Patent HU-9902707-A2 (HU)
Title: Inhibitors of interleukin-1beta converting enzyme
Inventor: BATCHELOR MARK J
IPC: A61K38/08
Filed: 1996-12-20
Abstract: Amine derivatives of formula (~a), (I) and (II) are new: X1 = CH; g = 0 or 1; J = H, OH or F; provided that when one J = OH the other is H; m = 0-2; T = OH, COCO2H, COOH or a bio-isosteric replacement for COOH; R1 = a group of formula (w), in which any ring may be optionally C-substituted by Q1, N-substituted by R5 or substituted by O,OH,COOH or halo, and any saturated ring may be unsaturated at 1 or 2 bonds; ring A = benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimidino, imidazolo, cyclopentyl or cyclohexyl; R3 = CN, CH=CHR9, CH=NOR9, (CH2)1-3T1R9, CJ2R9, COR13 or COCONR5R10; R4 = H, Ar1, R9, T1R9 or (CH2)1- 3T1R9; T1 = CH=CH, O, S, SO, NR10, NR10CO, CO, OCO, COO, CONR10, OCONR10, NR10COO, NR10COONR10, SO2NR10, NR10SO2 or NR10SO2NR10; R5 = H, Ar1, COAr1, SO2Ar1, CONH2, SO2NH2, R9, COR9, COOR9, SO2R9, CONR10Ar1, SO2Ar1R10, CONR9R10 or SO2NR9R10; R6 = H, AR1, R9, (CH2)1-3 T1R9 or an ~a-amino acid residue; R9 = 1-6C alkyl optionally substituted by OH, F or O and optionally substituted by 1 or 2 Ar1; R10 = H or 1-6C alkyl; R13 = Ar2, R4 or NR5OH; Ar1 = 6, 10, 12 or 14C mono, bi or tri cyclic aryl, 3-15C optionally benzo fused mono-, bi- or tri-cycloalkyl or 3-15C mono-, bi- or tri-cyclic heterocyclyl containing one or more O, S, N, SO, SO2 or NH, optionally containing one or more double bonds and comprising one or more aromatic rings, all optionally substituted by NH2, CO2H, Cl, F, Br, I, NO2, CN, O, OH, 1-3C perfluoroalkyl, OCH2O or Q1; Ar2 = a group of formula (hh), (ii), (jj) or (kk) all optionally substituted by Q1 and/or Q2; Q1 = Ar1, OAr1, R9, T1R9 or (CH2)1-3T1R9; Q2 = OH, NH2, COOH, Cl, Br, I, NO2, CN, CF3, or OCH2O; provided that when Ar1 is substituted with a Q1 group which comprises Ar1 the additional Ar1 are not substituted by Q1; X = N or CH; X2 = O, CH2, NH, S, SO or SO2; Y = O, S or NH; provided that when g = 0, J= H, m =1, T =CO2H, X2 = O, R5 =benzyloxycarbonyl, and ring A = benzo then R3 cannot be COR13 when R13 = CH2OAr1 and Ar1 = 1-phenyl-3-trifluoromethylpyrazol-5-yl optionally ring substituted by Cl, or when R13 = CH2OCOAr1 and Ar1 = 2,6-dichlorophenyl; R1a = a group of formula (e10) - (e12), (w2), (y1), (y2) or (z): R2 = a group of formula (a) or (b): m1 = 1 or 2; R51 = COR101, COOR91, CONR101R101, SO2R91, COCH2OR91, COCOR101, R91, H or COCOOR101; X5 = CH or N; Y2 = H2 or O; X7 = NR8 or O; R6 = H or Me; R8 = COR101, COOR91, CONHR101, SO2R91, SO2NHR101, COCH2OR101, COCOR101, COCH2NR101R101, COCH2COOR91, COCH2COR91, H or COCOOR101; R91 = H or optionally unsaturated 1-6C alkyl optionally substituted by Ar3; R101 = H, Ar3, 3-6C cycloalkyl or optionally unsaturated 1-6C alkyl optionally substituted by Ar3; R13 = H, Ar3 or 1-6C alkyl optionally substituted by Ar3, CONH2, OR5, OH, OR91 or COOH; or in (II) R13 is optionally NHOH (sic); R5a = R91, COR91 or CONHR91; or R51+R51 = 4-8 membered carbocyclyl or heterocyclyl containing O, S or NH; R21 = H or 1-6C alkyl; Ar3, Ar4 = 6, 10, 12 or 14C mono-, bi- or tri-cyclic aryl, 3-15C optionally benzo-fused mono-, bi- or tri- cycloalkyl or 3-15C mono, bi or tri cyclic heterocyclyl containing one or more O, S, N, SO, SO2 or NH, optionally containing one or more double bonds and comprising one or more aromatic rings, all optionally substituted by Q11; Q11 = NH2, CO2H, Cl, F, Br, I, NO2, CN, O, OH, 1-3C perfluoroalkyl, R51, OR51, NHR51, OR91, NHR91 COR101 or OCH2O; provided that when Ar3 is substituted with a Q11 group which comprises Ar3 the additional Ar3 are not substituted by Q11; R31 = CN, CHO, COCH2T1R11, COCH2F, C=NOR91 or COAr21; T1 = O, S, SO or SO2; R11 = Ar4, (CH2)1-3Ar4, H or COAr4; Ar21 = A group of formula (hh') or (ii') both optionally substituted by Q11 or phenyl optionally substituted by Q11; Y' = O or S; provided that in (II) when R1a = (e10) then X5 = N. Also claimed are (i) a further 13 new classes of compound, 2 analogous to (I) e.g. in which R1a = a group (w2) and R5 is broader; and 11 analogous to (II) e.g. R1a = a group (e10) and X5 = CH; and (ii) a process for preparing a N-acylamino