Claims
- 1. A method for the inducement of sphincter continence in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of one or more estrogens, or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of a compound of the formulae I or II: wherein Z is a moiety selected from the group consisting of: wherein:R1 is selected from H, OH or the C1-C12 esters or C1-C12 alkyl ethers thereof, benzyloxy, or halogen; or C1-C4 halogenated ethers; R2, R3, R5 and R6 are independently selected from H, OH or the C1-C12 esters or C1-C12 alkyl ethers thereof, halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl, or trifluoromethyl, with the proviso that, when R1 is H, R2 is not OH; R4 is selected from H, OH or the C1-C12 esters or C1-C12 alkyl ethers thereof, halogens, or C1-C4 halogenated ethers, benzyloxy, cyano, C1-C6 alkyl, or trifluoromethyl; X is selected from H, C1-C6 alkyl, cyano, nitro, trifluoromethyl, halogen; n is 1, 2 or 3; Y is selected from: a) the moiety: wherein R7 and R8 are independently selected from the group consisting of H, C1-C6 alkyl, and phenyl optionally substituted by CN, C1-C6 alkyl, C1-C6 alkoxy, halogen, —OH, —CF3, or —OCF3; b) a five-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C1C4 alkyl)—, —N═, and —S(O)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, 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)alkylamino, —NHSO2R1—, —NHCOR1—, —NO2, and phenyl optionally substituted with 1-3 (C1-C4)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(C1C4 alkyl)—, —N═, and —S(O)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, 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)alkylamino, —NHSO2R1—, —NHCOR1—, —NO2, and phenyl optionally substituted with 1-3 (C1-C4)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(C1-C4 alkyl)—, —N═, and —S(O)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, 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)alkylamino, —NHSO2R1—, —NHCOR1—, —NO2, and phenyl optionally substituted with 1-3 (C1-C4)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(C1C4 alkyl)—, and —S(O)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, 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)alkylamino, —NHSO2R1—, —NHCOR1—, —NO2, and phenyl optionally substituted with 1-3 (C1-C4) alkyl; or a pharmaceutically acceptable salt thereof.
- 2. The method of claim 1 wherein in the compound of the formulae I or II:R1 is selected from H, OH or the C1-C12 esters or alkyl ethers thereof, benzyloxy, or halogen; R2, R3, R5, and R6 are independently selected from H, OH or the C1-C12 esters or alkyl ethers thereof, halogen, cyano, C1-C6 alkyl, or trihalomethyl; with the proviso that, when R1 is H, R2 is not OH; R4 is selected from H, OH or the C1-C12 esters or alkyl ethers thereof, benzyloxy, halogen, cyano, C1-C6 alkyl, or trihalomethyl; X is selected from H, C1-C6 alkyl, cyano, nitro, trifluoromethyl, 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, —CN, —CONH(C1-C4), —NH3, C1-C4 alkylamino, C1-C4 dialkylamino, —NHSO2(C1-C4), —NHCO(C1-C4), and —NO3; or a pharmaceutically acceptable salt thereof.
- 3. The method of claim 2 wherein, in the compound of the formulae I or II, the ring formed by a the combination of R7 and R8 by —(CH2)p— is selected from aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneamine or heptamethyleneamine.
- 4. The method of claim 1 utilizing a compound of the formulae I or II, wherein R1 is OH; R2-R6 are as defined in claim 1; X is selected from the group of Cl, NO2, CN, CF3, or CH3; and 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, —CN, —CONH(C1-C4)alkyl, —NH2, C1-C4 alkylamino, di(C1-C4)alkylamino, —NHSO2(C1-C4)alkyl, —NHCO(C1-C4)alkyl, and —NO2;or a pharmaceutically acceptable salt thereof.
- 5. The method of inducing sphincter continence of claim 1 wherein the sphincter is a urinary sphincter.
- 6. The method of inducing sphincter continence of claim 1 wherein the sphincter is an anal sphincter.
- 7. The method of inducing sphincter continence of claim 1 wherein the sphincter is a lower esophageal sphincter.
- 8. The method of claim 1 wherein the one or more estrogens are selected from the group of estrone, estriol, equilin, estradiene, equilenin, ethinyl estradiol, 17β-estradiol, 17α-dihydroequilenin, 17β-dihydroequilenin, 17α-dihydroequilin, 17β-dihydroequilin, menstranol, conjugated estrogenic hormones, equol, enterolactone, or a pharmaceutically acceptable salt thereof.
- 9. A method for inducement of sphincter continence in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of one or more estrogens, or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of a compound of the formulae (III) or (IV): wherein R1, R2, R3, R4, R5, R6, n, X, and Y are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
- 10. A method for inducement of sphincter continence in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of one or more estrogens, or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of a compound of the formulae (V) or (VI): wherein R1, R2, R3, R4, R5, R6, X, and Y are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
- 11. A method for inducement of sphincter continence in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of one or more estrogens, or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of a compound of the formulae VII or VIII: wherein R1, R2, R3, R4, R5, R6, n, X, and Y are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
- 12. A method for inducement of sphincter control in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of 1-[4-(2-Azepan-1yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol, or a pharmaceutically effective salt thereof, and one or more estrogens, or a pharmaceutically acceptable salt thereof.
- 13. The method of claim 12 wherein the one or more estrogens are conjugated estrogenic hormones.
- 14. The method of inducing sphincter continence of claim 12 wherein the sphincter is a urinary sphincter.
- 15. The method of inducing sphincter continence of claim 12 wherein the sphincter is an anal sphincter.
- 16. A method for the inducement of sphincter control in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of 2-(4-Hydroxy-phenyl)-3-methyl-1-(4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol, or a pharmaceutically effective salt thereof, one or more estrogens, or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of a bisphosphonate, or a pharmaceutically effective salt thereof.
- 17. The method of claim 16 wherein the one or more estrogens are conjugated estrogenic hormones.
- 18. The method of inducing sphincter continence of claim 16 wherein the sphincter is a urinary sphincter.
- 19. The method of inducing sphincter continence of claim 16 wherein the sphincter is an anal sphincter.
Parent Case Info
This application claims the benefit of U.S. Provisional Application No. 60/216,186, filed Jul. 6, 2000.
This invention relates to methods of using substituted indole compounds and one or more estrogens in the inducement of sphincter continence or competence or in the treatment, prevention, inhibition or alleviation of sphincter incontinence.
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Patent Grant
6455568
