New piperazine amide derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new piperazine amide derivatives of formula wherein X represents N or CH; Y represents N or CH; R1 represents lower alkyl, phenyl, phenyl-lower alkyl wherein phenyl can be optionally substituted by 1-2 substitutes independently specified in a group consisting of halogen, lower alkyl; R2 represents lower alkyl, phenyl, naphthyl or heteroaryl specified in dimethylisoxazolyl, quinolinyl, thiophenyl or pyridinyl wherein phenyl or heteroaryl are optionally substituted by 1 substitute optionally specified in a group consisting of halogen, lower alkoxy group, fluor-lower alkyl, lower alkoxy-carbonyl and phenyl; R3 represents phenyl, pyridinyl or pyrazinyl wherein phenyl, pyridinyl or pyrazinyl are substituted by 1-2 substituted optionally specified in a group consisting of halogen, lower alkyl and fluor-lower alkyl; R4, R5, R6, R7, R8, R9, R10 and R11 independently represent hydrogen, as well as to their physiologically acceptable salts. These compounds are bound with LXR alpha and LXR beta, and are applicable as therapeutic agents for treatment and/or prevention of high lipid levels, high cholesterol levels, low HDL cholesterol, high LDL cholesterol, atherosclerotic diseases, diabetes, non insulin dependent diabetes mellitus, metabolic syndrome, dislipidemia, sepsis, inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis, liver fibrosis, psoriasis, Alzheimer's disease, etc.

EFFECT: preparing new piperazine amide derivatives.

15 cl, 88 ex

 

The present invention relates to new piperazinone derivative of the formula (I):

where

X represents N or CH;

Y represents N or CH;

R1represents lower alkyl, lower alkoxymethyl alkyl, halogen-lower alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl, aryl, arlinski alkyl, heterocyclyl, heterocyclyl-lower alkyl, heteroaryl or heteroalicyclic alkyl, where cycloalkyl, aryl, heterocyclyl or heteroaryl optionally may be substituted by 1-5 substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxygroup, Vernissage of alkyl and fornessa alkoxygroup;

R2represents lower alkyl, fornisce alkyl, lower alkoxylate alkyl, cycloalkyl, cycloalkyl-lower alkyl, aryl, arlinski alkyl, heterocyclyl, heterocyclyl-lower alkyl, heteroaryl or heteroalicyclic alkyl, where cycloalkyl, aryl, heterocyclyl or heteroaryl optionally may be substituted by 1-5 substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxygroup, Vernissage of alkyl, fornessa alkoxygroup, lower alkoxycarbonyl and phenyl;

R3represents aryl or heteroaryl, where the aryl or heteroaryl may not necessarily be the replacement of the puppy 1-5 substituents, independently selected from the group consisting of halogen, CN, lower alkyl, Vernissage of alkyl, lower alkoxy and fornessa alkoxygroup;

R4, R5, R6, R7, R8, R9, R10and R11independently from each other represent hydrogen or lower alkyl, or

R4and R5linked together, or R6and R7linked together, or R8and R9linked together, or R10and R11linked together to form a ring together with the carbon atom to which they are attached, and-R4-R5-, -R6-R7-, -R8-R9- and/or-R10-R11- represents -(CH2)2-6-;

and their pharmaceutically acceptable salts.

Also the present invention relates to a method for producing the above compounds, pharmaceutical preparations which contain such compounds and to the use of these compounds for the manufacture of pharmaceutical products.

X-receptors of the liver (LXR) are members of the superfamily of nuclear receptors of the hormone. LXR is activated by endogenous oxysterols and glucose and regulate the transcription of genes controlling multiple metabolic pathways of signal transmission. Described two subtypes, LXR and LXR (articles Willy, P.J., and others, Genes Dev., 1995, 9, s-45; Song, S. and others, Proc Natl Acad Sci USA, 1994, 91, SS-13). LXR expressive is commonplace, while LXR preferably is expressed in tissues, metabolizing cholesterol such as liver, adipose tissue, intestine and macrophages. LXR modulate various physiological responses, including the regulation of cholesterol absorption, splitting cholesterol (the synthesis of bile acids) and the transport of cholesterol from peripheral tissues by plasma lipoproteins in the liver. LXR, as it turned out, also regulate genes involved in glucose metabolism, cholesterol metabolism in the brain, cell differentiation and apoptosis, inflammation and infectious diseases (article Geyeregger, R. and others, Cell. Mol. Life. Sci., 2006, 63, s-539).

About half of all patients with coronary artery disease have low plasma concentrations of cholesterol, high density lipoprotein (HDL-C). Terazosina HDL function was first established almost 25 years ago and has stimulated the study of genetic and environmental factors that affect the levels of HDL-C (article Miller NE., Lipids, 1978, 13, s-9). The protective function of HDL cholesterol stems from his participation in a process called reverse transport of cholesterol (article Forrester, J.S., and Shah, R.K., Am. J. Cardiol., 2006, 98, s-49). HDL mediates the excretion of cholesterol from the cells of peripheral tissues, including macrophilia foam cells in atherosclerotic lesions of arterial walls. HDL delivers cholesterol in pecan and bodies, metabolizing Sterol, for conversion into bile acids and cleavage in excrement. Studies have shown that the levels of HDL-C predicts the risk of coronary artery disease regardless of cholesterol levels of low density lipoprotein (LDL-C) (article Gordon, T. and others, Am J Med., 1977, 62, s-14).

Currently, the estimated age number of Americans age 20 and older with HDL-C less than 35 mg/DL is 16% (men) and 5.7% (women). A significant decrease in HDL-C in the present time is achieved by treatment with Niacin in various preparations. However, significant unwanted side effects limit therapeutic potential of this approach.

Found that 90% of the 14 million patients diagnosed with diabetes mellitus type 2 in the United States are overweight or obese, and the majority of patients with diabetes type 2 have violated the concentration of lipoproteins. Studies have shown that the value of total cholesterol > 240 mg/DL is 37% in men with diabetes and 44% in women. The values of LDL->160 mg/DL are 31% and 44%, and HDL-C <35 mg/DL are 28% and 11% in men with diabetes and in women, respectively. Diabetes is a disease in which the patient's ability to control glucose levels in the blood is reduced due to partial degradation of the response to the action of insulin. Diabetes mellitus type II (TD) is also called non-insulin-dependent diabetes mellitus (NIDDM), and as shown, is 80-90% of the total number of patients with diabetes in developed countries. When T2D pancreatic islets of Langerhans continue to produce insulin. However, the target organs for insulin action, mostly muscle, liver and adipose tissue, have shown strong resistance to stimulation by insulin. The body continues to compensate for the production of non-physiological high levels of insulin, which in the end reduced in the later stages of the disease due to depletion and impaired ability of the pancreas to produce insulin. So, T2D is a cardiovascular and metabolic syndrome associated with multiple concomitant diseases, including insulin resistance, dyslipidemia, hypertension, endothelial dysfunction and inflammatory atherosclerosis.

The first line of treatment of dyslipidemia and diabetes currently typically includes low-fat diet and a diet with low content of glucose, exercise, and weight reduction. However, the results may be reduced, and the development of the disease becomes necessary treatment of various metabolic disorders using lipid-modulating agents, such as statins and fibrates for dyslipidemia, and hypoglycemic drugs such as sulfonylureas, Metformin, or substances is a, increasing insulin sensitivity class of preparations of thiazolidinediones (TZD) PPARγ-agonists, insulin resistance. Recent studies show that LXR modulators are compounds with high therapeutic potential, and as such, the LXR modulators improve lipid profile in plasma and increase the levels of HDL-C (article Lund, E.G., and others, Arterioscler. Thromb. Vasc. Biol., 2003, 23, s-77; Mitro, N., and others, Nature, 2007, 445, s.219-23). LXR known to control the outflow of cholesterol from macrofouling foam cells of atherosclerotic plaques, and LXR agonists, as shown, are terazosine agents (article Joseph, S.B., and Tontonoz, P., Curr. Opin. Pharmacol., 2003, 3, p.á192-7). So, the LXR modulators could be an effective drug for the treatment of atherosclerotic disease, which is a cause of cardiovascular morbidity and mortality from stroke and heart disease. Recent studies also show that there is an independent LXR-mediated effect on the activation of insulin in addition to terazosina action (article Cao, G., and others, J Biol Chem., 2003, 278, s-6). So, the LXR modulators can also show excellent therapeutic effectiveness at raising HDL and teresadeca, with additional effects in diabetes compared to currently used drugs.

It was found that h what about the new compounds of the present invention are associated and selectively activate LXR alpha and LXR beta or deaktiveret LXR alpha and LXR beta. Consequently, reduces the absorption of cholesterol content increases HDL cholesterol and decreases inflammatory atherosclerosis. Because of numerous aspects together dyslipidemia and cholesterol homeostasis are associated with LXR modulators, the new compounds of the present invention have an increased therapeutic potential compared to the compounds known from the prior art. Therefore, they can be used for treatment and prophylaxis of diseases which are modulated by LXR agonists alpha and/or LXR beta. Such diseases include elevated levels of lipids 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/fibrosis of the liver, psoriasis and other inflammatory skin diseases, and diseases that have an inflammatory component, such as Alzheimer's disease or impaired/measurable improvement in cognitive function. Moreover, the new compounds of the present invention can be used for the treatment of infectious diseases such as HIV, cancer, and prevention of age and hereditary (for example, illness is targanta) forms of macular degeneration.

Other compounds that bind and activate LXR alpha and LXR beta described previously (for example, international patent application WO 03/099769). However, there is still a need for new compounds with improved properties. The present invention relates to new compounds of formula I that bind to LXR alpha and/or LXR beta. Compounds of the present invention unexpectedly showed improved pharmacological properties compared to the compounds known from the prior art in relation to, for example, metabolic stability, selectivity, bioavailability and activity.

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

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

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

The term "alkyl", alone or in combination with other groups, denotes a branched or linear monovalent saturated aliphatic hydrocarbon radical containing from one to twenty carbon atoms, preferably from one to shestnadc and carbon atoms, more preferably one to ten carbon atoms. The lower alkyl groups as defined below are also preferred alkyl groups.

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

The lower alkyl groups can be substituted, for example, 1-5, preferably 1-3 halogen atoms. Such groups are referred to as "halogen-lower alkyl". Examples of the halogen-lower alkyl groups are, for example, chlorethylene or idproperty group.

The term "fornisce alkyl" refers to lower alkyl groups which are mono - or polyamideimide fluorine. Examples fornessa alkyl groups are, for example, CFH2, CF2H, CF3, CF3CH2, CF3(CH2)2, (CF3)2CH and CF2H-CF2.

The term "alkenyl", alone or in combination with other groups, denotes a linear or branched hydrocarbon residue containing olefinic bond and up to 20, preferably up to 16 carbon atoms. The term "ness the th of alkenyl" denotes a linear or branched hydrocarbon residue, containing olefinic bond and up to 7, preferably up to 4 carbon atoms, such as, for example, 2-propenyl.

The term "amino", alone or in combination, signifies a primary, secondary or tertiary amino group connected through the nitrogen atom of the secondary amino group containing alkyl or cycloalkenyl Deputy, and tertiary amino group containing two identical or different alkyl or cycloalkyl Deputy or two Deputy nitrogen, together forming a ring, such as, for example, -NH2methylaminopropyl, atramentaria, dimethylaminopropyl, diethylaminopropyl, methylaminopropyl, pyrrolidin-1-yl or piperidino etc.

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

The term "alkoxy" denotes a group R'-O-, where R' represents alkyl. The term "lower alkoxy" denotes a group R'-O-, where R' is a lower alkyl.

The term "fornisce alkoxy" denotes a group R ' -O-, where R" represents furnissii alkyl. Examples fornessa of alkoxygroup are, for example, CFH2-O, CF2H-O, CF3-Oh, CF3CH2-Oh, CF3(CH2)2-O (CF3)2SN-O CF 2H-CF2-O.

The term "alkylene" denotes a linear 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, described later, are also preferred alkionovymi groups. The term "lower alkylene" denotes a linear or branched divalent saturated aliphatic hydrocarbon group containing from 1 to 7, preferably from 1 to 6 or from 3 to 6 carbon atoms. Linear alkylene or lower alkylene group are preferred.

The term "aryl", alone or in combination, refers to phenyl or naftilos group, preferably the phenyl group, which optionally may be substituted by 1-5, preferably 1-3 substituents, independently selected from the group consisting of lower alkyl, lower alkoxygroup, halogen, hydroxy-group, CN, CF3, amino, aminocarbonyl, carboxy, NO2dioxo-lower alkylene (forming, for example, benzodioxolyl group), lower alkylsulfonyl, aminosulfonyl, lower alkylsulphonyl, lower alkylcarboxylic, lower alkylsulphonyl-NH, lower alkoxycarbonyl, Vernissage of alkyl, fornessa alkoxygroup, lower alkoxides the th alkyl, cycloalkyl, phenyloxy. Unless otherwise stated, preferred substituents are halogen, lower alkyl, fornisce alkyl, CN, and lower alkoxycarbonyl. In addition, the aryl group preferably may be substituted as defined herein in the description and the claims.

The term "heterocyclyl", separately or in combination, refers to a saturated or partially unsaturated 4-10 membered mono - or bicyclic a heterocycle that contains one or more heteroatoms, preferably from one to three, selected from nitrogen, oxygen and sulfur. Examples of such heterocyclyl groups are piperidinyl, piperazinil, pyrrolidinyl, imidazolidinyl, pyrazolidine, pyranyl, morpholinyl and oxetanyl. Preferred are piperidinyl and pyranyl. Heterocyclyl group optionally may have a Deputy, as described above in relation to the term "aryl". In addition, heterocyclyl group preferably can be substituted as described below in the description and in the claims.

The term "heteroaryl" denotes an aromatic 5-6 membered monocyclic ring or 9-10-membered bicyclic ring which may include 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulphur, such as furyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, isoxazolyl, oxazolyl, oxadiazolyl, imide is alil, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazole, 1,2,3-thiadiazolyl, benzoimidazolyl, indolyl, indazoles, benzothiazoles, benzoxazoles, benzisoxazole, 3-thieno[3,2-C]pyridine-4-yl and chinoline. Preferred heteroaryl groups are isoxazolyl, chinoline, thiophenyl, pyridinyl and pyrazinyl. Heteroaryl group optionally can contain a Deputy, as described above in relation to the term "aryl". In addition, the heteroaryl group preferably can be substituted as described below in the description and in the claims.

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 with organic acids, such as methanesulfonate acid, p-toluensulfonate acid, acetic acid, lactic acid, triperoxonane acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.

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

where

X represents the Wallpaper is N or CH;

Y represents N or CH;

R1represents lower alkyl, lower alkoxymethyl alkyl, halogen-lower alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl, aryl, arlinski alkyl, heterocyclyl, heterocyclyl-lower alkyl, heteroaryl or heteroalicyclic alkyl, where cycloalkyl, aryl, heterocyclyl or heteroaryl optionally can be substituted by 1-5 substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxygroup, Vernissage of alkyl and fornessa alkoxygroup;

R2represents lower alkyl, fornisce alkyl, lower alkoxylate alkyl, cycloalkyl, cycloalkyl-lower alkyl, aryl, arlinski alkyl, heterocyclyl, heterocyclyl-lower alkyl, heteroaryl or heteroalicyclic alkyl, where cycloalkyl, aryl, heterocyclyl or heteroaryl optionally can be substituted by 1-5 substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxygroup, Vernissage of alkyl, fornessa alkoxygroup, lower alkoxycarbonyl and phenyl;

R3represents aryl or heteroaryl, where the aryl or heteroaryl optionally can be substituted by 1-5 substituents independently selected from the group consisting of halogen, CN, lower alkyl, Vernissage of alkyl, lower alkoxy and fornessa alkoxy PPI;

R4, R5, R6, R7, R8, R9, R10and R11independently from each other represent hydrogen or lower alkyl, or

R4and R5linked together, or R6and R7linked together, or R8and R9linked together, or R10and R11linked together to form a ring together with the carbon atom to which they are attached, and-R4-R5-, -R6-R7-, -R8-R9- and/or-R10-R11- represents -(CH2)2-6-;

and their pharmaceutically acceptable salts.

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

The compounds of formula (I) contain one or more asymmetric C 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 compounds in which X represents N. in Other preferred compounds are compounds in which X represents CH. In addition, preferred compounds in which Y is N.

Other preferred compounds of the present and the gain are compounds in which R1represents lower alkyl, aryl or arlinski alkyl, where aryl optionally substituted by 1-3 substituents, independently selected from the group consisting of halogen and lower alkyl. More preferably, R1represents lower alkyl or phenyl, where phenyl optionally substituted by 1 or 2 substituents, independently selected from the group consisting of halogen and lower alkyl. Even more preferably, R1represents n-butyl, phenyl, 4-fluoro-2-were, 2nd were, 4-forfinal, 2-fluoro-4-were or 2,4-differenl.

Another preferred implementation of the present invention relates to compounds of formula (I) as described above, where R2represents lower alkyl, aryl or heteroaryl selected from the group consisting of isoxazolyl, chinoline, thiophenyl and pyridinyl, where the aryl or heteroaryl optionally substituted by 1-3 substituents, independently selected from the group consisting of halogen, lower alkyl, lower alkoxygroup, Vernissage of alkyl, lower alkoxycarbonyl and phenyl. Preferably, R2represents lower alkyl, phenyl or heteroaryl selected from the group consisting of chinoline and pyridinyl, where phenyl or heteroaryl optionally substituted by 1 or 2 substituents, independently selected from the group consisting of halo is s, lower alkoxy and Vernissage of alkyl. More preferably, R2represents methyl, isopropyl, 3-methoxyphenyl, 3-chlorophenyl, 2-triptoreline, quinoline-8-yl or pyridin-3-yl.

In addition, preferably, when R3represents aryl or heteroaryl selected from the group consisting of pyridinyl and pyrazinyl, where the aryl or heteroaryl optionally substituted by 1-3 substituents, independently selected from the group consisting of halogen, lower alkyl and Vernissage of alkyl. More preferably, R3represents phenyl or pyrazinyl, where phenyl or pyrazinyl optionally substituted by 1 or 2 substituents, independently selected from the group consisting of halogen and lower alkyl. Even more preferably, R3is a 2.5 dimetilfenil, 2-methyl-5-chlorophenyl, 2,5-dichlorophenyl or 3,6-dimethylpyrazine-2-yl.

In addition, preferably, when at least 4 of R4, R5, R6, R7, R8, R9, R10and R11represent hydrogen. It is also preferred that no more than two of R4-R5-, -R6-R7-, -R8-R9and R10-R11- are linked together by the formation of rings. Particularly preferred compounds in accordance with the present invention are compounds in which R4, R5, R6, R7, R 8, R9, R10and R11represent hydrogen.

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

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

[4-(2,5-dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]metano,

[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano,

(-)-[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano,

[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-(4-o-tailpipes-1-yl)methanon,

[4-(2,5-dichlorophenyl)piperazine-1-yl]-[4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-yl]metano,

[4-(2,5-dimetilfenil)piperazine-1-yl]-[4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-yl]metano,

[4-(3-chlorbenzol hanil)-1-o-tailpipes-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano,

[4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

[4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[1-benzyl-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

(-)-[1-benzyl-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[1-benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[1-benzyl-4-(3,5-dimethylisoxazol-4-sulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[4-(3-chlorobenzenesulfonyl)-1-propylpiperidine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[1-butyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[4-(3-chlorobenzenesulfonyl)-1-pentylpyridine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[4-(3-chlorobenzenesulfonyl)-1-isobutylpyrazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[4-(3-chlorobenzenesulfonyl)-1-feiticeira-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[4-(4-chlorobenzenesulfonyl)-1-pentylpyridine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[1-butyl-4-(4-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[4-(4-chlorobenzenesulfonyl)-1-phenylpiperazin-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-ylmethanone,

[4-(2-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano,

[4-(2-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

[4-(2-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[4-(2,5-dichlorophenyl)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-yl]metano,

[4-(2,5-dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-yl]metano,

[1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-yl]-[4-(3-triptorelin-2-yl)piperazine-1-yl]metano,

[4-(2,5-dichlorophenyl)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-yl]metano,

[4-(2,5-dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-yl]metano,

[4-(2,5-dichlorophenyl)piperazine-1-yl]-[4-(propane-2-sulfonyl)-1-o-tailpipes-2-yl]metano,

[4-(biphenyl-4-sulfonyl)-1-o-tailpipes-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano,

methyl ester of 3-{3-[4-(2,5-dichlorophenyl)piperazine-1-carbonyl]-4-o-tailpipes-sulfonyl}thiophene-2-carboxylic acid,

[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon,

[1-benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon,

[4-(3-chlorophenyl)piperidine-1-yl]-[1-(4-fluoro-2-were)-4-(propane-2-sulfonyl)piperazine-2-yl]metano,

[4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon,

CIS-[4-(2,5-dimetilfenil)piperazine-1-yl]-[-1-(3-methoxybenzenesulfonyl)-4-phenylpiperidine-3-yl]metano,

[4-(2,5-dimetilfenil)piperazine-1-yl]-[(3S,4S)-1-(3-methoxybenzenesulfonyl)-4-phenylpiperidine-3-yl]metano,

[TRANS-1-(3-chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[TRANS-1-(3,5-dimethylisoxazol-4-sulfonyl)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[4-(2,5-dimetilfenil)piperazine-1-yl]-[(3S,4S)-1-(3-methoxybenzenesulfonyl)-4-o-tripeptides-3-yl]metano,

[(3S,4S)-1-(3-chlorobenzenesulfonyl)-4-o-tripeptides-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[4-(2,5-dimetilfenil)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-o-tripeptides-3-yl)methanon,

[(3S,4S)-1-(3-chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[4-(2,5-dimetilfenil)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-phenylpiperidine-3-yl)methanon,

[(3R,4R)-1-(3-chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[4-(2,5-dimetilfenil)piperazine-1-yl]-[(3S,4R)-1-(3-methoxybenzenesulfonyl)-4-o-tripeptides-3-yl]metano,

[(3S,4S)-1-(3-chlorobenzenesulfonyl)-4-(4-forfinal)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-(4-forfinal)-1-(2-trifloromethyl)piperidine-3-yl]metano,

[(3S,4R)-1-(3-chlorobenzenesulfonyl)-4-(4-forfinal)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

[(3S,4R)-1-(2-chlorobenzenesulfonyl)-4-(4-forfinal)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-(4-forfinal)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,

[(3S,4S)or (3R,4R)-1-(3-chlorobenzenesulfonyl)-4-(2-fluoro-4-were)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

[(3S,4S)or (3R,4R)-1-(2-chlorobenzenesulfonyl)-4-(2-fluoro-4-were)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

(3S,4S)or (3R,4R)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)-1-(2-trifloromethyl)piperidine-3-yl]metano,

(3S,4S)or (3R,4R)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,

(3S,4S)or (3R,4R)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)-1-(propane-2-sulfon the l)piperidine-3-yl]metano,

[(3S,4R)-1-(3-chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-phenyl-1-(2-trifloromethyl)piperidine-3-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-phenyl-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,

[(3S,4R)-1-(3-chlorobenzenesulfonyl)-4-o-tripeptides-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-o-tolyl-1-(2-trifloromethyl)piperidine-3-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-1-(pyridine-3-sulfonyl)-4-o-tripeptides-3-yl]metano,

[(3S,4R)- or (3R,4S)-1-(3-chlorobenzenesulfonyl)-4-(2,4-differenl)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

(3S,4R)- or (3R,4S)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2,4-differenl)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,

[(3S,4S)-1-(3-chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-phenyl-1-(2-trifloromethyl)piperidine-3-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-phenyl-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-phenyl-1-(propane-2-sulfonyl)piperidine-3-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-penilee the one-3-yl)methanon,

[(3S,4S)-1-(3-chlorobenzenesulfonyl)-4-o-tripeptides-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-o-tolyl-1-(2-trifloromethyl)piperidine-3-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-1-(pyridine-3-sulfonyl)-4-o-tripeptides-3-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-o-tripeptides-3-yl)methanon,

[(3S,4S)or (3R,4R)-1-(3-chlorobenzenesulfonyl)-4-(4-fluoro-2-were)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)-1-(2-trifloromethyl)piperidine-3-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)-1-methanesulfonamido-3-yl]metano,

[(3S,4S)or (3R,4R)-1-(3-chlorobenzenesulfonyl)-4-(2,4-differenl)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-(2-trifloromethyl)piperidine-3-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)--methanesulfonanilide-3-yl]metano and

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-(propane-2-sulfonyl)piperidine-3-yl]metano,

and their pharmaceutically acceptable salts.

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

[4-(2,5-dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]metano,

[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano,

[4-(2,5-dimetilfenil)piperazine-1-yl]-[4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-yl]metano,

[4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[1-butyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,

[4-(2,5-dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-yl]metano,

[4-(2,5-dichlorophenyl)piperazine-1-yl]-[4-(propane-2-sulfonyl)-1-o-tailpipes-2-yl]metano,

[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon,

[4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon,

[4-(2,5-dimetilfenil)piperazine-1-yl]-[(3S,4R)-1-(3-methoxybenzenesulfonyl)-4-o-tripeptides-3-yl]metano,

[4-(chlor-2-were)piperazine-1-yl]-[(3S,4R)-4-(4-forfinal)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,

(3S,4S)or (3R,4R)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)-1-(2-trifloromethyl)piperidine-3-yl]metano,

[(3S,4R)-1-(3-chlorobenzenesulfonyl)-4-o-tripeptides-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,

(3S,4R)- or (3R,4S)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2,4-differenl)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano and

[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-methanesulfonamido-3-yl]metano

and their pharmaceutically acceptable salts.

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

The present invention further relates to a method for producing compounds of formula (I) as described above, which includes:

a) reaction of compounds of formula (II):

with the compound of the formula (III):

,

or

b) reaction of compounds of formula (IV):

connection R2SO2Cl,

where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11X and Y are as defined above.

The above reaction can be carried out in the condition is s, well-known specialist in the art, for example as described below in schemes 2, 3 and 4.

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

The compounds of formula (I) can be obtained by methods known from the prior art, or as described below in schemes 1-4, or similar to that described below. All starting materials are either commercially available, described in the prior art, or can be obtained by methods known from the prior art, or by methods similar to those described hereinafter. Unless otherwise stated, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11X and Y are as defined above.

Specialist in the art it is clear that to obtain enantiomerically pure products should be used in enantiomerically pure starting materials. Additionally, the compounds of formula (I) can be divided into enantiomerically pure compounds by chromatography on a chiral HPLC column, chromatography with a chiral eluent or by crystallization using diastereomeric salts.

Obtaining raw materials to piperazine derivatives of the formula (I)in which X=N, is rivelino in figure 1. The synthesis begins with chloroacetanilide 2 and benzylamine 3, which in turn N-benzyl-2-chloracetamide 4 in the presence of bases, such as triethylamine, N,N-diisopropylethylamine or N-ethylmorpholine, in solvents such as diethyl ether or tetrahydrofuran, at room temperature (stage a). Compound 4 can be converted to amine 5 with an excess of the appropriate amine or amine derivatives NH2R1in a suitable solvent such as DMA or DMF, at a temperature from CT to 100°C in the presence of a base such as triethylamine or N,N-diisopropylethylamine (stage b). Reconnection 5 complex with borane-tetrahydrofuran leads to the production of amine 6, which in turn piperazine derivatives 8 and 9 processing esters of 2,3-dibromopropionate acid 7 in the presence of bases, such as triethylamine or N,N-diisopropylethylamine in toluene at boiling (stage d).

Scheme 2 describes the synthesis of compounds of General formula (I)in which X=N, from the intermediate compound 8. Compound 8 can be converted to acid 10 in 3 stages: Cleavage of benzyl residue by hydrogenation in a solvent, such as methanol, ethanol, ethyl acetate, using Pd/C (stage a), sulfonylamine unprotected piperazine-sulphonylchloride in solvents such as dichlo is methane, THF, DMF or dioxane, with bases, such as N-ethyldiethanolamine or triethylamine, optionally in the presence of DMAP, at a temperature from 0°C to room temperature (stage b), then saponification of ester by treatment with sodium hydroxide or lithium hydroxide in a solvent such as water, methanol, ethanol, tetrahydrofuran or mixtures thereof, at temperatures from 0°C to 60°C.

The condensation of compounds 10 and 11 with compounds of formula (I) can be carried out using well-known methods of education amide using condensing agents, such as hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI), hexaflurophosphate 2-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (HBTU), tetrafluoroborate O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N,N-tetramethylurea (TPTU), hexaphosphate O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium (HATU) or hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (THIEF), in the presence of a base, such as ethyldiethanolamine, triethylamine, N-methylmorpholine, optionally in the presence of 4-dimethylaminopyridine or 1-hydroxybenzotriazole (HOBt) in a solvent such as dichloromethane, dimethylformamide, dimethylacetamide or dioxane, at temperatures from 0°C to room temperature (stage g). The alternative, can be used two-step method: the treatment of acid 10 oxalylamino in CH Cl2in the presence of DMF or thionyl chloride in toluene, followed by reaction with amine 11. Alternatively, the acid 10 can be condensed with the amine 11b (Y=N) to obtain a secure connection 12. Cleavage of the protective group (PG) can be carried out in acidic conditions, such as TFUK in CH2Cl2or HCl in dioxane for the BOC-group (stage d). Compound 13 can be converted into compounds of formula (I) processing halogenguidesrealestate substances in the presence of bases, such as N,N-Diisopropylamine or triethylamine in solvents such as DMF or acetonitrile, heteroaromatic groups, R3. For compounds with R3= aryl can be used in the amination reaction of Buchwald-Hartwig (for example, aryl-LG (LG = Br, Cl, I, triflate), Pd(OAc)2, 2-(dicyclohexylphosphino)biphenyl, NaOBu in toluene or Tris(dibenzylideneacetone)dipalladium, 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane, tert-butyl sodium in toluene).

In an alternative method, a derivative of piperazine 8 make a secure connection 14 the removal of benzyl residue by hydrogenation in a solvent, such as methanol, ethanol, ethyl acetate, using Pd/C (stage a), with subsequent N-BOC-protected using di-tert-BUTYLCARBAMATE in solvents such as diethyl ether, THF or CH2Cl2not necessarily in p is outstay DMAP, at room temperature (stage g). The alternative, can be used single-stage method. Hydrogenation in methanol or ethanol using Pd/C as catalyst in the presence of di-tert-BUTYLCARBAMATE and amine, such as triethylamine or diisopropylethylamine results directly connection 14. Saponification of ester 14 or 8 by treatment with sodium hydroxide or lithium hydroxide in a solvent such as water, methanol, ethanol, tetrahydrofuran or mixtures thereof, at temperatures from 0°C to 60°C results in acid 15 (stage b). The condensation of compounds 15 and 11 in amides 16 can be carried out as described for compound 10, the known methods of education amide using condensing agents, such as hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI), hexaflurophosphate 2-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (HBTU), tetrafluoroborate O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N,N-tetramethylurea (TPTU)hexaphosphate O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium (HATU) or hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (THIEF), in the presence of a base, such as ethyldiethanolamine, triethylamine, N-methylmorpholine, optionally in the presence of 4-dimethylaminopyridine or 1-hydroxybenzotriazole (HOBt) in a solvent such as dichloromethane, dimethylformamide, demethylate the amide or dioxane, at a temperature of from 0°C. to room temperature (stage g). The alternative, can be used two-step method: the treatment of acid 10 oxalylamino in CH2Cl2in the presence of DMF or thionyl chloride in toluene, followed by reaction with amine 11. Compound 16 can be converted into compounds of formula (I) in two stages: cleavage of the protective group under acidic conditions, such as TFUK in CH2Cl2or HCl in dioxane to RE-group or by hydrogenation in a solvent, such as methanol, ethanol, ethyl acetate, using Pd/C for benzyl groups (stage C), with subsequent sulfonylamine unprotected piperazine with sulphonylchloride in solvents such as dichloromethane, THF, DMF or dioxane, with bases, such as N-ethyldiethanolamine or triethylamine, optionally in the presence of DMAP, at a temperature from 0°C to room temperature (stage b).

Figure 3 describes another method of synthesis of compounds of formula (I). Monodimensional connection 17 in connection 18a is carried out in accordance with a method described in the article S.Gubert*, .Braojos, A.Sacristán, J.A.Ortiz, Synthesis, 1991, s (stage a: 1) 1-chloroethylphosphonic, dichloroethane, boiling; 2) Meon, boiling). Sulfonylamine unprotected piperazine 18a or 18b by sulphonylchloride in solvents such as dichloromethane, THF, DMF and the and dioxane, with bases, such as N-ethyldiethanolamine or triethylamine, optionally in the presence of DMAP, at a temperature from 0°C to room temperature (stage b), with subsequent saponification of ester by treatment with sodium hydroxide or lithium hydroxide, in a solvent such as water, methanol, ethanol, tetrahydrofuran or mixtures thereof, at temperatures from 0°C to 60°C results in acid 20 (stage b). Getting amide 21 or 22 can be carried out by condensation of the acid 20 with the connection 11 or 11b, respectively, as described for compound 10, using condensing agents, such as hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI), hexaflurophosphate 2-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (HBTU), tetrafluoroborate O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N,N-tetramethylurea (TPTU), hexaflurophosphate O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium (HATU) or hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (THIEF), in the presence of a base, such as ethyldiethanolamine, triethylamine, N-methylmorpholine, optionally in the presence of 4-dimethylaminopyridine or 1-hydroxybenzotriazole (HOBt) in a solvent such as dichloromethane, dimethylformamide, dimethylacetamide or dioxane, at temperatures from 0°C to room temperature (stage g). Cleavage of the protective group (PG) can be carried out in acidic conditions, that is as TFUK in CH 2Cl2or HCl in dioxane for the BOC-group (stage d). Compound 23 can be converted to compound 21 (stage e) processing halogenguidesrealestate compounds in the presence of bases, such as N,N-Diisopropylamine or triethylamine in solvents such as DMF or acetonitrile to heteroaromatic groups R3. To connect with R3= aryl can be used in the amination reaction of Buchwald-Hartwig (for example, Pd(OAc)2, 2-(dicyclohexylphosphino)biphenyl, NaOBu in toluene or Tris(dibenzylideneacetone)dipalladium, 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane, tert-butyl sodium in toluene). Cleavage of benzyl residue by hydrogenation in a solvent, such as methanol, ethanol, ethyl acetate, using Pd/C (stage C), followed by alkylation with R1-LG' LG' = leaving group such as Cl, Br, I, mesilate, toilet or triflate), in the presence of a base such as potassium carbonate or cesium carbonate, in a solvent such as acetone, DMF or DMA, leads to the formation of compounds (I). For compounds with R1= aryl can be used in the amination reaction of Buchwald-Hartwig (for example, aryl-LG (LG = Br, Cl, I, triflate), Pd(OAc)2, 2-(dicyclohexylphosphino)biphenyl, NaOBu in toluene or Tris(dibenzylideneacetone)dipalladium, 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane, the pet-butyl sodium in toluene).

Scheme 4 describes the formation of compounds of formula (I) with X=C. on the Basis of commercially available compounds 24, cleavage of benzyl residue by hydrogenation in methanol or ethanol using Pd/C as catalyst in the presence of di-tert-BUTYLCARBAMATE and amine, such as triethylamine or diisopropylethylamine, results in compound 25 (stage a). Taltigolt 26 can be obtained from compound 25 by treatment with N-phenyltrimethylammonium in the presence of bases such as NaH, KN or NaN(TMS)2in solvents such as diethyl ether, THF or DMF (stage b). Paladikulama cross-condensation of anatifera 26 with tsinkorganicheskih halides R1ZnBr or R1ZnCl in THF, DMF or mixtures at 65°C in the presence of

bis(dibenzylideneacetone)palladium(0) [Pd(dba)2]

bis(diphenylphosphino)ferrocene (dppf) yields a connection 27.

Alternatively, it may be R1boric acid in the presence of LiCl, bases, such as Na2CO3To2CO3and catalysts, such as

Tris(dibenzylideneacetone)dipalladium(0) or

tetrakis(triphenylphosphine)palladium(0) in 1,2-dimethoxyethane, 1,2-diethoxyethane toluene, or THF, or R1stannane in the presence

Tris(dibenzylideneacetone)diplegia(0) or

tetranitroaniline)palladium(0) in solvents, such as THF,

diethyl ether or toluene (stage b). Saponification of ester 27 by treatment with sodium hydroxide or lithium hydroxide in a solvent such as water, methanol, ethanol, tetrahydrofuran or mixtures thereof, at temperatures from 0°C to 60°C leads to the production of acid 28 (stage g). Hydrogenation of the acid 28 using Pd/C as catalyst in solvents such as methanol, ethanol, ethyl acetate or THF, leads to obtain the desired intermediate compound 29 (stage d), which can be divided into CIS - and TRANS-products. Further separation of the enantiomers can be chiral HPLC or crystallization of diastereomeric salts derived from acids 29 with chiral bases. Enantiomerically enriched or pure CIS-piperidine (R1= aryl, heteroaryl) can be obtained by enantioselective hydrogenation using ruthenium catalyst, such as [Ru(SLA)2((R)-2-furyl)-MeOBIPHEP)], with the addition of, for example, triethylamine and a solvent such as methanol, for about 42 hours at a temperature of 20-80°C at 40 bar of hydrogen. Appropriate transpeptidase can be obtained from the CIS-compounds selective epimerization of the chiral center α to the carboxyl group, using three-stage methodology: the formation of ester in Mitsunobu with alcohol, triphenylphosphine and IER is justicability (DEAD) or diisopropylcarbodiimide (DIAD) in THF, the epimerization of sodium alcoholate in toluene at boiling, followed by saponification of ester in basic conditions by treatment with sodium hydroxide or lithium hydroxide in a solvent such as water, methanol, ethanol, tetrahydrofuran or mixtures thereof.

Getting amide 30 can be carried out by condensation of the acid 29 connection 11 as described for compound 10 using condensing agents, such as hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI), hexaflurophosphate 2-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (HBTU), tetrafluoroborate O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N,N-tetramethylurea (TPTU), hexaflurophosphate O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium (HATU) or hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (THIEF), in the presence of a base, such as ethyldiethanolamine, triethylamine, N-methylmorpholine, optionally in the presence of 4-dimethylaminopyridine or 1-hydroxybenzotriazole (HOBt) in a solvent such as dichloromethane, dimethylformamide, dimethylacetamide or dioxane, at temperatures from 0°C to room temperature (stage e).

Cleavage of the protective group (PG) can be carried out in acidic conditions, such as TFUK in CH2Cl2or HCl in dioxane for the BOC-group (stage g). Sulfonylamine unprotected piperidine-sulphonylchloride in solvents such as dichloro the Academy of Sciences, THF, DMF or dioxane, with bases, such as N-ethyldiethanolamine or triethylamine, optionally in the presence of DMAP at a temperature of from 0°C. to room temperature, leads to the formation of compounds of formula (I) (stage C).

The transformation of compounds of formula (I) into a pharmaceutically acceptable salt can be carried out by treatment of such compounds, inorganic acid, for example, halogen acid, such as, for example, hydrochloric acid or Hydrobromic acid, or other inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, etc. or organic acid, such as, for example, acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulfonate acid or n-toluensulfonate acid. One way of obtaining such salts include, for example, adding 1/n of acid equivalent, where n = the number of acid groups of the acid to a solution of the compound in a suitable solvent (e.g. ethanol, a mixture of ethanol-water mixture of tetrahydrofuran-water) and removal of solvent by evaporation or lyophilization.

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

As described above, it was found that the new compounds of the present invention are associated and selectively activate LXR alpha and LXR beta or deaktiveret LXR alpha and LXR beta. Consequently, reduces the absorption of cholesterol, increases HDL cholesterol and decreases inflammatory atherosclerosis. Therefore, they can be used for treatment and prophylaxis of diseases which are modulated by LXR agonists alpha and/or LXR beta. Such diseases include elevated levels of lipids and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases such as colitis, pancreatitis, cholestasis/fibrosis of the liver, psoriasis and other inflammatory skin diseases, and diseases that have an inflammatory component, such as Alzheimer's disease or impaired/measurable improvement in cognitive function. Moreover, the new compounds of the present invention can be used for the treatment of infectious diseases such as HIV and cancer, and prevention of age and hereditary (for example, b is disease of Stargardt) forms of macular degeneration.

Therefore, the present invention also relates to pharmaceutical compositions comprising a compound as described above and a pharmaceutically acceptable carrier and/or adjuvant.

Also the present invention includes compounds as described above for use as therapeutically active substances, especially as therapeutically active substances for the treatment and/or prevention of diseases which are modulated by LXR agonists alpha and/or LXR beta, especially 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, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, liver fibrosis, psoriasis, Alzheimer's disease, weakened/measurable improvement in cognitive function, HIV, cancer, age-related forms of macular degeneration, inherited forms of macular degeneration and/or illness of Stargardt.

In another preferred embodiment, the present invention relates to a method of therapeutic and/or prophylactic treatment of ill the deposits, modulated by agonists of LXR alpha and/or LXR beta, especially 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, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, liver fibrosis, psoriasis, Alzheimer's disease, weakened/measurable improvement in cognitive function, HIV, cancer, age-related forms of macular degeneration, inherited forms of macular degeneration and/or illness of Stargardt, which includes the introduction of a compound as defined above to a human or animal.

The present invention also includes the use of compounds as defined above for therapeutic and/or prophylactic treatment of diseases which are modulated by LXR agonists alpha and/or LXR beta, particularly 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, Sep the ISA, inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, liver fibrosis, psoriasis, Alzheimer's disease, weakened/measurable improvement in cognitive function, HIV, cancer, age-related forms of macular degeneration, inherited forms of macular degeneration and/or illness of Stargardt.

The present invention also relates to the use of compounds as defined above for the manufacture of drugs for therapeutic and/or prophylactic treatment of diseases which are modulated by LXR agonists alpha and/or LXR beta, particularly 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, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, liver fibrosis, psoriasis, Alzheimer's disease, weakened/measurable improvement in cognitive function, HIV, cancer, age-related forms of macular degeneration, inherited forms of macular degeneration and/or illness of Stargardt. Such medicines include Obedinenie as defined above.

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

The following tests are carried out for determining the activity of compounds of the present invention. Information from the prior art about the ongoing analy described in the article: Nichols JS, and others, "Development of a scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain", Anal Biochem., 1998, 257, s.112-119.

The expression vectors of the mammal designed for expression poliocephala LXR alpha and LXR beta man. Vectors for bacterial expression designed to obtain labeled variants of the domain, a ligand-binding (LBD) LXR-alpha (amino acids 164 to 447) and LXR beta human (amino acids 155 to 460). For this part of the sequences encoding the LBD, amplified from poliocephala clones using PCR and then subcloned into plasmid vectors. The final clones were verified by analysis of p the coherence DNA (articles Willy and others, Genes Dev., 1995, 9, s-45; Song and others, Proc Natl Acad Sci USA, 1994, 91, s-13).

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

Analysis of the binding of radioligands

The binding of receptor LXR alpha and LXR beta was carried out in a buffer containing 50 mm HEPES, pH 7.4, 10 mm NaCl, 5 mm MgCl2. For each 96-well reaction, 500 ng of protein LXRα-LBD or 700 ng LXRβ-LBD bound with 80 µg or 40 µg SPA pellets, respectively, in a final volume of 50 ál with shaking. The obtained suspension were incubated for 1 h at RT and centrifuged for 2 min at 1300×g. The supernatant containing unbound protein was removed and the dry residue containing coated with receptor pellets re-suspended in 50 µl of buffer. Added radioligand (for example, 100,000 dpm (N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]benzosulfimide)), and the reaction mixture was incubated at RT for 1 h in the presence of test compounds, and then carried scintillation proximal processing. All analyses on binding was carried out in 96-well tablets, and the amount of bound ligand was measured on a Packard TopCount using OptiPlates (Packard). Curves of the dose was measured in the concentration range from 10-10M to 10-4M

Analysis the s with transcriptional reporter gene luciferase

The kidney cells of young hamsters (VNC ADS CCL10) were grown in DMEM containing 10% FBS at 37°C in an atmosphere of 95% O2:5% CO2. Cells were planted in 6-hole tablets with a density of 105cells/well and then portions were transferrable or plasmid expression poliocephala LXRα or poliocephala LXRβ plus a reporter plasmid expressing the luciferase under the control elements of the LXR response. The transfection was carried out with reagent Fugene 6 (Roche Molecular Biochemicals) according to the proposed Protocol. Six hours after transfection the cells were collected by trypsinization and were planted in 96-well tablets with a density of 104cells/well. After 24 hours, the binding of cells the medium was removed and replaced by 100 μl of medium containing no phenol red, containing a test substance or reference ligand (final concentration of DMSO is 0.1%). After incubation of cells for 24 hours with substances unloaded 50 μl of the supernatant, and then add 50 ál of luciferase continuous light (Roche Molecular Biochemicals) for lysis of cells and initiation of the reaction with luciferase. The luminescence measured as luciferase activity was determined on a Packard TopCount. Transcriptional activation in the presence of the test substance was expressed as the ratio of changes in luminescence compared to the luminescence of the cells, inkubirovanija no substance. Values EU50was calculated using XLfit (ID Business Solutions Ltd. UK).

The compounds of formula (I) have activity in at least one of the above tests (ES or IC50) ranging from 1 nm to 100 μm, preferably from 1 nm to 10 μm, more preferably from 1 nm to 1 μm.

For example, the following compounds shown by the following IC50 values in the analysis of the binding:

ExampleLinking LXR
IC50[µmol/l]
Linking LXR
IC50[µmol/l]
418,00,72
84,10,77
87the 15.62,8

These results were obtained using the above described test.

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

Manufacture of pharmaceutical preparations can be effected in a manner which is known to any expert in the art by introducing described compounds of formula I and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a form for herbal injection together with suitable, non-toxic, inert, therapeutically compatible solid or liquid materials of the carrier, and, if necessary, with the usual pharmaceutical adjuvants.

Suitable materials media are not only inorganic materials media, but also organic materials media. So, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts can be used as materials of media tablets, coated tablets, dragées and hard gelatin capsules. Suitable materials media for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-liquid and liquid is alioli (depending on the nature of the active ingredient carriers, however, may not be required for soft gelatin capsules). Suitable materials of the carrier for the manufacture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and the like. Appropriate media materials for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable materials media for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable materials media for local 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, moisturizing and emulsifying agents that improve the consistency of agents that improve the smell of agents, salts for regulating the osmotic pressure, buffer substances, soljubilizatory, dyes and masking agents and antioxidants are used as pharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limits depending on the controlled disease, age and individual condition of the patient and the route of administration, and, of course, will be determined in accordance with the individual who requirements in each particular case. For adult patients used daily dosage of from about 1 to 2000 mg, especially from about 1 to 500 mg depending on the severity of the disease and the precise pharmacokinetic profile of the compound may be one or more dosage units per day, for example, 1 to 3 dosage units.

Pharmaceutical compositions typically contain about 1-500 mg, preferably 1-200 mg of the compounds of formula I.

The following examples serve to further illustrate the present invention. However, they are in no way intended to limit its scope.

Examples

Reduction

BOC = tert-butyloxycarbonyl, DEAD = diethylazodicarboxylate, DMF = dimethylformamide, HBTU = hexaphosphate 2-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea, TWO = tert-butyl methyl ether, THF = tetrahydrofuran, TFUK = triperoxonane acid.

Ligands:

td align="justify"> 3,5-Xyl,4-MeO-MeOBIPHEP1)
MeOBIPHEP1)(6,6'-Dimethoxy[1,1'-biphenyl]-2,2'-diyl)bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphine)
2-Furyl-MeOBIPHEP1)(6,6'-Dimethoxybiphenyl-2,2'-diyl)bis(di-2-furifosmin)
BITIANP2)3,3'-bidimensional-1H,1 N-[4,4']-beestekraal
(6,6'-Dimethoxy[1,1'-biphenyl]-2,2'-diyl)bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphine)

1) Ligands known from the prior art and/or can be obtained in accordance with examples or by methods described in the documents EP 0398132, WO 92/16535, EP 0104375 or EP 0580331.

2) article Benincori, T.; Brenna, E.; Sannicolo, F.; Trimarco, L.; Antognazza, P.; Cesarotti, E.; Demartin, F.; Pilati, T. J. Org. Chem., 1996, 61, s.

Example 1

[4-(2,5-Dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]metano

Stage 1: 1 tert-Butyl ester 4-(4-fluoro-2-were)piperazine-1,3-dicarboxylic acid (CAS Reg. No.: [499780-10-8]) (100 mg) in DMF (2.5 ml) was treated with 1-(2,5-dimetilfenil)piperazine (62 mg), hexaflurophosphate 2-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (HBTU) (123 mg) and triethylamine (124 μl) at room temperature for 5 hours was Added water, the phases were separated and the inorganic phase was extracted with tert-butylmethylamine ether (TME). The combined organic phases are washed with water and saturated sodium chloride solution, dried (Na2SO4), was filtered and was evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 2:1) yielded tert-butyl ester 3-[4-(2,5-dimetilfenil)piperazine-1-carbonyl]-4-(4-fluoro-2-were)piperazine-1-carboxylic acid as a white solid which substances (143 mg), MS: 511,5 ([M+H]+).

Stage 2: To a solution of tert-butyl ester 3-[4-(2,5-dimetilfenil)piperazine-1-carbonyl]-4-(4-fluoro-2-were)piperazine-1-carboxylic acid (133 mg) in ethanol (5 ml) was added a saturated solution of hydrogen chloride in ethanol (1 ml). The mixture was stirred at room temperature for 2 h and then concentrated to obtain hydrochloride [4-(2,5-dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)piperazine-2-yl]methanone in the form of a crude white solid, MS: 411,5 ([M+H]+).

Stage 3: To a solution of hydrochloride [4-(2,5-dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)piperazine-2-yl]methanone (42 mg) in DMF (1 ml) was added 3-methoxybenzenesulfonamide (21,4 mg) and triethylamine (40 μl). The reaction mixture was stirred at room temperature for 2 h, diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The combined organic phases are washed with water and saturated sodium chloride solution, dried (Na2SO4), was filtered and was evaporated. The crude product was purified column chromatography (SiO2, n-heptane/ethyl acetate 2:1) to give [4-(2,5-dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]methanone (42 mg) as a white solid, MS: 581,3 ([M+H]+).

Example 2

[4-(3-Chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-and the]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Step 1: To a solution of benzylamine (60,3 ml) and triethylamine (96,3 ml) in THF (800 ml) was added chlorocatechol (45,8 ml) at 0°C. the Reaction mixture was left to warm up to the temperature during the night. Added additional chloroacetanilide (4.6 ml) and the stirring continued until the disappearance of starting material. The reaction mixture was filtered, washed with ethyl acetate and concentrated. The crude product was recrystallized from dichloromethane to obtain N-benzyl-2-chloroacetamide (71,6 g) in the form of a whitish solid.

Stage 2: To a solution of N-benzyl-2-chloroacetamide (20 g) in DMF (200 ml) was added 4-fluoro-2-methylaniline (13.3 ml) and N,N-diisopropylethylamine (22,2 ml). The reaction mixture was heated at 100°C overnight, cooled to room temperature and the mixture was diluted with ethyl acetate and washed with water. United inorganic phase was extracted with ethyl acetate and the combined organic phases were dried (Na2SO4), was filtered and was evaporated. The crude product was purified by chromatography (SiO2, n-heptane/ethyl acetate 1:2) to give N-benzyl-2-(4-fluoro-2-methylphenylimino)ndimethylacetamide (20 g) as a gray solid, MS: 273,0 ([M+H]+).

Stage 3: To a solution of N-benzyl-2-(4-fluoro-2-methylphenylimino)ndimethylacetamide (17 g) in THF (500 ml) solution was added to complex with borane-tetrahydrofuran (499,4 ml, 1M in THF). The solution to what was patili under reflux for 4 h, concentrated and dissolved in a mixture of 2M HCl and TBME. The inorganic phase was extracted with TWO, the organic phase washed with 2M HCl. The pH value of the combined inorganic phase was brought to pH 11 by adding kontsentrirovannoe NaOH solution and the solution was extracted with TWO. The combined organic phases were dried (Na2SO4), was filtered and was evaporated to obtain N-benzyl-N'-(4-fluoro-2-were)ethane-1,2-diamine (15.1 g) as a crude product, MS: 259,3 ([M+H]+).

Stage 4: N-benzyl-N'-(4-fluoro-2-were)ethane-1,2-diamine (15.1 g) in toluene (150 ml) was added N,N-diisopropylethylamine cases (33.8 ml) and ethyl ester of 2,3-dibromopropionate acid (25,61 ml) in toluene (350 ml). The reaction mixture was heated at 135°C for 18 h, cooled to room temperature and the precipitated solid was removed by filtration. The solution was concentrated and the crude material was dissolved in TWO and washed with 2M aqueous solution of Na2CO3and a saturated solution of sodium chloride, dried (Na2SO4), was filtered and was evaporated. Chromatography (SiO2, n-heptane/ethyl acetate 97:3) to give the ethyl ester of 4-benzyl-1-(4-fluoro-2-were)piperazine-2-carboxylic acid (5.5 g) as a yellow oil, MS: 357,3 ([M+H]+) and ethyl ester of 1-benzyl-4-(4-fluoro-2-were)piperazine-2-carboxylic acid (3.3 g) as a yellow oil, MS: 357,1 ([M+H]+).

Stage 5: This is levy ether 4-benzyl-1-(4-fluoro-2-were)piperazine-2-carboxylic acid (1 g) in ethyl acetate (10 ml) was first made in the presence of 10% Pd/C (149 mg) and acetic acid (1 ml). After removal of the catalyst and evaporation of the solvent the residue was dissolved in DMF (8 ml) and was treated with 3-chlorobenzenesulfonamide (280 μl) and triethylamine (1,96 ml) at room temperature until disappearance of starting material according to TLC. The mixture was diluted with ethyl acetate and washed with aqueous solution of NaHCO3, dried (Na2SO4), was filtered and was evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 2:1) resulted in obtaining the ethyl ester of 4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-carboxylic acid as a white solid (750 mg), MS: 441,3 ([M+H, 1Cl]+).

Step 6: To a solution of ethyl ester of 4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-carboxylic acid (730 mg) in tetrahydrofuran (20 ml) was added 1 M aqueous LiOH solution (16.6 ml) and methanol to obtain a clear solution. The mixture is stirred at the boil under reflux for 1 h, was added 1M KHSO4(20 ml) and the inorganic phase was extracted with ethyl acetate. The combined organic phases were dried (Na2SO4), was filtered and was evaporated to obtain 4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-carboxylic acid as light yellow solid, MS: 411,0 ([M-H, 1Cl]-).

Stage 7: Analogously to example 1, step 1, from 4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-methylp the Nile)piperazine-2-carboxylic acid, 1-(2,5-dimetilfenil)piperazine, HBTU and triethylamine in DMF was received [4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a white solid, MS: 584,7 ([M+H, 1Cl]+).

Example 3

[4-(3-Chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano

Analogously to example 1, step 1, from 4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-carboxylic acid and 1-(5-chloro-ortho-tolyl)piperazine was obtained [4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano in the form of a white solid, MS: 604,8 ([M+H, 1Cl]+).

Example 4

[4-(3-Chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano

Analogously to example 1, step 1, from 4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-carboxylic acid dihydrochloride and 1-(2,5-dichlorophenyl)piperazine was obtained [4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano in the form of a white solid, MS: 624,5 ([M+H, 1Cl]+).

Example 5

(-)-[4-(3-Chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano

[4-(3-Chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano example 4) was separated into the enantiomers of chiral HPLC on Chiralpak AD, using a mixture of n-heptane/30% ethanol as the mobile phase, to obtain (+)-[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]methanone in the form of a whitish solid, MS: 624,5 ([M+H, 1Cl]+) and (-)-[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]methanone in the form of a whitish solid, MS: 624,5 ([M+H, 1Cl]+).

Example 6

[4-(3-Chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-(4-o-tailpipes-1-yl)methanon

Analogously to example 1, step 1, from 4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-carboxylic acid and 1-(2-were)piperazine was obtained [4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-(4-o-tailpipes-1-yl)methanon in the form of a light yellow foam, MS: 571,2 ([M+H, 1Cl]+).

Example 7

[4-(2,5-Dichlorophenyl)piperazine-1-yl]-[4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-yl]metano

Stage 1-4: Analogously to example 2, stage 1-4, from benzylamine, chloracetamide, aniline and ethyl ester of 2,3-dibromopropionate acid was obtained ethyl ester of 4-benzyl-1-phenylpiperazin-2-carboxylic acid as light yellow oil, MS: 325,5 ([M+H]+).

Stage 5: as in example 2, step 5, of the ethyl ester of 4-benzyl-1-phenylpiperazin-2-carboxylic acid and 3-methoxybenzenesulfonamide received ethanol is the ester of 4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-carboxylic acid as a pale yellow oil, MS: 405,3 ([M+H]+).

Stage 6: Analogously to example 2, stage 6, of the ethyl ester of 4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-carboxylic acid was obtained 4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-carboxylic acid in the form of a whitish solid, MS: 375,5 ([M+H]+).

Stage 7: Analogously to example 1, step 1, from 4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-carboxylic acid dihydrochloride and 1-(2,5-dichlorophenyl)piperazine was obtained [4-(2,5-dichlorophenyl)piperazine-1-yl]-[4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-yl]metano in the form of a white solid, MS: 589,0 ([M+H, 1Cl]+).

Example 8

[4-(2,5-Dimetilfenil)piperazine-1-yl]-[4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-yl]metano

Analogously to example 1, step 1, from 4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-carboxylic acid and 1-(2,5-dimetilfenil)piperazine was obtained [4-(2,5-dimetilfenil)piperazine-1-yl]-[4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-yl]metano in the form of a white solid, MS: 548,8 ([M+H]+).

Example 9

[4-(5-Chloro-2-were)piperazine-1-yl]-[4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-yl]metano

Analogously to example 1, step 1, from 4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-carboxylic acid and 1-(5-chloro-2-were)piperazine was obtained [4-(5-chloro-2-were)piperazine-1-yl]-[4-(3-methoxybenzenesulfonyl)-1-finalpaper the Jn-2-yl]metano in the form of a white solid, MS: 568,8 ([M+H, 1Cl]+).

Example 10

[4-(3-Chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano

Stage 1-4: Analogously to example 2, stage 1-4, from benzylamine, chloracetamide, o-toluidine and ethyl ester of 2,3-dibromopropionate acid was obtained ethyl ester of 4-benzyl-1-o-tailpipes-2-carboxylic acid as an orange oil, MS: 339,4 ([M+H]+).

Stage 5: as in example 2, step 5, of the ethyl ester of 4-benzyl-1-o-tailpipes-2-carboxylic acid and 3-chlorobenzenesulfonamide received ethyl ester 4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-carboxylic acid as white solid, MS: 422,9 ([M+H, 1Cl]+).

Stage 6: Analogously to example 2, stage 6, of the ethyl ester of 4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-carboxylic acid was obtained 4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-carboxylic acid as light yellow solid, MS: to 393.3 ([M-H, 1Cl]-).

Stage 7: Analogously to example 1, step 1, from 4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-carboxylic acid dihydrochloride and 1-(2,5-dichlorophenyl)piperazine was obtained [4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano in the form of a white solid, MS: 606,6 ([M+H, 1Cl]+).

Example 11

[4-(3-Chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-[4-(5-chloro-2-IU is ylphenyl)piperazine-1-yl]metano

Analogously to example 1, step 1, from 4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-carboxylic acid and 1-(5-chloro-ortho-tolyl)piperazine was obtained [4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano in the form of a light yellow solid, MS: 586,8 ([M+H, 1Cl]+).

Example 12

[4-(3-Chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Analogously to example 1, step 1, from 4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-carboxylic acid and 1-(2,5-dimetilfenil)piperazine was obtained [4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a light yellow solid, MS: 567,3 ([M+H, 1Cl]+).

Example 13

[1-Benzyl-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Stage 1: In an argon atmosphere at 0°C, to a solution of ethyl 1,4-dibenzylpiperazine-2-carboxylate (10 g) in dichloroethane (40 ml) was added dropwise a solution of 1-chloroethylphosphonic (4,73 ml) in dichloroethane (14 ml) for 10 minutes, the Reaction mixture was stirred for 15 minutes at 0°C and then boiled under reflux during the night. The solvent was evaporated and the crude material was dissolved in ethanol and boiled under reflux during the night. The solvent was evaporated and the residue was dissolved in water and was extracted on the ethyl ether (×2) and CH 2Cl2(×2). To the aqueous phase was then added to a saturated solution of NaHCO3and the inorganic phase was extracted with CH2Cl2(×2). The organic layers were then combined, washed with a saturated solution of sodium chloride, dried (Na2SO4), was filtered and was concentrated to obtain ethyl ester of 1-benzylpiperazine-2-carboxylic acid as a crude product, MS: 248,9 ([M+H]+).

Stage 2: a Solution of ethyl ester of 1-benzylpiperazine-2-carboxylic acid (300 mg) in DMF (13 ml) was treated with triethylamine (0.5 ml) and 3-methoxybenzenesulfonamide (274,6 mg) at RT for 2 hours. Added water and the inorganic layer was extracted with ethyl acetate (×3). The combined organic layers were dried (Na2SO4), was filtered and was evaporated to obtain ethyl ester of 1-benzyl-4-(3-methoxybenzenesulfonyl)piperazine-2-carboxylic acid as a colourless oil (417 mg), MS: 419,3 ([M+H]+).

Stage 3: same as example 2, step 6, of the ethyl ester of 1-benzyl-4-(3-methoxybenzenesulfonyl)piperazine-2-carboxylic acid was obtained 1-benzyl-4-(3-methoxybenzenesulfonyl)piperazine-2-carboxylic acid, which was used in the next reaction without further purification. MS: to 389.5 ([M-H]-).

Stage 4: Analogously to example 1, step 1, from 1-benzyl-4-(3-methoxybenzenesulfonyl)piperazine-2-carboxylic acid and 1-(2,5-is iletiler)piperazine was obtained [1-benzyl-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a white foam, MS: 563,5 ([M+H]+).

Example 14

(-)-[1-Benzyl-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

1-Benzyl-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano separated enantiomers on chiral HPLC on Chiralpak AD using a mixture of n-heptane/25% isopropanol as mobile phase to obtain (+)-[1-benzyl-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone in the form of a colorless oil, MS: 563,3 ([M+H]+and (-)-[1-benzyl-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone in the form of a colorless oil, MS: 563,3 ([M+H]+).

Example 15

[1-Benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Stage 1: Analogously to example 1, stage 1, of the 1.4-dibenzylpiperazine-2-carboxylic acid (CAS Reg. No.: [215597-67-4]) and 1-(2,5-dimetilfenil)piperazine was obtained (1,4-dibenzylpiperazine-2-yl)-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a white foam, MS: 483,3 ([M+H]+).

Stage 2: same as example 13, stage 1-2, from (1,4-dibenzylpiperazine-2-yl)-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone and 3-chlorobenzenesulfonamide received [1-benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a white foam, MS: 567,3 ([M+H, 1Cl]+).

Example 16

[1-Benzyl-4-(3,5-dimetyl oxazol-4-sulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Analogously to example 13, stage 1-2, from (1,4-dibenzylpiperazine-2-yl)-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone and 3.5-dimethylisoxazol-4-sulphonylchloride received [1-benzyl-4-(3,5-dimethylisoxazol-4-sulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a white foam, MS: 552,3 ([M+H]+).

Example 17

[4-(3-Chlorobenzenesulfonyl)-1-propylpiperidine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Step 1: To a solution of methyl ester of N-1-Boc-2-piperazinecarboxamide acid (CAS Reg. No: [129799-15-1]) (1 g) in DMF (5 ml) was added 3-chlorobenzenesulfonamide (0.95 g) and triethylamine (1,71 ml). The reaction mixture was stirred at RT over night. Added water and the mixture was extracted with ethyl acetate (×2). The combined organic layers were washed with water (×2) and saturated sodium chloride solution, dried (Na2SO4), was filtered and was evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 3:1) resulted in the receipt of 1-tert-butyl ester 2-methyl ester 4-(3-chlorobenzenesulfonyl)piperazine-1,2-dicarboxylic acid as a white foam (1.66 g), MS: 436,3 ([M+NH4, 1Cl]+).

Stage 2: same as example 2, stage 6 (room temperature), 1-tert-butyl ester 2-methyl ester 4-(3-chlorobenzenesulfonyl)piperazine-1,2-dicarboxylic acid was obtained 1-tert-butyl ester 4-(3-chlorobenzenesulfonyl)piperazine-1,2-dicarboxylic what islote in the form of a white foam, MS: 403,2 ([M-H, 1Cl]-).

Stage 3: same as example 1, step 1, from 1-tert-butyl ester 4-(3-chlorobenzenesulfonyl)piperazine-1,2-dicarboxylic acid and 1-(2,5-dimetilfenil)piperazine was obtained tert-butyl ester 4-(3-chlorobenzenesulfonyl)-2-[4-(2,5-dimetilfenil)piperazine-1-carbonyl]piperazine-1-carboxylic acid as a white foam, MS: 577,4 ([M+H, 1Cl]+).

Stage 4: To a solution of tert-butyl ester 4-(3-chlorobenzenesulfonyl)-2-[4-(2,5-dimetilfenil)piperazine-1-carbonyl]piperazine-1-carboxylic acid (2,18 g) in ethanol (21,8 ml) was added a saturated solution of HCl in ethanol (21,8 ml) at 0°C. the Reaction mixture was stirred at room temperature overnight, the solution was concentrated and the residue was dissolved in a mixture solution of NaHCO3and ethyl acetate. The inorganic phase was extracted with ethyl acetate (×3), and the combined organic layers were washed with a saturated solution of sodium chloride, dried (Na2SO4), was filtered and was evaporated to obtain [4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone in the form of a crude product (1,79 g), MS: 477,0 ([M+H, 1Cl]+).

Stage 5: To a solution of [4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone (100 mg) in acetone (4 ml) was added cesium carbonate (82 mg), then 1-bromopropane (21 μl). The reaction mixture was stirred at boiling reverse, chilling the nickname during the night. Added water and the reaction mixture was extracted with ethyl acetate (×2). The combined organic layers were washed with a saturated solution of sodium chloride, dried (Na2SO4), was filtered and was evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 3:1) resulted in the receipt of [4-(3-chlorobenzenesulfonyl)-1-propylpiperidine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone in the form of a white foam (75 mg), MS: 519,3 ([M+H, 1Cl]+).

Example 18

[1-Butyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Analogously to example 17, step 5, from [4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone and 1-bromobutane received [1-butyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a white foam, MS: 533,4 ([M+H, 1Cl]+).

Example 19

[4-(3-Chlorobenzenesulfonyl)-1-pentylpyridine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Analogously to example 17, step 5, from [4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone and 1-bromopentane received [4-(3-chlorobenzenesulfonyl)-1-pentylpyridine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a white foam, MS: 547,3 ([M+H, 1Cl]+).

Example 20

[4-(3-Chlorobenzenesulfonyl)-1-isobutylpyrazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Analogously to example 17, step 5 of [4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone and 1-bromo-2-methylpropane received [4-(3-chlorobenzenesulfonyl)-1-isobutylpyrazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a white foam, MS: 533,2 ([M+H, 1Cl]+).

Example 21

[4-(3-Chlorobenzenesulfonyl)-1-feiticeira-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Analogously to example 17, step 5, from [4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone and (2-bromacil)benzene was obtained [4-(3-chlorobenzenesulfonyl)-1-feiticeira-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a colorless oil, MS: 581,3 ([M+H, 1Cl]+).

Example 22

[4-(4-Chlorobenzenesulfonyl)-1-pentylpyridine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Stage 1-3: Analogously to example 17, stages 1-3, methyl ester N-1-BOC-2-piperazinecarboxamide acid (CAS Reg. No: [129799-15-1]), 4-chlorobenzenesulfonamide and 1-(2,5-dimetilfenil)piperazine was obtained tert-butyl ester 4-(4-chlorobenzenesulfonyl)-2-[4-(2,5-dimetilfenil)piperazine-1-carbonyl]piperazine-1-carboxylic acid as light yellow foam, MS: 577,4 ([M+H, 1Cl]+).

Stage 4: To a solution of tert-butyl ester 4-(4-chlorobenzenesulfonyl)-2-[4-(2,5-dimetilfenil)piperazine-1-carbonyl]piperazine-1-carboxylic acid (1.64 g) in ethanol (16.4 ml) was added a saturated solution of HCl in ethanol (16.4 ml) at 0°C. the Reaction mixture was stirred at room temperature for 2 h and then concentrated to obtain hydrochloride [4-(4-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone, MS: 477,0 ([M+H, 1Cl]+)

Stage 5: To a solution of hydrochloride [4-(4-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone (100 mg) in acetone (4 ml) was added cesium carbonate (254 mg), then 1-bromopentane (27 μl). The reaction mixture was stirred at room temperature for 1 h was Added an additional amount of cesium carbonate (127 mg) and 1-bromopentane (14 μl) and stirring continued at boiling under reflux overnight. Added water and the reaction mixture was extracted with ethyl acetate (×2). The combined organic layers were washed with a saturated solution of sodium chloride, dried (Na2SO4), was filtered and was evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 3:1) resulted in the receipt of [4-(4-chlorobenzenesulfonyl)-1-pentylpyridine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone in the form of a white foam, MS: 547,3 ([M+H, 1Cl]+).

Example 23

[1-Butyl-4-(4-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Analogously to example 20, step 5, from hydrochloride [4-(4-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone and 1-bromobutane received [1-butyl-4-(4-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a white foam, MS: 533,3 ([M+H, 1Cl]+).

Example 24

[4-(4-Chlorobenzenesulfonyl)-1-phenylpiperazin-2-yl]-[4-(2,5-dimethylpent the l)piperazine-1-yl]metano

In an argon atmosphere in a kiln dried flask was loaded Tris(dibenzylideneacetone)dipalladium (9.6 mg), tert-butyl sodium (40 mg) and 2-(di-tert-butylphosphino)biphenyl (6.3 mg). Then was added [4-(4-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano (100 mg), obtained in advance from the hydrochloride [4-(4-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone extraction in basic conditions in toluene (5 ml), then a solution of bromine benzol (55 μl) in toluene (3 ml). The reaction mixture was stirred at 80°C during the night. The mixture was cooled to room temperature, was added an aqueous solution of NaHCO3the phases were separated and the inorganic layer was extracted with ethyl acetate (×3). The combined organic layers were dried (Na2SO4), was filtered and was evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 3:1; ISOLUTE Flash NH2, n-heptane/ethyl acetate) and processing of n-heptane resulted in the receipt of [4-(4-chlorobenzenesulfonyl)-1-phenylpiperazin-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]methanone in the form of a white solid, MS: 553,3 ([M+H, 1Cl]+).

Example 25

[4-(2-Chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano

Stage 1: Analogously to example 2, stage 5, of the ethyl ester of 4-benzyl-1-(4-fluoro-2-were)piperazine-2-carboxylic acid and 2-Harbin is alcohomicide received ethyl ester 4-(2-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-carboxylic acid as a yellow oil, MS: 441,1 ([M+H, 1Cl]+).

Stage 2: as in example 2, step 6, of the ethyl ester of 4-(2-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-carboxylic acid was obtained 4-(2-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-carboxylic acid as white solid, MS: 410,9 ([M-H, 1Cl]-).

Stage 3: same as example 1, step 1, from 4-(2-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-carboxylic acid dihydrochloride and 1-(2,5-dichlorophenyl)piperazine was obtained [4-(2-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano in the form of a white solid, MS: 626,8 ([M+H, 1Cl]+).

Example 26

[4-(2-Chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano

Analogously to example 1, step 1, from 4-(2-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-carboxylic acid (example 25, step 2) and 1-(5-chloro-ortho-tolyl)piperazine was obtained [4-(2-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano in the form of a white solid, MS: 604,8 ([M+H, 1Cl]+).

Example 27

[4-(2-Chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Analogously to example 1, step 1, from 4-(2-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-carboxylic acid is (example 25, stage 2) and 1-(2,5-dimetilfenil)piperazine was obtained [4-(2-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a white solid, MS: 584,8 ([M+H, 1Cl]+).

Example 28

[4-(2,5-Dichlorophenyl)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-yl]metano

Stage 1: Analogously to example 2, stage 5, of the ethyl ester of 4-benzyl-1-(4-fluoro-2-were)piperazine-2-carboxylic acid and 1-naphthalenesulfonate received ethyl ester 1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-carboxylic acid as white solid, MS: 457,3 ([M+H]+).

Stage 2: as in example 2, step 6, of the ethyl ester of 1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-carboxylic acid was obtained 1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-carboxylic acid as white solid, MS: 427,0 ([M-H]-).

Stage 3: same as example 1, step 1, from 1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-carboxylic acid dihydrochloride and 1-(2,5-dichlorophenyl)piperazine was obtained [4-(2,5-dichlorophenyl)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-yl]metano in the form of a white solid, MS: 641,2 ([M+H, 1Cl]+).

Example 29

[4-(5-Chloro-2-were)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(naphthalene-1-sulf the Nile)piperazine-2-yl]metano

Analogously to example 1, step 1, from 1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-carboxylic acid and 1-(5-chloro-ortho-tolyl)piperazine was obtained [4-(5-chloro-2-were)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-yl]metano in the form of a white solid, MS: 621,0 ([M+H, 1Cl]+).

Example 30

[4-(2,5-Dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-yl]metano

Analogously to example 1, step 1, from 1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-carboxylic acid and 1-(2,5-dimetilfenil)piperazine was obtained [4-(2,5-dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-yl]metano in the form of a white solid, MS: 601,0 ([M+H]+).

Example 31

[1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-yl]-[4-(3-triptorelin-2-yl)piperazine-1-yl]metano

Analogously to example 1, step 1, from 1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-carboxylic acid and 1-(3-triptorelin-2-yl)piperazine (CAS Reg. No.: [87394-63-6]) received [1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-yl]-[4-(3-triptorelin-2-yl)piperazine-1-yl]metano in the form of a white solid, MS: 642,3 ([M+H]+).

Example 32

[4-(2,5-Dichlorophenyl)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-yl]metano

With the adiya 1: Analogously to example 2, stage 5, of the ethyl ester of 4-benzyl-1-(4-fluoro-2-were)piperazine-2-carboxylic acid and 8-chinaincorporated received ethyl ester 1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-carboxylic acid as white solid, MS: 458,3 ([M+H]+).

Stage 2: as in example 2, step 6, of the ethyl ester of 1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-carboxylic acid was obtained 1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-carboxylic acid as white solid, MS: 428,4 ([M-H]-).

Stage 3: same as example 1, step 1, from 1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-carboxylic acid dihydrochloride and 1-(2,5-dichlorophenyl)piperazine was obtained [4-(2,5-dichlorophenyl)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-yl]metano in the form of a white solid, MS: 642,0 ([M+H, 1Cl]+).

Example 33

[4-(5-Chloro-2-were)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-yl]metano

Analogously to example 1, step 1, from 1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-carboxylic acid and 1-(5-chloro-ortho-tolyl)piperazine was obtained [4-(5-chloro-2-were)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-yl]metano in the form of a white solid, MS: 621,8 ([M+H, 1Cl]+).

Example 34

[4-(2,5-Dimethyl who enyl)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-yl]metano

Analogously to example 1, step 1, from 1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-carboxylic acid and 1-(2,5-dimetilfenil)piperazine was obtained [4-(2,5-dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-yl]metano in the form of a white solid, MS: 602,0 ([M+H]+).

Example 35

[4-(2,5-Dichlorophenyl)piperazine-1-yl]-[4-(propane-2-sulfonyl)-1-o-tailpipes-2-yl]metano

Stage 1: Analogously to example 2, stage 6, of the ethyl ester of 4-benzyl-1-o-tailpipes-2-carboxylic acid (example 10, stages 1-4) was obtained 4-benzyl-1-o-tailpipes-2-carboxylic acid as white solid, MS: 309,3 ([M-H]-).

Stage 2: Analogously to example 1, step 1, from 4-benzyl-1-o-tailpipes-2-carboxylic acid dihydrochloride and 1-(2,5-dichlorophenyl)piperazine was obtained (4-benzyl-1-o-tailpipes-2-yl)-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano in the form of a white solid, MS: 522,8 ([M+H, 1Cl]+).

Stage 3: same as example 2, step 5, from (4-benzyl-1-o-tailpipes-2-yl)-[4-(2,5-dichlorophenyl)piperazine-1-yl]methanone and ISO-propylsulfonyl received [4-(2,5-dichlorophenyl)piperazine-1-yl]-[4-(propane-2-sulfonyl)-1-o-tailpipes-2-yl]metano in the form of a white foam, MS: to 539.3 ([M+H, 1Cl]+).

Example 36

[4-(Biphenyl-4-sulfonyl)-1-o-tailpipes-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano

Similarly, p is the iMER 35, stage 3, from (4-benzyl-1-o-tailpipes-2-yl)-[4-(2,5-dichlorophenyl)piperazine-1-yl]methanone and 4-biphenylmethanol received [4-(biphenyl-4-sulfonyl)-1-o-tailpipes-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano in the form of a white foam, MS: 649,3 ([M+H, 1Cl]+).

Example 37

Methyl ester of 3-{3-[4-(2,5-dichlorophenyl)piperazine-1-carbonyl]-4-o-tailpipes-1-sulfonyl}thiophene-2-carboxylic acid

Analogously to example 35, step 3, from 4-benzyl-1-o-tailpipes-2-yl)-[4-(2,5-dichlorophenyl)piperazine-1-yl]methanone and 2-(methoxycarbonyl)thiophene-3-sulphonylchloride received methyl ester 3-{3-[4-(2,5-dichlorophenyl)piperazine-1-carbonyl]-4-o-tailpipes-1-sulfonyl}thiophene-2-carboxylic acid as a white foam, MS: 637,0 ([M+N]+).

Example 38

[4-(3-Chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon

Stage 1: Analogously to example 1, step 1, from 4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-carboxylic acid (example 2, step 5) and N-Boc-piperazine was obtained tert-butyl ester 4-[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-carbonyl]piperazine-1-carboxylic acid as white solid, MS: 580,8 ([M+H, 1Cl]+).

Stage 2: same as example 17, step 4, tert-butyl ester 4-[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-carbonyl]piperazin the-1-carboxylic acid was obtained [4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]piperazine-1-ylmethanol in the form of a white solid, MS: 481,0 ([M+H, 1Cl]+).

Stage 3: [4-(3-Chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]piperazine-1-ylmethanone (60 mg), 3-chloro-2,5-dimethylpyrazine (18,1 μl) and triethylamine (20,8 μl) in acetonitrile (1 ml) was heated at 170°C in a microwave oven. Added water and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with a saturated solution of sodium chloride, dried (Na2SO4), was filtered and was evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 1:2) resulted in the receipt of [4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanone in the form of a yellow oil, MS: 587,3 ([M+H, 1Cl]+).

Example 39

[1-Benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon

Stage 1: Analogously to example 13, step 2, of the ethyl ester of 1-benzylpiperazine-2-carboxylic acid and 3-chlorobenzenesulfonamide received ethyl ester of 1-benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-carboxylic acid as a yellow oil, MS: 423,1 ([M+H, 1Cl]+).

Stage 2: as in example 2, step 6, of the ethyl ester of 1-benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-carboxylic acid was obtained 1-benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-carboxylic acid in the form of a whitish solid, MS: 593,0 ([M-H, 1Cl]sup> -).

Stage 3: same as example 1, step 1, from 1-benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-carboxylic acid and 1-BOC-piperazine was obtained tert-butyl ester 4-[1-benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-carbonyl]piperazine-1-carboxylic acid as a white foam, MS: 562,8 ([M+H, 1Cl]+).

Stage 4: Analogously to example 38, step 2, tert-butyl ester 4-[1-benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-carbonyl]piperazine-1-carboxylic acid was obtained [1-benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]piperazine-1-ylmethanol in the form of a white foam, MS: 463 ([M+H, 1Cl]+).

Stage 5: Analogously to example 38, step 3, from [1-benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]piperazine-1-ylmethanone and 3-chloro-2,5-dimethylpyrazine received [1-benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon in the form of a yellow oil, MS: 569,3 ([M+H, 1Cl]+).

Example 40

[4-(3-Chlorophenyl)piperidine-1-yl]-[1-(4-fluoro-2-were)-4-(propane-2-sulfonyl)piperazine-2-yl]metano

Stage 1: Analogously to example 2, stage 5, of the ethyl ester of 4-benzyl-1-(4-fluoro-2-were)piperazine-2-carboxylic acid and ISO-propylsulfonyl received ester 1-(4-fluoro-2-were)-4-(propane-2-sulfonyl)piperazine-2-carboxylic acid as a colourless oil, MS: 373,1 ([M+H, 1Cl]+).

Stage 2: as in example 2, step 6, from ether 1-(4-ft is R-2-were)-4-(propane-2-sulfonyl)piperazine-2-carboxylic acid was obtained 1-(4-fluoro-2-were)-4-(propane-2-sulfonyl)piperazine-2-carboxylic acid as a yellow solid, MS: 343,1 ([M-H, 1Cl]-).

Stage 3: same as example 1, step 1, from 1-(4-fluoro-2-were)-4-(propane-2-sulfonyl)piperazine-2-carboxylic acid and 4-(3-chlorophenyl)piperidine was obtained [4-(3-chlorophenyl)piperidine-1-yl]-[1-(4-fluoro-2-were)-4-(propane-2-sulfonyl)piperazine-2-yl]metano in the form of a white solid, MS: 522,2 ([M+H, 1Cl]+).

Example 41

[4-(3-Chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon

Analogously to example 1, step 1, from 4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-carboxylic acid and 3',6'-dimethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl (CAS Reg. No.: [59215-42-8]) received [4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon in the form of a white solid, MS: 569,3 ([M+H, 1Cl]+).

Example 42

CIS-[4-(2,5-Dimetilfenil)piperazine-1-yl]-[-1-(3-methoxybenzenesulfonyl)-4-phenylpiperidine-3-yl]metano

Stage 1: Hydrochloride CIS-4-familyvacation acid (CAS Reg. No. [858430-42-9]) (195 mg) (three times, suspended in toluene and one stripped off under reduced pressure to remove water) suspended in hexamethyldisilazane (4 ml) and boiled under reflux for 3 hours, the Solution was evaporated under reduced pressure and was dissolved in THF (4 ml). Added 3-methoxybenzenesulfonamide (0,13 ml) and the solution was stirred for 16 h Ave the room temperature. Added H2O and after 1 h the solvent was evaporated. The residue was separated between water and ethyl acetate (3×), the organic phase was washed with a saturated solution of sodium chloride, dried (Na2SO4), was filtered and was evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 1:1) yielded CIS-1-(3-methoxybenzenesulfonyl)-4-phenylpiperidine-3-carboxylic acid as white solid, MS: 374,3 (M-N])-.

Stage 2: same as example 1, stage 1, from CIS-1-(3-methoxybenzenesulfonyl)-4-phenylpiperidine-3-carboxylic acid and 1-(2,5-dimetilfenil)piperazine was obtained CIS-[4-(2,5-dimetilfenil)piperazine-1-yl]-[-1-(3-methoxybenzenesulfonyl)-4-phenylpiperidine-3-yl]metano in the form of a white solid (tPL192°C), MS: 548,4 ([M+H])+.

Example 43

[4-(2,5-Dimetilfenil)piperazine-1-yl]-[(3S,4S)-1-(3-methoxybenzenesulfonyl)-4-phenylpiperidine-3-yl]metano

CIS-[4-(2,5-dimetilfenil)piperazine-1-yl]-[-1-(3-methoxybenzenesulfonyl)-4-phenylpiperidine-3-yl]metano separated enantiomers on chiral HPLC on Chiralpak AD using a mixture of n-heptane/25% isopropanol as mobile phase, to obtain [4-(2,5-dimetilfenil)piperazine-1-yl]-[(3S,4S)-1-(3-methoxybenzenesulfonyl)-4-phenylpiperidine-3-yl]methanone in the form of a white foam, MS: 548,3 ([M+H])+and [4-(2,5-dimetilfenil)piperazine-1-yl]-[(3R,4R)-1-(3-methoxybenzenesulfonyl)-4-phenylpiperidine-3-yl]methane is in the form of a white foam, MS: 548,3 ([M+H])+.

Example 44

[TRANS-1-(3-Chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Stage 1: Analogously to example 1, step 1, from TRANS-N-Boc-4-familyvacation acid (CAS Reg. No.: [170838-49-0]) and 1-(2,5-dimetilfenil)piperazine was obtained tert-butyl ether TRANS-3-[4-(2,5-dimetilfenil)piperazine-1-carbonyl]-4-phenylpiperidine-1-carboxylic acid as a white foam, MS: 478,2 ([M+H])+.

Stage 2: Analogously to example 22, step 4, tert-butyl ether TRANS-3-[4-(2,5-dimetilfenil)piperazine-1-carbonyl]-4-phenylpiperidine-1-carboxylic acid was obtained the hydrochloride of TRANS-[4-(2,5-dimetilfenil)piperazine-1-yl]-(-4-phenylpiperidine-3-yl)methanone in the form of a white foam, MS: 378,4 ([M+H])+.

Stage 3: same as example 1, stage 3, hydrochloride, TRANS-[4-(2,5-dimetilfenil)piperazine-1-yl]-(-4-phenylpiperidine-3-yl)methanone and 3-chlorobenzenesulfonamide received [TRANS-1-(3-chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a white foam, MS: 552,1 ([M+H, 1Cl])+.

Example 45

[TRANS-1-(3,5-Dimethylisoxazol-4-sulfonyl)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Analogously to example 1, stage 3, hydrochloride, TRANS-[4-(2,5-dimetilfenil)piperazine-1-yl]-(-4-phenylpiperidine-3-yl)methanone and 3.5-dimethylisoxazol-4-sulphonylchloride (CAS Reg. No.: [80466-79-1]) received [TRANS-1-(35-dimethylisoxazol-4-sulfonyl)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a white foam, MS: 537,4 ([M+H])+.

Example 46

[4-(2,5-Dimetilfenil)piperazine-1-yl]-[(3S,4S)-1-(3-methoxybenzenesulfonyl)-4-o-tripeptides-3-yl]metano

Step 1: To a solution of chloride of 2-methylphenylene ([84109-17-1], obtained in advance from chloride o-talismania (44,07 ml) and zinc chloride (8,81 g) in THF (200 ml)) was added to a mixture of 1-tert-butyl ester 3-methyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (CAS Reg. No. [161491-25-4]) (11.4 g) in THF (90 ml), and then tetrakis(triphenylphosphine)palladium(0) (1,02 g). The reaction mixture was stirred at room temperature overnight and then switched off the ice. The mixture was diluted with tert-butylmethylamine ether and washed with 2 M aqueous solution of sodium carbonate. The aqueous phase was extracted with tert-butylmethylamine ether. The combined organic layers were washed with a saturated solution of sodium chloride, dried (Na2SO4), was filtered and was evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 5:1) resulted in the receipt of 1-tert-butyl ester 3-methyl ester 4-o-tolyl-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid as a light yellow oil, MS: 332,0 ([M+H])+.

Stage 2: as in example 2, step 6, from 1-tert-butyl ester 3-methyl ester 4-o-tolyl-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid was obtained 1-tert-butyl ether 4-o-tolyl-5,6-dihydro-2H-pyridine-1,3-dicarbonate in the form of a white solid, MS: 316,2 ([M-N])-.

Stage 3: In a protective camera with gloves in the autoclave was downloaded 1-tert-butyl ether 4-o-tolyl-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (2.5 g), [Ru(OAc)2((R)-(2-furyl)-MeOBIPHEP)] (24 mg), triethylamine (1.1 ml) and methanol (25 ml). Asymmetric hydrogenation was carried out for 60 h at 80°C at 40 bar of hydrogen. After cooling to room temperature the pressure of the autoclave was lowered, the methanol solution was diluted with tert-butylmethylamine ether (320 ml) and was extracted with 1 M aqueous sodium hydroxide solution (2×, 320 ml). The aqueous layer was poured into ice, acidified ice 2 M aqueous hydrochloric acid solution to pH 1 and extracted with ethyl acetate (3×). The combined organic layers were dried (Na2SO4), was filtered and was concentrated in vacuo and treated with n-heptane to obtain 1-tert-butyl ether (3S,4S)-4-o-tripeptides-1,3-dicarboxylic acid as a white solid, MS: 318,2.

Stage 4: Analogously to example 1, step 1, from 1-tert-butyl ether (3S,4S)-4-o-tripeptides-1,3-dicarboxylic acid and 1-(2,5-dimetilfenil)piperazine was obtained tert-butyl ether (3S,4S)-3-[4-(2,5-dimetilfenil)piperazine-1-carbonyl]-4-o-tripeptides-1-carboxylic acid as a white foam, MS: 492,3 ([M+H])+.

Stage 5: Analogously to example 22, step 4, tert-butyl methyl ether (3S,4S)-3-[4-(2,5-d who were)piperazine-1-carbonyl]-4-o-tripeptides-1-carboxylic acid was obtained hydrochloride [4-(2,5-dimetilfenil)piperazine-1-yl]-((3S,4S)-4-o-tripeptides-3-yl)methanone in the form of a colorless oil, MS: 392,4 ([M+H])+.

Stage 6: Analogously to example 1, stage 3, hydrochloride [4-(2,5-dimetilfenil)piperazine-1-yl]-((3S,4S)-4-o-tripeptides-3-yl)methanone and 3-methoxybenzenesulfonamide received [4-(2,5-dimetilfenil)piperazine-1-yl]-[(3S,4S)-1-(3-methoxybenzenesulfonyl)-4-o-tripeptides-3-yl]metano in the form of a white foam, MS: 562,5 ([M+N])+.

Example 47

[(3S,4S)-1-(3-Chlorobenzenesulfonyl)-4-o-tripeptides-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Analogously to example 1, stage 3, hydrochloride [4-(2,5-dimetilfenil)piperazine-1-yl]-((3S,4S)-4-o-tripeptides-3-yl)methanone and 3-chlorobenzenesulfonamide received [(3S,4S)-1-(3-chlorobenzenesulfonyl)-4-o-tripeptides-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a white foam, MS: 566,4 ([M+H, 1Cl])+.

Example 48

[4-(2,5-Dimetilfenil)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-o-tripeptides-3-yl)methanon

Analogously to example 1, stage 3, hydrochloride [4-(2,5-dimetilfenil)piperazine-1-yl]-((3S,4S)-4-o-tripeptides-3-yl)methanone and methanesulfonanilide received [4-(2,5-dimetilfenil)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-o-tripeptides-3-yl)methanon in the form of a white foam, MS: 470,1 ([M+H])+.

Example 49

[(3S,4S)-1-(3-Chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Stage 1: Analogously to example 1, step 1, from 1-tert-butyl ether (3S,4S)-4-phenylpiperidine-1,3-is karbonovoi acid (CAS Reg. No.: [197900-77-9]) and 1-(2,5-dimetilfenil)piperazine was obtained tert-butyl ether (3S,4S)-3-[4-(2,5-dimetilfenil)piperazine-1-carbonyl]-4-phenylpiperidine-1-carboxylic acid as a white foam, MS: 478,28 ([M+H])+.

Stage 2: Analogously to example 22, step 4, tert-butyl methyl ether (3S,4S)-3-[4-(2,5-dimetilfenil)piperazine-1-carbonyl]-4-phenylpiperidine-1-carboxylic acid was obtained hydrochloride [4-(2,5-dimetilfenil)piperazine-1-yl]-((3S,4S)-4-phenylpiperidine-3-yl)methanone in the form of a crude product, MS: 392,4 ([M+H])+.

Stage 3: same as example 1, stage 3, hydrochloride [4-(2,5-dimetilfenil)piperazine-1-yl]-((3S,4S)-4-phenylpiperidine-3-yl)methanone and 3-chlorobenzenesulfonamide received [(3S,4S)-1-(3-chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a white foam, MS: 552,2 ([M+H, 1Cl])+.

Example 50

[4-(2,5-Dimetilfenil)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-phenylpiperidine-3-yl)methanon

Analogously to example 1, stage 3, hydrochloride [4-(2,5-dimetilfenil)piperazine-1-yl]-((3S,4S)-4-phenylpiperidine-3-yl)methanone and methanesulfonanilide received [4-(2,5-dimetilfenil)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-phenylpiperidine-3-yl)methanon in the form of a white foam, MS: 456,3 ([M+H])+.

Example 51

[(3R,4R)-1-(3-Chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano

Stage 1: Analogously to example 1, step 1, from 1-tert-b is delovogo ether (3R,4R)-4-phenylpiperidine-1,3-dicarboxylic acid (CAS Reg. No.: [197900-84-8]) and 1-(2,5-dimetilfenil)piperazine was obtained tert-butyl ether (3R,4R)-3-[4-(2,5-dimetilfenil)piperazine-1-carbonyl]-4-phenylpiperidine-1-carboxylic acid as a white foam, MS: 478,27 ([M+H])+.

Stage 2: Analogously to example 22, step 4, tert-butyl methyl ether (3R,4R)-3-[4-(2,5-dimetilfenil)piperazine-1-carbonyl]-4-phenylpiperidine-1-carboxylic acid was obtained hydrochloride [4-(2,5-dimetilfenil)piperazine-1-yl]-((3R,4R)-4-phenylpiperidine-3-yl)methanone, which is directly used in the next reaction, MS: 378,4 ([M+H, 1Cl])+.

Stage 3: same as example 1, stage 3, hydrochloride [4-(2,5-dimetilfenil)piperazine-1-yl]-((3R,4R)-4-phenylpiperidine-3-yl)methanone and 3-chlorobenzenesulfonamide received [(3R,4R)-1-(3-chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano in the form of a white foam, MS: 552,2 ([M+H, 1Cl])+.

Example 52

[4-(2,5-Dimetilfenil)piperazine-1-yl]-[(3S,4R)-1-(3-methoxybenzenesulfonyl)-4-o-tripeptides-3-yl]metano

Stage 1: Analogously to example 46, step 3, from 1-tert-butyl ester 4-o-tolyl-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid, using Ru(OAc)2((S)-BITIANP as a catalyst for enantioselective hydrogenation received 1-tert-butyl ether (3R,4R)-4-o-tripeptides-1,3-dicarboxylic acid as a white solid, MS: 318,4 ([M-N])-.

Stage 2: To a solution of triphenylphosphine is a (2.66 g) in THF (30 ml) was added diethylazodicarboxylate (1,58 ml) at 0°C. After 30 minutes consistently added methanol (1,58 ml) and a solution of 1-tert-butyl ether (3R,4R)-4-o-tripeptides-1,3-dicarboxylic acid in THF (30 ml) at 0-5°C. the Reaction mixture was stirred for 3 h at room temperature. The reaction extinguished saturated aqueous NH4Cl, was added tert-butyl methyl ether and the phases were separated. The inorganic phase was extracted with tert-butylmethylamine ether (3×100 ml). The combined organic layers were dried (Na2SO4), was filtered and was evaporated. Purification by chromatography (SiO2from CH2Cl2until CH2Cl2/Meon 95:5) yielded 1-tert-butyl ester 3-methyl ester (3R,4R)-4-o-tripeptides-1,3-dicarboxylic acid as colorless resinous substance, MS: 334,1 ([M+H])+.

Stage 3: a Mixture of 1-tert-butyl ester 3-methyl ester (3R,4R)-4-o-tripeptides-1,3-dicarboxylic acid (200 mg) and sodium methoxide (65 mg) in anhydrous toluene (6 ml) was boiled under reflux overnight. After cooling to room temperature the reaction mixture was extinguished with water and concentrated in vacuum. The residue was dissolved in a mixture of 1,4-dioxane (3 ml) and 2 M aqueous sodium hydroxide solution (3 ml). After stirring at RT for 5 h the mixture was diluted with water and washed with two portions of tert-butyl methyl ether. The aqueous layer was cooled to 0°C, kislali to pH 1-2 with ice 1 M aqueous solution of KHSO 4and were extracted with ethyl acetate. The combined organic layers were dried (Na2SO4), was filtered and was evaporated to obtain 1-tert-butyl ether (3S,4R)-4-o-tripeptides-1,3-dicarboxylic acid as a white solid, MS: 318,4 ([M-N])-.

Stage 4: Analogously to example 1, step 1, from 1-tert-butyl ether (3S,4R)-4-o-tripeptides-1,3-dicarboxylic acid and 1-(2,5-dimetilfenil)piperazine was obtained tert-butyl ether (3S,4R)-3-[4-(2,5-dimetilfenil)piperazine-1-carbonyl]-4-o-tripeptides-1-carboxylic acid as white solid, MS: 492,1 ([M+H])+.

Stage 5: Analogously to example 22, step 4, tert-butyl methyl ether (3S,4R)-3-[4-(2,5-dimetilfenil)piperazine-1-carbonyl]-4-o-tripeptides-1-carboxylic acid was obtained hydrochloride [4-(2,5-dimetilfenil)piperazine-1-yl]-((3S,4R)-4-o-tripeptides-3-yl)methanone in the form of a white solid, MS: 392,3 ([M+H])+.

Stage 6: Analogously to example 1, stage 3, hydrochloride [4-(2,5-dimetilfenil)piperazine-1-yl]-((3S,4R)-4-o-tripeptides-3-yl)methanone and 3-methoxybenzenesulfonamide received [4-(2,5-dimetilfenil)piperazine-1-yl]-[(3S,4R)-1-(3-methoxybenzenesulfonyl)-4-o-tripeptides-3-yl]metano in the form of a white solid, MS: 562,3 ([M+H]+.

Example 53

[(3S,4S)-1-(3-Chlorobenzenesulfonyl)-4-(4-forfinal)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano

stage 1: Analogously to example 46, stage 1-2, 1-tert-butyl ester 3-methyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (CAS Reg. No. [161491-25-4]) and bromide 4-forfinancing received 1-tert-butyl ester 4-(4-forfinal)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid as a white foam, MS: 320,5 ([M-N])-.

Stage 2: same as example 46, step 3, from 1-tert-butyl ester 4-(4-forfinal)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid, using [Ru(OAc)2((R)-MeOBIPHEP)] as a catalyst for enantioselective hydrogenation, received 1-tert-butyl ether (-)-(3S,4S)-4-(4-forfinal)piperidine-1,3-dicarboxylic acid in the form of a whitish solid, MS: 322,5 ([M+H])+.

Stage 3: same as example 1, step 1, from 1-tert-butyl ether (-)-(3S,4S)-4-(4-forfinal)piperidine-1,3-dicarboxylic acid and 1-(5-chloro-2-were)piperazine was obtained tert-butyl ether (3S,4S)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-(4-forfinal)piperidine-1-carboxylic acid in the form of white foam, MS: 516,3 ([M+H, 1Cl])+.

Stage 4: Analogously to example 22, step 4, tert-butyl methyl ether (3S,4S)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-(4-forfinal)piperidine-1-carboxylic acid was obtained hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-(4-forfinal)piperidine-3-yl]methanone in the form of a white foam, MS: 416,4 ([M+H, 1Cl])+.

Stage 5: Analogously to example , stage 3, from hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-(4-forfinal)piperidine-3-yl]methanone and 3-chlorobenzenesulfonamide received [(3S,4S)-1-(3-chlorobenzenesulfonyl)-4-(4-forfinal)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano in the form of white foam, MS: 590,3 ([M+H, 1Cl])+.

Example 54

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-(4-forfinal)-1-(2-trifloromethyl)piperidine-3-yl]metano

Analogously to example 1, stage 3, hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-(4-forfinal)piperidine-3-yl]methanone and 2-(trifluoromethyl)benzosulfimide received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-(4-forfinal)-1-(2-trifloromethyl)piperidine-3-yl]metano in the form of a white foam, MS: 624,2 ([M+H, 1Cl])+.

Example 55

[(3S,4R)-1-(3-Chlorobenzenesulfonyl)-4-(4-forfinal)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano

Stage 1: Analogously to example 46, step 3, from 1-tert-butyl ester 4-(4-forfinal)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid, using [Ru(OAc)2((S)-(3,5-Xyl,4-MeO-MeOBIPHEP)] as catalyst for the enantioselective hydrogenation received 1-tert-butyl ether (3R,4R)-4-(4-forfinal)piperidine-1,3-dicarboxylic acid as a white foam, MS: 322,5 ([M-N])-.

Stage 2: Analogously to example 52, steps 2-3, 1-tert-butyl ether (3R,4R)-4-(4-forfinal)piperidine-1,3-di is arbonboy acid was obtained 1-tert-butyl ether (3S,4R)-4-(4-forfinal)piperidine-1,3-dicarboxylic acid as a white foam, MS: 322,5 ([M-N])-.

Stage 3: same as example 1, step 1, from 1-tert-butyl ether (3S,4R)-4-(4-forfinal)piperidine-1,3-dicarboxylic acid and 1-(5-chloro-2-were)piperazine was obtained tert-butyl ether (3S,4R)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-(4-forfinal)piperidine-1-carboxylic acid as light yellow foam MS: 516,3 ([M+H, 1Cl])+.

Stage 4: Analogously to example 22, step 4, tert-butyl methyl ether (3S,4R)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-(4-forfinal)piperidine-1-carboxylic acid was obtained hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-(4-forfinal)piperidine-3-yl]methanone in the form of a white foam, MS: 416,4 ([M+H, 1Cl])+.

Stage 5: Analogously to example 1, stage 3, hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-(4-forfinal)piperidine-3-yl]methanone and 3-chlorobenzenesulfonamide received [(3S,4R)-1-(3-chlorobenzenesulfonyl)-4-(4-forfinal)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano in the form of a white foam, MS: 590,3 ([M+H, 1Cl])+.

Example 56

[(3S,4R)-1-(2-Chlorobenzenesulfonyl)-4-(4-forfinal)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano

Analogously to example 1, stage 3, hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-(4-forfinal)piperidine-3-yl]methanone and 2-chlorobenzenesulfonamide received [(3S,4R)-1-(2-chlorobenzenesulfonyl)-4-(4-forfinal)piperidine-3-yl]-[4-(5-chlorine is-2-were)piperazine-1-Il]metano in the form of a white foam, MS: 590,3 ([M+H, 1Cl])+.

Example 57

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-(4-forfinal)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano

Analogously to example 1, stage 3, hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-(4-forfinal)piperidine-3-yl]methanone and pyridine-3-sulphonylchloride received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-(4-forfinal)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano in the form of a white foam, MS: 557,1 ([M+H, 1Cl])+.

Example 58

[(3S,4S)or (3R,4R)-1-(3-Chlorobenzenesulfonyl)-4-(2-fluoro-4-were)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano

Stage 1: Analogously to example 46, step 1, from 1-tert-butyl ester 3-methyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (CAS Reg. No. [161491-25-4]) and bromide 2-fluoro-4-methylpentane (CAS Reg. No. [737797-14-7]) received 1-tert-butyl ester 3-methyl ester 4-(2-fluoro-4-were)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid as a light yellow oil, MS: 350,4 ([M+H])+.

Stage 2: same as example 46, step 2, from 1-tert-butyl ester 3-methyl ester 4-(2-fluoro-4-were)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid was obtained 1-tert-butyl ester 4-(2-fluoro-4-were)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid as a white solid, MS: 334,2 (M-N])-.

Stage 3: same as example 46, step 3, from 1-the pet-butyl ester 4-(2-fluoro-4-were)-5,6-dihydro 2H-pyridine-1,3-dicarboxylic acid, using [Ru(SLA)2((R)-(2-furyl)-MeOBIPHEP)] as catalyst for the enantioselective hydrogenation received 1-tert-butyl ether (3S,4S)or (3R,4R)-4-(2-fluoro-4-were)piperidine-1,3-dicarboxylic acid as a white foam, MS: 336,2 (M-N])-; [α]D=-62,82 (=0,962 g/100 ml CHCl3).

Stage 4: Analogously to example 1, step 1, from 1-tert-butyl ether (3S,4S)or (3R,4R)-4-(2-fluoro-4-were)piperidine-1,3-dicarboxylic acid and 1-(5-chloro-2-were)piperazine was obtained tert-butyl ether (3S,4S)or (3R,4R)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-(2-fluoro-4-were)piperidine-1-carboxylic acid as a white foam, MS: us $ 530, 3 ([M+H, 1Cl])+.

Stage 5: Analogously to example 22, step 4, tert-butyl methyl ether (3S,4S)or (3R,4R)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-(2-fluoro-4-were)piperidine-1-carboxylic acid was obtained the hydrochloride of (3S,4S)or (3R,4R)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)piperidine-3-yl]methanone in the form of a crude product, MS: 430,4 ([M+H, 1Cl])+.

Stage 6: Analogously to example 1, stage 3, hydrochloride (3S,4S)or (3R,4R)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)piperidine-3-yl]methanone and 3-chlorobenzenesulfonamide received [(3S,4S)or (3R,4R)-1-(3-chlorobenzenesulfonyl)-4-(2-fluoro-4-were)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano in the form of a white foam, MS: 604,1 ([M+H, 1Cl])+;[α] D=+14,03 (=0,442 g/100 ml CHCl3).

Example 59

[(3S,4S)or (3R,4R)-1-(2-Chlorobenzenesulfonyl)-4-(2-fluoro-4-were)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano

Analogously to example 1, stage 3, hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-(2-fluoro-4-were)piperidine-3-yl]methanone and 2-chlorobenzenesulfonamide received [(3S,4S)or (3R,4R)-1-(2-chlorobenzenesulfonyl)-4-(2-fluoro-4-were)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano in the form of a white foam, MS: 604,1 ([M+H, 1Cl])+; [α]D=-8,8 (c=0,659 g/100 ml CHCl3).

Example 60

(3S,4S)or (3R,4R)-[4-(5-Chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)-1-(2-trifloromethyl)piperidine-3-yl]metano

Analogously to example 1, stage 3, hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-(2-fluoro-4-were)piperidine-3-yl]methanone and 2-(trifluoromethyl)benzosulfimide was obtained (3S,4S)or (3R,4R)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)-1-(2-trifloromethyl)piperidine-3-yl]metano in the form of a white foam, MS: 638,3 ([M+H, 1Cl])+; [α]D=-13,63 (=0,477 g/100 ml CHCl3).

Example 61

(3S,4S)or (3R,4R)-[4-(5-Chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano

Analogously to example 1, stage 3, hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-(2-fluoro-4-were)p is piridin-3-yl]methanone hydrochloride and pyridine-3-sulphonylchloride was obtained (3S,4S)or (3R,4R)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano in the form of a white foam, MS: 571,3 ([M+H, 1Cl])+; [α]D=+0,67 (=0,446 g/100 ml CHCl3).

Example 62

(3S,4S)or (3R,4R)-[4-(5-Chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)-1-(propane-2-sulfonyl)piperidine-3-yl]metano

Analogously to example 1, stage 3, hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-(2-fluoro-4-were)piperidine-3-yl]methanone and 2-propanesulfinamide was obtained (3S,4S)or (3R,4R)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)-1-(propane-2-sulfonyl)piperidine-3-yl]metano in the form of a white foam, MS: 536,4 ([M+H, 1Cl])+; [α]D=-16,22 (=0,746 g/100 ml CHCl3).

Example 63

[(3S,4R)-1-(3-Chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano

Stage 1: Analogously to example 52, steps 2-3, 1-tert-butyl ether (3R,4R)-4-phenylpiperidine-1,3-dicarboxylic acid (CAS Reg. No.: [197900-84-8]) received 1-tert-butyl ether (3S,4S)-4-phenylpiperidine-1,3-dicarboxylic acid in the form of a whitish solid, MS: 304,3 (M-N])-.

Stage 2: Analogously to example 1, step 1, from 1-tert-butyl ether (3S,4S)-4-phenylpiperidine-1,3-dicarboxylic acid and 1-(5-chloro-2-were)piperazine was obtained tert-butyl ether (3S,4R)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-phenylpiperidine-1-carboxylic acid (Cas Reg. No. [652971-20-5]) in the form of a white foam, MS: 500,5 ([M+H, 1Cl])+.

Stage 3: same as example 22, step 4, tert-butyl EF is RA (3S,4R)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-phenylpiperidine-1-carboxylic acid and 1-(5-chloro-2-were)piperazine was obtained hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4R)-4-phenylpiperidine-3-yl)methanone in the form of white foam, MS: 400,5 ([M+H, 1Cl])+.

Stage 4: Analogously to example 1, step 3, using isorg2NEt as a base and CH2Cl2as a solvent, hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4R)-4-phenylpiperidine-3-yl)methanone and 3-chlorobenzenesulfonamide received [(3S,4R)-1-(3-chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano in the form of a white foam, MS: 572,15 ([M+H, 1Cl])+.

Example 64

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-phenyl-1-(2-trifloromethyl)piperidine-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4R)-4-phenylpiperidine-3-yl)methanone and 2-(trifluoromethyl)benzosulfimide received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-phenyl-1-(2-trifloromethyl)piperidine-3-yl]metano in the form of a white foam MS: 606,2 ([M+H, 1Cl])+.

Example 65

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-phenyl-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4R)-4-phenylpiperidine-3-yl)methanone hydrochloride and pyridine-3-sulphonylchloride received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-phenyl-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano in the form of white foam, MS: to 539.3 ([M+H, 1Cl])+.

Example 66

[(3S,4R)-1-(3-Harbin alsultany)-4-o-tripeptides-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano

Stage 1: Analogously to example 46, step 1, from 1-tert-butyl ester 4-o-tolyl-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid, using [Ru(OAc)2((S)-(BITIANP))] as catalyst for the enantioselective hydrogenation received 1-tert-butyl ether (3R,4R)-4-o-tripeptides-1,3-dicarboxylic acid as a white foam, MS: 318,2 ([M-N])-.

Stage 2: Analogously to example 52, steps 2-3, 1-tert-butyl ether (3R,4R)-4-o-tripeptides-1,3-dicarboxylic acid was obtained 1-tert-butyl ether (3S,4R)-4-o-tripeptides-1,3-dicarboxylic acid as a white solid, MS: 318,4 ([M-N])-.

Stage 3: same as example 1, step 1, from 1-tert-butyl ether (3S,4R)-4-o-tripeptides-1,3-dicarboxylic acid and 1-(5-chloro-2-were)piperazine was obtained tert-butyl ether (3S,4R)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-o-tripeptides-1-karbonvansty in the form of a white foam, MS: 512,5 ([M+H])+.

Stage 4: Analogously to example 22, step 4, tert-butyl methyl ether (3S,4R)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-o-tripeptides-1-carboxylic acid was obtained hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4R)-4-o-tripeptides-3-yl)methanone in the form of a crude product, MS: 512,5 ([M+H, 1Cl])+.

Stage 5: Analogously to example 63, step 4, of the hydrochloride of 4-(5-chloro-2-were)piperazine-1-yl]-((3S,4R)-4-o-tripeptides-3-yl)methanone and 3 is albenzaalbenza received [(3S,4R)-1-(3-chlorobenzenesulfonyl)-4-o-tripeptides-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano in the form of a white foam, MS: 586,1 ([M+H, 1Cl])+.

Example 67

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-o-tolyl-1-(2-trifloromethyl)piperidine-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride of 4-(5-chloro-2-were)piperazine-1-yl]-((3S,4R)-4-o-tripeptides-3-yl)methanone and 2-(trifluoromethyl)benzosulfimide received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-o-tolyl-1-(2-trifloromethyl)piperidine-3-yl]metano in the form of a white foam, MS: 620,3 ([M+H, 1Cl])+.

Example 68

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4R)-1-(pyridine-3-sulfonyl)-4-o-tripeptides-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride of 4-(5-chloro-2-were)piperazine-1-yl]-((3S,4R)-4-o-tripeptides-3-yl)methanone hydrochloride and pyridine-3-sulphonylchloride received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-1-(pyridine-3-sulfonyl)-4-o-tripeptides-3-yl]metano in the form of a white foam, MS: 553,2 ([M+H, 1Cl])+.

Example 69

[(3S,4R)- or (3R,4S)-1-(3-Chlorobenzenesulfonyl)-4-(2,4-differenl)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano

Stage 1: Analogously to example 46, step 1, from 1-tert-butyl ester 3-methyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (CAS Reg. No. [161491-25-4]) and bromide 2,4-difconference received 1-tert-butyl ester 4-(2,4-differenl)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid in the ideal light yellow oil, MS: 354,2 (M+N)+.

Stage 2: same as example 46, step 2, from 1-tert-butyl ester 3-methyl ester 4-(2,4-differenl)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid was obtained 1-tert-butyl ester 4-(2,4-differenl)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid as a white solid, 338,1 (M-N)-.

Stage 3: same as example 46, step 3, from 1-tert-butyl ester 4-(2,4-differenl)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid, using [Ru(OAc)2((S)-(BITIANP))] as catalyst for the enantioselective hydrogenation received 1-tert-butyl ether (3R,4R)- or (3S,4S)-4-(2,4-differenl)piperidine-1,3-dicarboxylic acid as a white solid, MS: 340,1 ([M-N])-; [α]D=+61,90 (=0,806 g/100 ml CHCl3).

Stage 4: Analogously to example 52, steps 2-3, 1-tert-butyl ether (3R,4R)- or (3S,4S)-4-(2,4-differenl)piperidine-1,3-dicarboxylic acid was obtained 1-tert-butyl ether (3S,4R)- or (3R,4S)-4-(2,4-differenl)piperidine-1,3-dicarboxylic acid in the form of a white foam, MS: 340,4 ([M-N])-; [α]D=-8,11 (=0,271 g/100 ml CHCl3).

Stage 5: Analogously to example 1, step 1, from 1-tert-butyl ether (3S,4R)- or (3R,4S)-4-(2,4-differenl)piperidine-1,3-dicarboxylic acid and 1-(5-chloro-2-were)piperazine was obtained tert-butyl ether (3S,4R)- or (3R,4S)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-(2,4-differenl)piperidine-1-ka is oil acid as a white foam, MS: 534,2 ([M+H, 1Cl])+.

Stage 6: Analogously to example 22, step 4, tert-butyl methyl ether (3S,4R)- or (3R,4S)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-(2,4-differenl)piperidine-1-carboxylic acid was obtained the hydrochloride of (3S,4R)- or (3R,4S)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2,4-differenl)piperidine-3-yl]methanone in the form of a crude product, MS: 434,3 ([M+H, 1Cl])+.

Stage 7: Analogously to example 63, step 4, of the hydrochloride of (3S,4R)- or (3R,4S)-[4-(5-chloro-2-were)piperazine-1-yl]-[-4-(2,4-differenl)piperidine-3-yl]methanone and 3-chlorobenzenesulfonamide received [(3S,4R)- or (3R,4S)-1-(3-chlorobenzenesulfonyl)-4-(2,4-differenl)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano in the form of a white foam, MS: 607,1 ([M+H, 1Cl])+; [α]D=-66,8 (=0,434 g/100 ml CHCl3).

Example 70

(3S,4R)- or (3R,4S)-[4-(5-Chloro-2-were)piperazine-1-yl]-[4-(2,4-differenl)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride of (3S,4R)- or (3R,4S)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2,4-differenl)piperidine-3-yl]methanone hydrochloride and pyridine-3-sulphonylchloride was obtained (3S,4R)- or (3R,4S)-[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-(2,4-differenl)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano in the form of a white foam, MS: 575,4 ([M+H, 1Cl])+; [α]D=-66,76 (=0,454 g/100 ml CHCl3).

Example 71

[(3S,4S)-1-(3-Chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl][4-(5-chloro-2-were)piperazine-1-yl]metano

Stage 1: Analogously to example 1, step 1, from 1-tert-butyl ether (3S,4S)-4-phenylpiperidine-1,3-dicarboxylic acid (CAS Reg. No.: [197900-77-9]) and 1-(5-chloro-2-were)piperazine was obtained tert-butyl ether (3S,4S)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-phenylpiperidine-1-carboxylic acid as a white foam, MS: 498,5 ([M+H, 1Cl])+.

Stage 2: Analogously to example 22, step 4, tert-butyl methyl ether (3S,4S)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-phenylpiperidine-1-carboxylic acid was obtained hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-4-phenylpiperidine-3-yl)methanone in the form of a crude product, MS: 398,4 ([M+H, 1Cl])+.

Stage 3: Analogously to example 63, step 4, of the hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-4-phenylpiperidine-3-yl)methanone and 3-chlorobenzenesulfonamide received [(3S,4S)-1-(3-chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano in the form of a white foam, MS: 572,2 ([M+H, 1Cl])+.

Example 72

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-phenyl-1-(2-trifloromethyl)piperidine-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-4-phenylpiperidine-3-yl)methanone and 2-(trifluoromethyl)benzosulfimide received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-phenyl-1-(2-trifloromethyl)piperidine-3-yl]metano as a white foam, MS: 606,0 ([M+H, 1Cl])+.

Example 73

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-phenyl-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-4-phenylpiperidine-3-yl)methanone hydrochloride and pyridine-3-sulphonylchloride received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-phenyl-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano in the form of white foam, MS: 539,2 ([M+H, 1Cl])+.

Example 74

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-phenyl-1-(propane-2-sulfonyl)piperidine-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-4-phenylpiperidine-3-yl)methanone and 2-propanesulfinamide received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-phenyl-1-(propane-2-sulfonyl)piperidine-3-yl]metano in the form of a white foam, MS: 504,1 ([M+H, 1Cl])+.

Example 75

[4-(5-Chloro-2-were)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-phenylpiperidine-3-yl)methanon

Analogously to example 63, step 4, of the hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-4-phenylpiperidine-3-yl)methanone and methanesulfonanilide received [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-phenylpiperidine-3-yl)methanon in the form of a white foam, MS: 476,1 ([M+H, 1Cl])+.

Example 76

[(3S,4S)-1-(3-Chlorobenzenesulfonyl)-4-o-tripeptides-3-yl]-[4-(5-chloro-2-were)PI is erasin-1-yl]metano

Stage 1: Analogously to example 1, step 1, from 1-tert-butyl ether (3S,4S)-4-o-tripeptides-1,3-dicarboxylic acid (example 46, step 3) and 1-(5-chloro-2-were)piperazine was obtained tert-butyl ether (3S,4S)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-o-tripeptides-1-carboxylic acid as a white foam, MS: 512,3 ([M+H, 1Cl])+.

Stage 2: Analogously to example 22, step 4, tert-butyl methyl ether (3S,4S)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-o-tripeptides-1-carboxylic acid was obtained hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-4-o-tripeptides-3-yl)methanone as a crude product, MS: 412,5 ([M+H, 1Cl])+.

Stage 3: Analogously to example 63, step 4, of the hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-4-o-tripeptides-3-yl)methanone and 3-chlorobenzenesulfonamide received [(3S,4S)-1-(3-chlorobenzenesulfonyl)-4-o-tripeptides-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano in the form of a white foam, MS: 586,2 ([M+H, 1Cl])+.

Example 77

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-o-tolyl-1-(2-trifloromethyl)piperidine-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-4-o-tripeptides-3-yl)methanone and 2-(trifluoromethyl)benzosulfimide received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-o-tolyl-1-(2-trifloromethyl)PI is uridin-3-yl]metano in the form of a white foam, MS: 620,5 ([M+H, 1Cl])+.

Example 78

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4S)-1-(pyridine-3-sulfonyl)-4-o-tripeptides-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-4-o-tripeptides-3-yl)methanone hydrochloride and pyridine-3-sulphonylchloride received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-1-(pyridine-3-sulfonyl)-4-o-tripeptides-3-yl]mechanon in the form of a white foam, MS: 553,2 ([M+H, 1Cl])+.

Example 79

[4-(5-Chloro-2-were)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-o-tripeptides-3-yl)methanon

Analogously to example 63, step 4, of the hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-4-o-tripeptides-3-yl)methanone and methanesulfonanilide received [4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-o-tripeptides-3-yl)methanon in the form of a white foam, MS: 490,2 ([M+H, 1Cl])+.

Example 80

[(3S,4S)or (3R,4R)-1-(3-Chlorobenzenesulfonyl)-4-(4-fluoro-2-were)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano

Stage 1: Analogously to example 46, stage 1-2, 1-tert-butyl ester 3-methyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (CAS Reg. No. [161491-25-4]) and bromide 4-fluoro-6-methylphenylene (previously obtained from 4-fluoro-6-methylphenylethylamine and zinc chloride) was obtained 1-tert-butyl ester 4-(4-fluoro-2-were)-5,6-digit what-2H-pyridine-1,3-dicarboxylic acid as a white solid, MS: 334,3 (M-N])-.

Stage 2: same as example 46, step 3, from 1-tert-butyl ester 4-(4-fluoro-2-were)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid, using [Ru(SLA)2((R)-(2-furyl)-MeOBIPHEP)] as catalyst for the enantioselective hydrogenation received 1-tert-butyl ether (3S,4S)or (3R,4R)-4-(4-fluoro-2-were)piperidine-1,3-dicarboxylic acid as a white foam, MS: 336,2 (M-N])-; [α]D=-52,53 (=0,643 g/100 ml CHCl3).

Stage 3: same as example 1, step 1, from 1-tert-butyl ether (3S,4S)or (3R,4R)-4-(4-fluoro-2-were)piperidine-1,3-dicarboxylic acid and 1-(5-chloro-2-were)piperazine was obtained tert-butyl ether (3S,4S)or (3R,4R)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-(4-fluoro-2-were)piperidine-1-carboxylic acid as a white foam, MS: 530,2 ([M+H, 1Cl])+.

Stage 4: Analogously to example 22, step 4, tert-butyl methyl ether (3S,4S)or (3R,4R)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-(4-fluoro-2-were)piperidine-1-carboxylic acid was obtained hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)piperidine-3-yl]methanone as a crude product, MS: 430,4 ([M+H, 1Cl])+.

Stage 5: Analogously to example 63, step 4, of the hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)piperidine-3-yl]methanone and 3-chlorobenzenesulfonamide recip is whether [(3S,4S)or (3R,4R)-1-(3-chlorobenzenesulfonyl)-4-(4-fluoro-2-were)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano in the form of a white foam, MS: 604,0 ([M+H, 1Cl])+; [α]D=-32,13 (=0,426 g/100 ml CHCl3).

Example 81

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)-1-(2-trifloromethyl)piperidine-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)piperidine-3-yl]methanone and 2-(trifluoromethyl)benzosulfimide received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)-1-(2-trifloromethyl)piperidine-3-yl]metano in the form of a white foam, MS: 638,2 ([M+H, 1Cl])+; [α]D=-60,75 (=0,423 g/100 ml CHCl3).

Example 82

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)piperidine-3-yl]methanone hydrochloride and pyridine-3-sulphonylchloride received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano in the form of a white foam, MS: 571,2 ([M+H, 1Cl])+; [α]D=-49,92 (=0,535 g/100 ml CHCl3).

Example 83

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)-1-methanesulfonamido-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride [4-(5-chloro-2-METI is phenyl)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)piperidine-3-yl]methanone and methanesulfonanilide received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)-1-methanesulfonamido-3-yl]metano in the form of a white foam, MS: 508,3 ([M+H, 1Cl])+; [α]D=-77,86 (=0,434 g/100 ml CHCl3).

Example 84

[(3S,4S)or (3R,4R)-1-(3-Chlorobenzenesulfonyl)-4-(2,4-differenl)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano

Stage 1: Analogously to example 46, step 1, from 1-tert-butyl ester 3-methyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (CAS Reg. No. [161491-25-4]) and bromide 2,4-difconference received 1-tert-butyl ester 3-methyl ester 4-(2,4-differenl)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid as a light yellow oil, MS: 354,2 ([M+H])+.

Stage 2: same as example 46, step 2, from 1-tert-butyl ester 3-methyl ester 4-(2,4-differenl)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid was obtained 1-tert-butyl ester 4-(2,4-differenl)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid as a white solid, MS: 338,0 (M-N])-.

Stage 3: same as example 46, step 3, from 1-tert-butyl ester 4-(2,4-differenl)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid, using [Ru(OAc)2((S)-(BITIANP))] as catalyst for the enantioselective hydrogenation received 1-tert-butyl ether (3S,4S)or (3R,4R)-4-(2,4-differenl)piperidine-1,3-dicarboxylic acid as a white solid, MS: 340,1 (M-N])-; [α]D=-61,33 (=0,473 g/100 ml CHCl3).

Stage 4: Analogously to example 1, tadia 1, from 1-tert-butyl ether (3S,4S)or (3R,4R)-4-(2,4-differenl)piperidine-1,3-dicarboxylic acid and 1-(5-chloro-2-were)piperazine was obtained tert-butyl ether (3S,4S)or (3R,4R)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-(2,4-differenl)piperidine-1-carboxylic acid in the form of white foam, MS: 534,2 ([M+H, 1Cl])+.

Stage 5: Analogously to example 22, step 4, tert-butyl methyl ether (3S,4S)or (3R,4R)-3-[4-(5-chloro-2-were)piperazine-1-carbonyl]-4-(2,4-differenl)piperidine-1-carboxylic acid was obtained hydrochloride [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)piperidine-3-yl]methanone in the form of a crude product, MS: 434,5 ([M+H, 1Cl])+.

Stage 6: Analogously to example 63, step 4, of the hydrochloride of 4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)piperidine-3-yl]methanone and 3-chlorobenzenesulfonamide received [(3S,4S)or (3R,4R)-1-(3-chlorobenzenesulfonyl)-4-(2,4-differenl)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano in the form of a white foam, MS: 608,0 ([M+H, 1Cl])+; [α]D=+10,71 (=0,392 g/100 ml CHCl3).

Example 85

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-(2-trifloromethyl)piperidine-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride of 4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)piperidine-3-yl]methanone and 2-(trifluoromethyl)benzonal is vanilloid received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-(2-trifloromethyl)piperidine-3-yl]metano in the form of a white foam, MS: 642,3 ([M+H, 1Cl])+; [α]D=-22,86 (=0,442 g/100 ml CHCl3).

Example 86

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride of 4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)piperidine-3-yl]methanone hydrochloride and pyridine-3-sulphonylchloride received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano in the form of a white foam, MS: 575,3 ([M+H, 1Cl])+; [α]D=-5,09 (=0,746 g/100 ml CHCl3).

Example 87

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-methanesulfonamido-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride of 4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)piperidine-3-yl]methanone and methanesulfonanilide received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-methanesulfonamido-3-yl]metano in the form of a white foam, MS: 512,1 ([M+H, 1Cl])+; [α]D=-44,38 (=0,388 g/100 ml CHCl3).

Example 88

[4-(5-Chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-(propane-2-sulfonyl)piperidine-3-yl]metano

Analogously to example 63, step 4, of the hydrochloride of 4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)piperidine-3-yl]metano and 2-propanesulfinamide received [4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-(propane-2-sulfonyl)piperidine-3-yl]metano in the form of a white foam, MS: 540,3 ([M+H, 1Cl])+; [α]D=-36,27 (=0,623 g/100 ml CHCl3).

Example

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

Ingredients

Kernel:

The compound of formula (I)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Anhydrous lactose60,0 mg70.0 mg
Povidone K12.5 mg15,0 mg
Nitroglicerine starch12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(Kernel weight)120,0 mg350,0 mg

Film coating:

The hypromellose3.5 mg7,0 mg
Polyethylene glycol 60000.8 mg1.6 mg
Talc1.3 mg2.6 mg
Iron oxide (yellow)0.8 mg1.6 mg
Titanium dioxide0.8 mg1.6 mg

The active ingredient was sieved and mixed with microcrystalline cellulose and the mixture was granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with Nitroglycerinum starch and magnesium stearate and pressed to obtain cores 120 or 350 mg, respectively. Cores were covered with aq. a solution/suspension of the above film coating.

Example B

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

IngredientsOn capsule
The compound of formula (I)25.0 mg
Lactose150,0 mg
Corn starch20.0 mg
That is RC 5.0 mg

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

The example In

Injectable solutions may have the following composition:

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

Example D

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

The contents of the capsules

The compound of formula (I)5.0 mg
Yellow wax8.0 mg
Hydrogencarbon the soybean oil 8.0 mg
Partially hydrogenated vegetable oil34,0 mg
Soybean oil110,0 mg
The weight of the contents of the capsules165,0 mg

Gelatin capsule

Gelatin75,0 mg
Glycerol 85%32,0 mg
The Karion 838.0 mg (dry matter)
Titanium dioxide0.4 mg
Iron oxide yellow1.1 mg

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

Example D

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

The compound of formula (I)50.0 mg
Lactose, onlinelicensing powder 1015,0 mg
Microcristalina cellulose (AVICEL PH 102)1400,0 mg
The sodium carboxymethyl cellulose14,0 mg
Polyvinylpyrrolidone K10.0 mg
Magnesium stearate10.0 mg
Odorants1.0 mg

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

1. The compounds of formula (I):

where X represents N or CH;
Y represents N or CH;
R1represents lower alkyl, phenyl, phenyl-lower alkyl, where phenyl optionally may be substituted by 1-2 substituents independently selected from the group consisting of halogen, lower alkyl;
R2represents lower alkyl, phenyl, naphthyl or heteroaryl selected from dimethylisoxazole, chinoline, thiophenyl or pyridinyl, where phenyl or heteroaryl optionally can be substituted by 1 Deputy independently selected the C group, consisting of halogen, lower alkoxygroup, fluoro-lower alkyl, lower alkoxy-carbonyl and phenyl;
R3represents phenyl, pyridinyl or pyrazinyl, where the phenyl, pyridinyl or pyrazinyl substituted by 1-2 substituents independently selected from the group consisting of halogen, lower alkyl and fluoro-lower alkyl;
R4, R5, R6, R7, R8, R9, R10and R11independently of one another represent hydrogen,
and their pharmaceutically acceptable salts.

2. Compounds according to claim 1, where X represents N.

3. Compounds according to claim 1, where X represents CH.

4. Compounds according to claim 1, where Y is N.

5. Compounds according to claim 1, where R1represents lower alkyl or phenyl, where phenyl optionally substituted by 1 or 2 substituents, independently selected from the group consisting of halogen and lower alkyl.

6. Compounds according to claim 1, where R1represents n-butyl, phenyl, 4-fluoro-2-were, 2nd were, 4-forfinal, 2-fluoro-4-were or 2,4-differenl.

7. Compounds according to claim 1, where R2represents lower alkyl, phenyl or heteroaryl selected from the group consisting of chinoline and pyridinyl, where phenyl or heteroaryl optionally substituted by 1 Deputy independently selected from the group consisting of halogen, lower alkoxygroup and fluoro-lower and the Qila.

8. Compounds according to claim 1, where R2represents methyl, isopropyl, 3-methoxyphenyl, 3-chlorophenyl, 2-triptoreline, quinoline-8-yl or pyridin-3-yl.

9. Compounds according to claim 1, where R3represents phenyl or pyrazinyl, where phenyl or pyrazinyl substituted by 1 or 2 substituents, independently selected from the group consisting of halogen and lower alkyl.

10. Compounds according to claim 1, where R3is a 2.5 dimetilfenil, 2-methyl-5-chlorophenyl, 2,5-dichlorophenyl or 3,6-dimethylpyrazine-2-yl.

11. Compounds according to claim 1, selected from the group consisting of the following compounds:
[4-(2,5-dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]metano,
[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,
[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano,
(-)-[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano,
[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-(4-o-tailpipes-1-yl)methanon,
[4-(2,5-dichlorophenyl)piperazine-1-yl]-[4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-yl]metano,
[4-(2,5-dimetilfenil)piperazine-1-yl][4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-yl]metano,
[4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano,
[4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,
[4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[1-benzyl-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
(-)-[1-benzyl-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[1-benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[1-benzyl-4-(3,5-dimethylisoxazol-4-sulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[4-(3-chlorobenzenesulfonyl)-1-propylpiperidine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[1-butyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[4-(3-chlorobenzenesulfonyl)-1-pentylpyridine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[4-(3-chlorobenzenesulfonyl)-1-isobutylpyrazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[4-(3-chlorobenzenesulfonyl)-1-feiticeira-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[4-(4-chlorobenzenesulfonyl)-1-pentylpyridine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[1-a bout the l-4-(4-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[4-(4-chlorobenzenesulfonyl)-1-phenylpiperazin-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[4-(2-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano,
[4-(2-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,
[4-(2-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[4-(2,5-dichlorophenyl)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-yl]metano,
[4-(2,5-dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-yl]metano,
[1-(4-fluoro-2-were)-4-(naphthalene-1-sulfonyl)piperazine-2-yl]-[4-(3-triptorelin-2-yl)piperazine-1-yl]metano,
[4-(2,5-dichlorophenyl)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-yl]metano,
[4-(2,5-dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-yl]metano,
[4-(2,5-dichlorophenyl)piperazine-1-yl]-[4-(propane-2-sulfonyl)-1-o-tailpipes-2-yl]metano,
[4-(biphenyl-4-sulfonyl)-1-o-tailpipes-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1-yl]metano,
marked the th ether 3-{3-[4-(2,5-dichlorophenyl)piperazine-1-carbonyl]-4-o-tailpipes-1-sulfonyl}thiophene-2-carboxylic acid,
[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon,
[1-benzyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon,
[4-(3-chlorophenyl)piperidine-1-yl]-[1-(4-fluoro-2-were)-4-(propane-2-sulfonyl)piperazine-2-yl]metano,
[4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon,
CIS-[4-(2,5-dimetilfenil)piperazine-1-yl]-[-1-(3-methoxybenzenesulfonyl)-4-phenylpiperidine-3-yl]metano,
[4-(2,5-dimetilfenil)piperazine-1-yl]-[(3S,4S)-1-(3-methoxybenzenesulfonyl)-4-phenylpiperidine-3-yl]metano,
[TRANS-1-(3-chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[TRANS-1-(3,5-dimethylisoxazol-4-sulfonyl)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[4-(2,5-dimetilfenil)piperazine-1-yl]-[(3S,4S)-1-(3-methoxybenzenesulfonyl)-4-o-tripeptides-3-yl]metano,
[(3S,4S)-1-(3-chlorobenzenesulfonyl)-4-o-tripeptides-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[4-(2,5-dimetilfenil)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-o-tripeptides-3-yl)methanon,
[(3S,4S)-1-(3-chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[4-(2,5-dimetilfenil)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-phenylpiperidine-3-yl)methanon,
[(3R,4R)-1-(3-chlorbenzol Lionel)-4-phenylpiperidine-3-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[4-(2,5-dimetilfenil)piperazine-1-yl]-[(3S,4R)-1-(3-methoxybenzenesulfonyl)-4-o-tripeptides-3-yl]metano,
[(3S,4S)-1-(3-chlorobenzenesulfonyl)-4-(4-forfinal)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-(4-forfinal)-1-(2-trifloromethyl)piperidine-3-yl]metano,
[(3S,4R)-1-(3-chlorobenzenesulfonyl)-4-(4-forfinal)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,
[(3S,4R)-1-(2-chlorobenzenesulfonyl)-4-(4-forfinal)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-(4-forfinal)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,
[(3S,4S)or (3R,4R)-1-(3-chlorobenzenesulfonyl)-4-(2-fluoro-4-were)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,
[(3S,4S)or (3R,4R)-1-(2-chlorobenzenesulfonyl)-4-(2-fluoro-4-were)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,
(3S,4S)or (3R,4R)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)-1-(2-trifloromethyl)piperidine-3-yl]metano,
(3S,4S)or (3R,4R)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,
(3S,4S)or (3R,4R)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)-1-(propane-2-sulfonyl)piperidine-3-yl]metano,
[(3S,4R)-1-(3-chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]Manon,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-phenyl-1-(2-trifloromethyl)piperidine-3-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-phenyl-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,
[(3S,4R)-1-(3-chlorobenzenesulfonyl)-4-o-tripeptides-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-o-tolyl-1-(2-trifloromethyl)piperidine-3-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-1-(pyridine-3-sulfonyl)-4-o-tripeptides-3-yl]metano,
[(3S,4R)- or (3R,4S)-1-(3-chlorobenzenesulfonyl)-4-(2,4-differenl)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,
(3S,4R)- or (3R,4S)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2,4-differenl)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,
[(3S,4S)-1-(3-chlorobenzenesulfonyl)-4-phenylpiperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-phenyl-1-(2-trifloromethyl)piperidine-3-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-phenyl-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-4-phenyl-1-(propane-2-sulfonyl)piperidine-3-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-phenylpiperidine-3-yl)methanon,
[(3S,4S)-1-(3-chlorobenzenesulfonyl)-4-o-tripeptides-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)-1-(pyridine-3-sulfonyl)-4-o-tripeptides-3-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-((3S,4S)-1-methanesulfonyl-4-o-tripeptides-3-yl)methanon,
[(3S,4S)or (3R,4R)-1-(3-chlorobenzenesulfonyl)-4-(4-fluoro-2-were)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)-1-(2-trifloromethyl)piperidine-3-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(4-fluoro-2-were)-1-methanesulfonamido-3-yl]metano,
[(3S,4S)or (3R,4R)-1-(3-chlorobenzenesulfonyl)-4-(2,4-differenl)piperidine-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S or 3R,4R)-4-(2,4-differenl)-1-(2-trifloromethyl)piperidine-3-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-methanesulfonamido-3-yl]metano and
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-(propane-2-sulfonyl)piperidine-3-yl]metano, and
their pharmaceutically acceptable salts.

12. Compounds according to claim 1, selected is from the group consisting of the following compounds:
[4-(2,5-dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(3-methoxybenzenesulfonyl)piperazine-2-yl]metano,
[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-[4-(2,5-dichlorophenyl)piperazine-1'-yl]metano,
[4-(2,5-dimetilfenil)piperazine-1-yl]-[4-(3-methoxybenzenesulfonyl)-1-phenylpiperazin-2-yl]metano,
[4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[1-butyl-4-(3-chlorobenzenesulfonyl)piperazine-2-yl]-[4-(2,5-dimetilfenil)piperazine-1-yl]metano,
[4-(2,5-dimetilfenil)piperazine-1-yl]-[1-(4-fluoro-2-were)-4-(quinoline-8-sulfonyl)piperazine-2-yl]metano,
[4-(2,5-dichlorophenyl)piperazine-1-yl]-[4-(propane-2-sulfonyl)-1-o-tailpipes-2-yl]metano,
[4-(3-chlorobenzenesulfonyl)-1-(4-fluoro-2-were)piperazine-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon,
[4-(3-chlorobenzenesulfonyl)-1-o-tailpipes-2-yl]-(3',6'-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon,
[4-(2,5-dimetilfenil)piperazine-1-yl]-[(3S,4R)-1-(3-methoxybenzenesulfonyl)-4-o-tripeptides-3-yl]metano,
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4R)-4-(4-forfinal)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano,
(3S,4S)or (3R,4R)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2-fluoro-4-were)-1-(2-trifloromethyl)piperidine-3-yl]metano,
[(3S,4R)-1-(3-chlorobenzenesulfonyl)-4-o-tailpipe the Jn-3-yl]-[4-(5-chloro-2-were)piperazine-1-yl]metano,
(3S,4R)- or (3R,4S)-[4-(5-chloro-2-were)piperazine-1-yl]-[4-(2,4-differenl)-1-(pyridine-3-sulfonyl)piperidine-3-yl]metano and
[4-(5-chloro-2-were)piperazine-1-yl]-[(3S,4S)or (3R,4R)-4-(2,4-differenl)-1-methanesulfonamido-3-yl]metano,
and their pharmaceutically acceptable salts.

13. Pharmaceutical compositions intended for therapeutic and/or prophylactic treatment of diseases which are modulated by LXR agonists alpha and/or LXR beta, particularly 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, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, liver fibrosis, psoriasis, Alzheimer's disease, weakened/measurable improvement in cognitive function, HIV, cancer, age-related forms of macular degeneration, inherited forms of macular degeneration and/or illness of Stargardt containing compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier and/or adjuvant.

14. Compounds according to any one of claims 1 to 12 for use as therapeutically active substances is La therapeutic and/or prophylactic treatment of increased lipid levels, elevated levels of cholesterol, low HDL cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, liver fibrosis, psoriasis, Alzheimer's disease, weakened/measurable improvement in cognitive function, HIV, cancer, age-related forms of macular degeneration, inherited forms of macular degeneration and/or illness of Stargardt.

15. Compounds according to any one of claims 1 to 12 for use as therapeutically active substances for the treatment and/or prevention of diseases which are modulated by LXR agonists alpha and/or LXR beta.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula , where R1 denotes OH, OPO3H2 or OCOR5; R2 denotes H, OH or OPO3H2; A denotes N or CR6; R3 denotes fluorine; R4 denotes H, C1-3alkyl or C3-6cycloalkyl; R5 denotes an alanine residue; R6 denotes H, C1-6alkoxy group or halogen; and n=0 or 1; and to pharmaceutically acceptable salts of compounds of formula I. The invention also relates to a pharmaceutical composition having antibacterial activity, and to use of compounds of formula I to obtain a medicinal agent for preventing or treating bacterial infections.

EFFECT: compounds of formula I, having antibacterial activity.

14 cl, 3 dwg, 2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I):

, where: R=NO2, or and Het denotes an azolyl radical selected from nitroazolyl and tetrazolyl radicals; except 3- and nitro-4-(4-nitro-1,2,3-triazol-1-yl)furazan. The invention also describes a method of producing a compound of formula I and an energy composition based on said compounds.

EFFECT: compounds have high energy characteristics, low sensitivity and high thermal stability.

11 cl, 7 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention describes isoxazolines of formula (I), in which A denotes C or N; R denotes C1-4 haloalkyl; X denotes identical or different halogens or C1-4 haloalkyl; l equals 0, 1 or 2; Y denotes halogen or C1-4 alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, nitro, amino, C1-4 alkylcarbonylamino, benzoylamino or C1-4 alkoxycarbonylamino; m equals 1 or 1; and G denotes any group selected from heterocyclic groups given in the description, and a method of producing said compounds and use as insecticides for controlling the population of harmful insects or arthropods.

EFFECT: high efficiency of using said compounds.

11 cl, 28 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel azoles of general formula 1A and 1B and pharmaceutically acceptable salts thereof, having activity on hepatitis C and hepatitis GBV-C virus. Said compounds have NS5A viral protein ligand properties and can be used as active components for a pharmaceutical composition and a medicinal agent for treating diseases caused by said viruses. In general formula 1A and 1B, the solid lines accompanied by dotted lines denote a single or double bond, wherein if one of them is a single bond, the other is a double bond; X and Y optionally assume different values and denote a nitrogen, oxygen or sulphur atom or a NH group; R1 and R2 optionally denote identical radicals 2.1-2.20, in which the asterisk (*) indicates site of the bond to azole fragments. Said fragments and values of A and B are given in the claim.

EFFECT: more value of the compounds.

10 cl, 1 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, where: n equals 0, 1, 2; G denotes CH2, CHR3; R1 denotes H, C1-C6-alkyl, C3-C6-alkenyl, -CH2Ph; R2, R3, R4 independently denote H, CH3, -CH2F, -CHF2, CF3; A denotes 1,4-Ph, 1,3-Ph, which can be optionally substituted with 1-4 substitutes selected from halogen, C1-C4-alkyl, C1-C4alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4alkoxy; E denotes NR5, where R5 denotes H, C1-C3-alkyl; Ar denotes a radical of formula

and

where: Ra denotes halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenyl sulphonyl, CN, -NR6R7, where R6 and R7, together with an N atom, form a 5- or 6-member saturated ring or denotes a 5-member saturated or unsaturated aromatic or non-aromatic heterocyclic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heterocyclic ring can carry 1, 2 or 3 substitutes selected from halogen and C1-C6-alkyl, or denotes a 6-member saturated heterocyclic ring containing, as ring members, one N and one O atom; Rb and Rc independently denote H, halogen, CH3, OCH3, CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3, CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2, CH2CF3 or OCH2CF3; Rd denotes Ra or a 5- or 6-member heteroaromatic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heteroaromatic ring can carry 1 substitute selected from C1-C6-alkyl and C1-C6-alkylthio; Re denotes H or is defined as Ra; Rf is defined as Ra; k equals 0, 1, 2, 3; j equals 0, 1, 2, 3, 4; provided that Ra does not denote F, CH2F, CHF2, CF3, OCF3, if A denotes 1,4-Ph, Ar denotes a radical of formula (A) and Rb and Rc denote H, halogen; except compounds, where R1 denotes propyl, G denotes CH2, n equals 1, A denotes 1,4- Ph, E denotes NH, Ar denotes a radical of formula (F) and Rd denotes halogen, C1-C6-alkyl, C2-C6-alkenyl or a 5-member heteroaromatic ring; and physiologically acceptable acid addition salts thereof.

EFFECT: compounds exhibit 5HT6 receptor simulating activity, which allows for their use in a pharmaceutical composition.

25 cl, 6 tbl, 107 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds specified in cl. 1, and also to a pharmaceutical composition possessing binding activity with respect to Bcl proteins, to applying the declared compounds for preparing a drug for treating cancer and for treating a bcl-mediated disorder.

EFFECT: use of the compounds as Bcl protein inhibitors.

18 cl, 2 tbl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I): or pharmaceutically acceptable salt thereof, or stereoisomer, in which: n equals 0 or 1; X denotes CH2, C=O; R1 denotes a) -(CH2)mR3 or -CO(CH2)mR3, where m equals 0, 1; and R3 denotes a 5-10-member aryl or heteroaryl, where the heteroaryl denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected oxygen, nitrogen or sulphur, optionally substituted with one or more halogens; b) -C=YR4, where Y denotes O; and R4 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; (C0-C10)alkyl-(5-10-member heteroaryl), where "heteroaryl" denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected from oxygen, nitrogen or sulphur, said heteroaryl is optionally substituted with one or more substitutes selected from halogen, oxo or 2-(C1-C6)alkyl, where Z denotes S; (C0-C10)alkyl-(5-10-member aryl), said aryl is optionally substituted with one or more substitutes selected from halogen; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; or -Z-(C1-C6)alkyl, where Z denotes S or SO2, and where said (C1-C6)alkyl can be optionally substituted with one or more halogens; or (C1-C6)alkyl-CO-O-R12, where R12 denotes H or (C1-C6)alkyl; or c) -C=ZNHR6, where Z denotes O or S; and R6 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; 5-10-member aryl or heteroaryl, where "heteroaryl" denotes a bicyclic aromatic ring containing 9 ring atoms, from which at least one or two atoms are oxygen atoms; optionally substituted with one or more substitutes selected from halogen; cyano; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; and R2 denotes H or (C1-C6)alkyl. Also described is a pharmaceutical composition for inhibiting TNFα, based on the compound of formula I.

EFFECT: novel compounds which can regulate production of certain cytokines, including TNF-α, are obtained and described.

27 cl, 81 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (IB) or to their pharmaceutically acceptable salts:

, wherein R means formula: R1 means -C(O)NR3R4, -C(O)R3 and -C(O)OR3; each R3 and R4 independently means H, C1-10 alkyl, wherein alkyl is optionally substituted by one -OH; R3 and R4 are bound together with N atoms to form a 5-6-member heterocyclic ring which additionally contains one O heteroatom; R5 means H; R6 means CN; R7 means H; W means C. What is described is a method for producing both them and intermediate compounds of formula (1-1c): , wherein: R1 means -C(O)NR3R4; R3 and R4 are specified above.

EFFECT: compounds (IB) shows DPP-IV inhibitory activity that allows them being used in a pharmaceutical composition.

9 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I),

, where groups and radicals R1, R2 independently denote H, C1-8-alkyl or C3-7-cycloalkyl, where the alkyl or cycloalkyl group can be mono- or poly-substituted with identical or different groups R11; or R2 denotes a -CH2- or -CH2-CH2- bridge which is bonded with a group Y, and R1 is as defined above, or denotes a group selected from C1-4-alkyl-CO-, C1-4-alkyl-O-CO-, (C1-4-alkyl)NH-CO- or (C1-4-alkyl)2N-CO-, where the alkyl groups can be mono- or polyfluorinated; or R1 and R2 form an alkylene bridge such that R1R2N- denotes a group selected from: azetidine, pyrrolidine, piperdine, azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine, in which the free amino group is substituted with R13, piperidin-4-one, morpholine, thiomorpholine, 4-C1-4-alkoxy iminopiperidin-1-yl and 4-hydroxy iminopiperidin-1-yl. Wherein, when R1 and R2 form an alkylene bridge, one or more H atoms in the alkylene bridge can be substituted with identical or different groups R14, and X denotes a C1-3-alkylene bridge which can contain one, two or three identical or different C1-3-alkyl substitutes; and Y denotes a group of subformula selected from: and , where the group can be mono-substituted with a substitute R20; Z denotes -CH2-CH2- or -C(=O)-CH2-; U, V both denote CH, one of groups U, V denotes N, and the other of U, V denotes CH, where CH can be substituted with L; and L independently denotes halogen, cyano or C1-3-alkyl; and k equals 0, 1 or 2; W is selected from a group consisting of -CH2-O- and -O-CH2-; B is selected from a group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thiophenyl and thiazolyl; each of which can be mono- or poly-substituted with identical or different substitutes R20; radicals R11, R13, R14, R20 assume values given in claim 1. The invention also relates to a pharmaceutical composition containing at least one compound of formula I and having action on MCH receptor.

EFFECT: disclosed pharmaceutical compositions are useful in treating metabolic disorders or eating disorders, especially obesity, bulimia, anorexia, hyperphagia and diabetes.

FIELD: chemistry.

SUBSTANCE: invention relates to novel azoles of general formula 1A and 1B and pharmaceutically acceptable salts thereof, having activity on hepatitis C and hepatitis GBV-C virus. Said compounds have NS5A viral protein ligand properties and can be used as active components for a pharmaceutical composition and a medicinal agent for treating diseases caused by said viruses. In general formula 1A and 1B, the solid lines accompanied by dotted lines denote a single or double bond, wherein if one of them is a single bond, the other is a double bond; X and Y optionally assume different values and denote a nitrogen, oxygen or sulphur atom or a NH group; R1 and R2 optionally denote identical radicals 2.1-2.20, in which the asterisk (*) indicates site of the bond to azole fragments. Said fragments and values of A and B are given in the claim.

EFFECT: more value of the compounds.

10 cl, 1 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, where: n equals 0, 1, 2; G denotes CH2, CHR3; R1 denotes H, C1-C6-alkyl, C3-C6-alkenyl, -CH2Ph; R2, R3, R4 independently denote H, CH3, -CH2F, -CHF2, CF3; A denotes 1,4-Ph, 1,3-Ph, which can be optionally substituted with 1-4 substitutes selected from halogen, C1-C4-alkyl, C1-C4alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4alkoxy; E denotes NR5, where R5 denotes H, C1-C3-alkyl; Ar denotes a radical of formula

and

where: Ra denotes halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenyl sulphonyl, CN, -NR6R7, where R6 and R7, together with an N atom, form a 5- or 6-member saturated ring or denotes a 5-member saturated or unsaturated aromatic or non-aromatic heterocyclic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heterocyclic ring can carry 1, 2 or 3 substitutes selected from halogen and C1-C6-alkyl, or denotes a 6-member saturated heterocyclic ring containing, as ring members, one N and one O atom; Rb and Rc independently denote H, halogen, CH3, OCH3, CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3, CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2, CH2CF3 or OCH2CF3; Rd denotes Ra or a 5- or 6-member heteroaromatic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heteroaromatic ring can carry 1 substitute selected from C1-C6-alkyl and C1-C6-alkylthio; Re denotes H or is defined as Ra; Rf is defined as Ra; k equals 0, 1, 2, 3; j equals 0, 1, 2, 3, 4; provided that Ra does not denote F, CH2F, CHF2, CF3, OCF3, if A denotes 1,4-Ph, Ar denotes a radical of formula (A) and Rb and Rc denote H, halogen; except compounds, where R1 denotes propyl, G denotes CH2, n equals 1, A denotes 1,4- Ph, E denotes NH, Ar denotes a radical of formula (F) and Rd denotes halogen, C1-C6-alkyl, C2-C6-alkenyl or a 5-member heteroaromatic ring; and physiologically acceptable acid addition salts thereof.

EFFECT: compounds exhibit 5HT6 receptor simulating activity, which allows for their use in a pharmaceutical composition.

25 cl, 6 tbl, 107 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula in which: X denotes S, N-R5 or O; R denotes H; alkyl; heteroaryl, which is a thienyl optionally substituted with alkyl; R1 denotes alkyl; aryl, optionally substituted with a halogen; heteroaryl which is a thienyl optionally substituted with an alkyl, a a halogen, a methoxy group; R2 denotes heteroaryl which is 2-, 3- or 4-pyridyl; R3 denotes H; aryl, optionally substituted with a halogen, a methoxy group; heteroaryl, which is a thienyl optionally substituted with a halogen; alkyl, optionally substituted with oxytetrahydropyranyl; R4 denotes H; R5 denotes H; alkyl; or salt thereof.

EFFECT: invention also relates to a method of producing said compounds, which can be used as antifungal agents for crops, as well as agents against other pests, such as insects or mites and weeds which can harm crops.

10 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I): or pharmaceutically acceptable salt thereof, or stereoisomer, in which: n equals 0 or 1; X denotes CH2, C=O; R1 denotes a) -(CH2)mR3 or -CO(CH2)mR3, where m equals 0, 1; and R3 denotes a 5-10-member aryl or heteroaryl, where the heteroaryl denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected oxygen, nitrogen or sulphur, optionally substituted with one or more halogens; b) -C=YR4, where Y denotes O; and R4 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; (C0-C10)alkyl-(5-10-member heteroaryl), where "heteroaryl" denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected from oxygen, nitrogen or sulphur, said heteroaryl is optionally substituted with one or more substitutes selected from halogen, oxo or 2-(C1-C6)alkyl, where Z denotes S; (C0-C10)alkyl-(5-10-member aryl), said aryl is optionally substituted with one or more substitutes selected from halogen; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; or -Z-(C1-C6)alkyl, where Z denotes S or SO2, and where said (C1-C6)alkyl can be optionally substituted with one or more halogens; or (C1-C6)alkyl-CO-O-R12, where R12 denotes H or (C1-C6)alkyl; or c) -C=ZNHR6, where Z denotes O or S; and R6 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; 5-10-member aryl or heteroaryl, where "heteroaryl" denotes a bicyclic aromatic ring containing 9 ring atoms, from which at least one or two atoms are oxygen atoms; optionally substituted with one or more substitutes selected from halogen; cyano; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; and R2 denotes H or (C1-C6)alkyl. Also described is a pharmaceutical composition for inhibiting TNFα, based on the compound of formula I.

EFFECT: novel compounds which can regulate production of certain cytokines, including TNF-α, are obtained and described.

27 cl, 81 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to 6-piperidinyl-substituted isoquinoline derivatives of formula (I)

, where values of radicals are given in the claim, and compositions containing said compounds.

EFFECT: said compounds and compositions can be useful in treating and preventing diseases associated with Rho-kinase and mediated by Rho-kinase through myosin light chain phosphatase phosphorylation.

31 cl, 378 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of the formula (I) that are characterized by the properties of M3 muscarine receptor antagonist that is applicable in treatment or prevention of the disease or state (the abnormity of) which includes activity of the M3 muscarine receptor such as respiratory diseases. In the formula (I) A is represented by the oxygen atom or the group -N(R12)-; (i) R1 is represented by C1-C6-alkyl or the hydrogen atom; and R2 is represented by the hydrogen atom or the group -R5, -Z-Y-R5, -Z-NR9R10, -Z-NR9CO-R5 or -Z-CO2H; and R3 is absent or is represented by C1-C6-alkyl, and in this case the nitrogen atom to which it is bound is represented by tetradic nitrogen and bears a positive charge; or (ii) R1 and R2 together with nitrogen to which they are bound form heterocycloalkyl ring; the mentioned ring is displaced by the group -Y-R5 or -Z-Y-R5, and R3 is absent or is represented by C1-C6-alkyl, and in this case the nitrogen atom to which it is bound is represented by tetradic nitrogen and bears a positive charge; R4 is represented by the formula group (a), (b), (c) or (d); Z is represented by C1-C16-alkylene group; Y is represented by the link or the oxygen atom; R5 is represented by C1-C6-alkyl, aryl, phenyl condensed with C3-C6cycloalkyl, phenyl condensed with heterocycloalkyl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, C3-C6cycloalkyl or heteroC3-C6cycloalkyl group; R6 is represented by C1-C6-alkyl or the hydrogen atom; n and m equal 0; R8a and R8b are independently chosen from the group consisting of aryl, phenyl condensed with heterocycloalkyl, heteroaryl, C1-C6-alkyl, C3-C6cycloalkyl; R8c is represented by -OH or C1-C6-alkyl; R9 and R10 are represented independently by the hydrogen atom, C1-C6-alkyl, aryl, phenyl condensed with heterocycloalkyl and other components mentioned in the invention formula.

EFFECT: new compounds applicable in treatment or prevention of the disease or state (the abnormity of) which includes activity of the M3 muscarine receptor such as respiratory diseases.

10 cl, 49 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to quinoline derivatives of formula I

, or to its pharmaceutically acceptable salts, wherein X1 represents O; p represents 0, 1 or 2; each group R1 which can be identical or different and which can be located only in positions of 6- and/or 7-quinoline ring, specified in halogen, cyano, carboxy, (1-6C)alkoxycarbonyl, carbamoyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, or in a group of formula: Q1-X2-, wherein X2 represents CO and Q1 represents pyrrolidine, q represents 0 or 1; R2 represents (1-6C)alkoxy; R3 represents hydrogen or (1-6C)alkyl; R4 represents hydrogen; R5 represents hydrogen, methyl, ethyl, propyl, allyl, 2-propynyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-cyanoethyl or 3-cyanopropyl; the ring A represents a 5-membor monocyclic heteroaryl ring with up to three ring heteroatoms specified in oxygen, nitrogen and sulphur; r represents 0, 1 or 2; and each group R6 which can be identical or different is specified in amino, (1-6C)alkyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, or in a group of formula: -X6-R15 wherein X6 represents a single link and R15 represents (1-6C)alkoxy-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl or in a group of formula: -X7-Q3 wherein X7 represents C(R17)2N(R17) wherein each R17 represents hydrogen and Q3 represents (3-8C)cycloalkyl, and wherein any CH2 group within the R6 group optionally carries a hydroxy group on each said group. Also, the invention refers to methods for making the compound of formula I, to a pharmaceutical composition on the basis of the compound of formula I, to applying the compound of formula I and the combinations on the basis of the compound of formula I and additional anticancer drugs.

EFFECT: there are produced new quinoline derivatives effective in treating diabetic retinopathy and disturbed cell proliferation.

15 cl, 6 tbl, 32 ex

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