Antagonists of thrombin receptor

FIELD: medicine, pharmaceutics.

SUBSTANCE: tricyclic compounds of formula I: $ substituted with heterocycle are disclosed, or pharmaceutically acceptable salt or solvate of specified compound, isomer or racemic mixture, where stands for optional double link, dotted line stands for link or does not stand for link, which results in double or single link according to requirements of valency and where A, B, G, M, X, J, n, Het, R3, R10, R11, R32 and R33 and other substituents are such as indicated in formula of invention. Invention also relates to pharmaceutical compositions, which contain them, method of thrombin receptor or cannabinoid receptor inhibition, and to method for treatment of disease related to thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, cardiac failure and cancer by administration of specified compounds.

EFFECT: production of compounds having properties of antagonists of thrombin receptors.

33 cl, 6 tbl, 2 ex

 

The present invention relates to Nord-samopromzvolny himbacine applicable as antagonists of thrombin receptor in the treatment of diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina, arrhythmia, heart failure, cerebral ischemia, stroke, neurodegenerative diseases and cancer. Antagonists of thrombin receptor also known as antagonists of protease-activated receptor (APR-1). Compounds corresponding to the present invention are also applicable as inhibitors of cannabinoid receptor (CB2) in the treatment of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, stroke, cerebral, cerebral ischemia, nephritis, inflammatory diseases of the lungs and gastrointestinal tract and disorders of the respiratory tract, such as reversible obstruction of the Airways, chronic asthma and bronchitis. The present invention also relates to pharmaceutical compositions containing these compounds.

It is known that different cell types thrombin exhibits a different activity, and it is known that thrombin receptors found in these types of cells as a human platelets, vascular smooth muscle cells, endothelial cells and fibroblasts. Therefore, predpoll who is, that antagonists of thrombin receptor are useful for treating platelet-mediated, inflammatory, atherosclerotic and fibroproliferative diseases, and other disorders, the pathogenesis of which involves thrombin and its receptor.

The peptide antagonists of thrombin receptor identified on the basis of studies of the dependency structure-activity comprising the amino acid substitution thrombin receptors. In the publication Bernatowicz et al., J. Med. Chem., 39 (1996), p.4879-4887 described Tetra - and Pentapeptide as being active antagonists, thrombin receptor, for example, N-TRANS-cynnamoyl-p-h-p-h-Lu-AGD-NH2and N-TRANS-cynnamoyl-p-h-p-h-Lu-AGD-AGD-NH2. The peptide-receptor antagonists thrombin also disclosed in WO 94/03479, published February 17, 1994

Cannabinoid receptors belong to the superclass receptor binding and G-protein. They are divided into mainly neural receptors SV1and mainly peripheral receptors SV2. These receptors exert their biological effects through modulation of adenylate cyclase and fluxes of CA+2and+. While the impact of receptors CB1mainly associated with the Central nervous system, it is assumed that receptors SV1my peripheral impacts associated with the European the of the bronchi, immunomodulation and inflammation. It is assumed that as such a reagent that selectively bind to the receptor SV1may find therapeutic use in combating diseases associated with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, stroke, cerebral, cerebral ischemia, nephritis, inflammatory diseases of the lungs and gastrointestinal tract and disorders of the respiratory tract, such as reversible obstruction of the Airways, chronic asthma and bronchitis (R.G.Pertwee, Curr. Med. Chem. 6(8), (1999), 635; M.Bensaid, Molekular Pharmacology, 63(4), (2003), 908).

It is established that himbacine, piperidinyl alkaloid of the formula

is an antagonist of muscarinic receptor. Total synthesis of (+)-himbacine described in the publication Chackalamannil et al., J.Am.Chem. Soc.118 (1996), p.9812-9813.

Substituted tricyclic antagonists of thrombin receptor are disclosed in US 6063847, US 6326380 and U.S. Serial Nos. 09/880222 (WO 01/96330) and 10/271715.

The present invention relates to compounds described by formula I

or pharmaceutically acceptable salts of such compounds, in which

means a double bond or an ordinary communication in accordance with the requirements of valence; provided that R3no is the duty to regulate, if the carbon atom to which R3must be attached participates in a double bond;

In means -(CH2)n3-, -(CH2)-O-, -(CH2)S-, -(CH2)-NR6-, -C(O)NR6-, -NR6C(O)- ,, -(CH2)n4CR12=CRl2a(CH2)n5- or -(CH2)n4C=C(CH2)n5if n3is 0-5, n4and n5independently equal to 0 to 2, and R12and Rl2aindependently selected from the group comprising hydrogen, alkyl and halogen;

E. meansor-S(O)m-where m is 0, 1 or 2;

A, G, M and J are independently selected from the group comprising-N(R54)-, -(CR1R2)-, -

X means, -CH - or-N-, provided that the choice of A, G, M and X does not lead to the presence of neighboring atoms of oxygen or sulfur;

each n is 0, 1 or 2 provided that all variables n cannot be 0;

Het denotes a mono-, bi - or tricyclic heteroaromatic group containing from 5 to 14 atoms, including from 1 to 13 carbon atoms and from 1 to 4 heteroatoms, independently selected from the group comprising N, O and S, provided that in the heteroaromatic group does not include adjacent oxygen atoms or sulfur, where the ring nitrogen atom may form an N-oxide or a Quaternary group with alkyl group, where Het when is outinen to a cyclic carbon atom and where the group Het is substituted by 1-4 fragments, W, where each W is independently selected from the group comprising hydrogen; alkyl; foralkyl; diferuloyl; triptorelin; cycloalkyl; heteroseksualci; heteroseksualci, substituted alkyl or alkenyl; alkenyl; R21-arylalkyl; R21-arylalkyl; heteroaryl; heteroaromatic; heteroaromatic; hydroxyalkyl; dihydroxyaryl; aminoalkyl; acylaminoalkyl; di-(alkyl)-aminoalkyl; thioalkyl; alkoxygroup; alkenylacyl; halogen; -NR4R5; -CN; -IT; -C(O)OR17; -COR16; -OS(O2CF3; -CH2OCH2CF3; alkylthiols; -C(O)NR4R5; -OCHR6is phenyl; phenoxyethyl; -NHCOR16; -NHSO2R16; biphenyl; -OC(R6)2COOR7; -OC(R6)2C(O)NR4R5; alkoxygroup, substituted alkyl, amino, or-NHC(O)OR17; aryl; aryl containing 1-3 substituent, independently selected from the group comprising alkyl, halogen, alkoxy, methylenedioxy, carboxylic acid, carboxamide, amine, urea, amide, sulfonamide, -CN, -CF3, -OCF3HE, alkylamino, di(alkyl)amino group, -NR25R26alkyl-, hydroxyalkyl-, -C(O)OR17, -COR17, -NHCOR16, -NHS(O)2R16, -NHS(O)2CH2CF3, -C(O)NR25R26, -NR25-C(O)-NR25R26, -S(O)R13, -S(O)2R13and-SR13; or alkyl, optionally substituted with-NR1 R2, -NR1COR2, -NR1CONR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OH, -C(O)OR1, -CONR1R2heteroaryl, hydroxyalkyl, alkyl or-S(O)2-alkyl; -C(O)NR4R5or heteroaryl;

where adjacent carbon atoms of the ring Het optionally may form a ring with methylendioxyphenyl;

R1and R2independently selected from the group comprising hydrogen, alkyl, foralkyl, littoralis, triptorelin, cycloalkyl, alkenyl, alkoxy, arylalkyl, arylalkyl, heteroaryl al Kyl, heteroaromatic, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl; or

R1and R2in the case of accession to the nitrogen atom, taken together, form a mono - or bicyclic heterocyclic ring containing from 4 to 10 atoms including 1-3 heteroatoms selected from the group comprising-O-, -N-, -S-, -S(O)-, -S(O)2andprovided that the ring atoms S and O are next to each other, where the aforementioned heterocyclic ring is unsubstituted or substituted one or more groups selected from the group comprising alkyl, halogen, hydroxy, alkoxy, aryloxy, Allakaket;

R3means urlcategory, alloctype, heteroaryl, heteroaromatic, -CN, -NO2/sub> , -O-aryl, -O-heteroaryl, N3, -C(O)NR18R19, -C(=NR1)NR1R2, -N(R1)C=(NR1)NR1R2; -N=C(R1)NR1R2, -NR18C(O)R19, -NR18C(O)NR18R19, -NR18C(O)OR19, -NR18S(O)2R19, -NR18S(O)2NR18R19, -NHNR18R19, -NR18NR18R19and-alkyl-NR18R19;

R6means hydrogen, alkyl or phenyl;

R7means hydrogen or alkyl;

each R13independently selected from the group comprising hydrogen, alkyl, cycloalkyl, halogenated, halogen, -(CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b,

-(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16, (CH2)n6NHSO2NR4R5and -(CH2)n6C(O)NR28R29where n6 is 0-4;

each R14independently selected from the group comprising hydrogen, alkyl, -HE, alkoxygroup, arylalkyl, heteroaryl, heteroaromatic, heterocyclic, geterotsiklicheskikh, halogen, halogenated, -(CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b, -(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16, (CH2)n6NHSO2NR4R5and -(CH2)n6C(O)NR28R29where n6 is 0 to 4; where R4and R5independently selected from the group which Lucaya hydrogen, alkyl, phenyl, benzyl and cycloalkyl, or R4and R5together may form a ring together with the nitrogen atom to which they are attached, where the specified ring formed by the groups R4and R5, optionally substituted with =O, HE, OR1or-C(O)IT; or

R13and R14taken together, constitute spirocyclohexane or heteroeroticism ring containing 3-6 ring atoms, where the specified heteroeroticism ring contains from 2 to 5 ring carbon atoms and 1 or 2 ring heteroatoms selected from the group comprising O, S and N;

R16independently selected from the group comprising hydrogen, alkyl, phenyl and benzyl;

R16aindependently selected from the group comprising hydrogen, alkyl, phenyl and benzyl;

R16bmeans hydrogen, alkoxygroup, alkyl, alkoxyalkyl-, R22-O-C(O)-alkyl-, cycloalkyl, R21-aryl, R21-arylalkyl, halogenated, alkenyl, halogensubstituted of alkenyl, quinil, halogensubstituted quinil, R21-heteroaryl, (R21-heteroaryl)-alkyl-, (R21-heteroseksualci)-alkyl-, R28R29N-alkyl-, R28R29N-C(O)-alkyl-, R28R29N-C(O)O-alkyl-, R28OC(O)N(R29)-alkyl-, R28S(O)2N(R29)-alkyl-, R28R29N-C(O)-N(R29)-alkyl-, R28R29N-S(O)2N(R29)-alkyl-, R28-C(O)N(R29)-alkyl-, 28R29N-S(O)2-alkyl-, HOS(O)2-alkyl-, (OH)2P(O)2-alkyl, R28-S-alkyl-, R28-S(O)2-alkyl - or hydroxyalkyl; R17independently selected from the group comprising hydrogen, alkyl, phenyl and benzyl;

R18and R19mean hydrogen, alkyl, aryl, R21-aryl, heteroaryl, cycloalkyl, heterocyclyl, alkoxyalkyl, halogenoacetyl, aryloxyalkyl, aryloxyalkyl, heteroepitaxial, heteroarylboronic, cycloalkenyl, (heterocyclyl)alkyloxyalkyl, alkoxylalkyl, -S(O)2-alkyl, -C(NH)NR1R2or alkyl substituted by one or more fragments selected from the group comprising cycloalkyl, halogen, hydroxy group, -NR1R2, -NR1C(O)R2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OH, -C(O)OR1and-C(O)NR1R2; or

R18and R19together with the nitrogen atom to which they are attached, form a mono - or bicyclic heterocyclic ring containing from 4 to 10 atoms including 1-3 heteroatoms selected from the group comprising - O-, -N-, -S-, -S(O)-, -S(O)2andprovided that the atoms of S and O are next to each other, the ring is unsubstituted or substituted one or more groups, you the early group, includes alkyl, halogen, hydroxy-group, alkoxygroup, alloctype, arielalexisxrp, -NR1R2, -NR1COR2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1C(O)2OR2, -NR1S(O2)NR1R2, -C(O)OR1, -CONR1R2and alkyl, substituted-NR1R2, -NR1COR2, -NR1CONR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OR1or-CONR1R2;

R21means from 1 to 3 slices, and each R21independently selected from the group comprising hydrogen, -CN, -CF3, -F3, halogen, -NO2, alkyl, -HE, alkoxygroup, alkylamino, di(alkyl)amino group, -NR25R26alkyl-, hydroxyalkyl-, -C(O)ORl7, -COR17, -NHCOR16, -NHS(O)2R16, -C(NH)-NH2, -NHS(O)2CH2CF3, -C(O)NR25R26, -NR25-C(O)-NR25R26, -S(O)R13, -S(O)2R13, -SR13; -SO2NR4R5and-CONR4R5; or two adjacent fragment R21can form methylenedioxy;

R22means hydrogen, alkyl, phenyl, benzyl, -COR16, -CONR18R19, -COR23, -S(O)R31, -S(O)2R31, -S(O2)NR24R25or-C(O)OR27;

R23means

g is e R 35and R36independently selected from the group comprising hydrogen, alkyl and R37-substituted alkyl, where R37selected from the group including BUT-, HS-, CH2S-, -NH2, phenyl, p-hydroxyphenyl and indolyl; or R23means alkyl; halogenated; alkenyl; halogenoalkanes; quinil; cycloalkyl; cycloalkenyl; cycloalkyl containing from 1 to 3 substituents selected from the group comprising alkoxyalkyl, alkyl, halogen, hydroxy-group, alkoxygroup, alloctype, arielalexisxrp, -NR1R2, -NR1C(O)R2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OH, -C(O)OR1and-CONR1R2; aryl; arylalkyl; heteroaryl; heteroseksualci; alkyl substituted with-NR1R2, -NR1COR2, -NR1CONR1R2, -NR1C(O)OR2, -NR1S(O2R2, -NR1S(O2)NR1R2, -C(O)OH, -C(O)OR1, -CONR1R2and-SO3H;

R24, R25and R26independently selected from the group comprising hydrogen, alkyl, halogenated, alkenyl, quinil, aryl, aralkyl, cycloalkyl, halogenosilanes, alkoxyalkyl, the hydroxy-group and alkoxygroup;

R27means from 1 to 3 slices, and each R27selected from the group comprising hydrogen, alkyl and cycloalkyl, where R27the optional is tion substituted-HE, -C(O)HE, halogen and alkoxygroup;

R28and R29independently selected from the group comprising hydrogen, alkyl, alkoxygroup, arylalkyl, heteroaryl, heteroaromatic, hydroxyalkyl, alkoxyalkyl, heterocyclyl, geterotsiklicheskikh and halogenated; or

R28and R29taken together, constitute spirocyclohexane or heteroeroticism ring containing 3-6 ring atoms;

R32and R33independently selected from the group comprising hydrogen, R34-alkyl, R34alkenyl, R34-quinil, R40-heteroseksualci, R38-aryl, R38-aralkyl, R42-cycloalkyl, R42-cycloalkenyl, -OH, -OC(O)R43, -C(O)OR43, -C(O)R43, -C(O)NR43R44, -NR43R44, -NR43C(O)R44, -NR43C(O)NR44R45, -NHS(O)2R43, -OC(O)NR43R44, R37-alkoxygroup, R37-alkenylacyl, R37-alkyloxy, R40-geterotsiklicheskikh, R42-cycloalkylation, R42-cycloalkanones, R42-cycloalkyl-NH-, -NHSO2Other16and-CH(=NOR17);

or R32and R33can be combined with the formation of a ring structure Q below

in which

R9means hydrogen, HE, alkoxygroup, halogen or halogenated;

Q means R-substituted aryl, R-substituted Goethe is auril, R-substituted heterocyclic ring comprising 4 to 8 atoms containing 1-3 heteroatoms selected from the group comprising O, S, S(O), S(O)2and NR22provided that S and can not be next to each other; or

Q means

where R10and R11independently selected from the group comprising R1and-OR1provided that when ring Q is aromatic and the carbon atoms to which are attached R10and R11connected by a double bond, R10and R11no;

R is from 1 to 5 and each R is independently selected from the group comprising hydrogen, alkyl, halogen, hydroxy-group, amino group, alkylamino, dialkylamino, alkoxygroup, -COR16, -C(O)OR17-C(O)NR4R5, -SOR16, -S(O2R16, -NR16COR16a, -NR16C(O)OR16a, - NR16CONR4R5, -NR16S(O2)NR4R5foralkyl, littoralis, triptorelin, cycloalkyl, alkenyl, arylalkyl, arylalkyl, heteroallyl, heteroaromatic, hydroxyalkyl, aminoalkyl, aryl and thioalkyl;

R34means from 1 to 3 slices, and each R34independently selected from the group comprising hydrogen, halogen, -HE, alkoxygroup, R47-aryl, al is Il-C(O)-, alkenyl-C(O)-, quinil-C(O)-, heteroseksualci, R39-cycloalkyl, R39-cycloalkenyl, -OC(O)R43, -C(O)OR43, -C(O)R43, -C(O)NR43R44, -NR43R44, -NR43C(O)R44, -NR43C(O)NR44R45, -NHSO2R43, -OC(O)NR43R44, R34-alkenylacyl, R34-alkyloxy, R40-geterotsiklicheskikh, R42 - cycloalkylation, R42-alkenylacyl, R42-cycloalkyl-NH-, -NHSO2Other16and-CH(=NOR17);

R38means from 1 to 3 slices, and each R38independently selected from the group comprising hydrogen, heteroseksualci, halogen, -C(O)OR48, -CN, -C(O)NR49R50, -NR51C(O)R52, -OR48cycloalkyl, cycloalkenyl, alkylcyclohexanes, halogenallylacetic, hydroxyalkyl, alkoxyalkyl and R52-heteroaryl; or two groups R38the adjacent ring carbon atoms form a condensed methylendioxy;

R39means from 1 to 3 slices, and each R39independently selected from the group comprising hydrogen, halogen and alkoxygroup;

R40means from 1 to 3 slices, and each R40independently selected from the group comprising hydrogen, R41-alkyl, R41alkenyl and R41-quinil;

R41means hydrogen, -HE or alkoxygroup;

R42means from 1 to 3 fragment and each R 42independently selected from the group comprising hydrogen, alkyl, -HE, alkoxygroup and halogen;

R43, R44and R45independently selected from the group comprising hydrogen, alkyl, alkoxyalkyl, R38-arylalkyl, R46-cycloalkyl, R53-cycloalkenyl, R38-aryl, heteroseksualci, heteroaryl, geterotsiklicheskikh and heteroaromatic;

R46means hydrogen, alkyl, hydroxyalkyl or alkoxygroup;

R47means from 1 to 3 slices, and each R47independently selected from the group comprising hydrogen, alkyl, -HE, halogen, -CN, alkoxygroup, trigonocarpus, alkylamino, di(alkyl)amino group, -OCF3hydroxyalkyl, -Cho, -C(O)alkylamino, -C(O)di(alkyl)amino group, -NH2, -NH(O)alkyl and-N(alkyl)C(O)alkyl;

R48means hydrogen, alkyl, halogenated, dehalogenated or triptorelin;

R49and R50independently selected from the group comprising hydrogen, alkyl, aralkyl, phenyl and cycloalkyl, or R49and R50together denote -(CH2)4-, -(CH2)5- or -(CH2)2-NR39-(CH2)2- and form a ring together with the nitrogen atom to which they are attached;

R51and R52independently selected from the group comprising hydrogen, alkyl, aralkyl, phenyl and cycloalkyl, or R51and R52in the group-NR39C(O)R40 together with the nitrogen atoms to which they are attached, form a cyclic lactam containing 5-8 ring members;

R53means hydrogen, alkoxygroup, -SOR16, -SO2R17, -C(O)OR17, - C(O)NR18R19, alkyl, halogen, foralkyl, littoralis, triptorelin, cycloalkyl, alkenyl, aralkyl, arylalkyl, heteroallyl, heteroaromatic, hydroxyalkyl, aminoalkyl, aryl, thioalkyl, alkoxyalkyl or acylaminoalkyl and

R54selected from the group comprising hydrogen; alkyl; foralkyl; diferuloyl; triptorelin; cycloalkyl; cycloalkyl substituted from 1 to 3 substituents selected from the group comprising alkoxyalkyl, alkyl, halogen, hydroxy-group, alkoxygroup, alloctype, arielalexisxrp, -NR1R2, -NR1C(O)R2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OH, -C(O)OR1and-CONR1R2; alkenyl; alkoxygroup; arylalkyl; arylalkyl; heteroaromatic; heteroaromatic; a hydroxy-group; alkoxygroup; hydroxyalkyl; alkoxyalkyl; aminoalkyl; aryl; heteroaryl; dialkyl and alkyl substituted with 1-3 substituents, independently selected from the group comprising urea, sulfonamide, carboxamide, carboxylic acid, ether carboxylic acids and a sulfonylurea;

and its farmaci is almost acceptable salts.

Also provided pharmaceutical compositions comprising at least one compound of formula I and a pharmaceutically acceptable carrier. Compounds corresponding to the present invention, can be used as antagonists of thrombin receptor APR-1 for the treatment of cardiovascular or related to disorder of circulatory diseases or pathological conditions, inflammatory diseases or pathological conditions, diseases or pathological conditions of the respiratory tract, cancer, acute renal failure, astrogliosis, fibrotic disorders of the liver, kidneys, lungs or intestines, Alzheimer's, diabetes, diabetic neuropathy, rheumatoid arthritis, neurodegenerative disease, neurotoxic disease, systemic lupus erythematosus, multiple sclerosis, osteoporosis, glaucoma, macular degeneration, psoriasis, radiation fibrosis, endothelial dysfunction, wound or lesion of the spinal cord, or its symptoms, or effects.

Connection-antagonists, thrombin receptor, corresponding to the present invention, may have antiplatelet, preventing platelet aggregation, anti-sclerotic, antirestenotic and/or antikoaguliruyuschey activity. Associated with thrombosis diseases that can be cured compounds and, relevant to the present invention, are thrombosis, atherosclerosis, restenosis, hypertension, angina, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, platelet and thromboembolic stroke, peripheral vascular disease, other cardiovascular disease, cerebral ischemia, inflammatory diseases and cancer, and other disorders, the pathogenesis of which involves thrombin and its receptor.

An additional object of the invention avalist the use of compounds according to the above formulas (I) to obtain medicines for the treatment of thrombosis, atherosclerosis, restenosis, hypertension, angina associated with angiogenesis disorders, arrhythmia, cardiovascular or related to disorder of circulatory disease or condition, heart failure, myocardial infarction, glomerulonephritis, platelet stroke, thromboembolic stroke, peripheral vascular disease, cerebral ischemia, rheumatoid arthritis, rheumatism, astrogliosis, fibrotic disorders of the liver, kidney, lung or bowel, systemic lupus erythematosus, multiple sclerosis, osteoporosis, glomerulonephritis, kidney disease, acute renal failure, chronic renal failure, renal vascular homeostasis, renal ischemia,inflammation of the bladder, diabetes, diabetic neuropathy, cerebral stroke, cerebral ischemia, nephritis, cancer, such as, for example, pochernkletocny carcinoma or associated with angiogenesis violation, melanoma, pochernkletocny carcinoma, neuropathy and/or malignant tumors, neurodegenerative and/or neurotoxic diseases, conditions or lesions, such as, for example, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease or Wilson's disease, inflammation, such as, for example, irritable bowel syndrome, Crohn's disease, nephritis or radiation-induced or chemotherapy proliferative or inflammatory violation gastrointestinal tract, lung, bladder, gastrointestinal tract or other body, asthma, glaucoma, macular degeneration, psoriasis, endothelial dysfunction, disorders of the liver, kidneys or lungs, inflammatory disorders of the lungs and gastrointestinal tract, disease or condition of the respiratory tract, such as, for example, reversible obstruction of the Airways, asthma, chronic asthma, bronchitis or chronic airway disease, radiation fibrosis, endothelial dysfunction, periodontal diseases or wounds or lesions of the spinal cord, or its symptoms, or effects.

Variant domestic the present invention relates to the use of an antagonist of thrombin receptor, disclosed in any of documents US 6063847, US 6326380, US 6645987, U.S. Serial No. 10/271715, which are included in the present invention for reference, in combination with one or more additional cardiovascular drugs for the treatment of thrombosis, aggregation, coagulation of platelets, cancer, inflammatory diseases or respiratory diseases. In particular, the present invention relates to a method of applying the specified combination for the treatment of thrombosis, atherosclerosis, restenosis, hypertension, angina associated with angiogenesis disorders, arrhythmia, cardiovascular or related to disorder of circulatory disease or pathological condition, heart failure, myocardial infarction, glomerulonephritis, platelet stroke, thromboembolic stroke, peripheral vascular disease, cerebral ischemia, rheumatoid arthritis, rheumatism, astrogliosis, fibrotic disorders of the liver, kidney, lung or bowel, systemic lupus erythematosus, multiple sclerosis, osteoporosis, glomerulonephritis, kidney disease, acute renal failure, chronic renal failure, renal vascular homeostasis, renal ischemia, inflammation of the bladder, diabetes, diabetic neuropathy, cerebral stroke, cerebral ischemia, nephritis, cancer, melanoma, pocetnike the full carcinoma, neuropathy and/or malignant tumors, neurodegenerative and/or neurotoxic diseases, pathological conditions or lesions, inflammation, asthma, glaucoma, macular degeneration, psoriasis, endothelial dysfunction, disorders of the liver, kidneys or lungs, inflammatory disorders of the liver and gastrointestinal tract, diseases or pathological conditions of the respiratory tract, radiation fibrosis, endothelial dysfunction, periodontal diseases or wounds or lesions of the spinal cord, or its symptoms, or effects. Provided pharmaceutical compositions comprising an antagonist of thrombin receptor, disclosed in any of documents US 6063847, US 6326380, US 6645987, U.S. Serial No. 10/271715, and cardiovascular drug with a pharmaceutically acceptable carrier.

In addition, the scope of the present invention enables the combination corresponding to the present invention, which may be provided in the form of a kit comprising in a single package at least one compound of formula I in the pharmaceutical composition and at least one separate pharmaceutical composition that includes a cardiovascular drug.

In one embodiment, the present invention relates to compounds described by structural formula I, or their pharmaceutically acceptable salts, in which time the ranks fragments are as explained above.

For compounds of formula I, the preferred embodiments of the compounds of formula I are the following:

where X represents-CH - or-N-.

Additional preferred embodiments of the compounds of formula I are the following:

More preferred embodiments of formula I are the following:

More preferred embodiments of formula I are the following:

In one embodiment, the compounds of formula I, R3absent and there is a double bond between X and the carbon atom to which otherwise attached R3.

In the embodiment, the compounds of formula I, R32and R33combined with the formation of the ring Q.

In another embodiment, the compounds of formula I, And means Q.

In another embodiment, the compounds of formula I, An, n is 1.

In another embodiment is sushestvennee the compounds of formula I, in Mn, n is 0.

In another embodiment, the compounds of formula I, G means-CR1R2-.

In another embodiment, the compounds of formula I, R1means hydrogen and R2means methyl.

In the embodiment, the compounds of formula I, J means-CR1R2-.

In another embodiment, the compounds of formula I, Jn, n is 1.

In another embodiment, the compounds of formula I, X is CH.

In another embodiment, the compounds of formula I, means -(CH2)n4CR12=CR12a(CH2)n5-, where n4and n50.

In another embodiment, the compounds of formula I, R3means heteroaryl, -C(O)NR18R19, -NR18C(O)R19, -NR18C(O)OR19, -NR18S(O)2R19or-NR18C(O)NR18R19.

In another embodiment, the compounds of formula I, R18and R19mean hydrogen, alkyl, heteroaryl, -C(NH)-NH2, aryl, R21-aryl, or alkyl substituted by one or more fragments selected from the group comprising cycloalkyl, halogen, a hydroxy-group, -NR1R2, -NR1C(O)R2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OH, -C(O)OR1or-C(O)NR1R2; where R 1and R2mean hydrogen, alkyl or alkoxygroup; or

R18and R19together with the nitrogen atom to which they are attached, form a mono - or bicyclic heterocyclic ring containing from 4 to 10 atoms including 1-3 heteroatoms selected from the group comprising O, N, S, S(O), S(O)2and C=O, provided that the S atoms or are not next to each other, unsubstituted or substituted by one or more groups selected from the group comprising alkyl, halogen, hydroxy-group, alkoxygroup, alloctype, arielalexisxrp, -NR1R2, -NR1COR2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O2)NR1R2, -C(O)OH, -C(O)OR1, -CONR1R2and alkyl, optionally substituted by-NR1R2, -NR1COR2, -NR1CONR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OH, -C(O)OR1or-CONR1R2.

In another embodiment, the compounds of formula I, Het means heteroaryl.

In another embodiment, the compounds of formula I, W stands for aryl, heteroaryl or aryl substituted by halogen or-CN.

In another embodiment, the compounds of formula I, R32and R33mean hydrogen or alkyl, or R32and R33the volume of dynany with the formation of a ring structure Q, where Q means

In an additional embodiment, the compounds of formula I, In the mean CIS - or TRANS-(CH2)n4CR12=CR12a(CH2)n5-, where n4and n50;

Andnmeans Oh where n is 1;

Gnmeans of CH2, SN(alkyl) or C(alkyl)2;

X is-CH-;

Jnmeans of CH2where n is 1;

R3means-C(O)NR18R19;

R10and R11mean hydrogen;

R18and R19mean hydrogen, alkyl, heteroaryl, -C(NH)-NH2, aryl, R21-aryl or alkyl substituted by one or more fragments selected from the group comprising cycloalkyl, halogen, a hydroxy-group, -NR1R2, -NR1C(O)R2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, - NR1S(O)2NR1R2, -C(O)OH, -C(O)OR1or-C(O)NR1R2; where R1and R2mean hydrogen, alkyl or alkoxygroup; or

R18and R19together with the nitrogen atom to which they are attached, form a mono - or bicyclic heterocyclic ring containing from 4 to 10 atoms including 1-3 heteroatoms selected from the group comprising O, N, S, S(O), S(O)2and C=O, provided that the S atoms or are not next to each other, unsubstituted or substituted odnosili a large number of groups, selected from the group comprising alkyl, halogen, hydroxy-group, alkoxygroup, alloctype, arielalexisxrp, -NR1R2, -NR1COR2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O2)NR1R2, -C(O)OH, -C(O)OR1, -CONR1R2and alkyl, optionally substituted with-NR1R2, -NR1COR2, -NR1CONR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OH, -C(O)OR1or-CONR1R2;

Het means heteroaryl;

W stands for aryl, heteroaryl or aryl substituted by halogen or-CN; and

R32and R33mean hydrogen or alkyl, or R32and R33optional merged to form a ring structure Q, where Q means

In an additional embodiment, the compounds of formula I, means-CH=CH-;

Het means heteroaryl substituted with W;

W stands for aryl, substituted with halogen or CN;

R32and R33combined with the formation of Q and Q means

and R3is defined as follows:

R3

In an additional embodiment, the compounds of formula I, In the mean CIS - or TRANS-(CH2)n4CR12=CR12a(CH2)n5where n4and n50;

Anmeans Oh where n is 1;

Gnmeans of CH2, SN(alkyl) or C(alkyl)2;

X is-CH-;

Jnmeans of CH2where n is 1;

R3means heteroaryl, -NR18C(O)R19, -NR18C(O)OR19or-NR18S(O)2R19;

R10and R11mean hydrogen;

R18and R19mean hydrogen, alkyl, heteroaryl, heterocyclyl, -C(NH)-NH2, aryl, R21-aryl, or alkyl substituted by one or more fragments selected from the group comprising cycloalkyl, halogen, a hydroxy-group, -NR1R2, -NR1C(O)R2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1C(O)2NR1R2, -C(O)OH, -C(O)OR1or-C(O)NR1R2; where R1and R2mean hydrogen, alkyl or alkoxygroup; or

R18and R19together with the nitrogen atom to which they are attached, form a mono - or bicyclic heterocyclic ring containing from 4 to 10 atoms including 1-3 heteroatoms selected from the group comprising O, N, S, S(O), S(O)2and C=O, provided that the S atoms or are not next to each other, unsubstituted or substituted by one or more groups selected from the group comprising alkyl, halogen, hydroxy-group, alkoxygroup, alloctype, arielalexisxrp, -NR1R2, NR1COR2, NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)NR1R2-C(O)OH, -C(O)OR1, CONR1R2and alkyl, optionally substituted by-NR1S(O)2NR1R2, -C(O)OH, -C(O)OR1or-C(O)NR1R2;

Het means heteroaryl;

W stands for aryl, heteroaryl or aryl substituted by halogen or-CN;

and

R32and R33mean hydrogen or alkyl, or R32and R33optional merged to form a ring structure Q, where Q means

In an additional embodiment, the compounds of formula I, means-CH=CH-;

Het means heteroaryl substituted with W;

W stands for aryl, substituted with halogen;

R32and R33combined with the formation of Q and Q Osnach is no

and R3is defined as follows:

R3

In an additional embodiment, the compounds of formula I, In the mean CIS - or TRANS-CH2)n4CR12=CR12a(CH2)n5where n4and n50;

Andnmeans Oh where n is 1;

Gnmean CR1R2where n is 1, where R1and R2mean alkyl or hydrogen;

X is-CH-;

Jnmean CR1R2where n is 1, where R1and R2mean hydrogen;

R3means heteroaryl, heteroaromatic, -O-aryl, N3, -NR18C(O)OR19, -NR18COR19, -NHNR18R19, -NR18S(O)2R19, -NR18C(O)NR18R19or-NR18NR18R19;

R9, R10and R11mean hydrogen;

R18means hydrogen;

R19means O-alkyl or NH2;/p>

Het means heteroaryl;

W means aryl substituted by 1-3 substituents, independently selected from the group comprising halogen, -CF3, CN, alkyl, alkoxygroup and-C(O)OR17;

and

R32and R33mean alkyl, or R32and R33and with the carbon atoms to which they are attached, are combined with the formation of Q.

In another embodiment, the compounds of formula I, Q means cycloalkyl, preferably, if Q denotes cyclohexyl.

In another embodiment, the compounds of formula I, W stands for a phenyl, substituted with halogen or CN.

In another embodiment, the compounds of formula I specified halogen is F.

In another embodiment, the compounds of formula I, R3means N(O)O-ethyl, -C(O)NHCH2CH2OH, -NHC(NH)-NH2N3, -O-phenyl, or

The group of the compounds of the present invention is selected from the group including:

and

In another embodiment, the compounds of formula 1 is a compound of the following structure:

where R3, R32and R33defined nastojashem the invention.

In another embodiment, the compounds of formula 1 is a compound of the following structure:

where R3defined in this invention.

In another embodiment, the compounds of formula I, In the mean CIS - or TRANS-(CH2)n4CR12=CRl2a(CH2)n5where n4and n50;

Anmeans Oh where n is 1;

Gnmean CR1R2where n is 1, where R1and R2mean alkyl or hydrogen;

Jnmean CR1R2where n is 1, where R1and R2mean hydrogen;

R9, R10and R11mean hydrogen;

Het means heteroaryl;

W means aryl substituted by 1-3 substituents, independently selected from the group comprising halogen, -CF2, CN, alkyl, alkoxygroup and-C(O)ORl7;

and

R32and R33mean alkyl, or R32and R33and with the carbon atoms to which they are attached, are combined with the formation of Q.

In another embodiment, the compounds of formula 1 is a compound of the following structure:

where W meansor

In another embodiment, the compounds of formula 1 it is the conjunction of the following with the touch

where W meansor

When used above and throughout the description it should be understood that the following terms, unless otherwise indicated, have the following values.

"Patient" includes humans and animals.

"Subject" includes mammals and memleketim animals.

"Mammal" refers to people and other mammals animals.

The following definitions apply regardless of whether the term itself or in combination with other terms, unless otherwise indicated. Therefore, the definition of "alkyl" applies to "alkyl"and "alkyl" fragments "of hydroxyalkyl", "halogenoalkane", "alkoxygroup" etc.

"Alkyl" means an aliphatic hydrocarbon group which may be linear or branched and contains from about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain from about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain from about 1 to about 6 carbon atoms in the chain. "Branched" means that one or more lower alkyl groups such as methyl, ethyl or sawn, with uedineny to a linear alkyl chain. "Lower alkyl" means a group containing from about 1 to about 6 carbon atoms in the chain, which may be linear or branched. The term "substituted alkyl" means that the alkyl group may be substituted by one or more substituents, which may be the same or different, each Deputy is independently selected from the group comprising halogen, alkyl, aryl, cycloalkyl, cyano, hydroxy-group, alkoxygroup, allylthiourea, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2carboxypropyl and-C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, heptyl, nonyl, decyl, vermeil, trifluoromethyl and cyclopropylmethyl.

"Arylalkyl" or "arylalkyl" means arylalkyl group in which the aryl and alkyl are as described above. Preferred arylalkyl contain lower alkyl group. Non-limiting examples of suitable, arylalkyl groups include benzyl, 2-phenethyl and naphthaleneacetic. The link with the main fragment via alkyl.

"Alkylaryl" means alcylaryl group, in which alkyl and aryl are as described above. Preferred alkylaryl contain lower alkyl group. A non-limiting example of a suitable alcylaryl group one is camping tolyl. The link with the main fragment via aryl.

"Alkenyl" means an aliphatic hydrocarbon group containing a linear or branched chain containing one carbon-carbon double bond in the chain, which may be paired or unpaired. Suitable for use alkeneamine group may contain in the chain from 2 to about 15 carbon atoms in the chain, preferably from 2 to about 12 carbon atoms in the chain; and more preferably from 2 to about 6 carbon atoms in the chain. Alchemilla group may contain one or more substituents independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, cyano and alkoxygroup. Non-limiting examples of suitable alkenyl groups include ethynyl, propenyl, n-butenyl, 3-methylbut-2-enyl and n-pentenyl.

If alkyl or Alchemilla circuit connects the other two groups and thus is divalent, it uses the terms "alkylene and albaniles" respectively.

"Quinil" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be linear or branched and contains from about 2 to about 15 carbon atoms in the chain. Preferred alkyline groups contain from about 2 to about 12 carbon atoms in the chain;and more preferably from about 2 to about 4 carbon atoms in the chain. Branched means that one or more alkyl groups such as methyl, ethyl or through attached to linear alkenylphenol chain. "Lower quinil contains from about 2 to about 6 carbon atoms in the chain, which may be linear or branched. Non-limiting examples of suitable etkinlik groups include ethinyl, PROPYNYL, 2-butynyl, 3-methylbutyl, n-pentenyl and decenyl. The term "substituted quinil" means that Alchemilla group may be substituted by one or more substituents, which may be the same or different, each Deputy is independently selected from the group including alkyl, aryl and cycloalkyl.

"Aryl" means an aromatic monocyclic or polycyclic ring system containing from about 6 to about 14 carbon atoms, preferably from about 6 to about 10 carbon atoms. The aryl group may be optionally substituted by one or more "ring system substituents"which may be the same or different and are as defined in the present invention. Non-limiting examples of suitable aryl groups include phenyl, naphthyl, indenyl, tetrahydronaphthyl and indanyl. "Allen" means a divalent phenyl group, R is ortho-, meta - and para-substituted.

"Deputy ring system" means the Deputy attached to aromatic or non-aromatic ring system which, for example, replaces the existing ring system hydrogen. The ring system substituents may be the same or different and each is independently selected from the group comprising alkyl, alkenyl, quinil, aryl, heteroaryl, aralkyl, alkylaryl, heteroalkyl, heteroallyl, heteroallyl, alkylether, the hydroxy-group, hydroxyalkyl, alkoxygroup, alloctype, urlcategory, acyl, aroyl, halogen, the nitro-group, a cyano, carboxyl, alkoxycarbonyl, aryloxyalkyl, arelaxation, alkylsulfonyl, arylsulfonyl, heteroarylboronic, allylthiourea, killigrew, heterogroup, kilkiltgroupt, heterokedasticity, cycloalkyl, heterocyclyl, -C(=N-CN)-NH2, -C(=NH)-NH2-C(=NH)-NH(alkyl), Y1Y2N, Y1Y2N-alkyl-, Y1Y2NC(O)-, Y1Y2NSO2- and-SO2NY1Y2in which Y1and Y2may be the same or different and independently selected from the group comprising hydrogen, alkyl, aryl, cycloalkyl and arylalkyl. "Deputy ring system" can also mean one piece, which simultaneously replaces two available hydrogen atoms in two adjacent ATO is s carbon (one H on each carbon atom ring system. Examples of such fragments are methylendioxy, atlantoxerus, -C(CH3)2and so on, which form fragments, such as, for example:

and

The term "BOC" means N-tert-buckeyeboy.

"Cycloalkyl" means a non-aromatic monocyclic or polycyclic ring system containing from about 3 to about 10 carbon atoms, preferably from 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain from about 5 to about 7 ring atoms. Cycloalkyl may be optionally substituted by one or more "ring system substituents"which may be the same or different and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. non-limiting examples of suitable polycyclic cycloalkyl include 1-decaline, norbornyl, substituted and the like, and partially saturated systems, such as, for example, indanyl, tetrahydronaphtyl etc.

"Cycloalkenyl" means a non-aromatic monocyclic or polycyclic ring system containing from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 and the Ohm carbon, which contains at least one double carbon-carbon bond. Preferred cycloalkenyl rings contain from about 5 to about 7 ring atoms. Cycloalkenyl may be optionally substituted by one or more "ring system substituents"which may be the same or different and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl etc. non-limiting examples of suitable polycyclic cycloalkenyl is norbornylene.

"Cycloalkyl" means the corresponding divalent ring, in which the provisions of joining other groups meet all positional isomers.

"Dihydroxyaryl" means an alkyl chain substituted by two hydroxy groups at two different carbon atoms.

"Foralkyl", "diferuloyl and triptorelin" means an alkyl chain in which the terminal carbon atom is substituted with 1, 2 or 3 fluorine atoms, for example-CF3, -CH2CF3, -CH2CHF2or-CH2CH2F.

"Halide" means fluoride, chloride, brainy or ideny radicals. Preferred are fluoride, chloride or brainy and more preferred are fluoride and chloride.

"Halogen" means f the PR, chlorine, bromine or iodine. Preferred are fluorine, chlorine and bromine.

"Heteroaryl" means an aromatic monocyclic or polycyclic ring system containing from about 5 to about 14 ring atoms, preferably from about 5 to about 10 ring atoms in which one or more ring atoms are items that are not atoms of carbon, for example nitrogen, oxygen or sulfur, alone or in combination provided that the rings do not include adjacent oxygen atoms and/or sulfur. Also includes N-oxides of the ring nitrogen atoms, and compounds in which the ring nitrogen atom is substituted by an alkyl group with a tertiary amine. Preferred heteroaryl contain from about 5 to about 6 ring atoms. "Heteroaryl" may be optionally substituted by one or more "ring system substituents"which may be the same or different and are as defined in the present invention. The prefix Aza-, oxa - or thia - before root heteroaryl means that at least a nitrogen atom, oxygen or sulfur is a ring atom. The nitrogen atom of heteroaryl optional can be oxidized to the corresponding N-oxide. Non-limiting examples of suitable heterocycles include pyridyl, pyrazinyl, furanyl, Anil, pyrimidinyl, pyridone (including N-substituted pyridone), isoxazolyl, isothiazolin, oxazolyl, thiazolyl, pyrazolyl, oxadiazolyl, tetrazolyl, pyrimidyl, furutani, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, honokalani, phthalazine, oxindoles, naphthyridin (for example, 1,5 - or 1,7-), pyrido[2,3]imidazolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofuranyl, benzofurazanyl, indolyl, isoindolyl, benzimidazolyl, benzothiazyl, chinoline, imidazolyl, cyanopyridyl, hintline, thienopyrimidines, pyrrolopyridine, imidazopyridine, ethenolysis, benzoxazinones, 1,2,4-triazinyl, benzoxazolyl, benzothiazolyl, pyridopyrimidines, 7-isoindolyl, etc. the Term "heteroaryl also includes partially saturated heteroaryl fragments, such as, for example, tetrahydroisoquinoline, tetrahydroquinoline etc. Includes all positional isomers, such as 2-pyridyl, 3-pyridyl and 4-pyridyl.

Examples of "Het" is a single ring, bicyclic and condensed with the benzene ring heteroaryl group, as defined above. Group Het is connected to In the cyclic carbon atom, for example Het represents 2-pyridyl, 3-pyridyl or 2-chinolin. The Het ring may be substituted on any available ring carbon atom by a group of W; in the Het ring may contain from 1 to 4 substituents W.

"Heterocyclyl" or "gets rocklouder" means a non-aromatic monocyclic or polycyclic ring system, containing from about 3 to about 10 ring atoms, preferably from about 5 to about 10 ring atoms in which one or more atoms of the ring system are items that are not atoms of carbon, for example nitrogen, oxygen or sulfur, alone or in combination. In the ring system there are no adjacent oxygen atoms and/or sulfur. Preferred heterocyclyl contain from about 5 to about 6 ring atoms. The prefix Aza-, oxa - or thia - before root heterocyclyl means that at least a nitrogen atom, oxygen or sulfur is a ring atom. Any group-NH in heterocycles the ring can be protected and represent, for example, a group-N(Boc), -N(CBz), -N(Tos) and the like; such protective groups are also considered part of the present invention. Heterocyclyl optionally may contain one or more "ring system substituents"which may be the same or different and are as defined in the present invention. The nitrogen atom or sulfur heterocyclyl optional can be oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinil, morpholinyl, thiomorpholine, thiazolidine, 1,3-dioxane, 1,4-dio who sanil, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophene, lactam, lactone, etc.

It should be noted that in the containing heteroatom ring systems of the present invention, there are no hydroxyl groups at carbon atoms adjacent to N, O and S, and there are no groups N or S at the carbon atoms adjacent to another heteroatom. Thus, for example, in the ring

no-HE attached directly to the carbon atoms marked with numbers 2 and 5.

It should also be noted that tautomeric forms, such as, for example, fragments

and

in some embodiments, implementation of the present invention are equivalent.

The term "heteroeroticism" means spirocyclic structure containing 3 to 5 carbon atoms and 1 or 2 heteroatoms selected from the group comprising N, S and O, provided that heteroatoms are not adjacent.

"Alkylamino" means alkylamino, in which the alkyl group is as described above. The link with the main fragment via the amino group.

"Acylaminoalkyl" means acylaminoalkyl group in which the alkyl group is the same as described above. The link with the main fragment is carried out across the alkyl.

"Alkylcyclohexanes" means alkylcyclohexane group, in which alkyl and cycloalkyl group is such as described above. The link with the main fragment via alkyl.

"Alkylglycerol" means alkylglycerols group, in which alkyl and heteroaryl group is such as described above. The link with the main fragment is carried out through heteroaryl.

"Alkylchlorosilanes" means alkylchlorosilanes group, in which alkyl and heterocytolysine group is such as described above. The link with the main fragment through geterotsyklicescoe group.

"Alkoxylalkyl" means alkoxyalkyl-O-alkyl group, in which alkoxygroup and alkyl groups are as described above. The link with the main fragment is through the alkyl group.

"Alkenylacyl" means alkynylamino group, in which quinil and alkyl are as defined above. Preferred alkenylacyl contain lower alkylamino and lower alkyl groups. The link with the main fragment via alkyl. Non-limiting examples of suitable alkenylamine groups include propargylation.

"Halogenated" means halogenating group in which the alkyl group is a Taco is, as explained above. The link with the main fragment via alkyl. Non-limiting examples of suitable halogenating groups include vermeil and deformity.

"Heteroaromatic" or "heteroaromatic" means heteroallyl group, in which heteroaryl and alkyl are as defined above. Preferred heteroaromatic contain lower alkyl group. Non-limiting examples of suitable heteroarylboronic groups include pyridylmethyl and quinoline-3-ylmethyl. The link with the main fragment via alkyl.

"Heteroaromatic" means heteroallyl group, in which heteroaryl and alkenyl are as described above. Preferred heteroaromatic contains lower alkenylphenol group. The link with the main fragment through alkenylphenol group.

"Geterotsiklicheskikh" or "geterotsiklicheskikh" means heterocyclisation group, in which heterocyclyl and alkyl groups are as described above. The link with the main fragment is through the alkyl group.

"Geterotsiklicheskikh" means a group heteroseksualci-O-, in which a group of geterotsiklicheskie is the same as described above. The link with the main fragment is carried out through the ether oxygen atom.

"Heteroaromatics is alkyl" means heteroatomcontaining group, in which heteroaryl and alkoxyalkyl groups are as described above. The link with the main fragment is through the alkyl group.

"Hydroxyalkyl" means the group-alkyl-in which alkyl is as defined above. Preferred hydroxyalkyl contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"Acyl" means a group N-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, in which different groups are as described above. The link with the main fragment is through the carbonyl. Preferred atilov contain lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanol.

"Aminoalkyl" means aminoalkyl group in which the alkyl group is as described above. The link with the main fragment via alkyl.

"Aroyl" refers to the group aryl-C(O)-, where the aryl group is as described above. The link with the main fragment is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphtol.

"Alkenylacyl" means a group of alkenyl-O-, in which Alchemilla group is the same as described above. The link with the main fragment through essential atomiclord.

"Alkyloxy" means a group quinil-O-, in which Alchemilla group is the same as described above. The link with the main fragment is carried out through the ether oxygen atom.

"Alkoxygroup" refers to the group alkyl-O-, in which alkyl group is as described above. Non-limiting examples of suitable alkoxygroup include methoxy, ethoxy-, n-propoxy, isopropoxy - and n-butoxypropyl. The link with the main fragment is carried out through the ether oxygen atom.

"Urlcategory" or "arielalexisxrp" means a group arylalkyl-O-, in which arylalkyl group is the same as described above. The link with the main fragment via an oxygen atom.

"Alkoxyalkyl" or "alkyloxyalkyl" refers to the group alkyl-O-alkyl, in which alkyl groups are as described above. Non-limiting examples of suitable alkyloxyalkyl groups include methoxymethyl and ethoxymethyl. The link with the main fragment is through the alkyl group.

"Alloctype" refers to the group aryl-O-, where the aryl group is as described above. Non-limiting examples of suitable aryloxy include fenoxaprop and NATEXPO. The link with the main fragment is carried out through the ether oxygen atom.

"Aryloxyalkyl" refers to the group aryl-alkyl, in which the aryl and alkyl groups are as described above. Non-limiting examples of suitable aryloxyalkyl groups include phenoxymethyl and neftechemical. The link with the main fragment is through the alkyl group.

"Allakariallak" means arilalkilamin group, in which aryl and alkoxyalkyl groups are as described above. The link with the main fragment is through the alkyl group.

"Arancelaria" means a group aralkyl-O-, in which kalkilya group is the same as described above. Non-limiting examples of suitable aralkylated include benzyloxy and 1 - and 2-naphthalenyloxy. The link with the main fragment is carried out through the ether oxygen atom.

"Arylalkyl" means arylalkyl group, in which aryl and Alchemilla groups are as described above. The link with the main fragment is carried out through alkenyl.

"Allylthiourea" refers to the group alkyl-S-, in which alkyl group is as described above. Non-limiting examples of suitable alkylthio include metalcorp and ethylthiourea. The link with the main fragment via the sulfur atom.

"Aristocrata" refers to the group aryl-S-, where the aryl group is as described above. NaOH unicefusa examples of suitable aricioglu include phenylthiourea and naphthylthiourea. The link with the main fragment via the sulfur atom.

"Kalkiliya" means a group aralkyl-S-, in which arylalkyl group is the same as described above. A non-limiting example of a suitable aralkylamines group is menzilcioglu. The link with the main fragment via the sulfur atom.

"Alkoxycarbonyl" refers to the group alkyl-O-CO-. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and etoxycarbonyl. The link with the main fragment is through the carbonyl.

"Aryloxyalkyl" refers to the group aryl-O-C(O)-. Non-limiting examples of suitable aryloxyalkyl groups include phenoxycarbonyl and mattoxicator. The link with the main fragment is through the carbonyl.

"Arelaxation" means a group arylalkyl-O-C(O)-. A non-limiting example of a suitable alcoxycarbenium group is benzyloxycarbonyl. The link with the main fragment is through the carbonyl.

"Alkylsulfonyl" refers to the group alkyl-S(O2)-. Preferred groups are those in which the alkyl group is lower alkyl. The link with the main fragment is carried out through sulfonyl.

"Arylsulfonyl" refers to the group aryl-S(O2)-. The link with the main fragment through self the Nile.

"Cycloalkanones" means a group cycloalkenyl-O-, in which cycloalkenyl group is the same as described above. The link with the main fragment is carried out through the ether oxygen atom.

"Cycloalkenyl" means cycloalkylcarbonyl group, in which cycloalkyl and alkyl groups are as described above. The link with the main fragment is through the alkyl group.

"Cycloalkylation" or "cycloalkanes" means a group cycloalkyl-O-, in which cycloalkyl group is the same as described above. The link with the main fragment is carried out through the ether oxygen atom.

"Cycloalkenyl" means a group cycloalkyl-O-alkyl, in which cycloalkyl and alkyl groups are as described above. The link with the main fragment is through the alkyl group.

"Halogenoacetyl" means halogenoacetyl group, in which alkoxyalkyl group is the same as described above. The link with the main fragment is through the alkyl group.

"Geterotsiklicheskikh" means geterotsiklicheskikh group, in which alkoxyalkyl group is the same as described above. The link with the main fragment is through the alkyl group.

An optional double bond, known what I use that means that there must be at least ordinary communication, but may contain a double bond; if it contains a double bond,R is absent.

If R4and R5are connected to each other and form a ring together with the nitrogen atom to which they are attached, formed rings represent 1-pyrrolidinyl, 1-piperidinyl or 1-piperazinil where piperazinilnom ring on the nitrogen atom in position 4 can also be substituted by a group R7.

The above provisions that, for example, indicate that R4and R5independently selected from the group of substituents, means that R4and R5chosen independently when attaching to the same nitrogen atom, and also that if R4or R5contained in the molecule more than once, in each case selected independently. Similarly, in each case appearing in the same ring Q is R13or R14does not depend on the value of any other R13or R14. Experts in the art should understand that the size and nature of the Deputy (deputies) affect the amount contained deputies.

The term "substituted" means that one or more hydrogen atoms of the specified atom is replaced with a selection from the indicated group, provided that at which Musasa situation normal valency of the specified atom is not exceeded, and that the substitution results in a stable connection. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is durable enough to withstand isolation from the reaction mixture to a usable degree of purity, and is suitable for inclusion in an effective therapeutic drug.

The term "optionally substituted" means an optional substitution of specified groups, radicals or fragments.

The term "isolated" or "in a highlighted form" in relation to the connection refers to the physical state of the compounds after separation as a result of implementation of synthesis or from natural source, or combinations thereof. The term "purified" or "purified form" in relation to the connection refers to the physical condition of the specified connection after receiving using the method or methods of purification described in this invention are well known to the person skilled in the art with sufficient purity, characterized by standard methods of analysis described in this invention are well known to the person skilled in the technical field.

Structurein the compound of formula 1 indicates an optional DV is you communication, the dotted line indicates the connection or does not denote a bond that leads to double or ordinary communication in accordance with the requirements of valence; provided that R3is absent when the carbon atom to which R3must be attached, is involved in the double bond.

It should also be noted that in the text, schemes, examples and tables in the present invention, it is understood that any atom of carbon and heteroatom with unsaturated valences has the atom (atoms) of hydrogen, sufficient to saturate the valences.

If the functional group in the compound called "protective group", this means that this group is in modified form to eliminate undesirable side reactions in the center with a protective group in the case when the connection is introduced into the reaction. Suitable protective groups must be known to specialists with General training in the art and described in standard textbooks, such as, for example, .W. Greene et al., Protective Groups in organic Synthesis (1991), Wiley, New York.

If any variable (e.g. aryl, heterocycle, R2and so on) in any component or in formula I appears more than once, in each case, its definition does not depend on its definition in any other case.

When used in the present invention, the term "comp the position includes the preparation, containing the specified ingredients in the specified amounts, as well as any drug that directly or indirectly formed from combinations of the specified ingredients in the specified amounts.

The present invention also includes prodrugs, joint crystals and a solvate of the compounds of the present invention. When used in the present invention, the term "prodrug" means a compound that is a precursor of a drug, which after administration to a subject due to leakage of metabolic or chemical processes undergoes chemical transformation with the formation of the compounds of formula 1 or its salt and/or MES. A discussion of prodrugs is provided in the publication .Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in the publication Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, which are included in the present invention for reference.

"MES" means a physical Association of a compound corresponding to the present invention, one or more solvent molecules. This physical Association involves different degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the MES shall be suitable for allocation, for example, when one or more solvent molecules on the obtained in the lattice of the crystalline solid. "MES" includes both the dissolved phase, and is able to release the solvate. Non-limiting examples of the solvate include ethanolate, methanolate etc. "Hydrate" is a MES, in which the solvent molecule is H2O.

Joint crystal means crystalline superstructure formed by combining the active pharmaceutical intermediate product with an inert molecule that leads to the formation of crystalline combination forms. Joint crystals are often formed from dicarboxylic acids such as fumaric acid, succinic acid and the like, and the primary amine, such as represented by connection I corresponding to the present invention, in different proportions depending on the nature of joint crystal (Rmenar, J.F. et. al. J Am. Chem. Soc. 2003, 125, 8456).

It is understood that "an effective amount" or "therapeutically effective amount" describes the amount of compound or composition corresponding to the present invention is effective as an antagonist of thrombin receptor and thereby resulting in the desired therapeutic improving, inhibitory or preventive action.

The compounds of formula I can form salts which are also included in the scope of the present invention. Unless otherwise stated, should animate, the reference compound of formula I refers to the inclusion of a link on its salts. When used in the present invention, the term "salt (salt)" means salts with acids, formed with inorganic and/or organic acids, and salts with bases formed with inorganic and/or organic bases. In addition, if the compound of formula I contains both a fragment of a base, such as (without restrictions) pyridine or imidazole, and a portion of the acid, such as (without restrictions) carboxylic acid, can be formed zwitterions ("inner salts"), and when used in the present invention are included in the term "salt (salt)". Preferred pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts, although applicable, and other salts. Salts of compounds of formula I can be formed, for example, through reaction of compounds of formula I with an amount of acid or base, such as an equivalent amount, in a medium such as the medium in which the salt precipitates or in an aqueous medium followed by lyophilization.

Examples of salts with acids include acetates, ascorbates, benzoate, bansilalpet, bisulfate, borates, butyrate, citrates, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactates, maleate, methanesulfonate, Naftal sulfonate, nitrates, oxalates, phosphates, propionate, salicylates, succinate, sulphates, tartratami, thiocyanates, toluensulfonate (also known under the name of tozilaty), etc. additionally, acids which are generally considered suitable for the formation of pharmaceutically applicable salts from basic pharmaceutical compounds are discussed, for example, in the publications of R. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in the publication of The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are included in the present invention for reference.

Examples of salts with bases include ammonium salts, alkali metal salts, such as salts of sodium, lithium and potassium, salts of alkaline earth metals such as calcium salts and magnesium salts, salts with organic bases (for example, organic amines)such as dicyclohexylamine, tert-butylamine, and salts with amino acids such as arginine, lysine and other Basic nitrogen-containing groups can be converted into a Quaternary group with the help of compounds such as the halides of lower Akilov (for example, methyl-, ethyl - and butylchloride, -bromides and iodides), diallylsulfide (for example, dimethyl-, diethyl - and dibutylaniline), halides with long chains (for example, ecil-, lauryl - and sterilgarda, -bromides and iodides), arylalkylamine (for example, benzyl and peptibody) and other

In the scope of the present invention assumes that all such salts of acids and bases are pharmaceutically acceptable salts and for the purposes of the present invention, all salts of acids and bases are considered equivalent to the free forms of the corresponding compounds.

The compounds of formula I and their salts, solvate and prodrug may exist in their tautomeric form (for example, in the form of simple amido - or aminoether). It is implied that all such tautomeric forms are part of the present invention.

In the scope of the present invention includes all stereoisomers (for example, geometric isomers, optical isomers and the like) compounds of the present invention (including isomers salts, solvate, co-crystal and prodrugs of these compounds, and salts, solvate and joint crystals of the prodrugs), such as those which may exist due to the presence of asymmetric carbon atoms in various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotary isomeric forms, atropisomers and diastereoisomers shape and positional isomers (such as, for example, 4-the feast of the deal, and 3-pyridyl). Individual stereoisomers of compounds of the present invention, may, for example, generally do not contain other isomers, or may be mixed, for example, as racemates or with all other, or other selected stereoisomers. Chiral centers corresponding to the present invention can have the S - or R-configuration in accordance with the definition given in the IUPAC 1974 Recommendations. It is implied that the use of the terms "salt", "MES", "prodrug" and the like, they equally apply to the salt, MES and prodrug of enantiomers, stereoisomers, rotary isomers, tautomers, positional isomers, racemates or prodrugs of the compounds of the present invention.

This also implies that the polymorphic forms of the compounds of formula I and salts, solvate, co-crystal and prodrugs of the compounds of formula I are also included in the present invention.

Compounds corresponding to the present invention have pharmacological properties; in particular, the compounds of formula I can be the nor-samopromzvolny himbacine applicable as antagonists of thrombin receptor.

Compounds corresponding to the present invention, contain at least one asymmetric carbon atom and therefore all isomers, including the Enan is jomary, stereoisomers, rotary isomers, tautomers and racemates of the compounds of formula (I) (if they exist), are considered part of the present invention. The present invention includes d - and l-isomers, in pure form and in mixtures, including racemic mixtures. The isomers can be obtained by conventional methods, the reaction of the optically pure or optically enriched starting compounds or by separating isomers of compounds of formula I. the Isomers can also include geometric isomers, for example, if contains the double bond. Polymorphic forms of the compounds of formula (I), crystalline or amorphous, are also considered part of the present invention.

Experts in the art should understand that some of the compounds of formula I, one isomer has greater pharmacological activity than other isomers.

Typical preferred compounds corresponding to the present invention, have the following stereochemical configuration:

and compounds having the absolute stereochemical configuration are preferred.

Experts in the art should understand that some of the compounds of formula I one isomer has greater pharmacological activity than other isomers.

Compounds corresponding to this is obreteniyu, usually get on techniques, as appropriate.

Some of the following compounds, intermediates can be obtained by the techniques described in any of the following documents: US 6063847, US 6326380, US 6645987, U.S. Serial No. 10/271715, which are included in the present invention for reference.

Examples get the source substances and compounds of formula I. In these methods used the following abbreviations:

CTroom temperature
THFtetrahydrofuran
Et2Oethyl ester
Memethyl
Etethyl
EtOActhe ethyl acetate
BnOCH2Clbenzylcarbamoyl ether
BuLiutility
DBADdi-tert-utilisationbased
DCE1,2-decorated
DCM dichloromethane
DMFN,N-dimethylformamide
DMSOthe sulfoxide
HATUhexaphosphate
HOBT or HOBthydroxybenzotriazole
KHMDSbis(trimethylsilyl)amide and potassium
LiHMDS or LHMDSbis(trimethylsilyl)amide lithium
N(O2CLO3)3Ntriacetoxyborohydride sodium
PhSeBrphenylselenenyl
PSon a polymeric substrate
PS-EDCdimethylaminopropionitrile
on a polymeric substrate
PS-NCOisocyanate on a polymer substrate
PS-Tris-NH2trisamin on polymer substrates
TFAtriperoxonane acid
THF tetrahydrofuran
Ti(OiPr)4isopropoxide titanium
TLCthin-layer chromatography
TMSItrimethylsilylmethyl or attributively
MCBPmass spectrometry, high-resolution

7A-CARBOXYLIC ACIDS AND AMINES

7a-Carboxylic acid can be obtained by the following typical procedure:

With stirring to a solution of 2.5 g of compound 1 (6,59 mmol) in 50 ml dry THF at 0°C in an atmosphere of argon was added LHMDS (9,88 mmol, 9,9 ml of 1.0 M solution in THF) and the mixture is stirred for 30 minutes the Temperature is reduced to -78°C and added 785 μl (9,88 mmol) medicinepharmacy. After 2 h, add about 75 ml of an aqueous solution of uranyl sulfate ammonium-iron(II) (10% wt./about.) and the mixture is then extracted with three portions of ethyl acetate. The combined organic extracts washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. Purification using flash chromatography using 15% ethyl acetate in hexano gives 2,47 g of compound 2. MS (mass spectrometry) (EEC) (electrospray ionization) m/z 424 (MN+).

Under stirring to RA is Toru 2,47 g of compound 2 (5,65 mmol) in 50 ml dry THF at 0°C in an atmosphere of N 2add tribromide boron (11.3 mmol) and the mixture is stirred for about 30 minutes, the Reaction mixture is diluted with about 50 ml of dichloromethane and the pH value was adjusted to about pH 4 aqueous solution of sodium bicarbonate and the mixture extracted with three portions of dichloromethane. The combined organic extracts washed with brine, dried over magnesium sulfate, filtered and evaporated and get 2,32 g of compound 3.

MS (EEC) m/z 424,1 (MN+).

7A-CARBOXAMIDE

This acid can be converted into amide 4 using standard methods of combinations. Using commercially available amines or amines, which can be obtained by synthesis, receive a variety of amide analogues. Some of these analogs are shown in the table below.

ExampleR3R32R33WData analysis
And-CH3Et MS (MN+) 518,1
In-CH3EtMS (MN+) 490,1
-CH3EtMS (MN+) 463,1
D-CH3EtMsvr (MN+) 539,1674
E-CH3-CH3Msvr (MN+) 466,2512
F-CH3-CH3Msvr (MN+) 93,2507
G-CH3-CH3Msvr (MN+) 467,2343

ExampleR3R32R33WData analysis
H-CH3-CH3Msvr (MN+) 492,2655
I-CH3-CH3Msvr (MN+) 520,2980
J-CH3-CH3msvr (MN +) 520,2979
To-CH3-CH3MS (MN+) 500,1
L-CH3-CH3Msvr (MN+) 493,2510
M-CH3-CH3Msvr (MN+) 474,2397
N-CH3-CH3MS (MN+) 537,1
O-CH3-CH3 Msvr (MN+) 481,2135
P-CH3-CH3MS (MN+) 474,3
Q-CH3-CH3Msvr (MN+) 524,2569

ExampleR3R32R33WData analysis
R-CH3-CH3Msvr (MN+) 538,2713
S-CH3-CH3 Msvr (MN+) 481,2503
T-CH3-CH3Msvr (MN+) 481,2503
U-CH3-CH3Msvr (MN+) 558,2434
V-CH3-CH3Msvr (MN+) 495,2651
W-CH3-CH3Msvr (MN+) 481,2498
X-CH3-CH3 Msvr (MN+) 481,2498
Y-CH3-CH3Msvr (MN+) 493,2503
Z-CH3-CH3Msvr (MN+) 480,2299
AA-CH3-CH3Msvr (MN+)

exampleR3R32R33WData analysis
544,2601
BB -CH3-CH3MS (MN+) 500,1
CC-CH3-CH3Msvr (MN+) 488,2549
DD-CH3-CH3Msvr (MN+) 488,2549
IT-CH3-CH3MS (MN+) 502,1
FF-CH3-CH3Msvr (MN+)

The following drugs and alogi get a similar technique:

ExampleR3Data analysis
GGMC (MH+) 493,1
HHMC (MH+) 527,1
JJMC (MN+) 550,1
KKMC (MN+) 491,1
LLMC (MN+) 567,1

7a-Amino derivatives

7a-Amino derivatives can be obtained by the following typical procedure:

To a solution of 5 (1.01 g, 2.57 mmol) in 20 ml THF at 0°C was added 1 M solution of LHMDS in THF (3,34 ml) and stirred for 20 minutes It is cooled to -78°C. and add a solution of di-tert-utilization.bacteria (890 mg, a 3.87 mmol) in 2.5 ml THF. It was stirred at -78°C for 2 h and at 0°C for 1 h and the reaction stopped by adding volnogorskoe NH 4CL. The aqueous layer was extracted with tO and dried over gSO4and concentrate.

The crude product is stirred with 5 ml of DCM and 10 ml triperoxonane acid at 0°C for 1 h His concentrated and suspended in 100 ml of an aqueous solution To a2CO3. The aqueous phase is extracted with DCM and get the crude hydrazide.

This crude substance was dissolved in 10 ml of glacial acetic acid and 2 ml of acetone. To him portions are added 2 g of zinc dust. The suspension is vigorously stirred for 2 h and filtered through a layer of celite and washed with a large amount of DCM. The DCM layer was washed with water and then aqueous solution Panso3and brine. It is dried over MgSO4concentrate and purify by chromatography and receive 500 mg 6. MS:409,2 (MH+).

7a-Amino derivatives can also be obtained by the following alternative method:

To a solution of 7 (2.0 g, 5.18 mmol) in 40 ml THF at 0°C was added a 0.5 M solution of KHMDS in toluene (13.5 ml, 13.5 mmol, 1.3 EQ.) and the mixture is stirred for 15 min, then cooled to -78°C. thereto was added a solution of trailside (2.4 g, 7,76 mmol, 1.5 EQ.) in 8 ml of THF and stirred for about 3 minutes the Reaction is stopped by adding acetic acid (0.9 mg, 15,72 mmol, 3 EQ.) and immediately heated to KG using a water bath. The mixture is stirred for 1H and THF is evaporated under reduced pressure. The residue is dissolved in 100 ml of CH2CL2and washed with 2×50 ml of an aqueous solution Panso3and 50 ml of brine, dried over MgSO4, filtered, concentrated and purified using flash chromatography and get 1.8 g 8 resin. MS: 428,2 (MH+).

To a solution of 8 (3.6 g, 8,42 mmol) in 50 ml of EtOAc and 5 ml of H2O added 1 M solution of RME3in THF (of 12.6 ml, 12.6 mmol, 1.5 EQ.) and the mixture is stirred over night at KG. The solution is concentrated and purified using chromatography and obtain 2.7 g of 9 as a white foam substance. MS:402,1 (MH+).

Amines, such as 6, can be converted into amide 10 by combining with miniconomy acid. Similarly, the amines can be introduced into the reaction with such chemicals as aldehydes, alkylhalogenide, acids or acid anhydrides and isocyanates, and to obtain secondary and tertiary amines, amides, carbamates and urea. Some of these analogs are shown in the table below.

ExampleR3R32R33WData analysis
MM -CH3EtMS (MN+) 491,1
NN-NEtMS (MN+) 477,1
O.O-NEtMS (MN+) 449,1
PP-CH3EtMsvr (MN+) 463,1
QQ-CH3-EtMsvr (MN+) 481,249
RR-CH3-CH3Msvr (MN+) 467,2356
SS-CH3-EtMsvr (MN+) 514,2501
TT-CH3EtMsvr (MN+) 514,2506

ExampleR3R32R33WData analysis
UU-CH3-CH3Msvr (MN+) 500,2341
VV-CH3-CH3Msvr (MN+) 500,2352
WW-CH3EtMsvr (MN+) 480,2658
XX-CH3-CH3Msvr (MN+) 466,2512
YY-CH3-CH3Msvr (MN+) 476,2924
ZZ-CH3-CH3Msvr (MN+) 474,2771
AAA-CH3-CH3 Msvr (MN+) 488,2904
BBB-CH3-CH3Msvr (MN+) 507,2405
CCC-CH3-CH3Msvr (MN+) 498,2389
DDD-CH3-CH3MS (MN+) 431,1

ExampleR3R32R33WData analysis
EEE-CH3-CH3 Msvr (MN+) 474,2387
FFF-CH3-CH3Msvr (MN+) 474,2387
GGG-CH3-CH3MS (MN+) 480,1
IUU-CH3-CH3MS (MN+) 494,1
III-CH3-CH3MS (MN+) 506,1
JJJ-CH3 -CH3MS (MN+) 542,1

The following tricyclic analogues receive a similar technique:

Table 2
ExampleR3Data analysis
KKKMC (MH+) 493,1
LLLMC (MH+) 479,1
MMMMC (MH+) 515,1
NNNMC (MH+) 463,1

High-performance synthesis

The technique of high-performance synthesis used for combining 7a-carboxylic acid 11 with amines to obtain a set of 128 7a-carboxamido 12. Similarly, 7a-amine analogue 9 is converted into a set of 48 ureas 13 and set amides 14.

Compound 11 can be obtained by using m is using the technique, similar to the one used to obtain 3.

Set 7a-carboxamido

144 wells of two 96-well plastic plates to micrometrology with deep holes added about 36 mg of PS-EDC (3 EQ.), and then 1 ml of the original solution containing 1.2 g of basic carboxylic acids 9 and 565 mg NOWT (1.5 equiv.) dissolved in DMF (30 ml), MeCN (70 ml) and THF (50 ml). To each well was added 1.2 EQ. 144 individual amines (1.0 M solution), one amine in the hole and then the tablet is sealed and shaken for 20 h the Solution was filtered through a polypropylene porous filter in the second set of tablets, each well containing approximately 36 mg of PS-isocyanate resin (3 EQ.) and 26 mg of PS-trisamino resin (6 EQ.). Then each well of the first tablets washed with 0.5 ml of MeCN, the second tablet is sealed and shaken for 20 hours and Then the contents of the second tablets filtered through a polypropylene porous filter in 96-well plates to collect, each well is washed with 0.5 ml of MeCN. Solutions from tablets to collect transferred into 2 vial and evaporated to dryness in a SpeedVac evaporator and receive carboxamide.

Set 7a-ureas

In 48 wells 96-well plastic tablet for micrometrology with deep holes are added 1 ml of a solution containing the basis of the Noah Amin 9, dissolved in 48 ml of DCE/MeCN (1:1). Then the wells, add 80 ál of 0.5 M solutions (DCE) 48 individual isocyanates, one isocyanate in the hole. The tablet is sealed and shaken for 20 hours Then the cover is removed and to each well was added approximately 33 mg of PS-isocyanate resin (3 EQ.) and 30 mg PS-trisamino resin (6 EQ.). The tablet re-sealed and shaken for 20 h the Solution was filtered through a polypropylene porous filter in the tablet collection, each well is washed with 0.5 ml N. Solutions from tablets to collect transferred into 2 vial and evaporated to dryness in a SpeedVac evaporator and receive urea.

Set 7a-amides

In each well of polyethylene tablet for micrometrology with deep wells (96-well) was added to about 56 mg of PS-EDC (3 EQ.), and then 1 ml of the original solution containing 0.8 g of primary amine 9 and 520 mg NOWT (1.5 equiv.) dissolved in MeCN (96 ml). Then to each well was added 1,3 EQ. 96 individual carboxylic acid (1.0 M solution), one carboxylic acid to the isocyanate in the hole, and the plate sealed and shaken for 20 h the Solution was filtered through a polypropylene porous filter in the second tablet in each well containing approximately 44 mg of PS-isocyanate resin (3 EQ.) and 42 mg of PS-trisamino resin (6 EQ.). Then each well of the first plan the ETA is washed with 0.5 ml of MeCN, the second tablet is sealed and shaken for 20 hours and Then the contents of the second tablet filtered through a polypropylene porous filter in a 96-well plate for collection, each well is washed with 0.5 ml of MeCN. The solution from the tablet to collect transferred into 2 vial and evaporated to dryness in a SpeedVac evaporator and receive amides.

Typical examples of this set of analogues to the following:

tr> /tr>
Table 3
ConnectionMS (MH+)
470,26
472,26
483,27
484,27
486,27
502,28
510,28
514,28
520,29
526,29
538,8
to 544.3
546,3
546,3
of 551.3
of 551.3
554,3
555,31
564,31
570,31
586,32
588,32
588,32
549,3
488,27
643,35
501,28
515,28
537,3
538,3
to 541.3
USD 542.3
543,3
569,31
570,31
584,32
589,32
591,33
604,33
498,27
500,27
502,28
512,28
516,28
516,28
525,29
532,29
534,29
to 541.3
to 541.3
543,3
546,3
556,31
570,31
589,32
597,33
597,33
624,34
513,28
527,29
575,32
576,32
585,32
589,32
604,33
506,12
487,27
513,28
535,29
to 539.3
550,3
549,3
of 551.3
553,3
557,31
561,31
565,31
571,31
580,32
597,33
611,34
470,26
484,27
490,27
497,27
496,27
500,27
507,28
513,28
516,28
518,28
522,29
526,29
527,29
531,29
534,29
534,29
545,3
545,3
of 551.3
556,31
559,31
560,31
563,31
564,31
566,31
570,31
571,31
574,32
553,3
582,32
587,32
588,32
598,33
598,33
445,24
507,28

7a-Hydroxymethyl

To 0.65 g (1,71 mmol) of compound 1 in dry THF at -10°C in an atmosphere of argon was added LHMDS (to 2.06 mmol) and the mixture is stirred for 30 minutes Then add benzylcarbamoyl ester (2.57 mmol) and after 60 min the mixture was poured into an aqueous solution of ammonium chloride and extracted with three portions of diethyl ether. The combined organic extracts washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. Purification using flash chromatography gives 0,69 g of compound 15.

MS (EEC) m/z 500 (MH+).

To 2,19 g (of 4.38 mmol) of compound 15 in dry dichloromethane was added godtime isilon (87,6 mmol) and the mixture is refluxed in an argon atmosphere for 2.5 hours The reaction mixture is cooled to room temperature, poured into aqueous sodium bicarbonate solution and extracted with three portions of dichloromethane. The combined organic extracts washed with aqueous solution of sodium sulfite, dried over magnesium sulfate, filtered and evaporated to dryness. Purification using flash chromatography network connection 16.

MS (EEC) m/z 410,1 (MN+).

The following connection receive similar method.

7a-Benzyloxyethyl

Turning hydroxymethyl in Amin

To 0.10 g (2,44 mmol) of compound 16 in dry dichloromethane was added 50 mg of sodium bicarbonate and 0,155 g periodinane dessa-Martin (3,66 mmol) and the mixture is stirred under nitrogen atmosphere for 1 h the mixture is Then poured into sodium thiosulfate and extracted with three portions of dichloromethane. The combined organic extracts washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. Purification using flash chromatography gives 0,087 g of compound 17.

MC (EEC) m/z 408 (MH+).

To 0,150 g (0,368 mmol) of compound 17 in dry dichloromethane was added 0,074 g of N-methylpiperazine (0,736 mmol) and 0,117 g triacetoxyborohydride sodium,552 mmol) and the mixture stirred for 18 h under nitrogen atmosphere. The reaction mixture was poured into water and extracted with three portions di is loretana. The combined organic extracts washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. Purification using flash chromatography gives 0,099 g of compound 18. MS (EEC) m/z 492 (MH+).

The following connections get the same methodology.

Table 4
ExampleR3R32R33WData analysis
LLC-CH3-CH3MS (MN+) 463,1
PPP-CH3-CH3Msvr (MN+) 492,3026
QQQ-CH3-CH3 MS (MN+) 477,1
RRR-CH3-CH3Msvr (MN+) 478,2865

4-Hydroxylation

A mixture of 19 (200 mg, 0.51 mmol) and SeO2(225 mg, 2.03 mmol, 4 equiv.) in 4 ml of dioxane is heated in a sealed vessel at 120°C for 1.5 hours It is filtered through a layer of Florisil and washed with tO. Eluent was washed with 2 with N2O, brine and dried over MgSO4. It is filtered, concentrated and purified using preparative TLC, elwira using 10% acetone in CH2Cl2and get 190 mg 20. Msvr: 408,2181 (MH+calculated 408,2175.

GETTING BICYCLIC AND TRICYCLIC DERIVATIVES of ALKENE

A double bond is introduced into I by treatment of compound I with LHMDS, and then with PhSeBr. Received selenide oxidized by hydrogen peroxide and after elimination get the connection II.

Alternatively, Aldagi the s III can be introduced into the reaction mix with phosphonate IV and get the connection V. It similarly can be converted into unsaturated lactone VI, which can be introduced in the reaction mix with different baronowie acids and to obtain analogues VII. Similarly, compound VIII can be converted into analogues X.

Obtaining unsaturated lactones

To a solution of I (2.0 g, 4,39 mmol) in 20 ml THF at 0°C was added 1 M solution of LHMDS in THF (8,8 ml of 8.8 mmol). The mixture is stirred for 20 min at 0°C, cooled to -78°C. and add a solution of PhSeBr (2.1 g, 8.9 mmol) in 10 ml of THF. The mixture is stirred for 30 min at -78°C, for 1 h at 0°C. the reaction is stopped by addition of aqueous solution of NH4Cl and extracted with tO and get the crude selenide.

Selenide is dissolved in 30 ml of CH2Cl2and to this solution was added to 3.8 ml of 30% aqueous solution of N2About2. The mixture is stirred for 1 h at RT, diluted with tO and washed with an aqueous solution Panso3and brine. It is dried over gSO4, filtered, concentrated and purified using chromatography and get 1,59 g II.

MS:454,1 (MN+).

To a solution of IV (1.7 g, 5,52 mmol) in 20 ml THF at 0°C was added 1 M solution of LHMDS in THF (5.5 ml, 5.5 mmol) and the mixture p is remediat within 30 minutes It added Ti(OiPr)4 (1.9 ml, 6,44 mmol), and then a solution of III (of 14.2 mmol) in 5 ml of THF. The mixture is stirred for 30 min at 0°C and the reaction stopped by adding an aqueous solution of potassium tartrate of sodium and extracted with tO and get the crude product, which was purified using chromatography and obtain 1.26 g V. MS:390,1 (MN+)

By the method similar to the one used to obtain II, compound V is transformed into a VI that is administered in a standard reaction mix by Suzuki and get the product VII.

EXAMPLEWData analysis
SSSMC (MN+) 404,1
NNNMC (MH+) 411,1
UUUMC (MN+) 404,1
VVVMC (MN+) 411,1

Similarly VIII can be converted into product X by the same methods si is thesis, as explained above.

Table 6
ExampleWData analysis
WWWMC (MH+) 385,1
XXXMS (MH+) 378,1
YYYMS ((MH+) 385,1

Other embodiments of the present invention encompass the introduction of the compounds of formula 1 with at least one additional cardiovascular drug. The estimated additional cardiovascular drug is such that atomic structure or configuration different from the compounds of formula I. Additional cardiovascular agent can be used in combination with the new compounds disclosed in this invention, including drugs that have antiplatelet, preventing platelet aggregation, anti-sclerotic, antirestenotic and/or anticoa Wirayuda activity. Those drugs are applicable in the treatment-related thrombosis diseases, including thrombosis, atherosclerosis, restenosis, hypertension, angina associated with angiogenesis disorders, arrhythmia, cardiovascular or related to disorder of circulatory disease or pathological condition, heart failure, myocardial infarction, glomerulonephritis, platelet-derived stroke, thromboembolic stroke, peripheral vascular disease, cerebral ischemia, rheumatoid arthritis, rheumatism, astroglia, fibrotic disorders of liver, kidney, lung or bowel, systemic lupus erythematosus, multiple sclerosis, osteoporosis, glomerulonephritis, kidney disease, acute renal failure, chronic renal failure, renal vascular homeostasis, ischemia of the kidneys, inflammation of the bladder, diabetes, diabetic neuropathy, cerebral stroke, cerebral ischemia, nephritis, cancer, melanoma, pochernkletocny carcinoma, neuropathy and/or malignant tumors, neurodegenerative and/or neurotoxic diseases, pathological conditions or lesions, inflammation, asthma, glaucoma, macular degeneration, psoriasis, endothelial dysfunction, liver disorder, kidney or lung, inflammatory disorders of the liver and gastrointestinal tract, disease or patol the environmental condition of the respiratory tract, radiation fibrosis, endothelial dysfunction, disease or periodontal wound or lesion of the spinal cord, or its symptoms, or effects, and other disorders, the pathogenesis of which involves thrombin and its receptor. Suitable cardiovascular drugs selected from the group comprising the inhibitors of the biosynthesis of thromboxane A2, such as aspirin; antagonists of thromboxane, such as seratrodast, picotamide and ramatroban; inhibitors of adenosine diphosphate (ADP), such as clopidogrel; cyclo-oxygenase inhibitors such as aspirin, meloxicam, rofecoksib and celecoxib; antagonists of angiotensin, such as valsartan, telmisartan, candesartan, irbesartan, losartan and eprosartan; endothelin antagonists, such as tezosentan; phosphodiesterase inhibitors such as milrinone and enoximone; inhibitors angiotenzinkonvertiruyuschego enzyme (ACE)such as captopril, enalapril, enalaprilat, spirapril, quinapril, perindopril, ramipril, fosinopril, trandolapril, lisinopril, moexipril and benazepril; inhibitors of neutral endopeptidase, such as candoxatril and ecadotril; anticoagulants, such as ximelagatran, fondaparinux and enoxaparin; diuretics, such as chlorothiazide, hydrochlorothiazide, ethacrynic acid, furosemide and amiloride; platelet aggregation inhibitors, such as abciximab and eptifibatide; and antagonis the s GP IIb/IIIa.

Preferred types of drugs intended for use in combination with the new compounds disclosed in this invention are inhibitors of the biosynthesis of thromboxane A2 antagonists of GP IIb/IIIa antagonists of thromboxane inhibitors of adenosine, cyclo-oxygenase inhibitors, antagonists of angiotensin, endothelin antagonists, inhibitors angiotenzinkonvertiruyuschego enzyme, inhibitors of neutral endopeptidase, anticoagulants, diuretics and inhibitors of platelet aggregation. Especially preferred for use in the combinations are aspirin, cangrelor and clopidogrelbisulfate.

If the present invention includes a combination of compounds of formula I and another cardiovascular drug, these two active components may be administered simultaneously or sequentially or as a single pharmaceutical composition comprising a compound of formula I and other cardiovascular drug in a pharmaceutically acceptable carrier. The components of the combination can be entered separately or together in any conventional dosage form such as capsule, tablet, powder, capsule, suspension, solution, suppository, nasal spray drug etc. Dosage cardiovascular drug can be determined from published materials and it can SOS is hawlati from 1 to 1000 mg per dose.

In the present description, the expression "at least one compound of formula I" means that the pharmaceutical composition or method of treatment you can use from 1 to 3 different compounds of formula I. Preferably one compound of formula I. Similarly, the expression "one or more additional cardiovascular drugs" means in combination with the compound of the formula I can be used from 1 to 3 additional medicines; preferably in combination with the compound of the formula I one additional connection. Additional cardiovascular drugs can be entered sequentially or simultaneously with the compound of the formula I.

If individual compounds of formula I and other cardiovascular drugs must be entered as separate compositions, they can be produced in the form of a set, which in one package includes a container comprising a compound of formula I in a pharmaceutically acceptable carrier, and a separate container comprising another cardiovascular drug in a pharmaceutically acceptable carrier and a compound of formula I and other cardiovascular drug contained in such quantities that the combination was therapeutically effective. Set for the introduction of combination, when, for example, the components are not bhodemon to enter through different periods of time or when they are in different dosage forms.

The following drugs are examples of some dosage forms of the present invention. In them, the term "active compound" denotes a compound of formula I.

EXAMPLE AS Tablets
No. 1Ingredient
Active connection
mg tablet
100
mg tablet
500
2Lactose United States Pharmacopeia122113
3Corn starch, food, in the form of a 10% paste in purified water3040
4Corn starch food4540
5Magnesium stearate37
Only300700

Method of cooking

Mix components 1 and 2 in a suitable mixer in ECENA 10-15 minutes To pelletize the mixture with component No. 3. If necessary, the wet granules are passed through a sieve with large cells (e.g., 1/4 inch, 0,63 cm). To dry the wet granules. If you need to sift the dried granules and mixed with component # 4 and mix for 10-15 minutes Add component # 5 and mix for 1 -3 minutes to Extrude the mixture into tablets of appropriate size and weight on a suitable teletrauma machine.

The EXAMPLE IN Capsules
No.Ingredientmg/capsulemg/capsule
1Active connection100500
2Lactose United States Pharmacopeia106123
3Corn starch food4070
4Magnesium stearate, national formulary47
Only250700

Method of cooking

Mix components 1, 2 and 3 in a suitable mixer for 10-15 minutes Add component # 4 and mix for 1-3 minutes Put the mixture in a suitable two-component capsules of hard gelatin on a suitable kapsulirujushchej machine.

The activity of the compounds of formula I can be determined by the following methods.

Research methodology antagonists, thrombin receptor in vitro

Preparation of [3H]haTRAP

A(pF-F)R(ChA)(hR)(l2-Y)-NH2(1,03 mg) and 10% Pd/C (5,07 mg) are suspended in DMF (250 μl) and diisopropylethylamine (10 μl). The vessel is connected to a supply of tritium, frozen in liquid nitrogen and pumped. Then in a vessel add gaseous tritium (342 MCI) and stirred at room temperature for 2 hours After completion of the reaction the excess tritium is removed and reacted the peptide solution was diluted with DMF (0.5 ml) and filtered to remove the catalyst. The collected solution of the crude peptide in DMF is diluted with water and dried by freezing to remove unbound tritium. Solid peptide re-dissolved in water and repeat the procedure of freeze-drying. Tretirovanie peptide ([3H]haTRAP) dissolved in 0.5 ml of 0.1% aqueous TFA and purified by HPLC (in socioaffective liquid chromatography) under the following conditions: column, Vydac™ C18, 25 cm×9.4 mm inner diameter; mobile phase, (A) 0.1% aqueous TFA solution, (B) 0.1% solution of TFA in CH3SP; gradient mode (a/b) from 100/0 to 40/60 over 30 min; flow rate, 5 ml/min; detection, using a UV detector at a wavelength of 215 nm. According to the analysis by HPLC radiochemical purity of [3H]haTRAP is 99%. Get the party activity 14,9 MkI when the specific activity, 18.4 CI/mmol.

Preparation of membranes of platelets

Membranes of platelets prepared using modified methods Natarajan et al. (Natarajan et al. Int. J. Peptide Protein Res. 45:145-151 (1995)) of 20 units of platelet concentrates obtained from North Jersey Blood Center (East Orange, NJ) within 48 h after collection. All steps carried out at 4°C when approved for use conditions of biological safety. Platelets are centrifuged at 100×g for 20 min at 4°C to remove red blood cells. The supernatant liquid is drained and at 3000×g for 15 min to obtain tablets of platelets. Platelets re-suspended in 10 mm Tris-HCl, pH 7.5, 150 mm NaCl, 5 mm add (ethylenediaminetetraacetic acid) in a total volume of 200 ml, and centrifuged at 4400×g for 10 minutes This stage, repeat 2 more times. Platelets re-suspended in 5 mm Tris-HCl, pH 7.5, 5 mm add in the final volume of approximately 30 ml and homogenized using 20 steps in a Dounce homogenizer™. Member who were turned into pill at 41000×g, re-suspended in 40-50 ml of 20 mm Tris-HCl, pH 7.5, 1 mm etc, 0.1 mm of dithiothreitol, and aliquots of 10 ml frozen in liquid N2and stored at -80°C. For the preparation of membranes aliquot was thawed, pooled and homogenized with 5 steps in a Dounce homogenizer. The membrane is transformed into a pill and washed 3 times with 10 mm triethanolamine-HCl, pH 7,4, 5 mm add and re-suspended in 20 - 25 ml of 50 mm Tris-HCl, pH 7.5, 10 mm MgCl2, 1 mm EGTC (etilenvinilatsetata acid) and 1% DMSO. Aliquots of membranes frozen in liquid N2and stored at -80°C. Membranes are stable for at least 3 months. 20 units of platelet concentrates usually give 250 mg of membrane protein. The protein concentration was determined by analysis of Lowry (Lowry et al., J. Biol. Chem., 193:265-275 (1951)).

High-performance analysis of binding of radioligand the thrombin receptor

Antagonists of thrombin receptor examined using a modified analysis of binding of radioligand the thrombin receptor hn et al. (Ahn et al., Mol. Pharmacol., 51:350-356 (1997)). The analysis is performed in 96-well tablets Nunc (Cat. No. 269620) when the final volume of the analyzed material, equal to 200 ál. Membranes of platelets and [3H]haTRAP diluted to 0.4 mg/ml and 22.2 nm, respectively, in binding buffer (50 mm Tris-HCI, pH 7.5, 10 mm MgCl2, 1 mm EGTC, 0.1% of BSA (bovine serum albumin)). The original solutions (10 mm in 100% DMSO) and the subjugated compounds optionally diluted in 100% DMSO. If not specified, then each well was added 10 μl of diluted solutions of compounds and 90 μl of solutions of radioligand (final concentration is 10 nm in 5% DMSO) and the reaction start by adding 100 μl of membranes (40 μg protein/well). Inhibition of binding with 5% DMSO is not essential. Compounds tested at 3 concentrations of 0.1, 1 and 10 μm). The wells are shut and the tablet should be gently mixed by shaking on a shaker device, Lab-Line™ Titer Plate Shaker for 1 h at room temperature. Filter plates Packard UniFilter™ GF/C soaked for at least 1 h in 0.1% polyethylenimine. Incubated the membrane is collected by the instrument Packard FilterMate™ Universal Harvester and quickly washed four times with 300 μl of ice a mixture of 50 mm Tris-HCl, pH 7.5, 10 mm MgCl2, 1 mm EGTC. To each well add scintillation mixture of MicroScint™ 20 (25 μl) and the radioactivity of the tablets was measured with a scintillation counter for microplate Packard TopCount™. Specific binding is defined as the full binding minus nonspecific binding measured in the presence of excess (50 μm) unlabeled haTRAP. Expressed as % inhibition of compound binding of [3H]haTRAP with thrombin receptor estimated using the following relationship:

Materials

A(pF-F)R(ChA)(hR)Y-NH2 and A(pF-F)R(ChA)(hR)(l2-Y)-NH2synthesized according to the order in AnaSpec Inc. (San Jose, CA). The purity of these peptides is>95%. Gaseous tritium (97%) was purchased from a company EG&G Mound, Miamisburg, Ohio. The gas is then placed in the container and stored in/US Systems Inc. Trisorber. Scintillation mixture of MicroScint™ 20 received from a company Packard Instrument Co.

The method of aggregation ex vivo platelet count in whole blood Cynomolgus Introduction drug and blood collection

In consciousness and a seated Cynomolgus monkeys were allowed to rest for 30 minutes In the brachial vein type needle catheter for infusion of investigational medicinal products. Another needle catheter is introduced into the other shoulder or subcutaneous veins of the legs and are used for blood collection. In experiments in which the compound is administered orally, use only one catheter. A baseline blood sample (1-2 ml) is taken in evacuated tubes containing thrombin inhibitor CVS 2139 (100 µg/0.1 ml saline) as an anticoagulant. Then the drug injected intravenously within 30 minutes of blood Samples (1 ml) taken after 5, 10, 20, 30 min during and after 30, 60, 90 min after injection. In experiments with orally administered drug is administered to animals with the help of a gastric probe. Blood samples are taken through 0, 30, 60, 90, 120, 180, 240, 300, 360 min after injection. 0.5 ml of Blood using the t for aggregation whole blood and another 0.5 ml is used to determine the concentration of a drug or its metabolites in the plasma. Operatiu performed immediately after blood collection as described below.

Aggregation whole blood

A blood sample volume of 0.5 ml was added to 0.5 ml of physiological solution and heated to 37°C in a survey instrument aggregation Chronolog whole blood. At the same time in the physiological solution is heated to 37°C. the electrode to determine the impedance. The blood sample from the rod for mixing is placed in the hole of the heating unit, the electrode for determining the impedance is placed in a blood sample and run the software for data collection. The software works to stabilize the baseline, and then carry out the calibration at 20 Ω. 20 Ω corresponds to the 4 blocks on the graph constructed by the software of the computer. Agonist (haTRAP) was added using a pipette with adjustable volume (5-25 μl) and graph aggregation register within 10 min. Measured value is the maximum aggregation within 6 min after administration of the agonist.

The procedure of platelet aggregation in vitro

The study of platelet aggregation is carried out by the method Bednar et al. (Bednar, C., Condra, C., Gould, R.J., and Connolly, T.M., Throm. Res., 77:453-463 (1995)). Blood is collected from healthy adults who are not less than 7 days did not take aspirin, by venipuncture using ACD as anticoagulant. Platelet-rich plasma produces the t by centrifugation at 100×g for 15 min at 15°C. Platelets make a pill at 3000×g and washed twice in buffered saline solution containing 1 mm EGTC and 20 µg/ml apyrase for inhibition of aggregation. The aggregation was performed at room temperature in buffered physiological solution, which added 0.2 mg/ml human fibrinogen. The analyzed connection and platelets pre-incubated in 96-well flat-bottom plates for 60 min Aggregation initiated by adding 0.3 microns haTRAP or 0.1 U/ml thrombin and faster stirring the mixture by shaking the device, Lab-Line™ Titer Plate Shaker (speed 7). For aggregation, expressed in percentage, following the increase of transmittance at 405 nm using a reader tablets Spectromax™.

Methodology antitumor effects in vivo

Research model of breast carcinoma person on naked mice conducted according to the technique described in the publication of S. Even-Ram et al., Nature Medicine. 4, 8 (1988), p.909-914.

The analysis of binding to cannabinoid receptor SV2

Binding to cannabinoid receptor SV2man spend according to the method Showalter. et al. (1996, J. Pharmacol Exp Ther. 278(3), 989-99) with slight modifications. All tests conducted in the final volume of 100 μl. The compounds re-suspended up to 10 mm in DMSO, then serially diluted in 50 mm Tris, pH of 7.1, 3 mm MgCl21 mm etc, 50% DMSO. Then aliquots (10 ál) of each diluted sample is transferred into individual wells of 96-hole tablet for micrometrology. Membrane transfitsirovannykh using ST2human cells CHO/Ki (Receptor Biology, Inc.), re-suspended in binding buffer (50 mm Tris, pH of 7.1, 3 mm MgCl2, 1 mm etc, 0,1% not containing free acid bovine serum albumin), then added to the reaction mixture bind (~15 µg in 50 µl per assay). The reaction initiated by addition of [3H] CP-55, 940, diluted in binding buffer (specific activity=180 CI/mmol; New England Nuclear, Boston, Mass.). The final concentration of the ligand in the binding assays equal to 0.48 nm. After incubation at room temperature for 2 h, the membranes are collected by filtration through a pre-heated (0.5% polyethylenimine; Sigma P-3143) filter plates GF-C (Unifilter-96, Packard) using a 96-well device for collecting cells TomTec™ Mach 3U (Hamden, Ct). Tablets washed 10 times in 100 μl of binding buffer and the membranes allow to air dry. The radioactivity of the membranes was measured after addition of scintillation fluid Packard Omniscint™ 20 using the device for measuring the scintillation and luminescence microplate TopCount™ NXT (Packard, Meriden, Ct). Nonlinear regression analysis is performed using the software Prism™ 20b (GraphPad Software, San Dieo, Ca).

Using the procedures described above study found that the typical compounds of formula I have the meanings IC50for thrombin receptor (i.e. the concentration at which 50% inhibition of thrombin receptor), is equal to from 1 to 1000 nm, preferably 1-100 nm, more preferably 1-20 nm. Values SV2Ki ranges from 1 to 1000 nm, preferably 1-200 nm, more preferably 1-100 nm.

1. The compound represented by structural formula I:

or pharmaceutically acceptable salt of the compounds, wheremeans a double bond or single bond in accordance with the requirements of valence; provided that R3is absent when the carbon atom to which R3attached, participates in a double bond;
In means -(CH2)n4CR12=CR12a(CH2)n5-, where n4and n5independently equal to 0 to 2, and R12and R12amean hydrogen;
E. means;
And means-O-:
G and J means -(CR1R2)-;
X is-CH-;
each n is 1;
Mnno;
Het denotes pyridyl, where the group Het is substituted by 1-4 fragments, W, where each W is independently selected from the group comprising hydrogen; alkyl; foralkyl; diferuloyl; triptorelin; R21-arylalkyl; aryl; alseny 1-3 substituents, independently selected from the group comprising halogen, amino or cyano;
R1and R2independently selected from the group comprising hydrogen, alkyl, foralkyl, cycloalkyl, aryl and thioalkyl; or
R1and R2in the case of accession to the nitrogen atom are taken together form a mono - or bicyclic heterocyclic ring containing from 4 to 10 atoms including 1-3 heteroatoms selected from the group comprising-O-, -N-, -S-, provided that the ring atoms S and O are next to each other, where the aforementioned heterocyclic ring is unsubstituted or substituted one or more groups selected from alkyl, halogen, hydroxy-group, alkoxygroup;
R3means-C(O)NR18R19, -N(R1)C=(NR1)NR1R2; -NR18C(O)R19, -NR18C(O)OR19, -NR18C(O)NR18R19, -NR18S(O)2R19or-alkyl-NR18R19;
R18and R19mean hydrogen, alkyl, aryl, R21-aryl, heteroaryl, cycloalkyl, heterocyclyl, alkoxyalkyl, halogenoacetyl, aryloxy-alkyl, allakariallak, heteroepitaxial, heteroarylboronic, cycloalkylcarbonyl, (heterocyclyl)alkyloxyalkyl, alkoxyalkyl-oxyalkyl, -S(O)2-alkyl, -C(NH)NR1R2or alkyl substituted with one or two fragments, selected from the group including the MT cycloalkyl, halogen, a hydroxy-group, -NR1R2, -NR1C(O)R2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OH, -C(O)OR1and-C(O)NR1R2; or
R18and R19together with the nitrogen atom to which they are attached, form a mono - or bicyclic heterocyclic ring containing from 4 to 10 atoms including 1-3 heteroatoms selected from the group comprising-O-, -N-, -S-, -S(O)-, -S(O)2andprovided that the atoms of S and O are next to each other, the ring is unsubstituted or substituted one or more groups selected from the group comprising alkyl, halogen, hydroxy-group, alkoxygroup, alloctype, arielalexisxrp, -NR'r R2, -NR1COR2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O2)NR1R2, -C(O)OR1, -CONR1R2and alkyl substituted by a group-NR1R2, -NR1COR2, -NR1CONR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OR1or-CONR1R2;
R21means from 1 to 3 slices, and each R21independently selected from the group comprising hydrogen, -CN, -CF3, halogen, alkyl, -HE, alkoxygroup, -NHCOR16where R16OZNA the AET alkyl; -C(NH)-NH2,
R32and R33independently selected from the group comprising hydrogen, alkyl, or R32and R33combined with the formation of a ring structure Q below

in which
R9means hydrogen;
Q means a group
;
in which each R13and R14means hydrogen;
R10and R11independently selected from the group comprising hydrogen or alkyl, provided that when ring Q is aromatic, and the carbon atoms to which are attached R10and R11, connected by a double bond, R10and R11no;
provided that when R3means the group-C(O)NR18R19the radicals R18and R19both are not simultaneously hydrogen atoms;
and its pharmaceutically acceptable salts.

2. The compound according to claim 1, in which there is no R3and there is a double bond between X and the carbon atom to which otherwise attached R3.

3. The compound according to claim 2, in which R32and R33combined with the formation of ring structures Q.

4. The compound according to claim 1, in which R1and R2mean hydrogen.

5. The compound according to claim 1, in which R1means hydrogen, and R2means methyl.

6. The compound according to claim 1, having the following structure:

where G means-CH(CH3).

7. The compound according to claim 1, in which R3means-C(O)NR18R19, -NR18C(O)R19, -NR18C(O)OR19, -NR18S(O)2R19or NR18C(O)NR18R19.

8. The compound according to claim 1, in which R18and R19mean hydrogen, alkyl, heteroaryl, -C(NH)-NH2, aryl, R21-aryl, or alkyl substituted with one or two fragments, selected from the group comprising cycloalkyl, halogen, a hydroxy-group, -NR1R2, -NR1C(O)R2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OH, -C(O)OR1or-C(O)NR1R2; where R1and R2mean hydrogen or alkyl;
or
R18and R19together with the nitrogen atom to which they are attached, form a mono - or bicyclic heterocyclic ring containing from 4 to 10 atoms including 1-3 heteroatoms selected from the group comprising O, N, S, S(O), S(O)2and C=O, provided that the atoms S or O are not next to each other, the ring is unsubstituted or substituted one or more groups selected from the group comprising alkyl, halogen, hydroxy-group, alkoxygroup, alloctype, arielalexisxrp, -NR1R2, -NR1COR2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR 1S(O)2NR1R2, -C(O)OR1, -CONR1R2and alkyl substituted by a group-NR1R2, -NR1COR2, -NR1CONR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OR1or-CONR1R2.

9. The compound according to claim 1, in which W stands for aryl or aryl substituted by halogen or cyano.

10. The compound according to claim 1, in which R32and R33mean hydrogen or alkyl, or in which R32and R33combined with the formation of a ring structure Q, where Q means

11. The compound according to claim 1, in which
In the mean CIS - or TRANS-(CH2)n4CR12=CR12a(CH2)n5-, where n4and n50;
Gnmeans of CH2, SN(alkyl) or C(alkyl)2;
Jnmeans of CH2where n is 1;
R3means-C(O)NR18R19;
R10and R11mean hydrogen;
R18and R19mean hydrogen, alkyl, heteroaryl, -C(NH)-NH2, aryl, R21-aryl, or alkyl substituted with one or two fragments selected from cycloalkyl, halogen, hydroxy-group, -NR1R2, -NR1C(O)R2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OH, -C(O)OR1or-C(O)NR1/sup> R2; where R1and R2mean hydrogen or alkyl;
or
R18and R19together with the nitrogen atom to which they are attached, form a mono - or bicyclic heterocyclic ring containing from 4 to 10 atoms including 1-3 heteroatoms selected from the group comprising O, N, S, S(O), S(O)2and C=O, provided that the S atoms or are not next to each other, the ring is unsubstituted or substituted one or more groups selected from the group comprising alkyl, halogen, hydroxy-group, alkoxygroup, alloctype, arielalexisxrp, -NR1R2, -NR1COR2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2NR1R2, -C(O)OR1, -CONR1R2and alkyl substituted by a group-NR1R2, -NR1COR2, -NR1CONR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OR1or-CONR1R2;
Het denotes pyridyl;
W stands for phenyl, substituted by: halogen or cyano and
R32and R33mean hydrogen or alkyl, or R32and R33combined with the formation of a ring structure Q, where Q means.

12. Connection by claim 11, in which R3, R32, R33and W are defined as follows:

R3R32R33W
-CH3Et

R3R32R33W
-CH3Et
-CH3Et
-CH3Et

-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3

R3R32R33W
-CH3-CH3
-CH3-CH3

-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3

R3R32R33W
-CH3-CH3
-CH3-CH3

-CH3-CH3
-CH3-CH3
-CH3-CH3
-With the 3-CH3
-CH3-CH3

Me = methyl
Et = ethyl.

13. The connection section 12, in which
In means-CH=CH-;
Het denotes pyridyl, attached through a ring carbon atom substituted with W;
W stands for phenyl, substituted by halogen or cyano,
R32and R33combined with the formation of Q, and Q means;
and
the radical R3defined as follows:

R3

.

14. The compound according to claim 1, in which
In the mean CIS - or TRANS-(CH2)n4CR12=CR12a(CH2) n5where n4and n50;
Gnmeans of CH2, SN(alkyl) or C(alkyl)2;
Jnmeans of CH2where n is 1;
R3means-NR18C(O)R19, -NR18C(O)OR19or-NR18S(O)2R19;
R10and R11mean hydrogen;
R18and R19mean hydrogen, alkyl, heteroaryl, heterocyclyl, -C(NH)-NH2, aryl,
R21-aryl, or alkyl substituted with one or two fragments, selected from the group comprising cycloalkyl, halogen, a hydroxy-group, -NR1R2, -NR1C(O)R2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OH, -C(O)OR1or-C(O)NR1R2; where R1and R2mean hydrogen or alkyl; or
R18and R19together with the nitrogen atom to which they are attached, form a mono - or bicyclic heterocyclic ring containing from 4 to 10 atoms including 1-3 heteroatoms selected from the group comprising O, N, S, S(O), S(O)2and C=O, provided that the S atoms or are not next to each other, the ring is unsubstituted or substituted one or more groups selected from alkyl, halogen, hydroxy-group, alkoxygroup, alloctype, arialcategory, -NR1R, -NR1COR2, -NR1C(O)NR1R2, -NR 1C(O)OR2, -NR1S(O)2NR1R2, -C(O)OR1, -CONR1R2and alkyl substituted by a group-NR1R2, -NR1COR2, -NR1CONR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OR1or-CONR1R2;
Het denotes pyridyl;
W stands for a phenyl, substituted with halogen or cyano;
and
R32and R33mean hydrogen or alkyl, or R32and R33combined with the formation of a ring structure Q, where Q means.

15. The connection 14, in which R3, R32, R33and W are defined as follows:

R3R32R33W
-CH3Et
NEt
NEt
-CH3Et
-CH3Et

R3R32R33W
-CH3-CH3
-CH3Et
-CH3Et

-CH3-The n 3
-CH3-CH3
-CH3Et
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3
-CH3-CH3

R3R32R33W
-CH3-CH3
-CH3-CH3
-CH3-CH3

-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3

16. The connection 14, in which
In means-CH=CH-;
Het denotes pyridyl, substituted with W;
W stands for aryl, substituted with halogen or cyano;
R32and R33combined with the formation of Q, and Q oz is ACHAT ;
and the radical R3defined as follows:

R3

.

17. The compound according to claim 1, selected from the group including:

and

18. The compound according to claim 1, having the following structure:

in which W, R3, R32and R33defined as follows:


R3R32R33W
-CH3Et
R3R32R33W
-CH3Et
-CH3Et
-CH3Et
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3

-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3

R3R32 R33W
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH

-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3

R3R32R33W
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3

19. The compound according to claim 1 with SL is blowing structure:

in which the radical R3defined as follows:

R3

20. The compound according to claim 1 with the following structure:

in which R3, R32, R33and W are defined as follows:

R3R32R33W
-CH3Et
NEtimg src="https://img.russianpatents.com/1068/10687267-s.jpg" height="26" width="16" />

R3R32R33W
NEt
-CH3Et
-CH3Et
-CH3-CH3
-CH3Et
-CH3Et

-CH3-CH3
-CH3-CH3
-CH3Et
-CH3-CH3
-CH3-CH3
-CH3-CH3

R3R32R33 W
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3

-CH3 -CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3
-CH3-CH3

td align="center"> -CH3
R3R32R33W
-CH3

21. The compound according to claim 1, having the following structure:

in which the radical R3defined as follows:

R3

22. The compound according to claim 1, in which there is no R3and in which there is a double bond in the ring pairing between X and the carbon between the carbonyl group and Jn:
In the mean CIS - or TRANS-(CH2)n4CR12=CR12a(CH2)n5where n4and n50;
Gnmean CR1R2where n is 1, where R1and R2mean alkyl or hydrogen;
Jnmean CR1R2where n is 1, where R1and R2mean hydrogen;
R9, R10and R11mean hydrogen;
Het denotes pyridyl;
W means aryl substituted by 1-3 substituents, independently researched the Simo selected from the group including halogen and CN;
and
R32and R33mean alkyl, or R32and R33and with the carbon atoms to which they are attached, are combined with the formation of Q.

23. Connection p.22 with the following formula:

in which W meansor

24. Connection p.22 with the following formula:

in which W means
or.

25. The compound according to claim 1 in purified form.

26. The compound according to claim 1 in the selected form.

27. Pharmaceutical composition having the properties of a receptor antagonist of thrombin containing an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

28. A method of inhibiting thrombin receptors or cannabinoid receptors, comprising the administration to a mammal in need of such treatment, an effective amount of a compound according to claim 1.

29. The use of compounds according to claim 1 for obtaining a medicinal product for the treatment of thrombosis, atherosclerosis, restenosis, hypertension, angina associated with angiogenesis disorders, arrhythmia, cardiovascular or related to disorder of the circulatory Zab the diseases or condition, heart failure, myocardial infarction, glomerulonephritis, platelet stroke, thromboembolic stroke, peripheral vascular disease, cerebral ischemia, rheumatoid arthritis, rheumatism, astrogliosis, fibrotic disorders of the liver, kidney, lung or bowel, systemic lupus erythematosus, multiple sclerosis, osteoporosis, glomerulonephritis, kidney disease, acute renal failure, chronic renal failure, renal vascular homeostasis, renal ischemia, inflammation of the bladder, diabetes, diabetic neuropathy, cerebral stroke, cerebral ischemia, nephritis, cancer, melanoma, pochernkletocny carcinoma, neuropathy and/or malignant tumors, neurodegenerative and/or neurotoxic diseases, conditions or lesions, inflammation, asthma, glaucoma, macular degeneration, psoriasis, endothelial dysfunction, disorders of the liver, kidneys or lungs, inflammatory disorders of the lungs and gastrointestinal tract, disease or condition of the respiratory tract, radiation fibrosis, endothelially dysfunction, periodontal diseases or wounds or lesions of the spinal cord, or its symptoms or consequences.

30. The application of clause 29, in which the inflammatory disease or condition is a irritable bowel syndrome, Bo is esgn Crown, jade or radiation-induced or chemotherapy proliferative or inflammatory disturbance of the gastrointestinal tract, lung, bladder, gastrointestinal tract or other body.

31. The application of clause 29, in which the violation or condition of the respiratory tract is a reversible obstruction of the Airways, asthma, chronic asthma, bronchitis or chronic disease of the respiratory tract.

32. The application of clause 29, in which the cancer is a pochernkletocny carcinoma or associated with angiogenesis violation.

33. The application of clause 29, in which the neurodegenerative disease is a Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease or Wilson's disease.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: use of compounds of formula (I): where: X denotes >CR1R2 or, when R6 denotes H, X denotes >SO2; Y denotes >CR1R2; Z denotes >C=O, >CH2, single bond; R1 denotes H, R2 denotes H, -COOH, -OH; or R1 and R2 together denote =O, ethylenedioxy or hydroxyimino group; R3 denotes H, lower alkyl group; R4 denotes two H, =O, hydroxyimino group; R5 denotes H, lower alkyl group, halogen; R6 denotes H, lower alkoxy, COOH; R7 and R8 are identical or different from each other and each denotes H, lower alkyl, halogen; and pharmaceutically acceptable salts thereof and esters for preparing a medicinal agent.

EFFECT: agent having neuroprotective action against hypoxia.

2 tbl, 24 ex, 13 cl

FIELD: chemistry.

SUBSTANCE: invention describes novel benzothiazinone derivatives of formula (I) and their use as antibacterial agents in infectious diseases caused by bacteria, especially mycobacterium tuberculosis (TB) and leprosy, in which R1 and R2 independently denote NO2, CN, CONR7R8, COOR9 CHO, halogen, SO2NR7R8, OCF3, trifluromethyl; R3 and R4 independently denote H or methyl; R5 and R6 independently denote a straight or branched aliphatic radical having 1-8 members in the chain, or R5 and R6 together denote a divalent radical -(CR92)m- or R5 and R6 together denote a divalent radical: R7, R8 and R9 independently denote H or a straight or branched aliphatic radical having 1-7 members in the chain, or phenyl.

EFFECT: design of an efficient method of obtaining benzothiazinone derivatives, a pharmaceutical composition having anti-mycobacterial activity.

12 cl, 6 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new a compound of formula I or formula II, or to its pharmaceutically acceptable salts, I II, where X is S; R1 is H or C1-C6alkyl; R2 is NR5R6; R3 is aryl, substituted with a halogen; R4 is H; R5 is H; R6 is H; R7 is CH2NR8R9 where R8 is H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl), heterocycle(C2-C6alkenyl), hydroxyl(C1-C6alkyl), hydroxyl(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbamoyl(C1-C6alkyl); where the above mentioned aryl is an aromatic ring and is not substituted or substituted with one to three substituting groups, each of which, independently from the others, is chosen from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, trifluoromethoxy, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy), R9 is H, C1-C10alkyl, heterocycle(C1-C6alkyl) or heterocycle(C2-C6alkenyl); where the above mentioned heterocycle represents a 5-member saturated monocyclic ring system, consisting of carbon atoms, as well as heteroatoms, chosen from a group comprising N, O, and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes NO2, aryl(C1-C6alkyl), arylsulphonyl; or R8 and R9 together with nitrogen, to which they are bonded, form a heterocycle, which represents a 5 - 7-member saturated monocyclic ring system, consisting of carbon atoms, as well as one to three heteroatoms, chosen from a group comprising N, O and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes C1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6-alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidin-2-yl; and m equals 0. The invention also relates to a pharmaceutical composition, as well as to use of formula I or formula II compounds.

EFFECT: obtaining new biologically active compounds, with inhibitory properties towards casein kinase 1ε.

32 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds -(Z)-1'-R-6',6'-dimethyl-3-(phenyl(arylamino)methylene)-6',7'-dihydro-3H-spiro[furane-2,3'-indol]-2',4,4',5(1'H,5'H)-tetraons of formula: , where Ar=phenyl, n-methoxyphenyl, n-tollyl; R=allyl, benzyl, phenyl, n-tollyl, n-methoxyphenyl, α-naphtyl, as well as to method of their obtaining, which consists in the following: isopropyl 2-(1-aryl-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-yl)-2-oxoacetates are subjected to interaction with N-substituted 3-amino-5,5-dimethylcyclohex-2-enons in medium of inert aprotonic solvent with further separation of target products. Process is carried out at temperature 20-22°C. As solvent, absolute chloroform is used.

EFFECT: obtaining compounds possessing analgesic activity.

4 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds, and more specifically to 5-formyl-substituted indoline spirobenzopyrans with general formula 1 where R1, R2 - Alk or c-Alk; R3 -CHO or NO2 group (electron-acceptor substitute), with photochromic properties. The invention also relates to the method of producing 5-formyl substituted derivatives of indoline spirobenzopyrans with formula 1. Spirobenzopyrans, which have electron-acceptor substitutes in the pyran part of the molecule, are subjected to direct selective formylation in position 5 in a trifluoroacetic acid medium with urotropine (hexamethylenetetramine) at boiling point of the mixture in an inert atmosphere for 1-1.5 hours. The obtained 5-formyl-substituted spirobenzopyrans are photochromic compounds are photochromic and can be used for making new photochromic materials (recording devices or information storage; photo-switching activity of biological objects and polymer matrices, complex formation; information security media, maps, special document protection equipment) or as advanced initial compounds for further synthesis of a large number of new photochromic objects.

EFFECT: wider field of application of the compounds.

2 cl, 1 tbl, 3 ex

FIELD: chemistry.

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

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry.

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

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

45 cl, 300 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to new compounds with formula I, their pharmaceutical salts and to complex esters. The invented compounds have inhibiting propertied towards catepsin K and can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved, for example, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumorous diseases. In general formula I R represents H, R13 represents (inferior)alkyl, C3-C10cylcloalkyl or C3-C10cycloalkyl(inferior)alkyl, each of which is independently optionally substituted with a halogen atom, hydroxyl, CN, NO2 or optionally mono- or di(inferior)alkyl substituted amino group; and R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(inferior)alkyl-W-, C3-C10cycloalkyl, C3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl -W-. Substitutes of the indicated values of radicals are shown in the formula of invention. The invention also relates to methods of obtaining the compounds.

EFFECT: obtaining pyrrolopyrimidines with inhibiting properties towards catepsin K, which can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved.

4 cl, 59 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula I and its pharmaceutically acceptable salts. In formula (I) , R stands for 6-unit ring, containing one ore two heteroatoms of nitrogen, and substituted with group selected from the following groups: (lower)alkyl, -C(O)-R1, (lower)alkyl, substituted with group -SO2-(lower)alkyl, (lower)alkyl, substituted with group -C(O)-R1, -SO2-(lower)alkyl, or 5-unit saturated ring, containing one heteroatom of nitrogen, R1 is selected from group, including (lower)alkyl, -N((lower)alkyl)2, or R1 stands for 6-unit saturated ring, containing two heteroatoms, selected from N and O, X1 and X2 are independently selected from group, including hydrogen, (lower)alkoxy, each Y1 and Y2 are independently selected from group, including -Cl and -Br, and absolute stoichiometric configuration in position 4 and 5 imidazoline ring includes S and R configuration, accordingly. Invention also relates to pharmaceutical composition, having inhibiting activity regarding interaction of MDM2 - p-53, containing efficient amount of invention compound.

EFFECT: production of compounds, having inhibiting activity as regards interaction of MDM2-p-53.

12 cl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new compounds of formula (1) or its pharmaceutically acceptable salts, with properties of antagonist CXCR2 of human neutrophils receptor. In formula (1) R1 represents a group selected from C1-8alkyl; where this group is possibly substituted with 1 substituent, independently selected from phenyl or 5-6-unit heteroaryl, containing 1-2 heteroatoms selected from N, S; where phenyl and heteroaryl are possibly substituted by 1, 2 or 3 substitutors, independently selected from halogeno, cyano, -OR4, -COOR7, -SO2R10, C1-6alkyl; X represents -CH2-, oxygen, sulfur; R2 represents C3-7carbocyclil, possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4; or R2 represents 5-unit ring, containing 2 heteroatoms, selected from O, -NR8, and where this ring is possibly substituted with 1 substituent, independently selected from C1-3alkyl; or R2 represents group, selected from C1-8alkyla, where this group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-C1-6alkylcarbamoyl, N,N-di(C1-6alkyl)carbamoyl, carboxy, -NR8COR9 and -CONR5R6; R3 represents group -NR5R6, or R3 represents phenyl, possibly condensed with 6-unit heterocyclil, containing nitrogen, naphthyl, 4-8-unit monocyclic heterocyclil, containing 1-3 heteroatoms, selected from N, O, S, possibly condensed with benzole ring or 3-unit nitrogen-containing ring, where heteroring may be non-saturated, partially or fully saturated, and one or more than one circular atom of carbon may form carbonyl group, and where each phenyl or heterocyclil group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, phenyl, 5-6-unit heteroaryl, containing 1-2 atoms of nitrogen, -OR4, -NR5R6, -CONR5R6, -COR7, -COR20, -COOR7, -NR8COR9, -SO2R10, -SO2NR5R6 or C1-6alkyl [possibly additionally substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR20, -COOR20, -NR18R19, -CONR18R19, phenyl or 5-6-unit of monocyclic heteroaryl, containing 1-2 heteroatoms O, N, S, or 10-unit bicyclic heteroaryl, containing 1 heteroatom O, where heteroring may be partially or fully saturated, and where each phenyl or heteroaryl is group possibly substituted with 1 or 2 substituents, independently selected from halogeno, cyano, nitro, -OR20, -NR5R6, -COOR7, -NR8COR9, 6-unit heterocyclil, containing two heteroatoms, selected from O and N, 5-unit heteroaryl, containing 3 heteroatoms N, C1-6alkyl (possibly additionally substituted with 1 substituent, independently selected from halogeno, cyano, nitro, -OR20, -COOR20; or R3 represents group, selected from C3-7carbocyclil, C1-8alkyl, where this group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6; R4 represents hydrogen; R5 and R6 independently represent hydrogen or group, selected from C1-6alkyl and monocyclic 6-unit saturated heterocyclil containing 1 heteroatom N; where C1-6alkyl is possibly substituted with 1 substituent, independently selected from -NR15R16; or R5 and R6 together with atom of nitrogen, to which they are linked, form 4-7-unit saturated heterocyclic circukar system, possibly containing additional heteroatom, selected from oxygen, -SO(n)- (where n equals 0, 1 or 2) and atoms of nitrogen; R10 represents hydrogen or group, selected from C1-6alkyl; and each of R7, R8, R9, R15, R16, R17 independently represents hydrogen, C1-6alkyl; R18, R19 and R20 represent hydrogen or group, selected from C1-6alkyl, where this group is possibly substituted with 1 substituent, independently selected from -NR8R9, -CONR8R9.

EFFECT: production of new compounds, which may find application in production of medicinal agent for use in treatment of diseases and disorders mediated with chemokines, such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, inflammatory intestine disease, irritable colon syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis or psoriasis, and also for treatment of cancer.

12 cl, 155 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-cyclopropyl-1 -{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate of formula:

. The invention also relates to salts and solvates of the said compound, a method of producing said compound, a pharmaceutical agent having angiotensin II antagonist activity, based on said compound.

EFFECT: compound can be used in medicine to prevent and treat blood circulatory system diseases.

18 cl, 1 dwg, 8 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula:

, A and B denote a pair of condensed saturated or unsaturated 5- or 6-member rings, where the said system of condensed rings A/B contains 0-2 nitrogen atoms, and said rings are further substituted with 0-4 substitutes independently selected from halogen, lower alkyl or oxo; and a and b are bonding positions for residues Y and D, respectively, and these positions a and b are in the peri-position relative each other on the said condensed ring system A/B; d and e are condensed positions between ring A and ring B in the said condensed ring system A/B; D is an aryl or heteroaryl cyclic system which denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S; which can be further substituted with 0-4 substitutes independently selected from lower alkyl and amine; Y is selected from -CH2 and -O-; M is selected from aryl, aryl substituted with a halogen or alkoxy; R1 is selected from aryl, aryl substituted with a halogen, heteroaryl, heteroaryl substituted with a halogen, where heteraryl denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S, and CF3; and if Y denotes -CH2- or -O-, then R1 further denotes a lower alkyl. The invention also pertains to use of compounds in claim 1, a pharmaceutical composition, a screening method on selective ligands of prostanoid receptors, as well as compounds of the formula.

EFFECT: obtaining novel biologically active compounds for inhibiting binding of prostanoid E2 with EP3 receptor.

25 cl, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to uniformly tritium-labelled (R)-(+)-[5-methyl-3-(4-morpholinylmethyl)-2,3-dihydro-[1,4]oxazine[2,3,4-hi]-6-indolyl]-1-naphthalinylmethanone acetate of formula I: .

EFFECT: wide range of labelled analogues of physiologically active compounds.

1 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel thiophene derivatives of formula (I): ,

where the ring system A is characterised by formula ,

R1 denotes hydrogen, C1-C5alkyl or C1-C5alkoxy, R2 denotes hydrogen, C1-C5alkyl, C1-C5alkoxy or trifluoromethyl, R3 denotes hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH, -CH2-(CH2)n-CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2-(CH2)m-NR31R32, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy, 2-morpholin-4-ylethoxy, 3-morpholin-4-ylpropoxy, 3-[(pyrrolidin-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidin-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropoxy; R31 denotes hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, 2-(C1-C5)alkoxyethyl, 3-(C1-C5)alkoxypropyl, 2-aminoethyl, 2-(C1-C5alkylamino)ethyl or 2-(di-(C1-C5alkyl)amino)ethyl; R32 denotes hydrogen, methyl, ethyl, m equals 1 or 2; n equals 1; and R4 denotes hydrogen, (C1-C5)alkyl or halogen, and configuration isomers thereof, such as optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts of said compounds of formula (I), synthesis thereof and use as therapeutically active compounds.

EFFECT: compounds have the effect of immunosuppressive agents.

20 cl, 2 tbl, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula: I, where R1 is selected from group, consisting of ethyl, 2-fluorethyl and isopropyl; R2 is selected from group, consisting of hydrogen, C1-7-alkyl, hydroxy, C1-7-alkoxy, C3-7-cycloalkyl, halogen, -C(O)OR6, where R6 represents C1-7-alkyl, amino, phenyl, phenyl, substituted with 1-3 substituents, selected from group, consisting of halogen, halogen-C1-7-alkyl and halogen-C1-7-alkoxy, pyridyl, imidazolyl, triazolyl and pyrrolyl; R3 is selected from group, consisting of hydrogen, C1-7-alkoxy, amino, -O-benzyl and -o-tetrahydropyranyl; or R2 and R3 are bound to each other with formation of cycle together with carbon atoms to which they are bound, and R2 and R3 together represent -CH=CH-NH-; R4 is selected from group, consisting of hydrogen, halogen, pyridyl and pyrimidyl; R5 and R5' independently on each other are selected from hydrogen or methyl; A is selected from group, consisting of isphenyl; phenyl, substituted with 1-3 substituents, selected from group, consisting of C1-7-alkyl, C3-7-cycloalkyl, C1-7-alkylsulfonyl, -O-C1-7-alkylsulfonyl, hydroxy, C1-7-alkoxy, hydroxy-C1-7-alkyl, hydroxy-C2-7-alkoxy, dihydroxy-C3-7-alkoxy, C1-7-alkylamino, di-C1-7-alkylamino, amino-C2-7-alkoxy, amino-C1-7-alkyl, -C(O)NR10R11, -O-C1-7-alkylene-C(O)NR10R11, -C(O)OR10, -C1-7-alkylene-C(O)OR10, -O-C1-7-alkylene-C(O)OR10, halogen, halogen-C1-7-alkoxy, cyano- C1-7-alkoxy, fluorphenyl, pyridyl, tetrazolyl and tetrazolyl- C1-7-alkoxy; 1,3-benzodioxolyl; naphtyl; pyrimidinyl; pyridyl, substituted with one or two substituents, selected from group, consisting of C1-7-alkyl, C1-7-alkoxy, amino, C1-7-alkylamino, di-C1-7-alkylamino, C3-7-cycloalkylamino, halogen, cyano, morpholinyl, imidazolyl and -NH-C(O)-R9, where R9 represents C1-7-alkyl or C3-7-cycloalkyl, and indolyl; R10 and R11 independently on each other represent hydrogen or C1-7-alkyl; and to their pharmaceutically accdeptable salts. Invention also relates to pharmaceutical compositions.

EFFECT: obtaining novel biologically active compounds, which are antagonists of somatostatin receptor subtype 5 (SSTR5).

26 cl, 266 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula:

, A and B denote a pair of condensed saturated or unsaturated 5- or 6-member rings, where the said system of condensed rings A/B contains 0-2 nitrogen atoms, and said rings are further substituted with 0-4 substitutes independently selected from halogen, lower alkyl or oxo; and a and b are bonding positions for residues Y and D, respectively, and these positions a and b are in the peri-position relative each other on the said condensed ring system A/B; d and e are condensed positions between ring A and ring B in the said condensed ring system A/B; D is an aryl or heteroaryl cyclic system which denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S; which can be further substituted with 0-4 substitutes independently selected from lower alkyl and amine; Y is selected from -CH2 and -O-; M is selected from aryl, aryl substituted with a halogen or alkoxy; R1 is selected from aryl, aryl substituted with a halogen, heteroaryl, heteroaryl substituted with a halogen, where heteraryl denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S, and CF3; and if Y denotes -CH2- or -O-, then R1 further denotes a lower alkyl. The invention also pertains to use of compounds in claim 1, a pharmaceutical composition, a screening method on selective ligands of prostanoid receptors, as well as compounds of the formula.

EFFECT: obtaining novel biologically active compounds for inhibiting binding of prostanoid E2 with EP3 receptor.

25 cl, 46 ex

Up!