Patent EA-003834-B1 (EA)
Title: 2-amino-6-(2-substituted-4-phenoxy)-substituted-pyridines as a nitric oxide synthase inhibitors
Inventor: LOWE JOHN ADAMS III
IPC: C07D401/12
Filed: 1998-01-29
Abstract: 1. A compound of the formula wherein R<1> and R<2> are selected, independently, from hydrogen, halo, hydroxy, (C1-C6)alkoxy, (C1 - C7)alkyl, (C2-C6)alkenyl, and (C2 - C10)alkoxyalkyl; and G is selected from hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy-(C1-C3)alkyl, aminocarbonyl-(C1-C3)alkyl-, (C1-C3) alkylaminocarbonyl (C1-C3) alkyl-, di-[(C1-C3)alkyl]aminocarbonyl-(C1-C3) alkyl-, and N(R<3>)(R<4>)(C0-C4)alkyl-, wherein R<3> and R<4> are selected, independently, from hydrogen, (C1-C7) alkyl, tetrahydronaphthalene and 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 (C1-C7) 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, nitro, hydroxy, cyano, amino, (C1-C4) alkoxy, and (C1-C4) alkylamino; or R<3> and R<4> form, together with the nitrogen to which they are attached, a piperazine, piperidine, azetidine or pyrrolidine ring or a saturated or unsaturated azabicyclic ring system containing from 6 to 14 ring members, from 1 to 3 of which are nitrogen, from zero to two of which are oxygen, and the rest of which are carbon; and wherein said piperazine, piperidine, azetidine and pyrrolidine rings and said azabicyclic ring systems 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 ring 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; and wherein said piperazine, piperidine, azetidine and pyrrolidine rings and said azabicyclic ring systems may be attached to -(C0-C4)alkyl-O- (wherein the oxygen of said -(C0-C4)alkyl-O- is the oxygen atom depicted in structural formula I) at a nitrogen atom of the NR<3>R<4> ring or any other atom of the ring having an available bonding site; or G is a group of the formula A wherein Z is nitrogen or CH, n is zero or one, q is zero, one, two or three and p is zero, one or two; and wherein the 2-amino piperidine ring depicted in structure 1 above may optionally be replaced with or a pharmaceutically acceptable salt of such compound. 2. A compound according to claim 1, wherein G is NR<3>R<4>(C0-C4)alkyl and NR<3>R<4> is a piperidine, piperazine or pyrrolidine ring. 3. A compound according to claim 1 wherein R<1> and R<2> are selected from hydrogen and (C1-C2)alkyl. 4. A compound according to claim 1 wherein G is NR<3>R<4>(C0-C4)alkyl and NR<3>R<4> is a group of the formula 5. A compound according to claim 1 wherein G is a group of the formula A and Z is nitrogen. 6. A compound according to claim 1 wherein G is a group of the formula A, Z is nitrogen, each of n and p is one and q is two. 7. A pharmaceutical composition for treating or preventing a condition comprising 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. 8. A method of treating or preventing a condition associated with excess of nitric oxide, produced by nitric oxide synthase 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. 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 nephrosopathy 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 method of treating or preventing a condition associated with excess of nitric oxide, produced by nitric oxide synthase 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 nephrosopathy and cancer in a mammal, comprising administering to said mammal a NOS inhibiting effective amount of a compound according to claim 1. 13. A compound of the formula wherein R<1> and R<2> are selected, independently, from hydrogen, halo, hydroxy, (C1-C6)alkoxy, (C1-C7)alkyl, (C2-C6)alkenyl, and (C2 - C10)alkoxyalkyl; and G is selected from hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy-(C1-C3)alkyl, aminocarbonyl-(C1-C3)alkyl-, (C1-C3) alkylaminocarbonyl -(C1-C3) alkyl-, di-[(C1-C3)alkylaminocarbonyl-(C1-C3) alkyl-, and N(R<3>)(R<4>)(C0-C4)alkyl-, wherein R<3> and R<4> are selected, independently, from hydrogen, (C1-C7) alkyl, tetrahydronaphthalene and 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 (C1-C7) 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, nitro, hydroxy, cyano, amino, (C1-C4) alkoxy, and (C1-C4) alkylamino; or R<3> and R<4> form, together with the nitrogen to which they are attached, a piperazine, piperidine, azetidine or pyrrolidine ring or a saturated or unsaturated azabicyclic ring system containing from 6 to 14 ring members, from 1 to 3 of which are nitrogen, from zero to two of which are oxygen, and the rest of which are carbon; and wherein said piperazine, piperidine, azetidine and pyrrolidine rings and said azabicyclic ring systems 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 ring 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; and wherein said piperazine, piperidine, azetidine and pyrrolidine rings and said azabicyclic ring systems may be attached to -(C0-C4)alkyl-O- (wherein the oxygen of said -(C0-C4)alkyl-O- is the oxygen at