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Claims for Patent: 4,418,068

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Claims 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.
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