Novel cyclohexane derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol substituted derivatives of cyclohexane of formula (I) with LXRα- and/or LXRβ agonist modulation properties, as well as to their pharmaceutically acceptable salts. In formula (I) R1 denotes hydrogen, lower alkyl, fluoro-lower alkyl, lower alkyl-carbonyl, fluoro-lower alkyl-carbonyl, phenyl-lower alkyl, C3-C6-cycloalkyl-lower alkyl, C3-C6-cycloalkylcarbonyl or C3-C6-cycloalkyl-lower alkyl-carbonyl; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, phenyl-lower alkyl, where phenyl is possibly substituted with lower alkoxycarbonyl, lower alkoxycarbonyl, or if X represents a single bond and m is not equal to 0, R3 can also denote a hydroxy group; R4 denotes phenyl or heterocyclyl, where heterocyclyl is a five-member aromatic heterocyclic ring containing two heteroatoms selected from nitrogen and sulphur, optionally substituted with 1-3 substitutes independently selected from a group which includes lower alkyl and halogen; X denotes a single bond, SO2, CO or C(O)O; m equals 0, 1, 2 or 3; n equals 0 or 1. The invention also relates to a pharmaceutical composition containing formula (I) compounds.

EFFECT: novel compounds have useful biological properties.

20 cl, 35 ex

 

The invention relates to new hexafluoroisopropylidene derivative of cyclohexane of the formula (I)

where R1denotes hydrogen, lower alkyl, fluoro-lower alkyl, lower alkyl-carbonyl, fluorine-lower alkyl-carbonyl, aryl-lower alkyl, cycloalkyl-lower alkyl, cycloalkyl-carbonyl or cycloalkyl-lower alkyl-carbonyl;

R2denotes hydrogen or lower alkyl;

R3denotes lower alkyl, aryl-lower alkyl, heterocyclyl-lower alkyl or lower alkoxygroup-carbonyl, or, if X represents a simple bond, or, if X represents a simple bond, and m is not equal to 0, R3can also be a hydroxy-group;

R4denotes aryl or heterocyclyl;

R5denotes hydrogen, lower alkyl, aryl, heterocyclyl, aryl-lower alkyl or heterocyclyl-lower alkyl;

X represents a simple bond, SO2, CO, C(O)O or C(O)N(R5);

m denotes 0, 1, 2 or 3;

n denotes 0 or 1;

and their pharmaceutically acceptable salts and esters.

In addition, the invention relates to a method for producing the above-mentioned compounds, pharmaceutical preparations containing such compounds and to the use of these compounds for pharmaceutical preparations.

X-receptors of the liver (LXRs) are members of the family of nuclear hormone prescriptions the Directors. LXRs are activated by endogenous oxysterols and regulate the transcriptional control of multiple pathways of metabolism. Described two subtypes, LXRα and LXRβ (Willy et al., Genes Dev. 1995, 9:1033-45; Song et al., Proc Natl Acad Sci USA.1994, 91:10809-13). LXRβ expresses through ubiquitination, while LXRα preferably expresses in tissues, metaboliziruemah cholesterol such as liver tissue, fat, intestine and macrophages. LXRs modulate various physiological responses, including the regulation of cholesterol absorption, elimination of cholesterol (synthesis of bile acids) and the transport of cholesterol from peripheral tissues through the plasma lipoproteins in the liver. LXRs are also included in the glucose metabolism, cholesterol metabolism in the brain, cell differentiation and inflammation.

Currently, approximately half of all patients with coronary artery disease have low concentrations of HDL cholesterol (high density lipoprotein) in the plasma. Atheroprotective function HDL for the first time attracted the attention of almost 25 years ago and stimulated the involvement of genetic and environmental factors influencing HDL levels (Miller N.E., Lipids, 1978, 13^ 914-9). The protective function of HDL derives from their role in the process associated with the reverse transport of cholesterol. HDL mediates the removal of cholesterol from cells in the peripheral parodentium is, including foam cell macrophages in atherosclerotic damaged artery walls. HDL then take this cholesterol to the liver and Sterol-metabolizing organs for conversion into bile and remove from the body. Studies have shown that HDL-X levels predict risk of coronary artery disease regardless of the levels of LDL (low density lipoprotein) (Gordon et al., Am. J. Med. 1977, 62, 707-714).

Conducted in the present study among Americans aged 20 years and older showed that the proportion with HDL-X less than 35 mg/DL, is 16% (men) and 5.7% (women). A significant increase in HDL-X is achieved by treatment with Niacin in various compositions. However, significant unwanted side effects limit therapeutic efficacy of this method.

It was found that up to 90% of the 14 million patients diagnosed with type 2 diabetes in the United States are overweight or obese, and a high proportion of patients with type 2 diabetes has anomalous concentrations of lipoproteins. The study showed that the prevalence of total cholesterol > 240 mg/DL was detected in 37% of diabetic men and 44% in diabetic women. The corresponding figures for LDL-X >160 mg/DL are 31% and 44%, respectively, indicators of HDL-X <35 mg/DL are 28% and 11% in diabetic male and diabetic women, respectively. Diab is t is a disease, in which the patient's ability to control glucose levels in the blood is reduced due to partial disturbance response to the effects of insulin. Type 2 diabetes (TD), also called non-insulin dependent diabetes mellitus (NIDDM), affects 80-90% of patients with diabetes patients in developed countries. When TD the islets of Langerhans of the pancreas continues to produce insulin. However, target organs, are sent to the action of insulin, mainly muscle, liver and adipose tissue, show complete resistance to insulin stimulation. To compensate for the apparent lack of insulin, the body continues to produce non-physiological high levels of insulin, which eventually reduced to the last stage of illness due to exhaustion and the inability of the pancreas to produce insulin. Thus, TD is a cardiovascular metabolic syndrome is associated with many comorbidities, including insulin resistance, dyslipidemia, hypertension, endothelial dysfunction and inflammatory atherosclerosis.

The first stage of treatment of dyslipidemia and diabetes at the present time usually includes reduced fat and glycosomal diet, exercise and weight loss. However, the results of treatment can be mild and as progresser the of the disease becomes necessary treatment of various metabolic deficiency States, for example, lipid-modulating agents such as statins and fibrates for dyslipidemia, and hypoglycemic drugs such as sulfonylureas, Metformin or sensitizing agents related to thiazolidinedione (TZD) class of PPARγ-agonists in the case of insulin resistance. Recent studies have provided evidence that the modulators of LXRs may lead to compounds with enhanced therapeutic potential and as a consequence, the modulators of LXRs should improve plasma lipid profile and to increase HDL-X-levels (Lund et al., Arterioscler. Thromb. Vase. Biol. 2003, 23:1169-77). It is also known that LXRs in control of the outflow of cholesterol from foam cells are macrophages in atherosclerotic povrezhdeniya artery walls, and agonists LXRs have been shown to exhibit atheroprotective properties (Joseph and Tontonoz, Curr. Opin. Pharmacol. 2003, 3:192-7). Thus, modulators of LXRs should be effective in the treatment of atherosclerotic disease, which causes cardiovascular disease and mortality from stroke and heart disease. Recent studies suggest that there is an independent LXR, causing effects on insulin sensitization in addition to his role at heterotaxia (Cao et al., J Biol Chem. 2003, 278:1131-6). Thus, LXR modulators can be very therapeutic effective is the industry while increasing HDL and heterotaxia with additional effects on diabetes, compared with standard therapy.

The new compounds of the present invention, it has been found that simultaneously and very efficiently connected with the selective activity of LXRα and LXRβ, and with the joint activity of LXRα and LXRβ. Therefore, there is a decrease absorption of cholesterol, increased HDL cholesterol, decreased inflammatory atherosclerosis. As numerous cases of combined homeostasis dyslipidemia and cholesterol are related to the LXR modulators, the new compounds of the present invention have a high therapeutic potential compared to the compounds already known from the prior art. As a result, they can be applied in the prevention and treatment of diseases mediated LXRα and/or LXRβ agonists. Such diseases include increased lipid and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis and inflammatory diseases such as colitis, pancreatitis, cholestasis is a liver fibrosis, psoriasis and other inflammatory skin diseases, and diseases that have an inflammatory component such as Alzheimer's disease or the deterioration of cognitive function. In addition, new connections this is the overarching invention can be used for treatment and prevention of age and hereditary (for example, disease Stargardt) maculano degeneration.

Other compounds which are connected and activate LXRα and LXRβ were previously proposed (for example, in WO 03/099769). However, there is still a need for new compounds with improved properties. The present invention provides new compounds of formula (I)that are associated with LXRα and/or LXRβ. Compounds of the present invention unexpectedly discovered an improved pharmacological properties compared to the compounds already known from the prior art in relation to, for example, metabolic stability, bioavailability and activity.

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

In the present description, the term "lower" is used to refer to groups containing from one to seven, preferably from one to four, carbon atoms.

The term "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine are preferred.

The term "alkyl", alone or in combination with other groups, refers to a branched or linear monovalent, saturated aliphatic hydrocarbon radical containing from one to twenty carbon atoms, preferably from one to sixteen at the MOU carbon more preferably one to ten carbon atoms. The lower alkyl groups described below are also preferred alkyl groups.

The term "lower alkyl", alone or in combination with other groups, refers to a branched or linear monovalent alkyl, the radical containing from one to seven carbon atoms, preferably from one to four carbon atoms. This term is further illustrated by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and the like.

The term "fluoro-lower alkyl" refers to lower alkyl group that is mono - or multiply substituted with fluorine. Examples of fluoro-lower alkyl groups are CFH2, CF2H, CF3, CF3CH2, CF3(CH2)2, (CF3)2CH and CF2H-CF2.

The term "amino", alone or in combination with other groups, means a primary, secondary or tertiary group connected through the nitrogen atom, with the secondary amino group with an alkyl or cycloalkyl Deputy, and tertiary amino group having two identical or different alkyl or cycloalkyl Deputy or two nitrogen substituent, together forming a cycle, for example, -NH2methylaminopropyl, ethylamino, dimethylaminopropyl, diethylaminopropyl, meth is Letellier, pyrrolidin-1-yl or piperidino group, etc.

The term "cycloalkyl" refers to a monovalent carbocyclic to radical containing from 3 to 10, preferably from 3 to 6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "alkoxygroup" refers to the group R'-O-, where R' represents alkyl. The term "lower alkoxygroup" refers to the group R'-O-, where R' denotes a lower alkyl.

The term "fluoro-lower alkoxygroup" refers to the group R-O-, where R" denotes fluorine-lower alkyl. Examples of fluoro-lower alkoxygroup are CFH2-O, CF2H-Oh, CF3-Oh, CF3CH2-Oh, CF3(CH2)2-O (CF3)2CH-O and CF2H-CF2-O.

The term "alkylene" refers to straight or branched divalent saturated aliphatic hydrocarbon group containing from 1 to 20 carbon atoms, preferably from 1 to 16 carbon atoms, more preferably up to 10 carbon atoms. Lower alkylene group, as described below, are also preferred alkionovymi groups. The term "lower alkylene" refers to straight or branched divalent saturated aliphatic hydrocarbon group containing from 1 to 7 carbon atoms, preferably from 1 to 6 or from 3 to 6 carbon atoms. Straight alkylene or lower alkylene the group are preferable.

The term "aryl", alone or in combination with other groups, refers to phenyl or naftilos group, preferably by phenyl group which may be optionally substituted by from 1 to 5, preferably from 1 to 3, substituents, independently selected from the group comprising lower alkyl, lower alkoxygroup, halogen, a hydroxy-group, CN, CF3, an amino group, aminocarbonyl, carboxyl group, NO2dictograph lowest alkylene (forming, for example, benzodioxolyl group, lower alkylsulfonyl, aminosulfonyl, lower alkylsulphonyl, lower alkylcarboxylic, lower alkylsulphonyl-NH, lower alkoxycarbonyl, fluoro-lower alkyl, fluoro-lower alkoxygroup, cycloalkyl and fenoxaprop. Preferred substituents are halogen, lower alkyl, fluoro-lower alkyl, CN, and lower alkoxycarbonyl.

The term "heterocyclyl", alone or in combination with other groups, means saturated, partially unsaturated, or aromatic 5-10-membered, mono - or bicyclic heterocyclic group containing one or more heteroatoms, preferably from one to three, selected from nitrogen, oxygen and sulfur. If necessary, it can be substituted with one or more carbon atoms, for example, halogen, lower alkyl, lower alkoxygroup, exography, etc. and/or secondary atom and the PTA (for example, -NH-) lower alkyl, cycloalkyl, phenyl-lower alkoxycarbonyl, lower alkylcarboxylic, phenyl or phenyl-lower alkyl, or tertiary nitrogen atom (e.g., =N-) oxide group, with preferred are halogen and lower alkyl. Examples of such heterocyclic groups are pyrrolidinyl, pyrrolyl, piperidinyl, piperazinil, morpholinyl, thiomorpholine, pyrazolyl, thiazolyl, tetrazolyl, isothiazolin, imidazolyl (for example, imidazolyl-4-yl and 1-benzyloxycarbonyl-4-yl), benzimidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, hexahydropyridine, furyl, thienyl, thiazolyl, oxazolyl, isooxazolyl, indolyl (e.g., 2-indolyl), indazole, chinolin (for example, 2-chinolin, 3-chinolin and 1 oxido-2-chinolin), ethanolic (for example, 1-ethanolic and 3-ethanolic), tetrahydropyranyl (for example, 1,2,3,4-tetrahydro-2-chinolin), 1,2,3,4-tetrahydroisoquinoline (for example, 1,2,3,4-tetrahydro-1-exagerately), tetrahydropyranyl, honokalani, oxopyrrolidin and benzo[b]thiophenyl. Preferred are thiazolyl, imidazolyl and pyrazolyl. The heterocyclic group may also have a structure replacement, described previously in connection with the term "aryl". Aromatic heterocyclic groups are preferred.

The term "tsepliaeva group" refers to a group which can be replaced pose the STV nucleophilic substitution (for example, secondary amine). Typical atmasamyama groups are, for example: Cl, Br, I, O,-SO2- lower alkyl (where the O-SO2-CH3= OMs), O-SO2-fluorine-lower alkyl (where the O-SO2-CF3= OTf), O-SO2aryl (where OH-SO2-p-tolyl = OTs), O- (p-nitrophenyl).

The term "protective group" refers to groups that are temporarily used to protect functional groups, in particular hydroxyl groups. Examples of protective groups are benzyl, p-methoxybenzyl, tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl and tert-butyldiphenylsilyl.

The compounds of formula (I) can form pharmaceutically acceptable acid salt additive. Examples of such pharmaceutically acceptable salts are salts of compounds of formula (I) with physiologically compatible mineral acids such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or 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" refers to salts. The compounds of formula (I) can also form salts with bases. Examples of such saleables alkaline, alkaline earth and ammonium salts such as, for example,

Na-, K-, CA - and trimethylammonium salt. The term "pharmaceutically acceptable

salt" also refers to such salts. Salts formed by joining the Foundation, are preferred.

The term "pharmaceutically acceptable esters" includes derivatives of compounds of formula (I), in which the carboxyl group is converted into a hard-essential. Lower alkyl, hydroxy-group-lower alkyl, lower alkoxygroup-lower alkyl, amino-lower alkyl, mono - or di-lower alkyl-amino-lower alkyl, morpholino-lower alkyl, pyrrolidino-lower alkyl, piperidino-lower alkyl, piperazine derivatives-lower alkyl, lower alkyl-piperazine derivatives-lower alkyl and aralkyl esters are examples of such esters. Methyl, ethyl, propyl, butyl and benzyl esters are the preferred esters. The term "pharmaceutically acceptable esters" includes, in addition, derivatives of the compounds of formula (I), in which the hydroxyl group can be converted into the corresponding hard-ester group by means of inorganic or organic acids such as nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, malic acid, acetic acid, succinic acid, tartaric acid, meth is Sultonova acid, p-toluensulfonate acid and the like, which are non-toxic in relation to a living organism.

Specifically, the present invention relates to compounds of formula (I)

where R1denotes hydrogen, lower alkyl, fluoro-lower alkyl, lower alkyl-carbonyl, fluorine-lower alkyl-carbonyl, aryl-lower alkyl, cycloalkyl-lower alkyl, cycloalkyl-carbonyl or cycloalkyl-lower alkyl-carbonyl;

R2denotes hydrogen or lower alkyl;

R3denotes lower alkyl, aryl-lower alkyl, heterocyclyl-lower alkyl or lower alkoxygroup-carbonyl, or, if X represents a simple bond, or, if X represents a simple bond, and m is not equal to 0, R3can also be a hydroxy-group;

R4denotes aryl or heterocyclyl;

R5denotes hydrogen, lower alkyl, aryl, heterocyclyl, aryl-lower alkyl or heterocyclyl-lower alkyl;

X represents a simple bond, SO2, CO, C(O)O or C(O)N(R5);

m denotes 0, 1, 2 or 3;

n denotes 0 or 1;

and their pharmaceutically acceptable salts and esters.

The compounds of formula (I) individually are preferred and their physiologically acceptable salts separately are preferred and their pharmaceutically acceptable esters separately are preferred, with the especially preferred are the compounds of formula (I).

The compounds of formula (I) have two or more asymmetric carbon atoms and can therefore exist as enantiomeric mixtures, mixtures of stereoisomers or in the form of optically pure compounds.

Preferred compounds of the present invention are TRANS-compounds. Preferred compounds of formula (I) described above and is characterized by the following formula (IA)

where R1, R2, R3, R4, X, m and n described above, and their pharmaceutically acceptable salts and esters.

Preferred compounds of formula (I) as described above are compounds where R1denotes hydrogen, lower alkyl, fluoro-lower alkyl, lower alkyl-carbonyl, fluorine-lower alkyl-carbonyl, aryl-lower alkyl, cycloalkyl-lower alkyl or cycloalkyl-carbonyl. Preferably, R1denotes fluorine-lower alkyl, aryl-lower alkyl or cycloalkyl-lower alkyl. More preferably, R1means 2,2,2-triptorelin, benzyl or cyclopropylmethyl.

Other preferred compounds of formula (I) as described above are compounds where n is 1, R2denotes hydrogen or lower

alkyl, and R3denotes lower alkyl, aryl-lower alkyl or lower alkoxygroup-carbonyl, or, if X represents a simple bond, or, if X oboznachaet is a simple bond and m is not equal to 0, R3may also be a hydroxyl group. Preferably, R2denotes lower alkyl. More preferably, R2denotes methyl. Other preferred compounds are those where R3denotes lower alkyl, in particular where R3denotes methyl.

Another preferred variant of the present invention relates to compounds of formula (I) as described above, where R4denotes aryl or heterocyclyl selected from the group comprising thiazolyl, imidazolyl and pyrazolyl, while thiazolyl, imidazolyl and pyrazolyl optionally substituted from 1 to 3 substituents, independently selected from the group comprising lower alkyl and halogen. Compounds where R4denotes aryl are preferred, especially preferred are compounds where R4denotes phenyl.

Other preferred compounds of formula (I) as described above are such compounds where m=0 or 1. Compounds, where m=0, and compounds, where m=1, separately represent preferred variants of the present invention. Preferably, m=0. Another preferred variant of the present invention relates to compounds of formula (I) as described above, where n=0.

The following preferred variant of the present invention relates to compounds of formula (I) described the th above where X represents a simple bond, SO2, Or C(O)O. Preferably, X denotes SO2.

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

Preferred compounds of formula (I) are compounds selected from the group including:

TRANS-N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,

TRANS-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,

TRANS-N-benzyl-2,2,2-Cryptor-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]acetamide", she ethyl ester

TRANS-phenyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexylamino]acetic acid,

TRANS-N-benzyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]acetamide", she

TRANS-N-benzyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,

[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-2,4-dimethylthiazol-5-sulfonic acid,

[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazole-4-sulfonic acid,

(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-triform teletel)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazole-4-sulfonic acid,

ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazole-4-sulfonic acid,

ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-4-methyl-2-propertiesa-5-sulfonic acid,

(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-2,4-dimethylthiazol-5-sulfonic acid,

cyclopropylmethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-2,4-dimethylthiazol-5-sulfonic acid,

ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-2,4-dimethylthiazol-5-sulfonic acid,

TRANS-N-cyclopropylmethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,

TRANS-N-ethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,

(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-5-chloro-1,4-dimethyl-1H-pyrazole-3-sulfonic acid,

[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-5-chloro-1,4-dimethyl-1H-pyrazole-3-sulfonic acid,

TRANS-2-[4-(benzylamino)cyclohexyl]-1,1,1,3,3,3-hexaferrite-2-ol,

TRANS-2-[4-(benzyldimethylamine)cyclohexyl]-1,1,1,3,3,3-hexaferrite-2-ol,

TRANS-2-[4-(benzylisoquinoline)cyclohexyl]-1,1,1,3,3,3-hexaferrite-2-ol,

TRANS-N-Ben is Il-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]propionamide,

benzyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)hexyl]amide, TRANS-cyclopropanecarboxylic acid,

TRANS-cyclopropylmethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzamide,

TRANS-N-cyclopropylmethyl-2-phenyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]acetamide", she phenyl ether

TRANS-cyclopropylmethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]carbamino acid, benzyl ester

TRANS-cyclopropylmethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]carbamino acid,

(PMA)-TRANS-2-{4-[cyclopropylmethyl-(2-hydroxy-2-phenylethyl)amino]cyclohexyl}-1,1,1,3,3,3-hexaferrite-2-ol,

TRANS-benzyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]-sulfonamide,

TRANS-benzyl-N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]sulfonamide,

(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide(rat)-TRANS-1-phenylethanolamine acid,

(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-2-phenylpropane-2-sulfonic acid,

(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide(rat)-TRANS-1,2-diphenylethanol acid, methyl ester

(rat)-TRANS-3-(2-phenyl-2-{(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-thrift methylethyl)cyclohexyl]sulfamoyl}ethyl)benzoic acid, CIS-N-ethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide, and their pharmaceutically acceptable salts and esters.

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

TRANS-N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,

TRANS-N-benzyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,

TRANS-N-cyclopropylmethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,

TRANS-benzyl-N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]sulfonamide and

(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-2-phenylpropane-2-sulfonic acid, and their pharmaceutically acceptable salts and esters.

It is clear that the compounds of General formula (I) according to the present invention can be converted to functional groups in derivatives, which are capable of being converted into the parent compound in vivo.

The invention relates further to a method for producing compounds of formula (I) as defined above, including

a) reaction of compounds of formula (II)

with a compound LG-R1,

where R1, R2, R3, R4, X, m and n determine the Helena above, And denotes hydrogen or a protective group, LG denotes tsepliaeva group (such as I, Br, Cl, triflate, mesilate, toilet),

or

b) reaction of compounds of formula (III)

with a compound LG-X-(CH2)m(CR2R3)n-R4,

where R1, R2, R3, R4, X, m and n are defined above, And denotes hydrogen or a protective group, and LG denotes tsepliaeva group (such as, e.g. I, Br, Cl, or, if X represents a simple bond, LG can also refer to triplet, mesilate, toilet),

and removing the protective group A.

The reaction of the compound of formula (II) with a compound LG-R1and removing the protective group And, if necessary, can be conducted under conditions known to specialists in this field of technology. Such reaction of compounds of formula (II) standard carried out by treatment with a strong base such as bis(trimethylsilyl)amide, lithium, or in some cases in the presence of a base such as TLDs in a solvent such as, for example, THF or DMF at an appropriate temperature. The reaction of the compound of formula (II) with a compound LG-X-(CH2)m(CR2R3)n-R4and removing the protective group And, if necessary, can be conducted under conditions known to specialists in this field of technology. Such reaction of compounds of formula (III) can the be normally conducted in the presence of a base such as, for example NEt3in the solvent type dichloromethane or tetrahydrofuran at an appropriate temperature. The protective group is removed using standard techniques commonly known in the prior art, such as disilylgermane using tetrabutylammonium (TBAF).

The present invention relates also 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 by the methods described above. Unless otherwise specified, the substituents R1, R2, R3, R4, R5, X, m and n described above.

Obtaining derivatives, in which R1denotes hydrogen, is carried out in accordance with the following scheme 1.

Scheme 1

Aniline 1A may be O-protected with the formation of compound 1B (stage a) using a suitable protective group "PG", such as triethylsilyl or tert-butyldimethylsilyl group, through processing silylium agent (for example, triethylsilane or tert-butyldimethylsilyloxy respectively) in the presence of a suitable base (e.g., TLD, imidazole). Unprotected aniline 1A or protected aniline 1B can be converted into a mixture of TRANS-/CIS-cyclohexane 2A and 2B in the ratio 1:1, accordingly, by hydrogenation in an appropriate solvent such as Asón, methanol or ethanol, in the presence of a catalyst, for example, Pt coal or PtO2in acidic conditions (stage b). Filtration and evaporation of the solvent leads to compounds 2A or 2B in the form of their ammonium salts with deprotonization acid in the form of the counterion. Free amines can be obtained by alkaline treatment (for example, the distribution between aqueous NaOH solution and AcOEt). The free amines of TRANS - and CIS-isomers of TRANS-2 and CIS-2B can be separated using chromatography (stage b).

Introduction X-(CH2)m-CR2R3)nR4"fragment (stage g), resulting in a derivative 3A, 3b or TRANS-3b or CIS-3b, may be conducted by one of the methods described below. To obtain compounds 3A, 3b, TRANS-3b or CIS-3b, in which X represents a simple bond, 2A, 2B, TRANS-2-or CIS-2B treated with aldehyde CHO-(CH2)m-1-(CR2R3)n-R4(where m=1-3) in the presence of a reductive agent such as NaBCNH3, in an appropriate solvent such as, for example, ethanol or methanol. The use of ketone R3-CO-R4instead of CHO-(CH2)m-1-(CR2-R3)n-R4leads to a derivative in which X represents a simple bond, m=0, n=1 and R2denotes hydrogen. The alternative is actively, compound 2A, 2B preferably, the TRANS-2B, or CIS-2B can be treated with the alkylating agent LG-(CH2)m-(CR2R3)n-R4where LG denotes tsepliaeva group such as Cl, Br, I, OSO2aryl, OSO2CH3, OSO3CF3. This alkylation is carried out preferably in the presence of a base (for example, K2CO3) in a suitable solvent type, acetonitrile, DMF, DMA or THF. To obtain compounds 3A, 3b, TRANS-3b or CIS-3b, in which X denotes CO, COO, CONR5or SO22A, 2B, TRANS-2-or CIS-2B can be introduced into the reaction with chloride Cl-X-(CH2)m-(CR2R3)n-R4in the presence of an appropriate base such as, for example, DIPEA, NEt3or N-methylmorpholine. When X represents CO and SO23A, 3b, TRANS-3b or CIS-3b can be obtained by introducing into the reaction with carboxylic acid HOCO-(CH2)m-(CR2R3)n-R4or sulfonic acid HOSO2-(CH2)m-(CR2R3)n-R4in the presence of normal peptide condensing reagent such as ethylene dichloride or N,N-dicyclohexylcarbodiimide (if necessary, in combination with 1-hydroxybenzotriazole), in a suitable solvent (such as dichloromethane, THF or DMF). Compounds 3A, 3b, TRANS-3b or CIS-3b, to what PR X represents CONH, can be also obtained by introducing into the reaction 2A, 2B, TRANS-2-or CIS-2B with isocyanate O=C=N-(CH2)m-(CR2R3)n-R4. Derivatives, in which R3denotes a hydroxy-group, X represents a simple bond, and m=1, can be obtained by processing 2A, 2B, TRANS-2-or CIS-2 oxirane (4).

TRANS-3A, TRANS-3b and the corresponding CIS-analogs can be obtained, if necessary, of compounds 3A and 3b, respectively, using chromatography (stage d). The removal of the protective group (stage e) is carried out in accordance with known standard techniques such as described in "Protective groups in organic chemistry" by T.W. Greene and P.G.M.Wutts, 2ndEd., 1991, N.Y. (for example, disilylgermane using tetrabutylammonium).

Obtaining derivatives, in which R1denotes lower alkyl, fluoro-lower alkyl, lower alkyl-carbonyl, fluorine-lower alkyl-carbonyl, aryl-lower alkyl, cycloalkyl-lower alkyl, cycloalkyl-carbonyl, cycloalkyl-lower alkyl-carbonyl, perform one of the methods described below in scheme 2.

Scheme 2

Treatment of 2A, 2B, TRANS-2, TRANS-2, CIS-2A or CIS-2B allermuir agent such as, for example, acetylchloride R1-Cl or acetic anhydride (R1)2O, where

R1denotes lower alkyl-carbonyl, fluorine-lower ALK is l-carbonyl, cycloalkyl-carbonyl, cycloalkyl-lower alkyl-carbonyl, in the presence of a base such as DIPEA, NEt3or N-methylmorpholine in solvent type dichloromethane, THF or DMF leads to the derivatives 5A, 5B, TRANS-5A, TRANS-5B, CIS-5A or CIS-5B (stage g). Alternatively, this acylation can be carried out using a carboxylic acid in the presence of normal peptide condensing reagent such as ethylene dichloride or disclocation (if necessary, in combination with 1-hydroxybenzotriazole) in a suitable solvent (such as dichloromethane, THF or DMF).

Carbonyl group optionally may be subsequently removed by treatment regenerating reagent such as NRCin a solvent such as THF, resulting in 5A, 5B, TRANS-5A, TRANS-5B, CIS-5A or CIS-5B, where R1denotes lower alkyl, fluoro-lower alkyl, cycloalkyl-lower alkyl (stage C). The last derivative can also be obtained by treating 2A, 2B, TRANS-2, TRANS-5B, CIS-5A or CIS-5B appropriate aldehyde or ketone in the presence of a reducing reagent such as NaBCNHa (stage I) or treatment with alkylating reagent such as lower alkyl-LG, fluoro-lower alkyl-LG, aryl-lower alkyl-LG, cycloalkyl-lower alkyl-LG, where LG denotes tsepliaeva group such example is, as Cl, Br, I, OSO2aryl, OSO2CH3, OSO2CF3(stage). Processing alkylating reagent is carried out preferably in the presence of a base (such as DBU,2CO3), or after deprotonization 2A, 2B, TRANS-2, TRANS-2, CIS-2, CIS-2B, a strong base (for example, bis(trimethylsilyl)amidon lithium or diisopropylamide lithium). The same methods (W-th) can be used for the conversion of 3A, 3b, TRANS-3A, TRANS-3, CIS-3A, CIS-3b to 6A, 6b, TRANS-6A, TRANS-6b, CIS-6A, CIS-6b, respectively. For derivatives 5A, 5B, TRANS-5A, TRANS-5B, CIS-5A or CIS-5B, in which R1limited to R1denoting lower alkyl, fluoro-lower alkyl, aryl-lower alkyl, cycloalkyl-lower alkyl, X is-(CH2)m-(CR2R3)n-R4the fragment can be entered using one of the methods described in stage g of figure 1 (stage K).

Deprotonization derivatives 6b, TRANS-6b or CIS-(6b), where X denotes the SO2, CO, m=1 and n=0, a strong base, for example, bis(trimethylsilyl)amidon lithium or diisopropylamide lithium, and subsequent treatment with oxygen lower alkyl-LG, aryl-lower alkyl-LG, heterocyclyl-lower alkyl-LG (where LG denotes tsepliaeva group such as Cl, Br, I, OSO2aryl, OSO2CH3, OSO2CF3) leads to a derivative 6b, TRANS-6b or CIS-6b with R3denoting the hydroxy-group,a lower alkyl, aryl-lower alkyl, heterocyclyl-lower alkyl, respectively, and where X denotes the SO2, CO, m=0 and n=1.

Derivative 6 (TRANS-6b or CIS-6b), where X denotes the SO2WITH m=0 and n=1, can be deproteinizirovanny strong base, for example, bis (trimethylsilyl) amidon lithium or diisopropylamide lithium and sequentially processed "lower alkyl-LG (where LG denotes tsepliaeva group such as Cl, Br, I, OSO2aryl, OSO2CH3, OSO2CF3), with derivatives 6 (TRANS-6b or CIS-6b), where X denotes the SO2WITH m=0, n=1 and R2denotes lower alkyl.

TRANS-5A, TRANS-5B, TRANS-6A, TRANS-6b and the corresponding CIS-analogs can be obtained if necessary from 3A and 3b, respectively, using chromatography (stage m). The removal of the protective group (stage m) is carried out in accordance with known standard techniques such as described in "Protective groups in organic chemistry" by T.W.Greene and P.G.M.Wutts, 2ndEd., 1991, N.Y. (for example, disilylgermane using tetrabutylammonium).

A large number of compounds Cl-X-(CH2)m-(CR2R3)n-R4CHO-(CH2)m-1-(CR2R3)n-R4, LG-(CH2)m-(CR2R3)n-R4are commercially available. They can also be obtained from the related commercial d is accessible starting compounds such for example, as ester alkilani-(CH2)m-1-(CR2R3)n-R4, carboxylic acid HOCO-(CH2)m-1(CR2R3)n-R4alcohol HO-(CH2)m-(CR2R3)n-R4in either case, when X denotes SO2from sulfonic acid HOSO2-(CH2)m-(CR2R3)n-R4according to standard literature methods known to experts in the field of engineering. As typical examples of such transformations selected three examples: 1) the transformation of the carboxylic acid HOCO(CH2)m-1-(CR2R3)n-R4into the corresponding acid chloride of carboxylic acid Cl-CO(CH2)m-1-(CR2R3)n-R4the processing. SOCl2or POCl3in an appropriate solvent, such as dichloromethane; 2) oxidation of the alcohol HO-(CH2)m-(CR2R3)n-R4nin the aldehyde CHO(CH2)m-1-(CR2R3)n-R4(for example, by oxidation Svernu); 3) conversion of the alcohol HO-(CH2)m-(CR2R3)n-R4in a derived LG-(CH2)m-(CR2R3)n-R4using, for example, PBr3with derivatization, where LG denotes Br, or using, for example, methanesulfonamide (in the presence of the evidence of such, for example, as NEt3) to obtain the derivative, where LG denotes OSO2CH3.

Epoxides 4, if they are not available commercially, can be obtained by epoxydecane alkenes CH2=CR3R4using commonly used epoxidised agent such as m-chlorbenzene acid, in an appropriate solvent such as dichloromethane.

If 3A, 3b, 6A, 6b, TRANS-3A, TRANS-3, TRANS-6A, TRANS-6b, CIS-3A, CIS-3, CIS-6A or CIS-6b contain a functional group that is not compatible with one of the TRANS-compounds described above, the functional group may be respectively substituted before the transformation(s) and deprotonation again at a later stage. Such protection and deprotonization carried out in accordance with known standard techniques such as described in "Protective groups in organic chemistry" by T.W.Greene and P.G.M.Wutts, 2ndEd., 1991, N.Y., and well-known specialists in this field of technology.

The conversion of compounds of formula (I) pharmaceutically acceptable salts can be carried out by treating this compound with inorganic acid, for example, halogen acid, such as hydrochloric acid or Hydrobromic acid, or inorganic acids such as sulfuric acid, nitric acid, forstora acids and so on, or organic acid such as, for example, acetic acid, citric acid, malic acid, fumaric acid, tartaric acid, methanesulfonate acid or p-toluensulfonate acid. One method of formation of such salts is adding 1/n equivalents of acid, where n = the number of protons acid, to a solution of the compound in an appropriate solvent (e.g. ethanol, an ethanol water mixture, a mixture of tetrahydrofuran-water) and removal of solvent by evaporation or lyophilization. The compounds of formula (I) can also form salts with physiologically compatible bases. Examples of such salts are the alkali, alkaline earth and ammonium salts such as. Na-, K-, CA - and trimethylammonium salt. One method of formation of such salts is adding 1/n equivalents of a basic salt such as M(OH)nwhere M denotes a metal cation or ammonium, and n = the number of hydroxide cations to a solution of the compound in an appropriate solvent (e.g. ethanol, an ethanol water mixture, a mixture of tetrahydrofuran-water) and removal of solvent by evaporation or lyophilization.

Turning seizure ratio formula (I) into pharmaceutically acceptable esters can be carried out, for example, by treatment of the corresponding amino or hydroxy-group present in the molecule, the carb is a new acid such as acetic acid, condensing reagents such as hexaphosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium (THIEF), N,N-dicyclohexylcarbodiimide (DCC), hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI) or tetrafluoroborate O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N,N-tetramethylurea (TPTU), with the formation of ester or amide. Pharmaceutically acceptable esters can be obtained by treating the corresponding carboxylic groups present in the molecules, the corresponding alcohol using one of the condensing agents noted above.

If the receipt is not described in the examples, the compounds of formula (I), and all intermediate products can be obtained by similar methods or by methods corresponding to the methods presented above. The source compounds are commercially available or known from the prior art.

As noted above, the new compounds of the present invention, as installed, at the same time and very effectively connected with the selective activity of LXRα and LXRβ, and with the joint activity of LXRα and LXRβ. This leads to reduced absorption of cholesterol, increasing HDL-cholesterol, reduce the inflammatory atherosclerosis. As numerous cases of combined homeostasis dyslipidemia and cholesterol are related to the LXR modulators, novaeseelandiae of the present invention have a high therapeutic potential in comparison with connections, already known from the prior art. As a result, they can be applied in the prevention and treatment of diseases modulated LXRα and/or LXRβ agonists. Such diseases include increased lipid and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis and inflammatory diseases such as colitis, pancreatitis, cholestasis is a liver fibrosis, psoriasis and other inflammatory skin diseases, and diseases, including inflammatory component such as Alzheimer's disease or worsened/improve cognitive function. Furthermore, the new compounds of the present invention can be used for treatment and prevention of age and hereditary (e.g., disease Stargardt) macular degeneration.

The invention therefore relates also to pharmaceutical compositions comprising the compound according to the definition above and a pharmaceutically acceptable carrier and/or adjuvant.

In addition, the invention includes compounds according to the definition above for use as therapeutically active substances, especially as therapeutically active substances for the treatment and/or prevention of pain is SNA, modulated LXRα and/or LXRβ agonists, particularly as therapeutically active substances for the treatment and/or prevention of increased lipid levels, increased cholesterol levels, low HDL cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, liver fibrosis, macular degeneration and/or Alzheimer's disease.

In another preferred embodiment, the invention relates to a method of therapeutic and/or prophylactic treatment of diseases modulated LXRα and/or LXRβ agonists, particularly as therapeutically active substances for the treatment and/or prevention of increased lipid levels, increased cholesterol levels, low HDL cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, liver fibrosis, macular degeneration and/or Alzheimer's disease, comprising introducing the compound by definition above a person or an animal.

The invention also includes the application is connected to the second definition above for therapeutic and/or prophylactic treatment of diseases, modulated LXRα and/or LXRβ agonists, particularly as therapeutically active substances for the treatment and/or prevention of increased lipid levels, increased cholesterol levels, low HDL cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, liver fibrosis, macular degeneration and/or Alzheimer's disease.

The invention relates also to the use of the compounds defined above to obtain drugs for therapeutic and/or prophylactic treatment of diseases modulated LXRα and/or LXRβ agonists, particularly as therapeutically active substance for therapeutic and/or prophylactic treatment of increased lipid levels, increased cholesterol levels, low HDL cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, liver fibrosis, macular degeneration and/or illness Alzheimer's disease. Such medicines include connection to determine the structure above.

Prevention and/or treatment of elevated lipid levels, elevated holesterinovykh levels, atherosclerotic diseases, dyslipidemia or diabetes is the preferred reading, in particular, the preferred prophylaxis and/or treatment of increased lipid levels, increased cholesterol levels, atherosclerotic diseases or dyslipidemia, particularly preferred prophylaxis and/or treatment of atherosclerotic disease or dyslipidemia. Diabetes, particularly non-insulin dependent diabetes mellitus, is another preferred disease.

To determine the activity of compounds of the present invention conducted the following tests. Basic information on testing can be found in: J.S. Nichols et al. "Development of and scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain". Anal. Biochem. 1998, 257: 112-119.

The expression vectors mammals were designed to produce a full-sized human LXRα and LXRβ. The expression vectors of bacterial and mammalian designed to producirovanie glutathione-s-transferase (GST), hybridized with the ligand-binding domain (LBD) of the human LXRα (AA 164 to 447) and human LXRβ (AA 155 to 460). To achieve this, areas of the cloned sequences encoding LBDs were amplified from panoreserve the clones by PCR and then subcloned into plasmid vectors. The final clones were verified by analysis of the DNA sequence (Willy et al., Genes Dev. 1995, 9:1033-45; Song et al., Proc. Natl. Acad. Sci. USA.1994, 91:10809-13).

The induction, expression and purification of GST-LBD hybridized proteins is carried out in E. coli lines BL21(pLysS) cells by standard methods (Ref: Current Protocols in Molecular Biology, Wiley Press, edited by Ausubel et al).

Analysis of radioligand binding

The binding of LXRα and LXRβ receptors analyzed in a buffer consisting of 50 mm HEPES, pH 7.4, 10 mm NaCl, 5 mm MgCl2. In each reaction well of 96-hole tablet 500 ng of GST-LXRα-LBD or 700 ng GST-LXRβ-LBD hybrid proteins bind with 80 µg or 40 µg SPA granules (Amersham Pharmacia), respectively, for a final volume of 50 µl by shaking. The resulting suspension is incubated for 1 h at RT and centrifuged for 2 min at 1300 Supernatant containing unbound protein is removed and the moist precipitate containing coated with receptor pellets, re-suspended in 50 µl of buffer. Add radioligand (for example, 100,000 disintegrations/min N-(2,2,2-tryptophanyl)-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]benzosulfimide)), the reaction incubated at RT for 1 h, and count pellets impregnated with scintillation, carried out in the presence of test compounds. All analyses linking is carried out in 96-well tablets and the amount of bound ligand is measured on a Packard TopCount using ptiPlates (Packard). Curves dose-response represented in the concentration range from 10-4M

Analysis using transcriptional reporter gene luciferase

Kidney cells baby hamster (VNC ADS CCL10) are grown in DMEM medium containing 10% FBS, at 37°C in an atmosphere of 95%O2:5%CO2. The cells are sown in 6-well plate with a density of 105cells/well and then parties transferout or full-LXRα or full-LXRβ expression plasmids with the addition of reporter plasmid expressing the luciferase under the control of LXR response. Transfection was completed using Fugene 6 reagent (Roche Molecular Biochemicals) according to the Protocol. After 6 h after transfection cells were harvestroad by trypsinization and seeded into a 96-well plate with a density of 104cells/well. After 24 h, provided for binding of the cells, the medium is removed and replaced by 100 µl without red phenol medium containing the test substance or reference ligand (final concentration of DMSO is 0.1%). After incubation of the cells with the compounds for 24 h discard 50 ál of the supernatant, and then add 50 ál of Luciferase Constant-Light Reagent (Roche Molecular Biochemicals) for lizirovania cells and initiate the luciferase reaction. Luminescence as a measure luciferase activity, detects in a Packard TopCount. Transcri is ment activation in the presence of the test substance is expressed raised to the power value of activation compared with cells incubated in the absence of substance. EU50values were calculated using XLfit software (ID Business Solutions Ltd. UK).

The compounds of formula (I) have an activity of at least one of the above analyses (EC50or IC50from 1 nm to 100 μm, preferably from 1 nm to 10 μm, more preferably from 1 nm to 1 μm.

For example, these compounds have the following IC50values in the analysis of binding:

ExampleLXRα binding
IC50[mmol/l]
LXRβ binding
IC50[mmol/l]
10,020,07
171,51,4

These results were obtained using the above tests.

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 introduced, for example, orally, for example in the form of tablets, pills in the shell, coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions; rectally, for example, in the Orme suppositories, parenterally, e.g. in the form of injection or infusion solutions, topically, e.g. in the form of ointments, creams or oils. Oral introduction is preferred.

Manufacture of pharmaceutical preparations can be carried out using methods known to anyone skilled in the art, by making the required compounds of formula (I) and their pharmaceutically acceptable derivatives in dosage form for administration together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carriers and, if desired, usual pharmaceutical adjuvants.

Suitable carriers are not only inorganic carriers, but also organic media. So, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as materials for tablets, pellets in the shell, coated tablets and hard gelatin capsules. Suitable carriers 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 no carriers are, however, not required in the case of soft gelatin capsules). Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sugar is a, invert sugar and the like. Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats and semi-solid and liquid polyols. Suitable carriers for local products are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, glycols and derivatives of cellulose.

Conventional stabilizers, preservatives, wetting agents and emulsion, improvers consistency, taste enhancers, salts to adjust osmotic pressure, buffer substances, solvents, 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 subject to the control of the disease, age and individual condition of the patient and the route of administration and, of course, must satisfy the individual requirements in each particular case. For adult patients seen daily dose of approximately 1 mg to 2000 mg, in particular from about 1 mg to 500 mg depending on the severity of the disease and t is knogo pharmacokinetic profile of the compound can be introduced in the form of one or more dosage units per day, for example, from 1 to 3 dosage units.

The pharmaceutical preparations normally contain about 1-500 mg, preferably 1-200 mg, of the compounds of formula (I).

The following examples illustrate the present invention in more detail, in no way limiting, however, its volume.

Examples

Abbreviations:

Asón = acetic acid, n-BuLi = n-utility, CH2Cl2= dichloromethane, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, DIPEA = N-ethyldiethanolamine, DMF = dimethylformamide, EtOAc = ethyl acetate; EtOH = ethanol, Et2O = diethyl ether, heptane = n-heptane, i.v. = in vacuum, the Meon = methanol, TBAF = tetrabutylammonium, TAGS = triethylchlorosilane, TPA = triperoxonane acid, THF = tetrahydrofuran, RT = room temperature.

General remarks

All reactions were conducted in an argon atmosphere.

Example 1: TRANS-N-(2,2,2-triftoretil}-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide

1.1. A solution of 10 g (38.6 mmol) of 2-(4-AMINOPHENYL)-1,1,1,3,3,3-hexaferrite-2-ol in 100 ml of DMF is treated with 6.3 ml (42.4 mmol) of DBU, and then added dropwise to 6.5 ml (38.6 mmol) TECH. After stirring the mixture at RT overnight, the solvent was partially removed under vacuum. The distribution of the crude mixture between dilute aqueous NaOH solution and Et2O and drying the combined organic phases over Na2SO4leads to 13 g (90%) -(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenylamine in the form of a colorless oil, MS: 374 (M+N)+.

1.2. A solution of 5 g (13.4 mmol) of 4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenylamine in 150 ml of Asón treated with 2.5 g of Pt/C (10%) and hydronaut for 72 h at atmospheric pressure with vigorous stirring. Filtration and evaporation of solvent gives a yellow semi-solid substance which distribute between 1-molar aqueous solution of NaOH and ethyl acetate. The combined organic phases are dried over Na2SO4and evaporated, receiving 4 g crude product. Chromatography on silica gel using EtOAc, then EtOAc/MeOH in a ratio of 10:1, gives about 1.9 g (37%) of CIS-4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexylamine and about 1.9 g (37%) of TRANS-4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexylamine in the form of a slightly yellow oil, MS: 380 (M+H)+.

1.3. A solution of 0.71 g (of 1.87 mmol) of TRANS-4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexylamine in 5 ml of CH2Cl2process of 0.64 ml (3.74 mmol) of DIPEA and 0.24 ml (1,87 mmol) benzosulfimide and stirred at room temperature for 3 hours distribution of the crude mixture between dilute aqueous HCl solution and ether, drying the combined organic phases over Na2SO4and chromatography on silica gel using a mixture of EtOAc/heptane 1:1 gives 0.9 g (93%) of TRANS-N-[-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]benzosulfimide in the form of a slightly yellow semi-solid substances, MS: 518 (M-N)-.

1.4. A solution of 0.45 g (0.87 mmol) of TRANS-N-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]benzosulfimide in 5 ml of dry THF cooled to -78°C and added to it dropwise 0.7 ml (1.13 mmol) of a 1.6 molar solution of n-BuLi in hexane. The solution is heated to -40°C, treated with 1.0 g (4,33 mmol) 2,2,2-triptoreline ether triftormetilfullerenov acid and allowed to warm to room temperature. The mixture is stirred for 30 min at RT, and then heated under reflux for 2 hours the Solvent is evaporated, and the residue is dissolved in 2 ml of THF and treated with an excess of tetrabutylammonium fluoride. The distribution between the aqueous solution of NH4Cl and Et2O, drying the combined organic phase and chromatography on silica gel using a mixture of heptane/EtOAc 2:1 yield 0.17 g (40%) of TRANS-N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide in the form of a slightly yellow oil, MS: 486 (M-N)-.

Example 2: TRANS-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide

2.1. A solution of 350 mg (is 0.135 mmol) of 2-(4-AMINOPHENYL)-1,1,1,3,3,3-hexaferrite-2-ol in 10 ml of acetic acid is treated with 100 mg of Pt/C (10%) and hydronaut at atmospheric pressure with vigorous stirring for 24 hours of Filtering and cypriani the solvent gives 400 mg (91%) of the acetate of 2-(4-aminocyclohexane)-1,1,1,3,3,3-hexaplar-propan-2-ol in the form of a slightly brown solid, MS: 266 (M+N)+.

2.2: Solution of 100 mg (0.37 mmol) of the acetate of 2-(4-aminocyclohexane)-1,1,1,3,3,3-hexaferrite-2-ol in 5 ml of DMF is treated with 0.2 ml (1.16 mmol) of DIPEA and 0,144 ml (1.1 mmol) of benzosulfimide. The mixture is stirred for 1 h and partitioned between dilute aqueous HCl solution and diethyl ether. The combined organic phases are dried over Na2SO4and the solvent is evaporated. Column chromatography on silica gel using a mixture of EtOAc/heptane 1:1 yield 90 mg (72%) of N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl] benzosulfimide in the form of a pink solid, MS: 404 (M-N)-.

2.3: Chromatography of 50 mg (0.12 mmole) of N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide on silica gel using a mixture of EtOAc/heptane 2:1 gives about 19 mg (38%) of CIS-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide and about 20 mg (40%) of TRANS-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide in the form of a colorless semi-solid substances, MS: 404 (M-N)-.

Example 3: TRANS-N-benzyl-2,2,2-Cryptor-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl-1-ndimethylacetamide

3.1. A solution of 17 g (78, 23 mmol) of the acetate of 2-(4-aminocyclohexane)-1,1,1,3,3,3-hexaferrite-2-ol (example 2.1) in 250 ml of ethanol is treated to 27.2 ml (196 mmol what th) of triethylamine and 8.75 ml (86,1 mmol) of benzaldehyde. The mixture is stirred over night at room temperature, and the solvent is evaporated in vacuum. The obtained brown oil was dissolved in 120 ml of DMF and treated 8,76 ml (58.7 mmol) of DBU, and then added dropwise 9,85 ml (58.7 mmol) of triethylchlorosilane. The mixture is stirred for 4 h at RT and partitioned between saturated aqueous NH4Cl and Et2O. the Crude product obtained after drying the combined organic phases over Na2SO4and evaporation of the solvent, dissolved in 250 ml of ethanol, the portions treated with 2.2 g (58.7 mmol) NaBH4and stirred for 2 h at RT. Evaporation of the solvent, the distribution between ethyl ether and aqueous NaOH solution, drying the combined organic phases over Na2SO4and chromatography on silica gel using a mixture of heptane/EtOAc (gradient in the ratio of from 6:1 to 2:1) gives 3.3 g (14%) of CIS-benzyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine and 4.7 g (20%) of TRANS-benzyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine as yellow oil, MS: 470 (M+N)+.

3.2. A solution of 100 mg (0.28 mmol) of TRANS-benzyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine (example 2) in 2 ml of CH2Cl2treated with 0.1 ml (1.24 mmol) of pyridine and 0.1 ml (to 0.72 mmol) of anhydride of triperoxonane the th acid and stirred at RT over night. Treatment with excess TBAF, stirring for 30 min, and the distribution of the mixture between dilute aqueous HCl solution and ethyl ether, drying the combined organic phases over Na2SO4and evaporation gives approximately 100 mg (79%) of TRANS-N-benzyl-2,2,2-Cryptor-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]ndimethylacetamide in the form of a yellow oil, MS: 452 (M+N)+.

Example 4: ethyl ester of TRANS-phenyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexylamino]acetic acid

A solution of 300 mg (1.0 mmol) of the acetate of 2-(4-aminocyclohexane)-1,1,1,3,3,3-hexaferrite-2-ol (example 2.1) in 5 ml of ethanol is treated with 227 mg (1.0 mmol) of ethyl ether oxopentanoic acid and 87 mg (1.0 mmole) of laborgerate sodium. The mixture is stirred over night at RT and partitioned between saturated aqueous Na2HCO3and ethyl ether. Drying the combined organic phases over Na2SO4and chromatography on silica gel with a mixture of heptane/EtOAc in a ratio of 4:1 gives approximately 100 mg (25%) of the ethyl ester of CIS-phenyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexylamino] acetic acid and approximately 100 mg (25%) of ethyl ester of TRANS-phenyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexylamino]acetic acid as a colourless oil, MS: 428 (M+N)+.

Example 5: TRANS-N-gasoline is-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]ndimethylacetamide

A solution of 50 mg (0.11 mmole) of TRANS-benzyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine (example 3.1) in 1 ml of CH2Cl2treated with 0.1 ml of triethylamine, cooled to 0°C and treated of 0.14 ml (1.97 mmol) of acetylchloride. The mixture is stirred for 30 min and partitioned between saturated aqueous NH4Cl and ethyl ether. The crude product obtained after drying the combined organic phases over Na2SO4and solvent evaporation, dissolved in 1 ml of THF, treated with excess TBAF and left under stirring for 1 h the Distribution between saturated aqueous NH4Cl and ethyl ether, drying the combined organic phases over Na2SO4the evaporation of the solvent and chromatography on silica gel using a mixture of EtOAc/heptane 1:1 yield 50 mg (95%) of TRANS-N-benzyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]ndimethylacetamide in the form of a colorless viscous oil, MS: 398 (M+N)+.

Example 6: TRANS-N-benzyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide

By analogy with example 5 of the TRANS-benzyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine (example 3.1) and benzosulfimide obtain TRANS-N-benzyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]b is solarpanel in the form of a colorless oil, MS: 494 (M-N)-.

Example 7: [4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]medtrans-2,4-dimethylthiazol-5-sulfonic acid

By analogy with example 5 TRANS-4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexylamine (example 1, 2) and 2,4-dimethyl-1,3-thiazole-5-sulphonylchloride receive [4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]medtrans-2, 4-dimethylthiazol-5-sulfonic acid as a yellow oil, MS: 441 (M+N)+

Example 8: [4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazole-4-sulfonic acid

By analogy with example 5, from TRANS-4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexylamine (example 1, 2) and 1,2-dimethyl-1H-imidazol-4-sulphonylchloride receive [4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazole-4-sulfonic acid in the form of a bright solid, MS: 424 (M+N)+.

Example 9: (2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazole-4-sulfonic acid

9.1. By analogy with example 1.3 from TRANS-4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexylamine and 1,2-dimethyl-N-imidazol-4-sulphonylchloride receive [4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazol-sulfonic acid in the form of a white solid, MS: 538 (M+N)+.

9.2. By analogy with example 1, 4 of [4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazole-4-sulfonic acid and 2,2,2-triptoreline ether triftormetilfullerenov acid get (2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazole-4-sulfonic acid in the form of a slightly brown solid, MS: 506 (M+N)+.

Example 10 ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazole-4-sulfonic acid

10.1. A solution of 150 mg (0,28 mmole) of [4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazole-4-sulfonic acid (example 9.1) in 1 ml DMF process of 0.66 ml (0.44 mmol) DBU, stirred for 15 min and treated with 0.9 ml of 0.58 mmole) of ethyliodide. The mixture is stirred at 60°C for 4 h and partitioned between saturated aqueous NH4Cl and ethyl ether. Drying the combined organic phases over Na2SO4and evaporation of solvent gives 150 mg (95%) of ethyl[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-N-imidazole-4-sulfonic acid in the form of a slightly yellow liquid, MS: 566 (M+N)+.

10.2. A solution of 130 mg (0,23 mmole) of ethyl-[4-(2,2,2-Cryptor-1 triethylsilane is hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazole-4-sulfonic acid in 2 ml of THF is treated with an excess of tetrabutylammonium fluoride and stirred for 2 h at room temperature. The distribution between saturated aqueous NH4Cl and Et2O, drying the combined organic phase, evaporation of solvent and column chromatography on silica gel with a mixture of EtOAc/heptane 1:1 yield 42 mg (25%) of ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazole-4-sulfonic acid as a yellow colorless oil, MS: 452 (M+N)+.

Example 11 ethyl[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-4-methyl-2-propertiesa-5-sulfonic acid

11.1. By analogy with example 1.3 from TRANS-4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexylamine (example 1.2) and 2,4-dimethyl-1,3-thiazole-5-sulphonylchloride receive [4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]medtrans-2,4-dimethylthiazol-5-sulfonic acid in the form of a white solid, MS: 555 (M+N)+.

11.2. A solution of 200 mg (0.36 mmol) [4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]aminotrans-2,4-dimethylthiazol-5-sulfonic acid in 5 ml of THF cooled to -78°C and added dropwise 0.25 ml of a 1.6 molar solution of n-BuLi in hexane. The solution is heated to -30°C, treated with 1 ml (1.2 mmol) of ethyliodide, leave to warm up to CT, and then heated under reflux for 2 hours Distribution between saturated aqueous N 4Cl and Et2O, drying the combined organic phases over Na2SO4and evaporation of solvent gives a residue which is dissolved in THF and treated with excess TBAF. The distribution between saturated aqueous NH4Cl and ethyl ether, drying the combined organic phases over Na2SO4the evaporation of the solvent and chromatography on silica gel with a mixture of heptane/EtOAc to 2:1 ratio gives 20 mg (11%) of ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]aminotrans-4-methyl-2-propertiesa-5-sulfonic acid as a yellow oil, MS: 497 (M+N)+.

Example 12: (2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexylamin TRANS-2,4-dimethylthiazol-5-sulfonic acid

By analogy with example 1, 4 of [4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amide, TRANS-2,4-dimethylthiazol-5-sulfonic acid (example 11.1) and 2,2,2-triptoreline ether triftormetilfullerenov acid get (2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-N-imidazole-4-sulfonic acid as a yellow viscous oil, MS: 523 (M+N)+.

Example 13: cyclopropylmethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]medtrans-2,4-dimethylthiazol-5-sulfonic acid

By analogy with example 10 [4-(2,2,2-Cryptor-triethylsilyl-1-trifloromethyl)cyclohexyl]aminotrans-2,4-dimethylthiazol-5-sulfonic acid (example 11.1) and bromelicola get cyclopropylmethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide TRANS-2,4-dimethylthiazol-5-sulfonic acid in the form of a yellow resin, MS: 495(M+H)+.

Example 14 ethyl[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]medtrans-2,4-dimethylthiazol-5-sulfonic acid

By analogy with example 10 [4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]aminotrans-2,4-dimethylthiazol-5-sulfonic acid (example 11.1) and ethyliodide obtain ethyl[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]medtrans-2,4-dimethylthiazol-5-sulfonic acid as a yellow oil, MS: 469 (M+H)+.

Example 15: TRANS-N-cyclopropylmethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide

A solution of 500 mg (0,89 mmole) of TRANS-N-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]benzosulfimide (example 1.3) in 10 ml of THF is cooled to -78°C and added dropwise to 0.72 ml of a 1.6 molar solution of n-BuLi in hexane. The solution is heated to -40°C for 30 min, treated of 0.43 ml (4.45 mmol) of bromelicola, left to warm to room temperature and then heated under reflux over night. Add excess TBAF and the mixture is additionally stirred for one hour. The distribution of the crude mixture between saturated aqueous NH4Cl and Et2O, drying the combined organic phases over Na2SO4viparita the s and chromatography on silica gel using dichloromethane to give 200 mg (49%) of TRANS-N-cyclopropylmethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide in the form of a colorless viscous oil, MS: 460 (M+H)+.

Example 16: TRANS-N-ethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide

By analogy with example 10 of TRANS-N-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]benzosulfimide (example 1.3) and ethyliodide get TRANS-ethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide in the form of a colorless oil, MS: 434 (M+N)+.

Example 17: (2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-5-chloro-1,4-dimethyl-1H-pyrazole-3-sulfonic acid

17.1. By analogy with example 1.3 from TRANS-4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexylamine and 5-chloro-1,3-dimethylpyrazol-4-sulphonylchloride receive [4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amide, TRANS-5-chloro-1,4-dimethyl-1H-pyrazole-3-sulfonic acid in the form of a light amorphous solid, MS: 528 (M+N)+.

17.2. By analogy with example 10 [4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amide, TRANS-5-chloro-1,4-dimethyl-1H-pyrazole-3-sulfonic acid and 2,2,2-triptoreline ether triftormetilfullerenov acid get (2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-5-chloro-1,4-dimethyl-1H-pyrazole-3-sulfonic acid in the form of a slightly yellow oil, MS: 540 ((IS+M) +1Cl).

Example 18: [4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-5-chloro-1,4-dimethyl-1H-pyrazole-3-sulfonic acid

By analogy with example 10.2 of [4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amide, TRANS-5-chloro-1,4-dimethyl-1H-pyrazole-3-sulfonic acid (example 17.1) receive [4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-5-chloro-1,4-dimethyl-1H-pyrazole-3-sulfonic acid in the form of semi-solid substances, MS: 458 (M+N)+1 Cl)

Example 19: TRANS-2-[4-(benzylamino)cyclohexyl]-1,1,1,3,3,3-hexaplar-propan-2-ol

A solution of 200 mg (0.43 mmole) of TRANS-benzyl[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine (example 3.1) in 2 ml of pyridine is treated with 0.05 ml of acetic anhydride (0,51 mmole), stirred overnight at RT and partitioned between saturated aqueous NH4Cl and Et2O. After drying the combined organic phases over Na2SO4and the solvent is evaporated, the residue dissolved in 3.5 ml of THF and treated 0,86 ml of 1-molar solution NR3in THF. The mixture is stirred at room temperature for 2 h, and the solvent is evaporated. The residue is dissolved in THF, treated with an excess of tetrabutylammonium fluoride and stirred for 2 hours Evaporation of the solvent and chromatography on silica gel with a mixture of g is Xan/EtOAc in a ratio of 4:1 yield 64 mg (39%) of TRANS-2-[4-(benzylamino)cyclohexyl]-1,1,1,3,3,3-hexaferrite-2-ol in the form of a slightly yellow oil, MS: 384 (M+N)+.

Example 20: TRANS-2-[4-(benzyldimethylamine)cyclohexyl]-1,1,1,3,3,3-hexaferrite-2-ol

By analogy with example 19 TRANS-benzyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine (example 3.1) and propionitrile get TRANS-2-[4-(benzyldimethylamine)cyclohexyl]-1,1,1,3,3,3-hexaferrite-2-ol as a colourless oil, MS: 398 (M+N)+.

Example 21: TRANS-2-[4-(benzylisoquinoline)cyclohexyl]-1,1,1,3,3,3-hexaferrite-2-ol

By analogy with example 19 TRANS-benzyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine (example 3.1) and cyclopropanecarbonitrile get TRANS-2-[4-(benzylisoquinoline)cyclohexyl]-1,1,1,3,3,3-hexaferrite-2-ol as a colourless oil, MS: 310 (M+H)+.

Example 22: TRANS-N-benzyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]propionamide

By analogy with example 5 of the TRANS-benzyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine (example 3.1) and propionitrile obtain TRANS-N-benzyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]propionamide in the form of a slightly yellow oil, MS: 412 (M+H)+.

Example 23: benzyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-cyclopropanecarboxylic acid

By analogy with example 5 of the TRANS-benzyl-[4-(2,2,2-crypto is-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine (example 3.1) and cyclopropanecarbonitrile receive benzyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-cyclopropanecarbonyl acid in the form of slightly yellow oil, MS: 424 (M+H)+.

Example 24: TRANS-N-cyclopropylmethyl-]-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl-1-benzamid

24.1. A solution of 930 mg (1.73 mmol) of TRANS-benzyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine (example 3.1) in 2 ml of CH2Cl2treated with 0.6 ml (3.5 mmol) of DIPEA and 0.23 ml (2.56 mmol) of cyclopropanecarbonitrile. The mixture is stirred at room temperature overnight and partitioned between saturated aqueous NH4Cl and Et2O. the combined organic phases are dried over Na2SO4and the solvent is evaporated. The crude obtained product is dissolved in 10 ml of THF, treated of 3.46 ml of 1-molar solution NR3in THF and heated under reflux for 6 hours Distribution between dilute aqueous NaOH solution and Et2O, drying the combined organic phases over Na2SO4and evaporation of the solvent to give 1 g of crude TRANS-benzylcarbamoyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine as yellow oil, MS: 524 (M+N)+.

24.2. 1 g (approximately 2.0 mmol) of crude TRANS-benzylcarbamoyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine dissolved in 50 ml of acetic acid, contribute 300 mg Pd/C (10%) and hydronaut during the night when the atmosphere is nom pressure with vigorous stirring. Filtration and evaporation of the solvent give 775 mg (about 82%) of crude TRANS-cyclopropylmethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine as yellow oil, MS: 434 (M+N)+

24.3. A solution of 50 mg (0.12 mmole) of TRANS-cyclopropylmethyl[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine in 3 ml of a mixture (in the ratio 1:2) THF and 1,2-dichloroethane process of 0.03 ml (0.23 mmol) of triethylamine and 0.02 ml (0.4 mmol) of benzoyl chloride. The mixture is stirred at RT for 2 h and partitioned between saturated aqueous NH4Cl and Et2O. After drying the combined organic phases over Na2SO4and the solvent is evaporated, the residue is dissolved 2 ml of THF, treated with an excess of tetrabutylammonium fluoride and partitioned between saturated aqueous

a solution of NH4Cl and Et2O. Drying the combined organic phases over Na2SO4and column chromatography on silica gel with a mixture of heptane/ethyl acetate 2:1 ratio give 35 mg (72%) of TRANS-N-cyclopropylmethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzamide as a white solid, MS: 424 (M+N)+.

Example 25: TRANS-N-cyclopropylmethyl-2-phenyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]ndimethylacetamide

By analogy with example 24.3 of the TRANS-cyclopropylmethyl-[4-(2,2,2-crypto is-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine (example 24.2) and phenylacetylide obtain TRANS-N-cyclopropylmethyl-2-phenyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl] ndimethylacetamide in the form of a slightly brown oil, MS: 438 (M+N)+.

Example 26: phenyl ether TRANS-cyclopropylmethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]carbamino acid

By analogy with example 24.3 of the TRANS-cyclopropylmethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine (example 24.2) and phenylcarbamate get a phenyl ester, TRANS-cyclopropylmethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]carbamino acid in the form of a slightly brown oil, MS: 440 (M+N)+.

Example 27: benzyl ether of TRANS-cyclopropylmethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]carbamino acid

By analogy with example 24.3 of the TRANS-cyclopropylmethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine (example 24.2) and benzylchloride receive benzyl ether of TRANS-cyclopropylmethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]carbamino acid in the form of a slightly brown oil, MS: 454 (M+N)+.

Example 28: (rat)-TRANS-2-{4-[cyclopropylmethyl-(2-hydroxy-2-phenylethyl)amino]cyclohexyl}-1,1,1,3,3,3-hexaferrite-2-ol

28.1. A solution of 100 mg (0,23 mmole) TRANS-cyclopropylmethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amine (example 24.2) in 0.5 ml of acetonitrile is treated with 41 mg (0.38 mmol) of literarity and 46 mg (0.38 mmol) (rat)-FeNi is of ethylene oxide. The mixture is stirred in a sealed tube at 80°C for 6 h and partitioned between saturated aqueous NH4Cl and Et2O. Drying the combined organic phases over Na2SO4the evaporation of solvent and column chromatography on silica gel with a mixture of heptane/ethyl acetate 1:1 ratio give 52 mg (49%) (rat) TRANS-2-{cyclopropylmethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amino}-1-phenylethanol in the form of a colorless oil, MS: 554 (M+N)+.

28.2. By analogy with example 10.2 (rat)-TRANS-2-{cyclopropylmethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amino}-1-phenylethanol get (rat)-TRANS-2-{4-[cyclopropylmethyl-(2-hydroxy-2-phenylethyl)amino]cyclohexyl}-1,1,1,3,3,3-hexaferrite-2-ol in the form of a slightly yellow semi-solid substances, MS: 440 (M+N)+.

Example 29: TRANS-benzyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]sulfonamide

29.1. By analogy with example 1.3 from TRANS-4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexylamine and phenylmethanesulfonyl get TRANS-benzyl-N-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]the sulfonamide as a yellow solid, MS: 534 (M+N)+.

29.2. By analogy with example 10.2 of TRANS-benzyl-N-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)is illogical]sulfonamida get TRANS-benzyl-1-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]sulfonamide, in the form of a slightly brown resin, MS: 420 (M+N)+.

Example 30: TRANS-benzyl-N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]sulfonamide

30.1. A solution of 200 mg (0.37 mmole) of TRANS-benzyl-N-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]sulfonamida (example 29.1) in 2 ml of THF cooled to -78°C and treated dropwise 0.4 ml of 1-molar solution of bis(trimethylsilyl)amide lithium in THF. The mixture is heated to -40°C, treated 609 mg (2.6 mmol) of 2,2,2-triptoreline ether triftormetilfullerenov acid and allowed to warm to room temperature. Then after 4 h of heating under reflux the mixture is cooled to room temperature and partitioned between saturated aqueous NH4Cl and Et2O. the combined organic phases are dried over Na2SO4and the solvent is evaporated. Chromatography on silica gel with a mixture of heptane/ethyl acetate in a ratio of 9:1 to give 140 mg (61%) of TRANS-benzyl-N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]sulfonamida in the form of a slightly yellow oil, MS: 614 (M-N)-.

30.2. By analogy with example 10.2 of TRANS-benzyl-N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]sulfonamida get TRANS-benzyl-N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifluoromethyl what Teal)cyclohexyl]the sulfonamide in the form of a slightly yellow foam, MS: 502 (M+N)+.

Example 31: (2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide (rat) TRANS-1-phenylethanolamine acid

31.1. A solution of 128 mg (0.21 mmol) of TRANS-benzyl-N-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]sulfonamida (example 30.1) in 2 ml of THF cooled to -78°C, treated dropwise at 0.42 ml of 1-molar solution of bis(trimethylsilyl)amide lithium in THF and allowed to warm to -40°C. After addition of 0.13 ml (2.1 mmol) of iodomethane the mixture is stirred at room temperature for 4 h and partitioned between saturated aqueous NH4Cl and Et2O. the combined organic phases are dried over Na2SO4and the solvent is evaporated, receiving 130 mg (98%) of crude (2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amide (rat)-TRANS-1-phenylethanolamine acid in the form of a slightly yellow oil, MS: 648 (M+NH4)+.

31.2. A solution of 30 mg (2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amide in methanol process of 0.12 ml of 2-molar solution of NaOMe in methanol. The distribution between saturated aqueous NH4Cl and Et2O and column chromatography with a mixture of heptane/ethyl acetate 2:1 ratio give 18 mg (73%) (2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohex the yl]amide (rat)-TRANS-1-phenylethanolamine acid in the form of a colorless oil, MS: 514 (M-H)-.

Example 32: (2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-2-phenylpropane-2-sulfonic acid

A solution of 100 mg (0.16 mmol) (2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]amide 1-phenylethanolamine acid (example 31.1) in THF cooled to -78°C and treated dropwise to 0.17 ml of 1-molar solution of bis(trimethylsilyl)amide lithium wtgf. The mixture is heated to 0°C and treated to 0.22 ml (0.35 mmole) of iodomethane, left to warm to room temperature and then heated under reflux for 4 hours the mixture Distribution between saturated aqueous NH4Cl and ethyl ether, drying the combined organic phases over Na2SO4and evaporation of solvent gives a residue which is dissolved in 2 ml Meon and treated with 0.5 ml of 2-molar solution of NaOMe. The distribution of this solution between saturated aqueous NH4Cl and ethyl ether, drying the combined organic phases over Na2SO4, evaporation and column chromatography on silica gel with a mixture of dichloromethane/heptane 1:2 to give 6 mg (7%) (2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-2-phenylpropane-2-sulphonic acid in the form of a white resin, MS: 528 (M-N)-.

Example 33: (2,2,2-thrift ratil)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide (rat)-TRANS-1,2-diphenylethanol acid

A solution of 50 mg (0.08 mmol) of TRANS-benzyl-N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]sulfonamida (example 30.1) in 0.5 ml THF cooled to -78°C and treated of 0.11 ml of 1-molar solution of bis(trimethylsilyl)amide lithium in THF. The mixture is left to warm to approximately -5°C for 30 min and treated of 0.11 ml (0.1 mmole) of benzylbromide. The mixture is stirred overnight and partitioned between dilute aqueous HCl solution and Et2O. the combined organic phases are dried over Na2SO4and the solvent is evaporated. The residue is dissolved in methanol and treated with 0.5 ml of 2-molar solution of NaOMe in methanol. The distribution of this solution between saturated aqueous NH4Cl and El2O, drying the combined organic phases over Na2SO4, evaporation and column chromatography on silica gel with a mixture of heptane/ethyl acetate in the ratio of 4:1 to give 50 mg (76%) (2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide (rat)-TRANS-1,2-diphenylethanol acid as a colourless foam, MS: 590 (M-N)-.

Example 34: methyl ether (rat)-TRANS-3-(2-phenyl-2-{(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]sulfamoyl}ethyl)benzoic acid

By analogy with example 33 from benzyl-N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1-Tr is ethylcellulose-1-trifloromethyl)cyclohexyl]sulfonamida (example 30.1) and methyl-3-(methyl bromide)benzoate instead of benzylbromide get methyl ether (rat)-TRANS-3-(2-phenyl-2-{(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]sulfamoyl}ethyl)benzoic acid in the form of a colorless oil, MS: 648 (M-N)-.

Example 35: CIS-N-ethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl-1-benzosulfimide

35.1. By analogy with example 1.3 from CIS-4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexylamine (example 1.2) to obtain CIS-N-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]benzosulfimide in the form of a colorless oil, MS:518(M-N)-

35.2. By analogy with example 10 from CIS-N-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)cyclohexyl]benzosulfimide and ethyliodide obtain CIS-N-ethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide in the form of a slightly yellow viscous oil, MS: 434 (M+N)+

Example

The coated tablets containing the following ingredients can be obtained with the standard method:

IngredientsPills
Core:
The compound of formula (I)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Water lactose60,0 mg70.0 mg
Polydon C12.5 mg15,0 mg
Alkaline starch glycolate12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(Earth core)120,0 mg350,0 mg
Shell:
The hypromellose3.5 mg7,0 mg
Polyethylene glycol 60000.8 mg1.6 mg
Talc1.3 mg2.6 mg
IngredientsPills
Iron oxide (yellow)0.8 mg1.6 mg
Titanium dioxide 0.8 mg1.6 mg

The active ingredients are screened, mixed with microcrystalline cellulose and granularit mixture in a solution of polyvinylpyrrolidone in water. The granulate is mixed with an alkaline starch glycolate and magnesium stearate and pressed, receiving the core tablets weighing 120 or 350 mg, respectively. The core varnished using an aqueous solution/suspension of the above-mentioned film shell.

Example B

Capsules containing the following ingredients can be obtained with the standard method:

IngredientsOn capsule
The compound of formula (I)25.0 mg
Lactose150,0 mg
Corn starch20.0 mg
talc5.0 ml

Components sift, mix and put in the capsule size 2.

The example In

Injectable solutions may have the following composition:

Ingredients
The compound of formula (I)3.0 mg
The polyethylene glycol 400150,0 mg
Acetic acidto pH 5.0
Water for injection solutionsto 1.0 ml

The active ingredient dissolved in a mixture of polyethylene glycol 400 and water for injection, using a part of it. Bring the pH to 5.0 with acetic acid. The volume was adjusted to 1.0 ml by adding the remaining amount of water. The solution is filtered, filled into vials, using the appropriate device, and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can be obtained with the standard method:

Ingredients

The contents of the capsules

The compound of formula (I)5.0 mg
Yellow wax8.0 mg
Gidrirovannoe soybean oil8.0 mg
Partially hydrogenated vegetable oil34,0 mg
Soybean oil110,0 mg
Mass content capsules165,0 mg

Gelatin is the first capsule

Gelatin75,0 mg
Glycerol 85%32,0 mg
The Karion 838.0 mg (dry matter)
Titanium dioxide0.4 mg
Iron oxide (yellow)1.1 mg

The active ingredient is dissolved in warm melt the other ingredients and the mixture is filled soft gelatin capsules of appropriate size. Filled soft gelatin capsules are processed using conventional methods.

Example D

A wafer containing the following ingredients can be obtained with the standard method:

Ingredients

The compound of formula (I)50.0 mg
Lactose, finely ground powder1015,0 mg
Microcrystalline cellulose1400,0 mg

(AVICELPH 102)

Ingredients

/tr>
The sodium carboxymethyl cellulose14,0 mg
Polyvinylpyrrolidone K 3010.0 mg
Magnesium stearate10.0 mg
Flavorings1.0 mg

The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose, and then granularit with a mixture of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavors and bring in a wafer.

1. The compounds of formula (I)

where R1denotes hydrogen, lower alkyl, fluoro-lower alkyl, lower alkyl-carbonyl, fluorine-lower alkyl-carbonyl, phenyl-lower alkyl, C3-C6-cycloalkyl-lower alkyl, C3-C6-cycloalkylcarbonyl or3-C6-cycloalkyl-lower alkyl-carbonyl;
R2denotes hydrogen or lower alkyl;
R3denotes lower alkyl, phenyl-lower alkyl, where the phenyl possibly substituted lower alkoxycarbonyl, lower alkoxycarbonyl, or, if X represents a simple bond, and m is not equal to 0, R3can also denote a hydroxy-group;
R4denotes phenyl or heterocyclyl where heterocyclyl represents a five-membered aromatic heterocyclic ring containing two heteroatoms selected from nitrogen and sulfur, optionally substituted from 1 to 3 substituents, independently selected from the group comprising lower alkyl and halogen;
X represents a simple bond, SO2, Or C(O)O;
m denotes 0, 1, 2 or 3;
n denotes 0 or 1;
in the form of the racemates, CIS - or TRANS-isomers or mixtures thereof, and their pharmaceutically acceptable salts.

2. Compounds according to claim 1, characterized by formula (IA)

where R1, R2, R3, R4, X, m and n are defined in claim 1, and their pharmaceutically acceptable salts.

3. Compounds according to claim 1, where R1denotes fluorine-lower alkyl, phenyl-lower alkyl or C3-C6-cycloalkyl-lower alkyl.

4. Compounds according to claim 1, where R1means 2,2,2-triptorelin, benzyl or cyclopropylmethyl.

5. Compounds according to claim 1, where n=1, R2denotes hydrogen or lower alkyl and R3denotes lower alkyl, phenyl-lower alkyl or lower alkoxycarbonyl, or, if X represents a simple bond, or, if X represents a simple bond, and m is not equal to 0, R3may also indicate a hydroxyl group.

6. Compounds according to claim 5, where R2denotes lower alkyl.

7. Compounds according to claim 6, where R2denotes methyl.

8. Compounds according to claim 1 or claim 2, where R3denotes lower alkyl.

9. Compounds according to claim 5, where R3denotes methyl.

10. Compounds according to claim 1, where R denotes Fanelli heterocyclyl, selected from the group comprising thiazolyl, imidazolyl and pyrazolyl, while thiazolyl, imidazolyl and pyrazolyl optionally substituted from 1 to 3 substituents, independently selected from the group comprising lower alkyl and halogen.

11. Compounds according to claim 1, where R4denotes phenyl.

12. Compounds according to claim 1, where m denotes 0 or 1.

13. Compounds according to claim 1, where m denotes 0.

14. Compounds according to item 13, where n denotes 0.

15. Compounds according to claim 1, where X denotes the SO2.

16. The compound of claim 10 selected from the group including
TRANS-N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,
TRANS-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,
TRANS-N-benzyl-2,2,2-Cryptor-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]acetamide", she
ethyl ester of TRANS-phenyl[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexylamino]acetic acid,
TRANS-N-benzyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]acetamide", she
TRANS-N-benzyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,
[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-2,4-dimethylthiazol-5-sulfonic acid,
[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazole-4-sulfonic acid,
(a,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazole-4-sulfonic acid,
ethyl[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-1,2-dimethyl-1H-imidazole-4-sulfonic acid,
ethyl[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-4-methyl-2-propertiesa-5-sulfonic acid,
(2,2,2-triptorelin)[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]medtrans-2,4-dimethylthiazol-5-sulfonic acid,
cyclopropylmethyl[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]medtrans-2,4-dimethylthiazol-5-sulfonic acid,
ethyl[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-2,4-dimethylthiazol-5-sulfonic acid,
TRANS-N-cyclopropylmethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,
TRANS-N-ethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,
(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-5-chloro-1,4-dimethyl-1H-pyrazole-3-sulfonic acid,
[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-5-chloro-1,4-dimethyl-1H-pyrazole-3-sulfonic acid,
TRANS-2-[4-(benzylamino)cyclohexyl]-1,1,1,3,3,3-hexaferrite-2-ol,
TRANS-2-[4-(benzyldimethylamine)cyclohexyl]-1,1,1,3,3,3-hexaferrite-2-ol,
TRANS-2-[4-(benzylisoquinoline)cyclohexyl]-1,1,1,3,3,3-hexaferrite-2-ol,
TRANS-N-benzyl-N-[4-(2,2,2-Cryptor-1 hydroc the and-1-trifloromethyl)cyclohexyl]propionamide,
benzyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-cyclopropanecarboxylic acid,
TRANS-N-cyclopropylmethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzamide,
TRANS-N-cyclopropylmethyl-2-phenyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]acetamide", she
phenyl ether TRANS-cyclopropylmethyl[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]carbamino acid,
benzyl ether of TRANS-cyclopropylmethyl[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)diclohexal]carbamino acid,
(rat)-TRANS-2-{4-[cyclopropylmethyl-(2-hydroxy-2-phenylethyl)amino]cyclohexyl}-1,1,1,3,3,3-hexaferrite-2-ol,
TRANS-benzyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]sulfonamide,
TRANS-benzyl-N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]sulfonamide,
(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide(rat)-TRANS-1-phenylethanolamine acid,
(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide, TRANS-2-phenylpropane-2-sulfonic acid,
(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]amide (rat)-TRANS-1,2-diphenylethanol acid,
methyl ether (rat)-TRANS-3-(2-phenyl-2-{(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)qi is logical]sulfamoyl}ethyl)benzoic acid, and CIS-N-ethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,
and their pharmaceutically acceptable salts.

17. Connection para.12 selected from the group including
TRANS-N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,
TRANS-N-benzyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,
TRANS-N-cyclopropylmethyl-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]benzosulfimide,
TRANS-benzyl-N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl]sulfonamide and
(2,2,2-triptorelin)-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)cyclohexyl] amide, TRANS-2-phenylpropane-2-sulfonic acid,
and their pharmaceutically acceptable salts.

18. Pharmaceutical composition having the properties of modulation LXRα and/or LXRβ agonist comprising the compound according to claim 1 and a pharmaceutically acceptable carrier and/or adjuvant.

19. Compounds according to claim 1, having the properties of modulation LXRα and/or LXRβ agonist.

20. Compounds according to claim 1 as therapeutically active substances for obtaining medicines for the treatment and/or prevention of diseases modulated LXRα and/or LXRβ agonists.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention proposes compound of N-phenylarylsulfonylamide of the formula (I): wherein R1 represents -COOH and so on; R2 represents hydrogen atom, methyl and so on; R3 and R4 represent combination of methyl and methyl and so on; R5 represents isopropyl and so on; Ar represents thiazolyl, pyridyl, 5-methyl-2-furyl wherein each is substituted optionally with methyl; n = 0 or 1, intermediate compound used in synthesis of this compound and a method for its synthesis. Compound of the formula (I) binds with prostaglandin E2 receptors, in particular, with subtype of EP1 and shows antagonistic properties. This compound shows low binding with protein and therefore it possesses the satisfactory activity in vivo. Also, invention claims a method for preparing a pharmaceutical composition possessing antagonistic activity with respect to EP1 receptors that comprises compound of the formula (I) as active component and an inert excipient. Proposed pharmaceutical composition is designated for prophylaxis and/or treatment of pollakiuria (more frequent diuresis) or enuresis.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition, improved method of synthesis.

16 cl, 4 tbl, 3 sch, 270 ex

The invention relates to a method for obtaining compounds of formula I in each case in free form and in salt form, where Q denotes CH or N, Y represents the NO2or CN, Z means СНR3OH , NR3or S, R1and R2each independently of one another denotes hydrogen, unsubstituted or R4-substituted C1-C8alkyl or together form Allenby bridge of two or three carbon atoms, and Allenby bridge may optionally contain a heteroatom selected from the group comprising NR5, O or S, R3means H, unsubstituted or R4-substituted C1-C12lcil, R4means unsubstituted or substituted aryl or heteroaryl, R5means N or C1-C12alkyl, by transformation of compounds of formula II in which R is cyclohexyl, phenyl, benzyl or a group of formula (a)1means a leaving group, using a halogenation agent in the compound of formula IV, where X is halogen, the conversion of the compounds of formula IV by reacting with the compound of the formula V to the compound of formula VI, which is then transformed using glorieuses agent in the compound of formula I

FIELD: chemistry.

SUBSTANCE: compounds of the invention can be used for treating or preventing diseases and conditions, mediated by peroxisome proliferator activated gamma receptor (PPARγ). In formula (I) W represents a COOH group or -COOC-C1-C4alkyl; Y represents NH; Z represents S or O; X represents O; R1-R6 each independently represents a hydrogen atom or substitute, chosen from a group consisting of: C1-C4-alkyl, thienyl or phenyl, where phenyl is optionally substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, a halogen atom; -NO2 and -CN; A represents C1-C4-alkyl, -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, aryl, chosen from a group consisting of phenyl, naphthyl, or heteroaryl, chosen from a group consisting of oxazolyl, isoxazolyl, thienyl, pyridyl, thiazolyl, thiadiazolyl, benzo[b]thienyl, imidazolyl, indolyl and carbazolyl, where aryl and heteroaryl are substituted or not substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, phenyl and a halogen atom; and n is an integer from 0 to 4. The invention also relates to a pharmaceutical composition, containing the invented compound as an active component, use of the compounds to make a medicinal agent, and method of treatment.

EFFECT: obtaining new biologically active compounds.

22 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a malononitrile compound with formula (I): where one of X1, X2, X3 and X4 stands for CR100, where R100 is a group with formula (II) each three of the other X1, X2, X3 and X4 is nitrogen or CR5, under the condition that, from one to three of X1, X2, X3 and X4 stands for nitrogen, Z is oxygen, sulphur or NR6. The malononitrile compound can be used a pesticide in agriculture.

EFFECT: obtaining a new pest control compound and its use as an active ingredient of a pesticide composition.

18 cl, 180 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to α-2A/α-1A selective agonist, which is a compound with formula , as well as to a pharmaceutical composition, which contains a pharmaceutical carrier and a therapeutic effective quantity of α-2A/α-1A selective agonist, which contains a compound with structure 1.

EFFECT: obtaining selective agonist which can be used for preventing or alleviating neurological conditions without an accompanying sedative effect during extraneous administration.

6 cl, 2 tbl, 2 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to the compound of formula I: , where R1, R2 and R3 are equal or different and represent hydrogen, halogen, alkyl, aloxy, hydroxyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group, R4 represents hydrogen, alkyl or alkylaryl group; X represents CH2, oxygen atom and sulphur atom; n represents 2 or 3, and individual (R)- and (S)-enantiomers or the mixture of enantiomers and its pharmaceutically acceptable salts; where alkyl termine denotes straight and branched hydrocarbon chains, containing fro one to six atoms of carbon, optionally substituted by aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl groups, termine aryl denotes phenyl or naphtyl group, optionally substituted alkyloxy group, halogen or nitro group, termine halogen denotes fluorine, chlorine, bromine or iodine. The compounds have valuable pharmaceutical properties and perspectives for the treatment of cardiovascular disorder, such as hypertension and chronic heart failure. The method of production of individual (R)- and (S)-enantiomers or the mixture of enantiomers and pharmaceutically acceptable salts of the compound of formula I, pharmaceutical composition having inhibitor dophamine-β-hydrolaze potency, containing therapeutic effective volume of the compound of formula I, different variants of formula I compound application and intermediate compounds are described.

EFFECT: production of new compounds, imidazole derivatives having useful biological properties.

21 cl, 2 tbl, 46 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to compounds of the formula: , wherein variable value Y in ring is not obligatory and represents heteroatom chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms under condition that N atom is trivalent and O or S atoms are bivalent; k means a whole number from 0 to 1; n means a whole number 0, 1 or 2; p means a whole number 0, 1 or 2; X means O or S atom; dotted lines represent a bond or its absence under condition that ring comprises only a single double bond and two adjoining lines are not a bond; R1, R2, R3 and R represent independently hydrogen atom (H), phenyl wherein indicated phenyl group is substituted optionally with one, two or three substitutes represented by (C1-C6)-alkyl, -SO3H, -N3, halogen atom, -CN, -NO2, -NH2, (C1-C6)-alkoxy-, (C1-C6)-thioalkoxy-, (C1-C6)-alkylamino-, (C1-C6)-dialkylamino-group, (C2-C6)-alkynyl, (C2-C6)-alkenyl; 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms wherein indicated heteroaryl groups are substituted optionally and independently with one, two or three substitutes represented by (C1-C6)-alkyl, -SO3H, -N3, halogen atom, -CN, -NO2, -NH2, (C1-C6)-alkoxy- (C1-C6)-thioalkoxy-, (C1-C6)-alkylamino-, (C1-C6)-dialkylamino-group, (C2-C6)-alkynyl, (C2-C6)-alkenyl, or indicated groups R1, R2, R3 and R4 represent independently alkyl comprising from 1 to 4 carbon atoms, cycloalkyl comprising from 3 to 5 carbon atoms, -CH2CN, -CH2SR5, -CH2NR6R6, -COR5, -CH2OR5, -OR6, -SR6, -NR6R6, alkenyl comprising from 1 to 4 carbon atoms, alkynyl comprising from 1 to 4 carbon atoms, cycloalkyl comprising from 3 to 6 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom, -CF3 or -CN, oxygen atom bound by a double bond with ring carbon under condition that adjoining dotted line inside of ring means absence of a bond; R5 means H, -OR7, alkyl comprising from 1 to 4 carbon atoms, -CF3, cycloalkyl comprising from 3 to 6 carbon atoms, phenyl, phenyl substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3, either R5 represents 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms, and 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atoms, bromine atom, iodine atom or -CF3; R6 means H, alkyl comprising from 1 to 4 carbon atoms, allyl, cycloalkyl comprising from 3 to 6 carbon atoms, phenyl, phenyl substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3, either R6 represents 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms, either 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3; R7 means H, alkyl comprising from 1 to 4 carbon atoms, allyl, cycloalkyl comprising from 3 to 6 carbon atoms, phenyl, phenyl substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3; R1 and R2 or R2 and R3, or R3 and R4 can form in common a ring with corresponding carbon atoms to which they are bound; fragments represented by substitutes R1 and R2 or R2 and R3, or R3 and R4 have the following formulae (i): , (ii): , (iii): , (iv): or (v): - wherein m means a whole number from 0 to 3; R8 represents independently H, alkyl comprising from 1 to 6 carbon atoms, alkenyl comprising from 2 to 6 carbon atoms, alkynyl comprising from 2 to 6 carbon atoms, -SO3H, -N3, -CN, - NO2, F, Cl, Br, J atoms, -CF3, -COR9, -CH2OR9, -OR10, -SR10, (C1-C)-alkylamino- or (C1-C6)-dialkylamino-group wherein R9 means H, alkyl comprising from 1 to 6 carbon atoms, or -OR10 wherein R10 represents independently H or alkyl comprising from 1 to 6 carbon atoms. Also, invention relates to compounds of the formula: and , and to a method for activation of alpha2B- or alpha2C-adrenergic receptors. Invention provides synthesis of novel biologically active compound possessing activity as agonists of alpha-2B and alpha-2C-adrenergic receptors.

EFFECT: valuable medicinal properties of compounds.

34 cl, 5 tbl, 33 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes compound of the general formula (3): wherein R15 represents a heterocyclic group chosen from 3-7-membered saturated or 4,7-membered unsaturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom, or 7-14-membered polycyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R16 represents a cycloalkyl group comprising 3-7 carbon atoms, monocyclic aromatic hydrocarbon group comprising 6-14 carbon atoms, or heterocyclic group chosen from 3-7-membered saturated or 4-7-membered unsaturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R17 represents a monocyclic aromatic hydrocarbon group comprising 6-14 carbon atoms or heterocyclic group chosen from 4-7-membered saturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R18 represents hydrogen atom or (C1-C)-alkyl group; X represents -S-, -SO- or -SO2; or N-oxide or S-oxide of this compound; their salt; or solvate of above described compound. Proposed compounds possess the inhibitory activity against producing/secretion of β-amyloid protein and can be used in treatment of such diseases as Alzheimer's disease, Down's disease and other diseases associated with amyloid deposition.

EFFECT: valuable medicinal properties of inhibitors.

7 cl, 1 tbl, 410 ex

The invention relates to the five-membered heterocycles with biphenylmethanol substitution of formula I

R1means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; CandH2A-phenyl, where a = 0, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, J, CF3, metoxygroup; CdH2d(C3-7-cycloalkyl, where d = 0; R2and R3independently from each other denote hydrogen, F, Cl, J, C=N; COR6where R6denotes hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, OR30where R30- alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; OR7where R7denotes hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; phenyl; or R2and R3, independently of one another, denote CqH2q-phenyl, where q=0; or R2and R3independently from each other mean-SOnR22where n stands for zero, R22- alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; R4and R5independently of one another denote hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, F, Cl, Br, J, CF3and their physiologically acceptable salts; and to medicines, inhibiting Na+dependent Cl-/HCO-3- exchange rate is

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to an improved process for the preparation of compounds of formula III

< / BR>
where R1is hydrogen or heteroaromatic, R2is a group selected from CH2-O-aralkyl, CH2OCO-alkyl, CH2ОСОNН2CH2ОСОРh, CH2LLC-alkyl; R3- C3-alkyl; R4- dichlorophenyl, including interaction of the compounds of formula I

< / BR>
where R1, R2and R3such as defined above, with a compound of formula II: R4-S-Hal, where R4like is definitely above and Hal represents halogen, in the presence of a base

FIELD: medicine.

SUBSTANCE: new compounds of thienopyrazole are described with formula (1) , where R1 means non-substituted C3-C8-cycloalkyl group or tetrahydropyranyl, R2 means non-substituted C1-C3alkyl group, R3 means atom of hydrogen, R4 means various groups mentioned in invention formula. Compounds inhibit PDE 7 and, accordingly, increase cell level of cyclic adenosine monophosphate. Pharmaceutical composition is also described, as well as method for inhibition of PDE, methods for production of compound with formula (1), where R4 means CO2R7, and intermediate compounds.

EFFECT: possibility to use for treatment of various types of such diseases as allergic diseases, inflammatory diseases or immunological diseases.

20 cl, 138 tbl, 440 ex

FIELD: chemistry.

SUBSTANCE: invention relates to antagonists of serotonin 5-HT6 receptors - substituted 4-sulphonylpyrazoles and 3-sulphonyl-pyrazolo[1,5-a]pyrimidines of general formula 1 or general formula 1.2. These compounds can be used for treating and preventing development of different cognitive and neurodegenerative diseases of the central nervous system. In general formulae 1 and 1.2, 1 1.2 respectively, Ar is optionally substituted phenyl or optionally substituted 5-6-member heteroaryl, containing a nitrogen, oxygen or sulphur atom as a heteroatom; R1 is a hydrogen atom, optionally substituted C1-C5 alkyl, lower acyl or optionally substituted phenyl; R2 is an optionally substituted amino group or substituted hydroxy group or R1, together with the nitrogen atom to which it is bonded, and R2, together with the carbon atom to which it is bonded, form a substituted pyrimidine ring; R3 is a hydrogen atom, optionally substituted C1-C5alkyl, substituted hydroxyl group or substituted sulphanyl group, R5 is a hydrogen atom, optionally substituted C1-C5alkyl, substituted hydroxyl group or substituted sulphanyl group, R7 and R9 independently represent a hydrogen atom, C1-C3alkyl or phenyl, R8 is a hydrogen atom.

EFFECT: new compounds have useful biological properties.

13 cl, 2 dwg, 4 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel malononitryl derivatives of formula (I), which can be applied to fight pest insects. In formula (I) R1 represents hydrogen atom; R2 represents hydrogen atom; R represents hydrogen atom; R4 represents C1-C5-alkyl group substituted with at least one halogen atom, C2-C5-alkenyl group; R5 represents hydrogen atom, halogen atom, C1-C5-alkyl group; at least one of X1, X2 and X3 values represents CR6, the other represent nitrogen atoms; R represents hydrogen atom, halogen atom, cyanogroup, nitrogroup, formyl group, C1-C5-alkyl group optionally substituted with at least one halogen atom, C1-C5-alkyltiogroup, substituted with at least one halogen atom, C2-C6-alkylcarbonyl group substituted with at east one halogen atom, C2-C5-alkoxycarbonyl group or group (CH2)mQ, where m = 0, and Q stands for phenyl; and in case when one of R5 and R6 is bonded with two atoms in adjacent positions or two R6 are bonded with two atoms in adjacent positions, they can be bonded to each other in end positions with formation of C2-C6-alkandiyl group, or C4-C6-alkenediyl group. Invention also relates to composition and method used to fight pest-insects.

EFFECT: obtaining novel malononitryl derivatives of formula (I), which can be applied to fight pest-insects.

11 cl, 90 ex

FIELD: chemistry.

SUBSTANCE: in compounds with formula (1) A is a nitrogen atom or CR4, where R4 is a hydrogen atom, halogen atom; B is a sulphur atom or NR9, where R9 is a hydrogen atom, hydroxyl group, formyl group, C1-6 alkyl group, under the condition that, when A is a nitrogen atom, B is not NH; R1 is a phenyl group, which can be substituted with one or several substitutes, chosen from a group comprising: a halogen atom, C1-10 alkyl group, where C1-10 alkyl group, can optionally be substituted with one or several substitutes, chosen from a group containing a halogen atom; L1 is a bond; X is OR13, where R13 is a hydrogen atom; R2 is a hydrogen atom, C1-10 alkyl group, phenyl group; L2 is a bond, CR34R35 where each of R34 and R35 independently represent a hydrogen atom or C1-4 alkyl group; L3 is a NR19 bond, where R19 is a hydrogen atom; L4 is a bond or NR22, where R22 is a hydrogen atom; Y is an oxygen atom, sulphur atom; and R3 is an aryl group, chosen from phenyl or thienyl, where the aryl group is substituted with a substitute, chosen from a carboxyl group, sulphamide group, C1-4 alkoxycarbonyl group, tetrazole group and possibly also substituted with a substitute, chosen from halogen atoms, nitro, hydroxyl group, C1-10 alkylcarbonylamino group.

EFFECT: higher thrombocyte level.

33 cl, 13 dwg, 7 tbl, 181 ex

FIELD: organic chemistry, medicinal virology, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazole of the formula (I-A):

wherein R1 means (C1-C12)-alkyl that can be optionally substituted with 1-3 substitutes taken among fluorine, chlorine and bromine atoms, (C3-C8)-cycloalkyl, phenyl, pyridyl or (C1-C4)-alkyl substituted with phenyl; R2' means optionally substituted phenyl wherein phenyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano- and nitro-group; R3 means (C1-C12)-alkyl or (C1-C4)-alkoxy-(C1-C4)-alkyl; A' means (C1-C4)-alkyl optionally substituted with phenyl or optionally substituted with 4-pyridyl wherein phenyl or 4-pyridyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH2-U-heterocyclyl wherein U represents O, S or NR'' wherein R'' means hydrogen atom or (C1-C4)-alkyl and wherein heterocyclyl means pyridyl or pyrimidinyl that is optionally substituted with 1-2 substitutes taken among (C1-C4)-alkyl, fluorine, chlorine and bromine atoms, cyano-, nitro-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH(OH)-phenyl; or A' means the group CH=CHW wherein W means phenyl; X means S or O, and their pharmaceutically acceptable salts. These compounds are inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and, therefore, can be used in treatment of HIV-mediated diseases. Also, invention relates to a pharmaceutical composition used in treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 5 tbl, 32 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new heterocyclylsulfonyl alkylcarboxylic acids and their derivatives of the general formula (1): or their pharmaceutically acceptable salts, N-oxides or hydrates possessing the inhibitory effect on kinase activity and to the focused library for search of active leader-compounds comprising at least abovementioned compound. In the general formula 91) W represents optionally substituted heterocyclic radical, among them: pyrrole-3-yl, thiophene-2-yl, isooxazole-4-yl, pyrazole-4-yl, imidazole-4-yl, pyridine-3-yl, 1H-2,4-dioxopyrimidine-5-yl, 2,3-dihydro-1H-indole-5-yl, 2,3-dihydro-1H-indole-7-yl, 1,3-dihydro-2-oxoindole-5-yl, 2,3-dioxo-1H-indole-5-yl, 2-oxo-3H-benzoxazole-6-yl, benzothiazole-6-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazole-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinoline-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxoquinoxaline-6-yl, 3-oxo-4H-benzo[1,4]oxazine-7-yl, 3-oxo-4H-benzo[1,4]thiazine-7-yl, 2,4-dioxo-1H-quinazoline-6-yl, 2,4-dioxo-1,5-dihydrobenzo[b][1,4]diazepine-7-yl or 2,5-dioxo-3,4-dihydrobenzo[b][1,4]diazepine-7-yl; Y represents optionally substituted methylene group; R1 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; n = 1, 2 or 3; or Yn represents carbon atom of optionally substituted (C3-C7)-cycloalkyl or optionally substituted (C4-C7)-heterocyclyl. Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injections placed into pharmaceutically acceptable package.

EFFECT: valuable properties of compounds.

5 cl, 3 sch, 5 tbl, 6 ex

Up!