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US 7,459,461 B2Granted
Phosphonic acid compounds as inhibitors of serine proteases
AssigneeOrtho-McNeil Pharmaceutical, Inc.
InventorsMichael N. Greco, Harold R. Almond, Lawrence de Garavilla, Michael J. Hawkins, Michael J. Humora, Yun Qian, Donald Gilmore Walker, Sergio Cesco-Cancian, Christopher Norman Nilsen, Mitul N. Patel, Kirk Leonard Sorgi, Eugene Powell
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Abstract
The present invention is directed to phosphonic acid compounds useful as serine protease inhibitors, compositions thereof and methods for treating inflammatory and serine protease mediated disorders.
Claims36
A compound of Formula (Ic):
- wherein
- R2 and R3 are attached to a benzene ring and R2 and R3 together form a 6-membered carbocyclic ring fused to the benzene ring;
- thereby providing a multiple ring system;
- wherein the multiple ring system is selected from the group consisting of benzo fused cyclohexyl, benzo fused cyclohexenyl, and naphthalenyl, and, wherein the multiple ring system can optionally be substituted with one to four substituents independently selected from the group consisting of:
- da) C1-4 alkyl optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of:
- amino,
- substituted with two substituents independently selected from the group consisting of:
- hydrogen, and
- C1-4 alkyl,
- (halo)1-3, and
- hydroxy;
- db) C1-4 alkoxy optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of:
- (halo)1-3 and hydroxy;
- dc) amino substituted with two substituents independently selected from the group consisting of:
- hydrogen and C1-4 alkyl;
- dd) halogen;
- de) hydroxy;
- and
- df) nitro;
- R4 is selected from the group consisting of:
- C1-4 alkyl, optionally substituted on a terminal carbon atom with aryl, and aryl,
- wherein aryl and the aryl portions of the substituted alkyl are optionally substituted with one to four substituents independently selected from the group consisting of:
- C1-4 alkyl,
- amino, substituted with two substituents independently selected from the group consisting of:
- hydrogen, and
- C1-4 alkyl,
- cyano,
- halogen,
- hydroxy, and
- (halo)1-3(C1-8)alkyl;
- R5 is selected from the group consisting of:
- hydrogen,
- C1-8 alkyl, optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of:
- amino, substituted with two substituents independently selected from the group consisting of:
- hydrogen, and
- C1-4 alkyl,
- (halo)1-3, and
- hydroxy
- and aryl, optionally substituted with one to four substituents independently selected from the group consisting of:
- C1-8alkyl, and
- halogen;
- R6 is selected from the group consisting of:
- C1-8 alkyl, aryl(C1-8)alkyl, C1-8 alkoxy, aryl(C1-8)alkoxy, C2-8 alkenyl, C2-8 alkenyloxy, aryl(C2-8)alkenyl, aryl(C2-8)alkenyloxy, aryl, aryloxy and hydroxy;
- and racemates, enantiomers, diastereomers and salts thereof.
41 more elements
A process for preparing a compound of Formula (Ic) comprising the step of reacting a first compound of Formula (A):
- with a second compound of Formula (B) in a suitable solvent for a suitable time and at a suitable temperature:
- to produce a third compound of Formula (D):
- wherein
- R7 is methyl;
- R8 is 1-(2-naphthalenylcarbonyl)-4-piperidinyl;
- R4 is selected from the group consisting of:
- C1-4 alkyl, optionally substituted on a terminal carbon atom with aryl, and aryl,
- wherein aryl and the aryl portions of the substituted alkyl are optionally substituted with one to four substituents independently selected from the group consisting of:
- C1-4 alkyl,
- amino, substituted with two substituents independently selected from the group consisting of:
- hydrogen, and
- C1-4 alkyl,
- cyano,
- halogen,
- hydroxy, and
- (halo)1-3(C1-8)alkyl;
- R2 and R3 are attached to a benzene ring and R2 and R3 together form a 6-membered carbocyclic ring fused to the benzene ring;
- thereby providing a multiple ring system;
- wherein the multiple ring system is selected from the group consisting of:
- benzo fused cyclohexyl,
- benzo fused cyclohexenyl, and
- naphthalenyl,
- wherein the multiple ring system can optionally be substituted with one to four substituents independently selected from the group consisting of:
- da) C1-4 alkyl optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of:
- amino, substituted with two substituents independently selected from the group consisting of:
- hydrogen, and
- C1-4 alkyl,
- (halo)1-3, and
- hydroxy;
- db) C1-4 alkoxy optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of:
- (halo)1-3, and
- hydroxy;
- dc) amino substituted with two substituents independently selected from the group consisting of:
- hydrogen, and
- C1-4 alkyl;
- dd) halogen;
- de) hydroxy;
- and
- df) nitro;
- R5 is selected from the group consisting of:
- hydrogen,
- C1-8 alkyl, optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of:
- amino, substituted with two substituents independently selected from the group consisting of:
- hydrogen, and
- C1-4 alkyl,
- (halo)1-3 and
- hydroxy, and
- aryl, optionally substituted with one to four substituents independently selected from the group consisting of:
- C1-8 alkyl, and
- halogen;
- R6 is selected from the group consisting of:
- C1-8 alkyl, aryl(C1-8)alkyl, C1-8 alkoxy, aryl(C1-8)alkoxy, C2-8 alkenyl, C2-8 alkenyloxy, aryl(C2-8)alkenyl, aryl(C2-8)alkenyloxy, aryl, aryloxy and hydroxy;
- X is O;
- and
- Z is hydrogen,
- and racemates, enantiomers, diastereomers and salts thereof.
53 more elements
Dependencies are inferred from the claim text.