| PATENT ASSIGNEE'S COUNTRY | USA |
| UPDATE | 05.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 02.05.00 |
| PATENT TITLE |
Lactam metalloprotease inhibitors |
| PATENT ABSTRACT | The present application describes novel lactams and derivatives thereof of formula I: ##STR1## or pharmaceutically acceptable salt forms thereof, wherein rings ring B is a 4-8 membered cyclic amide containing from 0-3 additional heteroatoms selected from N, O, and S, which are useful as metalloprotease inhibitors |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 02.10.98 |
| PATENT REFERENCES CITED | This data is not available for free |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed as new and desired to be secured by Letter Patent of United States is: 1. A compound of formula I: ##STR168## or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein; A is selected from COR.sup.5, --CO.sub.2 H, CH.sub.2 CO.sub.2 H, --CO.sub.2 R.sup.6, --CONHOH, --CONHOR.sup.5, --CONHOR.sup.6, --NHR.sup.a, --N(OH)COR.sup.5, --SH, --CH.sub.2 SH, --SO.sub.2 NHR.sup.a, SN.sub.2 H.sub.2 R.sup.a, PO(OH).sub.2, and PO(OH)NHR.sup.a ; ring B is a 4-8 membered cyclic amide containing 0-1 additional carbonyl groups and 0-1 double bonds; R.sup.1 is U--X--Y--Z--U.sup.a --X.sup.a --Y.sup.a --Z.sup.a ; U is absent or is selected from: O, NR.sup.a, C(O), C(O)O, OC(O), C(O)NR.sup.a, NR.sup.a C(O), OC(O)O, OC(O)NR.sup.a, NR.sup.a C(O)O, NR.sup.a C(O)NR.sup.a, S(O).sub.p, S(O).sub.p NR.sup.a, NR.sup.a S(O).sub.p, and NR.sup.a SO.sub.2 NR.sup.a ; X is absent or selected from C.sub.1-10 alkylene, C.sub.2-10 alkenylene, and C.sub.2-10 alkynylene; Y is absent or selected from O, NR.sup.a, S(O).sub.p, and C(O); Z is absent or selected from a C.sub.3-13 carbocyclic group substituted with 0-5 R.sup.b and a 5-6 membered heterocyclic group containing 1 heteroatom from the group consisting of N, O, and S and substituted with 0-5 R.sup.b ; U.sup.a is absent or is selected from: O, NR.sup.a, C(O), C(O)O, OC(O), C(O)NR.sup.a, NR.sup.a C(O), OC(O)O, OC(O)NR.sup.a, NR.sup.a C(O)O, NR.sup.a C(O)NR.sup.a, S(O).sub.p, S(O).sub.p NR.sup.a, NR.sup.a S(O).sub.p, and NR.sup.a SO.sub.2 NR.sup.a ; X.sup.a is absent or selected from C.sub.1-10 alkylene, C.sub.2-10 alkenylene, C.sub.2-10 alkynylene; Y.sup.a is absent or selected from O, NR.sup.a, S(O).sub.p, and C(O); Z.sup.a is quinolinyl substituted with 0-5 R.sup.c ; R.sup.2 is selected from H, Q', C.sub.1-10 alkylene-Q', C.sub.2-10 alkenylene-Q', C.sub.2-10 alkynylene-Q', (CRR').sub.r' O(CRR').sub.r --Q', (CRR').sub.r' NR.sup.a (CRR').sub.r' --Q', (CRR').sub.r' NR.sup.a C(O)(CRR').sub.r --Q', (CRR').sub.r' C(O)NR.sup.a (CRR').sub.r --Q', (CRR').sub.r' C(O)(CRR').sub.r --Q', (CRR').sub.r' C(O)O(CRR').sub.r --Q', (CRR').sub.r' S(O).sub.p (CRR').sub.r --Q', (CRR').sub.r'SO.sub.2 NR.sup.a (CRR').sub.r --Q', (CRR').sub.r' NR.sup.a C(O)NR.sup.a (CRR').sub.r --Q', (CRR').sub.r' OC(O)NR.sup.a (CRR').sub.r --Q', and (CRR').sub.r' NR.sup.a C(O)O(CRR').sub.r --Q'; R, at each occurrence, is independently selected from H, CH.sub.3, CH.sub.2 CH.sub.3, CH.dbd.CH.sub.2, CH.dbd.CHCH.sub.3, and CH.sub.2 CH.dbd.CH.sub.2 ; R', at each occurrence, is independently selected from H, CH.sub.3, CH.sub.2 CH.sub.3, and CH(CH.sub.3).sub.2 ; alternatively, R.sup.1 and R.sup.2 combine to form a C.sub.3-13 carbocyclic group substituted with R.sup.1' and 0-3 R.sup.b or a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S and substituted with R.sup.1' and 0-3 R.sup.b ; Q' is selected from H, a C.sub.3-13 carbocyclic group substituted with 0-5 R.sup.b and a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S and substituted with 0-5 R.sup.b ; R.sup.1' is U.sup.a --X.sup.a --Y.sup.a --Z.sup.a ; R.sup.3 is selected from H, Q, C.sub.1-10 alkylene-Q, C.sub.2-10 alkenylene-Q, C.sub.2-10 alkynylene-Q, (CRR').sub.r' (CRR').sub.r --Q, (CRR').sub.r' NR.sup.a (CRR').sub.r --Q, (CRR').sub.r C(O)(CRR').sub.r --Q, (CRR').sub.r C(O)O(CRR').sub.r --Q, (CRR').sub.r' OC(O)(CRR').sub.r --Q, (CRR').sub.r C(O)NR.sup.a (CRR').sub.r --Q, (CRR').sub.r' NR.sup.a C(O)(CRR').sub.r --Q, (CRR').sub.r' OC(O)O(CRR').sub.r --Q, (CRR').sub.r' OC(O)NR.sup.a (CRR').sub.r --Q, (CRR').sub.r' NR.sup.a C(O)O(CRR').sub.r --Q, (CRR').sub.r' NR.sup.a C(O)NR.sup.a (CRR').sub.r --Q, (CRR').sub.r' S(O).sub.p (CRR').sub.r --Q, (CRR').sub.r' SO.sub.2 NR.sup.a (CRR').sub.r --Q, (CRR').sub.r' NR.sup.a SO.sub.2 (CRR').sub.r --Q, (CRR').sub.r' NR.sup.a SO.sub.2 NR.sup.a (CRR').sub.r --Q, (CRR').sub.r' NR.sup.a C(O)(CRR').sub.r" NHQ, (CRR').sub.r' NR.sup.a C(O)(CRR').sub.r NHC(O)OR.sup.a, and (CRR').sub.r' NR.sup.a C(O)(CRR').sub.r NHC(O)(CRR').sub.r NHC(O)OR.sup.a, Q is selected from H, a C.sub.3-13 carbocyclic group substituted with 0-5 R.sup.b and a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S and substituted with 0-5 R.sup.b ; R.sup.4 is selected from H, C.sub.1-10 alkylene-H, C.sub.2-10 alkenylene-H, C.sub.2-10 alkynylene-H, (CRR').sub.r' O(CRR').sub.r --H, (CRR').sub.r' NR.sup.a (CRR').sub.r --H, (CRR').sub.r' C(O)(CRR').sub.r --H, (CRR').sub.r' C(O)O(CRR').sub.r --H, (CRR').sub.r' OC(O)(CRR').sub.r --H, (CRR').sub.r' C(O)NR.sup.a (CRR').sub.r --H, (CRR').sub.r' NR.sup.a C(O)(CRR').sub.r --H, (CRR').sub.r' OC(O)O(CRR').sub.r --H, (CRR').sub.r' OC(O)NR.sup.a (CRR').sub.r --H, (CRR').sub.r' NR.sup.a C(O)O(CRR').sub.r --H, (CRR').sub.r' NR.sup.a C(O)NR.sup.a (CRR').sub.r --H, (CRR').sub.r' S(O).sub.p (CRR').sub.r --H, (CRR').sub.r' SO.sub.2 NR.sup.a (CRR').sub.r --H, (CRR').sub.r' NR.sup.a SO.sub.2 (CRR').sub.r --H, and (CRR').sub.r' NR.sup.a SO.sub.2 NR.sup.a (CRR').sub.r --H; alternatively, R.sup.3 and R.sup.4 combine to form a C.sub.3-13 carbocyclic group substituted with R.sup.1' and 0-3 R.sup.b or a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S and substituted with R.sup.1' and 0-3 R.sup.b ; R.sup.a, at each occurrence, is independently selected from H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.a', at each occurrence, is independently selected from H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.a", at each occurrence, is independently selected from H, C.sub.1-4 alkyl, benzyl, C.sub.3-7 carbocyclic group, or a 5 to 6 membered heteroaromatic ring containing 1 heteroatom selected from the group consisting of N, O, and S; alternatively, R.sup.a and R.sup.a" taken together with the nitrogen to which they are attached form a 5 or 6 membered ring; R.sup.b, at each occurrence, is independently selected from C.sub.1-6 alkyl, OR.sup.a, Cl, F, Br, I, .dbd.O, CN, NO.sub.2, NR.sup.a R.sup.a', C(O)R.sup.a", C(O)OR.sup.a, C(O)NR.sup.a R.sup.a', S(O).sub.2 NR.sup.a R.sup.a', S(O).sub.p R.sup.a, CF.sub.3, and CF.sub.2 CF.sub.3 ; R.sup.c, at each occurrence, is independently selected from C.sub.1-6 alkyl, OR.sup.a, Cl, F, Br, I, .dbd.O, CN, NO.sub.2, NR.sup.a R.sup.a', C(O)R.sup.a, C(O)OR.sup.a, C(O) NR.sup.a R.sup.a', NR.sup.a C(O)NR.sup.a R.sup.a', S(O).sub.2 NR.sup.a R.sup.a', S(O).sub.p R.sup.a, CF.sub.3, CF.sub.2 CF.sub.3, --CH(.dbd.NOH), --C(.dbd.NOH)CH.sub.3, (CRR').sub.s O(CRR').sub.s' R.sup.d, (CRR').sub.s S(O).sub.p (CRR').sub.s' R.sup.d, (CRR').sub.s NR.sup.a (CRR').sub.s' R.sup.d, phenyl, and a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S; R.sup.5, at each occurrence, is selected from C.sub.1-10 alkyl substituted with 0-2 R.sup.b, and C.sub.1-8 alkyl substituted with 0-2 R.sup.d ; R.sup.d, at each occurrence, is independently selected from phenyl substituted with 0-3 R.sup.b, biphenyl substituted with 0-2 R.sup.b, naphthyl substituted with 0-3 R.sup.b and a 5-6 membered heteroaryl group containing 1 heteroatom selected from the group consisting of N, O, and S and substituted with 0-3 R.sup.b ; R.sup.6, at each occurrence, is selected from phenyl, naphthyl, C.sub.1-10 alkyl-phenyl-C.sub.1-6 alkyl-, C.sub.3-11 cycloalkyl, C.sub.1-6 alkylcarbonyloxy-C.sub.1-3 alkyl-, C.sub.1-6 alkoxycarbonyloxy-C.sub.1-3 alkyl-, C.sub.2-10 alkoxycarbonyl, C.sub.3-6 cycloalkylcarbonyloxy-C.sub.1-3 alkyl-, C.sub.3-6 cycloalkoxycarbonyloxy-C.sub.1-3 alkyl-, C.sub.3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C.sub.1-3 alkyl-, phenylcarbonyloxy-C.sub.1-3 alkyl-, C.sub.1-6 alkoxy-.sub.1-6 alkylcarbonyloxy-C.sub.1-3 alkyl-, --C.sub.1-10 alkyl-NR.sup.7 R.sup.7a, --CH(R.sup.8)OC(.dbd.O)R.sup.9, --CH(R.sup.8)OC(.dbd.O)OR.sup.9 ; R.sup.7 is selected from H and C.sub.1-10 alkyl, C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyl-C.sub.1-3 alkyl-, and phenyl-C.sub.1-6 alkyl-; R.sup.7a is selected from H and C.sub.1-10 alkyl, C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyl-C.sub.1-3 alkyl-, and phenyl-.sub.1-6 alkyl-; R.sup.8 is selected from H and C.sub.1-4 linear alkyl; R.sup.9 is selected from H, C.sub.1-8 alkyl substituted with 1-2 R.sup.e, C.sub.3-8 cycloalkyl substituted with 1-2 R.sup.e, and phenyl substituted with 0-2 R.sup.b ; R.sup.e, at each occurrence, is selected from C.sub.1-4 alkyl, C.sub.3-8 cycloalkyl, C.sub.1-5 alkoxy, and phenyl substituted with 0-2 R.sup.b ; p, at each occurrence, is selected from 0, 1, and 2; r, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5; r', at each occurrence, is selected from 0, 1, 2, 3, 4, and 5; r", at each occurrence, is selected from 1, 2, and 3; s, at each occurrence, is selected from 0, 1, 2, and 3; and, s', at each occurrence, is selected from 0, 1, 2, and 3. 2. A compound according to claim 1, wherein: A is selected from COR.sup.5, --CO.sub.2 H, CH.sub.2 CO.sub.2 H, --CONHOH, --CONHOR.sup.5, --CONHOR.sup.6, --N(OH)COR.sup.5, --SH, and --CH.sub.2 SH; ring B is a 4-7 membered cyclic amide containing 0-1 additional carbonyl groups and 0-1 double bonds; U is absent; Y is absent; Z is absent or selected from a C.sub.5-10 carbocyclic group substituted with 0-5 R.sup.b and a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S and substituted with 0-5 R.sup.b ; U.sup.a is absent or is selected from: O, NR.sup.a, C(O), C(O)NR.sup.a, NR.sup.a C(O), OC(O)NR.sup.a, NR.sup.a C(O)O, NR.sup.a C(O)NR.sup.a, S(O).sub.p NR.sup.a, and NR.sup.a S(O).sub.p ; R.sup.2 is selected from H, Q', C.sub.1-5 alkylene-Q', C.sub.2-5 alkenylene-Q', C.sub.2-5 alkynylene-Q', (CRR').sub.r' O(CRR').sub.r --Q', (CRR').sub.r' NR.sup.a (CRR').sub.r --Q',(CRR').sub.r' NR.sup.a C(O)(CRR').sub.r --Q', (CRR').sub.r' C(O)NR.sup.a (CRR').sub.r --Q', (CRR').sub.r' NR.sup.a C(O)NR.sup.a (CRR').sub.r --Q', (CRR').sub.r' C(O)(CRR').sub.r --Q', (CRR').sub.r' C(O)O(CRR').sub.r --Q', (CRR').sub.r' S(O).sub.p (CRR').sub.r --Q', and (CRR').sub.r' SO.sub.2 NR.sup.a (CRR').sub.r --Q'; Q' is selected from H, phenyl substituted with 0-3 R.sup.b and a 5-6 membered heteroaryl group containing 1 heteroatom selected from the group consisting of N, O, and S and substituted with 0-3 R.sup.b ; R.sup.3 is selected from H, Q, C.sub.1-10 alkylene-Q, C.sub.2-10 alkenylene-Q, C.sub.2-10 alkynylene-Q, (CRR').sub.r' O(CRR').sub.r --Q, (CRR').sub.r' NR.sup.a (CRR').sub.r --Q, (CRR').sub.r C(O)(CRR').sub.r --Q, (CRR').sub.r C(O)NR.sup.a (CRR').sub.r --Q, (CRR').sub.r 'NR.sup.a C(O)(CRR').sub.r --Q, (CRR').sub.r' OC(O)NR.sup.a (CRR').sub.r --Q, (CRR').sub.r' NR.sup.a C(O)O(CRR').sub.r --Q, (CRR').sub.r' NR.sup.a C(O)NR.sup.a (CRR').sub.r --Q, (CRR').sub.r' S(O).sub.p (CRR').sub.r --Q, (CRR').sub.r' SO.sub.2 NR.sup.a (CRR').sub.r --Q, (CRR').sub.r' NR.sup.a SO.sub.2 (CRR').sub.r --Q, and (CRR').sub.r' NR.sup.a SO.sub.2 NR.sup.a (CRR').sub.r --Q; R, at each occurrence, is independently selected from H, CH.sub.3, and CH.sub.2 CH.sub.3 ; R', at each occurrence, is independently selected from H and CH.sub.3 ; Q is selected from H, a C.sub.3-10 carbocyclic group substituted with 0-5 R.sup.b and a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S and substituted with 0-5 R.sup.b ; and, R.sup.c, at each occurrence, is independently selected from C.sub.1-6 alkyl, OR.sup.a, Cl, F, Br, I, .dbd.O, CN, NO.sub.2, NR.sup.a R.sup.a', C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.a R.sup.a', S(O).sub.2 NR.sup.a R.sup.a', S(O).sub.p R.sup.a, CF.sub.3, CF.sub.2 CF.sub.3, and a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S. 3. A compound according to claim 2, wherein: A is selected from --CO.sub.2 H, CH.sub.2 CO.sub.2 H, --CONHOH, --CONHOR.sup.5, and --N(OH)COR.sup.5 ; ring B is a 4-6 membered cyclic amide containing 0-1 additional carbonyl groups and 0-1 double bonds; Z is absent or selected from a C.sub.5-6 carbocyclic group substituted with 0-3 R.sup.b and a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S and substituted with 0-5 R.sup.b ; U.sup.a is absent or is selected from: O, NR.sup.a, C(O), C(O)NR.sup.a, NR.sup.a C(O), and S(O).sub.p NR.sup.a ; X.sup.a is absent or C.sub.1-10 alkylene; R.sup.2 is selected from H, C.sub.1-5 alkylene-Q', (CH.sub.2).sub.r' O(CH.sub.2).sub.r --Q', (CH.sub.2).sub.r' NR.sup.a (CH.sub.2).sub.r --Q', (CRR').sub.r' NR.sup.a C(O)(CRR').sub.r --Q', (CH.sub.2).sub.r' C(O)NR.sup.a (CH.sub.2).sub.r --Q',(CRR').sub.r' NR.sup.a C(O)NR.sup.a (CRR').sub.r --Q', and (CH.sub.2).sub.r C(O)(CH.sub.2).sub.r --Q'; R.sup.c, at each occurrence, is independently selected from C.sub.1-6 alkyl, OR.sup.a, Cl, F, Br, I, .dbd.O, CN, NO.sub.2, NR.sup.a R.sup.a', C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.a R.sup.a', S(O).sub.2 NR.sup.a R.sup.a', S(O).sub.p R.sup.a, CF.sub.3, CF.sub.2 CF.sub.3, and a 6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S; and, Q is selected from H, a C.sub.5-6 carbocyclic group substituted with 0-5 R.sup.b and a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S and substituted with 0-5 R.sup.b. 4. A compound according to claim 3, wherein: A is selected from --CO.sub.2 H, CH.sub.2 CO.sub.2 H, --CONHOH, and --CONHOR.sup.5 ; ring B is a 4-5 membered cyclic amide containing 0-1 additional carbonyl groups and 0-1 double bonds; X is absent or selected from C.sub.1-4 alkylene, C.sub.2-4 alkenylene, and C.sub.2-4 alkynylene; Z is absent or selected from phenyl substituted with 0-3 R.sup.b and a 5-6 membered aromatic heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S and substituted with 0-3 R.sup.b ; X.sup.a is absent or C.sub.1-4 alkylene; Y.sup.a is absent or selected from O and NR.sup.a ; R.sup.4 is selected from H, C.sub.1-4 alkylene-H, (CH.sub.2).sub.r' O(CH.sub.2).sub.r --H, and (CH.sub.2).sub.r' NR.sup.a (CH.sub.2).sub.r --H; and, R.sup.c, at each occurrence, is independently selected from C.sub.1-6 alkyl, OR.sup.a, Cl, F, Br, I, .dbd.O, CN, NO.sub.2, NR.sup.a R.sup.a', C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.a R.sup.a', S(O).sub.2 NR.sup.a R.sup.a', S(O).sub.p R.sup.a, CF.sub.3, CF.sub.2 CF.sub.3, and a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S. 5. A compound according to claim 1, wherein: [1(R)]-3-[4-[[4-chloro-2-(trifluoromethyl)-6-quinolinyl]methoxy]phenyl]-N-h ydroxy-.alpha.,3-dimethyl-2-oxo-1-pyrrolidineacetamide; [1(R)]-N-hydroxy-.alpha.,3-dimethyl-2-oxo-3-[4-(4-quinolinylmethoxy)phenyl] -1-pyrrolidineacetamide; [1(R)]-N-hydroxy-.alpha.,3-dimethyl-2-oxo-3-[4-[(4-quinolinyloxy)methyl]phe nyl]-1-pyrrolidineacetamide; [1(R)]-N-hydroxy-.alpha.,3-dimethyl-2-oxo-3-[4-[(4-quinolinylmethyl)amino]p henyl]-1-pyrrolidineacetamide; [1(R)]-N-hydroxy-3-methyl-.alpha.-(1-methylethyl)-2-oxo-3-[4-(4-quinolinylm ethoxy)phenyl]-1-pyrrolidineacetamide; [1(R)]-N-hydroxy-3-methyl-.alpha.-[2-(methylsulfonyl)ethyl]-2-oxo-3-[4-(4-q uinolinylmethoxy)phenyl]-1-pyrrolidineacetamide; [1(R) ]-1,1-dimethylethyl 4-[2-(hydroxyamino)-1-[3-methyl-2-oxo-3-[4-(4-quinolinylmethoxy)phenyl]-1- pyrrolidinyl]-2-oxoethyl]-1-piperidinecarboxylate; [1(R)]-N-hydroxy-.alpha.-[3-methyl-2-oxo-3-[4-(4-quinolinylmethoxy)phenyl]- 1-pyrrolidinyl]-4-piperidineacetamide; [1(R)]-N-hydroxy-.alpha.-[3-methyl-2-oxo-3-[4-(4-quinolinylmethoxy)phenyl]- 1-pyrrolidinyl]-1-(methylsulfonyl)-4-piperidineacetamide; [1(R)]-1-(2-furanylcarbonyl)-N-hydroxy-.alpha.-[3-methyl-2-oxo-3-[4-(4-quin olinylmethoxy)phenyl]-1-pyrrolidinyl]-4-piperidineacetamide; [1(R)]-3-amino-N-hydroxy-alpha-(2-methylpropyl)-2-oxo-3-[4-(2-quinolinylmet hoxy)phenyl]-1-pyrrolidineacetamide; [1(R)]-3-amino-N-hydroxy-alpha-(2-methylpropyl)-2-oxo-3-[4-(4-quinolinylmet hoxy)phenyl]-1-pyrrolidineacetamide; [1(R)]-3-amino-N-hydroxy-3-[4-[(2-methoxy-4-quinolinyl)methoxy]phenyl]-alph a-(2-methylpropyl)-2-oxo-1-pyrrolidineacetamide; [1(R)]-3-amino-N-hydroxy-alpha-(2-methylpropyl)-2-oxo-3-[4-[(2-phenyl-4-qui nolinyl)methoxy]phenyl]-1-pyrrolidineacetamide; [1(R)]-3-amino-3-[4-[(2,6-dimethyl-4-quinolinyl)methoxy]phenyl]-N-hydroxy-a lpha-(2-methylpropyl)-2-oxo-1-pyrrolidineacetamide; [1(R)]-3-amino-3-[4-[(2-chloro-4-quinolinyl)methoxy]phenyl]-N-hydroxy-alpha -(2-methylpropyl)-2-oxo-1-pyrrolidineacetamide; [1(R)]-3-amino-N-hydroxy-alpha-(2-methylpropyl)-3-[4-[(2-methyl-4-quinoliny l)methoxy]phenyl]-2-oxy-1-pyrrolidineacetamide; [1(R)]-3-amino-3-[4-[(2-chloro-4-quinolinyl)methoxy]phenyl]-N-hydroxy-alpha -[2-(methylsulfonyl)ethyl]-2-oxo-1-pyrrolidineacetamide; [1(R)]-3-amino-N-hydroxy-3-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-alpha -[2-(methylsulfonyl)ethyl]-2-oxo-1-pyrrolidineacetamide; [1(R)]-3-amino-N-hydroxy-3-[4-[(2-methoxy-4-quinolinyl)methoxy]phenyl]-alph a-[2-(methylsulfonyl)ethyl]-2-oxo-1-pyrrolidineacetamide; [1(R)]-N-hydroxy-3-(methylamino)-alpha-(2-methylpropyl)-3-[4-[(2-methyl-4-q uinolinyl)methoxy]phenyl]-2-oxo-1-pyrrolidineacetamide; [1(R)]-.alpha.-[3-amino-2-oxo-3-[4-(4-quinolinylmethoxy)phenyl]-1-pyrrolidi nyl]-N-hydroxy-4-piperidineacetamide; [1(R)]-3-amino-N-hydroxy-.alpha.-(1-methylethyl)-2-oxo-3-[4-(4-quinolinylme thoxy)phenyl]-1-pyrrolidineacetamide; [1(R)]-3-amino-.alpha.-cyclohexyl-N-hydroxy-2-oxo-3-[4-(4-quinolinylmethoxy )phenyl]-1-pyrrolidineacetamide; [1(R)]-3-amino-.alpha.-(1,1-dimethylethyl)-N-hydroxy-2-oxo-3-[4-(4-quinolin ylmethoxy)phenyl]-1-pyrrolidineacetamide; [1(R)]-3-amino-.alpha.-(1,1-dimethylethyl)-N-hydroxy-2-oxo-3-[4-[(2-methyl- 4-quinolinyl)methoxy]phenyl]-1-pyrrolidineacetamide; [1(R)]-3-amino-N-hydroxy-.alpha.-(1-methylethyl)-2-oxo-3-[4-[(2-methyl-4-qu inolinyl)methoxy]phenyl]-1-pyrrolidineacetamide; [1(R)]-3-amino-N-hydroxy-.alpha.-(1-methylethyl)-2-oxo-3-[4-[(2,6-dimethyl- 4-quinolinyl)methoxy]phenyl]-1-pyrrolidineacetamide; or a pharmaceutically acceptable salt form thereof. 6. A compound according to claim 1, wherein: A is selected from COR.sup.5, --CO.sub.2 H, CH.sub.2 CO.sub.2 H, --CONHOH, --CONHOR.sup.5, --CONHOR.sup.6, --N(OH)COR.sup.5, --SH, and --CH.sub.2 SH; ring B is a 4-7 membered cyclic amide containing 0-1 additional carbonyl groups and 0-1 double bonds; R.sup.1 and R.sup.2 combine to form a C.sub.5-14 carbocyclic group substituted with R.sup.1' and 0-3 R.sup.b or a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S and substituted with R.sup.1' and 0-3 R.sup.b ; Z.sup.a is selected from H, a C.sub.5-10 carbocyclic group substituted with 0-5 R.sup.c and quinolinyl substituted with 0-5 R.sup.c ; R.sup.3 is selected from H, Q, C.sub.1-10 alkylene-Q, C.sub.2-10 alkenylene-Q, C.sub.2-10 alkynylene-Q, (CRR').sub.r' O(CRR').sub.r --Q, (CRR').sub.r' NR.sup.a (CRR').sub.r --Q, (CRR').sub.r' C(O)(CRR').sub.r --Q, (CRR').sub.r' C(O)NR.sup.a (CRR').sub.r --Q, (CRR').sub.r' NR.sup.a C(O)(CRR').sub.r --Q, (CRR').sub.r' OC(O)NR.sup.a (CRR').sub.r --Q, (CRR').sub.r' NR.sup.a C(O)O(CRR').sub.r --Q, (CRR').sub.r' NR.sup.a C(O)NR.sup.a (CRR').sub.r --Q, (CRR').sub.r' S(O).sub.p (CRR').sub.r --Q, (CRR').sub.r' SO.sub.2 NR.sup.a (CRR').sub.r --Q, (CRR').sub.r' NR.sup.a SO.sub.2 (CRR').sub.r --Q, and (CRR').sub.r' NR.sup.a SO.sub.2 NR.sup.a (CRR').sub.r --Q; R, at each occurrence, is independently selected from H, CH.sub.3, CH.sub.2 CH.sub.3, CH.dbd.CH.sub.2, CH.dbd.CHCH.sub.3, and CH.sub.2 CH.dbd.CH.sub.2 ; R', at each occurrence, is independently selected from H, CH.sub.3, CH.sub.2 CH.sub.3, and CH(CH.sub.3).sub.2 ; Q is selected from H, a C.sub.3-10 carbocyclic group substituted with 0-5 R.sup.b and a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S and substituted with 0-5 R.sup.b ; R.sup.4 is selected from H; R.sup.c, at each occurrence, is independently selected from C.sub.1-6 alkyl, OR.sup.a, Cl, F, Br, I, .dbd.O, CN, NO.sub.2, NR.sup.a R.sup.a', C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.a R.sup.a', S(O).sub.2 NR.sup.a R.sup.a', S(O).sub.p R.sup.a, CF.sub.3, CF.sub.2 CF.sub.3, and a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S. 7. A compound according to claim 6, wherein the compound is of formula II: ##STR169## wherein, A is selected from --CO.sub.2 H, CH.sub.2 CO.sub.2 H, --CONHOH, and --CONHOR.sup.5 ; ring C is fused to ring G and is a phenyl ring or 5-6 membered aromatic heterocycle containing 1 heteroatom selected from O, N, and S(O).sub.p, and ring C is substituted with 1 R.sup.1' ; ring G is a 4-8 membered carbocyclic ring substituted with 0-1 carbonyl groups alternatively, ring G is a 4-8 membered heterocyclic ring containing from 1 heteroatom selected from O and NR.sup.a and substituted with 0-2 carbonyl groups and 0-1 double bonds; U.sup.a is absent or is selected from: O, NR.sup.a, C(O), C(O)NR.sup.a, NR.sup.a C(O), and S(O).sub.p NR.sup.a ; X.sup.a is absent or C.sub.1-4 alkylene; Y.sup.a is absent or selected from O and NR.sup.a ; Z.sup.a is selected from H, phenyl substituted with 0-5 R.sup.c and quinolinyl substituted with 0-5 R.sup.c ; Q is selected from H, a C.sub.5-6 carbocyclic group substituted with 0-5 R.sup.b and a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S and substituted with 0-5 R.sup.b ; and, R.sup.c, at each occurrence, is independently selected from C.sub.1-6 alkyl, OR.sup.a, Cl, F, Br, I, .dbd.O, CN, NO.sub.2, NR.sup.a R.sup.a', C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.a R.sup.a', S(O).sub.2 NR.sup.a R.sup.a', S(O).sub.p R.sup.a, CF.sub.3, CF.sub.2 CF.sub.3, and a 5-6 membered heterocyclic group containing 1 heteroatom selected from the group consisting of N, O, and S. 8. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof. 9. A method for treating or preventing an inflammatory disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof. 10. A method of treating a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof. 11. A method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, multiple sclerosis, or psoriasis in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof. 12. A method of treating a condition or disease wherein the disease or condition is referred to as fever, cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease or HIV infection in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof. 13. A compound according to claim 1, wherein: [1(R)]-3-amino-N-hydroxy-alpha-(2-methylpropyl)-2-oxo-3-[4-(2-quinolinylmet hoxy)phenyl]-1-pyrrolidineacetamide. 14. A compound according to claim 1, wherein: [1(R)]-3-amino-N-hydroxy-alpha-(2-methylpropyl)-2-oxo-3-[4-(4-quinolinylmet hoxy)phenyl]-1-pyrrolidineacetamide. 15. A compound according to claim 1, wherein: [1(R)]-3-amino-N-hydroxy-3-[4-[(2-methoxy-4-quinolinyl)methoxy]phenyl]-alp ha-(2-methylpropyl)-2-oxo-1-pyrrolidineacetamide. 16. A compound according to claim 1, wherein: [1(R)]-3-amino-N-hydroxy-alpha-(2-methylpropyl)-2-oxo-3-[4-[(2-phenyl-4-qui nolinyl)methoxy]phenyl]-1-pyrrolidineacetamide. 17. A compound according to claim 1, wherein: [1(R)]-3-amino-3-[4-[(2,6-dimethyl-4-quinolinyl)methoxy]phenyl]-N-hydroxy-a lpha-(2-methylpropyl)-2-oxo-1-pyrrolidineacetamide. 18. A compound according to claim 1, wherein: [1(R)]-3-amino-3-[4-[(2-chloro-4-quinolinyl)methoxy]phenyl]-N-hydroxy-alpha -(2-methylpropyl)-2-oxo-1-pyrrolidineacetamide. 19. A compound according to claim 1, wherein: [1(R)]-3-amino-N-hydroxy-alpha-(2-methylpropyl)-3-[4-[(2-methyl-4-quinoliny l)methoxy]phenyl]-2-oxo-1-pyrrolidineacetamide. 20. A compound according to claim 1, wherein: [1(R)]-3-amino-3-[4-[(2-chloro-4-quinolinyl)methoxy]phenyl]-N-hydroxy-alpha -[2-(methylsulfonyl)ethyl]-2-oxo-1-pyrrolidineacetamide. 21. A compound according to claim 1, wherein: [1(R)]-3-amino-N-hydroxy-3-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-alpha -[2-(methylsulfonyl)ethyl]-2-oxo-1-pyrrolidineacetamide. 22. A compound according to claim 1, wherein: [1(R)]-3-amino-N-hydroxy-3-[4-[(2-methoxy-4-quinolinyl)methoxy]phenyl]-alph a-[2-(methylsulfonyl)ethyl]-2-oxo-1-pyrrolidineacetamide. 23. A compound according to claim 1, wherein: [1(R)]-N-hydroxy-3-(methylamino)-alpha-(2-methylpropyl)-3-[4-[(2-methyl-4-q uinolinyl)methoxy]phenyl]-2-oxo-1-pyrrolidineacetamide. 24. A compound according to claim 1, wherein: [1(R)]-.alpha.-[3-amino-2-oxo-3-[4-(4-quinolinylmethoxy)phenyl]-1-pyrrolidi nyl]-N-hydroxy-4-piperidineacetamide. 25. A compound according to claim 1, wherein: [1(R)]-3-amino-N-hydroxy-.alpha.-(1-methylethyl)-2-oxo-3-[4-(4-quinolinylme thoxy)phenyl]-1-pyrrolidineacetamide. 26. A compound according to claim 1, wherein: [1(R)]-3-amino-.alpha.-cyclohexyl-N-hydroxy-2-oxo-3-[4-(4-quinolinylmethoxy )phenyl]-1-pyrrolidineacetamide. 27. A compound according to claim 1, wherein: [1(R)]-3-amino-.alpha.-(1,1-dimethylethyl)-N-hydroxy-2-oxo-3-[4-(4-quinolin ylmethoxy)phenyl]-1-pyrrolidineacetamide. 28. A compound according to claim 1, wherein: [1(R)]-3-amino-.alpha.-(1,1-dimethylethyl)-N-hydroxy-2-oxo-3-[4-[(2-methyl- 4-quinolinyl)methoxy]phenyl]-1-pyrrolidineacetamide. 29. A compound according to claim 1, wherein: [1(R)]-3-amino-N-hydroxy-.alpha.-(1-methylethyl)-2-oxo-3-[4-[(2-methyl-4-qu inolinyl)methoxy]phenyl]-1-pyrrolidineacetamide. 30. A compound according to claim 1, wherein: [1(R)]-3-amino-N-hydroxy-.alpha.-(1-methylethyl)-2-oxo-3-[4-[(2,6-dimethyl- 4-quinolinyl)methoxy]phenyl]-1-pyrrolidineacetamide. 31. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt form thereof. 32. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 3 or a pharmaceutically acceptable salt form thereof. 33. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt form thereof. 34. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt form thereof. 35. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 6 or a pharmaceutically acceptable salt form thereof. 36. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 7 or a pharmaceutically acceptable salt form thereof. 37. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 13 or a pharmaceutically acceptable salt form thereof. 38. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 14 or a pharmaceutically acceptable salt form thereof. 39. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 15 or a pharmaceutically acceptable salt form thereof. 40. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 16 or a pharmaceutically acceptable salt form thereof. 41. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 17 or a pharmaceutically acceptable salt form thereof. 42. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 18 or a pharmaceutically acceptable salt form thereof. 43. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 19 or a pharmaceutically acceptable salt form thereof. 44. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 20 or a pharmaceutically acceptable salt form thereof. 45. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 21 or a pharmaceutically acceptable salt form thereof. 46. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 22 or a pharmaceutically acceptable salt form thereof. 47. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 23 or a pharmaceutically acceptable salt form thereof. 48. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 24 or a pharmaceutically acceptable salt form thereof. 49. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 25 or a pharmaceutically acceptable salt form thereof. 50. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 26 or a pharmaceutically acceptable salt form thereof. 51. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 27 or a pharmaceutically acceptable salt form thereof. 52. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 28 or a pharmaceutically acceptable salt form thereof. 53. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 29 or a pharmaceutically acceptable salt form thereof. 54. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 30 or a pharmaceutically acceptable salt form thereof. |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION This invention relates generally to novel lactam metalloprotease inhibitors, pharmaceutical compositions containing the same, and methods of using the same. BACKGROUND OF THE INVENTION There is now a body of evidence that metalloproteinases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of metalloproteinase), which form inactive complexes with the MP's. Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteinases. The available evidence supports that it is the metalloproteinases which are responsible for the degradation of the extracellular matrix of articullar cartillage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase (a newly identified metalloproteinase enzymatic activity) has been identified that provides the specific cleavage product of proteoglycan, found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22). Therefore metalloproteinases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990). Tumor necrosis factor (TNF) is a cell associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn's disease (Macdonald T. et al. Clin. Exp. Immunol. 81, 1990, 301). Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that a matrix metalloproteinase or family of metalloproteinases, hereafter known as TNF-convertases (TNF-C), as well as other MP's are capable of cleaving TNF from its inactive to active form (Gearing et al Nature, 1994, 370, 555). This invention describes molecules that inhibit this conversion and hence the secretion of active TNF-a from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrom, post ischaemic reperfusion injury, malaria, Crohn's disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, osteo and rheumatoid arthritis, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV and non-insulin dependent diabetes melitus. Since excessive TNF production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may also have a particular advantage in diseases where both mechansisms are involved. There are several patents which disclose hydroxamate and carboxylate based MMP inhibitors. W095/09841 describes compounds that are hydroxamic acid derivatives and are inhibitors of cytokine production. ##STR2## European Patent Application Publication No. 574,758 A1, discloses hydroxamic acid derivatives as collagenase inhibitors having the general formula: ##STR3## GB 2 268 934 A and WO 94/24140 claim hydroxamate inhibitors of MMPs as inhibitors of TNF production. The compounds of the current invention act as inhibitors of MMPS, in particular aggrecanase and TNF. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibiton of aggrecanase, TNF-C, and other metalloproteinases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of osteo- and rheumatoid arthritis. SUMMARY OF THE INVENTION Accordingly, one object of the present invention is to provide novel lactams which are useful as metalloprotease inhibitors or pharmaceutically acceptable salts or prodrugs thereof. It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof. It is another object of the present invention to provide a method for treating inflammatory disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof. These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I): ##STR4## or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are defined below, are effective metalloprotease inhibitors. |
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| PATENT PHOTOCOPY | Available on request |
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