Patent EA-001113-B1 (EA)
Title: 5-substituted -3-(1,2,3,6-tetrahydropyridin-4-yl)- and 3-(piperidin-4-yl)-1h-indoles and their pharmaceutically acceptable salts and solvates, pharmaceutical composition on their basem method for activation of 5-ht receptors, and method for inhibition of neuronal protein extravasation
Inventor: AUDIA JAMES E
IPC: C07D401/14
Filed: 1996-03-15
Abstract: 1. 5-substituted -3-(1,2,3,6-tetrahydropyridin-4-yl)-3-(piperidin-4-yl)-indoles of general formula I;   in which  A-B is -CH-CH2- or -C=CH-; R is H or C1-C6 alkyl; R<1> is H or C1-C4 alkyl; X is -C(O)NR<4>R<15>, -NR<5>R<6>, -NR<7>SO2R<8>, -NHC(Q)NR<10>R<11>, -NHC(O)OR<12> or -NR<13> C(O)R<14>; where Q is O, or S; R<4> is heteroaryl, substituted heteroaryl, heteroaryl (C1-C4 alkyl), or substituted heteroaryl (C1-C4 alkyl); R<4> and R<15> taken together with the nitrogen atom form a pyrrolidine, piperidine; substituted hydroxy, hydroxymethyl or N,N-di (C1-C4 alkyl) carboxamide group piperidine; substituted C1-C6 alkyl, C1-C4 alkoxy, substituted C1-C6 alkyl, phenyl, phenyl (C1-C4 alkenyl), heteroaryl or heteroaryl (C1-C4 alkenyl) in position 4 piperazine, morpholine or thiomorpholine ring; R<5> and R<6> are both trifluoromethanesulfonyl; R<7> is H or C1-C4 alkyl; R<8> is phenyl, substituted by one substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C8 alkoxy, C1-C4 alkylthio, nitro, ciano, di(C1-C4 alkyl)amino, trifluoromethyl, trifluoromethoxy, phenyl, C1-C4 acyl, benzoyl or (C1-C4-alkyl)sulfonyl, or by two or three substituents independently selected from halogen, nitro, C1-C4 alkyl or C1-C4 alkoxy phenyl or di (C1-C4 alkyl)amino; R<10> and R<11> are independently selected from the group consisting of C1-C6 alkyl, C3-C6 alkenyl, C3-C8 cycloalkyl, phenyl, substituted halogen, C1-C4 alkyl, C1-C8 alkoxy, C1-C4 alkylthio, nitro, ciano, di (C1-C4 alkyl)amino, trifluoromethyl, trifluoromethoxy, phenyl, C1-C4 acyl, benzoyl or (C1-C4 alkyl)sulfonyl or by two or three substituents independently selected from halogen, nitro, C1-C4 alkyl or C1-C4 alkoxyphenyl; phenyl (C1-C4 alkylene); phenyl (C1-C4 alkylene), substituted in a phenyl ring; ((C1-C4  alkyl or C1-C4 alkoxycarbonyl substituted) C1-C4-alkyl)phenyl; C1-C4 alkyl, α-substituted with C1-C4 alkoxycabonyl; R<10> and R<11> taken together with the nitrogen atom form a pyrrolidine, piperidine, piperazine, substituted with C1-C6 alkyl, C1-C4 alkoxy, substituted with C1-C6 alkyl, phenyl, phenyl (C1-C4 alkylene), heteroalkyl or heteroaryl (C1-C4 alkylene) in position 4 piperazine, morpholine or thiomorpholine ring; R<12> is C1-C6 alkyl, C3-C6 alkenyl, phenyl, substituted with halogen, C1-C4 alkyl, C1-C8 alkoxy, C1-C4 alkylthio, nitro, ciano, di(C1-C4 alkyl)amino, trifluoromethyl, trifluoromethoxy, phenyl, C1-C4 acyl, benzoyl or (C1-C4 alkyl)sulfonyl, or by two or three substituents independently selected from halogen, nitro, C1-C4 alkyl or C1-C4 alkoxyphenyl, C3-C8 cycloalkyl, C1-C4 alkyl .ω-substituted with C1-C4 alkoxy group; R<13> is H or C1-C4 alkyl; R<14> is C1-C10 alkyl substituted with up to three substituents selected from the group consisting of hydroxy, C1-C4 alkoxy, halo, aryloxy, C1-C4 alkoxycarbonyl and heteroaryloxy, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, phenyl, substituted with halogen, C1-C4 alkyl, C1-C8 alkoxy, C1-C4 alkylthio, nitro, ciano, di (C1-C4 alkyl)amino, trifluoromethyl, trifluoromethoxy, phenyl, C1-C4 acyl, benzoyl or (C1-C4 alkyl)sulfonyl, or by two or three substituents, independently selected from halogen, nitro, C1-C4 alkyl or C1-C4 alkoxyphenyl; naphthyl, phenyl(C1-C4 alkylene), phenyl(C1-C4 alkylene) substituted on the phenyl ring, 2-phenylethylen-1-yl, diphenylmethyl, benzofused C4-C8 cycloalkyl, C1-C4 alkylene ω-substituted with C3-C6 cycloalkyl, or a heterocycle; R<15> is H or C1-C6 alkyl; and pharmaceutically acceptable acid addition salts with an acid and solvates thereof. 2. A compound of claim 1, in which A-B is -C=CH-. 3. A compound of claim 1, in which A-B is -CH-CH2-. 4. A compound of claim 1, in which R<1> is H. 5. A compound of claim 1, in which X is -NR<13>C(O)R<14>. 6. A compound of claim 5 which is 5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole and pharmaceutically acceptable salt with acid or solvate thereof. 7. A compound of claim 6 which is 5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole hydrochloride. 8. A pharmaceutical formulation which comprises an active ingredient in association with a pharaceutically acceptable carrier, diluent or excipient, wherein comprises an effective amount of a compound as an active ingredient of formula I of claim 1. 9. A pharmaceutical formulation of claim 8, in which A-B is -C=CH-. 10. A pharmaceutical formulation of claim 8, in which A-B is -CH-CH2-. 11. A pharmaceutical formulation of claim 8, in which R is H. 12. A pharmaceutical formulation of claim 8, in which X is -NR<13>C(O)R<14>. 13. A pharmaceutical formulation of claim 12, in which the compound is 5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole and pharmaceutically acceptable acid addition salt and solvate thereof. 14. A pharmaceutical formulation of claim 13, in which the compound is 5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole hydrochloride. 15. A method for the activation of serotonic 5-HT1F receptors in mammals, comprising administering to a mammal in need of such activation an effective amount of a compound of claim 1. 16. A method of claim 15 where the mammal is a human. 17. A method for the inhibition of neuronal protein extravasation, comprising administering to a mammal in need thereof an effective amount of a compound of claim 1. 18. A method of claim 17 where the mammal is a human. 19. A method of claim 15 for the treatment and/or the prevention of migraine, comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1. 20. A method of claim 19 where the mammal is human.