁₆ alkene with 3 double bonds disrupted by a methylene group in the Z configuration, one of the groups R ₁ and R ₂ is methoxy, ethoxy or propoxy, and the other is a hydrogen atom. 30. The compound according to claim 1, where Y is a C ₁₆ alkene with 3 double bonds interrupted by a methylene group in the Z configuration, one of the groups R ₁ and R ₂ is thiomethyl, thioethyl or thiopropyl, and the other is a hydrogen atom. 31. The compound according to claim 1, where Y is a C ₁₆ alkene with 3 double bonds interrupted by a methylene group in the Z configuration, one of the groups R ₁ and R ₂ is ethylamino, diethylamino, and the other is a hydrogen atom. 32. The compound according to claim 1, where Y is a C ₁₆ alkene with 3 double bonds interrupted by a methylene group in the Z configuration, one of the groups R ₁ and R ₂ is amino, and the other is a hydrogen atom. 33. The compound according to any one of p-32, where the double bonds are located at positions 9, 12 and 15 of the specified omega-3 lipid compounds. 34. The compound according to claim 1, where Y is a C ₂₀ alkene with 5 double bonds interrupted by a methylene group in the Z configuration, one of the groups R ₁ and R ₂ is methyl, ethyl or propyl, and the other is a hydrogen atom. 35. The compound according to claim 1, where Y is a C ₂₀ alkene with 5 double bonds disrupted by a methylene group in the Z configuration, one of the groups R ₁ and R ₂ is methoxy, ethoxy or propoxy, and the other is a hydrogen atom. 36. The compound according to claim 1, where Y is a C ₂₀ alkene with 5 double bonds interrupted by a methylene group in the Z configuration, one of the groups R ₁ and R ₂ is thiomethyl, thioethyl or thiopropyl, and the other is a hydrogen atom. 37. The compound according to any one of claims 34-36, wherein the double bonds are located at positions 7, 10, 13, 16 and 19 of said omega-3 lipid compound. 38. The compound according to claim 1, where X is ethylcarboxylate. 39. The compound according to claim 1, 12, 14, 17, where R ₁ and R ₂ are different. 40. The compound of claim 39 in racemic form. 41. The compound of claim 40 as an R-stereoisomer. 42. The compound of claim 40 as an S-stereoisomer. 43. The compound according to any one of claims 1 to 42 for use in the treatment and / or prevention of a condition associated with enhancing the functions of at least one of the isoforms of a human receptor (PPAR) activated by a peroxisome proliferator. 44. The compound according to item 43, where the aforementioned activated peroxisome proliferator receptor (PPAR) is a receptor (PPAR) a and / or y, activated by the peroxisome proliferator. 45. The compound according to any one of claims 1 to 42 for use in the treatment and / or prevention of peripheral insulin resistance and / or diabetes, for example, type 2 diabetes, elevated levels of triglycerides and / or levels of non-HDL cholesterol, LDL cholesterol and VLDL cholesterol a hyperlipidemic state, for example, hypertriglyceridemia (HTG), obesity or overweight, liver fatty liver disease, for example, non-alcoholic fatty liver (NAFLD), or an inflammatory disease or condition. 46. The compound according to any one of claims 1 to 42 for use in lowering plasma insulin levels, blood glucose and / or serum triglycerides, for use in increasing human serum HDL levels, or for use in reducing body weight and / or to prevent weight gain. 47. The compound according to any one of claims 1 to 42 for use as a PPAR-activating or modulating drug. 48. A pharmaceutical composition for activating or modulating at least one of a peroxisome proliferator activated receptor isoform (PPAR), comprising an effective amount of a compound according to any one of claims 1 to 42 and a pharmaceutically acceptable carrier, excipient or diluent, or any combination thereof . 49. The pharmaceutical composition according to p. 48, formulated for oral administration, for example, in the form of a capsule, sachet or solid dosage form. 50. The pharmaceutical composition according to p. 48, formulated to receive a daily dose of from 1 mg to 10 g, for example, from 50 mg to 1 g, for example, from 50 mg to 200 mg of the above compound. 51. The pharmaceutical composition according to any one of claims 48-49 for use as a PPAR-activating or modulating drug. 52. A food lipid composition comprising an effective amount of an omega-3 lipid compound according to any one of claims 1-42. 53. The food lipid composition according to paragraph 52, where at least 60%, for example at least 80 wt.% Of the lipid composition is the specified compound. 54. The food lipid composition according to any one of claims 52-53, also comprising fatty acids selected from (all-Z) -5,8,11,14,17-eicosapentaenoic acid (EPA), (all-Z) -4 , 7,10,13,16,19-docosahexaenoic acid (DHA), (all-Z) -6,9,12,15,18-genecosapentaenoic acid (HPA) and / or (all-Z) -7,10 , 13,16,19-docosapentaenoic acid (DPA). 55. The food lipid composition according to item 54, where these fatty acids are present in the form of their alpha-substituted forms. 56. The food lipid composition according to paragraph 52, also containing a pharmaceutically acceptable antioxidant, for example, tocopherol. 57. The use of a compound according to any one of claims 1 to 42 for the manufacture of a medicament for activating or modulating at least one of the isoforms of a human receptor activated by a peroxisome proliferator (PPAR). 58. The use of claim 57, wherein the aforementioned peroxisome proliferator-activated receptor (PPAR) is a (PPAR) α and / or γ receptor activated by a peroxisome proliferator. 59. The use of a compound according to any one of claims 1 to 42 for the manufacture of a medicament for the treatment and / or prevention of peripheral insulin resistance and / or diabetes, for example, type 2 diabetes, elevated levels of triglycerides and / or levels of non-HDL cholesterol (not HDL cholesterol (LDL) and VLDL cholesterol (VLDL), hyperlipidemic conditions, such as hypertriglyceridemia (HTG), obesity or overweight, liver fatty liver disease, such as non-alcoholic fatty liver infiltration (NAFLD), or at an inflammatory disease or condition. 60. The use of a compound according to any one of claims 1 to 42 for the manufacture of a medicament for reducing plasma insulin, blood glucose and / or triglycerides in serum, for increasing HDL levels in human serum, or for reducing body weight and / or to prevent overweight.