N-(mercaptoacyl) peptidyl derivatives as antidegenerative agents
AssigneeMerck & Co., Inc.
InventorsWilliam Hagmann, Ihor Kopka
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Abstract
Novel N-(mercaptoacyl)peptidyl compounds are useful as inhibitors of matrix metalloendoproteinases which degrade major components of articular cartilage and basement membranes causing degenerative diseases such as arthritis, periodontal disease, corneal ulceration, are described. For example, N-(2-thiomethyl-4-phenyl-butanoyl)-L-leucinamide was prepared and its inhibitory activity against stromelysin was tested in vitro.
Claims13
A compound of formula I ##STR8## wherein R.sub.1 is hydrogen, acetyl or benzoyl, R.sub.2 is hydrogen or methyl,
- R.sub.3 is 2-phenylethyl or 2-[4-(C.sub.1-3 alkyl)phenyl]ethyl, ##STR9## is an L-amino acid, ##STR10## is a residue of .beta.-alanine, L-alanine, glycine and aniline.
A compound of formula I ##STR11## or a pharmaceutically acceptable salt thereof wherein:
- R.sub.1 is H, C.sub.1-6 alkylmercapto, C.sub.2-6 alkanoyl, C.sub.7-11 aroyl:
- R.sub.2 is H, C.sub.1-6 alkyl, substituted C.sub.1-6 alkyl wherein the substituent is carboxyl, carboxamido, hydroxy, sulfonamide;
- R.sub.3 is C.sub.6-10 arylC.sub.2-3 alkyl or C.sub.6-10 aryl substituted C.sub.2-3 alkyl wherein the substituent is C.sub.1-3 alkyl or hydroxy, and wherein the aryl group is selected from the group consisting of:
- (1) phenyl,
- (2) naphthyl,
- (3) pyridyl,
- (4) pyrryl,
- (5) furyl,
- (6) thienyl,
- (7) isothiazolyl,
- (8) imidazolyl,
- (9) benzimidazolyl,
- (10) tetrazolyl,
- (11) pyrazinyl,
- (12) pyrimidyl,
- (13) quinolyl,
- (14) isoquinolyl,
- (15) benzofuryl,
- (16) isobenzofuryl,
- (17) benzothienyl,
- (18) pyrazolyl,
- (19) indolyl,
- (20) isoindolyl,
- (21) purinyl,
- (22) carbazolyl,
- (23) isoxazolyl,
- (24) thiazolyl,
- (25) oxazolyl
- (26) benzthiazolyl, and
- (27) benzoxazolyl,
- and mono and di-substituted C.sub.6-10 aryl as defined above in items (1) to (27) wherein the substituents are independently selected from C.sub.1-6 alkyl, C.sub.1-6 alkaloxy, halo, hydroxy, amino, C.sub.1-6 alkylamino, aminoC.sub.1-6 alkyl, carboxyl, C.sub.1-6 alkyl, and C.sub.1-6 alkylcarbonyl;
- R.sub.e and R.sub.f are individually selected from:
- (a) hydrogen
- (b) C.sub.1-6 alkyl,
- (c) mercapto C.sub.1-6 alkyl,
- (d) hydroxy C.sub.1-6 alkyl,
- (e) carboxy C.sub.1-6 alkyl,
- (f) amino substituted C.sub.2-6 alkyl,
- (g) aminocarbonyl C.sub.1-6 alkyl,
- (h) mono- or di-C.sub.1-6 alkylamino C.sub.2-6 alkyl,
- (i) guanidino C.sub.2-6 alkyl,
- (j) substituted phenylC.sub.1-6 alkyl, wherein the substituent is hydrogen, hydroxy, carboxy, C.sub.1-4 alkyl, or C.sub.1-4 alkyloxy,
- (k) substituted indolylC.sub.1-6 alkyl, wherein the substituent is hydrogen, hydroxy, carboxy, C.sub.1-4 alkyl, or C.sub.1-4 alkyloxy,
- (l) substituted imidazolylC.sub.2-6 alkyl wherein the substituent is hydrogen, hydroxy, carboxy, C.sub.1-4 alkyl, or C.sub.1-4 alkyloxy,
- (m) substituted pyridylC.sub.1-6 alkyl wherein the substituent is hydrogen, hydroxy, carboxy, C.sub.1-4 alkyl, or C.sub.1-4 alkyloxy,
- (n) substituted pyridylaminoC.sub.1-6 alkyl wherein the substituent is hydrogen, hydroxy, carboxy, C.sub.1-4 alkyl, or C.sub.1-4 alkyloxy;
- R.sub.5 is selected from the group consisting of:
- (a) H,
- (b) C.sub.1-10 alkyl,
- R.sub.6 is selected from the group consisting of:
- (a) carboxy C.sub.1-2 alkyl, and
- (b) C.sub.6-10 aryl wherein the aryl group is selected from the group consisting of:
- (1) phenyl,
- (2) naphthyl,
- (3) pyridyl,
- (4) pyrryl,
- (5) furyl,
- (6) thienyl,
- (7) isothiazolyl,
- (8) imidazolyl,
- (9) benzimidazolyl,
- (10) tetrazolyl,
- (11) pyrazinyl,
- (12) pyrimidyl,
- (13) quinolyl,
- (14) isoquinolyl,
- (15) benzofuryl,
- (16) isobenzofuryl,
- (17) benzothienyl,
- (18) pyrazolyl,
- (19) indolyl,
- (20) isoindolyl,
- (21) purinyl,
- (22) carbazolyl,
- (23) isoxazolyl,
- (24) benzthiazolyl,
- (25) benzoxazolyl,
- (26) thiazolyl, and
- (27) oxazolyl.
A compound which is N-(2-thiomethyl-4-phenylbutanoyl)-(L)-leucine, N-benzylamide, or a pharmaceutical acceptable salt thereof.
Dependencies are inferred from the claim text.