8-oxy-quinoline derivatives as bradykinin b2 receptor modulators

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A is a 6-member heteroaryl, having 1 nitrogen atom as a heteroatom, substituted with 2-3 substitutes such as indicated in the claim, R5 is a halogen atom, cyano or C1-C6alkyl, optionally substituted with a halogen atom; R6 is C1-C6 alkyl, optionally substituted with OH; C1-C3 alkenyl; a 5-member heteroaryl, having 2-4 heteroatoms, each independently selected from N, O or S, substituted with 0-2 substitutes such as indicated in the claim, R10 is a 5-member heteroaryl, having 2-3 heteroatoms, each selected from N, O or S, substituted with 0-2 substitutes, which are C1-C3 alkyl; R7, R8, R17 denote a hydrogen or halogen atom. The invention also relates to a pharmaceutical composition, having BK B2 receptor inhibiting activity, which contains compounds of formula (I), a method of inhibiting, a method of localising or detecting the BK B2 receptor in tissue, use of the compounds of compositions to produce a medicinal agent and methods for treatment.

EFFECT: compounds of formula (I) as BK B2 receptor inhibitors.

22 cl, 1 tbl, 54 ex

 

This invention relates to new derivatives of 8-(heteroaromatics)quinoline containing their compositions and use of these compounds. These compounds act as selective modulators of receptor B2 bradykinin (BK), and therefore they can be used in pharmaceutical compositions for the treatment of conditions susceptible to modulation of receptor B2 VK. Compounds of the invention are also applicable as probes for the localization of receptors B2 VK and as standards in assays of binding of the receptor B2 VK.

Bradykinin (BK) is a vasoactive nonapeptide, H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH formed by the action of various enzymes in the plasma, such as kallickrein, kininogen. In some respects it has some actions similar to the actions of histamine, and the like histamine is released from venules, and not from the arterioles.

In mammals identified two types of receptors VK, B1 and B2 (Leeb-Lundberg, et al. Pharmacol. Rev. 2005, 57, 27-77). Steps VK, mediated by the B2 receptor, are important physiological functions, such as the increase in vascular permeability, modulation of inflammatory reactions and pain, and vasoactive action (vasodilation, vasoconstriction). These actions of B2 receptor are responsible for the role of VC in numerous diseases, such as inflammation, with techno-vascular disease and pain. Therefore, tools that block the binding of VK with its B2 receptor, can inhibit or at least to weaken pathogenic cases.

Numerous peptide and ones antagonists of the receptor B2 VK described in the prior art. For example, in WO 2006/40004, WO 03/103671, WO 03/87090, WO 00/23439, WO 00/50418, WO 99/64039, WO 97/41104, WO 97/28153, WO 97/07115, WO 96/13485, EP 0795547, EP 0796848, EP 0867432 and EP 1213289 describes quinoline derivatives which are antagonists of the receptor B2 VK.

Due to the severe conditions associated with pathophysiological levels of bradykinin, both acute and chronic, there is still a need in the highly selective B2 receptor modulators with improved properties.

Therefore, the problem underlying the present invention is to offer highly selective B2 receptor modulators, preferably with improved properties.

The problem underlying the present invention is resolved through the connections described by the attached claims.

In the first aspect the problem underlying the present application, is permitted by the compound of formula (I)

or its pharmacologically acceptable salt, MES or hydrate, where

A represents a 6-membered heteroaryl having from 1 to 3 heteroatoms, each withwhich independently selected from N or O, where indicated 6-membered heteroaryl substituted by from 2 to 4 substituents, each of which is independently selected from a halogen atom, oxygen atom, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, quinil, heteroalkyl, cycloalkyl, geterotsiklicheskie, alkylcyclohexane, heteroalicyclic, aryl, heteroaryl, aralkyl or heteroalkyl;

R5represents a halogen atom, hydroxy, cyano, nitro, mercapto, alkyl, alkenyl, quinil or heteroalkyl;

R6represents an optionally substituted alkyl; optionally substituted of alkenyl; 5-membered heteroseksualci having from 1 to 3 heteroatoms, each of which is independently selected from N, O or S, or cycloalkyl where the specified 5-membered heteroseksualci or cycloalkyl substituted by from 0 to 3 substituents, each of which is independently selected from a halogen atom, oxygen atom, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, quinil, heteroalkyl, cycloalkyl, geterotsiklicheskie, alkylcyclohexane, heteroalicyclic, aryl, heteroaryl, aralkyl or heteroalkyl; 5-membered heteroaryl having from 1 to 4 heteroatoms, each of which is independently selected from N, O or S, where the specified 5-membered heteroaryl substituted by from 0 to 3 substituents, each independently selected from a halogen atom, oxygen atom, hydroxy, cyano, AMI is about, nitro, mercapto, alkyl, alkenyl, quinil, heteroalkyl, optionally substituted aryl or optionally substituted heteroaryl; or-S-R10;

R10represents a 5-membered heteroseksualci having from 1 to 3 heteroatoms, each of which is independently selected from N, O or S, or cycloalkyl where the specified 5-membered heteroseksualci or cycloalkyl substituted by from 0 to 4 substituents, each independently selected from a halogen atom, oxygen atom, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, quinil, heteroalkyl, cycloalkyl, geterotsiklicheskie, alkylcyclohexane, heteroalicyclic, aryl, heteroaryl, aralkyl or heteroalkyl; or 5-membered heteroaryl having from 1 to 4 heteroatoms, each of which is independently selected from N, O or S, where the specified 5-membered heteroaryl substituted by from 0 to 4 substituents, each independently selected from a halogen atom, oxygen atom, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, quinil, heteroalkyl, cycloalkyl, geterotsiklicheskie, alkylcyclohexane, heteroalicyclic, aryl, heteroaryl, aralkyl or heteroalkyl;

R7represents a hydrogen atom, halogen atom, hydroxy, cyano, amino, nitro, alkyl or heteroalkyl;

R8represents a hydrogen atom or halogen atom, and

R17 represents a hydrogen atom or a halogen atom.

In the embodiment of the first aspect of the present invention heteroaryl And compounds contains from 1 to 3 nitrogen atoms.

In the embodiment of the first aspect of the present invention And is a

where

W represents N, or NO CR9;

Y is N, NO or CR2;

Z represents N or NO CR3;

with the proviso that at least one of W, Y or Z represents N or NO;

R1represents a halogen atom, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, quinil, heteroalkyl or heteroalicyclic;

R2represents a hydrogen atom, hydroxyl, halogen atom, cyano, nitro, mercapto, alkyl, alkenyl, quinil or heteroalkyl;

R3represents a hydrogen atom, halogen atom, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, quinil, heteroalkyl, cycloalkyl, heteroseksualci, alkylsilanes, heteroalicyclic, aryl, heteroaryl, aralkyl or heteroalkyl;

R4represents a halogen atom, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, quinil, heteroalkyl, cycloalkyl, heteroseksualci, alkylsilanes, heteroalicyclic, aryl, heteroaryl, aralkyl or heteroalkyl and

R9 represents a hydrogen atom, a halogen atom or With1-C6alkyl.

In the embodiment of the first aspect of the present invention R6represents a

where

And1And2And3And4and5each independently selected from O, S, N, N-H, NO, C or C-H and

R11and R12each independently selected from a hydrogen atom, halogen atom, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, quinil, heteroalkyl, cycloalkyl, geterotsiklicheskie, alkylcyclohexane, heteroalicyclic, aryl, heteroaryl, aralkyl or heteroalkyl.

In the embodiment of the first aspect of the present invention R6represents a

where

And1And2And3And4and5each independently selected from O, S, N, N-H, NO, C or C-H and

R11and R12each independently selected from a hydrogen atom, halogen atom, hydroxy, cyano, amino, nitro, mercapto, alkyl, alkenyl, quinil, heteroalkyl, cycloalkyl, geterotsiklicheskie, alkylcyclohexane, heteroalicyclic, aryl, heteroaryl, aralkyl or heteroalkyl.

In the embodiment of the first aspect of the present invention

R4selected from heteroalkyl, geterotsiklicheskie, heteroalicyclic, aralkyl and the and heteroalkyl;

W represents CR9;

Y is N, NO or CR2;

Z represents N or NO CR3;

with the proviso that at least one of Y or Z represents N or NO;

R1represents a halogen atom, hydroxy, cyano, -O-C1-C6alkyl or C1-C6alkyl;

R2represents a hydrogen atom, halogen atom, hydroxy, cyano, -O-C1-C6alkyl or C1-C6alkyl and

R3represents a hydrogen atom, halogen atom, hydroxy, cyano, amino, nitro, -O-alkyl or alkyl.

In one embodiment of the first aspect of the present invention R4selected from the groups-S-Ya-L, -S,-Ya-CO-NRaRb, -Ya-NRc-CO-NRaRb, -Ya-NRc-CO-O-Re, -Ya-NRc-CO-Re, -Ya-O-CO-NRaRb, -Ya-CO-NRaRb, -Ya-CO-NRcL-O-Ya-CO-NRaRb, -Ya-NRc-CO-L-Ya-L, -Ya-O-CO-O-Rc, -Ya-O-CO-Rc, -Ya-NRc-SO2-NRaRb, -Ya-SO2-NRaRbor-Ya-NRc-SO2-Re,

where

Yais a relationship With1-C6alkylen,2-C6albaniles or2-C6akinyan;

Rarepresents a hydrogen atom, a C1-C62-C6alkenyl,2-C6quinil or connected with Rbwith the formation of 4-10-membered cycloalkyl or geterotsiklicheskie;

Rbrepresents a hydrogen atom, a C1-C6alkyl, C2-C6alkenyl,2-C6quinil or Rbtaken together with Ra, form a 4-10-membered cycloalkyl or heteroseksualci;

Rcand Reeach independently selected from a hydrogen atom, optionally substituted C1-C6the alkyl, optionally substituted C2-C6alkenyl or optionally substituted C2-C6the quinil; and

L represents cycloalkyl, heteroseksualci, alkylsilanes, heteroalicyclic, aryl, optionally substituted heteroaryl, aralkyl or heteroalkyl.

In the embodiment of the first aspect of the present invention R4represents a

where

Xarepresents N, O or CH;

Xbis a C, S or S=O;

Xcrepresents N, O or CH;

R13if there is a1-C6alkyl;

R14if there is a1-C6alkyl, C2-C6alkenyl or R14connected to R15education

(i) a 5-10 membered cycloalkyl;

(ii) a 5-10 crannog is geterotsiklicheskie;

(iii) 5-10-membered heteroaryl or

(iv) 6-10-membered aryl;

R15represents alkyl, alkenyl or connected with R14education

(i) a 5-10 membered cycloalkyl;

(ii) a 5-10 membered geterotsiklicheskie;

(iii) 5-10-membered heteroaryl or

(iv) 6-10-membered aryl; and/or

R15taken together with R16education

(i) 4-10-membered cycloalkyl;

(ii) 4-10-membered geterotsiklicheskie;

(iii) 5-10-membered heteroaryl or

(iv) 6-10-membered aryl, and

R16represents hydrogen, alkyl, alkenyl, aryl, heteroaryl or R16taken together with R15forms

(i) 4-10-membered cycloalkyl;

(ii) 4-10-membered heteroseksualci;

(iii) 5-10-membered heteroaryl or

(iv) 6-10-membered aryl.

In the embodiment of the first aspect of the present invention R4represents a

where

R13represents an atom of hydrogen or C1-C6alkyl;

R18and R19each independently selected from a hydrogen atom, halogen atom, hydroxy, cyano, amino, nitro, C1-C6of alkyl, -O-C1-C6of alkyl, -CO-NRaRbor-SO2-NRaRbwhere

Raand Rbeach independently selected from hydrogen or C1-C6the alkyl.

In the embodiment of the first aspect of the infusion is his invention R 5represents a halogen atom, cyano or1-C6alkyl.

In the embodiment of the first aspect of the present invention R7, R8and R17each independently selected from H or F.

In the embodiment of the first aspect of the present invention R5represents methyl or ethyl.

In the embodiment of the first aspect of the present invention R6selected from the group

In the embodiment of the first aspect of the present invention

R1represents methyl, Cl, F, CN or-CH3;

W represents CH;

Y is N, NO, CH, C-CH3C-OH or C-OCH3;

Z represents N, NO, CH, C-CH3C-OH or C-OCH3and

with the proviso that at least one of Y or Z represents N or NO.

In the embodiment of the first aspect of the present invention R4represents a

where

R13represents a hydrogen atom or methyl;

R20represents Cl, F, cyano or CF3and

R21represents a hydrogen atom or F.

In the embodiment of the first aspect of the present invention R7, R8and R17represent N.

In the embodiment of the first aspect of the present invention is Obedinenie according to the present invention or its salt or MES manifests IC 50500 nm or less in a standard in vitro assays mediated by the B2 receptor VK.

In a second aspect the problem underlying the present invention is resolved through the connection, and this connection is preferably a compound according to the first aspect of the present invention, which is a

1-{3-[4-(5-chlorothiazole-4-yl)-2-methyl-quinoline-8-intoximeter]-4-methylpyridin-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,

1-{4-chloro-3-[4-(5-chlorothiazole-4-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,

1-{4-chloro-3-[4-(5-chlorothiazole-4-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,

1-{4-methyl-3-[2-methyl-4-(4-methyl-2H-pyrazole-3-yl)quinoline-8-intoximeter]pyridine-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,

1-{4-chloro-3-[4-(5-chloro-1-methyl-1H-imidazol-2-yl)-2-methylinosine-8-intoximeter]pyridine-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,

1-{5-chloro-2-methoxy-4-[2-methyl-4-(2-methyl-2H-[1,2,4]triazole-3-yl)quinoline-8-intoximeter]pyridine-3-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,

1-(3-{4-[4-(2-aminoethoxy)-1H-pyrazole-3-yl]-2-methylinosine-8-intoximeter}-4-methylpyridin-2-ylmethyl)-3-trifluoromethyl-1H-pyridine-2-it,

1-{4-chloro-3-[4-(1,5-dimethyl-1H-imidazol-2-yl)-2-methylinosine-8-intoximeter]pyridine-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,

1-{3-[4-(4-hydroxymethyl-2H-pyrazole--yl)-2-methylinosine-8-intoximeter]-4-methylpyridin-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,

N-(3-{2-methyl-8-[4-methyl-2-(2-oxo-3-trifluoromethyl-2H-pyridine-1-ylmethyl)pyridine-3-ylethoxy]quinoline-4-yl}-1H-pyrazole-4-ylmethyl)ndimethylacetamide,

1-{3-[4-(4-aminomethyl-1H-pyrazole-3-yl)-2-methylinosine-8-intoximeter]-4-methylpyridin-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,

N-(5-{8-[4-chloro-2-(2-oxo-3-trifluoromethyl-2H-pyridine-1-ylmethyl)pyridine-3-ylethoxy]-2-methylinosine-4-yl}-1H-pyrazole-4-ylmethyl)ndimethylacetamide,

2-{8-[4-chloro-6-methyl-2-(2-oxo-3-trifluoromethyl-2H-pyridine-1-ylmethyl)pyridine-3-ylethoxy]-2-methylinosine-4-yl}-3-methyl-3H-imidazol-4-carbonitril,

1-{4-chloro-6-methyl-3-[2-methyl-4-(4-methyl-2H-pyrazole-3-yl)quinoline-8-intoximeter]pyridine-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,

1-{4-chloro-6-methyl-3-[2-methyl-4-(4-methyl-1H-pyrazole-3-yl)quinoline-8-intoximeter]pyridine-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,

5-{8-[4-chloro-2-(2-oxo-3-trifluoromethyl-2H-pyridine-1-ylmethyl)pyridine-3-ylethoxy]-2-methylinosine-4-yl}-3-methyl-3H-imidazol-4-carbonitril,

1-{4-chloro-3-[4-(4-chlorothiazole-5-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,

1-{4-chloro-3-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,

1-{3-[4-(5-chlorothiazole-4-yl)-2-methylinosine-8-intoximeter]-4-methoxypyridine-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,

1-{4-chloro-3-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-methylinosine-8 iloxi ethyl]pyridine-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,

amide 5-{8-[4-chloro-6-methyl-2-(2-oxo-3-trifluoromethyl-2H-pyridine-1-ylmethyl)pyridine-3-ylethoxy]-2-methylinosine-4-yl}-1-methyl-1H-pyrrole-2-carboxylic acid,

amide 5-{8-[4-chloro-2-(3-cyano-2-oxo-2H-pyridin-1-ylmethyl)-6-methylpyridin-3-ylethoxy]-2-methylinosine-4-yl}-1-methyl-1H-pyrrole-2-carboxylic acid,

1-{4-chloro-3-[4-(4-hydroxymethyl-2H-pyrazole-3-yl)-2-methylinosine-8-intoximeter]pyridine-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,

1-{4-chloro-3-[4-(4-hydroxy-1H-pyrazole-3-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,

1-{4-chloro-3-[4-(4-hydroxy-1H-pyrazole-3-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,

1-{4-chloro-3-[4-(4-perperson-1-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,

1-{3-[4-(5-chlorothiazole-4-yl)-2-methylinosine-8-intoximeter]-4-methoxypyridine-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,

2-{8-[5-fluoro-2-methoxy-3-(2-oxo-3-trifluoromethyl-2H-pyridine-1-ylmethyl)pyridine-4-ylethoxy]-2-methylinosine-4-yl}-3-methyl-3H-imidazol-4-carbonitril,

1-{4-chloro-6-methyl-3-[2-methyl-4-(5-methyl-1H-imidazol-4-yl)quinoline-8-intoximeter]pyridine-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,

1-(1-{4-chloro-3-[2-methyl-4-(4-methyl-1H-pyrazole-3-yl)quinoline-8-intoximeter]pyridine-2-yl}ethyl)-2-oxo-1,2-dihydropyridines-3-carbonitril,

1-(1-{4-chloro-3-[4-(4-hydroc and-1H-pyrazole-3-yl)-2-methylinosine-8-intoximeter]pyridine-2-yl}ethyl)-2-oxo-1,2-dihydropyridines-3-carbonitril,

amide 5-{8-[4-chloro-2-(3-cyano-2-oxo-2H-pyridin-1-ylmethyl)pyridine-3-ylethoxy]-2-methylinosine-4-yl}-1-methyl-1H-pyrrole-2-carboxylic acid,

1-{4-chloro-3-[4-(4-perperson-1-yl)-2-methylinosine-8-intoximeter]pyridine-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,

1-(1-{4-chloro-3-[4-(4-hydroxy-1H-pyrazole-3-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-yl}ethyl)-2-oxo-1,2-dihydropyridines-3-carbonitril,

1-{4-chloro-6-methyl-3-[2-methyl-4-(3-methylisoxazol-4-yl)quinoline-8-intoximeter]pyridine-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,

1-{5-chloro-4-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-methylinosine-8-intoximeter]-2-hydroxypyridine-3-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,

1-{4-methoxy-6-methyl-3-[2-methyl-4-(4-methyl-1H-pyrazole-3-yl)quinoline-8-intoximeter]pyridine-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,

1-{4-chloro-3-[4-(4-hydroxymethyl-1H-pyrazole-3-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,

1-{4-chloro-3-[4-(5-cortisol-2-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitrile.

In the third aspect the problem underlying the present invention is permitted by pharmaceutical composition that contains one or more compounds according to the first and/or second aspect of the present invention and optionally at least one washes is in the media, excipient and/or adjuvant.

In the embodiment of the third aspect the pharmaceutical composition is manufactured in the form of an aerosol, cream, gel, pills, capsules, syrup, solution, dermal patch or device for delivery of pharmaceutical agents.

In a fourth aspect the problem underlying the present invention is resolved by way of inhibiting the binding of BK to the receptor B2 VK in vitro, the method comprises contacting the receptor B2 VK at least one compound according to the first and/or second aspect of the present invention or its salt under the conditions and in sufficient quantity for the detectable inhibition of binding VK or any other substance to the receptor B2 VK.

In a fifth aspect the problem underlying the present invention is resolved by way of localization or detection of receptor B2 VK in fabric, preferably of a piece of tissue, in vitro, including

(a) contacting the tissue sample containing the receptor B2 VK, with detectable labeled compound according to the first and/or second aspect of the present invention under conditions that allow the compound to contact the receptor B2 VK, and

(b) detection of the associated connection.

In the embodiment of the fifth aspect, the compound is in the state of the radioactive isotope, labeled marker fluorescence or labeled marker luminescence or labeled antibody.

In a sixth aspect the problem underlying the present invention is permitted due to the use of compounds according to the first and/or second aspect of the present invention or a pharmaceutical composition according to the third aspect of the present invention for the manufacture of a medicinal product for treating and/or preventing the disease or condition.

In the embodiment of the sixth aspect of the present invention, the condition or disease is susceptible to modulation of receptor B2 VK.

In the variant of the sixth aspect of the state are skin disorders, eye diseases, ear diseases, diseases of the mouth, throat, and respiratory diseases; gastrointestinal diseases; diseases of liver, gallbladder and pancreas; diseases of the urinary tract and kidneys; diseases of the male genitalia and female genital organs; diseases of the hormonal system; metabolic diseases; cardiovascular diseases; diseases of the blood; lymphatic diseases; disorders of the Central nervous system; disorders of the brain; diseases of the musculoskeletal system; allergic disorders; pain; infectious diseases; inflammatory disorders; trauma; they ontologicheskie violations; cancer; hereditary disease; or swelling.

In a seventh aspect the problem underlying the present invention is permitted owing to the method of treatment of a subject in need of such treatment, comprising introducing the compound according to the first and/or second aspect of the present invention or a pharmaceutical composition according to the third aspect.

Offered here is the receptor modulators B2 VK exhibit high activity against receptor B2 VK person (i.e. have an inhibition constant (IC50) to compete with the binding of labeled VK with receptor B2 VK person less than 5 micromoles) or very high activity against receptor B2 VK person (i.e. have IC50to compete with the binding of labeled VK with receptor B2 VK person preferably less than 50 nanomoles). In some embodiments, the implementation of such modulators are active receptor B2 VK other than species, such as rats, mice, gerbils, Guinea pigs, rabbits, dogs, cats, pigs or abacadabra monkeys.

Activity and more specifically the pharmacological activity of the B2 receptor modulators according to the present invention can be analyzed using appropriate in vitro assays. For example, the value of the IC50modulators according to N. the present invention to the receptor B2 can be determined by analyzing the binding of radioligand, such as the analysis presented in example 754, which, thus, is a variation of the implementation of the standard in vitro assays mediated by receptor B2 VK. Inhibiting action of modulators of receptor B2, proposed here for the B2 receptor, it is possible to determine, for example, by analyzing the mobilization of calcium, such as the analysis proposed in example 755.

Preferred compounds of the invention have the IC50(premaxilla inhibitory concentration) of about 5 micromoles or less, even more preferably IC50approximately 500 nm or less, or even 50 nm or less, even more preferably IC50approximately 10 nm or less or even 1 nanomoles or less in the above tests.

The present invention additionally relates to other aspects to pharmaceutical compositions containing at least one modulator of the receptor B2 VK, as described here, in combination with a physiologically acceptable carrier or excipient. Also proposed methods for such pharmaceutical compositions. Such compositions are particularly applicable in the treatment mediated by the B2 receptor of the diseases described below.

These and other aspects of the present invention will become apparent after reference to the following detailed description.

Join in on the eating described here, using standard nomenclature. In the case of compounds having asymmetric centers, it should be clear (unless noted)that includes all optical isomers and their mixtures. Compounds with two or more asymmetric elements may also be present as mixtures of diastereomers. In addition, compounds with carbon-carbon double bond may be present in the Z - and E-forms, and the present invention includes all isomeric forms of the compounds, unless otherwise stated. When the connection exists in various tautomeric forms, described the connection is not limited to any one particular tautomerism, but rather is intended to include all tautomeric forms. Further assume that the described compounds include compounds in which one or more atoms are replaced by isotopes (i.e. the atom that has the same sequence number but different mass number). As a General example and not limited to isotopes of hydrogen include tritium and deuterium and isotopes of carbon include11C,13C and14C.

Compounds according to the formulas presented here, which have one or more stereogenic centers, have an enantiomeric excess of at least 50%. For example, such compounds may have the enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95% or 98%. In some vari is ntah the communication have the enantiomeric excess of at least 99%. It should be obvious that the individual enantiomers (optically active form) can be obtained by asymmetric synthesis, synthesis from optically pure precursors or racemate separation. The separation of the racemates can be accomplished, for example, conventional methods such as crystallization in the presence of a separating agent, or chromatography using, for example, HPLC with chiral column.

Some compounds described here using the General formula, which includes characters (e.g. A, R1-R12, W, Y, Z). Unless otherwise noted, each symbol in the formula has a value independent of any other character, and any character that appears in the formula more than once, is set independently for each case. For example, if it is shown that the group is substituted by 0-2 R*, the group may be unsubstituted or substituted by groups R* up to two and R* in each case selected independently from the definition of R*. In addition, combinations of substituents and/or symbols are permissible only if such combinations result in stable compounds (i.e. compounds that can be identified, characterized and tested for biological activity).

The term “8-(heteroaromatics)quinoline”used here refers to the here presented compounds of the formula (I)and their salts predpochtitelno pharmaceutically acceptable salts. It should be obvious that such connections may be, as indicated, optionally substituted.

“Pharmaceutically acceptable salt described herein, the compound is a salt of the acid or the base, which is usually considered in this area, is suitable for use in contact with the tissues of humans or animals without excessive toxicity or carcinogenicty and preferably without irritation, allergic reactions or other problems or complications. Such salts include salts with mineral and organic acids of the basic residues such as amines, and salts with alkali metals or organic bases acidic residues such as carboxylic acids.

Suitable pharmaceutical salts include, but are not limited to, salts of acids, such as hydrochloric, phosphoric, Hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluensulfonate, methanesulfonate, benzolsulfonat, ethicality, 2-hydroxyethansulfonate, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, amoeba, succinic, fumaric, maleic, propionic, hydroxymaleimide, itestosterone, phenylacetic, alcamovia acid, such as acetic who, HOOC-(CH2)n-COOH, where n is any integer from 0 to 4 (i.e. 0, 1, 2, 3, or 4), and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. The average person skilled in the art should know further pharmaceutically acceptable salts for the proposed connection. In General, pharmaceutically acceptable salt, acid or base can be synthesized from the parent compound which contains a basic or acidic part, by any conventional chemical methods. Briefly, such salts can be obtained by reaction of these compounds in the form of free acids or bases with the stoichiometric amount of the appropriate base or acid in water or in an organic solvent or a mixture of the two. Usually it is preferable to use non-aqueous environments, such as a simple ether, ethyl acetate, ethanol, isopropanol or acetonitrile.

It should be obvious that each compound of formula (I) may, if necessary, be present in the form of a hydrate, MES or non-covalent complex. In addition, the scope of the present invention have various crystalline forms and polymorphs, as well as prodrugs provided compounds of formula (I).

“Prodrug” is a compound that is may not fully satisfy the structural requirements of the proposed compounds, but is modified in vivo after administration to a subject or patient education offered here is the compounds of formula (I). For example, the prodrug may be acylated derivative of the proposed connection. Prodrugs include compounds in which the hydroxy, carboxy, amine or sulfhydryl groups linked to any group which when administered to a subject, the mammal is cleaved with the formation of free hydroxy, carboxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formiate, phosphate and benzoate derivatives of alcohol and amine functional groups in the proposed connections. Prodrugs of the compounds suggested here can be obtained by modifying functional groups present in the compounds in such a way that the modifying group tsapralis in vivo with the formation of the “parent” compounds.

The term “Deputy”, used here, refers to the molecular part, which is covalently linked to the atom of interest in the molecule. For example, “Deputy ring may be such as halogen, an alkyl group, halogenation group, hydroxy, cyano, amino, nitro, mercapto or other described here, Deputy, which is covalently bonded with and the Ohm (preferably a carbon atom or nitrogen), which is a member of the ring. The term “substituted”as used here, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the normal valency of the specified atom is not exceeded, and that the substitution results in the formation of stable compounds (i.e. compounds that can be identified, characterized and tested for biological activity). When a Deputy is oxo (i.e. =O)on the atom are replaced by 2 hydrogen atom. Oxoprop, which is Deputy aromatic carbon atom leads to the turning-CH - b-C(=O)- and the loss of aromaticity. For example, peredelnoj group substituted by oxo, is pyridone.

The expression alkyl refers to a saturated hydrocarbon group, an unbranched or branched chain, containing from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, more preferably from 1 to 6 carbon atoms, for example methyl, ethyl, sawn, ISO-propyl, n-butilkoi, isobutylene, second-butilkoi, tert-butilkoi, n-Pintilei, n-hexylene, 2,2-dimethylbutyl or n-aktiline group.

Expression of alkenyl and quinil are at least partially unsaturated hydrocarbon groups with unbranched or branched chain, containing from 2 d is 20 carbon atoms, preferably from 2 to 12 carbon atoms, more preferably from 2 to 6 carbon atoms, for example atenolol, allyl, acetylenyl, propargyl, isoprenaline or Gex-2-Tilney group. Alkeneamine groups preferably have one or two (preferably one) double bond and alkyline groups have one or two (preferably one) triple bond.

In addition, the terms alkyl, alkenyl and quinil belong to groups in which one or more hydrogen atoms is replaced, each independently, a halogen atom (preferably F or Cl), such as 2,2,2-trichlorethylene or triptorelin group.

Expression heteroalkyl refers to alkyl, alkenylphenol or alkenylphenol group (for example, heteroalkyl, heteroalkyl), in which one or more (preferably 1, 2 or 3) carbon atoms are replaced, each independently, an oxygen atom, nitrogen, phosphorus, boron, selenium, silicon, or sulfur, preferably oxygen, sulfur or nitrogen). In addition, the expression of heteroalkyl refers to a carboxylic acid, or a group formed from carboxylic acids, such as, for example, acyl, arylalkyl, alkoxycarbonyl, acyloxy, aryloxyalkyl, carboxyaniline, alkylcarboxylic, alkylcarboxylic, alkylenedioxy or alkoxycarbonyl.

Examples hetaeras the alkyl groups are groups of the formula-S-Y a-L, -S,-Ya-CO-NRaRb, -Ya-NR-CO-NRaRb, -Ya-NRc-CO-O-Rc, -Ya-NRc-CO-Rc, -Ya-O-CO-NRaRb, -Ya-CO-NRaRb-O-Ya-CO-NaRb, -Ya-NRc-CO-L-Ya-L, -Ya-O-CO-O-Rc, -Ya-O-CO-Rc, Rc-O-Ya-, Rc-S-Ya-, Ra-N(Rb)-Ya-, Rc-CO-Ya-, Rc-O-CO-Ya-, Rc-CO-O-Ya-, Rc-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-Ya-, Rc-SO-Ya-, Rc-SO2-Ya-, -Ya-NRc-SO2-NRaRb, -Ya-SO2-NRaRb, -Ya-NRc-SO2-Rc, Ra-O-CO-N(Rb)-Ya-, Ra-N(Rb)-C(=NRd)-N(Rc)-Ya-, Rc-S-CO-Ya-, Rc-CO-S-Ya-, Rc-S-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-S-Ya-, Rc-S-CO-O-Ya-, Rc-O-CO-S-Ya-, Rc-S-CO-S-Ya-; and Rarepresents a hydrogen atom, a C1-C6alkyl, C2-C6alkenyl,2-C6alkinyl or connected with Rbwith the formation of 4-10-membered cycloalkyl or geterotsiklicheskie; Rbrepresents a hydrogen atom, a C1-C6alkyl, C2-C6alkenyl or2-C6alkinyl, or Rbtaken together with Ra, form a 4-10-membered cycloalkyl is or heteroseksualci; Rcrepresents a hydrogen atom, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl or optionally substituted C2-C6quinil; Rdrepresents a hydrogen atom, a C1-C6alkyl, C2-C6alkenyl or2-C6quinil; L represents cycloalkyl, heteroseksualci, alkylsilanes, heteroalicyclic, aryl, optionally substituted heteroaryl, aralkyl or heteroalkyl and Yais a relationship With1-C6alkylenes,2-C6alkenylamine or2-C6alkynylamino group; each heteroalkyl group contains at least one carbon atom and possibly one or more hydrogen atoms are replaced by fluorine atoms or chlorine. Specific examples heteroalkyl groups are methoxy, triptoreline, ethoxy, n-propyloxy, isopropoxy, tert-Butylochka, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino, dimethylamino, diethylamino, isopropylethylene, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyl, simple enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, atomic charges, methoxycarbonyl, etoxycarbonyl, isobutylamine, N-ethyl-N-methylcarbamoyl and N-methylcarbamoyl. The trail is relevant examples heteroalkyl groups are nitrile, isonitrile, lanata, thiocyanate, isocyanate, isothiocyanate and alternately group. Example heterouncinata group is a group of formula-CH2-CH(OH) -, or-CONH-.

Expression cycloalkyl refers to a saturated or partially unsaturated cyclic group that contains one or more rings (preferably 1 or 2)containing from 3 to 14 carbon atoms in the ring, preferably from 3 to 10 (preferably 3, 4, 5, 6 or 7) of the carbon atoms of the ring. In the embodiment, partially unsaturated cyclic group has one, two or more double bonds, for example, is cycloalkenyl group. Expression cycloalkyl, in addition, refers to groups in which one or more hydrogen atoms is replaced, each independently, fluorine atoms, chlorine, bromine or iodine or groups HE, =O, SH, =S, NH2, =NH, CN or NO2so, for example, a cyclic ketone, such as cyclohexanone, 2-cyclohexenone or Cyclopentanone. The following specific examples cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentamine, Spiro[4,5]dekanalna, norbornylene, tsiklogeksilnogo, cyclopentadiene, cyclohexadiene, Detelinara, bicyclo[4.3.0]Danilina, tetralinyl, Cyclopentasiloxane, tortilleria or cyclohex-2-anilina group is A.

Expression heteroseksualci refers to cycloalkyl group, the definition of which is indicated above and in which one or more (preferably 1, 2 or 3) carbon atoms of the ring are replaced, each independently, an oxygen atom, nitrogen, silicon, selenium, phosphorus or sulfur, preferably oxygen, sulfur or nitrogen). Heterocytolysine group preferably has 1 or 2 ring containing from 3 to 10 (preferably 3, 4, 5, 6 or 7) of the carbon atoms of the ring. In addition, the expression of heteroseksualci refers to groups in which one or more hydrogen atoms is replaced, each independently, fluorine atoms, chlorine, bromine or iodine or groups HE, =O, SH, =S, NH2, =NH, CN or NO2. Examples are piperideine, piperazinilnom, morpholinyl, retropinnidae, pyrrolidinyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolidinone group, as well as the lactam, lactone, cyclic imide and a cyclic anhydride.

Expression alkylsilanes refers to a group containing both cycloalkyl, and also alkyl, alkenylphenol or alkenylphenol group according to the above definitions, for example, alkylcyclohexanes, cycloalkylation, alkylcyclobutanones, alkenylsilanes and alkylcyclohexanes groups. Alkylcyclohexane gr is the PAP preferably contains cycloalkyl group, which system contains one or two rings having from 3 to 10 (preferably 3, 4, 5, 6 or 7) carbon atoms, and one or two alkyl, alkeline or alkyline group having from 1 or 2 to 6 carbon atoms, and cyclic groups are optionally substituted.

Expression heteroalicyclic refers to alkylcyclohexanes groups, definitions of which are listed above and have one or more (preferably 1, 2 or 3) carbon atoms are replaced, each independently, an oxygen atom, nitrogen, silicon, selenium, phosphorus or sulfur, preferably oxygen, sulfur or nitrogen). Heteroalicyclic group preferably contains 1 or 2 ring, having from 3 to 10 (preferably 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkeline, alkyline or heteroalkyl group having from 1 or 2 to 6 carbon atoms. Examples of such groups are alkylchlorosilanes, alkylchlorosilanes, alkenylsilanes, alginolyticus, heteroalicyclic, heterooligomerization and heterooligomerization, and cyclic groups are optionally substituted and saturated or mono-, di - or trimensional.

The expression aryl or Ar refers to an aromatic group that contains one or more rings, the content is from 6 to 14 carbon atoms in the ring, preferably from 6 to 10 (preferably 6) carbon atoms of the ring. In addition, the expression of aryl (or Ar) refers to groups in which one or more hydrogen atoms is replaced, each independently, fluorine atoms, chlorine, bromine or iodine or groups HE, SH, NH2, CN or NO2. Examples are phenyl, naftalina, biphenylene, 2-Fortunella, onlineline, 3-nitroaniline or 4-hydroxyproline group.

Expression heteroaryl refers to an aromatic group that contains one or more rings containing from 5 to 14 ring atoms, preferably from 5 to 10 (more preferably 5 or 6) ring atoms, and contains one or more (preferably 1, 2, 3, or 4 atoms of oxygen, nitrogen, phosphorus or sulfur ring (preferably O, S or N). In addition, the expression of heteroaryl refers to groups in which one or more hydrogen atoms is replaced, each independently, fluorine atoms, chlorine, bromine or iodine or groups HE =OH, SH, NH2, =NH, CN or NO2. Examples are 4-pyridyl, 2-imidazolyl, 3-phenylpyrrole, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazoles, indolyl, benzimidazolyl, pyridazinyl, chinoline, purinol, carbazolyl, acridines, pyrimidyl, 2,3'-biphenyl, 3-pyrazolyl and ethenolysis.

Expression aralkyl refers to a group containing both aryl is s, so also alkyl, alkenylphenol, alkenylphenol and/or cycloalkyl group according to the above definitions, such as, for example, arylalkyl, arylalkylamine, arylalkylamine, arylcyclohexylamine, arylcyclohexylamine, alkylarylsulfonate and alkylaminocarbonyl group. Specific examples of aralkyl are toluene, xylene, mesitylene, styrene, benzylchloride, o-vtortola, 1H-inden, tetralin, dihydronaphthalene, indanan, vinylcyclopentane, cumene, cyclohexylphenol, fluoren and indan. Kalkilya group preferably contains a system of one or two aromatic rings (1 or 2 rings)that contain from 6 to 10 carbon atoms, and one or two alkyl, alkeline and/or alkyline group containing from 1 or 2 to 6 carbon atoms, and/or cycloalkyl group containing 5 or 6 carbon atoms of the ring.

Expression heteroalkyl refers to Uralkaliy group, the definition of which is indicated above, one or more (preferably 1, 2, 3, or 4) carbon atoms are replaced, each independently, an oxygen atom, nitrogen, silicon, selenium, phosphorus, boron or sulfur, preferably oxygen, sulfur or nitrogen), that is, groups containing both aryl or heteroaryl, and alkyl, alkenylphenol, alkenylphenol and/or heteroalkyl, and/or cycloalkyl, and/or heterocyclyl the ilen group according to the above definitions. Heteroalkyl group preferably contains a system of one or two aromatic rings (1 or 2 rings)that contain from 5 or 6 to 10 ring atoms, and one or two alkyl, alkeline and/or alkyline group containing from 1 or 2 to 6 carbon atoms, and/or cycloalkyl group containing 5 or 6 carbon atoms in the ring, with 1, 2, 3 or 4 of the carbon atoms is replaced, each independently of the other, atoms of oxygen, sulfur or nitrogen.

Examples heteroalkyl groups are arigatomina, aalgaardaalgaardgina, allgemeinreaktion, arrangement.alitalia, allakariallak, arrangedelementcollection, arrangementvalentine, heteroallyl, heteroarylboronic, heteroallyl, heterooligomerization, heteroalicyclic, heteroarylboronic, heterooligomerization, heterooligomerization, heterokedasticity, heterooligomerization, heterooligomerization, heterooligomerization, heterooligomerization and heterooligomerization group, and the cyclic group is saturated or mono-, di - or trimensional. Specific examples are tetrahydroisoquinolinium what I benzoline, 2 - or 3-ationally, 4-methylpyridine, 2-, 3 - or 4-metoksifenilny, 4-ethoxyphenyl, 2-, 3 - or 4-carboxypenicillins group.

Expression cycloalkyl, heteroseksualci, alkylsilanes, heteroalicyclic, aryl, heteroaryl, aralkyl and heteroaryl refers to groups in which one or more hydrogen atoms in these groups are replaced, each independently, fluorine atoms, chlorine, bromine or iodine or groups HE, =O, SH, =S, NH2, =NH, CN or NO2.

The expression “optionally substituted” refers to groups in which one or more hydrogen atoms is replaced, each independently, fluorine atoms, chlorine, bromine or iodine or groups HE, =O, SH, =S, NH2, =NH, CN or NO2. In addition, this expression refers to groups in which one or more hydrogen atoms is replaced, each independently, unsubstituted With1-C6alkyl, unsubstituted With2-C6alkenylphenol, unsubstituted With2-C6alkenylphenol, unsubstituted With1-C6heteroalkyl, unsubstituted With3-C10cycloalkyl, unsubstituted With2-C9geteroseksualnoe, unsubstituted With6-C10aryl, unsubstituted With1-C9heteroaryl, unsubstituted With7-C12aranceles or unsubstituted With2-C11heteroalkyl the Noah group.

Used here expressing words, the definition limits the range of chain length, such a range, such as “1 to 5”means any integer from 1 to 5, i.e 1, 2, 3, 4 and 5. In other words, it is assumed that any range defined by two precisely specified integers, contains and describes any integer defined by these limits, and any integer that is included in the specified range.

The present invention also includes all isotopes of atoms described compounds. Isotopes are atoms with the same atomic number but different mass number. For example, tritium and deuterium are isotopes of hydrogen. Examples of isotopes of carbon are11C,13C and14C.

Therapeutic use of compounds of formula I, their pharmacologically acceptable salts, solvate or hydrate, and also containing products and pharmaceutical compositions is within the scope of the present invention. The present invention relates also to the use of these compounds of formula (I) as active ingredients for the manufacture of a medicinal product.

The pharmaceutical compositions according to the present invention contain at least one compound of formula (I) and, optionally, one or more substances-carriers, excipients and/or adjuvantation compositions can optionally contain, for example, one or more components from water, buffers (e.g., neutral buffered saline or phosphate buffered saline solution), ethanol, mineral oil, vegetable oil, dimethyl sulfoxide, carbohydrates (e.g. glucose, mannose, sucrose or dextrans), mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione, and/or preservatives. In addition, in the proposed pharmaceutical compositions can be included (but not necessarily) one or more other active ingredients. For example, the compounds of the invention can appropriately be used in combination with antibiotic, antifungal or antiviral agent, an antihistamine, non-steroidal anti-inflammatory drug, disease modifying Antirheumatic drug, a cytotoxic drug, drug activity, modulating the activity of smooth muscles, or mixtures of the above components.

The pharmaceutical compositions can be manufactured in a form suitable for any route of administration, including, for example, local (for example, dermal or ocular), oral, transbukkalno, nasal, vaginal, rectal is or parenteral administration. Used herein, the term " parenteral administration includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, eye, intraorbital, intra-articular and intraperitoneal injection, as well as any similar way of injections or infusions. In some embodiments, implementation of the preferred compositions are in a form suitable for oral administration. Such forms include, for example, tablets, lozenges, pellets, aqueous or oil suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. In the following other embodiments, the implementation presented here, the composition can be made in the form of a lyophilisate. For some States (for example, when treating such skin conditions as burns, or itching) may be the preferred drug for local injection.

Compositions intended for oral use may optionally contain one or more components, such as sweetening agents, corrigentov, coloring agents and/or preservatives to obtain attractive in appearance and palatable preparations. Tablets contain the active ingredient mixed with physiologically acceptable excipients, to the E. are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating or dezintegriruetsja agents (for example, corn starch, or alginic acid), binding agents (e.g. starch, gelatin or the Arabian gum) and lubricating agents (for example, magnesium stearate, stearic acid or talc). Tablets may be uncoated or may be coated by known methods to delay disintegration and absorption in the gastrointestinal tract and thereby provide steadfastly supported actions for a longer period of time. You can apply, for example, a substance for the time delay, such as glycerylmonostearate or glycerylmonostearate.

Preparations for oral administration can also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (for example, peanut oil, liquid paraffin or olive oil).

Aqueous suspensions contain the active ingredient(s) in a mixture with excipients suitable for the manufacture of aqueous suspensions. Still the excipients include suspendresume agents (for example, sodium salt of carboxymethylcellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and Arabic gum), and dispersing or wetting agents (e.g., existing in the nature phosphatides, such as lecithin, condensation products of accelerated with fatty acids, such as polyoxyethylenated, condensation products of ethylene oxide with aliphatic alcohols with long chain, such as heptadecafluorooctane, condensation products of ethylene oxide with partial esters formed from fatty acids and exit, such as monooleate polyoxyethylenesorbitan, or condensation products of ethylene oxide with partial esters formed from fatty acids, and anhydrides of exit, such as monooleate of polyoxyethylenesorbitan). Aqueous suspensions can also contain one or more preservatives, for example ethyl or n-propyl-p-hydroxybenzoate, one or more coloring agents, one or more corrigentov and one or more sweetening agents such as sucrose or saccharin.

Oil suspensions can be made by suspendirovanie active ingredients in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oil suspense may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as agents listed above, and/or corrigent(s), can be added to provide a pleasant taste of oral drugs. Such drugs can be protected from damage by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for obtaining aqueous suspension by the addition of water, contain the active ingredient mixed with dispersing or wetting agent, suspenders agent and one or more preservatives. Suitable dispersing or wetting agents and suspendresume agents are illustrated by such agents, already mentioned above. May also contain additional excipients, such as sweeteners, coloring agents and corrigentov.

Pharmaceutical compositions may also be in the form of emulsions of the type oil-in-water. The oil phase may be a vegetable oil (such as olive oil or peanut oil), mineral oil (e.g., liquid paraffin) or their mixture. Suitable emulsifying agents include existing in nature gums (e.g., Arabian gum or tragacanth gum)present in nature phosphatides (e.g., soy lecithin, and esters or partial esters formed from fatty sour is and exit), anhydrides (for example, monooleate sorbitan) and condensation products of partial esters formed from fatty acids and exit, with ethylene oxide (for example, monooleate of polyoxyethylenesorbitan). The emulsion may also contain one or more sweetening agents, and/or corrigentov.

Syrups and elixirs can be made with sweetening agents such as glycerin, propylene glycol, sorbitol or sucrose. Such preparations can also contain one or more of the demulsifying agents, preservatives, corrigentov and/or coloring agents.

The compounds may be formulated into preparations for local or local administration, such as local application to the skin or mucous membranes such as the eyes. The preparations for the local introduction typically contain local filler, combined with the active ingredient(s), with additional optional components or without them. Appropriate local fillers, and additional components are well known in this area and it should be obvious that the choice of filler will depend on the particular physical form and method of delivery. Local fillers include water; organic solvents, such as alcohols (e.g. ethanol or isopropyl alcohol) or glycerol; glycols (e.g., butylene, isoprene or propyl is glycol); aliphatic alcohols (such as lanolin); mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerin; substance-based lipids, such as fatty acids, acylglycerides (including oils, such as mineral oil, and fats of natural or synthetic origin), phosphoglycerides, sphingolipids and waxes; substance-based proteins, such as collagen and gelatin; substances based on silicone (both non-volatile and volatile) and substance-based hydrocarbons such as microcube and polymer matrix. The composition may further include one or more components adapted to improve the stability or effectiveness of the applied drug, such as stabilizing agents, suspendresume agents, emulsifying agents, viscosity regulators, gel-forming agents, preservatives, antioxidants, agents that enhance penetration through the skin, moisturizing agents and substance that provides steadfastly supported the release. Examples of such components are described in Martindale-The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington''s Pharmaceutical Sciences. The preparations can contain microcapsules, such as microcapsules of hydroxymethylcellulose or gelatin, liposomes, albumin microspheres, microemulsions, nanoparticles, or nanocapsules.

Drug product for which applications can be obtained in various physical forms, includes, for example, solid forms, pastes, creams, foams, lotions, gels, powders, aqueous liquids, emulsions, sprays, skin patches. Physical appearance and viscosity of such forms can be regulated by the presence and amount of emulsifier(s) and agent(s)regulating the viscosity present in the drug. Solid forms are usually dense and are not suitable for pouring, they are usually made in the form of plates or rods, or in the form of particles; solid forms may be opaque or transparent and may not necessarily contain solvents, emulsifiers, moisturizers, softeners, fragrances, dyes/coloring agents, preservatives and other active ingredients that increase or enhance the effectiveness of the final product. Creams and lotions are often similar to each other, differing mainly in their viscosity; as lotions and creams can be opaque, transparent or bright and often contain emulsifiers, solvents and regulating the viscosity agents, and moisturizers, softeners, fragrances, dyes/coloring agents, preservatives and other active ingredients that increase or enhance the effectiveness of the final product. Gels can be obtained with a viscosity range from high viscosity or viscosity, giving density to low viscosity or viscosity, making the gel Razi the military. These drugs like lotions and creams can also contain solvents, emulsifiers, moisturizers, softeners, fragrances, dyes/coloring agents, preservatives and other active ingredients that increase or enhance the effectiveness of the final product. Liquids are more mobile than the creams, lotions or gels, and often do not contain emulsifiers. Liquid local products often contain solvents, emulsifiers, moisturizers, softeners, fragrances, dyes/coloring agents, preservatives and other active ingredients that increase or enhance the effectiveness of the final product.

Suitable emulsifiers for use in the preparations for the local introduction include but are not limited to, ionic emulsifiers, Cetearyl alcohol, nonionic emulsifiers, such Aeronomy ether of polyoxyethylene, stearate PEG-40, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth-alcohol, stearate PEG-100 and literallayout. Appropriate regulatory viscosity agents include, but are not limited to, protective colloids or non-ionic gums such as hydroxyethylcellulose, xanthan gum, magnesium silicate of aluminium, silicon dioxide, microcrystalline wax, beeswax, paraffin, cetylpalmitate. The gel composition can be obtained by adding gelora the ith agent, such as chitosan, methyl cellulose, ethylcellulose, polyvinyl alcohol, polyquaternium, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, carbomer or ammoniaand the glycyrrhizinate. Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants. For example, local products, it is possible to apply one or more components of dimethiconol, Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, lauramide DEA, cocamide DEA and cocamide MEA, olivetan, chloride cocamidopropylbetaine-PG-demonia and sulphate of ammoniuria.

Suitable preservatives include, but are not limited to, antimicrobial agents, such as methylparaben, propylparaben, sorbic acid, benzoic acid and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, a mixture of sodium ascorbate/ascorbic acid and propylgallate. Suitable humectants include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol and butyleneglycol. Suitable softeners include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, its earlinet and mineral oil. Suitable flavoring agents and coloring tools include, but are not limited to, FD&C red No. 40 and FD&C yellow No. 5. Other suitable additional ingredients that can be included in the local drug include, but are not limited to, abrasives, absorbents, protivozmeinaya agents, proteopedia agents, antistatic agents, astringents (e.g., extract of witch hazel, alcohol, and plant extracts such as chamomile extract), binders/excipients, buffering agents, chelating agents, agents, film forming, conditioning agents, propellants, agents which impart opacity, pH regulators and substance protectors.

An example of a suitable local filler for the preparation of the gel system is hydroxypropylcellulose (2,1%); a mixture of 70/30 isopropyl alcohol/water (90,9%); propylene glycol (5.1%) and Polysorbate 80 (1.9 per cent). An example of a suitable local filler for the preparation of a foam is a mixture of cetyl alcohol (1,1%); stearyl alcohol (0,5%); quaterni 52 (1,0%); propylene glycol (2,0%); ethanol 95 PGF3 (61,05%); deionized water (30,05%); hydrocarbon propellant R75 (4,30%). All percentages are mass.

Typical methods of local delivery compositions include applying them using your fingers, apply with skin is of a physical applicator, such as fabric, cloth, swab, stick or brush; spray including spray with the formation of a light mist, aerosol or foam); the application of drops; rubbing; soaking and washing. You can also use fillers for controlled release and can be made of a composition for percutaneous administration, such as transdermal patch.

The pharmaceutical composition can be manufactured in the form of preparations for inhalation, including sprays, light mists or aerosols. These drugs are particularly applicable for the treatment of asthma or other respiratory conditions. For inhalation drugs connection, proposed here, can be delivered through any means of inhalation, well-known specialist in this field. Such methods and devices for inhalation include, but are not limited to, inhalers filing measured doses, containing such propellants as CFC or HFA, or propellants which are physiologically acceptable and sustainable for the environment. Other suitable devices are an inhaler for the inhalation, the inhaler with many doses of a dry powder or aerosol sprays. Aerosol preparations for use in the present method typically include propellants, surfactants and the solvents they can fill in the conventional aerosol containers, which are closed with a suitable metering valve.

Composition formulations for inhalation may contain liquid or powder composition containing the active ingredient, which is suitable for spraying and intrabronchial administration, or aerosol composition introduced by means of the aerosol device that supplies the measured dose. Suitable liquid compositions contain the active ingredient in an aqueous, pharmaceutically acceptable inhaled solvent, such as isotonic saline or bacteriostatic water. Solutions imposed by means of a pump or activated by squeezing device for spraying or any other accepted method, which causes the flow or makes it possible to supply the desired metered quantity of a liquid composition, which inhalation is introduced into the lungs of the patient. Drugs, in which the carrier is a liquid and which are suitable for administration in the form of, for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.

Preparations or compositions suitable for nasal administration, in which the carrier is a solid include a coarse powder having RA which measures particles, for example, in the range of 20-500 microns, which is administered by the manner in which the drug powder is inhaled through the nose (i.e. by rapid inhalation through the nasal passage of powder from the container, which held close to the nose). Suitable powder composition include, as an illustration, powdered preparations of the active ingredient is thoroughly mixed with lactose or other inert powders acceptable for intrabronchial administration. Powder composition can be entered using aerosol inhaler or can be included in destructible capsule, which the patient may insert a device that breaks the capsule and blows the powder into a uniform stream, suitable for inhalation.

Pharmaceutical compositions can also be obtained in the form of suppositories (e.g., for rectal administration). Such compositions can be obtained by mixing the drug with a suitable not cause irritation excipient, which is solid at normal temperature but becomes liquid at rectal temperature and therefore will melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.

The pharmaceutical compositions can be manufactured in the form of drugs with firmly support ivemy release (i.e. this drug, like a capsule, which provides slow release of the modulator after the introduction). Hard drugs are usually obtained using well-known techniques, and introduce, for example, oral, rectal or subcutaneous implantation, or by implantation at a desired destination target. Carriers for use in such preparations are biocompatible and can be biorazlagaemykh; preparation preferably provides a relatively constant release rate of the modulator. The number of modulator contained in the product with steadfastly supported release, depends, for example, from the site of implantation, the rate and expected duration of release and the nature of the state, which is subjected to treatment or which prevent.

For the prevention and/or treatment of diseases mediated VK or its equivalent, the dose of biologically active compounds according to the invention can be varied within wide limits and can be adjusted to individual requirements. The active compounds according to the present invention is usually administered in therapeutically effective amounts. The preferred dose is from about 0.1 mg to about 140 mg per kilogram of body weight per day (from about 0.5 mg to about 7 g per patient per day). Daily the RAM can be entered as a single dose or as many doses. The amount of active ingredient which can be combined with substances-carriers to obtain a single dosage form will vary depending on the subject therapy master and a specific way of introduction. Dosage forms typically contain from about 1 mg to about 500 mg of the active ingredient.

It should be clear, however, that the specific dose level for any particular patient will depend on various factors, including the activity of a used compound, the age, body weight, General health, sex, diet of the patient, time of administration, route of administration and excretion rate, combination of drugs (i.e. combination with other drugs used for the treatment of the patient and the severity of the particular disease under therapy.

Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to the above, the oral bioavailability, so that the preferred oral dosage form, discussed above, can provide therapeutically effective levels of the compounds in vivo.

8-(Heteroaromatics)quinoline, proposed here, can be used as agonists and the and (preferably) receptor antagonists B2 VK for various applications, both in vitro and in vivo. The B2 receptor antagonists according to the present invention can be used for inhibiting the binding of ligands to the receptor B2 VK (for example, BK) B2 receptor VK in vitro or in vivo. The modulator(s) of the receptor B2 VK, proposed here, is preferably administered to a patient (e.g. human) orally or topically, and it is present in at least one fluid or tissue of the patient's body when the modulation of the activity of the receptor B2 VK.

Modulators of receptor B2 VK according to the present invention are particularly applicable for the treatment and/or prevention and/or prophylaxis of conditions or diseases which are susceptible to modulation of receptor B2 VK, including skin diseases; ear diseases; eye diseases, diseases of the mouth, throat, and respiratory diseases; gastrointestinal diseases; diseases of the liver, gallbladder and pancreas; diseases of the urinary tract and kidneys; diseases of the male genitalia and female genital organs; diseases of the hormonal system; metabolic diseases; cardiovascular diseases; diseases of the blood; lymph diseases; disorders of the Central nervous system; brain damage; diseases of the musculoskeletal system; allergic disorders; pain; infectious diseases; inflammatory disorders;injuries; immunological disorders; cancer; hereditary diseases, edema or syndrome(s) leaking capillaries, and to apply a certain methodology. In the present invention the compounds according to the invention is used as a diagnostic agent or for the manufacture of a diagnostic agent, resulting in such diagnostic agent suitable for diagnosis of diseases and conditions that can be used to detect the compounds of the present invention for therapeutic purposes described here.

Below are further outlined various diseases and conditions, which are susceptible to modulation of receptor B2 VK, and the use of compounds according to the present invention in a special methodology and diagnostics.

Skin disorders. In this application, the term “skin disorders” includes, but is not limited to, such violations as the aging of the skin, redness of the skin, including Namin, decubitus ulcers, irritable, sensitive and unaesthetic skin, erythema, rash, swelling of the skin, psoriasis, eczema, herpes, infectious skin diseases induced by bacteria, viruses, fungi and parasites, including furuncle, abscess, phlegmon, erysipelas, folliculitis and impetigo, pediculosis, scabies and herpes simplex, acne, exanthema, dermatitis, and including epicheskii dermatitis, allergic contact dermatitis (Scholzen, T.E.; Luger. T.A. Exp Dermatol. 2004; 13 Suppl 4:22-6) neurodermitis, radiation damage, sunburn, itching, suneva scabies, urticaria (EP 0622361; Frigas, E.; Park, M. Immunol. Allergy Clin. North Am. 2006, 26, 739-51; Luquin, E.; Kaplan, A.P.; Ferrer, M. Clin. Exp. Allergy 2005, 35, 456-60; Kaplan, A.P.; Greaves, M.W.J. Am. Acad. Dermatol. 2005, 53, 373-88; quiz 389-92), psoriasis, fungal infection, ulceration on the fabric, congenital bullous bullosa, wounds, including the healing of atypical wounds, burns (Nwariaku, F.E.; Sikes, P.J.; Lightfoot, E.; Mileski, W.J.; Baxter, C. Burns 1996, 22, 324-7; Neely, A.N.; Imwalle, A.R.; Holder, I.A. Burns 1996, 22, 520-3), frostbite, inflammation and swelling of the skin caused by poison, alopecia, scales hair, toes, wart, and paronychia.

Diseases of the eye. In this application, the term “eye disease” includes, but is not limited to, inflammatory disorders such as scleritis, conjunctivitis, chemosis, iritis, iridocyclitis, uveitis, chorioretinal, as well as violations such as retinochoroiditis circulatory disorders, bacterial infectious diseases of the eye, nonspecific conjunctivitis and irritation of the eyes, retinopathy early development, proliferative vitreoretinopathy, spotted degeneration (including related to age spotted degeneration and including both wet and dry forms), diseases of the cornea, which includes the rejection of corneal transplant, corneal damage, the root of the aspects of scarring, corneal ulcer, corneal burn, keratoconus, glaucoma (preferably open-angle glaucoma, myopia, ocular hypertension, eye damage blood vessels, angiogenesis, ocular fibrosis (e.g., anterior subcapsular fibrosis, posterior subcapsular opacity, posterior capsular opacities, corneal darkening after laser surgery, subconjunctival scarring after glaucoma surgery), the proliferative vitreoretinopathy (PVR), bacterial eye infections, which includes barley and Philos.

Diseases of the ears. In this application, the term “ear problems” includes, but is not limited to, such violations as disease Miniera, inflammation of the middle ear, inflammation of the external ear canal and acute hearing loss.

Diseases of the mouth, nose and respiratory diseases. In this application, the term “diseases of the mouth, nose and respiratory disease” includes, but is not limited to, such violations as inflammation of mucous membranes and gums of the oral cavity, including the aft and stomatitis, periodontitis, epiglottitis, pharyngitis, laryngotracheitis, tonsillitis, rhinitis, sore throat, rhinitis, including seasonal allergic rhinitis or perennially allergic rhinitis, rhinorrhea, sinusitis any type, etiology or pathogenesis is or sinusitis, which is sinusitis selected from the group consisting of purulent or nagnagnag sinusitis, acute and chronic sinusitis and sinusitis sinus ethmoid, frontal, maxillary or sphenoid sinus, expectoration, pneumoconiosis any type or Genesis, including, for example, aluminas, antraks, asbestosis, helicos, sideros, silicosis, tobacco pneumoconiosis and especially bissines, bronchitis, cough, tracheitis, congestion, pneumonia, eosinophilic lung infiltration, chronic eosinophilic pneumonia, idiopathic pulmonary fibrosis and other fibrotic lung diseases associated with treatment vibrationthe pulmonary disease, for example, associated with radiation therapy with methotrexate, a chemotherapy, therapy with amiodarone or nitrofurantoin, sarcoidosis, acute respiratory distress syndrome (ARDS), asthma of any type (Akbary, A.M.; Wirth, K.J.; Scholkens, B.A. Immunopharmacology 1996, 33, 238-42; WO 00/75107 A2), etiology or pathogenesis, or asthma, which is asthma selected from the group reinfection allergic bronchial (atopic) asthma, diatopically asthma, allergic and non-allergic asthma, acquired bronchial asthma caused by environmental factors, hereditary asthma caused by pathophysiologic disturbances, bronchial asthma, IgE-mediated asthma, essentialine asthma and essential asthma of unknown or inapparent reasons true asthma, emphysematous asthma, asthma voltage, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection that begins asthma syndrome Striganova breathing infants, increased bronchial reactivity, chronic obstructive pulmonary disease (COPD), a disease COPD that is characterized by irreversible airway obstruction, acute respiratory distress syndrome (ARDS) and acute exacerbation of increased reactivity of the Airways due to other drug therapy, shortness of breath, gipertoksicheskaya alveolar damage, pulmonary emphysema, pleurisy, tuberculosis, exposure to high altitude, i.e., an acute painful condition in the highlands and preferably pulmonary edema in the highlands (NARA).

Gastrointestinal diseases. In this application, the term “gastrointestinal disease” includes, but is not limited to, violations, including esophagitis, gastritis, irritable stomach, gastric ulcer and duodenal ulcer, ileus, irritable bowel syndrome, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, enteritis, hypertension, gastro - and kalapati, colitis, peritonitis, appendicitis, proctitis, gastrointestinal bleeding caused by portal is Noah hypertension, collateral circulation or flushing, drop syndrome after gastrectomy, discomfort, digestion, diarrhea, hemorrhoids, diseases caused by helminths, spastic abdominal pain and spastic pain parts of the gastrointestinal system.

Diseases of liver, gallbladder and pancreas (Cugno, M.; Salerno, F.; Nussberger, J.; Bottasso, B.; Lorenzano, E.; Agostoni, A. Clin. Sci. (Lond) 2001, 101, 651-7; WO 01/56995 Al; EP 0797997 Bl; Wirth, K.J.; Bickel, M.; Hropot, M.; Gunzler, V.; Heitsch, H.; Ruppert, D.; Scholkens, B.A. Eur J. Pharmacol. 1997, 337, 45-53). In this application, the term “diseases of liver, gallbladder and pancreas” includes, but is not limited to, such violations as hepatitis, cirrhosis, fibrosis (e.g., due to viral (HBV/HCV) infections, toxins (alcohol), fatty degeneration of the liver, cholestasis, hypoxia), portal hypertension, hepatic-renal syndrome, hepatogenic swelling, cholangitis, cholecystitis, acute and chronic pancreatitis and biliary pain.

Diseases of the urinary tract and kidneys. In this application, the term “urinary tract infections and kidney disease” includes, but is not limited to, infectious diseases, urinary tract infections, such as acute and chronic cystitis, interstitial cystitis (Campbell, D.J. Clin. Exp. Pharmacol. Physiol. 2001, 28, 1060-5; Meini, S.; Patacchini, R.; Giuliani, S.; Lazzeri, M.; Turini, D.; Maggi, C.A.; Lecci, A. Eur. J. Pharmacol. 2000, 388, 177-82; Zuraw, B. .; Sugimoto, S.; Parsons, C.L.; Hugli, T.; Lotz, M.; Koziol, J.J. Urol. 1994, 152, 874-8; Rosamilia, A.; Clements, J.A.; Dwyer, P.L.; Kende, M.; Campbell, D.J.J. Urol. 1999, 162, 129-34), irritable bladder, overactive bladder (WO 2007003411 A2), incontinence, including, but not limited to the above, the stress, the imperative and reflex incontinence, benign hyperplasia of the prostate (Srinivasan, D.; Kosaka, A.H.; Daniels, D.V.; Ford, A.P.; Bhattacharya, A. Eur J Pharmacol. 2004, 504(3):l55-67), urethritis, inflammatory kidney disease, including glomerulonephritis, glomerular kidney disease, interstitial nephritis, pyelonephritis, diuresis, proteinuria, natriuresis, kallioras, the disturbance of the water balance, electrolyte derangement, disturbance of acid-base balance and renal colic, renal fibrosis and chronic dysfunction of the renal allograft.

Diseases of the male genitalia and female genital organs. In this application, the term “diseases of the male genitalia and female genital organs” includes, but is not limited to, altered sperm motility, male infertility, orchitis, prostatitis, enlarged prostate, mastitis, an inflammatory disease of the pelvis, vaginal infections and pain, adnexitis, colpitis, soft sanr and pain, syphilis, gonorrhea and ovarian hyperstimulation syndrome (Ujioka, T.; Matsuura, K.; Tanaka, N.; Okamura, H. Hum Reprod. 1998 Nov;13(11):3009-15.

Diseases of the hormonal system. In this application, the term “diseases of the hormonal system” includes, but is not limited to, menstrual disorders and pain, climacteric disturbance, vomiting, premature uterine contractions and premature labor, endometriosis, endometritis, uterine.

Metabolic diseases. In this application, the term “metabolic disease” includes, but is not limited to, such violations as diabetes, including non-insulin dependent diabetes mellitus, diabetic retinopathy, diabetic macular edema (Speicher, M.A.; Danis, R.P.; Criswell, M.; Pratt, L. Expert Opin. Emerg. Drugs 2003, 8, 239-50; Gao, B.B.; Clermont, A.; Rook, S.; Fonda, S. J.; Srinivasan, V.J.; Wojtkowski, M.; Fujimoto, J.G.; Avery, R.L.; Arrigg, P.G.; Bursell, S.E.; Aiello, L.P.; Feener, E.P. Nat. Med. 2007, 13, 181-8; Tranos, P.G.; Wickremasinghe, S.S.; Stangos, N.T.; Topouzis, F.; Tsinopoulos, I; Pavesio, C.E. Surv. Ophthalmol 2004, 49, 470-90), diabetic nephropathy and diabetic neuropathy, insulin resistance and diabetic ulcers, disorders of protein and purine metabolism, such as gout, and violation of lipometabolism.

Cardio-vascular diseases. In this application, the term “cardiovascular disease” includes, but is not limited to, disorders, including vascular permeability, vasodilation, impaired peripheral circulation, disorders of arterial the CSOs circulation, including aortic aneurysm, aneurysm of the abdominal aorta, aortic brain, hypertension and hypotension associated with sepsis, restenosis after subcutaneous transluminal operations on coronary artery, atherosclerosis, including rupture of atherosclerotic plaques (Fernando, A.N.; Fernando, L.P.; Fukuda, Y.; Kaplan, A.P. Am J Physiol Heart Circ Physiol. 2005 Jul; 289(l):H251-7), hemangioma, angiofibroma, venous disorders, such as thrombosis, varicose veins, phlebitis, thrombophlebitis, phlebothrombosis, cardiopathy, congestive heart failure, carcinoid syndrome, angina, cardiac arrhythmias, inflammatory heart diseases, including endocarditis, pericarditis and constrictive pericarditis, myocarditis, myocardial infarction, syndrome postmyocardial infarction, left ventricular dilation, damage after ischemic reperfusion, shock and collapse, including septic, allergic, posttraumatic and hemodynamic shock, embolism amniotic fluid (Robillard, J.; Gauvin, F.; Molinaro, G.; Leduc, L.; Adam, A.; Rivard, G.E. Am J Obstet Gynecol. 2005 Oct;193(4):1508-12), a syndrome of systemic inflammatory response (SIRS), including SIRS caused by cardiac bypass surgery during surgery, sepsis, and internal and external complications during surgery with extracorporeal circulation (including, but not limited to, listed the, adverse hemodynamic action after lifting action of heparin by Protamine sulfate (Pretorius, M.; Scholl, F.G.; McFarlane, J.A.; Murphey, L.J.; Brown, N.J., Clin Pharmacol Ther. 2005 Nov;78(5):477-85).

Diseases of the blood. In this application, the term “blood disease” includes, but is not limited to, such violations as coagulation, disseminated intravascular coagulopathy, hemorrhage, hemorrhagic diathesis, hypercholesterolemia and hyperlipemia.

Lymphatic diseases. In this application, the term “lymphatic disease” includes, but is not limited to, splenomegaly, lymphangitis, lymphadenitis and hyperplastic adenoids.

Disorders of the Central nervous system. In this application, the term “disorders of the Central nervous system” includes, but is not limited to, such violations as inflammatory diseases of the Central nervous system, including encephalitis, meningitis, encephalomyelitis, encephalitis, hydrocephalus, amyotrophic lateral sclerosis, spinal cord injury, swelling of the spinal cord, demieliniziruyushchee diseases of the nervous system, multiple sclerosis, acute and chronic neurodegenerative disorders, including Alzheimer's and Parkinson's disease, narit and peripheral neuropathy, depression, anorexia, anxiety and sysopen the Y.

Disorders of the brain. In this application, the term “disorders of the brain” includes, but is not limited to, violations that require improvement nootropic or cognition, cerebral amyloid angiopathy, stroke, head trauma and brain injury, traumatic brain injury (Marmarou, A.; Guy, M.; Murphey, L.; Roy, F.; Layani, L.; Combal, J.P.; Marquer, C.; American Brain Injury Consortium J Neurotrauma 2005 Dec; 22(12): 1444-55), cerebral thermal damage, cerebral ischemia, bleeding in the brain, posttraumatic and policheiiskie cerebral edema, a common brain edema, acute painful condition in the highlands and preferably cerebral edema high altitude (NASA), cytotoxic brain edema, vasogenic brain edema, policyrelease brain edema, brain edema associated with metabolic diseases, increased permeability of blood-brain barrier or the blood-brain barrier tumors.

Diseases of the musculoskeletal system. In this application, the term “diseases of the musculoskeletal system” includes, but is not limited to, such violations as inflammatory musculoskeletal disorders, osteoarthritis, osteoarthrosis, osteoarthritis, chondrophores after joint injuries or relatively long not is odvisnosti joint after injury meniscus or kneecap or torn ligaments, rheumatoid arthritis of any type, etiology or pathogenesis, including acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, vertebral arthritis, septic arthritis, psoriatic arthritis, chronic polyarthritis, rheumatoid arthritis, Sjogren syndrome, lumbago, spondylitis, spondylarthritis, ankylosing spondylitis, osteomyelitis, tension, tendosynovitis induced inflammation resorption, fracture or the like, osteoporosis, musculoskeletal pain and hardening, the syndrome of the intervertebral disc.

Allergic disorders. In this application, the term “allergic disorders” includes, but is not limited to, such violations as common allergic reactions, food Allergy, anaphylactic shock, allergic contact hypersensitivity, allergic skin reactions, allergic asthma, vernal conjunctivitis and seasonal or chronic allergic rhinitis (Summers, C.W.; Pumphrey, R. S.; Woods, C.N.; McDowell, G.; Pemberton, P.W.; Arkwright, P.D.J Allergy Clin Immunol. 2008).

Pain. In this application, the term “pain” includes, but is not limited to, pain, mediated by the Central and peripheral nervous system, vascular pain, visceral pain, pain, mediated vocal the tion, neuralgic pain reflected pain, nociceptive pain, reflex pain, psychosomatic pain, acute pain, such as pain caused by acute injury, trauma or surgery to bone, muscle, tissue, soft tissue, organs, pain after insect bites, pain syndrome after a stroke, pain after surgery, pain associated with advanced disease, chronic pain, such as pain, called neuropathic pain States (including, but not limited to, the syndrome complex local pain (WO 00/75107 A2; Yamaguchi-Sase, S.; Hayashi, L; Okamoto, H.; Nara, Y.; Matsuzaki, S.; Hoka, S.; Majima, M. Inflamm. Res. 2003, 52, 164-9; Petersen, M.; Eckert, A.S.; Segond von Banchet, G.; Heppelmann, B.; Klusch, A.; Kniffki, K.D. Neuroscience 1998, 83, 949-59; Birklein, F.; Schmelz, M.; Schifter, S.; Weber, M. Neurology 2001, 57, 2179-84; Weber, M.; Birklein, F.; Neundorfer, B.; Schmelz, M. Pain 2001, 91, 251-7), causalgia, disease Sudek, reflex sympathetic dystrophy), diabetic peripheral neuropathy, poligeneticheskie neuralgia, trigeminal neuralgia, pain associated with cancer, pain associated with rheumatoid arthritis, osteoarthritis (Bond, A.P.; Lemon, M.; Dieppe, P.A.; Bhoola, K.D. Immunopharmacology 1997, 36, 209-16; Cassim, B.; Naidoo, S.; Ramsaroop, R.; Bhoola, K.D. Immunopharmacology 1997, 36, 121-5; Calixto, J.B.; Cabrini, D.A.; Ferreira, J.; Campos, M.M. Pain 2000, 87, 1-5; Kaneyama, K.; Segami, N.; Sato, J.; Fujimura, K.; Nagao, T.; Yoshimura, H. J. Oral. Maxillofac. Surg. 2007, 65, 242-7), tendosynovitis, gout, menstruation and angina, fibromyalgia, eye pain, back pain, headache pain is, “histamine” headache, migraine (Ebersberger, A.; Ringkamp, M.; Reeh, P.W.; Handwerker, H.O.J Neurophysiol. 1997 Jun; 77(6):3122-33), hyperalgesia, and fever. In addition, the compounds of the invention are applicable as an analgesic agent for use during shared and controlled anesthesia.

Infectious diseases. In this application, the term “infectious disease” includes, but is not limited to, diseases, including diseases, mediated by bacteria, viruses, fungi, parasites, protozoa, prions, or mycobacterial infections. In particular, the present invention is applicable for the treatment of bacterial infections caused by Streptococcus, Escherichia, Salmonella, Staphylococcus, Klebsiella, Moracella, Haemophilus and Yersinia. Examples of bacterial infections that are intended for inclusion in the scope of the present invention, include, but are not limited to, such diseases as plague, fever, epidemic typhus, food poisoning, tetanus, scarlet fever, whooping cough, diphtheria. Examples of viral infections that are intended for inclusion in the scope of the present invention, include, but are not limited to, diseases such as chickenpox and herpes zoster, AIDS, influenza, smallpox, and childhood diseases such as measles, urticaria, mumps, acute poliomyelitis anterior, which is the spinal cord. The present invention is applicable for the treatment of protozoal and parasitic infections caused by Schistosoma mansoni, Dermatofagoides farinae and Plasmodium, including malaria. Examples Pranovich infections intended to be included in the scope of the present invention, include, but are not limited to, diseases such as bovine spongiform encephalopathy (BSE), a disease of Creutzfeldt-Jakob disease and Kuru.

Inflammatory disorders. In this application, the term “inflammatory disease” includes, but is not limited to, such violations as inflammation in the acute phase, local and systemic inflammation and inflammation caused by other diseases of any type, etiology or pathogenesis, and caused by inflammatory diseases specified in this application.

Damage. In this application, the term “damage” includes, but is not limited to, multiple trauma, head injury, lung injury, external, internal and surgical wounds.

Immunologic disorders. In this application, the term “immunologic disorders” includes, but is not limited to, such violations as hyperesthesia, autoimmune disorders, graft rejection in transplantation, transplant toxicity, granulomatous inflammation/remodeli the Finance tissue, severe myasthenia, immunosuppression, disease, immune complexes, overproduction and insufficient production of antibodies, vasculitis.

The cancer. In this application, the term “cancer” includes, but is not limited to, such violations as cancer type solid tumors, including breast cancer, lung cancer (non-small cell lung cancer and small cell lung cancer), prostate cancer, cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, colon, rectum, gallbladder and biliary tract, pancreas, larynx, lung, bone, osteosarcoma, a cancer of the connective tissue cancer of the skin, including the syndrome sarcoma, melanoma and skin metastasis, epidermoid cancer, carcinoma, basal cell cancer of the cervix, body of the endometrium, cancer of the ovary, testis, bladder, ureter and mocheispuskanija channel, kidneys, eyes, brain and Central nervous system, false brain tumor, sarcoma, sarcoid thyroid gland and other endocrine glands (including, but not limited to, carcinoid tumors), Hodgkin's disease, non-Hodgkins lymphoma, multiple myeloma, hematopoietic malignancy, including leukemia, and lymphoma that includes l is mposite, granulocyte and monocyte lymphoma, tumor invasion, metastasis, ascites, tumor growth and angiogenesis.

Hereditary diseases. In this application, the term “genetic disease” includes, but is not limited to, such violations as hereditary angioedema (Davis, A.E. et al., 3rd Transfus. Apher. Sci. 2003, 29, 195-203; Zuraw, B. L. Immunol. Allergy Clin. North Am. 2006, 26, 691-708; Bas, M. et al. Allergy 2006, 61, 1490-2) and angioedema, chondrocalcinosis, Huntington's disease, cystic fibrosis.

The swelling. In this application, the term “swelling” includes, but is not limited to, General edema and edema caused by inflammation, other drugs, for example, induced drug angioedema (Mathelier-Fusade, P. Clin. Rev. Allergy Immunol. 2006, 30, 19-23; Finley, C.J. et al. Am. J Emerg Med. 1992, 10, 550-2; Bielory, L. et al. Allergy Proc. 1992, 13, 85-7), especially infection, burns, injuries, trauma, frostbite, surgery, distortion, fractures, exposure to high altitude (e.g., pulmonary edema high altitude (NARA) and cerebral edema high altitude (NASA)), hereditary, autoimmune, and other diseases and disorders, especially, but not limited to, violations specified in this application.

The syndrome(s) leaking capillaries. In this application the term “syndrome leakage of capillaries includes himself, but not limited to, a syndrome of systemic leakage of capillaries in sepsis (Marx, G. Eur J Anaesthesiol. 2003 20(6):429-42; Traber, D.L. Crit Care Med. 2000, 28(3):882-3), burn (Jonkam, C.C; Enkhbaatar, P.; Nakano, Y.; Boehm, T.; Wang, J.; Nussberger, J. Esechie, A.; Traber, L.D.; Herndon, D.; Traber, D.L., Shock. 2007 Dec; 28(6):704-9), allergies, conditions, induced drug/toxin, transplantation of organs and IL-2 cytokine therapy.

Methodology and diagnostics. Compounds of the invention can be marked with isotopes, markers, fluorescence and luminescence, antibodies or fragments of antibodies, any other affinity label, such nanocell, aptamers, peptides, etc., enzymes or are substrates of enzymes. These labeled compounds of this invention are applicable for mapping the location of the bradykinin receptor in vivo, ex vivo, in vitro and in situ (e.g., in tissue sections by using autoradiography) and as radioactive labels to produce images of positron emission tomography (PET), single photon emission computed tomography (mect) and the like for the characterization of these receptors in living subjects or other materials.

The present invention relates also to methods for changing the signal-transducers activity of the bradykinin receptor in vitro and in vivo. For example, the compounds of the present invention and labeled derivatives can the be used as standards and reagents in determining the ability of a potential pharmaceutical agents to contact the receptor B2 VK.

The present invention relates also to methods of localization or detection of receptor B2 VK in the tissue, preferably in a tissue section, such methods comprise contacting a tissue sample containing the receptor B2 VK with detectable labeled compound according to the present invention under conditions that allow the compound to contact the receptor B2 VK and allow to detect the associated connection. Such methods and their appropriate conditions known to the person skilled in the art and include, for example, the analysis of binding of radioligand described in example 754.

The present invention relates also to methods of inhibiting the binding VK or any other ligand receptor B2 with B2 receptor VK, such methods include contacting the solution containing this compound-receptor antagonist B2 VK, with cells expressing the receptor B2 VK, under the conditions and in sufficient quantity for the detectable inhibition of binding VK or any other substance to the receptor B2 VK. Such methods and their appropriate conditions known to the person skilled in the art and include, for example, analysis of the mobilization of calcium described in example 755.

The present invention further relates to methods of treating patients suffering from status is s, susceptible to modulation of receptor B2 VK, as described above. Used herein, the term “treatment” includes both disease modifying treatment and symptomatic treatment, any of which may be prophylactic (i.e. before the onset of symptoms, to prevent, delay the occurrence or reduce the severity of symptoms) or therapeutic (i.e. after the onset of symptoms to lessen the severity and/or duration of symptoms). The state is susceptible to modulation of receptor B2 VK”, if the modulation of the activity of the receptor B2 VK leads to alleviation of the condition or symptom. Patients may represent, but is not limited to, primates (especially humans), pet-companions (such as dogs, cats, horses and livestock (such as cows, pigs, sheep), for which use is described here dose.

In the present invention the compounds according to the invention is also used as a diagnostic tool or for the manufacture of diagnostic tool, resulting in such a diagnostic tool is suitable for diagnosis of diseases and conditions that can be used to detect the compounds of the present invention for therapeutic purposes described here.

The compounds of formula (I) according to the present which the invention have improved properties compared with the antagonists of the receptor B2 VK, known in the prior art, particularly high selectivity, low toxicity, low interaction drug - drug, increased bioavailability (especially when administered orally), increased metabolic stability, high stability analysis of microsome degradation, and increased solubility.

The present invention is now further illustrated by the following examples, of which we can understand the additional features, options for implementation and advantages of the present invention.

EXAMPLES

Getting connections

Compounds of the present invention can be obtained a number of ways, well known specialist in the field of organic synthesis. Compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the field of synthetic organic chemistry, or variations recognized expert in this field. Preferred methods include, but are not limited to, the methods described below. Each of the references cited below, therefore, included here as a reference.

Abbreviations used in the following examples, are as follows:

ACN means acetonitrile,

VK means bradykinin,

BS means bovine serum albumin,

cpm means the number of beats per minute

DCM means dichloromethane,

DIBAL means diisobutylaluminium,

DIPEA means ethyldiethanolamine,

DMF means dimethylformamide,

DMSO means dimethylsulfoxide,

EA means ethyl acetate;

ELISA means enzyme linked immunosorbent assay,

HBTU means hexaphosphate benzotriazol-1-yl(bidirectionnelle)hydronium;

HBSS means balanced salt solution Hanks,

SPLA means glacial acetic acid,

HPLC means high performance liquid chromatography,

LDA means diisopropylamide lithium

NMP is 1-methylpyrrolidine-2-it,

Pd(OAc)2means palladium(II)acetate,

PBS means phosphate buffered saline,

PIPES means piperazine-N,N'-bis-(2-econsultancy acid)

p-TsOH means toluene-4-sulfonic acid,

CT means room temperature

THF means tetrahydrofuran,

TNR means tetrahydropyranyl,

TFA means triptorelin or triperoxonane acid,

the feast upon. means rich,

WSC mean hydrochloride (3-dimethylaminopropyl)ethylcarbodiimide,

Pd(dppf)Cl2means (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II)·DCM

Compounds shown in table 1, are representative examples of compounds of the Fort the uly (I) according to the present invention.

Table 1

/p>

1. The compound of formula (I)

or its pharmacologically acceptable salt, where
A represents a 6-membered heteroaryl having 1 nitrogen atom as a heteroatom, where the indicated 6-membered heteroaryl substituted 2-3 substituents, each of which is independently selected from:
the halogen atom,
oxygen atom,
hydroxy,
C1-C6the alkyl, optionally substituted by 1-2 groups selected from C1-C6alkoxy, HE, CN, oxygen atom;
With2-C6alkenyl, replaced IT, CN;
heteroalkyl, which represents a C1-C6is laksi or one of the groups: -S-Y a-L, -S,-Ya-CO-NRaRb, -Ya-NRc-CO-NRaRb, -Ya-NRc-CO-Rc, -Ya-CO-NRa-Rb, -Ya-NRc-CO-L-Ya-L, Ra-NRb-Ya- (optionally substituted by heteroalkyl selected from the group: -Ya-NRc-CO-Rc, -Ya-CO-NRaRb, Ra-NRb-Yaor one of the groups: IT, C1-C6alkoxy, NH2), Rc-S-Y3-, Rc-O-CO-Ya-, Rc-SO-Ya-, Rc-SO2-Ya, -Ya-NRc-SO2-Rc;
5-6-membered heteroalicyclic containing 1-2 heteroatoms selected from N, O, optionally substituted by a group selected from cyano, NH2or =O;
heterooligomerization where heteroalkyl selected from the group: Rc-O-CO-Ya-, -Ya-CO-NRaRb, Rb-NRb-Ya; heteroseksualci is a 4-6-membered heterocyclization containing N atom as the heteroatom;
5-membered heteroaryl containing the atom O as heteroatom;
where
Rarepresents a hydrogen atom, a C1-C6alkyl, optionally substituted NH2;
Rbrepresents a hydrogen atom, a C1-C6alkyl, or Rbtaken together with Ra, form a 4-10-membered cycloalkyl, optionally substituted by 1-2 substituents representing is a HE or a C 1-C6alkyl;
Rcrepresents a hydrogen atom, a C1-C6alkyl, optionally substituted by CN; and
L represents 5-9-membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, optionally substituted with 1-2 substituents selected from C1-C6of alkyl, phenyl, =O, halogen atom, and CN, or a 4-6-membered heteroseksualci containing 1-2 heteroatoms selected from N, O, and
Yarepresents a bond, C1-C6alkylenes or2-C6alkenylamine group;
R5represents a halogen atom, cyano or C1-C6alkyl, optionally substituted by a halogen atom;
R6represents a C1-C6alkyl, optionally substituted HE group; C1-C3alkenyl; 5-membered heteroaryl having 2-4 heteroatoms, each of which is independently selected from N, O, or S, where the specified 5-membered heteroaryl substituted by 0-2 substituents, each of which is independently selected from a halogen atom, oxygen atom, hydroxy, cyano, C1-C6the alkyl, optionally substituted by a halogen atom or one of the groups, HE or NH2, phenyl, heteroalkyl, which represents a C1-C6alkoxycarbonyl, C1-C6alkoxy, allylcarbamate or one of the groups: Rc-O-Ya, -Ya-NRc-CO-Rc, -Ya-NRc 2-Rc, Rc-O-CO-Ya, -Ya-CO-NRaNRb, -Ya-NR-CO-NRaRb, -Ya-NRc-CO-L, where Raand Rbrepresent a hydrogen atom, Rcrepresents a C1-C6alkyl, optionally substituted HE, NH2or phenyl, L is a phenyl, and Yarepresents a bond, C1-C6alkylenes group; or-S-R10;
R10represents a 5-membered heteroaryl having 2-3 heteroatoms, each of which is selected from N, O or S, where the specified 5-membered heteroaryl substituted by 0-2 substituents, each of which is independently selected from C1-C3of alkyl;
R7represents a hydrogen atom or a halogen atom;
R8represents a hydrogen atom or a halogen atom;
and
R17represents a hydrogen atom or a halogen atom.

2. The compound or its pharmaceutically acceptable salt according to claim 1, where
But a

3. The compound or its pharmaceutically acceptable salt according to claim 1, where R6represents a

4. The compound or its pharmaceutically acceptable salt according to claim 1, where R5represents methyl or ethyl.

5. The compound or its pharmaceutically acceptable salt according to claim 1, where R6selected from the group

6. The compound or its pharmaceutically acceptable salt according to claim 1, where R7, R8and R17represent N.

7. The compound according to claim 1 or its pharmaceutically acceptable salt, where the connection detects the IC50500 nm or less in a standard in vitro assays mediated by the B2 receptor VK.

8. The compound according to claim 1, which is 1-{3-[4-(5-chlorothiazole-4-yl)-2-methyl-quinoline-8-intoximeter]-4-methylpyridin-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,
1-{4-chloro-3-[4-(5-chlorothiazole-4-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,
1-{4-chloro-3-[4-(5-chlorothiazole-4-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,
1-{4-methyl-3-[2-methyl-4-(4-methyl-2H-pyrazole-3-yl)quinoline-8-intoximeter]pyridine-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,
1-{4-chloro-3-[4-(5-chloro-1-methyl-1H-imidazol-2-yl)-2-methylinosine-8-intoximeter]pyridine-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,
1-{5-chloro-2-methoxy-4-[2-methyl-4-(2-methyl-2H-[1,2,4]triazole-3-yl)quinoline-8-intoximeter]pyridine-3-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,
1-(3-{4-[4-(2-aminoethoxy)-1H-pyrazole-3-yl]-2-methylinosine-8-intoximeter}-4-methylpyridin-2-ylmethyl)-3-trifluoromethyl-1H-pyridine-2-it,
1-{4-chloro-3-[4-(1,5-dimethyl-1H-imidazol-2-yl)-2-methylinosine-8-intoximeter]pyridine-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,
1-{3-[4-(4-hydroxymethyl-2H-Piras the l-3-yl)-2-methylinosine-8-intoximeter]-4-methylpyridin-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,
N-(3-{2-methyl-8-[4-methyl-2-(2-oxo-3-trifluoromethyl-2H-pyridine-1-ylmethyl)pyridine-3-ylethoxy]quinoline-4-yl}-1H-pyrazole-4-ylmethyl)ndimethylacetamide,
1-{3-[4-(4-aminomethyl-1H-pyrazole-3-yl)-2-methylinosine-8-intoximeter]-4-methylpyridin-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,
N-(5-{8-[4-chloro-2-(2-oxo-3-trifluoromethyl-2H-pyridine-1-ylmethyl)pyridine-3-ylethoxy]-2-methylinosine-4-yl}-1H-pyrazole-4-ylmethyl)ndimethylacetamide,
2-{8-[4-chloro-6-methyl-2-(2-oxo-3-trifluoromethyl-2H-pyridine-1-ylmethyl)pyridine-3-ylethoxy]-2-methylinosine-4-yl}-3-methyl-3H-imidazol-4-carbonitril,
1-{4-chloro-6-methyl-3-[2-methyl-4-(4-methyl-2H-pyrazole-3-yl)quinoline-8-intoximeter]pyridine-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,
1-{4-chloro-6-methyl-3-[2-methyl-4-(4-methyl-1H-pyrazole-3-yl)quinoline-8-intoximeter]pyridine-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,
5-{8-[4-chloro-2-(2-oxo-3-trifluoromethyl-2H-pyridine-1-ylmethyl)pyridine-3-ylethoxy]-2-methylinosine-4-yl}-3-methyl-3H-imidazol-4-carbonitril,
1-{4-chloro-3-[4-(4-chlorothiazole-5-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,
1-{4-chloro-3-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,
1-{3-[4-(5-chlorothiazole-4-yl)-2-methylinosine-8-intoximeter]-4-methoxypyridine-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,
1-{4-chloro-3-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-methylinosine-8-intoximeter]pyrid is n-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,
amide 5-{8-[4-chloro-6-methyl-2-(2-oxo-3-trifluoromethyl-2H-pyridine-1-ylmethyl)pyridine-3-ylethoxy]-2-methylinosine-4-yl}-1-methyl-1H-pyrrole-2-carboxylic acid,
amide 5-{8-[4-chloro-2-(3-cyano-2-oxo-2H-pyridine-1-ylmethyl)-6-methylpyridin-3-ylethoxy]-2-methylinosine-4-yl}-1-methyl-1H-pyrrole-2-carboxylic acid,
1-{4-chloro-3-[4-(4-hydroxymethyl-2H-pyrazole-3-yl)-2-methylinosine-8-intoximeter]pyridine-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,
1-{4-chloro-3-[4-(4-hydroxy-1H-pyrazole-3-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,
1-{4-chloro-3-[4-(4-hydroxy-1H-pyrazole-3-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,
1-{4-chloro-3-[4-(4-perperson-1-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,
1-{3-[4-(5-chlorothiazole-4-yl)-2-methylinosine-8-intoximeter]-4-methoxypyridine-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,
2-{8-[5-fluoro-2-methoxy-3-(2-oxo-3-trifluoromethyl-2H-pyridine-1-ylmethyl)pyridine-4-ylethoxy]-2-methylinosine-4-yl}-3-methyl-3H-imidazol-4-carbonitril,
1-{4-chloro-6-methyl-3-[2-methyl-4-(5-methyl-1H-imidazol-4-yl)quinoline-8-intoximeter]pyridine-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,
1-(1-{4-chloro-3-[2-methyl-4-(4-methyl-1H-pyrazole-3-yl)quinoline-8-intoximeter]pyridine-2-yl}ethyl)-2-oxo-1,2-dihydropyridines-3-carbonitril,
1-(1-{4-chloro-3-[4-(4-hydroxy-1H-pyrazole--yl)-2-methylinosine-8-intoximeter]pyridine-2-yl}ethyl)-2-oxo-1,2-dihydropyridines-3-carbonitril,
amide 5-{8-[4-chloro-2-(3-cyano-2-oxo-2H-pyridine-1-ylmethyl)pyridine-3-ylethoxy]-2-methylinosine-4-yl}-1-methyl-1H-pyrrole-2-carboxylic acid,
1-{4-chloro-3-[4-(4-perperson-1-yl)-2-methylinosine-8-intoximeter]pyridine-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,
1-(1-{4-chloro-3-[4-(4-hydroxy-1H-pyrazole-3-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-yl}ethyl)-2-oxo-1,2-dihydropyridines-3-carbonitril,
1-{4-chloro-6-methyl-3-[2-methyl-4-(3-methylisoxazol-4-yl)quinoline-8-intoximeter]pyridine-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,
1-{5-chloro-4-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-methylinosine-8-intoximeter]-2-hydroxypyridine-3-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,
1-{4-methoxy-6-methyl-3-[2-methyl-4-(4-methyl-1H-pyrazole-3-yl)quinoline-8-intoximeter]pyridine-2-ylmethyl}-3-trifluoromethyl-1H-pyridine-2-it,
1-{4-chloro-3-[4-(4-hydroxymethyl-1H-pyrazole-3-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitril,
1-{4-chloro-3-[4-(5-cortisol-2-yl)-2-methylinosine-8-intoximeter]-6-methylpyridin-2-ylmethyl}-2-oxo-1,2-dihydropyridines-3-carbonitrile or pharmaceutically acceptable salt of these compounds.

9. Pharmaceutical composition having inhibitory activity against receptor B2 VK, which contains one or more compounds according to any one of claims 1 to 8 or its pharmaceutically acceptable salt in a therapeutically effective the m number, and optionally at least one substance carrier, excipient and/or adjuvant.

10. The pharmaceutical composition according to claim 9, made in the form of an aerosol, cream, gel, pills, capsules, syrup, solution, dermal patch or device for delivery of pharmaceutical agents.

11. Method of inhibiting the binding of BK to the receptor B2 VK in vitro, comprising contacting the receptor B2 VK at least one compound according to any one of claims 1 to 8 or its salt under the conditions and in sufficient quantity for the detectable inhibition of binding VK or any other substance to the receptor B2 VK.

12. Method of localization or detection of receptor B2 VK in the tissue, preferably in the cut tissue, in vitro, including
(a) contacting the tissue sample containing the receptor B2 VK, with detectable labeled compound according to any one of claims 1 to 8 under conditions that allow the compound to contact the receptor B2 VK, and
(b) detection of the associated connection.

13. The method according to item 12, where the compound is labeled with radioactive isotope-labeled marker fluorescence or labeled marker luminescence or labeled antibody.

14. The use of the compounds or pharmaceutical compositions according to any one of claims 1 to 8 for the manufacture of a medicinal product, showing antagonistic activity against receptor B2 VK.

15. The application is .14, where the drug is intended to treat and/or prevent diseases or conditions that are skin disorders, eye diseases, ear diseases, diseases of the mouth, throat, and respiratory diseases; gastrointestinal diseases; diseases of liver, gallbladder and pancreas; diseases of the urinary tract and kidneys; diseases of the male genitalia and female genital organs; diseases of the hormonal system; metabolic diseases; cardiovascular diseases; diseases of the blood; lymphatic diseases; disorders of the Central nervous system; disorders of the brain; diseases of the musculoskeletal system; allergic disorders; pain; infectious diseases; inflammatory disorders; trauma; immunologic disorders; cancer; hereditary disease or swelling.

16. A method of inhibiting the activity of the receptor VK B2 in in need thereof of a subject, comprising introducing the compound according to any one of claims 1 to 8.

17. Method of treating inflammatory disease in a subject in need of such treatment, including keeping to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 8.

18. The method according to 17, where the inflammatory disease is a hereditary angioneurotic about the EC.

19. The compound of the formula:

or its pharmaceutically acceptable salt.

20. Pharmaceutical composition having inhibitory activity against receptor B2 VK, which contains a compound according to claim 19 or its pharmaceutically acceptable salt in a therapeutically effective amount and optionally at least one substance carrier, excipient and/or adjuvant.

21. The pharmaceutical composition according to claim 20, made in the form of an aerosol, cream, gel, pills, capsules, syrup, solution, dermal patch or device for delivery of pharmaceutical agents.

22. The method of treatment of hereditary angioedema with the subject in need of such treatment, including keeping to the subject a therapeutically effective amount of a compound according to claim 19.



 

Same patents:

FIELD: biotechnologies.

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

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to 5-phenyl-1H-pyrazin-2-one derivatives of general formula II or pharmaceutically acceptable salts thereof, where R denotes -R1 or - R1-R2-R3; R1 denotes aryl or heteroaryl, and is optionally substituted with one or two R1'; where each R1' independently denotes C1-6alkyl, halogen or C1-6halogenalkyl; R2 denotes -C(=O), -CH2-; R3 denotes R4; where R4 denotes an amino group or heterocycloalkyl, and is optionally substituted with one or two substitutes selected from C1-6alkyl, hydroxy group, oxo group, C1-6hydroxyalkyl, C1-6alkoxy group; Q denotes CH2; Y1 denotes C1-6alkyl; Y2 denotes Y2b; where Y2b denotes C1-6alkyl, optionally substituted with one Y2b'; where Y2b' denotes a hydroxy group, n and m are equal to 0; Y4 denotes Y4c or Y4d; where Y4c denotes lower cycloalkyl, optionally substituted with halogen; and Y4d denotes an amino group, optionally substituted with one or more C1-6alkyl; where "aryl" denotes phenyl or naphthyl, "heteroaryl" denotes a monocyclic or bicyclic radical containing 5 to 9 atoms in the ring, which contains at least one aromatic ring containing 5 to 6 atoms in the ring, with one or two N or O heteroatoms, wherein the remaining atoms in the ring are carbon atoms, under the condition that the binding point of the heteroaryl radical is in the aromatic ring, "heterocycloalkyl" denotes a monovalent saturated cyclic radical consisting of one ring containing 5 to 6 atoms in the ring, with one or two ring heteroatoms selected from N, O or SO2. The invention also relates to use of the compound of formula II or a pharmaceutical composition based on the compound of formula II.

EFFECT: obtaining novel compounds that are useful for modulating Btk activity and treating diseases associated with excessive activity of Btk.

7 cl, 2 tbl, 53 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I in which R1 represents halogen, methoxy group or cyano group; each of Y1 and Y2 represents CH, and one or two from U, V, W and X represent N, and each remaining one represents CH, or in case X, cam also represent CRa, or Ra represents halogen; A represents CH2CH(OH), CH2CH(NH2), CH(OH)CH(NH2) or CH(NH2)CH2, B represents CH2CH2, CH2NH or CONH, and D represents CH2, or A represents CH(OH)CH2, and B represents CH2NH, N(R2)CO or CONH, and D represents CH2, or B represents N(R2a)CH2, and D represents CH(OH), or A represents CH(OH)CH(OH), B represents CH2NH or CONH and D represents CH2, or A represents CH2CH2, and B represents CH2CH2, CH2NR3, NHCO, CONR4, CH2O, COCH2 or CH2CH2NH, and D represents CH2, or B represents CH2NH, and D represents CO, or A also represents CH2CH2, B represents NR4bCH2 and D represents CH(OH), or A represents CH=CH, B represents CH2NR5 or CONR6, and D represents CH2, or A represents C≡C, B represents CH2NH and D represents CO, or A represents COCH2, B represents CONH and D represents CH2, or A represents CH2N(R7), and B represents CH2CH2, a D represents CH2, or B represents CH2CH(OH), a D represents CH(OH), or A represents NHCH2, and B represents CH2NH, a D represents CH2, or B represents CH2NH, a D represents CO, or A represents NHCO, B represents CH(R8)NH or CH2CH2, and D represents CH2, or A represents OCH2, B represents CH=CH or CONH, and D represents CH2; R2 represents (C1-C4)alkyl; R2a represents hydrogen; R3 represents hydrogen, CO-(CH2)p-COOR3', (CH2)p-COOR3, (C2-C5)acyl or amino(C1-C4)alkyl, or also R3 represents (C1-C4)alkyl, which can be one or two times substituted with hydroxygroup, p stands for integer number from 1 to 4, and R3 represents hydrogen or (C1-C4)alkyl; R4 represents hydrogen or (C1-C4)alkyl; R4b represents hydrogen; R5 represents hydrogen or (C2-C5)acyl; R6 represents hydrogen or (C1-C4)alkyl; R7 represents hydrogen or (C1-C4)alkyl, which can be one or two times substituted with group, independently selected from hydroxygroup and aminogroup, R8 represents hydrogen or (C1-C4)alkyl; E represents one of the following groups (a-a1) where Z represents CH or N, and Q represents O or S, or E represents phenyl group, which is one or two times substituted in meta- and/or para-position with substituents, each of which is independently selected from group, including halogen, (C1-C3)alkyl and trifluoromethyl; or pharmaceutically acceptable salt of such compound. Formula I compound or its pharmaceutically acceptable salt is applied for obtaining medication or pharmaceutical composition for prevention or treatment of bacterial infection.

EFFECT: derivatives of oxazolidine antibiotics for obtaining medication for treatment of bacterial infections.

15 cl, 2 tbl, 214 ex

FIELD: chemistry.

SUBSTANCE: described are 1,2-disubstituted heterocyclic compounds of formula (I) where HET, X, Y and Z values are presented in description, which are phosphodiesterase 10 inhibitors. Also described are pharmaceutical composition and methods of treating central nervous system (CNS) disorders and other disorders, which can influence CNS function.

EFFECT: among disorders that can be subjected to treatment, there are neurological, neurodegenerative and psychiatric disorders, which include, but are not limited by them, disorders, associated with impairment of cognitive ability or schizophrenic symptoms.

14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) where "----" denotes a bond or is absent; R1 is a C1-4alkoxy group or halogen; R1b is H or C1-3alkyl; U and V each independently denote CH or N; W is CH or N, or, if "----" is absent, W is CH2 or NH; under the condition that at least one of U, V and W is CH or CH2; A is -CH2-CH(R2)-B-NH-* or -CH(R3)-CH2-N(R4)-[CH2]m-*; where asterisks indicate a bond which binds said fragments through a CH2-group with an oxazolidinone fragment; B is CH2 or CO; and R2 is hydrogen, OH or NH2; R3 and R4 both denote hydrogen, or R3 and R4 together form a methylene bridge; m equals 0, 1 or 2; and G is a phenyl which is monosubstituted in position 3 or 4, or disubstituted in positions 3 and 4, where each substitute is independently selected from a group comprising C1-4alkyl, C1-3alkoxy group and halogen; or G is a group selected from groups G1 and G5 where M is CH or N; Q' is S or O; Z1 is N, Z2 is CH and Z3 is CH; or Z1 is CH, Z2 is N and Z3 is CH or N; or Z1 is CH, Z2 is CR5 and Z3 is CH; or Z1 is CH, Z2 is CH and Z3 is N; and R5 is hydrogen or fluorine; or a pharmaceutically acceptable salt thereof. The compound of formula (I) or a pharmaceutically acceptable salt thereof are used as a medicinal agent for preventing or treating bacterial infections.

EFFECT: oxazolidinone derivatives used as antimicrobial agents.

15 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyridin-2-one and pyridazin-3-one derivatives, having Btk inhibiting activity. In formulae I-IV:

,

R denotes -R1-R2-R3 or -R2-R3; R1 denotes a heteroaryl containing 6 ring atoms, including one N heteroatom; R2 denotes -C(=O), -C(=O)N(R2'), where R2' denotes H; R3 denotes R4; where R4 is a lower alkyl, heterocycloalkyl, (lower alkyl) heterocycloalkyl or heterocycloalkyl (lower alkyl), where the heterocycloalkyl contains 6 ring atoms, including two heteroatoms selected from N and O; and where R4 can be substituted with one or more substitutes selected from lower alkyl, oxo group and lower alkoxy group; X denotes CH or N; Y1 denotes lower alkyl; n and m are equal to 0; values of radicals Y2, Y4 are given in the claim.

EFFECT: improved properties of compounds.

6 cl, 2 tbl, 42 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or a pharmaceutically acceptable salt thereof, wherein G1 is phenyl or pyridyl, each of which is optionally additionally substituted by one substitute presented by T; G2 is phenyl, 1,3-thiazolyl or 1,3-oxazolyl, wherein G2 is bound to G1 in the para position in relation to a place of attachment of G1 to group NH in formula (I), wherein G2 means phenyl, G3 is bound to G2 in the para position of G2 in relation to G1, and wherein provided G2 represents 1,3-thiazolyl or 1,3-oxazolyl, G2 is bound to G1 in the position of 5 G2 and G3 is bound to G2 in the position of 2 G2; T in each case is independently specified in a group containing C1-6alkyl and halogen; G3 is presented by formula or by formula ; W1 is -C(R3)(R4)-C(R3)(R4)-, and W2 represents N; or W3 represents O; W4 is -C(R3)(R4) -; each R3 and R4 is hydrogen; each R5 and R6 kis hydrogen; Rc and Rd together with a carbon atom whereto attached, are a 4-5-member cycloalkyl or monocyclic heterocycle of formula ; wherein one hydrogen atoms attached to the carbon atom of the cycloalkyl ring and monocyclic heterocycle is optionally substituted by a radical specified in a group -C(O)O(R8); W5 is -CH2- or -CH2-CH2-; W6 is O or N(RX), wherein Rx is hydrogen, C1-6alkyl or -C(O)O(Rz); RZ in each case is independently C1-6alkyl; R8 is hydrogen; L1 is O; and X is hydrogen, C1-6alkyl, or - (CRgRh)u-C(O)O(R10); or L1 is -CH2- and X is -C(O)OH; R10 is hydrogen; or Q is G4 or Y1-Y3; or Q is described for formula wherein Z is phenyl; G4 is benzothiazole or benzoxazole optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of C1-6alkyl, halogen and -OR1; Y1 in each case is independently -C(O)-, -C(O)O- or -C(O)N(Rw)-, wherein the right side -C(O)O- and -C(O)N(Rw)- of the groups is attached to Y3 or (CRJRk)v, Y3 in each case is independently phenyl, benzyl, piperidinyl or bicyclo[4.2.0]octa-1,3,5-triene, wherein the phenyl and benzyl residues are optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of halogen and haloC1-6alkyl; Rg and Rh in each case is independently hydrogen, or C1-6alkyl; R1 in each case is independently halogenC1-6alkyl; Rw is hydrogen; and u means 1.

EFFECT: compounds being the type 1 diacylglycerol O-acyltransferase (DGAT-1) enzyme inhibitors.

7 cl, 1 tbl, 61 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzodiazepine compounds of general formula , wherein each R1, R2, R3 and R4 independently represent hydrogen or alkyl, or R2 and R3 together represent lower alkylene; A1 is lower alkylene optionally substituted by hydroxy; and R5 is a fragment of formula , wherein each R6 and R7 independently represents hydrogen, lower alkyl, cycloalkyl, phenyl, furyl, thienyl, pyrazolyl, etc.; each XA and XB independently represents a bond, lower alkylene, -CO-, -SO2- etc., a pharmaceutical composition containing them, and using the above compound as the pharmaceutical composition or for preparing the same.

EFFECT: new compounds may be used for preventing and treating cardiac arrhythmia.

8 cl, 1047 ex, 78 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a 2,4-diamino-1,3,5-triazine derivative of general formula I, having protein kinase inhibitor properties, use thereof and a pharmaceutical composition based thereon. In general formula I Y is CH2, CHR', O, S, S(O) or S(O)2; X1, X2, X3 are independently selected from a CH groups or N; R1 is a C1-8 aliphatic group, C3-8 cycloalkyl, C6-10 aryl, ethylene-dioxyphenyl, methylene dioxyphenyl, pyridyl, each of which is optimally substituted with one or more identical or different groups R"; R' is hydrogen, OH, halogen, such as F, Cl, Br, I, or carboxyl or carboxamide, optimally N-substituted with (C1-6)alkyl, or cyano or halo(C1-8)alkyl, (C1-8)alkoxy, piperidinyl, optimally substituted with methyl; R" is R' or RD; R21, R22, R23, R24 are independently selected from groups F, Cl, Br, I, CN, (C1-16)alkyl; furthermore, R21 and R22 and/or R23 and R24 can be combined and represent one oxo (=O) group or together with a carbon atom can form a spirocycle containing 3 to 7 carbon atoms; furthermore, R21 and R24 together with two carbon atoms can form an aliphatic or aromatic ring containing 4 to 8 atoms, optionally substituted with one or more groups R'; RD is an oxo group =O or =S.

EFFECT: invention can be used to treat autoimmune or cancerous diseases, rheumatoid arthritis and non-Hodgkin lymphoma.

13 cl, 12 ex

FIELD: biotechnologies.

SUBSTANCE: in a compound of formula ,

X means N or CH, R1 means hydrogen or cyano, R2 means saturated 4-7-membered residue of heterocyclyl, which is bound through a nitrogen atom that contains 1 to 2 heteroatoms chosen from N and O. Besides, heterocyclyl residue can be replaced with one substituent chosen from a group consisting of C3-C6-cycloalkyl, or with 1-4 fluorine atoms. The invention also refers to a method for obtaining compounds and to a medicine on their basis.

EFFECT: compounds can be used for production of a medicine suitable for being used in a method of treatment or prophylaxis of cardiovascular diseases, cardiac insufficiency, anemia, chronic diseases of kidneys and kidney failure.

16 cl, 1 tbl, 29 ex

FIELD: biotechnologies.

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

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to 5-phenyl-1H-pyrazin-2-one derivatives of general formula II or pharmaceutically acceptable salts thereof, where R denotes -R1 or - R1-R2-R3; R1 denotes aryl or heteroaryl, and is optionally substituted with one or two R1'; where each R1' independently denotes C1-6alkyl, halogen or C1-6halogenalkyl; R2 denotes -C(=O), -CH2-; R3 denotes R4; where R4 denotes an amino group or heterocycloalkyl, and is optionally substituted with one or two substitutes selected from C1-6alkyl, hydroxy group, oxo group, C1-6hydroxyalkyl, C1-6alkoxy group; Q denotes CH2; Y1 denotes C1-6alkyl; Y2 denotes Y2b; where Y2b denotes C1-6alkyl, optionally substituted with one Y2b'; where Y2b' denotes a hydroxy group, n and m are equal to 0; Y4 denotes Y4c or Y4d; where Y4c denotes lower cycloalkyl, optionally substituted with halogen; and Y4d denotes an amino group, optionally substituted with one or more C1-6alkyl; where "aryl" denotes phenyl or naphthyl, "heteroaryl" denotes a monocyclic or bicyclic radical containing 5 to 9 atoms in the ring, which contains at least one aromatic ring containing 5 to 6 atoms in the ring, with one or two N or O heteroatoms, wherein the remaining atoms in the ring are carbon atoms, under the condition that the binding point of the heteroaryl radical is in the aromatic ring, "heterocycloalkyl" denotes a monovalent saturated cyclic radical consisting of one ring containing 5 to 6 atoms in the ring, with one or two ring heteroatoms selected from N, O or SO2. The invention also relates to use of the compound of formula II or a pharmaceutical composition based on the compound of formula II.

EFFECT: obtaining novel compounds that are useful for modulating Btk activity and treating diseases associated with excessive activity of Btk.

7 cl, 2 tbl, 53 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I in which R1 represents halogen, methoxy group or cyano group; each of Y1 and Y2 represents CH, and one or two from U, V, W and X represent N, and each remaining one represents CH, or in case X, cam also represent CRa, or Ra represents halogen; A represents CH2CH(OH), CH2CH(NH2), CH(OH)CH(NH2) or CH(NH2)CH2, B represents CH2CH2, CH2NH or CONH, and D represents CH2, or A represents CH(OH)CH2, and B represents CH2NH, N(R2)CO or CONH, and D represents CH2, or B represents N(R2a)CH2, and D represents CH(OH), or A represents CH(OH)CH(OH), B represents CH2NH or CONH and D represents CH2, or A represents CH2CH2, and B represents CH2CH2, CH2NR3, NHCO, CONR4, CH2O, COCH2 or CH2CH2NH, and D represents CH2, or B represents CH2NH, and D represents CO, or A also represents CH2CH2, B represents NR4bCH2 and D represents CH(OH), or A represents CH=CH, B represents CH2NR5 or CONR6, and D represents CH2, or A represents C≡C, B represents CH2NH and D represents CO, or A represents COCH2, B represents CONH and D represents CH2, or A represents CH2N(R7), and B represents CH2CH2, a D represents CH2, or B represents CH2CH(OH), a D represents CH(OH), or A represents NHCH2, and B represents CH2NH, a D represents CH2, or B represents CH2NH, a D represents CO, or A represents NHCO, B represents CH(R8)NH or CH2CH2, and D represents CH2, or A represents OCH2, B represents CH=CH or CONH, and D represents CH2; R2 represents (C1-C4)alkyl; R2a represents hydrogen; R3 represents hydrogen, CO-(CH2)p-COOR3', (CH2)p-COOR3, (C2-C5)acyl or amino(C1-C4)alkyl, or also R3 represents (C1-C4)alkyl, which can be one or two times substituted with hydroxygroup, p stands for integer number from 1 to 4, and R3 represents hydrogen or (C1-C4)alkyl; R4 represents hydrogen or (C1-C4)alkyl; R4b represents hydrogen; R5 represents hydrogen or (C2-C5)acyl; R6 represents hydrogen or (C1-C4)alkyl; R7 represents hydrogen or (C1-C4)alkyl, which can be one or two times substituted with group, independently selected from hydroxygroup and aminogroup, R8 represents hydrogen or (C1-C4)alkyl; E represents one of the following groups (a-a1) where Z represents CH or N, and Q represents O or S, or E represents phenyl group, which is one or two times substituted in meta- and/or para-position with substituents, each of which is independently selected from group, including halogen, (C1-C3)alkyl and trifluoromethyl; or pharmaceutically acceptable salt of such compound. Formula I compound or its pharmaceutically acceptable salt is applied for obtaining medication or pharmaceutical composition for prevention or treatment of bacterial infection.

EFFECT: derivatives of oxazolidine antibiotics for obtaining medication for treatment of bacterial infections.

15 cl, 2 tbl, 214 ex

FIELD: chemistry.

SUBSTANCE: described are 1,2-disubstituted heterocyclic compounds of formula (I) where HET, X, Y and Z values are presented in description, which are phosphodiesterase 10 inhibitors. Also described are pharmaceutical composition and methods of treating central nervous system (CNS) disorders and other disorders, which can influence CNS function.

EFFECT: among disorders that can be subjected to treatment, there are neurological, neurodegenerative and psychiatric disorders, which include, but are not limited by them, disorders, associated with impairment of cognitive ability or schizophrenic symptoms.

14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) where "----" denotes a bond or is absent; R1 is a C1-4alkoxy group or halogen; R1b is H or C1-3alkyl; U and V each independently denote CH or N; W is CH or N, or, if "----" is absent, W is CH2 or NH; under the condition that at least one of U, V and W is CH or CH2; A is -CH2-CH(R2)-B-NH-* or -CH(R3)-CH2-N(R4)-[CH2]m-*; where asterisks indicate a bond which binds said fragments through a CH2-group with an oxazolidinone fragment; B is CH2 or CO; and R2 is hydrogen, OH or NH2; R3 and R4 both denote hydrogen, or R3 and R4 together form a methylene bridge; m equals 0, 1 or 2; and G is a phenyl which is monosubstituted in position 3 or 4, or disubstituted in positions 3 and 4, where each substitute is independently selected from a group comprising C1-4alkyl, C1-3alkoxy group and halogen; or G is a group selected from groups G1 and G5 where M is CH or N; Q' is S or O; Z1 is N, Z2 is CH and Z3 is CH; or Z1 is CH, Z2 is N and Z3 is CH or N; or Z1 is CH, Z2 is CR5 and Z3 is CH; or Z1 is CH, Z2 is CH and Z3 is N; and R5 is hydrogen or fluorine; or a pharmaceutically acceptable salt thereof. The compound of formula (I) or a pharmaceutically acceptable salt thereof are used as a medicinal agent for preventing or treating bacterial infections.

EFFECT: oxazolidinone derivatives used as antimicrobial agents.

15 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a medicinal agent for antagonistic action on angiotensin II, which contains a compound of formula (I) , in which R1 is a group of formula or , in which R2, R3, R4, R5, R6, R7 and R8, each independently, denote a hydrogen atom or a C1-6alkyl or salt thereof, which is intended for preventing or treating blood circulation disorders such as diabetes and diseases caused by insulin resistance. The invention relates to a medicinal agent which further contains a calcium antagonist and diuretic. The invention relates to use of said medicinal agents to treat said diseases, as well as methods of treating and preventing said diseases and disorders.

EFFECT: high efficiency of using said compounds.

17 cl, 2 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyridin-2-one and pyridazin-3-one derivatives, having Btk inhibiting activity. In formulae I-IV:

,

R denotes -R1-R2-R3 or -R2-R3; R1 denotes a heteroaryl containing 6 ring atoms, including one N heteroatom; R2 denotes -C(=O), -C(=O)N(R2'), where R2' denotes H; R3 denotes R4; where R4 is a lower alkyl, heterocycloalkyl, (lower alkyl) heterocycloalkyl or heterocycloalkyl (lower alkyl), where the heterocycloalkyl contains 6 ring atoms, including two heteroatoms selected from N and O; and where R4 can be substituted with one or more substitutes selected from lower alkyl, oxo group and lower alkoxy group; X denotes CH or N; Y1 denotes lower alkyl; n and m are equal to 0; values of radicals Y2, Y4 are given in the claim.

EFFECT: improved properties of compounds.

6 cl, 2 tbl, 42 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

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