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

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

 

The technical field

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

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

Background of invention

Dietary polyunsaturated fatty acids (PUFA)(Pufas) affect diverse physiological processes, affecting the normal health and chronic diseases, such as regulation of the levels of plasma lipids, cardiovascular and immune function, insulin action, and the development of neurons and visual function. The intake of polyunsaturated fatty acids (usually in the form of esters, e.g. in the form of glycerides or phospholipids) will lead to their distribution in almost every cell of the body, affecting the structure and function of membranes, the synthesis of eicosanoids, signal transmission in the cell and the regulation of gene expression.

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

Polyunsaturated fatty acids or their metabolites have been shown to modulate gene transcription by interaction with several nuclear receptors. There are activated proliferation peroxisome receptor (PPAR), hepatic nuclear factor-4 (HNF-4), X-receptor liver (LXR) and the receptor for 9-CIS-retinoic acid (retinoic X receptor, RXR). The processing of polyunsaturated fatty acids may also contribute to the regulation of the relative amounts of many transcription factors in the nucleus, including SREBP, NFkB, c/EBPβ and HIF-1α. These effects are not due to direct binding of fatty acids with a transcription factor, but rather includes the mechanisms that influence the content of the transcription factors in the nucleus.

Regulation of gene transcription by fatty acids has a strong impact on cellular and tissue metabolism and creates the possibility of possible explanations involving interactions nutrient-gene in the occurrence and avoidance or mitigation 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, Eiko is pentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduces the risk of cardiovascular disease, in part, by reducing the concentration of triglycerides in the blood. Specified favorable effect is the result, primarily, the combined effect of the processes of inhibition of lipogenesis by reducing SPEBP-1 and stimulation of fatty acid oxidation through activation of PPAR-α in the liver.

It has been shown that omega-3 PUFA in fish oil improves the prognosis of some chronic inflammatory diseases characterized by the accumulation of leukocytes and mediate leukocyte 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 stability in vivo and the absence of their biological specificity, DHA has not achieved wide application as therapeutic agents. Chemical modification of omega-3 polyunsaturated fatty acids were carried out by several research groups to change or increase their metabolic effects.

For example, lipid-lowering effects of EPA were strengthened by the introduction of methyl or ethyl in the α-position of ethyl ether complex EPA. (Vaagenes et al. Biochemical Pharm. 1999, 58, 1133).

In the last work published by L. Larsen (Larsen, L. et al., Lipids, 2005, 40, 49), the authors showed that the α-methyl PR is spodnie EPA and DHA increased activation of the nuclear receptor PPARa and thus, the expression of L-FABP in comparison with EPA/DHA. The authors suggest that a slow catabolism of these α-methyl derivatives of DHA contributes to improving their impact.

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

The activity of many nuclear receptors is controlled by the binding of small lipophilic ligands, including hormones, metabolites, such as fatty acids, bile acids, oxidation products of cholesterol and Xeno - and endobiotic. Nuclear receptors can bind as monomers, homodimers, or the RXR heterodimer with DNA.

The transcription factor NF-kB is induced by eukaryotic transcription factor Rel family. He is the main component in the sequence of reactions of stress, which regulates the activation of early response genes involved in the expression of vos is Alitalia cytokines, adhesion molecules, heat shock proteins, cyclooxygenase, lipooxygenase and redox enzymes.

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

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

The invention

One purpose of the present invention is the provision of omega-3 lipid compounds with pharmaceutical activity.

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

where

- R1and R2are the same or different and may be selected from the group of substituents consisting of a hydrogen atom, hydroxy-group, the alkyl GRU is dust, the halogen atom, alkoxygroup, alloctype, acyl group, alkenylphenol group, alkenylphenol group, aryl group, allylthiourea, alkoxycarbonyl group, carboxypropyl, alkylsulfonyl group, alkylsulfonyl group, amino group and alkylamino;

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

- Y is C16-C22the alkene with two or more double bonds with E and/or Z-configuration,

or any pharmaceutically acceptable complex, salt, MES or prodrug,

provided that:

- R1and R2are 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 carboxylic acid, carboxylate, carboxylic acid anhydride or a 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 ester;

- (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-is arbucci-6,9,12,15,18,21-tetracosapentaenoic acid;

- ethyl (all-Z)-2-etoxycarbonyl-6,9,12,15,18,21-tetracosapentaenoic.

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

Y is C16-C20the alkene from 2 to 6 double bonds;

Y is C16-C20the alkene from 2 to 6 double bonds, interrupted methylene group in the Z-configuration;

Y is C16-C20the alkene with 3 to 5 double bonds;

Y is C16-C20the alkene with 3 to 5 double bonds, interrupted methylene group in the Z-configuration;

Y is C20the alkene with 5 double bonds in Z-configuration;

Y is C20the alkene with 5 double bonds, interrupted methylene group in the Z-configuration;

Y is C16the alkene with 3 double bonds in Z-configuration; or

Y is C16the alkene with 3 double bonds, interrupted methylene group in the Z-configuration.

The invention also relates to salts of compounds of formula (I). Such salts can be represented

where X is soo-,

Z is chosen from the group consisting of Li+, Na+, K+, NH4+,

Meglumine,

Tris(hydroxymethyl)aminomethane,

Diethylamine,

and

Arginine;

or connection

where X=COO-,

Z2+selected from the group consisting of Mg2+Ca2+,

Ethylenediamine,

and

Piperazine.

Another characteristic of salt is

where X is soo-,

Zn+is

Chitosan.

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

where

Z is

or

and

where

Z is

or

or

where

Z is

or

The compounds of formula (I), where X is a carboxylic acid in the form of triglycerides, 1-monoglyceride and 2-monoglyceride t is the train included in the present invention. These compounds represented by formulas (V), (VI) and (VII), respectively.

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

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

- (all-Z)-6,9,12,15-octadecatetraenoic 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-tetracosapentaenoic 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 acid anhydride or a carboxamide,

or any pharmaceutically acceptable complex, salt, MES or prodrug;

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

hydrogen atom, hydroxy-group, alkyl group, halogen atom, alkoxygroup, alloctype, acyl group, alkenylphenol group, alkenylphenol group, aryl group, alkylthio the dust, alkoxycarbonyl group, carboxypropyl, alkylsulfonyl group, alkylsulfonyl group, amino group and alkylamino;

provided that the omega-3 lipid compound is not

is replaced by two hydrogen atoms

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

- ethyl (all-Z)-2-etoxycarbonyl-6,9,12,15,18,21-tetracosapentaenoic

- (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,

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

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

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

or any f rmaceuticals acceptable complex, salt, MES or prodrug, where

- R1and R2are the same or different and may be selected from the group consisting of a hydrogen atom, hydroxy-group, With3-C7alkyl group, halogen atom, alkoxygroup, alloctype, acyl group, alkenylphenol group, alkenylphenol group, allylthiourea, alkoxycarbonyl group, carboxypropyl, alkylsulfonyl group, alkylsulfonyl group, amino group and alkylamino, provided that R1and R2are not simultaneously a hydrogen atom. Usually, R1and R2selected from a hydrogen atom, a C3-C7alkyl group, alkoxygroup, allylthiourea, amino, alkylamino, alkoxycarbonyl group and carboxypropyl. More precisely, R1and R2selected from a hydrogen atom, a C3-C7alkyl groups, preferably propyl,1-C7alkoxygroup, preferably methoxy, epoxy or propoxy,1-C7allylthiourea, preferably methylthio, ethylthio or propylthio, amino, C1-C7alkylamino, preferably acylamino or diethylaminopropyl,1-C7alkoxycarbonyl group and carboxypropyl.

Connection is substituted at carbon 2, counted from the functional group of the omega-3 lipid compounds, two deputies who, presents R1and R2selected from the group consisting of hydroxy-group, alkyl group, halogen atom, alkoxygroup, alloctype, acyl group, alkenylphenol group, alkenylphenol group, aryl group, allylthiourea, alkoxycarbonyl group, carboxypropyl, alkylsulfonyl group, alkylsulfonyl group, amino group and alkylamino, provided that the above connection is not 2,2,-dimethyl-5,8, 11,14,17-eicosapentaenoic acid. Usually, R1and R2selected from alkyl groups, alkoxygroup, allylthiourea, amino, alkylamino, alkoxycarbonyl group and carboxypropyl. More precisely, R1and R2choose from C1-C7alkyl group, preferably methyl, ethyl or propyl, With1-C7alkoxygroup, preferably methoxy, ethoxy or propoxy,1-C7allylthiourea, preferably methylthio, ethylthio or propylthio, amino, C1-C7alkylamino, preferably acylamino or diethylamino,1-C7alkoxycarbonyl group and carboxypropyl.

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

In addition, we are Aasee connection belongs to the 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, three-, di - or monoglyceride, carboxylate, carboxylic acid anhydride or a carboxamide, represented by X,

or any pharmaceutically acceptable complex, salt, MES or prodrug,

where R1and R2are the same or different and may be selected from the group consisting of a hydrogen atom, hydroxy-group, alkyl group, halogen atom, alkoxygroup, alloctype, acyl group, alkenylphenol group, alkenylphenol group, aryl group, allylthiourea, alkoxycarbonyl group, carboxypropyl, alkylsulfonyl group, alkylsulfonyl group, amino group and alkylamino, provided that R1and R2are 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.

Usually, R1and R2are the same or different and selected from hydrogen atom, alkyl group, alkoxygroup, allylthiourea, amino, alkyl is of aminogruppy, alkoxycarbonyl group and carboxypropyl. More precisely, R1and R2selected from a hydrogen atom, a C1-C7alkyl group, preferably methyl, ethyl or propyl, C1-C7alkoxygroup, preferably methoxy, ethoxy or propoxy, C1-C7allylthiourea, preferably methylthio, ethylthio or propylthio, amino, C1-C7alkylamino, preferably acylamino or diethylamino, C1-C7alkoxycarbonyl group and carboxypropyl.

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

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

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

In addition, the group X can also be represented carboxylic acid in the form of triglycerides according to the formula (V)above. An example of such compounds is

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

The group X can also be represented carboxylic KIS the Auteuil in the form of 2-monoglyceride formula (VII). An example of such compounds is

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

In connection according to the invention, the above alkyl group may 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 alkoxygroup can be selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, sec-butoxy, phenoxy, benzyloxy, OCH2CF3and OCH2CH2OCH3; the above Alchemilla group can be selected from the group consisting of allyl, 2-butenyl and 3-hexenyl; the above Alchemilla group can be selected from the group consisting of propargyl, 2-butinyl and 3-hexenyl; the above aryl group may be selected from benzyl groups and substituted benzyl groups; the above allylthiourea can be selected from the group consisting of methylthio, ethylthio, isopropylthio, phenylthio; the above alkoxycarbonyl group can be selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl; specified above alkylsulfonyl group can be selected from the group consisting of methanesulfonyl, econsulting and isopropanolamine;the above alkylsulfonyl group can be selected from the group consisting of methanesulfonyl, acanalonia and isopropanolamine; and the above alkylamino can be selected from the group consisting of methylamino, dimethylamino, ethylamino, diethylamino.

Derivatives of carboxylic acid may be a phospholipid or a tri-, di - or monoglyceride, i.e. the connection according to the invention can exist in the form of a phospholipid, three-, di - or monoglyceride or in the form of the free acid.

According to the present invention, the above carboxylate group can be selected from the group consisting of ethylcarboxylate, methylcarbamate, n-propellerblade, isopropylcarbonate, n-butylcarbamoyl, sec-butylcarbamoyl and n-lexiscanlexiscan, and the above carboxamide group can be selected from the group consisting of primary carboxamide, N-methylcarbamyl, N,N-dimethylcarbamate, N-ethylcarbodiimide and N,N-diethylbenzamide.

Examples of compounds according to the invention are such compounds in which X is ethylcarboxylate, and Y is a C16the alkene with 3 double bonds, interrupted methylene group that has a Z-configuration at positions 9, 12 and 15, where:

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

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

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

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

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

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

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

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

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

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

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

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

Other examples of compounds according to the invention are such compounds in which X is ethylcarboxylate, and Y is a C20the alkene with 5 double bonds, interrupted methylene group that has a Z-configuration at positions 7, 10, 13, 16 and 19, where:

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

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

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

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

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

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

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

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

one of the groups R1and R2is thiopropyl, and the other is a hydrogen atom.

In the omega-3 lipid compound of formula (I) according to the present invention, R1and R2may be the same or different. When these groups are different, the compounds of formula (I) can exist in stereoisomeric forms. It should be understood that the invention includes all optical isomers of compounds of formula (I) and mixtures thereof, including racemates. Therefore, the present invention includes, when R1differs from R2the compounds of formula (I), which are racemic or enantiomerically pure or in the form of (S)-or (R)-enantiomer.

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

In addition, the present invention relates to pharmaceutical compositions containing omega-3 lipid compound of formula (I). The pharmaceutical composition may contain a pharmaceutically acceptable carrier, excipient or diluent, or any combination thereof, and the appropriate way prepared for oral administration, for example, in the form of capsules or package-Sasha. A suitable daily dose of a compound of formula (I) is from 1 mg to 10 g of the compounds; from 50 mg to 1 g of the compounds or from 50 mg to 200 mg of the compounds.

The present invention also relates to a lipid composition containing omega-3 lipid compound of formula (I). Is appropriate when at least 60% of the mass. or, at least 80% of the mass. lipid composition is specified connection. The lipid composition may also include a fatty acid selected from (all-Z)-5,8,11,14,17-eicosapentaenoic acid (EPA)and (all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), (all-Z)-6,9,12,15,18-heneicosanol acid (HPA) and/or (all-Z)-7,10,13,16,19-docosapentaenoic acid (DPA) or their derivatives, that is, presented in their alpha-substituted form and/or pharmaceutically acceptable antioxidant, such as tocopherol.

In addition, the invention relates to the use of omega-3 lipid soy is inane formula (I) to obtain medicines for:

activation or modulation of at least one of the isoforms of the receptor (PPAR) human activated proliferation peroxisome, where specified activated proliferation peroxisome receptor (PPAR) is activated proliferation peroxisome receptor (PPAR)α and/or γ.

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

- reduce the level of plasma insulin, blood glucose and/or serum triglycerides.

- treatment and/or prevention of type 2 diabetes.

- the prevention and/or treatment of elevated levels of triglycerides and/or non-HDL cholesterol (non-HDL), LDL-cholesterol (LDL cholesterol) and VLDL-cholesterol (VLDL).

- the prevention and/or treatment gipolipidemicheskoe state, for example, hypertriglyceridemia (HTG).

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

- treatment and/or prevention of obesity or condition of being overweight.

- reduction of body weight and/or prevent gaining the body weight.

- treatment and/or prevention of diseases of fatty infiltration of the liver, for example, non-alcoholic liver (NAFLD).

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

- obtain drugs for the treatment and/or prevention of an inflammatory disease or condition.

The invention also relates to the compound of formula (I) for the treatment and/or prevention of conditions listed above, and to methods of treatment and/or prevention of the above listed conditions, comprising the administration to a mammal in need of this, a pharmaceutically active amount of a compound of formula (I).

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

Detailed description of the invention

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

It is known that PPARα is the most diverse of PPAR interacting with saturated and unsaturated fatty acids. The PPARδ receptor interacts with saturated and unsaturated fatty acids, albeit less efficiently than PPARα. Receptor PPARγ has the limited profile of binding to fatty acids, interacting effectively with DHA and only weakly with monounsaturated fatty acids (Xu et al., Molecular Cell, 1999, 397-403).

The effect of PUFA on these nuclear receptors caused not only by the structure and affinity of fatty acids to the receptor. Factors influencing the levels of the components of UNOTIL the exact neeterificirovannah fatty acids (NEFA)(nezhk), presented is also important. On a specified pool nezhk affected by the concentration of exogenous fatty acids coming into the cell, and the number of endogenously synthesized fatty acids, their removal through incorporation into lipids, and their way of oxidation. (Pawar, A. & Jump, DB, Journal of Biological Chem., 2003, 278, 35931).

According to the invention, the introduction of at least one of the substituent in the α-position of various polyunsaturated fatty acids leads to the accumulation of fatty acids derivatives in the pool nezhk rather than incorporation into neutral lipids or oxidation of these fatty acids. Omega-3 lipid compounds according to the present invention accumulate in the intracellular pool nezhk and start the mechanism of action of the local nuclear receptors to a greater extent than unsubstituted fatty acids.

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

Since polyunsaturated fatty acids are accumulated differently in different tissues, the above modified Pufas have the potential ability to act as tones the specific ligands of nuclear receptors. Since many of the nuclear receptors are distributed differently in different tissues, it is important to develop ligands, which in vivo may be directed to certain cells to bind and activate the receptor target.

Besides the fact that the derivatives according to the invention are the best ligands of nuclear receptors, they are not easily degraded by α - and β-oxidation, as natural DHA, by substitution in the α-position.

Nomenclature and terminology

Fatty acids are hydrocarbon straight chain having a carboxyl (COOH) group at one end (α) and (usually) methyl group from another (ω)-end. In physiology, fatty acid called on the position of the first double bond from the ω-end. The term ω-3 (omega-3) means that the first double bond exists as the third carbon-carbon bond from the terminal CH3groups (ω) carbon chain. In chemistry, the numbering of the carbon atoms starts from α-end.

As used in the description, the expression “double bond, methylene interrupted by a group” refers to the case when the methylene group located between the individual double bonds in the carbon chain omega-3 lipid compounds.

In this description, the terms “2-substituted”, substituted in position 2, and “substituted at carbon 2, counting on the functional group of the omega-3 lipid compounds” refers to the substitution at the carbon atom, marked 2 in accordance with the above numbering of the carbon chain. Alternatively, such a replacement can be named “alpha-substitution”.

In this description, the term “omega-3 lipid compound” (corresponding to ω-3 or n-3) refers to the lipid connection with the first double bond at the third carbon from the ω-end of the carbon chain, as defined above.

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

where

- R1and R2are the same or different and may be selected from the group of substituents consisting of a hydrogen atom, hydroxy-group, alkyl group, halogen atom, alkoxygroup, alloctype, acyl group, alkenylphenol group, alkenylphenol group, aryl group, allylthiourea, alkoxycarbonyl group, carboxypropyl, alkylsulfonyl group, alkylsulfonyl group, amino group and alkylamino;

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

- Y is C16-C22the alkene with two or more double bonds with E and/or Z-configuration.

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

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

- (all-Z)-6,9,12,15-octadecatetraenoic 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-tetracosapentaenoic 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, the lower alkyl groups, particularly methyl and ethyl groups, has proved to be extremely suitable to achieve the desired pharmaceutical activity. Other very suitable substituents are lower ancilliary and lower alkylamino, for example, having 1-3 carbon atoms. Substitution or R1group, or R2-g is uppy 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, which proved to be suitable for substitution in the alpha-position of the acid, as proposed according to the present invention. For EPA, suitable substituents are lower ancilliary and lower alkylamino, for example, having 1-3 carbon atoms. By analogy with the above, the substitution or R1group, or R2group one of these deputies, while the other group is hydrogen is believed to provide the most effective result. The case when both groups of R1and R2are ethyl, represents a more suitable replacement OPTION.

Preferred omega-3 lipid compounds according to the present invention is 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 acid anhydride or a carboxamide, substituted in position 2:

Y=C16alkene with 3 double bonds in Z-configuration at positions 9, 12 and 15;

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

Y=C20alkene with 5 double bonds in Z-configuration at positions 7, 10, 13, 16 and 19;

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

Y=C18alkene with 3 double bonds in Z-configuration at positions 11, 14 and 17;

Category D - (4E, 8Z, 11Z, 14Z, 17Z)-eicosapentaenoic acid as carboxylic acid or its derivative, carboxylate, carboxylic acid anhydride or a carboxamide, substituted in position 2:

Y=C18alkene with 5 double bonds in positions 4, 8, 11, 14 and 17, where the double bond at position 8, 11, 14 and 17 have a Z-configuration, and the double bond in position 4 has the 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 acid anhydride or a carboxamide, substituted in position 2:

Y=C18alkene with 5 double bonds in Z-configuration at positions 5, 8, 11, 14 and 17;

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

Y=C20alkene with 6 double bonds in positions 4, 7, 10, 13, 16 and 19, where the double bond in position 7, 10, 13, 16 and 19 have a Z-configuration, and the double bond in position 4 has the E-configuration.

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

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

For all examples(1)-(12):

X = ethylcarboxylate

Y=C16alkene with 3 double bonds in Z-configuration at positions 9, 12 and 15

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

R1= methyl and R2= a hydrogen atom, or

R2= methyl and R1= hydrogen atom

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

R1= ethyl and R2= a hydrogen atom, or

R2= ethyl and R1= hydrogen atom

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

R1= propyl and R2= a hydrogen atom, or

R2= propyl and R1= hydrogen atom

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

R1= methoxy and R2= a hydrogen atom, or

R2= methoxy and R1= hydrogen atom

E is Il (all-Z)-2-ethoxy-9,12,15-octadecatrienoic (5)

R1= ethoxy and R2= a hydrogen atom, or

R2= ethoxy and R1= hydrogen atom

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

R1= propoxy and R2= a hydrogen atom, or

R2= propoxy and R1= hydrogen atom

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

R1= methylthio and R2= a hydrogen atom, or

R2= methylthio and R1= hydrogen atom

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

R1= atillio and R2= a hydrogen atom, or

R2= atillio and R1= hydrogen atom

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

R1= propylthio and R2= a hydrogen atom, or

R2= propylthio and R1= hydrogen atom

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

R1= ethylamino and R2= a hydrogen atom, or

R2= ethylamino and R1= hydrogen atom

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

R1= diethylamino and R2= a hydrogen atom, or

R2= diethylamino and R1= hydrogen atom

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

R1 = amino and R2= a hydrogen atom, or

R2= amino and R1= hydrogen atom

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

For all examples(13)-(21):

X = ethylcarboxylate

Y=C20alkene with 5 double bonds in Z-configuration at positions 7, 10, 13, 16 and 19

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

R1= methyl and R2= a hydrogen atom, or

R2= methyl and R1= hydrogen atom

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

R1= ethyl and R2= a hydrogen atom, or

R2= ethyl and R1= hydrogen atom

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

R1= propyl and R2= a hydrogen atom, or

R2= propyl and R1= hydrogen atom

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

R1= methoxy and R2= a hydrogen atom, or

R2= methoxy and R1= hydrogen atom

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

R1= ethoxy and R2= a hydrogen atom, or

R2= ethoxy and R1= hydrogen atom

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

R1= propoxy and R2= a hydrogen atom, or

R2= p is epoxy and R 1= hydrogen atom

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

R1= methylthio and R2= a hydrogen atom, or

R2= methylthio and R1= hydrogen atom

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

R1= atillio and R2= a hydrogen atom, or

R2= atillio and R1= hydrogen atom

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

R1= propylthio and R2= a hydrogen atom, or

R2= propylthio and R1= hydrogen atom

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

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

Y=C18alkene with 3 double bonds in Z-configuration at positions 11, 14 and 17

Ethyl (all-Z)-2-ethyl,2-etoxycarbonyl-11,14,17-eicosatrienoic (23)

R1= etoxycarbonyl and R2= ethyl, or

R2= etoxycarbonyl and R1= ethyl

X = ethylcarboxylate

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

R1= carboxy and R2= ethyl, or

R2= carboxy and R1= ethyl

X = acetic acid

For all examples(27)-(35):

X = ethylcarboxylate

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

R1= methyl and R2 = a hydrogen atom, or

R2= methyl and R1= hydrogen atom

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

R1= ethyl and R2= a hydrogen atom, or

R2= ethyl and R1= hydrogen atom

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

R1= propyl and R2= a hydrogen atom, or

R2= propyl and R1= hydrogen atom

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

R1= methoxy and R2= a hydrogen atom, or

R2= methoxy and R1= hydrogen atom

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

R1= ethoxy and R2= a hydrogen atom, or

R2= ethoxy and R1= hydrogen atom

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

R1= propoxy and R2= a hydrogen atom, or

R2= propoxy and R1= hydrogen atom

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

R1= methylthio and R2= a hydrogen atom, or

R2= methylthio and R1= hydrogen atom

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

R1= atillio and R2= a hydrogen atom, or

R2= atillio and R1= ATO is hydrogen

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

R1= propylthio and R2= a hydrogen atom, or

R2= propylthio and R1= hydrogen atom

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

For all examples(36)-(44):

Y=C18alkene with 5 double bonds in positions 4, 8, 11, 14 and 17, where the double bond in positions 8, 11, 14 and 17 have a Z-configuration, and the double bond in position 4 has the E-configuration

X = ethylcarboxylate

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

R1= methyl and R2= a hydrogen atom, or

R2= methyl and R1= hydrogen atom

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

R1= ethyl and R2= a hydrogen atom, or

R2= ethyl and R1= hydrogen atom

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

R1= propyl and R2= a hydrogen atom, or

R2= propyl and R1= hydrogen atom

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

R1= methoxy and R2= a hydrogen atom, or

R2= methoxy and R1= hydrogen atom

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

R1= ataxi the R 2= a hydrogen atom, or

R2= ethoxy and R1= hydrogen atom

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

R1= propoxy and R2= a hydrogen atom, or

R2= propoxy and R1= hydrogen atom

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

R1= methylthio and R2= a hydrogen atom, or

R2= methylthio and R1= hydrogen atom

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

R1= atillio and R2= a hydrogen atom, or

R2= atillio and R1= hydrogen atom

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

R1= propylthio and R2= a hydrogen atom, or

R2= propylthio and R1= hydrogen atom

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

For all examples(45)-(50):

X = ethylcarboxylate

Y=C18alkene with 5 double bonds in Z-configuration at positions 5, 8, 11, 14 and 17

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

R1= methoxy and R2= a hydrogen atom, or

R2= methoxy and R1= hydrogen atom

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

R1= ataxia R 2= a hydrogen atom, or

R2= ethoxy and R1= hydrogen atom

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

R1= propoxy and R2= a hydrogen atom, or

R2= propoxy and R1= hydrogen atom

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

R1= methylthio and R2= a hydrogen atom, or

R2= methylthio and R1= hydrogen atom

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

R1= atillio and R2= a hydrogen atom, or

R2= atillio and R1= hydrogen atom

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

R1= propylthio and R2= a hydrogen atom, or

R2= propylthio and R1= hydrogen atom

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

For all examples(51)-(59):

X = ethylcarboxylate

Y=C20alkene with 6 double bonds in positions 4, 7, 10, 13, 16 and 19, where the double bond in positions 7, 10, 13, 16 and 19 have a Z-configuration, and the double bond in position 4 has the E-configuration

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

R1= methyl and R2= a hydrogen atom, or

R2= methyl and R1= hydrogen atom

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

R1= ethyl and R2= a hydrogen atom, or

R2= ethyl and R1= hydrogen atom

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

R1= propyl and R2= a hydrogen atom, or

R2= propyl and R1= hydrogen atom

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

R1= methoxy and R2= a hydrogen atom, or

R2= methoxy and R1= hydrogen atom

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

R1= ethoxy and R2= a hydrogen atom, or

R2= ethoxy and R1= hydrogen atom

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

R1= propoxy and R2= a hydrogen atom, or

R2= propoxy and R1= hydrogen atom

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

R1= methylthio and R2= a hydrogen atom, or

R2= methylthio and R1= hydrogen atom

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

R1= atillio and R2= a hydrogen atom, or

R2= atilt is o and R 1= hydrogen atom

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

R1= propylthio and R2= a hydrogen atom, or

R2= propylthio and R1= hydrogen atom

Other examples of compounds according to the invention

Additional preferred compounds include the following compounds/intermediate connection:

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

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

Compounds according to the categories from A to F can be represented 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, solvate or prodrug omega-3 lipid compounds of formula (I).

“Prodrugs” are substances that may have or may not possess pharmacological activity as such, but can be introduced in such a way as oral or parenteral) and, therefore, subject to bioactivate (for example, to metabolize in the body with the formation means according to the present invention, which is pharmacologically active.

“Pharmaceutically active amount is in the” applies to the number, which will produce the desired pharmacological and/or therapeutic effects, i.e. the amount of omega-3 lipid compound that is effective to achieve the intended purpose. Although the requirements of the individual patient can vary, determination of optimal ranges of effective amounts of omega-3 lipid compound is in the competence of a person skilled in the art. Usually, the dosage regimen for treating the condition with the compounds and/or compositions according to the invention are chosen in accordance with several factors, including the type, age, weight, sex, diet and medical condition of the patient.

Under “drug” means omega-3 lipid compound of formula (I) in any form suitable for use in medical purposes, such as medicinal agents, pharmaceutical agents, or product, diet product, food product or food additive.

“Treatment” includes any therapeutic application, which can positively affect the human or non-human mammal. Treatment, both human and veterinary, included in the scope of the present invention. Treatment may be directed to an existing state or prevention.

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

Acceptable carriers, excipients and diluents for therapeutic use are well known in the pharmaceutical field and can be selected based on the intended route of administration and standard pharmaceutical practice. The examples include binders, lubricants, suspendresume means, means for coating, solubilizing means, preservatives, wetting means, emulsifiers, sweeteners, colorants, flavouring flavouring substances, fragrances, buffers, suspendresume means, stabilizing means and/or salt.

The pharmaceutical composition according to the invention are preferably formulated for oral administration to a human or animal. The pharmaceutical composition may also be formulated for administration in any other way, where the active ingredients can be effectively absorbed and utilized, for example, intravenous, subcutaneous, intramuscular, by vnutrimyshernm, rectal, vaginal or local method.

In a separate embodiment of the invention, the pharmaceutical composition set up shop data the van in the form of capsules, which also may be a microcapsule forming powder or package-Sasha. The capsule can be aromatized. This variant implementation of the invention includes a capsule capsule and encapsulated composition according to the invention is flavored. Thanks flavoring capsule becomes more attractive for the user. As for the above purposes, therapeutic use, enter the dosage, of course, will vary depending on the compound, the route of administration, the desired treatment such violations.

The pharmaceutical composition may be formulated to provide a daily dosage, for example, from 5 mg to 10 g; from 50 mg to 1 g, or from 50 mg to 200 g of omega-3 lipid compounds. Under daily dose mean dose 24 hours.

Enter the dosage, of course, will vary depending on the compound, the route of administration, the desired treatment such violations. Typically, the attending physician will determine the actual dosage which will be most suitable for an individual subject. Individual dose level and frequency of dosage for any particular patient may vary and will depend on a number of factors including the activity of the individual connections in use, the metabolic stability and prod is littelest actions specified connection, age, body weight, General health, sex, diet, mode and time of administration, rate of excretion, combination of drugs, the severity of individual condition and treatment, which is subjected to the individual. Omega-3 lipid compound and/or pharmaceutical composition according to the present invention can be introduced in accordance with the mode 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 dose level of funds 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 containing omega-3 lipid compounds of formula (I). The lipid composition can contain in the range from 60 to 100% of the mass. omega-3 lipid compounds of formula (I), and all interest of the masses. 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. lipid compositions comprise omega-3 lipid compounds of formula (I).

The lipid composition may also contain at least one fatty acid (all-Z)-5,8,11,14,17-eykozapentaenovuyu acid (EPA)and (all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), (all-Z)-6,9,12,15,18-heneicosane acid (NDA), (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 their derivatives, i.e. present in the form of alpha-substituted compounds.

In some embodiments of the invention, the lipid composition is a pharmaceutical composition, a food composition or a composition for the diet.

The lipid composition may also contain an effective amount of pharmaceutically acceptable antioxidant, such as tocopherol or a mixture of Tocopherols, up to 4 mg / g, for example, from 0.05 to 0.4 mg per g of tocopherol by weight of the total lipid composition.

Omega-3 compounds and compositions according to the invention are suitable for 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 physical activity, in many cases, is characterized by gradual onset, usually in adults and is caused by decreased sensitivity of tissues to the action of the insulin, the so-called peripheral insulin resistance. This leads to a compensatory increase in the production of insulin. The specified stage of development fully developed type 2 diabetes 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 omega-3 lipid compounds of formula (I) for drugs for treatment and/or prevention of multilateralism syndrome called “metabolic syndrome and related conditions mentioned above. In a later period, when the production of insulin is inhibited, developing diabetes type 2. In one embodiment of the invention, the compounds of formula (I) can be applied for the treatment of 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 endocrine disorders or drugs, or of exceptional forms of diabetes, such as lipotropics is s, Metodicheskie or disease caused by a violation of insulin receptors.

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

Omega-3 lipid compounds of formula (I) can also be used to treat and/or prevent obesity. Generally, obesity is associated with increased insulin resistance, and fat people are at high risk of developing type 2 diabetes, which is a major risk factor for cardiovascular disease. Obesity is a chronic disease that affected an increasing proportion of the population in Western societies, and it is not only a social problem, but also with decreased life span and numerous problems, for example, diabetes, insulinorezistentnost and hypertension. The present invention thus helps to meet a long-felt needs in medicine, which will reduce overall body weight, or fat, preferably in obese people, leading to ideal body weight without significant adverse side effects.

In addition, non-alcoholic fatty infiltration pecan what is the General condition associated with metabolic syndrome. More precisely, fatty infiltration of the liver initially associated with hyperinsulinemia and insulin resistance. In one embodiment of the invention, the omega-3 lipid compound of formula (I) can act as sensitive to insulin tool and reduce fatty degeneration of the liver.

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

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

The present invention also relates to the use of omega-3 lipid compounds of formula (I) to obtain a medicine for lowering triglycerides in the blood of mammals and/or increase levels of HDL-cholesterol (HDL) in serum of a human patient.

In another aspect, the present invention relates to the use of omega-3 lipid compounds of formula (I) to obtain drugs or pharmaceuticals for the treatment and/or prevention of at least one of atherosclerosis, or IgA nephropathy, prevention of multiple risk factors for cardiovascular diseases, heart failure, atrial fibrillation and/or postmyocardial heart attack, stroke, cerebral or transient ischaemic disorders associated with atherosclerosis of certain arteries, treatment FA or HIV (HIV) and the treatment of HTG patients with HIV.

In one embodiment of the invention, the present invention also relates to the use of omega-3 lipid compounds of formula (I) to obtain drugs or pharmaceuticals 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 l is penye the compounds of formula (I), are at least one of the activators or modulators of the receptor (PPAR)α, γ and/or δ person, activated by proliferation peroxisome. As was previously known, the receptor PPARα is more “promiscuous” in comparison with PPARγ, which means that the receptor PPARα is associated with a large number of fatty acids as ligands in comparison with PPARγ. However, because patients with metabolic syndrome or type 2 diabetes, usually, are obese or are overweight, and blood contain abnormal lipids, mainly elevated levels of triglycerides and low levels of cholesterol, high-density (HDL-hol), activation of the receptor PPARα is 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)α human activated proliferation peroxisome. In addition, the ideal drug for the treatment of metabolic syndrome or type 2 diabetes may act as a ligand of both of these receptors. Thus, the present invention relates to the use of compounds of formula (I) as a dual activator or modulator activated proliferation peroxisome receptor (PPAR) human α/γ and/or α/δ, preferably activator or modulator the PPAR α/γ. The present invention also includes the case where the compounds of formula (I) are pan-PPAR agonists (i.e. agonists alpha-, beta - and gamma-receptors).

Methods for producing compounds according to the invention

Omega-3 lipid compound of formula (I), where R1(or R2is hydrogen, can be obtained in the following ways (scheme 1). Omega-3 lipid compounds represented by the General formula (I), where R1is hydrogen, and R2means1-C6alkyl group, benzyl, halogen, alkenyl, quinil produced by the interaction of long-chain polyunsaturated complex ester with a strong dinucleophiles base, such liedeseplein, hexamethyldisilazide potassium/sodium or KH/NaH in DMF in a solvent such as tetrahydrofuran, diethyl ether at a temperature of from -60 to -78°C To produce a complex ester enol (method 1).

The way I

Scheme 1: R3= an alkyl group (methyl, ethyl, propyl)

The specified ester enolate interacts with an electrophilic reagent, such halide, the alkyl represented by ethyl iodide, benzylchloride, galodamadruga carboxylic acid represented by acetylchloride, benzylbromide, carboxylic acid anhydride, presents acetic anhydride, or electrophilic the halogenation reagent, presents N-forbindelsesfanebladet (NFSI), N-bromosuccinimide or iodine, etc, to obtain the substituted derivative (method 2). 2-halogen-substituted derivatives of compounds can interact with the nucleophilic reagent, such as thiols, obtaining 2-alkylthio-derived compounds.

Ester then hydrolyzed in a solvent such as ethanol or methanol, to derived compounds carboxylic acid by adding a base such as lithium hydroxide/sodium/potassium in water at temperatures between 15°C and the temperature of education phlegmy.

Condensation of Clausena long-chain polyunsaturated ether complex occurs during the processing of an ether of a strong base. (The condensation product may possess interesting biological activity. Thus, in one embodiment, the invention discloses the condensation product (intermediate compound), mentioned above, as well as the use of this product for the treatment and/or prevention of diseases according to the present invention).

In addition, in another embodiment of the invention, the compounds represented by the General formula (I), are synthesized in the following ways (scheme 2).

Method II:

Scheme 2: R3= an alkyl group (methyl, ethyl, propyl)

Connections, performance is undertaken General formula (I), where R1is hydrogen, and R2means a hydroxy-group, alkoxygroup, alloctype produced by the interaction of long-chain polyunsaturated complex ester with a strong dinucleophiles base, such liedeseplein or hexamethyldisilazide potassium/sodium in a solvent such as tetrahydrofuran, diethyl ether at temperatures from -60 to -78°C To produce a complex ester enol (method 4). This ester Enola communicates with a source of oxygen, such dimethyldioxirane, 2-(phenylsulfonyl)-3-phenyloxazolidine, molecular oxygen with various auxiliary substances, such trimethylphosphite or different catalysts, such complex Ni(II), with a complex ester of an alpha-hydroxy acid (method 5). The reaction of the secondary alcohol with a base, such Nutrilite, in a solvent like THF or DMF, formed alcoholate, which interacts with various electrophilic reagents, for example, alkylation, methyliodide, ethyliodide; benzylbromide or halogenerator carboxylic acid, for example, acetylchloride, benzylbromide (method 6). Ester is hydrolyzed in a solvent such as ethanol or methanol, to the carboxylic acid derivative by adding a base such as lithium hydroxide/matricule in water at temperatures between 15°C and the temperature of education phlegmy (method 7).

Ester alpha-hydroxy acid is suitable intermediate connection for the introduction of other functional groups in α-position according to the invention. Hydroxyl function can be activated by conversion to halogen or tosylate to interact with various nucleophiles such as ammonia, amines, thiols, etc. Reaction Mitsunobu also applicable for the conversion of the hydroxyl groups into other functional groups. (Mitsunobu, O., Synthesis, 1981, 1).

Compounds represented by the General formula (I), where R1is hydrogen, and R2means alkyl, phenyl, hydroxymethyl, carboxyl, alkoxycarbonyl, hydroxy, alkoxygroup, acyloxy can be obtained by reacting long-chain polyunsaturated tosilata, nelfinavir or halogen with diallylmalonate or substituted by diallylmalonate. Method III, scheme 3. Hydrolysis of diapir and lead to decarboxylation of alpha-substituted products.

Method III

Scheme 3

Long-chain polyunsaturated tozilaty used in method III can be obtained from the corresponding long-chain polyunsaturated alcohol. Such alcohols can be obtained directly from esters of carboxylic acids of natural unsaturated fatty acids: alpha-linolenic acid, conjugated is linolenovoi acid, eicosapentaenoic acid, etc. by the reaction of recovery through a reducing reagent, such sociallyengaged or diisobutylaluminium at a temperature of from -10 to 0°C. Using alcohol, obtained from ethyl (all-Z)-5,8,11,14,17-eicosapentaenoate in the sequence of reactions described in method III can be obtained 2-substituted derivatives of DPA. Alcohols can also be obtained by degradation of polyunsaturated fatty acids EPA and DHA, as described Holmeide et al. (J. Chem. Soc., Perkin Trans. 1, 2000, 2271). In this case, the method can begin with purified EPA or DHA, but it can also start with fish oil containing EPA and DHA in the mixture. The reason for this is that the DHA reacts faster in reaction iodoacetonitrile 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-Octadecatetraenoic can be obtained from DHA by the method described in the above literature. Using the above-mentioned alcohol as a reactant in the ways III, can be obtained 2-substituted derivatives of EPA.

Combining method III with the way I can get disubstituted derivatives.

Method IV

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

Acelerou the tion sn-glycero-3-phosphocholine (GPC) of the activated fatty acid, such as imidazoline fatty acids, is a standard procedure in the synthesis of phosphatidylcholine. Usually, the synthesis is carried out in the presence of DMSO anion with DMSO as solvent (Hermetter; Chemistry and Physics of lipids, 1981, 28, 111). Sn-Glycero-3-phosphocholine as adduct of cadmium(II), may also interact with imidazolium activated fatty acid in the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) with the receipt of the corresponding phosphatidylcholine fatty acids (international application number PCT/GB2003/002582). Enzymatic transpeptidation can lead to the transformation of phosphatidylcholine to 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, the enzymatic esterification and transesterification of phospholipids or enzymatic transpeptidation phospholipids. (Hosokawa, J. Am. Oil Chem. Soc. 1995, 1287, Lilja-Hallberg, Biocatalysis, 1994, 195). In the case of enzymes, the preferred embodiment of the invention is a compound of formula (I), where R1or R2represents hydrogen.

The compounds of formula (I), where X is a carboxylic acid in the form of triglycerides can be obtained in the following ways. A new surplus fatty acids can be ocean with glycerol using dimethylaminopyridine (DMAP) and 2-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylethylenediamine (HBTU).

The compounds of formula (I), where X is a carboxylic acid in the form of diglyceride, can be obtained by the reaction of fatty acids (2 equivalent) 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 in the form of monoglyceride can be obtained in the following ways. The acylation of 1,2-O-isopropylidene-sn-glycerol fatty acid using DCC and DMAP in chloroform leads to managerorganization. Remove protective isopropylidenebis group can be carried out by treating the protected glycerol acid (HCl, acetic, etc.) (O Brian, J. Org. Chem., 1996, 5914).

There are several General synthetic methods for producing monoglycerides and fatty acid in the 2-position. In the same way using the esterification of fatty acids by glycidol in the presence of hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 4-dimethylaminopyridine (DMAP) to give goldlenovo derived. Processing goldlenovo derived triperoxonane anhydride (TFAA) before transesterification get monoglyceride (Parkkari et al, Bioorg. Med. Chem. Lett. 2006, 2437).

Other common methods of obtaining mono-, di - and triglycerides of fatty acids derivatives described in International the th patent application, PCT/FR02/02831.

It is also possible to use enzymatic methods (reaction with lipase) for the conversion of fatty acids into mono-, di-, triglyceride. 1,3-Regiospecific lipase from Mucor miehei can be used to produce triglycerides or diglycerides of fatty acids and glycerol. Another lipase, prehispanica lipase yeast Candida antartica is highly effective in the formation of triglycerides of polyunsaturated fatty acids (Haraldsson, pharmazie, 2000, 3). For this enzymatic reaction, the preferred embodiment of the invention is a compound of formula I, where R1and R2are hydrogen.

The synthesis protocols

The invention will be described in more detail by 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 CDCl3. Values of J are given in Hz.

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

Utility (of 0.96 ml, 1.54 mmol, 1.6 M in hexane) was added dropwise to a stirred solution of Diisopropylamine (0,23 ml of 1.60 mmol) in dry THF (5 ml) in an atmosphere of N2at 0°C. the Resulting solution was stirred at 0°C for 20 min, cooled to -78°C and stirred for more the 10 min before adding dropwise ethyl (all-Z)-7,10,13,16,19-docosapentaenoic (0.50 g, of 1.40 mmol) in dry THF (5 ml) for 10 minutes, the green Solution was stirred at -78°C for 10 min before adding ethyliodide (0.16 ml, of 2.09 mmol). The resulting solution was allowed to reach ambient temperature over one hour, was distributed between water (10 ml) and heptane (10 ml). The aqueous layer was extracted with heptane (20 ml)and the combined organic layer washed with 1 M HCl and dried (Na2SO4). Concentration under reduced pressure and purification with flash chromatography (heptane:EtOAc 98:2) led to 0,37 g (68%) indicated in the title compound 14 as a colorless oil.

1H NMR (200 MHz, CDCl3) δ 0,83 is 0.99 (m, 6H), 1,20-1,60 (m, 11H), was 2.05 (m, 4H), 2,19 (m, 1H), 2,81 (m, 8H), 4,11 (kV, 2H), 5,35 (m, 10H);

13C-NMR (50 MHz, CDCl3) 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 (elektrorazpredelenie): 409,3 [M+Na].

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

A solution of KHMDS (533,9 mg, 2.68 mmol) in THF, 10 ml, was cooled to -78°C in an atmosphere of N2before adding dropwise the solution of (all-Z)-7,10,13,16,19-docosapentaenoic (478,8 mg of 1.33 mmol) in THF and 2.5 ml and the Mixture was stirred at -78°C for 30 minutes before adding dropwise the solution of TRANS-2-(phenylsulfonyl)-3-phenyloxazolidine (reagent Davis) (525,3 mg, a 2.01 mmol) in THF and 1.5 ml of the Reaction mixture changes ivali at -78°C for 1 hour 50 minutes before quenching the reaction with saturated solution of NH 4Cl, 20 ml, after heating to room temperature the mixture was extracted with diethyl ether, 50 ml×2, the organic phase is washed with saturated salt solution, 20 ml, dried (Na2SO4), filtered and evaporated in vacuum. The obtained crude product was subjected to flash chromatography on silica gel, elwira a mixture of heptane/EtOAc(100:1)-(95:5), to obtain 293 mg (59%) of product 65 in the form of a colourless liquid.

1H NMR (200 MHz, CDCl3) δ of 0.95 (t, J=7.5 Hz, 3H), of 1.28 (t, J=7,1 Hz, 3H), 1,38 of 1.46 (m, 4H), 1,49-of 1.81 (m, 2H), 2,02 and 2.13 (m, 4H), was 2.76-to 2.85 (m, 9H), of 4.12 (DD, J=2.5 and 6.9 Hz, 1H), 4,22 (kV, J=7,1 Hz, 2H), 5,32-5,41 (m, 10H).

13C NMR (50 MHz, CDCl3) 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 invisible).

MS (elektrorazpredelenie): 397 [M+Na]+.

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

A suspension of 35% KN (92,4 mg, 0,806 mmol KN) in DMF, 3 ml, cooled in an atmosphere of N2to 0°C was added dropwise a solution of ethyl (all-Z)-2-hydroxy-7,10,13,16,19-docosapentaenoic (65) (101 mg, 0.27 mmol) in DMF, 2 ml and the Mixture was stirred for 30 minutes at 0°C before adding the EtI (0,22 ml, 2,73 mmol). Then, the mixture was left to slowly reach room temperature and was stirred for 4 hours. The reaction was suppressed with saturated solution of NH4Cl, 20 ml) and was extracted with diethyl ether, 50 ml×2. The organic phase is washed of NASA the military solution of salt, 20 ml, dried (Na2SO4), was filtered and was evaporated in vacuo and subjected to flash chromatography on silica gel, elwira a mixture of heptane:EtOAc(100:1)-(95:5), with the receipt of 19.4 mg (18%) of the product 17 as a colourless liquid.

1H NMR (300 MHz, CDCl3) δ of 0.95 (t, J=7.5 Hz, 3H), of 1.20 (t, J=7.0 Hz, 3H), of 1.26 (t, J=7,1 Hz, 3H), of 1.31 to 1.47 (m, 5H), 1,66-1,72 (m, 2H), 2,03-2,11 (m, 5H), 2.77-to 2,84 (m, 6H), 3.33 and-3,47 (m, 1H), 3,55-the 3.65 (m, 1H), 3,78 (t, J=6,4 Hz, 1H), 4,14-4,22 (m, 2H), 5,27 of 5.39 (m, 10H).

13C NMR (75 MHz, CDCl3) δ 14,3, 15,2, 20,6, 25,0, 25,5, 25,6 (2 signal), 27,0, 29,3, 32,9, 60,6, 65,9, 79,0, 127,0, 127,9 (2 signal), 128,0, 128,1, 128,2, 128,4, 128,5, 130,0, 132,0, 173,2 (2 signal invisible).

MS (elektrorazpredelenie): 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-docosapentaenoic (17) (66,1 mg, 0,164 mmol) in EtOH (5 ml) was added a solution of LiOH·H2O (57,7 mg, 1.38 mmol) in water (5 ml). The reaction mixture was stirred in an atmosphere of N2at 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 (MgSO4) and was evaporated in vacuum to obtain 55 mg (90%) indicated in the title compound as a pale yellow oil.

1H NMR (200 MHz, CDCl3) δ of 0.95 (t, J=7.5 Hz, 3H), 1,24 (t, J=7.0 Hz, 3H), 1,38-of 1.41 (m, 4H), 1,75-of 1.85 (m, 2H), 2,03 and 2.13 (m, 4H), 2,80-and 2.83 (m, 8H), 3.46 in-3,71 (m, 2H), 3,88 (t, J=5.8 Hz, 1H), 5,23-5,44 (m, 10H).

MS (elektrorazpredelenie): 373 [M-N -.

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

To a solution of Diisopropylamine (265 μl, 1.88 mmol) in dry THF, 5 ml, in an atmosphere of N2at 0°C was added dropwise 1.6 M BuLi in hexane (1,15 ml of 1.84 mmol). The resulting mixture was stirred at -78°C for 20 minutes before adding dropwise the solution of ethyl (all-Z)-9,12,15-octadecatrienoic (502 mg, of 1.64 mmol) in THF, 5 ml of the resulting reaction mixture was stirred for 30 minutes at -78°C. before adding dropwise EtI (0,20 ml, 2.48 mmol). The cooling bath was sacked, the reaction mixture was stirred for 3 hours 45 minutes before quenching the reaction with water, 25 ml) and was extracted with diethyl ether, 50 ml×2. The organic phase is washed with 1 M HCl (aq.), 20 ml, dried (Na2SO4), filtered and evaporated in vacuum. The obtained crude product was subjected to flash chromatography on silica gel, elwira a mixture of heptane/EtOAc (100:1), to obtain 216 mg (39%) of ethyl (all-Z)-2-ethyl-9,12,15-octadecatrienoic (2) in the form of a colourless liquid.

1H NMR (200 MHz, CDCl3) δ is 0.84 (t, J=7.4 Hz, 3H), of 0.93 (t, J=7.5 Hz, 3H), 1,21 (t, J=7,1 Hz, 3H), 1,25 (m, 8H), 1,33-of 1.65 (m, 4H), 2,02 (kV, J=7,0 Hz, 4H), 2,13-of 2.27 (m, 1H), was 2.76 (t, J=5.6 Hz, 4H), 4,10 (kV, J=7,1 Hz, 2H), 5,20-5,41 (m, 6H).

13C NMR (50 MHz, CDCl3) 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 signal invisible)

MS (elektrorazpredelenie): 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-octadecatrienoic (2) (111 mg, 0,312 mmol) in EtOH (10 ml) was added a solution of LiOH·H2O (108 mg, 2.57 mmol) in water (10 ml). The reaction mixture was stirred in an atmosphere of N2at 80°C for 15 hours. After cooling, was added 1 M HCl (to pH ~2). The resulting mixture was extracted with diethyl ether (50 ml), dried (MgSO4) and was evaporated in vacuum to obtain 81 mg (79%) indicated in the title compound as a yellow oil.

1H NMR (200 MHz, CDCl3) δ 0,83 is 0.99 (m, 6H), 1,20-of 1.29 (m, 8H), 1.41 to of 1.78 (m, 4H), 1,99 and 2.13 (m, 4H), 2.21 are of 2.30 (m, 1H), was 2.76-2.82 from (m, 4H), 5,23-5,44 (m, 6H).

MS (elektrorazpredelenie): 305 [M-N]-.

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

To a solution of Diisopropylamine (322 μl, 2.28 mmol) in dry THF, 5 ml, in an atmosphere of N2at 0°C was added dropwise 1.6 M BuLi in hexane (1.25 ml, 2.0 mmol). The resulting mixture was stirred at -78°C for 20 minutes before adding dropwise the solution of ethyl (all-Z)-9,12,15-octadecatrienoic (501 mg, and 1.63 mmol) in THF, 5 ml of the reaction mixture is yellow was stirred for 35 minutes at -78°C. before adding dropwise the solution of I2(704 mg, 2.77 mmol) in THF, 5 ml of the Reaction mixture was stirred at -78°C for 25 minutes before quenching the reaction of 1 M HCl, 20 ml) and was extracted with heptane, 50 ml of the Organic phase is washed with 10% Na 2S2O3(aq.), 25 ml), dried (Na2SO4), filtered and evaporated in vacuum. The obtained crude product was subjected to flash chromatography on silica gel, elwira a mixture of heptane/EtOAc (100:1), with 152 mg (22%) of ethyl (all-Z)-2-iodine-9,12,15-octadecatrienoic (60) in the form of a colourless liquid.

1H NMR (200 MHz, CDCl3) δ of 0.95 (t, J=7.5 Hz, 3H), 1,25 (t, J=7,1 Hz, 3H), of 1.30 (m, 8H), 1,89-of 2.09 (m, 6H), 2,78 (t, J=5.5 Hz, 4H), 4,13-to 4.28 (m, 3H), 5.25 to 5 (m, 6H).

13C NMR (50 MHz, CDCl3) 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 (elektrorazpredelenie): 455 [M+Na]+.

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

Ethyl (all-Z)-2-iodine-9,12,15-octadecatrienoic (60) (146 mg, 0,338 mmol) was dissolved in THF, 5 ml, and cooled to 0°C in an atmosphere of N2to add MeSNa. The reaction mixture was stirred at 0°C for 1 hour to dilute it heptane, 50 ml, washed with water, 2×20 ml), dried (Na2SO4), filtered and evaporated in vacuum. The obtained crude product was subjected to flash chromatography on silica gel, elwira a mixture of heptane/EtOAc(100:1)-(95:5), to obtain 110 mg (92%) of ethyl (all-Z)-2-thiomethyl-9,12,15-octadecatrienoic (7) in the form of a colourless liquid.

1H NMR (200 MHz, CDCl3) δ were 0.94 (t, J=7.5 Hz, 3H), of 1.23 (t, J=7,1 Hz, 3H), of 1.29 (m, 8H), (m, 1H), (m, 1H), 2,09 (c, 3H), 1,97 and 2.13 (m, 8H), 2,77 (t, J=5.6 Hz, 4H), of 3.12 (DD, J=6,8, 8,3 Hz, 1H), 4,17 (kV, J=7,1 Hz, 2H), 5,265,37 (m, 6H).

13C NMR (50 MHz, CDCl3) 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 the signal is not visible).

MS (elektrorazpredelenie): 375 [M+Na]+.

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

A solution of KHMDS (5,24 g, to 26.2 mmol) in THF, 100 ml, was cooled to -78°C in an atmosphere of N2to add (dropwise) a solution of ethyl (all-Z)-9,12,15-octadecatrienoic (4,01 g of 13.1 mmol) in THF, 25 ml, and the Mixture was stirred at -78°C for 30 minutes before adding dropwise the solution of TRANS-2-(phenylsulfonyl)-3-phenyloxazolidine (reagent Davis) (5,13 g and 19.6 mmol) in THF, 15 ml of the Reaction mixture was stirred at -78°C for 1½ hours before quenching the reaction with saturated solution of NH4Cl, 30 ml, after heating to room temperature the mixture was extracted with diethyl ether, 100 ml×2, the organic phase is washed with saturated salt solution, 30 ml), dried (Na2SO4), filtered and evaporated in vacuum. The obtained crude product was subjected to flash chromatography on silica gel, elwira a mixture of heptane/EtOAc(100:1)-(95:5), to obtain 2.67 g (63%) of ethyl (all-Z)-2 - hydroxy-9,12,15-octadecatrienoic (61) in the form of a colourless liquid.

1H NMR (200 MHz, CDCl3) δ to 0.92 (t, J=7.5 Hz, 3H), 1,24 (t, J=7,1 Hz, 3H), of 1.28 (m, 8H), 1,53 is 1.75 (m, 2H), 1,96 is 2.10 (m, 4H), was 2.76 (t, J=5.6 Hz, 5H), 4,11 (DD, J=4,0, 6,7 Hz, 1H), 4,19 (kV, J=7,1 Hz, 2H), 5,22-5,41 (m, 6H).

13C NMR (50 MHz, CDCl ) 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 (elektrorazpredelenie): 345 [M+Na]+.

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

A suspension of 35% KN (84,3 mg, 0,735 mmol KN) in DMF, 2 ml, cooled in an atmosphere of N2to 0°C and a solution of ethyl (all-Z)-2-hydroxy-9,12,15-octadecatrienoic (61) (119,7 mg of 0.37 mmol) in DMF, 2 ml, was added dropwise. The mixture was stirred for 30 minutes at 0°C before adding the EtI (0.15 ml, of 1.87 mmol). Then, the mixture was left to slowly reach room temperature and was stirred overnight. The reaction was suppressed with saturated solution of NH4Cl, 20 ml, and the reaction mixture was extracted with diethyl ether, 50 ml×2. The organic phase is washed with saturated salt solution, 20 ml, dried (Na2SO4), was filtered and was evaporated in vacuo and subjected to flash chromatography on silica gel, elwira a mixture of heptane:EtOAc(100:1)-(95:5), getting to 31.5 mg (24%) of product 5 as a colorless liquid.

1H NMR (200 MHz, CDCl3) δ of 0.95 (t, J=7.5 Hz, 3H), of 1.20 (t, J=7.0 Hz, 3H), 1,22-of 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 and is-3.45 (m, 1H), 3,52-to 3.64 (m, 1H), 3,78 (t, J=6,4 Hz, 1H), 4,12-4,24 (m, 2H), 5,27-of 5.40 (m, 6H).

13C NMR (50 MHz, CDCl3) 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 signal), 130,2, 131,9, 173,3.

MS (elektrorazpredelenie): 373 [M+Na]+.

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

A solution of ethyl (all-Z)-2-hydroxy-9,12,15-octadecatrienoic (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 in an atmosphere of N2before adding diisopropylcarbodiimide (DIAD) (128 μl, 0,660 mmol). The cooling bath was set aside, and the mixture was stirred for 22 hours. The reaction mixture was evaporated in vacuo and subjected to flash chromatography on silica gel, elwira a mixture of heptane:EtOAc(95:5)-(4:1), obtaining 153,8 mg (62%) of ethyl (all-Z)-2-phthalimide-9,12,15-octadecatrienoic (62) in the form of a colourless liquid.

1H NMR (200 MHz, CDCl3) δ to 0.92 (t, J=7.5 Hz, 3H), of 1.18 (t, J=7,1 Hz, 3H), of 1.29 (m, 8H), 1,97 is 2.10 (m, 4H), 2,17-of 2.24 (m, 2H), 2,72-2 ,79 (m, 4H), 4,17 (kV, J=7,1 Hz, 2H), 4,79 (DD, J=9,6, 6.0 Hz, 1H), 5,24 to 5.35 (m, 6H), 7.68 per-7,74 (m, 2H), 7,79-a 7.85 (m, 2H).

13C NMR (50 MHz, CDCl3) 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 (elektrorazpredelenie): 474 [M+Na]+.

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

To a solution of ethyl (all-Z)-2-phthalimide-9,12,l5-octadecadienoate (62) (104,6 mg, 0,232 mmol) in EtOH, 4 ml, was added hydrazine hydrate (17 μl, 0.35 mmol)and the mixture is boiled under reflux in an atmosphere of N2within 15 hours. The reaction mixture was cooled, evaporated in vacuo and subjected to flash chromatography on silica gel, elwira mixture is Yu CH 2C12:2M NH3in MeOH (97,5:2,5), with 58,4 mg (78%) of ethyl (all-Z)-2-amino-9,12,15-octadecatrienoic (12) in the form of a colourless liquid.

1H NMR (200 MHz, CDCl3) δ to 0.92 (t, J=7.5 Hz, 3H), 1,21 (t, J=7,1 Hz, 3H), of 1.27 (m, 8H), 1,37 was 1.69 (m, 4H), 1,95-of 2.09 (m, 4H), to 2.74 (t, J=5.6 Hz, 4H), 3,36 (users, 1H), 4,11 (kV, J=7,1 Hz, 2H), 5,22 lower than the 5.37 (m, 6H).

13C NMR (50 MHz, CDCl3) 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 (elektrorazpredelenie): 322 [M+H]+, 344 [M+Na]+.

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

To a mixture of ethyl (all-Z)-2-amino-9,12,15-octadecatrienoic (12) (551,7 mg, 1,72 mmol), LiOH·H2O (144,6 mg of 3.45 mmol) and molecular sieves 4Å (507 mg) in DMF, 4 ml, was added ethylbromide (2,6 ml, 34.8 mmol)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 is washed with 1 M NaOH, 20 ml), and saturated salt solution, 20 ml, dried (Na2SO4), was filtered and was evaporated in vacuo and subjected to flash chromatography on silica gel, elwira a mixture of heptane:EtOAc (95:5)-CH2Cl2:2M NH3in MeOH (98:2), with 357 mg (55%) diethylamino-derived complex ester 10 in the form of colourless liquid and 161 mg (27%) ethylamino-derived complex ester 11 in the form of liquid is yellow.

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

1H NMR (200 MHz, CDCl3) δ of 0.93 (t, J=7.5 Hz, 3H), 0,99 (t, J=7,1 Hz, 6H), to 1.22 (t, J=7,1 Hz, 3H), of 1.27 (m, 8H), 1,51 is 1.70 (m, 2H), 1,96-2,11 (m, 4H), 2,43 (sextet, J=6,8 Hz, 2H), 2,66 (kV, J=7,3 Hz, 2H), 2.71 to and 2.79 (m, 4H), of 3.28 (t, J=7,4 Hz, 1H), 4,10 (kV, J=7,1 Hz, 2H), 5,22 is 5.38 (m, 6H).

13C NMR (50 MHz, CDCl3) 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 (elektrorazpredelenie): 378 [M+H]+, 400 [M+Na]+.

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

1H NMR (200 MHz, CDCl3) δ of 0.91 (t, J=7.5 Hz, 3H), of 1.02 (t, J=1.1 Hz, 3H), 1,24 (m, 11H), of 1.55 (m, 3H), 1,94-of 2.08 (m, 4H), 2,35-to 2.65 (m, 2H), by 2.73 (t, J=5.6 Hz, 4H), 3,14 (t, J=6,6 Hz, 1H), 4,11 (kV, J=7,1 Hz, 2H), 5,17 is 5.38 (m, 6H).

13C NMR (50 MHz, CDCl3) 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 (elektrorazpredelenie): 350 [M+H]+, 372 [M+Na]+.

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

A solution of ethyl (all-Z)-4,7,10,13,16,19-docosahexaenoate (of 10.72 g, 30.0 mmol) in THF, 30 ml, was added dropwise to a suspension of LiAlH4in THH, 140 ml, in an atmosphere of N2at 0°C. the Resulting mixture was stirred at 0°C for 50 minutes before quenching the reaction with water, 50 ml, was added 1 M HCl, 100 ml, 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 is washed with 1M HCl, 50 is l, dried (Na2SO4), filtered and evaporated in vacuum to obtain 8,56 g (91%) of (all-Z)-4,7,10,13,16,19-docosahexaenoic (63) in the form of a colourless liquid.

1H NMR (200 MHz, CDCl3) δ 1.00 each (t, J=7.5 Hz, 3H), 1,63-of 1.73 (m, 2H), 1,83 (users, 1H), 2,04-of 2.24 (m, 4H), 2,88 (users, 10H)to 3.67 (t, J=6.4 Hz, 2H), 5,41 (users, 12H).

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

A solution of (all-Z)-4,7,10,13,16,19-docosahexaenoic (63) (8,50 g of 27.0 mmol) and taillored (5,41 g, 28.4 mmol) in dry CH2Cl2, 30 ml, was cooled to 0°C before the addition of Et3N (4,15 ml, to 29.8 mmol). The reaction mixture was placed in a refrigerator. After 17 hours, added more taillored (774 mg, 4,06 mmol) and Et3N (565 μl, 4,06 mmol)and the mixture was placed in a refrigerator at 21½ hours. The reaction mixture was poured into ice water and was extracted with CH2Cl250 ml×2, and evaporated in vacuum. The residue was dissolved in heptane, 100 ml, washed with water, 30 ml, 1M HCl, 30 ml×2, and saturated salt solution, 30 ml), dried (Na2SO4), filtered and evaporated in vacuum. To the residue was added pyridine, 1.6 ml, and water, 1.25 ml, 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, saturated salt solution, 25 ml, dried (Na2SO4), filtered and evaporated in vacuum to obtain 10,27 g (81%) tosilata 64 in the form of bescot the CSOs oil.

1H NMR (200 MHz, CDCl3) δ were 0.94 (t, J=7.5 Hz, 3H), 1,61 is 1.75 (m, 2H), 1,97-2,12 (m, 4H), 2,41 (c, 3H), 2,70-2,89 (m, 10H), of 4.00 (t, J=6.4 Hz, 2H), 5,27 is 5.38 (m, 12H), 7,31 (d, 2H), 7,76 (d, 2H).

MS (elektrorazpredelenie): 491 [M+Na]+.

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

To a stirred suspension of LAH (0,130 g of 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 - octadecatrienoic (1.0 g, 3,26 mmol) in dry THF (15 ml). The resulting solution was stirred at 0°C for one hour, was added 10% solution of NH4Cl (15 ml) and filtered through a low layer of celite. Celite was rinsed 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 saturated salt solution (20 ml) and dried (MgSO4). The synthesis resulted in 0,78 g (91%) of (all-Z)-9,12,15-octadecatrienoic (66) as a colourless oil.

1H NMR (200 MHz, CDCl3) δ of 0.95 (t, 3H), of 1.20 and 1.35 (m, 10H), 1,48 is 1.58 (m, 2H), 1,98-of 2.09 (m, 4H), was 2.76-2.82 from (m, 4H), 5,23-5,44 (m, 6N);

MS (elektrorazpredelenie): 287,3 [M+Na]+.

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

To a stirred solution of (all-Z)-9,12,15-octadecatrienoic (66) (0,78 g, 2,95 mmol) in dry CH2Cl2(15 ml)which was kept at 0°C in an inert atmosphere, was added toluene-4-sulphonylchloride (1.12 g, 5,90 mmol) and Et3 N (0,82 ml 5,90 mmol). 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 CH2Cl2(20 ml)and the combined organic layer was concentrated. To the crude product were added 2 ml of pyridine and 1.6 ml of water, 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 saturated salt solution (30 ml). Drying (MgSO4) and concentration under reduced pressure resulted in 0,68 g (55%) tosilata 67 in the form of a colorless oil.

1H NMR (200 MHz, CDCl3) δ of 0.91 (t, 3H), 1,15-1,35 (m, 10H), 1,53 is 1.60 (m, 2H), 1,98-2,12 (m, 4H), 2,43 (c, 3H), 2.70 height is 2.80 (m, 4H), 5,22-of 5.40 (m, 6H), 7,31 (d, 2H), 7,76 (d, 2H);

MS (elektrorazpredelenie): 441,2 [M+Na].

Ethyl (all-Z)-2-ethyl-2-etoxycarbonyl-ll,14,17-eicosatrienoic (23)

To a stirred suspension of NaH (60%, 0,098 g of 2.44 mmol) in dry THF (15 ml) and dry DMF (3 ml), which was kept at 0°C in an inert atmosphere, was added dropwise diethyl-ethylmalonate (and 0.61 ml, 3.25 mmol). The resulting mixture was stirred at 0°C for ten minutes, brought the temperature to ambient temperature and was stirred for another 20 minutes. Toilet 67 (0.68 g, of 1.62 mmol) in dry THF (3 ml) was added, followed d is the addition of NaI (0,098 g, of 0.65 mmol). Then, the resulting solution was stirred at 70°C for four hours, cooled and distributed between 10% NH4Cl (30 ml) and heptane (30 ml). The aqueous layer was extracted with heptane (20 ml)and the combined organic layer was washed with saturated salt solution (30 ml) and dried (Na2SO4). This synthesis resulted 0,70 g (quantitative yield) specified in the title compound 23 as a colourless oil.

1H NMR (200 MHz, CDCl3) δ of 0.91 (t, 3H), 1.18 to 1.30 on (m, 19H), 1,80-2,10 (m, 10H), 2,75-of 2.81 (m, 4H), to 4.16 (m, 4H), 5,28 is 5.38 (m, 6H);

MS (elektrorazpredelenie): 457,3 [M+Na].

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

Ethyl (all-Z)-2-ethyl,2-etoxycarbonyl-11,14,17-eicosatrienoic (23) (0,70 g of 1.61 mmol) was dissolved in 96% ethanol (20 ml) was added 5M KOH (2.6 ml, 13 mmol). The resulting mixture was stirred while boiling under reflux for 19 hours, cooled and concentrated under reduced pressure. To the obtained crude product was added 1M HCl (20 ml) and was extracted twice with diethyl ether (30 ml). The combined organic layer was washed with saturated salt solution (30 ml) and dried (MgSO4). Concentration under reduced pressure resulted 0,60 g (quantitative yield) specified in the title compound 24 as a light brown oil.

MS (elektrorazpredelenie): 377,2 [M-H].

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

Pure (all-Z)-2-ethyl,2-carboxy-11,14,17-eicosatrienoic acid (24) (0,60 g of 1.59 mmol) under inert atmosphere was heated at 160°C for two hours, cooled and purified flash chromatography (heptane:EtOAc 9:1 then 4:1). This procedure led to 0.33 g (62%) indicated in the title (all-Z)-2-ethyl-l1,14,17-eicosatrienoic acid (68) as a colourless oil.

1H NMR (200 MHz, CDCl3) δ 0,84 is 0.99 (m, 8H), 1,15-1,35 (m, 10H), 1,35 is 1.70 (m, 4H), 2.00 in to 2.15 (m, 4H), 2,20-of 2.30 (m, 1H), 2,75-to 2.85 (m, 4H), 5.25 to the 5.45 (m, 6H);

MS (elektrorazpredelenie): 333,2 [M-H].

Ethyl (all-Z)-2-ethyl-ll,14,17-eicosatrienoic (28)

(all-Z)-2-Ethyl-l1,14,17-eicosatrienoic acid (0.15 g, 0.45 mmol) was dissolved in absolute EtOH (5 ml)was added dropwise concentrated H2SO4and stirred while boiling under reflux in an inert atmosphere for 18 hours. The mixture was cooled, concentrated and purified flash chromatography (heptane:EtOAc 95:5). This procedure led to 0,13 g (80%) specified in the connection header 28 in the form of a colorless oil.

1H NMR (200 MHz, CDCl3) δ of 0.85 (t, 3H), were 0.94 (t, 3H), of 1.18 to 1.34 (m, 13H), 1,45-to 1.59 (m, 4H), 1,97-of 2.08 (m, 4H), of 2.25 (m, 1H), 2,74-to 2.85 (m, 4H), 4.09 to (q, 4H), 5,24-5,42 (m, 6H);

13C NMR (50 MHz, CDCl3) 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 (elektrorazpredelenie): 385,3 [M+Na]+./p>

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

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

eicosapentaenoic

A 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), hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (585 mg, of 3.05 mmol) and DMAP (372 mg, of 3.05 mmol) in dry CH2Cl2(10 ml) was stirred for 18 hours in an atmosphere of N2at room temperature. The mixture was evaporated in vacuum. The residue was purified flash chromatography on silica gel, elwira a mixture of heptane - heptane:EtOAc (95:5), with 647 mg (55%) indicated in the title product as a slightly yellow liquid.

1H NMR (200 MHz, CDCl3) δ 0,85 is 0.99 (m, 6H), 1,42 and 1.80 (m, 5H), 2,03-of 2.09 (m, 4H), 2,28-to 2.42 (m, 1H), 2,60-of 2.64 (m, 1H), 2,79-2,82 (m, 8H), 3,14-is 3.21 (m, 1H), 3,88-of 3.97 (m, 1H), 4,36-to 4.46 (m, 1H), 5,23-5,51 (m, 10H).

MS (elektrorazpredelenie): 409 [M+Na]+

Stage 2: 1,3-di(triptorelin)-2-((Z)-2-ethyl-5,8, 11,14,17-eicosapentaenoic)-sn-glycerol

The solution glycidyl (all-Z)-2-ethyl-5,8,11,14,17-eicosapentaenoate (641 mg, of 1.66 mmol) in dry free from alcohol CH2Cl2(6.5 ml) was cooled to -20°C in an atmosphere of N2. A solution of anhydride triperoxonane acid (TFAA) (0,93 ml, 6,69 mmol) in dry CH2Cl2(6.5 ml) was added dropwise. The cooling bath was set aside, and the mixture was stirred for 70 minutes. Races shall foretell and unreacted TFAA was evaporated in vacuum (t< 40°C), and the residue was dissolved in toluene (15 ml)and the solution was passed through a layer of silica gel (16.5 g), elwira toluene (350 ml). This synthesis resulted in 607 mg (61%) crude specified in the header of the product as a yellow oil.

1H NMR (200 MHz, CDCl3) δ 0,83 is 0.99 (m, 6H), 1,54-to 1.67 (m, 4H), 1,99 and 2.13 (m, 4H), 2,27-of 2.38 (m, 1H), 2,63-2,82 (m, 8H), of 4.44 (DD, J=11.8 Hz, 5.7 Hz, 2H), to 4.62(DD, J=11,9 Hz to 4.1 Hz, 2H), 5,20-of 5.45 (m, 11H).

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

A solution of 1,3-di(triptorelin)-2-((Z)-2-ethyl-5,8,11,14,17-eicosapentaenoic)-sn-glycerol (607 mg, of 1.02 mmol) in a mixture of pentane/CH2Cl2(2:1, 10 ml) was cooled to -20°C in an atmosphere of N2. A solution of pyridine (0,83 ml of 10.3 mmol) and MeOH (of 0.62 ml of 15.3 mmol) in a mixture of pentane/CH2Cl2(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 vacuum. Flash chromatography on silica gel, elwira a mixture of heptane - heptane:EtOAC 1:1 received 352 mg (86%) indicated in the title product as a slightly yellow oil.

1H NMR (200 MHz, CDCl3) δ 0,86 is 0.99 (m, 6H), 1,43-of 1.81 (m, 4H); 1,94 (users, 2H), 2,02 and 2.13 (m, 4H), 2,29 is 2.43 (m, 1H), 2,79-and 2.83 (m, 8H), 3,81 (d, J=4.8 Hz, 4H), 4,89-to 4.98 (m, 1H), 5,22-5,43 (m, 10H).

MS (elektrorazpredelenie): 427 [M+Na]+

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

(all-Z)-2-Ethyl-5,8,11,14,17-eicosa antenova acid (501 mg, of 1.52 mmol), DMAP (185 mg, of 1.52 mmol), hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (295 mg, 1.54 mmol) and dry CH2Cl2(5 ml) was added to a solution of glycerine (of 31.6 mg, 0,343 mmol) in DMF (2 ml). The resulting mixture was stirred for 17½ hours in an atmosphere of N2at room temperature. Diethyl ether (50 ml) was added, and the resulting mixture was washed with 1M HCl (20 ml) and saturated salt solution (20 ml), dried (Na2SO4) and was evaporated in vacuum. Repeated flash chromatography on silica gel with elution with a mixture of heptane - heptane:EtOAc(100:1)-(95:5) received 206 mg (58%) indicated in the title product as a colourless oil.

1H NMR (200 MHz, CDCl3) δ 0,83 is 0.99 (m, 18H), 1,43-to 1.77 (m, 12H), 1,98 and 2.13 (m, 12H), 2,23-is 2.37 (m, 3H), 2.77-to 2,85 (m, 24H), Android 4.04-4,18 (m, 2H), 4,28 was 4.42 (m, 2H), 5,23-5,49 (m, 31H).

MS (elektrorazpredelenie): 1051 [M+Na]+.

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

The case when R1and R2are the reverse is also included. ∗ the case where X represents a carboxylic acid or its derivative, carboxylate, carboxylic acid anhydride or carboxamide.

The case when R1and R2are the reverse is also included; ∗ the case where X represents a carboxylic acid or its derivative, carboxy is at, the carboxylic acid anhydride or carboxamide; ∗∗ the case where X represents a carboxylic acid anhydride, carboxamide, mono-, di - or triglyceride or a phospholipid.

The case when R1and R2are the reverse is also included. ∗ the case where X represents a carboxylic acid or its derivative, carboxylate, carboxylic acid anhydride or carboxamide.

The invention should not be limited presents variants of carrying out the invention and examples.

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

where
- R1and R2are the same or different and may be selected from the group of substituents consisting of a hydrogen atom, hydroxy-group, C1-C7alkyl group, halogen atom, With1-C7alkoxygroup,1-C7allylthiourea,1-C7alkoxycarbonyl group, carboxypropyl, amino and1-C7alkylamino;
- X represents a carboxylic acid or a carboxylate selected from ethylcarboxylate, methylcarbamate, n-propellerblade, isopropylcarbonate, n-butylcarbamoyl, sec-butylcarbamoyl or n-lexiscanlexiscan carboxylic acid in the form of triglycerides, diglycerides, 1-monoglyceride or 2-monoglyceride, or the carb is camid, selected from primary carboxamide, N-methylcarbamyl, N,N-dimethylcarbamate, N-ethylcarbodiimide or N,N-diethylbenzamide; and
- Y is C16-C22the alkene with two or more double bonds,
with E and/or Z-configuration
or any pharmaceutically acceptable salt,
provided that:
- R1and R2are 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)-docosa-4,7,10,13,16,19-hexaenoic acid in the form of carboxylic acid, carboxylate, diglyceride, triglyceride, or carboxamide;
- (5Z,8Z,11Z,14Z,17Z)-2-metrakos-5,8,11,14,17-pentaenoic acid, ethyl ester or 4-(tert-butyl)phenyl ether;
- (5Z,8Z,11Z,14Z,17Z)-2-etilicos-5,8,11,14,17-pentaenoic acid ethyl ester or its methicillin ether;
- (5Z,8Z,11Z,14Z,17Z)-2,2-dimethylacetal-5,8,11,14,17-pentaenoic acid, ethyl ester or 4-(tert-butyl)phenyl ether;
- (5Z,8Z,11Z,14Z,17Z)-Meisel 2,2-diethylacetal-5,8,11,14,17-pentaenoic;
- (5Z,8Z,11Z,14Z,17Z)-2-Basilicata-5,8,11,14,17-pentaenoic acid or its ethyl ester;
- (9Z,12Z,15Z)-2-hydroxyacetate-9,12,15-Teenboy acid, its methyl ester or its ethyl ester;
- diethyl-2-((3Z,6Z,9Z,12Z,15Z)-octadeca-3,6,9,12,15-pentaen-1-yl)malonate;
- diethyl-2-((5Z,9Z,12Z)-octadeca-5,9,12-trien-1-yl)malonate;
- diethyl-2-((6Z,9Z,12Z,15Z)-octadeca-6,,12,15-tetraen-1-yl)malonate;
- diethyl-2-((5Z,8Z,11Z,14Z)-eicosa-5,8,11,14-tetraen-1-yl)malonate;
- diethyl-2-((5Z,8Z,11Z,14Z,15Z)-eicosa-5,8,11,14,15-pentaen-1-yl)malonate;
- ethyl (4Z,7Z,10Z,13Z,16Z,19Z)-2,2-diethylacetal-4,7,10,13,16,19-hexaenoic.

2. The compound according to claim 1, where Y is a C16-C20the alkene from 2 to 6 double bonds, for example 2-6 double bonds, interrupted methylene group in the Z-configuration.

3. The compound according to claim 1, where Y is a C16-C20the alkene with 3 to 5 double bonds, for example, 3-5 double bonds, interrupted methylene group in the Z-configuration.

4. The compound according to claim 1, where Y is a C20the alkene with 5 double bonds in Z-configuration, for example, 5 double bonds, interrupted methylene group in the Z-configuration.

5. The compound according to claim 1, where Y is C16the alkene with 3 double bonds in Z-configuration, for example, 3 double bonds, interrupted 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=C16alkene with 3 double bonds in Z-configuration at positions 9, 12 and 15;
Category b - (all-Z)-7,10,13,16,19-docosapentaenoic acid (kopandanova acid, DPA)

Y=C20alkene with 5 double bonds in Z-configuration at positions 7, 10, 13, 16 and 19;
ategory With - (all-Z)-11,14,17-eicosatrienoic acid

Y=C18alkene with 3 double bonds in Z-configuration at positions 11, 14 and 17;
Category D - (4E,8Z,11Z,14Z,17Z)-eicosapentaenoic acid

Y=C18alkene with 5 double bonds in positions 4, 8, 11, 14 and 17, where the double bond at position 8, 11, 14 and 17 are in 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=C18alkene with 5 double bonds in Z-configuration at positions 5, 8, 11, 14 and 17;
Category F - (4E,7Z,10Z,13Z,16Z,19Z)-docosahexaenoic acid (TRANS-DHA)

Y=C20alkene with 6 double bonds in positions 4, 7, 10, 13, 16 and 19, where the double bond 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 salt

where X is COO-,
Z is chosen from the group consisting of Li+, Na+, K+, NH4+,

Meglumine,

Tris(hydroxymethyl)aminomethane,

Diethylamine, and

Arginine; or

where X=COO ,
Z2+selected from the group consisting of Mg2+Ca2+,

Ethylenediamine, and

Piperazine; or

where X is soo-,
Zn+is

Chitosan.

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

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

(all-Z)-2-ethyl-7,10,13,16,19-docosapentaenoic acid Tris(hydroxymethyl)aminometanului 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, where the specified derivative of carboxylic acid is a tri-, di - or monoglyceride.

10. The connection according to claim 9, where X is a carboxylic acid in the form of a triglyceride represented by the formula (V):

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

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

11. Omega-3 lipid compound selected is from the group consisting of:
- (all-Z)-6,9,12,15-octadecatetraenoic acid
- (all-Z)-6,9,12,15,18,21-tetracosapentaenoic acid
- (all-Z)-8,11,14,17-eicosatetraenoic acid
in the form of a carboxylic acid or carboxylate selected from ethylcarboxylate, methylcarbamate, n-propellerblade, isopropylcarbonate, n-butylcarbamoyl, sec-butylcarbamoyl or n-lexiscanlexiscan, carboxylic acid in the form of triglycerides, diglycerides, 1-monoglyceride or 2-monoglyceride, or a carboxamide selected from the primary carboxamide, N-methylcarbamyl, N,N-dimethylcarbamate, N-ethylcarbodiimide or N,N-diethylbenzamide;
or any pharmaceutically acceptable salt;
where the above compound substituted at carbon 2, counted from the functional group of the omega-3 lipid compound, at least one Deputy, selected from the group consisting of:
hydrogen atom, hydroxy-group, C1-C7alkyl group, halogen atom, a C1-C7alkoxygroup,1-C7allylthiourea, C1-C7alkoxycarbonyl group, carboxypropyl, amino, and C1-C7alkylamino;
provided that the omega-3 lipid compound is not:
is replaced by two atoms of hydrogen
- (all-Z)-2-carboxy-6,9,12,15,18,21-tetracosapentaenoic acid
- ethyl (all-Z)-2-etoxycarbonyl-6,9,12,1518,21-tetracosapentaenoic
- diethyl-2-((6Z,9Z,12Z,15Z)-octadeca-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 carboxylate selected from ethylcarboxylate, methylcarbamate, n-propellerblade, isopropylcarbonate, n-butylcarbamoyl, sec-butylcarbamoyl or n-lexiscanlexiscan, carboxylic acid in the form of triglycerides, diglycerides, 1-monoglyceride or 2-monoglyceride, or a carboxamide selected from the primary carboxamide, N-methylcarbamyl, N,N-dimethylcarbamate, N-ethylcarbodiimide or N,N-diethylcarbamyl represented by X, or its pharmaceutically acceptable salt, where R1and R2are the same or different and may be selected from the group of substituents consisting of a hydrogen atom, a C3-C7alkyl group, a C1-C7alkoxygroup, C1-C7allylthiourea, C1-C7alkoxycarbonyl group, carboxypropyl, amino, and C1-C7alkylamino,
provided that R1and R2are not simultaneously a hydrogen atom; and the lipid compound is diethyl 2-((3Z,6Z,9Z,12Z,15Z)-octadeca-3,6,9,12,15-pentaen-1-yl)malonate.

13. The connection section 12, where R1and R2the choice is up from the group, consisting of a hydrogen atom, a C3-C7alkyl groups, for example, propyl, C1-C7alkoxygroup, for example, methoxy, ethoxy or propoxy, C1-C7allylthiourea, for example, methylthio, ethylthio or propylthio, amino, C1-C7alkylamino, for example, ethylamino or diethylamino, C1-C7alkoxycarbonyl group and carboxypropyl.

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 carboxylate selected from ethylcarboxylate, methylcarbamate, n-propellerblade, isopropylcarbonate, n-butylcarbamoyl, sec-butylcarbamoyl or n-lexiscanlexiscan, carboxylic acid in the form of triglycerides, diglycerides, 1-monoglyceride or 2-monoglyceride, or a carboxamide selected from the primary carboxamide, N-methylcarbamyl, N,N-dimethylcarbamate, N-ethylcarbodiimide or N,N-diethylcarbamyl represented by X,
or its pharmaceutically acceptable salt,
where the above compound substituted at carbon 2, counted from the functional group of the omega-3 lipid compounds, the two substituents represented by R1and R2selected from C1-C7alkyl group,
if th the above compound is 2,2-dimethyl-5,8,11,14,17-eicosapentaenoic acid, ethyl ester or 4-(tert-butyl)phenyl ether; or (all-Z)-mesityl 2,2-diethyl-5,8,11,14,17-eicosapentaenoate.

15. The connection 14, where R1and R2selected from the group consisting of C1-C7alkyl groups, e.g. methyl, ethyl or propyl.

16. Omega-3 lipid compound according to any one of § § 11 and 15, where the specified derivative of carboxylic acid is a tri-, di - or monoglyceride.

17. Omega-3 lipid compound, which is a three - or a monoglyceride
(all-Z)-5,8,11,14,17-eicosapentaenoic acid (EPA), represented by formula (VIII)

where three or monoglyceride represented by X,
or any pharmaceutically acceptable salt,
where R1and R2are the same or different and may be selected from the group consisting of a hydrogen atom, a C1-C7alkyl group, provided that
- R1and R2are not simultaneously a hydrogen atom.

18. The connection 17, where R1and R2selected from the group consisting of a hydrogen atom, a C1-C7alkyl groups, e.g. methyl, ethyl or propyl.

19. The connection 17, where the specified connection selected from 1,2,3-Tris((all-Z)-2-ethyl-5,8,11,14,17-eicosapentaenoic)-sn-glycerol

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

20. The compound according to any one of claims 1, 11, 12, or 14, where the specified carboxylate group selected from the group consisting of ethylcarboxylate, methylcarbamate, n-propellerblade, isopropylcarbonate, n-butylcarbamoyl, sec-butylcarbamoyl and n-lexiscanlexiscan.

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, where the specified alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and n-hexyl.

23. The connection section 12, where the specified alkyl group 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, where the specified halogen atom is fluorine.

25. The compound according to any one of claims 1, 11 or 12, where the above alkoxygroup selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, sec-butoxy, OCH2CF3and co2CH2Och3.

26. The compound according to any one of claims 1, 11 or 12, where the specified allylthiourea selected from the group consisting of methylthio, ethylthio, isopropylthio.

27. The compound according to any one of claims 1, 11, 12, or 14, where the above carboxamido group selected from the group consisting of primary carboxamide, N-methylcarbamyl, N,N-dimethyl who carboxamide, N-ethylcarbodiimide and N,N-dimethylcarbamate.

28. The compound according to claim 1, where Y is C16the alkene with 3 double bonds, interrupted methylene group in Z configuration, one of the groups R1and R2is methyl, ethyl or propyl, and the other is a hydrogen atom.

29. The compound according to claim 1, where Y is C16the alkene with 3 double bonds, interrupted methylene group in Z configuration, one of the groups R1and R2is methoxy, ethoxy or propoxy, and the other is a hydrogen atom.

30. The compound according to claim 1, where Y is C16the alkene with 3 double bonds, interrupted methylene group in Z configuration, one of the groups R1and R2is thiomethyl, thioethyl or thiopropyl, and the other is a hydrogen atom.

31. The compound according to claim 1, where Y is C16the alkene with 3 double bonds, interrupted methylene group in Z configuration, one of the groups R1and R2is ethylamino, diethylamino, and the other is a hydrogen atom.

32. The compound according to claim 1, where Y is C16the alkene with 3 double bonds, interrupted methylene group in Z configuration, one of the groups R1and R2is amino and the other is a hydrogen atom.

33. The compound according to any one of p-32, where 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 C20the alkene with 5 double bonds, interrupted methylene group in Z configuration, one of the groups R1and R2is methyl, ethyl or propyl, and the other is a hydrogen atom.

35. The compound according to claim 1, where Y is a C20the alkene with 5 double bonds, interrupted methylene group in Z configuration, one of the groups R1and R2is methoxy, ethoxy or propoxy, and the other is a hydrogen atom.

36. The compound according to claim 1, where Y is C20the alkene with 5 double bonds, interrupted methylene group in Z configuration, one of the groups R1and R2is thiomethyl, thioethyl or thiopropyl, and the other is a hydrogen atom.

37. The compound according to any one of p-36, where double bonds are located at positions 7, 10, 13, 16 and 19 of the said omega-3 lipid compounds.

38. The compound according to claim 1, where X is ethylcarboxylate.

39. The compound according to claim 1, 12, 14, 17, where R1and R2are different.

40. Connection § 39 in racemic form.

41. Connection p in the form of the R-stereoisomer.

42. Connection p in the form of 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 increased functions, at least one of the isoforms of the receptor (PPAR) human activated proliferation what eroxia.

44. Connection p.43, where the above-activated proliferation peroxisome receptor (PPAR) is a receptor (PPAR) a and/or activated proliferation peroxisome.

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 condition of diabetes, such as type 2 diabetes, elevated levels of triglycerides and/or levels of non-HDL cholesterol, LDL cholesterol and VLDL cholesterol, gipolipidemicheskoe state, for example, hypertriglyceridemia (HTG), obesity or condition of overweight, disease fatty infiltration of the liver, for example, non-alcoholic fatty infiltration of the liver (NAFLD) or inflammatory disease or condition.

46. The compound according to any one of claims 1 to 42 for use in reducing levels of insulin in the blood plasma, blood glucose and/or serum triglycerides for use in the increased levels of serum HDL in humans or for use in reducing body weight and/or to prevent gaining the body weight.

47. The compound according to any one of claims 1 to 42 for use as PPAR-activating or modulating drugs.

48. Pharmaceutical composition for the activation or modulation of at least one of the isoforms of the receptor human activated proliferation peroxisome (PPAR)containing effective the number of compounds 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 p prepared for oral administration, for example, in the form of a capsule, packet, sachet or solid dosage forms.

50. The pharmaceutical composition according p, is designed to provide 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 p-49 for use as PPAR-activating or modulating drugs.

52. Dietary lipid composition comprising an effective amount of omega-3 lipid compound according to any one of claims 1 to 42.

53. Dietary lipid composition according to paragraph 52, where at least 60%, such as at least 80 wt.% lipid composition is specified connection.

54. Dietary lipid composition according to any one of p-53, also contains fatty acids selected from (all-Z)-5,8,11,14,17-eicosapentaenoic acid (EPA)and (all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), (all-Z)-6,9,12,15,18-heneicosanol acid (NDA) and/or (all-Z)-7,10,13,16,19-docosapentaenoic acid (DPA).

55. Dietary lipid composition according to item 54, where these fatty acids are present in the form of alpha-substituted forms.

56. Dietary lipid composition according to paragraph 52, also containing a pharmaceutically acceptable antioxidant, for example the EP, tocopherol.

57. The use of compounds according to any one of claims 1 to 42 for receiving medicines for activation or modulation of at least one of the isoforms of the receptor human activated proliferation peroxisome (PPAR).

58. The application of § 57, where the above-activated proliferation peroxisome receptor (PPAR) is a receptor (PPAR) α and/or γ-activated proliferation peroxisome.

59. The use of compounds according to any one of claims 1 to 42 for obtaining a medicinal product for the treatment and/or prevention of peripheral insulin resistance and/or condition of diabetes, such as type 2 diabetes, elevated levels of triglycerides and/or levels of non-HDL cholesterol (non-HDL), LDL-cholesterol (LDL cholesterol) and VLDL-cholesterol (VLDL), gipolipidemicheskoe state, for example, hypertriglyceridemia (HTG), obesity or condition of overweight, disease fatty infiltration of the liver, for example, non-alcoholic fatty infiltration of the liver (NAFLD) or inflammatory disease or condition.

60. The use of compounds according to any one of claims 1 to 42 for receiving drugs to reduce insulin levels in plasma, blood glucose and/or triglycerides in the serum, and to increase HDL levels in human serum or body weight reduction and/or prevention of overweight.



 

Same patents:

FIELD: food industry.

SUBSTANCE: this invention relates to a crystalline maltitol powder composition; its specificity consist in the fact that the average particle size across the bulk (according to laser diffraction results) is equal to 10 - 150 mcm; the content of maltitol in the composition is 80 - 99.9 wt %; at least 50 wt % of the particles pass through a sieve having retention threshold equal to 2000 mcm according to A1 test; at least 35 wt % of the particles pass through a sieve having retention threshold equal to 2000 mcm according to A2 test; the composition includes 0.1 - 20 wt % of at least one water-insoluble anti-clogging agent; the said anti-clogging agent has hydroscopic property (determined according to Test B) equal to 2.5 - 25%; the said anti-clogging agent is selected from the group including pyretogenous silicon dioxide, sodium aluminosilicate, anhydrous tricalcium phosphate and dehydrated potato starch (especially dehydrated potato starch containing less than 12% residual water, preferably containing less than 10% residual water, preferably containing less than 8% residual water, preferably containing less than 6% residual water) and their mixtures.

EFFECT: this composition is not prone to clogging and finds application in the food and pharmaceutical branches.

13 cl, 5 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: method of producing modified alkyl polyglucoside by reacting glucose or water syrup of glucose with a C10-C16 alcohol in the presence of an acid catalyst, which is a strong organic or inorganic acid. Said catalyst is a mixture of alkyl polyalkoxy carboxylic acid and a strong acid in molar ratio of 4:1. The molar ratio glucose:alcohol is equal to 1:1.5; glucose:acid catalyst ranges from 1:0.025 to 1:0.03.

EFFECT: obtaining modified alkyl polyglucoside - a surfactant with improved properties.

1 cl, 5 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of general formula I [X]n-Y-ZR1R2, wherein the radicals are specified in the description, effective as heparan sulphate-binding protein inhibitors. The invention also refers to a pharmaceutical or veterinary composition having heparan sulphate-binding protein inhibitory activity for preventing or treating a disorder in a mammal, and to the use of these compounds and compositions for antiangiogenic, antimetastatic, anti-inflammatory, antimicrobial, anticoagulant and/or antithrombotic therapy in a mammal.

EFFECT: preparing the new compounds of general formula I [X]n-Y-ZR1R2, wherein the radicals are specified in the description, effective as the heparan sulphate binding protein inhibitors.

10 cl, 31 ex, 11 tbl, 40 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new method for the chemical synthesis of asymmetrically or symmetrically substituted β-(1→6)-bound glucosamine disaccharide of formula (1), as well as to a method for purifying it. The invention declared the intermediate compounds referred to the given method.

EFFECT: invention refers to a pharmaceutical composition comprising the mentioned compounds, and to the use of the compounds in treating the disorders affected by immune system activity modulation, including the inhibition or activation of the immune system, such as a disorder selected from immune disorders and/or cancer.

26 cl, 8 ex, 26 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to methods of producing diastereoismerically pure (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol (6), as well as a novel intermediate compound (3aR,4S,6aS)-4-methoxytetrahydrofuro [3,4-b]furan-2-one (4) for use in said methods. More specifically, the invention relates to a stereo-selective method of producing diastereoisomerically pure (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol, as well as methods for crystallisation of (3aR,4S,6aS)-4-methoxytetrahydrofuro[3,4-b]furan-2-one and epimerisation of (3aR,4S,6aS)-4-methoxytetrahydrofuro[3,4-b]furan-2-one to (3aR,4S,6aS)-4- methoxytetrahydrofuro[3,4-b]furan-2-one.

EFFECT: improved method.

25 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to group of compounds of general formula where R1, R2, R3, R4, R5 and R6 independently on each other represent C1-4 alkyl, -SO3H, polysulfated β-glycosyl or polysulfated diglycosyl group, on condition that, at least, one of R1-R6 represents polysulfated β-glycosyl or polysulfated diglycosyl group, or their pharmaceutically acceptable salts, where glycosyl group contains pentopyranose or hexopyranose molecule with configuration of choice, and diglycosyl group contains pentopyranose or hexopyranose molecule with configuration of choice, one hydroxyl group of which is glycosylated by other pentopyranose or hexopyranose molecule with configuration of choice. Invention also relates to pharmaceutical composition to be used in treatment of acute or chronic inflammatory diseases of respiratory ways in mammals on the basis of said compounds or their pharmaceutically acceptable salts.

EFFECT: application of said compounds or their pharmaceutically acceptable salts for obtaining medication for treatment of acute or chronic inflammatory diseases of respiratory ways in mammals.

37 cl, 4 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to oligosaccharide, suitable for vaccine against meningitis A, which includes first mannose unit, which has spacer in alfa-configuration in C-1, where said spacer is able to conjugate with protein, and bound to second mannose unit by 1,6-bond, which binds C-6 of first unit with C-1 of second unit, 1,6-bond including phosphonate. Invention also relates to methods of obtaining oligosaccharide and improved methods of obtaining mannose derivative, suitable for obtaining immunogenic oligosaccharide. Invention also relates to pharmaceutical composition for induction of immune response, immunogenic composition, capable of inducing formation of protective antibodies against meningitis A and vaccine against meningitis A, which include oligosaccharide.

EFFECT: obtained glycoconjugates have C-phosphonate bond, which is much more stable than natural phosphodiester bonds, as well as higher immunologic activity.

51 cl, 4 dwg, 3 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to carbohydrate-containing polycationic amphiphiles (1-3) which are trihydrochlorides of rac-N-[6-(β-D-glycopyranosyloxy)hexyl]-N-[2,3-di(tetradecyloxy)prop-1-yl]-4-[(12-amino-4,9-diazadodec-1-yl)amino-succinylamino]benzenesulfonamide of the given general formula , where A is a 1,2-di-O-tetradecyl-rac-glycerin residue, B is a galactose residue (for (1)), galactose (for (2)) and mannose (for (3)), C is a spermine residue, n= 6, m = 2.

EFFECT: obtaining compounds which are capable of delivering nucleic acid into mammal cells.

1 cl, 4 tbl, 2 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: in method of obtaining compound aminoalkyl glucosaminide 4-phosphate of formula , X represents , Y represents -O- or NH-; R1, R2 and R3, each is independently selected from hydrogen and saturated and unsaturated (C2-C24) aliphatic acyl groups; R8 represents -H or -PO3R11R11a, where R11a and R11a, each is independently -H or (C1-C4) aliphatic groups; R9 represents -H, -CH3 or -PO3R13aR14, where R13a and R14, each is independently selected from -H and (C1-C4) aliphatic groups, and where indices n, m, p, q each independently is a integer from 0 to 6 and r is independently integer from 2 to 10; R4 and R5 are independently selected from H and methyl; R6 and R7 are independently selected from H, OH, (C1-C4) oxyaliphatic groups -PO3H2, -OPO3H2, -SO3H, -OSO3H, -NR15R16, -SR15, -CN, -NO2, -CHO, -CO2R15, -CONR15R16, -PO3R15R16, -OPO3R15R16, -SO3R15 and -OSO3R15, where R15 and R16, each is independently selected from H and (C1-C4) aliphatic groups, where aliphatic groups are optionally substituted with aryl; and Z represents -O- or -S-; on condition that one of R8 and R9 represents phosphorus-containing group, but R8 and R9 cannot be simultaneously phosphorus-containing group, including: (a) selective 6-O- silylation of derivative of 2-amino-2-desoxy-β-D-glucopyranose of formula , where X represents O or S; and PG independently represent protecting group, which forms ester, ether or carbonate with oxygen atom of hydroxy group or which forms amide or carbamate with amino group nitrogen atom, respectively; by means of tri-substituted chlorosilane RaRbRcSi-Cl, where Ra, Rb and Rc are independently selected from group, consisting of C1-C6alkyl C3-C6cycloalkyl and optionally substituted phenyl, in presence of tertiary amin, which gives 6-silylated derivative; (b) selective acylation of 4-OH position of obtained 6-O-silylated derivative with 6-3-alkanoyloxyalcanoic acid or hydroxyl-protected (R)-3-hydroxyalkanoic acid presence of a carbodiimide reagent and catalytic 4-dimethylaminopyridine or 4-pyrrolidinopyridine to give a 4-O-acylated derivative; (c) selectively deprotecting the nitrogen protecting groups, sequentially or simultaneously and N,N-diacylating the resulting diamine with (R)-3-alkanoyloxyalkanoic acid or a hydroxy-protected (R)-3-hydroxyalkanoic acid in presence of peptide condensation reagent; (d) introducing a protecting phosphate group at 3-position with a chlorophosphate or phosphoramidite reagent to give a phosphotriester; and (e) simultaneous or sequential deprotecting phosphate, silyl, and remaining protecting groups.

EFFECT: method improvement.

11 cl, 3 ex

The invention relates to an improved process for the preparation of agglomerates and molded products containing isomaltulose and/or gidrirovannoe isomaltulose

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (3) which can be used in the method for synthesis of precursors to immunological adjuvant E6020. In formula (3), R1, R2, R3 denote a C5-C15 alkyl group, C5-C15 alkenyl group or C5-C15 alkynyl group. The invention also relates to compounds of formula (4), which can also be used in synthesis of precursors to said adjuvant. In formula (4) R4 is a C1-C6 alkyl group, C3-C5 alkenyl group, C3-C5 alkynyl group, cycloalkyl group, ethyl group substituted in position 2, halogen ethyl group, aryl group, benzyl group or silyl group; R5, R6 independently denote a C1-C6 alkyl group, C3-C6 alkenyl group or C3-C6 alkynyl group; or R5 and R6 together a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring.

EFFECT: invention also relates to methods for synthesis of compounds of formulae (3) and (4) and crystalline forms of specific representations thereof.

34 cl, 8 dwg, 2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an amine compound of formula (I), pharmaceutically acceptable addition salts, hydrates or solvates thereof, having immunodepressive effect , where R - H or P(=O)(OH)2; X - O or S; Y denotes -CH2CH2- or -CH=CH-; Z denotes C1-5-alkylene, C2-5-alkenylene or C2-5-alkynylene; R1 denotes CF3, R2 denotes C1-4-alkyl, substituted with OH or halogen; R3 and R4 independently denotes H < or C1-4-alkyl; A denotes optionally substituted C6-10-aryl, heteroaryl containing 5-10 ring atoms, where 1 or 2 atoms are selected from N, O and S, C3-7-cycloalkyl optionally condensed with optionally substituted benzene, or heterocycloalkyl containing 5-7 ring atoms, where 1 or 2 atoms are selected from N and O, where said substitutes are selected from C1-4-alkylthio, C1-4-alkylsulphanyl, C1-4-alkylsulphonyl, C2-5-alkylcarbonyl, halogen, cyano, nitro, C3-7-cycloalkyl, C6-10-aryl, C7-14-aralkyloxy, C6-10-aryloxy, optionally substituted with oxo or halogen, C2-3-alkyleneoxy, C3-4-alkylene or C1-2-alkylenedioxy, optionally substituted with halogen C1-4-alkyl or C1-4-alkoxy.

EFFECT: novel compound which is effective in reducing the level of lymphocytes in peripheral blood, suppresses tissue breakdown and exhibiting less side effects, such as bradycardia, is disclosed.

20 cl, 237 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing phosphorus- and chlorine-containing methacrylates of general formula: ,

where R = lower alkyl, chloroalkyl, alkoxyl, phenoxyl or a group -

R1 = lower alkoxyl, phenoxyl or a group

,

which can be used to produce polymer materials, including uncoloured, optically transparent materials, as well as low-inflammability composite materials. The method involves reaction of acid chlorides of pentavalent phosphorus with glycidyl ether of methacrylic acid in the presence of a quaternary ammonium salt as a catalyst, as well as a polymerisation inhibitor when adding the glycidyl ether of methacrylic acid to the mixture of acid chloride of pentavalent phosphorus with the catalyst and polymerisation inhibitor and raising temperature from 40°C to 75°C, and then heating the reaction mass to 70÷80°C.

EFFECT: method enables stabilisation of the temperature conditions of the process and avoiding formation of polymer in the reaction mass.

2 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a biocidal composition containing hydrogen peroxide in concentration of 0.05-50% (wt/wt) and a compound of formula 1: (OH)(2-m)(X)(O)P-[(O)p-(R')q-(CH(Y)-CH2-O)n-R]m, where X is H or OH; each Y is independently H or CH3; m equals 1 and/or 2; each p and q is independently equal to 0 or 1, provided that if p equals 0, q equals 1; each n is independently equal to 2-10; each R' is independently an alkylene radical containing 1-18 carbon atoms; each R is independently H or an alkyl radical containing 1-18 carbon atoms; and R'+R≤20; in concentration of 0.01-60% (wt/wt), as a biocidal composition. The invention also relates to use of the disclosed composition as a biocidal composition, as well as for purposes where there is need for disinfection and/or sanitation activity.

EFFECT: composition has excellent biocidal activity.

25 cl, 9 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound, represented by the following formula (I), where R represents hydrogen atom or P(=O)(OH)2, X represents oxygen atom or sulphur atom, Y represents CH2CH2 or CH=CH, R1 represents trifluoromethyl, difluoromethyl or cyano, R2 represents alkyl, which has 1-4 carbon atoms, and optionally substituted with hydroxyl group (groups) or halogen atom (atoms), R3 and R4 can be similar or different, and each represents hydrogen atom or alkyl, which has 1-4 carbon atoms, and n=5-8, or its pharmaceutically acceptable acid-additive salt. Invention also relates to 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propan-1,3-diol or its hydrochloride and pharmaceutical composition, containing said compounds.

EFFECT: elaboration of pharmaceutical composition, applied for treatment or prevention of autoimmune diseases, prevention or suppression of resistance or acute rejection or chronic rejection of organ or tissue transplant; treatment or prevention of graft-versus-host disease (GvH) resulting from transplantation of bone marrow; or treatment or prevention of allergic diseases.

16 cl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to aminophosphate derivatives of general formula (1a), pharmaceutically acceptable salts or hydrates thereof, which can be used in medicine as S1P (sphingosine-1-phosphate) receptor modulators,

where R3 is a straight alkyl group containing 1-3 carbon atoms; X is an oxygen or sulphur atom and n equals 2 or 3.

EFFECT: obtaining novel biologically active compounds with high S1P receptor modulating action.

9 cl, 59 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing di-(2-ethylhexyl) phosphoric acid, which is used in extraction processes, ion exchangers, and neodymium salt thereof, which is used during catalysis. Disclosed is a method of producing di-(2-ethylhexyl) phosphoric acid and a solution of its neodymium salt in an aliphatic or acyclic solvent by reacting phosphorus trichloride with 2-ethylhexanol, followed by chlorination of the formed di-(2-ethylhexyl)phosphate and hydrolysis of di-(2-ethylhexyl) chlorophospate, wherein in order to obtain di-(2-ethylhexyl) phosphoric acid and its high-purity neodymium salt, hydrolysis is carried out through successive treatment of chlorophophate with jet steam at temperature 95-100°C and then with 20% aqueous solution of sodium hydroxide at temperature 105 -115°C, followed by treatment with hydrochloric acid in an organic solvent to obtain di-(2-ethylhexyl) phosphoric acid or with aqueous solution of neodymium chloride to obtain a solution of neodymium tris-[di-(2-ethylhexyl)] phosphate.

EFFECT: novel method of producing a high-purity compound and its neodymium salt.

9 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a phosphoric acid ester and its salt of formula I, which can be used as wetting substances or dispersants where fragment A is a derivative of groups C1-C20-alkyl (AO)x-OH, acyl(AO)x-OH, C1-C20alkyl-(AO)x-(GK)y-OH, acyl(AO)x-(GK)y-OH, C1-C20alkyl-(AO)x-(DK-AO)y-OH, acyl(AO)x-(DK-AO)y-OH, MS-(GK)y-OH OR MS-(DK-AO)y-OH; where acyl is a residue of lauric, myristic, stearic, arachic, oleinic or linolic acid; AO denotes a polyC2-C3alkylene glycol residue, GK denotes a ε-caprolactone or δ- valerolactone residue; DK denotes a residue of succinic, maleic, glutaric, adipinic, phthalic, sebacic, oxalic, diglycolic acid and anhydrides of these acids; MS denotes a residue of n-butanol, 2-ethyl-1-hexanol, acetyl alcohol, oleyl alcohol, linoleyl alcohol, oxo alcohols, cyclohexanol, phenol, phenylethanol or benzyl alcohol; x and y are numbers between 2 and 50, B denotes a malic or citric acid residue; n denotes a number from 1 to 2; m denotes a number from 1 to 4.

EFFECT: obtaining novel effective wetting substances and dispersants.

2 cl, 19 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to monolysine salts of azole derivatives of general formula (I), a method of producing said salts and use in treating fungal infections.

, where R and R1 denote hydrogen or (C1-C6)alkyl; and A is a triazole derivative, including a derivative of general formula (i) , where R3 is a halogen-substituted phenyl; R4 is hydrogen or CH3; R5 is hydrogen or together with R4 denotes =CH2; R6 is optionally substituted triazolyl, pyrimidinyl, triazolyl or phenyl.

EFFECT: obtaining novel salts which are effective in treating fungal infections.

33 cl, 16 dwg, 12 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to phosphatised 2-propylheptanol alkoxylates containing 2-4 ethylene oxide links and 1-3 phosphoric acid residues in the form of phosphoric or polyphosphoric acid or acid salt ethers, and to application of phosphatised 2-propylheptanol or phosphatised 2-propylheptanol alkoxylates containing 1-3 phosphoric acid residues, 1-20 ethylene oxide links and 0-3 propylene oxide and/or butylenes oxide links in the form of phosphoric or polyphosphoric acid or acid salt ethers, as hydrotrope for C8-C18 alcohol alkoxylate containing 1-20 ethylene oxide links and 0-3 propylene oxide and/or butylenes oxide links, in alkaline solution, especially in compositions for commercial cleaning of solid surfaces.

EFFECT: obtainment of novel hydrotropes and efficient detergent compositions based on them.

12 cl, 7 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

in which m equals 1; n equals 1 or 2; t equals 0 or 1; and A is phenyl, substituted with 2 alkyl groups containing 1 or 2 carbon atoms.

EFFECT: compounds of the disclosed formula can be used as intermediate compounds for producing compounds used to treat various metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidaemia, bacony liver, cachexia, obesity, atherosclerosis and arteriosclerosis.

17 tbl, 2 dwg, 53 ex

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