Details for Patent: 7,247,624
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Title: | 2-Phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents |
Abstract: | The present invention relates to new 2-Phenyl-1-[4-(2-Aminoethoxy)-Benzyl]-Indole compounds having the general structures below: ##STR00001## which are useful in treating colon cancer. |
Inventor(s): | Miller; Chris P. (Strafford, PA), Collini; Michael D. (Clifton Heights, PA), Tran; Bach D. (Baltimore, MD), Santilli; Arthur A. (Havertown, PA) |
Assignee: | Wyeth (Madison, NJ) |
Filing Date: | Aug 23, 2006 |
Application Number: | 11/508,547 |
Claims: | 1. A method of treating colon cancer in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formula I or II, having the structures ##STR00181## wherein: R.sub.1 is selected from H, OH or the C.sub.1-C.sub.12 esters (straight chain or branched) or C.sub.1-C.sub.12 (straight chain or branched or cyclic) alkyl ethers thereof, or halogens; or C.sub.1-C.sub.4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether; R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected from H, OH or the C.sub.1-C.sub.12 esters (straight chain or branched) or C.sub.1-C.sub.12 alkyl ethers (straight chain or branched or cyclic) thereof, halogens, or C.sub.1-C.sub.4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether, cyano, C.sub.1-C.sub.6 alkyl (straight chain or branched), or trifluoromethyl, with the proviso that, when R.sub.1 is H, R.sub.2 is not OH; X is selected from H, C.sub.1-C.sub.6 alkyl, cyano, nitro, trifluoromethyl, halogen; n is 2 or 3; Y is selected from: a) the moiety: ##STR00182## wherein R.sub.7 and R.sub.8 are independently selected from the group of H, C.sub.1-C.sub.6 alkyl, or phenyl optionally substituted by CN, C.sub.1-C.sub.6 alkyl (straight chain or branched), C.sub.1-C.sub.6 alkoxy (straight chain or branched), halogen, --OH, --CF.sub.3, or --OCF.sub.3; b) a five-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of --O--, --NH--, --N(C.sub.1C.sub.4 alkyl)-, --N.dbd., and --S(O).sub.m--, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C.sub.1-C.sub.4 alkyl, trihalomethyl, C.sub.1-C.sub.4 alkoxy, trihalomethoxy, C.sub.1-C.sub.4 acyloxy, C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 alkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl, hydroxy (C.sub.1-C.sub.4)alkyl, --CO.sub.2H--, --CN--, --CONHR.sub.1--, --NH.sub.2--, C.sub.1-C.sub.4 alkylamino, di(C.sub.1-C.sub.4)alkylamino, --NHSO.sub.2R.sub.1--, --NHCOR.sub.1--, --NO.sub.2, and phenyl optionally substituted with 1-3 (C.sub.1-C.sub.4)alkyl; c) a six-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of --O--, --NH--, --N(C.sub.1C.sub.4 alkyl)-, --N.dbd., and --S(O).sub.m--, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C.sub.1-C.sub.4 alkyl, trihalomethyl, C.sub.1-C.sub.4 alkoxy, trihalomethoxy, C.sub.1-C.sub.4 acyloxy, C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 alkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl, hydroxy (C.sub.1-C.sub.4)alkyl, --CO.sub.2H--, --CN--, --CONHR.sub.1--, --NH.sub.2--, C.sub.1-C.sub.4 alkylamino, di(C.sub.1-C.sub.4)alkylamino, --NHSO.sub.2R.sub.1--, --NHCOR.sub.1--, --NO.sub.2, and phenyl optionally substituted with 1-3 (C.sub.1-C.sub.4)alkyl; d) a seven-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of --O--, --NH--, --N(C.sub.1C.sub.4 alkyl)-, --N.dbd., and --S(O).sub.m--, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C.sub.1-C.sub.4 alkyl, trihalomethyl, C.sub.1-C.sub.4 alkoxy, trihalomethoxy, C.sub.1-C.sub.4 acyloxy, C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 alkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl, hydroxy (C.sub.1-C.sub.4)alkyl, --CO.sub.2H--, --CN--, --CONHR.sub.1--, --NH.sub.2--, C.sub.1-C.sub.4 alkylamino, di(C.sub.1-C.sub.4)alkylamino, --NHSO.sub.2R.sub.1--, --NHCOR.sub.1--, --NO.sub.2, and phenyl optionally substituted with 1-3 (C.sub.1-C.sub.4)alkyl; or e) a bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing up to two heteroatoms selected from the group consisting of --O--, --NH--, --N(C.sub.1C.sub.4 alkyl)-, and --S(O).sub.m--, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C.sub.1-C.sub.4 alkyl, trihalomethyl, C.sub.1-C.sub.4 alkoxy, trihalomethoxy, C.sub.1-C.sub.4 acyloxy, C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 alkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl, hydroxy (C.sub.1-C.sub.4)alkyl, --CO.sub.2H--, --CN--, --CONHR.sub.1--, --NH.sub.2--, C.sub.1-C.sub.4 alkylamino, di(C.sub.1-C.sub.4)alkylamino, --NHSO.sub.2R.sub.1--, --NHCOR.sub.1--, --NO.sub.2, and phenyl optionally substituted with 1-3 (C.sub.1-C.sub.4)alkyl; and the pharmaceutically acceptable salts thereof. 2. The method according to claim 1 wherein: R.sub.1 is selected from H, OH or the C.sub.1-C.sub.4 esters or alkyl ethers thereof, halogen; R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected from H, OH or the C.sub.1-C.sub.4 esters or alkyl ethers thereof, halogen, cyano, C.sub.1-C.sub.6 alkyl, or trifluoromethyl, with the proviso that, when R.sub.1 is H, R.sub.2 is not OH; X is selected from H, C.sub.1-C.sub.6 alkyl, cyano, nitro, trifluoromethyl, halogen; Y is the moiety ##STR00183## R.sub.7 and R.sub.8 are selected independently from H, C.sub.1-C.sub.6 alkyl, or combined by --(CH.sub.2).sub.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, C.sub.1-C.sub.4 alkyl, trihalomethyl, C.sub.1-C.sub.4 alkoxy, trihalomethoxy, C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 alkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl, hydroxy (C.sub.1-C.sub.4)alkyl, --CO.sub.2H, --CN, --CONH(C.sub.1-C.sub.4), --NH.sub.2, C.sub.1-C.sub.4 alkylamino, di(C.sub.1-C.sub.4)alkylamino, --NHSO.sub.2(C.sub.1-C.sub.4), --NHCO(C.sub.1-C.sub.4), and --NO.sub.2; or a pharmaceutically acceptable salt thereof. 3. The method according to claim 1, wherein: R.sub.1 is OH; R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected from H, OH or the C.sub.1-C.sub.4 esters or alkyl ethers thereof, halogen, cyano, C.sub.1-C.sub.6 alkyl, or trifluoromethyl, with the proviso that, when R.sub.1 is H, R.sub.2 is not OH; X is selected from the group of Cl, NO.sub.2, CN, CF.sub.3, or CH.sub.3; Y is the moiety ##STR00184## R.sub.7 and R.sub.8 are concatenated together as --(CH.sub.2).sub.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, C.sub.1-C.sub.4 alkyl, trihalomethyl, C.sub.1-C.sub.4 alkoxy, trihalomethoxy, C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 alkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl, hydroxy (C.sub.1-C.sub.4)alkyl, --CO.sub.2H, --CN, --CONH(C.sub.1-C.sub.4), --NH.sub.2, C.sub.1-C.sub.4 alkylamino, di(C.sub.1-C.sub.4)alkylamino, --NHSO.sub.2(C.sub.1-C.sub.4), --NHCO(C.sub.1-C.sub.4), and --NO.sub.2; or a pharmaceutically acceptable salt thereof. 4. A method of treating colon cancer in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formula I or II, having the structures ##STR00185## wherein: R.sub.1 is selected from H, OH or the C.sub.1-C.sub.4 esters or alkyl ethers thereof, halogen; R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected from H, OH or the C.sub.1-C.sub.4 esters or alkyl ethers thereof, halogen, cyano, C.sub.1-C.sub.6 alkyl, or trifluoromethyl, with the proviso that, when R.sub.1 is H, R.sub.2 is not OH; X is selected from H, C.sub.1-C.sub.6 alkyl, cyano, nitro, trifluoromethyl, halogen; n is 2 or 3; and Y is the moiety ##STR00186## R.sub.7 and R.sub.8 are selected independently from H, C.sub.1-C.sub.6 alkyl, or combined by --(CH.sub.2).sub.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, C.sub.1-C.sub.4 alkyl, trihalomethyl, C.sub.1-C.sub.4 alkoxy, trihalomethoxy, C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 alkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl, hydroxy (C.sub.1-C.sub.4)alkyl, --CO.sub.2H, --CN, --CONH(C.sub.1-C.sub.4), --NH.sub.2, C.sub.1-C.sub.4 alkylamino, di(C.sub.1-C.sub.4)alkylamino, --NHSO.sub.2(C.sub.1-C.sub.4), --NHCO(C.sub.1-C.sub.4), and --NO.sub.2; or a pharmaceutically acceptable salt thereof. 5. The method according to claim 4, wherein: R.sub.1 is OH; R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected from H, OH or the C.sub.1-C.sub.4 esters or alkyl ethers thereof, halogen, cyano, C.sub.1-C.sub.6 alkyl, or trifluoromethyl, with the proviso that, when R.sub.1 is H, R.sub.2 is not OH; X is selected from the group of Cl, NO.sub.2, CN, CF.sub.3, or CH.sub.3; Y is the moiety ##STR00187## R.sub.7 and R.sub.8 are concatenated together as --(CH.sub.2).sub.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, C.sub.1-C.sub.4 alkyl, trihalomethyl, C.sub.1-C.sub.4 alkoxy, trihalomethoxy, C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 alkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl, hydroxy (C.sub.1-C.sub.4)alkyl, --CO.sub.2H, --CN, --CONH(C.sub.1-C.sub.4), --NH.sub.2, C.sub.1-C.sub.4 alkylamino, di(C.sub.1-C.sub.4)alkylamino, --NHSO.sub.2(C.sub.1-C.sub.4), --NHCO(C.sub.1-C.sub.4), and --NO.sub.2; or a pharmaceutically acceptable salt thereof. 6. The method according to claim 4, wherein the compound is 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indo- l-5-ol or a pharmaceutically acceptable salt thereof. 7. The method according to claim 4, wherein the compound is 2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-i- ndol-5-ol or a pharmaceutically acceptable salt thereof. |