Piperidine derivatives as modulators of activity of ccr5 receptor, method and intermediate compounds for obtaining them, and pharmaceutical compositions containing them

FIELD: chemistry.

SUBSTANCE: description is given of a piperidine derivative with general formula (I) , where L represents CH or N; M represents CH or N; under the condition that, L and M both do not represent CH; R1 represents phenyl (possibly substituted with a halogen or C1-4alkyl), S(O)2(C1-4alkyl), S(O)2(C1-4fluroalkyl), S(O)2phenyl (possibly substituted with CF3 or OCF3), benzyl, benzoyl (possibly substituted with a halogen) or C(O)NHphenyl (possibly substituted with a halogen); R2 represents phenyl, possibly substituted with a halogen; R3 represents hydrogen or C1-4alkyl; R4 represents methyl or ethyl; R5 represents phenyl-NH, phenyl (C1-2alkyl), phenyl(C1-C2)alkyl-NH or pyridyl(C1-2alkyl). The phenyl can be substituted with a halogen, cyano, C1-4alkyl, C1-4alkoxy, S(O)k(C1-4alkyl) or S(O)2NR8R9; k is equal to 2; R8 and R9 represent hydrogen or its pharmaceutical salts. The compound is a modulator of the activity of the CCR5 receptor. Description is given of the method of obtaining the compound, where L represents N, and the pharmaceutical composition based on a compound with formula (I).

EFFECT: design of a method of obtaining a compound, where L represents N, and a pharmaceutical composition based a compound with formula (I).

7 cl, 7 tbl, 16 ex

 

The present invention relates to heterocyclic derivatives having pharmaceutical activity, to methods for obtaining such derivatives, to pharmaceutical compositions containing such derivatives and to the use of such derivatives as active therapeutic agents.

Pharmaceutically active derivatives of piperidine derivatives are disclosed in PCT/SE01/01053, EP-A1-1013276, WO 00/08013, WO 99/38514 and WO 99/04794.

Chemokines are chemotactic cytokines that are released a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and play a role in the maturation of cells of the immune system. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules represent a growing superfamily of proteins 8-14 kDa characterized by conservative motif of four cysteines. The superfamily of chemokines can be divided into two main groups, with characteristic structural motifs: a family of Cys-X-Cys (C-X-C, or α) and Cys-Cys (C-C, or β). These families differ on the basis of a single amino acid insertion in NH-proximal pair sistei the new residues and sequence similarity.

Chemokines of the C-X-C include several effective chemoattractants and activators of neutrophils, such as interleukin-8 (IL-8), and activates the neutrophil peptide-2 (NAP-2, neutrophil-activating peptide 2).

Chemokines C-C include strong chemoattractant monocytes and lymphocytes, but not neutrophils, such as macrophage chemotactic proteins person 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (regulated by activation of factor expressed and secretory normal T-cells; Regulated on Activation, Normal T Expressed and Secreted), eotaxin and macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

Studies have shown that the actions of chemokines is mediated by subfamilies of receptors associated with G-protein, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors are good targets for drug development, because the agents that modulate these receptors, can be useful in the treatment of disorders and diseases such as those mentioned above.

The CCR5 receptor is expressed on T-lymphocytes, monocytes, macrophages, dendritic cells, microglia and other cell types. They detect and respond to several chemokines, mainly on "adjustable activating factors expressed and secreted normal T-cells" (RANTES), macrophage inflammatory the nutrient protein (MIP) MIP-1α and MIP-1β and macrophage protein-chemoattractant 2 (MCP-2).

These events result in the recruitment of immune cells to sites of disease. In many diseases it is the cells expressing CCR5, contribute, directly or indirectly, in tissue damage. Therefore, inhibition of the recruitment of these cells is useful for a wide range of diseases.

CCR5 is also a coreceptor for HIV-1 and other viruses, allowing these viruses to enter cells. Blocking this receptor CCR5 antagonist or induction of internalization of this receptor CCR5 agonist protects cells from viral infection.

According to the present invention proposed a compound of formula (I)

where L represents CH or N; M represents CH or N, provided that L and M do not represent both SN;

R1represents hydrogen, C1-6alkyl [substituted by phenyl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, OCF3, (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)} or heteroaryl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, (C1-4alkyl)C(O)NH, S(O)2NH2With1-4 alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)}], phenyl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, OCF3, (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)}, heteroaryl {could be replaced by halogen, C1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, (C1-4alkyl)C(O)NH, S(O)2NH2C1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)}, S(O)2R6, S(O)2NR10R11C(O)R7, groups C(O)2(C1-6alkyl) (for example, tert-butoxycarbonyl), (O)2(phenyl(C1-2alkyl)) (for example, benzyloxycarbonyl), or C(O)other7; and when M represents SN, R1can also be an NHS(O)2R6NHS(O)2Other7, NHC(O)R7or NHC(O)other7;

R2represents phenyl or heteroaryl, each of which may substituted, halogeno,1-4the alkyl, C1-4alkoxy, S(O)n(C1-4alkyl), nitro, cyano or CF3;

R3represents hydrogen or C1-4alkyl;

R4represents hydrogen, methyl, ethyl, allyl or cyclopropyl;

R5represents phenyl, heteroaryl, NH, NH, phenyl(C1-2alkyl), heteroaryl(C1-2alkyl), phenyl(which 1-2alkyl)NH or heteroaryl(C1-2alkyl)NH, while the phenyl and heteroaryl rings in R5possibly substituted, halogen, cyano, nitro, hydroxy, C1-4the alkyl, C1-4alkoxy, S(O)k(C1-4alkyl), S(O)2NR8R9NHS(O)2(C1-4alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)NH2C(O)NH2With(O)NH(C1-4alkyl), NHC(O)(C1-4alkyl), CO2N, CO2(C1-4alkyl), C(O)(C1-4alkyl), CF3, CHF2CH2F, CH2CF3or OCF3;

k, m and n are independently 0, 1 or 2;

R6represents a C1-6alkyl [substituted by halogen (e.g., fluorescent)1-4alkoxy, phenyl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, OCF3, (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)} or heteroaryl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)}], C3-7cycloalkyl, pyranyl, phenyl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, OCF3, (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)} or heteroaryl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)};

R7represents hydrogen, C1-4alkyl [substituted by halogen (e.g., fluorescent)1-4alkoxy, phenyl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, OCF3, (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)} or heteroaryl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)}], C3-7cycloalkyl, pyranyl, phenyl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, OCF3, (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)} or heteroaryl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, (C1-4alkyl)C(O)NH, S(O)2NH2With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4Ala is l)};

R8and R9independently represent hydrogen or C1-4alkyl, or together with the nitrogen atom or oxygen can be connected with the formation of 5 - or 6-membered ring which may be substituted With1-4the alkyl, C(O)H or C(O)(C1-4alkyl);

R10and R11independently represent hydrogen or C1-4alkyl or can be connected with the formation of 5 - or 6-membered ring which may be substituted With1-4the alkyl or phenyl (which phenyl ring may substituted, halogen, cyano, nitro, hydroxy, C1-4the alkyl, C1-4alkoxy, a group S(O)mWith1-4alkyl, S(O)2NH2, S(O)2NH(C1-4alkyl), S(O)2N(C1-4alkyl)2NHS(O)2(C1-4alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)NH2C(O)NH2With(O)NH(C1-4alkyl), NHC(O)(C1-4alkyl), CO2N, CO2(C1-4alkyl), C(O)(C1-4alkyl), CF3, CHF2CH2F, CH2CF3or OCF3),

or its pharmaceutically acceptable salt or MES,

provided that when R1is hydrogen or unsubstituted alkyl, R4is hydrogen, stands or ethyl, L represents CH and M is represented by N, then the phenyl or heteroaryl part in R5substituted one of the following: S(O)kC1-4 alkyl, NHC(O)NH2With(O)(C1-4alkyl), CHF2CH2F, CH2CF3or OCF3and maybe optionally substituted by one or more than one of the following: halogen, cyano, nitro, hydroxy, C1-4alkyl, C1-4alkoxy, S(O)kWith1-4alkyl, S(O)2NR8R9NHS(O)2(C1-4alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)NH2C(O)NH2With(O)NH(C1-4alkyl), NHC(O)(C1-4alkyl), CO2N, CO2(C1-4alkyl), C(O)(C1-4alkyl), CF3, CHF2CH2F, CH2CF3or OCF3.

Some compounds of the present invention may exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention includes all such isomers and mixtures thereof in any proportion.

Suitable salts include salts obtained by joining acids, such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluensulfonate.

The compounds of this invention can exist in the form of a solvate (e.g. hydrate), and the present invention covers all such solvate.

Alkyl groups and groups are straight or branched chain and are, for example, stands, ethyl, what-propylene, the isopropyl, n-bootrom, second-bootrom or tert-bootrom. Sometimes hereafter methyl designated by the abbreviation Me.

Foralkyl includes, for example, from one to six, for example from one to three fluorine atoms and includes, for example, a group of CF3. Foralkyl represents, for example, CF3or CH2CF3.

Cycloalkyl represents, for example, cyclopropyl, cyclopentyl or cyclohexyl.

Phenyl(C1-2alkyl)alkyl represents, for example, benzyl, 1-(phenyl)ETH-1-yl or 1-(phenyl)ETH-2-yl.

Heteroaryl(C1-2alkyl)alkyl represents, for example, pyridinylmethyl, pyrimidinyl or 1-(pyridinyl)ETH-2-yl.

Phenyl(C1-2alkyl)NH represents, for example, benzylamino. Heteroaryl(C1-2alkyl)NH represents, for example, pyridinyl2NH, pyrimidinyl2NH or peridinin(CH3)NH.

Heteroaryl represents an aromatic 5 - or 6-membered ring, possibly condensed with one or more than one ring comprising at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; or an N-oxide or S-oxide or S-dioxide. Heteroaryl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, thiazolyl, isothiazolin, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, [1,2,4]triazolyl, pyridinyl, is rimidine, indolyl, benzo[b]furyl (also known as bankfull), benzo[b]thienyl (also known as benzothiazyl or benzothiophene), indazole, benzimidazole, benzotriazole, benzoxazole, benzthiazole, 1,2,3-benzothiadiazoles, imidazopyridines (for example, imidazo[1,2-a]pyridinyl, thieno[3,2-b]pyridine-6-yl, 1,2,3-benzoxadiazole (also known as benzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazole, benzofurazan (also known as 2,1,3-benzoxadiazole), honokalani, pyrazolopyrimidine (for example, 1H-pyrazolo[3,4-b]pyridinyl), chinoline, ethenolysis, naphthyridines (for example [1,6]naphthyridine or [1,8]naphthyridine), benzothiazolyl or dibenzothiophene (also known as dimenstional); or N-oxide or S-oxide or S-dioxide. Heteroaryl can also be pyrazinium. Heteroaryl represents, for example, pyridinyl, pyrimidinyl, indolyl or benzimidazolyl.

In one particular aspect of the present invention proposed a compound of formula (I), where L represents CH or N; M represents CH or N, provided that L and M do not represent both CH; R1represents hydrogen, C1-6alkyl [substituted by phenyl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)} or heteroaryl {to the nd itself possibly substituted, halogen, With1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)}], phenyl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)}, heteroaryl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)}, S(O)2R6, S(O)2Other7C(O)R7With(O)2(C1-6alkyl), or C(O)other7; and when M represents SN, R1can also be an NHS(O)2R6NHS(O)2Other7, NHC(O)R7or NHC(O)other7; R2represents phenyl or heteroaryl, each of which may substituted in ortho - or meta-position halogeno,1-4the alkyl, C1-4alkoxy, S(O)n(C1-4alkyl), nitro, cyano or CF3; R3represents hydrogen or C1-4alkyl; R4represents hydrogen, methyl, ethyl, allyl or cyclopropyl; R5represents phenyl, heteroaryl, NH, NH, phenyl(C1-2)alkyl, heteroaryl(C1-2)alkyl, phenyl(C1-2alkyl)NH or heteroaryl(C1-2alkyl)NH, while the phenyl and heteroaryl rings in R5possibly substituted, halogeno, C is ANO, nitro, hydroxy, C1-4the alkyl, C1-4alkoxy, a group S(O)kC1-4alkyl, S(O)2NR8R9NHS(O)2(C1-4alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)NH2C(O)NH2With(O)NH(C1-4alkyl), NHC(O)(C1-4alkyl), CO2N, CO2(C1-4alkyl), C(O)(C1-4alkyl), CF3, CHF2CH2F, CH2CF3or OCF3; R8and R9independently represent hydrogen or C1-4alkyl, or together with the nitrogen atom or oxygen can be connected with the formation of 5 - or 6-membered ring which may be substituted With1-4the alkyl, C(O)H or C(O)(C1-4alkyl); k and n are independently 0, 1 or 2; R6represents a C1-6alkyl [substituted by phenyl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)} or heteroaryl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)}], C3-7cycloalkyl, phenyl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)} or heteroaryl {POS is but substituted halogeno, With1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)}; R7represents hydrogen, C1-6-alkyl [substituted by phenyl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)} or heteroaryl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)}], C3-7cycloalkyl, phenyl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)} or heteroaryl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3With1-4alkylthio, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)} or its pharmaceutically acceptable salt or MES, provided that when R1is hydrogen or unsubstituted alkyl, R4is hydrogen, stands or ethyl, L represents CH and M is represented by N, then the phenyl or heteroaryl part in R5substituted one of the following: S(O)kWith1-4alkyl, NHC(O)NH2With(O)(C1-4Ala is l), CHF2CH2F, CH2CF3or OCF3and it is also possible optionally substituted by one or more than one of the following: halogen, cyano, nitro, hydroxy, C1-4alkyl, C1-4alkoxy, S(O)k(C1-4alkyl), S(O)2NR8R9NHS(O)2(C1-4alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)NH2C(O)NH2With(O)NH(C1-4alkyl), NHC(O)(C1-4alkyl), CO2N, CO2(C1-4alkyl), C(O)(C1-4alkyl), CF3, CHF2CH2F, CH2CF3or OCF3.

In another aspect of the present invention proposed a connection according to this invention, in which L and M both represent N and R1represents hydrogen, C1-4alkyl or phenyl (where the phenyl is substituted by 0, 1 or 2 substituents selected from a list containing the fluorescent, chloro,1-4alkyl, C1-4alkoxy, cyano, CF3, OCF3, (C1-4alkyl)C(O)NH and S(O)2NH2); in addition, phenyl or heteroaryl group, R5has Deputy S(O)2(C1-4alkyl), and possibly one or more than one additional Deputy.

In an additional aspect of this invention, heteroaryl is pyrrolyl, thienyl, imidazolyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or chinoline.

In another aspect, M is ecstasy a N and L represents CH or N.

In yet one other aspect of L and M both represent n

In an additional aspect, L represents CH and M is an n

In yet another additional aspect, L is a N and M represents SN.

In another aspect of the invention R1represents hydrogen, C1-6alkyl [substituted by phenyl {which itself is possibly substituted, halogeno}], S(O)2R6, S(O)2Other7C(O)R7With(O)2(C1-6alkyl), or C(O)other7 ,and when M represents SN, R1may also be an NHS(O)2R6NHS(O)2Other7, NHC(O)R7or NHC(O)other7; R6represents a C1-6alkyl [substituted by phenyl {which itself is possibly substituted, halogeno}], C3-7cycloalkyl, phenyl {could be replaced by halogeno} and R7represents hydrogen, C1-6alkyl [substituted by phenyl {which itself is possibly substituted, halogeno}], C3-7cycloalkyl, phenyl {could be replaced by halogeno}.

In another aspect of the invention R1represents a C1-6alkyl [substituted by phenyl {which itself is possibly substituted, halogeno}], S(O)2R6, S(O)2Other7C(O)R7With(O)2(C1-6alkyl), or C(O)other7and when M represents SN, R1can also be an NHS(O)2R6NHS(O)2 Other7, NHC(O)R7or NHC(O)other7; R6represents a C1-6alkyl [substituted by phenyl {which itself is possibly substituted, halogeno}], C3-7cycloalkyl, phenyl {could be replaced by halogeno} and R7represents hydrogen, C1-6alkyl [substituted by phenyl {which itself is possibly substituted, halogeno}], C3-7cycloalkyl, phenyl possibly substituted, halogeno}.

In an additional aspect of the invention R1represents S(O)2R6C(O)R7With(O)2(C1-6alkyl), or C(O)other7and when M represents SN, R1may also be an NHS(O)2R6or NHC(O)R7; R6and R7such as defined above.

In another aspect of the invention R1represents hydrogen, C1-6alkyl [substituted by phenyl {which itself is possibly substituted, halogeno}], S(O)2R6C(O)R7With(O)2(C1-6alkyl), or C(O)other7and when M represents SN, R1may also be an NHS(O)2R6or NHC(O)R7; R6represents a C1-6alkyl [substituted by phenyl {which itself is possibly substituted, halogeno}], C3-7cycloalkyl, phenyl {could be replaced by halogeno} and R7represents hydrogen, C1-6alkyl [substituted by phenyl {which itself is in Sogno replaced halogeno}], With3-7cycloalkyl, phenyl {could be replaced by halogeno}.

In an additional aspect, R1represents phenyl (possibly substituted, halogen (e.g., fluorescent)1-4the alkyl (e.g., stands), C1-4alkoxy (e.g. methoxy), CF3or OCF3), S(O)2(C1-4alkyl) (for example S(O)2CH3, S(O)2CH2CH3or S(O)2CH(CH3)2), S(O)2(C1-4foralkyl) (for example S(O)2CF3or S(O)2CH2CF3), S(O)2phenyl (possibly substituted (for example monosubstituted) halogen (e.g., chloro), cyano, C1-4the alkyl, C1-4alkoxy, CF3, OCF3, S(O)2(C1-4alkyl) (for example S(O)2CH3or S(O)2CH2CH2CH3) or S(O)2(C1-4foralkyl) (for example S(O)2CH2CF3)), benzyl (possibly substituted, halogen (e.g., chloro or fluorescent)1-4the alkyl, C1-4alkoxy (e.g. methoxy), CF3or OCF3), benzoyl (possibly substituted, halogen (e.g., chloro or fluorescent)1-4the alkyl (e.g., stands), With1-4alkoxy, CF3or OCF3), C(O)NH (possibly substituted, halogen (e.g., fluorescent), C1-4the alkyl, C1-4alkoxy, CF3or OCF3), S(O)2thiophenyl, CH2pyridinyl, CH2chinoline or CH2tiaso the mud.

In yet another aspect, R1represents phenyl (possibly substituted (for example, monosubstituted) halogen (e.g., fluorescent), C1-4the alkyl (e.g., stands) or (C1-4alkoxy (e.g. methoxy)), S(O)2(C1-4alkyl) (for example S(O)2CH3, S(O)2CH2CH3or S(O)2CH(CH3)2), S(O)2(C1-4foralkyl) (for example S(O)2CF3or S(O)2CH2CF3), S(O)2phenyl (possibly substituted (for example, monosubstituted) halogen (e.g., chloro), cyano, CF3, OCF3, S(O)2(C1-4alkyl) (for example S(O)2CH3or S(O)2CH2CH2CH3) or S(O)2(C1-4foralkyl) (for example S(O)2CH2CF3)), benzyl (possibly substituted, halogen (e.g., chloro or fluorescent) or (C1-4alkoxy (e.g. methoxy)), benzoyl (possibly substituted, halogen (e.g., chloro or fluorescent) or (C1-4the alkyl (e.g., stands)), C(O)NH (possibly substituted, halogen (e.g., fluorescent)), S(O)2thiophenyl, CH2pyridinyl, CH2chinoline or CH2thiazolyl.

In an additional aspect, R1represents phenyl (possibly substituted (for example, monosubstituted) halogen (e.g., fluorescent) or C1-4the alkyl (e.g., stands)), S(O)2(C1-4alkyl) (for example S(O)2 CH3, S(O)2CH2CH3or S(O)2CH(CH3)2), S(O)2(C1-4foralkyl) (for example S(O)2CF3or S(O)2CH2CF3), S(O)2phenyl (possibly substituted (for example, monosubstituted) CF3, OCF3or S(O)2(C1-4alkyl) (for example S(O)2CH3)), benzyl (possibly substituted, halogen (e.g., chloro or fluorescent) or (C1-4alkoxy (e.g. methoxy)), benzoyl (possibly substituted, halogen (e.g., chloro or fluorescent)), C(O)NH (possibly substituted, halogen (e.g., fluorescent)), CH2pyridinyl, CH2chinoline or CH2thiazolyl.

In yet another additional aspect, R1represents hydrogen, C1-6alkyl [substituted by phenyl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, OCF3, (C1-4alkyl)C(O)NH, S(O)2NH2or S(O)2(C1-4alkyl)} or heteroaryl {which itself is possibly substituted, halogeno,1-4the alkyl or (C1-4alkyl)C(O)NH}], phenyl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, OCF3, (C1-4alkyl)C(O)NH, S(O)2NH2or S(O)2(C1-4alkyl)}, heteroaryl {could be replaced by halogeno,1-4the alkyl or (C1-4alkyl)C(O)NH}, S(O)2R6, S(O)2 NR10R11C(O)R7or C(O)other7and when M represents SN, R1can also represent NHC(O)R7; R6represents a C1-6alkyl [substituted by halogen (e.g., fluorescent), phenyl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, OCF3, (C1-4alkyl)C(O)NH, S(O)2NH2or S(O)2(C1-4alkyl)} or heteroaryl {which itself is possibly substituted, halogeno,1-4the alkyl or (C1-4alkyl)C(O)NH}], phenyl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, OCF3, (C1-4alkyl)C(O)NH, S(O)2NH2or S(O)2(C1-4alkyl)} or heteroaryl {could be replaced by halogeno,1-4the alkyl or (C1-4alkyl)C(O)NH}; R7represents hydrogen, C1-6alkyl [substituted by halogen (e.g., fluorescent)1-4alkoxy, phenyl {which itself is possibly substituted, halogeno,1-4the alkyl, C1-4alkoxy, cyano, nitro, CF3, OCF3, (C1-4alkyl)C(O)NH, S(O)2NH2or S(O)2(C1-4alkyl)} or heteroaryl {which itself is possibly substituted, halogeno,1-4the alkyl or (C1-4alkyl)C(O)NH}], C3-7cycloalkyl, pyranyl, phenyl {could be replaced by halogeno,1-4the alkyl, C1-4alkoxy, cyano, NIT is about, CF3, OCF3, (C1-4alkyl)C(O)NH, S(O)2NH2or S(O)2(C1-4alkyl)} or heteroaryl {could be replaced by halogeno,1-4the alkyl or C1-4alkyl)C(O)NH} and R10and R11independently represent hydrogen or C1-4alkyl.

In an additional aspect, R1represents phenyl (possibly substituted (for example, monosubstituted) halogen (e.g., fluorescent) or C1-4the alkyl (e.g., stands)), S(O)2(C1-4alkyl) (for example S(O)2CH3or S(O)2CH2CH3), S(O)2(C1-4foralkyl) (for example S(O)2CF3), S(O)2phenyl (possibly substituted (for example, monosubstituted) CF3or OCF3), benzyl, benzoyl (possibly substituted, halogen (e.g., chloro or fluorescent)or S(O)NH (possibly substituted, halogen (e.g., fluorescent)).

In another aspect of the invention R2represents phenyl or heteroaryl, each of which may substituted in ortho - or meta-position halogeno,1-4the alkyl, C1-4alkoxy, S(O)n(C1-4alkyl), nitro, cyano or CF3while n is 0, 1 or 2, such as 0 or 2. (ortho - and meta-Positions are specified as ortho - and meta - position of attaching the ring to the structure of formula (I).)

In yet another aspect, R2represents a possibly substituted FeNi is (for example, possibly substituted, halogeno (such as chloro or fluorescent), cyano, stands, ethyl, methoxy, ethoxy or CF3). In one aspect, the substitution takes place at the ortho - or meta-position of the phenyl ring.

In another aspect, R2represents a possibly substituted phenyl (such as, possibly substituted, halogen or CF3). For example, R2is a 3-forfinal, 3-chlorophenyl, 4-forfinal or 4-CF3is phenyl. In an additional aspect, R2represents phenyl, 3-forfinal, 4-forfinal, 3-chlorophenyl, 3,4-differenl or 3.5 differenl. In another aspect, R2represents phenyl, 3-forfinal, 4-forfinal, 3,4-differenl or 3.5 differenl. In yet another additional aspect of the invention R2represents phenyl or 3-forfinal.

In another aspect of the invention R3represents hydrogen or methyl. In an additional aspect of the invention, when R3represents a C1-4alkyl (e.g. methyl), a carbon atom that is attached to R3has absolute R-configuration. In another aspect of the invention R3represents hydrogen.

In an additional aspect of the invention R4is ethyl.

In yet another additional aspect of the present invention proposed a connection according to the invention, where R5represents phenyl(C1- alkyl), phenyl(C1-2alkyl)NH, phenyl, heteroaryl or heteroaryl(C1-2alkyl, where the phenyl and heteroaryl ring possibly substituted, halogen, cyano, nitro, hydroxy, C1-4the alkyl, C1-4alkoxy, S(O)kC1-4alkyl, S(O)2NR8R9NHS(O)2(C1-4alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2NHC(O)NH2C(O)NH2With(O)NH(C1-4alkyl), NHC(O)(C1-4alkyl), CO2N, CO2(C1-4alkyl), C(O)(C1-4alkyl), CF3, CHF2CH2F, CH2CF3or OCF3; R8and R9independently represent hydrogen or C1-4alkyl, or together with the nitrogen atom or oxygen can be connected with the formation of 5 - or 6-membered ring which may be substituted With1-4the alkyl, C(O)H or C(O)(C1-4alkyl), and k is 0, 1 or 2 (e.g. 2).

In another aspect of the invention proposed connection according to the invention, where R5represents phenyl(C1-2alkyl) or phenyl(C1-2alkyl)NH, with the phenyl ring in R5possibly substituted, halogen, cyano, nitro, hydroxy, C1-4the alkyl, C1-4alkoxy, S(O)kWith1-4alkyl, S(O)2NR8R9NHS(O)2(C1-4alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)NH2C(O)NH2With(O)NH(C1-4alkyl), NHC(O)(C1-4alkyl), CO2N, CO2 (C1-4alkyl), C(O)(C1-4alkyl), CF3, CHF2CH2F, CH2CF3or OCF3; R8and R9independently represent hydrogen or C1-4alkyl, or together with the nitrogen atom or oxygen can be connected with the formation of 5 - or 6-membered ring which may be substituted C1-4the alkyl, C(O)H or C(O)(C1-4alkyl), and k is 0, 1 or 2.

In yet another additional aspect of the invention R5represents phenyl, heteroaryl, phenyl(C1-2alkyl) or heteroaryl(C1-2alkyl), phenyl and heteroaryl ring possibly substituted, halogen, cyano, nitro, hydroxy, C1-4the alkyl, C1-4alkoxy, S(O)kWith1-4alkyl, S(O)2NR8R9NHS(O)2(C1-4alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)NH2C(O)NH2With(O)NH(C1-4alkyl), NHC(O)(C1-4alkyl), CO2N, CO2(C1-4alkyl), C(O)(C1-4alkyl), CF3, CHF2CH2F, CH2CF3or OCF3; k is 0, 1 or 2 and R8and R9independently represent hydrogen or C1-4alkyl, or together with the nitrogen atom or oxygen can be connected with the formation of 5 - or 6-membered ring which may be substituted With1-4the alkyl, C(O)H or C(O)(C1-4alkyl).

In another aspect, R5represents phenyl or benzyl,where the aromatic ring, possibly substituted, halogen, cyano, nitro, hydroxy, C1-4the alkyl, C1-4alkoxy, S(O)kWith1-4alkyl, S(O)2NR8R9NHS(O)2(C1-4alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)NH2C(O)NH2With(O)NH(C1-4alkyl), NHC(O)(C1-4alkyl), CO2N, CO2(C1-4alkyl), C(O)(C1-4alkyl), CF3, CHF2CH2F, CH2CF3or OCF3; k is 0, 1 or 2 and R8and R9independently represent hydrogen or C1-4alkyl, or together with the nitrogen atom or oxygen can be connected with the formation of 5 - or 6-membered ring which may be substituted With1-4the alkyl, C(O)H or C(O)(C1-4alkyl).

In an additional aspect, R5represents phenyl or benzyl, with an aromatic ring, possibly substituted, halogen, cyano, nitro, hydroxy, C1-4the alkyl, C1-4alkoxy, S(O)2With1-4alkyl, S(O)2NR8R9NHS(O)2(C1-4alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)NH2C(O)NH2C(O)NH(C1-4alkyl), NHC(O)(C1-4alkyl), CO2N, CO2(C1-4alkyl), C(O)(C1-4alkyl), CF3and R8and R9independently represent hydrogen or C1-4alkyl.

In another aspect, R5represents NHCH2phenyl, where the phenyl ring may substituted, halogeno, C is ANO, nitro, hydroxy, C1-4the alkyl, C1-4alkoxy, S(O)2With1-4alkyl, S(O)2NR8R9NHS(O)2(C1-4alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)NH2C(O)NH2With(O)NH(C1-4alkyl), NHC(O)(C1-4alkyl), CO2N, CO2(C1-4alkyl), C(O)(C1-4alkyl), CF3and R8and R9independently represent hydrogen or C1-4alkyl.

In yet another aspect, R5represents benzyl, where the phenyl ring may substituted, halogen, cyano, nitro, hydroxy, C1-4the alkyl, C1-4alkoxy, S(O)2With1-4alkyl, S(O)2NR8R9NHS(O)2(C1-4alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)NH2C(O)NH2With(O)NH(C1-4alkyl), NHC(O)(C1-4alkyl), CO2N, CO2(C1-4alkyl), C(O)(C1-4alkyl), CF3and R8and R9independently represent hydrogen or C1-4alkyl.

In another aspect, R5represents NHCH2phenyl, where the aromatic ring, possibly substituted, halogen (e.g., fluorescent, chloro or bromo), cyano, C1-4the alkyl (e.g., stands), With1-4alkoxy (e.g. methoxy) or S(O)2With1-4alkyl (for example, S(O)2CH3).

In yet another aspect, R5represents benzyl, where aromatizes the ring possibly substituted, halogeno (for example, with fluorescent, chloro or bromo), cyano, C1-4the alkyl (e.g., stands), With1-4alkoxy (e.g. methoxy) or S(O)2With1-4alkyl (for example, S(O)2CH3).

In yet another additional aspect, R5represents phenyl or benzyl, where the aromatic ring may substituted (for example, para-position) group S(O)2With1-4alkyl and the ring may be additionally substituted, halogen, cyano, nitro, hydroxy, C1-4the alkyl or C1-4alkoxy.

In another aspect, R5represents NHCH2phenyl or benzyl, where the aromatic ring is substituted (for example, para-position) group S(O)2With1-4alkyl (for example, S(O)2CH3and this ring may be additionally substituted, halogen, cyano, nitro, hydroxy, C1-4the alkyl or C1-4alkoxy.

In another aspect, R5represents NHCH2phenyl, where the aromatic ring is substituted (for example, para-position) group S(O)2With1-4alkyl (for example, S(O)2CH3), R5represents, for example, NHCH2(4-S(O)2CH3-C6H4).

In another aspect, R5represents benzyl, where the aromatic ring is substituted (for example, para-position) group S(O)2With1-4alkyl (for example, S(O)2CH3), R5represents for example, CH2(4-S(O)2CH3-C6H4).

The carbon atom marked with iconthe image of the formula (I)below, is always chiral.

When L represents N, indicated by ^, the carbon atom has, for example, the absolute S-configuration. When L represents CH, indicated by ^, the carbon atom has, for example, the absolute R-configuration.

In another aspect of the present invention proposed a compound of formula (Ia)

where L, M and R1such as defined above.

In an additional aspect of the present invention proposed a compound of formula (Ib)

where L, M and R1such as defined above, R represents hydrogen, one or two fluorine atom, S(O)n(C1-4alkyl) or (C1-4alkoxy and n is 0, 1 or 2 (e.g. 2).

In another aspect of the present invention proposed a compound of formula (Ic)

where L, M and R1such as defined above, R represents hydrogen, one or two fluorine atom, S(O)n(C1-4alkyl) or (C1-4alkoxy and n is 0, 1 or 2 (e.g. 2).

In yet another additional aspect of the present invention proposed a compound of formula (Id)/p>

where L, M and R1such as defined above; R represents hydrogen, one or two fluorine atom, S(O)n(C1-4alkyl) or (C1-4alkoxy; X represents NHCH2, NH or CH2; n is 0, 1 or 2 (e.g. 2) and R* represents halogen (e.g., fluorescent, chloro or bromo), cyano, C1-4alkyl (e.g. methyl), C1-4alkoxy (e.g. methoxy) or S(O)2With1-4alkyl (for example, S(O)2CH3).

In another aspect of the present invention proposed a compound of formula (Ie)

where L, M and R such as defined above.

In still another aspect of the present invention proposed a compound of formula (If)

where L, M, X and R1such as defined above.

In yet another additional aspect of the present invention proposed a compound of formula (Ig)

where R5such as defined above.

The compounds listed in Tables I-VI, illustrate the invention.

In another aspect of the invention proposed each individual link presented above in tables.

The compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) and (Ig) can be obtained as shown below (for example, in Schemes 2 and 3, while figure 1 shows the production of intermediate compounds). In Schemes 1-3 PG denotes a protective group; AC is acetyl; the First is tert-butoxycarbonyl; Bn is benzyl; Bz is benzoyl; DIBAL is diisobutylaluminum hydride; Et is ethyl; Ms is mesilim; TFA is triperoxonane acid.

The connection according to the invention, where L represents N, can be obtained by reacting the compounds of formula (II)

where R2, R3, R4and R5such as defined above, with a compound of formula (III)

where R1such as defined above, in the presence of sodium iodide and a suitable base (for example, three(C1-6alkyl)amine, such as triethylamine or base Chunga) in a suitable solvent (such as chlorinated solvents is ü, for example dichloromethane) and, for example, at room temperature (for example 10-30°).

The connection according to the invention, where L represents CH may be obtained by reacting the compounds of formula (IV)

where R2, R3, R4and R5such as defined above, with the following, depending on which connection according to the invention, it is desirable to obtain:

a) with an acid of formula R1CO2H in the presence of a suitable agent combinations (for example, PyBrOP [bromo-Tris-pyrrolidinedithiocarbamate] or HATU) in the presence of a suitable base (such as three(C1-6alkyl)amine, such as diisopropylethylamine) in a suitable solvent (for example, N-methylpyrrolidinone or chlorinated solvent, such as dichloromethane) at room temperature (for example 10-30°);

b) with the acid chloride of the acid of formula R1C(O)Cl or sulphonylchloride formula R1C(O)2Cl in the presence of a suitable base (such as three(C1-6alkyl)amine, such as triethylamine or diisopropylethylamine) in a suitable solvent (for example, chlorinated solvent, such as dichloromethane) at room temperature (for example 10-30°or

C) with the aldehyde of formula R1CHO in the presence of NaBH(SLA)3(where AC represents C(O)CH3)and acetic acid in a suitable solvent (such as C 1-6aliphatic alcohol, for example ethanol) at room temperature (for example 10-30°).

The alternate connection according to the invention can be obtained by combining the compounds of formula (V)

where L, M, R1, R2, R3and R4such as defined above, with:

a) an acid of formula R5CO2H in the presence of a suitable agent combinations (for example, PyBrOP or HATU) in the presence of a suitable base (such as, for example, three(C1-6alkyl)amine, such as diisopropylethylamine) in a suitable solvent (for example, N-methylpyrrolidinone or chlorinated solvent, such as dichloromethane) at room temperature (for example 10-30°or

b) the acid chloride of the acid of formula R5C(O)Cl in the presence of a suitable base (such as three(C1-6alkyl)amine, such as triethylamine or diisopropylethylamine) in a suitable solvent (for example, chlorinated solvent, such as dichloromethane) at room temperature (for example 10-30°).

The source materials for these methods or are commercially available or can be obtained by methods described in the literature, or adapting methods described in the literature, or following Ways here or adaptation of Methods described here.

In an additional aspect of this is bretania proposed intermediate compound of formula (V).

In yet another additional aspect of the present invention the methods of obtaining compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) and (Ig). Many intermediate compounds in these methods are new, and they are proposed as additional objects of the present invention.

Compounds according to the invention have activity as pharmaceuticals, in particular as modulators (such as agonists, partial agonists, inverse agonists or antagonists) activity of receptors chemokines (in particular, CCR5), and can be used in the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically mediated diseases including acquired immunodeficiency syndrome (AIDS)).

Compounds of the present invention is also valuable in the inhibition of viral penetration (as, for example, human immunodeficiency virus (HIV)in target cells and, therefore, valuable in the prevention of infection by viruses (e.g. HIV)infection treatment of viruses (e.g. HIV) and in the prevention and/or treatment of acquired immunodeficiency syndrome (AIDS).

According to another aspect of the invention proposed compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) (for example, (I) or (Ia)or its pharmaceutically acceptable salt or MES for use in the method l the treatment of warm-blooded animal (for example, man) by therapy (including prophylaxis).

According to another aspect of the present invention, a method of modulating the activity of chemokine receptors (in particular, the activity of the receptor CCR5) in a warm-blooded animal, such as man, in need of such treatment, which indicated the animal is administered an effective amount of the compounds of the present invention or its pharmaceutically acceptable salt or MES.

According to the present invention also proposed the use of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) (for example, (I) or (Ia)or its pharmaceutically acceptable salt or MES as drugs, in particular drugs for the treatment of transplant rejection, respiratory disease, psoriasis or rheumatoid arthritis (especially rheumatoid arthritis). [Respiratory disease is, for example, chronic obstructive pulmonary disease (COPD), asthma {such as bronchial, allergic, hereditary, acquired asthma and pneumoconiosis, particularly chronic or inveterate asthma (for example late asthma or increased airway reactivity)} or rhinitis {acute, allergic, atrophic rhinitis or chronic rhinitis including caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, dry rhinitis or medicamen the religious rhinitis; membranous rhinitis including croupous, fibrinous or pseudobinary rhinitis, or scrupulously rhinitis; seasonal rhinitis including nervous rhinitis (hay fever) or vasomotor rhinitis}; and, in particular, asthma or rhinitis].

According to another aspect of the present invention proposed the use of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) (for example, (I) or (Ia)or its pharmaceutically acceptable salt or MES in the production of drugs for use in therapy (for example modulating the activity of chemokine receptors (in particular, the activity of the receptor CCR5 (particularly rheumatoid arthritis)) in a warm-blooded animal, such as man).

According to this invention proposed the connection of the formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) (for example, (I) or (Ia)or its pharmaceutically acceptable salt or MES for use as drugs, in particular drugs for the treatment of rheumatoid arthritis.

In another aspect of the present invention proposed the use of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) (for example, (I) or (Ia)or its pharmaceutically acceptable salt or MES in the production of drugs for use in therapy (for example modulating the activity of receptors chemokines (in particular, the activity of the receptor CCR5 (especially rheumatoid arthritis)) talklounge animal, for example a person).

According to the proposed invention is also the use of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) (for example, (I) or (Ia)or its pharmaceutically acceptable salts in the manufacture of medicaments for use in the treatment of:

(1) (the respiratory tract) obstructive respiratory diseases, including chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as, for example, bronchial, allergic, hereditary, acquired asthma and pneumoconiosis, particularly chronic or inveterate asthma (e.g. late onset asthma or increased airway reactivity)}; bronchitis {as, for example, eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, dry rhinitis or rhinitis medication; membranous rhinitis including croupous, fibrinous or pseudobinary rhinitis, or scrupulously rhinitis; seasonal rhinitis including nervous rhinitis (hay fever) or vasomotor rhinitis; sarcoidosis; exogenous allergic alveolitis and related diseases; nasal polyposis; pneumosclerosis or idiopathic interstitial pneumonia;

(2) (bone and joints) arthritis, including rheumatoid, infectious, autoimmune, seronegative spondyl the arthropathies (such as ankylosing spondylitis, psoriatic arthritis or disease Reiter), Behcet's disease, Sjogren syndrome or systemic sclerosis;

(3) (eye and skin) psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatitis, seborrheic eczema, flat shingles, bladderworts, bullous bladderworts, congenital bullous of bullosa, urticaria, inflammation of the skin vessels, vasculitis, eritem, skin eosinophilia, uveitis, alopecia areata or vernal conjunctivitis;

(4) (gastrointestinal tract) diseases of the abdominal cavity, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel syndrome or food allergies that give remote from intestinal effects (e.g., migraine, rhinitis or eczema);

(5) (allograft rejection) acute and chronic transplant rejection, for example, after transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea or chronic disease graft-versus-host and/or

(6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus disorders (such as lupus erythematosus or systemic lupus erythematosus), eritematoso, thyroiditis Hashimoto, severe myasthenia gravis, diabetes type I, nefret the ical syndrome, eosinophilic fasciitis syndrome elevated IgE, leprosy (such as lepromatous leprosy), periodontal disease, syndrome Cesari, idiopathic thrombocytopenic purpura or disorders of the menstrual cycle

warm-blooded animal such as man.

Further, in the present invention, a method of treatment mediated by chemokines painful conditions (in particular, mediated CCR5 painful condition) in a warm-blooded animal, such as man, in which the mammal in need of such treatment is administered an effective amount of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) (for example, (I) or (Ia)or its pharmaceutically acceptable salt or MES.

To apply the compound according to the invention, or its pharmaceutically acceptable salt, or MES for therapeutic treatment of warm-blooded animal, such as man, in particular for modulating the activity of receptors chemokines (for example, the CCR5 receptor), this ingredient is usually prepared as part of the preparation of a pharmaceutical composition according to standard pharmaceutical practice.

Therefore, in another aspect of the present invention proposed a pharmaceutical composition which contains a compound of the formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) (for example, (I) or (Ia)or its pharmaceutical preparations is automatic acceptable salt or MES (active ingredient) and a pharmaceutically acceptable adjuvant, the diluent or carrier. In another aspect of the present invention, a method for preparation of specified composition in which the active ingredient is mixed with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on how the introduction of this pharmaceutical composition preferably contains from 0.05 to 99 wt.% (mass%), more preferably from 0.05 to 80 wt.%, even more preferably from 0.10 to 70 wt.% and even more preferably from 0.10 to 50 wt.%, the active ingredient, where the weight percents are calculated on the total weight of the composition.

The pharmaceutical compositions according to this invention it is possible to enter a standard manner for the disease condition that it is desirable to treat, for example, by local (as, for example, in the lung and/or Airways or to the skin), oral, rectal or parenteral administration. For these purposes, the preparations of the compounds of this invention can be prepared by methods known in the art, in the form of, for example, aerosols, dry powder, tablets, capsules, syrups, powders, granules, aqueous or oil solutions or suspensions (liquid), emulsions, sprayable powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.

Approach the of the present pharmaceutical composition according to this invention is a composition suitable for oral administration in the form of standard dosage forms, for example tablets or capsules, containing the active ingredient in an amount of from 0.1 mg to 1 g

In another aspect the pharmaceutical composition according to the invention is a composition suitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, intravenous, subcutaneous or intramuscular dose of the compounds in the range from 0.01 to 100 mg·kg-1, preferably in the range from 0.1 to 20 mg·kg-1compounds according to this invention, and this composition is administered 1 to 4 times per day. Intravenous, subcutaneous and intramuscular dose can be administered by bolus injection. Alternative intravenous dose can be administered by continuous infusion over a period of time. Or, each patient can receive a daily oral dose, which is approximately equivalent to the daily parenteral dose, and such a composition is administered 1 to 4 times per day.

The following examples illustrate typical pharmaceutical dosage forms containing the compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) (for example, (I) or (Ia)or its pharmaceutically acceptable salt or MES (hereinafter referred to as Compound X), for therapeutic or prophylactic use in humans:

To prepare the drug can be used buffers, pharmaceutically acceptable co-solvents, such as glycol, polypropyleneglycol, glycerol or ethanol, or complexing agents, such as hydroxypropyl-β-cyclodextrin.

The above preparations can be prepared using conventional techniques well known in the pharmaceutical field. The tablets (a)-(C) can be coated enteric-soluble shell of conventional ways, such as applying a coating of acatitla pulp.

Further, the invention is illustrated in the following non-limiting examples in which, unless stated otherwise:

(1) temperatures are given in degrees Celsius (°C); operations were carried out at room temperature or at ambient temperature, i.e. at temperatures in the range of 18-25°C;

(2) organic solutions were dried over anhydrous magnesium sulfate; evaporation of solvent was performed using a rotary evaporator under reduced pressure (600-4000 PA; a 4.5-30 mm RT. Art.) with a bath temperature of up to 60°C;

(3) under chromatography, unless otherwise specified, refers to flash chromatography on silica gel; thin layer chromatography (TLC) was performed on plates with silica gel; where there is a link to the column "Bond Elut", this means a column containing 10 g or 20 g of silica compound is El with a particle size of 40 microns, where silica gel is placed in a 60 ml disposable syringe and supported by a porous disc, obtained from Varian, Harbor City, California, USA, under the name of "Honey Bond Elut SI". Where is the link to "column Isolute™ SCX", this means a column containing benzosulfimide acid (without cover on the end) from International Sorbent Technology Ltd., 1stHouse, Duffryn Industrial Estate, Ystrad Mynach, Hengoed, Mid Glamorgan, UK. Where is the link to "ArgonautTMPS-Tris-amine acceptor resin"means Tris-(2-amino-ethyl)amine-polystyrene resin from Argonaut Technologies Inc., 887 Industrial Road, Suite G, San Carlos, California, USA;

(4) as a rule, the course of reactions was followed by TLC, and the reaction times are given for illustration only;

(5) the values of the outputs, if they are given, are given for illustration only and do not necessarily will be as careful development process; obtaining repeated, if necessary, an additional amount of the substance;

(6) if the given data1H-NMR, and they are presented in the form of Delta values for major diagnostic protons, given in ppm (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz using predeterminado DMSO (CD3SOCD3) as solvent unless otherwise indicated; constants vzaimodeistvie (J) are given in Hz;

(7) chemical symbols have their usual mn of the treatment; used units and symbols of SI units;

(8) the ratio of solvents is given in volume percent;

(9) mass spectra (MS) were obtained at an electron energy of 70 electron volts in the way chemical ionization (APCI)using probe direct exposure, where indicated ionization was carried out by electrocapillary (ES); if given the values of m/z, as a rule, are only ions which indicate the source mass, and, unless otherwise specified mass ion is the positive mass ion - (M+N)+;

(10) IHMS-characterization was performed using a pair of pumps Gilson 306 with dispenser Gilson 233 XL and mass spectrometer Waters ZMD4000. In liquid chromatography (LC) used a balanced water column 4,6×50 C18 with a particle size of 5 microns. Eluent consisted of the following: A : water with 0.05% of formic acid In acetonitrile with 0.05% of formic acid. The gradient of eluent ranged from 95% a to 95% b for 6 minutes. Where indicated ionization was carried out by electrocapillary (ES); where values for m/z, as a rule, are only ions which indicate the source mass, and, unless otherwise specified mass ion is the positive mass ion - (M+N)+and

(11) used the following abbreviations:

DMF
DMSOdimethyl sulfoxide;
N-dimethylformamide;
DCMdichloromethane;
THFtetrahydrofuran;
DIPEAN,N-diisopropylethylamine;
NMPN-methylpyrrolidinone;
HATUO-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaphosphate;
HBTUO-(7-benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexaphosphate;
The firsttert-butoxycarbonyl;
Meonmethanol;
EtOHethanol and
EtOActhe ethyl zett.

EXAMPLE 1

This example illustrates the obtaining N-[1-(3-phenyl-3-[4-methylpiperazin-1-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Compound No. 6 of Table I).

To a solution of 1-methylpiperazine (42 μl; 0.38 mmol) in DCM (10 ml) was added triethylamine (0.1 ml; to 0.72 mmol), then N-[1-(3-phenyl-3-chloropropyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Method A; 180 mg, 0.38 mmol) and sodium iodide (50 mg). The resulting mixture was stirred at room temperature for 48 h, then washed with water and brine, dried (MgSO4) and was evaporated. The residue was purified by elution through a 20 g BondElut 10%methanol in ethyl acetate, then methanol, then 1%of treat what is designed in methanol to obtain specified in the title compound (58 mg). NMR: 1.2 (t, 1H), 1.3 (t, 2H), 1.4 (m, 1H), 1.6 (m, 2H), 1.8 (m, 4H), 1.9 (m, 2H), 2.1 (m, 2H), 2.2 (s, 3H), 2.4 (m, 8H), 2.9 (m, 2H), 3.0 (s, 3H), 3.3 (m, 2H), 3.8 (s, 2H), 7.2 (m, 2H), 7.4 (m, 2H), 7.9 (d, 2H). MC:541.

The procedure described in Example 1 can be repeated using a variety of secondary amines (such as 4-formylpiperazine, 4-isobutylpyrazine or 4-benzylpiperidine) instead of 1-methylpiperazine.

EXAMPLE 2

This example illustrates the obtaining N-[1-(3-phenyl-3-[piperidine-4-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Compound No. 17 of Table I).

N-[1-(3-Phenyl-3-[1-tert-butylcarbamoyl-4-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Example 3, 4 g) was dissolved in triperoxonane acid (25 ml) and the resulting mixture was stirred at room temperature for 2 hours the Mixture was evaporated and the residue azeotropic drove with toluene. The resulting material was stirred with 2 M aqueous sodium hydroxide (25 ml) and the resulting mixture was extracted with DCM (8×25 ml). The combined extracts were dried and evaporated to obtain specified in the title compound (2.5 g). MS (mass spectrometry): 526.

EXAMPLE 3

This example illustrates the obtaining N-[1-(3-phenyl-3-[1-tert-butylcarbamoyl-4-yl]propyl)-piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Compound No. 23 of Table I).

To a solution of 3-phenyl-3-(1-tert-butylcarbamoyl-4-yl)Propionaldehyde Way; 14.4 mmol) in DCM (100 ml) was added N-(4-piperidinyl)-N-ethyl-4-methanesulfonylaminoethyl (the Way In; 4.6 g, 14.4 mmol) and the resulting mixture was stirred at room temperature for 30 minutes was Added triacetoxyborohydride sodium (3,05 g; 14.4 mmol) and the resulting mixture was stirred at room temperature for 2 hours, the Reaction mixture was washed with 2 M aqueous sodium hydroxide (3×25 ml), dried and suirable through a SCX cartridge (50 g) using DCM (3×25 ml), ethyl acetate (4×25 ml), methanol (4×25 ml) and then 1 M ammonia in methanol (4×50 ml) to give the crude product, which was purified by chromatography on silica gel (eluent: ethyl acetate, then 10%methanol in ethyl acetate) to obtain specified in the connection header (4,2 g). MS:626.

EXAMPLE 4

This example illustrates the obtaining N-[1-(3-phenyl-3-[1-methylpiperidin-4-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Compound No. 26 of Table I).

To a mixture of N-[1-(3-phenyl-3-[piperidine-4-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Example 2; 250 mg, 4.76 mmol) and formaldehyde (0.2 ml 37%aqueous) in DCM (10 ml) was added triacetoxyborohydride sodium (9,52 mmol) and the resulting mixture was stirred at room temperature for 18 hours the Mixture was washed with 2 M aqueous sodium hydroxide (10 ml) and was suirable through a SCX cartridge (10 g) through the Yu DCM (2× 10 ml), methanol (2×10 ml) and then 1 M ammonia in methanol (4×10 ml), which allowed to obtain the specified title compound (172 mg). MS:540.

The procedure described in Example 4 can be repeated using different aldehydes (such as acetaldehyde and benzaldehyde) instead of formaldehyde.

EXAMPLE 5

This example illustrates the obtaining N-[1-(3-phenyl-3-[1-acetylpiperidine-4-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Compound No. 21 of Table I).

To a mixture of N-[1-(3-phenyl-3-[piperidine-4-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Example 2; 250 mg, 4.76 mmol) and triethylamine (48 mg, 4.76 mmol) in DCM was added acetylchloride (37 mg, 4.76 mmol). The resulting mixture was stirred at room temperature for 18 h, washed with saturated aqueous sodium bicarbonate (10 ml), dried and suirable through a SCX cartridge (10 g) using DCM (2×10 ml), methanol (4×10 ml) and then 1 M ammonia in methanol (4×10 ml), which allowed to obtain the specified title compound (180 mg). MS:568.

The procedure described in Example 5 can be repeated using different acid anhydrides (e.g., acid chloride phenylacetic acid and the acid chloride of 4-chlorbenzoyl acid) or sulphonylchloride (such as methanesulfonamide) instead of the acid chloride of acetic acid.

This example illustrates the obtaining N-[1-(3-phenyl-3-[1-cyclohexanecarbonitrile-4-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Compound No. 22 of Table I).

To a mixture of N-[1-(3-phenyl-3-[piperidine-4-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Example 2; 250 mg, 4.76 mmol) and DCM (10 ml) was added cyclohexylsulfamate (59 mg, 4.6 mmol) and the resulting mixture was stirred at room temperature for 18 hours the Mixture was suirable through a SCX cartridge (10 g) using DCM (4×10 ml), methanol (2×10 ml) and then 1 M ammonia in methanol (4×10 ml), which allowed to obtain the specified title compound (300 mg). MS:651.

EXAMPLE 7

N-[1-(3-Phenyl-3-[4-(2-chlorophenylsulfonyl)piperazine-1-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Compound No. 150, Table I)

2-Chlorophenylsulfonyl (40,1 mg) was added to a solution of N-[1-(3-phenyl-3-[piperazine-1-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (100 mg) and triethylamine (53 μl) in dichloromethane (5 ml) and the mixture was stirred for 1 hour. The reaction mixture was washed with water, with brine and dried. The solvent was removed and the residue was chromatographically on BondElut-column (10 g silica) with elution with a gradient of solvents (ethyl acetate - 20%methanol/ethyl acetate), giving specified in the title compound, yield 90 mg MH+/sup> 701.

N-[1-(3-Phenyl-3-[piperazine-1-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Connection 86 from Table I), used as starting material, was obtained by the method described in Example 2, using the appropriate (1-tert-butyloxycarbonyl)pieperazinove similar.

N-[1-(3-Phenyl-3-[1-tert-butyloxycarbonyl-1-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Compound 152 Table I), used as starting material, was obtained according to the method described in Example 1 using (1-tert-butyloxycarbonyl)piperazine as aminocompounds.

EXAMPLE 8

(R or S) - N-[1-(3-phenyl-3-[(4-{2,2,2-triftormetilfullerenov}propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Compound No. 15 of Table II) Triethylamine (50 μl) was added to a solution of (R or S) - N-[1-(3-phenyl-3-piperazinil}propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonyl-ndimethylacetamide (175 mg) in dichloromethane (5 ml) followed by addition of 2,2,2-triftoruranmetilidina (37 μl) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with water and dried. The residue obtained after solvent removal, was chromatographically on BondElut-column (20 g of silica with elution with a gradient of solvents (ethyl acetate - 40%methanol/ethyl acetate), giving specified in the header is VCE compound as a white foam, yield 79 mg MH+673. NMR (CDCl3): 1.2 (t, 1H), 1.3 (t, 2H), 1.4 (m, 1H), 1.6-1.8 (m, 8H), 2.1 (m, 2H), 2.25 (m, 1H), 2.5 (m, 4H), 2.9 (m, 2H), 3.0 (s, 3H), 3.3 (m, 5H), 3.4 (m, 1H), 3.6 (q, 2H), 3.8 (m, 2H), 7.2 (m, 2H,), 7.3 (m, 3H), 7.4 (m, 2H), 7.9 (d, 2H).

EXAMPLE 9

(R or S) - N-[1-(3-phenyl-3-(BOC-piperazinil)propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl

(R or S) - N-[1-(3-phenyl-3-chloropropyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (594 mg) was added to a solution of triethylamine (0.35 ml) and BOC-piperazine (233 g) in dichloromethane (10 ml) at room temperature and the mixture was stirred for 14 hours. The reaction mixture was added to BondElut-column (20 g) and suirable gradient solvents (ethyl acetate - 40%methanol/ethyl acetate), giving specified in the title compound as a foam, yield 440 mg of MN+627.

(R or S) - N-[1-(3-Phenyl-3-chloropropyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl

Methanesulfonanilide (0.5 ml) was added to a stirred mixture of S is N-[1-(3-phenyl-3-hydroxypropyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (2.7 g) and triethylamine (1,64 ml) in dichloromethane (50 ml) at 0°and the mixture was stirred at ambient temperature for 15 hours. The reaction mixture was washed with water and dried. Removal of solvent gave specified in the title compound as an orange foam, the output of 2.4, MH+477.

(S) N-[1-(3-Phenyl-3-hydroxyprop who yl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl

(S) 1-Phenyl-3-(4-toluensulfonate)propan-1-ol (5 g) was added to a mixture of N-(piperidine-4-yl)-N-ethyl-4-methanesulfonylaminoethyl (5.3g) and potassium carbonate (2,71 g) in DMF (100 ml), the mixture was stirred and heated at 80-90°C for 6 hours. The reaction mixture was left to cool and was evaporated to dryness. The obtained residue was dissolved in dichloromethane (50 ml), washed with water and dried. The solvent was removed and the residue was passed through BondElut-column (90 g silica with elution with a gradient of solvents (ethyl acetate - 20%methanol/ethyl acetate), giving specified in the title compound as a white foam, yield of 2.7, MN+459. NMR (CDCl3): 1.2 (t, 1H), 1.3 (t, 2H), 1.6 (m, 2H), 1.75 (m, 3H), 1.85 (m, 3H), 2.2 (m, 1H), 2.55-2.7 (m, 2H), 3.0 (s, 3H), 3.1-3.2 (m, 2H), 3.3 (q, 2H), 3.8 (m, 2H), 4.9 (m, 1H), 7.3 (m, 5H), 7.45 (d,, 2H), 7.9 (d, 2H).

(S) 1-Phenyl-3-(4-toluensulfonate)propan-1-ol is a known compound (CAS No. 156453-52-0).

EXAMPLE 10

(R or S) - N-[1-(3-phenyl-3-piperidinylmethyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl

Triperoxonane acid (5 ml) was added to a solution of (R or S) - N-[1-(3-phenyl-3-(BOC-piperazinylmethyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (440 mg) in dichloromethane (10 ml) and the mixture was stirred for 1 hour. The reaction mixture was concentrated and the residue was dissolved in 2 M aqueous sodium hydroxide and was extracted twice di is loretana (each time 10 ml). The combined extracts were dried and evaporated, giving specified in the title compound as a foam, yield 370 mg of MN+527.

EXAMPLE 11

(R) - N-[1-(3-Phenyl-3-{1-(4-chlorobenzylidene-4-yl)propyl}piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Compound No. 26 of Table II)

To a mixture of (R) - N-[1-(3-phenyl-3-[piperidine-4-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (330 mg) and MP-resin (carbonate form) (670 mg of material 2.8 mm/g) in dichloromethane (10 ml) was added 4-chlorobenzylchloride (111 mg) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was filtered, the filtrate was added MP-resin (4-toluensulfonate form) (1 g) and was stirred for 30 minutes. The reaction mixture was filtered and the resin washed sequentially with dichloromethane (4×10 ml), 1 M Meon/NH3(3×10 ml). The combined washings were evaporated to dryness and the residue was passed through BondElut-column chromatography with gradient solvents (ethyl acetate - 20%methanol/ethyl acetate), giving specified in the title compound, yield 121 mg NMR (DMSOd6): 0.8-2.2 (m, 6H), 1.2-1.5 (m, 4H), 1.5-2.1 (m, 13H), 2.4 (m, 1H), 2.7 (m, MN), 3.3 (m, 4H), 3.8 (d, 2H), 7-7 .5 (m, 11H), 7.8 (d, 2H). Analytical HPLC on a column Chiralcel OJ (250 mm ×4.6 mm) with elution with methanol showed chiral purity >99%.

(R) - N-[1-(3-Phenyl-3-[piperidine-4-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonyl Itemid (Compound No. 35 of Table II)

A solution of (R) - N-[1-(3-phenyl-3-{1-(benzyloxycarbonylamino-4-yl)propyl}piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (1.5 g) in ethanol (100 ml), containing a catalyst of 20%palladium on coal (200 mg), was first made in hydrogen atmosphere, filled with hydrogen using a balloon. The catalyst was filtered and the filtrate was evaporated to dryness to obtain specified in the title compound, yield 1,1, MS (MN+) 526.

(R) - N-[1-(3-Phenyl-3-{1-(benzyloxycarbonylamino-4-yl)propyl}-piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Compound No. 24 of Table II)

Triacetoxyborohydride sodium (890 mg) was added to a solution of (R) - 3-phenyl-3-(benzyloxycarbonylamino-4-yl)propionic aldehyde (1,49 g) and N-(4-piperidinyl)-N-ethyl-4-methanesulfonylaminoethyl (1.4 g) in dichloromethane (25 ml) and the mixture was stirred for 1 hour. The reaction mixture was washed with 2 M NaOH (2×50 ml) and dried. The solvent was removed and the residue was passed through BondElut-column silica with elution with a gradient of solvents (ethyl acetate - 20%methanol/ethyl acetate), giving specified in the title compound, yield, 1,5 MS (MH+) 660.

(R) 3-Phenyl-3-(benzyloxycarbonylamino-4-yl)propionic aldehyde

Reagent dess-Martin (1,1,1-triacetoxy-1,1-dihydro-1,2-benzodioxol-3(1H)-one) (1.8 g) was added to a solution of (R) 3-FeNi is-3-(benzyloxycarbonylamino-4-yl)propanol in dichloromethane (25 ml) and the mixture was stirred for 1 hour, washed with 2 M NaOH (2×20 ml) and dried. Dichloromethane solution containing specified in the title compound was used directly in the next stage.

(R) 3-Phenyl-3-(benzyloxycarbonylamino-4-yl)propanol

Alumoweld lithium (9,46 ml of 1 M LAH in THF) was added dropwise to a solution of (R) 3-[3-phenyl-3-(benzyloxycarbonylamino-4-yl)propionyl]-(4R,5S)-1,5-dimethyl-4-phenyl-2-imidazolidinone (5,1 g) in THF (100 ml) at such a rate that the temperature did not exceed 0°C. the Reaction mixture was stirred at -5°C for 10 minutes and was added 2 M NaOH (10 ml). The reaction mixture was filtered through celite and the filtrate was evaporated to dryness. The residue was dissolved in dichloromethane (20 ml) and dried. Obtained after removal of solvent the residue was passed through BondElut-column chromatography with gradient solvents (isohexane - 60%ethyl acetate/isohexane)that gave specified in the title compound, yield of 1.6 g MS (MH+) 354.

3-[(R) - 3-Phenyl-3-(benzyloxycarbonylamino-4-yl)propionyl]-(4R,5S)-1,5-dimethyl-4-phenyl-2-imidazolidinone

TMEDA (2.4 g) was added to a suspension of copper iodide (I) (as 4.02 g) in THF (100 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to -78°and added bromide vinylmania (of 11.69 ml of 1 M solution in THF) and the mixture was stirred at -78°C for 30 mi the ut. Triplet dilutive (of 11.69 ml; 1 M solution in diethyl ether) was added to a solution of 3-[3-(benzyloxycarbonylamino-4-yl)acryloyl]-(4R,5S)-1,5-dimethyl-4-phenyl-2-imidazolidinone (4.9 g) in THF (50 ml) and this mixture was added dropwise during 10 minutes to a solution of cuprate reagent. The reaction mixture was stirred at -78°C for 1 hour, then left to warm to ambient temperature. The solvent is evaporated, the residue was dissolved in ethyl acetate and filtered through silica (100 g). An ethyl acetate solution was washed with 2 M HCI (1×100 ml), dried and evaporated to dryness. The residue was passed through BondElut-column and elution with a mixture of ethyl acetate and isohexane (1:1), giving specified in the title compound in the form of individual diastereoisomer according to NMR. The output of 5.1, NMR (DMSOd6): 0.5 (d, MN), 0.8-1.1 (m, 2H), 1.3 (d, 1H), 1.7 (m, 2H), 2.6 (m, 5H), 2.85-3.1 (m, 4H), 5.05 (s, 2H), 5.2 (d, 1H), 6.8 (m, 2H), 7.1-7.5 (m, 13H).

3-[3-(Benzyloxycarbonylamino-4-yl)acryloyl]-(4R,5S)-1,5-dimethyl-4-phenyl-2-imidazolidinone

1-Chloro-N,N,2-trimethyl-1-Propylamine (1,37 g) was added dropwise in the course of 10 minutes to a solution of 3-(benzyloxycarbonylamino-4-yl)propanolol acid (2.5 g) in THF (20 ml) and the mixture was stirred for 1.5 hours. Letibit(trimethylsilyl)amide (8,65 ml) was added to a solution of (4R,5S)-1,5-dimethyl-4-phenyl-2-imidazolidinone (1.64 g) in THF (20 ml) is -10° C and the mixture was stirred at -10°C for 10 minutes, left to warm to 0°and then again cooled to -10°C. was added dropwise a solution of carboxylic acid (prepared as above) and the mixture was left to warm to room temperature. The reaction mixture was poured into water (100 ml) and was extracted with ethyl acetate (3×50 ml). The combined extracts were dried, evaporated to dryness and the residue was chromatographically on BondElut-column with elution with a mixture of ethyl acetate/isohexane (1:1), giving specified in the title compound, yield of 3.6, NMR (DMSOd6): 0.6 (d, 3H), 0.95 (d, 1H), 1.2 (m, 2H), 1.55 (m, 2H), 2.4 (m, 1H), 2.3 (s, 3H), 2.8 (m, 2H), 3.95 (m, 3H), 5 (s, 2H), 5.3 (d, 1H), 6.9 (m, 1H), 7.1 (m, 2H), 7.2-7.4 (m, 8H).

3-(Benzyloxycarbonylamino-4-yl)Papanova acid

A mixture of N-benzyloxycarbonyl-4-formylpiperidine (10 g), malonic acid (4, 2), pyridine (4 ml) and piperidine (0.4 ml) was heated at 100°C for 2 hours. The reaction mixture was left to cool and was diluted with ethyl acetate (100 ml). The solution was washed with 2 M HCl (2×100 ml), dried and evaporated to dryness. The residue is triturated with isohexane that gave specified in the title compound, yield of 13.5 g NMR (DMSOd6): 1.2 (m, 2H), 1.7 (m, 2H), 2.35 (m, 1H), 2.85 (m, 2H), 4 (d, 2H), 5.05 (s, 2H), 5.75 (d, 1H), 6.75 (m, 1H), 7.35 (m, 5H), 12.25 (broadened peak, 1H).

EXAMPLE 12

N-[1-3-[(3-Forfinal)-3-[1-phenylpiperidine-4-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonyl ylacetamide (Compound No. 145 Table I)

2 M NaOH was added to the suspension dihydrochloride salt of N-[1-[3-(3-forfinal-3-[piperidine-4-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl of 0.85 g) in dichloromethane (25 ml) and the mixture was stirred to obtain a clear solution. The dichloromethane solution was dried and filtered. This dichloromethane solution was added bendovervideo acid (330 mg), triethylamine (280 mg) and the bivalent copper acetate (276 mg). The reaction mixture was stirred for 15 hours, washed with water and filtered through a cartridge ChemElute. The dichloromethane filtrate was washed with 2 M NaOH (3×20 ml), was dried, was poured into the SCX cartridge (20 g) and suirable methanol (6×20 ml) and 1 M ammonia in methanol (6×20 ml). United ammonia leaching was evaporated and the obtained residue was chromatographically on BonElut-column chromatography with gradient solvents (ethyl acetate - 20%methanol/ethyl acetate), giving specified in the title compound, yield 179 mg

Salt is the dihydrochloride of N-[1-3-(3-forfinal)-3-[piperidine-4-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (Compound No. 87 Table I), used as starting material, was obtained according to the procedures described in Example 3, and Method C.

EXAMPLE 13

Racemic N-[1-(3-(3-forfinal)-3-[4-(4-methanesulfonyl)phenylsulfonyl)piperazine-1-yl]propyl)piperidine-4-yl]-N-ethyl-4-methanesulfonyl enolacetate (78 mg) (Compound No. 59 of Table I) was separated into its individual enantiomers by chromatography on a Gilson for preparative HPLC, using column Chiracel OD (50 mm, 20 μm) with elution with a mixture of ethanol/isohexane (9:1).

The less polar isomer, yield 20 mg (Compound No. 16 of Table II). The more polar isomer, yield 22 mg (Compound No. 17 of Table II).

EXAMPLE 14

N1-[1-(3-Phenyl)-3-{1-(acanaloniidae-4-yl)propyl}piperidine-4-yl]-N1-ethyl-N3-4-methysulfonylmethane (Compound No. 7 of Table III)

4-Methanesulfonylaminoethyl (99 mg) in THF (10 ml) was added to 4-N-ethyl-[1-(3-phenyl)-3-{1-(acanaloniidae-4-yl)propyl}piperidine (200 mg) and the mixture was left to stand at room temperature for 16 hours. The reaction mixture was applied to a SCX cartridge (5 g) and suirable dichloromethane (3×10 ml), methanol (3×10 ml) and methanolic ammonia solution (1M, 3×10 ml). Methanol-ammonia leaching was evaporated, the residue was dissolved in dichloromethane (20 ml) and was added to the resin in isocyanate form (200 mg). The mixture was stirred for 16 hours, filtered and the filtrate was evaporated to dryness. The obtained residue was chromatographically on BondElut-column chromatography with gradient solvents (ethyl acetate - 25%methanol/ethyl acetate), giving specified in the title compound, yield 37 mg MS (MN+) 633.

4-N-Ethyl-[1-(3-phenyl)-3-{1-(acanaloniidae-4-yl)propyl}piperidine

A mixture of N-ethyl-N-[1-(3-phenyl)-3-{1-(acanaloniidae-4-yl)who ropyl}piperidine-4-yl]carbamino acid benzyl ester (5 g) and 10%palladium on carbon (2 g) in ethanol (200 ml) was first made in an atmosphere of hydrogen, using filled with a hydrogen balloon. The catalyst was filtered and the filtrate was evaporated to dryness to obtain specified in the connection header, the output 2,78,

N-Ethyl-N-[1-(3-phenyl-3-{1-(acanaloniidae-4-yl)propyl}piperidine-4-yl]carbamino acid benzyl ester

Acanaloniidae (2.3 g) was added to a solution of N-ethyl-N-[1-(3-phenyl)-3-{(piperidine-4-yl)propyl}piperidine-4-yl]carbamino acid benzyl ester dihydrochloride (8.5 g) and triethylamine (4.8 g) in dichloromethane (200 ml), maintained at 0°C. the Reaction mixture was left to warm to room temperature and was stirred for 4 hours. The reaction mixture was washed with 2 M NaOH (2×100 ml), dried and evaporated to dryness. The residue was chromatographically on BondElut-column chromatography with gradient solvents (ethyl acetate - 20%methanol/ethyl acetate), giving specified in the header of the connection, exit 5, NMR (DMSOd6): 1 (t, 3H), 1.1 (t, 3H), 1.3-3 (m, 14H), 2.2 (m, 1H), 2.55-2.9 (m, 5H), 2.95 (q, 2H), 3.1 (q, 2H), 3.4-3.7 (m, 3H), 5.05 (s, 2H), 7.1-7.4 (m, 10H). MS (MN+) 556.

The dihydrochloride of N-ethyl-N-[1-(3-phenyl)-3-{(piperidine-4-yl)propyl}piperidine-4-yl]carbamino acid benzyl ester

HCI in dioxane (50 ml, 4 M) was added to benzyl ether, N-ethyl-N-[1-(3-phenyl)-3-{1-(tert-butyloxycarbonyl-4-yl)propyl}piperidine-4-yl]carbamino acid (26 g) at 0°With a mix of octal is whether to warm to room temperature and was stirred for 2 hours. The reaction mixture was diluted with diethyl ether (200 ml) and precipitated precipitated solid salt is the dihydrochloride was filtered, and dried (hygroscopic). Exit 17, MC (MH+) 464.

N-Ethyl-N-[1-(3-phenyl)-3-{1-(tert-butyloxycarbonyl-4-yl)propyl}piperidine-4-yl]carbamino acid benzyl ester

A solution of 3-phenyl-3-(1-tert-butyloxycarbonyl-4-yl)propionic aldehyde (7,8 g) [prepared as described in Example 11 method] in dichloromethane (200 ml) was added to a mixture of the hydrochloride of N-ethyl-N-piperidine-4-ylcarbamate acid benzyl ester (7.4 g) (CAS No. 220395-87-9) and sodium acetate (2.17 g) in ethanol (50 ml) and was stirred for 30 minutes. Triacetoxyborohydride sodium (5,2 g) was added in small portions over 15 minutes and stirring was continued for 2 hours. Was added dropwise aqueous NaOH (2 M, 200 ml), the dichloromethane layer was collected and washed with 2 M NaOH (2×100 ml), dried and evaporated to dryness, which gave specified in the header of the connection, exit 26, NMR (DMSOd6): 1 (t, 3H), 1.35 (s, 9H), 1.4-2 (m, 14H), 2.3 (m, 2H), 2.6-2.7 (m, 4H), 3.15 (q, 2H), 3.4-4 (m, 3H), 5.05 (s, 2H), 7.1-7.2 (m, 10H). MS (MN+) 563.

4-Methanesulfonylaminoethyl

Diphenylphosphinite (260 mg) was added to a mixture of 4-methanesulfonylaminoethyl acid (200 mg) and triethylamine (191 mg) in THF (20 ml) and the reaction mixture is boiled under reflux for 4 hours. Rea is operating and the mixture was cooled and used directly in the next stage.

Method And

N-[1-(3-Phenyl-3-chloropropyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl

Stage 1: obtain N-[1-(3-phenyl-3-oxopropyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl

To a solution of N-(4-piperidinyl)-N-ethyl-4-methanesulfonylaminoethyl (the Way In; 3,24 g, 10 mmol) in DMF (50 ml) was added potassium carbonate (2.76 g, 20 mmol) followed by addition of 3-chloropropiophenone (1.85 g; 11 mmol). The resulting mixture was stirred at room temperature for 18 h, then evaporated. The residue was dissolved in DCM and the resulting solution was washed with water (4×10 ml), brine (10 ml), dried (MgSO4) and was evaporated, which gave the crude product, which was purified by elution through 50 g BondElut 10%methanol in ethyl acetate, which allowed us to obtain specified in the subtitle compound (2.4 g; 53%). NMR (CDCl3): 1.1 (t, 1H), 1.2 (m, 2H), 1.6 (m, 6H), 2.2 (m, 1H), 2.8 (m, 2H), 3.0 (m, 5H), 3.2 (m, 2H), 3.3 (m, 2H), 3.8 (m, 2H), 7.4 (m, 5H), 7.9 (m, 4H). MS: 457.

Stage 2: obtaining N-[1-(3-phenyl-3-hydroxypropyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl

To a solution of N-[1-(3-phenyl-3-oxopropyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (912 mg; 2 mmol) in ethanol (20 ml) at 0°With added borohydride sodium (76 mg; 2 mmol). The resulting mixture was stirred at room temperature for 30 min, then evaporated. The residue was dissolved in DCM and popucauses the solution was washed with water (2× 5 ml) and with brine (5 ml), dried (MgSO4) and evaporated, giving specified in the subtitle compound (812 mg; 87%). NMR (CDCl3): 1.1 (t, 1H), 1.2 (m, 2H), 1.6 (m, 8H), 2.0 (m, 1H), 2.2 (m, 1H), 2.6 (m, 2H), 3.0 (s, 3H), 3.2 (m, 2H), 3.3 (m, 2H), 3.8 (m, 2H), 4.9 (d, 1H), 7.3 (m, 5H), 7.4 (d, 2H), 7.9 (d, 2H). MS: 459.

Stage 3: obtaining specified in the connection header

To a mixture of N-[1-(3-phenyl-3-hydroxypropyl)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (400 mg; 0.87 mmol) and triethylamine (of 0.24 ml, 1.04 mmol) in DCM (10 ml) at 0°With added methanesulfonamide (67 μl; 0.87 mmol). The resulting mixture was stirred at room temperature for 30 min, then evaporated. The residue was purified by elution through a 20 g BondElut that gave specified in the title compound (180 mg; 44%). NMR (CDCl3): 1.1 (t, 1H), 1.2 (m, 2H), 1.6 (m, 7H), 2.2 (m, 2H), 2.4 (m, 2H), 2.8 (m, 2H), 3.0 (s, 3H), 3.3 (m, 2H), 3.8 (m, 2H), 5.0 (m, 1H), 7.3 (m, 5H), 7.4 (d, 2H), 7.9 (d, 2H). MS: 477.

Method In

N-(4-Piperidinyl)-N-ethyl-4-methanesulfonylaminoethyl

Stage 1: obtain 1-phenylmethyl-4-Ethylenediamine dihydrochloride

To a solution of 1-phenylmethyl-4-piperidone (25,0 g, 132 mmol) in THF (250 ml) was added ethylamine hydrochloride (12.0 g; 147 mmol) and methanol (50 ml) and the resulting mixture was stirred at room temperature for 10 minutes Portions was added triacetoxyborohydride sodium (40 g, 189 mmol) and the resulting mixture was stirred at room temperature for 1 is. Added 2 M sodium hydroxide solution (250 ml) and the resulting mixture was extracted with diethyl ether. The organic extracts were dried (K2CO3) and evaporated, giving 1-phenylmethyl-4-ethylenediamide in the form of oil. It was dissolved into ethanol (500 ml) was added concentrated hydrochloric acid (20 ml). The resulting crystals were collected, washed with diethyl ether, and dried, obtaining mentioned in the subtitle compound as a solid (38 g). NMR (CDCl3): 1.10 (t, 3H), 1.40 (m, 2H), 1.83 (m, 2H), 2.02 (m, 2H), 2.65 (q, 2H), 2.85 (m, 2H), 3.50 (s, 2H), 3.75 (m, 1H), 7.2-7.4 (m, 5H). MS: 219 (MH+).

Stage 2: obtain N-(1-phenylmethyl-4-piperidinyl)-N-ethyl-4-methanesulfonylaminoethyl

To a solution of 1-phenylmethyl-4-Ethylenediamine dihydrochloride (32,0 g; 110 mmol) in DCM (500 ml) was added N,N-diisopropylethylamine (60 ml) with stirring to achieve complete dissolution. Added 4-methanesulfonylaminoethyl acid (25,0 g, 117 mmol), 4-dimethylaminopyridine (2.0 g) and dicyclohexylcarbodiimide (25,0 g, 121 mmol) and the resulting mixture was stirred at room temperature for 20 hours the Precipitate was removed by filtration and the resulting solution was washed sequentially 2 N. aqueous HCl, water, and 1 N. aqueous NaOH, dried (MgSO4) and was evaporated. The residue was purified by chromatography on silica gel (eluent: 10%Meon/ethyl acetate), which allowed us to obtain specified in Pozega the information connection (35 g; 76%). NMR: 1.00 and 1.14 (t, 3H), 1.45 and 1.70 (m, 2H), 1.95 (br m, 2H), 2.80 (br m, 2H), 3.18 (s, 3H), 3.20 and 3.33 (q, 2H), 3.45 (s, 2H), 3.80 and 3.87 (s, 2H), 3.70-4.10 (m, 1H), 7.2-7.3 (m, 5H), 7.48 (m, 2H), 7.82 (m, 2H). MS: 415 (MH+).

Stage 3: obtaining specified in the connection header

To a solution of N-(1-phenylmethyl-4-piperidinyl)-N-ethyl-4-methanesulfonylaminoethyl (34 g, 82 mmol) in ethanol (600 ml) was added ammonium formate (40 g). The mixture was purged with argon and added 30%Pd on carbon (4,2 g). The resulting mixture was stirred while boiling under reflux for 4 h, then left to cool and filtered through diatomaceous earth. The filtrate was evaporated, which gave a thick oil which otverdel when standing with obtaining specified in the connection header (24,9 g; 94%). NMR: 1.02 and 1.15 (t, 3H), 1.4-1.6 (br m, 4H), 2.45 (m, 2H), 2.93 (br m, 2H), 3.18 (s, 3H), 3.20 and 3.32 (q, 2H), 3.72 and 4.18 (m, 1H), 3.80 and 3.87 (s, 2H), 7.50 (m, 2H), 7.85 (m, 2H). MS: 325 (MH+).

Way

3-Phenyl-3-(1-tert-butylcarbamoyl-4-yl)propionic aldehyde

Stage 1: obtain 1-tert-BUTYLCARBAMATE-4-benzoylpiperidine

To a solution of 4-benzoylpiperidine (6 g; of 26.5 mmol) in 2 M aqueous sodium hydroxide (26.5 ml) was added di-tert-BUTYLCARBAMATE (5,79 g of 26.5 mmol) and the resulting mixture was stirred at room temperature for 18 hours, the Solid product was isolated by filtration and dried under vacuum at 40°receiving specified in the subtitle compound (7 g). NMR 1.3-1.4 (m, 11H), 1.7 (m, 2H), 2.9 (m, 2), 3.6 (m, 1H), 3.95 (m, 2H), 7.5-7.6 (m, 3H), 7.95 (d, 2H).

Stage 2: getting ethyl-3-phenyl-3-(1-tert-butylcarbamoyl-4-yl)acrylate

To a solution of triethylphosphate (6.2 g, 27 mmol) in THF (100 ml) at 0°With added bis(trimethylsilyl)amide lithium (32,5 ml; 1 M, 32.5 mmol). The resulting mixture was stirred at 0°C for 20 minutes was Added 1-tert-BUTYLCARBAMATE-4-benzoylpiperidine (7 g, 25 mmol) and the resulting mixture was stirred at room temperature for 48 hours the Mixture was evaporated and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with 2 M hydrochloric acid (2×100 ml), dried and evaporated, getting mentioned in the subtitle of the connection.

Stage 3: getting ethyl-3-phenyl-3-(1-tert-butylcarbamoyl-4-yl)propionate

Ethyl-3-phenyl-3-(1-tert-butylcarbamoyl-4-yl)acrylate (˜25 mmol) was dissolved in ethanol (200 ml) and the solution was purged with argon. Was added 20%palladium hydroxide (2 g) and the resulting mixture was stirred at room temperature in an atmosphere of hydrogen (balloon) for 72 hours and the Mixture was purged with argon, filtered and the filtrate was evaporated. The crude product was purified by chromatography on silica gel (eluent: isohexane, then 35%ethyl acetate in isohexane)that gave specified in the subtitle compound (5.3g).

Stage 4: getting 3-phenyl-3-(1-tert-butylcarbamoyl-4-yl)propan-1-ol/p>

To a solution of ethyl-3-phenyl-3-(1-tert-butylcarbamoyl-4-yl)propionate (5,3 g; 14.6 mmol) in THF (100 ml) dropwise over 20 min was added alumoweld lithium (14,6 ml; 1 M, 14.6 mmol). The resulting mixture was stirred at 0°C for 1 h was added dropwise 2 M aqueous sodium hydroxide (20 ml). The mixture was filtered through Celite®by washing with ethyl acetate (3×25 ml). The filtrate and washing were combined and evaporated. The residue was dissolved in ethyl acetate (100 ml) and the resulting solution was washed with water (3×50 ml), dried and evaporated, giving specified in the subtitle compound (4.6 g). NMR 0.9-1 (m, 2H), 1.25 (m, 1H), 1.35 (s, 9H), 1.5-2 (m, 5H), 2.6 (m, 2H), 3.1 (m, 2H), 3.8-4 (m, 2H), 4.2 (t, 1H).

Stage 5: obtaining specified in the connection header

To a solution of 3-phenyl-3-(1-tert-butylcarbamoyl-4-yl)propan-1-ol (4.6 g; 14.4 mmol) in DCM (100 ml) was added a reagent dess-Martin (6,1 g; 14.6 mmol) and the resulting mixture was stirred at room temperature for 2 hours the Mixture was washed with 2 M aqueous sodium hydroxide (3×50 ml), dried and evaporated, giving specified in the header of the connection.

Method D

N-(tert-Butoxycarbonylamino-4-yl)-N-ethyl-4-methanesulfonylaminoethyl

To a solution of 4-methylsulfonylmethane acid (16.1 g) in toluene (200 ml) in an argon atmosphere was added diphenylphosphoryl (16.2 ml) and triethyl is in (10.4 ml). The mixture was heated at 90°C for 3 hours and then left to cool. Added tert-butyl 1-oxo-4-AMINOETHYLPIPERAZINE [CAS 264905-39-7] (17,10 g) in toluene (100 ml), the mixture was stirred for 18 hours and then was distributed between EtOAc/N2About (500 ml/400 ml), filtered and the organic layer was separated and washed with saturated solution of NaHCO3(2×300 ml), brine (300 ml), dried over MgSO4, was filtered and was evaporated. The resulting brown oil was purified on silica using a gradient elution from 0 to 3%Meon in EtOAc, giving specified in the title compound in the form of solid yellow (7,10 g). NMR: (DMSO): 1.4 (t, 3H), 1.40 (s, 9H), 1.52 (m, 4H), 2.73 (m, 2H), 3.15 (m, 5H), 4.02 (m, 3H), 4.32 (d, 2H), 6.89 (t, 1H), 7.43 (d, 2H), 7.87 (d, 2H). MS 340 (MH+- Boc).

N-(piperidine-4-yl)-N-ethyl-4-methanesulfonylaminoethyl

Piperidine (6,84 g) was dissolved in DCM (39 ml) and was slowly added TFA (39 ml). The mixture was left to stand for 40 minutes and then was evaporated. The residue was dissolved in 2 M NaOH, and was extracted with DCM (3×150 ml) and the extracts were dried over MgSO4, filtered and evaporated, giving specified in the title compound in the form of solid yellow (5,00 g). NMR: (DMSO): 1.05 (t, 3H), 1.41 (m, 4H), 2.42 (m, 2H), 2.96 (d, 2H), 3.20 (m, 5H), 3.90 (quint, 1H), 4.29 (d, 2H), 6.84 (t, 1H), 7.43 (d, 2H), 7.85 (d, 2H). MS 340 (MN+).

Method E

N-[1-(3-[3,4-Differenl]-3-hydro is sapropel)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl

A solution of sodium borohydride (7.7 mg) in ethanol (1 ml) was added to a solution of N-[1-(3-[3,4-differenl]-3-Ketoprofen)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (0.25 g) in ethanol (3.2 ml) at 0°in argon atmosphere and the reaction mixture was left to warm to room temperature for 20 hours. The reaction extinguished salt solution was extracted three times with diethyl ether and the combined extracts were dried. Then the filtrate was concentrated to obtain a clear oil, yield of 0.21 g MS (MN+) 495.

N-[1-(3-[3,4-Differenl]-3-Ketoprofen)piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl

DBU was added to a solution of [piperidine-4-yl]-N-ethyl-4-methanesulfonylaminoethyl (CAS No. 374725-04-9) (320 mg) and 3,4-differentiality (654 mg) in dichloromethane (9 ml) in an argon atmosphere and the reaction mixture was stirred for 36 hours. The reaction mixture was concentrated in vacuo and purified using flash column chromatography on silica with elution with a gradient of solvents (methanol 10-15%, methanol in dichloromethane), yield 250 mg of MN+493.

3,4-Differentillumination

Reagent dess-Martin (3,18 g) was added to a solution of 3,4-deferwindowpos alcohol (CAS No. 149946-84-9) (1.18 g) in dichloromethane (22 ml) at 0°in argon atmosphere and the reaction mixture was left PE mesyatsa for 1 hour. The mixture was applied directly to the column for purification by column flash chromatography, elwira gradient (ethyl acetate -10%, ethyl acetate and isohexane), the output 654 mg NMR (CDCl3): 6.0 (d, 1H), 6.50 (d, 1 H), 7.10 (dd, 1 H), 7.30 (m, 1 H), 7.80 (m, 2H).

EXAMPLE 15

The ability of compounds to inhibit the binding of RANTES was assessed by in vitro analysis of the binding of the radioactive ligand. Preparation membranes were prepared from cells of Chinese hamster ovary, which expressed the human CCR5 receptor. These membranes were incubated with 0.1 nm iodinated RANTES granules to determine scintillation proximity and compounds according to the invention in various concentrations in 96-well plates. The number of iodized RANTES, contacting the receptor was determined on the basis of accounts of the scintillations. Got curves of competition for connections and expected concentration of compounds that have replaced 50% of the associated iodized RANTES (IC50). Preferred compounds of formula (I) have the IC50less than 50 microns.

EXAMPLE 16

The ability of compounds to inhibit the binding of MIP-1α has been evaluated in vitro analysis of the binding of the radioactive ligand. Prepared membrane preparations from cells Chinese hamster ovary, which Express recombinant human CCR5 receptor. These membranes were incubated with 0.1 nm iodinated MIP-1α granules destinationname analysis and the compounds according to the invention in various concentrations in 96-well plates. The number of iodized MIP-1αby contacting the receptor was determined using a scintillation counter. Were obtained curves compete for connections and was calculated concentration of a compound that displaces 50% of the associated iodized MIP-1α (IC50). Preferred compounds of formula (I) have the IC50less than 50 microns.

The results of this test for some of the compounds according to the invention are presented in Table VII. The results in Table VII presents as Pic50 values. The Pic50 value represents the negative logarithm (base 10) values obtained IC50thus IC50equal to 1 μm (i.e. 1×10-6M), gives Pic50 equal to 6. If the connection is tested more than once, the following data represent the average of results designed to test samples.

Table VII
Connection # Table No.Pic50Connection # Table No.Pic50
4Ito 7.8442I9,2
6I6,4445I8,3
7I8,065Iof 8.37
9I6,5169Icent to 8.85
12I6,4799I8,2
18I8,05142I8,63
24I8,7815II8,25
27I8,918II8,46
34Iof 7.233III8,25
37Ito 7.84

SCHEME 1

SCHEME 2

SCHEME 3

Conditions

a) (1) (EtO)2P(=O)CH2CO2Et, base;

(2) hydrogenation (for example, Pd(OH)2H2)

b) Recovery (for example, LiAlH4) (R3represents H)

c) (1) the Recovery of the aldehyde (e.g. DIBAL-H); (2) R3MgBr

d) Oxidation (e.g., reagent dess-Martin)

e) (1) MeONHMe, AlMe3; (2) recovery (R3represents N or R3MgBr

f) Reductive amination of (NaBH(SLA)3The asón)

g) HCl or TFA

h) Formation of amide (acid and agent combinations or gelegenheid

acid, base)

(i) Education sulfonamida (sulphonylchloride, base)

j) Reductive amination of (aldehyde, NaBH(SLA)3)

1. A derivative of piperidine derivatives of the formula (I):

where L represents CH or N; M represents CH or N; provided that L and M both represent CH;

R1represents phenyl (possibly substituted, halogen or C1-4by alkyl), S(O)2(C1-4alkyl), S(O)2(C1-4foralkyl), S(O)2phenyl (possibly substituted CF3or OCF3), benzyl, benzoyl (possibly substituted, halogen) or S(O)NH (possibly substituted, halogeno);

R2represents phenyl, possibly substituted, halogeno;

R3represents hydrogen or C1-4alkyl;

R4represents methyl or ethyl;

R5represents phenyl-NH, phenyl(C1-2alkyl), phenyl(C1-2alkyl)-NH, or pyridyl(C1-2alkyl), the phenyl ring prob is tenderly replaced halogeno, cyano, C1-4the alkyl, C1-4alkoxy, S(O)k(C1-4alkyl) or S(O)2NR8R9;

k is equal to 2;

R8and R9independently represent hydrogen; or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where L represents CH.

3. The compound according to claim 1 or 2, where M is a n

4. The compound according to claim 1, where R3is hydrogen or stands.

5. The compound according to claim 1, where R4is ethyl.

6. A method of obtaining a compound according to claim 1, where L represents N, in which the interaction of the compounds of formula (II):

,

where R2, R3, R4and R5such as defined in claim 1, with a compound of formula (III):

where R1such as defined in claim 1,

in the presence of sodium iodide and a suitable base in a suitable solvent.

7. Pharmaceutical composition useful in modulating the activity of the CCR5 receptor containing the compound according to claim 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable adjuvant, diluent or carrier.



 

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19 cl, 5 tbl, 165 ex

FIELD: chemistry.

SUBSTANCE: new compounds with formula Ia are proposed, where: P represents pyridine or pyrimidine; R1 represents hydrogen; R2 is chosen from halogen, nitro, C0-6alkylheteroaryl, (CO)OR4, trifluoromethyl, C0-6alkylcyano, C0-6alkylNR4R5, OC1-6alkylNR4R5, C0-6alkylCONR4R5, C0-6alkyl(SO2)NR4R5 and X1R6 group, where X1 represents a direct link; R6 represents a 5- or 6-member heterocyclic group, containing one or two heteroatoms, independently chosen from N, O, and S, for which the given heterocyclic group can be unsaturated and can be substituted with by one substitute, chosen from W; m equals 0, 1, or 2; R3 is chosen from CO(OR4), C0-6alkylNR4R5, C0.6alkylCONR4R5, OC1-6alkylNR4R5 C1-6alkyl(SO2)NR4R5; n equals 1 or 2; R4 is chosen from hydrogen, C1-6alkyl; R5 is chosen from hydrogen, C1-6 alkyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6alkylheteroaryl and C1-6alkylNR14R15 or R4 and R5 together can form a 4-, 5-, 6- or 7-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O, where the given heterocyclic group can be substituted by group Y; and where any C1-6alkyl, indicated in defining R2-R5, can be substituted with one or more one Z group; R14 and R15 together can form a 5-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O; W and Z are independently chosen from halogen, CN, OR16, C1-6alkyl, trifluoromethyl, trifluoromethoxy, 5-member heterocyclic group, containing one heteroatom, independently chosen from N, for which the given heterocyclic group can be substituted with group Y; Y is chosen from oxo, halogen, C1-6alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where the phenyl and C0-6alkylaryl groups can be substituted with nitro, trifluoromethyl; R16 and R17 are independently chosen from hydrogen and C1-6alkyl, or where R16 and R17 together can form a 5-member heterocyclic group, containing one heteroatom, chosen from N; in form of a free base or pharmaceutical salt. Formula Ia compounds have inhibiting effect to glycogen-synthase-kinase-3 (GSK3). The invention also relates to the method of obtaining the proposed compounds and to new intermediate compounds, used in them, pharmaceutical compositions, containing the given therapeutically active compounds, and use of the given active compounds in therapy for treating conditions, related to GSK3.

EFFECT: new method of obtaining indole derivatives.

33 cl, 1 tbl, 112 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula: , where R is -(CH2)n-A, where A: where each of B and C independently represent phenyl or phenyl substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl) and -NO2; or n equals an integer from 0 to 3; n1 equals an integer from 1 to 3; n2 equals an integer from 0 to 4; n3 equals an integer from 0 to 3; n4 equals an integer from 0 to 2; X1 is chosen from a chemical bond -S-, -S(O)2-, -NH-, -NHC(O)- and -C=C-, R1 is chosen from C1-C6alkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, tetrahydropyranyl, CN, -N(C1-C6alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphtyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolydinyl, thiomopholinyl, tetrazolyl, benzoxazolyl, imidazolidine-2-thionyl, 7,7-dimethylbicyclo[2.2.1]heptane-2-onyl, benzo[1.2.5]oxadiazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl and pyrrolyl, each of which can be optionally substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, pyridyl, 2-methylazolyl, morpholino, 1-chloro-2-methylpropyl, phenyl, (optionally substituted with one or more halogens), benzyloxy, and , X2 selected from -O-, -CH2-, -S-, -SO-, -SO2-, -NH- and , R2 represents a ring group, chosen from a phenyl or thienyl group. Each ring group is substituted with a group with formula -(CH2)n4-CO2H; and besides that, the ring group can optionally be substituted with 1 or 2 extra substitutes, independently chosen from halogen, - C1-C6alkyl and -C1-C6alkoxy; R3 is chosen from H, halogen and -NO2; R4 is chosen from H, halogen and morpholino; or its salt form, used in pharmaceuticals. The invention also relates to pharmaceutical compositions, to methods of treatment, and to compounds with formula (A).

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on them, which have inhibiting effect on cytosolic phospholipase A2.

45 cl, 300 ex

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method for obtaining 5-{2-[5-{2-[1,3,5-ditiazinan-5-il]ethyl}-4-methyl-1,3,5-tiadiazinan-3-il]ethyl} 1,3,5-ditiazinan with formula including interaction of methyltriethyltetaraamin with water solution of formaldehide saturated with hydrogen sulphide. The given compound can find application as selective sorbents and extragents of precious metals and special reagents for inhibition of vital functions of bacteria in various technological media.

EFFECT: efficient method for obtaining 5-{2-[5-{2-[1,3,5-ditiazinan-5-il]ethyl}-4-methyl-1,3,5-tiadiazinan-3-il]ethyl} 1,3,5-ditiazinan.

1 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. The compounds claimed by the invention have inhibition effect on VR1 receptor activation and can be applied in pain prevention or treatment. In the general formula (I) , or , L is a low alkylene, E cycle is benzene or 5-membered heteroaromatic ring containing sulfur atom as a heteroatom, D cycle is a monocyclic or bicyclic hydrocarbon cycle optionally condensed with C5-7 cycloalkyl, 6-membered monocyclic heteroaromatic cycle containing nitrogen atom as heteroatom or 9-11-membered bicyclic heteroaromatic cycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O, G cycle is a 5-7-membered monocyclic saturated or partially saturated heterocycle or 10-membered bicyclic heterocycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O. The invention also concerns pharmaceutical composition based on the said compounds, and application thereof in obtaining pain prevention or treatment medication, and a method of pain prevention or treatment.

EFFECT: obtaining prevention or treatment medium against pain.

24 cl, 470 ex, 41 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds presented by the following formula (I), or to the pharmaceutically acceptable salts: , where R1 and R2 represent substitutes, adjoining with each other and with two carbonic atoms, to each of which they are adjoined forming the group presented by the following formula: 1) , or

2) , , , , , , , , or

3) or

4) , , or

where hydrogen atom in each cyclic group can be substituted bi 1-4 substitutes selected fro the following group of substitutes B1, R3 represents hydrogen atom or methyl group; and R6 represents substitute selected from the following group of A1 substitutes, the group of A1 substitutes: (1) hydrogen atom, (2) C1-C6 alkoxy group; substitute B1 group: (1) hydrogen atom, (2) hydroxyl group, (3) oxo group, (4) C1-C6 alkanoyl group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where C1-C6 alkyl group can be substituted by C1-C6 alkoxy group), (7) C1-C6 alkoxy group, (8) C1-C6 alkoxyimino group, (9) C5-C6 cycloalkyl group, derived by two C1-C3 alkyl groups joined to the same carbonic atom with hydrogen atom and the carbons. The invention is also relates to the pharmaceutical composition.

EFFECT: production of the new biologically active compounds and pharmaceutical compositions on their basis having inhibitor potency towards to serotonine1A receptor.

34 cl, 73 ex, 12 tbl, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns to new diamides of pyrimidine-4,6-dicarboxylic acid of I formula, selective inhibitors of collagenases possessing properties which concern to the metalloproteinase superfamily and the matrix metalloproteinases. The bonds render influence on hyperactivity of the matrix metalloproteinase-13 (MMP-13) and thus do not render influence on MMP-3 and MMP-8. In the formula I R1 means an atom of hydrogen, R2 means - (C1-C6)-alkyl where alkyl is unitary replaced by phenyl where phenyl is replaced 1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 identical or different and independently from each other mean i) atom of hydrogen or ii) - (C1-C6)-alkyl or R9 and R10 together with atom of nitrogen to which they are bound, form 5, 6-links the sated cycle, and instead of one or two other atoms of carbon there can be also a heteroatom from an oxygen row, sulphur and nitrogen, and in case of nitrogen atoms of nitrogen independently from each other can be unsubstituted or substituted with (C1-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-SN, 3) -O-(C0-C6)-alkyl-C(O)-N(R9)-(R10) where R9 and R10 have the specified above value, 4) -(C0-C6)-alkyl-C(O)-N (R8)-(C0-C6)-alkyl-N(R9)-(R10) where R8 means hydrogen, R9 and R10 have the specified above value, 5) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-Het, and R8 has the specified above value, and Het means the sated or nonsaturated monocyclic heterocyclic system with number of links from 3 to 6 which contains in a cycle of 1 or 2 identical or different heteroatoms from a number nitrogen, oxygen and sulphur and unsubstituted or one-, two- or triple independently from each other is replaced by halogen, b) hydroxy,) -(C1-C6)-alkyl, and alkyl is unsubstituted or one-, two- or triple is substituted by halogen, d)=0,e)-Het, R4 and R5 or R5 and R6 together with atom of Carboneum to which they are bound, independently from each other form 5 or 6-unit cycle which is sated and contains one or two heteroatoms from an oxygen row.

EFFECT: obtaining of bonds which can find application for treatment of degenerate diseases of joints, such as osteoarthritis, rheumatic disease.

7 cl, 3 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to derivatives of 4-[1-arylimidazol-4-yl ethynyl]-2-alkylpyridine and 4-[1-heteroarylimidazol-4-yl ethynyl]-2-alkylpyridine of general formula I having general formula I in which R1 stands for C1-C6alkyl; R2 stands for C1-C6alkyl or C3-C12cycloalkyl; R3 stands for aryl or heteroaryl, where aryl or heteroaryl are unsubstituted or contain substituents, selected from group, including halogen, C1-C6alkyl, S-C1-C6alkyl, C1-C6alkylhlogen, C1-C6alkoxygroup, halogen- C1-C6lkoxygroup, C3-C12cycloalkyl, C2-C11heterocycloakyl, C1-C6alkylminogroup,di- C1-C6alkylaminogroup, C1-C6alkoxyaminogroup, (C1-C6 alkoxy) C1-C6alkylaminogroup, C3-C12cycloalkylaminogroup, benzylaminogroup and cyanogroup, where said "aryl" represents phenyl, and said " heteroaryl" represents aromatic 5- or 6- member ring or one or more condensed rings, containing one or more heteroatoms, selected from group, which includes nitrogen, oxygen and sulfur; and R4 stands for hydrogen, C(O)H or CH2R5 , where R stands for hydrogen or its pharmaceutically acceptable salt. Invention also relates to method of obtaining compounds of general formula I, their application as anxiolytic, to based on them pharmaceutical composition and method of treatment or prevention of disorders, fully or partly mediated by metabotropic glutamate receptor of subtype 5.

EFFECT: obtaining novel heterocyclic compounds possessing useful biological properties.

15 cl, 18 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to agonist of receptor of glucagone-like peptide-1, which can be applied for treatment of diseases, caused by disturbance of glycometabolism, such as type II diabetes, insensibility to insulin or obesity. In structural formula each of Ar1 and Ar2 independently represents substituted phenyl, and group-substituents represent one, two or three groups selected from C1-C6alkoxyl, C1-C6-alkanoylamino, which is substituted with hydroxyl (which contains groups-substituents, including hydroxyl); C3-C6-cyclolkanoylamino, C2-C6-lkenoylamino; banzoylamino, banzyloxy C1-C6-alkanoylamino, thenoyloxy, tret-butoxyformamido, adamantanformamido; and mandeloylamino; X represents O; Y represents O. Invention also relates to method of obtaining agonist, and to its application for obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

EFFECT: obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

8 cl, 4 ex, 2 tbl, 2 dwg

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

Crystal form // 2339634

FIELD: chemistry.

SUBSTANCE: (E)-2-(5-Chlorothiene-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethensulfonamide in essentially crystal form has powder radiograph, expressed in angle values 20, and obtained by means of difractometer, including peaks, located in the following positions expressed in angles 2θ: 9.1-9.2 (±0.1), 16.0-16.1(±0.1), 18.0-18.2 (±0.1) and 18.3-18.4 (±0.1) degrees, and term "essentially crystal form" means that said form is mainly free from amorphous form of (E)-2-(5-Chlorothiene-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethensulfonamide, and by term "mainly free from" content of amorphous form less than 50% is meant.

EFFECT: increased activity.

15 cl, 2 dwg, 5 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of 2-pyridinecarboxamide and their pharmaceutical salts, which have glucokinase activating properties. In formula (I): D represents O or S; R2 and R3 each represents a hydrogen atom; formula (II) represents triazole group, imidazole group, thiazole group and pyridine group, which can have in the ring, 1 or 2 substitutes; formula (III) represents a thiazole group, thiadiazole group, isoxazolyl group, pyrazine group, pyridothiazolyl group or pyridyl group, ring B can have 1 or 2 substitutes. The invention also relates to pharmaceutical compositions based on the invented compounds.

EFFECT: new derivatives can be used for treating such diseases as sugar diabetes.

19 cl, 5 tbl, 165 ex

FIELD: chemistry.

SUBSTANCE: new compounds with formula Ia are proposed, where: P represents pyridine or pyrimidine; R1 represents hydrogen; R2 is chosen from halogen, nitro, C0-6alkylheteroaryl, (CO)OR4, trifluoromethyl, C0-6alkylcyano, C0-6alkylNR4R5, OC1-6alkylNR4R5, C0-6alkylCONR4R5, C0-6alkyl(SO2)NR4R5 and X1R6 group, where X1 represents a direct link; R6 represents a 5- or 6-member heterocyclic group, containing one or two heteroatoms, independently chosen from N, O, and S, for which the given heterocyclic group can be unsaturated and can be substituted with by one substitute, chosen from W; m equals 0, 1, or 2; R3 is chosen from CO(OR4), C0-6alkylNR4R5, C0.6alkylCONR4R5, OC1-6alkylNR4R5 C1-6alkyl(SO2)NR4R5; n equals 1 or 2; R4 is chosen from hydrogen, C1-6alkyl; R5 is chosen from hydrogen, C1-6 alkyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6alkylheteroaryl and C1-6alkylNR14R15 or R4 and R5 together can form a 4-, 5-, 6- or 7-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O, where the given heterocyclic group can be substituted by group Y; and where any C1-6alkyl, indicated in defining R2-R5, can be substituted with one or more one Z group; R14 and R15 together can form a 5-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O; W and Z are independently chosen from halogen, CN, OR16, C1-6alkyl, trifluoromethyl, trifluoromethoxy, 5-member heterocyclic group, containing one heteroatom, independently chosen from N, for which the given heterocyclic group can be substituted with group Y; Y is chosen from oxo, halogen, C1-6alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where the phenyl and C0-6alkylaryl groups can be substituted with nitro, trifluoromethyl; R16 and R17 are independently chosen from hydrogen and C1-6alkyl, or where R16 and R17 together can form a 5-member heterocyclic group, containing one heteroatom, chosen from N; in form of a free base or pharmaceutical salt. Formula Ia compounds have inhibiting effect to glycogen-synthase-kinase-3 (GSK3). The invention also relates to the method of obtaining the proposed compounds and to new intermediate compounds, used in them, pharmaceutical compositions, containing the given therapeutically active compounds, and use of the given active compounds in therapy for treating conditions, related to GSK3.

EFFECT: new method of obtaining indole derivatives.

33 cl, 1 tbl, 112 ex

Carbonyl compounds // 2337099

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to novel compounds of general formula(I) , where D represents phenyl, pyridyl or tienyl, each of which is single-substituted or double-substituted with Hal; R1 represents H, =O, COOR3, OH, OA, NH2, alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms, N3, ethinyl, vinyl, allyloxy, -OCOR3, NHCOA or NHSO2A; R2 represents H, =O, OH, OA or alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms; R1 and R2 together alternatively represent spirocyclically linked 3-6-member carbocyclic ring, R3 represents H or A, R4 represents H or A; represents pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4 or 3,5-diyl, thiazolidine-3,4-diyl, 2,5-dihydro-1H-pyrrol-1,5-diyl, 1,3-dioxolane-4,5-diyl; G represents (CH2)n or (CH2)nNH-; X represents CONH; Y represents 1,3- or 1,4-phenylene, which is not substituted or is single-substituted with methyl, trifluoromethyl, ethyl, propyl, Cl or F; T represents morpholine-4-yl, which is single-substituted or double-substituted with carbonyl oxygen; A represents non-branched or branched alkyl, which has 1-10 carbon atoms and in which 1-7 hydrogen atoms can be substituted with F; Hal represents F, CI, Br or I, n represents 0, 1 or 2; and their pharmaceutically acceptable derivatives, solvates, salts or sterioisomers, including their mixtures in all ratios. Invention also relates to method of obtaining formula I compounds, to medication based on formula I compound and application of formula I compounds for preparation of medication, which has inhibiting activity with respect to coagulation factors Xa and VIla.

EFFECT: obtained novel compounds have inhibiting activity with respect to said coagulation factors.

11 cl, 1 tbl, 14 ex

The invention relates to new nitrogen-containing heterocyclic compounds with biological activity, in particular to substituted derivatives of pyrazole and means of having a weed-killing activity
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