Conjugated lipid derivatives

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 α,β-unsaturated derivatives of fatty acids, unsaturated fatty acids, to methods of making such compounds, pharmaceutical and lipid compositions containing these compounds and to uses of these compounds and compositions in medicine.

The level of technology

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

PUFA or their metabolites, as shown, modulate gene transcription through interaction with several nuclear receptors. They are activated peroxisomal proliferator receptors (PPAR), a nuclear receptor of hepatocytes (HNF-4), X receptor liver (LXR) and the receptor for 9-CIS-retinoic acid (retinoic 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 binding of fatty acids with a transcription factor, but include mechanisms that affect the nuclear content of transcription factors.

Regulation of gene transcription using PUFA has a marked effect on the metabolism of cells and tissues and provides a credible explanation involving interactions nutrient-gene in the initiation and prevention or relief of diseases such as obesity, diabetes, cardiovascular disorders, immune-inflammatory diseases and cancer (Wahle, J., et al., Proceedings of Nutrition Society, 2003, 349).

Fish oils enriched in ω-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as shown, to reduce the risk of cardiovascular disease, in part by lowering the concentration of triglycer the species in the blood. This beneficial effect occurs mainly due to the combined effects of inhibition of lipogenesis by reducing the content SPEBP-1 and stimulation of fatty acid oxidation through activation of PPAR-α in the liver.

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

DHA is the most common ω-3 PUFA in most tissues and is contained in large quantities in neural membranes, accounting for approximately 30-40% of the phospholipids of the gray matter of cerebral cortex and photoreceptor cells in the retina. DHA accumulates at high levels in the postnatal CNS of mammals, showing that DHA is involved in the maturation of the CNS. There are several different types of lower levels of DHA in the brain and in the retina are associated with weakening of neural and visual function. Adding DHA may be useful in the treatment of depression, schizophrenia, hyperactivity, multiple sclerosis, Alzheimer's disease, degenerative sableman the th retina and peroxisomal disorders (Horrocks and Farooqui, Prostaglandins, Leukotrienes and Essential Fatty acids, 2004, 70, 361). Dietary DHA may 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 ω-3 PUFA have many positive biological impacts, their therapeutic value is limited, and therapeutic area, where ω-3 PUFA are the most promising, is a cardiovascular area, as agent for lowering the levels of triglycerides. However, in order to cause hypolipidemia required high doses of polyunsaturated fatty acids. One of the reasons is the degradation of polyunsaturated fatty acids in the liver by oxidation.

Nuclear receptors (NR) are a large and very conservative family of ligand-activated transcription factors that regulate diverse biological processes such as development, metabolism and reproduction. It is noticed that the ligands for these receptors can be used in the treatment of common diseases, such as atherosclerosis, diabetes, obesity and inflammatory diseases. As NR become important targets for drugs, and the identification of new ligands NR is of great interest. The activity of many nuclear receptors is controlled by swazilan what I small lipophilic ligands, which include hormones, metabolites, such as fatty acids, bile acids, existieren and Xeno - and endobiotic. Nuclear receptors can bind as monomers, homodimers or heterodimers with RXR DNA. There are three types of heterodimeric complexes: unoccupied heterodimer, nopermission heterodimer that can only be activated by ligands partners, but not the only one RXR ligand, and the permissive heterodimer, which can be activated using either RXR ligands or receptor-partner, and are synergistic in the presence of both ligands (Aranda and Pascual, Physiological Reviews, 2001, 81, 1269). As an obligatory heterodimeric partner for many nuclear receptors including the receptor for vitamin D (VDR), the receptor for thyroid hormone (TR), the receptor for all-TRANS retinoic acid (RAR), activated peroxisomal proliferator receptor (PPAR), X receptor liver (LXR) and others) RXR plays a role of the main coordinator of the set of paths nuclear receptors.

Ligands that regulate heterodimeric partner 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 is associated with abundant lipid ligands, oblad the sponding lower affinity (PPAR, LXR), and, apparently, act partially as lipid biosensors. Genes regulated by heterodimeric RXR include genes involved in various cellular processes, including cell cycle regulation and differentiation. They also regulate genes involved in transport, biosynthesis and metabolism of lipids (Goldstein, J.T. et al., Arch. Biochem. and Biophys., 2003, 420, 185).

Related RXR ligand is a 9-CIS-retinoic acid, a molecule that also binds to RAR and transactional them with very similar affinity and efficiency. On the other hand, all-TRANS-retinoic acid, a related ligand, RAR, it binds to the receptor RXR.

There is evidence that the RXR ligands can act as insulin sensitizers and can reduce hyperglycemia, hyperinsulinemia and hypertriglyceridemia in mice ob/ob and db/db (Mukherjee et al., Nature, 1997, 386, 407). It is also reported that chronic administration of RXR agonists to rats Zucker fa/fa reduces food intake and increased body weight, lowers the concentration of insulin in plasma, at the same time supporting normoglycemia (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 mouse brain, selectively activates RXR in the analysis of cell-based (Urquiza et al., Science 2000, 290, 2140, WO 01/73439). In these studies, DHA activates RAR. After this is about reported, several unsaturated fatty acids, including DHA, arachidonic acid and oleic acid, may be specific to bind and activate LBD (domain binding ligand) RXRα and therefore act as ligands in vivo of this receptor (Lengquist J., et. al. Molecular & Cellular Proteomics 3, 2004, 692). In research published by Fan et al., it is shown that DHA acts as a specific ligand for activation of RXRα in relation to n-6 PUFA in colonocytes (Carcinogenesis, 2003, 24, 1541).

Although RXR agonists are known, and these compounds were investigated on various biological systems, the literature does not describe the use of modified PUFA as potent ligands for RXR.

The transcription factor NF-κB is an inducible eukaryotic transcription factor of the rel family. It is a main component of the cascade of stress reactions, which regulates the activation of genes early response, involved in the expression of inflammatory cytokines, adhesion molecules, heat shock proteins, cyclooxygenase, lipoxygenase and redox enzymes. Zhao, G. et al. (Biochemical and Biophysical Research. Comm., 2005, 909) suggest that the anti-inflammatory effects of PUFA in the cells of human monocytes THP-1 partially mediated by by inhibiting activation of NF-κB through the activation of PPAR-γ. Others suggest that protivo Sporitelna impact PUFA mediated through PPAR-dependent-α inhibition of activation of NF-κB.

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

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

Since many nuclear receptors are distributed differently in different tissues, I what is important getting ligands, able in vivo to target these cells to bind and activate target receptor.

The invention

One of the purposes of the present invention is a lipid compounds having pharmaceutical activity.

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

where

- R1and R2are the same or different and may be selected from the group of substituents consisting of a hydrogen atom, alkyl group, halogen atom and alkoxy group;

- X represents a COR3or CH2OR4where

- R3selected from the group consisting of hydrogen, hydroxy, alkoxy, amino,

where X further includes derivatives of carboxylic acids when R3represents hydroxy; and

- R4selected from the group consisting of hydrogen, alkyl, or acyl,

- Y represents a C9-C21alkene with one or more double bonds with E - or Z-configuration.

or any pharmaceutically acceptable complex, MES or prodrugs.

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

When X is represented by the formula COR3and R3PR is dstanley a hydroxy, the present invention also relates to derivatives of carboxylic acids. For example, such derivatives of carboxylic acids may be selected from the group consisting of a phospholipid or mono-, di - or triglyceride.

In the lipid compound of the present invention R1and R2in the formula (I) are the same or different and may be selected from the group of substituents consisting of a hydrogen atom, a C1-C7alkyl group, a C1-C7alkoxy group and halogen atom.

Preferably, R1and R2are the same or different and selected from the group of substituents consisting of a hydrogen atom, a C1-C3alkyl group, a C1-C3alkoxy group and halogen atom. More preferably, R1and R2are the same or different and selected from methyl group, ethyl group and a hydrogen atom.

When R1and/or R2represent halogen atoms, preferred is a fluorine atom. In the lipid compound according to the present invention, X can be represented by the formula COR3. In such cases, R3can be a C1-C7-alkoxy group, or, more specifically, C1-C3the alkoxy group. Alternative, R3represents a hydroxy group.

In alternative embodiments, implementation of the X prex is represented by the formula CH 2OR4. In such scenarios, the implementation of R4can be a C1-C7is an alkyl group or, more specifically, C1-C3is an alkyl group. Alternative, R4represents a C1-C7acyl group, in particular C1-C3acyl group.

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

In embodiments implementing the present invention, where R1and R2are different and one represents a C1-C3alkoxy and the other represents hydrogen, a 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 C9-C21alkene with one or more double bonds with E - or Z-configuration. In particular, Y represents C14-C19alkene from 2 to 6 double bonds. In the variants of implementation Y represents a C14-C19alkene with 2-6 double bonds in Z - configuration, alternating with methylene groups. Alternatively, Y is unsubstituted. In preferred embodiments, the implementation of the present invention the lipid compound contains a double bond carbon-carbon ω-3 position Y.

Lipid connect the means of the present invention can be divided into categories in accordance with the number of conjugated systems, represented by an integer n in parentheses in the formula (I) or (II). As defined, n may vary between 0 and 2.

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

In addition, the lipid compounds represented by formula (III) according to the present invention, can be divided into sub-categories in the following preferred groups:

IIIa: X=COR3

• X=COR3where R3represents a hydroxy group or a C1-C3alkoxy group;

• R1and R2are the same or different and selected from hydrogen, C1-C3alkyl group, a C1-C3alkoxy group and halogen atom, and

• Y represents a C13-C19alkene having 2 to 6 double bonds.

IIIb: X=COR3R1≠ R2

• X=COR3where R3represents a hydroxy group or a C1-C2alkoxy group;

• R1and R2are different, and one of them is a hydrogen atom and the other is C1-C2alkyl group or a C1-C2alkoxy group; and

• Y represents a C17-C19alkene having 3-5 double bonds.

Preferred compounds of formula (III) and subgroups IIIa or IIIb represent the following lipiany the compounds 1-4, 6-8 and 26:

IIIc: X=CH2OR4

• X=CH2OR4where R4represents hydrogen or C1-C3acyl group;

• R1and R2are the same or different and selected from hydrogen, C1-C3alkyl group, a C1-C3alkoxy group and halogen atom, and

• Y represents a C13-C19alkene having 2 to 6 double bonds.

IIId: X=CH2OR4R1≠ R2

• X=CH2OR4where R4represents hydrogen; and

• R1and R2are different, and one of them is a hydrogen atom and the other is C1-C2alkyl group or a C1-C2alkoxy group;

• Y represents a C17-C19alkene having 3-5 double bonds.

Preferred compounds of formula (III) and subgroup IIIc and IIId are these lipid compounds 5, 9 and 27:

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

In addition, the lipid compounds represented by formula (IV) according to the present invention, can be divided into sub-categories in the following preferred groups:

IVa: X=COR 3

• X=COR3where R3represents a hydroxy group or a C1-C3alkoxy group;

• R1and R2are the same or different and selected from hydrogen, C1-C3alkyl group and halogen atom; and

• Y represents a C11-C17alkene having 2 to 6 double bonds.

IVb: X=COR3R1≠ R2

• X=COR3where R3represents a hydroxy group or a C1-C2alkoxy group; and

• R1and R2are different, and one of them is a hydrogen atom and the other is C1-C2alkyl group;

• Y represents a C15-C17alkene having 3-5 double bonds.

Preferred compounds of formula (IV) and sub-groups IVa and IVb are these lipid compounds 10-11, 17-18, 20, and 22.

IVc: X=COR3R1=R2

• X=COR3where R3represents a hydroxy group or a C1-C2alkoxy group;

• R1and R2represent hydrogen; and

• Y represents a C11-C17alkene having 2 to 6 double bonds.

IVd: X=COR3R1=R2

• X=COR3where R3represents a hydroxy group or a C 1-C2alkoxy group;

• R1and R2represent hydrogen; and

• Y represents a C15-C17alkene having 4-5 double bonds.

Preferred compounds of formula (IV) and subgroup IVc and IVd are these lipid compounds 12-15:

IVe: X=CH2OR4

• X=CH2OR4where R4represents a hydrogen atom or a C1-C3acyl group;

• R1and R2are the same or different and selected from hydrogen, C1-C3alkyl group and halogen atom; and

• Y represents a C11-C17alkene having 2 to 6 double bonds.

IVf: X=CH2OR4R1≠ R2

• X=CH2OR4where R4represents hydrogen;

• R1and R2are different, and one of them is a hydrogen atom and the other is C1-C2alkyl group; and

• Y represents a C15-C17alkene having 3-5 double bonds.

Preferred compounds of formula (IV) and subgroups IVe and IVf are these lipid compounds 19, 21 and 23:

IVg: X=CH2OR4R1=R

• X=CH2OR4where R4represents hydrogen;

• R1and R2are the same and represent hydrogen atoms; and

• Y represents a C11-C17alkene having 2 to 6 double bonds.

IVh: X=CH2OR4,R1=R2

• X=CH2OR4where R4represents hydrogen;

• R1and R2are the same and represent hydrogen atoms; and

• Y represents a C17alkene with 5 double bonds.

A preferred compound of formula (IV) and subgroups IVg and IVh represents the lipid connection 16:

When n=2, a lipid compound according to the present invention relates to formula (V)

In addition, the lipid compounds represented by formula (V) according to the present invention, can be divided into sub-categories in the following preferred groups:

Va: X=COR3

• X=COR3where R3represents a hydroxy group or a C1-C3alkoxy group;

• R1and R2are the same or different and selected from hydrogen, C1-C3alkyl group and halogen atom; and

• Y represents a C9-C16alkene having 1-4 double bonds.

Vb: XCOR 3R1≠ R2

• X=COR3where R3represents a hydroxy group or a C1-C2alkoxy group;

• R1and R2are different, and one of them is a hydrogen atom and the other is C1-C2alkyl group; and

• Y represents a C15alkene having 4 double bonds.

Preferred compounds of formula (V) and sub-groups Va and Vb represent the following lipid compounds 24 and 25:

The present invention also relates to a method for producing a lipid compound according to any of formulas (I)to(V) of the present invention.

In addition, the present invention relates to a lipid compound according to any of formulas (I)-(V) for use as a medicament or for diagnostic purposes, for example, positron emission tomography (PET).

The present invention also relates to pharmaceutical compositions containing the lipid compound according to any one of General formulas (I)-(V). The pharmaceutical composition may contain a pharmaceutically acceptable carrier, excipient or diluent, or any combination, and accordingly it is intended for oral administration. The corresponding daily dose of lipid in connection with the compliance with any of the formulas (I)-(V) is from 5 mg to 10 g of the indicated lipid compounds; from 50 mg to 1 g of the indicated lipid compounds or from 50 mg to 200 mg of the indicated lipid connection.

The present invention also relates to a lipid composition comprising a lipid compound according to any of formulas (I)-(V). Accordingly, at least 80 wt. -%, or, at least 90 wt. -%, or, at least 95% of the mass. lipid composition consists of the indicated lipid compounds. The lipid composition may further comprise pharmaceutically acceptable antioxidant, such as tocopherol.

In addition, the present invention relates to the use of a lipid compound according to any of formulas (I)-(V) to obtain the drug for

• activate or modulate at least one of the isoforms α, γ and/or δ-activated peroxisomal proliferator receptor (PPAR) person;

• activating or modulating RXR;

• inhibition or regulation of NF-ΚB;

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

• lowering insulin levels in plasma, blood glucose and/or triglyceride;

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

• significant others and/or treatment gipolipidemicheskoe state, for example hypertriglyceridemia (HTG);

• treatment and/or prevention of obesity or condition with overweight;

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

• reduce body weight and/or to 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 a condition of excessive body weight; and

• treatment and/or prevention of type 2 diabetes.

The present invention also relates to lipid compounds according to any of formulas (I)-(V) for the treatment and/or prevention of the conditions listed above.

In addition, the present invention relates to methods for treating and/or preventing conditions listed above, comprising the administration to a mammal in need of this, a pharmaceutically active amount of a lipid compound according to any of formulas (I)-(V).

Detailed description of the present invention

Suddenly discovered that the new polyunsaturated derivatives represented by the General formulas (I)to(V)have a greater affinity for the nuclear receptors of the PPAR family compared to DHA and EPA. Derivatives give the ago the East RXR, more potent than DHA.

RXR/PPAR represents the permissive heterodimer, which synergistically activated in the presence of both ligands. Since the new compounds of the present invention are ligands 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 tissue-specific ligands for nuclear receptors.

In addition to the fact that they are the best ligands for PPAR and RXR, derivatives of the present invention is not are being degraded easily by using ways of α - and β-oxidation, as natural PUFA, because of the substituent in the α - or β-position.

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

In addition, it provides new compounds that gain the functionality of retinoids: retinol and retinal. These compounds represent Proletarska, which are activated in vivo by using ways to oxidation.

Nomenclature and terminology

The lipid compounds of the present invention is Vlada substituted on carbon atom 2 and/or 3, counting from the functional group denoted by X in formulas (I)-(V). Such substitution may be called "alpha-substitution" or "beta-substitution". In the lipid compounds of the present invention there is a double bond between carbon atoms 2 and 3, which preferably isin the E-configuration.

As used here, the term "position of the ω-3" means that the first double bond exists as the third bond carbon-carbon end-end-CH3(ω) carbon chain.

In chemistry the numbering of the carbon atoms starts with α-end. Fatty acids are hydrocarbons with a straight chain having a carboxyl (COOH) group at one end (α) and (usually) a methyl group at the other (ω) the end.

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

In connection in accordance with the present invention mentioned alkyl group may be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and n-hexyl; specified halogen atom may be a fluorine, specified alkoxy group may be selected from the group consisting of methoxy, ethoxy about is hydroxy, isopropoxy, sec-butoxy, OCH2CF3and OCH2CH2OCH3;

Here, the indicated acyl group is a compound of the formula:

where A represents a C1-C7alkyl.

The main object of the present invention is a lipid compound of formula (I):

where

- R1and R2are the same or different and may be selected from the group of substituents consisting of a hydrogen atom, alkyl group, halogen atom and alkoxy group;

- X represents a COR3or CH2OR4where

- R3selected from the group consisting of hydrogen, hydroxy, alkoxy, amino,

where X further includes derivatives of carboxylic acids when R3represents hydroxy; and

- R4selected from the group consisting of hydrogen, alkyl, or acyl,

- Y represents a C9-C21alkene with one or more double bonds with E - or Z-configuration.

or any pharmaceutically acceptable complex, MES or prodrug.

Preferably, the lipid compound of the present invention represents an E-isomer and is represented by the formula (II):

When n=0, lipid compound of the present invention to depict what Avelino formula (III):

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

When n=2, a lipid compound of the present invention represented by formula (V):

The compounds mentioned above can be divided into subcategories based on whether an X COR3or CH2OR4on the basis of the substituents R1and R2and whether R1and R2different or the same, as well as on the basis of the length and number of double bonds in the chain y is Particularly preferred compounds are compounds (1)to(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

General formula (I)

Z - and E-isomers of the compounds described by the General formula (I), may be released from mixtures using various separation technologies. Flash chromatography (silica gel) is a common separation technology. Z - and E-isomers of the compounds described by the General formula above may be allocated in the form of esters of carboxylic acids, others, such as carboxylic acids or alcohols, with the help of a flash XP is matography. Carboxylic acids can re-tarifitsirovatsja through the use of primary alcohols and acid catalyst (H2SO4, HCl, BF3). The alcohols can be oxidized to obtain carboxylic acid.

Category A-1, Z - and/or E-isomers, n=0, X=COR3

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

X = ethylcarboxylate

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

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

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

Category A-2, Z - and/or E-isomers, n=0, X=CH2OR4

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

n=0

R4=H

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

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

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

Category A-1, n=1, X=COR3and X=CH2OR4

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

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

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

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

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

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

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

Category B: E-isomers

General formula (II), preferably where

Y=C9-C21alkene with one or more double bonds with E - or Z-configuration. X = hydroxymethyl (-CH2OH), a carbaldehyde (-C(O)H), or carboxylic acid, or its derivative, carboxylate, carboxylic acid anhydride or carboxamide. Each of R1and R2that may be the same or different, represents a hydrogen atom, a fluorine atom, alkoxy group or alkyl group.

Category B-1; E-isomers, n=0-2 and X=COR3

Category B-2; E-isomers, n=0-2 and X=CH2OR4

Category B-1; n=0, X=COR3and R=OCH2CH3

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

n=0

X = ethylcarboxylate

Ethyl (2E7Z,10Z,13Z,16Z,19Z)-2-methyl-docosa-2,7,10,13,16,19-hexenoate (1)

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

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

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

Category B-1: n=0, X=COR3and R3=OH

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

n=0

R3= hydroxy (OH)

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

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

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

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

Category b-2, n=0, X=CH2OR4and R4=H

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

n=0

Deputy represents alkyl or ethoxy.

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

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

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

Category B-1, E-isomer is, n=1

Formula (IV)

n=1

Category B-1, n=1 and X=COR3and R3=OCH2CH3

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

n=1

X=COR3

R3=OCH2CH3

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

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

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

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

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

Category B-1, E-isomers, n=1 and X=COR3and R3=OH

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

n=1

X=COOH

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

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

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

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

(2E,4E,13Z,16Z,19Z)-3-methyl-docosa-2,4,13,16,19-pontenova acid (0)

Category B-2, E-isomers, n=1, X-CH2OR4and R4=H

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

n=1

X=CH2OR4

R4= hydrogen (H)

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

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

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

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

Category B, TRANS-isomers, n=2

Formula (V)

n=2

Category B-1, n=2, X=COR3and R3=OCH2CH3

For example in this category (24):

n=2

X=COR3

R3=OCH2CH3

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

Category b-1, n=2, X=COR3and R3=OH

For example in this category (25):

n=2

X=COR3

R3= hydroxyl (OH)

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

You should understand that the present invention covers the NY possible pharmaceutically acceptable complexes, the solvate or prodrug of lipid compounds of formulas (I)-(V).

"Prodrugs" are substances, which may or may not possess pharmacological activity themselves, but can be entered (for example, oral or parenteral) and then subjected to biological activation (e.g., b) in the body with the formation of the agent according to the present invention, which is pharmacologically active.

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

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

"Pharmaceutically active amount" refers to the quantity that will produce the desired pharmacological and/or therapeutic effects, i.e. to the amount of lipid compound that is effective to achieve assume the th target. Although the needs of individual patients may vary, determination of optimal ranges of effective amounts of lipid compounds is within the knowledge specific to this region. Generally, the dosage regimen for treating the condition with the compounds and/or compositions of the present invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient.

Under "drug" refers to a lipid compound according to any of formulas (I)to(V), in any form, suitable for use in medical applications, for example in the form of a medical product, pharmaceutical composition, or product, diet product, food toppings or nutritional supplements.

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

Lipid compounds of formulas (I)to(V) can be used by themselves, but as a rule, will be introduced in the form of pharmaceutical compositions in which compounds of formulae (I)-(V) (active ingredient) are in Association with FA is matemticas acceptable carrier, filler or diluent (including combinations thereof).

Acceptable carriers, excipients and diluents for therapeutic use are well known in the pharmaceutical field and can be selected in connection with the proposed route of administration and standard pharmaceutical practice. Examples include binders, lubricants, suspendresume agents, agents for coating, solubilizing agents, preserving agents, wetting agents, emulsification, sweeteners, colorants, flavoring agents, fragrances, buffers, suspendresume agents, stabilizing agents and/or salt.

The pharmaceutical composition in accordance with the present invention is preferably intended for oral administration to a human or animal. The pharmaceutical composition may also be intended for introduction via any other method in which the active ingredients can effectively be absorbed and used, for example, intravenously, subcutaneously, intramuscularly, intranasally, rectally, vaginally, or topically.

In a specific embodiment of the present invention the pharmaceutical composition is formed in the form of a capsule, which may be a microcapsule generating powder or sachet. The capsule can aromatizirovat. This option is done by the means also includes a capsule, where as capsule and encapsulated composition in accordance with the present invention is flavored. By flavoring capsule becomes more attractive for the consumer. For the above therapeutic applications of the introduced dose will, of course, to change together with your connection with the method of administration, the desired treatment and shows disorder.

The pharmaceutical composition can be prepared by receiving daily doses, for example, from 5 mg to 10 g of 50 mg to 1 g; or from 50 mg to 200 g of lipid compounds. Daily dosing means for dosing within 24 hours.

Injected dose will, of course, to change together with your connection, by way of introduction, the desired treatment and shown the disorder. Typically, the physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular patient may vary and will depend on various factors, including the activity of the specific compound, the metabolic stability and length of action of that compound, the age, body weight, General health, sex, diet, mode and time of administration, rate of excretion, the combination of Les is arctonyx funds the severity of the condition and the individual undergoing therapy. Lipid compound and/or pharmaceutical composition of the present invention may be administered in accordance with the mode from 1 to 10 times a day, for example once or twice a day. For oral and parenteral administration to patients-the people, the daily dosage of the agent can be in single or in divided doses.

An additional aspect of the present invention relates to a lipid composition comprising a lipid compound of any of formulas (I)-(V). The lipid composition may contain from 80 to 100% of the mass. lipid compounds of formulas (I)to(V)all interest mass refers to the total weight 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 of any of formulas (I)-(V).

In specific embodiments, the implementation of the present invention the lipid composition is a pharmaceutical composition, a food composition or dietary composition.

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

Lipid modifications the texts 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, the lipid compound according to any of formulas (I)to(V) can activate the nuclear receptors PPAR (activated peroxisomal proliferator receptor), isoforms α and/or γ and/or δ and RXR.

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

Particularly preferred compounds for the inhibition and/or regulation of NFκB are compounds of the formulas (IV) and (V), i.e. lipid compounds represented by n=1 or n=2. Preferably, R1is represented by a hydrogen atom.

The present invention also provides the use of a lipid compound according to any of formulas (I)-(V) for the manufacture of a medicinal product for treating and/or preventing an inflammatory disease or condition.

Particularly preferred compounds for the treatment and/or prevention of an inflammatory disease or condition are compounds of the formulas (IV) and (V), i.e. lipid compounds represented by n=1 or n=2. Preferably, R1is represented by a hydrogen atom.

In an additional aspect, the present invention relates to the use of lipid compounds in soo is according to any of formulas (I)-(V) for the manufacture of a medicinal product, designed to reduce insulin levels in plasma, blood glucose and/or triglycerides in the serum.

In another aspect, the present invention relates to the use of a lipid compound according to any of formulas (I)-(V) for the manufacture of a medicinal product intended for the prevention and/or treatment of elevated levels of triglycerides, LDL cholesterol and/or VLDL cholesterol, gipolipidemicheskoe state, for example, hypertriglyceridemia (HTG), obesity or a condition of excessive body weight, weight gain, liver disease, associated with fatty acids, in particular non-alcoholic fatty liver disease (NAFLD), insulin resistance, hyperlipidemia, resistance of peripheral tissues to insulin and/or diabetic status, in particular type 2 diabetes.

The present invention also relates to lipid compounds according to any of formulas (I)-(V) for the treatment and/or prevention of the conditions listed above.

In addition, the present invention relates to methods for the treatment and/or prevention of conditions listed above, comprising the administration to a mammal in need of this, a pharmaceutically active amount of a lipid compound according to any of formulas (I)-(V).

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

In addition to pharmaceutical applications of lipid compounds according to any of formulas (I)to(V) can be used as food additives. For this reason, in an additional aspect, the present invention provides a food product, food Supplement, dietary Supplement or nutraceutical product containing lipid compound according to any of formulas (I)-(V).

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

In addition, in one of its aspects the present invention provides a radioactively labeled analogs of the compounds in accordance with formula (1). Such radioactively labelled analogues are particularly suitable for use in diagnostic methods, for example, upon receipt of the PET images.

Many of the intermediates formed during retrieval of lipid compounds of the present invention, are themselves new and useful compounds, and they form an additional aspect of the present izaberete the Oia. Specific examples of such intermediates can be found in the schemes of reactions below.

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

Example 1

Total synthesis

Lipid compounds of General formula (I) can be obtained by combination reactions referirovanija CARBONYLS, such reactions type Wittig reaction Peterson or reactions Julia. More specifically, the lipid compounds of General formula (I), where R1and R2represent hydrogen and X represents a carboxylate, obtained using the following methods.

Reaction of aldehyde (i) with phosphoryl-stabilized carbanion [(RO)2P(O)C-HCO2R1(ii) gives mainly (E)-α,β-unsaturated ester (iii) as the main product. Phosphoryl-stabilized carbanion can be generated by processing triethylphosphate or trimethylphosphate base, for example alkali metal hydride such as sodium hydride, metal alkoxide such as sodium methoxide, ORGANOMETALLIC compound, such as utility, amidon metal, such as lithium diisopropylamide, or other reasons in a solvent such as DME (dimethoxyethane), tetrahydrofuran, benzene, toluene. The reaction may be carried out is taken at the reaction temperature from -78°C to room temperature. Ester (iii) can hydralicious in a solvent such as ethanol or methanol, to form a carboxylic acid by adding a base such as lithium hydroxide/sodium/potassium in water at temperatures in the range of between 10-90°C. it Then, if desired, may tarifitsirovatsja or lidirovala. Ester (iii) can be restored to alcohol or aldehyde.

Lipid compounds of General formula (I), where R1represents an alkyl group, fluorine or alkoxy group, R2represents hydrogen and X represents a carboxylate, obtained using the following methods.

The method is similar to phase 1 except that the phosphonate substituted in position 2 alkyl group, fluorine or alkoxy group.

Lipid compounds of General formula (I), where R2represents an alkyl group, and R1represents hydrogen, and X is a carboxylate, can be obtained using the following methods.

Method 1the reaction Horner-Wordsworth-Emmons:

Method 2the reaction Peterson:

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

In stage 4 enolate α-trim is alililizslina used for the synthesis of α,β-unsaturated complex ester (vii) of the ketone (vi).

Lipid compounds of General formula (I), where R2represents an alkyl group, and R1represents hydrogen, and X is a carboxylate, can also be obtained using the following methods.

Unsaturated aldehydes, Y-C(O)H, can be obtained directly from esters of carboxylic acids existing in nature unsaturated fatty acids; alpha-linolenic acid, oleic acid, conjugated linoleic acid, linoleic acid, eicosapentaenoic acid, and the like through recovery using diisobutylaluminium hydride at -78°C or by using a two-step procedure, including recovery of the alcohol, and then oxidation to the 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, you can start with purified EPA or DHA, but you can also start with fish oil containing EPA and DHA in the mixture. The reason for this is that the DHA reacts faster than the EPA, in the reaction of iodoacetonitrile, with the formation of iodine-δ-lactone (Corey et al., Proc. Natl. Acad. Sci. USA, 1983, 3581, Wright et al., J. Org. Chem., 1987, 4399, Kuklev et al., Phytochemistry, 1992, 2401). Aldehydes can also be obtained from α,β-unsaturated esters covered by the present invention, e is the PTO recovery using hydride diisobutylaluminum at -78°C or by using a two-stage procedure, including the recovery of the alcohol, and then oxidation to the aldehyde.

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

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

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

Phospholipids containing polyunsaturated fatty acids, can be obtained in different ways, mainly through chemical synthesis of phospholipids, as described by enzymatic esterification and transesterification of phospholipids or enzymatic transpeptidation phospholipids (Hosokawa, J. Am. Oil Chem. Soc. 1995, 1287, Lilja-Hallberg, Biocatalysis, 1994, 195). For such enzymatic applications of the preferred embodiment of the present invention is a lipid compound according to General formula I, where R1and R2represent hydrogen.

Lipid compounds of General formula (I), where X represents a carboxylic acid and is in the form of triglycerides can be obtained using the following methods. A new surplus fatty acids may be contacted with glycerol using dimethylaminopyridine (DMAP) and 2-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium of hexaflurophosphate (HBTU).

Lipid compounds of General formula (I), where X represents a carboxylic acid and is in the form of diglyceride, can be obtained by reaction of fatty acid (2 EQ.) glycerol (1 EQ.) in the presence of 1,3-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP).

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

The acylation of 1,2-O-isopropylidene-sn-glycerol with fatty acids using DCC and DMAP in chloroform gives noneditorial. Removing protection from isopropylidenebis can be accomplished by treatment of the protected glycerol acid (HCl, acetic acid, and the like) (O Brian, J. Org. Chem., 1996, 5914).

There are several common methods of synthesis to obtain monoglycerides and fatty acid in position 2. One way uses the esterification of fatty acids with glycidol in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 4-dimethylaminopyridine (DMAP) to give goldlenovo derived. Processing goldlenovo derived using triperoxonane anhydride (TFAA) before TRANS-esterification of monoglyceride network (Parkkari et al., Bioorg. Med. Chem. Lett. 2006, 2437).

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

Also is it possible to use enzymatic methods (reactions lipase) to convert fatty acids into mono-, di-, triglyceride. 1,3-Regiospecific lipase from mushroomsMucormieheican be used DL is getting triglycerides or diglycerides of fatty acids and glycerol. Another lipase, prehispanica lipase yeast fromCandida antarticais very effective at generating triglycerides of polyunsaturated fatty acids (Haraldsson, Pharmazie, 2000, 3). For this enzymatic application of the preferred implementation of the present invention is a lipid compound according to General formula I, where R1and R2represent hydrogen.

Synthesis/receiving lipid compounds in accordance with the present invention

The present invention will now be described in more detail using the following examples, which should not be construed as limiting the present invention.

In addition, in the following examples, the patterns are checked by NMR. An NMR spectrum recorded in CDCl3with the help of the device Bruker Avance DPX 200 or by using a Bruker Avance DPX 300. The values of J are given in Hz. The mass spectrum recorded using LC/MS Agilent 1100 series mass spectrometer G 1956 a (elektrorazpredelenie, 3000 V). All reactions carried out in an inert atmosphere, is carried out in a nitrogen atmosphere.

Abbreviations

THF - tetrahydrofuran

EtOAc - ethyl acetate

DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene

LAH is lithium aluminum hydride

BuLi - utility

NaH - sodium hydride

t - triplet

s - singlet

d - doublet

kV - Quartet

m - multiplet

users broadened singlet

Example 1

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

Triethyl 2-phosphonopropionic (414 μl, 1.9 mmol) are added to a suspension of sodium hydride (81 mg, 60% dispersion in mineral oil, 2.0 mmol) in dry THF (5 ml) at 0°C. After 30 minutes at room temperature the mixture is cooled to 0°C and add (fully-Z)-icosa-5,8,11,14,17-pentenal (500 mg, 1.7 mmol) in THF (1 ml). The mixture is stirred for 40 minutes at 0°C. Add a saturated aqueous solution of NH4Cl and the phases are separated. The 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 (MgSO4). Evaporation of the solvents under reduced pressure, followed by flash chromatography on silica gel (9:1 hexane-EtOAc) to give ester 1 (550 mg, 85%), (2E:2Z=7:1 (GC)).

δH(300 MHz): of 0.95 (t, J=7.5 Hz, 3H, CH3), 1,25 (t, J=7,1 Hz, 3H)and 1.51 (m, 2H), 1,84 (d, J=1 Hz, CH3, 3H), 1,9-2,2 (m, 6N), 2,7-2,9 (m, 8H), 4,20 (kV, J=7,1 Hz, 2H), 5,2-5,5 (m, 10H), to 6.88 (TD, J=7.5 Hz, J=1 Hz, 1H).

Example 2

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

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

Connection 2: E-isomer:

δN(300 is Hz), of 0.96 (t, J=7.5 Hz, 3H, CH3), of 1.53 (m, 2H), 1,82 (d, J=1 Hz, CH3, 3H), 1,9-2,2 (m, 6N), 2,7-2,9 (m, 8H), 5,2-5,5 (m, 10H), 6,91 (TD, J=7.5 Hz, J=1 Hz, 1H); δWith(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.

Compound 28: Z-isomer: δH(300 MHz): of 0.95 (t, J=7.5 Hz, 3H, CH3), to 1.48 (m, 2H), 1,90 (userd, J=1.4 Hz, 3H, CH3), to 2.1-2.3 (m, 4H), of 2.53 (m, 2H), 2,7-2,9 (m, 8H), 5,2-5,5 (m, 10H), between 6.08 (dt, J=7,4 Hz, J=1.4 Hz, 1H); δC(75 MHz) 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

Obtain ethyl (2E,7Z,10Z,13Z,16Z,19Z)-3-methyl-docosa-2,7,10,13,16,19-hexenoate (3)

Triethylphosphate (288 μl, 1.4 mmol) are added to a suspension of sodium hydride (58 mg, 60% dispersion in mineral oil, 1.4 mmol) in dry benzene (8 ml) at room temperature. After 30 minutes, add a solution of (fully-Z)-generosa-6,9,12,15,18-penten-2-she (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 extracted with hexane. The extract is washed with water and dried (MgSO4). Evaporation of the solvents under reduced pressure, followed by flash chromatography on silica gel (95:5, hexane:EtOAc) to give ester 3 (270 mg, 53%) as oil.1H-NMR (200 MHz, CDCl3): δ were 0.94 (t, 3H), of 1.23 (t, 3H), 1,49-of 1.57 (m, 2H), 1,99-2,12 (m, 6H), 2,12 (c, 3H), was 2.76-and 2.83 (m, 8H), 4,10 (kV, 2H), 5,30 lower than the 5.37 (m, 10H), 5,63 (c, 1H);3 C-NMR (50 MHz, CDCl3): 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

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

Ethyl (2E,7Z,10Z,13Z,16Z,19Z)-3-methyl-docosa-2,7,10,13,16,19-hexenoate (3) is dissolved in methanol (9 ml) and added LiOH (220 mg, 4,89 mmol) in water (3 ml) and the mixture is heated at 50°C for 2 hours. The mixture is cooled and add dilute hydrochloric acid to establish a pH of 2. Extraction with diethyl ether, drying (MgSO4) and evaporation of the solvents under reduced pressure to give the acid 4. Acid purified using flash chromatography on silica gel (8:2, hexane:EtOAc); δH(300 MHz) of 0.95 (t, J=7.5 Hz, 3H, CH3), of 1.55 (m, 2H), of 2.0-2.2 (m, 6H), of 2.15 (d, J=1.3 Hz, 3H, CH3), 2,7-2,9 (m, 8H), 5,2-5,5 (m, 10H)5,68 (users, 1H); δC(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-docosa-2,7,10,13,16,19-HEXEN-1-ol (5)

Ethyl (2E,7Z,10Z,13Z,16Z,19Z)-3-methyl-docosa-2,7,10,13,16,19-hexenoate (2E:2Z=9:1), (0.40 g, a 1.08 mmol) dissolved in dry THF (5 ml) and added dropwise to a cold suspension of LAH (0,045 g, 1,19 mmol) in dry THF (10 ml). The mixture is stirred at 0°C in an inert atmosphere for 30 minutes and then 18 hours at ambient temperature. The reaction mixture was quenched by adding 10% NH4Cl (20 ml) and the mixture is extracted twice with heptane (30 ml). The combined organic extracts washed with saturated salt solution (20 ml) and dried (Na2SO4). Purification using flash chromatography (heptane:EtOAc, 4:1) to give 0.16 g (45%) of 3-methyl-(2E,7Z,10Z,13Z,16Z,19Z)-docosa-2,7,10,13,16,19-HEXEN-1-ol as a colourless oil.

Connection 3, E-isomer:1H-NMR (200 MHz, CDCl3): δ of 0.95 (t, 3H), 1.32 to 1,50 (m, 2H), 1,64 (c, 3H), 1,97-of 2.09 (m, 6H), was 2.76-to 2.85 (m, 8H), 4,11 (d, J=6,8 Hz, 2H), 5,27-5,42 (m, 11H);13C-NMR (50 MHz, CDCl3): δ 14,21, 16,12, 20,50, 25,48 (2 signals), 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 (elektrorazpredelenie): 351,2 [M+Na]+.

The connection 29, Z-isomer:

In addition, the elution give 0.01 g (28%) (fully Z)-3-methyl-docosa-2,7,10,13,16,19-HEXEN-1-ol (29) as a colourless oil.1H-NMR (200 MHz, CDCl3): δ of 0.95 (t, 3H), 1,30-1,50 (m, 2H), 1,71 (s, 3H), 2,02-of 2.09 (m, 6N), was 2.76-to 2.85 (m, 8H), 4.09 to (d, J=7,1 Hz, 2H), 5,28 (s, 1H), 5,31-5,41 (m, 10H); MC (elektrorazpredelenie): 351,2 [M+Na]+.

Example 6

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

Triethylphosphine (386 μl, 1.8 mmol) are added to a suspension of sodium hydride (72 mg, 60% dispersion in mineral oil, 1.8 mmol) in dry THF (5 ml) at 0°C. After 30 minutes, add a solution of (fully-Z)-octets the ka-9,12,15-trienal (300 mg, 1.15 mmol) in THF (2 ml). The mixture is stirred for 1 hour at 0°C. Add an aqueous solution of NH4Cl, and the mixture is extracted with EtOAc. The extract is washed with water and dried (MgSO4). Evaporation of the solvents under reduced pressure, followed by flash chromatography on silica gel (95:5, hexane:EtOAc) to give ester 6 (180 mg, 45%). δH(300 MHz) of 0.95 (t, J=7.5 Hz, 3H, CH3), 1.2 to 1.5 (m, 13H), of 1.80 (s, CH3, 3H), of 2.0-2.2 (m,), 2,78 (t, J=5.8 Hz, 4H), 4,16 (kV, J=7,1 Hz, 2H, CH2), 5,2-5,4 (m, 6N), was 6.73 (dt, J=7.5 Hz, J=1.3 Hz, 1H); δC(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-eicosa-2,11,14,17-terraenovae acid (7)

Ethyl (2E,11Z,14Z,17Z)-2-methyl-eicosa-2,11,14,17-tetraenoic (6) (160 mg, 0.46 mmol) dissolved in methanol (3 ml), and added LiOH (193 mg, 4.6 mmol) in water (3 ml), and the mixture is heated at 50°C for 2 hours. The mixture is cooled and add dilute hydrochloric acid to establish a pH of 2. Extraction with diethyl ether, drying (MgSO4) and evaporation of the solvents under reduced pressure to give the acid 7. Acid purified using flash chromatography on silica gel (8:2 hexane-EtOAc); δH(300 MHz) of 0.95 (t, J=7.5 Hz, 3H, CH3), 1.2 to 1.5 (m, 10H), 1,81 (c, 3H, CH3), of 2.0-2.2 (m, 6H), and 2.79 (t, J=5.8 Hz, 4H), 5,2-5,4 (m, 6H), 6.90 to (dt, J=7.5 Hz, J=1.3 Hz, 1H); δC(75 MHz) 11,93, 14,25, 20,53, 25,51, 25,60, 27,19, 28,40, 28,87, 29,16, 29,31, 2,58, 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-eicosa-2,11,14,17-tetraenoic (30)

NaH (60% in mineral oil, 0,080 g, 2.00 mmol) suspended in dry THF (10 ml) under inert atmosphere. The suspension is cooled to 0°C, is added dropwise triethyl 2-phosphonobutyric (of 0.47 ml, 2.00 mmol) and stirred at 0°C for 20 minutes. To this mixture add a solution of (fully-Z)-octadeca-9,12,15-trienal (PRB-73, 0.35 g, of 1.33 mmol) in dry THF (5 ml) and the resulting mixture stirred at ambient temperature for 30 minutes. The mixture is diluted with diethyl ether (25 ml), washed with water (20 ml) and dried (Na2SO4). Purification using flash chromatography (heptane:EtOAc, 98:2) gives 0,47 g (99%) specified in the connection header 30 (2E:2Z=mixture 1:1).

1H-NMR (200 MHz, CDCl3):

E-isomer: δ 0,91 of-1.04 (m, 6H), 1,23-of 1.41 (m, 13H), 2,01-of 2.26 (m, 8H), was 2.76-of 2.81 (m, 4H), to 4.17 (q, 2H), 5,28-5,41 (m, 6H), 6,86 (t, J=7,53 Hz, 1H).

Z-isomer: δ 0,91 of-1.04 (m, 6H), 1,23-of 1.41 (m, 13H), 2,01-of 2.26 (m, 8H), was 2.76-of 2.81 (m, 4H), to 4.17 (q, 2H), 5,28-5,41 (m, 6H), 5,80 (t, J=7,39 Hz, 1H).

13C-NMR (50 MHz, CDCl3):

Z - and E-isomer: δ 13,65, 13,94, 14,26 (two signals), 20,01, 20,54, 25,51, 25,60, 27,23 (two signals), 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 signals), 130,27, 130,33, 131,93, 133,63, 133,93, 140,30, 142,01, 168,35 (two signals).

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

Example 9

(2E,11Z,14Z,17Z)-2-ethyl-eicosa-2,1114,17-tetraen-1-ol (9)

A suspension of LAH (0,027 g, 0.70 mmol) in dry THF (7 ml) cooled to 0°C in an inert atmosphere is added dropwise a solution of ethyl (2E/Z,11Z,14Z,17Z) 2-ethyl-eicosa-2,11,14,17-tetraenoic (30) (2E:2Z=1:1), (0,23 g of 0.68 mmol). The mixture is stirred at 0°C for 30 minutes and then at ambient temperature for 30 minutes. Add saturated NH4Cl (15 ml) and the mixture is extracted twice with heptane (20 ml). The combined organic extracts washed with saturated salt solution (20 ml) and dried (Na2SO4). Purification using flash chromatography (heptane:EtOAc, 8:1) gives 0,050 g (23%) of (2E,11Z,14Z,17Z) 2-ethyl-eicosa-2,11,14,17-tetraen-1-ol (9) as a colourless oil.1H-NMR (200 MHz, CDCl3): δ 0,82 was 1.04 (2×t, 6H), 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);13C-NMR (50 MHz, CDCl3): 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 (elektrorazpredelenie): 341,3 [M+Na]+.

In addition, chromatography (heptane:EtOAc, 6:1) gives 0,020 g (18%) (fully-Z) 2-ethyl-eicosa-2,11,14,17-tetraen-1-ol (31) in the form of a pale yellow oil.1H-NMR (200 MHz, CDCl3): δ 0,82-0,99 (2×t, 6H), 1,15-of 1.40 (m, 10H), 1,95-2,15 (m, 8H), and 2.79 (m, 4H), was 4.02 (c, 2H), 5,23-5,44 (m, 7H);13C-NMR (50 MHz, CDCl3); (elektrorazpredelenie): 341,3 [M+Na]+.

Example 10

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

Triethyl 2-phosphonopropionic (366 μl, 1.7 mmol) are added to a suspension of sodium hydride (70 mg, 60% dispersion in mineral oil, about 1.75 mmol) in dry THF (5 ml) at 0°C. After 50 minutes at 0°C the mixture is cooled to -25°C and add (fully-Z)-octadeca-3,6,9,12,15-pentenal (400 mg, 1.55 mmol) in THF (1 ml). The mixture is stirred for 50 minutes at -25°C. Add saturated aqueous solution of NH4Cl and the phases are separated. The aqueous phase is extracted with hexane. The combined organic phases are washed with saturated salt solution, water and dried (MgSO4). Evaporation of the solvents under reduced pressure, followed by flash chromatography on silica gel (95:5, hexane:EtOAc) to give ester 8. δH(300 MHz): of 0.95 (t, J=7.5 Hz, 3H, CH3), of 1.26 (t, J=7,1 Hz, 3H), of 1.84 (d, J=1.3 Hz, 3H, CH3), was 2.05 (m, 2H), 2,7-2,9 (m, 8H), of 2.92 (t, J=6.9 Hz, 2H), 4,16 (kV, J=7,1 Hz, 2H), 5,2-5,5 (m, 11N); δWith(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)-ethoxy-docosa-2,7,10,13,16,19-hexenoate (32)

NaH (60% in mineral oil, 0.28 g, 7,07 mmol) suspended in dry THF (10 ml) under inert atmosphere and at 0°C. is Added dropwise a solution of triethyl-2-ethoxy-2-phosphonoacetate (3,79 g, 14.1 mmol) in dry THF (10 ml) and the resulting pale yellow solution was stirred at 0°C for 20 minutes. Then add octadeca-2E,6,9Z,12Z,15Z-pentenal (1.35 g, 4,71 mmol) in dry THF (10 ml), the mixture was stirred at ambient temperature for 2.5 hours and diluted with diethyl ether (100 ml). The organic layer was washed with water (50 ml) and dried (Na2SO4). Purification using flash chromatography (heptane:EtOAc, 98:2) gives 1,36 g (72%) indicated in the title compound 32 as a mixture of 2E and 2Z-isomer, 1:1, in the form of a colorless oil.1H-NMR (200 MHz, CDCl3): δ of 0.95 (t, 3H), of 1.23 to 1.34 (m, 6H), 1,35-of 1.52 (m, 2H), 1,95-2,10 (m, 4H), 2,20-2,50 (2×m, 2H), 2,70-2,90 (m, 8H), 3,60-3,90 (2×kV, 2H), 4,10-4,30 (2×kV, 2H) to 5.21-of 5.45 (m, 10,5H), 6,23 (t, 0,5H); MC (elektrorazpredelenie): 423,3 [M+Na]+.

Example 12

Ethyl (2Z,7Z,10Z,13Z,16Z,19Z)-ethoxy-docosa-2,7,10,13,16,19-hexenoate (33)

50 mg specified in the title compounds as a mixture of isomers, 1:1, heated to 100°C as it is in the presence of catalytic amounts of thiophenol (one drop) in an inert atmosphere for three hours. The mixture is cooled and purified using flash chromatography to obtain 20 mg (40%) of pure ethyl (2Z,7Z,10Z,13Z,16Z,19Z)-2-ethoxy-docosa-2,7,10,13,16,19-hexenoate in the form of a pale yellow oil.1H-NMR (200 MHz, CDCl3): δ of 0.95 (t, J=7,50 Hz, 3H), of 1.23 to 1.34 (m, 6N), 1,40-and 1.54 (m, 2H), 1,95-2,10 (m, 4H), 2,22 (kV, J=7,60 Hz, 2H), 2,70-2,90 (m, 8H), 3,82 (kV, J=7,05 Hz, 2H), 4,15-4.26 deaths (kV, J=7,11 Hz, 2H), to 5.21-of 5.45 (m, 11N), 6,23 (t, J=7,60 Hz, 1H); MC (elektrorazpredelenie): 423,3 [M+Na]+.

Example 13

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

A mixture of ethyl (2E/Z,7Z,10Z,13Z,16Z,19Z)-2-ethoxy-docosa-2,7,10,13,16,19-hexenoate (32) (E:Z=1:1, 0.40 g, 1.00 mmol) in ethanol (8 ml) in an inert atmosphere is added to the solution of LiOH×H2O (0.33 g, 8,00 mmol) in water (3 ml). The obtained turbid mixture is brought to 70°C for 30 minutes and then stirred at ambient temperature for 18 hours. Add 1M HCl to establish the pH=1 and the mixture is extracted twice with heptane (15 ml). The combined organic extracts dried (Na2SO4) and purified using flash chromatography (heptane:EtOAc, 9:1, then 4:1). This gives 0.18 g (48%) indicated in the title compound 26 as a colourless oil. (2E:2Z=1:3).

Z-isomer: δ 0.91-0.99 are equivocal (t, J=7.5 Hz, 3H), of 1.28 (t, J=7.0 Hz, 3H), 1,48 (kV, J=7,4 Hz, 2H), 1,98-of 2.09 (m, 4H), 2,24 (kV, J=7.5 Hz, 2H), 2,70-2,90 (m, 8H), 3,85 (kV, J=7,0 Hz, 2H), 5.25-in of 5.40 (m, 10H), 6.42 per (t, J=and 7.6 Hz, 1H), a 10.74 (users, 1H).

E-isomer: δ 0,86 (t, 3H), of 1.34 (t, J=7.0 Hz, 3H), of 1.42 (m, 2H), 1,98-of 2.09 (m, 4H), 2,54 (kV, J=7,6 Hz, 2H), 2,70-2,90 (m, 8H), 3,75 (kV, J=6,9 Hz, 2H), 5,20-of 5.40 (m, 11H), a 10.74 (users, 1H), (minor isomer);

E - and Z-isomer:13C-NMR (75 MHz, CDCl3): δ 14,23, 15,33, 20,53, 25,52 (2 signals), 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 (elektrorazpredelenie): 371,2 [M-H]-.

Example 14

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

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

LAH (0,021 g, 0.55 mmol) suspended in dry THF (8 ml) and incubated at 0°C in an inert atmosphere. To this suspension is added dropwise a solution of ethyl-(2E/Z,7Z,10Z,13Z,16Z,19Z)-2-ethoxy-docosa-2,7,10,13,16,19-hexenoate (32) (1:1, 0.20 g, 0.50 mmol) in dry THF (2 ml). The resulting mixture was stirred at 0°C for ten minutes, and then 50 minutes at ambient temperature. Add saturated NH4Cl (15 ml) and the mixture is extracted twice with heptane (20 ml). The combined organic extracts washed with saturated salt solution (15 ml) and dried (Na2SO4). Purification using flash chromatography (heptane:EtOAc 9:1) gives 0,033 g (18%) 2 ethoxy-docosa-2E,7Z,10Z,13Z,16Z,19Z-HEXEN-1-ol (27) as a colourless oil.1H-NMR (200 MHz, CDCl3): δ of 0.95 (t, J=7,49 Hz, 3H), of 1.28 (t, J=of 6.96 Hz, 3H), 1.30 and 1.44MB (kV, J=a 7.62 Hz, 2H), 1,95-of 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);13C-NMR (50 MHz, CDCl3): 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 (elektrorazpredelenie): 381,3 [M+Na]+.

0.11 g (61%) (fully-Z) 2-ethoxy-docosa-2,7,10,13,16,19-HEXEN-1-ol (34) also isolated in the form of a colourless oil.1H-NMR (200 MHz, CDCl3): δ were 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-of 2.15 (m, 6H), 2,70-to 2.85 (m, 8H), 3,84 (kV, J=7,02 Hz, 2H), 4,05 (users, 1H), 4,78 (t, J=7,21 Hz, 1H), 5,20-of 5.45 (m, 10H);13C-NMR (50 MHz, CDCl3): δ 14.24 from, 15,53, to 20.52, 2,45, 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 (elektrorazpredelenie): 381,3 [M+Na]+.

Example 15

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

Add potassium carbonate (395 mg, 2.9 mmol) in water (286 μl) to a vigorously stirred mixture of (2E,6Z,9Z,12Z,15Z)-octadeca-2,6,9,12,15-pentenal (370 mg, 1.4 mmol) and triethylphosphite (344 ml, 1,72 mmol) at room temperature. The mixture is stirred for 48 hours at room temperature, water is added and the phases are separated. The aqueous phase is extracted with hexane. The combined organic phases are washed with water and dried (MgSO4). Evaporation of the solvents under reduced pressure, followed by flash chromatography on silica gel (95:5, hexane:EtOAc) to give ester (180 mg, 39%) and extracted aldehyde (80 mg). δH(300 MHz): of 0.95 (t, J=7.5 Hz, 3H, CH3), of 1.26 (t, J=7,1 Hz, 3H), 2,04 (m, 2H), to 2.1-2.3 (m, 4H), 2,7-2,9 (m, 6N), 4,17 (kV, J=7,1 Hz, 2H), 5,2-5,5 (m, 8H), 5,77 (d, J=to 15.4 Hz, 1H), 6,1-6,2 (m, 2H), 7,22 (DD, J=to 15.4 Hz, J=9.9 Hz, 1H); δC(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)-icosa-2,4,8,11,14,17-hexatoma acid (13)

Ethyl (2E,4E,8Z,11Z,14Z,17Z)-icosa-2,4,6,11,14,17-hexenoate (340 mg, 1.04 mmol) was dissolved in isopropanol (13 ml), and added LiOH (87 mg, 2.1 mmol) in which e (5 ml), and the mixture is stirred at room temperature overnight. The reaction mixture was poured into water and the pH adjusted to pH 2-3 with HCl. The solution is extracted with ethyl acetate/hexane, dried (MgSO4), and evaporation of the solvents under reduced pressure gives the acid 13. Acid purified using flash chromatography on silica gel (8:2, hexane:EtOAc); to 0.96 (t, J=7.5 Hz, 3H, CH3), 2,04 (m, 2H), to 2.1-2.3 (m, 4H), 2,7-2,9 (m, 6N), 5,2-5,5 (m, 8H), 5,77 (d, J=15.3 Hz, 1H), 6,1-6,2 (m, 2H), 7,31 (DD, J=to 15.4 Hz, J=10.1 Hz, 1H); δC(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)-docosa-2,4,7,13,16,19-heptanoate (14)

Stage 1:

Ethyl (fully Z)-2-methanesulfonyl-docosa-4,7,10,13,16,19-hexaenoic (2.00 g, equal to 4.97 mmol) dissolved in CH2Cl2(50 ml) and cooled to -20°C in inert atmosphere. A solution of 3-chloroperbenzoic acid (mCPBA, 1.01 g, equal to 4.97 mol) in CH2Cl2(20 ml) is added dropwise to this mixture for five minutes, and the resulting mixture was stirred at -20°C for one hour. The cold mixture was partitioned between saturated Na2SO3(100 ml) and diethyl ether (100 ml). The organic layer is washed twice with saturated NaHCO3(100 ml) and dried (Na2SO4).

Purification using flash chromatography (heptane:EtOAC, 4:1, then 1:1, the m heptane:EtOAc) to give 0.73 g (35%) of ethyl (fully Z)-2-methanesulfonyl-docosa-4,7,10,13,16,19-hexaenoic in the form of a colorless oil. 1H-NMR (200 MHz, CDCl3): δ of 0.95 (t, 3H), of 1.28 (t, 3H), of 2.05 (m, 2H), 2,64 (c, 3H), 2.71 to 2,86 (m, 12H), of 3.48 (m, 1H), is 4.21 (q, 2H), 5,27-5,49 (m, 12H); MC (elektrorazpredelenie): 441,2 [M+Na]+.

Stage 2:

Ethyl (fully Z)-2-methanesulfonyl-docosa-4,7,10,13,16,19-hexaenoic (PRB-66, of 0.68 g of 1.62 mmol) dissolved in dry toluene (40 ml) and add CaCO3(0.16 g, of 1.62 mmol). This mixture was stirred at 105°C in an inert atmosphere for three hours, cooled, diluted with heptane (50 ml) and washed with 1M HCl (50 ml) and saturated salt solution (50 ml). The organic layer is dried (Na2SO4) and purified using flash chromatography (heptane:EtOAc, 97:3) to obtain 0,38 g (66%) indicated in the title compound 14 as a pale yellow oil.1H-NMR (200 MHz, CDCl3): δ of 0.95 (t, J=7,51 Hz, 3H), 1,25 (t, J=7,13 Hz, 3H), 2.05 is (kV, J=7,35 Hz, 2H), was 2.76-is 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), by 5.87 (d, J=15,22 Hz, 1H), 6,12 (dt, J=11,53 Hz, J=0,71 Hz, 1H), 7,53-to 7.67 (DDD, J=15,24 Hz, J=of 11.61 Hz, J=1,02 Hz, 1H);13C-NMR (75 MHz, CDCl3): 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 (elektrorazpredelenie): 377,2 [M+Na]+.

Example 18

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

Ethyl (2E,4E,7Z,10Z,13Z,16Z,19Z)-docosa-2,4,7,13,16,19-heptanoate (14), (0.26 g, 0.73 mmol) dissolved in EtOH (10 ml) and add mixture is LiOH (0.25 g, 5.9 mmol) in water (2.5 ml). The mixture was stirred at ambient temperature under inert atmosphere for 17 hours, add water (20 ml) and 1M HCl to establish a pH=1. This mixture is extracted twice with heptane (20 ml) and the organic layer dried (Na2SO4). Purification using flash chromatography (heptane:EtOAc, 2:1, then 1:1) gives 0,050 g (21%) indicated in the title compound 15 as a colourless oil.1H-NMR (200 MHz, CDCl3): δ of 0.95 (t, J=rate of 7.54 Hz, 3H), of 2.05 (Quint., J=7,51 Hz, 2H), was 2.76-is 2.88 (m, 9H), 3,06 (t, 2H), 5,31-5,43 (m, 10H), of 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-to 7.77 (DDD, J=15,21 Hz, J=11,66 Hz, J=0,90 Hz, 1H); MC (elektrorazpredelenie): 325,1 [M-H]-.

Example 19

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

Ethyl (2E,4E,7Z,10Z,13Z,16Z,19Z)-docosa-2,4,7,10,13,16,19-heptanoate (14) (0.12 g, 0.34 mmol) dissolved in dry THF (3 ml) and added dropwise to a stirred suspension of LAH (0,013 g, 0.35 mmol) in dry THF (7 ml) at 0°C. the Mixture was stirred at 0°C for 45 minutes, add saturated NH4Cl (5 ml) and filtered through a thin pad of celite. Celite is washed with water (10 ml) and heptane (10 ml) and the combined aqueous layer was extracted with heptane (10 ml). The combined organic layer is dried (MgSO4) and purified using flash chromatography (heptane:EtOAc, 7:1). This gives 0,070 g (66%) indicated in the title compound 16 as a colorless oil.1 H-NMR (200 MHz, CDCl3): δ of 0.95 (t, J=7,52 Hz, 3H), of 2.05 (Quint., J=7,34 Hz, 2H), was 2.76-2.91 in (m, 8H), 2,96 (m, 2H), 4,20 (d, J=5,67 Hz, 2H), 5,28-5,46 (m, 11H), 5,78-by 5.87 (dt, J=15,12 Hz, 5,80 Hz, 1H), 6,00 (t, J=10,81 Hz, 1H), of 6.52 (DD, J=15,12 Hz, 11,05 Hz, 1H);13C-NMR (50 MHz, CDCl3): 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 hidden); MC (elektrorazpredelenie): 335,2 [M+Na]+.

Example 20

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

Triethyl 2-phosphonopropionic (458 μl, 2,13 mmol) are added to a suspension of sodium hydride (88 mg, 60% dispersion in mineral oil, 2.2 mmol) in dry THF (6 ml) at 0°C. After 50 minutes at 0°C the mixture is cooled to -40°C and add (2E,6Z,9Z,12Z,15Z)-octadeca-2,6,9,12,15-pentenal (500 mg, 1.94 mmol) in THF (1 ml). The mixture is stirred for 60 minutes at a temperature of -40°C to -20°C. Add saturated aqueous solution of NH4Cl and the phases are separated. The aqueous phase is extracted with diethyl ether. The combined organic phases are washed with saturated salt solution, water and dried (MgSO4). Evaporation of the solvents under reduced pressure gives ester 10.

Example 21

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

To a solution of ethyl (2E,4E,8Z,11Z,14Z,17Z)-2-methyl-icosa-2,4,8,11,14,17-hexenoate (10) in methanol add water Rast is the PR KOH (8 EQ.) and the mixture is heated to 60-70°C for 2 hours. The solution is cooled, water is added and the mixture is acidified. The mixture is then extracted with ethyl acetate. The combined organic phases are washed with water and dried (MgSO4). Evaporation of the solvents under reduced pressure, followed by flash chromatography on silica gel (hexane-EtOAc, 8:2) gives the acid 11. δN(300 MHz): to 0.96 (t, J=7.5 Hz, 3H, CH3), at 1.91 (d, J=0.75 Hz, 3H, CH3), of 2.08 (m, 2H), 2,2-2,4 (m, 4H), 2,7-2,9 (m, 6N), 5,2-5,5 (m, 8H), 6,11 (dt, J=15,0, J=6,5 Hz, 1H), 6,37 (DD, J=to 15.0 Hz, J=11.3 Hz, 1H), 7,26 (userd, J=11.3 Hz, 1H); δWith(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-icosa-2,4,8,11,14,17-hexaenoic 17

A suspension of NaH (60% in mineral oil, 0.11 g, and 2.79 mmol) in dry THF (15 ml) was adjusted to 0°C in an inert atmosphere and added dropwise triethyl 2-phosphonobutyric (0,66 ml, and 2.79 mmol). The mixture is stirred at 0°C for ten minutes, add a solution of (2E,6Z,9Z,12Z,15Z)-octadeca-2,6,9,12,15-pentenal (0,48 g of 1.86 mmol) in dry THF (5 ml) and stirred at 0°C for an additional 30 minutes. The mixture is diluted with diethyl ether (30 ml), washed with water (30 ml) and dried (Na2SO4). Purification using flash chromatography (heptane:EtOAc, 98:2) to give 0.39 g (59%) of ester 17 (2E:2Z=9:1) as colourless oil.

The mixture of these products cleanse a second time, this time with the help of flash is-chromatography using the 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-eicosa-2,4,8,11,14,17-hexanoate (17) as a colourless oil.1H-NMR (200 MHz, CDCl3): δ of 0.95 (t, J=7,53 Hz, 3H), 1,01 (t, J=7,44 Hz, 3H), of 1.28 (t, J=7,12 Hz, 3H), 1,98-of 2.15 (m, 2H), 2,15-to 2.29 (m, 4H), of 2.38 (q, 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), 5,98-6,12 (m, 1H), 6,28-6,41 (DD, J=11,20 Hz, J=11,20 Hz, 1H), to 7.09 (d, J=11,17 Hz, 1H);13C-NMR (50 MHz, CDCl3): 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 hidden); MC (elektrorazpredelenie): to 379.2 [M+Na]+.

A small amount (20 mg, 3%) of ethyl (2Z,4E,8Z,11Z,14Z,17Z)-2-ethyl-eicosa-2,4,8,11,14,17-hexanoate (35) also isolated in the form of a colourless oil.1H-NMR (200 MHz, CDCl3): δ of 0.95 (t, J=7,52 Hz, 3H), was 1.04 (t, J=of 7.36 Hz, 3H), of 1.29 (t, J=7,14 Hz, 3H), 1,95-2,12 (m, 2H), 2,15 was 2.25 (m, 6N), and 2.27 (q, J=of 7.36 Hz, 2H), 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).

Example 23

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

hexatoma acid (18)

Ethyl-(2E,4E,8Z,11Z,14Z,17Z)-2-ethyl-eicosa-2,4,8,11,14,17-hexanoate (17) (0,040 g, 0,112 mmol) dissolved in ethanol (4 ml) and add a solution of LiOH × H2O (0,038 g, 0,898 mmol) in water (1 ml). The mixture was stirred at ambient temperature for 15 hours, and then five hours at 70°C. the Mixture is cooled add 1M HCl to establish the pH=1 and diluted with water (2 ml). The mixture is extracted twice with heptane (10 ml) and the combined organic extracts dried (Na2SO4). Purification using flash chromatography (heptane:EtOAc, 95:5, then 4:1) gives 0,028 g (76%) indicated in the title compounds as a pale yellow oil.1H-NMR (200 MHz, CDCl3): δ 0,90-1,07 (2×t, 6H), 2.00 in of 2.10 (m, 2H), 2,20-of 2.30 (m, 4H), 2,35-of 2.50 (q, 2H), 2,75-2,90 (m, 6H), 5,27-5,44 (m, 8H), 6,05-of 6.20 (m, 1H), 6.30-in-to 6.43 (m, 1H), 7,50-of 7.70 (m, 1H); MC (elektrorazpredelenie): 327,2 [M-H]-.

Example 24

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

A suspension of LAH (0,007 g has 0.168 mmol) in dry THF (2 ml) cooled to 0°C in an inert atmosphere. To this suspension is added dropwise a solution of ethyl-(2E,4E,8Z,11Z,14Z,17Z)-2-ethyl-eicosa-2,4,8,11,14,17-hexanoate (17) (E:Z=9:1, to 0.060 g, has 0.168 mmol). The mixture is stirred at 0°C for two hours, and then stirred at ambient temperature for 17 hours, and then add saturated NH4Cl (5 ml). The mixture is extracted twice with heptane (10 ml)and the combined organic extracts washed with saturated salt solution (10 ml) and dried (Na2SO4).

Purification using flash chromatography (heptane:EtOAc, 6:1) gives 0,030 g (57%) of (2E,4E,8Z,11Z,14Z,17Z)-2-ethyl-eicosa-2,4,8,11,14,17-HEXEN-1-ol (19) as a colourless oil.1H-NMR (200 MHz, CDCl3): δ of 0.95 (t, J=7.5 Hz, 3H), of 1.02 (t, J=7.5 Hz, 3H), 1,98-of 2.09 (m, 2H), 2,12-of 2.26 (m, 6H), 2.77-to 2,89 (m, 6H), 4,07 (c, 2H), 5,27-5,41 (m, 8H), 5,61-of 5.75 (m, 1H) 5,96 (d, J=10,9 Hz, 1H), 6,20-6,34 (DD, J=10,9 Hz, and 14.9 Hz, 1H);13C-NMR (50 MHz, CDCl3): 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 (elektrorazpredelenie): 337,2 [M+Na]+.

A small number of (2Z,4E,8Z,11Z,14Z,17Z)-2-ethyl-eicosa-2,4,8,11,14,17-HEXEN-1-ol (36, 0.004 g, 7%) was also isolated in the form of a colourless oil.1H-NMR (200 MHz, CDCl3): δ of 0.95 (t, J=7.5 Hz, 3H), of 1.05 (t, J=7.5 Hz, 3H), 1,95-of 2.09 (m, 2H), 2,14-of 2.24 (m, 6H), was 2.76-2,84 (m, 6H), 4,23 (c, 2H), 5,23-of 5.45 (m, 8H), 5,59-5,74 (m, 1H), of 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-docosa-2,4,13,16,19-pentenoate (37)

Triethyl-3-methyl-4-phosphono-2-butenoate (0,32 ml of 1.09 mmol) dissolved in dry THF (12 ml) and dry DMPU (3 ml) and brought to 0°C in an inert atmosphere. Added dropwise n-BuLi (0.68 ml, of 1.09 mmol), the mixture was stirred at 0°C for 20 minutes and then brought to -78°C. the Mixture was stirred at -78°C for five minutes, added dropwise (fully-Z)-octadeca-9,12,15-trienal (0,22 g, 0.84 mmol) in dry THF (3 ml) and the mixture was allowed to slowly reach -10°C for 80 minutes. Add saturated NH4Cl (20 ml) and the mixture is extracted twice with heptane (30 ml). The organic layer is dried (Na2SO4) and purified using flash chromatography (heptane:EtOAc, 98:2). This gives 0.31 g (95%) indicated in the title compounds as a mixture of Z - isomer of 1:1 as a colorless oil. 1H-NMR (200 MHz, CDCl3): δ of 0.95 (t, 6H), 1,20-1,50 (m, 26H), 1,95 (c, 3H), 1,98 to 2.35 (m, 12H), 2.40 a (c, 3H), 2,78 (m, 8H), 4,13 (kV, 4H), 5.25-in of 5.40 (m, 12H), 5,57 (c, 1H), 5,66 (c, 1H), 6,04-6,16 (m, 2H), 7,54 (d, 1H); MC (elektrorazpredelenie): 395,3 [M+Na]+.

Example 26

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

Ethyl (2E/Z,4E,13Z,16Z,19Z)-3-methyl-docosa-2,4,13,16,19-pentenoate (37) (2E:2Z=1:1, between 0.30 g, 0.81 mmol) was dissolved in EtOH (10 ml) and added LiOH × H2O (0.27 g, 6,44 mmol) in water (2.5 ml). The mixture was stirred at 70°C in an inert atmosphere for two hours, cool and add 1M HCl to establish a pH=1. The mixture is extracted twice with heptane (30 ml) and the combined organic layer is dried (Na2SO4). Purification using flash chromatography (heptane:EtOAc, 4:1) gives 0,090 g (32%) indicated in the title compounds as colorless oils.1H-NMR (200 MHz, CDCl3): δ of 0.95 (t, 3H), 1,25-1,50 (m, 10H), 1,98-of 2.15 (m, 7H), 2,20-of 2.30 (m, 2H), and 2.79 (m, 4H), 5,27-5,42 (m, 6H), 5,61 (c, 1H), 6,11-6,21 (dt, J=to 15.8 Hz, J=7,0 Hz, 1H), 7,53 (d, J=15,8 Hz, 1H), 11,70 (users, 1H);13C-NMR (75 MHz, CDCl3): 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 (elektrorazpredelenie): 345,3 [M+H]+, 367,3 [M+Na]+.

Example 27

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

A suspension of LAH (0,011 g, 0,282 mmol) in dry THF (8 ml) was adjusted to 0°C in inert and the atmosphere and add dropwise a solution of ethyl (2E/Z,4E,13Z,16Z,19Z)-3-methyl-docosa-2,4,13,16,19-pentenoate (2E:2Z=1:1, 0.10 g, 0,268 mmol) in dry THF (2 ml). The mixture is stirred at 0°C for one hour, then at ambient temperature for 30 minutes, and then add 10% NH4Cl (10 ml). The mixture is extracted twice with heptane (20 ml) and the combined organic extracts washed with saturated salt solution (20 ml) and dried (Na2SO4). Purification using flash chromatography (heptane:EtOAc, 9:1) gives 0,030 g (34%) of (2E,4E,13Z,16Z,19Z)-3-methyl-docosa-2,4,13,16,19-pentaen-1-ol (21) as a colourless oil.1H-NMR (200 MHz, CDCl3): δ of 0.96 (t, J=7.5 Hz, 3H), 1,20-1,40 (m, 10H), 1,76 (c, 3H), 1,99 and 2.13 (m, 6H), was 2.76-2.82 from (m, 4H), 4,24 (d, J=6,93 Hz, 2H), 5,26-5,41 (m, 6H), 5,54 (t, J=6,9 Hz, 1H), ceiling of 5.60-of 5.75 (dt, J=15.6 Hz, J=6,9 Hz, 1H), equal to 6.05 (d, J=15.6 Hz, 1H);13C-NMR (50 MHz, CDCl3): 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 (elektrorazpredelenie): 353,3 [M+Na]+.

(2Z,4E,13Z,16Z,19Z)-3-methyl-docosa-2,4,13,16,19-pentaen-1-ol (38) was isolated as a colourless oil (0.04 g, 45%)

1H-NMR (200 MHz, CDCl3): δ of 0.96 (t, J=7.5 Hz, 3H), 1,20-of 1.45 (m, 10H), 1,83 (c, 3H), 1,98-of 2.15 (m, 6H), was 2.76-2.82 from (m, 4H), 4,25 (d, J=7,19 Hz, 2H), 5,26-5,49 (m, 7H), 5,68-of 5.83 (dt, J=15,50 Hz, 6,95, 1H), to 6.39 (d, J=15,5 Hz, 1H);13C-NMR (50 MHz, CDCl3): 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 (elektrorazpredelenie): 353,3 [M+Na]+.

Example 28

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

Stage 1:

Diisopropylamine (from 0.84 ml, 5,98 mmol) dissolved in dry THF (20 ml) and cooled to 0°C in an inert atmosphere. Added dropwise n-BuLi (of 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. is Added dropwisea mixture of ethyl (fully Z)-2-ethyl-docosa-4,7,10,13,16,19-hexaenoic (2.00 g, 5,20 mmol) in dry THF (20 ml) for 20 minutes, the obtained dark green solution was stirred at -78°C for ten minutes, and then add a solution of I2(1.98 g, 7,80 mmol) in dry THF (10 ml). The mixture is allowed to reach ambient temperature for 80 minutes, and partitioned between saturated Na2SO3(40 ml) and heptane (40 ml). The aqueous layer was extracted with heptane (40 ml) and the combined organic extracts washed with 1M HCl (40 ml) and dried (Na2SO4). Purification using flash chromatography (heptane:EtOAc, 98:2) to give 1.70 g (64%) of ethyl (fully Z)-2-ethyl, 2-iodine-docosa-4,7,10,13,16,19-hexaenoic.1H-NMR (200 MHz, CDCl3): δ 0.88 to 0,99 (m, 6H), to 1.19 to 1.31 (m, 4H), 1,98-2,19 (m, 4H), of 2,75 2,95 (m, 12H), 5,28-of 5.45 (m, 12H); MC (elektrorazpredelenie): 533,2 [M+Na]+.

Stage 2:

Ethyl (fully Z)-2-ethyl-2-iodine-docosa-4,7,10,13,16,19-hexaenoic (1.55 g, 3.04 from mmol) dissolved in dry diethyl ether (50 ml) under inert atmospheres the sphere and add DBU (0.45 ml, totaling 3.04 mmol). The mixture was stirred at ambient temperature for 23 hours, diluted with heptane (50 ml) and the organic layer washed with saturated NH4Cl (50 ml). The aqueous layer was extracted with heptane (40 ml) and the combined organic extracts washed with 0,1M HCl (40 ml) and dried (Na2SO4). Purification using flash chromatography (heptane:EtOAc, 98:2) gives of 1.16 g (quantitative.) specified in the connection header 22 (E/Z=4:1) as colourless oil.

1H-NMR (200 MHz, CDCl3):

E-isomer: δ 0,84-0,99 (2×t, 6H), 1,19 of 1.28 (t, 3H), 2,01-of 2.09 (m, 4H), was 2.76-2.95 and (m, 10H), 4,11 (kV, 2H), 5,20-of 5.45 (m, 10H), 5,55-of 5.75 (m, 1H), 6,00-of 6.20 (m, 2H).

Z-isomer: δ 0,84-0,99 (2×t, 6H), 1,19 of 1.28 (t, 3H), 1,70-1,90 (m, 2H), 2,01-of 2.09 (m, 2H), was 2.76-2.95 and (m, 10H), to 4.23 (q, 2H), 5,20-of 5.45 (m, 11H), 5,55-of 5.75 (m, 1H), 6,10-of 6.20 (m, 1H). MC (elektrorazpredelenie): 405,3 [M+Na]+.

Example 29

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

A suspension of LAH (0,044 g, 1.15 mmol) in dry THF (10 ml) under inert atmosphere was adjusted to 0°C and added dropwise a mixture of ethyl (2E/Z,4E,7Z,10Z,13Z,16Z,19Z)-2-ethyl-docosa-2,4,7,10,13,16,19-heptanoate (2E:2Z=1:1, 0.40 g, 1.05 mmol) in dry THF (5 ml). The mixture is stirred at 0°C for one hour, then at ambient temperature for one hour and quenched by addition of saturated NH4Cl (10 ml). The mixture is extracted twice with heptane (20 ml) and the combined organic extracts washed with saturated is the first salt solution (20 ml) and dried (Na 2SO4). Purification using flash chromatography (heptane:EtOAc, 9:1) gives 0,110 (31%) of (2E,4E,7Z,10Z,13Z,16Z,19Z)-2-ethyl-docosa-2,4,7,10,13,16,19-hepten-1-ol (23) as a colourless oil.1H-NMR (200 MHz, CDCl3): δ 0,84-0,99 (2×t, 6H), 2,01-of 2.20 (m, 4H), 2.77-to 2,90 (m, 8H), 2,92 are 2.98 (m, 2H), 3,50 (m, 2H), 5,28-5,41 (m, 10H), 6,00-of 6.45 (m, 3H);13C-NMR (50 MHz, CDCl3): 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 (elektrorazpredelenie): 363,2 [M+Na]+.

0,040 g (11%) (2Z,4E,7Z,10Z,13Z,16Z,19Z)-2-ethyl-docosa-2,4,7,10,13,16,19-hepten-1-ol (39) also isolated in the form of a colourless oil.1H-NMR (200 MHz, CDCl3): δ 0,86-0,99 (2×t, 6H), 2,02-2,19 (m, 4H), was 2.76-2,90 (m, 10H), 3,53 (m, 2H), 5,23-5,44 (m, 13H);13C-NMR (50 MHz, CDCl3): 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-docosa-2,4,6,10,13,16,19-heptanoate (24)

A solution of triethyl 3-methyl-4-phosphono-2-butenoate (485 μl, a 1.96 mmol) in a mixture of anhydrous THF-DMPU 5:1 (20 ml) cooled to 0°C and added dropwise n-BuLi (2.5 M in hexane, 760 μl, 1,90 mmol). The mixture is stirred at 0°C for 20 min, and then cooled to -78°C. Add a solution of (2E,6Z,9Z,12Z,15Z)-octadeca-2,4,6,10,13,16,19-pentenal in THF (2 ml) and the reaction mixture stirred at -78°C for one hour. Then allow the mixture heated Atisa to 0°C within one hour. Then add saturated aqueous solution of NH4Cl and the phases are separated. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water and dried (MgSO4). Evaporation of the solvents under reduced pressure, followed by flash chromatography on silica gel (95:5, hexane-EtOAc) to give ester (120 mg).

Example 31

Ethyl (2E,4E,6E,10Z,13Z,16Z,19Z)-3-methyl-docosa-2,4,6,10,13,16,19-gatenby acid (25)

To a solution of ester in methanol is added an aqueous solution of KOH (8 EQ.) and the mixture is heated to 60-70°C for 2 hours. The solution is cooled, water is added and the mixture is acidified. The mixture is then extracted with ethyl acetate. The combined organic phases are washed with water and dried (MgSO4). Evaporation of the solvents under reduced pressure gives the acid. δN(300 MHz): of 0.95 (t, J=7.5 Hz, 3H, CH3), was 2.05 (2H, m), 2,15 was 2.25 (4H, m), 2,28 (d, J=0,93 Hz, 3H), 2,7-2,9 (m, 6H), 5,2-5,5 (m, 8H), 5,75 (users, 1H), 5,85-5,95 (m, 1H), 6,10 and 6.25 (2H, m), 6,60 (DD, J=15.3 Hz, J=10.4 Hz, 1H); δWith(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

Example study 1:Activation and binding to the binding domain of the ligand of PPARα,γ,δ and human RXRα

Measure the activation and binding of new compounds with the domain of the ligand binding (LBD) of nuclear receptors PPRα, PPARγ, PPARδ or human RXRα (h).

For this study used non-stationary system transfection gene/cell. Chimeric constructs derived from LBD person. DBD PPARα, PPARγ, PPARδ, or RXRα replace GAL4DBD. Get the following plasmid constructs: pSG5-GAL4-hPPARα, pSG5-GAL4-hPPARγ, pSG5-GAL4-hPPARδ and pSG5-GAL4-hRXRα. Plasmid LUC chimeras and LUC reporter transfairusa cells COS-1, and protein luciferase analyzed as described in methods.

The ligand for PPARα (Wy 14,643), the ligand for RXRα (9-CIS-retinoic acid) and the ligand for PPARγ: rosiglitazone, a ligand for PPARδ: bezafibrat used as positive controls.

Method:

Fatty acid ligands

Wy-14.643, 9-CIS-retinoic acid (9-CIS-RA) or rosiglitazone and new connections (original solution) is diluted to a final concentration of 0.1 M in DMSO. They are then diluted to 10 mm in DMSO and stored in 1.5-ml tubes (homopolymer, plastic tubes), rinsed with argon and stored at -20°C.

Cell culture

Cells COS-1 (ATCC no CRL 1650) were cultured in DMEM supplemented with L-glutamine (2 mm), penicillin (50 Units/ml), streptomycin (50 μg/ml), Fungizone (2.5 µg/ml) and 10% inactivated FBS. Cells are incubated at 37°C in a humidified atmosphere of 5% CO2and 95% of air and is used for non-stationary transliterowany. Every third day the cells in each flask is separated into a new flask containing fresh the environment.

Transferowania

Cells (1.5 x 1 million) placed in a 30 mm Cup for tissues (sectionone tablets), 1 day before transferowania. Unsteady transferowania using lipofectamine 2000 carried out as described (Invitrogen, Carlsbad, CA). Each hole takes 990 ng plasmid: 320 ng of reporter ((UAS)5-tk-LUC (UAS = located above the trigger sequence and LUC = luciferase), 640 ng pGL3 basic (empty vector) and 30 ng of plasmid for expression of pSG5-GAL4-hPPARα, pSG5-GAL4-hPPARγ, pSG5-GAL4-hPPARδ or pSG5-GAL4-hRXRα, which are chimeric expression constructs containing domain ligand binding (LBD) PPARα, PPARγ, PPARδ and human RXRα (h). LPG, Wy 14.643, 9-CIS-RA or BRL (10 μm) and DMSO (control) added to the media after 5 hours after transliterowany. Transfetsirovannyh cells maintained for 24 hours before legirovaniem using reporter lisanova buffer. Linking LPG or ligands with the LBD of PPAR activates the binding of GAL4 with UAS that, in turn, stimulates the tk promoter to launch the expression of luciferase. The luciferase activity is measured using a luminometer (luminometer TD-20/20; Turner Designs, Sunnycvale, CA) and normalized to protein content.

The results:

The results in table 1 show that some of the new compounds covered by this invention have the potential of selective modulators/activator the PPARα (compound 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 RXRα ligands (compound 25).

Table 1
Activating luciferase (fold activation) as a result of binding of the ligand with the new compounds at a concentration of 10 μm, with the binding domain of the ligand of PPARα, γ and δ person, in addition to human RXRα
ConnectionhPPARαhPPARγhPPARδhRXRα
Negative control1,001,001,001,00
Wy146432,27±0,04
9-(Z)-retinoic acid2,72±0,32
Bezafibrat0,99±0,01/td>
Rosiglitazoneof 13.27±0,56
DHA1,57±0,191,86±0,171,09±0,010,83±0,09
44,51±0,521,56±0,121,28±0,080,90±0,08
116,79±0,211,67±0,111,17±00,200,84±0,09
134,89±0,311,63±0,061,11±0,160,81±0,05
258,27±0,814,32±0,291,47±0,381,57±0,08

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

Way

Substance

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

Cell culture

Cells U937-3xkB-LUC (Carlsen, J. Immun, 2002) were cultured in medium RPMI-1640 with L-glutamine (2 nm), penicillin (50 Units/ml), streptomycin (50 mg/ml), hygromycin (75 µg/ml), 10% fetal calf serum at 37°C and 5% CO2. Cells were seeded in 24-hole tablets where to environment add 1% fetal calf serum. The activity of NF-kB to induce with lipopolysaccharide (LPS) (1 μg/ml) or TNF-α, human (10 ng/ml). Cells viability was measured by staining Trianon blue.

Analysis of luciferase activity

The luciferase activity is measured by obtaining images using the IVIS Imaging System from Xenogen Corp., USA. The luminescence detected after 1 min and 5 min after the addition of 0.2 mg d-luciferin per ml cell environment. The number of photons in each hole per second is calculated using the software Living Image Software (Xenogen Corp., USA.

Results

Some of the compounds covered by the present invention are potent inhibitors of the pathway NF-κB (compound 13 and 25). These two compounds have a strong inhibitory effect similar to that of dexamethasone, see figure 1.

1. Lipid compound of the formula:

where
n=0;
R1and R2are the same or different and may be selected from the group of substituents consisting of a hydrogen atom, a C1-C7alkyl is Noah group, the halogen atom and C1-C7alkoxygroup;
X represents a COR3or CH2OR4where
R3selected from the group consisting of hydrogen, hydroxy, C1-C7alkoxy and amino; and
R4selected from the group consisting of hydrogen, C1-C7the alkyl or C1-C7acyl,
Y represents a C9-C21alkene with one or more double bonds in the E - or Z-configuration, and the circuit Y is unsubstituted and contains a double bond in the ω-3 position;
provided that R1and R2cannot simultaneously represent a hydrogen atom.

2. The lipid compound according to claim 1, having the S-configuration, represented by the following formula:

3. The lipid compound according to claim 1, where R1and R2are the same or different and may be selected from the group of substituents consisting of a hydrogen atom, a C1-C7alkyl group, a C1-C7alkoxygroup and halogen atom.

4. The lipid compound according to claim 1, where R1and R2are the same or different and may be selected from the group of substituents consisting of a hydrogen atom, a C1-C3alkyl group, a C1-C3alkoxygroup and halogen atom.

5. The lipid compound according to claim 1, where R3represents a C1-C7al is oxygraph.

6. The lipid compound according to claim 5, where R3represents a C1-C3alkoxygroup.

7. The lipid compound according to claim 1, where R3is gyrochip.

8. The lipid compound according to claim 1, where R4represents a C1-C7alkyl group.

9. The lipid compound according to claim 1 or 8, where R4represents a C1-C3alkyl group.

10. The lipid compound according to claim 1, where R4represents a C1-C7acyl group.

11. Lipid compound of claim 10, where R4represents a C1-C3acyl group.

12. The lipid compound according to claim 1, where the double bond between carbon atoms 2 and 3 is in the E configuration.

13. The lipid compound according to claim 1, where R1and R2are the same or different and selected from methyl group, ethyl group and a hydrogen atom.

14. The lipid compound according to claim 1, where R1and R2are different, and one of them is a C1-C3alkoxy and the other represents hydrogen.

15. The lipid connection 14, where the double bond between carbon atoms 2 and 3 is Z-configuration.

16. The lipid compound according to claim 1, where the specified halogen atom is a fluorine.

17. The lipid compound according to claim 1, where Y represents a C14-C19alkene with 2-6 double with the IDE.

18. The lipid connection 17, where Y represents a C14-C19alkene with 2-6 double bonds in Z-configuration, alternating with methylene groups.

19. The lipid compound according to claim 1, where n=0, and Y represents a C13-C19alkene having 2 to 6 double bonds.

20. The lipid compound according to claim 1, where n=0, represented by the following formula:

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

21. The lipid compound according to claim 1, where R1and R2are different, and one of them is a hydrogen atom and the other is selected from the group of substituents consisting of C1-C7alkyl group, halogen atom and C1-C7alkoxygroup.

22. The lipid compound according to item 21, where the double bond between carbon atoms 2 and 3 is in the E configuration.

23. The lipid compound according to item 21 or 22, where
- n=0;
- X=COR3where R3is hirotsugu or C1-C3alkoxygroup;
- R1and R2are different, and one of them is a hydrogen atom and the other represents C1-C3alkyl group, a C1-C3alkoxygroup or halogen atom; and
- Y represents a C13-C19alkene having 2 to 6 double bonds.

24. The lipid compound according to item 21, where
- n=0;
- X=CO 3where R3is hirotsugu or C1-C3alkoxygroup;
- R1and R2are different, and one of them is a hydrogen atom and the other represents C1-C2alkyl group or a C1-C2alkoxygroup; and
- Y represents a C13-C19alkene having 2 to 6 double bonds.

25. The lipid compound according to item 21, where
- n=0;
- X=COR3where R3is hirotsugu or C1-C2alkoxygroup;
- R1and R2are different, and one of them is a hydrogen atom and the other represents C1-C2alkyl group or a C1-C2alkoxygroup; and
- Y represents a C17-C19alkene having 3-5 double bonds.

26. The lipid compound according to item 21, selected from the following lipid compounds 1-4 and 6-8, 26, 33, 41-44:

27. The lipid connection p selected from the following lipid compounds 33 and 41-44:

28. The lipid compound according to item 21, where
- n=0;
- X=CH2OR4where R4represents hydrogen or C1-C3acyl group;
- R1and R2are different, and one of them is a hydrogen atom and the other represents a C 1-C3alkyl group, a C1-C3alkoxygroup and halogen atom; and
- Y represents a C14-C20alkene having 2 to 6 double bonds.

29. The lipid compound according to item 21, where
- n=0;
- X=CH2OR4where R4represents hydrogen or C1-C3acyl group;
- R1and R2are different, and one of them is a hydrogen atom and the other represents C1-C2alkyl group or a C1-C2alkoxygroup; and
- Y represents a C14-C20alkene having 2 to 6 double bonds.

30. The lipid compound according to item 21, where
- n=0;
- X=CH2OR4where R4represents hydrogen; and
- R1and R2are different, and one of them is a hydrogen atom and the other represents C1-C2alkyl group or a C1-C2alkoxygroup;
- Y represents a C17-C19alkene having 3-5 double bonds.

31. The lipid compound according to item 21 or 22, selected from the following lipid compounds 5, 9 and 27:

32. The lipid compound according to claim 1, where R1and R2are the same or different and selected from the group of substituents consisting of a1-C7alkyl group, halogen atom and C1-C7alkoxygroup.

33. LIPI the Noah connection p, where the double bond between carbon atoms 2 and 3 is in the E configuration.

34. The lipid connection p or 33, where
- n=0;
- X=COR3where R3is hirotsugu or C1-C3alkoxygroup;
- R1and R2are the same or different and selected from C1-C3alkyl group, a C1-C3alkoxygroup and halogen atom; and
- Y represents a C13-C19alkene having 2 to 6 double bonds.

35. The lipid connection p or 33, where
- n=0;
- X=CH2OR4where R4represents hydrogen or C1-C3acyl group;
- R1and R2are the same or different and selected from C1-C3alkyl group, a C1-C3alkoxygroup and halogen atom; and
- Y represents a C14-C20alkene having 2 to 6 double bonds.

36. The lipid compound according to claim 1 for use as a medicinal product for treating and/or preventing a condition associated with elevated features NFkB, treatment and/or prevention of an inflammatory disease or condition, reduction of insulin levels in plasma and/or blood glucose, the treatment of insulin resistance, and treatment and/or prevention of resistance of peripheral tissues to insulin and/or diabetes status, for example, diabetes is type 2.

37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 35, for the treatment and/or prevention of a condition associated with elevated features NFkB, treatment and/or prevention of an inflammatory disease or condition, reduction of insulin levels in plasma and/or blood glucose, the treatment of insulin resistance, and treatment and/or prevention of resistance of peripheral tissues to insulin and/or a diabetic condition, such as type 2 diabetes, designed to provide a daily dose of 5 mg to 10,

38. The pharmaceutical composition according to clause 37, designed to provide a daily dose of 50 mg to 1 g of the specified connection.

39. The pharmaceutical composition according to clause 37, designed to provide a daily dose of 50 mg to 200 mg of the compounds.

40. The pharmaceutical composition according to clause 37, further containing a pharmaceutically acceptable carrier, excipient or diluent, or any combination.

41. The pharmaceutical composition according to clause 37, or 40, intended for oral administration.

42. A method of treating and/or preventing a condition associated with elevated features NFkB, including the introduction to a mammal in need this, pharmaceutically active amount of a compound according to any one of claims 1 to 35.

43. The method of treatment and/or prevention will nosplit the form of further disease or condition includes introduction to the mammal in need this, pharmaceutically active amount of a compound according to any one of claims 1 to 35.

44. A method of reducing levels of insulin in plasma, blood glucose and treatment of insulin resistance comprising the administration to a mammal in need of this, a pharmaceutically active amount of a compound according to any one of claims 1 to 35.

45. The method of treatment and/or prevention of resistance of peripheral tissues to insulin and/or a diabetic condition, such as type 2 diabetes comprising the administration to a mammal in need of this, a pharmaceutically active amount of a compound according to any one of claims 1 to 35.



 

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