Patent EA-002810-B1 (EA)
Title: Sulfamide-metalloprotease inhibitors
Inventor: BROCA CHRIS ALLEN
IPC: C07D295/22
Filed: 1998-01-14
Abstract: 1. A compound of the formula (I):   wherein: R<1> and R<2> are independently selected from hydrogen, C1-C6alkyl, C1-C6alkenyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclo, heteroalkyl, or -C1-C6alkylene-(CO)-X where X is disubstituted amino, hydroxy, or arylC1-C6alkyloxy, or R<1> and R<2> together with the carbon atom to which they are attached form a C1-C8carbocycle or a heterocycle; R<3> is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, aryl, arylC1-C6alkyl, heteroarylC1-C6alkyl, heterocycloC1-C6alkyl, heteroalkyl, (diphenylmethyl)C1-C6alkyl, or -(C1-C6alkylene)-C(O)-X where X is C1-C6alkyl; or R<3> together with either R<1> or R<2> and the atoms to which they are attached forms a heterocycloamino group; R<10> is -N-R<11>OR<12> wherein: R<11> and R<12> are independently selected from hydrogen, C1-C6alkyl, or arylC1-C6alkyl; R<20> and R<21> are independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, arylC1-C6alkyl, heteroarylC1-C6alkyl, or R<20> and R<21> together with the nitrogen atom to which they are attached form a heterocycloamino group or an optionally substituted tetrahydropyridine or hexahydroazepine ring; or either of R<20> or R<21> together with R<3> forms an C1-C6alkylene group; and their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers, provided that R<20> and R<21> together with the nitrogen atom to which they are attached do not form a morpholino ring either: (i) when R<1> and R<3> are hydrogen and R<2> is arylC1-C6alkyl; or (ii) when R<1> and R<3> together with the atoms to which they are attached form a tetrahydroisoquinoline ring and R<2> is hydrogen; wherein "aryl" relates to monovalent or bicyclic aromatic hydrocarbon radical with 6-10 ring atoms and are optionally independently substituted with one or more substituents, selected from the group C1-C6alkyl, haloC1-C6alkyl, halogen, nitro, cyano, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, optionally substituted phenyl, heteroaryl; OR (wherein R is hydrogen, C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkylC1-C6alkyl, optionally substituted phenyl, heteroaryl, optionally substituted phenylC1-C6alkyl or heteroarylC1-C6alkyl), -NRR' (wherein R and R' are independently hydrogen, C1-C6alkyl, C2-C6alkenyl, haloC1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, optionally substituted phenyl, optionally substituted phenylC1-C6alkyl, optionally substituted phenylC2-C6alkenyl, heteroaryl or heteroarylC1-C6alkyl) and -S(O)nR (wherein n is integer from 0 to 2 and R is hydrogen (with proviso, that n is 0), C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, optimally substituted phenyl, heteroaryl, optimally substituted phenylC1-C6alkyl or heteroarylC1-C6alkyl); and "heteroaryl" is monovalent monocyclic or bicyclic aromatic radical comprising 5-10 atoms in the ring, from which one, two or three atoms are heteroatoms, selected from N, O or S, and the rest of the atoms in the ring are carbon atoms, heteroaryl ring is optionally substituted independently from one another with one or more substituents, preferably with one or two substituents, which are selected from the group, comprising C1-C6alkyl, haloC1-C6alkyl, halo, nitro, cyano, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, -OR (wherein R is hydrogen, C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, optionally substituted phenyl or optionally substituted phenylC1-C6alkyl), -NRR' (wherein R and R' independently of each other are hydrogen, C1-C6alkyl, C2-C6alkenyl, haloC1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, optionally substituted phenyl, optionally substituted phenylC1-C6alkyl or optionally substituted phenylC2-C6alkenyl), -S(O)nR (wherein n is integer from 0 to 2, R is hydrogen (with proviso, that n is 0), C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, optionally substituted phenyl or optionally substituted phenylC1-C6alkyl), -NRC(O)R' (wherein R is hydrogen or C1-C6alkyl, R' is hydrogen, C1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, haloC1-C6alkyl, optionally substituted phenyl, optionally substituted phenylC1-C6alkyl or optionally substituted phenylC2-C6alkenyl) or amino-protected group and "heterocyclo" is saturated cyclic radical, which comprises in the ring 3 to 8 atoms, one or two of which atoms are heteroatoms, which are selected from N, O or S(O)n (wherein n is integer from 0 to 2), and the rest of atoms in the ring are atom C, at that one or two C can optionally be replaced with carbonyl group and heterocyclic ring can be optionally independently substituted with one, two or three substituents selected from the group, comprising C1-C6alkyl, C3-C6cycloalkyl, C1-C6cycloalkylC1-C6alkyl, -S(O)nR, wherein n is integer from 0 to 2, and R is hydrogen (with proviso, that n is 0), C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, amino, monosubstituted amino, disubstituted amino, aryl, heteroaryl, aryl C1-C6alkyl or heteroarylC1-C6alkyl or protecting aminogroup; and "monosubstituted amino" is radical -NHR, wherein R is aryl or protective aminogroup; and "disubstituted amino" is radical -NRR', wherein R and R' independently are C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl or protective aminogroup; and "acyl" is -C(O)R, wherein R is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, heteroaryl or heterocyclo; and "heteroalkyl" is C1-C6alkyl, C3-C6cycloalkyl or C3-C6cycloalkylC1-C6alkyl, groups, having a substituent, which is selected from the group, comprising -NR<a>R<b>, -OR<c> or -S(O)nR<d>, wherein n is integer from 0 to 2, R<a> is hydrogen, C1-C6alkyl, C3-C6cycloalkyl or C3-C6cycloalkylC1-C6alkyl, R<b> is hydrogen, C1-C6alkyl or -COOR (wherein R is hydrogen, C1-C6alkyl, arylC1-C6alkyl or heteroarylC1-C6alkyl), -CONRiR" (wherein Ri and R" are C1-C6alkyl), R<c >is hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, aryl or aryl C1-C6alkyl, acyl, R<d> is hydrogen (with proviso, n is 0), C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, aryl, arylC1-C6alkyl or heteroaryl; and "heterocycloamino" is saturated monovalent cyclic group, comprising in the ring from 4 to 8 atoms, and at least one of which is atom N, and one or two atoms optionally are additional heteroatoms, which are selected from the group, comprising N, O or S(O)n (wherein n is integer from 0 to 2), the rest of the atoms in the ring are carbon atoms, at that one or two carbon atoms are optionally replaced with carbonyl group and heterocycloamine ring can be fused with C3-C6cycloalkyl, aryl or heteroaryl ring and optionally can have one or more, preferably one or two substituents, which are selected from the group, comprising C1-C6alkyl, haloC1-C6alkyl, heteroalkyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, diphenylmethyl, (diphenylmethyl)C1-C6alkyl, halo, acyl, amino, monosubstituted amino, disubstituted amino, acylamino, -OR (wherein R is hydrogen, C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, acyl, aryl, heteroaryl, arylC1-C6alkyl or heteroarylC1-C6alkyl), -S(O)nR [wherein n is integer from 0 to 2, and R is hydrogen (with proviso, that n is 0), C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, amino, monosubstituted amino, disubstituted amino, aryl, heterocyclo, heteroaryl, arylC1-C6alkyl or heteroarylC1-C6alkyl], -P(O)(NR<b>R<c>)2 (wherein R<b> and R<c> independently from one another are selected from C1-C6alkyl or arylC1-C6alkyl), -COOH, -(C1-C6alkylen)COOH, -(C2-C6alkenylene)COON, -COOR<a>, -(C1-C6alkylene)COOR<a>, -(C2-C6alkenylene)COOR<a> (wherein R<a> is C1-C6alkyl, heteroalkyl, arylC1-C6alkyl or heteroarylC1-C6alkyl), -CONR'R", -(C1-C6alkylene) CONR'R" (wherein R' and R" independently from one another are selected from the group, comprising hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, aryl, arylC1-C6alkyl, heteroaryl or heteroarylC1-C6alkyl), -COCH(R')NH2, wherein R' is a side chain natural or non-natural alfa amino acid, wherein each functional group can be protected, or amino-protective group; and "optionally substituted phenyl" is phenyl ring, which optionally has one or more substituents, selected from the group, comprising C1-C6alkyl, haloC1-C6alkyl, halogen; and "optionally substituted tetrahydropyridine or hexahydroazepine ring" is tetrahydropyridine or hexahydroazepine ring, optionally substituted with one or two substituents, which are selected from the group, comprising C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, aryl, heteroaryl. 2. The compound of Claim 1, wherein R<10> is -NHOH. 3. The compound of Claim 1 or 2, wherein R<20> and R<21> together with nitrogen atom, to which they are attached, form heterocycloamino group. 4. The compound of any of Claims 1-3, wherein heterocycloamino group, formed by R<20> and R<21> together with nitrogen atom, to which they are attached, is a) substituted piperidino ring, wherein substituent is selected from the group, comprising aryl, heteroaryl, acyl, -CONR'R", (wherein R' and R" independently from one another are selected from the group, comprising hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl), -OR [wherein R is aryl or heteroaryl] or -S(O)nR [wherein n is integer from 0 to 2, and R is aryl or heteroaryl], or b) substituted piperazino ring, wherein substituent selected from the group, comprising aryl, heteroaryl, -SO2aryl or -CONR'R" (wherein R' and R" independently from one another are selected from the group, comprising hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkyl, aryl; arylC1-C6alkyl, heteroaryl and heteroarylC1-C6alkyl).