Patent TW-399042-B (TW)
Title: C-terminal ketone inhibitors of matrix metalloproteinases and TNF<alpha> secretion
Inventor: DAVIDSEN STEVEN K
IPC: C07D207/323
Filed: 1998-01-05
Granted: 2000-07-21
Abstract: A compound of formula (I) or pharmaceutically acceptable salt, ester or prodrug thereof wherein W is NHOH or -OH: R<1> and R<4> are independently selected at each occurrence from hydrogen or alkyl of one to four carbon atoms; V is O or NOR1; R2 is selected from the group consisting of (a) hydrogen, (b) hydroxy, (c) alkoxy of one to six carbon atoms, (d) alkyl of one to six carbon atoms, (e) alkyl of one to six carbon atoms substituted with (1) halogen, (2) hydroxy, (3) alkoxy of one to six carbon atoms, (4)cycloalkyl of three to eight carbon atoms, (5) alkanoyloxy wherein the alkyl portion is of one to four carbon atoms, (6) pyridyl, (7) pyridyl substituted with alkyl of one to four carbon atoms, (8) phenoxy wherein the phenyl ring is unsubstituted or substitued with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R7 wherein R7 is hydrogen or alkyl of one to four carbon atoms, -CONR7R8 wherein R7 is defined above and R8 is selected from hydrogen, alkanoyl of one to four carbon atoms, alkyl of one to four carbon atoms, phenyl, and phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CONR9R10 wherein R9 and R10 are independently selected from hydrogen and alkyl of one to four carbon atoms, and -CO2R9, and (9) (I) (10) -S(O)nR11 wherein n is 0.1 or 2 and R11 is selected from (a) alkyl of one to six carbon atoms, (b) phenyl, (c) phenyl substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R7, -CONR7R8, (d) thienyl, (e) thienyl substituted with alkyl of one to four carbon atoms, (f) phenylalkyl wherein the alkyl portion is of one to four carbon atoms, (g) phenylalkyl wherein the alkyl portion is of one to four carbon atoms, and the phenyl ring is substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R7, and -CONR7R8, (h) thienylalkyl wherein the alkyl portion is of one to four carbon atoms, and (I) thienylalkyl wherein the alkyl portion is of one to four carbon atoms and the thienyl ring is substituted with alkyl of one to four carbon atoms, and R5 is selected from the group consisting of (a) alkyl of one to six carbon atoms, (b) alkyl of one to six carbon atoms substituted with cycloalkyl of three to eight carbon atoms, hydroxy, alkoxy, -SR7, -NR7R8, -CO2R7, -CONR7R8, guanidyl, phenyl, phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, nitro, cyano, cyanoalkyl, carboxyalkyloxy, -S(O)nR16 wherein n is 0.1 or 2 and R16 is alkyl of one to four carbon atoms, -SO2NH2, -CO2R7, and -CONR7R8, and phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms, naphthyl, naphthyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, indolyl, indolyl substituted with alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, -SO2R13, -SO2NH2, -CO2R7 and -CONR7R8, pyridyl, pyridyl substituted with alkyl of one to four carbon atoms, pyrazolyl, pyrazol substituted with alkyl of one to four carbon atoms, 5-oxadiazolyl, imidazolyl, and imidazolyl substituted with alkyl of one to four carbon atoms, (c) phenyl and (d) phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms; R6 is selected from the group consisting of (a) alkyl of one to six carbon atoms, (b) alkyl of one to six carbon atoms substituted with hydroxy, alkoxy, halogen, and -CO2R17 wherein R17 is selected from hydrogen, alkyl of one to four carbon atoms and alkenyl of two to four carbon atoms, (c) phenyl, (d) phenyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, hydroxy, hydroxyalkyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, cyano, -NR7R8, -SO2NR7R8, -SO2R16, -CH2NR18R19, wherein R18 and R19, are independently selected at each occurrence from hydrogen and alkyl of one to four carbon atoms, or R18 and R19 together with the N atom to which they are attached define a a 5-or 6-membered heterocyclic ring selected from (1) morpholinyl, (2) thiomorpholinyl, (3) thiompholinyl sulfone, (4) pyrrolidinyl, (5) piperazinyl, (6) 3-ketopiperazinyl and (7) piperidinyl, -CONR7R8, -CO2R7, and phenyl, wherein the phenyl ring may be substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms, (e) 1, 2-benaodioxole, (f) indolyl, (g) indolyl substituted with alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, -SO2NR7R8, -CO2R7, and phenyl, wherein the phenyl ring may be substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, and alkoxy of one to four carbon atoms, (h) pyrrolyl, (I) pyrrolyl substituted with alkyl of one to four carbon atom (j) imidazolyl, (k) imidazolyl substituted with alkyl of one to four carbon atoms, (l) benzimidazolyl, (m) benzimidazolyl substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, halogen and haloalkyl of one to four carbon atoms, provided that in (f)-(m) above, when the heterocycle is attached  at a carbon atom, the N atom may bear a substituent selected from the group consisting of alkyl of one to six carbon atoms -CONR7R8, -SO2NR7R8 and -SO2R14, (n) pyridyl, (o) pyridyl substituted with alkyl of one to four carbon atoms, (p) thienyl, (q) thienyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (r) thiazolyl, (s) thiazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (t) oxazolyl, (u) oxazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (v)furyl, (w) furyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (x) benzofuryl, (y) benzofuryl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms, (z) benzothiazolyl, and (aa) benzothiazolyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms.