Patent EA-003839-B1 (EA)
Title: 2-aminopyridines containing fused ring substituents as nos inhibitors
Inventor: LOWE JOHN ADAMS
IPC: A61P25/16
Filed: 1998-08-11
Abstract: 1. A compound of the formula wherein ring A is a fused 5-7 membered saturated or unsaturated ring wherein from zero to two of the ring members are heteroatoms selected, independently, from nitrogen, oxygen and sulfur, with the proviso that no two adjecent ring members can both be heteroatoms; X is oxygen or a bond; n is an interger from two to six; and R<1> and R<2> are selected, independently, from (C1-C6) alkyl, aryl, tetrahydronaphthalene and aralkyl, wherein said aryl and 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 (C1-C6) alkyl, said aryl, 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, (C1-C4) alkoxy, and (C1-C4) alkylamino; or R<1> and R<2> form, together with the nitrogen to which they are attached, 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, azetidine, 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 (C1-C6) alkyl, amino, (C1-C6) alkylamino, [di-(C1-C6)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, (C1-C3) alkyl, (C1-C3) alkoxy, nitro, amino, cyano, CF3 and OCF3; also R<1> or R<2> may be connected onto the (CH2)n group to form a ring of from 4 to 7 members; and the pharmaceutically acceptable salt of such compounds. 2. A compound according to claim 1, wherein NR<1>R<2> is an optionally substituted piperidine, azetidine, piperazine or pyrrolidine ring or a 3-aza-bicyclo[3.1.0]hex-6-ylamine ring; and wherein said piperazine, azetidine, 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 (C1-C6) alkyl, amino, (C1-C6) alkylamino, [di-(C1-C6) 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, (C1-C3) alkyl, (C1-C3) alkoxy, nitro, amino, cyano, CF3 and OCF3. 3. A compound according to claim 1 wherein NR<1>R<2> forms an azabicyclic ring having the formula and wherein R<3> and R<4> are selected from hydrogen, (C1-C6) alkyl, phenyl, naphthyl, (C1-C6) alkyl-C(=O)-, HC(=O)-, (C1-C6) alkoxy-(C=O)-, phenyl,-C(=O)-, naphthyl-C(=O)-, and R<6>R<7>NC(=O)- wherein R<6> and R<7> are selected, independently, from hydrogen and (C1-C6) alkyl; and R<5> is selected from hydrogen, (C1-C6) alkyl, phenyl, naphthyl, phenyl-(C1-C6) alkyl- and naphthyl(C1-C6) alkyl-. 4. 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, depression, Parkinson's disease, multiple sclerosis, AIDS associated dementia, neurodegenerative diseases, neuron toxicity, Aizheimer'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, 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. 5. 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, depression, Parkinson's disease, 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, 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. 6. 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. 7. 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. 8. 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, depression, Parkinson's disease, 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, 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. 9. 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, depression, Parkinson's disease, 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, 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.