NOVEL LIPID COMPOUNDS

Description

FIELD OF THE INVENTION

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

wherein R₁, R₂, P, and Y are herein defined.

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

BACKGROUND OF THE INVENTION

Dietary polyunsaturated fatty acids (PUFAs) have effects on diverse physiological processes impacting normal health and chronic diseases, such as the regulation of plasma lipid levels, cardiovascular and immune functions, insulin action, and neuronal development and visual function. Ingestion of PUFAs (generally in ester form, e.g. glycerides and phospholipids) will lead to their distribution to virtually every cell in the body with effects on membrane composition and function, eicosanoid synthesis, cellular signaling, and regulation of gene expression. Variations in distribution of different fatty acids/lipids to different tissues in addition to cell specific lipid metabolism, as well as the expression of fatty acid-regulated transcription factors, is likely to play an important role in determining how cells respond to changes in PUFA composition. (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. These are the peroxisome proliferators-activated receptors (PPARs), the hepatic nuclear receptor (HNF-4), liver X receptor (LXR), and the 9-cis retinoic acid receptor (retinoic X receptor, RXR). Treatment with PUFAs can also regulate the abundance of many transcriptional factors in the nucleus, 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 involve mechanisms that affect the nuclear content of the transcription factors. The regulation of gene transcription by PUFAs has profound effects on cell and tissue metabolism and offers a credible explanation for the involvement of nutrient-gene interactions in the initiation and prevention or amelioration of diseases such as obesity, diabetes, cardiovascular disorders, immune-inflammatory diseases and cancers (Wahle, J., et al, Proceedings of the Nutrition Society, 2003, 349). Fish oils rich in the ω-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to reduce the risk of cardiovascular diseases partly by reduction of blood triglyceride concentration. This favorable effect mainly results from the combined effects of inhibition of lipogenesis by decrease of SPEBP-1 and stimulation of fatty acid oxidation by activation of PPAR-α in the liver.

Due to their limited stability in vivo and their lack of biological specificity, PUFAs have not achieved widespread use as therapeutic agents. Chemical modifications of the n-3 polyunsaturated fatty acids have been performed by several research groups in order to change or increase their metabolic effects.

For example, the hypolipidemic effects of EPA was potentiated by introducing methyl or ethyl in α-position of EPA ethyl ester (EE). (Vaagenes, et al, Biochemical Pharmacology, 1999, 58, 1133). Those compounds also reduced plasma free fatty acids, while the EPA EE compound had no effect.

In a recent work published by L. Larsen (Larsen, L. et al, Lipids, 2005, 40, 49), the authors show that the α-methyl derivatives of EPA and DHA increased the activation of the nuclear receptor PPARα and thereby the expression of L-FABP when compared to EPA/DHA. The authors suggest that delayed catabolism of these α-methyl PUFAs contribute to their increased effects.

SUMMARY OF THE INVENTION

One object of the present invention is to provide omega-3 lipid compounds having pharmaceutical activity.

This object is achieved by an omega-3 lipid compound of formula (I):

wherein

R₁and R₂are the same or different and are chosen from 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, a carboxy group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, and an alkylamino group;

P represents a hydrogen atom,

wherein P₁, P₂, and P₃are chosen from a hydrogen atom, an alkyl group, and a C₁₄-C₂₂alkenyl group, wherein the alkyl and alkenyl groups are optionally substituted with a hydroxy group,

Y is a C₁₄-C₂₂alkenyl group with at least one double bond, having E and/or Z configuration;

or any pharmaceutically acceptable complex, solvate, salt or pro-drug thereof, with the proviso that R₁and R₂are not simultaneously a hydrogen atom.

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

- Y is a C₁₆-C₂₂alkenyl with 2-6 double bonds;
- Y is a C₁₆-C₂₀alkenyl with 2-6 methylene interrupted double bonds in Z configuration;
- Y is a C₂₀alkenyl with 6 methylene interrupted double bonds in Z configuration;
- Y is a C₂₀alkenyl with 5 methylene interrupted double bonds in Z configuration
- Y is a C₁₆-C₂₀alkenyl with 3-5 double bonds;
- Y is a C₁₆-C₇₀alkenyl with 3-5 methylene interrupted double bonds in Z configuration;
- Y is a C₁₈alkenyl with 5 methylene interrupted double bonds in Z configuration;
- Y is a C₁₆alkenyl with 3 double bonds in Z-configuration; or
- Y is a C₁₆alkenyl with 3 methylene interrupted double bonds in Z configuration.

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

(all-Z)-4,7,10,13,16,19-docosahexaen-1-ol,
(all-Z)-5,8,11,14,17-eicosapentaen-1-ol,
(all-Z)-9,12,15-octadecatrien-1-ol,
(all-Z)-7,10,13,16,19-docosapentaen-1-ol,
(all-Z)-11,14,17-eicosatrien-1-ol,
(4E,8Z,11Z,14Z,17Z)-eicosapentaen-1-ol,
(5E,8Z,11Z,14Z,17Z)-eicosapentaen-1-ol, and
(4E,7Z,10Z,13Z,16Z,19Z)-docosahexaen-1-ol.

or any pharmaceutically acceptable complex, solvate, salt, or pro-drug thereof,

wherein said omega-3 lipid compound is substituted at carbon 2, counted from the hydroxyl functional group, with at least one substituent chosen from:

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, a carboxy group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, and an alkylamino group;

with the provisos that:
- R₁and R₂are not simultaneously a hydrogen atom.

In exemplary embodiments of the invention, an omega-3 lipid compound is chosen from:

In a compound according to the invention, said alkyl group may be chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, and n-hexyl; said halogen atom may be fluorine; said alkoxy group may be chosen from methoxy, ethoxy, propoxy, isopropoxy, sec-butoxy, phenoxy, benzyloxy, OCH₂CF₃, and OCH₂CH₂OCH₃; said alkenyl group may be chosen from allyl, 2-butenyl, and 3-hexenyl; said alkynyl group may be chosen from propargyl, 2-butynyl, and 3-hexynyl; said aryl group may be chosen from a benzyl group, and a substituted benzyl group; said alkylthio group may be chosen from methylthio, ethylthio, isopropylthio, and phenylthio; said alkoxycarbonyl group may be chosen from methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl; said alkylsulfinyl group may be chosen from methanesulfinyl, ethanesulfinyl, and isopropanesulfinyl; said alkylsulfonyl group may be chosen from methanesulfonyl, ethanesulfonyl, and isopropanesulfonyl; and said alkylamino group may be chosen from methylamino, dimethylamino, ethylamino, and diethylamino.

In particular, R₁and R₂may be chosen from a hydrogen atom; an alkyl group, e.g. a C₁-C₇alkyl group; an alkoxy group, e.g. a C₁-C₇alkoxy group; an alkylthio group, e.g. a C₁-C₇alkylthio group; an amino group, an alkylamino group, e.g. a C₁-C₇alkylamino, an alkoxycarbonyl group, e.g. a C₁-C₇alkoxycarbonyl group, and a carboxy group.

For example, said C₁-C₇alkyl group may be methyl, ethyl, or propyl; said C₁-C₇alkoxy group may be methoxy, ethoxy or propoxy; said C₁-C₇alkylthio group may be methylthio, ethylthio, or propylthio; said C₁-C₇alkylamino group may be ethylamino or diethylamino.

According to the present invention, P represents a hydrogen atom, or

P represents;

wherein P₁, P₂, and P₃are chosen from a hydrogen atom, an alkyl group, and a C₁₄-C₂₂alkenyl group, wherein the alkyl and alkenyl groups are optionally substituted with a hydroxy group, or

P represents;

Examples of compounds according to the invention are those in which P is a hydrogen, and Y is a C₂₀alkenyl with 6 methylene interrupted double bonds, located in Z configuration, wherein:

one of R₁and R₂is methyl and the other one is a hydrogen atom;

one of R₁and R₂is ethyl and the other one is a hydrogen atom;

one of R₁and R₂is propyl and the other one is a hydrogen atom;

one of R₁and R₂is methoxy and the other one is a hydrogen atom;

one of R₁and R₂is ethoxy and the other one is a hydrogen atom;

one of R₁and R₂is propoxy and the other one is a hydrogen atom;

one of R₁and R₂is thiomethyl and the other one is a hydrogen atom;

one of R₁and R₂is thioethyl and the other one is a hydrogen atom;

one of R₁and R₂is thiopropyl and the other one is a hydrogen atom;

one of R₁and R₂is ethylamino and the other one is a hydrogen atom;

one of R₁and R₂is benzyl and the other one is a hydrogen atom;

one of R₁and R₂is diethylamino and the other one is a hydrogen atom; or

one of R₁and R₂is amino and the other one is a hydrogen atom.

Other examples of compounds according to the invention are those in which P is a hydrogen, and Y is a C₂₀alkenyl with 5 methylene interrupted double bonds located in Z configuration, wherein: