Spirocycles inhibitors metalloprotease
The invention relates to new spirochetes formula Iwhere Ar is phenyl, substituted phenyl where the substituents are: alkoxy, alkyl, alkoxyalkyl, phenoxy, halogen, pyridyloxy, alkoxyalkane, halogenfree; R1- H; R2- H1-C4alkyl; W represents O or one or more1-C4alkyl fragments; Y is independently one or more members of the group consisting of H2, SR3, alkoxy; R3- H, alkyl; Z is a carbocyclic or heterocyclic Spiro-fragment with a 3-7 member ring system, where the heterocyclic fragment includes 2 oxygen atom or sulfur, or one nitrogen atom and spirits may be unsubstituted or substituted by hydroxy, C1-C4the alkyl, benzyloxy; n=1-3; optical isomers, diastereomers or enantiomers or its pharmaceutically acceptable salt. Compound I inhibited metalloprotease, which allows their use in pharmaceutical compositions for treating or preventing diseases associated with increased activity of metalloprotease. 2 C. and 8 C.p. f-crystals, 5 PL. Description text in facsimile form (see graphic part).
Form>where AG represents unsubstituted or substituted phenyl, where the substituents are alkoxy, alkyl, alkoxyalkyl, phenoxy, halogen, pyridyloxy, alkoxyalkane, halogenfree; R1is hydrogen; R2represents hydrogen, C1-C4alkyl; W is zero or one or more1-C4alkyl fragments; Y is independently one or more members of the group consisting of hydrogen, SR3and alkoxy;
R3represents hydrogen, alkyl;
Z represents a carbocyclic or heterocyclic Spiro-fragment with a 3-7 member ring system, where the heterocyclic fragment includes 2 oxygen atom or sulfur, or one nitrogen atom and spirits may be unsubstituted or substituted by hydroxy, C1-C4the alkyl, benzyloxy;
n = 1-3;
optical isomers, diastereomers or enantiomers of the compounds of formula (I) or their pharmaceutically acceptable salts.
< / BR>and/or a stereoisomeric form of the compounds of formula (I), and/or physiologically acceptable salts of the compounds of formula (I), where1- phenyl, phenyl, one - or twofold substituted linear or branched (C1-C7)-alkyl, hydroxyl, group (C1-C6)-alkyl-C(O)-O-group (C1-C6)-alkyl-O-, halogen, CN-group, methylenecyclopropane; group R4- (R5)N-, R2, R4and R5are the same or different and mean a hydrogen atom, (C1-C6)-alkyl; R3and G are the same or different and mean: 1
< / BR>and/or their stereoisomeric forms and/or physiologically acceptable salts, where R1means phenyl, phenyl, one or twice substituted by a group WITH1-C6-alkyl-Oh, halogen, trifluoromethyl, a group WITH1-C6-alkyl-O-C(O)-, methylenedioxy-, R4-(R5)N-; triazole, thiophene, pyridine; R2means H, C1-C6alkyl; R4and R5are adnikowymi or different and denote H, C1-C6-alkyl; R3means H, C1-C10-alkyl, where alkyl unsubstituted and/or one hydrogen atom of the alkyl residue substituted by hydroxyl,2-C10alkenyl, R2-S(O)n-C1-C6-alkyl, where n means 0, 1, 2; R2-S(O)(=NH)-(C1-C6)-alkyl and the other, or R2and R3together form a cycle with a carboxyl group as a substituent cycle of partial formula II:
< / BR>where r is 0, 1, 2, 3 and/or one of the carbon atoms in the cycle replaced by-O-, and/or the carbon atom in the cycle part of the formula II substituted once by phenyl; a represents a covalent bond, -O-;
< / BR>where X is O or S; R6and R7independently from each other selected from the group including hydrogen, C1-C6alkyl, CF3WITH1-C6alkylthio,1-C6alkoxy, halogen, nitro, hydroxy, and-NR9R10where R9and R10independently of one another denote hydrogen or C1-C6alkyl; R1means hydrogen, C1-C6alkyl, C1-C6alkoxy, hydroxy2-C6alkyloxy, hydroxy, halogen, cyano, carboxy, co2SOP(CH3)2, -СОNR9R10, -ОСОNR9R10or ОSO2R11where R9and R10have the meanings indicated above, and R11means1-C6alkyl or CF3; R3means-SO2R12or-SO2NR13R14where R12means1-C6alkyl; R13means hydrogen or C1-C6alkyl, and R14means hydrogen, C1-C6alkyl, C3-C6cycloalkyl,2-C6alkenyl, hydroxy SS1-C6alkyl, benzyl, phenethyl, naphtalate, acyl, morpholino-C1-C6alkyl, pyrrolidino-C1-C6alkyl, pyridyl-C1-C6alkyl, furanyl-C1-C6alkyl, or R13and R14together with the nitrogen atom to which they are attached, optionally form heterocyclization selected from piperidino, morpholino, di-(C1-C6alkyl)morpholino, pyrrolidino, methylpiperazine, phenylpiperazine, forfilipino; and their pharmaceutically acceptable salts or their esters or carbamates, individual isomers and mixtures of isomers and method thereof