Derivatives of aminopiperidine, their production and use in therapy

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of formula (I): , in which: Ra and Ra', identical or different, mean atom of hydrogen or alkyl, R1 means atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl or aryl, R2 means group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which, x = 0, 1, 2, 3 or 4, y = 0 or 1, Y means atom of hydrogen or the following group: hydroxyl, alkyl, cycloalkyl, alkyloxyl, aryl, heteroaryl or -NR11R12, besides, Y is not an atom of hydrogen, when x=y=0, R11 and R12, identical or different, mean atom of hydrogen or the following group: alkyl, cycloalkyl, alkyloxyl or -NR13R14, or R11 and R12 together with atom of nitrogen, to which they are connected, create mono- or bicyclic structure, which contains 4-10 links and unnecessarily contain additionally 1-3 heteroatoms and/or 1-3 ethylene unsaturated links, besides this cycle is not necessarily substituted in any of positions with 1-3 groups, selected from atoms of halogen and hydroxyl, alkyl, cycloalkyl and alkyloxygroups; R13 and R14, identical or different, mean atom of hydrogen or alkyl, R3 means 1-3 groups, identical or different, available in any position of cyclic structure, to which they are connected, and selected from atoms of halogen; R5 means atom of hydrogen, R4 is selected from groups of formulae (a), (b), (c), which are not necessarily substituted with aryl group, described below: (a), (b), (c), in which p=0,1,2 or 3; m=0,1 or 2, and either a) X means link -N(R10)-, in which R10 is selected from: -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, - or R10 with atom of nitrogen, with which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not with neighboring to mentioned atom of nitrogen, creates bridge, containing 3-5 links, or, b) X means link -C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0,1,2,3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocycloalkyl, condensed with aryl, besides, alkyl, cycloalkyl or aryl groups are not necessarily substituted with 1 or several groups, selected from groups: R, R', -OR, -NRR', -COR; R7 is selected from atoms of hydrogen and halogen and the following groups: alkyls, -OR, -NRR', -NR-CO-R', -NR-COOR', -R8 and R9 are selected, independently from each other, from atom of hydrogen and the following groups: alkyls, cycloalkyls, aryls, -CO-alkyls, besides, alkyls and aryls are unnecessarily substituted with one or several groups, selected from groups: R, R', -OR, or R8 and R9 together create heterocycloalkyl,- R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, besides, mentioned hetero aryl groups represent aromatic groups, including from 5 to 10 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen and/or sulfur; besides mentioned heterocycloalkyl groups represent cycloalkyl groups, including from 5 to 6 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (VI), (XVIII), (XIX).

EFFECT: new biologically active compounds have activity of agonists of melanocortin receptors.

27 cl, 16 ex, 1 tbl

 

The present invention relates to compounds which are agonists of the receptors melanocortins, to their preparation and application in therapy.

Receptors melanocortin (MC-Rs) belong to the superfamily of receptors associated with G proteins with seven transmembrane domains. Their way of transcription takes place through the production of camp (Cone, R.D., Recent Prog. Horm. Res., 1996. 51. 287). Currently, five receptor subtypes MS-Rs: MS-R, MC2-R, MC3-R, MC4-R and MC5-R, which is expressed in various tissues, such as brain (MC, 4, 5-R), exocrine gland (MC5-R), adrenal gland (MC2-R) and leather (MS-R). Natural ligands of receptors MC-Rs-agonists are ACTH, α-, β - and γ-MSH, and receptor-antagonists such ligands are agouti-protein and protein-related protein agouti. No natural ligand is not highly selective in respect of any of the subtypes of the receptor with the exception of γ-MSH, which shows some selectivity for receptor M-R.

Melanocarcinoma system is involved in numerous physiological processes, including pigmentation, inflammation, food and sexual behavior (in particular, erectile function), the creation of the energy balance (the regulation of body weight and the deposition of lipids), exocrine function, protection and regeneration of neurons, it is unmodulated, analgesia, etc.

In particular, it was shown that S-R is involved in the development of sexual behavior (Van der Ploeg, L.H., Proc. Natl. Acad. Sci. USA, 2002, 99, 11381; Martin, W.J., Eur. J. Pharmacol., 2002, 454, 71).It has also been demonstrated in mouse models, which were intentionally deleted some receptors MC-Rs (knockout mouse)that the Central receptors MC-Rs (MC3 and 4-R) were involved in the formation of eating behavior, obesity, metabolism and energy balance (Huszar, D., Cell, 1997, 88(1), 131; Chen, A.S., Nat. Genet., 2000, 26(1), 97; Butler, A.A., Trends Genet., 2001, 17, S50-S54).Thus, knockout mice with remote MS-R was observed hyperphagia and obesity. At the same time it was observed that the receptor antagonists MS and/or 4R encouraged to food intake and, conversely, stimulation of receptors MS-R endogenous agonist, such as α-MSH, created signal saturation. These observations suggest that stimulation of the Central receptor MC-R and/or MC4-R, resulting in reduced food intake and body weight, is a promising approach for the treatment of obesity, which is dangerous because complicates many other diseases (hypertension, diabetes, ...). Thus, the study allowed us to identify, in the first place, peptides, pseudopeptides or cyclic peptides capable of interacting with the MS-Rs and handling, so the meal.

In order to maintain long term effect and the percent loss of body weight and limit associated predisposition to the disease, it is necessary to develop a long-term treatment on each day. This means that the medicine appointed by therapist must be a simple way for the patient. In this case, the preferred shall be an oral way of taking the medicine. However, peptide compounds, as a rule, are not compounds that are most relevant to this requirement.

Therefore, the design of small molecules ones character is an important task.

In light of the above it can be called an international PCT applications published under the numbers WO02/059095, WO02/059108, WO03/009850 and WO03/061660 that describe derived pieperazinove type. In other applications, such as WO03/092690 and WO03/0932234 described derivatives piperidino type. In applications WO 99/64002 and WO01/70337 derivatives described type spirobiindane. In the application WO01/91752 described derivatives containing piperidine link, condensed with pyrazolinone cycle. In the application WO02/059107 described derivatives piperidinol and pieperazinove type, substituted bicyclic structure. In applications WO02/059117, WO02/068388 and WO03/009847 described derivatives piperidinol and/or pieperazinove type, substituted phenyl ring. With regard to the application WO03/094918, it is described derivatives pieperazinove type, substituted phenyl or pyridinium radical. You can also call application WO00/74679, WO01/70708, WO2/15909, WO02/079146, WO03/007949, and WO04/024720 that describe derived types of substituted piperidine, or an application WO 04/037797; the compounds described in these patent applications, always contains functional aminogroup like previously known peptide structures.

You can call the application WO02005/047251, which describes compounds that are agonists of melanocortin receptors and having the General formula:

Due to the need to continuously improve existing therapeutic agent, the inventors have set a goal to develop new compounds that are agonists of receptors melanocortins.

The present invention relates to compounds corresponding to the formula (I):

in which

RaandRa'the same or different from each other, represent a hydrogen atom or an alkyl or cycloalkyl,

R1denotes a hydrogen atom or alkyl, cycloalkyl, heteroseksualci or aryl,

R2denotes a group of the formula -(CH2)x-(CO)y-Yor -(CO)y-(CH2)x-Yin which

H = 0, 1, 2, 3,or 4

.y = 0 or 1,

.Ydenotes a hydrogen atom or a hydroxyl, alkyl, cycloalkyl, alkyloxy, aryl, heteroaryl or-NR11R12and Y is not a hydrogen atom when x=y=0,

.R and R12identical or different, denote a hydrogen atom or alkyl, cycloalkyl, alkyloxy or-NR13R14or R11and R12together with the nitrogen atom to which they are attached, form a mono - or bicyclic structure containing 4-10 links and optionally additionally contain 1-3 heteroatoms and/or 1-3 ethylene or acetylene bonds, and this cycle is optionally substituted in any of the positions 1 to 3 groups selected from halogen atoms and hydroxyl, alkyl, cycloalkyl and alkyloxy. As examples of such cyclic structures include the following groups: pyrrolidinyl, morpholinyl, Pasolini, isoindoline etc.

.R13and R14identical or different, denote a hydrogen atom or alkyl, cycloalkyl or alkyloxy, or R13and R14together with the nitrogen atom to which they are attached, form a mono - or bicyclic structure described above,

R3denotes 1 to 3 groups, identical or different, are in any position of the cycle to which they are attached, selected from halogen atoms and the following groups: alkyl, cycloalkyl, -OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN, and-COOR, in which R and R' have the following value,

R5denotes a hydrogen atom or alkyl group

R4choose from the groups of formulae (a), (b), (c), optionally substituted by oxopropoxy or mono - or polishmaster aryl or heteroaryl group described below (each of these cyclic structures (a), (b), (c) directly connected to the nitrogen atom in the formula (I), which it carries):

where p=0,1,2, or 3; m=0,1 or 2, and

or

a) X represents the group-N(R10)-in which

R10choose from:

group -(CH2)x-OR8, -(CH2)x-COOR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9or -(CH2)x-NR8-COR9, -(CH2)x-COR8where x=1,2,3 or 4,

- cycloalkyl or geterotsiklicheskie condensed with aryl or heteroaryl group,

- cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, alkylaryl, alkylglycerol, -CO-alkyl, -CO-cycloalkyl-WITH-geterotsiklicheskie, -CO-aryl, -CO-heteroaryl-WITH-alkylaryl-WITH-alkylglycerol, -CS-alkyl, -CS-cycloalkyl, -CS-geterotsiklicheskie, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylglycerol, -CS-NR8R9, -C(=NH)-NR8R9, -SO2-alkyl, -SO2-cycloalkyl, -SO2-geterotsiklicheskie, -SO2-aryl, -SO2-heteroaryl, -SO2-alkylaryl, -SO2-alkylglycerol or-SO2-NR8R9,

moreover alkyl, recloak the global, heterocytolysine, aryl or heteroaryl group optionally substituted by 1 or more groups selected from the groups R, R', -OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NO2, -CN, and-COOR, -OCOR, -COR, -OCONRR', NRCOOR', or

cycloalkyl or heterocytolysine group optionally condensed with aryl or heteroaryl group,

or R10with the nitrogen atom to which it is connected, and with the carbon atom located in any position of the cyclic structure of the formula (a), but not adjacent to the indicated nitrogen atom, forms a bridge containing 3-5 links

R8andR9choose, independently from each other, from a hydrogen atom and the following groups: alkali, cycloalkyl, heterocicluri, arily, heteroaryl, alkylaryl, Alkylglucoside-WITH-alkali-WITH-cycloalkyl-WITH-heterocicluri-WITH-arily-WITH-heteroaryl-WITH-alkylaryl-WITH-Alkylglucoside, -SO2-alkali, -SO2-cycloalkyl, -SO2-heterocicluri, -SO2-arily, -SO2-heteroaryl, -SO2-alkylaryl, -SO2-Alkylglucoside, -C(=NH)-NRR', -COOR, -CO-NRR', -CS-NRR' and -(CH2)x-OR, where x=0,1,2,3 or 4,

orR8andR9taken together, constitute cycloalkyl or heteroseksualci,

RandR'represent, independently from each other, a hydrogen atom or alkyl, cycloalkyl, heteroseksualci, aryl, heteroaryl, alkylaryl Il is alkylglycerol, or taken together may form cycloalkyl or heteroseksualci;

or

b)Xdenotes the group-C(R6)(R7)-, where

R6choose from:

Atom hydrogen, halogen atom,

Gruppy -(CH2)x-OR8, -(CH2)x-COOR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9or -(CH2)x-NR8-COR9where x=0,1,2,3 or 4,

Alkyl, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, alkylaryl or alkylglycerol, -CO-alkyl, -CO-cycloalkyl-WITH-geterotsiklicheskie, -CO-aryl, -CO-heteroaryl-WITH-alkylaryl or-CO-alkylglycerol, -CS-alkyl, -CS-cycloalkyl, -CS-geterotsiklicheskie, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylglycerol, -CS-NR8R9, -C(=NH)-NR8R9,

Cycloalkyl or geterotsiklicheskie, condensed or neskondensirovannyh in Spiro to a cycle of formula (a), to which it is attached,

Cycloalkyl or geterotsiklicheskie condensed with aryl or heteroaryl group,

moreover alkyl, cycloalkyl, heterocytolysine, aryl or heteroaryl group optionally substituted by 1 or more groups selected from the groups R, R', -OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NO2, -CN, and-COOR, -OCOR, -COR, -OCONRR', NRCOOR'; and

and cycloalkyl or GE is erotically group optionally condensed with aryl or heteroaryl group,

R7chosen from hydrogen atoms and halogen and the following groups: alkali, cycloalkyl, arily, heteroaryl, alkylaryl, Alkylglucoside, -OR, -O-arily, -O-heteroaryl, -O-alkylaryl, -O-Alkylglucoside, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN, and-COOR,

-R8andR9choose, independently from each other, from a hydrogen atom and the following groups: alkali, cycloalkyl, heterocicluri, arily, heteroaryl, alkylaryl, Alkylglucoside-WITH-alkali-WITH-cycloalkyl-WITH-heterocicluri-WITH-arily-WITH-heteroaryl-WITH-alkylaryl-WITH-Alkylglucoside, -SO2-alkali, -SO2-cycloalkyl, -SO2-heterocicluri, -SO2-arily, -SO2-heteroaryl, -SO2-alkylaryl, -SO2-Alkylglucoside, -C(=NH)-NRR', -COOR, -CO-NRR', -CS-NRR' and -(CH2)x-OR, where x=0,1,2,3 or 4, and alkali and arily optionally substituted by one or more groups selected from the groups R, R', -OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NO2, -CN, and-COOR, -OCOR, -COR, -OCONRR', NRCOOR',

orR8andR9taken together form cycloalkyl or heteroseksualci,

-RandR'represent, independently from each other, a hydrogen atom or the following group: alkyl, cycloalkyl, heteroseksualci, aryl, heteroaryl, alkylaryl or alkylether, or together can form cycloalkyl or heteroseksualci,

in the form of a base or sour the but-additive salt, and also in the form of a hydrate or of MES.

Preferably, whenXrepresents a group-C(R6)(R7in the compounds of formula (I), R6and R7are not simultaneously a hydrogen atom.

Of the compounds of formula (I) according to the invention also prefer those compounds in whichR4choose from the groups of formulae (a), (b) and (c), optionally mono - or polyamidine the aryl or heteroaryl, in which X represents a group-C(R6)(R7)-in whichR6chosen from:

Atom hydrogen

Gruppy -(CH2)x-Or SIG8, -(CH2)x-R8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9or -(CH2)x-NR8-COR9where x=0,1,2,3 or 4,

Alkyl, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, alkylaryl, alkylglycerol, -CO-alkyl, -CO-cycloalkyl-WITH-geterotsiklicheskie, -CO-aryl, -CO-heteroaryl-WITH-alkylaryl or-CO-alkylglycerol,

Cycloalkyl or geterotsiklicheskie located in Spiro-position to the cycle of the formula (a), to which it is attached,

Cycloalkyl or geterotsiklicheskie condensed with aryl or heteroaryl,

R7chosen from hydrogen atoms and halogen and the following groups: alkali, cycloalkyl, arily, heteroaryl, alkylaryl, alkylglycerol is s, -OR, -O-arily, -O-heteroaryl, -O-alkylaryl, -O-Alkylglucoside, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COR', -NO2, -CN,- COOR,

R8andR9choose, independently from each other, from a hydrogen atom and the following groups: alkali, cycloalkyl, heterocicluri, arily, heteroaryl, alkylaryl, Alkylglucoside-WITH-alkali-WITH-cycloalkyl-WITH-heterocicluri-WITH-arily-WITH-heteroaryl-WITH-alkylaryl-WITH-Alkylglucoside, -SO2-alkali, -SO2-cycloalkyl, -SO2-heterocicluri, -SO2-arily, -SO2-heteroaryl, -SO2-alkylaryl, -SO2-Alkylglucoside, -C(=NH)-NRR', -COOR, -CO-NRR', -CS-NRR' and -(CH2)x-OR, where x=0,1,2,3 or 4,

RandR'represent, independently from each other, a hydrogen atom or alkyl, cycloalkyl, heteroseksualci, aryl, heteroaryl, alkylaryl or alkylglycerol.

Of the compounds of formula (I) according to the invention also prefer those compounds in whichR4choose from the groups of formulae (a), (b) and (c), in which X represents a group-C(R6)(R7)-in whichR6is selected from a halogen atom or cycloalkyl or geterotsiklicheskie, condensed or neskondensirovannyh in sporopollenin with loop formulas (a)to which it is attached.

Of the compounds of formula (I) according to the invention also prefer those compounds in whichR4SEL is the select group of formula (a),(b) and (c), in which X represents a group-C(R6)(R7)-in whichR6is selected from-CS-alkyl, -CS-cycloalkyl, -CS-geterotsiklicheskie, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylglycerol, -CS-NR8R9, -C(=NH)-NR8R9.

Of the compounds of formula (I) according to the invention also prefer those compounds in whichR4choose from the groups of formulae (a), (b) and (c), in which X represents a group-C(R6)(R7)-, in which alkyl, cycloalkyl, heterocytolysine, aryl or heteroaryl optionally substituted by 1 or more groups selected from R, R', OCOR, COR, OCONRR', NRCOOR'.

Of the compounds of formula (I) according to the invention also prefer those compounds in whichR4choose from the groups of formulae (a),(b) and (c), in which X represents a group-C(R6)(R7)-in which cycloalkyl or heteroseksualci optionally condensed with aryl or heteroaryl.

Of the compounds of formula (I) according to the invention also prefer those compounds in whichR4choose from the groups of formulae (a), (b) and (c), in which X represents a group-C(R6)(R7)-in whichR8andR9chosen, independently of one another, from alkyl and aryl groups, optionally substituted by one or more groups selected from the groups R, R', COR, COR, OCONRR', NRCOOR'.

Of the compounds of formula (I) according to the invention also prefer those compounds in whichR4choose from the groups of formulae (a), (b) and (c), in which X represents a group-C(R6)(R7)-in whichRandR'taken together can form cycloalkyl or heteroseksualci.

Preferably, in compounds of formula (I)R7is a hydrogen atom.

Prefer those compounds in whichR4denotes a group of formula (a), in which p=2, as it is presented below:

Prefer those compounds in whichR4is selected from groups of the formulas (a),(b) and (c), optionally mono - or polyamidine aryl or heteroaryl group, in which X represents a group-N(R10)-in which

R10choose from:

Gruppy-CO-NR8R9, -R8,

Gruppy -(CH2)x-Or SIG8, -(CH2)x-R8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9or -(CH2)x-NR8-COR9where x=1,2,3 or 4,

Cycloalkyl or geterotsiklicheskie condensed with aryl or heteroaryl,

Cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, alkylaryl, alkylglycerol-WITH-cycloalkyl-WITH-geterotsiklicheskie-WITH-g is tetraaryl, -CO-alkylaryl-WITH-alkylglycerol, -CS-alkyl, -CS-cycloalkyl, -CS-geterotsiklicheskie, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylglycerol, -CS-NR8R9, -C(=NH)-NR8R9, -SO2-cycloalkyl, -SO2-geterotsiklicheskie, -SO2-heteroaryl, -SO2-alkylaryl, -SO2-alkylglycerol or-SO2-NR8R9;

orR10with the nitrogen atom to which it is attached and with the carbon atom located in any position of the cyclic structure of the formula (a), but not adjacent to the indicated nitrogen atom, form a bridge containing 3-5 links.

R8andR9choose, independently from each other, from a hydrogen atom and the following groups: alkali, cycloalkyl, heterocicluri, arily, heteroaryl, alkylaryl, Alkylglucoside-WITH-alkali-WITH-cycloalkyl-WITH-heterocicluri-WITH-arily-WITH-heteroaryl-WITH-alkylaryl-WITH-Alkylglucoside, -SO2-alkali, -SO2-cycloalkyl, -SO2-heterocicluri, -SO2-arily, -SO2-heteroaryl, -SO2-alkylaryl, -SO2-Alkylglucoside, -C(=NH)-NRR', -COOR, -CO-NRR', -CS-NRR' and -(CH2)x-OR, where x=0,1,2,3 or 4,

RandR'represent, independently from each other, a hydrogen atom or alkyl, cycloalkyl, heteroseksualci, aryl, heteroaryl, alkylaryl or alkylglycerol.

Prefer those compounds in which the R4is selected from groups of the formulas (a), (b) and (c)optionally substituted by oxo group, in which X represents the group-N(R10)-.

Of the compounds of formula (I) according to the invention also prefer those compounds in whichR4is selected from groups of the formulas (a), (b) and (c), in which X represents a group-N(R10)-, in which R8and R9taken together form cycloalkyl or heteroseksualci.

Prefer those compounds in whichR4is selected from groups of the formulas (a), (b) and (c), in which X represents the group-N(R10)-in whichR10is -(CH2)x-R8where x=1,2,3, or 4.

Prefer those compounds in whichR4is selected from groups of the formulas (a), (b) and (c), in which X represents the group-N(R10)- where alkyl, cycloalkyl, heterocytolysine, aryl or heteroaryl group optionally substituted by 1 or more groups selected from R, R', OCOR, COR, OCONRR', NRCOOR'.

Prefer those compounds in whichR4is selected from groups of the formulas (a), (b) and (c), in which X represents the group-N(R10)-in which cycloalkyl or heterocytolysine group optionally condensed with aryl or heteroaryl.

Prefer those compounds in whichR4denotes a group of formula (a), in which p=2, the, as it is presented below:

The compounds of formula (I) contain at least one asymmetric carbon atom. In this regard, they can exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as mixtures thereof, including racemic mixtures, form part of the invention.

Of the compounds of formula (I) according to the invention prefer those in which the carbon atom, called asterichesky * the following formula, has the configuration (R):

The compounds of formula (I) according to the invention may also exist in the form of mixtures of stereoisomers, which are also part of the invention. In addition, they can exist in the form of isomers, CIS or TRANS, or in the form of isomers, endo or Exo. These isomers and their mixtures, are also part of the invention.

The compounds of formula (I) can be in the form of bases or acid additive salts. These additive salts also form part of the invention.

Mostly, these salts will receive when interacting with pharmaceutically acceptable acids but the salts of other acids that are useful, for example, for the purification or separation of compounds of formula (I) also form part of the invention.

The compounds of formula (I) can also be in the form of the of Ignatov or solvate, in particular, in the form of associations or combinations with one or more water molecules or with a solvent. Such a hydrate or solvate are also part of the invention.

In the present description, unless given other instructions, see below:

the halogen atom include fluorine atom, chlorine, bromine or iodine;

- alkyl: saturated or unsaturated aliphatic group (that is, containing 1-3 ethylene or acetylene bonds)containing 1-6 carbon atoms, a linear, cyclic or branched. For example, we may refer to such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neo-pentyl etc. and cycloalkyl group, described below, as well as alkyl groups, partially cyklinowanie, such as group methylcyclopropyl. Such an alkyl group may be substituted by 1 or more groups (for example, 1-6 groups selected from halogen atoms (education, for example, the group-CF3and the groups R, R', -OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NO2, -CN, and-COOR, -OCOR, -COR, -OCONRR', NRCOOR'; where R and R', independently of one another, denote a hydrogen atom or an alkyl group, cycloalkyl, heteroseksualci, aryl, heteroaryl, alkylaryl or alkylether or together can form a group cycloalkyl or heteroseksualci;

- cycloalkyl: cyclic alkyl group containing 3 to 8 carbon atoms and all atoms of carbon are in the loop structure. For example, we may refer to such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Such cycloalkyl group may be substituted by the radicals R, R', which are described above for alkyl groups;

- heterocyclization: cycloalkyl group, as described above, additionally containing 1-4 heteroatoms such as nitrogen, oxygen and/or sulphur. This heterocytolysine group can be substituted as described above for cycloalkyl group, and may contain one or more (1 or 2) ethylene or acetylene bonds. For example, as such geterotsiklicheskikh groups can be called group piperidinyl and tetrahydropyran;

- alkoxy: a radical-O-alkyl, where the alkyl group described above;

- aryl: an aromatic cyclic group containing 5 to 10 parts, for example, phenyl. This aryl group may be substituted by 1 or more groups (for example, 1-6 groups selected from halogen atoms (education, for example, the group-CF3and the groups R, R', -OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NO2, -CN, and-COOR, -OCOR, -COR, -OCONRR', NRCOOR'; where R and R', independently of one another, denote a hydrogen atom or alkyl, cycloalkyl, heteroseksualci, aryl, heteroaryl, alkylaryl or alkylether or together can form cycloalkyl or heteroseksualci;

- alkylation: alkyl the second group, as described above, which is itself substituted by an aryl group as described above. This alcylaryl group may be, for example, benzyl;

- heteroaryl: aromatic cyclic group containing 5 to 10 units and containing 1-6 heteroatoms, such as nitrogen, oxygen and/or sulphur. For example, you can call pyridinyl. This heteroaryl group may be substituted in the same way as aryl, as described above;

- alkylglycerol: alkyl group, as described above, which is itself substituted heteroaryl group, as described above.

Of the compounds of formula (I) according to the invention include compounds in which Ra, Ra', R2, R3, R4and R5have the meanings indicated above and R1denotes alkyl, cycloalkyl or heteroseksualci. Mainly, the radical R1denotes cycloalkyl, such as cyclohexyl or cycloheptyl.

Of the compounds of formula (I) according to the invention can also include compounds in which Ra, Ra', R1, R3, R4and R5have the meanings indicated above and R2choose from the following groups:

-CO-R15, -CO-NR16R17, -CO-NR15-NR16R17, -CO-aryl, -CO-heteroaryl, -CO-(CH2)x'-NR16R17, -(CH2)x-NR16R17, -(CH2)x-OH, -(CH2)x-aryl, -(CH2)x-heteroaryl, -(CH2)x'-CO-R15and -(CH2)x'-CO-NR16R17in which

J = 0,1,2,3 or 4 and x'= 1,2,3 or 4,

.R15represent a hydrogen atom or alkyl, cycloalkyl or alkyloxy, and

.R16and R17identical or different, denote a hydrogen atom or alkyl, cycloalkyl or alkyloxy, or R16and R17together with the nitrogen atom to which they are attached, form a mono - or bicyclic structure containing 4-10 links and optionally containing 1-3 additional heteroatoms and/or 1-3 ethylene or acetylanthracene communication, and this cycle is optionally substituted in any position by 1-3 groups selected from halogen atoms and hydroxyl, alkyl, cycloalkyl or alkyloxy.

Of these compounds are those compounds in which R2choose from the following groups: -CO-R15, -CO-NR16R17, -CO-NR15-NR16R17, -CO-(CH2)x'-NR16R17, -(CH2)x-NR16R17, -(CH2)x-OH, -(CH2)x-aryl, -(CH2)x-heteroaryl, -(CH2)x'-CO-R15and -(CH2)x'-CO-NR16R17in which x, x', R15, R16and R17have the values specified above.

the C compounds of formula (I) according to the invention may also be called, in particular, those compounds in which R2represents a group-CO-NR16R17in which R16and R17denote alkyl or alkyloxy.

Of the compounds of formula (I) according to the invention can also be called those compounds in which Ra, Ra', R1, R2, R4and R5have the meanings indicated above, and R3denotes 1 to 3 groups, identical or different, chosen from halogen atoms. Mainly, R3refers to only one group, preferably chlorine.

Of the compounds of formula (I) according to the invention can also be called those compounds in which Ra, Ra', R1, R2, R3and R4have the meanings indicated above, and R5denotes a hydrogen atom or alkyl containing 1-4 carbon atoms. Preferably, R5denotes a hydrogen atom.

Of the compounds of formula (I) according to the invention can also be called those compounds in which R1, R2, R3, R4and R5have the meanings indicated above, and Raand Ra'represent a hydrogen atom or an alkyl group containing 1-4 carbon atoms. Mainly, Raand Ra'independently from each other, represent a hydrogen atom or methyl.

Of the previously listed groups R6can be called, in particular, such groups, in which R6denotes the atom of water is an ode or-or SIG 8, -NR8R9or-NR8-CO-R9in which R8and R9represent a hydrogen atom or alkyl.

Of the previously listed groups R7can be called, in particular, such groups, in which R7denotes a hydrogen atom or halogen or alkyl, hydroxyl (corresponding to the group-OR, where R is a hydrogen atom) or alkyloxy (corresponding to the group-OR where R is alkyl). Mainly, the radical R7is a hydrogen atom.

Of the previously listed groups R8and R9can be called, in particular, such groups, in which R8and R9represent a hydrogen atom or alkyl.

Of the previously listed groups R10can be called, in particular, such groups, in which R10denotes a hydrogen atom or alkyl or-CO-aryl (such as-CO-phenyl, or R10together with the nitrogen atom to which it is attached and with the carbon atom located in any position of the cyclic structure which it carries (such as a structure of formula (a) or (a-3)), but not in the neighboring position to the nitrogen atom, forms a bridge containing 3-5 links.

From the above values of the groups R and R' can be called, in particular, those in which R and R' represent a hydrogen atom or an alkyl group.

Each of the above values of the groups Ra, Ra', R1, R2, R3, Rsub> 4, R5, R6, R7, R8, R9, R10, R and R' may be combined with each other with the formation of certain subgroups of compounds of formula (I) according to the invention.

In accordance with another object of the invention relates to preferred compounds, the names of which are listed below.

In the proposed list of numbers before the names of the compounds correspond to the numbers of examples of the compounds listed in the table.

2:N{1-[N(4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N',N'-diethylcarbamyl

8:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-1,3-dihydro-2H-isoindole-2-carboxamide

9:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-2,5-dimethylpyridin-1-carboxamid

12:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

14:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N'methoxy-N'methylcarbamic

23:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-carboxamid

33:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]p is peridin-4-yl}- Ncycloheptyl-N',N'-diethylcarbamyl

35:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclooctyl-N',N'-diethylcarbamyl

38:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N'-(2,2,2-triptorelin)urea

48:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl (trance)

50:N{1-[N(TRANS4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl (trance)

67:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N'ethyl-N'-isopropylcarbamate

74:N(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin

N(TRANS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin

75:N{1-[N(1-benzoylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl

76:N{1-[N(TRANS4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'bis(2-foradil)urea

81: (2R,5S)-N-{1-[N/i> -(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,5-dimethylpyridin-1-carboxamid

82: (2R,5S)-N-(1-{4-chloro-N-[CIS-4-(dimethylamino)cyclohexyl]-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,5-dimethylpyridin-1-carboxamid

83: 4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N,N-dimethylpiperidin-1-carboxamid

84: 4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N,N-diethylpiperazine-1-carboxamid

85:N(1-{4-chloro-N[1-(pyrrolidin-1-ylcarbonyl)piperidine-4-yl]-D-i.e. phenylalanyl}piperidine-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl

86:N(1-{4-chloro-N[1-(piperidine-1-ylcarbonyl)piperidine-4-yl]-D-i.e. phenylalanyl}piperidine-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl

87:N(1-{4-chloro-N[1-(morpholine-4-ylcarbonyl)piperidine-4-yl]-D-i.e. phenylalanyl}piperidine-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl

88: 4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-Nphenylpiperidine-1-carboxamide

89: 4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-Nmethyl-Nphenylpiperidine-1-carboxamide

90:Nbenzyl-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}- Nmethylpiperidin-1-carboxamid

91:N(1-{4-chloro-N[1-(TRIFLUOROACETYL)piperidine-4-yl]-D-i.e. phenylalanyl}piperidine-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl

92:N-{1-[N(1-acetylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

93:N{1-[4-chloro-N(CIS-4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

N{1-[4-chloro-N(TRANS-4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

94:N(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin

N(TRANS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin

95:N[1-(4-chloro-N{CIS-4-[(4-forfinal)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

N[1-(4-chloro-N{TRANS-4-[(4-forfinal)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

98:N[1-(4-chloro-N{CIS-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

N[1-(-chloro- N{TRANS-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

102:N{1-[4-chloro-N(4-methoxycyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl (trance)

103:N{1-[4-chloro-N(4-phenylcyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl (trance)

104:N{1-[N(1-acetylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl (trance)

105:N(4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide (trance)

106:N(1-{4-chloro-N[1-(TRIFLUOROACETYL)piperidine-4-yl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl (trance)

107:N(4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin (trance)

108:N{1-[N(1-benzoylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

109:N(1-{4-chloro-N[1-(methylsulphonyl)piperidine-4-yl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl (trance)

110:N{1-[4-chloro-N(4-hydroxy-4-finalcolor the KSIL)D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}- Ncyclohexyl-N',N'-dimethylcarbamyl (trance)

111:N[1-(4-chloro-N{4-[(4-forfinal)amino]cyclohexyl}-D-i.e. phenylalanyl)-3-methylpiperidin-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

113:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl (trance)

115:N[1-(4-chloro-N{CIS-4-[(2-methoxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

N[1-(4-chloro-N{TRANS-4-[(2-methoxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

116:N(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide

N(TRANS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide

117:N(1-{4-chloro-N[CIS-4-(4-hydroxyphenyl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl

N(1-{4-chloro-N[TRANS-4-(4-hydroxyphenyl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl

118:N(1-{4-chloro-N[2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-NZiklag the KSIL- N',N'-dimethylcarbamyl (trance)

119:N{1-[4-chloro-N(1-isonicotinohydrazide-4-yl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl (trance)

120:N(1-{4-chloro-N[CIS-4-(1,3-dihydro-2H-isoindole-2-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl (trance)

121:N{1-[4-chloro-N(2-phenylpiperidine-4-yl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl (trance)

122:N(1-{4-chloro-N[4-(3-oxopiperidin-1-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl (trance)

Of the preferred compounds of formula (I)in which X represents-CR6R7include the following:

2:N{1-[N(4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N',N'-diethylcarbamyl

8:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-1,3-dihydro-2H-isoindole-2-carboxamid

9:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-2,5-dimethylpyridin-1-carboxamid

12:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

14:N{1-[N(CIS-4-aminocyclo exil)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}- Ncyclohexyl-N'methoxy-N'methylcarbamic

23:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-carboxamid

29:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclobutyl-N',N'-diethylcarbamyl

32:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclopentyl-N',N'-diethylcarbamyl

33:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncycloheptyl-N',N'-diethylcarbamyl

35:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclooctyl-N',N'-diethylcarbamyl

37:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N',N'-diethyl-N-phenylcarbamate

38:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N'(2,2,2-triptorelin)urea

45:N{1-[4-chloro-N(4-hydroxycyclohexyl)D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N',N'-diethylcarbamyl

48:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N N'diethylcarbamyl (trance)

49:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-<> Ncyclohexyl-N N'diethylcarbamyl (CIS)

50:N{1-[N(TRANS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N N'diethylcarbamyl (trance)

51:N{1-[N(TRANS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N N'diethylcarbamyl (CIS)

64:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N',N'-diethyl-N-(tetrahydro-2H-Piran-4-yl)urea

65:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N',N'-diethyl-N-piperidine-4-ylcarbamate

67:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N'ethyl-N'isopropylcarbamate

71:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,2-dimethylhydrogensiloxane

74:N(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin

N(TRANS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin

76:N{1-[N(TRANS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N N'bis(2-foradil)urea.

Of the preferred compounds of formula (I)in which X represents-CR6R7you can call the following:

77:N[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[2-(dimethylamino)ethyl]amino}piperidine-1-yl)-2-oxoethyl]cyclohexane-1,4-diamine

79:N(1-{4-chloro-N[CIS-4-(dimethylamino)cyclohexyl]-D-i.e. phenylalanyl}piperidine-4-yl)-Ncyclohexyl-3,4-diflorasone

80:N(1-{4-chloro-N[CIS-4-(dimethylamino)cyclohexyl]-D-i.e. phenylalanyl}piperidine-4-yl)-Ncycloheptyl-N',N'-dimethylcarbamyl

81: (2R,5S)-N-{1-[N-(CIS-4-aminocyclohexanol]-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,5-dimethylpyridin-1-carboxamid

82: (2R,5S)-N-(1-{4-chloro-[N-(CIS-4-dimethylamino)cyclohexyl]-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,5-dimethylpyridin-1-carboxamid

93:N{1-[4-chloro-N(CIS-4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

N{1-[4-chloro-N(TRANS-4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

94:N(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin

N(TRANS-4-{[(1R)-1-(4-chlorbenzyl)-2-4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin

95:N[1-(4-chloro-N{CIS-4-[(4-forfinal)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

N[1-(4-chloro-N{TRANS-4-[(4-forfinal)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

96:N{1-[4-chloro-N(4-methoxycyclohexyl)-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

97N[1-(4-chloro-N{CIS-4-[(4-methoxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

N[1-(4-chloro-N{TRANS-4-[(4-methoxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

98:N[1-(4-chloro-N{CIS-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

N[1-(4-chloro-N{TRANS-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

99:N[1-(4-chloro-N{4-[(dimethylamino)methyl]-4-phenylcyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

100: (2R,5S)-N-(1-{4-chloro-N-[CIS-4-(dimethylamino)cyclohexyl]D-i.e. phenylalanyl}piperidine-4-yl)-N-cyclohexyl-2,5-dimethylpyridin-1-carboxamid

101: (2R,5S)-N-(1-{chlor- N-[CIS-4-(dimethylamino)cyclohexyl]D-i.e. phenylalanyl}piperidine-4-yl)-N-cyclohexyl-2,5-dimethylpyridin-1-carboxamid

102:N{1-[4-chloro-N(4-methoxycyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

103:N{1-[4-chloro-N(4-phenylcyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

105:N(4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methyl-piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide

107:N(4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin

110:N{1-[4-chloro-N(4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

111:N[1-(4-chloro-N{4-[(4-forfinal)amino]cyclohexyl}-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

112:N(1-{4-chloro-N[CIS-4-(dimethylamino)cyclohexyl]-D-i.e. phenylalanyl}piperidine-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

113:N{1-[N(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

115:N[1-(4-chloro-N{CIS-4-[(2-methoxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl]piperidin-4-yl]- Ncyclohexyl-N',N'-dimethylcarbamyl

N[1-(4-chloro-N{CIS-4-[(2-methoxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl]piperidine-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

116:N(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide

N(TRANS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide

117:N(1-{4-chloro-N[CIS-4-(4-hydroxyphenyl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

N(1-{4-chloro-N[TRANS4-(4-hydroxyphenyl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

118:N(1-{4-chloro-N[4-(2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

120:N(1-{4-chloro-N[CIS-4-(1,3-dihydro-2H-isoindole-2-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

122:N(1-{4-chloro-N[4-(3-oxopiperidin-1-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl]-Ncyclohexyl-N',N'-dimethylcarbamyl

Of the preferred compounds of formula (I)in which X represents-NR10you can title the ü well as the following:

4:N[1-(N-8-azabicyclo[3.2.1]Oct-3-yl-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-diethylcarbamyl

5:N[1-(N-1-azabicyclo[2.2.2]Oct-3-yl-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-diethylcarbamyl

30:N[1-(N-8-azabicyclo[3.2.1]Oct-3-yl-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclobutyl-N',N'-diethylcarbamyl

75:N{1-[N-(1-benzoylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-diethylcarbamyl

Of the preferred compounds of formula (I)in which X represents-NR10you can call the following:

83: 4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N,N-dimethylpiperidin-1-carboxamid

84: 4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N,N-diethylpiperazine-1-carboxamid

85:N(1-{4-chloro-N[1-(pyrrolidin-1-ylcarbonyl)piperidine-4-yl]-D-i.e. phenylalanyl}piperidine-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl

86:N(1-{4-chloro-N[1-(piperidine-1-ylcarbonyl)piperidine-4-yl]-D-i.e. phenylalanyl}piperidine-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl

87:N(1-{4-chloro-N[1-(morpholine-4-ylcarbonyl)piperidine-4-yl]-D-i.e. phenylalanyl}piperidine-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl

R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N-phenylpiperidine-1-carboxamide

89: 4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N-methyl-N-phenylpiperidine-1-carboxamide

90:Nbenzyl-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N-methylpiperidin-1-carboxamid

91:N(1-{4-chloro-N[1-(TRIFLUOROACETYL)piperidine-4-yl]-D-i.e. phenylalanyl}piperidine-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl

92:N{1-[N(1-acetylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

104:N{1-[N(1-acetylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

106:N(1-{4-chloro-N[1-(TRIFLUOROACETYL)piperidine-4-yl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl

108:N{1-[N(1-benzoylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

109:N(1-{4-chloro-N[1-(methylsulphonyl)piperidine-4-yl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-Ncyclohexyl-N',N'-dimethylcarbamyl

114:N(1-{4-chloro-N[1-(methylsulphonyl)piperidine-4-yl]-D-i.e. phenylalanyl}Piperi the Jn-4-yl)- Ncyclohexyl-N',N'-dimethylcarbamyl

119:N{1-[4-chloro-N(1-isonicotinohydrazide-4-yl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

121:N{1-[4-chloro-N(2-Phenoperidine-4-yl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-Ncyclohexyl-N',N'-dimethylcarbamyl

In accordance with another object of the invention relates to a medicinal product, characterized in that it contains a compound of the formula (I)as described above, or additive salt of this compound with a pharmaceutically acceptable acid, or a hydrate or MES the compounds of formula (I).

In accordance with another object of the invention relates to pharmaceutical compositions, characterized in that it contains a compound of the formula (I)as described above, or a pharmaceutically acceptable salt, hydrate or MES this connection, and at least one pharmaceutically acceptable excipient.

In accordance with another object of the invention relates to the use of compounds of formula (I) for obtaining a medicinal product intended for the treatment and prevention of obesity, diabetes and sexual dysfunction in both sexes, in particular, erectile dysfunction, for the treatment of cardiovascular diseases as well as anti-inflammatory treatment or in the treatment of alcohol dependence

In accordance with another object of the invention relates to a method for obtaining compounds of formula (I), as described above, characterized in that exercise rehabilitation amination of the compounds of formula (V):

in the presence of a derivative group, R4ketone type, and R1, R2, R3, R4, R5, Raand Ra'have the values listed in any of the PP 1-23 claims.

In the further description text under the protective group (KMG) understand the group that, on the one hand, able to protect reactive group such as hydroxyl or amine in the synthesis process, and, on the other hand, to release the surviving reactive group at the end of the synthesis. Examples of protective groups, as well as ways of protecting and removing the protective groups described in “Protective Groups in Organic Synthesis”, Green W. et al., 1999, 3rdEdition (John Wiley & Sons, Inc., New York).

Under the deleted group (Lg) in the present description to understand a group, which is easily cleaved from a molecule by heterolytic rupture due simultaneously with the departure of the electron pair. Thus, this group can be easily replaced by another group, for example, during a substitution reaction. Such groups are removed, for example, Halogens or an activated hydroxyl gr is the PAP such as mesyl, Casilina, triftormetilfullerenov, acetyl group, etc. are Examples of the deleted groups, as well as documents describing their getting listed in the “March''s Advanced Organic Chemistry”, J.March et al., 5thEdition, 2001, EMinter Ed.

Under Vos understand tert-butoxycarbonyl group, under the group Bn understand benzyl group, under the CBz group benzyloxycarbonyloxy group, the Fmoc group refers to a group of 9-fluorenylmethoxycarbonyl, and the letter h denotes hours.

In accordance with another object of the invention relates to compounds of formula (VI), (XVIII) and (XIX)in which R1, R2, R3, R4, R5, Ra, Ra'have the meanings specified above, and Pg represents a protective group:

In accordance with the invention compounds of General formula (I) can be obtained according to the method presented in scheme 1.

Scheme 1

According to the scheme 1 the compounds of formula (IV) can be obtained by reaction of a combination of intermediate compounds of formula (II) with amino acids of formula (III), in which the amino group protected by a protective group Pg (for example, BOC, CBz or Fmoc), in a classic combination of peptide type using, for example, as an agent of a combination of disclocated, hydrochloride 1-(3-dimethylaminopropyl)-ethylcarbodiimide or bromo-Tris-pyrrolidinedithiocarbamate in the presence of gidroekstruziya or without it, and as grounds using triethylamine or diisopropylethylamine in a solvent such as dioxane, dichloromethane or acetonitrile.

Amino acids of General formula (III) are available on the market or get them according to the methods described in the literature (Williams, R., Synthesis of Optically Active α-Aminoacids, Pergamon Press, Oxford, 1989).

The compounds of formula (V) obtained by removal of the protection of the amino group in compounds of formula (IV) by methods chosen from those known to the specialist. They include, in particular, the use of triperoxonane or hydrochloric acid in dichloromethane, dioxane, tetrahydrofuran or diethyl ether, if protection was carried out by a group of Vos, or hydrogenation using a suitable metal in methanol or ethanol, if protection is carried out by CBz groups, and the use of piperidine, if the protecting group is Fmoc, at a temperature of from -10°C. to 100°C.

At the last stage of the method the compounds of formula (I) are obtained by the method of reductive amination carried out with compounds of the formula (V)in the presence of a derivative group, R4ketone type and reductant such as sodium borohydride, triacetoxyborohydride sodium or cyanoborohydride sodium, in the presence or without acid Bronsted (such as hydrochloric acid) or Lewis acid (such as tetraisopropoxide Titus is on) in a solvent, for example, dichloroethane, dichloromethane, acetic acid or methanol, at temperatures from -10°C to 30°C.

Derivative group, R4ketone type can be products that are commercially available, or they can be obtained by methods known to the expert, for example, by acylation of the free amino group or a hydroxyl group derived ketone type.

Compounds of General formula (I) can also be obtained according to the method presented in scheme 2.

Scheme 2

According to the scheme 2 compounds of formula (V), obtained as described above and shown in scheme 1, is introduced into reaction with a derivative group, R4ketone type (the reaction of reductive amination, as described above with reference to figure 1), and R4bear group Pg, protecting the amino group and get the compounds of formula (VI). Aminophenol compounds of the formula (VI) is then released from the protection methods known to the expert, as described above.

Alternatively, the compounds of formula (VI), which lead to compounds of formula (I)can be obtained in accordance with the method presented in scheme 3.

Scheme 3

According to scheme 3, the compounds of formula (VIII) can be obtained by the method of recovery minervan what I as described above, based on the amino acids of the formula (VII). The amino acid of formula (VII)in which R5=N, commercially available, or it can be obtained by the methods described in the literature (Williams, R., Synthesis of Optically Active α-Aminoacids, Pergamon Press, Oxford, 1989). In the case when R5denotes alkyl, amino acids of the formula (VII)in which R5denotes alkyl, can be obtained by alkylation of amino acids, commercially available protected amino group, in accordance with the classical methods of alkylation, well-known specialist.

The compounds of formula (IX) can be obtained by saponification of esters of the formula (VIII), for example, in the presence of sodium hydroxide or lithium hydroxide, in a solvent such as methanol, tetrahydrofuran or water, or in mixtures of these solvents.

Compounds of General formula (VI) can be obtained according to the method of combination of peptide type, carried out between the intermediate compounds of formula (II) and the amino acid of formula (IX) combining a peptide of the type described with reference to figure 1.

The compounds of formula (II) can be obtained in accordance with the method presented in scheme 4.

Scheme 4:

According to scheme 4, the compounds of formula (II) are obtained from the compounds of formula (X) (in which Pg denotes a protective group of the amine, one that described what about the reference to figure 1), which removes the protection of the amino group by methods known to the expert, as described above.

The compounds of formula (X) can be obtained in accordance with the methods described in the literature or known to the specialist and adapted taking into account the nature of the groups R1and R2. Scheme 5-9, below, illustrate examples of the preparation of compounds of formula (X) according to the different types of groups R2. For example, in the case when R2represents a group-CO-R15in which R15matter mentioned above, obtaining the corresponding compounds (Ha) can be carried out according to the scheme 5.

Scheme 5

According to scheme 5, compounds of formula (XI) can be obtained by reductive amination of piperidone whose AMINOPHENYL protected (for example, manufactured in the sale of Re-piperidin) in the above-described conditions. Then get the compounds of formula (Ha) by reacting the compounds of formula (XI) with an acid chloride of the acid R15COCl in the presence of an organic base such as triethylamine or pyridine, in a solvent such as dichloromethane or tetrahydrofuran.

Variant of the method according to scheme 5 is in the interaction of protected aminopiperidine (for example, manufactured in the sale of 1-BOC-4-aminopiperidine) oxopropanal the group R 1under conditions of reductive amination, as described above.

Scheme 6 illustrates the synthesis of compounds of formula (Xb) and (Xc), which are compounds of formula (X)in which R2represents, respectively,- CO-NR16R17and-CO-NR15-NR16R17in which R15, R16and R17have the above value.

Scheme 6

According to scheme 6, compounds of formula (XII) can be obtained from compounds of formula (XI) by reacting with phosgene, triphosgene or trichloromethylcarbonate, in dichloromethane or toluene in the presence of triethylamine or pyridine and amine at a temperature from -10°C to 80°C. the Interaction of compounds of formula (XII) with an amine of the formula HN(R16)(R17or with a hydrazine of the formula HN(R15)(NR16R17) leads to the formation of compounds respectively of formula (Xb) and (Xc).

Scheme 7 illustrates the synthesis of compounds of formula (Xd), which are compounds of formula (X)in which R2represents a group -(CH2)x-NR16R17where x=2,3 or 4 and R16and R17have the above value.

Scheme 7

According to scheme 7, compounds of formula (XIII) can be obtained by reductive amination carried out on the compounds of the formula (XI)in the presence of the of legido formula Q-CO-(CH 2)x-2CHO, in which Q is a group-O-alkyl or-N(O-alkyl)(alkyl), using a reducing agent, such as that described with reference to figure 1.

Then the compounds of General formula (XIII) can be reduced to aldehydes of the formula (XIV) using a reducing agent such as a hydride diisobutylaluminum or tetraalkyllead sodium in the case when Q is the group-O-alkyl, or repair using sociallyengaged, if Q is a group-N(O-alkyl)(alkyl)(for example, -N(OMe)Me), the connection with this group are obtained, for example, the interaction magyarkanizsa compounds, such as diisopropylaniline, with the compound of formula (XIII), in which Q is -O-alkyl, in the presence of alkylhydroxylamines, such as N,O-dimethylhydroxylamine, in solvents such as tetrahydrofuran or diethyl ether, at temperatures from -78°C to 20°C.

The compounds of formula (Xd) then get by reductive amination carried out in the presence of an amine of formula R17R16NH, using a reducing agent, such as that described above.

Scheme 8 illustrates the synthesis of compounds of formula (Heh), which are compounds of formula (X)in which R2is a group -(CH2)xaryl (where x=0,1,2,3 or 4) or -(CH2)x-heteroaryl (where x=1,2,3 or 4).

Scheme 8

According to scheme 8, compounds of formula (Heh)in which R2is a group -(CH2)x-heteroaryl (where x=1,2,3 or 4)can be obtained by reductive amination of compounds of formula (XI)i carried out in the presence of an aldehyde of the formula: heteroaryl-(CH2)x-1-SNO and using a reductant, such as that described above with reference to figure 1.

The same reaction can be used to obtain compounds of formula (Xd), but using the aldehyde of the formula R17R16N-(CH2)x-1-CHO.

The compounds of formula (XI)ii, in which R2is a group -(CH2)xaryl (where x=0,1,2,3 or 4)can be obtained by reductive amination of piperidone with a protected amino group, carried out in the presence of an amine of the formula: aryl-(CH2)x-NH2using a reductant, such as that described with reference to figure 1. Then the compounds of formula (Heh)in which R2is a group -(CH2)x-aryl, can be obtained by reductive amination of compounds of formula (XI)ii, carried out in the presence of a derivative group, R1Ossetia.

Figure 9 represents an alternative synthesis of compounds of formula (Heh)in which R2is a group -(CH2)x-heteroa the sludge, where x is 2 or 3.

Scheme 9

According to scheme 9, compounds of formula (XIII), in which Q is-O-alkyl, can be restored to the corresponding alcohol using a reducing agent, such as sociallyengaged in a solvent such as diethyl ether or tetrahydrofuran, at temperatures from -60°C to 20°C.

Hydroxyl group of compounds of formula (XV) make then remove the group (Lg)such as chloride or mutilata, for example, by the action of tetrabromomethane and triphenylphosphine in a solvent such as dichloromethane, or by the action of methanesulfonanilide in the presence of organic bases such as triethylamine, at temperatures from -20°C to room temperature, and obtain the compounds of formula (XVI).

The compounds of formula (Heh) then get a nucleophilic substitution reaction between the compounds of formula (XVI) and anion heteroaryl (”Het”).

According to a variant of the method presented in figure 1, if the compounds of formula (I) contain, as the values of R4, a group of formula (a) tsiklogeksilnogo type, i.e. a group of formula (a), in which p=2 and X=-C(R6)(R7)-, in which R6is group-OR8and R7and R8have the meanings specified above, then the compounds of formula (I) may be about is westline in accordance with scheme 10.

Scheme 10

According to scheme 10, compounds of formula (XVIII) can be obtained by the reaction of reductive amination between the compound of formula (XVII)are commercially available, and the compound of the formula (V) in circumstances which are described with reference to figure 1.

Removing protection from the carbonyl group in the compound of formula (XVIII)is carried out in the presence of acid, such as hydrochloric acid or pyridinylmethyl, tetrahydrofuran or acetone at temperatures from 0°C to 80°C, leads to the production of the compounds of formula (XIX).

The compounds of formula (If) is obtained by recovery of the compounds of formula (XIX) in the conditions described with reference to figure 6.

If R8is not a hydrogen atom, then carry out the functionalization of compounds of formula (If), for example, alkylating in the presence of a base such as sodium hydride, and a derivative group, R8that contains the deleted group Lg, which allows to obtain the compounds of formula (Ig).

Presented in schemes 1-10 of the initial compounds and the reagents, the receipt of which is not disclosed in the description, a commercially available or described in the literature or can be obtained in accordance with the methods described in the literature or by methods known to the expert.

The present invention relates also to compounds of the formula (II), (IV), (V), (VI), (VIII), (I), (XVIII) and (XIX); these compounds are useful as intermediates in obtaining the compounds of formula (I).

The following examples describe the obtaining of some compounds according to the invention. These examples do not limit the scope of the present invention, and only illustrate it. Rooms compounds obtained in the examples correspond to the same numbers appearing in the below table, which illustrates the chemical structure and physical properties of some compounds according to the invention.

Example 1:N-[1-(4-chloro-N-piperidine-4-yl-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-diethylcarbamyl(compound No. 1)

1.1: tert-butyl 4-(cyclohexylamino)piperidine-1-carboxylate

Placed in a nitrogen atmosphere 15.0 g of 1-BOC-piperidone in 370 ml of dichloromethane in the presence of 7.47 g of cyclohexylamine and 20.7 g of triacetoxyborohydride sodium. The reaction medium is stirred for 16 hours at room temperature. After adding 30 ml of methanol introduced 300 g of resin DOWEX® 50x2 and the contents stirred for 45 minutes. The resin is then centrifuged and washed with tetrahydrofuran, then with methanol. The target connection is transferred to the sediment by adding 2 n ammonium hydroxide solution in methanol. After evaporation to dryness receive 13,85 g of tert-butyl 4-(cyclohexylamino)piperidine-1-carboxylate, which is th is used without purification in the subsequent syntheses.

1.2: tert-butyl 4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-carboxylate

Placed in a nitrogen atmosphere of 5.92 ml diphosgene in 150 ml dichloromethane at 0°C. was Added dropwise a solution of 13,85 g of tert-butyl 4-(cyclohexylamino)piperidine-1-carboxylate and 34,18 ml of triethylamine. The solution is stirred 30 minutes at 0°C., then 1 hour at room temperature. The reaction mixture was again placed in the cold at 0°C and add of 5.92 ml diphosgene and 34,18 ml of triethylamine. After stirring for 1 hour at room temperature are added to 25.4 ml diethylamine. The mixture is stirred for 16 hours at room temperature. After evaporation of dichloromethane, add 200 ml of 0.5 N. hydrochloric acid. Extracted with dichloromethane until the depletion of the aqueous phase. After drying over MgSO4and evaporation to dryness the residue chromatographic on silica gel, elwira mixture 98/2 then 95/5 dichloromethane with methanol, and get 16,77 g of tert-butyl 4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-carboxylate.

1.3:N-cyclohexyl-N',N'-diethyl-N-piperidine-4-ylcarbamate

Put 16,77 g of a mixture of tert-butyl 4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-carboxylate with diethylcarbamazine in 54,9 ml of 4 n solution of hydrochloric acid in dioxane. The reaction medium is stirred for 16 hours at room temperature. After evaporation of the environment Dosh is add 1 to N. the sodium hydroxide solution to establish a pH of 10 and extracted with dichloromethane until the depletion of the aqueous phase. After drying over MgSO4and evaporation to dryness the crude residue chromatographic on silica gel, elwira mixture 98/2/0,2, 95/5/0,5, 9/1/0,1 then 5/5/0,5 dichloromethane, methanol with ammonium hydroxide, and get 11,27 gN-cyclohexyl-N',N'-diethyl-N-piperidine-4-ylcarbamate.

1.4: tert-butyl[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl-[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]-carbamate

Dissolve 2.85 gN-cyclohexyl-N',N'-diethyl-N-piperidine-4-ylcarbamate in 101 ml of dichloromethane in the presence totaling 3.04 g of 4-chloro-D-BOC-phenylalanine, 1,37 g of hydroxybenzotriazole, of 1.95 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1.77 ml diisopropylethylamine. The mixture is stirred for 16 hours at room temperature. After evaporation to dryness the residue is hydrolized and extracted with ethyl acetate to depletion of the aqueous phase. The organic phase was washed with 1 N. a solution of sodium hydroxide, then with water. After drying over MgSO4and evaporation to dryness the crude product chromatographic on silica gel, elwira mixture 98/2 then 95/5 dichloromethane with methanol, and get 5,04 g of tert-butyl[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl-[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]-carbamate.

1.5:N-[1-(4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-Nthe cycle is hexyl- N',N'-diethylcarbamyl

Put 5,16 g of tert-butyl[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]carbamate in 22,89 ml of 4 n solution of hydrochloric acid in dioxane. The reaction medium is stirred for 24 hours at room temperature. After evaporation to dryness the residue is absorbed by ethyl acetate and washed with saturated aqueous sodium bicarbonate, then saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness the crude product chromatographic on silica gel, elwira mixture 95/5 dichloromethane with methanol. Get 2.9 g:N-[1-(4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-diethylcarbamyl.

1.6: tert-butyl 4-{[(1R(-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}piperidine-1-carboxylate

Solubilizer in nitrogen atmosphere, 0.5 gN-[1-(4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-diethylcarbamyl in 5 ml of dichloromethane in the presence of 0.30 gNVos-piperidone and 0.42 g of triacetoxyborohydride sodium. Stirred for 18 hours at room temperature. After hydrolysis is extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with water. After drying over MgSO4and evaporation to dryness the crude product chromatografic on the specification of the gel, elwira with a mixture of cyclohexane with ethyl acetate (9/1). Obtain 0.2 g of tert-butyl 4-{[(1R(-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}piperidine-1-carboxylate.

1.7:N-[1-(4-chloro-N-piperidine-4-yl-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-diethylcarbamyl

Solubilizing 0.26 g of tert-butyl 4-{[(1R(-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}piperidine-1-carboxylate in 2 ml of diethyl ether, then add to 2.74 ml of 2 N. hydrochloric acid in diethyl ether. The reaction medium is stirred for 16 hours at room temperature. After partial evaporation of the precipitate centrifuged, which is then triturated in ethanol-dichloromethane. The crystals are centrifuged and washed with ethanol. The resulting hydrochloride is dried over P2About5under reduced pressure. Obtain 0.18 gN-[1-(4-chloro-N-piperidine-4-yl-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-diethylcarbamyl in the form of a white solid.

Melting point > 220°C.; M+N+546; [α]D20=+7,0 (C=0,g/100 ml, DMSO).

NMR1H (200 MHz, DMSO-d): 9,95-8,95 (N replaceable), 7,39 (d, J=8 Hz, 2H), 7,20 (d, J=8 Hz, 2H), 4,78 (m, 1H), 4,29 (t, J=12 Hz, 1H), 3,32 (array, 6N+N2O), 3,64-2,84 (m,N), 2,24-1,10 (m, N), and 0.98 (t, J=6N, 3H), of 0.95 (t, J=6 Hz, 3H), of 0.95 (t, J=6 Hz, 3H). Ale is ntny analysis: found%: 52,51, %N: 7,86, %N: 10,15; calculated: %C: 57,88, %H: 8,65, %N: 11,25.

Example 2: HydrochlorideN-[1-(N-1-azabicyclo[2.2.2]Oct-3-yl-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-diethylcarbamyl(compound No. 5)

2.1:N-[1-(N-1-azabicyclo[2.2.2]Oct-3-yl-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-diethylcarbamyl

Solubilizer in nitrogen atmosphere 0,23 gN-[1-(4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-diethylcarbamyl obtained at stage 1.5, described above in 3 ml of dichloromethane in the presence of 0,089 g of the hydrochloride of 3-binucleation and 0.22 g of triacetoxyborohydride sodium. Stirring is carried out for 18 hours at room temperature. After adding 0,044 g of the ketone and 0,222 g triacetoxyborohydride reaction medium is stirred for 48 hours. After adding 2 ml of methanol, the solution is transferred into a filter cartridge containing 4 g of resin DOWEX® 50x2. The resin is washed with tetrahydrofuran, water and then methanol. The target connection planted with 2 n ammonium hydroxide solution in methanol. After evaporation to dryness receive 0,212 g of a mixture of diastereoisomers (R,S) and (R,R)N-[1-(N-1-azabicyclo[2.2.2]Oct-3-yl-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-diethylcarbamyl.

2.2: hydrochloride diastereoisomers (R,S) and (R,R)N-[1-(N-1-azabicyclo[2.2.2]Oct-3-yl-4-chloro-D-fenilalanil)piperidine-4-yl]- Ncyclohexyl-N',N'-diethylcarbamyl.

Mixed 0.21 g of the hydrochloride of diastereoisomers (R,S) and (R,R)N-[1-(N-1-azabicyclo[2.2.2]Oct-3-yl-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-diethylcarbamyl from 0.37 ml of 2 N. hydrochloric acid in diethyl ether. The solution is rubbed. The resulting crystals are washed with diethyl ether and centrifuged. Get 0,204 g of the hydrochloride of diastereoisomers (R,S) and (R,R)N-[1-(N-1-azabicyclo[2.2.2]Oct-3-yl-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-Ncyclohexyl-N',N'-diethylcarbamyl in the form of a white solid. TPL=169°C.; M+N+=572.

Example 3: 1-[(2R)-3-(4-chlorophenyl)-2-(piperidine-4-ylamino)propionyl]-N-cyclohexyl-N-{2-[methoxy(methyl)amino]ethyl}piperidine-4-amine(compound No. 16)

3.1: tert-butyl 4-[cyclohexyl(2-ethoxy-2-oxoethyl)amino]piperidine-1-carboxylate

Solubilizer in nitrogen atmosphere 4.5 g of tert-butyl 4-(cyclohexylamino)piperidine-1-carboxylate in 159 ml of dichloromethane in the presence 4,88 g ethylglycol and 13.5 g of triacetoxyborohydride sodium. Stirring is carried out for 18 hours at room temperature. After the implementation of the water hydrolysis is extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with saturated aqueous sodium bicarbonate, then with water. After drying over MgSO4and pariva the Oia to dryness the crude product chromatographic on silica gel, elwira a mixture of dichloromethane with methanol (99/1). Get 3 g of tert-butyl 4-[cyclohexyl(2-ethoxy-2-oxoethyl)amino]piperidine-1-carboxylate.

3.2: tert-butyl 4-(cyclohexyl{2-[methoxy(methyl)amino]-2-oxoethyl}amino)piperidine-1-carboxylate

Dissolved in a nitrogen atmosphere to 3.09 g of tert-butyl 4-[cyclohexyl(2-ethoxy-2-oxoethyl)amino]piperidine-1-carboxylate in 84 ml of tetrahydrofuran and the solution is cooled to -20°C. After addition of 1.54 g of the hydrochloride of N,O-dimethylhydroxylamine enter 20,96 ml of 2M solution of chloride Isopropylamine in tetrahydrofuran, the temperature should not exceed -10°C. After stirring for 1 hour 30 minutes again added 0.51 g of the hydrochloride of N,O-dimethylhydroxylamine and 4.2 ml of a 2M solution of chloride Isopropylamine in tetrahydrofuran at -10°C. The stirring is continued for 30 minutes. After evaporation of the tetrahydrofuran, the resulting crude product absorb dichloromethane and hydrolyzing. Extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with water, then saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness the crude product chromatographic on silica gel, elwira a mixture of dichloromethane with methanol (95/5). Get 1,11 g of tert-butyl 4-(cyclohexyl{2-[methoxy(methyl)amino]-2-oxoethyl}amino)piperidine-1-carboxylate.

3.3: tert-butyl 4-[cyclohexyl(2-oxoethyl)amino]piperidin-1-carboxylate

Dissolved in a nitrogen atmosphere was 4.02 g of tert-butyl 4-(cyclohexyl{2-[methoxy(methyl)amino]-2-oxoethyl}amino)piperidine-1-carboxylate in 105 ml of anhydrous diethyl ether at -10°C. Add of 12.6 ml of a 1M solution of sociallyengaged in tetrahydrofuran. After stirring for 1 hour at 0°C is added a saturated aqueous solution of potassium sulfate to establish a pH of 6-7. Extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with water, then saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness receive 3,39 g of tert-butyl 4-[cyclohexyl(2-oxoethyl)amino]piperidine-1-carboxylate, which is used for further synthesis without purification.

3.4: tert-butyl 4-(cyclohexyl{2-[methoxy(methyl)amino]ethyl}amino)piperidine-1-carboxylate

Solubilizer in nitrogen atmosphere 1,69 g of tert-butyl 4-[cyclohexyl(2-oxoethyl)amino]piperidine-1-carboxylate in 52 ml of dichloromethane in the presence of 5.10 g of the hydrochloride of N,O-dimethylhydroxylamine and 4,43 g triacetoxyborohydride sodium. Stirring is carried out for 5 hours at room temperature. After addition of methanol and evaporation to dryness extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with saturated aqueous sodium bicarbonate, water, then saturated aqueous sodium chloride. Polessky over MgSO 4and evaporation to dryness the crude product chromatographic on silica gel, elwira a mixture of dichloromethane with methanol (98/2). Gain of 1.03 g of tert-butyl 4-(cyclohexyl{2-[methoxy(methyl)amino]ethyl}amino)piperidine-1-carboxylate.

3.5:N-cyclohexyl-N-{2-[methoxy(methyl)amino]ethyl}piperidine-4-amine

Put 1,033 g of tert-butyl 4-(cyclohexyl{2-[methoxy(methyl)amino]ethyl}amino)piperidine-1-carboxylate in 28 ml of diethyl ether and added dropwise 14 ml of 2 N. hydrochloric acid in diethyl ether. The reaction medium is stirred for 16 hours at room temperature. After evaporation to dryness the crude product absorb dichloromethane and add a saturated solution of sodium bicarbonate and extracted with dichloromethane until the depletion of the aqueous phase. After drying over MgSO4and evaporation to dryness obtain 0.18 gN-cyclohexyl-N-{2-[methoxy(methyl)amino]ethyl}piperidine-4-amine.

3.6: methylN-[1-(tert-butoxycarbonyl)piperidine-4-yl]-4-chloro-D-phenylalanine

Solubilizer in the atmosphere of nitrogen, 10 g of methyl ester of p-D-chlorophenylalanine in 248 ml of dichloromethane in the presence of 8.8 g of N-BOC-piperidone and 14.4 g of triacetoxyborohydride sodium. Stirred for 18 hours at room temperature. After addition of methanol and evaporation to dryness the crude product absorb saturated aqueous solution of sodium bicarbonate and extra the shape with ethyl acetate to depletion of the aqueous phase. After drying over MgSO4and evaporation to dryness receive $ 15.87 with g methyl-N-[1-(tert-butoxycarbonyl)piperidine-4-yl]-4-chloro-D-phenylalanine.

3.7:N-[1-(tert-butoxycarbonyl)piperidine-4-yl]-4-chloro-D-phenylalanine

Solubilizer to 15.8 g methyl-N-[1-(tert-butoxycarbonyl)piperidine-4-yl]-4-chloro-D-phenylalanine in 200 ml of a mixture of tetrahydrofuran/water (1/1) and add to 3.35 g of the hydrate of lithium hydroxide. Stirred for 16 hours at room temperature. Add potassium sulfate to establish a pH of 7. The obtained precipitate is centrifuged and washed with diethyl ether. After drying over P2About5get 11,38 gN-[1-(tert-butoxycarbonyl)piperidine-4-yl]-4-chloro-D-phenylalanine.

3.8: tert-butyl 4-({(1R)-1-(4-Chlorobenzyl)-2-[4-(cyclohexyl{2-[methoxy(methyl)amino]ethyl}amino)piperidine-1-yl]-2-oxoethyl}amino)piperidine-1-carboxylate

Solubilizing 0.18 gN-cyclohexyl-N-{2-[methoxy(methyl)amino]ethyl}piperidine-4-amine, obtained in stage 3.5, 6.8 ml of dichloromethane in the presence of 0.26 gN-[1-(tert-butoxycarbonyl)piperidine-4-yl]-4-chloro-D-phenylalanine (obtained at the stage 3.7), 0,092 g of hydroxybenzotriazole, of 0.13 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 0.12 ml of diisopropylethylamine. The mixture is stirred for 16 hours at room temperature. After hydrolysis is extracted with dichloromethane until the depletion of the aqueous phase. Organic the action phase is washed with water, then a saturated solution of sodium chloride. After drying over MgSO4and evaporation to dryness the crude product chromatographic on silica gel, elwira a mixture of dichloromethane with methanol 98/2, then 97/3, and obtain 0.15 g of tert-butyl 4-({(1R)-1-(4-Chlorobenzyl)-2-[4-(cyclohexyl{2-[methoxy(methyl)amino]ethyl}amino)piperidine-1-yl]-2-oxoethyl}amino)piperidine-1-carboxylate.

3.9: the hydrochloride of 1-[(2R)-3-(4-chlorophenyl)-2-(piperidine-4-ylamino)propanoic]-N-cyclohexyl-N-{2-[methoxy(methyl)amino]ethyl}piperidine-4-amine

Put 0,147 g of tert-butyl 4-({(1R)-1-(4-Chlorobenzyl)-2-[4-(cyclohexyl{2-[methoxy(methyl)amino]ethyl}amino)piperidine-1-yl]-2-oxoethyl}amino)piperidine-1-carboxylate in 2.3 ml of diethyl ether and type of 0.58 ml of 2 N. hydrochloric acid in diethyl ether. The reaction mixture is stirred for 16 hours at room temperature. After evaporation to dryness and hydrolysis is extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with saturated aqueous sodium bicarbonate, water, then saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness, add 2 ml of isopropanol and 2.43 ml of 0.1 G. of hydrochloric acid in isopropanol. After evaporation to dryness the residue is absorbed in diethyl ether and triturated solid product. The obtained crystals are centrifuged and washed with di is tilov ether. After drying over P2About5obtain 0.08 g of the hydrochloride of 1-[(2R)-3-(4-chlorophenyl)-2-(piperidine-4-ylamino)propanoic]-N-cyclohexyl-N-{2-[methoxy(methyl)amino]ethyl}piperidine-4-amine.

TPL=166°C.; M+N+=534

Example 4: hydrochloride of N-[1-(4-chloro-N-piperidine-4-yl-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-2-ethylbutylamine(compound No. 19)

4.1: tert-butyl 4-[cyclohexyl(2-ethylbutanol)amino]piperidine-1-carboxylate

Placed in a nitrogen atmosphere, 1.5 g of tert-butyl 4-(cyclohexylamino)piperidine-1-carboxylate, obtained in stage 1.1, in 27 ml of dichloromethane at 0°C. Add to 0.89 ml of triethylamine, then to 0.73 ml of 2-ethylbutylamine. Stirred for 16 hours at room temperature. After evaporation to dryness and hydrolysis is extracted with ethyl acetate to depletion of the aqueous phase. The organic phase is washed with saturated aqueous sodium chloride, dried over MgSO4and evaporated to dryness. The resulting crude product chromatographic on silica gel, elwira with a gradient of methanol in dichloromethane ranging from 0% to 3%. Obtain 1.39 g of tert-butyl 4-[cyclohexyl(2-ethylbutanol)amino]piperidine-1-carboxylate.

4.2:N-cyclohexyl-2-ethyl-N-piperidine-4-albuminemia

Put 1.5 g of tert-butyl 4-[cyclohexyl(2-ethylbutanol)amino]piperidine-1-carboxylate in 9.9 ml of 4 N. hydrochloric acid in dioxane. The reaction medium is stirred during 16 hours at room temperature. After evaporation to dryness was added 1 n sodium hydroxide solution to establish a pH of 10 and extracted with ethyl acetate to depletion of the aqueous phase. The organic phase is washed with saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness the crude product chromatographic on silica gel, elwira with a gradient of methanol in dichloromethane ranging from 0%to 5%. Receive 1.2 gN-cyclohexyl-2-ethyl-N-piperidine-4-albuminemia.

4.3: tert-butyl 4-[((1R)-1-(4-Chlorobenzyl)-2-{4-[cyclohexyl(2-ethylbutanol)amino]piperidine-1-yl}-2-oxoethyl)amino]piperidine-1-carboxylate

Solubilizing 0.3 gN-cyclohexyl-2-ethyl-N-piperidine-4-albuminemia in 9 ml dichloromethane in the presence of 0.36 g of 4-chloro-N-(1-BOC-piperidine-4-yl)-D-phenylalanine (obtained at the stage 3.7), 0,128 g of hydroxybenzotriazole, of 0.182 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide and 0.49 ml of diisopropylethylamine. The mixture is stirred for 16 hours at room temperature. After evaporation and hydrolysis extracted the product with ethyl acetate to depletion of the aqueous phase. The organic phase is washed with water, then saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness the crude product chromatographic on silica gel, elwira with a gradient of methanol in dichloromethane ranging from 0%to 5%, and get to 0.23 g of tert-butyl 4-[((1R)-1-(4-Chlorobenzyl)-2-{4-[cyclohe the forces(2-ethylbutanol)amino]piperidine-1-yl}-2-oxoethyl)amino]piperidine-1-carboxylate.

4.4:N-[1-(4-chloro-N-piperidine-4-yl-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-2-ethylbutane

Place of 0.23 g of tert-butyl 4-[((1R)-1-(4-Chlorobenzyl)-2-{4-[cyclohexyl(2-ethylbutanol)amino]piperidine-1-yl}-2-oxoethyl)amino]piperidine-1-carboxylate 1.35 ml 4 N. hydrochloric acid in dioxane. The reaction medium is stirred for 16 hours at room temperature. After evaporation to dryness was added 1 n sodium hydroxide solution to establish a pH of 10 and extracted with ethyl acetate to depletion of the aqueous phase. The organic phase is washed with saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness the crude product chromatographic on silica gel, elwira with a gradient mixture of methanol/ammonium hydroxide in dichloromethane from 0% to 5/0,5/95. Obtain 0.16 gN-[1-(4-chloro-N-piperidine-4-yl-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-2-ethylbutylamine.

4.5 HydrochlorideN-[1-(4-chloro-N-piperidine-4-yl-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-2-ethylbutylamine

Put 0.16 gN-[1-(4-chloro-N-piperidine-4-yl-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-2-ethylbutylamine in 2 ml of dichloromethane and added to 5.5 ml of 0.1 n solution of hydrochloric acid in isopropanol. After evaporation to dryness the residue is absorbed by ethyl acetate and pound. The obtained crystals are centrifuged and washed uh what racedata. After drying over P2About5gain of 0.13 g of hydrochlorideN-[1-(4-chloro-N-piperidine-4-yl-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-2-ethylbutylamine.

TPL=S; M+N+=545; [α]Hg36520=+5° (c=0,g/100ml, DMSO).

Example 5: HydrochlorideN-{1-[4-chloro-N-(tetrahydro-2H-Piran-4-yl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl(compound No. 3)

5.1:N-{1-[4-chloro-N-(tetrahydro-2H-Piran-4-yl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl

Solubilizer in nitrogen atmosphere 0,23 gN-[1-(4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-diethylcarbamyl obtained at the stage of 1,5 described above in 3 ml of dichloromethane in the presence of 0.05 ml of tetrahydro-4H-4-it and 0.22 g of triacetoxyborohydride sodium. Stirring is carried out at room temperature for 18 hours. After adding 0,044 g of the ketone and 0,222 g triacetoxyborohydride reaction medium is stirred for 48 hours. After adding 2 ml of methanol, the solution is transferred into a filter cartridge containing 4 g of resin DOWEX® 50x2.

The resin was washed with THF, water and then methanol. Target product are planted with 2 n ammonia solution in methanol. After evaporation to dryness receive 0,23 gN-{1-[4-chloro-N-(tetrahydro-2H-Piran-4-yl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'di is tinkerballa.

5.2: HydrochlorideN-{1-[4-chloro-N-(tetrahydro-2H-Piran-4-yl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl

Mix 0,23 gN-{1-[4-chloro-N-(tetrahydro-2H-Piran-4-yl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl and 0.37 ml of 2 N. hydrochloric acid in diethyl ether. The solution is rubbed. The resulting crystals are washed with diethyl ether and centrifuged. Get 0,22 g hydrochlorideN-{1-[4-chloro-N-(tetrahydro-2H-Piran-4-yl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl in the form of a white solid.

TPL > 200°C; M+N+= 547; [α]D20=+2,7° (C=0,g/100ml, DMSO).

Example 6: HydrochlorideN-{1-[N(aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl(compound No. 2)

6.1:N-{1-[N-(4-BOC-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl

Solubilizer in nitrogen atmosphere 0,23 gN-[1-(4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-diethylcarbamyl obtained at the stage of 1,5 described above in 3 ml of dichloromethane in the presence of 0.12 g of N-4-BOC-aminocyclohexanone and 0.22 g of triacetoxyborohydride sodium. Stirring is carried out for 18 hours at room temperature. After adding 2 m the methanol solution is placed in a filter cartridge, containing 4 g of resin DOWEX® 50x2. The resin was washed with THF, water and then methanol. The target product was transferred into the sediment using a 2 n solution of ammonia in methanol. After evaporation to dryness obtain 0.18 g of tert-butyl(4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)carbamate.

6.2: HydrochlorideN-{1-[N(aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl

Put 0.18 g of tert-butyl(4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)carbamate in 2 ml of diethyl ether and type of 0.77 ml of 2 N. hydrochloric acid in diethyl ether. The reaction medium is stirred at room temperature for 18 hours. The resulting crystals are washed with diethyl ether and centrifuged. Obtain 0.14 g of the hydrochloride a mixture of isomers of CIS and TRANSN-{1-[N(aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl.

TPL=195°C.; M+N+=560.

Example 7: Hydrochloride of N-[1-(N-8-azabicyclo[3.2.1]oxt-3-yl-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-diethylcarbamyl(compound No. 4)

7.1: tert-butyl 3-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-8-azabicyclo[3.2.1]Octan-carboxylate

Solubilizer in nitrogen atmosphere 0,46 gN-[1-(4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-diethylcarbamyl obtained at the stage of 1.5, as described above, in 10 ml dichloromethane in the presence 0,034 g Vos-nortropinone and 0.42 g of triacetoxyborohydride sodium. Stirring is carried out for 18 hours at room temperature. Add 0.10 g of the BOC-nortropinone and 0.10 g of triacetoxyborohydride sodium. Stirred for 24 hours. After hydrolysis of the extracted product dichloromethane to depletion of the aqueous phase. The organic phase is washed with water, then saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness the crude product chromatographic on silica gel, elwira mixture (90/10) cyclohexane with ethyl acetate. Gain of 0.37 g of tert-butyl 3-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate.

7.2: hydrochlorideN-[1-(N-8-azabicyclo[3.2.1]oxt-3-yl-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-diethylcarbamyl

Put 0,37 tert-butyl-3-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate in 2 ml of diethyl ether and add to 2.74 ml of 2 N. hydrochloric acid in diethyl ether. Reaction medium was stirred at whom atoi temperature for 18 hours. Add an additional 2 ml of 2 N. hydrochloric acid in diethyl ether. The resulting crystals are washed with diethyl ether and centrifuged. Get 0,30 g hydrochlorideN-[1-(N-8-azabicyclo[3.2.1]Oct-3-yl-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-diethylcarbamyl.

TPL=182°C.; M+N+=572; [α]D20=+9,2° (C=0,g/100ml, DMSO).

Example 8: HydrochlorideN-{1-[4-chloro-N-(1-isobutylpyrazine-4-yl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl(compound No. 6)

8.1:N-{1-[4-chloro-N-(1-isobutylpyrazine-4-yl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl

Solubilizer in nitrogen atmosphere 0.25 gN-[1-(4-chloro-N-piperidine-4-yl-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-diethylcarbamyl obtained at the stage of 1.7, in 4 ml of dichloromethane in the presence of 0.05 ml of Isobutyraldehyde and 0.16 g of triacetoxyborohydride sodium. Stirred for 3 days at room temperature. After hydrolysis with an aqueous solution of sodium hydroxide at pH 10 is extracted with ethyl acetate to depletion of the aqueous phase. The organic phase is washed with water, then with an aqueous solution of sodium chloride. After drying over MgSO4and evaporation to dryness the resulting crude product chromatographic on silica gel, elwira with a gradient mixture (9/1/0,1) dichlo is methane, methanol and aqueous ammonium hydroxide in dichloromethane from 0 to 100%. Obtain 0.14 gN-{1-[4-chloro-N-(1-isobutylpyrazine-4-yl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl.

8.2: HydrochlorideN-{1-[4-chloro-N-(1-isobutylpyrazine-4-yl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl

Put 0.14 gN-{1-[4-chloro-N-(1-isobutylpyrazine-4-yl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl in 2 ml of dichloromethane and add 4,48 ml of 0.1 G. of hydrochloric acid in isopropanol. After evaporation to dryness the residue is triturated in a mixture of diethyl ether and ethyl acetate. The resulting crystals are washed with diethyl ether, centrifuged and dried over P2About5. Get 0,115 g hydrochlorideN-{1-[4-chloro-N-(1-isobutylpyrazine-4-yl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl.

TPL >S; M+N+= 602; [α]D20= +10,6° (C=0,g/100ml, DMSO).

Example 9: Hydrochloride 1-[(2R)-3-(4-chlorophenyl-1-methylene-2-(piperidine-4-ylamino)propanoic]-N-cyclohexyl-N-(4-methoxyphenyl)piperidine-4-amine(compound No. 40)

9.1: tert-butyl 4-[(4-methoxyphenyl)amino]piperidine-1-carboxylate

Placed in an atmosphere of nitrogen, 2.0 g of 1-BOC-piperidone in 85 ml of acetic acid in the presence of 6,47 g of 4-methoxyaniline, 23 g su is that sodium and 10.3 g of triacetoxyborohydride sodium and the reaction medium is stirred for 16 hours at room temperature. After evaporation to dryness, add 30%aqueous solution of sodium hydroxide to establish an alkaline pH. Extracted with ethyl acetate to depletion of the aqueous phase. The organic phase is washed with water, then saturated sodium chloride solution. After drying over MgSO4and evaporation to dryness obtain 9 g of tert-butyl 4-[(4-methoxyphenyl)amino]piperidine-1-carboxylate.

9.2: tert-butyl 4-[cyclohexyl(4-methoxyphenyl)amino]piperidine-1-carboxylate

Placed in a nitrogen atmosphere 5.0 g of tert-butyl 4-[(4-methoxyphenyl)amino]piperidine-1-carboxylate in 55 ml of dichloromethane in the presence 5,78 ml of cyclohexanone and 4,84 g triacetoxyborohydride sodium. After 18 hours stirring of 2.9 ml of cyclohexanone and 2.4 g of triacetoxyborohydride sodium and the reaction medium is stirred for 5 days at room temperature. After adding 20 ml of methanol and 0.5 g of citric acid and 50 ml of water is stirred for 18 hours and extracted with dichloromethane until the depletion of the aqueous phase. After drying over Na2SO4and evaporation to dryness the resulting crude product chromatographic on silica gel, elwira a mixture of heptane/Et 7/3. Get 4 g of tert-butyl 4-[cyclohexyl(4-methoxyphenyl)amino]piperidine-1-carboxylate in the form of a mixture.

9.3:N-cyclohexyl-N-(4-methoxyphenyl)piperidine-4-amine

Place 10 g of tert-butyl 4-[cyclohexyl(4-methoxyphenyl)amino]Piperi the Jn-1-carboxylate in 50 ml of 4 N. hydrochloric acid in dioxane. The reaction medium is stirred for 18 hours at room temperature. After evaporation to dryness the residue chromatographic a mixture of dichloromethane, methanol and ammonium hydroxide gradient 95/5/0,5 to 85/15/1,5. Obtain 2.1 gN-cyclohexyl-N-(4-methoxyphenyl)piperidine-4-amine.

9.4: tert-butyl 4-[((1R)-1-(4-Chlorobenzyl)-2-{4-[cyclohexyl(4-methoxyphenyl)amino]piperidine-1-yl}-2-oxoethyl)amino]piperidine-1-carboxylate

Solubilizing 0.29 gramsN-cyclohexyl-N-(4-methoxyphenyl)piperidine-4-amine, obtained in stage 9.3, 10 ml dichloromethane in the presence of 0.38 gN-[1-(tert-butoxycarbonyl)piperidine-4-yl]-4-chloro-D-phenylalanine obtained at the stage of 3.7, 0.14 g of hydroxybenzotriazole, 0,19 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 0.17 ml of diisopropylethylamine. The mixture is stirred for 16 hours at room temperature. After hydrolysis is extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with saturated aqueous sodium bicarbonate. After drying over Na2SO4and evaporation to dryness the resulting crude product chromatographic, elwira a mixture of dichloromethane/methanol/ammonium hydroxide gradient 95/5/0 to 9/1/0,5. Obtain 0.32 g of tert-butyl 4-[((1R)-1-(4-Chlorobenzyl)-2-{4-[cyclohexyl(4-methoxyphenyl)amino]piperidine-1-yl}-2-oxoethyl)amino]piperidine-1-carboxylate is.

9.5: 1-[(2R)-3-(4-chlorophenyl)-2-(piperidine-4-ylamino)propanoic]-N-cyclohexyl-N-(4-methoxyphenyl)piperidine-4-Amin

Put 0.32 g of tert-butyl 4-[((1R)-1-(4-Chlorobenzyl)-2-{4-[cyclohexyl(4-methoxyphenyl)amino]piperidine-1-yl}-2-oxoethyl)amino]piperidine-1-carboxylate in 5 ml of dioxane and added to 1.22 ml 4 N. hydrochloric acid in dioxane. The reaction medium is stirred for 18 hours at room temperature. After evaporation to dryness the residue absorb methanol and again evaporated to dryness. The resulting crude product chromatographic, elwira a mixture of methanol/ammonium hydroxide in dichloromethane with gradient 95/5/0,5 to 9/1/0,1. Get 0,176 g of 1-[(2R)-3-(4-chlorophenyl)-2-(piperidine-4-ylamino)propanoic]-N-cyclohexyl-N-(4-methoxyphenyl)piperidine-4 amine.

9.6: the Hydrochloride of 1-[(2R)-3-(4-chlorophenyl)-2-(piperidine-4-ylamino)propanoic]-N-cyclohexyl-N-(4-methoxyphenyl)piperidine-4-amine

Put 0.17 g of 1-[(2R)-3-(4-chlorophenyl)-2-(piperidine-4-ylamino)propanoic]-N-cyclohexyl-N-(4-methoxyphenyl)piperidine-4 amine in 5 ml of dichloromethane and added to 3.2 ml of 0.1 G. of hydrochloric acid in isopropanol. After evaporation to dryness the residue is recrystallized from ethanol. Get 0.036 g of the hydrochloride of 1-[(2R)-3-(4-chlorophenyl)-2-(piperidine-4-ylamino)propanoic]-N-cyclohexyl-N-(4-methoxyphenyl)piperidine-4-amine. TPL=195°C.; M+N+=553.

Example 10: Hydrochlor the d 1-[(2R)-3-(4-chlorophenyl)-2-(piperidine-4-ylamino)propanoic]- N-cyclohexyl-N-[2-(1H-imidazol-1-yl)ethyl]piperidine-4-amine(compound No. 44)

10.1: tert-butyl 4-[cyclohexyl(2-ethoxy-2-oxoethyl)amino]piperidine-1-carboxylate

Solubilizer with 4.64 g of tert-butyl 4-(cyclohexylamino)piperidine-1-carboxylate, obtained in stage 1.1, in 164 ml of dichloromethane and add 9,77 ml ethyloxazole. Slowly introducing 13,93 g triacetoxyborohydride sodium. Stirred for 18 hours at room temperature. Again add to 3.25 ml ethyl ester of Glyoxylic acid and of 3.48 g of triacetoxyborohydride sodium. After stirring for 72 hours, the reaction medium is treated with methanol and evaporated to dryness. The remainder absorb saturated aqueous solution of sodium bicarbonate. Extracted with ethyl acetate to depletion of the aqueous phase. The organic phase is washed with saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness the resulting crude product chromatographic on silica gel, elwira with a gradient of methanol in dichloromethane ranging from 0%to 10%. Get 6,44 g of tert-butyl 4-[cyclohexyl(2-ethoxy-2-oxoethyl)amino]piperidine-1-carboxylate.

10.2: tert-butyl 4-[cyclohexyl(2-hydroxyethyl)amino]piperidine-1-carboxylate

Placed in a nitrogen atmosphere 6,44 g of tert-butyl 4-[cyclohexyl(2-ethoxy-2-oxoethyl)amino]piperidine-1-carboxylate in 175 ml of diethyl ether at 0°C. Slowly p is ibullet 29,71 ml of 1 N. the solution sociallyengaged in diethyl ether. After stirring for 1 hour at 0°C is added a saturated aqueous solution of potassium sulfate to establish a pH of 5-6. After adding 1 N. aqueous sodium hydroxide solution is extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with water, then saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness receive Android 4.04 g of tert-butyl 4-[cyclohexyl(2-hydroxyethyl)amino]piperidine-1-carboxylate, used without purification in the subsequent syntheses.

10.3: tert-butyl 4-(cyclohexyl{2-[(methylsulphonyl)oxy]ethyl}amino)piperidine-1-carboxylate

Solubilizing 0.75 g of tert-butyl 4-[cyclohexyl(2-hydroxyethyl)amino]piperidine-1-carboxylate in 23 ml of diethyl ether. Added 0.63 ml of triethylamine and 0.28 ml of methylchloride. After stirring at room temperature for 2 hours, the formed triethylamine hydrochloride is filtered off and the filtrate evaporated to dryness. Get 0,82 g of tert-butyl 4-(cyclohexyl{2-[(methylsulphonyl)oxy]ethyl}amino)piperidine-1-carboxylate, used without purification in the subsequent syntheses.

10.4: tert-butyl 4-{cyclohexyl[2-(1H-imidazol-1-yl)ethyl]amino}piperidine-1-carboxylate

Solubilizer of 0.82 g of tert-butyl 4-(cyclohexyl{2-[(methylsulphonyl)oxy]ethyl}amino)piperidine-1-carboxylate in 4 ml sociotechnical/dimethylformamide (1/1), then add 0,41 g of 1,2,4-triazole sodium. After stirring at room temperature for 18 hours product hydrolized and extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with water. After drying over MgSO4and evaporation to dryness the resulting crude product chromatographic on silica gel, elwira with a gradient of methanol in dichloromethane ranging from 0%to 10%. Gain of 0.37 g of tert-butyl 4-{cyclohexyl[2-(1H-imidazol-1-yl)ethyl]amino}piperidine-1-carboxylate in the form of red crystals.

10.5: N-cyclohexyl-N-[2-(1H-imidazol-1-yl)ethyl]piperidine-4-amine

Placed 0.45 g of tert-butyl 4-{cyclohexyl[2-(1H-imidazol-1-yl)ethyl]amino}piperidine-1-carboxylate in 12 ml of 4 N. hydrochloric acid in dioxane. The reaction medium is stirred for 18 hours at room temperature. After evaporation to dryness the residue absorb methanol and again evaporated to dryness. This operation is repeated several times. Obtain 0.51 g of N-cyclohexyl-N-[2-(1H-imidazol-1-yl)ethyl]piperidine-1-amine, used without purification in the subsequent syntheses.

10.6. tert-butyl 4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[2-(1H-imidazol-1-yl)ethyl]amino}piperidine-1-yl)-2-oxoethyl]amino}piperidine-1-carboxylate

Solubilizing 0.05 g of N-cyclohexyl-N-[2-(1H-imidazol-1-yl)ethyl]piperidine-1-amine, obtained in stage 10.5, 13 ml of dichloromethane in the presence of 0.51 gN-[1-(tert-buto is dicarbonyl)piperidine-4-yl]-4-chloro-D-phenylalanine, obtained at the stage 3.7, 0.18 g of hydroxybenzotriazole, 0.25 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 0.92 ml of diisopropylethylamine. The mixture is stirred for 16 hours at room temperature. After hydrolysis is extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with water, then saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness the resulting crude product chromatographic, elwira c with a gradient of methanol in dichloromethane ranging from 0%to 10%. Gain of 0.37 g of tert-butyl 4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[2-(1H-imidazol-1-yl)ethyl]amino}piperidine-1-yl)-2-oxoethyl]amino}piperidine-1-carboxylate.

10.7: 1-[(2R)-3-(4-chlorophenyl)-2-(piperidine-4-ylamino)propanoic]-N-cyclohexyl-N-[2-(1H-imidazol-1-yl)ethyl]piperidine-4-amine

Place of 0.37 g of tert-butyl 4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[2-(1H-imidazol-1-yl)ethyl]amino}piperidine-1-yl)-2-oxoethyl]amino}piperidine-1-carboxylate 5.7 ml of dioxane and add 1,43 ml 4 N. hydrochloric acid in dioxane. The reaction medium is stirred for 18 hours at room temperature. After evaporation to dryness the residue absorb saturated aqueous solution of sodium bicarbonate. Extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with water. After drying over MgSO4and evaporation to dryness received what ever got the product chromatographic, elwira c with a gradient mixture of methanol with ammonium hydroxide in dichloromethane from 100/0/0 to 8/2/0,2. Get to 0.19 g of 1-[(2R)-3-(4-chlorophenyl)-2-(piperidine-4-ylamino)propionyl]-N-cyclohexyl-N-[2-(1H-imidazol-1-yl)ethyl]piperidine-4-amine.

10.8: the Hydrochloride of 1-[(2R)-3-(4-chlorophenyl)-2-(piperidine-4-ylamino)propanoic]-N-cyclohexyl-N-[2-(1H-imidazol-1-yl)ethyl]piperidine-4-amine

Put to 0.19 g of 1-[(2R)-3-(4-chlorophenyl)-2-(piperidine-4-ylamino)propanoic]-N-cyclohexyl-N-[2-(1H-imidazol-1-yl)ethyl]piperidine-4-amine in 5 ml of methanol and add 3.5 ml 0,1N hydrochloric acid in isopropanol. After evaporation to dryness reaction medium was triturated in diethyl ether, then the precipitate centrifuged and washed with diethyl ether. The resulting hydrochloride is dried over P2About5under reduced pressure. Get 0,175 g of the hydrochloride of 1-[(2R)-3-(4-chlorophenyl)-2-(piperidine-4-ylamino)propanoic]-N-cyclohexyl-N-[2-(1H-imidazol-1-yl)ethyl]piperidine-4-amine as a white solid.

TPL=162°C.; M+N+=541; [α]D20=-3,9° (C=0,g/100ml, DMSO).

Example 11: HydrochlorideN{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,2-dimethylhydrogensiloxane(compound No. 71)

11.1: Tert-butyl 4-{cyclohexyl[(2,2-dimethylhydrazine)carbonyl]amino}piperidine-1-carboxylate

The room is up in the atmosphere of nitrogen at 0°From 0.43 ml diphosgene in 18 ml of dichloromethane. Add dropwise a solution of 1.0 g of tert-butyl 4-(cyclohexylamino)piperidine-1-carboxylate and 2,47 ml of triethylamine. The solution is stirred for 2 hours at room temperature. The reaction medium is again placed in an atmosphere at 0°C and again add 0,43 g diphosgene. After stirring for 2 hours at room temperature add 5,39 ml of dimethyl hydrazine. The mixture is stirred for 18 hours at room temperature. Add 30 ml of 0.5 N. hydrochloric acid. Extracted with dichloromethane until the depletion of the aqueous phase. After drying over MgSO4and evaporation to dryness the resulting residue chromatographic on silicagel, elwira c with a gradient of methanol in dichloromethane ranging from 2 to 10%, and obtain 0.28 g of tert-butyl 4-{cyclohexyl[(2,2-dimethylhydrazine)carbonyl]amino}piperidine-1-carboxylate.

11.2:N-cyclohexyl-2,2-dimethyl-N-piperidine-4-imageresizer.exe

Put 0.28 g of tert-butyl 4-{cyclohexyl[(2,2-dimethylhydrazine)carbonyl]amino}piperidine-1-carboxylate 3.8 ml 4 N. hydrochloric acid in dioxane. The reaction medium is stirred for 18 hours at room temperature. After evaporation to dryness the residue absorb 1N solution of sodium hydroxide and extracted with dichloromethane until the depletion of the aqueous phase. After drying over MgSO4get 0.2 gN-cyclohexyl-2,2-dimethyl-N-piperidine-4-argersinger the oksamida, which is used further without purification.

11.3: methylN{CIS-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-4-chloro-D-phenylalanine

Place 10 g of N-p-chloro-D-Cl-Phe-OMe, HCl and 8.5 g of tert-butyl(4-oxocyclohexyl)carbamate in 200 ml of dichloromethane. Add 11 g of NaBH(OAc)3and to 5.57 ml NEt3. Stirred for 18 hours at room temperature. The hydrolyzing solution 1 N. aqueous sodium hydroxide solution and extracted with dichloromethane until the depletion of the aqueous phase. After drying over MgSO4and evaporation to dryness the resulting crude product chromatographic on silica gel, elwira with a gradient mixture of AcOEt/MeOH in CH2Cl2from 95/5/1 to 85/15/3 (CH2Cl2/AcOEt/MeOH). Obtain 5.7 g of methylN-{CIS-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-4-chloro-D-phenylalanine.

11.4:N-{CIS-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-4-chloro-D-phenylalanine

Put 5.5 g of methylN-{CIS-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-4-chloro-D-phenylalanine in 133 ml Meon and add 40,15 ml of 1 N. aqueous sodium hydroxide solution. Stirred for 18 hours at room temperature. After evaporation of the Meon add 4 EQ. 1 N. aqueous solution of hydrochloric acid. The resulting white precipitate was filtered cold and washed with cold water. After drying over P2About5obtain 3.8 gN-{CIS-4-[(tert-butoxycarbonyl)and the eno]cyclohexyl}-4-chloro-D-phenylalanine.

11.5: tert-butyl-(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(2,2-dimethylhydrazine)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)carbamate

Solubilizing 0,22 gN-cyclohexyl-2,2-dimethyl-N-piperidine-4-imageresizeguide obtained at the stage 11.2, in 10 ml dichloromethane in the presence of 0.28 gN-{CIS-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-4-chloro-D-phenylalanine obtained at the stage 11.4, 0.11 g of hydroxybenzotriazole, 0.24 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 0.5 ml of diisopropylethylamine and 0.82 ml of hydrochloric acid in dioxane. The mixture is stirred for 18 hours at room temperature. After hydrolysis with an aqueous solution of sodium bicarbonate extracted with ethyl acetate to depletion of the aqueous phase. After drying over MgSO4and evaporation to dryness the resulting crude product chromatographic, elwira c with a gradient of methanol in dichloromethane ranging from 1 to 4%. Get 0,22 g of tert-butyl-(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(2,2-dimethylhydrazine)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)carbamate.

11.6:N{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,2-dimethylhydrogensiloxane

Put 0,22 g of tert-butyl-(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(2,2-dimethylhydrazine)carbonyl]amino}PIP is ridin-1-yl)-2-oxoethyl]amino}cyclohexyl)carbamate in 1.7 ml of dioxane and add 1,43 ml 4 N. hydrochloric acid in dioxane. The reaction medium is stirred for 3 hours at room temperature. After evaporation to dryness the residue absorb 1 N. aqueous sodium hydroxide solution. Extracted with dichloromethane until the depletion of the aqueous phase. After drying over MgSO4and evaporation to dryness the resulting crude product chromatographic, elwira c with a gradient mixture of methanol with ammonium hydroxide in dichloromethane from 95/5/0,5 to 9/1/0,1. Get 0.05 gN{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,2-dimethylhydrogensiloxane.

11.7: hydrochlorideN{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,2-dimethylhydrogensiloxane

Put 0.05 gN{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,2-dimethylhydrogensiloxane 10 diethyl ether and add 0,09 ml 2 N. hydrochloric acid in diethyl ether. The formed precipitate was filtered and dried over P2About5. Obtain 0.06 g of hydrochlorideN{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,2-dimethylhydrogensiloxane. TPL=124°C; M+N+=547.

Example 12: HydrochlorideN{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-<> N-cycloheptyl-N',N'-diethylcarbamyl(compound No. 33)

12.1: tert-butyl 4-(cycloheptylamine)piperidine-1-carboxylate

Placed in a nitrogen atmosphere 6,98 g of 1-BOC-piperidone in 175 ml of dichloromethane in the presence of 4.46 ml cycloheptylamine and 9,65 g triacetoxyborohydride sodium and the reaction medium is stirred for 16 hours at room temperature. After adding 80 ml of 0.5 N. aqueous solution of hydrochloric acid is extracted with ethyl acetate to depletion of the aqueous phase. After drying over MgSO4and evaporation to dryness obtain 5.6 g of tert-butyl 4-(cycloheptylamine)piperidine-1-carboxylate.

12.2: tert-butyl 4-{cycloheptyl[(diethylamino)carbonyl]amino}piperidine-1-carboxylate

Placed in a nitrogen atmosphere at 0°C and 0.98 ml of diphosgene in 20 ml of dichloromethane. Add dropwise a solution of 1.2 g of tert-butyl 4-(cycloheptylamine)piperidine-1-carboxylate and 5,64 ml of triethylamine. The solution is stirred 30 minutes at 0°C., then 3 hours at room temperature. Then add to 4.23 ml diethylamine. The mixture is stirred for 16 hours at room temperature. After evaporation of dichloromethane are added 50 ml of 0.5 N. hydrochloric acid. Extracted with dichloromethane until the depletion of the aqueous phase. After drying over MgSO4and evaporation to dryness the resulting residue chromatographic on silica gel, elwira a mixture of dichloromethane with methanol 99/1, then 98/2, andget 4,18 g of tert-butyl 4-{cycloheptyl[(diethylamino)carbonyl]amino}piperidine-1-carboxylate.

12.3:N-cycloheptyl-N',N'-diethyl-N-piperidine-4-ylcarbamate

Placed 1.6 g of tert-butyl 4-{cycloheptyl[(diethylamino)carbonyl]amino}piperidine-1-carboxylate in 20,25 ml 4 N. hydrochloric acid in dioxane. The reaction medium is stirred for 16 hours at room temperature. After evaporation to dryness, add about 10 ml of dichloromethane, 10 ml of tetrahydrofuran, 5 ml of water and 5 ml of methanol. Then add 25 g of resin DOWEX® g. Leave to mix for 1 hour at room temperature. After sequential washing of the resin tetrahydrofuran, dichloromethane and methanol target connection planted 2 N. the ammonium hydroxide solution in methanol. After evaporation to dryness receive 1 gN-cycloheptyl-N',N'-diethyl-N-piperidine-4-ylcarbamate in the form of oil red.

12.4: tert-butyl-(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cycloheptyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)carbamate

Solubilizing 0.24 gN-cycloheptyl-N',N'-diethyl-N-piperidine-4-ylcarbamate obtained at the stage 12.3, in 10 ml dichloromethane in the presence of 0.28 gN-{CIS-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-4-chloro-D-phenylalanine obtained at the stage 11.4, 0.11 g of hydroxybenzotriazole, of 0.23 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 0.5 ml of diisopropylethylamine then 0,81 ml of 2 N. hydrochloric acid in dioxane. The mixture is stirred for 18 hours at room temperature. After hydrolysis with a saturated aqueous solution of sodium bicarbonate extracted with ethyl acetate to depletion of the aqueous phase. After drying over MgSO4and evaporation to dryness the resulting crude product chromatographic, elwira with a gradient of methanol in dichloromethane ranging from 1 to 4%. Obtain 0.34 g of tert-butyl-(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cycloheptyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)carbamate.

12.5:N{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cycloheptyl-N',N'-diethylcarbamyl

Put 0.34 g of tert-butyl-(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cycloheptyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)carbamate in 1.43 ml 4 N. hydrochloric acid in dioxane. The reaction medium is stirred for 3 hours at room temperature. After evaporation to dryness the residue absorb 1 N. aqueous sodium hydroxide solution. Extracted with dichloromethane until the depletion of the aqueous phase. After drying over MgSO4and evaporation to dryness the resulting crude product chromatographic, elwira c with a gradient mixture of methanol with ammonium hydroxide in dichloromethane from 95/5/0,5-8/2/0,2. Get 0,22 gN{1-[N-(CIS-4-aminocyclohexane)-4-chlorine is-D-i.e. phenylalanyl]piperidine-4-yl}- N-cycloheptyl-N',N'-diethylcarbamyl.

12.7: hydrochlorideN{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cycloheptyl-N',N'-diethylcarbamyl.

Put 0,22 gN{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cycloheptyl-N',N'-diethylcarbamyl in 10 ml of diethyl ether and added to 0.38 ml of 2 N. hydrochloric acid in diethyl ether. The precipitate is filtered and dried over P2About5. Get to 0.23 g of hydrochlorideN{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cycloheptyl-N',N'-diethylcarbamyl.

TPL=105°C; M+N+=574; [α]D20= +3° (C=0,g/100ml, DMSO).

Example 13: HydrochlorideN(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(TRANS-4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide(compound No. 105)

13.1: N-(4-oxocyclohexyl)ndimethylacetamide

Place of 1.5 g of 4-aminocyclohexanone in 50 ml of acetonitrile and add 0,86 ml acetylchloride, then of 4.2 g of potassium carbonate. The reaction medium is stirred for 18 hours at room temperature. After evaporation to dryness the residue absorb 1 N. aqueous solution of hydrochloric acid. Extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with 1 N. aqueous solution is aristolochioides acid. After drying over MgSO4and evaporation to dryness obtain 0.45 g of N-(4-oxocyclohexyl)ndimethylacetamide, which is used without purification in the subsequent syntheses.

13.2: 3-methylpiperidin-4-one

Place of 12.2 g of 1-benzyl-3-methylpiperidin-4-she's in a Parr flask in the presence of 2.44 g of palladium hydroxide in 240 ml of ethanol. The reaction mixture is placed in an atmosphere of hydrogen with a pressure of 50 lb/in2and stirred at room temperature for 4 hours. The solution is filtered on celite, then evaporated to dryness. Obtain 6.8 g of 3-methylpiperidin-4-it is used without purification in the subsequent syntheses.

13.3: tert-butyl-3-methyl-4-oxopiperidine-1-carboxylate

Place of 6.8 g of 3-methylpiperidin-4-it, and 16.7 ml of triethylamine and 19.6 g of di-tert-BUTYLCARBAMATE and 0.7 g of dimethylaminopyridine in a mixture of 300 ml of THF and 30 ml of water. Stirred at room temperature for 18 hours. After evaporation of THF, the reaction medium is treated with a saturated aqueous solution of potassium hydrosulfate to establish pH 1, then extracted with ethyl acetate to depletion of the aqueous phase. Then the organic phase is washed with a saturated aqueous solution of potassium hydrosulfate, then saturated aqueous sodium hydrogen carbonate solution and finally with saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness the resulting crude product chromatografic on silicagel elwira a mixture of dichloromethane/methanol 98/2. Obtain 10.3 g of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate.

13.4: tert-butyl-TRANS-4-(cyclohexylamino)-3-methylpiperidin-1-carboxylate

Place of 7.7 g of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate and 4.1 ml of cyclohexylamine in 180 ml of methanol and adjusted pH to 6 with 4 ml of acetic acid. Add 4.5 g of cyanoborohydride sodium. Reaction medium was boiled in methanol under reflux for 18 hours. Then hydrolyzing solution 1 N. aqueous sodium hydroxide solution and extracted with ethyl acetate to depletion of the aqueous phase. After drying over MgSO4and evaporation to dryness the resulting crude product chromatografic on silicagel, elwira a mixture of dichloromethane/ethyl acetate/methanol/ammonium hydroxide gradient from 97/3/0,5/0,5 to 90/10/2/0,2. Gain of 1.9 g of tert-butyl-TRANS-4-(cyclohexylamino)-3-methylpiperidin-1-carboxylate and 2.25 g of tert-butyl-CIS-4-(cyclohexylamino)-3-methylpiperidin-1-carboxylate.

13.5: tert-butyl-TRANS-4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-carboxylate

Put 0.5 g of tert-butyl-TRANS-4-(cyclohexylamino)-3-methylpiperidin-1-carboxylate in 8.5 ml of dichloromethane, then add 0.35 ml of triethylamine and cooled environment to 0°C. is Slowly added 0.2 ml of diphosgene. The reaction medium is stirred for 15 minutes at 0°C, then 5 hours at room temp is the temperature. After hydrolysis in a mixture of ice and 1 N. aqueous sodium hydroxide solution is extracted with ethyl acetate to depletion of the aqueous phase. The organic phase is washed with water, then saturated aqueous sodium chloride, dried over MgSO4and evaporated to dryness. The resulting crude product solubilizer in 8 ml of acetonitrile. Added 0.71 g of dimethylamine hydrochloride and to 1.21 g of potassium carbonate. Stirred for 40 hours at room temperature. Hydrolized and extracted with ethyl acetate to depletion of the aqueous phase. The organic phase is washed with water, then 1 N. aqueous solution of hydrochloric acid and finally with saturated aqueous sodium chloride. The organic phase is dried over MgSO4and evaporated to dryness. Obtain 0.6 g of tert-butyl-TRANS-4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-carboxylate.

13.6:N-cyclohexyl-N',N'-dimethyl-N-[TRANS-3-methylpiperidin-4-yl]urea

Placed 0.6 g of tert-butyl-TRANS-4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-carboxylate in 2 ml of dioxane, then add 6,12 ml 4 N. hydrochloric acid in dioxane and allowed to mix for 4 hours at room temperature. After evaporation to dryness the residue absorb 1 N. aqueous sodium hydroxide solution and extracted with ethyl acetate to depletion of the aqueous phase. The organic the second phase is washed with 1 N. aqueous solution of sodium hydroxide, then with water and finally with saturated aqueous sodium chloride. After drying over MgSO4the resulting crude product chromatographic on silica gel, elwira a mixture of dichloromethane/methanol/ammonium hydroxide gradient from 10/0/0 to 9/1/0,1. Obtain 0.35 gN-cyclohexyl-N',N'-dimethyl-N-[TRANS-3-methylpiperidin-4-yl]urea.

13.7: tert-butyl[(1R)-1-(4-Chlorobenzyl)-2-(TRANS-4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2-oxoethyl]carbamate

Solubilizing 3,16 gN-cyclohexyl-N',N'-dimethyl-N-[TRANS-3-methylpiperidin-4-yl]urea, obtained at the stage of 13.6, and 118 ml of dichloromethane in the presence of 3.5 g of 4-chloro-D-BOC-phenylalanine, 1,60 g of hydroxybenzotriazole, and 2.27 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 2.10 ml diisopropylethylamine. The mixture is stirred for 18 hours at room temperature in a nitrogen atmosphere. After evaporation to dryness the residue is absorbed by ethyl acetate and water. Extracted with ethyl acetate to depletion of the aqueous phase. The organic phase is washed with saturated aqueous sodium chloride. After drying over MgSO4the resulting crude product chromatographic, elwira with a gradient of methanol in dichloromethane ranging from 0%to 10%. Get 5.29 g of tert-butyl[(1R)-1-(4-Chlorobenzyl)-2-(TRANS-4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperid the Jn-1-yl)-2-oxoethyl]carbamate.

13.8:N-[TRANS-1-(4-chloro-D-i.e. phenylalanyl)-3-methylpiperidin-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl

Put 5.29 g of tert-butyl[(1R)-1-(4-Chlorobenzyl)-2-(TRANS-4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2-oxoethyl]carbamate in 5 ml of dioxane. Then add 24,1 ml 4 N. hydrochloric acid in dioxane. The reaction medium is stirred for 18 minutes at room temperature. After evaporation to dryness the residue absorb dichloromethane and saturated aqueous sodium bicarbonate. Extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with water, then saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness obtain 4.3 gN-[TRANS-1-(4-chloro-D-i.e. phenylalanyl)-3-methylpiperidin-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamate.

13.9:N(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(TRANS-4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide

Solubilizing 0.5 gN-[TRANS-1-(4-chloro-D-i.e. phenylalanyl-3-methylpiperidin-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamate obtained at the stage of 13.8 in 11 ml of dichloromethane in the presence of 0.21 g of N-(4-oxocyclohexyl)ndimethylacetamide obtained at the stage of 13.2. Then add in nitrogen atmosphere 0.35 g of triacetoxyborohydride sodium. Per mesilat 18 hours at room temperature. After hydrolysis with a saturated aqueous solution of sodium bicarbonate extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with water, then saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness the resulting crude product chromatographic on silica gel, elwira a mixture of dichloromethane/acetone/methanol gradient from 100/0/0 to 70/25/5. Get 0,19 g and 0.39 gN(4-{[(1R)-1-(4-Chlorobenzyl)-2-(TRANS-4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide in the form of a mixture of stereoisomers, which configuration has not been defined.

13.10: hydrochlorideN(4-{[(1R)-1-(4-Chlorobenzyl)-2-(TRANS-4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide

Put 0,19 gN(4-{[(1R)-1-(4-Chlorobenzyl)-2-(TRANS-4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide in 2 ml of ethyl acetate and added 0.16 ml 2 N. hydrochloric acid in diethyl ether. After evaporation to dryness of the reaction environment absorb diethyl ether and triturated. The obtained precipitate is centrifuged and washed with diethyl ether. The resulting hydrochloride is dried over P2About5under reduced pressure. Get to 0.19 g of hydrochlorideN(4-{[(1R)-1-(4-Chlorobenzyl)-2-(i> TRANS-4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide.

TPL=168°C.; M+N+=588.

Example 14HydrochlorideN{(TRANS)-1-[4-chloro-N-(4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate (compound No. 110)

14.1: 4-phenyl-4-hydroxycyclohexanone

Placed in a nitrogen atmosphere at -78°C. 2.0 g of 1,4-cyclohexanedione in 20 ml of diethyl ether and 40 ml of anhydrous tetrahydrofuran. Slowly added 1,8 N. finelite in a mixture of cyclohexane/ether. Mix Wednesday at -78°C for 2 hours and 20 minutes. After hydrolysis with a saturated aqueous solution of ammonium chloride extracted the aqueous phase with ethyl acetate to depletion of the aqueous phase. The organic phase is washed with saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness the resulting crude product chromatographic on silica gel, elwira with a mixture of cyclohexane/ethyl acetate gradient from 8/2 to 6/4. Obtain 0.64 g of 4-phenyl-4-hydroxycyclohexanone.

14.2:N-{(TRANS)-1-[4-chloro-N-(4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate

Solubilizing 0.50 gN-[TRANS-1-(4-chloro-D-i.e. phenylalanyl)-3-methylpiperidin-4-yl]-cyclohexyl-N',N'-dimethylcarbamate obtained at the stage 13.8, B11,3 ml of dichloromethane in the presence of 0.25 g of 4-phenyl-4-hydroxycyclohexanone, obtained at the stage of 14.1. Then add in nitrogen atmosphere 0.35 g of triacetoxyborohydride sodium. Stirred for 18 hours at room temperature. After adding 0.125 g of 4-phenyl-4-hydroxycyclohexanone and 0,175 g triacetoxyborohydride sodium stirred for 24 hours. Hydrolized and extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with water, then saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness the resulting crude product chromatographic on silica gel, elwira a mixture of dichloromethane/acetone/methanol gradient from 100/0/0 to 70/25/5.

Receive from 0.17 g to 0.22 gN-{(TRANS)-1-[4-chloro-N-(4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate in the form of a mixture of stereoisomers, which configuration has not been defined.

14.3: hydrochlorideN-{(TRANS)-1-[4-chloro-N-(4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate

Put 0,22 gN-{(TRANS)-1-[4-chloro-N-(4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate in 2 ml of ethyl acetate and add to 0.71 ml of 0.5 N. hydrochloric acid in diethyl ether. After evaporation to dryness of the reaction environment of Pogos who have diethyl ether and triturated. Then the resulting precipitate is centrifuged and washed with diethyl ether. The resulting hydrochloride is dried over P2About5under reduced pressure. Obtain 0.20 g of hydrochlorideN-{(TRANS)-1-[4-chloro-N-(4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate.

TPL=194°C.; M+N+=623.

Example 15: HydrochlorideN-(TRANS)-1-{4-chloro-N-[4-(2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamate(compound No. 118)

15.1: 2-(1,4-dioxaspiro[4.5]Dec-8-ylamino)ethanol

Solubilizing 3.12 g of 1,4-dioxaspiro[4.5]decane-8-it is in 80 ml of dichloromethane in the presence of 1.16 g of ethanolamine. Then, in a nitrogen atmosphere add 6.75 triacetoxyborohydride sodium. Stirred for 18 hours at room temperature. After hydrolysis with a saturated 1 N. aqueous sodium hydroxide solution is extracted with dichloromethane until the depletion of the aqueous phase. After drying over MgSO4and evaporation to dryness obtain 4.0 g of 2-(1,4-dioxaspiro[4.5]Dec-8-ylamino)ethanol used without purification in the subsequent syntheses.

15.2: 3-(1,4-dioxaspiro[4.5]Dec-8-yl)-1,3-oxazolidin-2-he

Placed in a nitrogen atmosphere at 0°C 1.47 g of diphosgene in 50 ml of dichloromethane. Add one drop of 1.0 g of 2-(1,4-dioxaspiro[4.5]Dec-8-ylamino)ethanol obtained in stage 15.1, the mixture is 3,59 ml of triethylamine. Stirred for 5 hours at room temperature. After evaporation to dryness the resulting crude product absorb dichloromethane. The organic phase is washed with two times 1 N. aqueous solution of hydrochloric acid, then with water and saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness the resulting crude product chromatographic on silica gel, elwira with a gradient of methanol in dichloromethane ranging from 0%to 2%. Obtain 1.19 g of 3-(1,4-dioxaspiro[4.5]Dec-8-yl)-1,3-oxazolidin-2-it.

15.3: 3-(4-oxocyclohexyl)-1,3-oxazolidin-2-he

Dissolve 0.75 g of 3-(1,4-dioxaspiro[4.5]Dec-8-yl)-1,3-oxazolidin-2-it in 27.5 ml 6 N. HCl. The reaction medium is heated at 65 degree Celsius for 5 hours. After the temperature dropped to room, slowly add sodium carbonate to establish a pH of 9. Extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with water. After drying over MgSO4the resulting crude product chromatographic on silica gel, elwira with a gradient of methanol in dichloromethane ranging from 0%to 10%. Obtain 0.11 g of 3-(4-oxocyclohexyl)-1,3-oxazolidin-2-it.

15.4:N-(3S,4S)-1-{4-chloro-N-[4-(2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamyl

Solubilizing 0.4 gN-[TRANS-1-(4-chloro-D-i.e. phenylalanyl)-3-methylpiperidin-4-yl]-CEC is hexil- N',N'-dimethylcarbamate obtained at the stage of 13.8 in 9 ml dichloromethane in the presence of 0.20 g of 3-(4-oxocyclohexyl)-1,3-oxazolidin-2-it is obtained at the stage of 15.3. Then in an atmosphere of nitrogen was added 0.28 g of triacetoxyborohydride sodium. Stirred for 18 hours at room temperature. Hydrolyzing saturated aqueous sodium bicarbonate and extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with water, then saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness the resulting crude product chromatographic on silica gel, elwira a mixture of dichloromethane/acetone/methanol gradient from 100/0/0 to 70/25/5. Obtain 0.21 g and 0,19 gN-(3S,4S)-1-{4-chloro-N-[4-(2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamate in the form of a mixture of stereoisomers, which configuration is not defined.

15.5: hydrochlorideN-(TRANS-1-{4-chloro-N-[4-(2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamate

Put 0.21 gN-(TRANS-1-{4-chloro-N-[4-(2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamate in 2 ml of ethyl acetate and add 1.7 ml of 0.2 N. hydrochloric acid in dietro the second ether. After evaporation to dryness of the reaction environment absorb diethyl ether and triturated. Then the precipitate centrifuged and washed with diethyl ether. The resulting hydrochloride is dried over P2About5under reduced pressure. Obtain 0.18 g of hydrochlorideN-(TRANS-1-{4-chloro-N-[4-(2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamate.

TPL=189°C.; M+N+=616.

Example 16: HydrochlorideN-{TRANS-1-[4-chloro-N-(1-isonicotinohydrazide-4-yl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate(compound No. 119)

16.1: 8-isonicotinoyl-1,4-dioxa-8 azaspiro[4.5]Decan

Solubilizer of 1.34 ml of 1,4-dioxaspiro[4.5]decane-8-she's in 104 ml of dichloromethane in the presence of 1.4 g of isonicotinic acid, 1.56 g of hydroxybenzotriazole, of 2.21 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1,49 ml diisopropylethylamine. The mixture is stirred for 18 hours at room temperature in a nitrogen atmosphere. After evaporation to dryness the residue hydrolyzing 1 N. aqueous sodium hydroxide solution. Extracted with dichloromethane until the depletion of the aqueous phase. After drying over Na2SO4and evaporation to dryness the resulting crude product chromatographic, elwira a mixture of dichloromethane/methanol 85/5. Get 2,63 8-isonicotinoyl-1,4-dioxa-8 azaspiro the[4.5]decane.

16.2: 1-isonicotinohydrazide-4-one

Solubilizing 2.6 g 8-isonicotinoyl-1,4-dioxa-8 azaspiro[4.5]decane in 43 ml of 6 N. HCl. The reaction medium is heated at 65°C for 18 hours. The temperature of the reaction medium is brought to 0°C and slowly added sodium carbonate to establish a pH of 9. Extracted with dichloromethane until the depletion of the aqueous phase. After drying over Na2SO4the resulting crude product chromatographic on silica gel, elwira with a gradient of methanol in dichloromethane ranging from 0%to 10%. Get to 0.19 g of 1-isonicotinohydrazide-4-it.

16.3:N-{TRANS-1-[4-chloro-N-(1-isonicotinohydrazide-4-yl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamyl

Solubilizing 0.3 gN-[TRANS-1-(4-chloro-D-i.e. phenylalanyl)-3-methylpiperidin-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamate obtained at the stage of 13.8 in 7 ml of dichloromethane in the presence of 0.18 g of 1-isonicotinohydrazide-4-it is obtained at the stage of 16.2. Then in an atmosphere of nitrogen was added 0.21 g of triacetoxyborohydride sodium. Stirred for 18 hours at room temperature. Hydrolyzing saturated aqueous sodium bicarbonate and extracted with dichloromethane until the depletion of the aqueous phase. The organic phase is washed with water, then saturated aqueous sodium chloride. After drying over MgSO4and evaporation to dryness of the obtained si is the second product chromatographic on silica gel, elwira a mixture of dichloromethane/methanol/ammonium hydroxide gradient 100/0/0 to 90/10/1. Receive 0.075 g and 0.23 gN-{TRANS-1-[4-chloro-N-(1-isonicotinohydrazide-4-yl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate, in the form of a mixture of diastereoisomers, which configuration is not defined.

16.4: hydrochlorideN-{TRANS-1-[4-chloro-N-(1-isonicotinohydrazide-4-yl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate.

Put 0,23 gN-{TRANS-1-[4-chloro-N-(1-isonicotinohydrazide-4-yl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate in 2 ml of ethyl acetate and add 1.8 ml of 0.2 N. hydrochloric acid in diethyl ether. After evaporation to dryness of the reaction environment absorb diethyl ether and triturated. Then the resulting precipitate is centrifuged and washed with diethyl ether. The resulting hydrochloride is dried over P2About5under reduced pressure. Obtain 0.18 g of hydrochlorideN-{TRANS-1-[4-chloro-N-(1-isonicotinohydrazide-4-yl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate.

TPL=206°C.; M+N+=640.

The following table illustrates the chemical structure and physical properties of some compounds according to the invention, in particular compounds of formula (I bis)that meet the appropriate compounds of formula (I), in which Ra'=R5=H, R3denotes a chlorine atom, in paraprotein on the phenyl cycle to which it is attached.

In the table below:

the carbon atom carrying the group of 4-Cl-benzyl, has the configuration (R),

- in the column "salt" the sign "-" denotes a compound in the form of free base, whereas "HCl" represents a compound in hydrochloride and CF3COOH” connection triptoreline,

in the case where Ra is a methyl group, the compound obtained in the form of a mixture of diastereoisomers,

- TPL denotes the melting point of connection, and

- Me, Et and iPr denote respectively the group methyl, ethyl and isopropyl.

NRaR1R2R4SolTPL
oC
1HCyclohexyl-CO-N(Et)2HCl>
220
2 HCyclohexyl-CO-N(Et)2HCl195
3HCyclohexyl-CO-N(Et)2HCl>
200
4HCyclohexyl-CO-N(Et)2HCl82
5HCyclohexyl-CO-N(Et)2HCl169
6HCyclohexyl-CO-N(Et)2HCl>
250
7HCyclo is exil HCl220
8HCyclohexylHCl230
9HCyclohexylHCl110
10HCyclohexylHCl256
11HCyclohexyl-CO-N(Me)2HCl270
12H Cyclohexyl-CO-N(Me)2HCl139
13HCyclohexylHCl254
14HCyclohexylHCl119
15HCyclohexylHCl182
16HCyclohexylHCl166
17H CyclohexylNCl258
18HCyclohexylHCl178
19HCyclohexylHCl285
20HCyclohexylHCl230
21HCyclohexylHCl279
22 HCyclohexylHCl252
23HCyclohexylHCl12
24HCyclohexylHCl257
25HCyclohexylHCl244
26HCycloheptyl-CO-N(Et)2HCl238
27 HCycloheptyl-CO-N(Et)2HCl>
250
28HCycloheptyl-CO-N(Et)2HCl208
29HCyclobutyl-CO-N(Et)2HCl138
30HCyclobutyl-CO-N(Et)2HCl225
31HCyclopentyl-CO-N(Et)2HCl>
250
32HThe cycle is pentyl -CO-N(Et)2HCl200
33HCyclopentyl-CO-N(Et)2HCl105
34HCyclooctyl-CO-N(Et)2HCl190
35HCyclooctyl-CO-N(Et)2HCl128
36HPhenyl-CO-N(Et)2HCl>
250
37HPhenyl-CO-N(Et)2 HCl123
38HCyclohexyl-CONH-CH2CF3HCl230
39HCyclohexylHCl215
40HCyclohexylHCl95
41HCyclohexylHCl203
42HCyclohexyl Fuuma world KIS-lot122
43HCyclohexylHCl184
44HCyclohexylHCl62
45HCyclohexyl-CO-N(Et)2HCl>
200
46Me (trance)Cyclohexyl-CO-N(Et)2HCl220
47Me (Cys)CyclohexylHCl196
48Me (trance)Cyclohexyl-CO-N(Et)2HCl15
49Me (Cys)Cyclohexyl-CO-N(Et)2HCl110
50Me (trance)Cyclohexyl-CO-N(Et)2HCl238
51Me (Cys)Cyclohexyl-CO-N(Et)2HCl220
52Me (trance)Cyclohexyl-CO-N(Et)2 HCl145
53Me (Cys)Cyclohexyl-CO-N(Et)2HCl135
54HN-CO-N(Et)2HCl190
55HCyclohexylHCl>
240
56HCyclohexylHCl240
57HCyclohexyl HCl240
58HCyclohexylHCl>
200
59H-CO-N(Et)2HCl285
60H-CO-N(Et)2HCl219
61H-CO-N(Et)2HCl>
250
62HCyclohexyl HCl215
63H-CO-N(Et)2HCl>
240
64H-CO-N(Et)2HCl87
65H-CO-N(Et)2HCl>
250
66HCyclohexyl-CO-N(Et)(iPr)HCl>
240
67HCyclohex the Il -CO-N(Et)(iPr)HCl171
68HCyclohexyl-CO-N(Et)2HCl110
69HCyclohexylHCl>
240
70HCyclohexylHCl>
240
71HCyclohexylHCl124
72HCyclo is exil -CO-N(iPr)2HCl189
73HCyclohexylHCl88
74HCyclohexyl-CO-N(Et)2HCl144-173
**
75HCyclohexyl-CO-N(Et)2HCl>
230
76HCyclohexylHCl84
77HCyclohexyl HCl88
78HCyclohexylHCl250
79HCyclohexylHCl113
80HCycloheptyl-CO-N(Me)2HCl235
81HCyclohexylHCl131
82HCyclohexyl HCl78
83HCyclohexyl-CO-N(Me)2HCl256
84HCyclohexyl-CO-N(Me)2HCl265
85HCyclohexyl-CO-N(Me)2HCl264
86HCyclohexyl-CO-N(Me)2HCl275
87HCyclohexyl-CO-N(Me)2 HCl256
88HCyclohexyl-CO-N(Me)2HCl164
89HCyclohexyl-CO-N(Me)2HCl274
90HCyclohexyl-CO-N(Me)2HCl251
91HCyclohexyl-CO-N(Me)2HCl261
92HCyclohexyl-CO-N(Me)2 HCl251
93*HCyclohexyl-CO-N(Me)2HCl210-240
**
94*HCyclohexyl-CO-N(Me)2HCl170-190
**
95*HCyclohexyl-CO-N(Me)2HCl180-230
**
96HCyclohexyl-CO-N(Me)2HCl260
97*HCyclohexyl-CO-N(Me)2HCl 175-93
**
98*HCyclohexyl-CO-N(Me)2HCl180-185
**
99HCyclohexyl-CO-N(Me)2HCl250
100HCyclohexylHCl87
101HCyclohexylHCl220
102Me (trance)Cyclohexyl-CO-N(Me)2HCl 235
103Me (trance)Cyclohexyl-CO-N(Me)2HCl182-198
**
104Me (trance)Cyclohexyl-CO-N(Me)2HCl169
105Me (trance)Cyclohexyl-CO-N(Me)2HCl168-243
**
106Me (trance)Cyclohexyl-CO-N(Me)2HCl185
107Me (trance)Cyclohexyl-CO-N(Me)2HCl 188-229*
108Me (trance)Cyclohexyl-CO-N(Me)2HCl187
109Me (trance)Cyclohexyl-CO-N(Me)2HCl150-197
**
110Me (trance)Cyclohexyl-CO-N(Me)2HCl165-194
**
111Me (trance)Cyclohexyl-CO-N(Me)2HCl213
112HCyclohexyl-CO-N(Me)2HCl113Me (trance)Cyclohexyl-CO-N(Me)2HCl98-125
**
114HCyclohexyl-CO-N(Me)2HCl206
115*HCyclohexyl-CO-N(Me)2HCl133-153**
116*HCyclohexyl-CO-N(Me)2HCl131-133
**
117*HCyclohexyl-CO-N(Me)2HCl221-235
**
118Me (trance)Cyclohexyl-CO-N(Me)2HCl189-206
**
119Me (trance)Cyclohexyl-CO-N(Me)2HCl206
120Me (trance)Cyclohexyl-CO-N(Me)2HCl142-211
**
121Me (trance)Cyclohexyl-CO-N(Me)2HCl211
122Me (trance)Cyclohexyl-CO-N(Me)2HCl 133-207
**
* according to the isomer (CIS or TRANS)
** according to mixture of stereoisomers)

Compounds according to the invention underwent pharmacological studies with the purpose of studying agonistic action on receptors melanocortins, in particular, agonistic action at the receptor MS and/or MS.

Determination of the affinity of the compounds of formula (I) according to the invention to the receptor MS and MS.

This test on the affinity was carried out by measuring the binding of the ligand [125I]-[Nle4-D-Phe7]-α-MSH with cellular membranes: the displacement of the radioactive ligand used for the identification of inhibitors of specific binding to recombinant melanocortin receptors.

In this experiment, the used membranes obtained from cells Cho-K1 expressing the receptor for human MS high density (Euroscreen) or acquired membrane (Perkin Elmer Life Science, Receptor Biology) cells HEK-293 expressing receptors hMC3. Cells Cho-K1, transliterowany using receptor gene hMC4 (Euroscreen), was planted in culture medium DMEM/Nutrient Mix F12 containing 10% bovine serum (Biowhittaker), 1% sodium pyruvate, 1% L-glutamine, 1% non-volatile amino acids, 0.4 mg/ml geneticin (G418) and 0.5% PenStrep, these products were obtained from Gibco/BRI, except bovine serum. Cells Moskalev what if 80%confluently and cell sediments were frozen at -80°C.

Tubes with cells (about h6cells) were thawed on ice and re-suspended in 10 ml of binding buffer [25 mm HEPES, pH 7.0, 1 mm MgCl2, 1.5 mm CaCl2, 100mm NaCl, 1 mm 1,10-penetralia and 1 tablet CompleteTR(protease inhibitor Roche) in 50 ml buffer] using device Polytron within 20 seconds. The suspension was centrifuged for 20 minutes at speed 19500 rpm at 40°C. the Supernatant was discarded and the precipitate again suspended in 5 ml of binding buffer. Using test was determined by the Bradford protein present in the sample, and drove concentration of 3 µg/25 µl dilution in binding buffer.

Ligand [125I]-[Nle4-D-Phe7]-α-MSH was diluted in binding buffer + 0.2% BSA. The SPA beads (agglutinin wheat polyvinyltoluene, Amersham Pharmacia Biotech) was hydrational in binding buffer + 0.2% BSA and then mixed with the homogenate of cells with 3 μg of cellular protein and 250 μg of beads in 50 ál. Investigational products (dissolved in 10%DMSO) in an amount of 10 μl at a concentration of 10 times the final concentration, were placed in a white 96-well plate with clear bottom (CORNING 3604 Polystyrene Non-Binding Syrface). Nonspecific binding was determined using NDP-αMSH at a concentration of 10-7Meters of Total binding was measured by the number of pulses per minute in the presence only of the radioactive ligand. Distribution is Uspenie membranes with balls (50mkl/well) were tracked on the distribution of the solution of [ 125I]-[Nle4-D-Phe7]-α-MSH at a rate of 40 µl/well (100 PM final concentration) in final volume of 100 µl/well. After 6-hour incubation at room temperature was carried out by counting on scillations counter Microbeta TriLux. The value of the IC50compounds represents the concentration that reduces by 50% the specific binding with the displacement of the radioactive ligand.

Thus, it was determined that the compounds according to the invention have an affinity for the receptors MS and/or MS. The values of the IC50these compounds against the receptors MS and MS were below 10 μm, most compounds of this value was in the range of 1Nm - 1 mm. For example, compound No. 2 of table mattered IC50equal to 300 nm with respect to the receptor MS.

The definition of agonistic activity of the compounds of formula (I) according to the invention in relation to the receptors MS and MS.

This functional test is used to distinguish agonistic activity and antagonistic activity. This was determined by the formation of cyclic adenosine monophosphate (camp)produced during activation of the receptor MS or receptor MS.

Cells Cho-K1 expressing the receptor for human MS average density (Euroscreen), was planted in culture medium DMEM/Nutrient Mix F12 (Gibco/BRI)containing 10% bovine savored is, 0.5% sodium pyruvate, 1% L-glutamine, 1% non-volatile amino acids, 200 mg/l of hygromycin In 0.5% PenStrep, these products were obtained from Gibco/BRI, except bovine serum (Biowhittaker) and hygromycin (Sigma).

Cells CHO (dhfr-), espressione receptor human MS, was planted in the culture medium MEM Eagle (Sigma)containing 10% cialisbuynow bovine serum, 1% L-glutamine, 1% sodium pyruvate, 20 mg/500 ml L-Proline, 0.3 mg/ml geneticin and 0.5% PenStrep, these products were obtained from Gibco/BRI, except cialisbuynow bovine serum (Cambrex) and L-Proline (Sigma).

The compounds (diluted in 10%DMSO) in an amount of 10 μl of a concentration exceeding 10 times the final concentration, was placed on the cell plates (final volume=100 ál/well). After incubation for 1 hour (37°C, 5% CO2) analyzed the content of camp using kits TROPIX (Appelera) in accordance with the supplier's instructions. The inherent connections activity was estimated by comparing the stimulation of the production of camp produced by the studied compounds, with the stimulation produced by the connection NDP-αMSH concentration nm (100% maximum). Is EU50compounds represents the concentration at which celebrated 50% maximal stimulation produced by this connection.

Thus, it was determined that the compounds according of the briteney are agonists receptarea MS and/or MS. They have values EU50in relation to the receptors MS and MS below 10 μm, most compounds of this value is from 1 nm to 1 μm. For example, compounds No. 1 and 2 in the table have values EU50accordingly equal to 590 nm and 370 nm against the receptor MS and 80 nm and 30 nm with respect to the receptor MS.

Compounds according to the invention have an agonistic activity against receptor melanocortin and, therefore, they can be used to produce medicines. Thus, according to one aspect of the invention relates to pharmaceuticals which contain a compound of the formula (I) or additive salt of this compound with a pharmaceutically acceptable acid, or a hydrate or MES the compounds of formula (I).

These medicines can find use in the treatment of pathologies involving receptors melanocortins, in particular receptors MS and/or MS: it is, in particular, on the treatment and prevention of obesity, diabetes and sexual disorders that can affect both sexes, such as erectile dysfunction, cardiovascular diseases such as myocardial infarction or hypertension, and also be used with anti-inflammatory treatment or in the treatment of alcohol dependence.

According to another aspect of the invention the present izopet the tion relates to pharmaceutical compositions, containing as active principle a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention or a pharmaceutical salt or hydrate or MES specified connection, and at least one pharmaceutically acceptable excipient. These excipients are chosen depending on the pharmaceutical form and the desired method of administration, from the usual excipients known to the expert.

In the pharmaceutical compositions according to the present invention, intended for oral, sublingual, transcutaneous, intramuscular, intravenous, topical or local application for admission through the trachea or through the nose for transdermal or rectal administration, the active principle of formula (I)described above, or its salt, MES or perhaps hydrate, can be entered in a single form in a mixture with classical pharmaceutical excipients, to animals or humans for the prevention or treatment of disorders or diseases mentioned above.

Suitable one-forms for administration include forms for oral administration such as tablets, hard or soft gelatin capsules, powders, granules or solutions or suspensions for oral administration, forms for admission under asukile for resorption of the cheek, for insertion through the trachea through the nose or eye, forms for inhalation, forms for topical application, for trandermal, subcutaneous, intramuscular or intravenous administration, the forms for rectal administration as well as grafts. For topical application it is possible to use the compounds according to the invention in the form of creams, gels, ointments or lotions.

The preferred form of this introduction is oral path.

For example, the singular form of the introduction of the compounds according to the invention in the form of tablets may contain the following components:

The connection according to the invention50 mg
Mannitol223,75 mg
Croscarmellose sodium6.0 mg
Corn starch15,0 mg
The hypromellose2.25 mg
Magnesium stearate3.0 mg

May be special situations when the appropriate dose can be increased or reduced; such doses are included in the scope of the invention. According to the generally accepted practice is required on the I each patient, the dose is determined by the physician depending on the method of administration, from the weight of the patient and their personal reactions to the medication.

According to another aspect of the invention relates also to a method of treating the pathologies indicated above which comprises the administration to the patient an effective amount of the compounds according to the invention or its pharmaceutically acceptable salt or hydrate or solvate.

1. The compounds of formula (I):

in which Raand Ra'identical or different, denote a hydrogen atom or alkyl,
R1denotes a hydrogen atom or alkyl, cycloalkyl, heteroseksualci or aryl,
R2denotes a group of the formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which:
x=0, 1, 2, 3,or 4
y=0 or 1,
Y denotes a hydrogen atom or the following group: hydroxyl, alkyl, cycloalkyl, alkyloxy, aryl, heteroaryl or-NR11R12and Y is not a hydrogen atom when x=y=0,
R11and R12identical or different, denote a hydrogen atom or
the following group: alkyl, cycloalkyl, alkyloxy or-NR13R14or R11and R12together with the nitrogen atom to which they are attached, form a mono - or bicyclic structure containing 4-10 links and optionally additionally contain 1-3 heteroatoms and/or 1-3 ethylene unsaturated communication, and this cycle is not necessary for the of Eden in any of clauses 1 to 3 groups chosen from halogen atoms and hydroxyl, alkyl, cycloalkyl and alkyloxy;
R13and R14identical or different, denote a hydrogen atom or alkyl,
R3denotes 1 to 3 groups, identical or different, are in any position of the cyclic structure to which they are attached, selected from halogen atoms;
R5denotes a hydrogen atom,
R4choose from the groups of formulae (a), (b), (C), optionally substituted aryl group described below:

in which p=0, 1, 2 or 3; m=0, 1 or 2, and either
a) X represents the group-N(R10)-in which
R10choose from:
-CO-alkyl, -CO-cycloalkyl, -CO-geterotsiklicheskie, -CO-aryl, -CO-heteroaryl,
or R10with the nitrogen atom to which it is connected, and with the carbon atom located in any position of the cyclic structure of the formula (a), but not adjacent to the indicated nitrogen atom, forms a bridge containing 3-5 units, or
b) X denotes the group-C(R6)(R7)-where
R6choose from:
hydrogen atom, halogen atom,
group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9or -(CH2)x-NR8-COR9in which x=0, 1, 2, 3,or 4
of alkyl, cycloalkyl, geterotsiklicheskie,aryl,
geterotsiklicheskie condensed with aryl,
moreover alkyl, cycloalkyl or aryl group optionally substituted by 1 or more groups selected from the groups R, R', -OR, -NRR', -COR;
R7chosen from hydrogen atoms and halogen and the following groups: alkali, -OR, -NRR', -NR-CO-R', -NR-COOR',
R8and R9choose, independently from each other, from a hydrogen atom and the following groups: alkali, cycloalkyl, arily, -CO-alkali, and alkali and arily optionally substituted by one or more groups selected from the groups R, R', -OR, or R8and R9together form heteroseksualci,
R and R' denote, independently of one another, a hydrogen atom or alkyl, cycloalkyl,
moreover, these heteroaryl groups are
aromatic groups containing from 5 to 10 units and comprising from 1 to 4 heteroatoms, such as nitrogen atom, oxygen and/or sulfur;
moreover, these heterocytolysine groups are cycloalkyl groups containing from 5 to 6 units and comprising from 1 to 4 heteroatoms, such as nitrogen atom, oxygen and/or sulfur;
in the form of a base or an acid additive salt, and also in the form of a hydrate or of MES.

2. The compound of formula (I) according to claim 1, wherein R4chosen from groups of formula (a), (b) and (C) seabattle substituted aryl group, in which X denotes the veno-C(R 6)(R7)-, in which R6choose from:
hydrogen atom,
group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9or -(CH2)x-NR8-COR9in which x=0, 1, 2, 3,or 4
of alkyl, cycloalkyl, geterotsiklicheskie, aryl,
geterotsiklicheskie condensed with an aryl group,
R7chosen from hydrogen atoms and halogen and the following groups: alkali, arily, -OR, -NRR', -NR-CO-R', -NR-COOR',
R8and R9choose, independently from each other, from a hydrogen atom and the following groups: alkali, cycloalkyl, erily-WITH-alkali,
R and R' denote, independently of one another, a hydrogen atom or alkyl, cycloalkyl.

3. The compound of formula (I) according to claim 1, wherein R4chosen from groups of formula (a), (b) and (C), in which X denotes the group-C(R6)(R7)-, in which alkyl, cycloalkyl, heterocytolysine or aryl group optionally substituted by 1 or more groups selected from the groups R, R', -COR.

4. The compound of formula (I) according to claim 1, wherein R4chosen from groups of formula (a), (b) and (C), in which X denotes the group-C(R6)(R7)-in which heterocytolysine group optionally condensed with an aryl group.

5. The compound of formula (I) according to claim 1, wherein R4choose from group f is rmula (a), (b) and (C), in which X denotes the group-C(R6)(R7)-, in which R6and R7chosen, independently of one another, from alkyl groups and aryl groups, optionally substituted by one or more groups selected from the groups R, R'.

6. The compound of formula (I) according to claim 1, wherein R7is hydrogen.

7. The compound of formula (I) according to claim 1, wherein R4denotes a group of formula (a), in which p=2, as shown below:

8. The compound of formula (I) according to claim 1, wherein R4chosen from groups of formula (a), (b) and (C)optionally substituted aryl group, in which X represents the group-N(R10)-, in which R10choose from:
group -(CH2)x-NR8R9,
or R10with the nitrogen atom to which it is connected, and with the carbon atom,
in any position of the cyclic structure of the formula (a), but not adjacent to the indicated nitrogen atom, forms a bridge containing 3-5 units,
R8and R9choose, independently from each other, from a hydrogen atom and the following groups: alkali, erily-WITH-alkali,
R and R' denote, independently of one another, a hydrogen atom or alkyl, cycloalkyl.

9. The compound of formula (I) according to claim 1, wherein R4chosen from groups of formula (a), (b) and (C), in which X represents the group -(R 10)-, in which R8and R9together form heteroseksualci.

10. The compound of formula (I) according to claim 1, wherein R4denotes a group of formula (a), in which p=2, as shown below:

11. The compound of formula (I) according to claim 1, wherein R1denotes alkyl, cycloalkyl or geterotsyklicescoe group in the form of a base or an acid additive salt, hydrate, or MES.

12. The compound of formula (I) according to claim 1, wherein R2choose from the following groups:
-CO-R15, -CO-NR16R17, -CO-NR15-NR16R17, -CO-aryl, -CO-heteroaryl, -CO-(CH2)x'-NR16R17, -(CH2)x-NR16R17, -(CH2)x-OH, -(CH2)x-aryl, -(CH2)x-heteroaryl, -(CH2)x'-CO-R15and -(CH2)x'-CO-NR16R17in which
x=0, 1, 2, 3 or 4 and x'=1, 2, 3,or 4
R15represent a hydrogen atom or alkyl, cycloalkyl or alkyloxy, and
R16and R17identical or different, denote a hydrogen atom or alkyl, cycloalkyl or alkyloxy, or R16and R17together with the nitrogen atom to which they are attached, form a mono - or bicyclic structure containing 4-10 units, and optionally containing 1-3 additional heteroatoms and/or 1-3 ethylene or catilinarian communication moreover, this cycle is optionally substituted in any position by 1-3 groups selected from halogen atoms and hydroxyl, alkyl, cycloalkyl or alkyloxy, in the form of a base or an acid additive salt, hydrate, or MES.

13. The compound of formula (I) according to item 12, wherein R2refers to a group-CO-NR16R17in which R16and R17are alkyl or alkyloxybenzoic group, in the form of a base or an acid additive salt, hydrate, or MES.

14. The compound of formula (I) according to claim 1, wherein R3contains 1 to 3 groups, identical or different, chosen from halogen atoms, in the form of a base or an acid additive salt, hydrate, or MES.

15. The compound of formula (I) according to claim 1, wherein R5is a hydrogen atom in the form of a base or an acid additive salt, hydrate, or MES.

16. The compound of formula (I) according to claim 1, wherein Raand Ra'represent a hydrogen atom or an alkyl group containing 1-4 carbon atoms, in the form of a base or an acid additive salt, hydrate, or MES.

17. Compounds with the following names:
N-{1-[N-(4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]PI is uridin-4-yl}-N-cyclohexyl-1,3-dihydro-2H-isoindole-2-carboxamide
N-{1-[N-(IPR-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,5-dimethylpyridin-1-carboxamid
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamyl
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N'-methoxy-N'-methylcarbamic
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-carboxamid
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cycloheptyl-N',N'-diethylcarbamyl
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclooctyl-N',N'-diethylcarbamyl
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N'-(2,2,2-triptorelin)urea
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl(trance)
N-{1-[N-(TRANS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl(trance)
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N'-ethyl-N'-isopropylcarbamate
N-(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin
N-(TRANS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]the Mino}cyclohexyl)-2,2,2-triptorelin
N-{1-[N-(1-benzoylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-Tajikabad
N-{1-[N-(TRANS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-bis(2-foradil)urea
(2R,5S)-N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,5-dimethylpyridin-1-carboxamid
(2R,5S)-N-(1-{4-chloro-N-[CIS-4-(dimethylamino)cyclohexyl]-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,5-dimethylpyridin-1-carboxamid
4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N,N-dimethylpiperidin-1-carboxamid
4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N,N-diethylpiperazine-1-carboxamid
N-(1-{4-chloro-N-[1-(pyrrolidin-1-ylcarbonyl)piperidine-4-yl]-D-phenylalanyl}piperidine-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(1-{4-chloro-N-[1-(piperidine-1-ylcarbonyl)piperidine-4-yl]-D-i.e. phenylalanyl}piperidine-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(1-{4-chloro-N-[1-(morpholine-4-ylcarbonyl)piperidine-4-yl]-D-i.e. phenylalanyl}piperidine-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamyl
4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N-phenylpiperidine-1-carboxamide
4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N-methyl-N-finalpaper the DIN-1-carboxamid
N-benzyl-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N-methylpiperidin-1-carboxamid
N-(1-{4-chloro-N-[1-(TRIFLUOROACETYL)piperidine-4-yl]-D-i.e. phenylalanyl}piperidine-4-yl)-N-cyclohexyl-N', N'-dimethylcarbamyl
N-{1-[N-(1-acetylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamyl
N-{1-[4-chloro-N-(CIS-4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamyl
N-{1-[4-chloro-N-(TRANS-4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin
N-(TRANS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin
N-[1-(4-chloro-N-{CIS-4-[(4-forfinal)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-[1-(4-chloro-N-{TRANS-4-[(4-forfinal)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-[1-(4-chloro-N-{CIS-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-[1-(4-chloro-N-{TRANS-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-{1-[4-the ENT-N-(4-methoxycyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate(trance)
N-{1-[4-chloro-N-(4-phenylcyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate(trance)
N-{1-[N-(1-acetylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate(trance)
N-(4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide(trance)
N-(1-{4-chloro-N-[1-(TRIFLUOROACETYL)piperidine-4-yl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamate(TRANS) - N-(4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin(trance)
N-{1-[N-(1-benzoylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(1-{4-chloro-N-[1-(methylsulphonyl)piperidine-4-yl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamate(trance)
N-{1-[4-chloro-N-(4-hydroxy-4-phenylcyclohexyl)D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate(trance)
N-[1-(4-chloro-N-{4-[(4-forfinal)amino]cyclohexyl}-D-i.e. phenylalanyl)-3-methylpiperidin-4-yl]-N-cyclohexyl-N',N-dimethylcarbamyl
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate(trance)
N-[1-(4-chloro-N-{CIS-4-[(2-methoxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide
N-(TRANS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide
N-(1-{4-chloro-N-[CIS-4-(4-hydroxyphenyl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(1-{4-chloro-N-[TRANS-4-(4-hydroxyphenyl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(1-{4-chloro-N-[2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamate(trance)
N-{1-[4-chloro-N-(1-isonicotinohydrazide-4-yl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate(trance)
N-(1-{4-chloro-N-[CIS-4-(1,3-dihydro-2H-isoindole-2-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamate(trance)
N-{1-[4-chloro-N-(2-phenylpiperidine-4-yl)-N-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate(trance)
N-(1-{4-chloro-N-[4-(3-oxopiperidin-1-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamate(TRANS).

18. Compounds with the following names:
N-{1-[N-(4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-yl}-N-cyclohexyl-1,3-dihydro-2H-isoindole-2-carboxamide
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,5-dimethylpyridin-1-carboxamid
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-N-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamyl
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N'-methoxy-N'-methylcarbamic
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl)-N-cyclohexyl-2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-carboxamid
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclobutyl-N',N'-diethylcarbamyl
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclopentyl-N',N'-diethylcarbamyl
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cycloheptyl-N',N'-diethylcarbamyl
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclooctyl-N',N'-diethylcarbamyl
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N',N'-diethyl-N-phenylcarbamate
N-{1-[N - (CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N'-(2,2,2-triptorelin)urea
N-{1-[4-chloro-N-(4-hydroxycyclohexyl)D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-diethylcarbamyl
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N', N'-diethylcarbamyl(trance)
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-illogical-N, N'-diethylcarbamyl(CIS)
N-{1-[N-(TRANS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N', N'-diethylcarbamyl(trance)
N-{1-[N-(TRANS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N', N'-diethylcarbamyl(CIS)
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N',N'-diethyl-N-(tetrahydro-2H-Piran-4-yl)urea
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N',N'-diethyl-N-piperidine-4-ylcarbamate
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N'-ethyl-N'-isopropylcarbamate
N-{1-[N-(CIS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,2-dimethylhydrogensiloxane
N-(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin
N-(TRANS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin
N-{1-[N-(TRANS-4-aminocyclohexane)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N', N'-bis(2-foradil)urea.

19. Compounds with the following names:
N-[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[2-(dimethylamino)ethyl]amino}piperidine-1-yl)-2-oxoethyl]cyclohexane-1,4-diamine
N-(1-{4-chloro-N-[CIS-4-(dimethylamino)cyclohexyl]-D-i.e. phenylalanyl}piperidine-4-yl)-N-cyclohexyl-3,4-diflorasone
N-(1-{4-PI is the p-N-[CIS-4-(dimethylamino)cyclohexyl]-D-i.e. phenylalanyl}piperidine-4-yl)-N-cycloheptyl-N',N'-dimethylcarbamyl
(2R,5S)-N-{1-[N-(CIS-4-aminocyclohexane]-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,5-dimethylpyridin-1-carboxamid
(2R,5S)-N-(1-{4-chloro-[N-(CIS-4-dimethylamino)cyclohexyl]-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-2,5-dimethylpyridin-1-carboxamid
N-{1-[4-chloro-N-(CIS-4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]piperidine-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamyl
N-{1-[4-chloro-N-(TRANS-4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin
N-(TRANS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin
N-[1-(4-chloro-N-{CIS-4-[(4-forfinal)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-[1-(4-chloro-N-{TRANS-4-[(4-forfinal)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-{1-[4-chloro-N-(4-methoxycyclohexyl)-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamyl
N-[1-(4-chloro-N-{CIS-4-[(4-methoxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-[1-(4-chloro-N-{TRANS-4-[(4-methoxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-[1-(4-N-{CIS-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-[1-(4-chloro-N-{TRANS-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-[1-(4-chloro-N-{4-[(dimethylamino)methyl]-4-phenylcyclohexyl}-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
(2R,5S)-N-(1-{4-chloro-N-[CIS-4-(dimethylamino)cyclohexyl]D-i.e. phenylalanyl}piperidine-4-yl)-N-cyclohexyl-2,5-dimethylpyridin-1-carboxamid
(2R,5S)-N-(1-{4-chloro-N-[CIS-4-(dimethylamino)cyclohexyl]D-i.e. phenylalanyl}piperidine-4-yl)-N-cyclohexyl-2,5-dimethylpyridin-1-carboxamid
N-{1-[4-chloro-N-(4-methoxycyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamyl
N-{1-[4-chloro-N-(4-phenylcyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N', N'-dimethylcarbamyl
N-(4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide
N-(4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-triptorelin
N-{1-[4-chloro-N-(4-hydroxy-4-phenylcyclohexyl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamyl
N-[1-(4-chloro-N-{4-[(4-forfinal)amino]cyclohexyl}-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(1-{4-chloro-N-[CIS-4-(dimethylamino)cyclohexyl]-D-i.e. phenylalanyl}piperidine-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-{1-[N-(CIS-4-and initlogger)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamyl
N-[1-(4-chloro-N-{CIS-4-[(2-methoxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl]piperidine-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-[1-(4-chloro-N-{CIS-4-[(2-methoxyphenyl)amino]cyclohexyl}-D-i.e. phenylalanyl]piperidine-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(CIS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide
N-(TRANS-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}cyclohexyl)ndimethylacetamide
N-(1-{4-chloro-N-[CIS-4-(4-hydroxyphenyl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(1-{4-chloro-N-[TRANS-4-(4-hydroxyphenyl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(1-{4-chloro-N-[4-(2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(1-{4-chloro-N-[CIS-4-(1,3-dihydro-2H-isoindole-2-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl]-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(1-{4-chloro-N-[4-(3-oxopiperidin-1-yl)cyclohexyl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl]-N-cyclohexyl-N', N'-dimethylcarbamate.

20. Compounds with the following names:
N-[1-(N-8-azabicyclo[3.2.1]Oct-3-yl-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-diethylcarbamyl
N-[1-(N-1-azabicyclo[2.2.2]Oct-3-yl-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohe the power-N',N'-diethylcarbamyl
N-[1-(N-8-azabicyclo[3.2.1]Oct-3-yl-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-]N-cyclobutyl-N',N'-diethylcarbamyl
N-{1-[N-(1-benzoylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl)piperidine-4-yl]-N-cyclohexyl-N',N'-diethylcarbamyl.

21. Compounds with the following names:
4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N,N-dimethylpiperidin-1-carboxamid
4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N,N-diethylpiperazine-1-carboxamid
N-(1-{4-chloro-N-[1-(pyrrolidin-1-ylcarbonyl)piperidine-4-yl]-D-i.e. phenylalanyl}piperidine-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(1-{4-chloro-N-[1-(piperidine-1-ylcarbonyl)piperidine-4-yl]-D-i.e. phenylalanyl}piperidine-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(1-{4-chloro-N-[1-(morpholine-4-ylcarbonyl)piperidine-4-yl]-D-i.e. phenylalanyl}piperidine-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamyl
4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N-phenylpiperidine-1-carboxamide
4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N-methyl-N-phenylpiperidine-1-carboxamide
N-benzyl-4-{[(1R)-1-(4-Chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}piperidine-1-yl)-2-oxoethyl]amino}-N-methylpiperidin-1-carboxamid
N-(1-{4-chloro-N-[1-(TRIFLUOROACETYL)piperidine-4-yl]-D-Hairdryer is lalani}piperidine-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamyl
N-{1-[N-(1-acetylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl]piperidine-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamyl
N-{1-[N-(1-acetylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N,N'-dimethylcarbamyl
N-(1-{4-chloro-N-[1-(TRIFLUOROACETYL)piperidine-4-yl]-D-i.e. phenylalanyl)-3-methylpiperidin-4-yl)-N-cyclohexyl-N,N'-dimethylcarbamyl
N-{1-[N-(1-benzoylpiperidine-4-yl)-4-chloro-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(1-{4-chloro-N-[1-(methylsulphonyl)piperidine-4-yl]-D-i.e. phenylalanyl}-3-methylpiperidin-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamyl
N-(1-{4-chloro-N-[1-(methylsulphonyl)piperidine-4-yl]-D-i.e. phenylalanyl}piperidine-4-yl)-N-cyclohexyl-N',N'-dimethylcarbamyl
N-{1-[4-chloro-N-(1-isonicotinohydrazide-4-yl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamyl
N-{1-[4-chloro-N-(2-phenylpiperidine-4-yl)-D-i.e. phenylalanyl]-3-methylpiperidin-4-yl}-N-cyclohexyl-N',N'-dimethylcarbamate.

22. A drug intended for the treatment or prevention of obesity, diabetes and sexual dysfunction in both sexes, cardiovascular diseases, and also for anti-inflammatory treatment and the treatment of alcohol dependence, otlichayushiesya the fact that it contains a compound of the formula (I) according to any one of claims 1 to 21, or additive salt of this compound with a pharmaceutically acceptable acid, or a hydrate or MES the compounds of formula (I).

23 Pharmaceutical composition, intended for the treatment or prevention of obesity, diabetes and sexual dysfunction in both sexes, cardiovascular diseases, and also for anti-inflammatory treatment and the treatment of alcohol dependence, characterized in that it contains a compound of the formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, hydrate or MES this connection, and at least one pharmaceutically acceptable excipient.

24. The use of the compounds of formula (I) according to any one of claims 1 to 21 for obtaining a medicinal product intended for the treatment or prevention of obesity, diabetes and sexual dysfunction in both sexes, cardiovascular diseases, and also for anti-inflammatory treatment and treatment of alcohol dependency.

25. The application of paragraph 24, wherein the specified sexual dysfunction is erectile dysfunction.

26. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 16, characterized in that exercise rehabilitation amination of the compounds of formula (V):

in the presence of a derivative group, R4ketone type, in which R1, R2, R3, R4, R5, Raand Ra'have the meanings described in any one of claims 1 to 16.

27. Compounds of formula (VI), (XVIII) and (XIX)in which R1, R2, R3, R4, R5, Raand Ra'have the meanings described in any one of claims 1 to 16, and Pg is a protective group:

,



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of common formula (I) , in which: A, if available, means (C1-C6)-alkyl; R1 means group NR6R7, (C4-C7)-azacycloalkyl, (C5-C9)-azabicycloalkyl, besides, these groups, unnecessarily, are substituted with one or more substituents, selected from (C1-C5)-alkyl or halogen; A-R1 is such that nitrogen of radical R1 and nitrogen in position 1 of pyrazole are necessarily separated at least by two atoms of carbon; R3 means radical H, OH, NH2, ORc, NHC(O)Ra or NHSO2Ra; R4 means phenyl or heteroaryl, unnecessarily, substituted with one or more substituents, selected from halogen, CN, NH2, OH, ORc, C(O)NH2, phenyl, polyfluoroalkyl, linear or ramified (C1-C6)-alkyl, besides these substituents, unnecessarily, are substituted with halogen, and moreover, heteroaryl radicals are 3-10-member, containing one or more heteroatoms, selected from sulphur or nitrogen; R5 means radical H, linear or ramified (C1-C6)-alkyl; Ra means linear or ramified (C1-C6)-alkyl; Rc means linear or ramified (C1-C6)-alkyl, (poly)fluoroalkyl or phenyl; R6 and R7, independently from each other, means hydrogen, (C1-C6)-alkyl; R6 and R7 may create 5-, 6- or 7-member saturated or non-saturated cycle, which includes one heteroatom, such as N, and which, unnecessarily, substituted with one or more atoms of halogen; to its racemates, enantiomers, diastereoisomers and their mixtures, to their tautomers and their pharmaceutically acceptable salts, excluding 3-(3-pyridinyl)-1H-pyrazole-1- butanamine, 4-(3-pyridinyl)-1H-pyrazole-1-butanamine and N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine. Invention is also related to methods for production of compounds of formula (I) and to pharmaceutical composition intended for treatment of diseases that appear as a result of disfunction of nicotine receptors α7 or favorably responding to their modulation, on the basis of these compounds.

EFFECT: production of new compounds and pharmaceutically acceptable composition on their basis, which may find application in medicine for treatment, prophylaxis, diagnostics and observance over development of psychiatric or neurological disorders or diseases of central nervous system, when cognitive functions deteriorate or quality of sensor information processing drops.

16 cl, 106 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with formula I: , where D is O; E is CH2 or O; n equals 1 or 2, and R1 is chosen from hydrogen, halogen or substituted or unsubstituted 5- or 6-member aromatic or heteroaromatic ring with 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom, or is chosen from substituted or unsubstituted 8-, 9- or 10-member condensed heteroaromatic ring system with 0 or 1 nitrogen atom, 0 or 1 oxygen atom, where the said aromatic or heteroaromatic rings or ring systems, when they are substituted, have substitutes which are chosen from -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, halogen, -CF3, -S(O)mR2, where m equals 0, 1 or 2, -NR2R3, -NR2C(O)R3 or -C(O)NR2R3; R2 and R3 are in each case independently chosen from hydrogen, -C1-C4alkyl, -C3-C6cycloalkyl, aryl; or its stereoisomers, enantiomers or pharmaceutically acceptable salts; under the condition that the given compound is not 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydroisoindol-1-one. The invention also relates to compounds with formulae II or III, to a pharmaceutical composition, as well as to use of compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds with activity towards alpha 7 nicotinic acetylcholine receptors (α7 nAChRs).

8 cl, 72 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of formula I in the form of the salt or zwitter-ion, wherein R1 and R3 are independently phenyl, C3-C8 cycloalkyl or thienyl group, R2 is haloid or hydroxyl group; R4 is C1-C8 alkyl substituted with -NR5-CO-R6 or -CO-NR9R10; R5 is hydrogen ; R6 is C1-C8alkyl or C1-C8 alkoxy, each of them is optionally substituted with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R6 is 5-10-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur; R9 is hydrogen or C1-C8alkyl; R10 is C1-C8alkyl, optionally substituted with cyano group, C1-C8 alkoxy group or with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R10 is 5-9-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur. The invention refers also to the pharmaceutic composition, to the application of compound of any of claims 1-5 as well as to the preparation method of compound of formula I of claim 1.

EFFECT: preparation of the new biologically active compounds taking the effect of muscarin receptor M3.

9 cl, 247 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medical products and concerns the method of obtaining of a Solifenacin composition or its salts for use in a solid preparation which includes at least one stage chosen of the group consisting of (i) stage of wet granulation with use of a dissolvent for Solifenacin or its salts, thereat quantity of Solifenacin or its salts which should be dissolved in 1 ml of a dissolvent makes less than 0.1 mg, (ii) stage of dicrease of quantity or rate of addition of a dissolvent if the dissolvent moves Solifenacin or its salt in an amorphous condition, and quantity of Solifenacin or its salts which should be dissolved in 1 ml of a dissolvent 10 mg or more and (iii) stage of activisation of process of crystallisation of a composition of the wet granulation received by means of a usual way. Also the pharmaceutical composition for use in the solid preparation, showing selective opposing action against muscarinic M3 receptors is revealed.

EFFECT: rising of stability of the compositions containing Solifenacin or its salt.

12 cl, 3 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1-azabicycloalkyl of general formula I, , in which X represents CH2 or simple bond; Y represents group of formula or and, where R has values given in description, which are agonists of alpha 7 nicotine acetylcholine receptor (nAChR).

EFFECT: possibility of using as pharmaceutical preparations.

18 cl

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new derivative of cyclic amine or its salts with the following formula (I): (where symbols stand for the following: A: 5-8-member cyclic amine, which may contain a double bond, a bridged structure and may contain substitutes R7-R11 in the ring, or -NH2, -NH(inferior alkyl), -N(inferior alkyl)2 or ) morpholin-1-yl; ring B: benzole, thiophene, furane, pyrrole, 5-7-member cycloalkane or 5-7-member cycloalkene; X1: a bond or inferior alkylene; X2: -(CR12R13)n-, -N(R14)-, -N(R14)CO-, -CON(R14)-, -CO-, -CH(OH)-, -N(R14)- (CR12R13)n-, (CR12R13)n-N(R14)-, -CON(R14)-(CR12R13)n-, -n(R14)CO-(CR12R13)n-, -(CR12R13)n-N(R14)CO-, -(CR12R13)n-CON(R14)-, -CO-(CR12R13)n- or -(CR12R13)n-CO-; Y1: -OH, -O-inferior alkyl, NH2 or -N3; R1 and R2: are identical or different and stand for a halogen atom, inferior alkyl or inferior alkylene-OH; R3-R6: are identical or different and stand for a hydrogen atom, a halogen atom, inferior alkyl, inferior alkenyl, inferior alkynyl, -O-inferior alkyl, -OH, -NH2, -NH(inferior alkyl), -N(inferior alkyl)2, -NH-CO- inferior alkyl, -N(inferior alkyl)-CO- inferior alkyl, -CN-, -NO2, -CF3, -O-inferior alkylene-OH, -inferior alkylene-OH, -inferior alkylene-halogen, -inferior alkylene-O-inferior alkyl, -CO-5-8-member cyclic amine, -COOH-inferior alkyl, -COO-inferior alkylene-aryl, pyridine, thiophene, -inferior alkylene-morpholine, aryl, which may contain a substitute: -O-inferior alkyl or -CF3; R7: hydrogen atom, inferior alkyl, -inferior alkylene-aryl or -inferior alkylene-pyridine: R7 is substitute on the nitrogen atom of the cyclic amine; R8-R14: are identical or different and stand for a hydrogen atom or inferior alkyl; n: is an integer, equal to 1, 2 or 3; where R5 and R6, R4 and R5 or R3 and R4 can form an inferior alkylene together, -O-inferior alkylene-O-, -O-inferior alkylene-, -inferior alkylene-O-, -C(R15)=C(R16)-O-, -O-C(R15)=C(R16)-, -C(R15)=C(R16)-C(R17)=C(R18)-; R3 and Y1 together can form -O-inferior alkylene-O- or -inferior alkylene-O-; R1 and Y1 together can form -inferior alkylene-O-; and Y1 and a branch on - X1-A together can form -O- or -O-inferior alkylene; R15-R18 stand for a hydrogen atom, under the condition that, 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol is not included in the group of compounds). The invention also pertains to a derivative of cyclic amine or its salts with formula (II), to a derivative of cyclic amine or its salts with formula (III), to pharmaceutical composition, as well as their use.

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on these compounds, with antagonist effect on NMDA receptors NMDA.

7 cl, 160 ex, 45 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel quinuclidine derivatives and their using as pharmaceutical agents. Based on their pharmacological pattern proposed compounds can be useful in treatment of different diseases and disorders associated with cholinergic system of the central nervous system, peripheral nervous system, diseases and disorders associated with contraction of smooth muscle, endocrine diseases or disorders, diseases or disorders associated with neurodegeneration, diseases or disorders associated with inflammation, pain and abstinence syndrome caused by ceasing use of chemical substances.

EFFECT: valuable medicinal properties of compounds.

11 cl, 1 tbl, 46 ex

FIELD: organic chemistry, medicine, chemical technology.

SUBSTANCE: invention describes a method for synthesis of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represented by the formula: . Method involves interaction of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane with hydrobromic acid or its inorganic salt (for example, sodium bromide or potassium bromide) in water in the ionic exchange reaction. 1-Hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represents an immunotropic agent that shows versatile effect on human immune status and elicits antitumor, bacteriostatic and anti-aggregate effects. Invention proposes a method for synthesis of a novel synthetic low-molecular preparation possessing the expressed stimulating effect on the antitumor immunity system that is equal or exceeding by effectiveness effect of the modern domestic and foreign preparation - immunomodulators that represent natural high-molecular biologically active substances prepared by methods of genetic engineering.

EFFECT: improved method of synthesis, valuable medicinal and biological properties of substance.

1 cl, 6 tbl, 21 dwg, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds that represent quaternary ammonium salt of the formula (II): wherein R1 means group chosen from phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl; R2 means group chosen from (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, saturated or unsaturated (C3-C7)-cycloalkyl, saturated or unsaturated (C3-C7)-cycloalkylmethyl, phenyl, benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl and pyridylmethyl; cyclic groups in R1 and R2 are optionally substituted with one, two or three substitutes chosen from halogen atom, linear or branched (C1-C8)-alkyl, hydroxy, linear or branched (C1-C8)-alkoxy wherein (C1-C8)-alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy or (C1-C8)-alkoxy groups, and (C1-C8)-alkoxy group is unsubstituted or substituted with one or more halogen atoms or hydroxy groups; p means 1 or 2, and carbamate group is joined at positions 2, 3 or 4 of azoniabobicyclic ring system; m means a whole number from 1 to 6; n means 0 or 1; A represents -CH2-, -CH=CH-, -C(O)-, -O-, -S- and -NMe-group; B represents hydrogen atom or group chosen from linear or branched (C1-C8)-alkyl, hydroxy, linear or branched (C1-C8)-alkoxy, cyano, nitro, -CH=CR'R'', -C(O)OR', -OC(O)R', (C3-C7)-cycloalkyl, phenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1.3]dioxolyl, 5-10-membered heteroaryl or heterocyclyl group wherein each R' and R'' represents independently hydrogen atom or linear or branched (C1-C8)-alkyl group, and wherein cyclic groups represented as B are substituted optionally with one, two or three substitutes chosen from halogen atom, hydroxy, linear or branched (C1-C8)-alkyl, -OR', -CONR'R'', -CN, and -COOR'; R' and R'' are given above and wherein (C1-C8)-alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy or (C1-C8)-alkoxy groups, and (C1-C8)-alkoxy groups are unsubstituted or substituted with one or more halogen atoms or hydroxy groups; X- represents a pharmaceutically acceptable anion of mono- or polyvalent acid, and involving all individual stereoisomers of compound of the formula (II) and their mixtures. Also, invention relates to a method for inhibition, pharmaceutical composition, combined product and their using in therapeutic treatment as antagonists of M3 muscarinic receptors. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 187 ex

FIELD: medicine.

SUBSTANCE: invention is related to new compounds that comply with formula (I) , where: n is equal to 1, Ra, Ra', Rb, Rb', identical or different, mean atom of hydrogen or alkyl or cycloalkyl group, besides, Rb and Rb' may create carbon bridge having 4 links together with hydrogen atoms of cycle, to which they are connected, R1 means cyclohexyl group, R2 means 1,2,4-triazolyl group, R3 means 1-3 groups, selected from atoms of halogen, available in any position of cycle, to which they are connected, R5 means atom of hydrogen, R4 is selected from groups of formulas (a), (b) and (c), given below, mono- or polysubstituted with aryl group: (a), (b), (c), in which: p=0, 1, 2 or 3, m=0, 1 or 2, and either a) X means link -N(R10)-, where R10 is selected from: groups -CO-NR8R9, -COOR8, -(CH2)x-OR8, -(CH2)x-COOR8, -(CH2)x-COR8, in which x=1, 2, 3 or 4, heterocycloalkyl group, condensed with aryl group, cycloalkyl, aryl, heteroaryl, alkylaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl, -SO2-alkyl, -SO2-cycloalkyl, -SO2-aryl, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are unnecessarly substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CN, -COOR, COR; or R10 together with atom of nitrogen, to which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not in neighboring position to mentioned atom of nitrogen, creates a bridge that contains 3-5 links, R8 and R9 are selected, independently from each other, from atom of hydrogen and alkyl or cycloalkyl groups; R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, aryl groups; or b) X means link - C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, groups -(CH2)x-OR8, -(CH2)x-COOR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0, 1, 2, 3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl group, heterocycloalkyl group, condensed or non-condensed, available in spiro-position to cycle of formula (a), to which it is connected, heterocycloalkyl group, condensed with aryl group, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are unnecessarily substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CO-NRR', -CN, -COOR, OCOR, COR, NRCOOR'; and heterocycloalkyl groups are unnecessarily condensed with aryl group; R7 is selected from atoms of hydrogen and halogen and alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl groups, -OR, -O-aryl, -O-alkylaryl, -O-alkylheteroaryl, groups -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN and -COOR, R8 and R9 are selected, independently from each other, from atom of hydrogen and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl groups, -CO-alkyl, -CO-cycloalkyl, -CO-aryl, -(CH2)x-OR, where x=0, 1, 2, 3 or 4, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are unnecessarily substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CO-NRR', -CN, -COOR, OCOR, COR, NRCOOR'; or R8 and R9 create together cycloalkyl or heterocycloalkyl; R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl, aryl, or may together create cycloalkyl or heterocycloalkyl; besides heteroaryl group represents aromatic group that contains from 5 to 10 atoms and from 1 to 4 heteroatoms, selected from nitrogen, oxygen or sulfur; heterocycloalkyl group represents cycloalkyl group, which contains from 5 to 10 atoms and contains from 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (IV) , (V), (VI), (XXVIII), (XXIX), (II).

EFFECT: production of new biologically active compounds, having activity of agonists of melanocortin receptors.

36 cl, 22 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: described is a new uniformly tritium-labeled 4,4-fluoro-N-{(1S)-3-[3-(3-isopropyl-5-methyl-4H-1,2,4-trizol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclohexane carboiimide (maraviroc) of formula I .

EFFECT: said compound can be used in analysis of physiologically active compound-analogue.

1 cl, 1 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I), their optically active stereoisomers, as well as to pharmaceutically acceptable salts possessing properties of ORL1 and µ-opiate receptors. In general formula , R1 represents H, alkyl(1-6C), []m represents-(CH2)m-, in which m equals 0 or 1, R2 represents halogen, CF3, alkyl(1-6C), phenyl, cyano, cyanoalkyl(1-3C), hydroxy, (1-3C)alkoxy, OCF3, acyl(2-7C), trifluoroacetyl, (1-3C)alkylsulfonyl or trifluoromethylsulfonyl, and n represents integer number 0-4 on condition that when n equals 2, 3 or 4, R2 substituents can be similar or different, A represents saturated ring, []0 and []p represents -(CH2)o and -(CH2)p, and o and p independently correspond to 0, 1 or 2, R3, R4, R5 and R6 independently represent hydrogen, alkyl(1-3C), or (R4 and R6) together can form alkylene bridge, containing 1-3 carbon atoms on condition that when o equals 2, R3 represents hydrogen, and when p equals 2, R5 represents hydrogen, R7 represents H, halogen, alkyl(1-6C). Invention also relates to pharmaceutical composition, intermediate compounds for obtaining formula (1) compounds.

EFFECT: compounds can be used for preparing medication for treating disorders and diseases such as alimentary behaviour disturbances, arterial hypertension.

8 cl, 3 dwg, 1 tbl, 45 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: method involves production of N-substituted 3β-aminonortropanes of formula I or one of acid-additive salts , where R1 represents optionally substituted residue chosen from group, including C1-C8alkyl, C2-C8alkenyl, C3-C8cycloalkyl and C6-C10aryl-C1-C8alkyl, characterised that either a) related 3-oxonortropane of formula IIA reacts with arylmethylamine of formula IIIA H2N-CH2-Ar (IIIA) where Ar stands for optionally substituted phenyl residue or optionally substituted 5 or 6-merous heteroaromatic residue with at least one heteroatom chosen from group including N, O and S, or b) related 3α-aminonortropane of formula IIB reacts with arylaldehyde of formula IIIB O-CH-Ar (IIIB). Produced in each case imine of formula IVA or IVB is transformed to thermodynamically stable tautomer, respectively isomer of formula V , then hydrolysed and if required transformed to related acid-additive salt.

EFFECT: produced compounds of formula I are valuable intermediate in chemical synthesis of various pharmaceutical reactants or represent pharmaceutical reactant, first of all as NMDA-receptor modulators; method allows for high-yield commercial production of high-purity 3-aminonortropanes.

9 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

The invention relates to new cyclic amine derivatives of General formula I, where R1represents a phenyl group substituted by halogen atom,2represents C1- C8aliphatic acyl group or (C1- C4alkoxy)carbonyl group, R3represents a 3 - to 7-membered saturated cyclic amino group which may form a condensed ring, where the specified cyclic amino group substituted by the Deputy selected from the group comprising: mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, C1- C4alkyl group, substituted mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, and the number of protective groups for the specified mercaptopropyl includes C1- C20alcoholnye group, C3- C20alkenone group and benzoline group, and the said cyclic amino group, furthermore preferably a substituted group of the formula =CR4R5where R4represents a hydrogen atom, and R5represents a hydrogen atom, a C1- C4alkyl group, carboxypropyl, (C1- C4-alkoxy)carbonyl GRU

The invention relates to therapeutic active usacycling or azabicyclic compounds, method of their preparation and to pharmaceutical compositions comprising these compounds

The invention relates to derivatives of 3-(piperidinyl-1)-chroman-5,7-diol and 1-(4-hydroxyphenyl)-2-(piperidinyl-1)alkanol General formula I or their pharmaceutically acceptable salts accession acid, in which (a) R2and R5taken individually and R1, R2, R3and R4independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7and R5represents methyl; or (b) R2and R5taken together form a ring chroman-4-ol, a R1, R3and R4each independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7; R7represents methyl; and R6represents a substituted piperidinyl or 8-azabicyclo[3,2,1]octenidine derived; provided that (a) if R2and R5taken separately, at least one of R1, R2, R3and R4is not hydrogen; and (b) if R2and R5taken together, at least one of R1, R3and R4is not hydrogen, with the property that the NMDA antagonist

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of common formula IC1: , where A represents cyano; B represents hydrogen; R1, R2, R3 and R4 independently represent hydrogen; alkyl; halogen or nitro; R5 and R6 independently represent hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; heteroaryl; heteroarylalkyl; alkenyl; carboxyalkyl; cyanoalkyl; diphenylalkyl; aryl, arylalkoxyaryl, arylalkyl, arylalkylaryl, arylcarbonylaryl or aryloxyaryl, or R5 and R6, together with atom of nitrogen, to which they are connected, create heterocyclic ring system; or to salts of such compound; at the same time "heteroaryl" used separately or in combination, is related to mono-, bi- or tricyclic aromatic ring system, which contains up to 14 atoms included in ring, in which at least one ring contains at least one heteroatom, independently chosen from nitrogen, oxygen or sulfur, besides specified heteroaryl group may be unsubstituted or substituted with one to three substituents, independently selected from alkyl and alkoxy; "diphenylalkyl" is related to alkyl group, where each of two atoms of hydrogen is substituted with unsubstituted phenyl group; "aryl" is related to carbocyclic group, selected from group, which consists of phenyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, antryl, phenantryl, fluorenyl, indanyl, 2,3-dihydrobenzo[1,4]dioxynyl and benzo[1,3]dioxolyl group, besides specified aryl group may be unnecessarily substituted with functional groups in number from one to three, which are separately and independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, cyano, halogen, halogenlkoxy, halogenalkyl and nitro groups, where in certain specific cases, if aryl group represents condensed system from several rings, in which not all the rings are aromatic, one of carbon atoms of which is not included into aromatic ring may be in oxidised condition, and according fragment of ring -CH2- will be substituted by fragment-C(O); "arylalkoxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkoxygroup, where aryl group is unsubstituted; "arylalkyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkyl group, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "aryloxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via oxygen bridge, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "arylcarbonyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via carbonyl group, where aryl group is unsubstituted; "heterocyclic ring system", used separately or in combination, is related to monocyclic, bicyclic or polycyclic ring system, which contains up to 15 atoms included into ring, at least one of which represents heteroatom, independently selected from nitrogen, oxygen or sulfur, besides specified ring system may be saturated, partially unsaturated, unsaturated or aromatic, where specified heterocyclic fragment may be unnecessarily substituted with one or more substituents, every of which separately and independently is selected from group made of halogen and halogenalkyl, excluding the following compounds: {3-[(E)-2-cyano-2-(4-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-m-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(3-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-phenylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-benzylcarbamoyl-2-cyanovinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-o-tolylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-t-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(4-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-ethylphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2~cyano-2-(4- ethoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-isopropylcarbamoylvinyl)indole-1-yl]acetic acid; {3-[(E)-2-cyano-2-(3-etoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-[[2-(1H-indole-3-yl)ethyl]amino]-3-oxo-1-propenyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-chlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-(4-methyl-piperidine-1-yl)-3-oxopropenyl]indole-1-yl}acetic acid; {3-[(E)-2-(3-chloro-4-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(3-phenylpropylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2,3-dichlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-(5-chloro-2-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxybenzylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; and {3-[(E)-2-cyano-3-oxo-3-(4-phenyl-piperazine-1-yl)propenyl]indole-1-yl}acetic acid. Invention is also related to pharmaceutical composition, and also to application of compounds of clause 1.

EFFECT: production of biologically active compounds, which have activity of antagonist coupled with G-protein of chemoattractant receptor of molecules homologue released by Th2-cells.

11 cl, 156 ex, 8 tbl

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