Branched alkoxy-subsituted 2-aminopyridines

Abstract

The present invention relates to 6-phenyl-pyridin-2-ylamine derivatives of the formula wherein R 1 , R 2 , R 3 and R 4 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 X is CHOH, CH 2 , or CHR 10  wherein R 10 , together with X, the CH 2  group adjacent to X and the nitrogen of NR 1 R 2 , forms a five or six membered saturated ring;  
         R 1 , R 2 , R 3  and R 4  are selected, independently, from (C 1 -C 6 ) alkyl, tetrahydronaphthalene, aryl and aralkyl, wherein said aryl and the 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 said tetrahydronaphthalene and the aryl moiety of said aralkyl may optionally 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, iodo), nitro, hydroxy, cyano, amino, (C 1 -C 4 ) alkoxy, and (C 1 -C 4 ) alkylamino;  
         or R 1  and R 2 , together with the nitrogen to which they are attached, form a piperazine, piperidine or pyrrolidine ring or an azabicyclic ring containing from 6 to 14 ring members, from 1 to 3 of which are nitrogen and the rest of which are carbon;  
         and wherein said piperazine, piperidine and pyrrolidine rings may optionally be substituted with one or more substituents, preferably with from zero to two substituents that are selected, independently, from (C 1 -C 6 )alkyl, amino, (C 1 -C 6 ) alkylamino, [di-(C 1 -C 6 )alkyl]amino, phenyl substituted 5 to 6 membered heterocyclic rings containing from 1 to 4 rings nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein the phenyl moieties of any of the foregoing substituents may optionally be substituted with one or more substituents, preferably with from zero to two substituents, that are selected, independently, from halo, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, nitro, amino, cyano, CF 3  and OCF 3 ;  
         and the pharmaceutically acceptable salts of such compound.  
       
     
     
         2 . A compound according to  claim 1 , wherein R 1  and R 2 , together with the nitrogen to which they are attached, form a ring selected from  
       
         
           
           
               
               
           
         
         wherein R 5  and R 6  are selected from hydrogen, (C 1 -C 6 )alkyl, phenyl, naphthyl, (C 1 -C 6 )alkyl-C(═O)—, HC(═O)—, (C 1 -C 6 )alkoxy-(C═O)—, phenyl-C(═O)—, naphthyl-C(═O)—, and R 8 R 9 NC(═O)— wherein R 8  and R 9  are selected, independently, from hydrogen and (C 1 -C 6 )alkyl; and  
         R 7  is selected from hydrogen, (C 1 -C 6 )alkyl, phenyl, naphthyl, phenyl-(C 1 -C 6 )alkyl- and naphthyl(C 1 -C 6 )alkyl-.  
       
     
     
         3 . A compound according to  claim 1 , wherein R 1  and R 2 , together with the nitrogen to which they are attached, form an optionally substituted piperidine, piperazine pyrrolidine, or 3-aza-bicyclo[3.1.0]hex-6-ylamine ring.  
     
     
         4 . A compound according to  claim 1 , R 3  and R 4 , together with the carbon to which they are attached, form an optionally substituted carbocyclic ring of from 3 to 8 members.  
     
     
         5 . A pharmaceutical composition for treating or preventing a condition selected from the group consisting of migraine inflammatory diseases, asthma, psoriasis, 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, Alheimer's disease, Parkinson's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety, psychosis, depression, 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, 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 method of treating or preventing a condition selected from the group consisting of migraine inflammatory diseases, asthma, psoriasis, 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, Parkinson's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety, psychosis, depression, 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, 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.  
     
     
         7 . 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.  
     
     
         8 . 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 .  
     
     
         9 . A pharmaceutical composition for treating or preventing a condition selected from the group consisting of migraine, inflammatory diseases, asthma, psoriasis, 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, Parkinson's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety, psychosis, depression, 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, 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.  
     
     
         10 . A method of treating or preventing a condition selected from the group consisting of migraine, inflammatory diseases, asthma, psoriasis, 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, Parkinson's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety, psychosis, depression, 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, 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 .