Patent EA-002907-B1 (EA)
Title: 6-phenylpyridyl-2-amine derivatives useful as non inhibitors
Inventor: LOWE JOHN ADAMS III
IPC: A61P25/06
Filed: 1997-11-17
Abstract: 1. A compound of the formula   wherein R<1> and R<2> are selected, independently, from hydrogen, hydroxy, methyl and methoxy; and G is a group of the formula     wherein n is zero or one, Y is NR<3>R<4>, (C1-C6)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 (C1-C6)alkyl and the aryl moiety of said aralkyl may be substituted with from one to three substituents, that are selected, independently, from halo, nitro, hydroxy, cyano, amino, (C1-C4)alkoxy and (C1-C4) alkylamino; X is N when Y is (C1-C6) alkyl, aralkyl, or substituted (C1-C6)alkyl, and X is CH when Y is NR<3>R<4>; q is zero, one or two; m is zero, one or two; and R<3> and R<4> are selected, independently, from (C1-C6) 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-C6) alkyl and said tetrahydronaphthalene and the aryl moiety of said aralkyl may optionally be substituted with from one to three 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 optionally substituted piperazine, optionally substituted piperidine or optionally substituted 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; or a pharmaceutically acceptable salt of such compound. 2. A compound according to Claim 1, wherein q is zero or one. 3. A compound according to Claim 1, wherein NR<3>R<4> is piperidine, piperazine or pyrrolidine ring or a 3-aza-bicyclo[3.1.0]hex-6-ylamine ring, and wherein said piperazine, piperidine and pyrrolidine rings may optionally be substituted with one or more substituents, that are selected, independently, from 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, that are selected, independently, from halo, (C1-C3)alkyl, (C1-C3)alkoxy, nitro, amino, cyano, CF3 and OCF3; and the pharmaceutically acceptable salts of such compounds. 4. A compound according to Claim 3 wherein said piperazine, piperidine and pyrrolidine NR<3>R<4> rings are optionally substituted with one to two substituents, and wherein the phenyl moieties of any of the foregoing substituents are substituted with one to two substituents. 5. A compound according to Claim 1 wherein NR<3>R<4 >is 4-phenylethylpiperazin-1-yl, 4-methylpiperazin-1-yl, phenethylamino, or 3-aza-bicyclo[3.2.1]hex-6-ylamine. 6. A compound according to Claim 1 wherein NR<3>R<4> is a group of the formula   wherein NR<5>R<6> is NH2. 7. A compound, selected from the group, consisting of: 6-[4-((2-(phenetyl)-[2.2.1]bicyclohept-1-yl)methyl)phenyl]pyridin-2-ylamine; 6-[4-((2-(3-aza-bicyclo[3.1.0]hex-6-ylamino)-[2.2.1]bicyclohept-1-yl)methyl)phenyl]pyridin-2-ylamine; 6-[((-(N-phenetylamino)-5-phenylcyclohexylmethyl)methyl)phenyl]pyridin-2-ylamine; 6-[4-((2-(phenetyl)-[2.2.1]bicyclohept-1-yl)methyl)phenyl]pyridin-2-ylamine; 6-[((2-(3-aza-bicyclo[3.1.0]hex-6-ylamino)-5-phenylcyclohexylmethyl)methyl)phenyl]pyridin-2-ylamine; N-methyl-(2-aminopyride-6-yl-benzyliden)oxindole; N-methyl-(2-aminopyride-6-yl-benzyl)oxindole; N-(2-dimethylaminoethyl)-(2-aminopyride-6-yl-benzyliden)oxindole; N-(2-dimethylaminoethyl)-(2-aminopyride-6-yl-benzyl)oxindole; 6-[(N-5-isoxazolylmethyl)-4-(piperidine-4-yl)phenyl]pyridin-2-ylamine; 6-[(N-acetamido)-4-(piperidine-4-yl)phenyl]pyridin-2-ylamine; 6-[(N-benzoylmethyl)-4-(piperidine-4-yl)phenyl]pyridin-2-ylamine; 6-[(N-3,4-methylenedioxibenzyl)-4-(piperidine-4-yl)phenyl]pyridin-2-ylamine; 6-[(N-(2-furyl)methyl)-4-(piperidine-4-yl)phenyl]pyridin-2-ylamine; 6-[(N-(5-isothiazolyl)methyl)-4-(piperidine-4-yl)phenyl]pyridyn-2-ylamine; 6-[(N-(5-thiazolyl)methyl)-4-(piperidine-4-yl)phenyl]pyridyn-2-ylamine; 6-[(N-(2-pyridyl)methyl)-4-(piperidine-4-yl)phenyl]pyridyn-2-ylamine; 6-[(N-(3-pyridyl)methyl)-4-(piperidine-4-yl)phenyl]pyridin-2-ylamine; 6-[(N-(2-imidazolyl)methyl)-4-(piperidine-4-yl)phenyl]pyridin-2-ylamine; 6-[(N-(4-imidazolyl)methyl)-4-(piperidine-4-yl)phenyl]pyridin-2-ylamine; 6-[(N-(4-pyridyl)methyl)-4-(piperidine-4-yl)phenyl]pyridin-2-ylamine; 6-[(N-(2-furyl)methyl)-4-(pyrrolidine-3-yl)phenyl]pyridin-2-ylamine; 8-[4-(6-aminopyridin-2-yl)phenyl]-3-isobutyl-3-aza-bicyclo[3.2.1]octane-8-ol; 8-[4-(6-aminopyridin-2-yl)phenyl]-3-furan-2-ylmethyl-3-aza-bicyclo[3.2.1]octane-8-ol; and 8-[4-(6-aminopyridin-2-yl)phenyl]-3-benzyl-3-aza-bicyclo[3.2.1]octane-8-ol. 9. A compound of the formula   wherein R<1> and R<2> are selected, independently, from hydrogen, hydroxy, methyl and methoxy; G is selected from [2.2.1]bicyclohept-6-ylmethyl, substituted NR<3>R<4>; [2.2.1] bicyclohept-1-ylmethyl, substituted NR<3>R<4>; 3-azabicyclo [3.2.1]octane-8-ol, 3N- substituted with isopropyl, benzyl or furanylmethyl; (5-phenylcyclohexylmethyl), substituted NR<3>R<4>; oxindolylmethyl or oxindolylmethylene, N-substituted with methyl or 2-dimethylaminoethyl; and the group of formula   or   wherein n is zero or one, Y is hydrogen, NR<3>R<4>, (C1-C6)alkyl or aralkyl, wherein the aryl moiety of said aralkyl is phenyl, naphthyl, izoxazolyl, methylenedioxybenzyl, imidazolyl, pyridyl, furyl, thiazolyl or izothiazolyl, and the alkyl moiety is straight or branched and contains from 1 to 6 carbon atoms, and wherein said (C1-C6)alkyl and the aryl moiety of said aralkyl may be substituted with from one to three substituents, preferably from zero to two, that are selected, independently, from phenyl, -C(O)NH2, -C(O)phenyl, halo (e.g., chloro, fluoro, bromo or iodo), nitro, hydroxy, cyano, amino, (C1-C4) alkoxy, and (C1-C4) alkylamino; X is N when Y is (C1-C6) alkyl, aralkyl, or substituted (C1-C6)alkyl, and X is CH when Y is NR<3>R<4>; q is zero, one or two; m is zero, one or two; and R<3> and R<4> are selected, independently, from hydrogen, (C1-C6) alkyl, -C(O)(C1-C5)alkyl, cyclohexyl, 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-C6) alkyl and said -C(O)(C1-C5)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, that are selected, independently, from phenyl, halo (e.g., chloro, fluoro, bromo or iodo), 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 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, pyrrolidine or an azabicyclic ring, formed by R<3> and R<4>, may optionally be substituted with one or more substituents, preferably from zero to two, that are selected, independently, from (C1-C6)alkyl, amino, (C1-C6) alkylamino, [di-(C1-C6)alkyl]amino, (C1-C6) alkylacetamido, 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 from zero to two, that are selected, independently, from halo, (C1-C6)alkyl, (C1-C6)alkoxy, nitro, amino, cyano, CF3 and OCF3; and the pharmaceutically acceptable salts of such compounds. 10. A compound, selected from the group, consisting of: 6-[(N-(5-isothiazolyl)methyl)-4-(piperidine-4-yl)phenyl]pyridin-2-ylamine; 6-[(N-(5-thiazolyl)methyl)-4-(piperidine-4-yl)phenyl]pyridin-2-ylamine; 6-[(N-(2-furyl)methyl)-4-(pyrrolidine-3-yl)phenyl]pyridin-2-ylamine; 6-[(N-(2-methyl)propyl)-4-(pyrrolidine-3-yl)phenyl]pyridin-2-ylamine. 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, osteoarthoursitis, rheumatoid arthoursitis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington's disease, Parkinson's disease, glaucoma, macular degeneration, diabetic neuropathy, diabetic nephoursopathy and cancer in a mammal, comprising an amount of a compound according to Claim 1, 8, or 9, that is effective in treating or preventing such condition and a pharmaceutically acceptable carrier. 12. 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, inflammator