Carboxyl- or hydroxyl-substituted benzimidazole derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel carboxyl- or hydroxyl-substituted benzimidazole derivatives of formula (I), or pharmaceutically acceptable salts thereof, where R¹ is selected from and , R² is hydrogen; R³ is cyclohexyl or bicyclo[2.2.1]heptyl; R⁴ is phenyl, which is substituted in the 4th position with a halogen or a lower fluoroalkyl, or a pyridyl, which is substituted with 1 or 2 substitutes independently selected from halogen and a lower alkoxy group; R⁵ and R⁶ independently denote hydrogen or fluorine; R⁷ and R⁹ are independently selected from a group consisting of hydrogen, lower alkyl, halogen, lower alkoxy group, lower fluoroalkyl, lower fluoroalkoxy group and cyano group; R⁸ is -(CR¹²R¹³)_n-COOH, where n equals 0, 1 or 2, and R¹² and R¹³ are independently hydrogen or lower alkyl, or -O-(CR¹⁴R¹⁵)_p-COOH, where p equals 1 or 2, and R¹⁴ and R¹⁵ are independently hydrogen or lower alkyl, or R¹⁴ and R¹⁵ together with the carbon atom with which they are bonded form a cycloalkyl ring, or R⁸ is tetrazole; R¹⁰ is a hydroxy group or -(CH₂)_p-COOH, where p equals 0 or 1; m equals 0 or 1; R¹¹ is -COOH. The invention also relates to specific carboxyl- or hydroxyl-substituted benzimidazole derivatives and a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel carboxyl- or hydroxyl-substituted benzimidazole derivatives, having selective activity with respect to farnesoid X receptor, are obtained.

26 cl, 126 ex

The present invention relates to new carboxyl or hydroxylamines benzimidazole derivative, method for producing these compounds, to pharmaceutical compositions containing such compounds and to the use of these compounds for the manufacture of pharmaceutical compositions.

More specifically, the present invention relates to new derivatives of benzimidazole of the formula (I):

where

R¹selected from the

,and

R²represents hydrogen or lower alkyl;

R³represents a cyclohexyl or bicyclo[2.2.1]heptyl;

R⁴represents phenyl, which is substituted in the 4-position with halogen,

by cyano or fluoro-lower alkyl, or pyridyl, which is substituted by 1 or 2 substituents, independently selected from halogen, amino, ceanography and lower alkoxygroup;

R⁵and R⁶independently of one another represent hydrogen or fluorine;

R⁷and R⁹independently from each other selected from the group consisting of hydrogen, lower alkyl, halogen, lower alkoxygroup, fluoro-lower-alkyl, fluoro-lower alkoxygroup and cyanopropyl;

R⁸represents -(CR¹²R¹³)_n-COOH, where n denotes 0, 1 or 2, and R¹²and ¹³independently from each other represent hydrogen or lower alkyl, or R¹²and R¹³together with the carbon atom to which they are attached, form cycloalkyl ring,

or-O-(CR¹⁴R¹⁵)_p-COOH, where p denotes 1 or 2, and R¹⁴and R¹⁵independently from each other represent hydrogen or lower alkyl, or R¹⁴and R¹⁵together with the carbon atom to which they are attached, form cycloalkyl ring,

or R⁸is tetrazol;

R¹⁰represents a hydroxy-group or -(CH₂)_p-COOH, where R denotes 0, 1 or 2;

m denotes 0 or 1;

R¹¹represents-COOH;

and their pharmaceutically acceptable salts.

The compounds are selective modulators farnesoid-X-receptor.

Farnesoid-X-receptor (FXR) is a member of the family of nuclear hormone receptor transcription factors. FXR originally identified as a receptor that is activated by farnesol, and subsequent research has highlighted the major role of FXR as a receptor for bile acids [article Makishima, M., Okamoto, A.Y., Repa, J.J., Tu, H., Learned, R., Luk, A., Hull, M.V., Lustig, K. D., Mangelsdorf, D.J., and Shan, W., Science, 1999, 284, cc. 1362-5, Identification of a nuclear receptor for bile acids]. FXR is expressed in liver, intestine, kidney and adrenal glands. Four broshennyh isoforms have been cloned in human is E.

Among the major bile acids chenodeoxycholic acid is the most potent FXR agonist. The binding of bile acids or synthetic FXR ligands causes transcriptionally the expression of a small heterodimeric partner (SHP), a member of the family of atypical nuclear receptor that is associated with several other nuclear receptors of the hormone, including LRH-1 and LXR alpha and blocks their transcriptional functions [article Lu, TT, Makishima, M., Repa, J.J., Schoonjans, K., Kerr, T.A., Auwerx, J., and Mangelsdorf, D.J., Mol Cell 2000, 6, cc. 507-15, Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors.]. CYP7A1 and CYP8B are enzymes involved in the synthesis of bile acids in the liver. FXR suppresses their expression of activation-way SHP. FXR directly induces the expression of vector-exporters of bile acids to ABC family in hepatocytes, including export pump salt of bile acid (ABCB11) and resistance to many drugs, binding protein 2 (AVSS) [article Kast, .R., Goodwin, B., Tarr, GT, Jones, S.A., Anisfeld, A. M., Stoltz, S.M., Tontonoz, P., Kliewer, S., Willson, T.M., and Edwards, P. A., J Biol Chem, 2002, 277, cc. 2908-15, Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor.; Ananthanarayanan, M., Balasubramanian, N., Makishima, M, Mangelsdorf, D.J., and Suchy, F.J., J Biol Chem, 2001, 276, cc. 28857-65, Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor.]. Mice with blocked FXR have weakened resistant is here due to bile acid hepatotoxicity, and synthetic FXR agonists, as shown, are hepatoprotective in animal models of cholestasis [article Liu, Y., Binz, J., Numerick, M.J., Dennis, S., Luo, G., Desai, V., MacKenzie, K, Mansfield, T.A., Kliewer, S.A., Goodwin, W. and Jones, S.A., J Clin Invest 2003, 112, cc. 1678-87, Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra-and extrahepatic cholestasis; Sinal, C.J., Tohkin, M., Miyata, M., Ward, J.M., Lambert, G., and Gonzalez, F.J., Cell, 2000, 102, cc. 731-44, Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis.]. These data suggest that FXR protects hepatocytes from toxicity of bile acid suppression as cellular synthesis and import of bile acids, and promoting their excretion by the liver.

The process of enterohepatic circulation of bile acids is also a major regulator of homeostasis of cholesterol in serum. After biosynthesis from cholesterol in the liver, bile acids are secreted by the bile in the bile in the lumen of the small intestine with the purpose of digestion and absorption of fats and fat-soluble vitamins. The ratio of various bile acids determines the hydrophilicity of the total bile acid and its ability to dissolve cholesterol. Activation of FXR increases the hydrophilicity of the total mass, lowering intestinal solubility of cholesterol, effectively blocking its absorption. Reduced absorption, as expected, leads to a lowering of cholesterol levels in plasma. Indeed, direct inhibitors of cholesterol absorption, such as setmib, reduce cholesterol in plasma, providing some evidence in support of this hypothesis. However, ezetimib limited efficiency, which leads to back sverhnegativny of cholesterol synthesis in the cells, trying to compensate for the breakdown of cholesterol. Recent data showed that FXR stops this action is partly a direct suppression of the expression of HMGCoA reductase by involving SHP and LRH1 [article Datta, S., Wang, L., Moore, D.D., and Osborne, T.F., J Biol Chem, 2006, 281, cc. 807-12, Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase promoter by nuclear receptors liver receptor homologue-1 and small heterodimer partner: a mechanism for differential regulation of cholesterol synthesis and uptake]. FXR also reduces synthesis in liver triglycerides by suppressing the expression of SREBP1-c alternative means, including SHP and LXRaa. These compounds, which modulate the activity of FXR, can show greater than therapeutic activity against lowering cholesterol and triglyceride levels in plasma compared to therapies.

The majority of patients with coronary artery disease have high levels of atherogenic LDL in plasma. Inhibitors of HMGCoA reductase (statins) are effective in normalizing levels of LDL-C, but reduce the risk of cardiovascular diseases such as stroke and myocardial infarction, only 30%. Required additional therapy aimed at another reduction is tertogennogo LDL, and other lipid risk factors such as high levels of triglycerides in plasma and low levels of HDL-C.

A high proportion of patients with type 2 diabetes in the United States has violated the concentration of lipoproteins in the plasma. The prevalence of total cholesterol > 240 mg/DL was present in 37% of men with diabetes and 44% in women with diabetes, and the prevalence of LDL-> 160 mg/DL is 31% and 44% respectively for these groups. Diabetes is a disease in which the patient's ability to control glucose levels in the blood is reduced due to partial attenuation of the response to insulin. Type II diabetes (T2D), also called non-insulin-dependent diabetes mellitus (NIDDM), is 80-90% of all diabetes cases in developed countries. When T2D pancreatic islets of Langerhans produce insulin, but the primary target tissues (muscle, liver and adipose tissue) develop a strong resistance to its action. The body compensates by producing even more insulin, eventually leading to the inability to produce pancreatic insulin. So, T2D is a cardiovascular and metabolic syndrome, is associated with many comorbidities, including dyslipidemia and insulin resistance, and hypertension, endothelial dysfunction and inflammatory atherosclerosis.

First line treatment is Oia, dyslipidemia and diabetes is low-fat diet and a diet with low content of glucose, exercise and weight loss. The results can be very mild, and it becomes necessary treatment for a variety of developing metabolic deficits, for example, lipid-modulating agents, such as statins and fibrates, picolinamides drugs, such as sulfonylureas and Metformin, or substances that increase sensitivity to insulin, class thiazolidinedione (TZD) PPAR-agonists. Recent studies provide evidence that the FXR modulators may have a higher therapeutic potential, providing excellent normalization of the levels of LDL-C and triglycerides, currently attainable only by using combinations of existing drugs, and, in addition, can eliminate back-action at the cellular cholesterol homeostasis.

The new compounds of the present invention superior to the compounds known from the prior art, because they are associated and selectively modulate FXR very effectively. Consequently, reduces the absorption of cholesterol, decreases blood levels of LDL cholesterol and triglycerides, and reduced inflammatory atherosclerosis. Because multiple aspects of dyslipidemia and cholesterol homeostasis are associated with the FXR modulators, they are expected to have an increased therapeutic shall otential in comparison with connections, known from the prior art.

Unless otherwise stated, the following definitions are provided to illustrate and define the meaning and scope of various terms used to describe the present invention.

In this description, the term "lower" is used to denote a group consisting of one to seven, preferably one to four carbon atoms.

The term "halogen" denotes fluorine, chlorine, bromine and iodine, where fluorine, chlorine and bromine are preferred.

The term "alkyl", alone or in combination with other groups, denotes a branched or linear monovalent saturated aliphatic hydrocarbon radical containing from one to twenty carbon atoms, preferably from one to sixteen carbon atoms, more preferably one to ten carbon atoms. The term "C_1-10-alkyl" means a branched or linear monovalent saturated aliphatic hydrocarbon radical containing from one to ten carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 1,1,3,3-TETRAMETHYLBUTYL and the like. The lower alkyl groups described herein are also preferred alkyl groups.

The term "lower alkyl" or "C₁-C₇-alkyl", alone or in combination with other g what uppada, denotes a branched or linear monovalent alkyl radical containing from one to seven carbon atoms, preferably from one to four carbon atoms. This term is represented by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and the like. The lower alkyl groups optionally can be substituted, for example, hydroxy-group. Such substituted lower alkyl groups are referred to as "hydroxy-lower-alkyl".

The term "fluoro-lower alkyl" refers to lower alkyl groups which are mono - or several times substituted by fluorine. Examples of fluoro-lower alkyl groups are, for example, -CFH₂, -CF₂H, -CF₃, -CH₂CF₃, -(CH₂)₂CF₃, -CH(CF₃)₂and-CF₂-CF₂H.

The term "amino", alone or in combination, signifies a primary, secondary or tertiary amino group attached through a nitrogen atom, where the secondary amino group is alkyl or cycloalkyl Deputy, and tertiary amino group has two similar or different alkyl or cycloalkyl Deputy or two substituent of the nitrogen together form a ring, such as, for example, -NH₂methylamino, ethylamino, dimethylamino, diethylamino, methylethylamine, pyrrolidin-1-yl or piperidino etc., preferably a primary amino group, dim filamentgroup and diethylaminopropyl, and especially dimethylaminopropan.

The term "cycloalkyl" denotes a monovalent hydrocarbon radical containing from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Cycloalkenyl group optionally can be substituted as described in the description and the claims.

The term "alkoxy" denotes the group-O-R', where R' represents alkyl. The term "lower alkoxygroup" refers to the group-O-R', where R' is a lower alkyl. A preferred example is a methoxy group.

The term "fluoro-lower alkoxygroup" refers to the group R-O-, where R is a fluoro-lower alkyl. Examples of fluoro-lower alkoxygroup are, for example, -O-CFH₂, -O-CF₂H, -O-CF₃, -O-CH₂CF₃, -O-(CH₂)₂CF₃, -O-CH(CF₃)₂and-O-CF₂-CF₂H.

The term "protective group" means groups that are used to protect functional groups, especially hydroxyl groups, temporarily. Examples of protective groups are benzyl, p-methoxybenzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and (for the protection of amino groups) Vos and benzyloxycarbonyl.

The compounds of formula (I) can form pharmaceutically acceptable acid salt additive. Examples of such pharmaceutically acceptable salts having Auda salts of the compounds of formula (I) with physiologically compatible mineral acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulfonate acid, p-toluensulfonate acid, acetic acid, lactic acid, triperoxonane acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term "pharmaceutically acceptable salt" means a salt such. The compounds of formula (I), in which there is a group COOH, may form a salt with a base. Examples of such salts are salts with alkali, alkaline earth metal and ammonium, such as, for example, salt Na-, K-, Ca -, and trimethylammonium. The term "pharmaceutically acceptable salt" also refers to those salts.

More specifically, the present invention relates to compounds of formula (I):

where

R¹selected from the

,and

R²represents hydrogen or lower alkyl;

R³represents a cyclohexyl or bicyclo[2.2.1]heptyl;

R⁴represents phenyl, which is substituted in the 4-position by halogen, cyano or fluoro-lower alkyl, or pyridyl, which is substituted by 1 or 2 substituents, independently selected from halogen, is aminogruppy, ceanography and lower alkoxygroup;

R⁵and R⁶independently of one another represent hydrogen or fluorine;

R⁷and R⁹independently from each other selected from the group consisting of hydrogen, lower alkyl, halogen, lower alkoxygroup, fluoro-lower-alkyl, fluoro-lower alkoxygroup and cyanopropyl;

R⁸represents -(CR¹²R¹³)_n-COOH, where n denotes 0, 1 or 2, and R¹²and R¹³independently from each other represent hydrogen or lower alkyl, or R¹²and R¹³together with the carbon atom to which they are attached, form cycloalkyl ring, or-O-(CR¹⁴R¹⁵)_p-COOH, where p denotes 1 or 2, and R¹⁴and R¹⁵independently from each other represent hydrogen or lower alkyl, or R¹⁴and R¹⁵together with the carbon atom to which they are attached, form cycloalkyl ring;

R¹⁰represents a hydroxy-group or -(CH₂)_p-COOH, where p denotes 0, 1 or 2;

m denotes 0 or 1;

R¹¹represents-COOH;

and their pharmaceutically acceptable salts.

The compounds of formula (I) are individually preferred and their physiologically acceptable salts are individually preferred, where the compounds of formula (I) are particularly preferred.

the value of the formula (I) may contain one or more asymmetric With atoms, and, therefore, can exist as enantiomeric mixtures, diastereomeric mixture or in the form of optically pure compounds.

In particular, the preferred compounds are the compounds of formula (I)described in the examples as individual compounds, and their pharmaceutically acceptable salts, as well as optically pure compounds.

Preferred are the compounds of formula (I), where

R⁸represents -(CR¹²R¹³)_n-COOH, where n denotes 0, 1 or 2, and R¹²and R¹³independently from each other represent hydrogen or lower alkyl, or R¹²and R¹³together with the carbon atom to which they are attached, form cycloalkyl ring,

or-O-(CR¹⁴R¹⁵)_p-COOH, where p denotes 1 or 2, and R¹⁴and R¹⁵independently from each other represent hydrogen or lower alkyl, or R¹⁴and R¹⁵together with the carbon atom to which they are attached, form cycloalkyl ring.

Preferred further are compounds of the formula (I) in accordance with the invention, where R²represents hydrogen.

Especially preferred are also the compounds of formula (I) in accordance with the present invention, where R³represents cyclohexyl.

A preferred group of compounds of formula (I) are the two who is the group where R⁴represents phenyl, which is substituted in the 4-position by halogen, cyano or fluoro-lower-alkyl, more preferred compounds of formula (I), where R⁴is a 4-halogenfrei. Most preferably, R⁴represents 4-chlorophenyl.

Another group of preferred compounds of formula (I) are compounds where R⁴represents pyridyl, which is substituted by 1 or 2 substituents, independently selected from halogen, amino, ceanography and lower alkoxygroup. Most preferably, R⁴represents pyridin-3-yl, which is substituted by 1 or 2 substituents, independently selected from halogen, amino, ceanography and lower alkoxygroup. Most preferably, R⁴represents a 6-chloropyridin-3-yl or 2,6-dimethoxypyridine-3-yl.

Preferred further are compounds of the formula (I) in accordance with the present invention, where R⁵and R⁶represent fluorine.

A preferred group of compounds of formula (I) in accordance with the present invention are the compounds where R¹represents a

,

and where R⁷and R⁹independently from each other selected from the group consisting of hydrogen, lower alkyl, halogen, lower alkoxygroup, fluoro-lower Alky is a, fluoro-lower alkoxygroup and cyanopropyl; and

R⁸represents -(CR¹²R¹³)_n-COOH, where n denotes 0, 1 or 2, and

R¹²and R¹³independently from each other represent hydrogen or lower alkyl, or R¹²and R¹³together with the carbon atom to which they are attached, form cycloalkyl ring, or-O-(CR¹⁴R¹⁵)_p-COOH, where p denotes 1 or 2, and R¹⁴and R¹⁵independently from each other represent hydrogen or lower alkyl, or R¹⁴and R¹⁵together with the carbon atom to which they are attached, form cycloalkyl ring.

This indicates that these compounds of formula (I) have the formula:

where R¹-R⁹are as defined above.

The compounds of formula (I-i) are particularly preferred, where R⁸represents -(CR¹²R¹³)_n-COOH, n denotes 0, 1 or 2, and R¹²and R¹³independently from each other represent hydrogen or lower alkyl, or

R¹²and R¹³together with the carbon atom to which they are attached, form cycloalkyl ring. More preferably, R⁸represents-COOH.

Also preferred are the compounds of formula (I-i), where R⁸represents-O-(CR¹⁴R¹⁵)_p-COOH, where R o is means 1 or 2, and R¹⁴and R¹⁵independently from each other represent hydrogen or lower alkyl, or R¹⁴and R¹⁵together with the carbon atom to which they are attached, form cycloalkyl ring. Especially preferred are compounds where R denotes 1. Especially preferred are compounds where R¹⁴and R¹⁵are methyl, or R¹⁴and R¹⁵together with the carbon atom to which they are attached, form cyclopropyl ring.

Another group of preferred compounds of formula (I) in accordance with the present invention are the compounds where R¹represents a group:

,

and where R¹⁰represents hydroxy or -(CH₂)R-COOH, where R denotes 0, 1 or 2,

and m represents 0 or 1.

This indicates that these compounds of formula (I) have the formula:

where R¹-R⁶, R¹⁰and m are as defined above.

Preferred are the compounds of formula (I-ii), where m denotes 0.

Other preferred compounds of formula (I-ii) in accordance with the present invention are the compounds where R¹⁰represents a hydroxy-group or-COOH. Especially preferred are compounds where R¹⁰represents the hydroxypropy.

In addition, the compounds of formula (I) in accordance with the present invention are preferred, where R¹represents a group:

.

This indicates that these compounds of formula (I) have the formula:

where R¹-R⁶are as defined above.

Preferred compounds of formula (I) selected from the group consisting of the following compounds:

6-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}nicotinic acid,

3-chloro-4-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,

4-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,

4-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methylbenzoic acid,

(-)-3-chloro-4-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,

(+)-3-chloro-4-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,

TRANS-4-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexanecarbonyl acid,

2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-(4-hydroxycyclohexyl)ndimethylacetamide,

(+)-2-qi is logical-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-(TRANS-4-hydroxycyclohexyl)ndimethylacetamide,

TRANS-4-({cyclohexyl[2-(2,6-dimethoxypyridine-3-yl)-5,6-debtor-1H-benzimidazole-1-yl]acetyl}amino)cyclohexylcarbonyl acid,

(+)-4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetylamino}cyclohexanecarbonyl acid,

4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetylamino}-3-methylbenzoic acid,

4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetylamino}-3-Formentera acid,

4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5-perbenzoate-1-yl]acetylamino}cyclohexanecarbonyl acid,

(-)-4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5-perbenzoate-1-yl]acetylamino}cyclohexanecarbonyl acid,

(-)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexanecarbonyl acid,

(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexyl)acetic acid,

(+)-[TRANS-4-({2-[2-(4-chlorophenyl)-5,6-debtor-1H-benzimidazole-1-yl]-2-cyclohexylethyl}amino)cyclohexyl]acetic acid,

4-{2-bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}benzoic acid,

(-)-TRANS-4-[({-2-[2-(4-chlorophenyl)-5-fluoro-1H-benzimidazole-1-yl]-2-cyclohexylethyl}amino)methyl]cyclohexanecarbonyl acid,

3-chloro-4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-the l]-2-cyclohexylethylamine}benzoic acid,

4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,

(+)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,

(-)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,

4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methylbenzoic acid,

(+)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methylbenzoic acid,

(-)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methylbenzoic acid,

3-chloro-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,

(+)-3-chloro-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,

(-)-3-chloro-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,

4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,

(+)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,

(-)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,

4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}is 3.5-differentia acid,

(-)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}is 3.5-differentia acid,

4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyanobenzoic acid,

3-chloro-4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}benzoic acid,

(+)-3-chloro-4-{-2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}benzoic acid,

(-)-3-chloro-4-{-2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}benzoic acid,

4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methoxybenzoic acid,

4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid,

4-{2-cyclohexyl-2-[5,6-debtor-2-(4-triptoreline)benzoimidazol-1-yl]acetylamino}benzoic acid,

4-{2-cyclohexyl-2-[5-fluoro-2-(4-triptoreline)benzoimidazol-1-yl]acetylamino}benzoic acid,

4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cryptomaterial acid,

4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine} benzoic acid,

4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,

(4-{2-[2-(4-x is arvanil)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}phenyl)acetic acid,

2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid,

2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)-2-methylpropionate acid,

3-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}phenyl)propionic acid,

3-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid,

(-)-3-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid,

(+)-3-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid,

(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)acetic acid,

2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)propionic acid,

2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)-2-methylpropionate acid,

(+)-2-(4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)-2-methylpropionate acid,

(-)-2-(4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)-2-methylpropionate acid,

1-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl is thylamino}-3-pertenece)cyclopropanecarbonyl acid,

(+)-1-(4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid,

(-)-1-(4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid,

2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-TRANS-(4-hydroxycyclohexyl)ndimethylacetamide,

(-)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-(4-hydroxycyclohexyl)ndimethylacetamide,

(+)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-(4-hydroxycyclohexyl)ndimethylacetamide,

6-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine} nicotinic acid

and their pharmaceutically acceptable salts.

Also preferred are the compounds of formula (I)selected from the following compounds:

(+)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyanobenzoic acid,

(-)4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyanobenzoic acid,

(+)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methoxybenzoic acid,

(-)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methoxybenzoic acid,

(+)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid,

(+)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cryptomaterial acid,

(-)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cryptomaterial acid,

(-)-4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,

(+)-4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,

4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyano-5-Formentera acid,

(+)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyano-5-Formentera acid,

(-)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyano-5-Formentera acid,

1-(4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid,

(+)-1-(4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid,

(-)-1-(4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid,

4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid,

(+)-4-{2-[2(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid,

(-)-4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid,

4-{2-cyclohexyl-2-[5,6-debtor-2-(6-methoxypyridine-3-yl)benzoimidazol-1-yl]acetylamino}cyclohexanecarbonyl acid,

(-)-4-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexanecarbonyl acid,

(4-{2-[2-(6-chloro-2-methoxypyridine-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexyl)acetic acid,

4-{2-[2-(6-chloro-2-methoxypyridine-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexanecarbonyl acid,

4-{2-[2-(6-chloro-2-methoxypyridine-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,

(+)-4-{2-cyclohexyl-2-[5,6-debtor-2-(6-methoxypyridine-3-yl)benzoimidazol-1-yl]acetylamino}cyclohexanecarbonyl acid,

(-)-4-{2-[2-(6-chloro-2-methoxypyridine-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexanecarbonyl acid,

(-)-(4-{2-[2-(6-chloro-2-methoxypyridine-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexyl)acetic acid,

(+)-4-{(S)-2-[2-(6-chloro-2-methoxypyridine-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,

4-{2-bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}benzoic acid,

(4-{2-cyclohexyl-2-[5,6-debtor-2-(2-detoxify the DIN-3-yl)benzoimidazol-1-yl]acetylamino}cyclohexyl)acetic acid,

4-[2-cyclohexyl-2-(5,6-debtor-2-p-talibandominated-1-yl)acetylamino]benzoic acid,

4-[2-cyclohexyl-2-(5,6-debtor-2-p-talibandominated-1-yl)acetylamino]cyclohexanecarbonyl acid,

(-)-4-[2-cyclohexyl-2-(5,6-debtor-2-p-talibandominated-1-yl)acetylamino]benzoic acid,

(+)-[2-cyclohexyl-2-(5,6-debtor-2-p-talibandominated-1-yl)acetylamino]cyclohexanecarbonyl acid,

4-{2-bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}cyclohexanecarbonyl acid,

4-{2-cyclohexyl-2-[5,6-debtor-2-(4-methoxyphenyl)benzimidazol-1-yl]acetylamino}benzoic acid,

(-)-4-{2-bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}cyclohexanecarbonyl acid,

4-{2-cyclohexyl-2-[5,6-debtor-2-(4-methoxyphenyl)benzimidazol-1-yl]acetylamino}cyclohexanecarbonyl acid,

(-)-4-{2-cyclohexyl-2-[5,6-debtor-2-(4-methoxyphenyl)benzimidazol-1-yl]acetylamino}benzoic acid,

(4-{2-bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}cyclohexyl)acetic acid,

(-)-4-{2-bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}benzoic acid,

(-)-(4-{2-bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}cyclohexyl)acetic acid,

2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclo is exil-N-[4-(1H-tetrazol-5-yl)phenyl]acetamide", she

2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-N-[2-chloro-4-(1H-tetrazol-5-yl)phenyl]-2-cyclohexylacetate,

2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[2-fluoro-4-(1H-tetrazol-5-yl)phenyl]acetamide", she

(+ or -)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[2-fluoro-4-(1H-tetrazol-5-yl)phenyl]acetamide", she

(+ or -)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[2-fluoro-4-(1H-tetrazol-5-yl)phenyl]acetamide", she

2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,

(+)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,

(-)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,

2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,

(+)-2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,

(-)-2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,

2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-[2-fluoro-4-(1H-tetrazol-5-yl)phenyl]acetamide", she

2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide

and their headlights is asepticheski acceptable salt.

Especially preferred compounds of formula (I) are compounds selected from the group consisting of the following compounds:

2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-(4-hydroxycyclohexyl)ndimethylacetamide,

(+)-2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-(TRANS-4-hydroxycyclohexyl)ndimethylacetamide,

(-)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-(4-hydroxycyclohexyl)ndimethylacetamide,

and their pharmaceutically acceptable salts.

Other especially preferred compounds of formula (I) are compounds selected from the group consisting of the following compounds:

4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,

(-)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine} benzoic acid,

4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,

(-)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,

and their pharmaceutically acceptable salts.

Other especially preferred compounds of formula (I) are compounds selected from the group consisting of the following compounds:

2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)-2-m is dipropionate acid,

(-)-2-(4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)-2-methylpropionate acid,

1-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid,

(-)-1-(4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid,

and their pharmaceutically acceptable salts.

Other especially preferred compounds of formula (I) are compounds selected from the group consisting of the following compounds:

(-)4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyanobenzoic acid,

(-)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid,

(-)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyano-5-Formentera acid,

(-)-4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid,

and their pharmaceutically acceptable salts.

Other especially preferred compounds of formula (I) are compounds selected from the group consisting of the following compounds:

(+or -)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-]-N-[2-fluoro-4-(1H-tetrazol-5-yl)phenyl]acetamide", she

(-)-2-[2-(4-chlorophenyl)-5,6-differentim Gasol-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,

(-)-2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,

and their pharmaceutically acceptable salts.

It should be understood that compounds of General formula (I) of the present invention can be obtained derivative functional groups with obtaining derivatives, which can turn into the original compound in vivo.

The present invention also relates to a method for producing compounds of formula (I) as described above, which involves the cyclization of the compounds of formula (II):

where R¹, R², R³, R⁴, R⁵and R⁶are as defined above.

Cyclization of the compounds of formula (II) can be carried out under reaction conditions well known from the prior art. Such cyclization can usually be carried out, for example, in a suitable solvent, such as, for example, dichloromethane, at a suitable temperature in the presence of a suitable reagent, such as a free PPh₃or PPh₃on the pitch.

The present invention also relates to an alternative method of preparing compounds of formula (I) as described above, which includes the amide condensation of the acid of formula (III):

where R³, R⁴, R⁵and R⁶are such as is designated above, with an amine of formula (IV):

R¹-NH₂(IV)

where R¹is the same as defined above.

Amide condensation of compounds of formula (III) may be carried out under reaction conditions known to the person skilled in the art. Such condensation can usually be carried out, for example, in a suitable solvent such as N,N-dimethylformamide (DMF) or dioxane, at a suitable temperature in the presence of a suitable condensing agent, such as N,N'-carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), hexaflurophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide (HATU), 1-hydroxy-1,2,3-benzotriazole (NOVT) or tetrafluoroborate O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea (TBTU).

The present invention also relates to compounds of formula (I)as defined above, obtained by the method described above.

The compounds of formula (I) can be obtained by methods known from the prior art, or as described below. Unless otherwise specified, the substituents R¹-R⁸are as defined above.

The compounds of formula (I) in accordance with the present invention can be obtained, for example, the methods and techniques described next. A typical method of producing compounds of formulas is (I) shown below in scheme 1.

In a suitable organic solvent, such as, for example, Meon, 2-azidoaniline 1 carboxylic acid, 2, isonitrile 3 and aldehyde 4 condense with getting the connection 5 of the so-called reaction Ugi-type (stage a, the standard method can be found, for example, in the book "The Peptides" by Gross &Meienhofer, T. 2, Academic Press, N.Y., 1980, cc. 365-381). In subsequent intramolecular reaction type Staudinger with a suitable reagent, such as, for example, PPh₃, acidobasic 5 is converted into a benzimidazole 6. In those cases where the substituent R¹has an ester group, ester group can be chipped off in the major (for example, methyl or ethyl esters with lithium hydroxide in polar solvents, such as, for example, methanol, water or THF, or mixtures of these solvents) or in acidic conditions (for example, tert-butyl methyl ether, using concentrated hydrochloric acid in THF or formic acid in methanol) to obtain the final compounds IA (stage b). Not necessarily the benzimidazole 6 can be N-alkylated by deprotonation with a strong base (such as NaH or LiHMDA) and subsequent treatment with alkylating agent R²-X, where X is a standard leaving group, such as, for example, Cl, Br, I, SO₂alkyl, SO₂foralkyl, SO₂aryl (stage g). In the received connection 7, as for derivatives 6, the ester group can be chipped off, as described above in stage C. Many of the building blocks 2-4, in particular carboxylic acid 2, are commercially available. If not, they can be obtained from commercially available starting materials by methods described in the prior art, and are typically known to a person skilled in the art. Isonitrile 3, for example, can be obtained by dehydration of the corresponding formamide R¹-N-CHO using a suitable reagent, such as, for example, phosgene, POCl₃or Me₂N=CH⁺ClCl^-. Aldehyde 4, for example, can be obtained from the corresponding alcohol by oxidation with a suitable oxidizing agent, such as, for example, tetrapropylammonium (VII). 2-Azidoaniline 1 usually get in three stages from the corresponding 2-aminoalkanoic acid, which is converted into 2-azidoaniline acid oxidation NaNO₂in a suitable solvent (e.g. methanol) and subsequent processing of a suitable azide salt, such as NaN₃. The obtained 2-azidoaniline acid is then converted into compound 1 rearrangement of kurzius 2-azidoaniline azide obtained from 2-azidoaniline acid activating it with a suitable reagent (for example, characiformes in the presence of a base, such as tritium is h) and subsequent treatment with a suitable source of azide anions (e.g., sodium azide). 2-Azidoaniline 1 alternative can be obtained through 2-azidoaniline obtained by activation of 2-azidoaniline acid with a suitable reagent (for example, characiformes in the presence of a base, such as triethylamine) and subsequent treatment with ammonia. This amide is converted into a compound 1 of the so-called Hoffman rearrangement by treatment with a suitable reagent, such as NaOBr.

If one of the starting materials or compounds of formula (I) contains one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction stages, suitable protective groups (as described, for example, in the book "Protective Groups in Organic Chemistry", by T.W. Greene and P.G.M. Wutts, 2^-oeedition, 1991, Wiley N.Y.) can be introduced before a necessary stage, using methods well known from the prior art. Such protective groups can be removed at a later stage of the synthesis, using standard methods described in the prior art.

If the connection(1), (2), (3) or (4) contain stereogenic centers, the compound (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known from the prior art, for example, (chiral) HPLC or crystallization. azemina connection for example, can be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids, or by separation of the antipodes by specific chromatographic methods using chiral adsorbents or a chiral eluent.

An alternative approach to obtain the compounds of formula I are shown below in the diagram.

Compounds of General formula I can also be obtained as described in scheme 2. In this approach, mono-boc-protected ortho-arrangemen 8 carboxylic acid, 2, isonitrile 3 and aldehyde 4 condense in an organic solvent, such as, for example, methanol in the presence of acid (such as HCl) to bisimide 9 again condensation type Ugi (stage a). With basamid 9 remove the protective group using TFUK and cyclist to the target benzimidazole 6 (stage b). When the intermediate compound 9 has an ester group, it can be chipped off, as described in scheme 1, to obtain the compounds of formula IA. Optionally, the intermediate compound 9 can be N-alkylated as described above (stage b) to obtain the intermediate compounds 7, which, in turn, can be converted into compounds of formula IB according to the conditions described in scheme 1. Standard methods suitable for this approach are described, for example, articles Tempest and others, Tet. Lett., 2001, 42, cc. 4959 - 4962 and cc. 463-4968, or Zhang and others, Tet. Lett., 2004, 45, cc. 6757-6760. Mono-boc-protected ortho-arrangiamenti 1 are commercially available or can be obtained from the corresponding unprotected diamine processing di-tert-BUTYLCARBAMATE in an organic solvent, such as THF in the presence of a base, such as, for example, diisopropylethylamine.

If desired or necessary functional groups present in the compound I (such as CO₂alkyl, amino, ceanography and others), can form derivatives with other functional groups, using standard methods known to a person skilled in the art (for example, recovery-CO₂of alkyl of up-CH₂HE is using LiAlH₄the hydrolysis-CO₂the alkyl to CO₂H and subsequent optional conversion into amide, acylation of amino groups).

If one of the starting materials or compounds of formula (I) contains one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction stages, suitable protective groups (as described, for example, in the book "Protective Groups in Organic Chemistry", by T.W. Greene and P.G.M. Wutts, 2^-oeedition, 1991, Wiley N.Y.) can be introduced before a necessary stage, using methods well known from the prior uravnenii. Such protective groups can be removed at a later stage of the synthesis, using standard methods described in the prior art.

If the connection(2), (3), (4), (6), (7) or (9) contain stereogenic centers, the compound (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known from the prior art, for example, (chiral) HPLC or crystallization. Racemic compounds, for example, can be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids, or by separation of the antipodes by specific chromatographic methods using chiral adsorbents or a chiral eluent.

R¹present in the compound (I), after stages a and 6 or stages and 6 and described in the above schemes may be converted or replaced with another R¹using one-stage or a series of reaction stages. Two possible examples are listed below:

a) R¹=CH₂Ph, for example, can be removed using conditions dibenzylamine (for example, hydrolysis in a solvent such as methanol, in the presence of a catalyst such as Pd(0) on the corner), and a new R¹can be introduced, for example by deprotonation received CONHR²with the help of a strong base (for example, LiHMDA) and processing alkalinous the agent R ¹-X (X is a conventional leaving group such as, for example, Cl, Br, I, SO₂alkyl, SO₂foralkyl, SO₂aryl, and R¹represents a C_1-10-alkyl, lower-alkoxy-lower-alkyl, lower-alkoxy-carbonyl-lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl-lower-alkyl, diaryl-lower-alkyl, heteroaryl-lower-alkyl or heterocyclyl-lower-alkyl), or alternative Pd(II)-promoted condensation with R¹-X(R¹represents aryl or heteroaryl, and X represents Cl, Br, I or OSO₂CF₃).

b) Amidalas-CR³CON R¹R²group of compound (I)- CR³COOH can be carried out using suitable conditions, such as heating in isopropanol in the presence of NaOH or LiOH. A new amide bond can then be formed using amine HNR¹R²and the usual peptidylarginine reagent, such as EDCI, DCC or TPTU.

Functional groups present in (I) or any intermediate compounds that are not stable or are reactive under reaction conditions of one or more reaction stages may be protected by suitable protective groups (as described, for example, in the book "Protective Groups in Organic Chemistry", T.W.Greene and P.G.M. Wutts, 2^-oeedition, 1991, Wiley N.Y.), before the necessary stage, using methods that is all right known from the prior art. Such protective groups can be removed at a later stage of the synthesis, using standard methods described in the prior art.

An alternative way amidolysis Ugi reaction products is the treatment of benzimidazole, such as the connection 10, the sodium nitrite in a mixture of acetic acid and acetic anhydride to obtain the intermediate product of the reaction of diazotization, which, after rearrangement can be cleaved in the reaction mixture of alkali metal hydroxides (for example, LiOH, NaOH, KOH) and hydrogen peroxide into the corresponding free carboxylic acid 11 (scheme 3, step a; see article: ..White, J.Am.Chem. Soc, 1955, 77, cc. 6011-6014, D.A: Evans, P.H.Carter, C.J.Dinsmore, J.C.Barrow, J.L.Katz, D.W.Kung, Tetrahedron Lett., 1997, 38, cc. 4535-4538). The reaction of the amide cleavage is wider in relation to the nature of the amide, which can be used and is not limited to benzolamide. The use of chiral acids in the stage of Ugi reaction leads to the formation of diastereoisomers, which can be separated by standard chromatography on a conventional silicon-live on stage amide 10 or free acid 11. Alternatively, the chiral acid 11 can be separated by standard methods known to a person skilled in the art such as crystallization with chiral amines or keralaholiday.

Another approach of obtaining compounds of formula I are given below in figure 4.

Compounds of General formula IA and IB can also be obtained in accordance with scheme 4. The benzimidazole of the General structure 13 (commercially available or obtained, for example, by reaction of the appropriately substituted phenylenediamine 12 arylcarbamoyl acid 2, stage a) can be alkylated, for example, by means of ester 2-bromo (or another leaving group, such as, for example, SO₂alkyl, SO₂foralkyl, SO₂aryl)alkyloxy acid 14 in a suitable solvent, such as, for example, N,N'-dimethylformamide and a suitable base, such as, for example, cesium carbonate, to obtain the intermediate compound 12 (R⁹represents an alkyl group, such as, for example, methyl, ethyl or tert-butyl). Cleavage of the ester group using conditions described in scheme 1, leads to the production of acidic intermediates 15. Amide condensation of intermediate compounds 11c optionally substituted cycloalkyl/arylamine (commercially available or obtained by methods described in references or by methods known from the prior art) leads to the formation of compounds 6 (stage g). Amide condensation of this type are widely described in the previous level t is the transport (for example, book Comprehensive Organic Transformations: A Guide to Functional group Preparations, 2nd edition, Richard C. Larock. John Wiley & Sons, New York, NY., 1999) and can be implemented using a condensing reagent such as, for example, N,N-carbonyldiimidazole (CDI), 1-hydroxy-1,2,3-benzotriazole (NOVT) or tetrafluoroborate O-benzotriazol-1-yl-N,N,N,N-tetramethylurea (TBTU) in a suitable solvent, such as, for example, N,N-dimethylformamide (DMF) or dioxane, optionally in the presence of a base (e.g. triethylamine, diisopropylethylamine or 4-(dimethylamino)pyridine). Alternatively, the intermediate compound 6 can be obtained by transformation of the intermediates 11 in their anhydrides acid treatment, for example, thionyl chloride, optionally in a solvent such as, for example, dichloromethane, and the reaction of carboxylic acids with optionally substituted cycloalkyl/arylamine in a suitable solvent, such as dichloromethane and in the presence of a base, such as, for example, triethylamine, pyridine, diisopropylethylamine or 4-(dimethylamino)pyridine. The conversion of intermediate compounds 6 in compounds of General formula IA and IB can be carried out, as described in the above schemes.

Specialist in the art it is known that tetrazole can be obtained by a variety of standard techniques. For example, organic NITRILES can react with and is the home of sodium and ammonium chloride or chloride trialkyl or tetraalkyl of ammonia in a suitable solvent, such as, for example, DMF, DMSO, N-methylpyrrolidone or toluene, obtaining tetrazolo. Alternatively, organic azides, such as azides ORGANOTIN compounds, organosilicon compounds, organoboron compounds and alumoorganic compounds, such as, for example, triamcinolone or trimethylsilane, in a suitable solvent, such as toluene, may be subjected to reaction with NITRILES to form tetrazoles. For some of these reactions may require elevated temperatures, such as, for example, the boiling point of the solvent. Another way of obtaining tetrazolo involves the reaction of alkyl or urinaria with sodium azide in the presence of a Lewis acid such as boron TRIFLUORIDE or zinc bromide in solvents such as dichloromethane, N,N-dimethylformamide, or water, at temperatures from 0°C to the boiling point of the solvent.

The preferred method of obtaining tetrazolo involves the reaction derived from the nitrile group of the formula 6 and 7 (obtained as described in schemes 1-4) with sodium azide and salt of trialkylamine, such as, for example, the hydrochloride of triethylamine, in a suitable solvent, such as, for example, xylene, at elevated temperatures, preferably at the boiling temperature of the solvent. (Didier: I don't know whether specific predpochtitel the GE way (this way, which we still use). If not, I propose to omit it, because the other way may be a better/more appropriate, particularly in relation to technical process and production).

If the compounds of formula 6 or 7 contain stereogenic centers, the compound (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known from the prior art, for example, (chiral) HPLC or crystallization. Racemic compounds, for example, can be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids, or by separation of the antipodes by specific chromatographic methods using chiral adsorbents or a chiral eluent. Stage of education tetrazole can be carried out on a chiral or achiral the benzimidazole type 6 or 7.

Functional groups present in the compound (I) or any intermediate compounds that are not stable or are reactive under reaction conditions of one or more reaction stages may be protected by suitable protective groups (as described, for example, in the book "Protective Groups in Organic Chemistry", by T.W. Greene and P.G.M. Wutts, 2^-oeedition, 1991, Wiley N.Y.), before the necessary stage, using methods well-known from before stuudio prior art. Such protective groups can be removed at a later stage of the synthesis, using standard methods described in the prior art.

Despite the fact that obtaining them is not described in the examples, the compounds of formula (I), and all intermediate products can be obtained in accordance with the same methods or in accordance with the methods described above. Starting materials are commercially available or are known from the prior art.

As described above, it was found that the new compounds of the present invention are associated and selectively activate FXR. Therefore, they can be used for treatment or prevention of diseases and conditions which are modulated by FXR agonists. "Diseases and conditions), which are modulated by FXR agonists include elevated levels of lipids and cholesterol, especially high LDL cholesterol, high triglyceride levels, low HDL-cholesterol, dyslipidemia, atherosclerosis, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, a disease of cholesterol gall stone, cholestasis/fibrosis of the liver, diseases associated with cholesterol absorption, cancer, particularly gastrointestinal cancer, osteoporosis, peripheral occlusive disease, ischemic and the Soult, Parkinson's disease and Alzheimer's disease. Preferred diseases and conditions), which are modulated by FXR agonists are the prevention or the treatment of high levels of LDL cholesterol, high triglycerides, dyslipidemia, diseases of cholesterol gall stones, cancer, non-insulin-dependent diabetes mellitus and metabolic syndrome. Particularly preferred diseases which are modulated by FXR agonists are high LDL cholesterol, high triglyceride levels and dyslipidemia.

The present invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant

The present invention also includes compounds as described above for use as therapeutically active substances, especially as therapeutically active substances for the treatment or prevention of diseases which are modulated by FXR agonists, particularly as therapeutically active substances for the treatment or prevention of elevated levels of lipids and cholesterol, high LDL cholesterol, high triglycerides, low HDL-cholesterol, dyslipidemia, atherosclerosis, diabetes, particularly non-insulin dependent diabetes dia is ETA, metabolic syndrome, diseases of cholesterol gall stone, cholestasis/fibrosis of the liver, diseases associated with cholesterol absorption, cancer, gastrointestinal cancer, osteoporosis, peripheral occlusive disease, ischemic stroke, Parkinson's disease and/or Alzheimer's disease.

In another preferred embodiment, the present invention relates to a method of therapeutic or prophylactic treatment of diseases which are modulated by FXR agonists, especially therapeutic or prophylactic treatment of increased lipid and cholesterol, high LDL cholesterol, high triglycerides, low HDL-cholesterol, dyslipidemia, atherosclerosis, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, diseases of cholesterol gall stone, cholestasis/fibrosis of the liver, diseases associated with cholesterol absorption, cancer, gastrointestinal cancer, osteoporosis, peripheral occlusive disease, ischemic stroke, Parkinson's disease and Alzheimer's disease that includes the introduction of a compound as defined above to a human or animal.

The present invention also includes the use of compounds as defined above for therapeutic or prophylactic cured what I diseases, which are modulated by FXR agonists, particularly for therapeutic or prophylactic treatment of increased lipid and cholesterol, high LDL cholesterol, high triglycerides, low HDL-cholesterol, dyslipidemia, atherosclerosis, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, diseases of cholesterol gall stone, cholestasis/fibrosis of the liver, diseases associated with cholesterol absorption, cancer, gastrointestinal cancer, osteoporosis, peripheral occlusive disease, ischemic stroke, Parkinson's disease and Alzheimer's disease.

The present invention also relates to the use of compounds as described above for the preparation of medicinal products intended for therapeutic or prophylactic treatment of diseases which are modulated by FXR agonists, particularly for therapeutic or prophylactic treatment of increased lipid and cholesterol, high LDL cholesterol, high triglycerides, low HDL-cholesterol, dyslipidemia, atherosclerosis, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, diseases of cholesterol gall stone, cholestasis/fibrosis of the liver, diseases associated with the absorption of cholesterol is Rina, cancer, gastrointestinal cancer, osteoporosis, peripheral occlusive disease, ischemic stroke, Parkinson's disease and Alzheimer's disease. Such medicines include connection, as described above.

The following tests were carried out to determine the activity of compounds of the formula (I). The prior art analysis of binding can be found in the article: Nichols JS, etc., Anal. Biochem, 1998, 257, cc. 112-119, "Development of and scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain".

The expression vectors of bacterial and mammalian designed to produce glutathione-s-transferase (GST) and protein DNA-binding domain of Gal4 (GAL), merged with the ligand-binding domain (LBD) of the human FXR (amino acids 193-473). For this part of the sequences encoding FXR LBD, amplified polymerase chain reaction (PCR) from poliocephala clone using PCR and then subcloned into plasmid vectors. The final clone was verified by analysis of the DNA sequence.

The induction, expression and subsequent purification of fused protein GST-LBD was carried out in the cells of the strain E. coli BL21(pLysS) by standard methods (book Current Protocols in Molecular Biology, Wiley Press, edited by Ausubel and others).

The analysis of binding with radioligands

Binding of the test substances with the ligand-binding domain FXR was evaluated in radioligand analysis of substitution. The analysis done by ulali in the buffer, consisting of 50 mm Hepes, pH of 7.4, 10 mm NaCl, 5 mm MgCl₂. For each of the reaction wells in a 96-hole tablet 40 nm GST-FXR merged LBD protein was associated with a 10 µg granules glutathione-yttrium silicate SPA (PharmaciaAmersham) in a final volume of 50 ál with stirring. Added radioligand (for example, 40 nm) 2,N-DICYCLOHEXYL-2-[2-(2,4-acid)benzoimidazol-1-yl]ndimethylacetamide), and the reaction mixture was incubated at RT for 30 minutes in the presence of test compounds followed by treatment with a scintillation counter. All analyses on binding was carried out in 96-well tablets, and the amount of bound ligand was measured on a Packard TopCount using OptiPlates (Packard). Curves of the dose was built in the concentration range from 6×10^-9M to 2.5×10^-5M

Analyses with luciferase transcriptional reporter gene

The kidney cells of young hamsters (VNC ADS CCL10) were grown in DMEM containing 10% FBS, at 37°C in an atmosphere of 95% O2:5% CO₂. Cells were planted in 6-hole tablets with a density of 10⁵cells/well, and then transferrable using pFA-FXR-LBD or expression plasmids plus a reporter plasmid. Transfection was performed using reagent Fugene 6 (Roche Molecular Biochemicals) in accordance with the proposed regulations. Six hours after transfection, the cells were collected by trypsinization and placed in 96-well tablets with a density of 10 cells/well. After 24 hours, merge cells, the medium was removed and replaced by 100 μl of medium containing no phenol red, containing a test substance or reference ligand (final concentration of DMSO is 0.1%). After incubation of cells for 24 hours with substances, 50 μl of supernatant was separated, and then added 50 μl of Luciferase reagent Constant-Light (Roche Molecular Biochemicals) for lysis of cells and initiation of the luciferase reaction. Luminescence as a measure luciferase activity was determined on a Packard TopCount. Transcriptional activation in the presence of the test substance was expressed as fold change in luminescence compared to the luminescence of the cells incubated in the absence of matter. Values EU₅₀was calculated using XLfit (ID Business Solutions Ltd. UK).

Compounds in accordance with formula (I) have activity in at least one of the above tests (EU₅₀or IC₅₀), preferably in the range of from 0.5 nm to 10 μm, more preferably from 0.5 nm to 100 nm.

For example, the following compounds shown by the following values IC₅₀in the above analysis of binding:

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicines, for example, in the form of pharmaceutical preparations for enteral, parenteral or local administration. They can be entered, for example, orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or suspensions, or infusion solutions, or topically, e.g. in the form of ointments, creams or oils. Oral administration is preferred.

Obtaining pharmaceutical drugs can be performed in a manner known to any person skilled in the art by introducing described compounds of formula (I) and their pharmaceutically acceptable salts, optionally in combination with other therapeutically active substances in the form of herbal introduction together with suitable, non-toxic, inert, therapeutically compatible solid or sidematerial media and, if necessary, usual pharmaceutical adjuvants.

Suitable materials media are not only inorganic materials media, but also organic materials media. So, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as materials of media tablets, coated tablets, dragées and hard gelatin capsules. Suitable materials media for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient carriers may not be used, however, for soft gelatin capsules). Suitable materials of the carrier for the manufacture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and the like. Appropriate media materials for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable materials media for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable materials media for local trains are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, Terry, the glycols and derivatives of cellulose.

Conventional stabilizers, preservatives, moisturizing and emulsifying agents that improve the consistency agents, odorants, salts for regulating the osmotic pressure, buffer substances, soljubilizatory, dyes and masking agents and antioxidants are considered as pharmaceutical adjuvants.

The dosage of the compounds of formula (I) can vary within wide limits depending on the controlled disease, age and individual condition of the patient and the route of administration, and, of course, is determined for specific purposes in each case. For adult patients seen daily dosage of from about 1 to 1000 mg, especially from 1 to 300 mg, depending on the severity of the disease and the precise pharmacokinetic profile of the compound may be injected into one or more of the daily dosage units, for example, 1-3 metered units.

The pharmaceutical preparations normally contain about 1-500 mg, preferably 1-100 mg of the compounds of formula (I).

The following examples serve to further illustrate the present invention. They, however, must in no way limit its scope.

Examples

Abbreviations:

DHM = dichloromethane, DIPEA=N,N'-diisopropylethylamine, DMF = dimethylformamide, HATU = hexaphosphate 2-(7-Aza-1H-shall benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, HCl = hydrogen chloride, HPLC=high performance liquid chromatography, LiOH = lithium hydroxide, MPLC = liquid chromatography medium pressure, NaHCO₃= sodium bicarbonate, CT=room temperature, SiO₂= silica gel.

General remarks

Reactions were carried out in an atmosphere of nitrogen or argon, as appropriate.

Example 1

3-Chloro-4-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid

Specified in the title compound was obtained by heating [2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]cyclohexyloxy acid (200 mg, and 0.46 mmole) in 5 ml of thionyl chloride to 80°C for 4 h the Solvent was evaporated, and the residue was transferred into dichloromethane. Was added methyl ether 4-amino-3-chlorbenzoyl acid (85 mg, and 0.46 mmole)and the reaction mixture was stirred at RT over night. The crude product was treated with a solution of 1 M NaHCO₃and extraction of the aqueous layer with dichloromethane. The organic layers were combined, dried MgSO₄and was evaporated to dryness. The residue was transferred to a methanol (3 ml) was added 1N NaOH (1 ml). The mixture was stirred at RT overnight, the solvent was evaporated, and the product was isolated by preparative HPLC. MS (ES⁺): 560 (M+H).

Intermediate compounds

a) [2-(6-Chloropyridin-3-yl)-5,6-differentiality-1-yl]cyclohexyloxy acid

To a solution of tert-putilovo the ether (2-amino-4,5-differenl)carbamino acid (1.0 g, 4.1 mmole) in methanol (15 ml) was added cyclohexanecarboxaldehyde (of 0.82 ml, 6,14 mmole, 1.5 equiv.), 6-chloronicotinic acid (0,665 g, 4.1 mmole, 1.0 equiv.) and socialemotional (of 0.48 ml, 10,24 mmole, 1.0 equiv.) and stirred at RT for 16 h solution was Added 4M HCl in dioxane (10 ml)and the reaction mixture was stirred at RT for 3 h the Solution was concentrated by evaporation under reduced pressure, the pH was brought to 9 by adding a solution of 1 M NaHCO₃and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried MgSO₄and was concentrated by evaporation under reduced pressure. The crude material was dissolved in a mixture of acetic anhydride (40 ml) and acetic acid (20 ml)and cooled to 0°C. Portions were added sodium nitrite (7,4 g, 107 mmol). After the addition the reaction mixture was heated to CT and was stirred for 3 hours the Solution was concentrated by evaporation under reduced pressure, the pH was brought to 9 by adding a solution of 1 M NaHCO₃and the aqueous layer was extracted with ethyl acetate. The obtained brown oil was transferred into a mixture of THF: water (3:1, 20 ml)and was added dropwise prior LiOH solution (2.1 g, 48.7 per mmole) in hydrogen peroxide (10 ml, 30% solution in water). The mixture was stirred at RT for 30 min the Solution was concentrated by evaporation under reduced pressure, the pH was brought to 4 added the eat acetic acid, and the aqueous layer was extracted with ethyl acetate. The intermediate connection has not been further purified and used as raw material for further modification. MS (ES): 404 (M-H).

b) tert-Butyl ether (2-amino-4,5-differenl)carbamino acid

4,5-Debtor-2-nitrophenylamino (6.0 g, 34 mmole, 1 equiv.) was added to a solution of di-tert-BUTYLCARBAMATE (14.8 g, 68 mmol, 2 equiv.) and DMAP (211 mg, 0.2 mmole, 0,05 in THF (100 ml)and the mixture was stirred at room temperature for 72 hours. The solvent was evaporated, and the crude product was extracted from ethyl acetate and aq. NaHCO₃. The residue was transferred into DHM and cooled to 0°C. was Slowly added triperoxonane acid (of 7.75 g, 68 mmol, 2 equiv.), and the mixture was stirred for 48 h at 0°C. was Added 2N NaOH to bring the pH to 7. The organic layer was separated and evaporated. The residue was transferred into ethyl acetate and the product was extracted from aq. solution of NaHCO₃. The intermediate compound was isolated by chromatography on kieselgel. 4,28 g (16 mmol, 1 equiv.) was dissolved in DMF (50 ml) and was added 13 ml of a saturated solution of NH₄Cl. Added powdered zinc (5,1 g, 78 mmol, 5 equiv.), and the suspension was stirred for 30 minutes at 80°C and 2 hours at room temperature. The remaining solid was filtered, and the organic layer was evaporated. The product was extracted from ethyl acetate and aq. solution of NaHCO_{3/sub> and then was purified by chromatography on kieselgel.}

_{Example 2}

_{6-{2-[2-(6-Chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine)nicotinic acid}

_{Specified in the title compound was obtained analogously to example 1, replacing the methyl ester of 4-amino-3-methylbenzoic acid methyl ester 6-aminonicotinic acid. MS (ES⁺): 527 (M+H).}

_{Example 3}

_{4-{2-[2-(6-Chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}3-Formentera acid}

_{Specified in the title compound was obtained analogously to example 1, replacing the methyl ester of 4-amino-3-chlorbenzoyl acid methyl ester 4-amino-3-fermenting acid. MS (ES):544 (M+H).}

_{Example 4}

_{4-{2-[2-(6-Chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methylbenzoic acid}

_{Specified in the title compound was obtained analogously to example 1, replacing the methyl ester of 4-amino-3-fermenting acid methyl ester 4-amino-3-methylbenzoic acid. MS (ES⁺):540 (M+H).}

_{Example 5}

_{(-)-3-Chloro-4-{2-[2-(6-chloropyridin-3-yl]-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid}

_{Specified in the title compound was obtained analogously to example 1, carrying out the separation of the stereoisomers of chiral preparative HPLC. MS (ES⁺):560 (M+H).}

_{Example 6}

_{(+)-3-Chloro-4-{(2-[2-(6-chloropyridin-3-yl)-5,6-differentimages the-1-yl]-2-cyclohexylethylamine}benzoic acid}

_{Specified in the title compound was obtained analogously to example 1, carrying out the separation of the stereoisomers of chiral preparative HPLC. MS (ES):560 (M+H).}

_{The intermediate connection}

_{Methyl ester of TRANS-4-isocyanocyclohexane acid}

_{The hydrochloride of the methyl ester of TRANS-4-aminocyclohexanecarboxylic acid (2 g, 10.3 mmole) was dissolved in a mixture of DMF (10 ml) and DIPEA (2 ml). Was added ethyl formate (5 ml, 62 mmole)and the mixture was heated at 75°C during the night. The solvent was evaporated, and the crude product was extracted with ethyl acetate. Got a brown oil. MS (ES+):186 (M+H). The crude material was dissolved in dichloromethane (15 ml). Was added triethylamine (1.5 ml)and the reaction mixture was cooled to 0°C. Triphosgene (470 mg, 1.6 mmole) was dissolved in dichloromethane (4 ml)and added dropwise to the reaction mixture. The mixture was heated to CT and was stirred for 1 h the Product was isolated directly by chromatography on kieselgel, using ethyl acetate as eluent. The intermediate compound was used without further characterization.}

_{Example 7}

_{TRANS-4-{2-[2-(6-Chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexanecarbonyl acid}

_{To a solution of tert-butyl methyl ether (2-amino-4,5-differenl)carbamino acid (0.2 g, of 0.82 mmole) in methanol (4 ml) was added cyclohexanecarboxaldehyde (0.16 ml, 1,22 mmole, 1.5 equiv., 6-chloronicotinic acid (0,13 g of 0.82 mmole, 1.0 equiv.) and methyl ester of TRANS-4-isocyanocyclohexane acid (0,137 mg of 0.82 mmole, 1.0 equiv.), and stirred at RT for 16 h solution was Added 4M HCl in dioxane (4 ml)and the reaction mixture was stirred at RT for 3 h the Solution was concentrated by evaporation under reduced pressure, the pH was brought to 9 by adding a 1M solution of NaHCO3and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried MgSO4and was concentrated by evaporation under reduced pressure. The crude material was dissolved in methanol (15 ml), was added NaOH (5 ml) and DMF (1 ml), and the mixture was heated at 50°C during the night. The pH was brought to 4. Appeared light brown solid, which was then purified preparative HPLC. MS (ES⁺):532 (M+H).}

Example 8

2-Cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-(TRANS-4-hydroxycyclohexyl)ndimethylacetamide

To a solution of cyclohexyl-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetic acid (300 mg, 0.70 to mmole, 1.0 equiv.) in DHM (5 ml) was added triethylamine (142,1 mg, 194,7 μl, of 1.39 mmole, 2.0 equiv.) and HATU (341,6 mg of 0.90 mmole, 1.3 equiv.), and the mixture was stirred at 40°C. After 15 min was added the hydrochloride of TRANS-4-aminocyclohexanol (137,04 mg of 0.90 mmole, 1.3 equiv.; [CAS RN 50910-54-8]), and stirring continued at 50°C more than the s 2 o'clock Removal of solvent mixture under reduced pressure and purification by chromatography on a column of silica gel using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient heptane/ethyl acetate resulted in the receipt of 0.33 g (90%) specified in the connection header. MS (ES⁺):529 (M+H).

Intermediate compounds

a) N-Benzyl-2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]ndimethylacetamide

To a solution of tert-butyl methyl ether (2-amino-4,5-differenl)carbamino acid (2.50 g, 10,24 mmole, 1.0 equiv.; example 1, the intermediate compound b) in methanol (30 ml) was added cyclohexanecarboxaldehyde (1,15 g, 1.23 ml, 10,24 mmole, 1.0 equiv.; [2043-61-0]), and the mixture was stirred at RT. After 30 min was added 2,6-dimethoxytoluene acid (1.88 g, 10,24 mmole, 1.0 equiv.; [CAS RN 16727-43-8]) and socialemotional (1.20 g, 1.25 ml, 10,24 mmole, 1.0 equiv.; [931-53-3]), and stirring continued at RT for 2 h solution was Added 4M HCl in dioxane (20 ml)and the reaction mixture was stirred at RT over night. The solution was concentrated by evaporation under reduced pressure, the pH was brought to 9 by adding a 1M solution of NaHCO₃and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried MgSO₄and was concentrated by evaporation under reduced pressure. The crude material was purified column chromatography on silica gel, using a MPLC system (ombiFlash Companion, Isco Inc.), elwira gradient heptane/ethyl acetate to obtain 3.57 g (60%) specified in the connection header. MS (ES⁺):522 (M+H).

b) Cyclohexyl-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetic acid

To a solution of N-benzyl-2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]ndimethylacetamide (3.50 g, 6,72 mmole, 1.0 equiv.) in a mixture of acetic acid (25 ml) and acetic anhydride (50 ml) was added at 0°C in several small portions of sodium nitrite (10,20 g, 147,91 mmole, 22,0 equiv.) within 1 h the Reaction mixture was stirred over night, leaving heated to CT. The solution was concentrated by evaporation under reduced pressure, the pH was brought to 9 by adding a 1M solution of NaHCO₃and the aqueous layer was extracted with diethyl ether. The combined organic phases were dried MgSO₄and was concentrated by evaporation under reduced pressure. The crude material was transferred into a mixture of THF: water (3:1, 40 ml), was added prior LiOH solution (1,61 g, 67,23 mmole, of 10.0 equiv.) in hydrogen peroxide (15,24 g, 13,73 ml, 134,46 mmole, 20.0 equiv.; 30% solution in water)and stirred at RT for 30 min the Solution was concentrated by evaporation under reduced pressure, the pH was brought to 4 by addition of 1M HCl solution, and the aqueous layer was extracted with diethyl ether. The combined organic phases were dried MgSO₄he concentrically by evaporation under reduced pressure. Purification of column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient dichloromethane/methanol, resulted in obtaining a rate of 1.67 g (57%) specified in the connection header. MS (ES⁺):432 (M+H).

Example 9

(+)-2-Cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-(TRANS-4-hydroxycyclohexyl)ndimethylacetamide

Specified in the title compound was obtained in accordance with example 8, making separation of stereoisomers by using chiral preparative HPLC (Chiralpak-AD column), elwira gradient ethanol/heptane. MS (ES⁺):530 (M+H).

Example 10

TRANS-4-{2-Cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetylamino}cyclohexanecarbonyl acid

To a solution of ethyl ester of 4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetylamino}cyclohexanecarboxylic acid (350 mg, 0.60 mmole, 1.0 equiv.) in a mixture of acetonitrile/water (2:1.5 ml) was added 6 M aqueous NaOH solution (0.3 ml, of 1.80 mmole, 3.0 equiv.), and the reaction mixture was heated under microwave irradiation to 100°C for 30 minutes the Solvent was removed under reduced pressure and the crude reaction mixture was brought to pH=3 by addition of a solution of 1M HCl, and the aqueous layer was extracted with a mixture of dichloromethane/isopropanol (4:1). The combined organic phases were dried MgSO₄, was concentrated by evaporation when s is low pressure, and the crude material was purified by short column with silica gel, elwira gradient dichloromethane/methanol, getting 0.31 g (93%) specified in the connection header. MS (ES⁺):558 (M+H).

The intermediate connection

Ethyl ester of 4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5.6-differentiality-1-yl]acetylamino)cyclohexanecarbonyl acid

Specified in the title compound was obtained analogously to example 8, replacing hydrochloride, TRANS-4-aminocyclohexanol on the ethyl ester of TRANS-4-aminocyclohexanecarboxylic acid ([CAS RN 1678-68-8]). MS (ES⁺):585 (M+H).

Example 11

(+)-TRANS-4-{2-Cyclohexyl-2-[2-(2.6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetylamino}cyclohexanecarbonyl acid

Specified in the title compound was obtained in accordance with example 10, making separation of the stereoisomers of chiral preparative HPLC (Chiralpak-AD column), elwira gradient ethanol (a+0.5% formic acid)/heptane. MS (ES⁺):557 (M+H).

Example 12

4-{2-Cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetylamino}-3-methylbenzoic acid

Specified in the title compound was obtained analogously to example 10 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):566 (M+H).

The intermediate connection

Methyl ester of 4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine the-3-yl)-5,6-differentiality-1-yl]acetylamino}-3-methylbenzoic acid

Specified in the title compound was obtained analogously to example 8, replacing hydrochloride, TRANS-4-aminocyclohexanol on the methyl ester of 4-amino-3-methylbenzoic acid ([CAS RN 18595-14-7]). MS (ES⁺):579 (M+H).

Example 13

4-{2-Cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetylamino}-3-Formentera acid

Specified in the title compound was obtained analogously to example 10 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):569 (M+H).

The intermediate connection

Ethyl ester of 4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5.6-differentiality-1-yl]acetylamino}-3-fermenting acid

Specified in the title compound was obtained analogously to example 8, replacing hydrochloride, TRANS-4-aminocyclohexanol on the ethyl ester of 4-amino-3-fermenting acid ([CAS RN 73792-12-8]). MS (ES⁺):597 (M+H).

Example 14

TRANS-4-{2-Cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5-perbenzoate-1-yl]acetylamino}cyclohexanecarbonyl acid

Specified in the title compound was obtained analogously to example 10 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):540 (M+H).

Intermediate compounds

a) N-Benzyl-2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5-perbenzoate-1-yl]ndimethylacetamide

Specified in reception is e compound was obtained analogously to example 8, the intermediate connection and by replacing tert-butyl ether (2-amino-4,5-differenl)carbamino acid (example 1, intermediate compound b) in tert-butyl methyl ether (2-amino-5-forfinal)carbamino acid (obtained as described in article .J. Bamford, .J. Alberti, N. Bailey, S. Davies, D.. Dean, A. Gaiba, S. Garland, J.D. Hading, D.K. Jung, T.A. Panchal, C.A. Parr, J.G. Steadman, A.K. Takle, J.T. Townsend, D.M. Wilson, J. Witherington, Bioorg. Med. Chem. Lett., 2005, 15, cc.3402-3406). MS (ES⁺):504 (M+H).

b) Cyclohexyl-[2-(2,6-dimethoxypyridine-3-yl)-5-perbenzoate-1-yl]acetic acid

Specified in the title compound was obtained analogously to example 8, the intermediate compound B. MS (ES⁺):415 (M+H).

C) Ethylamide 4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5-perbenzoate-1-yl]acetylamino}cyclohexanecarboxylic acid

Specified in the title compound was obtained analogously to example 8, replacing hydrochloride, TRANS-4-aminocyclohexanol on the ethyl ester of TRANS-4-aminocyclohexanecarboxylic acid ([CAS RN 1678-68-8]). MS (ES⁺):568 (M+H).

Example 15

(-)-TRANS-4-{2-Cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5-perbenzoate-1-yl]acetylamino}cyclohexanecarbonyl acid

Specified in the title compound was obtained analogously to example 14, making separation of the stereoisomers of chiral preparative HPLC (Chiralpak-AD column), elwira gradient of isopropanol (to+0.5% formic acid)/heptane. MS (ES⁺):540 (M+H).

(-)-TRANS-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexanecarbonyl acid

Specified in the title compound was obtained analogously to example 8, substituting cyclohexyl-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetic acid [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid (example 22, intermediate the connection), and hydrochloride of TRANS-4-aminocyclohexanol on the ethyl ester of TRANS-A - aminocyclohexanecarboxylic acid ([CAS RN 1678-68-8]), after the ether hydrolysis analogously to example 10. Purification was performed chiral preparative HPLC (Chiralpak-AD column), elwira gradient ethanol (a+0.5% formic acid)/heptane. MS (ES⁺):530 (M+H).

Example 17

(TRANS-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexyl)acetic acid

Specified in the title compound was obtained analogously to example 10 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):544 (M+H).

The intermediate connection

Ethyl ester of (4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine} cyclohexyl)acetic acid

Specified in the title compound was obtained analogously to example 8, substituting cyclohexyl-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetic to the slot [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid (example 22, the intermediate connection), and hydrochloride of TRANS-4-aminocyclohexanol on hydrochloride ethyl ester, TRANS-(4-aminocyclohexane)acetic acid ([CAS RN 76308-26-4]). MS (ES⁺): 572 (M+H).

Example 18

(+)-TRANS-(4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexyl)acetic acid

Specified in the title compound was obtained in accordance with example 17, carrying out the separation of the stereoisomers of chiral preparative HPLC (Chiralcel-ODH column), elwira gradient of isopropanol (+0,5% triperoxonane acid)/heptane. MS (ES⁺):544 (M+H).

Example 19

4-{2-Bicyclo[2,2 .1[hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}benzoic acid

Specified in the title compound was obtained analogously to example 10 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):536 (M+H).

The intermediate connection

Methyl ester of 4-{2-bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}benzoic acid

Specified in the title compound was obtained analogously to example 8, the intermediate connection and replacing cyclohexanecarboxaldehyde on bicyclo[2.2.1]heptane-7-carbaldehyde ([CAS RN 53291-20-6]), 2,6-dimethoxytoluene acid 4-chlorbenzoyl acid ([CAS RN 74-11-3]), and socialemotional on methyl ether 4-isocyanante acid([CAS RN 198476-21-0]) after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):550 (M+H).

Example 20

(-)-TRANS-4-({2-[2-(4-Chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}methyl)cyclohexanecarbonyl acid

Specified in the title compound was obtained analogously to example 10 after cleaning chiral preparative HPLC (Chiralpak-AD column), elwira gradient of isopropanol (to+0.5% formic acid)/heptane. MS (ES⁺):527 (M+H).

The intermediate connection

Methyl ester of 4-({2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}methyl)cyclohexanecarboxylic acid

Specified in the title compound was obtained analogously to example 8, the intermediate connection and by replacing tert-butyl ether (2-amino-4,5-differenl)carbamino acid tert-butyl ether (2-amino-5-forfinal)carbamino acid (obtained as described in article .J. Bamford, .J. Alberti, N.Bailey, S.Davies, D..Dean, A. Gaiba, S. Garland, J.D. Harling, D.K. Jung, T.A. Panchal, C.A. Parr, J.G. Steadman, A.K. Takle, J.T. Townsend, D.M. Wilson, J. Witherington, Bioorg. Med. Chem. Lett., 2005, 15, cc. 3402-3406), 2,6-dimethoxytoluene acid 4-chlorbenzoyl acid ([CAS RN 74-11-3]), and socialemotional on methyl ether 4-socialmediaexaminer acid ([CAS RN 730964-84-8]) after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):540 (M+H).

Example 21

3-Chloro-4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-is illogicalities}benzoic acid

Specified in the title compound was obtained analogously to example 10 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):542 (M+H).

The intermediate connection

Methyl ether 3-chloro-4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}benzoic acid

Specified in the title compound was obtained analogously to example 8, the intermediate connection and by replacing tert-butyl ether (2-amino-4,5-differenl)carbamino acid tert-butyl ether (2-amino-5-forfinal)carbamino acid (obtained as described in article .J. Bamford, .J. Alberti, N. Bailey, S. Davies, D.. Dean, A. Gaiba, S. Garland, J.D. Harling, D.K. Jung, T.A. Panchal, C.A. Parr, J.G. Steadman, A.K. Takle, J.T. Townsend, D.M.Wilson, J. Witherington, Bioorg. Med. Chem. Lett., 2005, 15, cc. 3402-3406), 2,6-dimethoxytoluene acid 4-chlorbenzoyl acid ([CAS RN 74-11-3]), and socialemotional on methyl ether 3-chloro-4-isocyanante acid (obtained analogously to methyl ether 4-isocyanante acid ([CAS RN 198476-21-0]) of the methyl ester of 4-amino-3-chlorbenzoyl acid ([CAS RN 84228-44-4]) as described in the article S.Kamijo, .Jin, Y.Yamamoto, J.Am.Chem. Soc, 2001, 123, cc. 9453-9454) after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):554 (M+H).

Example 22

4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid

To a solution of these the new ester 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid (intermediate compound g) in 25 ml of dioxane was added 25 ml of water and 0.57 g (to 13.6 mmole) of the monohydrate of lithium hydroxide. The solution was stirred for 2 h at 100°C. After cooling to room temperature, was added 16 ml of a 1M aqueous solution of hydrochloric acid under stirring. The suspension was filtered, the filter residue washed with water and dried in high vacuum to obtain 2,46 g (99%) target compound as a colorless solid.

MS (ES⁺):524 (M-H)

Intermediate compounds

a) 2-(4-Chlorophenyl)-5,6-debtor-1H-benzoimidazol

A mixture of 50.7 g (0,35 mol) of 1,2-diamino-4,5-diferente, with 55.1 g (0,35 mol) of 4-chlorbenzoyl acid and 507 g of polyphosphoric acid was heated to 160°C and stirred at this temperature for 90 minutes After cooling to 55°C was added to 1000 ml of water and 500 ml of ethyl acetate. Under ice cooling was added about 1000 ml of 32% aqueous sodium hydroxide solution (pH about 9). The suspension was filtered on dicalite, and the filter residue was washed with 1.5 l of ethyl acetate. The phases were separated, and the aqueous phase was washed with 0.5 l of ethyl acetate. The organic phase is washed with 1M aqueous sodium hydroxide solution and saturated sodium chloride solution, dried with magnesium sulfate and was filtered. To the solution was added silica gel, and the solvent was evaporated. Raw adsorbed product was purified column chromatography on silica gel using a gradient of n-heptane: ethyl acetate (V/V, from 4:1 to 1:1) as eluent. Fractions containing the E. the product in pure form, were combined and evaporated. The remaining fraction was dissolved in ethyl acetate, washed twice 1M aqueous sodium hydroxide solution and saturated sodium chloride solution, the combined aqueous layers were extracted once with ethyl acetate, and the combined organic layers were dried with magnesium sulfate and was filtered. Chromatography on silica gel resulted in the receipt of the second party of the connection. Total yield: 75 g (80%) of light yellow solid. MS (ES⁺):265 (M+H).

b) Ethyl ester of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid

To a solution of 75 g (0,28 mol) of 2-(4-chlorophenyl)-5,6-debtor-1H-benzoimidazole in 750 ml of N,N-dimethylformamide was added 116 g (of 0.33 mol) of cesium carbonate and 88 g (0,35 mol) of ethyl ether bromocyclohexane acid (commercially available). The mixture was heated to 100°C, and after stirring for 90 min was added 116 g of cesium carbonate and 88 g of ethyl ether bromocyclohexane acid. After 6 h was added 116 g of cesium carbonate and 88 g of ethyl ether bromocyclohexane acid. After 22 hours (total reaction time), the reaction mixture was cooled to 30°C and was poured into 1 l of ice water and 2 l of ethyl acetate. The phases were separated, and the aqueous phase was extracted with 500 ml of ethyl acetate. The combined organic phases were washed three times with 500 ml of ice-cold water and once with a saturated solution of chloride of soda is I, was dried with magnesium sulfate and was filtered. To the solution was added silica gel, and the solvent was evaporated. Raw adsorbed product was purified column chromatography on silica gel using a mixture of n-heptane: ethyl acetate (9:1 V/V) as eluent. The fractions containing the product were combined, and the solvent was evaporated to obtain a suspension. The suspension was cooled in an ice bath and was filtered to obtain 92 g (75%) of the desired product as a colourless solid. MS (ES⁺):433 (M+H).

C) [2-(4-Chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid

To a solution of 24 g (by 0.055 mole) of ethyl ester of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid in 240 ml of dioxane, was added 240 ml of water and 7.0 g (0,166 mole) of the monohydrate of lithium hydroxide.

The solution was stirred for 2 h at 100°C. After cooling to room temperature, the organic solvent was evaporated. After stirring was added 162 ml of 1M hydrochloric acid. The resulting suspension was filtered, the filter residue washed with water and dried in high vacuum with the receipt of 21.7 g (95%) of target compound as a white solid. MS (ES^-):403 (M-H).

d) Ethyl ester of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid

A solution of 3.0 g (7.4 mmole) of [2-(4-chlorophenyl)-5,6-dif is orbitomeatal-1-yl]cyclohexyloxy acid in 5.4 ml of thionyl chloride was stirred at the boil under reflux. After 1 h the volatile components were removed on a rotary evaporator, the residue was transferred into toluene and evaporated (three times). The oil obtained was dissolved in 30 ml of dichloromethane, cooled to 0°C and added dropwise to a solution of ethyl 4-aminobenzoate (1.35 g, 8.1 mmole) and of 2.72 g (22,2 mmole) of 4-dimethylaminopyridine dissolved in 30 ml of dichloromethane. The cooling bath was removed and stirring was continued for 4 h the Reaction mixture was poured into 25% aqueous solution of hydrochloric acid, the phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with a saturated solution of sodium chloride, dried with magnesium sulfate, filtered and evaporated. The residue was purified column chromatography on silica gel using a mixture of heptane: ethyl acetate (1:0 to 1:1 V/V) as eluent to obtain specified in the title compound as a colourless solid (2.6 g, 62%). MS (ES⁺):552 (M+H).

Examples 23 and 24

Specified in the title compounds were obtained by separation of the stereoisomers of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid chiral preparative HPLC (Chiralpak-AD column).

(+)-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid

Colorless solid. MS (TS) m/e (M-N)⁺:522,2.

(-)-4-{2-[2-(4-Chlorophenyl)-5,6-ditto benzoimidazol-1-yl]-2-cyclohexylethylamine}benzoic acid

Colorless solid. MS (TS) m/e (M-N):522,2. Intermediate compounds

a) 2-(4-Chlorophenyl)-5,6-debtor-1H-benzoimidazol

A mixture of 50.7 g (0,35 mol) of 1,2-diamino-4,5-diferente, with 55.1 g (0,35 mol) of 4-chlorbenzoyl acid and 507 g of polyphosphoric acid was heated to 160°C and stirred at this temperature for 90 minutes After cooling to 55°C was added to 1000 ml of water and 500 ml of ethyl acetate. Upon cooling, was added about 1000 ml of 32% aqueous sodium hydroxide solution (pH about 9). The suspension was filtered through dekalim, and the filter residue was washed with 1.5 l of ethyl acetate. The phases were separated, and the aqueous phase was washed with 0.5 l of ethyl acetate. The organic phase washed with 1M aqueous sodium hydroxide solution and saturated sodium chloride solution, dried with magnesium sulfate and was filtered. To the solution was added silica gel, and the solvent was evaporated. Raw adsorbed product was purified column chromatography on silica gel using a gradient of n-heptane: ethyl acetate (V/V, from 4:1 to 1:1) as eluent. The fractions containing the product in a pure form, were combined and evaporated. The remaining fraction was dissolved in ethyl acetate, washed twice 1M aqueous sodium hydroxide solution and saturated sodium chloride solution, the combined aqueous layers were extracted once with ethyl acetate, and the combined organic layers were dried with magnesium sulfate and hotfil triviali. Chromatography on silica gel resulted in the receipt of the second party of the connection. Total yield: 75 g (80%) of light yellow solid.

MS (TS) m/e (M+N)⁺:264,9.

b) Ethyl ester of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid

To a solution of 75 g (0,28 mol) of 2-(4-chlorophenyl)-5,6-debtor-1H-benzoimidazole in 750 ml of N,N-dimethylformamide was added 116 g (of 0.33 mol) of cesium carbonate and 88 g (0,35 mol) of ethyl ether bromocyclohexane acid (commercially available). The mixture was heated to 100°C and after stirring for 90 min was added 116 g of cesium carbonate and 88 g of ethyl ether bromocyclohexane acid. After 6 h was added 116 g of cesium carbonate and 88 g of ethyl ether bromocyclohexane acid. After 22 hours (total reaction time), the reaction mixture was cooled to 30°C and was poured into 1 l of ice water and 2 l of ethyl acetate. The phases were separated and the aqueous phase was extracted with 500 ml of ethyl acetate. The combined organic phases were washed three times with 500 ml of ice-cold water and once with saturated sodium chloride solution, dried with magnesium sulfate and was filtered. To the solution was added silica gel and the solvent was evaporated. Raw adsorbed product was purified column chromatography on silica gel using a mixture of n-heptane: ethyl acetate (9:1 V/V) as eluent. The fractions containing the product were combined, and Rast is oritel was evaporated to obtain a suspension. The suspension was cooled in an ice bath, and filtered to obtain 92 g (75%) of the desired product as a colourless solid.

MS (TS) m/e (M+N)⁺:433,1.

C) [2-(4-Chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid

To a solution of 24 g (by 0.055 mole) of ethyl ester of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid in 240 ml of dioxane was added 240 ml of water and 7.0 g (0,166 mole) of the monohydrate of lithium hydroxide. The solution was stirred for 2 h at 100°C. After cooling to room temperature, the organic solvent was evaporated. Under stirring was added 162 ml of 1M hydrochloric acid. The resulting suspension was filtered, the filter residue washed with water and dried in high vacuum with the receipt of 21.7 g (95%) of target compound as a white solid.

MS (TS) m/e (M-N)^-:403,2.

d) Ethyl ester of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid

A solution of 3.0 g (7.4 mmole) of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid in 5.4 ml of thionyl chloride was stirred at the boil under reflux. After 1 h the volatile components were removed on a rotary evaporator, the residue was transferred into toluene and evaporated (three times). The oil obtained was dissolved in 30 ml of dichloromethane, cooled to 0°C and added dropwise to a solution of the ethyl 4-aminobenzoate (1.35 g, 8.1 mmole) and of 2.72 g (22,2 mmole) of 4-dimethylaminopyridine dissolved in 30 ml of dichloromethane. The cooling bath was removed and stirring was continued for 4 h the Reaction mixture was poured into 25% aqueous solution of hydrochloric acid, the phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with a saturated solution of sodium chloride, dried with magnesium sulfate, filtered and evaporated. The residue was purified column chromatography on silica gel using a mixture of heptane: these l acetate (1:0 to 1:1 V/V) as eluent to obtain specified in the title compound as a colourless solid (2.6 g, 62%).

MS (TS) m/e (M+N)⁺:552,1

Example 25

4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methylbenzoic acid

The compound was obtained analogously to example 22 of methyl ester 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methylbenzoic acid.

Colorless solid (97%), MS (TS) m/e (M-N)⁺:536,3.

Examples 26 and 27

Specified in the title compounds were obtained by separation of the stereoisomers of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methylbenzoic acid chiral preparative HPLC (Chiralpak-AD column).

(+)-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl what ethylamino}-3-methylbenzoic acid

Whitish solid (45%). MS (TS) m/e (M-N)⁺:536,2.

(-)-4-{2-[2-(4-Chlorophenyl)-5.6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methylbenzoic acid

Whitish solid (42%). MS (TS) m/e (M-N)⁺:536,2.

The intermediate connection

Methyl ester of 4-{2-[2-(4-chlorophenyl)-5.6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methylbenzoic acid

This compound was obtained analogously to example 22, intermediate connection g of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid and methyl 4-amino-3-methylbenzoate.

Colorless solid (97%). MS (TS) m/e (M+N)⁺:552,3.

Example 28

3-Chloro-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid

This compound was obtained analogously to example 22 of the methyl ester of 3-chloro-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid.

Light yellow solid (91%). MS (TS) m/e (M-N)^-:556,1.

Examples 29 and 30

Specified in the title compounds were obtained by separation of the stereoisomers of 3-chloro-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid chiral preparative HPLC (Chiralpak-AD column).

(+)-3-Chloro-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid

Colorless solid in the society (24%). MS (TS) m/e (M-N)^-:556,0.

(-)-3-Chloro-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid

Colorless solid (24%). MS (TS) m/e (M-N)^-:556,1.

The intermediate connection

Methyl ether 3-chloro-4-{2-[2-(4-chlorophenyl)-5.6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid

This compound was obtained analogously to example 22, intermediate connection g of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid and methyl 4-amino-3-chlorobenzoate.

Colorless solid (62%). MS (TS) m/e (M+N)⁺:572,2.

Example 31

4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-Formentera acid

This compound was obtained analogously to example 22 of methyl ester 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-fermenting acid.

Colorless solid (91%). MS (TS) m/e (M-H)': 540,2.

Examples 32 and 33

Specified in the title compounds were obtained by separation of the stereoisomers of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-fermenting acid chiral preparative HPLC (Chiralpak-AD column).

(+)-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine} -3-Formentera acid 15

Colorless solid (41%). MS(TS) m/e (M-H)^-540,2

(-)-4-{2-[2-(4-shall lorgeril)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-Formentera acid.

Colorless solid (35%). MS (TS) m/e (M-H)^-540,2

The intermediate connection

Methyl ester of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-fermenting acid

This compound was obtained analogously to example 22, intermediate connection g of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid, methyl 4-amino-3-perbenzoate, and using 4-(dimethylamino)pyridine as a base.

Colorless foam (70%). MS (TS) m/e (M+H)⁺556,1.

Example 34

4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}is 3.5-differentia acid

This compound was obtained analogously to example 22 of methyl ester 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}is 3.5-diferential acid.

Colorless solid (92%). MS (TS) m/e (M-H)^-: 558,1.

Examples 35 and 36

Specified in the title compounds were obtained by separation of the stereoisomers of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}is 3.5-diferential acid chiral preparative HPLC (Chiralpak-AD column).

(+)-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}is 3.5-differentia acid

Colorless solid (10%). MS (TS) m/e (M-H)^-: 558,1.

(-)-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-,5-differentia acid

Colorless solid (19%). MS (TS) m/e (M-H)^-: 558,1.

The intermediate connection

Methyl ester of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}is 3.5-diferential acid

This compound was obtained analogously to example 20, the intermediate connection g of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid, methyl ester 4-amino-3,5-diferential acid, and using pyridine as a base.

Light yellow foam (73%). MS (TS) m/e (M+H)⁺574,3.

Example 37

4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyanobenzoic acid

This compound was obtained analogously to example 22 of methyl ester 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyanobenzoic acid to obtain the target compound as a colourless solid (27%).

MS (TS) m/e (M-H)^-: 547,2.

The intermediate connection

Methyl ester of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyanobenzoic acid

This compound was obtained analogously to example 22, intermediate connection g of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid, methyl ester 4-amino-3-cyanobenzoic acid and N,N-diisopropylethylamine as a base.

Colorless foam (20%). MS (TS) /e (M+H) ⁺563,3.

Example 38

3-Chloro-4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}benzoic acid

This compound was obtained analogously to example 22 of the methyl ester of 3-chloro-4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}benzoic acid with obtaining the specified 10 title compound as a colourless solid (60%).

MS (TS) m/e (M-H)^-: 522,1.

Examples 39 and 40

Specified in the title compounds were obtained by separation of the stereoisomers of methyl ether 3-chloro-4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}benzoic acid chiral preparative HPLC (Chiralpak-AD column).

Methyl ester of (+)-3-chloro-4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}benzoic acid

Colorless solid (21%). MS (TS) m/e (M-H)^-: 520,2.

Methyl ester of (-)-3-chloro-4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}benzoic acid

Colorless solid (29%). MS (TS) m/e (M-H)^-: 520,2.

Intermediate compounds

a) Ethyl ester of [2-(4-chlorophenyl)benzoimidazol-1-yl]cyclohexyloxy acid

This compound is synthesized analogously to example 22, intermediate compound b, from 2-(4-chlorophenyl)-1H-benzoimidazole (commercially available), ethyl ether bromocyclohexane acid (commercially available) and the carbonate cases the final compound as a colourless solid (58%).

MS (TS) m/e (M+H)⁺397,2.

b) [2-(4-Chlorophenyl)benzoimidazol-1-yl]cyclohexyloxy acid

This compound is synthesized analogously to example 22, intermediate connection, ethyl ester [2-(4-chlorophenyl)benzoimidazol-1-yl]cyclohexyloxy acid to obtain the target compound as a colourless solid (99%).

MS (TS) m/e (M-N)^-:367,0.

C) Methyl ester of 3-chloro-4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine} benzoic acid

Specified in the title compound was synthesized analogously to example 22, intermediate connection g of [2-(4-chlorophenyl)benzoimidazol-1-yl]cyclohexyloxy acid, 4-amino-3-chlorbenzoyl acid, and using pyridine as a base.

MS (TS) m/e (M+N)⁺:537,4.

Example 41

4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methoxybenzoic acid

This compound is synthesized analogously to example 22 of methyl ester 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methoxybenzoic acid with obtaining specified in the title compound as a colourless solid (84%).

MS (TS) m/e (M-N)^-:552,0.

The intermediate connection

Methyl ester of 4-{2-[2-(4-chlorophenyl)-5.6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methoxybenzoic acid

It was sedimentational analogously to example 20, intermediate compound g of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid (example 22, intermediate connection), methyl ester 4-amino-3-methoxybenzoic acid, and using pyridine as a base with obtaining specified in the title compounds as a colorless solid (74%).

MS m/e (M+N)⁺: 568,1.

Example 42

4-{2-[2-(4-Chlorophenyl)-5.6-differentiality-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid

This compound is synthesized analogously to example 22 of methyl ester 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid with obtaining specified in the title compounds as a colorless solid (79%).

MS m/e (M+N)⁺:590,0.

The intermediate connection

Methyl ester of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid

This compound is synthesized analogously to example 20, the intermediate connection g of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid (example 20, the intermediate connection), methyl ester 4-amino-3-triftorperasin acid, and using pyridine as a base with obtaining specified in the title compounds as a colorless solid (74%).

MS m/ (M+N) ⁺: 606,1.

Example 43

4-{2-Cyclohexyl-2-[5,6-debtor-2-(4-triptoreline)benzoimidazol-1-yl]acetylamino}benzoic acid

This compound was obtained analogously to example 22 of the ethyl ester of 4-{2-cyclohexyl-2-[5,6-debtor-2-(4-triptoreline)benzoimidazol-1-yl]acetylamino}benzoic acid.

Colorless solid (95%). MS (TS) m/e (M-N)^-:555,9.

The intermediate connection

Ethyl ester of 4-{2-cyclohexyl-2-[5.6-debtor-2-(4-triptoreline)benzoimidazol-1-yl]acetylamino}benzoic acid

A solution of 0.30 g (1,23 mmole) of tert-butyl methyl ether (2-amino-4,5-differenl)carbamino acid and 0.15 ml (0.14 g, of 1.23 mmole) of cyclohexanecarboxaldehyde was stirred for 10 minutes Then added to 0.23 g (1,23 mmole) of 4-(trifluoromethyl)benzoic acid, and after 5 min 0,22 g (1,23 mmole) ethyl ester 4-isocyanante acid. After 21 h was added 3 ml of 4M aqueous hydrochloric acid solution, and stirring was continued for 16 hours the Solvent was evaporated, the residue was dissolved in a mixture of acetonitrile, water and N,N-dimethylformamide and purified preparative HPLC to obtain the desired compound as a colourless solid (7%).

MS m/e (M+N)⁺:586,1.

Example 44

4-{2-Cyclohexyl-2-[5-fluoro-2-(4-triptoreline)benzoimidazol-1-yl]acetylamino}benzoic acid

This compound was obtained analogously to example 22 from delovogo ether 4-{2-cyclohexyl-2-[5-fluoro-2-(4-triptoreline)benzoimidazol-1-yl]acetylamino}benzoic acid.

Colorless solid (64%). MS m/e 538,1 (M-N)^-.

The intermediate connection

Ethyl ester of 4-{2-cyclohexyl-2-[5-fluoro-2-(4-triptoreline)benzoimidazol-1-yl]acetylamino}benzoic acid

This compound was obtained analogously to example 43, the intermediate compound from tert-butyl ether (2-amino-5-forfinal)carbamino acid, cyclohexanecarboxaldehyde, 4-(trifluoromethyl)benzoic acid and ethyl ester of 4-isocyanante acid.

Light brown foam (21%). MS m/e (M+N)⁺:568,2.

Example 45

4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cryptomaterial acid

Specified in the title compound was synthesized analogously to example 22 of methyl ester 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cryptomaterial acid to obtain the target compound as colorless solid (84%).

MS (TS) m/e (M-N)^-:608,0.

The intermediate connection

Methyl ester of 4-{2-[2-(4-chlorophenyl)5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cryptomaterial acid

This compound is synthesized analogously to example 22, intermediate connection g of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid (example 22, intermediate connection), methyl ester 4-amino-3-what referencebinding acid, and using pyridine as a base, to obtain the specified title compound as a colourless solid (85%).

MS (TS) m/e (M+N)⁺:622,0.

Example 46

4-{2-[2-(4-Chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}benzoic acid

This compound is synthesized analogously to example 22 of the ethyl ester of 4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}benzoic acid. Colorless solid (86%).

MS (TS) m/e (M-N)^-:504,1.

The intermediate connection

Ethyl ester of 4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}benzoic acid

This compound is synthesized analogously to example 43, the intermediate compound from tert-butyl ether (2-amino-5-forfinal)carbamino acid, cyclohexanecarboxaldehyde, 4-chlorbenzoyl acid and ethyl ester of 4-isocyanante acid.

MS m/e (M+N)⁺:534,1.

Example 47

4-{2-[2-(4-Chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}-3-Formentera acid

This compound is synthesized analogously to example 22 of the methyl ester

4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}-3-fermenting acid. White solid (89%).

MS (TS) m/e (M-N)^-:522,2.

The intermediate connection

Methyl ester of 4-{2-[2-(4-chlorophenyl)-5-torbe tinidazol-1-yl]-2-cyclohexylethylamine}-3-fermenting acid

This compound is synthesized analogously to example 43, the intermediate compound from tert-butyl ether (2-amino-5-forfinal)carbamino acid, cyclohexanecarboxaldehyde, 4-chlorbenzoyl acid and methyl ester of 3-fluoro-4-isocyanante acid.

Light brown foam (15%). MS m/e (M+H)⁺:538,2.

Example 48

(4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}phenyl)acetic acid

Specified in the title compound was synthesized analogously to example 22 ethyl ester (4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}phenyl)acetic acid to obtain the target compound as a colourless solid (95%).

MS (TS) m/e (M-N)^-:536,3.

The intermediate connection

Ethyl ester of (4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}phenyl)acetic acid

This compound is synthesized analogously to example 22, intermediate connection g of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid (example 20, the intermediate connection), ethyl ether (4-AMINOPHENYL)acetic acid and hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea with obtaining the target compound as a yellow foam (82%).

MS m/e (M+N)⁺:566,3.

Example 49

2-(4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohex is ylacetamide}-3-forfinal)propionic acid

Specified in the title compound was synthesized analogously to example 22 of the ethyl ester of 2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid.

Colorless solid (93%). MS (TS) m/e (M-N)^-:568,0.

The intermediate connection

Ethyl ester of 2-(4-{2-[2-(4-chlorophenyl)-5.6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid

Specified in the title compound was synthesized analogously to example 22, intermediate connection g of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid (example 20, the intermediate connection), 2-(4-amino-3-forfinal)propionic acid, and using 4-(dimethylamino)pyridine as a base.

Colorless foam (74%). MS m/e (M+N)⁺:598,1.

Example 50

2-(4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)-2-methylpropionate acid

Specified in the title compound was synthesized analogously to example 22 of the methyl ester of 2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)-2-methylpropionic acid.

Colorless solid (88%). MS (TS) m/e (M-N)^-:582,0.

The intermediate connection

Methyl ester of 2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)-2-methylprop the Ionova acid

Specified in the title compound was synthesized analogously to example 22, intermediate connection g of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid (example 22, intermediate connection), methyl ester of 2-(4-amino-3-forfinal)-2-methylpropionic acid, and using 4-(dimethylamino)pyridine as a base.

Colorless foam (54%). MS m/e (M+N)⁺:598,2.

Example 51

3-(4-{2-[2-(4-Chlorophenyl)-5.6-differentiality-1-yl]-2-cyclohexylethylamine}phenyl)propionic acid

Specified in the title compound was synthesized analogously to example 22 of the ethyl ester of 3-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}phenyl)propionic acid.

Colorless solid (78%). MS (TS) m/e (M+N)⁺:552,1.

The intermediate connection

Ethyl ester of 3-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}phenyl)propionic acid

Specified in the title compound was synthesized analogously to example 20, the intermediate connection g of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid (example 20, the intermediate connection), ethyl ester of 3-(4-AMINOPHENYL)propionic acid, hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea and N-ethyldiethanolamine.

Colorless solid (48%). MS (TS) m/e (M+N)^{+ :580,2.}

^{Example 52}

^{3-(4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid}

^{Specified in the title compound was synthesized analogously to example 22 of the methyl ester of 3-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid (intermediate compound a).}

^{Colorless solid (80%). MS (TS) m/e (M-N)-:568,1.}

The intermediate connection

Methyl ester of 3-(4-{2-[2-(4-chlorophenyl)-5.6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid

Specified in the title compound was synthesized analogously to example 22, intermediate connection g of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid (example 22, intermediate connection), methyl ester 3-(4-amino-3-forfinal)propionic acid, hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea and N-ethyldiethanolamine.

Light brown foam (38%). MS m/e (M+N)⁺:584,1.

Examples 53 and 54

Stereoisomers of example 52 was synthesized by acid cleavage (formic acid/isopropanol (1/1 V/V), boiling, 17 h) chiral tert-butyl ether intermediate compounds B1 and B2, as described below.

(-)-3-(4-{2-[2-(4-Chlorophenyl)-5.6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propional the I acid

Colorless solid. MS (TS) m/e (M-N)^-:568,1.

(+)-3-(4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid

Colorless solid. MS (TS) m/e (M-N)^-:568,1.

Intermediate compounds

a) tert-Butyl ether 3-(4-{2-{2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid

Specified in the title compound was synthesized analogously to example 22, intermediate connection g of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid (example 20, the intermediate connection), tert-butyl ester 3-(4-amino-3-forfinal)propionic acid, and using 4-(dimethylamino)pyridine as a base. Light brown foam (78%).

MS m/e (M+N)⁺:626,3.

Stereoisomers described above intermediate compounds were obtained chiral preparative HPLC (Chiralpak-AD column).

B1) tert-Butyl ether (-)-3-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid

Colorless foam (30%). MS m/e (M+N)⁺:626,2.

B2) tert-Butyl ether (+)-3-(4-{2-[2-(4-chlorophenyl)-5.6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid

Colorless foam (35%). MS m/e (M+N)⁺:626,3.

Example 55

(4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl-2-cyclohexylethylamine}-3-pertenece)acetic acid

To a solution of tert-butyl methyl ether (4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)acetic acid (120 mg, 0,19 mmole) in dichloromethane (5 ml) was added triperoxonane acid (1.5 ml). After 2 h the solvent was removed under reduced pressure. The obtained oil (78 mg, 71%) hardened during storage in the refrigerator.

Light brown solid. MS m/e (M-N)^-:570,2.

Intermediate compounds

a) tert-Butyl methyl ether (3-fluoro-4-nitrophenoxy)acetic acid

To a solution of 3-fluoro-4-NITROPHENOL (of 1.57 g, 10 mmol) in N,N-dimethylformamide (10 ml) was added tert-butylbromide (1,95 g, 10 mmol) and potassium carbonate (1,38 g, 10 mmol). The mixture was stirred over night at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified column chromatography on silica gel (50 g, dichloromethane as eluent) to give the product as a pale yellow solid (2,22 g, 84%).

MS m/e (M+NH₄)⁺:289,0.

b) tert-Butyl ether (4-amino-3-pertenece)acetic acid

A solution of tert-butyl methyl ether (3-fluoro-4-nitrophenoxy)acetic acid (2.14 g, 8 mmol) in ethanol (3 ml) was first made for 5 h at room temperature and atmospheric pressure over 10% palladium on coal. The catalyst was removed by filtration, the solvent was evaporated under reduced is the first pressure, and the residue was purified column chromatography on silica gel (1:0 to 1:1 heptane/ethyl acetate eluent) to give the product as a brown oil (960 mg, 50%).

MS m/e (M+N)⁺:242,2.

C) tert-Butyl ether (4-{2-[2-(4-chlorophenyl)-5.6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)acetic acid

To a suspension of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid (example 22, intermediate compound (a), 150 mg, 0.37 mmole) in dichloromethane (5 ml) was added pyridine (2.5 equiv., 70 μl) and thionyl chloride (1.2 equiv., 30 μl). The mixture was stirred for 30 min at room temperature. Added pyridine (1.2 equiv., 30 μl) and tert-butyl ether 4-amino-3-pertenece)acetic acid of (0.95 equiv., 85 mg). The mixture was diluted with dichloromethane, and the organic phase is washed with 10% aqueous sodium bicarbonate solution, water and saturated sodium chloride solution, dried with magnesium sulfate, and the residue after evaporation was purified column chromatography on silica gel (1:0 to 3:2 heptane/ethyl acetate as eluent) to obtain the specified title compound as a light brown foam (137 mg, 58%).

MS m/e (M+N)⁺:628,4.

Example 56

2-(4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)propionic acid

This compound was obtained analogously to example 22 from the methyl ester is 2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)propionic acid with obtaining specified in the title compound as a colourless solid (76%).

MS (TS) m/e (M-N)^-:584,1.

The intermediate connection

Methyl ester of 2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)propionic acid

This compound was obtained analogously to example 57, the intermediate connection of the methyl ester [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid and 2-(4-amino-3-pertenece)propionic acid.

Light yellow foam (48%). MS (TS) m/e (M+N)⁺:600,2.

Example 57

2-(4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)-2-methylpropionate acid

This compound was obtained analogously to example 22 of the ethyl ester of 2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)-2-methylpropionic acid.

Colorless solid (78%). MS (TS) m/e (M-N)^-:598,1.

Examples 58 and 59

Specified in the title compounds were obtained by separation of the stereoisomers of 2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)-2-methylpropionic acid chiral preparative HPLC (Chiralpak-AD column).

(+)-2-(4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)-2-methylpropionate acid

Colorless solid (45%). MS (TS) m/e (M-N)^-:598,1.

(-)-2-(4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-is illogicalities}-3-pertenece)-2-methylpropionate acid

Colorless solid (31%). MS (TS) m/e (M-N)^-:598,1.

The intermediate connection

Ethyl ester of 2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)-2-methylpropionic acid

To a solution of 0.2 g (0,49 mmole) of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid (example 22, intermediate connection)) in 3 ml of N,N-dimethylformamide was added 0.21 g (0.55 mmole) of hexaflurophosphate 0-(7-asobancaria-1-yl)-N,N,N,N'-tetramethylurea, of 0.42 ml (0.32 g, 2.5 mmole) of N-ethyldiethanolamine and 0.13 g (0.54 mmole) of ethyl ester of 2-(4-amino-3-pertenece)-2-methylpropionic acid. After 18 h the reaction mixture was poured into water and ethyl acetate, the phases were separated, the organic layer was washed twice with water, then saturated sodium chloride solution, and dried with magnesium sulfate. After filtration the residue was purified column chromatography on silica gel to obtain 0.12 g (40%) of target compound as a pale yellow foam.

MS (TS) m/e (M+N)⁺:628,3.

Example 60

1-(4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid

This compound was obtained analogously to example 22 of methyl ester 1-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid.

Colorless solid prophetic is the proportion (97%). MS (TS) m/e (M-N)^-:596,1.

Examples 61 and 62

Specified in the title compounds were obtained by separation of the stereoisomers of 1-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid chiral preparative HPLC (Chiralpak-AD column).

(+)-1-(4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid

Colorless solid (45%). MS (TS) m/e (M-N)^-:596,2.

(+)-1-(4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid

Colorless solid (39%). MS (TS) m/e (M-N)^-:596,3.

The intermediate connection

Methyl ester 1-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid

This compound was obtained analogously to example 22, intermediate connection g of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid, methyl ester 1-(4-amino-3-pertenece)cyclopropanecarbonyl acid, and using 4-(dimethylamino)pyridine as a base.

Colorless foam (57%). MS(TS) m/e (M+N)⁺:612,2.

Example 63

2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-TRANS-(4-hydroxycyclohexyl)ndimethylacetamide

This compound was obtained analogously to example 22, the tick connection g from [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid, TRANS-4-aminocyclohexanol, and using diisopropylethylamine as a base.

Light brown foam (66%). MS(TS) m/e (M+N)⁺:502,2.

Examples 64 and 65

Specified in the title compounds were obtained by separation of the stereoisomers of 2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-TRANS-(4-hydroxycyclohexyl)ndimethylacetamide chiral preparative HPLC (Chiralpak-AD column).

(-)-2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-TRANS-(4-hydroxycyclohexyl)ndimethylacetamide

Colorless foam (37%). MS (TS) m/e (M+N)⁺:502,2.

(+)-2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-TRANS-(4-hydroxycyclohexyl)ndimethylacetamide

Colorless foam (39%). MS (TS) m/e (M+N)⁺:502,2.

Example 66

6-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine} nicotinic acid

Methyl ester of 6-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}nicotinic acid (24 mg, 0.04 mmole) was dissolved in water (0.5 ml) and dioxane (0.5 ml). Added monohydrate of lithium hydroxide (9 equiv., 17 mg)and the mixture was stirred for 3 h at room temperature. The dioxane was removed under reduced pressure, and the residue was acidified to pH2 values 3M aqueous solution of hydrochloric acid. The precipitate was filtered with getting pointed to by the th in the title compound as a white solid (20 mg, 84%).

MS m/e (M+N)⁺:525,1.

The intermediate connection

Methyl ester of 6-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine} nicotinic acid

Specified in the title compound was obtained in accordance with example 22, intermediate connection), from [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid and methyl 6-aminonicotinate.

Colorless solid (49%). MS m/e (M+N)⁺:539,2.

Examples 67 and 68

Specified in the title compounds were obtained by separation of the stereoisomers of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyanobenzoic acid (example 37) chiral preparative HPLC (Chiralpak-AD column).

(+)-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyanobenzoic acid

Colorless solid. MS (TS) m/e (M-N)^-:547,1.

(-)-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyanobenzoic acid

Colorless solid. MS (TS) m/e (M-N)^-:547,1.

Examples 69 and 70

Specified in the title compounds were obtained by separation of the stereoisomers of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methoxybenzoic acid (example 41) chiral preparative HPLC (Chiralpak-AD column).

(+)-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl is thylamino}-3-methoxybenzoic acid

Light yellow solid. MS (TS) m/e (M+N)⁺:554,2.

(-)-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methoxybenzoic acid

Light yellow solid. MS (TS) m/e (M+N)⁺:554,2.

Examples 71 and 72

Specified in the title compounds were obtained by separation of the stereoisomers of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid (example 42) chiral preparative HPLC (Chiralpak-AD column).

(+)-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid

Colorless solid. MS (TS) m/e (M+N)⁺:590,4.

(-)-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid

Colorless solid. MS (TS) m/e (M-N)^-:590,3.

Examples 73 and 74

Specified in the title compounds were obtained by separation of the stereoisomers of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cryptomaterial acid (example 45) chiral preparative HPLC (Chiralpak-AD column).

(+)-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cryptomaterial acid

Colorless solid. MS (TS) m/e (M-N)^-:606,2.

(-)-4-{2-[2-(4-Chlorophenyl)-5.6-differentiality-1-yl]-2-cyclohexylethylamine}--cryptomaterial acid

Colorless solid. MS (TS) m/e (M-N)^-:606,3.

Examples 75 and 76

Specified in the title compounds were obtained by separation of the stereoisomers of 4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}-3-fermenting acid (example 47) chiral preparative HPLC (Chiralpak-AD column).

(-)-4-{2-[2-(4-Chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}-3-Formentera acid

Colorless solid. MS (TS) m/e (M-N)^-:522,2.

(+)-4-{2-[2-(4-Chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}-3-Formentera acid

Colorless solid. MS (TS) m/e (M-N)^-:522,2.

Example 77

4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyano-5-Formentera acid

This compound was obtained analogously to example 22 of methyl ester 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyano-5-fermenting acid with obtaining specified in the title compound as a colourless solid (96%).

MS (TS) m/e (M-N)^-:565,2.

The intermediate connection

Methyl ester of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyano-5-fermenting acid

Specified in the title compound was obtained analogously to example 22, intermediate compound d), [2-(4-chlorophenyl)-5,6-differentiality-1-yl]t is kogaxinuyasha acid and methyl ester of 4-amino-3-cyano-5-fermenting acid (Arzneimittel Forschung, 34(11), Nr. 11a, 1984; cc. 1612-1624) to give the product as light brown solid (20%).

MS (TS) m/e (M+N)⁺:581,1.

Examples 78 and 79

Specified in the title compounds were obtained by separation of the stereoisomers of 4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyano-5-fermenting acid chiral preparative HPLC (Reprosil Chiral-NR column).

(+)-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyano-5-Formentera acid

Light brown foam. MS (TS) m/e (M-N)^-:565,2.

(-)-4-{2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyano-5-Formentera acid

Light brown foam. MS (TS) m/e (M-N)^-:565,2.

Example 80

1-(4-{2-[2-(4-Chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid

This compound was obtained analogously to example 22 of methyl ester 1-(4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid with obtaining specified in the title compound as a pale yellow solid (91%).

MS (TS) m/e (M-N)^-:560,1.

Intermediate compounds

a) Methyl ester of 1-(4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid

Specified in the title compound floor is made analogously to example 22, intermediate compound d), [2-(4-chlorophenyl)benzoimidazol-1-yl]cyclohexyloxy acid (example 39/40, intermediate compound b) and methyl ester 1-(4-amino-3-pertenece)cyclopropanecarbonyl acid to obtain the product as a pale yellow foam (21%).

MS (TS) m/e (M+N)⁺:576,2.

b) Methyl ester of 1-(4-amino-3-pertenece)cyclopropanecarbonyl acid

To a solution of 4.49 g (to 17.6 mmole) of methyl ester 1-(3-fluoro-4-nitrophenoxy)cyclopropanecarbonyl acid in 50 ml of ethanol was added 0.5 g of 10% palladium on coal, and the suspension was stirred for 8 h at room temperature in hydrogen atmosphere (1,7 bar). After adding 100 ml of ethyl acetate, the catalyst was filtered, the filtrate was evaporated and dried in high vacuum to obtain specified in the title compound as a brown oil (98%), which was used in the next stage without additional purification.

MS (TS) m/e (M+N)⁺: 226,1.

C) Methyl ester of 1-(3-fluoro-4-nitrophenoxy)cyclopropanecarbonyl acid

A solution of 7.5 g (22.3 mmole) of methyl ester of 4-bromo-2-(3-fluoro-4-nitrophenoxy)butane acid in 100 ml of tetrahydrofuran was cooled to - 15°C and added 2,63 g (23.4 mmole) of tert-butoxide potassium. The cooling bath was removed and the reaction mixture was stirred for 5 h at room temperature. The dark solution was poured into 200 ml ethyl acetate and 200 ml of water rest the RA hydrochloric acid were extracted, and the phases were separated. The organic layer was washed with a saturated solution of sodium chloride, and the aqueous layers were extracted with ethyl acetate. The combined organic layers were dried with magnesium sulfate, filtered and evaporated. The residue was purified column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient of heptane: ethyl acetate (100:30 70:30 V/V) to obtain the specified title compound as a pale yellow oil (79%).

MS (TS) m/e (M):255,0.

d) Methyl ester of 4-bromo-2-(3-fluoro-4-nitrophenoxy)butane acid

To a solution of 5.5 g (35,0 mmole) of 3-fluoro-4-NITROPHENOL in 55 ml of N,N-dimethylformamide was added 11.8 g (45,5 mmole) of methyl 2,4-dibromostyrene and 6.3 g (45,5 mmole) of potassium carbonate. After stirring for 3 h the reaction mixture was poured into ethyl acetate and 1 M aqueous hydrochloric acid solution and was extracted. The organic phase was washed with a saturated solution of sodium chloride, dried with magnesium sulfate, filtered and evaporated. The residue was purified column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient of heptane: ethyl acetate (1:0 to 1:1 V/V) to obtain the specified title compound as a pale yellow oil (64%)which was sufficiently pure for use in the next stage.

Examples 81 and 82

Specified in C is the head of the compounds were obtained by separation of the stereoisomers of 1-(4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid chiral preparative HPLC (Chiralpak-AD column).

(+)-1-(4-{2-[2-(4-Chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid

Colorless solid. MS (TS) m/e (M+N)⁺:562,4.

(-)-1-(4-{2-[2-(4-Chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid

Colorless solid. MS (TS) m/e (M-N)^-:560,2.

Example 83

4-{2-[2-(4-Chlorophenyl)benzoimidazol-1-yl-2-cyclohexylethylamine}-3-triftorperasin acid

This compound was obtained analogously to example 22 of methyl ester 4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid with obtaining specified in the title compounds as a colorless solid (79%).

MS (TS) m/e (M+N)⁺:556,2.

Intermediate compounds

a) Methyl ester of 4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid

Specified in the title compound was obtained analogously to example 22, intermediate compound d), [2-(4-chlorophenyl)benzoimidazol-1-yl]cyclohexyloxy acid (example 39/40, intermediate compound b) and methyl ester of 4-amino-3-triftorperasin acid to obtain the product as a pale yellow solid (57%).

MS (TS) m/e (M+N)⁺: 570,3.

b) Methyl ester of 4-amino-3-triftorperasin acid

To the R. is the target of 4.0 g (16,1 mmole) methyl ester 4-nitro-3-triftorperasin acid in 50 ml of methanol was added 0.4 g of 10% palladium on charcoal, and the suspension was stirred for 2 h at room temperature in hydrogen atmosphere (1,7 bar). After adding 100 ml of ethyl acetate, the catalyst was filtered, the filtrate was evaporated and dried in high vacuum to obtain specified in the title compound as a white solid (98%), which was used in the next stage without additional purification.

C) Methyl ester of 4-nitro-3-triftorperasin acid

A solution of 4.2 g (17.9 mmole) of 4-nitro-3-(trifluoromethyl)benzoic acid (commercially available) 5.1 ml of 1.25 M hydrochloric acid in methanol was heated under reflux for 5 hours After cooling to room temperature the solution was poured into saturated aqueous sodium bicarbonate solution, and the phases were separated. The aqueous layer was extracted three times with ethyl acetate, the combined organic layers were washed with a saturated solution of sodium chloride, dried with magnesium sulfate and evaporated. After filtration the solvent was evaporated, and the residue was purified column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient of heptane: ethyl acetate (100:0 to 60:40 V/V) to obtain the specified title compound as a pale yellow solid (90%)which was sufficiently pure for use in the next stage without additional purification.

Examples 8 and 85

Specified in the title compounds were obtained by separation of the stereoisomers of 4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid chiral preparative HPLC (Chiralpak-AD column).

(+)-4-{2-[2-(4-Chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid

Colorless solid. MS (TS) m/e (M-N)^-:554,0.

(-)-4-{2-[2-(4-Chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid

Colorless solid. MS (TS) m/e (M+N)⁺:554,0.

Example 86

TRANS-4-{2-Cyclohexyl-2-[5,6-debtor-2-(6-methoxypyridine-3-yl)benzoimidazol-1-yl]acetylamino}cyclohexanecarbonyl acid

Specified in the title compound was obtained analogously to example 7 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):527 (M+N)⁺.

Example 87

(-)-TRANS-4-{2-[2-(6-Chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexanecarbonyl acid

Specified in the title compound was obtained in accordance with example 7, making separation of the stereoisomers of chiral preparative HPLC (Chiralpak AD column), elwira gradient of ethanol and 0.5% acetic acid)/heptane. MS (ES⁺):531 (M+N)⁺.

The intermediate connection

Ethyl ester (TRANS-4-socialecological)acetic acid is acid

5 g (of 22.8 mmole) of the hydrochloride of the ethyl ester of TRANS-(4-aminocyclohexane)acetic acid suspended in a mixture of 40 ml (731 mmol) ethylformate and 10 ml DMF. Added 5.6 ml (25 mmol) of DIPEA, and the mixture was heated at 80°C for 72 h the Mixture solvent was evaporated to dryness, and the crude product was extracted from a mixture of ethyl acetate/water. Received of 4.2 g of a yellow solid, which was dissolved in 40 ml DHM. Added 6.6 ml (47 mmol) of triethylamine, and the mixture was cooled to 0-5°C. and 2.3 ml (7,9 mmole) of triphosgene was dissolved in 10 ml DHM and was added dropwise. The reaction mixture was heated to room temperature, and the product was isolated directly by chromatography on silica gel using a mixture of ethyl acetate/hexane as eluent. The intermediate compound was used without further characterization.

Example 88

(TRANS-4-{2-[2-(6-Chloro-2-methoxypyridine-3-yl)-5.6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexyl)acetic acid

Specified in the title compound was obtained analogously to example 7, using ethyl ester (TRANS-4-socialecological)acetic acid as isonitrile component, after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):575 (M+N)⁺.

Example 89

TRANS-4-{2-[2-(6-Chloro-2-methoxypyridine-3-yl)-5.6-differentiality-1-yl]-2-cyclohexylethyl the Ino}cyclohexanecarbonyl acid

Specified in the title compound was obtained analogously to example 7 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):561 (M+N)⁺.

Example 90

4-{2-[2-(6-Chloro-2-methoxypyridine-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid

Specified in the title compound was obtained analogously to example 7 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):555 (M+N)⁺.

Example 91

(+)-TRANS-4-{2-Cyclohexyl-2-[5,6-debtor-2-(6-methoxypyridine-3-yl)benzoimidazol-1-yl]acetylamino}cyclohexanecarbonyl acid

Specified in the title compound was obtained in accordance with example 7, making separation of the stereoisomers of chiral preparative HPLC (Chiralpak-AD column), elwira gradient of ethanol and 0.5% acetic acid)/heptane. MS (ES⁺):528 (M+N)⁺.

Example 92

(-)-TRANS-4-{2-[2-(6-Chloro-2-methoxypyridine-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}philogenetically acid

Specified in the title compound was obtained in accordance with example 7, making separation of the stereoisomers of chiral preparative HPLC (Chiralpak AD column), elwira gradient of ethanol and 0.5% acetic acid)/heptane. MS (ES⁺):561 (M+N)⁺.

Example 93

(-)-(TRANS-4-{2-[2-(6-Chloro-2-methoxypyridine-3-yl)-6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexyl)acetic acid

Specified in the title compound was obtained in accordance with example 7, making separation of the stereoisomers of chiral preparative HPLC (Chiralpak AD column), elwira gradient of ethanol and 0.5% acetic acid)/heptane. MS (ES⁺):575 (M+N)⁺.

Example 94

(+)-4-{(S)-2-[2-(6-Chloro-2-methoxypyridine-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid

Specified in the title compound was obtained in accordance with example 7, making separation of the stereoisomers of chiral preparative HPLC (Chiralcel-OD column), elwira gradient of ethanol and 0.5% acetic acid)/heptane. MS (ES⁺):555 (M+N)⁺.

The intermediate connection

Bicyclo[2.2.1]heptane-7-carbaldehyde

15.9 g (81 mmol) of 7-Brambilla[2.2.1]heptane was added dropwise to 2 g of magnesium (81 mmol) in 25 ml of diethyl ether and boiled under reflux for 2.5 hours the Mixture was cooled to 0-5°C. and was added dropwise 6.3 ml (81 mmol) of DMF. The mixture is then boiled under reflux for 2 h, cooled to room temperature and the white solid was filtered and washed with diethyl ether. The filtrate was evaporated, and got to 4.87 g of a white solid. The intermediate compound was used without further characterization.

Example 95

4-{2-Bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5.6-differentiality-1-yl]acetylamino}benzo is Naya acid

Specified in the title compound was obtained analogously to example 7 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):536 (M+N)⁺.

Example 96

(TRANS-4-{2-Cyclohexyl-2-[5,6-debtor-2-(2-methoxypyridine-3-yl)benzoimidazol-1-yl]acetylamino}cyclohexyl)acetic acid

Specified in the title compound was obtained analogously to example 7 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):541 (M+N)⁺.

Example 97

4-[2-Cyclohexyl-2-(5,6-debtor-2-p-talibandominated-1-yl)acetylamino]benzoic acid

Specified in the title compound was obtained analogously to example 7 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):504 (M+N)⁺.

Example 98

TRANS-4-[2-Cyclohexyl-2-(5,6-debtor-2-p-talibandominated-1-yl)acetylamino]cyclohexanecarbonyl acid

Specified in the title compound was obtained analogously to example 7 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):510 (M+N)⁺.

Example 99

(-)-4-[2-Cyclohexyl-2-(5,6-debtor-2-p-talibandominated-1-yl)acetylamino]benzoic acid

Specified in the title compound was obtained in accordance with example 7, making separation of stereoisomers hyral is Noah preparative HPLC (Reprosil Chiral NR column), elwira gradient of ethanol and 0.5% acetic acid)/heptane. MS (ES⁺):504 (M+N)⁺.

Example 100

(+)-TRANS-[2-Cyclohexyl-2-(5,6-debtor-2-p-talibandominated-1-yl)acetylamino]cyclohexanecarbonyl acid

Specified in the title compound was obtained in accordance with example 7, making separation of the stereoisomers of chiral preparative HPLC (Reprosil Chiral NR column), elwira gradient of ethanol and 0.5% acetic acid)/heptane. MS (ES⁺):510 (M+N)⁺.

Example 101

TRANS-4-{2-Bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}cyclohexanecarbonyl acid

Specified in the title compound was obtained analogously to example 7 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):542 (M+N)⁺.

Example 102

4-{2-Cyclohexyl-2-[5,6-debtor-2-(4-methoxyphenyl)benzimidazol-1-yl]acetylamino}benzoic acid

Specified in the title compound was obtained analogously to example 7 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):520 (M+N)⁺.

Example 103

(-)-TRANS-4-{2-Bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}cyclohexanecarbonyl acid

Specified in the title compound was obtained in accordance with example 7, making separation of the stereoisomers is icalneu preparative HPLC (Reprosil Chiral NR column), elwira gradient ethanol (+0,5% triperoxonane acid)/heptane. MS (ES⁺):542 (M+N)⁺.

Example 104

TRANS-4-{2-Cyclohexyl-2-[5,6-debtor-2-(4-methoxyphenyl)benzimidazol-1-yl]acetylamino}cyclohexanecarbonyl acid

Specified in the title compound was obtained in accordance with example 7, making separation of the stereoisomers of chiral preparative HPLC (Reprosil Chiral NR column), elwira gradient ethanol (+0,5% triperoxonane acid)/heptane. MS (ES⁺):526 (M+N)⁺.

Example 105

(-)-4-{2-Cyclohexyl-2-[5.6-debtor-2-(4-methoxyphenyl)benzimidazol-1-yl]acetylamino}benzoic acid

Specified in the title compound was obtained in accordance with example 7, making separation of the stereoisomers of chiral preparative HPLC (Chiralpak-AD column), elwira gradient ethanol and 0.5% acetic acid)/heptane. MS (ES^-):518 (M-N)^-.

Example 106

(TRANS-4-{2-Bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}cyclohexyl)acetic acid

Specified in the title compound was obtained analogously to example 7 after purification preparative HPLC reverse phase, elwira gradient acetonitrile/water. MS (ES⁺):556 (M+N)⁺.

Example 107

(-)-4-{2-Bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}benzoic acid

Specified in the title compound was obtained in the accordance with example 7, carrying out the separation of the stereoisomers of chiral preparative HPLC (Reprosil Chiral NR column), elwira gradient ethanol and 0.5% acetic acid)/heptane. MS (ES⁺):536 (M+N)⁺.

Example 108

(-)-(TRANS-4-{2-Bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}cyclohexyl)acetic acid

Specified in the title compound was obtained in accordance with example 7, making separation of the stereoisomers of chiral preparative HPLC (Chiralpak AD column), elwira gradient ethanol and 0.5% acetic acid)/heptane. MS (ES⁺):556 (M+N)⁺.

Example 109

2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)phenyl]ndimethylacetamide

A suspension of 0.13 g (0.25 mmole) 2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-N-(4-cyanophenyl)-2-cyclohexylacetate, 0.17 g (of 1.26 mmole) of the hydrochloride of triethylamine and 82 mg (1,26 mmole) of sodium azide in 3 ml of ortho-xylene was stirred at 145°C for 2.5 h Brown suspension was poured into 1M aqueous hydrochloric acid solution and was extracted three times with ethyl acetate. The combined organic layers were dried with magnesium sulfate, filtered, and evaporated to dryness. The residue was dissolved in acetonitrile and added a few drops of water, then deposited sediment. The resulting suspension was filtered, and the solid is washed with acetonitrile, containing a few to the drops of water to obtain the target compound as a white solid (68%). MS (ES⁺):548,3 (M+H).

The intermediate connection

2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-N-(4-cyanophenyl)-2-cyclohexylacetate

To a suspension of 0.5 g (1,24 mmole) of [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid (example 22, intermediate connection) in 3 ml dichloromethane was added dropwise 0.01 ml (0.12 mmole) of N,N-dimethylformamide, with 0.13 ml (1,54 mmole) of oxalicacid when the evolution of gas. The obtained transparent light-yellow solution was stirred for 1 h at room temperature, then was evaporated to dryness, and treated with twice 5 ml of dichloromethane and again evaporated to dryness. Light yellow solid substance was dissolved in 8 ml of dichloromethane and added dropwise to a stirred mixture of 0.13 g (1,24 mmole) of 4-aminobenzonitrile and 0.46 ml (3,31 mmole) of triethylamine in dichloromethane. After stirring for 3.75 hours transparent yellow solution was poured into water and was extracted twice with dichloromethane. The organic layers were washed with water and saturated sodium chloride solution, dried with magnesium sulfate, was filtered and, after the addition of the silica gel was evaporated to dryness. Purification of column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient from heptane to heptane/ethyl acetate (1:0 to 1:1 V/V) resulted in the receipt of 0.45 g (81%) indicated in the title compound as a light brown t is ejogo substances. MS (ES^-):(M-N):571,2.

Example 110

2-[2-(4-Chlorophenyl)-5.6-differentiality-1-yl]-N-[2-chloro-4-(1H-tetrazol-5-yl)phenyl]-2-cyclohexylacetate

Specified in the title compound was obtained analogously to example 109 N-(2-chloro-4-cyanophenyl)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylacetate without the use of water to precipitate to obtain the target compound as a white solid (85%). MS (ES^-):580,1 (M-N).

The intermediate connection

N-(2-Chloro-4-cyanophenyl)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylacetate

Specified in the title compound was obtained analogously to example 22, intermediate compound d), [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid and 4-amino-3-chlorobenzonitrile with obtaining the target compound as a white solid (62%). MS (ES⁺):M-N:539,2.

Example 111

2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[2-fluoro-4-(1H-tetrazol-5-yl)phenyl]ndimethylacetamide

Specified in the title compound was obtained analogously to example 109 2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-N-(4-cyano-2-forfinal)-2-cyclohexylacetate without the use of water for precipitation. The residue is suspended in acetonitrile and boiled under reflux, after which the formed solution. After cooling to room temperature again received the hydrated precipitate was collected by filtration, the same technique is used a second time to obtain the target compound in the form of a whitish solid (29%). MS (ES⁺):566,4 (M+H).

The intermediate connection

2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-N-[-(4-cyano-2-forfinal)-2-cyclohexylacetate

Specified in the title compound was obtained analogously to example 22, intermediate compound d), [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid and 4-amino-3-perbenzoate, and using a gradient of heptane:ethyl acetate (1:1 to 4:1) as eluent. Specified in the header of the product was recrystallized from tert-butyl methyl ether to obtain 0,79 g (61%) of a white solid (29%). MS (ES⁺):M+H:523,2.

Examples 112 and 113

Specified in the title compounds were obtained by separation of the stereoisomers of 2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[2-fluoro-4-(1H-tetrazol-5-yl)phenyl]ndimethylacetamide chiral preparative HPLC (Reprosil Chiral-NR column).

(+ or -)-2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[2-fluoro-4-(1H-tetrazol-5-yl)phenyl]ndimethylacetamide

Colorless solid. MS (TS) m/e (M+N)⁺: 566,4

(+or -)-2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[2-fluoro-4-(T-tetrazol-5-yl)phenyl]ndimethylacetamide

Colorless solid. MS (TS) m/e (M+N)⁺:566,4

Example 114

2-[2-(4-Chlorophenyl)-5,6-differentiality-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide

Specified in the title compound was obtained analogously to example 109 2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-N-(4-cyano-2-triptoreline)-2-cyclohexylacetate without the use of water for precipitation. Colorless solid (87%). MS (TS) m/e (M+N)⁺: 616,3.

The intermediate connection

2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-N-(4-cyano-2-triptoreline)-2-cyclohexylacetate

Specified in the title compound was obtained analogously to example 22, intermediate compound d), [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid and 4-amino-3-triftormetilfosfinov. The compound was purified by MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient from heptane to n-heptane/ethyl acetate (1:0 to 4:1 V/V) and subsequent purification preparative HPLC using a Gemini column and a gradient of acetonitrile: water (containing 0.5% formic acid). Colorless foam (47%). MS (ES⁺): M+H:573,2.

Examples 115 and 116

Specified in the title compounds were obtained by separation of the stereoisomers of 2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide chiral preparative HPLC (Reprosil Chiral-NR column)using a mixture of ethanol (containing 0.01 M ammonium acetate):n-heptane (30:70 V/V).

(+)-2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-reformational]ndimethylacetamide

Colorless solid. MS (TS) m/e (M+N)⁺:616,4

(-)-2-[2-(4-Chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide

Colorless solid. MS (TS) m/e (M+N)⁺:616,4

Example 117

2-[2-(4-Chlorophenyl)benzoimidazol-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide

Specified in the title compound was obtained analogously to example 109 2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-N-(4-cyano-2-triptoreline)-2-cyclohexylacetate without the use of water for precipitation. Colorless solid (89%). MS (TS) m/e (M+N)⁺:580,2.

The intermediate connection

2-[2-(4-Chlorophenyl)benzoimidazol-1-yl]-N-(4-cyano-2-triptoreline)-2-cyclohexylacetate

Specified in the title compound was obtained analogously to example 22, intermediate compound d), [2-(4-chlorophenyl)-5,6-differentiality-1-yl]cyclohexyloxy acid and 4-amino-3-triftormetilfosfinov. The compound was purified preparative HPLC using a Gemini column and a gradient of acetonitrile: water (containing 0.5% formic acid). Light brown foam (42%). MS (ES⁺):M+H:537,3.

Examples 118 and 119

Specified in the title compounds were obtained by separation of the stereoisomers of 2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide chiral drug is ate HPLC (Reprosil Chiral-NR column), using a mixture of ethanol (containing 0.01 M ammonium acetate):n-heptane (40:60 V/V).

(+)-2-[2-(4-Chlorophenyl)benzoimidazol-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide

Colorless solid. MS (TS) m/e (M+N)⁺:580,3

(-)-2-[2-(4-Chlorophenyl)benzoimidazol-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide

Whitish solid. MS (TS) m/e (M+N)⁺:580,2

Example 120

2-Cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-[2-fluoro-4-(1H-tetrazol-5-yl)phenyl]ndimethylacetamide

Specified in the title compound was obtained analogously to example 109 N-(4-cyano-2-forfinal)-2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]ndimethylacetamide. The crude product was purified by preparative HPLC system (Phenomenex Gemini column)using a gradient of acetonitrile and water (containing 0.5% formic acid). Whitish solid (44%). MS (TS) m/e (M-N)^-:591,4.

Example 121

2-Cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide

Specified in the title compound was obtained analogously to example 109 N-(4-cyano-2-triptoreline)-2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]ndimethylacetamide. The crude product was purified system preparative HPLC (Phenomenex Gemini column)using a gradient of acetonitril the a and water (containing 0.5% formic acid). Whitish solid (36%). MS (TS) m/e (M-N)^-:641,2.

The intermediate connection

N-(4-Cyano-2-triptoreline)-2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]ndimethylacetamide

Specified in the title compound was obtained analogously to example 22, intermediate compound g), cyclohexyl-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetic acid and 4-amino-3-triftormetilfosfinov. The crude product was purified system preparative HPLC (Phenomenex Gemini column)using a gradient of acetonitrile and water (containing 0.5% formic acid). Light brown foam (19%). MS (TS) (M+N⁺)⁺:600,3.

Example

Film-coated tablets containing the following ingredients can be obtained in the usual way:

The active ingredient was sieved and mixed with microcrystalline cellulose, and the mixture was granulated with a solution of the floor of the vinylpyrrolidone in water. The granulate was mixed with Nitroglycerinum starch and magnesium stearate and compressed to obtain cores 120 or 350 mg, respectively. The core was coated with an aqueous solution/suspension of the above film coating.

Example B

Capsules containing the following ingredients can be obtained in the usual way:

Components are sieved and mixed and filled into capsules of size 2.

The example In

Injectable solutions may have the following composition:

The active ingredient was dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH was brought to 5.0 with acetic acid. The volume was made up to 1.0 ml by adding the remaining amount of water. The solution was filtered, filled into vessels with the help of special equipment and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can be obtained in the usual way:

The active ingredient was dissolved in warm melt the other ingredients, and the mixture was filled in soft gelatin capsules of suitable size. Filled soft gelatin capsules were processed in accordance with conventional techniques.

Example D

The sachet containing the following ingredients can be obtained in the usual way:

The active ingredient is massively with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose, and granulated with a mixture of polyvinylpyrrolidone in water. The granules were mixed with magnesium stearate and fragrances and filled into sachets.

1. The compounds of formula (I):

where R¹selected from
and
R²represents hydrogen;
R³represents a cyclohexyl or bicyclo[2.2.1]heptyl;
R⁴represents phenyl, which is substituted in the 4-position by halogen or vernisson-alkyl, or pyridyl, which is substituted by 1 or 2 substituents, independently selected from halogen and lower alkoxygroup;
R⁵and R⁶independently of one another represent hydrogen or fluorine;
R⁷and R⁹independently from each other selected from the group consisting of hydrogen, lower alkyl, halogen, lower alkoxygroup, Vernissage of alkyl, fornessa alkoxygroup and cyanopropyl;
R⁸represents -(CR¹²R¹³)_n-COOH, where n denotes 0, 1 or 2, and R¹²and R¹³independently from each other represent hydrogen or lower alkyl,
or-O-(CR¹⁴R¹⁵)_p-COOH, where p denotes 1 or 2, and R¹⁴and R¹⁵independently from each other represent hydrogen or lower alkyl, or R⁴ and R¹⁵together with the carbon atom to which they are attached, form cycloalkyl ring,
or R⁸is tetrazol;
R¹⁰represents a hydroxy-group or -(CH₂)_p-COOH, where p denotes 0 or 1;
m denotes 0 or 1;
R¹¹represents-COOH;
and their pharmaceutically acceptable salts.

2. The compounds of formula (I) according to claim 1, where
R⁸represents -(CR¹²R¹³)_n-COOH, where n denotes 0, 1 or 2, and R¹²and R¹³independently from each other represent hydrogen or lower alkyl,
or-O-(CR¹⁴R¹⁵)_p-COOH, where p denotes 1 or 2, and R¹⁴and R¹⁵independently from each other represent hydrogen or lower alkyl, or R¹⁴and R¹⁵together with the carbon atom to which they are attached, form cycloalkyl ring.

3. The compounds of formula (I) according to claim 1, where R³represents cyclohexyl.

4. The compounds of formula (I) according to claim 1, where R⁴represents phenyl, which is substituted in the 4-position by halogen or vernisson-alkyl.

5. The compounds of formula (I) according to claim 1, where R⁴is a 4-halogenfrei.

6. The compounds of formula (I) according to claim 1, where R⁴represents 4-chlorophenyl.

7. The compounds of formula (I) according to claim 1, where R⁴represents pyridyl, which is substituted by 1 or 2 mandated what teli, independently selected from halogen and lower alkoxygroup.

8. The compounds of formula (I) according to claim 1, where R⁴represents pyridin-3-yl, which is substituted by 1 or 2 substituents, independently selected from halogen and lower alkoxygroup.

9. The compounds of formula (I) according to claim 1, where R⁵and R⁶represent fluorine.

10. The compounds of formula (I) according to claim 1, where R¹is:

and where R⁷and R⁹independently from each other selected from the group consisting of hydrogen, lower alkyl, halogen, lower alkoxygroup, Vernissage of alkyl, fornessa alkoxygroup and cyanopropyl; and
R⁸represents -(CR¹²R¹³)_n-COOH, where n denotes 0, 1 or 2, and R¹²and R¹³independently from each other represent hydrogen or lower alkyl,
or-O-(CR¹⁴R¹⁵)_p-COOH, where p denotes 1 or 2, and R¹⁴and R¹⁵independently from each other represent hydrogen or lower alkyl, or R¹⁴and R¹⁵together with the carbon atom to which they are attached, form cycloalkyl ring.

11. The compounds of formula (I) according to claim 10, where R⁸represents -(CR¹²R¹³)_n-COOH, n denotes 0, 1 or 2, and R¹²and R¹³independently from each other represent hydrogen or lower alkyl.

12. The compounds of formula (I) is .10, where R⁸represents-COOH.

13. The compounds of formula (I) according to claim 10, where R⁸represents-O-(CR¹⁴R¹⁵)_p-COOH, where p denotes 1 or 2, and R¹⁴and R¹⁵independently from each other represent hydrogen or lower alkyl, or R¹⁴and R¹⁵together with the carbon atom to which they are attached, form cycloalkyl ring.

14. The compounds of formula (I) according to claim 1, where R¹is:

and where R¹⁰represents a hydroxy-group or -(CH₂)_p-COOH, where p denotes 0 or 1, and m denotes 0 or 1.

15. The compounds of formula (I) 14 where R¹⁰represents a hydroxy-group or-COOH.

16. The compounds of formula (I) 14 where R¹⁰represents a hydroxy-group.

17. The compounds of formula (I) according to claim 1, where R¹is:

18. The compounds of formula (I) according to claim 1, selected from the group consisting of the following compounds:
6-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}nicotinic acid,
3-chloro-4-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,
4-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,
4-{2-[2-(6-chloropyridin-3-yl)-5,6-diferential the evils-1-yl]-2-cyclohexylethylamine}-3-methylbenzoic acid,
(-)-3-chloro-4-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,
(+)-3-chloro-4-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,
TRANS-4-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexanecarbonyl acid,
2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-(4-hydroxycyclohexyl)ndimethylacetamide,
(+)-2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-(TRANS-4-hydroxycyclohexyl)ndimethylacetamide,
TRANS-4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetylamino}cyclohexanecarbonyl acid,
(+)-4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetylamino}cyclohexanecarbonyl acid,
4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetylamino}-3-methylbenzoic acid,
4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]acetylamino}-3-Formentera acid,
4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5-perbenzoate-1-yl]acetylamino}cyclohexanecarbonyl acid,
(-)-4-{2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5-perbenzoate-1-yl]acetylamino}cyclohexanecarbonyl acid,
(-)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl what ethylamino}cyclohexanecarbonyl acid,
(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexyl)acetic acid,
(+)-[TRANS-4-({2-[2-(4-chlorophenyl)-5,6-debtor-1H-benzimidazole-1-yl]-2-cyclohexylethyl}amino)cyclohexyl]acetic acid,
4-{2-bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}benzoic acid,
(-)-TRANS-4-[({2-[2-(4-chlorophenyl)-5-fluoro-1H-benzimidazole-1-yl]-2-cyclohexylethyl}amino)methyl]cyclohexanecarbonyl acid,
3-chloro-4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}benzoic acid,
4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,
(+)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,
(-)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,
4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methylbenzoic acid,
(+)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methylbenzoic acid,
(-)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methylbenzoic acid,
3-chloro-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,
(+)-3-chloro-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic Ki the lot,
(-)-3-chloro-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,
4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,
(+)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,
(-)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,
4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}is 3.5-differentia acid,
(+)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}is 3.5-differentia acid,
(-)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}is 3.5-differentia acid,
4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyanobenzoic acid,
3-chloro-4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}benzoic acid,
(+)-3-chloro-4-{-2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}benzoic acid,
(-)-3-chloro-4-{-2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}benzoic acid,
4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methoxybenzoic acid,
4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid,
4-{2-cyclohexyl-2-[5-debtor-2-(4-triptoreline)benzoimidazol-1-yl]acetylamino}benzoic acid,
4-{2-cyclohexyl-2-[5-fluoro-2-(4-triptoreline)benzoimidazol-1-yl]acetylamino}benzoic acid,
4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cryptomaterial acid,
4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}benzoic acid,
4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,
(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}phenyl)acetic acid,
2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid,
2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)-2-methylpropionate acid,
3-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}phenyl)propionic acid,
3-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid,
(-)-3-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid,
(+)-3-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-forfinal)propionic acid,
(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)acetic acid,
2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl what ethylamino}-3-pertenece)propionic acid,
2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)-2-methylpropionate acid,
(+)-2-(4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)-2-methylpropionate acid,
(-)-2-(4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)-2-methylpropionate acid,
1-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid,
(+)-1-(4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid,
(-)-1-(4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid,
2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-TRANS-(4-hydroxycyclohexyl)ndimethylacetamide,
(-)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-(4-hydroxycyclohexyl)ndimethylacetamide,
(+)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-(4-hydroxycyclohexyl)ndimethylacetamide,
6-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}nicotinic acid,
(+)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyanobenzoic acid,
(-)4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyanobenzoic acids is,
(+)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methoxybenzoic acid,
(-)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-methoxybenzoic acid,
(+)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid,
(-)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid,
(+)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cryptomaterial acid,
(-)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cryptomaterial acid,
(-)-4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,
(+)-4-{2-[2-(4-chlorophenyl)-5-perbenzoate-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,
4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyano-5-Formentera acid,
(+)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyano-5-Formentera acid,
(-)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyano-5-Formentera acid,
1-(4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid,
(+)-1-(4-{2-[2-(4-chlorophenyl)benzoimidazol-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid,
(-)-1-(4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid,
4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid,
(+)-4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid,
(-)-4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid,
4-{2-cyclohexyl-2-[5,6-debtor-2-(6-methoxypyridine-3-yl)benzoimidazol-1-yl]acetylamino}cyclohexanecarbonyl acid,
(-)-4-{2-[2-(6-chloropyridin-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexanecarbonyl acid,
(4-{2-[2-(6-chloro-2-methoxypyridine-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexyl)acetic acid,
4-{2-[2-(6-chloro-2-methoxypyridine-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexanecarbonyl acid,
4-{2-[2-(6-chloro-2-methoxypyridine-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,
(+)-4-{2-cyclohexyl-2-[5,6-debtor-2-(6-methoxypyridine-3-yl)benzoimidazol-1-yl]acetylamino}cyclohexanecarbonyl acid,
(-)-4-{2-[2-(6-chloro-2-methoxypyridine-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}cyclohexanecarbonyl acid,
(-)-(4-{2-[2-(6-chloro-2-methoxypyridine-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethyl the Mino}cyclohexyl)acetic acid,
(+)-4-{(S)-2-[2-(6-chloro-2-methoxypyridine-3-yl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,
4-{2-bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}benzoic acid,
(4-{2-cyclohexyl-2-[5,6-debtor-2-(2-methoxypyridine-3-yl)benzoimidazol-1-yl]acetylamino}cyclohexyl)acetic acid,
4-{2-bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}cyclohexanecarbonyl acid,
(-)-4-{2-bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}cyclohexanecarbonyl acid,
(4-{2-bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}cyclohexyl)acetic acid,
(-)-4-{2-bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}benzoic acid,
(-)-(4-{2-bicyclo[2.2.1]hept-7-yl-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]acetylamino}cyclohexyl)acetic acid,
2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)phenyl]acetamide", she
2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-N-[2-chloro-4-(1H-tetrazol-5-yl)phenyl]-2-cyclohexylacetate,
2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[2-fluoro-4-(1H-tetrazol-5-yl)phenyl]acetamide", she
(+ or -)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[2-fluoro-4-(1H-tetrazol-5-yl)phenyl]acetamide", she
(+ or -)-2-[2-(4-chlorophenyl)-5,6-di is torrentomega.com-1-yl]-2-cyclohexyl-N-[2-fluoro-4-(1H-tetrazol-5-yl)phenyl]acetamide", she
2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,
(+)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,
(-)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,
2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,
(+)-2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,
(-)-2-[2-(4-chlorophenyl)benzoimidazol-l-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,
2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-[2-fluoro-4-(1H-tetrazol-5-yl)phenyl]acetamide", she
2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,
and their pharmaceutically acceptable salts.

19. The compounds of formula (I) according to claim 1, selected from the group consisting of the following compounds:
2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-(4-hydroxycyclohexyl)ndimethylacetamide,
(+)-2-cyclohexyl-2-[2-(2,6-dimethoxypyridine-3-yl)-5,6-differentiality-1-yl]-N-(TRANS-4-hydroxycyclohexyl)ndimethylacetamide,
(-)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-(4-hydroxycyclohexyl)ndimethylacetamide,br/> and their pharmaceutically acceptable salts.

20. The compounds of formula (I) according to claim 1, selected from the group consisting of the following compounds:
4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,
(-)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}benzoic acid,
4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,
(-)-4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-Formentera acid,
and their pharmaceutically acceptable salts.

21. The compounds of formula (I) according to claim 1, selected from the group consisting of the following compounds:
2-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)-2-methylpropionate acid,
(-)-2-(4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)-2-methylpropionate acid,
1-(4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid,
(-)-1-(4-{-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-pertenece)cyclopropanecarbonyl acid,
and their pharmaceutically acceptable salts.

22. The compounds of formula (I) according to claim 1, selected from the group consisting of the following compounds:
(-)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]2-cyclohexylethylamine}-3-cyanobenzoic acid,
(-)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid,
(-)-4-{2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexylethylamine}-3-cyano-5-Formentera acid,
(-)-4-{2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexylethylamine}-3-triftorperasin acid,
(+ or -)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[2-fluoro-4-(1H-tetrazol-5-yl)phenyl]acetamide", she
(-)-2-[2-(4-chlorophenyl)-5,6-differentiality-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,
(-)-2-[2-(4-chlorophenyl)benzoimidazol-1-yl]-2-cyclohexyl-N-[4-(1H-tetrazol-5-yl)-2-triptoreline]ndimethylacetamide,
and their pharmaceutically acceptable salts.

23. Compounds selected from the group consisting of the following compounds:
4-[2-cyclohexyl-2-(5,6-debtor-2-p-talibandominated-1-yl)acetylamino]benzoic acid,
4-[2-cyclohexyl-2-(5,6-debtor-2-p-talibandominated-1-yl)acetylamino]cyclohexanecarbonyl acid,
(-)-4-[2-cyclohexyl-2-(5,6-debtor-2-p-talibandominated-1-yl)acetylamino]benzoic acid,
(+)-[2-cyclohexyl-2-(5,6-debtor-2-p-talibandominated-1-yl)acetylamino]cyclohexanecarbonyl acid,
4-{2-cyclohexyl-2-[5,6-debtor-2-(4-methoxyphenyl)benzimidazol-1-yl]acetylamino}benzoic acid,
4-{2-cyclohexyl-2-[5,6-debtor-2-(4-methoxyphenyl)benzimidazol-1-yl]acetylamino}cyclohex karbonova acid,
(-)-4-{2-cyclohexyl-2-[5,6-debtor-2-(4-methoxyphenyl)benzimidazol-1-yl]acetylamino}benzoic acid,
and their pharmaceutically acceptable salts.

24. Pharmaceutical composition having selective activity against farnesoid-X-receptor (FXR), comprising the compound of formula (I) according to any one of claims 1 to 23 and a pharmaceutically acceptable carrier and/or adjuvant.

25. The compounds of formula (I) according to claim 1 for use as therapeutically active substances, which are selective modulators farnesoid-X-receptor.

26. The compounds of formula (I) according to claim 1 for use as therapeutically active substances for the treatment or prevention of diseases which are modulated by FXR agonists.