Derivatives of 1h pyrrolo 3, 4 pyrazole - C, a process for their preparation, Pharmaceutical compositions containing same and their use in the manufacture of a Medicament for the Treatment or prophylaxis of diseases associated with the coagulation factor Xa

摘要

These compounds inhibit the coagulation factor of XA and can be used as drugs and pharmaceutical components. Item 1: formula compound (1)wherein: A is a heteroaryl ring, which is a monocyclic or bicyclic aromatic ring of 5 to 12 atoms in the ring, which contains one, two or three heteroatoms in the ring, chosen from N, O and S, the other atoms of the ring are C, one or two carbon atoms of said ring are optionally replaced by a carbonyl group; R1 and R2 independently of one another are hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 fluororalkoxy, C1-6 hydroxyalkoxy, C1-6 alkoxyC1-6 alkoxy, mono- or di-substituted aminoC1-6 alkoxy C1-6 alkyl, halogen, cyano, nitro, -N (R ') -CO- (C1-6 alkyl optionally substituted with one or more fluorine atoms),Where R 'is hydrogen, C1-6 tar or C1-6, - n (R) fluorinated tar-co-o - (C1-6 tar can optionally be replaced by one or more fluorinated atoms),If R 'is hydrogen, C1-6 hydrocarbon or c1-6-fluorohydrocarbon, - n (R) - Co-N (R) (` r'),There, RR" and "R" are independent of each other, referring to hydrogen, C1-6 hydrocarbon or C1-6 o-n (R) fluorotar-so2 - (C1-6 tar can optionally be replaced by one or more fluorine atoms),R 'is hydrogen, C1-6 hydrocarbon or C1-6 fluorinated hydrocarbon; or R1 and R2 are independent of - so2-n (R',-C (o) - n (R) (R) or n (R) (R),Where R 'and R' 'are independent of each other' is hydrogen, C1-6 or C1-6 or R 'and R',In addition to the nitroglycerin atoms attached to them, they form an isomerization; x1 es-c (o) - tar 0-6-nr3-tar 0-6 -.-C0-6-C (O) -NR3-C0-6- alkylene,1-6-nr3-c (o) - tar 0-6, C (o) - tar 0-6,0-6,2-tar 0-6-1-6-so2-nr3-1-6 - or 1 formula (2);X2 is arileno, isopropene or isopropene, which can be replaced by one or more independently selected substitutes from C1-6, alcoxi C1-6, halogen, cyanogen, nitrate, amino-co (C1-6 optional tar replaces one or more substances). Fluorinated atom,Where R 'is hydrogen, C1-6 tar or C1-6, - n (R) fluorinated tar-co-o - (C1-6 tar can optionally be replaced by one or more fluorinated atoms),If R 'is hydrogen, C1-6 hydrocarbon or c1-6-fluorohydrocarbon, - n (R) - Co-N (R) (` r'),There, RR" and "R" are mutually independent, referring to hydrogen, C1-6 hydrocarbon or C1-6, ` C (o) - n (R) (` r '), where R' and "R" are mutually independent, referring to hydrogen, C1-6 or C1-6 or R 'and R'. And the nitroglycerin atoms they're linked to form a heteromorphic moleculeWhere R 'and R' 'are independent of each other' are hydrogen, C1-6 hydrocarbon or C1-6 fluorinated hydrocarbon, or R 'and R',In addition to the nitroglycerin atoms attached to them, they form an isomerization, or a formula (3),Where R 'and R' 'are independent of the hydrocarbon groups of C1-6 or C1-6 or R' and R ',With the nitroglycerin atoms attached to them, they form an isomerization, or a formula (4),Where R 'and R' 'are independent of the hydrocarbon groups of C1-6 or C1-6 or R' and R ',The nitroglycerin atom connected with it forms an isomerization, or a formula (5),R 'is a C1-6 fluorescent tar or a formula (6),R 'is a C1-6 fluorescent tar, and one or two carbon atoms of arileno, heterocyclic or heterocyclic propylene can be replaced by one carbon group; X3 is hydrogen, arilo, heterocyclic or heterocyclic propylene, In the group of C1-6 tar, Alcoy C1-6, halogeno, Ciano, nitro, amino, amino, amino, C1-6 tar, C1-6 tar and C1-6 tar, one or more substitutes can be selected to replace isopropene and isopropene, C1-6 carbon dioxide and difluoro sulfur dioxide of C1-6 tar, SO2 tar 1-6 o, so2-nh2,-SO2-NH-C1-6 alkyl and -SO2-N (C1-6 alkyl) 2; and one or two carbon atoms of said aryl, heteroaryl and heterocyclyl are optionally substituted with a carbonyl group; R3 is hydrogen or C1-6 alkyl; Y1 is C0-6-C (O) -NR3-C0-6 alkylene, C0-6 -C3-C (O) -C0-6- alkylene or C0-6 alkylene; Y2 is arylene, heteroarylene or heterocyclylene, said arylene, heteroarylene and heterocyclylene are optionally substituted with one or more substituents independently selected from each other from the group consisting of C1-6 alkyl, C1-6 alkoxy, halogen, cyano, nitro, amino, -N (R ') - CO- (C1-6 alkyl optionally substituted with one or more fluorine atoms),Where R 'is hydrogen, C1-6 tar or C1-6, - n (R) fluorinated tar-co-o - (C1-6 tar can optionally be replaced by one or more fluorinated atoms),If R 'is hydrogen, C1-6 hydrocarbon or c1-6-fluorohydrocarbon, - n (R) - Co-N (R) (` r'),There, RR" and "R" are independent of each other. They are hydrogen, C1-6 hydrocarbon or C1-6, ` C (o) - n (R) (` r '), where R' and "R" are independent of each other. They are hydrogen, C1-6 or halo tar 1-6 or R 'and R'. ogether with the nitrogen atom to which they are attached they form a heterocyclyl, -NR'R '',R" and "R" are independent of each other. They are hydrogen, C1-6, or C1-6, or R 'and R',In addition to the nitroglycerin atoms attached to them, they form an isomerization, or a formula (3),Where R 'and R' 'are independent of the hydrocarbon groups of C1-6 or C1-6 or R' and R ',With the nitroglycerin atoms attached to them, they form an isomerization, or a formula (4),Where R 'and R' 'are independent of the hydrocarbon groups of C1-6 or C1-6 or R' and R ',The nitroglycerin atom connected with it forms an isomerization, or a formula (5),R 'is a C1-6 fluorescent tar and a formula (6),wherein R 'is C1-6 alkyl; and one or two carbon atoms of said arylene, heteroarylene or heterocyclylene are optionally substituted with a carbonyl group; Y3 is hydrogen, aryl, heteroaryl or heterocyclyl, said aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from each other from the group consisting of C1-6 alkyl, C1-6 alkoxy, halogen, cyano, nitro, amino, amino monosubstituted with C1-6 alkyl, amino disubstituted with C1-6 alkyl, amino- C1-6 alkyl monosubstituted with C1-6 alkyl, C1-6 aminoalkyl disubstituted with C1-6 alkyl, -SO2-C1-6 alkyl or, -SO2 -NH2, -SO2-NH-C1-6 alkyl and -SO2-N (C1-6 alkyl) 2;One or two carbon atoms, namely arilo, isopropene and isoacrylonitrile, can be replaced by one carbon group; Z is connected to the same carbon atom, namely - y1-y2-y3, and is hydrogen or hydrocarbon radical of C1-6; n is 0, 1 or 2; m is 0, 1 or 2m + n is equal to 2 or 3; or an integer from 1 to 5; Unless otherwise specified, prophas and sales are acceptable for drugs; arilom refers to phenyl or naphthalene; heterosexual refers to the remaining 5 to 12 atoms of single or double ring aromatic in the ring, including 1, 2 or 3 heteroatoms in the ring, Select from n, O and SThe other atoms in the ring are C, and one or two carbon atoms in the ring are replaced by one carbon group, because the connection point of other heteromorphic atoms is in the aromatic ring; the term heteromorphic ring refers to the non aromatic, single or double ring residues of three or eight carbon atoms. A ring, one or both of which have atoms selected from n, O, and S (o) n (where n is an integer from 0 to 2),Other ring atoms are C. claim 18: a process for preparing a formula compound (7)Acidification by one-step formula compound (8),X2, X3, Y2, Y3, R1, and R2 all have defined meanings