Patent EA-000304-B1 (EA)
Title: Indole derivaties as 5-ht receptor antagonist
Inventor: GASTER LARAMIE MARY
IPC: C07D409/14
Filed: 1996-01-26
Abstract: 1. A compound of formula (I) or a salt thereof:   wherein: P<1> and P<2> are independently phenyl, aromatic or partially saturated monocyclic or bicyclic heterocyclic rings containing up to three heteroatoms selected from nitrogen, oxygen or sulphur, A is a bond, a chain of 1 to 5 atoms optionally substituted by CI.Q alkyi or A is an optionally substituted phenyl or an optionally substituted 5- to 7-membered heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur, R<1> and R<2> groups are each independently hydrogen, C1-6alkyl optionally substituted by NR<12>R<13>, C2-6 alkenyl, C2-6alkynyl, C1-6alkylthio, cyano, nitro, halogen, CF3, C2F5, NR<12>R<13>, CONR<12>R<13>,. NR<12>COR<13>, S(0)p NR<12>R<13>, CHO. OCF3, SCF3, COR<14>, CH2OR<14>,. CO2R<14> or OR<14> where p is 1 or 2 and R<12>, R<13> and R<14> are independently hydrogen, C1-6alkyl, optionally substituted aryl or optionally substituted arylC1-6 alkyI; n and m are independently 0,1 or 2; R<3> is hydrogen or C1-6alkyl; R<4> is a group of formula (i):   in which: X and Y are both nitrogen, one is nitrogen and the other is carbon or a CR<5> group or one is a CR<5> group and the other is carbon or a CR<5> group; R<5>, R<6>, R<7> and R<8> groups are independently hydrogen, C1-6alkyl optionally substituted by one or more fluorine atoms, C2-6alkenyl, C3-6cycloalkyl, C3-6cycloalkylC1-6alkoxy, C2-6alkynyl, C3-6cycloalkyloxy, C3-6 cycloalkyl-C1-6alkyl, C1-6alkylthio, C3-6cycloalkylthio, C3-6cycloalkyl-C1-6alkylthio, C1-6alkoxy, hydroxy, halogen, nitro, OCF3, SCF3, S02CF3, SO2F, formyl, C2-6alkanoyl, cyano, optionally subsdtuted phenyl or thienyl, NR<12>R<13>, CONR<12>R<13> or CO2R<14> where where R<12>, R<13> and R<14> are as defined for R<1>; or R<6> and R<7> form part of an optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring; R<9> and R<10> are independently hydrogen or C1-6alkyl. 2. A compound according to Claim 1 in which A is a bond or a group CH2O, OCH2. or 0. 3. A compound according to Claim 1 or 2 in which R<2> is hydrogen, halogen, methyl, CF3 or OCF3. 4. A compound according to any one of Claims 1 to 3 in which R<3> is hydrogen. 5. A compound according to any one of Claims 1 to 4 in which R<4> is a group of formula (A):   in which R<6> and R<7> are as defined in formula (i). 6. A compound according to any one of Claims 1 to 5 in which R<6> is trifluoromethyl or halogen and R<7> is C1-6alkoxy, C1-6alkylthio or C1-6alkyl. 7. A compound according to Claim 1 which is: l-[(3-Pyridyl)-3-phenyl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[(4-Pyridyl)-3-phenyl carbamoyl]-5-methylthio-6-trifluoromethyl indoline, l-[(3-Pyridyl)-3-phenyl caroamoyl]-5-incthylthio-6-trifluoiomethyl indoline, l-[(3-Pyridyl)-4-phenylcarbainoyl]-5-methoxy-6-triflouromethyl indoline, 1-(4-Pyridyl)-4-phenyl carbamoyl]-5-incthoxy-6-triflouromethyl indoline, l-[(2-Pyridyl)-3-phenyl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[4-Methyl-3-(3-Pyridyl)-phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, 1-[3-Fluoro-5-(3-Pyridyl)phenylcarbomoyl]-5-methoxy-6-trifluoroinethyl indoline, l-[2-Fluoro-5-(3-Pyridyl) phenyl carbainoyl]-5-methoxy-6-trifluoromethyl indoline, l-(5-Phenyl pyrid-3-yl carbamoyl)-5-methoxy-6-trifluoromethyl indoline, l-(5-Phenyl pyrid -3-yl carbamoyl)-5-methylthio-6-trifluoromethyl indoline, l-[5-(3-Pyridyl)-pyrid-3-yl carbamoyl]-5-methoxy-6-trifluoromethyl indoline l-[5-(4-Trifluoromethylphenyl)-pyrid-3-yl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[5-(4-Methylphenyl)-pyrid-3-yl carbamoyl]-5-methoxy-6-trifluoromnethyl indoline, l-[5-(2-Thienyl)-pyrid-3-yl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[5-(3-Thienyl)-pyrid-3-yl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[5-(2-Pyrrolyl)-pyrid-3-yl carbamoyl)-5-niethoxy-6-trifluoromethyl indoline, l-[5-(4-Pyridyl)-pyrid-3-yl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[2-(3-Pyridyl)-thiazol-4-yl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[2-(2-Pyridyl)-thien-5-yl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-(3-Fluoro-5-(4-methyl-3-pyridyl)phenylcarbamoyI)-5-methoxy-6-trifluoromethyl indoline, l-(5-(2,6-Difluorophenyl)-3-pyridylcarbamoyl)-5-methoxy-6-trifluoromethyl indoline, 6-Chloro-5-methyl- 1-(4-methyl-3-(pyrid-3-yl)-phenylcarbamoyl) indoline, l-(4-Methyl-3-(pyrid-3-yl)phenylcarbamoyl)-5-thiomethyl-6-trifluoromethyl indoline, l-(3-Fluoro-5-(pyrid-3-yl)phenylcarbamoyl)-5-thiomethyl-6-trifluoromethyl-indolinc, l-(4-Chloro-3-(pyrid-3-yl)phenylcarbamoyl)-5-methoxy-6-trifluoromethyl indolinc, 5-Methoxy-l-(5-methyl-(l,2-4-oxadiazol-3-yl)-phenylcarbamoyl)-6-trifluoromethyl indoline, l-[4-Methyl-3-(4-methyl-3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[5-Bromo-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[4-t-Butyl-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[4-Methoxy-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[5-Fluoro-4-methoxy-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[3-Bromo-4-methyl-5-(3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[3-(4-Isoquinolyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[5-(4-Methyl-3-pyridyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[6-(3-Pyridyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[5-(2-Furyl)-pyrid-3-ylcarbamoyl-5-methoxy-6-trifluoromethyl indoline, l-[2-(Pyrazinyl)-thriazol-4-ylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[3-(5-Pyrimidyl)phenylcarbamoyl]-5-methoxy-6-trifluromethyl indoline, l-[3-(4-Methyl-3-pyridyl)phenylcarbamoyI]-5-methoxy-6-trifluoromethyl indoline, l-[5-Ethyl-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, 5-Methoxy-l-[5-phenyl-3-(pyrid-3-yl)phenylcarbamoyl]-6-trifluoromethyl indoline, 6-Chloro-5-methyl-l-[4-methyl-3-(4-methyl-3-pyridyl)phenyl carbamoyl indoline, 1-[3-pyrid-3-ylaminocarbonyl)-phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[3-(Pyrid-3-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-trifluoromethyl indoline, l-[3-(Pyrid-4-ylaminocarbonyl)-phenylcarbamoyl]-5-methyltfiio-6-trifluoromethyl indoline, l-[4-(Pyrid-3-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-trifluoromethyl indoline, l-[4-(Pyrid-4-ylaminocarbonyI)-phenylcarbamoyl]-5-methylthio-6-trifluoromethyl indoline, 1-[3-(3-pyridylcarbonyl)phenylcarbamoyl]-5-niethoxy-6-trifluoromethyl indoline, l-[3-(Pyrid-3-yI-aniinosulphonyl)-phenylcarbamoyl]5-methoxy-6-trifluoromethyl indoline, 5-Methylthio-6-trifluoromethyl-1 -[6-(pyridin-3-yloxy)pyridin-3-ylcarbamoyl)]indoline, 5-Methoxy-6-trifluoromethyl-l-[6-(pyridin-3-yloxy)pyridin-3-ylcarbamoyl]indoline, 5-Methoxy-6-trifluoromethyl-1-[4-(pyridin-4-ylmethyloxy)phenyl carbamoyl]indoline, 5-Methoxy-6-trifluoromethyl-l-[6-(pyridin-4-ylmethyloxy)pyridin-3-ylcarbamoyl]indoline, 5-Methylthio-6-trifluoromethyl-l-[4-(pyrid-4-yl-incthylaniinocarbonyl)phenyl carbamoyl]indoline, Trans-5-Methylthio-6-trifluoromethyl-l-{4-l2-ethenyl-(4-pyridyl)]-phenyl carbamoyl}-indoline, 5-Methylthio-6-trifluoromethyl-1-{4-[2-ethyl(4-pyridyl)]phenyl carbamoyl) indoline, l-(l-(4-Pyridyl)-5-indolylcarbamoyl)-5-methoxy-6-trifluoromethyl indolinc, 5-Methoxy-6-trifluoromethyl-l-[4-(pyridin-4-ylthiomethyl)phenyl carbamoyl]indoline, 5-Methoxy-6-trifluoromethyl-l-[4-(pyridin-4-ylsulphonyhmethyl) phenylcarbamoyl]indoline, 5-Methoxy-6-lrifluoromethyl-l-[4-(pyridin-4-yhmethyltluo)phenyl carbamoyl]indoline, 5-Methylthio-6-trifluoromethyl-l-[(6-phenoxy)-3-pyridylcarbamoyl-indoline, 5-Methoxy-6-trifluoromethyl-l-[2-(pyridin-3-yloxy)pyridin-4-ylcarbamoyl)]indolinc, 5-Methylthio-6-trifluoromethyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-ylcarbmoyl]indoline, 5-Methylthio-6-trifluoromethyl-l-[6-(6-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyljindoline, 5-Methoxy-6-trifluoromethyl-l-[6-(pyridin-3-ylthio)pyridin-3-ylcarbamoyl]indoline, 5-Methylthio-6-trifluoromethyl-l-[4-(pyrid-3-ylmethyl)amidophenyl carbamoyl]indoline, 5-Methylthio-6-trifluoromethyl-1 -[3-(pyrid-4-yhnethyl) amidophenylcarbamoyl] indoline, 5-Methylthio-6-trifluoromethyl-l-[4-(pyrid-2-ylmethyl)amidophenylcarbamoyl] indoline, l-(l-(3-Pyridylmethyl)-5-indolylcarbamoyl)-5-methoxy-6-trifluoromethyl indoline, l-(l-(4-Pyridylmethyl)-5-indolylcarbamoyl)-5-methoxy-6-trifuoromethyl indoline, 1-(l-(3-pyridyl)-5-indolylcarbamoyl)-5-methoxy-6-trifluoromethyl indoline, 5-Methylthio6 -trifluoromethyl-1-{3-[2-(3-pyridyl)thiazol-4-yl]phenylcarbamoyl) indoline, 5-Methylthio-6-trifluoromethyl-l-{4-[2-(4-pyridyl)-thiazol-4-yl]phenyl carbamoyl}indoline, 5-Methylthio-6-trifluoromethyl-l-(4-[2-(3-pyridyl)-thiazol-4-yl]phenylcarbamoyl) indoline, l-[4-Fluoro-3-(3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indolinc, l-[3-Fluoro-5-(pyrimidin-5-yl)plenylcarbamoyl-5-methoxy-6-trifluoromethyl indoline, 1-[4-Chloro-3-(4-methyl-3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[2.3-Dihydro-7"(pyrid-3-yl)benzofuran-5-ylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, 5-Methoxy-6-trifluoromethyl-1-(2-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl]indolinc, 5-Methoxy-6-trifluoromethyl-l-[6-(4-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl]indoline, and pharmaceutically acceptable salts thereof. 8. A compound according to any one of Claims 1 to 7 for use in therapy. 9. A pharmaceutical composition which compriss a compound according to any one of Claims 1 to 7 and a pharmaceutically acceptable carrier or excipient. 10. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises: (a) the coupling of a compound of formula (II);   with a compound of formula (III) D-R<4>' wherein A, P<1> and p2 are as defined in formula (I), C and D contain the appropriate functional group(s) necessary to form the moiety -NR<3>' CO when coupled, the variables R<1>'. R<2>', R<3>' and R<4>' are R<1>, R<2>, R<3> and R<4> respectively, as defined in formula (I)