Patent EA-003781-B1 (EA)
Title: Benzofuran derivatives, their preparation and use
Inventor: ANDERSEN KIM
IPC: C07D307/87
Filed: 1999-12-03
Abstract: 1. An isobenzofuran having the general Formula I: wherein R<1> is hydrogen, halogen, trifluoromethyl, trifluoromethylsulfonyloxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C1-6 alkoxy, hydroxy, formyl, acyl, amino, C1-6 alkylamino, C2-12 dialkylamino, acylamino, C1-6 alkoxycarbonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, C2-12 dialkylaminocarbonylamino, nitro, cyano, COOH, or COO- C1-6 alkyl; R<2> and R<3> are each independently selected from hydrogen, trifluoromethyl, C1-6 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-8 cycloalkyl and C1-6 alkoxy; n is 1, 2, 3, 4 or 5; m is 0 or 1; A is selected from the following groups: wherein Z is O or S; s is 0 or 1; q is 0 or 1; R<4> is hydrogen, C1-6 alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6 alkyl-Aryl, or C1-6 alkyl-O-Aryl; D is a spacer group selected from branched or straight chain C1-6 alkylene, C2-6-alkenylene and C2-6-alkynylene; B is a group selected from a group of formula (II), (III), and (IV) wherein R<5>, R<6>, R, R<8>, R<9> and R<10> are each independently selected among the R<1> substituents; or R<8> and R<9> together form a fused 5-or 6-membered ring optionally containing further heteroatoms; and the resulting heterocycle is optionally substituted with substituents selected among the R<1> substituents; or two of the groups of R<5>, R<6> and R<7> are linked together thereby forming a -O-(CH2)P-O- bridge wherein p is 1 or 2; Ar and Aryl are independently selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrimidyl, 1-indolyl, 2-indolyl, 3-indolyl, 1-indol-2-onyl, 3-indol-2-onyl, 2-or 3-benzofuranyl, 2-or 3-benzothiophenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, hydroxy, C1-6 alkylsulfonyl, cyano, trifluoromethyl, trifluoromethylsulfonyloxy, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-6 alkyl, nitro, amino, C1-6 alkylamino, C2-12 dialkylamino, acylamino or alkylenedioxy; its enantiomers, and pharmaceutically acceptable acid addition salt thereof. 2. A compound of Claim 1, characterised in that A is a group of formula (1). 3. A compound of Claim 1, characterised in that A is a group of formula (2). 4. A compound of Claim 1, characterised in that A is a group of formula (3). 5. A compound of Claim 1, characterised in that A is a group of formula (4). 6. A compound of Claim 2, characterised in that R<4> is methyl, ethyl, propyl, 2propen-1-yl, 2-furylmethyl, 2-phenoxyethyl. 7. A compound of any of the Claims 2-6, characterised in that q = 0. 8. A compound of any of the Claims 2 and 6, characterised in that q = 1 and Z is O. 9. A compound of any of the Claims 1-8, characterised in that B is a group of formula (II). 10. A compound of any of the Claims 1-8, characterised in that B is a group of formula (III). 11. A compound of any of the Claims 1-8, characterised in that B is a group of formula (IV). 12. A compound of Claim 9, characterised in that at least one of R<5>, R<6> and R<7> is methoxy. 13. A compound of Claim 9, characterised in that Formula (II) is a benzodioxan group or a 1,2-methylenedioxybenzene group. 14. A compound of Claim 10, characterised in that Formula (III) is a 3-indolyl. 15. A compound of Claim 14, characterised in that the 3-indolyl is substituted in 5position by methyl, fluoro, chloro, bromo, iodo, t-butyl or i-propyl, or in 7-position by fluoro, chloro or carboxy; or disubstituted by 5,7-difluoro, 4-fluoro-7-methyl or 4-chloro7-methyl or the two substituents together form a pyridyl ring fused to the 3-indolyl. 16. A compound of Claim 11, characterised in that Formula (IV) is a 4-indolyl or a 5indolyl group. 17. A compound of any of the Claims 1-16, characterised in that Ar is phenyl or phenyl substituted with halogen or CF3. 18. A compound of Claim 17, characterised in that Ar is phenyl which may be substituted with Cl or F in the 4-position or Cl or CF3 in the 3-position. 19. A compound of any of the Claims 1-18, characterised in that R<1> is H, CN or F in the 5-position of the isobenzofuran group. 20. A compound of any of the Claims 1-19, characterised in that R<2> and R<3> are selected from hydrogen or methyl. 21. A compound of any of the Claims 1-20, characterised in that n = 2,3 or 4. 22. A compound of claim 21, characterised in that n = 3. 23. A compound of any of the Claims 1-22, characterised in that m = 0. 24. A compound of any of the Claims 1,18,19,20,21,22 and 23, characterised in that R<2> and R<3> are both hydrogen; R<1> is H, CN or F in the 5-position of the isobenzofuran group; and Ar is phenyl which may be substituted with F or Cl in the 4-position or with Cl or CF3 in the 3-position. 25. A compound of any of the Claims 1 and 24, characterised in that A is a group of formula (1); q = 0; R<4> is methyl; D is propylene; m = 0; and B is a 1,4-benzodioxan group of Formula (II) attached in the 5-position. 26. A compound of any of the Claims 1 and 24, characterised in that A is a group of formula (1); R<4> is CH3 or prop-2-en-1-yl; n = 3; D is ethylene or propylene; and B is a phenyl group wherein at least one substituent is OMe. 27. A compound of any of the Claims 1 and 24, characterised in that A is a group of formula (1); q is 0; R<4> is methyl, ethyl, propyl, 2-propen-1-yl, 2-furylmethyl or 2-phenoxyethyl; D is ethylene or propylene; m = 0; and B is a 3-indolyl group of Formula (III). 28. A compound according to claim 27, characterised in that the 3-indolyl group is substituted by methyl, fluoro, chloro, bromo, iodo, t-butyl or i-propyl in the 5-position; or fluoro, chloro or carboxy in the 7-position; or by 5,7-difluoro, 4-fluoro-7-methyl or 4chloro-7-methyl; or the two substituents together form a pyridyl ring fused to the 3-indolylgroup. 29. A compound of any of the Claims 1 and 24, characterised in that A is a group of formula (2) or (3); n = 3; m = 0; and B is an 4-or 5-indolyl-group of Formula (IV) wherein R<10> is hydrogen; R<1> is CN in the 5-position of the isobenzofuran and Ar is 4-fluorophenyl. 30. The compound according to claim 1 which is (-)-1-[3-[[4-(1,4-Benzodioxan-5-yl)butyl]methylamino]propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, 1-[3-[[3-(1,4-Benzodioxan-5-yl)propyl]methylamino]propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile oxalate, 1-[3-[[2-(1,4-Benzodioxan-5-yl)ethyl]methylamino]propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile oxalate, 1-[3-[[1,4-Benzodioxan-5-ylmethyl]methylamino]propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile oxalate, 1-(4-Fluorophenyl)-1-[3-[4-(2-methoxyphenyl)piperazinyl]propyl]-1,3-dihydroisobenzofuran-5-carbonitrile, 1-(4-Fluorophenyl)-1-3-methyl 2-(2-methoxyphenoxy)ethyl]amino]propyl-1,3-dihydroisobenzofuran-5-carbonitrile, 1-(4-Fluorophenyl)-1-[3-[methyl[2-(3-methoxyphenoxy)ethyl]amino]propyl]-1,3-dihydroisobenzofuran-5-carbonitrile, (S)-1-[3-[[4-(1H-Indol-3-yl)butyl]methylamino]propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, 1-[3-[[4-(1H-Indol-3-yl)butyl]methylamino]propyl]-1-phenyl-1,3-dihydroisobenzofuran, (S)-1-[3-[[3-(1H-Indol-3-yl)propyl]methylamino]propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, 1-[3-[[3-(1H-Indol-3-yl)propyl]methylamino]propyl]-1-phenyl-1,3-dihydroisobenzofuran, 5-[3-[[3-(1-Phenyl-1,3-dihydroisobenzofuran-1-yl)propyl]-methylamino]propyl]-1,4-benzodioxane, 5-[3-[[3-[1-(3-Chlorophenyl)-1,3-dihydroisobenzofuran-1-yl]-propyl]methylamino]propyl]-1,4-benzodioxane, 5-[3-[[3-[1-(4-Fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-propyl]methylamino]propyl]-1,4-benzodioxane, 5-[3-[[3-[1-(3-Trifluoromethylphenyl)-1,3-dihydroisobenzofuran-1-yl]propyl]methylamino]propyl]-1,4-benzodioxane, 1-[3[[-3-(1,4-Benzodioxan-5-yl)propyl]methylamino]propyl]-1-(4-chlorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, 1-[3-[4-(1H-Indol-4-yl)piperazinyl]propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, 1-[3-[4-(1H-Indol-5-yl)piperazinyl]propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, 1-[3-[4-(1H-Indol-3-yl)piperidinyl]propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, 5-[3-[[3-[5-Fluoro-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]propyl]methylamino]propyl]-1,4-benzodioxane, 1-[3-[[2-(1H-Indolyl-3-yl)ethyl]methylamino]propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, 1-(4-Fluorophenyl)-1-[3-[[2-(3-methoxyphenyl)ethyl]methylamino]propyl]-1,3-dihydroisobenzofuran-5-carbonitrile, 1-(4-Fluorophenyl)-1-[3-[[2-(3-methoxyphenyl)ethyl](prop-2-en-1-yl)amino]propyl]-1,3-di-hydroisobenzofuran-5-carbonitrile, 1-(4-Fluorophenyl)-1-[3-[[2-(2-methoxyphenyl)ethyl](prop-2-en-1-yl)amino]propyl]-1,3-dihydroisobenzofuran-5-carbonitrile, 1-[3-[[2-(2,5-Dimethoxyphenyl)ethyl]methylamino]propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, 1-[3-[[2-(2,5-Dimethoxyphenyl)ethyl] (prop-2-en-1-yl)amino]propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, 1-(4-Fluorophenyl)-1-[3-[[2-phenoxyethyl]methylamino]propyl]-1,3-dihydroisobenzofuran-5-carbonitrile, 1-[3-[[2-(1H-Indolyl-3-yl) ethyl](prop-2-en-1-yl)amino]propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, 1-(4-Fluorophenyl)-1-[3-[[2-phenoxyethyl](prop-2-en-1-yl)amino]propyl]-1,3-dihydroisobenzofuran-5-carbonitrile, 1-(4-Fluorophenyl)-1-[3-[[3-(2-methoxyphenyl)propyl]methylamino]propyl]-1,3-dihydroisobenzofuran-5-carbonitrile, 1-(4-Fluorophenyl)-1-[3-[[3-(2-methoxyphenyl)propyl](prop-2-en-1-yl)amino]propyl]-1,3-dihydroisobenzofuran-5-carbonitrile, 1-(4-Fluorophenyl)-1-[3-[[3-(3-methoxyphenyl)propyl](prop-2-en-1-yl)amino]propyl]-1,3-dihydroisobenzofuran-5-carbonitrile, 1-(4-Fluorophenyl)-1-[3-[[3-(2-methoxyphenoxy)propyl]methylamino]propyl]-1,3-dihydroisobenzofuran-5-carbonitrile, 1-(4-Fluorophenyl)-1-[3-[[3-(2-methoxyphenoxy)propyl](prop-2-en-1-yl)amino]propyl]-1,3-dihydroisobenzofuran-5-carbonitrile, 1-(4-Fluorophenyl)-1-[3-[[3-(3-methoxyphenoxy)propyl]methylamino]propyl]-1,3-dihydroisobenzofuran-5