Patent EA-000815-B1 (EA)
Title: Indole derivatives as estrogenic agents
Inventor: MILLER CHRIS P
IPC: A61P15/12
Filed: 1997-04-18
Abstract: 1. A compound having the structure:   wherein: R1 is selected from H, OH, OC (=O) (C1-C4 alkyl), -O(C1-C4 alkyl) or halogen; R2, R3, R4, R5, and R6 are independently selected from H, OH, OC (=O) (C1-C4 alkyl), -O(C1-C4 alkyl) or halogen or C1-C6 alkyl with the proviso that, when R1 is H, R2 is not OH; X is selected from H, C1-C6 alkyl, nitro or halogen; Z is selected from   n is 1, 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, phenyl, 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 hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, -CO2H, -CN, -CONH(C1-C4) alkyl, -NH2, C1-C4 alkylamino, di(C1-C4) alkylamino, -NHSO2(C1-C4) alkyl, -NHCO(C1-C4) alkyl, and -NO2; 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)- and -N=, optionally substituted with 1-3 substituents independently selected from the group consisting of 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-, -CN-, -CONHR1-, -NH2-, C1-C4 alkylamino, di (C1-C4 alkyl) amino, -NHSO2R1-, -NHCOR1-, -NO2-, and phenyl optionally substituted with 1-3 C1-C4 alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1 wherein: R1, R2, R3, R4, R5, R6, Z and X have the values defined in claim 1, Y is the moiety   wherein 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 hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4) alkyl, -CO2H,  -CN, -CONH(C1-C4) alkyl, -NH2, C1-C4 alkylamino, di (C1-C4 alkyl) amino, -NHSO2 (C1-C4) alkyl, -NHCO (C1-C4) alkyl, and -NO2. 3. A compound of claim 2 wherein R7 and R8 are concatenated together as -(CH2)p- to form a ring, wherein p is an integer of from 2 to 6, the ring being optionally substituted with 1-3 substituents selected from the group of C1-C3 alkyl, trifluoromethyl, halogen, hydrogen, phenyl, nitro, or -CN. 4. A compound of claim 1 which is one of the following: (E)-N,N-Diethyl-3-[4-[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-indol-1-ylmethyl]-phenyl]-acrylamide; (E)-N-tert-butyl-3-[4-[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-indol-1-ylmethyl]-phenyl]-acrylamide; (E)-Pyrollidino-3-[4-[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-indol-l-ylmethyl]-phenyl]-acrylamide; (E)-N,N-Dimethyl-3-[4-[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-indol-l-ylmethyl]-phenyl]-acrylamide; (E)-N,N-Dibutyl-3-[4-[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-indol-l-ylmethyl]-phenyl]-acrylamide; (E)-N-Butyl, N'-methyl-3-[4-[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-indol-l-ylmethyl]-phenyl]-crylamide; (E)-Morpholino-3-[4-[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-indol-l-ylmethyl]-phenyl] acrylamide; (E)-3-[4-[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-indol-l-ylmethyl]-phenyl]-acrylamide; (E)-N,Methyl-3-[4-[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-indol-l-ylmethyl]-phenyl]-acrylamide; (E)-N,N-Dibutyl-3-[4-[5-hydroxy-2-(4-fluorophenyl)-3-methyl-mdol-l-ylmethyl]-phenyl]-acrylamide; (E)-N-Butyl,N'-Methyl-3-[4-[5-hydroxy-2-(4-fluorophenyl)-3-methyl-indol-l-ylmethyl]phenyl]-acrylamide; 2-(4-Hydroxyphenyl)-3-methyl-l-[4-(3-N,N-dimethyl-l-yl-prop-l-ynyl) benzyl]-lH-indol-5-ol; 2-(4-Hydroxyphenyl)-3-methyl-l-[4-(3-piperidin-l-yl prop-l-ynyl) benzyl]-lH-indol-5-ol; or 2-(4-Hydroxyphenyl)-3-methyl-1-[4-(3-pyrrolidin-1-yl prop-1-ynyl) benzyl]-lH-indol-5-ol; or a pharmaceutically acceptable salt thereof. 5. A method of treating or preventing bone loss in a mammal, the method comprising administering to a mammal in need thereof an effective amount of a compound of Claim 1, or a pharmaceutically acceptable salt thereof. 6. A pharmaceutical composition comprising a compound of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 7. A process for preparing a compound of formula I which comprises reacting a compound of formula:   wherein R1-R6 and X are as defined in Claim 1 with an acrylamide of formula:   wherein Y is as defined in Claim 1 to give a compound of formula I wherein Z is -CH=CH-COY. 8. A process for preparing a compound of formula I which comprises reacting a compound of formula:   wherein R1-R6 and X are as defined in claim 1 with a compound of formula:   wherein n and Y are as defined in claim 1 to give a corresponding compound of Formula I wherein Z is