Patent DE-19921680-A1 (DE)
Title: New sulfonylamino- or carbonylamino-phosphinic or phosphonic acids, used as matrix metalloproteinase inhibitors for treating, e.g. degenerative joint diseases
Inventor: SCHUDOK MANFRED
IPC: C07F9/38
Filed: 1999-05-12
Abstract: (Hetero)aralkyl sulfonylamino or (carbonylamino) alkanephosphinic or -phosphonic acid derivatives (I) are new.  Phosphinic or phosphonic acid derivatives of formula (I) and their stereoisomers and salts are new: R1  = phenyl or Het (both optionally substituted (os) by 1 or 2 Q); or OT;  Het  = pyrrole, pyrazole, imidazole, triazole, thiophene, thiazole, oxazole, isoxazole, pyridine, pyrimidine, indole, benzothiophene, benzimidazole, benzoxazole or benzothiazole;  Q  = T, 3-6C cycloalkyl, OH, TCOO TO-(1-4C alkylene)-O-, halo, CF3, CN, NO2, COOH, COOT, OCH2O, CONR4R5 or NR4R5;  T  = 1-6C alkyl;  R2, R4, R5  = H, T, -T-COOH, Ph-(CH2)n- (os in the ring by 1 or 2 of Q or 2-4C alkanoylamino) or picolyl;  or NR4R5  = 4-7 membered ring, optionally having one C replaced by O, S or NH or having two adjacent C as part of a benzo residue;  n  = 0-2;  R, R3  = H, 1-10C alkyl (os by one OH), 2-10C alkenyl, R2O-T-, R2S(O)n-T-, R2S(O)(=NH)-T-, heterocyclylthioalkyl of formula (a), Ph(CH2)m (os by one OH in (CH2)m and os in the ring by 1 or 2 of Q, -O(CH2)mPh' and -CO(CH2)mPh'), Het(CH2)m (os by one OH in (CH2)m and os in the ring by 1 or 2 of Q, CHO, -SO2Ph' and -O(CH2)mPh), -(CH2)mP(O)(OH)-(1-3C) alkyl, aminoacid residue, R6CO-T-, -(CH2)pNR9R10, OH, =O or T;  or C(R)(R3)  = NH or NR2;  t  = 1-4;  or R2 + R3  = (CH2)p (in which one C is optionally replaced by O, S or N(R11)), where the obtained ring is os by one or more of T, Ph, (CH2)mPh or OH;  W  = N, O or S;  m  = 0-6;  Ph'  = phenyl (os by 1 or 2 Q);  R6  = H, T, 3-6C cycloalkyl, Ph', Het (os by 1 or 2 of Q and carboxy-(1-4C) alkyl), OH, OR2, NR4R5, Het-(CH2)m-NH- (os in the ring by 1 or 2 Q), NHNR4R5 or NHCHR3COOH;  p  = 1-4;  R9, R10  = H, (CH2)qPh', CORx, COORx, CONCH(NH2)Rx, CONR7R8, SO2Rx, C(=NR'7)NHR'x, -SO2(CH2)qPh' or heterocyclyl of formula (b);  q  = 0-3;  Rx  = T, 2-6C alkenyl, (CH2)qPh' or (CH2)qHet (os in the ring by 1 or 2 Q);  R7  = H or T; R8  = H, T, (CH2)qPh' or (CH2)qHet (os in the ring by 1 or 2 Q);  or NR7R8  = 4-7 membered ring, optionally having one C replaced by O, S or NH;  R'7, R'x  = as R7, Rx; or -COT, NO2 or -SO2(CH2)qPh';  or NR9R10  = succinimido, maleimido, 2-oxo-pyrrolidino, pyrrol-1-yl or imidazol-1-yl (all os by one R7); phthalimido or 2-oxoindolino (both os by one Q); indol-1-yl; benzimidazol-1-yl; 3,5-dioxo-1,2-di-(R7)-1,2,4-triazolidin-4-yl; 2,5-dioxo-3,4,4-tri-(R7)-imidazolidin-1-yl; 2,6-dioxo-3-(R7)-1,2,3,6-tetrahydropyrimidin-1-yl; pyrrolidino, piperidino, perhydroazepino or perhydroazocino; or a group of formula (c);  r  = 1 or 2;  R11  = H, T, Ph', CH2Ph' or R2N-C(=NH)- (sic);  U = SO2 or CO;  Y1, Y2  = H, OH, 1-4C alkyl, Ph, CH2Ph, 1-4C alkoxy, OPh or or OCH2Ph;  A  = direct bond, O, CH=CH or CC;  B'  = (CH2)m, O(CH2)s or CH=CH;  s  = 1-5;  X  = O, S or CH=CH. Independent claims are included for the following:  (1) intermediates of formula (VI) (including stereoisomers and salts), and (2) the preparation of (I): L  = H, T, Ph or benzyl (os).