Amide and ester matrix metalloproteinase inhibitors
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IPC분류정보
국가/구분
United States(US) Patent
공개
국제특허분류(IPC7판)
A61K-031/549
A61K-031/513
A61K-031/53
A61K-031/4965
A61K-031/50
출원번호
US-0481886
(2006-07-06)
공개번호
US-0247231
(2006-11-02)
발명자
/ 주소
Bunker,Amy
Picard,Joseph
출원인 / 주소
Warner Lambert Company LLC
대리인 / 주소
WARNER LAMBERT COMPANY
인용정보
피인용 횟수 :
0인용 특허 :
0
초록▼
This invention provides compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein G1, Q, D, and G2 are as defined above for Formula I. Compounds of Formula I, or a pharmaceutically acceptable salt thereof, are inhibitors of MMP-13. The compounds are useful for treating disease
This invention provides compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein G1, Q, D, and G2 are as defined above for Formula I. Compounds of Formula I, or a pharmaceutically acceptable salt thereof, are inhibitors of MMP-13. The compounds are useful for treating diseases mediated by MMP-13, including the diseases recited herein such as breast cancer, cartilage damage, rheumatoid arthritis, and osteoarthritis.
대표청구항▼
What is claimed is: 1. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein: Each G1 and G2 independently is an unsubstituted or substituted group selected from: C3 to C7 cycloalkyl-(C1-C8 alkylenyl)m-;. C5 or C6 cycloalkyl-(C1-C8 alkylenyl)m-; C8-C10 bicycloalkyl-(
What is claimed is: 1. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein: Each G1 and G2 independently is an unsubstituted or substituted group selected from: C3 to C7 cycloalkyl-(C1-C8 alkylenyl)m-;. C5 or C6 cycloalkyl-(C1-C8 alkylenyl)m-; C8-C10 bicycloalkyl-(C1-C8 alkylenyl)m-; 3-to 7-membered heterocycloalkyl-(C1-C8 alkylenyl)m-; 5-or 6-membered heterocycloalkyl-(C1-C8 alkylenyl)m-; 8-to 10-membered heterobicycloalkyl-(C1-C8 alkylenyl)m-; Phenyl-(C1-C8 alkylenyl)m-; Naphthyl-(C1-C8 alkylenyl)m-; 5-or 6-membered heteroaryl-(C1-C8 alkylenyl)m-; 8-to 10-membered heterobiaryl-(C1-C8 alkylenyl)m-; 5-or 6-membered heterocycloalkyl-phenylenyl-(C1-C8 alkylenyl)m-; Biphenyl-(C1-C8 alkylenyl)m-; 5-or 6-membered heteroaryl-phenylenyl-(C1-C8 alkylenyl)m-; 5-or 6-membered heteroaryl-(5-or 6-membered heteroarylenyl)-(C1-C8 alkylenyl)m-; Phenyl-L-(phenylenyl)-(C1-C8 alkylenyl) m-; Phenyl-L-(5-or 6-membered heteroarylenyl)-(C1-C 8 alkylenyl)m-; 8-to 10-membered heterobiaryl-phenylenyl-(C1-C8 alkylenyl)m-; Phenyl-(5-or 6-membered heteroarylenyl)-(C1-C8 alkylenyl)m-; Naphthyl-(5-or 6-membered heteroarylenyl)-(C1-C 8 alkylenyl)m-; Phenyl-O--(C1-C8 alkylenyl)m-; Phenyl-S--(C1-C8 alkylenyl)m-; Phenyl-S(O)--(C1-C8 alkylenyl)m-; Phenyl-S(O)2-(C1-C8 alkylenyl) m-; Phenyl-(8-to 10-membered heterobiarylenyl)-(C1-C 8 alkylenyl)m-; and any of the above G1 and G2 groups independently substituted with from 1 to 6 substituents, each independently on a carbon or nitrogen atom, independently selected from: C1-C6 alkyl; C1-C6 alkyl-(G)m-; CN; CF3; HO; (C1-C6 alkyl)-O; (C1-C6 alkyl)-S; (C1-C6 alkyl)-S(O); (C1-C6 alkyl)-S(O)2; O2N; H2 N; (C1-C6 alkyl)-N(H); (C1-C6 alkyl) 2-N; (C1-C6 alkyl)-C(O)O--(C1-C8 alkylenyl)m-; (C1-C6 alkyl)-C(O)O-(1-to 8-membered heteroalkylenyl)m-; (C1-C6 alkyl)-C(O)N(H)--(C1-C8 alkylenyl)m-; (C1-C6 alkyl)-C(O)N(H)-(1-to 8-membered heteroalkylenyl)m-; H2NS(O)2--(C1-C8 alkylenyl)m-; (C1-C6 alkyl)-N(H)S(O)2--(C1-C 8 alkylenyl)m-; (C1-C6 alkyl)2-NS(O)2--(C1-C8 alkylenyl)m-; 3-to 6-membered heterocycloalkyl-(G)m-; 5-or 6-membered heteroaryl-(G) m-; (C1-C6 alkyl)-S(O)2--N(H)--C(O)--(C1-C8 alkylenyl)m-; and (C1-C6 alkyl)-C(O)--N(H)--S(O)2--(C1-C8 alkylenyl)m-; wherein each substituent on a carbon atom of G1 or G2 may further be independently selected from Halo and HO 2C; wherein 2 substituents on the same carbon atom of G1 or G2 may be taken together with the carbon atom to which they are both bonded to form the group C═O; wherein G1 and G2 are not both independently selected from: phenyl; benzyl; naphthyl; C3 to C7 cycloalkyl-(C1-C8 alkenyl)m-; C8-C10 bicycloalkyl-(C1-C8 alkenyl)m-; 3-to 7-membered heterocycloalkyl-(C1-C8 alkenyl)m-; and 8-to 10-membered heterobicycloalkyl-(C1-C8 alkenyl)m-; Each m is independently an integer of 0 or 1; Each G and L is independently selected from: CH2; C(O); N(H); N(C1-C6 alkyl); O; S; S(O); and S(O) 2; Q is O, N(H), or N(C1-C6 alkyl); D is a cyclic diradical group selected from: wherein the group D may be unsubstituted or substituted on carbon and nitrogen atoms with 1 or 2 groups independently selected from: CH3; CF3; N≡C--; CH3C(O); HO; CH 3O; C(F)H2O; C(H)F2O; and CF3O; and the substituent on a carbon atom in the group D may be further selected from F and Cl; and V is a 5-membered heteroarylenyl diradical containing carbon atoms and from 1 to 4 heteroatoms selected from: 1 O; 1 S; 1 NH; 1 N(C 1-C6 alkyl); and 4 N; wherein the O and S atoms are not both present, and wherein the heteroarylenyl may optionally be unsubstituted or substituted on a carbon atom or a nitrogen atom with 1 group selected from: CH3; CF3; N≡C--; CH3 C(O); HO; CH3O; C(F)H2O; C(H)F2O; and CF 3O; and the substituent on the carbon atom in the group V may be further selected from F. 2. The compound according to claim 1, or the pharmaceutically acceptable salt thereof, wherein m is 1 and each C 1-C8 alkylenyl is independently CH2, CHF, CF 2, or C(═O). 3. The compound according to claim 2, or the pharmaceutically acceptable salt thereof, wherein D is selected from: 4. The compound according to claim 2, or the pharmaceutically acceptable salt thereof, wherein D is selected from: 5. The compound according to claim 2, or the pharmaceutically acceptable salt thereof, wherein D is selected from: 6. The compound according to claim 2, or the pharmaceutically acceptable salt thereof, wherein D is selected from: 7. The compound according to claim 2, or the pharmaceutically acceptable salt thereof, wherein D is selected from: 8. The compound according to claim 2, or the pharmaceutically acceptable salt thereof, wherein D is selected from: 9. The compound according to claim 2, or the pharmaceutically acceptable salt thereof, wherein G1 and G2 each independently are 5-or 6-membered heteroaryl-CH2, 8-to 10-membered heterobiaryl-CH2, or a substituted phenyl-CH 2; wherein 5-or 6-membered heteroaryl-CH2 and 8-to 10-membered heterobiaryl-CH2 may be independently unsubstituted or substituted. 10. The compound according to claim 8, or the pharmaceutically acceptable salt thereof, wherein V is tetrazol-2,5-diyl. 11. The compound according to claim 2, or the pharmaceutically acceptable salt thereof, wherein Q is N(H). 12. A pharmaceutical composition, comprising a compound according to claim 1, or the pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent. 13. A method of treating a disease selected from rheumatoid arthritis, osteoarthritis, breast cancer, heart failure, and atherosclerotic plaque rupture in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to claim 1, or the pharmaceutically acceptable salt thereof.
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