Patent EA-001448-B1 (EA)
Title: 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole compounds as estrogenic agents
Inventor: MLLER CHRIS P
IPC: C07D209/52
Filed: 1997-04-18
Abstract: 1. 2-phenyl-1-[4-(2-aminoethoxy)benzyl]indole derivatives of general structural formula I or II:   wherein: R1 is selected from H, OH, -O-(C=O)-(C1-C12) alkyl (wherein alkyl is straight chain or branched), -O-(C1-C12) alkyl (wherein alkyl is straight chain or branched or cyclic), halogen; or a -O-(C1-C4)-halogenated alkyl (including trifluoromethoxy and trichloromethoxy). R2, R3, R4, R5 and R6 are independently selected from H, OH, -O-(C=O)-(C1-C12) alkyl (wherein alkyl is straight chain or branched), -O-(C1-C12) alkyl (wherein alkyl is straight chain or branched or cyclic), halogen; or a -O-(C1-C4)halogenated alkyl (including trifluoromethoxy and trichloromethoxy), cyano, (C1-C6)alkyl (straight chain or branched), or trifluoromethyl, with the proviso that, when R1 is H, R2 is not OH group. X is selected from H, (C1-C6) alkyl, cyano, trifluoromethyl, halogen; n is 2 or 3; Y is selected from: a) the moiety:   wherein R7 and R8 are independently selected from the group of H, (C1-C6)alkyl, or phenyl optionally substituted by (C1-C6)alkyl (straight chain or branched), (C1-C6)alkoxy (straight chain or branched), halogen, -OH, -CF3, or -OCF3; or R7 and R8 are concatenated together as -(CH2)p, wherein p is an integer of from 2 to 6, preferably 4 to 6, the ring so formed is optionally substituted with 1-3 substituents selected from a group containing (C1-C3) alkyl, trifluoromethyl, halogen, hydrogen, phenyl, b) a five, six or seven -membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms or substituted heteroatoms selected from the group consisting of -O-, -NH-, -N(C1-C4-alkyl)-, -N=, and optionally substituted with 1-3 substituents independently selected from hydroxyl, halo, (C1-C4)-alkyl, trihalomethyl, (C1-C4)alkoxy, trihalomethoxy, (C1-C4)acyloxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, hydroxy(C1-C4)alkyl, -CO2H, -CONHR1, -NH2, (C1-C4)alkylamino, di(C1-C4)alkylamino, -NHSO2R1, -NHCOR1, and phenyl optionally substituted with 1-3 (C1-C4)alkyl; c) a bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing up to two heteroatoms or substituted heteroatoms selected from the group consisting of -O-, -NH-, and -N(C1-C4alkyl)-, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, (C1-C4) alkyl, trihalomethyl, (C1-C4)alkoxy, trihalomethoxy, (C1-C4)acyloxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, hydroxy (C1-C4)alkyl, -CO2H, -CONHR1, -NH2, (C1-C4)alkylamino, di(C1-C4)alkylamino, -NHSO2R1, -NHCOR1, and phenyl optionally substituted with 1-3 (C1-C4) alkyl; and the pharmaceutically acceptable salts thereof. 2. A compound of claim 1 wherein: R1 is selected from H, OH, -O-(C=O) (C1-C4) alkyl, -C(C1-C4) alkyl or halogen; R2, R3, R4, R5, and R6 are independently selected from H, OH or -O-(C=O) (C1-C4) alkyl, -O-(C1-C4) alkyl, halogen, cyano, (C1-C6)alkyl, or trifluoromethyl, with the proviso that, when R1 is H, R2 is not OH; X is selected from H, (C1-C6)alkyl, cyano, trifluoromethyl or halogen; Y is the moiety   R7 and R8 are selected independently from H, (C1-C6)alkyl, or combined by -(CH2)p-, wherein p is an integer of from 2 to 6, so as to form a ring, the ring being optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, (C1-C4)alkyl, trihalomethyl, (C1-C4)alkoxy, trihalomethoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, hydroxy (C1-C4)alkyl, -CO2H, -CONH(C1-C4)alkyl, -NH2, (C1-C4)alkylamino, di(C1-C4)alkylamino, -NHSO2(C1-C4)alkyl, and -NHCO(C1-C4) alkyl; or pharmaceutically acceptable salts thereof. 3. A compound of claim 1 wherein: R1 is OH; R2, R3, R4, R5, and R6 are independently selected from H, OH, -O-(C=O) (C1-C4) alkyl, -O-(C1-C4) alkyl, halogen, cyano, (C1-C6)alkyl, or trifluoromethyl, with the proviso that, when R1 is H, R2 is not OH; X is selected from the group of Cl, CN, CF3, or CH3; Y is the moiety   and R7 and R8 are concatenated together as -(CH2)r- wherein r is an integer of from 4 to 6, to form a ring optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, (C1-C4)alkyl, trihalomethyl, (C1-C4)alkoxy, trihalomethoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, hydroxy (C1-C4)alkyl. -CO2H, -CONH(C1-C4)alkyl, -NH2, (C1-C4)alkylamino, di(C1-C4)alkylamino, -NHSO2(C1-C4) alkyl, -NHCO(C1-C4) alkyl; or pharmaceutically acceptable salts thereof. 4. A compound of claim 1 which is one of the following: 5-Benzyloxy-2-(4-ethoxyphenyl)-3-methyl-1-[4-(2-piperidin-1-ylethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-phenyl-3-methyl-1-[4-(2-azepan-1-ylethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1-[4-(2-diisopropylamino-1-ylethoxy)benzyl]-1H-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1-[4-(2-butylmethylamino-1-ylethoxy)benzyl]-1H-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-l-{2-[4-(dimethylamino)ethoxy]benzyl}-1H-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-l-{4-[2-(2-methylpiperidin-l-yl)ethoxy]benzyl}-lH-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1-{4-[2-(3-methylpiperidin-1-yl)ethoxy]benzyl}-lH-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1-{4-[2-(4-methylpiperidin-1-yl)ethoxy]benzyl}-lH-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1-{4-[2-((cis)-2,6-dimethylpiperidin-1-yl)ethoxy]benzyl}-lH-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-{4-[2-(l,3,3-trimethyl-6-azabicyclo[3,2,1]oct-6-yl)ethoxy]benzyl}-lH-indole or a pharmaceutically acceptable salt thereof; (lS,4R)-5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-{4-[2-(2-azabicyclo[2,2,1]hept-6-yl)ethoxy]benzyl}-lH-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-fluorophenyl)-3-methyl-1-[4-(2-azepan-1-ylethoxy)benzyl]-1H-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-fluorophenyl)-3-methyl-l-[4-(2-piperidin-1-ylethoxy)benzyl]-1H-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-chlorophenyl)-3-methyl-1-[4-(2-piperidin-1-ylethoxy)benzyl]-1H-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(3,4-methylenedioxyphenyl)-3-methyl-l-[4-(2-piperidin-l-ylethoxy)benzyl]-lH-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-isopropoxyphenyl)-3-methyl-1-[4-(2-piperidin-1-ylethoxy)benzyl]-1H-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-methylphenyl)-3-methyl-1-[4-(2-piperidin-1-ylethoxy)benzyl]-1H-indole or a pharmaceutically acceptable salt thereof; l-[4-(2-Azepan-l-ylethoxy)benzyl]-5-benzyloxy-2-(3-benzyloxyphenyl)-3-methyl-1H-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-benzyloxy-3-fluorophenyl)-3-methyl-l-[4-(2-piperidin-l-ylethoxy)benzyl]-lH-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-benzyloxy-3-fluorophenyl)-3-methyl-l-[4-(2-azepan-l-ylethoxy)benzyl]-lH-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(3-methoxyphenyl)-1-[4-(2-piperidin-1-ylethoxy)benzyl]-3-methyl-1H-indole or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-3-methyl-1-[4-(2-piperidin-1-ylethoxy)benzyl]-2-(4-trifluoromethoxyphenyl)-lH-indole or a pharmaceutically acceptable salt thereof; (2-{4-[5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methylindol-1-ylmethyl]phenoxy}ethyl)cyclohexylamine or a pharmaceutically acceptable salt thereof; 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1-{4-[2-(4-methylpiperazin-1-yl)ethoxy]benzyl}-lH-indole or a pharmaceutically acceptable salt thereof; l-[4-(2-Azepan-1-ylethoxy)benzyl]-5-benzyloxy-2-(3-methoxyphenyl)-3-methyl-1H-indole or a pharmaceutically acceptable salt thereof; 4-{3-Methyl-l-[4-(2-piperidin-1-ylethoxy)benzyl]-1H-indole} (HC1); 4-{3-Methyl-1-[4-(2-piperidin-1-ylethoxy)benzyl]-lH-indole-2-yl}phenol hydrochloride (HC1); 3-Methyl-2-phenyl-l-[4-(2-piperidine-l-ylethoxy)benzyl]-lH-indole-5-ol (HCl); 4-{5-Methoxy-3-methyl-l-{4-[2-piperidin-l-ylethoxy]benzyl}-lH-indol-2-yl}phenol or a pharmaceutically acceptable salt thereof; 2-(4-Methoxyphenyl)-3-methyl-l-{4-[2-piperidin-1-ylethoxy]benzyl}-lH-indol-5-ol or a pharmaceutically acceptable salt thereof; 5-Methoxy-2-(4-methoxyphenyl)-3-methyl-1-[4-(2-piperidin-1-ylethoxy)benzyl]-1H-indole (HCL); 1-[4-(2-Azepan-l-ylethoxy)benzyl]-5-methoxy-2-(4-methoxyphenyl)-3-methyl-lH-indole (HCL); 2-(4-Ethoxyphenyl)-3-methyl-1-[4-(2-piperidin-1-ylethoxy)-benzyl]-1H-indole-5-ol or a pharmaceutically acceptable salt thereof; 1-[4-(2-Azepan-1-ylethoxy)benzyl]-2-(4-ethoxyphenyl)-3-methyl-1H-indole-5-ol or a pharmaceutically acceptable salt thereof; 4-{5-Fluoro-3-methyl-1-[4-(2-piperidin-1-ylethoxy)benzyl]-1H-indole-2-yl}phenol (HC1); 1-[4-(2-Azepan-1-ylethoxy)benzyl]-3-methyl-2-phenyl-1H-indol-5-ol (HC1); 2-(4-Hydroxyphenyl)-3-methyl-l-[4-(2-pyrollidin-l-ylethoxy)benzyl]-lH-indole-5-ol or a pharmaceutically acceptable salt thereof; l-[4-(2-Azepan-l-ylethoxy)benzyl]-2-(4-hydroxyphenyl)-3-methyl-lH-indole-5-ol (HC1); l-[4-(2-Azepan-l-ylethoxy)benzyl]-2-(4-hydroxyphenyI)-3-methyl-lH-indole-5-ol Acetate Salt; 1-[4-(2-Azocan-l-ylethoxy)benzyl]-2-(4-hydroxyphenyl)-3-methyl-lH-indole-5-ol or a pharmaceutically acceptable salt thereof; 2-(4-Hydroxyphenyl)-3-methyl-1-[4-(2-dimethylaminoethoxy)-benzyl]-1H-indole-5-ol or a pharmaceutically acceptable salt thereof; 2-(4-Hydroxyphenyl)-3-methyl-l-[4-(2-diethylaminoethoxy)-benzyl]-lH-ind