Patent EA-003669-B1 (EA)
Title: Aryl fused azapolycyclic compounds
Inventor: COE JOTHAM WADSWOTH
IPC: C07D221/22
Filed: 1999-04-08
Abstract: 1. A compound of the formula wherein Z is CH2; R<1> is hydrogen, (C1-C6) alkyl or benzyl; R<2> and R<3> are selected independently, from hydrogen, hydroxy, nitro, halo, -SOq(C1-C6) alkyl, wherein q is zero, one or two, CO2R<4>, aryl-(C0-C3) alkyl or aryl-(C0-C3) alkyl-O-, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl or heteroaryl-(C0-C3) alkyl-O-, wherein said heteroaryl is selected from pyridine and pyrimidine, and (C0-C6) alkoxy-(C0-C6) alkyl, wherein said (C0-C6) alkoxy-(C0-C6) alkyl contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C0-C6) alkoxy-(C0-C6) alkyl moiety may optionally be replaced by an oxygen atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C0-C6) alkoxy-(C0-C6) alkyl may be optionally substituted with up to two fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(C0-C3) alkyl and said heteroaryl-(C0-C3) alkyl may optionally be replaced by an oxygen atom, and wherein each of the foregoing aryl groups may optionally be substituted with one or more substituents, independently selected from (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy optionally substituted with up to two fluorine atoms; or R<2> and R<3>, together with the carbons to which they are attached, form a four to seven membered monocyclic carbocyclic ring, wherein from one to three of the nonfused carbon atoms of said monocyclic rings may optionally and independently be replaced by an oxygen; R<4> is selected, independently, from hydrogen and (C1-C6) alkyl; with the proviso that: (a) at least one of R<1>, R<2> and R<3> must be the other than hydrogen, (b) when R<2> and R<3> are hydrogen, R<1> cannot be methyl or hydrogen; and (c) no fluorine atom in any of the fluoro substituted alkyl or alkoxy moieties of R<2> and R<3> can be attached to a carbon that is attached to a heteroatom; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein R<2> and R<3>, do not, together with the benzo ring of formula I, form a bicyclic or tricyclic ring system. 3. A compound according to claim 1, wherein one of R<2> and R<3> is fluoro. 4. A pharmaceutical composition for use in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a mammal, comprising an amount of a compound according to claim 1 that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use and a pharmaceutically acceptable carrier. 5. A method for reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a mammal, comprising administering to said mammal an amount of a compound according to claim 1 that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use. 6. A pharmaceutical composition for treating a disorder or condition selected from inflammatory bowel disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstridion, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amytotropic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac anythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions, headache, stroke, TBI, psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome in a mammal, comprising an amount of a compound according to daim 1 that is effective in treating such disorder or condition and a pharmaceutically acceptable carrier. 7. A method for treating a disorder or condition selected from inflammatory bowel disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstridion, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amylotropic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac anythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions, headache, stroke, TBI, psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age related cognitive dedine, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimers type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound according to claim 1 that is effective in treating such disorder or condition. 8. A compound of the formula wherein Z is CH2; P is hydrogen; -C (=O) H, -C (=O) (C1-C6) alkyl wherein the alkyl moiety may optionally be substituted with from 1 to 3 halo atoms; benzyl; and R<14> and R<15> are selected, independently, from hydrogen, hydroxy, nitro, -O (C1-C6) alkyl or halo; with the proviso that R<14> and R<15> cannot both be hydrogen when P is hydrogen, methyl or -C (=O) H. 9. A compound according to claim 1 selected from the group consisting of 5,6-difluoro-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2,4,6-triene; 11-benzyl-6-methoxy-11aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 6-methoxy-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-trien-6-ol; 6-fluoro-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 11-benzyl-5-methoxy-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 11-benzyl-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-trien-5-ol; 5-methoxy-11-aza-tricyclo[7,3,1,0<2,7>)trideca-2(7),3,5-triene; 11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-trien-5-ol; 11-benzyl-5-difluoromethoxy-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 5-difluoromethoxy-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 11-benzyl-5-ethoxy-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 5-ethoxy-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 5-isopropoxy-11-aza-tricyclo[7,3,1,0<2,7>)trideca-2(7),3,5-triene; 11-benzyl-4-methoxy-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 4-methoxy-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-trien-4-ol; 11-benzyl-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 4-nitro-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 5-nitro-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 3-nitro-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 11-benzyl-5-fluoro-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 5-fluoro-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 5,7-dioxa-14-azatetracyclo[10,3,1,0<2,10>,0<4,8>]hexadeca-2(10),3,8-triene; 11-benzyl-6-bromo-5-methoxy-11-aza-tricyclo(7,3,1,0<2,7>]trideca-2(7),3,5-triene; 11-benzyl-6-hydroxy-5-methoxy-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene, 6-hydroxy-5-methoxy-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; trifluoromethanesulfonic acid-11-benzyl-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-trien-5-yl ester; 5-(4-trifluoromethyl-phenyl)-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 5-(4-methoxy-phenyl)-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene; 11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene-5-carboxylic acid methyl ester; 2-(11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-trien-5-yl)-propan-2-ol; 5-pyridin-yl-11-aza-tricyclo[7,3,1,0<2,7>]trideca-2(7),3,5-triene and pharmaceutically acceptable salts and optical isomers thereof.