2-oxo-imidazolidine-4-carboxylic acid hydroxamide compounds that inhibit matrix metalloproteinases

Abstract

The present invention relates to a compound of the formula wherein R 1 , R 2 , R 3 and R 4 are as defined above, and pharmaceutically acceptable salts and solvates thereof, that are useful, for example, as matrix metalloproteinase inhibitors. The present invention is also directed to pharmaceutical compositions comprising such compounds and methods of treatment for diseases such as osteoarthritis, rheumatoid arthritis, cancer, osteoporosis, tissue ulceration, restinosis, periodontal disease, inflammation, epidermolysis bullosa, scleritis, stroke, Alzheimer's disease, and the like, characterized by inappropriate matrix metalloproteinase activity. Processes for the synthesis of compounds of formula (I) are also disclosed.

1 . A compound according to formula (1)  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein 
 R 1  is (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 1 -C 9 )heteroaryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 9 )heteroaryl (C 1 -C 9 )heteroaryl(C 1 -C 9 )heteroaryl, (C 6 -C 10 )aryloxy(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryloxy(C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy(C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy(C 1 -C 9 )heteroaryl, (C 6 -C 10 )aryloxy(C 1 -C 6 )alkyl, (C 1 -C 9 )heteroaryloxy(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl(C 1 -C 6 )alkyl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl(C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryl(C 1 -C 6 )alkyl(C 1 -C 9 )heteroaryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 1 -C 9 )heteroaryl, (C 6 -C 10 )aryloxy(C 1 -C 6 )alkyl(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryloxy(C 1 -C 6 )alkyl(C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy(C 1 -C 6 )alkyl(C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryloxy(C 1 -C 6 )alkyl(C 1 -C 9 )heteroary, (C 6 -C 10 )aryl(C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 1 -C 9 )heteroaryl(C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C   9 )heteroaryl(C 1 -C 6 )alkyl, (C 1 -C 9 )heteroaryl(C 1 -C 9 )heteroaryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, or (C 1 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl,  
 wherein, independently, each of the ring carbon atoms of said (C 6 -C 10 )aryl and (C 1 -C 9 )heteroaryl moieties that is capable of forming an additional bond is optionally substituted by a group selected from fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and perfluoro(C 1 -C 3 )alkyl, and perfluoro(C 1 -C 3 )alkoxy;  
 R 2  and R 3  are each independently selected from hydrogen and (C 1 -C 6 )alkyl, or taken together form a spiro ring of the formula  
                     
 wherein X is a bond, CH 2 , O, S, NH or N(C 1 -C 6 )alkyl, n is independently 1 or 2, and m is independently 1 or 2; and  
 
         R 4  is hydrogen or (C 1 -C 6 )alkyl.  
       
     
     
         2 . A compound according to  claim 1  of the formula (I′)  
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound according to  claim 1  wherein R 2 , R 3  and R 4  are hydrogen.  
     
     
         4 . A compound according to  claim 1  wherein R 4  is hydrogen.  
     
     
         5 . A compound according to  claim 1  wherein R 4  is (C 1 -C 6 )alkyl.  
     
     
         6 . A compound according to  claim 1  wherein R 2  and R 3  are hydrogen.  
     
     
         7 . A compound according to  claim 1  wherein R 2  and R 3  are (C 1 -C 6 )alkyl such that R 2  is the same as R 3 .  
     
     
         8 . A compound according to  claim 1  wherein R 2  and R 3  taken together form a spiro ring of the formula  
       
         
           
           
               
               
           
         
         wherein X is a bond, CH 2 , O, S, NH or N(C 1 -C 6 )alkyl, n is 1 or 2, and m is 1 or 2 such that n is the same as m.  
       
     
     
         9 . A compound according to  claim 1  wherein R 1  is selected from the group consisting of (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 6 -C 10 )aryloxy(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryloxy(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, and (C 1 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl.  
     
     
         10 . A compound according to  claim 1  wherein R 1  is selected from the group consisting of 4-[(C 6 -C 10 )aryl]phenyl, 4-[(C 6 -C 10 )aryloxy]phenyl and 4-[(C 6 -C 10 )aryl(C 1 -C 6 )alkoxy]phenyl.  
     
     
         11 . A compound according to  claim 1  wherein R 1  is selected from the group consisting of 4-[(C 1 -C 1 )heteroaryl]phenyl, 4-[(C 1 -C 9 )heteroaryloxy]phenyl and 4-[(C 1 -C 9 )heteroaryl(C 1 -C 6 )alkoxy]phenyl.  
     
     
         12 . A compound according to  claim 1  wherein R 1  is 4-(4-fluorophenoxy)phenyl.  
     
     
         13 . A compound according to  claim 1 , wherein R 1  is 4-(4-chlorophenoxy)phenyl.  
     
     
         14 . A compound according to  claim 1 , wherein R 1  is 4-(naphthalen-2-yloxy)phenyl.  
     
     
         15 . A compound according to  claim 3 , wherein R 1  is selected from the group consisting of (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 6 -C 10 )aryloxy(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryloxy(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 1 -C 10 )heteroaryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, and (C 1 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl.  
     
     
         16 . A compound according to  claim 4 , wherein R 1  is selected from the group consisting of (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 6 -C 10 )aryloxy(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryloxy(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, and (C 1 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl.  
     
     
         17 . A compound according to  claim 5 , wherein R 1  is selected from the group consisting of (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 6 -C 10 )aryloxy(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryloxy(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, and (C 1 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl.  
     
     
         18 . A compound according to  claim 6 , wherein R 1  is selected from the group consisting of (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 6 -C 10 )aryloxy(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryloxy(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 1 -C)heteroaryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, and (C 1 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl.  
     
     
         19 . A compound according to  claim 7 , wherein R 1  is selected from the group consisting of (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 6 -C 10 )aryloxy(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryloxy(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, and (C 1 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl.  
     
     
         20 . A compound according to  claim 8 , wherein R 1  is selected from the group consisting of (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, (C 6 -C 10 )aryloxy(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryloxy(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, and (C 1 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl.  
     
     
         21 . A compound according to  claim 1  selected from the group consisting of: 
 (4R)-1-[4-(4-Fluorophenoxy)benzyl]-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-1-[4-(Naphthalen-1-yloxy)benzyl]-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-1-[4-(Naphthalen-2-yloxy)benzyl]-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-1-(4-Methoxybenzyl)-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-1-[3-(4-Fluorophenoxy)benzyl]-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-1-Naphthalen-2-ylmethyl-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-1-(4′-Fluorobiphenyl-4-ylmethyl)-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-1-(4-Benzyloxybenzyl)-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide; and  
 (4R)-1-[4-(2-Chloro-4-fluorobenzyloxy)benzyl]-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 
     
     
         22 . A compound according to  claim 1  selected from the group consisting of: 
 (4R)-1-[4-(4-Chlorophenoxy)benzyl]-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-1-[4-(4-Fluorophenoxy)benzyl]-2-oxo-7-oxa-1,3-diazaspiro[4.4]nonane-4-carboxylic acid hydroxyamide;  
 (4R)-2-Oxo-1-[4-(pyridin-4-yloxy)benzyl]imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-4-Methyl-2-oxo-1-[4-(pyridin-4-yloxy)benzyl]imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-5,5-Dimethyl-2-oxo-1-[4-(pyridin-4-yloxy)benzyl]imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-1-[4-(4-Fluorophenoxy)benzyl]-5,5-dimethyl-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-1-[4-(4-Chlorophenoxy)benzyl]-5,5-dimethyl-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-1-[4-(4-Fluorophenoxy)benzyl]-4-methyl-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-1-[4-(4-Chlorophenoxy)benzyl]-4-methyl-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-1-[4-(4-Fluorophenoxy)benzyl]-2-oxo-1,3-diazaspiro[4.4]nonane-4-carboxylic acid hydroxyamide;  
 (4R)-1-[4-(4-Chlorophenoxy)benzyl]-2-oxo-1,3-diazaspiro[4.4]nonane-4-carboxylic acid hydroxyamide;  
 (4R)-1-[4-(4-Fluorophenoxy)benzyl]-4,5,5-trimethyl-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-1-[4-(4-Chlorophenoxy)benzyl]-4,5,5-trimethyl-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-4-Methyl-1-[4-(naphthalen-2-yloxy)benzyl]-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-5,5-Dimethyl-1-[4-(naphthalen-2-yloxy)benzyl]-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-1-[4-(5-Fluoropyridin-2-yloxy)benzyl]-4-methyl-2-oxo-imidazolidine-4-carboxylic acid hydroxyamide;  
 (4R)-2-Oxo-1-(4-pyridin-4-ylbenzyl)imidazolidine-4-carboxylic acid hydroxyamide and  
 (4R)-2-Oxo-1-(4-pyridylmethyl)imidazolidine-4-carboxylic acid hydroxyamide.  
 
     
     
         23 . A pharmaceutical composition for the treatment of a condition selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, inflamamation, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, bums, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis and septic shock in a mammal, including a human, comprising an amount of a compound of  claim 1  effective in such treatment, and a pharmaceutically acceptable carrier.  
     
     
         24 . A method for treating a condition selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, inflammation, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, bums, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis and septic shock in a mammal, including a human, comprising administering to said mammal an amount of a compound of  claim 1 , effective in treating such a condition.  
     
     
         25 . A pharmaceutical composition for the treatment of a condition which can be treated by the inhibition of matrix metalloproteinases in a mammal, including a human, comprising an amount of a compound of  claim 1  effective in such treatment and a pharmaceutically acceptable carrier.  
     
     
         26 . A pharmaceutical composition for the treatment of a condition which can be treated by the inhibition of a mammalian reprolysin in a mammal, including a human, comprising an amount of a compound of  claim 1  effective in such treatment and a pharmaceutically acceptable carrier.  
     
     
         27 . A method for the inhibition of matrix metalloproteinases in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of  claim 1 .  
     
     
         28 . A method for the inhibition of a mammalian reprolysin in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of  claim 1.