6-Phenylpyridyl-2-amine derivatives useful as NOS inhibitors

Abstract

The present invention relates to 6-phenyl-pyridin-2-ylamine derivatives of the formula wherein G, R 1 and R 2 are defined as in the specification, that exhibit activity as nitric oxide synthase (NOS) inhibitors, to pharmaceutical compositions containing them, and to their use in the treatment and prevention of central nervous system and other disorders.

1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are selected, independently, from hydrogen, hydroxy, methyl and methoxy;  
 G is a group of the formula  
                     
  wherein 
 n is zero;  
 Y is hydrogen, (C 1 -C 6 )alkyl or aralkyl, wherein the aryl moiety of said aralkyl is phenyl, naphthyl, isoxazolyl, methylenedioxybenzyl, imidazolyl, pyridyl, furyl, thiazolyl, or isothiazolyl, and the alkyl moiety is straight or branched and contains from 1 to 6 carbon atoms, and wherein said (C 1 -C 6 )alkyl and the aryl moiety of said aralkyl may be substituted with from one to three substituents, preferably from zero to two substituents, that are selected, independently, from phenyl, —C(O)NH 2 , —C(O)phenyl, halo (e.g., chloro, fluoro, bromo or iodo), nitro, hydroxy, cyano, amino, (C 1 -C 4 )alkoxy and (C 1 -C 4 ) alkylamino;  
 X is n; and  
 q is zero, one or two;  
 or a pharmaceutically acceptable salt of such compound.  
 
 
     
     
         2 . A compound according to  claim 1 , wherein G is a group of the formula  
       
         
           
           
               
               
           
         
       
         
       wherein 
 n is zero;  
 Y is (C 1 -C 6 )alkyl or aralkyl, wherein the aryl moiety of said aralkyl is phenyl or naphthyl and the alkyl moiety is straight or branched and contains from 1 to 6 carbon atoms, and wherein said (C 1 -C 6 )alkyl and the aryl moiety of said aralkyl may be substituted with from one to three substituents, preferably from zero to two substituents, that are selected, independently, from halo (e.g., chloro, fluoro, bromo or iodo), nitro, hydroxy, cyano, amino, (C 1 -C 4 )alkoxy and (C 1 -C 4 ) alkylamino;  
 X is N; and  
 q is zero, one or two;  
 or a pharmaceutically acceptable salt of such compound.  
 
     
     
         3 . A compound according to  claim 1 , wherein q is zero or one.  
     
     
         4 . A compound according to  claim 1  selected from the group consisting of 
 6-[(N-(2-furyl)methyl)-4-(pyrrolidin-3-yl)-phenyl]-pyridin-2-ylamine; and  
 6-[(N-(2-methyl)propyl)-4-(pyrrolidin-3-yl)-phenyl]-pyridin-2-ylamine;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         5 . A pharmaceutical composition for treating or preventing a condition selected from the group consisting of migraine, inflammatory diseases, stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS associated dementia, neurodegenerative diseases, neuron toxicity, Alzheimer's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety, psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine induced tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington's disease, Parkinson's disease, glaucoma, macular degeneration, diabetic neuropathy, diabetic nephropathy and cancer in a mammal, comprising an amount of a compound according to  claim 1  that is effective in treating or preventing such condition and a pharmaceutically acceptable carrier.  
     
     
         6 . A pharmaceutical composition for treating or preventing depression in a mammal comprising and amount of a compound according to  claim 1  that is effective in treating or preventing depression and a pharmaceutically acceptable carrier.  
     
     
         7 . A method of treating or preventing a condition selected from the group consisting of migraine, inflammatory diseases, stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS associated dementia, neurodegenerative diseases, neuron toxicity, Alzheimer's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety, psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine induced tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington's disease, Parkinson's disease, glaucoma, macular degeneration, diabetic neuropathy, diabetic nephropathy and cancer in a mammal, comprising administering to said mammal an amount of a compound according to  claim 1 , that is effective in treating or preventing such condition.  
     
     
         8 . A method of treating or preventing depression in a mammal comprising administering to said mammal an amount of a compound according to  claim 1  that is effective in treating or preventing depression.  
     
     
         9 . A pharmaceutical composition for inhibiting nitric oxide synthase (NOS) in a mammal, according to  claim 1 , comprising a NOS inhibiting effective amount of a compound according to  claim 1 , and a pharmaceutically acceptable carrier.  
     
     
         10 . A method of inhibiting NOS in a mammal, comprising administering to said mammal a NOS inhibiting effective amount of a compound according to  claim 1 .  
     
     
         11 . A pharmaceutical composition for treating or preventing a condition selected from the group consisting of migraine, inflammatory diseases, stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS associated dementia, neurodegenerative diseases, neuron toxicity, Alzheimer's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety, psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine induced tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington's disease, Parkinson's disease, glaucoma, macular degeneration, diabetic neuropathy, diabetic nephropathy and cancer in a mammal, comprising a NOS inhibiting effective amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         12 . A pharmaceutical composition for treating or preventing depression in a mammal, comprising a NOS inhibiting effective amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         13 . A method of treating or preventing a condition selected from the group consisting of migraine, inflammatory diseases, stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS associated dementia, neurodegenerative diseases, neuron toxicity, Alzheimer's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety, psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine induced tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington's disease, Parkinson's disease, glaucoma, macular degeneration, diabetic neuropathy, diabetic nephropathy and cancer in a mammal, comprising administering to said mammal a NOS inhibiting effective amount of a compound according to  claim 1 .  
     
     
         14 . A method of treating or preventing depression in a mammal, comprising administering to said mammal a NOS inhibiting effective amount of a compound according to  claim 1.