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US 5,514,716 AGranted
Hydroxamic acid and carboxylic acid derivatives, process for their preparation and use thereof
AssigneeSterling Winthrop Inc.
InventorsMadhusudhan R. Gowravaram, Jeffrey Johnson, Ewell R. Cook, Robert C. Wahl, Alan M. Mathiowetz, Bruce E. Tomczuk, Ashis K. Saha
Life of this patent
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Abstract
This disclosure relates to a novel class of hydroxamic and carboxylic acid based matrix metalloproteinase inhibitor derivatives. The disclosure further relates to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in the treatment of matrix metalloproteinase induced diseases.
Claims15
A compound having matrix metalloproteinase inhibitory activity, wherein the compound has the formula:
- ##STR4## wherein A is A.sup.1 --A.sup.2 --A.sup.3
- A.sup.1 is C.sub.1-10 alkyl, C.sub.2-10 alkene, or C.sub.2-10 alkyne having C.sub.1-5 in the backbone;
- A.sup.2 is X--Y--Z;
- wherein
- X is a chemical bond, or --NH--;
- Y is --CO--, --CH.sub.2 -- or --CH(CH.sub.3);
- Z is --O--, --NH--, or a chemical bond;
- A.sup.3 is
- hydrogen,
- C.sub.1-6 alkyl,
- substituted C.sub.1-6 alkyl,
- phenyl,
- substituted phenyl,
- phenyl C.sub.1-6 alkyl, or
- substituted phenyl C.sub.1-6 alkyl;
- wherein the substitution is C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or halo;
- with the proviso that
- (a) at least one of X, Y and Z must contain a heteroatom;
- (b) when Y is --CH.sub.2 -- or --CH(CH.sub.3)--, then only one of X and Z can be a heteroatom;
- and
- (c) when A.sup.1 is alkyl, X is a chemical bond, Y is CHR.sup.9 and Z is --O-- or --S--, then A.sup.3 cannot be H or C.sub.1-6 alkyl;
- R.sup.1 is
- HN(OH)CO--
- HCON(OH)--,
- CH.sub.3 CON(OH)--,
- HO.sub.2 C--, or
- phosphinate;
- R.sup.2 is
- OR.sup.6 or NR.sup.10 R.sup.6
- wherein
- R.sup.6 is
- hydrogen,
- phenyl, or
- (CH.sub.2).sub.n R.sup.7,
- wherein
- R.sup.7 is
- hydrogen,
- phenyl,
- substituted phenyl,
- hydroxy,
- C.sub.1-6 alkoxy,
- C.sub.2-7 acyloxy,
- C.sub.1-6 alkylthio,
- phenylthio,
- sulfoxide of a thio,
- sulfone of a thio,
- carboxyl,
- (C.sub.1-6 alkyl) carbonyl,
- (C.sub.1-6 alkoxy) carbonyl,
- (C.sub.1-6 alkyl)aminocarbonyl,
- phenylaminocarbonyl,
- amino,
- substituted acyclic amino,
- N-oxide of an amine, or
- C.sub.2-7 acylamino, and
- n is 1 to 6;
- or
- R.sup.3 is a characterizing group of an alpha amino acid
- C.sub.1-6 alkyl,
- C.sub.3-10 cycloalkyl,
- phenyl methylene,
- substituted phenyl methylene,
- C.sub.3-10 cycloalkyl methylene
- phenyl,
- substituted phenyl,
- fused bicycloaryl methylene,
- fused substituted bicycloaryl methylene,
- conjugated bicycloaryl methylene, or
- conjugated substituted bicycloaryl methylene;
- R.sup.4 is hydrogen or C.sub.1-4 alkyl;
- R.sup.5 is
- hydrogen,
- phenyl,
- substituted phenyl,
- amino,
- hydroxy,
- mercapto,
- C.sub.1-4 alkoxy,
- C.sub.1-6 alkylamino,
- C.sub.1-6 alkylthio,
- C.sub.1-6 alkyl or C.sub.2-6 alkenyl,
- optionally substituted by
- alkyl,
- phenyl,
- substituted phenyl,
- heterocylic,
- substituted heterocyclic,
- amino,
- acylated amino,
- protected amino,
- hydroxy,
- protected hydroxy,
- mercapto,
- protected mercapto,
- carboxy,
- protected carboxy, or
- amidated carboxy;
- wherein the heterocyclic is furan, pyrrole, thiophen,
- morpholine, pyridine, dioxane, imidazoline,
- pyrimidine, or pyridazine;
- R.sup.9 is hydrogen or C.sub.1-4 alkyl;
- R.sup.10 is hydrogen or C.sub.1-4 alkyl;
- and the salts, solvates and hydrates thereof.
100 more elements
A compound of the structure:
- ##STR5## wherein A is A.sup.1 --A.sup.2 --A.sup.3
- wherein
- A.sup.1 is (CH.sub.2).sub.n, and n is 3-5,
- A.sup.2 is X--Y--Z,
- wherein,
- X is a chemical bond or --NH--;
- Y is --CO--, --CH.sub.2 --, or --CH(CH.sub.3)--,
- Z is --O--, --NH--, or a chemical bond;
- and
- A.sup.3 is
- hydrogen, methyl, ethyl, propyl, butyl, pentyl, phenyl,
- methylphenyl, chlorophenyl, methoxyphenyl,
- phenylmethylene, methoxyphenylmethylene,
- methylphenylmethylene, or phenylethylene,
- with the proviso that
- (a) at least one of X, Y and Z must contain a heteroatom;
- (b) when Y is --CH.sub.2 -- or --CH(CH.sub.3)--, then only one of X and Z can be a heteroatom;
- and
- (c) when A.sup.1 is alkyl, X is a chemical bond, Y is CHR.sup.9 and Z is --O--, then A.sup.3 cannot be H or C.sub.1-6 alkyl;
- R.sup.1 is
- HN(OH)CO--, or HO.sub.2 C--,
- R.sup.3 is
- tertiary butyl,
- phenylmethylene,
- cyclohexyl methylene, or
- 3.
23 more elements
Dependencies are inferred from the claim text.