Conjugated lipid derivatives. RU patent 2480447.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new lipid compound of general formula , wherein n=0; R₁ and R₂ are identical or different, and may be specified in a group of substitutes consisting of a hydrogen atom, a C₁-C₇alkyl group, a halogen atom and a C₁-C₇alkoxy group; X represents COR₃ or CH₂OR₄, wherein R₃ is specified in a group consisting of hydrogen, hydroxy, C₁-C₇alkoxy and amino; and R₄ is specified in a group consisting of hydrogen, C₁-C₇alkyl or C₁-C₇acyl, Y represents C₉-C₂₁ alkene with one or more double bonds in E- or Z-configurations with the chain Y being unsubstituted and containing a double bond in the ω-3 position; provided R₁ and R₂ cannot simultaneously represent a hydrogen atom.

EFFECT: invention refers to pharmaceutical compositions containing the lipid compounds which are used for treating and/or preventing the conditions related to high NFkB functions, treating and/or preventing an inflammatory disease or a condition, lower plasma insulin and/or blood glucose levels, treating insulin resistance, treating and/or preventing peripheral tissue insulin resistance and/or diabetic condition, eg type 2 diabetes mellitus.

45 cl, 1 tbl, 1 dwg, 31 ex

The technical field to which the invention relates

The present invention relates to new alpha,beta-unsaturated derived fatty acids, unsaturated fatty acids, the ways of obtaining of such compounds, pharmaceutical and lipid compositions containing these compounds, and to applications of these compounds and compositions in medicine.

The level of technology

Dietary polyunsaturated fatty acids (PUFA) influence various physiological processes affecting the normal state of health and chronic diseases, such as regulation of lipid levels in the plasma, cardiovascular and immune function, and insulin action and the development of neurons and visual function. The absorption of PUFA (as a rule, in ester form, for example as part of glycerides or phospholipids) will lead to their distribution on the merits in every cell of the body, affecting the composition and function of membranes, synthesis of eicosanoids, the transmission of cellular signals and regulation of expression of genes. Variations in the distribution of various fatty acids/lipids in different tissues, in addition to the specific cellular lipid metabolism, as well as adjustable fatty acids expression of transcription factors will probably play an important role in determining exactly how cells react to the changes song PUFA (Benatti, P. et al., J. Am. Coll. Nutr. 2004, 23, 281).

PUFA or their metabolites, as shown to modulate gene transcription by interacting with several nuclear receptors. They are activated receptor (PPAR), nuclear receptor hepatocytes (HNF-4), X receptor liver (LXR) and receptor 9-CIS-retinoic acid ( X receptor, RXR). Treatment with PUFA may also regulate many transcription factors in the nucleus, including SREBP, NFκB, c/EBPβ and HIF-1α. These effects are not associated with direct linking fatty acid with a transcription factor, but include mechanisms that affect the nuclear content of transcription factors.

Transcriptional regulation of genes by PUFA has a pronounced effect on the metabolism of cells and tissues and gives reliable explanation involving interactions nutrient-gene in initiating and prevention or relief of diseases such as obesity, diabetes, cardiovascular disorders, immune inflammatory diseases and cancer (Wahle, J. et al., Proceedings of the Nutrition Society, 2003, 349).

Fish oil, enriched V-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as shown to reduce the risk of cardiovascular diseases, in part by lowering the concentration of triglycerides in the blood. This favorable effect occurs in mainly due to the combined effects of inhibition of lipogenesis by reducing the fraction of SPEBP-1 and stimulation of fatty acid oxidation by activation of PPAR-alpha in the liver.

V-3 Polyunsaturated fatty acids in fish oil, reportedly improves the prognosis of several chronic inflammatory disease characterized by the accumulation of leukocytes, and leikotitami tissue damage, including atherosclerosis, IgA nephropathy, inflammatory disease of the stomach, rheumatoid arthritis, psoriasis, and the like (Mishra, A., Arterioscler. Thromb. Vasc. Biol., 2004, 1621).

DHA is the most common V-3 PUFA in most tissues and is found in high amounts in neural membranes, accounting for approximately 30-40% of phospholipids gray matter of the cerebral cortex and the photoreceptor cells in the retina. DHA is accumulated at high levels in the postnatal CNS mammals, showing that DHA is involved in the maturation of CNS. Several different types of reduced levels of DHA in the brain and the retina associated with the weakening of neural and visual functions. Adding DHA can also be useful in the treatment of depression, schizophrenia, ADHD, multiple sclerosis, Alzheimer's disease, degenerative diseases of the retina and disorders (Horrocks and Farooqui, Prostaglandins, Leukotrienes and Essential Fatty acids, 2004, 70, 361). Dietary DHA can also be useful in the treatment of atherosclerosis, inflammation and cancer (Horrocks et al., Pharmacol. Res. 1999, 40: 211; Rose, et al., 1999, 83, 217).

Although V-3 PUFA have many positive biological effects, their therapeutic value is limited, and therapeutic area, where V-3 PUFA are the most promising, is a cardiovascular area, as agent for lowering triglyceride levels. However, in order to cause , higher doses are required, polyunsaturated fatty acids. One reason for this is a degradation of polyunsaturated fatty acids in the liver by oxidation.

Nuclear receptors (NR) are large and very conservative family-activated ligands of transcription factors that regulate a variety of biological processes such as development, metabolism, and reproduction. It is noticed that ligands to these receptors can be used in the treatment of common diseases, such as atherosclerosis, diabetes, obesity and inflammatory diseases. In this capacity, NR become important targets for drugs, and identification of new ligands NR is of great interest. The activity of the multitude nuclear receptors is controlled by linking small lipophilic ligands, which include hormones, metabolites, such as fatty acids, bile acids, and Xeno - and . Nuclear receptors can communicate as monomers, or heterodimers RXR with DNA. There are three types of complexes: unoccupied heterodimers, heterodimers that can only be activated ligands partners, but not the only one ligand RXR, and heterodimers that can be activated with either the ligands RXR, or its receptor partner, and activated synergistically in the presence of both ligands (Aranda and Pascual, Physiological Reviews, 2001, 81, 1269). As a mandatory partner for many of nuclear receptor (including vitamin D receptor (VDR), the receptor for thyroid hormone (TR), receptor all-TRANS retinoic acid (RAR), activated receptor (PPAR), X receptor liver (LXR) and others) RXR plays the role of chief coordinator of the many ways to nuclear receptors.

Ligands, which regulate partners RXR, can roughly be divided into two subsets. One subset contains with high affinity, highly specific ligands steroids/hormones (VDR and TR) and act as endocrine modulators. Another subset associated with the existing excess lipid ligands with lower affinity (PPAR, LXR), and, apparently, are partly as a lipid biosensors. Genes is regulated RXR, include the genes involved in various cellular processes, including the regulation of cell cycle and differentiation. They also regulate the genes involved in the transfer, biosynthesis and metabolism of lipids (Goldstein, J.T. et al., Arch. Biochem. and Biophys., 2003, 420, 185).

Related ligand RXR is a 9-CIS-retinoic acid, the molecule that is also associated with RAR and them with very similar affinity and efficiency. On the other hand, all-TRANS-retinoic acid, related ligand RAR, no binds to the receptor RXR.

There is evidence that ligands RXR can function as insulin sensitizers and may reduce hyperglycemia, giperinsulinemia and medications known to exacerbate hypertriglyceridemia in mice ob/ob and db/db (Mukherjee et al., Nature, 1997, 386, 407). It is also reported that chronic administration agonists RXR Zucker rats fa/fa reduces food intake and weight gain, lowers the concentration of insulin in the plasma, while maintaining (Liu, et al., Int. J. Obesity., 2000, 997; Ogilvie, K. et al., Endocrinology, 2004, 145, 565).

In 2000 it was reported that DHA isolated from the brain of mice, selectively activates RXR analyses on the basis of cells (Urquiza et al., Science, 2000, 290, 2140, WO 01/73439). In these studies, DHA does not activate the RAR. After that, it was reported that several of unsaturated fatty acids including DHA arachidonic acid and oleic acid can specifically bind and activate LBD (domain binding ligand) RXRα and for this reason act as ligands in vivo this receptor (Lengquist J., et. al. Molecular & Cellular Proteomics 3, 2004, 692). Studies published Fan et al., it is shown that DHA serves as a specific ligand to activate RXRα in relation to the n-6 PUFA in (Carcinogenesis, 2003, 24, 1541).

Although agonists RXR known, and these compounds are investigated on various biological systems, the literature describes the use of the modified PUFA as a potent ligands for RXR.

Transcription factor NF-κB is an induced eukaryotic transcription factor family rel. He is a chief component of the cascade of stress reactions, which regulates activating genes early response involved in the expression of inflammatory cytokines, adhesion molecules, heat shock proteins, , and redox enzymes. Zhao, G. et al. (Biochemical and Biophysical Research. Comm., 2005, 909) suggest that the anti-inflammatory impact of PUFA in the cells of the human monocytes THP-1 partially mediated through inhibition of activation of NF-κB through activation of PPAR-g. Others suggest that anti-inflammatory effects PUFA mediated through the dependent PPAR-alpha inhibition of activation of NF-κB.

Receptor-selective ligands are of high priority when searching for intermediates for medicines on the basis of NR, because the native ligands NR give systemic side effects and toxicity due to lack of binding specificity.

9-CIS-retinoic acid regulates a variety of biological functions through a mechanism that involves linking as RXR, and RAR. These receptors are involved in a variety of different functions. Their far-reaching biological impacts motivate the search for a RAR or RXR-selective ligands. Non-selective retinoid ligands when used as medicines have side effects, such as teratogenicity and toxicity skin and mucous membranes, which are significantly reduced when used specific to RXR agonists. In addition, it is shown that under the action of RXR-selective agonists may be apoptosis. Selective agonists RXR can offer an alternative approach for the treatment of metabolic disorders. Thus, there is a need for easily accessible RXR-selective ligands that can provide the above benefits without side effects selective ligands.

As many nuclear receptors are distributed differently in different tissues, and is an important receiving ligands which are capable of in vivo target these cells to bind and activate the target receptor.

The essence of the invention

One of the purposes of the present invention is to create a lipid compounds with pharmaceutical activity.

This goal is achieved by lipid compounds in accordance with the formula (I):

where

- R 1 and R 2 are similar or different, and can be selected from a group of deputies, consisting of a hydrogen atom, an alkyl group, halogen atom and alkoxy groups;

- X is a COR 3 or CH 2 OR 4 , where

- R 3 is selected from the group consisting of hydrogen, hydroxy, alkoxy and amino,

- where X additionally includes derivatives of carboxylic acid, when R 3 is a hydroxy; and

- R 4 is selected from the group consisting of hydrogen alkyl or ,

- Y is 9 C-C 21 alkene with one or more double bonds with E -, or Z-configuration;

or any of its pharmaceutically acceptable complex, or prodrugs.

In particular, the present invention relates to a lipid compounds with E-configuration in accordance with the formula (II):

When X is represented by the formula COR 3 and R 3 is a hydroxy, the present invention also relates to derivatives of carboxylic acids. For example, these derivatives of carboxylic acids can be selected from the group consisting of phospholipid or mono-, di - or triglyceride.

In lipid connection according to the present invention R 1 and R 2 in the formula (I) are the same or different and can be selected from a group of deputies, consisting of a hydrogen atom, C 1-C 7 an alkyl group C 1-C 7 alkoxy groups and halogen atom.

Preferably, R 1 and R 2 are similar or different, and are chosen from a group of deputies, consisting of a hydrogen atom, C 1-C 3 an alkyl group C 1-C 3 alkoxy groups and halogen atom. Preferably, R 1 and R 2 are similar or different, and selected from the methyl group, etilnoy group and hydrogen atoms.

When R 1 and/or R 2 are halogen atoms is preferred fluorine atom. In lipid connection according to the present invention X can be represented by the formula COR 3 . In such cases, R 3 can be a C 1-C 7-alkoxy group, or, more specifically, C 1-C 3-alkoxy group. Alternatively, R 3 represents the hydroxy group.

In the alternatives of implementation of the X is represented by the formula CH 2 OR 4 . In such scenarios, the implementation of the R 4 can be a C 1-C 7-alkyl group or, more specifically, C 1-C 3-alkyl group. Alternatively, R 4 is a C 1-C 7 group, in particular C 1-C 3 group.

In lipid connection in accordance with the present invention of double bond between carbon atoms 2 and 3 is preferably in E-configuration.

In variants of the implementation of the present invention, where R 1 and R 2 are different and one of them is a C 1-C 3 alkoxy, and the other is a hydrogen double bond between carbon atoms 2 and 3 may be in the Z-configuration.

As defined in the General formula (I), Y can be a C 9-C 21 alkene with one or more double bonds with E -, or Z-configuration. In particular, Y is a C 14-19 C alkene with 2-6 double bonds. The options for implementing Y is a C 14-19 C alkene with 2-6 double bonds in the Z - configuration, alternating with groups. Alternatively, Y is unaltered. In the preferred options for the implementation of the present invention lipid connection contains one double bond between carbon-carbon bonds in the V-3 position Y.

Lipid compounds according to the present invention can be divided into categories according to the number of conjugated systems represented using the integer n in brackets in the formula (I) or (II). As defined, n may vary between 0 and 2.

When n=0, lipid connection the present invention relates to the formula (III):

In addition, lipid compounds presented by the formula (III) of the present invention, can be divided into subcategories in the preferred form of the following groups:

IIIa: X=COR

3

• X=COR 3 , where R 3 represents the hydroxy group or C 1-C 3 alkoxy group;

• Y is 13 C-C 19 alkene, having 2-6 double bonds.

IIId: X=CH

2

OR

4

, R

1

PD R

2

• X=CH 2 OR 4 , where R 4 is a hydrogen; and

• R 1 and R 2 are different, and one of them represents a hydrogen atom, and the other C 1-C 2 alkyl group or C 1-C 2 alkoxy group;

• Y is a C 17-19 alkene, having 3-5 double bonds.

The preferred compounds of formula (III) and subgroups IIIc and IIId represent the following lipid compounds 5, 9 and 27:

When n=1, lipid connection according to the present invention refers to the formula (IV):

In addition, lipid compounds presented by the formula (IV) of the present invention, can be divided into subcategories in the preferred form of the following groups:

IVa: X=COR

3

• X=COR 3 , where R 3 represents the hydroxy group or C 1-C 3 alkoxy group;

• R 1 and R 2 are similar or different, and selected from the hydrogen atom, C 1-C 3 an alkyl group and halogen atom; and

• Y is a C 11-C 17 alkene, having 2-6 double bonds.

IVb: X=COR

3

, R

1

PD R

2

• X=COR 3 , where R 3 represents the hydroxy group or C 1-C 2 alkoxy group; and

• R 1 and R 2 are different, and one of them represents a hydrogen atom, and the other C 1-C 2 alkyl group;

• Y is a C 15 C 17 alkene, having 3-5 double bonds.

The preferred compounds of formula (IV) and sub-groups IVa and IVb represent the following lipid compounds 10-11, 17-18, 20, and 22.

IVc: X=COR

3

, R

1

=R

2

• X=COR 3 , where R 3 represents the hydroxy group or C 1-C 2 alkoxy group;

• R 1 and R 2 are hydrogen; and

• Y is a C 11-C 17 alkene, having 2-6 double bonds.

IVd: X=COR

3

, R

1

=R

2

• X=COR 3 , where R 3 represents the hydroxy group or C 1-C 2 alkoxy group;

• R 1 and R 2 are hydrogen; and

• Y is a C 15 C 17 alkene, having 4-5 double bonds.

The preferred compounds of formula (IV) and subgroups IVc and IVd are the following lipid compounds 12-15:

IVe: X=CH

2

OR

4

• X=CH 2 OR 4 , where R 4 represents hydrogen atom or C 1-C 3 group;

• R 1 and R 2 are similar or different, and selected from the hydrogen atom, C 1-C 3 an alkyl group and halogen atom; and

• Y is a C 11-C 17 alkene, having 2-6 double bonds.

IVf: X=CH

2

OR

4

, R

1

PD R

2

• X=CH 2 OR 4 , where R 4 is a hydrogen;

• R 1 and R 2 are different, and one of them represents a hydrogen atom, and the other C 1-C 2 alkyl group; and

• Y is a C 15 C 17 alkene, having 3-5 double bonds.

Preferred the compounds of formula (IV) and subgroups IVe and IVf represent the following lipid compounds 19, 21 and 23:

IVg: X=CH

2

OR

4

, R

1

=R

2

• X=CH 2 OR 4 , where R 4 is a hydrogen;

• R 1 and R 2 are the same and are atoms of hydrogen; and

• Y is a C 11-C 17 alkene, having 2-6 double bonds.

IVh: X=CH

2

OR

4

,

R

1

=R

2

• X=CH 2 OR 4 , where R 4 is a hydrogen;

• R 1 and R 2 are the same and are atoms of hydrogen; and

• Y is a C 17 alkene, has 5 double bonds.

Preferred connection formula (IV) and subgroups IVg and IVh represents the following lipid connection 16:

When n=2, lipid connection according to the present invention refers to the formula (V)

In addition, lipid compounds presented by the formula (V) of the present invention, can be divided into subcategories in the form of the following preferred groups:

Va: X=COR

3

• X=COR 3 , where R 3 represents the hydroxy group or C 1-C 3 alkoxy group;

• R 1 and R 2 are similar or different, and selected from the hydrogen atom, C 1-C 3 an alkyl group and halogen atom; and

• Y is a C 9-16 C alkene, having 1-4 double connection.

Vb: X-COR

3

, R

1

PD R

2

• X=COR 3 , where R 3 represents the hydroxy group or C 1-C 2 alkoxy group;

• R 1 and R 2 are different, and one of them represents a hydrogen atom, and the other C 1-C 2 alkyl group; and

• Y is a C 15 alkene has 4 double connection.

The preferred compounds of formula (V) and subgroups Va and Vb are the following lipid compounds 24 and 25:

The present invention also relates to a method for lipid compounds in accordance with any of the formula (I)to(V) of the present invention.

In addition, the present invention relates to a lipid connection under any of formula (I)to(V) for use as a medicine or for diagnostic purposes, such as positron emission tomography (PET).

The present invention also refers to the pharmaceutical compositions containing lipid connection in accordance with any of the General formula (I)-(V). Pharmaceutical composition may contain a pharmaceutically acceptable carrier and filler or thinner, or any combination of them, and accordingly is intended for oral administration. The corresponding daily dose of lipid compounds in accordance with any of the formula (I)-(V) is 5 mg to 10 g specified lipid compounds; from 50 mg to 1 g specified lipid compounds or from 50 mg to 200 mg specified lipid compounds.

The present invention also relates to the lipid composition containing lipid connection in accordance with any of the formula (I)-(V). Accordingly, at least 80% of the mass., or, at least 90% by mass., or, at least 95% of the mass. lipid composition consists of the specified lipid compounds. The lipid composition may optionally contain a pharmaceutically acceptable antioxidant, such as tocopherol.

In addition,the the present invention relates to the use of lipid compounds in accordance with any of the formula (I)-(V) to obtain the drug for

• activate or a modulation of at least one of isoforms α, γ and/or δ activated receptor (PPAR) rights;

• activate or a modulation RXR;

• inhibition or regulation of NF-ΚB;

• treatment and/or prevention of inflammatory disease or condition;

• lowering insulin levels in the plasma, blood glucose and/or triglycerides in serum;

• prevention and/or treatment of elevated levels of triglyceride levels of LDL cholesterol (low density lipoprotein) and/or VLDL cholesterol levels (lipoproteins of low density);

• prevention and/or treatment state, for example, hypertriglyceridemia (HTG);

• treatment and/or prevention of obesity or condition with excessive body weight;

• treatment and/or prevention of resistance of peripheral tissues to insulin and/or diabetic status;

• reducing the body weight and/or prevent weight gain;

• treatment and/or prevention of fatty liver disease, such as non-alcoholic fatty liver disease (NAFLD);

• treatment of insulin resistance, hyperlipidemia and/or obesity or state overweight; and

• treatment and/or prevention of type 2 diabetes.

The present invention also relates to a lipid compounds in accordance with any of the formula (I)to(V) for the treatment and/or prevention of the conditions listed above.

In addition, the present invention relates to methods of treatment and/or prevention of States listed above, including the introduction of the mammal, in need of this, pharmaceutically active number of lipid compounds in accordance with any of the formula (I)-(V).

A detailed description of the present invention

Unexpectedly found that new polyunsaturated derivatives are presented by General formula (I)-(V), have a greater affinity for nuclear receptor family PPAR compared with DHA and EPA. Derivative give agonists RXR, more potent than DHA.

RXR/PPAR is a d) an heterodimer, which synergistically are activated in the presence of both ligands. As new compounds according to the present invention are ligands as for PPAR and RXR, they can act as agonists double action. Because different PUFA are accumulated differently in different tissues, these modified PUFA have the potential to be ligands for nuclear receptors.

In addition to the fact that they are the best ligands for PPAR and RXR, derivatives according to the present invention are being degraded not easily use the paths of alpha - and beta-oxidation of natural PUFA, because of the Deputy in α or β position.

New connections can be used in therapy either one by one or in combination with other ligands to PPAR with high affinity. In this case, the derivative PUFA will act as a ligand for RXR, synergistically increasing influence of the ligand PPAR on the transcription of the gene.

In addition, provide for new connections, which acquire the functionality of retinoids: retinol and retinal. These connections are , which are activated in vivo by oxidation pathways.

Nomenclature and terminology

Lipid compounds according to the present invention are substituted by atom of carbon 2 and/or 3, counting from the functional group indicated by the X in formulas (I)-(V). Such substitution can be called "alpha-replacement" or "beta-replacement". In lipid compounds according to the present invention, there is a double bond between carbon atoms 2 and 3, which preferably is

in E-configuration.

As used here, the term "position of the V-3" means that the first double bond exists as the third relationship carbon-carbon from the end of the final CH 3 (W) of the carbon chain.

In chemistry the numbering of carbon atoms begins with alpha-end. Fatty acids are hydrocarbons with direct chain, having carboxyl (COOH) group at one end (a) and (usually) a methyl group to another (W) end.

As used here, the expression "double bonds, alternating with methylene group refers to the case when group is situated between separate double bonds of the carbon chain in the lipid connection.

In the connection in accordance with the present invention specified an alkyl group can be selected from the group consisting of methyl, ethyl, n-cut, isopropyl nitrate, n-butyl, , sec-butyl n-; specified halogen atom can be a fluorine; the alkoxy group can be selected from the group consisting of methoxy, , propoxy, , sec-, OCH 2 CF 3 and OCH 2 CH 2 OCH 3 ;

- R 1 and R 2 are similar or different, and can be selected from a group of deputies, consisting of a hydrogen atom, an alkyl group, halogen atom and alkoxy groups;

- X is a COR 3 or CH 2 OR 4 , where

- R 3 is selected from the group consisting of hydrogen, hydroxy, alkoxy and amino,

- where X additionally includes derivatives of carboxylic acid, when R 3 is a hydroxy; and

- R 4 is selected from the group consisting of hydrogen alkyl or ,

- Y is a C 9-21 alkene with one or more double bonds with E -, or Z-configuration;

or any of its pharmaceutically acceptable range, or prodrug.

Preferably, lipid connection according to the present invention is an E-isomer and represented by (II):

When n=0, lipid connection according to the present invention is represented by the formula (III):

When n=1, lipid the connection of the present invention is represented by the formula (IV):

When n=2, lipid connection according to the present invention is represented by the formula (V):

The connections defined above, can be divided into subcategories based on whether the X COR 3 or CH 2 OR 4 , on the basis of deputies R 1 and R 2 , and whether R 1 and R 2 different or the same, and also on the basis of the length and number of double bonds chain Y. Especially preferred connections are connections (1)-(27)listed above.

Preferred lipid compounds in accordance with the present invention can also be divided into the following categories A-1, A-2, B-1 and B-2.

Category A-Z and/or E-isomers

The General formula (I)

Z - E-isomers compounds described General formula (I), may be released from mixtures of various technologies division. Flash chromatography (silica gel) is a common technology division. Z - E-isomers compounds, described the General formula above can be allocated in the form of esters of carboxylic acids, other, as carboxylic acids or as alcohols, with the help of a flash chromatography. Carboxylic acids can re- through the use of primary alcohols and acid catalyst (H 2 SO 4 , HCl, BF 3 ). Alcohols can oxidize with obtaining carboxylic acid.

Category A-1, Z - and/or E-isomers, n=0, X=COR

3

For all the examples in this category, (30), (32) and (33): n=0

X =

Ethyl (2Z/E,11E,14E,17E)-2-ethyl--2,11,14,17- (30)

Ethyl (2Z/E,7Z,10Z,13Z,16Z,19Z)-2---2,7,10,13,16,19- acid (32)

Ethyl (2Z,7Z,10Z,13Z,16Z,19Z)-2---2,7,10,13,16,19- acid (33)

Category A-2, Z - and/or E-isomers, n=0, X=CH

2

OR

4

For all the examples in this category, (29), (31) and (34):

n=0

R 4 =H

(fully Z)-2-ethyl--2,11,14,17--1-ol (31)

(fully Z)-3-methyl--2,7,10,13,16,19--1-ol (29)

(fully Z)-2---2,7,10,13,16,19--1-ol (34)

Category A-1, n=1, X=COR

3

and X=CH

2

OR

4

For all the examples in this category, (35), (36), (37), (38), (39) and (40): n=1

Ethyl (2Z,4E,8Z,11Z,14Z,17Z)-2-ethyl--2,4,8,11,14,17-hexanoate (35)

(2Z,4E,8Z,11Z,14Z,17Z)-2-ethyl--2,4,8,11,14,17--1-ol (36)

Ethyl (2E/Z,4E,13Z,16Z,19Z)-3-methyl--2,4,13,16,19- (37)

(2Z,4E,13Z,16Z,19Z)-3-methyl--2,4,13,16,19--1-ol (38)

(2Z,4E,7Z,10Z,13Z,16Z,19Z)-2-ethyl--2,4,7,10,13,16,19--1-ol (39)

Ethyl (2Z/2E,4E,13Z,16Z,19Z)-2-ethyl--2,4,13,16,19- (40)

Category B: E-isomers

The General formula (II)where preferably

Y=C 9-21 alkene with one or more double bonds with E -, or Z-configuration. X = hydroxymethyl (-CH 2 OH), (-C(O) (H), or carboxylic acid, or its derivative, carboxylate, carboxylic acid anhydride or karboksamid. Each of the R 1 and R 2 , which may be similar or different, is an atom of hydrogen, fluorine atom, alkoxy group or an alkyl group.

Category B-1; E-isomers, n=0-2 and X=COR

3

Category B-2; E-isomers, n=0-2 and X=CH

2

OR

4

Category B-1; n=0, X=COR

3

and R=OCH

2

CH

3

For all of the examples in this category, (1), (3), (6) and (8):

n=0

X =

Ethyl (2E,7Z,10Z,13Z,16Z,19Z)-2-methyl--2,7,10,13,16,19- (1)

Ethyl (2E,7Z,10Z,13Z,16Z,19Z)-3-methyl--2,7,10,13,16,19- (3)

Ethyl (2E,11Z,14Z,17Z)-2-methyl--2,11,14,17- (6)

Ethyl (2E,5Z,8Z,11Z,14Z,17Z)-2-methyl--2,5,8,11,14,17- (8)

Category B-1: n=0, X=COR

3

and R

3

=OH

For all the examples in this category, (2), (4), (7) and (26):

n=0

R 3 = hydroxy (OH)

(2E,7Z,10Z,13Z,16Z,19Z)-2-methyl--2,7,10,13,16,19- acid (2)

(2E,7Z,10Z,13Z,16Z,19Z)-3-methyl--2,7,10,13,16,19- acid (4)

(2E,11E,14E,17E)-2-methyl--2,11,14,17- acid (7)

(2Z,7Z,10Z,13Z,16Z,19Z)-2---2,7,10,13,16,19- acid (26)

Category C-2, n=0, X=CH

2

OR

4

and R

4

=H

For all the examples in this category; and (5), (9) and (27):

n=0

Deputy represents an alkyl or .

(2E,7Z,10Z,13Z,16Z,19Z)-3-methyl--2,7,10,13,16,19--1-ol (5)

(2E,11Z,14Z,17Z)-2-ethyl--2,11,14,17--1-ol (9)

2E,7Z,10Z,13Z,16Z,19Z)-2---2,7,10,13,16,19--1-ol (27)

Category B-1, E-isomers, n=1

Formula (IV)

n=1

Category B-1, n=1 and X=COR 3 and R 3 =OCH 2 CH 3

For all the examples in this category, (10), (12), (14), (17) and (22):

n=1

X=COR 3

R 3 =OCH 2 CH 3

Ethyl (2E,4E,8Z,11Z,14Z,17Z)-2-methyl--2,4,8,11,14,17- (10)

Ethyl (2E,4E,8Z,11Z,14Z,17Z)--2,4,6,11,14,17- (12)

Ethyl (2E,4E,7Z,10Z,13Z,16Z,19Z)--2,4,7,10,13,16,19- (14)

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

Ethyl (2E,4E,7Z,10Z,13Z,16Z,19Z)-2-ethyl--2,4,7,10,13,16,19- (22)

Category B-1, E-isomers, n=1 and X=COR

3

and R

3

=OH

For all the examples in this category, (11), (13), (15), (18) and (20):

n=1

X=COOH

(2E,4E,8Z,11Z,14Z,17Z)-2-methyl--2,4,8,11,14,17- acid (11)

(2E,4E,8Z,11Z,14Z,17Z)-2-ethyl--2,4,8,11,14,17- acid (18)

(2E,4E,13Z,16Z,19Z)-3-methyl--2,4,13,16,19- acid (20)

Category B-2, E-isomers, n=1, X-CH

2

OR

4

and R

4

=H

For all the examples in this category, (16), (19), (21) and (23):

n=1

X=CH 2 OR 4

R 4 = hydrogen (H)

(2E,4E,7Z,10Z,13Z,16Z,19Z)--2,4,7,10,13,16,19--1-ol (16)

(2E,4E,8Z,11Z,14Z,17Z)-2-ethyl--2,4,11,14,17--1-ol (19)

(2E,4E,13Z,16Z,19Z)-3-methyl--2,4,13,16,19--1-ol (21)

(2E,4E,13Z,16Z,19Z)-2-ethyl--2,4,13,16,19--1-ol (23)

Category B, TRANS-isomers, n=2

Formula (V)

n=2

Category B-1, n=2, X=COR

3

and R

3

=OCH

2

CH

3

For the examples in this category (24):

n=2

X=COR 3

R 3 =OCH 2 CH 3

Ethyl (2E,4E,6E,10Z,13Z,16Z,19Z)-3-methyl--2,4,6,10,13,16,19- (24)

Category-1, n=2, X=COR

3

and R

3

=OH

For the example in this category (25):

n=2

X=COR 3

R 3 = hydroxyl (OH)

(2E,4E,6E,10Z,13Z,16Z,19Z)-3-Methyl--2,4,6,10,13,16,19- acid

You must understand that this invention covers any possible pharmaceutically acceptable complexes, or prodrug of lipid compounds of formula (I)-(V).

"Prodrugs" are substances which may or may not have pharmacological activity, but can be introduced (for example, oral or parenteral) and then subjected to biological be invoked (for example, metabolization) in the body with the formation agent of the present invention, which is pharmacologically active.

When X is a carboxylic acid, present invention also includes derivatives of carboxylic acids. For example, these derivatives of carboxylic acids can be selected from the group consisting of phospholipid or mono-, di - or triglyceride.

In addition, salts of carboxylic acids are also included in the present invention. Relevant pharmaceutically acceptable salt carboxy groups include the salts of metals, such as aluminum, alkali salts such as lithium, sodium or potassium salts of alkali-earth metals such as calcium or magnesium, and ammonium salts or substituted ammonium.

"Pharmaceutically active amount" refers to the number, which will lead to the desired pharmacological and/or therapeutic treatment, i.e. to the number of lipid compounds, which is effective in achieving the intended objective. Although the needs of individual patients may vary, determination of the optimal ranges of effective quantities of lipid compounds is within the knowledge, typical for the region. As a rule, dosage regimen for the treatment of joints and/or compositions of the present invention is selected in accordance with a variety of factors, including the type, age, weight, gender, diet and medical condition of the patient.

Under the "drug" means a lipid connection under any of formula (I)-(V)in any form suitable for use in the medical purposes, for example, in the form of a medical product, the pharmaceutical composition or product, dietary product, food toppings or food additive.

"Treatment" includes any therapeutic applications that can benefit the person or mammal, not a man. Both medical and veterinary treatments is in the framework of the present invention. Treatment may relate to an existing condition, or it may be preventive.

Lipid compounds of formula (I)-(V) can be used by themselves, but as a rule, to be introduced in the form of pharmaceutical composition, in which connection formula (I)to(V) (active ingredient) are Association with a pharmaceutically acceptable carrier, filler or diluent (including their combination).

Acceptable media, excipients and diluents for therapeutic use are well known in the field of pharmaceutics and can be selected in connection with the proposed way of introduction and standard of pharmaceutical practice. Examples include binders, lubricants, agents, agents for the coating, solubilizing agents, preserving agents, wetting agents, emulsifiers, sweeteners, dyes, perfumes agents, perfume, buffers, agents, stabilizing agents and/or salt.

Pharmaceutical composition in accordance with the present invention preferably intended for oral administration of a person or an animal. Pharmaceutical composition can also be used for the introduction via any other method, in which the active ingredients can effectively absorbed and used, for example intravenously, subcutaneously, intramuscularly, intranasal, rectal, vaginal, or topically.

In the specific embodiment of the present invention pharmaceutical composition is formed in the form of a capsule, which could also constitute a microcapsule generating powder, or sachets. The capsule can . This option implementation also includes as a capsule, where as a capsule and encapsulated composition in accordance with the present invention is flavored. By aromatase capsule becomes more attractive for the consumer. For the above therapeutic applications input dose will, of course, change together with your connection to, with the way of introduction, the desired treatment and shown disorder.

Pharmaceutical composition can be prepared with getting your daily dose for example, from 5 mg to 10 g of 50 mg to 1 g; or from 50 mg to 200 g lipid compounds. Under daily dosing is meant dosing for 24 hours.

Input dose will, of course, change together with your connection way of introduction, the desired treatment and shown disorder. As a rule, the doctor will identify the actual dosage that will be most suitable for the individual subject. The specific level of dose and frequency dosing for any individual patient may vary and will depend on a variety of factors, including the activity of a specific connection, metabolic stability and duration of this connection, age, weight, General health status, gender, diet, the manner and time of speed selection, combination of medications, the severity of the condition and the individual undergoing therapy. Lipid connection and/or a pharmaceutical composition of the present invention may be introduced in accordance with the regime from 1 to 10 times a day, e.g. once or twice a day. For the oral and parenteral administration to patients-people level of daily dosage of the agent can be in the same or in divided doses.

An additional aspect of the present invention relates to the lipid composition containing lipid any connection of the formulas (I)-(V). The lipid composition can be from 80 to 100% of the mass. lipid compounds of formula (I)-(V), all interest mass refer to the total mass of the lipid composition. For example, at least 80%at least 90%, or, at least 95% of the mass. lipid composition consists of lipid compounds any of formula (I)-(V).

In particular the implementation of the present invention lipid composition is a pharmaceutical composition, nutritional composition or nutritional composition.

The lipid composition can optionally contain an effective amount of pharmaceutically acceptable antioxidant, such as tocopherol or mixed Tocopherols, up to 4 mg / g, for example from 0,05 to 0,4 mg / g, Tocopherols, of the total mass of the lipid composition.

Lipid compounds and compositions in accordance with the present invention are suitable for treatment of a wide range of diseases and conditions, as will be described in more detail below.

Accordingly, lipid compounds in accordance with any of the formula (I)-(V) can activate nuclear receptors PPAR (activated receptor), isoforms α, and/or g, and/or coth and RXR.

In addition, lipid compounds in accordance with the present invention may regulate or inhibit the activity of NFκB (nuclear factor Kappa B).

Especially preferred connection for the inhibition of and/or control of NFκB represent the connection of the formulas (IV) and (V)that is a lipid compounds presented with n=1 or n=2. Preferably, R 1 is represented by a hydrogen atom.

The present invention also provides for the application of lipid compounds in accordance with any of the formula (I)to(V) for the manufacture of a medicament for the treatment and/or prevention of inflammatory disease or condition.

Especially preferred connection for the treatment and/or prevention of inflammatory diseases or conditions are the connection of the formulas (IV) and (V)that is a lipid compounds presented with n=1 or n=2. Preferably, R 1 is represented by a hydrogen atom.

Additional aspect of the present invention relates to the use of lipid compounds in accordance with any of the formula (I)to(V) for the production of the drug for lowering insulin levels in the plasma, blood glucose and/or triglycerides in the serum.

In addition, lipid compounds in accordance with any of the formula (I)-(V) can be used to control the disease, selected from atherosclerosis, inflammation and cancer, and chronic inflammatory diseases like psoriasis, rheumatoid arthritis and the like, and with disorders of the brain (MS, Alzheimer's disease).

In addition to pharmaceutical applications of lipid compounds in accordance with any of the formula (I)-(V) can be used as food additives. For this reason, an additional aspect of the present invention provides food, food supplements, food additive or preparation containing lipid connection in accordance with any of the formula (I)-(V).

Cosmetic compositions or products containing lipid compounds any of formula (I)-(V)form an additional aspect of the present invention.

In addition, another aspect of the present invention provides radioactively labelled analogs of compounds in accordance with the formula (1). Such radioactively labelled analogues are particularly suitable for use in diagnostic methods, such as obtaining a PET images.

Many of the intermediate compounds formed during receiving lipid compounds according to the present invention, are themselves with new and useful connections, and they form an additional aspect of the present invention. Concrete examples of such intermediate compounds can be found in the schemes reactions below.

Now the present invention will be further described by the following non-limiting examples.

Example 1

Total synthesis

Lipid compounds of General formula (I) can be obtained by a combination of reactions CARBONYLS, such reactions such Wittig reaction Peterson or reactions Julia. More specifically: lipid compounds of General formula (I), where R 1 and R 2 are hydrogen and X represents the carboxylate, received with the help of the following methods.

The reaction of aldehyde (i) phosphoryl-stable [(RO) 2 P(O)C - HCO R 2 1 (ii) results mainly (E)-alpha,beta-unsaturated ester (iii) as the main product. Phosphoryl-stable can be generated through the processing or basis, for example alkali metal such as sodium hydride, metal such as sodium methoxide, connection, such as , amide metal, such as lithium , or other grounds in a solvent such as DME (), tetrahydrofuran, benzene, toluene. The reaction can be carried out at the reaction temperature of -78°C to room temperature. Ester (iii) may in a solvent such as ethanol or methanol to form carbonic acid by adding grounds, such as lithium hydroxide/sodium/potassium in water at temperatures in the redistribution between 10-90°C. He then, if desired, can or . Ester (iii) can be restored to alcohol and aldehyde.

Lipid compounds of General formula (I), where R 1 represents an alkyl group, fluorine or alkoxy group, R 2 is a hydrogen and X represents the carboxylate, received with the help of the following methods.

The method is similar stage 1 except that phosphonate substituted in position 2 an alkyl group, fluorine or alkoxy group.

Lipid compounds of General formula (I)wherein R 2 represents an alkyl group, and R 1 represents hydrogen, and X represents the carboxylate, can be obtained using the following methods.

Method 1, the reaction Horner--:

Method 2, the reaction Peterson:

Stage 3 is similar to stages 1 and 2, except that the temperature of the reaction should be increased to 0-80°C.

In stage 4 α used for the synthesis of alpha,beta-unsaturated ester (vii) of ketone (vi).

Lipid compounds of General formula (I)wherein R 2 represents an alkyl group, and R 1 represents hydrogen, and X represents the carboxylate, can also be obtained using the following methods.

Unsaturated aldehydes, Y-C(O)H, can be obtained directly from the esters of carboxylic acids, existing in nature, unsaturated fatty acid, alpha-linolenic acid, oleic acid, conjugated linoleic acid, linolenic acid, eicosapentaenoic acid and things like that, through the restoration of using hydride at -78 C or using a two-stage procedure, including restoration to the alcohol, and then oxidation to aldehyde. Aldehydes can also be obtained through the degradation of polyunsaturated fatty acids EPA and DHA, as described Holmeide et al. (J. Chem. Soc., Perkin Trans. 1, 2000, 2271). In this case, start with purified EPA or DHA, but you can also start with fish oil contains EPA and DHA in the mixture. The reason for this is that DHA reacts faster than the EPA, in reaction , with the formation of iodine Delta-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). Aldehydes can also be obtained from alpha,beta-unsaturated esters covered by the present invention, by restoring using hydride at -78 C or using a two-stage procedure, including restoration to the alcohol, and then oxidation to aldehyde.

Ketones can be obtained from existing in the nature of unsaturated acids through reaction with two equivalents at -78°C in a solvent such ether. They can also be obtained from aldehydes, similar to those already described, by reaction with anion β-keto phosphonate, such ethyl(2-oxo-propyl).

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

Acylation sn-glycero-3- (GPC) with activated fatty acid, for example, using fatty acids represents a standard procedure in the synthesis of phosphatidylcholine. It is usually done in the presence of anion DMSO, with DMSO solvent (Hermetter; Chemistry and Physics of lipids, 1981, 28, 111). Sn-glycero-3-phosphocholine as adduct of cadmium (II)may also interact with activated fatty acid in the presence of the DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)] obtaining phosphatidylcholine corresponding fatty acid (international patent number PCT/GB2003/002582). Enzymic may exercise the conversion of phosphatidylcholine in (Wang et al., J. Am. Chem. Soc., 1993, 115, 10487).

Phospholipids, containing polyunsaturated fatty acids can be obtained in different ways, mainly by means of chemical synthesis of phospholipids, as described by enzymatic esterification and transesterification phospholipids or enzymatic phospholipids (Hosokawa, J. Am. Oil Chem. Soc. 1995, 1287, Lilja-Hallberg, Biocatalysis, 1994, 195). For such enzymatic applications the preferred embodiment of the present invention is a lipid connection in accordance with the General formula I, where R 1 and R 2 are hydrogen.

Lipid compounds of General formula (I), where X is a carboxylic acid and is in the form of triglycerides can be obtained using the following methods. The excess of the new fatty acid can communicate with glycerin using (DMAP) and 2-(1H--1-yl)-N,N,N',N'- (HBTU).

Lipid compounds of General formula (I), where X is a carboxylic acid and is in the form of , can be obtained through the reaction of the fatty acid (2 EQ.) with glycerine (1 EQ.) in the presence of 1,3- (DCC) and 4- (DMAP).

Lipid compounds of General formula (I), where X is a carboxylic acid and is in the form of , can be obtained using the following methods.

Acylation of 1,2-O-isopropylidene-sn-glycerin using fatty acid using DCC and DMAP in chloroform gives . Unprotect group may be through the secure processing of glycerin acid (HCl, acetic acid, etc.) (O'brian, J. Org. Chem., 1996, 5914).

There are several common ways of synthesis for the with fatty acid in position 2. One way uses dismal substantial fatty acid using in the presence of 1-(3-)-3- (EDC) and 4- (DMAP) obtaining derived. Processing derived with the help of trifluoroacetic anhydride (TFAA) before the TRANS-esterification independent (Parkkari et al., Bioorg. Med. Chem. Lett. 2006, 2437).

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

Ethyl (2E,7Z,10Z,13Z,16Z,19Z)-2-methyl--2,7,10,13,16,19- (1)

Triethyl 2- (414 ml of 1.9 mmol) add to the suspension of the hydride sodium (81 mg, 60% of the variance in mineral oil, 2.0 mmol) in a dry THF (5 ml) at 0 degrees C. After 30 minutes at room temperature of the mixture is cooled to 0 C and type (fully Z)--5,8,11,14,17- (500 mg, 1.7 mmol) in THF (1 ml). The mixture is stirred for 40 minutes at 0 degrees C. Add the saturated aqueous solution NH 4 Cl and the phases are separated. Aqueous phase is extracted with a mixture of hexane:EtOAc (8:2). The combined organic phases are washed with saturated salt solution, water and dried (MgSO 4 ). Evaporation of solvents under reduced pressure, and then flash chromatography on silica gel (9:1 hexane-EtOAc) give ester 1 (550 mg, 85%), (2E:2Z=7:1 (GC)).

δh (300 MHz): 0,95 (t, J=7.5 Hz, 3H, CH 3 ), 1,25 (t, J=7,1 Hz, 3H)and 1.51 (m 2N), 1,84 (d, J=1 Hz, CH 3 , 3H), 1.9 to 2.2 m, 6N), a 2.7-2.9 (the m, 8H), 4,20 (kV, J=7,1 Hz, 2H), 5,2-5,5 m, 10H), 6,88 (TD, J=7.5 Hz, J=1 Hz, 1H).

Example 2

(2E,7Z,10Z,13Z,16Z,19Z)-2-methyl--2,7,10,13,16,19- acid (2)

Ethyl (2E,7Z,10Z,13Z,16Z,19Z)-2-methyl--2,7,10,13,16,19- (1) and stereoisomers share using a flash chromatography on silica gel (8:2 hexane-EtOAc).

Connection 2: E-isomers:

δ N (300 MHz), 0,96 (t, J=7.5 Hz, 3H, CH 3 ), 1,53 (m 2N), to 1.82 (d, J=1 Hz, CH 3 3H), 1.9 to 2.2 m, 6N), a 2.7-2.9 (the m, 8H), 5,2-5,5 m, 10H), 6,91 (TD, J=7.5 Hz, J=1 Hz, 1H); δ (75 MHz), 11,93, 14,23, 20,51, 25,50, 25,60, 26,82, 28,29, 28,39, 126,97, 127,26, 127,83, 128,04, 128,06, 128,20, 128,27, 128,51, 129,29, 131,97, 144,87, 173,80.

Connection 28: Z-isomer: δh (300 MHz): 0,95 (t, J=7.5 Hz, 3H, CH 3 ), 1,48 (m, 2H), 1,90 (., J=1,4 Hz, 3H, CH 3 ), in 2.1-2.3 (m, 4H), 2,53 (m, 2H), a 2.7-2.9 (the m, 8H), 5,2-5,5 m, 10H), between 6.08 (TD, J=7,4 Hz J=1,4 Hz, 1H); δ C (75 MHz) from 14.25, 20,48, 20,54, 25,53, 25,62, 26,92, 29,35, 29,45, 126,83, 127,02, 127,89, 128,01, 128,14, 128,17, 128,20, 128,38, 128,54, 129,69, 132,02, 146,45, 173,21.

Example 3

Getting ethyl (2E,7Z,10Z,13Z,16Z,19Z)-3-methyl--2,7,10,13,16,19- (3)

(288 mm, 1.4 mol) add to the suspension of the hydride sodium (58 mg, 60% of the variance in mineral oil, 1.4 mol) in dry benzene (8 ml) at room temperature. After 30 minutes, add the solution (fully Z)--6,9,12,15,18--2-one (400 mg, 1.3 mmol) in benzene (4 ml). The mixture is stirred for 48 hours at room temperature. Water is added and the mixture is extracted with hexane. Extract washed with water and dried (MgSO 4 ). Evaporation solvents under reduced pressure, and then flash chromatography on silica gel (95:5, hexane:EtOAc) give ester 3 (270 mg, 53%) in the form of oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,94 (t, 3H), 1,23 (t, 3H), 1,49-1.57 in (m, 2H), 1,99 of 2.12 (m, 6H), 2,12 (c, 3H), 2,76-2,83 (m, 8H), 4,10 (kV, 2H), and 5.30-5,37 (m, 10H), 5,63 (c, 1H); 13 C NMR (50 MHz, CDCl 3 ): δ 14,18, 14,25, 18,61, 20,48, 25,46, 25,56, 25,59, 26,63, 27,26, 28,06, 40,33, 59,33, 126,93, 127,78, 128,00 (2 signal), 128,16, 128,17, 128,42, 128,47 (2 signal), 129,29, 131,92, 159,64, 166,68.

Example 4

Obtaining (2E,7Z,10Z,13Z,16Z,19Z)-3-methyl--2,7,10,13,16,19- acid (4)

Ethyl (2E,7Z,10Z,13Z,16Z,19Z)-3-methyl--2,7,10,13,16,19- (3) dissolved in methanol (9 ml) and add LiOH (220 mg, 4,89 mmol) in water (3 ml) and the mixture is heated at 50 C for 2 hours. The mixture cool and add diluted hloristovodorodnuyu acid to establish pH 2. Extracting diethyl ether, drying (MgSO 4 ) and evaporation of solvent under reduced pressure give acid 4. Acid cleaned using a flash chromatography on silica gel (8:2, hexane:EtOAc); δh (300 MHz) of 0.95 (t, J=7.5 Hz, 3H, CH 3 ), 1,55 (m, 2H), 2,0-2,2 m, 6H), to 2.15 (d, J=1.3GHz, 3H, CH 3 ), a 2.7-2.9 (the m, 8H), 5,2-5,5 m, 10H), 5,68 (., 1H); δ C (75 MHz) 14,24, 19,04, 20,53, 25,51, 25,60, 25,62, 25,64, 26,67, 27,28, 40,67, 115,24, 126,99, 127,84, 128,05, 128,11, 128,19, 128,22, 128,53, 128,57, 129,23, 132,00, 163,05, 172,31.

Example 5

(2E,7Z,10Z,13Z,16Z,19Z)-3-methyl--2,7,10,13,16,19--1-ol (5)

Ethyl (2E,7Z,10Z,13Z,16Z,19Z)-3-methyl--2,7,10,13,16,19- (2E:2Z=9:1), (0.40 g, 1,08 mmol) is dissolved in a dry THF (5 ml) and added dropwise to cold suspension LAH (0,045 g, 1,19 mmol) in a dry THF (10 ml). The mixture was stirred at 0 C in an inert atmosphere within 30 minutes, and then 18 hours at the ambient temperature. The reaction mixture was quenched by the addition of 10% NH 4 Cl (20 ml) and the mixture is extracted, double-heptane (30 ml). The combined organic extracts washed with saturated salt solution (20 ml) and dried (Na 2 SO 4 ). Cleaning with the help of a flash chromatography (heptane:EtOAc, 4:1) gives 0.16 g (45%) 3-methyl-(2E,7Z,10Z,13Z,16Z,19Z)--2,7,10,13,16,19--1-ol in the form of colorless oil.

Junction 3, E-isomer: 1 H-NMR (200 MHz, CDCl 3 ): δ 0,95 (t, 3H), 1,32-1,50 m, 2H), 1,64 (c, 3H), 1,97-2,09 (m, 6H), 2,76-2,85 m, 8H), 4,11 (d, J=6,8 Hz, 2H), 5,27-5,42 (m, 11H); 13 C NMR (50 MHz, CDCl 3 ): δ 14,21, 16,12, 20,50, 25,48 (2 signal), 25,58 (3 signal), 26,79, 27,59, 39,04, 59,28, 123,42, 126,96, 127,83, 127,94, 127,98, 128,08, 128,16, 128,37, 128,50, 130,23, 131,98; MC (): 351,2 [M+Na] + .

Connection 29, Z-isomer:

In addition, the elution gives 0.01 g (28%) (fully Z)-3-methyl--2,7,10,13,16,19--1-ol (29) as a colourless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,95 (t, 3H), 1,30-1,50 m, 2N), 1,71 (C, 3H), 2,02-2,09 (m, 6N), 2,76-2,85 m, 8H), of 4.09 (d, J=7,1 Hz, 2N), 5,28 (1H), 5,31-5,41 (m, 10H); MC (): 351,2 [M+Na] + .

Example 6

Ethyl (2E,11Z,14Z,17Z)-2-methyl--2,11,14,17- (6)

(386 mm, 1.8 mmol) add to the suspension of the hydride sodium (72 mg, 60% of the variance in mineral oil, 1.8 mmol) in a dry THF (5 ml) at 0 degrees C. after 30 minutes, add the solution (fully Z)--9,12,15- (300 mg, 1.15 mmol) in THF (2 ml). The mixture is stirred for 1 hour at 0 degrees C. Add aqueous solution NH 4 Cl, and the mixture is extracted EtOAc. Extract washed with water and dried (MgSO 4 ). Evaporation of solvents under reduced pressure, and then flash chromatography on silica gel (95:5, hexane:EtOAc) give ester 6 (180 mg, 45%). δ H (300 MHz) of 0.95 (t, J=7.5 Hz, 3H, CH 3 ), 1,2-1,5 m, 13H), 1,80 (, CH 3 3H), 2,0-2,2 m), 2,78 (t, J=5.8 Hz 4H)and 4.16 (kV, J=7,1 Hz, 2H, CH 2 ), 5,2-5,4 (m, 6N), of 6.73 (dt, J=7.5 Hz, J=1.3GHz, 1H); δ C (75 MHz) 12,31, 14,25, 20,53, 25,51, 25,60, 27,20, 28,56, 28,66, 29,178, 29,34, 29,60, 60,33, 127,10, 127,70, 128,26, 130,27, 131,94, 142,37, 168,30.

Example 7

(2E,11E,14E,17E)-2-methyl--2,11,14,17- acid (7)

Ethyl (2E,11Z,14Z,17Z)-2-methyl--2,11,14,17- (6) (160 mg, 0,46 mmol) was dissolved in methanol (3 ml), and add LiOH (193 mg of 4.6 mmol) in water (3 ml), and the mixture is heated at 50 C for 2 hours. The mixture cool and add diluted hloristovodorodnuyu acid to establish pH 2. Extracting diethyl ether, drying (MgSO 4 ) and evaporation of solvent under reduced pressure give acid 7. Acid cleaned using a flash chromatography on silica gel (8:2 hexane-EtOAc); δh (300 MHz) of 0.95 (t, J=7.5 Hz, 3H, CH 3 ), 1,2-1,5 m, 10H)1,81 (c, 3H, CH 3 ), 2,0-2,2 m, 6H), 2,79 (t, J=5.8 Hz 4H), 5,2-5,4 (m, 6H), 6,90 (dt, J=7.5 Hz, J=1.3GHz, 1H); δ C (75 MHz) 11,93, 14,25, 20,53, 25,51, 25,60, 27,19, 28,40, 28,87, 29,16, 29,31, 29,58, 126,94, 127,10, 127,71, 128,24, 128,25, 130,25, 131,93, 145,41, 173,76.

Example 8

Ethyl (2Z/E,11E,14E,17E)-2-ethyl--2,11,14,17- (30)

NaH (60% in mineral oil, 0,080 g, from 2.00 mmol) suspended in a dry THF (10 ml) in an inert atmosphere. Suspension is cooled to 0 C, added dropwise triethyl 2- (0,47 ml, from 2.00 mmol) and stirred at 0 C for 20 minutes. To this mixture add a solution of (fully Z)--9,12,15- (PRB-73, 0.35 g, 1,33 mmol) in a dry THF (5 ml) and the mixture was stirred at room temperature for 30 minutes. Mixture is diluted with diethyl ether (25 ml), washed with water (20 ml) and dried (Na 2 SO 4 ). Cleaning with the help of a flash chromatography (heptane:EtOAc, 98:2) gives 0.47 g (99%) is specified in the header connection 30 (2E:2Z=mixture of 1:1).

1 H-NMR (200 MHz, CDCl 3 ):

E-isomer: δ of 0.91-1,04 m, 6H), 1,23-1,41 (m, 13H), 2,01-2,26 (m, 8H), 2,76-2,81 (m, 4H), to 4.17 (kV, 2H), 5,28-5,41 (m, 6H), 6,86 (t, J=7,53 Hz, 1H).

Z-isomer: δ of 0.91-1,04 m, 6H), 1,23-1,41 (m, 13H), 2,01-2,26 (m, 8H), 2,76-2,81 (m, 4H), to 4.17 (kV, 2H), 5,28-5,41 (m, 6H), 5,80 (t, J=7,39 Hz, 1H).

13 C NMR (50 MHz, CDCl 3 ):

Z - E-isomer: δ 13,65, 13,94, 14,26 (two signal), 20,01, 20,54, 25,51, 25,60, 27,23 (two signal), 27,54, 28,33, 28,87, 29,18, 29,23, 29,30, 29,38, 29,51, 29,63, 59,63, 60,22, 127,10, 127,65, 127,70, 128,25 (two signal), 130,27, 130,33, 131,93, 133,63, 133,93, 140,30, 142,01, 168,35 (two signal).

MC (): 383,8 [M+Na] + .

Example 9

(2E,11Z,14Z,17Z)-2-ethyl--2,11,14,17--1-ol (9)

Suspension LAH (0,027 g, 0.70 mmol) in a dry THF (7 ml) is cooled to 0 C in an inert atmosphere and added dropwise to the solution of ethyl (2E/Z 11Z,14Z,17Z) 2-ethyl--2,11,14,17- (30) (2E:2Z=1:1), (0.23 g, 0,68 mmol). The mixture is stirred at 0 degrees C for 30 minutes, and then when the ambient temperature for 30 minutes. Add rich NH 4 Cl (15 ml) and the mixture is extracted twice heptane (20 ml). The combined organic extracts washed with saturated salt solution (20 ml) and dried (Na 2 SO 4 ). Cleaning using flash chromatography (heptane:EtOAc, 8:1) gives 0,050 g (23%) (2E,11Z,14Z,17Z) 2-ethyl--2,11,14,17--1-ol (9) in the form of colorless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,82 was 1.04 (2 x t, 6H), measuring 1.20-1.40 (m, 10H)1,99-2,17 (m, 8H), 2,78 (m, 4H), 4,12 (c, 2H), 5,24-5,44 (m, 7H); 13 C NMR (50 MHz, CDCl 3 ): δ 12,87, 14,24, 20,52, 25,49, 25,58, 27,19, 27,48, 27,78, 29,22 (2 signal), 29,39, 29,61, 30,08, 60,30, 127,09, 127,59, 127,64, 128,23 (2 signal), 130,29, 131,91, 139,84; MC (): 341,3 [M+Na] + .

In addition, the elution (heptane:EtOAc, 6:1) gives 0,020 g (18%) (fully Z) 2-ethyl--2,11,14,17--1-ol (31) in the form of a pale yellow oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,82-0,99 (2 x t, 6H), 1,15-of 1.40 (m, 10H)to 1.95-2.15 per (m, 8H), 2,79 m, 4H), of 4.02 (c, 2H), 5,23-5,44 (m, 7H); 13 C NMR (50 MHz, CDCl 3 ); (): 341,3 [M+Na] + .

Example 10

Ethyl (2E,5Z,8Z,11Z,14Z,17Z)-2-methyl--2,5,8,11,14,17- (8)

Triethyl 2- (366 ml 1.7 mmol) add to the suspension of the hydride sodium 70 mg, 60% of the variance in mineral oil, a 1.75 mmol) in a dry THF (5 ml) at 0 degrees C. After 50 minutes at 0 C the mixture is cooled to-25oC and add (fully Z)--3,6,9,12,15- (400 mg of 1.55 mmol) in THF (1 ml). The mixture is stirred for 50 minutes at 25 degrees C. Add the saturated aqueous solution NH 4 Cl and the phases are separated. Aqueous phase is extracted with hexane. United organic phases are washed with saturated salt solution, water and dried (MgSO 4 ). Evaporation of solvents under reduced pressure, and then flash chromatography on silica gel (95:5, hexane:EtOAc) give ester 8. δh (300 MHz): 0,95 (t, J=7.5 Hz, 3H, CH 3 ), 1,26 (t, J=7,1 Hz, 3H), 1,84 (d, J=1,3 Hz, 3H, CH 3 ), of 2.05 (m 2N), a 2.7-2.9 (the m, 8H), 2,92 (t, J=6,9 Hz, 2H)and 4.16 (kV, J=7,1 Hz, 2H), 5,2-5,5 m, 11N); δ (75 MHz) 12,36, 14,22, 20,52, 25,50, 25,59, 25,61, 25,68, 26,95, 60,42, 125,86, 126,95, 127,72, 127,78, 127,92, 128,09, 128,30, 128,41, 128,56, 129,48, 131,99, 139,69, 168,03.

Example 11

Ethyl (2E/Z,7Z,10Z,13Z,16Z,19Z)---2,7,10,13,16,19- (32)

50 mg specified in the header connection in the form of a mixture of isomers, 1:1, heated to 100 C as in the presence of a catalytic amount of (one drop in the inert atmosphere for three hours. The mixture is cooled and cleaned using a flash chromatography, receiving 20 mg (40%) of pure ethyl (2Z,7Z,10Z,13Z,16Z,19Z)-2---2,7,10,13,16,19- in the form of a pale yellow oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,95 (t, J=7,50 Hz, 3H), 1,23-1,34 (m, 6N), 1,40-of 1.54 (m 2N), 1,95-2,10 m, 4N), 2,22 (kV, J=7,60 Hz, 2H), 2,70-2,90 m, 8H), 3,82 (kV, J=7,05 Hz, 2H), and 4.15-4,26 (kV, J=7,11 Hz, 2H), to 5.21-5,45 (m, 11N), 6,23 (t, J=7,60 Hz, 1H); MC (): 423,3 [M+Na] + .

Example 13

2---2E,7Z,10Z,13Z,16Z,19Z- acid (26)

A mixture of ethyl (2E/Z,7Z,10Z,13Z,16Z,19Z)-2---2,7,10,13,16,19- (32) (E:Z=1:1, 0.40 g, 1.00 mol) in ethanol (8 ml) in inert atmosphere add in a solution LiOH x H 2 O (0.33 g, 8,00 mmol) in water (3 ml). Received muddy mixture is brought to 70 C for 30 minutes and then mix at an ambient temperature within 18 hours. Add 1M HCl to establishing pH=1 and a mixture of double-extracted with heptane (15 ml). The combined organic extracts are dried (Na 2 SO 4 ) and purified using a flash chromatography (heptane:EtOAc, 9:1 and 4:1). This gives 0.18 g (48%) indicated in the header connection 26 in the form of colorless oil. (2E:2Z=1:3).

Z-isomer: δ of 0.91-0.99 (t, J=7.5 Hz, 3H), 1,28 (t, J=7,0 Hz, 3H), 1,48 (kV, J=7,4 Hz, 2N), 1,98-2,09 (m, 4N), 2,24 (kV, J=7.5 Hz, 2H), 2,70-2,90 m, 8H), 3,85 (kV, J=7,0 Hz, 2H), the 5.25-5,40 (m, 10H), 6.42 per (t, J=7.6 Hz, 1H), a 10.74 (., 1H).

E-isomer: δ 0,86 (t, 3H), to 1.34 (t, J=7,0 Hz, 3H), 1,42 (m, 2H), 1,98-2,09 (m, 4H)2,54 (kV, J=7.6 Hz, 2H), 2,70-2,90 m, 8H), to 3.75 (kV, J=6,9 Hz, 2H), to 5.20-5.40 to (m, 11H), a 10.74 (., 1H), (minor isomer);

E - and Z-isomer: 13 C NMR (75 MHz, CDCl 3 ): δ 14.23 per, 15,33, 20,53, 25,52 (2 signal), 25,61 (3 signal), 26,94, 28,45, 28,55, 30,05, 30,34, 68,30, 98,01, 126,99, 127,85, 128,05, 128,07 (2 signal), 128,18, 128,22, 128,25, 128,46, 128,53, 129,33, 131,72, 132,00, 174,90, (both isomers); MC (): 371,2 [M-H).

Example 14

(2E,7Z,10Z,13Z,16Z,19Z)-2---2,7,10,13,16,19--

1-ol (27) and (fully Z) 2---2,7,10,13,16,19--1-ol (34)

LAH (at 0.021 g, 0,55 mmol) suspended in a dry THF (8 ml) and kept at 0 C in an inert atmosphere. To this suspension is added dropwise to the solution of ethyl(2E/Z,7Z,10Z,13Z,16Z,19Z)-2---2,7,10,13,16,19- (32) (1:1, 0.20 g, of 0.50 mmol) in a dry THF (2 ml). The resulting mixture was stirred at 0 C for ten minutes, and then 50 minutes at ambient temperature. Add rich NH 4 Cl (15 ml) and the mixture is extracted twice heptane (20 ml). The combined organic extracts washed with saturated salt solution (15 ml) and dried (Na 2 SO 4 ). Cleaning with the help of a flash chromatography (heptane:EtOAc 9:1) independent of 0.033 g (18%) 2---2E,7Z,10Z,13Z,16Z,19Z--1-ol (27) in the form of colorless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,95 (t, J=7,49 Hz, 3H), 1,28 (t, J=6.96 per Hz, 3H), 1,30-1,44 (kV, J=7,62 Hz, 2H), 1,95-2,09 (m, 6H), 2,70-2,90 m, 8H), 3,68 (kV, J=6,97 Hz, 2H), 4,12 (d, J=5,31 Hz, 2H), 4,46 (t, J=7,58 Hz, 1H), 5,26 is 5.38 (m, 10H); 13 C NMR (50 MHz, CDCl 3 ): δ 14,24, 14,56, 20,53, 25,51, 25,60, 25,74, 26,62, 30,91, 59,43, 62,20, 99,42, 126,99, 127,86, 127,98, 128,05, 128,11, 128,20, 128,39, 128,54, 129,85, 132,01, 153,48 (2 signal hidden); MC (): 381,3 [M+Na] + .

0.11 g (61%) (fully Z) 2---2,7,10,13,16,19--1-ol (34) also emit as a colourless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,94 (t, J=7,51 Hz, 3H), 1,25 (t, J=7,02 Hz, 3H), 1,30-1,50 (kV, J=7,82 Hz, 2H), 1,98-2,15 (m, 6H), 2,70-2,85 m, 8H), 3,84 (kV, J=7,02 Hz, 2H), 4,05 (., 1H), 4,78 (t, J=7,21 Hz, 1H), 5,20-5,45 (m, 10H); 13 C NMR (50 MHz, CDCl 3 ): δ 14,24, 15,53, 20,52, 24,45, 25,51, 25,60, 26,94, 29,61, 62,45, 64,77, 112,63, 126,99, 127,86, 127,92, 128,12, 128,18, 128,45, 128,53, 129,99, 131,99, 152,87 (3 signal hidden); MC (): 381,3 [M+Na] + .

Example 15

Ethyl (2E,4E,8Z,11Z,14Z,17Z)--2,4,6,11,14,17- (12)

Add potassium carbonate (395 mg, 2.9 mmol) in water (286 mm) to vigorously stirred mixture (2E,6Z,9Z,12Z,15Z)--2,6,9,12,15- (370 mg, 1.4 mol) and (344 ml, 1,72 mmol) at room temperature. The mixture is stirred for 48 hours at room temperature, add water and the phases are separated. Aqueous phase is extracted with hexane. The combined organic phase washed with water and dried (MgSO 4 ). Evaporation of solvents under reduced pressure, and then flash chromatography on silica gel (95:5, hexane:EtOAc) give ester (180 mg, 39%) and extracted aldehyde (80 mg). δh (300 MHz): 0,95 (t, J=7.5 Hz, 3H, CH 3 ), 1,26 (t, J=7,1 Hz, 3H), 2,04 (m 2N), in 2.1-2.3 (m, 4N), a 2.7-2.9 (the m, 6N), to 4.17 (kV, J=7,1 Hz, 2H), 5,2-5,5 m, 8H), 5,77 (d, J=15,4 Hz, 1H), a 6.1 and 6.2 (m 2N), 7,22 (DD, J=15,4 Hz, J=9.9 Hz, 1H); δ C (75 MHz) 14,23, 14,28, 20,53, 25,51, 25,60, 25,65, 26,41, 32,88, 60,14, 119,56, 126,97, 127,81, 128,02, 128,20, 128,53, 128,64, 128,75, 132,00, 143,45, 144,77, 167,18.

Example 16

(2E,4E,8Z,11Z,14Z,172)--2,4,8,11,14,17- acid (13)

Ethyl (2E,4E,8Z,11Z,14Z,17Z)--2,4,6,11,14,17- (340 mg, the 1.04 mmol) was dissolved in isopropanol (13 ml), and add LiOH (87 mg, 2.1 mmol) in water (5 ml), and the mixture was stirred at room temperature during the night. The reaction mixture was poured into the water and bring the pH to pH 2-3 using HCl. Solution extracted /hexane, dry MgSO 4 ), and evaporation of solvent under reduced pressure gives acid 13. Acid cleaned using a flash chromatography on silica gel (8:2, hexane:EtOAc); 0,96 (t, J=7.5 Hz, 3H, CH 3 ), 2,04 (m 2N), in 2.1-2.3 (m, 4N), a 2.7-2.9 (the m, 6N), 5,2-5,5 m, 8H), 5,77 (d, J=15,3 Hz, 1H), a 6.1 and 6.2 (m 2N), 7,31 (DD, J=15,4 Hz J=10,1 Hz, 1H); δ C (75 MHz) 14,25, 20,55, 25,54, 25,63, 25,67, 26,33, 32,96, 118,49, 126,99, 127,82, 128,00, 128,26, 128,58, 128,64, 128,88, 132,05, 145,05, 147,26, 172,08.

Example 17

Ethyl (2E,4E,7Z,10Z,13Z-16Z-19Z)--2,4,7,13,16,19- (14)

Stage 1:

Cleaning with the help of a flash chromatography) (heptane:EtOAC, 4:1, then 1:1, then heptane:EtOAc) gives 0.73 g (35%) ethyl (fully Z)-2---4,7,10,13,16,19- as a colourless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,95 (t, 3H), 1,28 (t, 3H), of 2.05 (m, 2H), 2,64 (c, 3H), 2.71 to 2,86 (m, 12H), 3,48 (m, 1H), 4,21 (kV, 2H), 5,27-the 5.49 (m, 12H); MC (): 441,2 [M+Na] + .

Stage 2:

Ethyl (fully Z)-2---4,7,10,13,16,19- (PRB-66, 0.68 g, 1,62 millimole) is dissolved in a dry toluene (40 ml) and add the CaCO 3 (0.16 g, 1,62 mmol). This mixture was stirred at 105 C in an inert atmosphere during three hours, cooled, diluted with heptane (50 ml) and washed 1M HCl (50 ml) and saturated salt solution (50 ml). Organic layer is dried (Na 2 SO 4 ) and purified using a flash chromatography (heptane:EtOAc, 97:3) obtaining 0,38 g (66%) indicated in the header connection 14 in the form of a pale yellow oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,95 (t, J=7,51 Hz, 3H), 1,25 (t, J=7,13 Hz, 3H), of 2.05 (kV, J=7,35 Hz, 2H), 2,76-2,88 (m, 8H), 3,06 (t, J=7,25 Hz, 2H), 4,19 (Quint., J=7,13 Hz, 2H), 5,28-5,44 (m, 10H), 5,70-5,79 (m, 1H), 5,87 (l, J=15,22 Hz, 1H), 6,12 (dt, J=11,53 Hz J=0,71 Hz, 1H), 7,53-7,67 (DDD, J=15,24 Hz J=to 11.61 Hz J=1,02 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ): δ 14,20, 14,24, 20,49, 25,48, 25,57, 25,59, 25,62, 26,50, 60,23, 121,80, 126,45, 126,58, 126,96, 127,68, 127,79, 127,92, 128,26, 128,43, 128,50, 129,40, 131,94, 138,53, 138,86, 167,01; MC (): 377,2 [M+Na] + .

Example 18

(2E,4E,7Z,10Z,13Z,16Z,19Z)--2,4,7,10,13,16,19- acid (15)

Ethyl (2E,4E,7Z,10Z,13Z,16Z,19Z)--2,4,7,13,16,19- (14), (0.26 g, 0.73 mmol) dissolved in EtOH (10 ml) and add the mixture LiOH (0.25 g of 5.9 mmol) in water (2.5 ml). The mixture is stirred at the ambient temperature in inert atmosphere for 17 hours, adding water (20 ml) and 1M HCl to establish pH=1. This mixture is extracted, double-heptane (20 ml) and the organic layer is dried (Na 2 SO 4 ). Cleaning with flashchromatography (heptane:EtOAc, 2:1, then 1:1) gives 0,050 g (21%) indicated in the header connection 15 as a colourless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,95 (t, J=7,54 Hz, 3H), of 2.05 (Quint., J=7,51 Hz, 2H), 2,76-2,88 (m, 9H), 3,06 (t, 2H), 5,31-5,43 (m, 10H), 5,84-5,91 (m, 1H), 5,88 (d, J=15,17 Hz, 1H), 6,16 (dt, J=11,36 Hz, 0,70, 1H), 7,63-7,77 (DDD, J=15,21 Hz J=11,66 Hz J=0,90 Hz, 1H); MC (): 325,1 [M-H).

Example 19

(2E,4E,7Z,10Z,13Z,16Z,19Z)--2,4,7,10,13,16,19--1-ol (16)

Ethyl (2E,4E,7Z,10Z,13Z,16Z,19Z)--2,4,7,10,13,16,19- (14) (0,12 g 0,34 mmol) is dissolved in a dry THF (3 ml) and added dropwise to mixed suspension LAH (0.013 g, 0,35 mmol) in a dry THF (7 ml) at 0 degrees C. the Mixture was stirred at 0 C for 45 minutes, add rich NH 4 Cl (5 ml) and filtered through a thin pad of . Celite washed with water (10 ml) and heptane (10 ml) and the joint water layer extracted with heptane (10 ml). The combined organic layer is dried (MgSO 4 ) and purified using a flash chromatography (heptane:EtOAc, 7:1). This gives kg 0.070 g (66%) indicated in the header connection 16 in the form of colorless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,95 (t, J=7,52 Hz, 3H), of 2.05 (Quint., J=7,34 Hz, 2H), 2,76-2,91 (m, 8H), 2,96 (m, 2H), 4,20 (d, J=5,67 Hz, 2H), 5,28-5,46 (m, 11H), 5,78 and 5.87 (dt, J=15,12 Hz, 5,80 Hz, 1H), 6,00 (t, J=10,81 Hz, 1H), 6,52 (DD, J=15,12 Hz, 11,05 Hz, 1H); 13 C NMR (50 MHz, CDCl 3 ): δ 14,26, 20,55, 22,68, 25,53, 25,65, 26,08, 31,87, 63,49, 126,37, 127,00, 127,60, 127,86, 127,91, 128,02 (2 signal), 128,30 (2 signal), 128,59, 130,40, 132,05, 132,32 (one signal is hidden); MC (): 335,2 [M+Na] + .

Example 20

Ethyl (2E,4E,8Z,11Z,14Z,17Z)-2-methyl--2,4,8,11,14,17- (10)

Triethyl 2- (458 ml 2,13 mmol) add to the suspension of the hydride sodium (88 mg, 60% of the variance in mineral oil, 2.2 mmol) in a dry THF (6 ml) at 0 degrees C. After 50 minutes at 0 C mixture is cooled down to -40 C and type (2E,6Z,9Z,12Z,15Z)--2,6,9,12,15- (500 mg, 1.94 mmol) in THF (1 ml). The mixture is stirred for 60 minutes at a temperature of -40 C to -20 degrees C. Add the saturated aqueous solution NH 4 Cl and the phases are separated. Aqueous phase is extracted with diethyl ether. The combined organic phases are washed with saturated salt solution, water and dried (MgSO 4 ). Evaporation of solvents under reduced pressure gives ester 10.

Example 21

(2E,4E,8Z,11Z,14Z,17Z)-2-methyl--2,4,8,11,14,17- acid (11)

To a solution of ethyl (2E,4E,8Z,11Z,14Z,17Z)-2-methyl--2,4,8,11,14,17- (10) in methanol add aqueous solution of KOH (8 EQ.) and the mixture is heated up to 60-70°C for 2 hours. The solution is cooled, water is added and the mixture was acidified with. The mixture is then extracted . The combined organic phase washed with water and dried (MgSO 4 ). Evaporation of solvents under reduced pressure, and then flash chromatography on silica gel (hexane-EtOAc, 8:2) gives acid 11. δ N (300 MHz): 0,96 (t, J=7.5 Hz, 3H, CH 3 ), 1,91 (d, J=0.75 Hz, 3H, CH 3 ), 2,08 (m, 2H), 2,2-2,4 (m, 4H), a 2.7-2.9 (the m, 6N), 5,2-5,5 m, 8H), 6,11 (dt, J=15,0, J=6,5 Hz, 1H), 6,37 (DD, J=15,0 Hz J=11,3 Hz, 1H), 7,26 (., J=11,3 Hz, 1H); δ (75 MHz), 12,16, 14,24, 20,53, 25,52, 25,61, 25,67, 26,57, 33,24, 124,44, 126,34, 126,97, 127,82, 128,04, 128,21, 128,54, 128,70, 128,74, 132,01, 140,79, 143,47, 174,28.

Example 22

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

Suspension NaH (60% in mineral oil, 0.11 g, 2,79 mmol) in a dry THF (15 ml) lead up to 0 C in an inert atmosphere and added dropwise triethyl 2- (0,66 ml, 2,79 mmol). The mixture was stirred at 0 C for ten minutes, add the solution (2E,6Z,9Z,12Z,15Z)--2,6,9,12,15- (0.48 g 1,86 mmol) in a dry THF (5 ml) and stirred at 0 degrees C for 30 minutes. Mixture is diluted with diethyl ether (30 ml), washed with water (30 ml) and dried (Na 2 SO 4 ). Cleaning with the help of a flash chromatography (heptane:EtOAc, 98:2) gives 0.39 g (59%) of ester 17 (2E:2Z=9:1) in the form of colorless oil.

The mixture of these products purify the second time, this time using flash chromatography using a tool to flash chromatography (heptane:EtOAc, 99:1). This gives 0,095 g (14%) of pure ethyl-(2E,4E,8Z,11Z,14Z,17Z)-2-ethyl--2,4,8,11,14,17- (17) in the form of colorless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,95 (t, J=7,53 Hz, 3H), 1,01 (t, J=7,44 Hz, 3H), 1,28 (t, J=7,12 Hz, 3H), 1,98-2,15 (m, 2H), 2,15-2,29 (m, 4H), 2,38 (kV, J=7,44 Hz, 2H), 2,70-2,90 m, 6H), 4,18 (kV, J=7,11 Hz, 2H), 5,22-5,44 (m, 8H), to 5.98-6,12 (m, 1H), 6,28-6,41 (DD, J=11,20 Hz, J=11,20 Hz, 1H), 7,09 (d, J=11,17 Hz, 1H); 13 C NMR (50 MHz, CDCl 3 ): δ 14,22, 14,30, 20,24, 20,54, 25,52, 25,61, 25,67, 26,65, 33,18, 60,30, 126,05, 126,98, 127,84, 128,09, 128,17, 128,54, 128,64, 128,82, 131,86, 132,01, 137,93, 142,14, 173,05 (one signal is hidden); MC (): to 379.2 [M+Na] + .

A small amount (20 mg, 3%) ethyl (2Z,4E,8Z,11Z,14Z,17Z)-2-ethyl--2,4,8,11,14,17- (35) also emit as a colourless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,95 (t, J=7,52 Hz, 3H), the 1.04 (t, J=7,36 Hz, 3H), 1,29 (t, J=7,14 Hz, 3H), 1,95 of 2.12 (m 2N), 2,15-2,25 (m, 6N), 2,27 (kV, J=7,36 Hz, 2H), the 2.75-2,90 m, 6N), 4,18 (kV, J=7,14 Hz, 2H), 5,22-5,44 (m, 8H), 5,77-5,95 (m, 1H), 6,29-6,34 (DD, J=0,82 Hz J=11,09 Hz, 1H), 6,97-7,11 (DD, J=11,10 Hz J=11,08 Hz, 1H).

Ex 23

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

acid (18)

Ethyl(2E,4E,8Z,11Z,14Z,17Z)-2-ethyl--2,4,8,11,14,17-hexanoate (17) (0,040 g, 0,112 mmol) is dissolved in ethanol (4 ml) and add a solution LiOH x H 2 O (0,038 g, 0,898 mmol) in water (1 ml). The mixture is stirred at room temperature for 15 hours, and then five hours at 70 degrees C. the Mixture is cooled, add 1M HCl to establish pH=1 and dilute with water (2 ml). The mixture is extracted, double-heptane (10 ml) and the combined organic extracts are dried (Na 2 SO 4 ). Cleaning with using flash chromatography (heptane:EtOAc, 95:5, then 4:1) gives 0.028 g (76%) indicated in the header connection in the form of a pale yellow oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,90-1,07 (2 x t, 6H), 2,00-2,10 m 2H), of 2.20-2.30 a (m, 4H), 2,35-2,50 (kV, 2H), the 2.75-2,90 m, 6H), 5,27-5,44 (m, 8H), 6,05-6,20 m, 1H), 6,30-6,43 (m, 1H), 7,50-7,70 (m, 1H); MC (): 327,2 [M-H).

Example 24

(2E,4E,8Z,11Z,14Z,17Z)-2-ethyl--2,4,11,14,17--1-ol (19)

Suspension LAH (0,007 g, 0,168 mmol) in a dry THF (2 ml) is cooled to 0 C in an inert atmosphere. To this suspension is added dropwise to the solution of ethyl(2E,4E,8Z,11Z,14Z,17Z)-2-ethyl--2,4,8,11,14,17- (17) (E:Z=9:1, 0,060 g, 0,168 mmol). The mixture was stirred at 0 C for two hours, and then stirred at room temperature for about 17 hours, and then add rich NH 4 Cl (5 ml). Blend double-extracted with heptane (10 ml), and the combined organic extracts washed with saturated salt solution (10 ml) and dried (Na 2 SO 4 ).

Cleaning with the help of a flash chromatography) (heptane:EtOAc, 6:1) gives 0.030 g (57%) (2E,4E,8Z,11Z,14Z,17Z)-2-ethyl--2,4,8,11,14,17--1-ol (19) in the form of colorless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,95 (t, J=7.5 Hz, 3H), 1,02 (t, J=7.5 Hz, 3H), 1,98-2,09 (m, 2H), 2,12-2,26 (m, 6H), 2,77-2,89 (m, 6H), of 4.07 (c, 2H), 5,27-5,41 (m, 8H), 5,61-5,75 (m, 1H), 5,96 (d, J=10,9 Hz, 1H), 6,20-6,34 (DD, J=10,9 Hz, 14,9 Hz, 1H); 13 C NMR (50 MHz, CDCl 3 ): δ 13,46, 14,24, 20,53, 21,52, 25,51, 25,59, 25,67, 27,11, 32,89, 66,63, 124,91, 125,95, 127,00, 127,90, 128,07, 128,25 (2 signal), 128,51, 129,28, 132,01, 134,33, 141,07; MC (): 337,2 [M+Na] + .

A small amount (2Z,4E,8Z,11Z,14Z,17Z)-2-ethyl--2,4,8,11,14,17--1-ol (36, 0,004 g, 7%) also emit as a colourless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,95 (t, J=7.5 Hz, 3H), 1,05 (t, J=7,5 Hz, 3H), 1,95-2,09 (m, 2H), 2,14-2,24 (m, 6H), 2,76-2,84 (m, 6H), 4,23 (c, 2H), 5,23-5,45 (m, 8H), 5,59-5,74 (m, 1H), 5,89 (d, J=10,9 Hz, 1H), 6,29-6.42 per DD, J=10,9 Hz J=16,8 Hz, 1H).

Example 25

Ethyl (2E/Z,4E,13Z,16Z,19Z)-3-methyl--2,4,13,16,19- (37)

Triethyl-3-methyl-4--2- (0.32 ml, 1,09 mmol) is dissolved in a dry THF (12 ml) and dry DMPU (3 ml) and bring to 0 C in an inert atmosphere. Added dropwise n-BuLi (0,68 ml, 1,09 mmol), the mixture was stirred at 0 C for 20 minutes, and then brought to -78°C. The mixture is stirred at -78°for five minutes, added dropwise (fully Z)--9,12,15- (0,22 g, 0,84 mmol) in a dry THF (3 ml) and mixtures are slowly reach 10oC for 80 minutes. Add rich NH 4 Cl (20 ml) and the mixture is extracted, double-heptane (30 ml). Organic layer is dried (Na 2 SO 4 ) and purified using a flash chromatography (heptane:EtOAc, 98:2). This gives 0.31 g (95%) indicated in the header connection in the form of a mixture of E - and Z-isomer 1:1 in the form of colorless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,95 (t, 6H), 1,20-1,50 m, 26H), 1,95 (c, 3H), 1,98-2,35 (m, 12H), 2,40 (c, 3H), 2,78 (m, 8H), 4,13 (kV, 4H), the 5.25-5,40 (m, 12H), 5,57 (c, 1H), 5,66 (c, 1H), 6,04-6,16 (m, 2H), 7,54 (d, 1H); MC (): 395,3 [M+Na] + .

Example 26

(2E,4E,13Z,16Z,19Z)-3-methyl--2,4,13,16,19- acid (20)

Ethyl (2E/Z,4E,13Z,16Z,19Z)-3-methyl--2,4,13,16,19- (37) (2E:2Z=1:1, 0.30 g, 0,81 mmol) dissolved in EtOH (10 ml) and add LiOH x H 2 O (0.27 g, 6,44 mmol) in water (2.5 ml). The mixture was stirred at 70 C in an inert atmosphere within two hours, cool and add 1M HCl to establish pH=1. The mixture is extracted double-heptane (30 ml) and the joint organic layer is dried (Na 2 SO 4 ). Cleaning with the help of a flash chromatography (heptane:EtOAc, 4:1) gives 0,090 g (32%) indicated in the header connection in the form of colorless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,95 (t, 3H), 1,25-1,50 m, 10H), 1,98-2,15 (m, 7H), 2,20-2,30 (m, 2H), 2,79 m, 4H), 5,27-5,42 (m, 6H), 5,61 (c, 1H), 6,11-6,21 (dt, J=15,8 Hz J=7,0 Hz, 1H), 7,53 (d, J=15,8 Hz, 1H), 11,70 (., 1H); 13 C NMR (75 MHz, CDCl 3 ): δ 14,25, 20,53, 21,33, 25,51, 25,60, 27,21, 29,06, 29,20, 29,26, 29,36, 29,61, 33,41, 115,01, 127,11, 127,59, 127,66, 128,24, 128,26, 130,32, 131,92, 140,31, 153,89, 171,81; MC (): 345,3 [M+H] + , 367,3 [M+Na] + .

Example 27

(2E,4E,13Z,16Z,19Z)-3-methyl--2,4,13,16,19- acid (21)

Suspension LAH (0,011 g, 0,282 mmol) in a dry THF (8 ml) lead up to 0 C in an inert atmosphere and added dropwise to the solution of ethyl (2E/Z,4E,13Z,16Z,19Z)-3-methyl--2,4,13,16,19- (2E:2Z=1:1, 0.10 g, 0,268 mmol) in a dry THF (2 ml). The mixture was stirred at 0 C for one hour, then at ambient temperature for 30 minutes, and then add 10% NH 4 Cl (10 ml). Blend double-extracted with heptane (20 ml) and the combined organic extracts washed with saturated salt solution (20 ml) and dried (Na 2 SO 4 ). Cleaning with the help of a flash chromatography (heptane:EtOAc, 9:1) gives 0.030 g (34%) (2E,4E,13Z,16Z,19Z)-3-methyl--2,4,13,16,19--1-ol (21) in the form of colorless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,96 (t, J=7.5 Hz, 3H), measuring 1.20-1.40 (m, 10H), 1,76 (c, 3H), 1,99-2,13 (m, 6H), 2,76-2,82 (m, 4H), 4,24 (l, J=6,93 Hz, 2H), 5,26-5,41 (m, 6H), 5,54 (t, J=6,9 Hz, 1H), 5,60-5,75 (dt, J=15,6 Hz J=6,9 Hz, 1H), 6,05 (d, J=15,6 Hz, 1H); 13 C NMR (50 MHz, CDCl 3 ): δ 12,59, 14,26, 20,54, 25,51, 25,61, 27,22, 29,18, 29,23, 29,38, 29,48, 29,62, 32,83, 59,35, 127,11, 127,66 (2 signal), 128,26 (2 signal), 130,34, 130,66, 131,94, 133,88, 136,62; MC (): 353,3 [M+Na] + .

(2Z,4E,13Z,16Z,19Z)-3-methyl--2,4,13,16,19--1-ol (38) allocate in the form of colorless oil (0.04 g, 45%)

1 H-NMR (200 MHz, CDCl 3 ): δ 0,96 (t, J=7.5 Hz, 3H), 1,20-1,45 (m, 10H)and 1.83 (c, 3H), 1,98-2,15 (m, 6H), 2,76-2,82 (m, 4H), 4,25 (d, J=7,19 Hz, 2H), 5,26-the 5.49 (m, 7H), 5,68-5,83 (dt, J=15,50 Hz, 6,95, 1H), 6,39 (d, J=15,5 Hz, 1H); 13 C NMR (50 MHz, CDCl 3 ): δ 14,07, 20,59, 22,68, 25,51, 25,60, 27,22, 29,01, 29,22, 29,39, 29,63, 31,87, 33,24, 58,38, 126,06, 126,21, 127,11, 127,67, 128,25 (2 signal), 130,32, 131,93, 133,16, 135,76; MC (): 353,3 [M+Na] + .

Example 28

Ethyl (2Z/2E,4E,13Z,16Z,19Z)-2-ethyl--2,4,13,16,19- (22)

Stage 1:

(0,84 ml, 5,98 mmol) is dissolved in a dry THF (20 ml) and cooled to 0 C in an inert atmosphere. Added dropwise n-BuLi (1,6 M in hexane, to 3.58 ml, 5,72 mmol), the mixture was stirred at 0 C for ten minutes and then cooled to -78°C. Added dropwise

a mixture of ethyl (fully Z)-2-ethyl--4,7,10,13,16,19- (2,00 g, 5,20 mmol) in a dry THF (20 ml) for 20 minutes, the resulting dark green solution is stirred at -78°C for ten minutes, and then add a solution I 2 (1.98 g, 7,80 mmol) in a dry THF (10 ml). The mixture is allowed the opportunity to reach ambient temperature for 80 minutes, distribute between rich Na 2 SO 3 (40 ml) and heptane (40 ml). The water layer is extracted with heptane (40 ml) and the combined organic extracts washed 1M HCl (40 ml) and dried (Na 2 SO 4 ). Cleaning with flash chromatography (heptane:EtOAc, 98:2) gives 1.70 g (64%) ethyl (fully Z)-2-ethyl 2-iodine--4,7,10,13,16,19-. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,88-0,99 (m, 6H), 1,19-1,31 (m, 4H), 1,98-2,19 (m, 4H), the 2.75-2,95 m, 12H), 5,28-5,45 (m, 12H); MC (): 533,2 [M+Na] + .

Stage 2:

Ethyl (fully Z)-2-ethyl-2-iodine--4,7,10,13,16,19- (1.55 g, 3,04 mmol) is dissolved in a dry diethyl ether (50 ml) in inert atmosphere and add DBU (0.45 ml, 3,04 mmol). The mixture is stirred at room temperature for 23 hours, diluted with heptane (50 ml) and the organic layer is washed with rich NH 4 Cl (50 ml). The water layer is extracted with heptane (40 ml) and the combined organic extracts washed 0,1M HCl (40 ml) and dried (Na 2 SO 4 ). Cleaning with using flash chromatography (heptane:EtOAc, 98:2) gives 1,16 g (quantitative.) specified in the header connection 22 (E/Z=4:1) as a colourless oil.

1 H-NMR (200 MHz, CDCl 3 ):

E-isomer: δ 0,84-0,99 (2 x t, 6H), 1,19 of 1.28 (t, 3H), 2,01-2,09 (m, 4H), 2,76-2,95 m, 10H)4,11 (kV, 2H), 5,20-5,45 (m, 10H), 5,55-5,75 (m, 1H), 6,00-6,20 (m, 2H).

Z-isomer: δ 0,84-0,99 (2 x t, 6H), 1,19 of 1.28 (t, 3H), 1,70-1,90 m, 2H), 2,01-2,09 (m, 2H), 2,76-2,95 m, 10H)to 4.23 (kV, 2H), 5,20-5,45 (m, 11H), 5,55-5,75 (m, 1H), 6,10-6,20 (m, 1H). MC (): 405,3 [M+Na] + .

Example 29

(2E,4E,13Z,16Z,19Z)-2-ethyl--2,4,13,16,19--1-ol (23)

Suspension LAH (0,044 g, 1.15 mmol) in a dry THF (10 ml) in inert atmosphere lead up to 0 C and added dropwise mixture of ethyl (2E/Z,4E,7Z,10Z,13Z,16Z,19Z)-2-ethyl--2,4,7,10,13,16,19- (2E:2Z=1:1, 0.40 g, 1,05 mmol) in a dry THF (5 ml). The mixture was stirred at 0 C for one hour, then at ambient temperature for one hour and quenched by the addition of a busy NH 4 Cl (10 ml). Blend double-extracted with heptane (20 ml) and the combined organic extracts washed with saturated salt solution (20 ml) and dried (Na 2 SO 4 ). Cleaning with the help of a flash chromatography (heptane:EtOAc, 9:1) gives 0,110 (31%) (2E,4E,7Z,10Z,13Z,16Z,19Z)-2-ethyl--2,4,7,10,13,16,19--1-ol (23) in the form of colorless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,84-0,99 (2 x t, 6H), 2,01-2,20 m, 4H), 2,77-2,90 m, 8H), 2,92-2,98 m, 2H), 3,50 (m, 2H), 5,28-5,41 (m, 10H)6,00-6,45 (m, 3H); 13 C NMR (50 MHz, CDCl 3 ): δ 11,64, 14,25, 20,54, 24,00, 25,52, 25,62, 25,63, 26,16, 47,80, 65,78, 126,80, 126,99, 127,70, 127,83, 127,97, 128,30, 128,50, 128,56, 128,71, 130,03, 132,02, 132,68, 133,09, 135,51; MC (): 363,2 [M+Na] + .

0,040 g (11%) (2Z,4E,7Z,10Z,13Z,16Z,19Z)-2-ethyl--2,4,7,10,13,16,19--1-ol (39) also emit as a colourless oil. 1 H-NMR (200 MHz, CDCl 3 ): δ 0,86-0,99 (2 x t, 6H), 2,02-2,19 (m, 4H), 2,76-2,90 m 10H), 3,53 (m, 2H), 5,23-5,44 (m, 13H); 13 C NMR (50 MHz, CDCl 3 ): δ 11,38, 14,25, 20,54, 23,41, 25,52, 25,63 (2 signal), 28,51, 42,58, 65,23, 126,99, 127,86, 128,10, 128,12, 128,14, 128,16, 128,26 (2 signal), 128,56, 129,09, 132,03, (3 signal hidden).

Example 30

Ethyl (2E,4E,6E,10Z,13Z,16Z,19Z)-3-methyl--2,4,6,10,13,16,19- (24)

To the solution of ester in methanol add aqueous solution of KOH (8 EQ.) and the mixture is heated up to 60-70°C for 2 hours. The solution is cooled, water is added and the mixture was acidified with. The mixture is then extracted . The combined organic phase washed with water and dried (MgSO 4 ). Evaporation of solvents under reduced pressure gives acid. δ N (300 MHz): 0,95 (t, J=7.5 Hz, 3H, CH 3 ), of 2.05 (2H, m), 2,15-2,25 (4H, m)2.28 in (d, J=0,93 Hz, 3H), a 2.7-2.9 (the m, 6H), 5,2-5,5 m, 8H), 5,75 (., 1H), to 5.85-5,95 (m, 1H), 6,10-6,25 (2H, m), 6,60 (DD, J=15,3 Hz J=10,4 Hz, 1H); δ (75 MHz) 13,91, 14,27, 20,55, 25,54, 25,63, 25,69, 26,76, 32,92, 117,70, 126,99, 127,86, 128,13, 128,17, 128,56, 128,60, 128,92, 130,48, 132,05, 133,54, 135,78, 139,02, 155,21, 172,15.

Biological activity

Case study 1: activating and linking with the domain binding ligand PPARα,y,δ and RXRα man

Measure activating and linking of new compounds with ligand binding domain (LBD) nuclear receptors PPARα, PPARγ, PPARδ or RXRα rights (h).

This study will use the non-stationary system of gene transfection/cell. Himernye constructs derived from LBD person. DBD PPARα, PPARγ, PPARδ or RXRα replace GAL4DBD. Receive the following constructs plasmids: pSG5-GAL4-hPPARα, pSG5-GAL4-hPPARγ, pSG5-GAL4-hPPARδ and pSG5-GAL4-hRXRα. Plasmids, LUC chimeras and reporter LUC in cells COS-1, and protein luciferase system is analyzed, as described in the how to.

Ligand for PPARα (Wy 14,643), ligand for RXRα (9-CIS-retinoic acid) and ligand for PPARγ: that the antidiabetic drug rosiglitazone, and ligand for PPARδ: bezafibrat used as a positive control.

Method:

Fatty acids/ligands

Wy-14.643, 9-CIS-retinoic acid (9-CIS-RA) or that the antidiabetic drug rosiglitazone and new connections (original solutions) diluted to a final concentration of 0,1 M in DMSO. Then diluted to 10 mm in DMSO and stored in 1.5-ml test tubes (, plastic tubes), rinsed with argon and stored at -20 degrees C.

Cell culture

Cells COS-1 (ATCC no CRL 1650) cultured in DMEM supplemented with L- (2 mm), penicillin (50 U./ml), streptomycin (50 mcg/ml), (2.5 mg/ml) and 10% of inactivated FBS. Cells are incubated at 37 C in a humidified atmosphere of 5% CO2 and 95% air and use for non-stationary . Every third day of cells in each flask is separated in the new bulb, containing a fresh environment.

Cells (1.5 x 1 million) placed in 30 mm cups for tissues ( tablets), per 1 day before . Nonstationary using 2000 carried out, as described (Invitrogen, Carlsbad, CA). Each hole takes 990 ng plasmids: 320 ng reporter ((UAS)5-tk-LUC (UAS = above activating sequence and LUC = luciferase system), 640 ng pGL3 main (empty vector) and 30 ng plasmid expression of pSG5-GAL4-hPPARα, pSG5-GAL4-hPPARγ, pSG5-GAL4-hPPARδ or pSG5-GAL4-hRXRα, which are chimeric constructs expression containing domain-binding ligand (LBD) PPARα, PPARγ, PPARδ and RXRα rights (h). LPG, Wy 14.643, 9-CIS-RA or BRL 10 microns) and DHS (control) add to the Wednesday after 5 hour after . cells support within 24 hours before using reporter buffer. Linking LPG or ligands with LBD PPAR activates linking GAL4 with UAS that, in turn, stimulates the promoter of tk to launch luciferase expression. Luciferase activity was measured using a luminometer (luminometer TD-20/20; Turner Designs, Sunnycvale, CA) and normalized on the protein content.

Results:

The results in table 1 show that some of the new compounds covered by the present invention, have the potential selective modulators/activators PPARα (junction 4, 11 and 13). The results also show that some of the compounds are modulators/activators pan PPAR, in addition to the fact that they are ligands RXRα (connection 25).

Table 1 activating enzyme (multiple activation) as a result of binding ligand with new compounds in the the concentration of 10 microns, with the domain binding ligand PPARα, γ and δ in addition to the human RXRα

Connection

hPPARα

hPPARγ

hPPARδ

hRXRα

Negative control

1,00

1,00

1,00

1,00

Wy14643

2,27±0,04

9-(Z)-retinoic acid

2,72±0,32

Bezafibrat

0,99±0,01

That the antidiabetic drug rosiglitazone

13,27±0,56

DHA

1,57±0,19

1,86±0,17

1,09±0,01

0,83 ħ 0.09

4

4,51±0,52

1,56±0,12

1,28±0,08

0,90±0,08

11

6,79±0,21

1,67±0,11

1,17±00,20

0,84 ħ 0.09

13

4,89±0,31

1,63±0,06

1,11±0,16

0,81±0,05

25

8,27±0,81

4,32±0,29

1,47±0,38

1,57±0,08

Examples of research 2: Inhibition of NF-κB in cell lines human monocytes.

Way

Substance

New connections and DHA dissolve to 12.5 microns in DMSO, rinsed with argon and stored at -20 degrees C. 10 microns dexamethasone in DMSO is used as a positive control.

Cell culture

U937 cells-3xkB-LUC (Carlsen, J. Immun, 2002) cultivated in the environment RPMI-1640 with L- (2 nm), penicillin (50 U./ml), streptomycin (50 mg/ml), (75 mg/ml), 10% fetal calf serum at 37 C and 5% CO2 . Cells were seeded in 24-hole tablets where to environment add a 1% calf serum. The activity of NF-kB induce by lipopolysaccharide (LPS) (1 mcg/ml) or TNF-alpha rights (10 ng/ml). The survival rate measure dyeing by blue.

Analysis of the activity of luciferase

1. Lipid connection formula:

where n=0; R 1 and R 2 are similar or different, and can be selected from a group of deputies, consisting of a hydrogen atom, With 1-7 an alkyl group, halogen atom and 1 From 7 ; X represents the COR 3 or CH 2 OR 4 , where R 3 is selected from the group consisting of hydrogen, hydroxy, C 1-7 of alkoxy and amino; and R 4 is selected from the group consisting of hydrogen, With 1-7 alkyl or 1-7 , Y is 9-21 alkene with one or more double bonds in the E - Z-configuration, the chain Y is and contains a double bond in the V-3 position; provided that R 1 and R 2 may not simultaneously represent a hydrogen atom.

2. Lipid compound according to claim 1 having E-configuration, submitted by the following formula:

3. Lipid compound according to claim 1, where R 1 and R 2 are similar or different, and can be selected from a group of deputies, consisting of a hydrogen atom, C 1-7 an alkyl group C 1-7 and halogen atom.

4. Lipid compound according to claim 1, where R 1 and R 2 are similar or different, and can be selected from a group of deputies, consisting of a hydrogen atom, C 1-3-an alkyl group C 1-3 and halogen atom.

5. Lipid compound according to claim 1, wherein R 3 is a C 1-7 .

6. Lipid connection of claim 5, wherein R 3 is a C 1-3 .

7. Lipid compound according to claim 1, wherein R 3 is a .

8. Lipid compound according to claim 1, wherein R 4 is a C 1-7 alkyl group.

9. Lipid compound according to claim 1 or 8, where R 4 is a C 1-3-alkyl group.

10. Lipid compound according to claim 1, wherein R 4 is a C 1-7 group.

11. Lipid connection to 10, where R 4 is a C 1-3 group.

12. Lipid compound according to claim 1, where double bond between carbon atoms 2 and 3 is E-configuration.

13. Lipid compound according to claim 1, where R 1 and R 2 are similar or different, and selected from the methyl group, etilnoy group and hydrogen atoms.

14. Lipid compound according to claim 1, where R 1 and R 2 are different, and one of them is a C 1-3 alkoxy, and the other is the hydrogen.

15. Lipid connection to paragraph 14, where double bond between carbon atoms 2 and 3 is Z-configuration.

16. Lipid compound according to claim 1, of the halogen atom is a fluorine.

17. Lipid compound according to claim 1, where Y is a C 14-19 alkene with 2-6 double bonds.

18. Lipid connection to paragraph 17, where Y is a C 14-19 alkene with 2-6 double bonds in the Z-configuration, alternating with groups.

19. Lipid compound according to claim 1, where n=0, and Y is a C 13-19 alkene, having 2-6 double bonds.

20. Lipid compound according to claim 1, where n=0, submitted by the following formula:

where double bond between carbon atoms 2 and 3 is E-configuration.

21. Lipid compound according to claim 1, where R 1 and R 2 are different, and one of them represents a hydrogen atom, and the other is selected from a group of deputies, consisting of C 1-7 an alkyl group, halogen atom and 1 From 7 .

22. Lipid connection item 21, where double bond between carbon atoms 2 and 3 is E-configuration.

23. Lipid connection item 21 or 22, where n=0; X=COR 3 , where R 3 is a or C 1-3 ; - R 1 and R 2 are different, and one of them is an atom of hydrogen, and the other is a C 1-3-alkyl group, C 1-3 or halogen atom; and Y is a 13-19 alkene, having 2-6 double bonds.

24. Lipid connection item 21, where n=0; X=COR 3 , where R 3 is a or C 1-3 ; - R 1 and R 2 are different, and one of them represents a hydrogen atom, and the other is a C 1-2-alkyl group or C 1-2 ; and Y is a C 13-19 alkene, having 2-6 double bonds.

25. Lipid connection item 21, where n=0; X=COR 3 , where R 3 is a or C 1-2 ; - R 1 and R 2 are different, and one of them represents a hydrogen atom, and the other is a C 1-2-alkyl group or C 1-2 ; and Y is a C 17-19 alkene, having 3-5 double links.

26. Lipid connection item 21, selected from the following lipid compounds 1-4 and 6-8, 26, 33, 41-44:

27. Lipid connection .26 selected from the following lipid compounds 33 and 41-44:

28. Lipid connection item 21, where n=0; X=CH 2 OR 4 , where R 4 is a hydrogen or C 1-3 group; - R 1 and R 2 are different, and one of them represents a hydrogen atom, and the other is a C 1-3-alkyl group, C 1-3 and halogen atom; and Y is a 14-20 alkene, having 2-6 double bonds.

29. Lipid connection item 21, where n=0; X=CH 2 OR 4 , where R 4 is a hydrogen or C 1-3 group; - R 1 and R 2 are different, and one of them represents a hydrogen atom, and the other is a C 1-2-alkyl group or C 1-2 ; and Y is a C 14-20 alkene, having 2-6 double bonds.

32. Lipid compound according to claim 1, where R 1 and R 2 are similar or different, and are chosen from a group of deputies, consisting of 1-7 an alkyl group, halogen atom and C 1-7 .

33. Lipid connection .32 where double bond between carbon atoms 2 and 3 is E-configuration.

34. Lipid connection .32 or 33, where n=0; X=COR 3 , where R 3 is a or C 1-3 ; - R 1 and R 2 are the same or different and selected from C 1 -With 3 an alkyl group C 1-3 and halogen atom; and Y is a 13-19 alkene, having 2-6 double bonds.

35. Lipid connection .32 or 33, where n=0; X=CH 2 OR 4 , where R 4 is a hydrogen or C 1-3 group; - R 1 and R 2 are the same or different and selected from C 1-3-an alkyl group C 1-3 and halogen atom; and Y is a C 14-20 alkene, having 2-6 double bonds.

36. Lipid compound according to claim 1 for use as a drug to treat and/or prevent the state, associated with enhanced features NFkB, treatment and/or prevention of inflammatory diseases or conditions, lowering insulin levels in plasma and/or blood glucose, treatment of insulin resistance, and treatment and/or prevention of resistance of peripheral tissues to insulin and/or diabetic status, such as type 2 diabetes.

37. Pharmaceutical composition, containing a connection on any one of claims 1 to 35, to treat and/or prevent the state associated with enhanced features NFkB, treatment and/or prevention of inflammatory diseases or conditions, lowering levels of insulin in plasma and/or blood glucose, treatment of insulin resistance, and treatment and/or prevention of resistance of peripheral tissues to insulin and/or diabetic status, for example, type 2 diabetes, which was designed to provide daily dose of 5 mg to 10,

38. Pharmaceutical composition on clause 37, which was designed to provide daily dosage of 50 mg to 1 g of the specified connection.

39. Pharmaceutical composition on clause 37, which was designed to provide daily dosage of 50 mg to 200 mg specified connection.

40. Pharmaceutical composition on clause 37, optionally containing pharmaceutically acceptable carrier filler or thinner, or any combination of them.

41. Pharmaceutical composition on clause 37 or 40, intended for oral administration.

42. Way to treat and/or prevent the state associated with enhanced features NFkB, including the introduction of a mammal, in need of this, pharmaceutically active number of connections on any one of claims 1 to 35.

43. Method of treatment and/or prevention of inflammatory diseases or conditions, including the introduction of a mammal, in need of this, pharmaceutically active number of connections on any one of claims 1 to 35.

44. Way of lowering the levels of insulin in the plasma, blood glucose and treatment of insulin resistance, including the introduction of a mammal, in need of this, pharmaceutically active number of connections on any one of claims 1 to 35.

45. A method of treating and/or preventing resistance of peripheral tissues to insulin and/or diabetic status, for example, type 2 diabetes, including the introduction of a mammal, in need of this, pharmaceutically active number of connections on any one of claims 1 to 35.