Patent NZ-504088-A (NZ)
Title: Lactam derivatives useful as metalloprotease inhibitors, and a method of treating/preventing inflammatory disorders in non-human mammals, and a method for treating conditions mediated by MMPs, TNF and aggrecanase in non-human mammals
Inventor: DECICCO CARL P
IPC: A61K31/4709
Filed: 1998-10-02
Abstract: A compound of formula I or pharmaceutical, stereoisomer or salt thereof, where: A is -COR5, -CO2H, -CH2CO2H, -CO2R6, -CONHOH, -CONHOR5, -CONHOR6, -NHRa, -N(OH)COR5, -SH, -CH2SH, -SO2NHRa, SN2H2Ra, PO(OH)2, or PO(OH)NHRa; Ring B is a 4-8 membered cyclic amide containing from 0-3 additional heteroatoms selected from O, NRa, and S(O)p, 0-1 additional carbonyl groups and 0-1 double bonds; R1 is U-X-Y-Z-Ua-Xa-Ya-Za; R2 is H, Q', alkylene-Q', alkenylene-Q', alkynylene-Q', (CRR')r'O(CRR')r-Q', (CRR')r'NRa(CRR')r-Q', (CRR')r'NRaC(O)(CRR')r-Q', (CRR')r'C(O)NRa(CRR')r-Q', (CRR')r'C(O)(CRR')r-Q', (CRR')r'C(O)O(CRR')r-Q', (CRR')r'S(O)p(CRR')r-Q', (CRR')r'SO2NRa(CRR')r-Q', (CRR')r'NRaC(O)NRa(CRR')r-Q', (CRR')r'OC(O)NRa(CRR')r-Q', or (CRR')r'NRaC(O)O(CRR')r-Q'; or R1 and R2 combine to form a carbocyclic residue substituted with R1' and 0-3 Rb or a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with R1' and 0-3 Rb; R3 is H, Q, alkylene-Q, alkenylene-Q, alkynylene-Q, (CRR')r'O(CRR')r-Q, (CRR')r'NRa(CRR')r-Q, (CRR')rC(O)(CRR')r-Q, (CRR')rC(O)O(CRR')r-Q, (CRR')r'OC(O)(CRR')r-Q, (CRR')rCONRa(CRR')r-Q, (CRR')r'NRaC(O)(CRR')r-Q, (CRR')r'OC(O)O(CRR')r-Q, (CRR')r'OC(O)NRa(CRR')r-Q, (CRR')r'NRaC(O)O(CRR')r-Q, (CRR')r'NRaC(O)NRa(CRR')r-Q, (CRR')r'S(O)p(CRR')r-Q, (CRR')r'SO2NRa(CRR')r-Q, (CRR')r'NRaSO2(CRR')r-Q, (CRR')r'NRaSO2NRa(CRR')r-Q, (CRR')r'NRaC(O)(CRR')r"NHQ, (CRR')r'NRaC(O)(CRR')rNHC(O)ORa, or (CRR')r'NRaC(O)(CRR')rNHC(O)(CRR')rNHC(O)ORa; R4 is H, alkylene-H, alkenylene-H, alkynylene-H, (CRR')r'O(CRR')r-H, (CRR')r'NRa(CRR')r-H, (CRR')r'C(O)(CRR')r-H, (CRR')r'C(O)O(CRR')r-H, (CRR')r'OC(O)(CRR')r-H, (CRR')r'C(O)NRa(CRR')r-H, (CRR')r'NRaC(O)(CRR')r-H, (CRR')r'OC(O)O(CRR')r-H, (CRR')r'OC(O)NRa(CRR')r-H, (CRR')r'NRaC(O)O(CRR')r-H, (CRR')r'NRaC(O)NRa(CRR')r-H, (CRR')r'S(O)p(CRR')r-H, (CRR')r'SO2NRa(CRR')r-H, (CRR')r'NRaSO2(CRR')r-H, or 15(CRR')r'NRaSO2NRa(CRR')r-H; or R3 and R4 combine to form a carbocyclic residue substituted with R1' and 0-3 Rb or a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with R1' and 0-3 Rb; Q and Q' are independently H, a carbocyclic residue substituted with 0-5 Rb, or a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O and S and substituted with 0-5 Rb; R is H, CH3, CH2CH3, CH=CH2, CH=CHCH3, or CH2CH=CH2;R', is H, CH3, CH2CH3, or CH(CH3)2; Ra is H, alkyl, phenyl or benzyl; p is 0-2; r is 0-5; r' is 0-5; r" is 1-3 U is absent or is O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC()ONRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, or NRaSO2NRa;  Also described is a method of treating or preventing the following conditions or diseases in non-human animals by the administration of a compound of formula I: conditions or diseases mediated by MMPs, TNF, aggrecanase, or a combination thereof; inflammatory disorders, rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumour growth and tumour invasion by secondary metastases, neovascular glaucoma, multiple sclerosis, or psoriasis, fever, cardiovascular effects, haemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease or HIV infection. The compounds of formula I are used to prepare a medicament for treating or preventing (not limited to a non-human mammal) the diseases or conditions described above.