Patent EA-003991-B1 (EA)
Title: 2-aminopyridines derivatives, nitric oxide synthase inhibiting method, pharmaceutical compositions and method of treating
Inventor: LOWE JOHN ADAMS III
IPC: C09K23/16
Filed: 1999-05-07
Abstract: 1. 2-aminopyridine derivatives of the formula wherein n and m in the bridging rings are independently 1, 2 or 3, and a carbon in one of said bridging rings may be substituted by a heteroatom selected from O, S and N, with the proviso that a bridgehead carbon can only be substituted by nitrogen, and R<1> and R<2> are independently selected from C1 to C6 alkyl, which may be linear, branched or cyclic or contain both linear and cyclic branched and cyclic moieties, wherein each of R<1> and R<2> may independently be optionally substituted with from one to three substituents, preferably from zero to two substituents, that are selected, independently, from halo, nitro, hydroxy, cyano, amino, C1 to C4 alkoxy, and C1 to C4 alkylamino; or R<1> and R<2> form, together with the nitrogen to which they are attached, a piperazine, azetidine, 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, wherein the distal nitrogen on said piperazine or azabicyclic ring is optionally substituted with groups R<3> and R<4> wherein R<3> and R<4> are selected from hydrogen, C1 to C6 alkyl, phenyl, naphthyl, C1 to C6 alkyl-C(=O)-, HC(=O)-, C1 to 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 to C6 alkyl, with the proviso that when said azabicyclic ring is a spirocyclic ring, the distal nitrogen on said spirocyclic ring is optionally substituted with R<5> wherein R<5> is selected from hydrogen, C1 to C6 alkyl, phenyl, naphthyl, phenyl-C1 to C6 alkyl- and naphthyl C1 to C6 alkyl-; 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 to C6 alkyl, amino, C1 to C6 alkylamino, [di C1 to C6alkyl] 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 mote substituents, preferably with from zero to two substituents, that are selected, independently, from halo, C1 to C3 alkyl, C1 to C3 alkoxy, nitro, amino, cyano, CF3 and OCF3; with the proviso that no carbon atom is substituted with more than one substituent selected from hydroxy, amino, alkoxy, alkylamino and dialkylamino; and the pharmaceutically acceptable salts of said compound. 2. A compound preferred according to claim 1, said compound selected from 6-[8-(2-Dimethylamino-ethoxy)-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl]-pyridin-2-ylamine; 6-[8-(2-Pyrrolidin-1-yl-ethoxy)-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl]-pyridin-2-ylamine; 6-[8-(2-Dimethylamino-ethoxy)-1,2,3,4-tetrahydro-1,4-ethano-naphthalen-5-yl]-pyridin-2-ylamine; 6-[8-(2-Pyrrolidin-1-yl-ethoxy)-1,2,3,4-tetrahydro-1,4-ethano-naphthalen-5-yl]-pyridin-2-ylamine; 6-[8-(4-methylpiperazin-1-yl-ethoxy)-1,2,3,4-tetrahydro-1,4-ethano-naphthalen-5-yl]-pyridin-2-ylamine; and 6-[8-(4-(2-phenethyl)-piperazin-1-yl-ethoxy)-1,2,3,4-tetrahydro-1,4-ethano-naphthalen-5-yl] pyridin-2-ylamine. 3. 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, pyrrolidine and 3-aza-bicyclo[3.1.0]hex-6-ylamine rings may optionally be substituted with one or more substituents, preferably with from zero to two substituents that are selected, independently, from C1 to C6 alkyl, amino, C1 to C6 alkylamino, [di- C1 to 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 to C3 alkyl, C1 to C3 alkoxy, nitro, amino, cyano, CF3 and OCF3. 4. A compound according to claim 1 wherein NR<1>R<2> forms an azabicyclic ring having the formula or wherein R<3> and R<4> are selected from hydrogen, C1 to C6 alkyl, phenyl, naphthyl, C1 to C6 alkyl-C(=O)-, HC(=O)-, C1 to 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 to C6 alkyl; and R<5> is selected from hydrogen, C1 to C6 alkyl, phenyl, naphthyl, phenyl- C1 to C6 alkyl- and naphthyl C1 to C6 alkyl-. 5. A pharmaceutical composition for treating or preventing a condition selected from the group consisting of migraine inflammatory diseases, psoriasis, asthma, 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 including Parkinson's disease, neuron toxicity, Alzheimer's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety, depression, 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, ocular diseases, 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, psoriasis, asthma, 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 including Parkinson's disease, neuron toxicity, Alzheimer'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, ocular diseases, 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, psoriasis, asthma, 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 including Parkinson's disease, neuron toxicity, Alzheimer's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety, depression, 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, ocular diseases, 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, psoriasis, asthma, 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 including Parkinson's disease, neuron toxicity, Alzheimer's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety, depression, 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, ocular diseases, 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. 11. A compound of the formula wherein n and m in the bridging rings are independently 1, 2 or 3, and a carbon in one of said bridging rings may be substituted by a heteroatom selected from O, S and N, with the proviso that a bridgehead carbon can only be substituted by nitrogen, and R<1> and R<2> are independently selected from C1 to C6 alkyl, which may be linear, branched or cyclic or contain both linear and cyclic branched and cyclic moieties, wherein each of R<1> and R<2> may independently be optionally substituted with from one to three substituents, preferably from zero to two substituents, that are selected, independently, from halo, nitro, hydroxy, cyano, amino, C1 to C4 alkoxy, and C1 to C4 alkylamino; or R<1> and R<2> form, together with t