Claims for Patent: 4,418,068

Summary for Patent: 4,418,068

Title:	Antiestrogenic and antiandrugenic benzothiophenes
Abstract:	6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thio phene, its ethers and esters, and the physiologically acceptable acid addition salts thereof, are valuable antiestrogens and antiendrogens.
Inventor(s):	Jones; Charles D. (Indianapolis, IN)
Assignee:	Eli Lilly and Company (Indianapolis, IN)
Application Number:	06/331,042
Patent Claims:	1. A compound of the formula ##STR5## a physiologically acceptable ester or ether thereof, or a physiologically acceptable acid addition salt thereof. 2. A compound of claim 1 of the formula ##STR6## wherein R and R.sup.1 independently are hydrogen, --COR.sup.2 or R.sup.3 ; R.sup.2 is hydrogen, C.sub.1 -C.sub.14 alkyl, C.sub.1 -C.sub.3 chloroalkyl, C.sub.1 -C.sub.3 fluoroalkyl, C.sub.5 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.4 alkoxy, phenyl, or phenyl mono- or disubstituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, nitro, chloro, fluoro or tri(chloro or fluoro)methyl; R.sup.3 is C.sub.1 -C.sub.4 alkyl, C.sub.5 -C.sub.7 cycloalkyl or benzyl; or a physiologically acceptable acid addition salt thereof. 3. The compound of claim 2 which is 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thi ophene, or a physiologically acceptable acid addition salt thereof. 4. A compound of claim 2 wherein R and R.sup.1 are the same, and are a group other than hydrogen. 5. A compound of claim 2 wherein one of R and R.sup.1 is hydrogen. 6. A compound of claim 2 wherein one or both of R and R.sup.1 is --COR.sup.2. 7. A compound of claim 2 wherein one or both of R and R.sup.1 is R.sup.3. 8. A compound of any one of claims 2, 4 or 6 wherein R.sup.2 is C.sub.1 -C.sub.14 alkyl. 9. A compound of any one of claims 2, 4 or 6 wherein R.sup.2 is C.sub.1 -C.sub.3 chloroalkyl or C.sub.1 -C.sub.3 fluoroalkyl. 10. A compound of any one of claims 2, 4 or 6 wherein R.sup.2 is C.sub.5 -C.sub.7 cycloalkyl. 11. A compound of any one of claims 2, 4 or 6 wherein R.sup.2 is C.sub.1 -C.sub.4 alkoxy. 12. A compound of any one of claims 2, 4 or 6 wherein R.sup.2 is phenyl. 13. A compound of any one of claims 2, 4 or 6 wherein R.sup.2 is substituted phenyl. 14. A compound of any one of claims 2, 4, 5 or 7 wherein R.sup.3 is C.sub.1 -C.sub.4 alkyl. 15. A compound of any one of claims 2, 4, 5 or 7 wherein R.sup.3 is C.sub.5 -C.sub.7 cycloalkyl. 16. A compound of any one of claims 2, 4, 5 or 7 wherein R.sup.3 is benzyl. 17. A compound of any one of claims 1-7 which is a free base. 18. A compound of any one of claims 1-7 which is a physiologically acceptable acid addition salt. 19. A compound of any one of claims 1-7 which is a hydrochloride. 20. The compound of claim 1 which is 6-acetoxy-2-(4-acetoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thi ophene, or a physiologically acceptable acid addition salt thereof. 21. The compound of claim 1 which is 6-benzoyloxy-2-(4-benzoyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo [b]thiophene, or a physiologically acceptable acid addition salt thereof. 22. The compound of claim 1 which is 6-ethoxycarbonyloxy-2-(4-ethoxycarbonyloxyphenyl)-3-[4-(2-piperidinoethoxy )benzoyl]benzo[b]thiophene, or a physiologically acceptable acid addition salt thereof. 23. The compound of claim 1 which is 6-methoxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thi ophene, or a physiologically acceptable acid addition salt thereof. 24. An antiestrogenic and antiandrogenic pharmaceutical composition comprising a pharmaceutically acceptable diluent and an effective amount of a compound of the formula ##STR7## a physiologically acceptable ester or ether thereof, or a physiologically acceptable acid addition salt thereof. 25. A composition of claim 24 wherein the compound is of the formula ##STR8## wherein R and R.sup.1 independently are hydrogen, --COR.sup.2 or R.sup.3 ; R.sup.2 is hydrogen, C.sub.1 -C.sub.14 alkyl, C.sub.1 -C.sub.3 chloroalkyl, C.sub.1 -C.sub.3 fluoroalkyl, C.sub.5 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.4 alkoxy, phenyl, or phenyl mono- or disubstituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, nitro, chloro, fluoro or tri(chloro or fluoro)methyl; R.sup.3 is C.sub.1 -C.sub.4 alkyl, C.sub.5 -C.sub.7 cycloalkyl or benzyl; or a physiologically acceptable acid addition salt thereof. 26. A composition of claim 25 wherein the compound is 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thi ophene, or a physiologically acceptable acid addition salt thereof. 27. A composition of claim 26 wherein the compound is the hydrochloride. 28. A composition of claim 25 wherein the compound is a compound wherein R and R.sup.1 are the same, and are a group other than hydrogen. 29. A composition of claim 28 wherein the compound is a compound wherein R and R.sup.1 are --COR.sup.2. 30. A composition of claim 29 wherein the compound is a compound wherein R.sup.2 is C.sub.1 -C.sub.14 alkyl. 31. A composition of claim 30 wherein the compound is 6-acetoxy-2-(4-acetoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thi ophene, or a physiologically acceptable acid addition salt thereof. 32. A composition of claim 29 wherein the compound is a compound wherein R.sup.2 is phenyl. 33. A composition of claim 32 wherein the compound is 6-benzoyloxy-2-(4-benzoyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo [b]thiophene, or a physiologically acceptable acid addition salt thereof. 34. A composition of claim 29 wherein the compound is a compound wherein R.sup.2 is C.sub.1 -C.sub.4 alkoxy. 35. A composition of claim 34 wherein the compound is 6-ethoxycarbonyloxy-2-(4-ethoxycarbonyloxyphenyl)-3-[4-(2-piperidinoethoxy )benzoyl]benzo[b]thiophene, or a physiologically acceptable acid addition salt thereof. 36. A composition of claim 28 wherein R and R.sup.1 and R.sup.3. 37. A composition of claim 36 wherein the compound is 6-methoxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thi ophene, or a physiologically acceptable acid addition salt thereof. 38. A composition of claim 25 wherein the compound is a compound wherein one of R and R.sup.1 is hydrogen. 39. A method of alleviating a pathological condition of an endocrine target organ, which condition is dependent or partially dependent on an estrogen or on an androgen, which comprises administering to a subject suffering from such a condition an effective dose of a compound of the formula ##STR9## a physiologically acceptble ester or ether thereof, or a physiologically acceptable acid addition salt thereof. 40. A method of claim 39 wherein the pathological condition is dependent or partially dependent on an estrogen. 41. A method of claim 40 wherein the dose of the compound is from about 0.05 mg./kg./day to about 50 mg./kg./day. 42. A method of claim 41 wherein the target organ is the breast, and the pathological condition is mammary cancer. 43. A method of claim 42 wherein the dose of the compound is from about 0.1 mg./kg./day to about 10 mg./kg./day. 44. A method of claim 41 wherein the target organ is the breast, and the pathological condition is fibrocystic disease. 45. A method of claim 44 wherein the dose of the compound is from about 0.1 mg./kg./day to about 10 mg./kg./day. 46. A method of claim 39 wherein the pathological condition is dependent or partially dependent on an androgen. 47. A method of claim 46 wherein the dose of the compound is from about 0.05 mg./kg./day to about 50 mg./kg./day. 48. A method of claim 47 wherein the target organ is the prostate, and the pathological condition is prostatic cancer. 49. A method of claim 48 wherein the dose of the compound is from about 0.1 mg./kg./day to about 10 mg./kg./day. 50. A method of claim 47 wherein the target organ is the prostate, and the pathological condition is benign prostatic hypertrophy. 51. A method of claim 50 wherein the dose is from about 0.1 mg./kg./day to about 10 mg./kg./day. 52. A method of any one of claims 39-51 wherein the compound is of the formula ##STR10## wherein R and R.sup.1 independently are hydrogen, --COR.sup.2 or R.sup.3 ; R.sup.2 is hydrogen, C.sub.1 -C.sub.14 alkyl, C.sub.1 -C.sub.3 chloroalkyl, C.sub.1 -C.sub.3 fluoroalkyl, C.sub.5 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.4 alkoxy, phenyl, or phenyl mono- or disubstituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, nitro, chloro, fluoro or tri(chloro or fluoro)methyl; R.sup.3 is C.sub.1 -C.sub.4 alkyl, C.sub.5 -C.sub.7 cycloalkyl or benzyl; or a physiologically acceptable acid addition salt thereof. 53. A method of claim 52 wherein the compound is 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thi ophene, or a physiologically acceptable acid addition salt thereof. 54. A method of claim 53 wherein the compound is the hydrochloride. 55. A method of claim 52 wherein the compound is a compound wherein R and R.sup.1 are the same, and are a group other than hydrogen. 56. A method of claim 55 wherein the compound is a compound wherein R and R.sup.1 are --COR.sup.2. 57. A method or claim 56 wherein the compound is 6-acetoxy-2-(4-acetoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thi ophene, or a physiologically acceptable acid addition salt thereof. 58. A method of claim 56 wherein the compound is 6-benzoyloxy-2-(4-benzoyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo [b]thiophene, or a physiologically acceptable acid addition salt thereof. 59. A method of claim 56 wherein the compound is 6-ethoxycarbonyloxy-2-(4-ethoxycarbonyloxyphenyl)-3-[4-(2-piperidinoethoxy )benzoyl]benzo[b]thiophene, or a physiologically acceptable acid addition salt thereof. 60. A method of claim 55 wherein the compound is a compound wherein R and R.sup.1 are R.sup.3. 61. A method of claim 60 wherein the compound is 6-methoxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thi ophene, or a physiologically acceptable acid addition salt thereof. 62. A method of claim 52 wherein the compound is a compound wherein one of R and R.sup.1 is hydrogen.