Claims for Patent: 5,545,644

Summary for Patent: 5,545,644

Title:	Indole derivatives
Abstract:	Compounds of the formula I wherein n is 0, 1, or 2; X is hydrogen, chlorine, bromine or iodine; R1 is hydrogen; R3 is selected from hydrogen and C1 to C6 linear or branched alkyl; and R2 is as defined in the specification and the pharmaceutically acceptable salts thereof are useful psychotherapeutics and are potent serotonin (5-HT1) agonists and may be used in the treatment of depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain, chronic paroxysmal hemicrania and headache associated with vascular disorders, and other disorders arising from deficient serotonergic neurotransmission. The compounds can also be used as centrally acting antihypertensives and vasodilators. A process for forming indoles by transition metal catalyzed cyclization of a dihalogenated intermediate is also disclosed.
Inventor(s):	John E. Macor, Martin J. Wythes
Assignee:	Pfizer Corp SRL
Application Number:	US08/466,644
Patent Claims:	1. A compound of the formula ##STR47## wherein n is 0, 1, or 2; X is hydrogen, chlorine, bromine, or iodine; R1 is hydrogen; R2 is selected from hydrogen, halogen, cyano, --OR4, --(CH2)m --(C═O)NR5 R6, [--(CH2)m --SO2 NR4 R5,]--(CH2)m --NR7 (C═O)R8, --(CH2)m --NR7 SO2 R8, --(CH2)m --S(O)x R8, --(CH2)m --NR7 (C═O)NR5 R6, --(CH2)m --NR7 (C═O)OR9, and --CH═CH(CH2)y R10 ; R3 is hydrogen, C1 to C6 linear or branched alkyl; R4 is selected from hydrogen, C1 to C6 alkyl, and aryl; R5 and R6 are independently selected from hydrogen, C1 to C6 alkyl, aryl, and C1, to C3 alkyl-aryl or R5 and R6 taken together to form a 4, 5, or 6 membered ring; R7 and R8 are independently selected from hydrogen, C1 to C6 alkyl, aryl, and C1 to C3 alkyl-aryl; R9 is selected from hydrogen, C1 to C6 alkyl, aryl, and C1 to C3 alkyl-aryl; R10 is selected from --(C═O)NR5 R6 and --SO2 NR5 R6, wherein R5 and R6 are defined as above, and --NR7 (C═O)R8, --NR7 SO2 R8, --NR7 (C═O)NR5 R6, --S(O)x R8 and --NR7 (C═O)OR9, wherein R7, R8, and R9 are as defined above; y is 0, 1, or 2; x is 1 or 2; m is 0, 1, 2, or 3; and the above aryl groups and the aryl moieties of the above alkylaryl groups are independently selected from phenyl and substituted phenyl, wherein-said substituted phenyl may be substituted with one to three groups selected from C1 to C4 alkyl, halogen, hydroxy, cyano, carboxamido, nitro, and C1 to C4 alkoxy, with the proviso that when R2 is hydrogen or --OR4 and R4 is hydrogen, n is 0 or 1, or the pharmaceutically acceptable salts thereof. 2. The R enantiomer of a compound according to claim 1. 3. A compound according to claim 1 wherein R1 is hydrogen; R2 is --(CH2)m --SO2 R8, --(CH2)m --SO2 R8, --(CH2)m --(C═O)NHR5, or --(CH2)m --NH(C═O)R8 ; R3 is hydrogen or methyl; and m, R5 and R8 are as defined in claim 1. 4. A compound according to claim 1, said compound being selected from:(R)-5-methoxy-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole; (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (R)-5-(2-ethylsulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole; [(R)-5-(2-methylaminosulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole; (R)-5-(methylaminosulfonylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole; (R)-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;] (R)-5-carboxamido-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole; (R)-5-(2-methylsulfonylethyl)-3-(N-methylpyrrolidin-2-yl-methyl)-1H-indole; (R)-5-(2-methylsulfonamidoethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole; (R)-5-(2-aminosulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole [(R)-5-(2-aminosulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole; (R)-5-(2-N,N-dimethylaminosulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;] (R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole hemisuccinate; (R)-5-(2-ethylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole hemisuccinate; (R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole; (R)-5-(3-benzenecarbonylaminoprop-1-enyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole; (R)-5-(2-(4-methylphenylsulphonyl)ethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole; (R)-5-(3-methylsulphonylaminoprop-1-enyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole; (R)-5-(2-ethylsulphonylethyl)-3-(N-2-propylpyrrolidin-2-ylmethyl)-1H-indole; and (R)-5-(2-ethylsulphonylethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole[; and (R)-7-Bromo-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole]. 5. A pharmaceutical composition for treating a condition selected from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain, and chronic paroxysmal hemicrania and headache associated with vascular disorders comprising an amount of a compound according to claim 1 effective in treating such condition and a pharmaceutically acceptable carrier. 6. A pharmaceutical composition for treating disorders arising from deficient serotonergic neurotransmission comprising an amount of a compound according to claim 1 effective in treating such a disorder and a pharmaceutically acceptable carrier. 7. A method for treating a condition selected from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders comprising administering to a mammal requiring such treatment an amount of a compound according to claim 1 effective in treating such condition. 8. A method for treating disorders arising from deficient serotonergic neurotransmission comprising administering to a mammal requiring such treatment an amount of a compound according to claim 1 effective in treating such a disorder. 9. The compound 5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 9, wherein the compound is (R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole. 11. A pharmaceutical composition for treating a condition selected from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain, and chronic paroxysmal hemicrania and headache associated with vascular disorders comprising an amount of a compound according to claim 9 effective in treating such condition and a pharmaceutically acceptable carrier. 12. A pharmaceutical composition for treating disorders arising from deficient serotonergic neurotransmission comprising an amount of a compound according to claim 9 effective in treating such a disorder and a pharmaceutically acceptable carrier. 13. A method for treating a condition selected from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders comprising administering to a mammal requiring such treatment an amount of a compound according to claim 9 effective in treating such condition. 14. A method for treating disorders arising from deficient serotonergic neurotransmission comprising administering to a mammal requiring such treatment an amount of a compound according to claim 9 effective in treating such a disorder. 15. A pharmaceutical composition for treating a condition selected from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain, and chronic paroxysmal hemicrania and headache associated with vascular disorders comprising an amount of a compound according to claim 10 effective in treating such condition and a pharmaceutically acceptable carrier. 16. A pharmaceutical composition for treating disorders arising from deficient serotonergic neurotransmission comprising an amount of a compound according to claim 10 effective in treating such a disorder and a pharmaceutically acceptable carrier. 17. A method for treating a condition selected from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders comprising administering to a mammal requiring such treatment an amount of a compound according to claim 10 effective in treating such condition. 18. A method for treating disorders arising from deficient serotonergic neurotransmission comprising administering to a mammal requiring such treatment an amount of a compound according to claim 10 effective in treating such a disorder.