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Details for Patent: 5,834,498

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Details for Patent: 5,834,498

Title: Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents
Abstract:The invention relates to the use of derivatives of F-type prostaglandins as ocular hypotensives. The PGF derivatives used in accordance with the invention are represented by the following formula I: ##STR1## wherein wavy line attachments indicate either the alpha (.alpha.) or beta (.beta.) configuration; hatched segments indicate .alpha. configuration, solid triangles are used to indicate .beta. configuration, dashed bonds represent a double bond, or a single bond, R is a substituted heteroaryl radical, R.sup.1 is hydrogen or a lower alkyl radical having up to six carbon atoms, X is selected from the group consisting of --OR.sup.1 and --N(R.sup.1).sub.2, Y is .dbd.O or represents 2 hydrogen radicals. Certain of the compounds represented by Formula I comprise another aspect of the present invention.
Inventor(s): Burk; Robert M. (Laguna Beach, CA)
Assignee: Allergan (Waco, TX)
Filing Date:Oct 07, 1996
Application Number:08/726,921
Claims:1. A method of treating ocular hypertension which comprises administering topically to a mammal having ocular hypertension a therapeutically effective amount of a compound represented by formula II: ##STR36## wherein the hatched segments represent .alpha. bonds, the solid triangle represents a .beta. bond, wavy line attachments indicate either the alpha (.alpha.) or beta (.beta.) configuration; R.sup.1 is hydrogen or a lower alkyl radical having up to six carbon atoms, X is selected from the group consisting of --OR.sup.1 and --N(R.sup.1).sub.2, Y is .dbd.O or represents 2 hydrogen radicals;

Z is selected from the group consisting of O and S, A is selected from the group consisting of --CH, and C, R.sup.2 is selected from the group consisting of hydrogen, lower alkyl or alkoxy having from 1 to 6 carbon atoms, trifluoro methyl, COR.sub.1, COCF.sub.3, SO.sub.2 NH.sub.2, NO.sub.2 and CN, R.sup.3 and R.sup.4 are selected from the group consisting of hydrogen, halogen, lower alkyl or alkoxy having from 1 to 6 carbon atoms trifluoromethyl, COR.sub.1, COCF.sub.3, SO.sub.2 NH.sub.2, and CN, provided however at least one of R.sup.2, R.sup.3 or R.sup.4 must be halogen or alkyl.

2. The method of claim 1 wherein said compound is represented by formula III: ##STR37## wherein R.sup.5 is hydrogen or methyl.

3. The method of claim 2 wherein X is --OH or --NH.sub.2.

4. The method of claim 2 wherein Y is .dbd.O and X is --OH.

5. The method of claim 2 wherein Y is .dbd.O and X is --NH.sub.2.

6. The method of claim 2 wherein Z is S.

7. The method of claim 6 wherein at least one of R.sup.2, R.sup.3 and R.sup.4 are selected from the group consisting of halogen, lower alkyl having from 1 to 4 carbon atoms and lower alkoxy having from 1 to 4 carbon atoms.

8. The method of claim 6 wherein at least one of R.sup.2, R.sup.3 and R.sup.4 is selected from the group consisting of chloro and bromo.

9. The method of claim 6 wherein at least one of R.sup.2, R.sup.3 and R.sup.4 are chloro.

10. The method of claim 9 wherein at least two of R.sup.2, R.sup.3 and R.sup.4 are chloro.

11. The method of claim 2 wherein Y is .dbd.O, X is --OH or --NH.sub.2 and Z is S.

12. The method of claim 11 wherein at least one of R.sup.2, R.sup.3 and R.sup.4 is selected from the group consisting of chloro and bromo.

13. The method of claim 11 wherein at least one of R.sup.2, R.sup.3 or R.sup.4 are bromo or at least two of R.sup.2, R.sup.3 or R.sup.4 are chloro.

14. The method of claim 13 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(2-(4-bromo)thienyl)- 1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

15. The method of claim 13 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(3-(2,5-dichloro)thie nyl-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

16. The method of claim 13 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(2-(5-bromo)thienyl)- 1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

17. The method of claim 13 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(2-(3-chloro)thienyl) -1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

18. The method of claim 13 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(3-(2-chloro)thienyl- 1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

19. The method of claim 13 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(3-(2,5-dichloro)thie nyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide.

20. The method of claim 11 wherein at least one of R.sup.2, R.sup.3 or R.sup.4 is a lower alkyl radical having from 1 to 4 carbon atoms.

21. The method of claim 20 wherein at least one of R.sup.2, R.sup.3 or R.sup.4 are ethyl, propyl or butyl.

22. The method of claim 21 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(2-(5-ethyl)-thienyl) -1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

23. The method of claim 21 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(2-(5-propyl)thienyl- 1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

24. The method of claim 22 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(2-(5-butyl)thienyl-1 E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

25. An ophthalmic solution comprising a therapeutically effective amount of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a non-toxic, ophthalmically acceptable liquid vehicle, packaged in a container suitable for metered application.

26. The ophthalmic solution of claim 25 wherein said compound is a compound of Formula III.

27. A pharmaceutical product, comprising a container adapted to dispense the contents of said container in metered form; and an ophthalmic solution in said container comprising a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a non-toxic, ophthalmically acceptable liquid vehicle.

28. The product of claim 27 wherein said compound is a compound of Formula III.

29. The compound represented by Formula II: ##STR38## wherein the hatched segments represent .alpha. bonds, the solid triangle represents .beta. bond, wavy line attachments indicate either the alpha (.alpha.) or beta (.beta.) configuration: A is selected from the group consisting of --CH and C, R.sup.1 is hydrogen or a lower alkyl radical having up to six carbon atoms, R.sup.2 is selected from the group consisting of hydrogen, halogen lower alkyl or alkoxy having from up to six carbon atoms, trifluoromethyl, COR.sub.1, COCF.sub.3, SO.sub.2 NH.sub.2, NO.sub.2 and CN, R.sup.3 and R.sup.4 are selected from the group consisting of hydrogen, halogen, lower alkyl or lower alkoxy having up to six carbon atoms, trifluoromethyl, COR.sub.1, COCF.sub.3, SO.sub.2 NH.sub.2, NO.sub.2 and CN, provided at least one of the R.sub.2, R.sub.3 or R.sub.4 must be halogen or alkyl, Y is .dbd.O and X is --OH or --NH.sub.2 and Z is S.

30. The compound of claim 29 wherein at least one of R.sup.2, R.sup.3 and R.sup.4 are selected from the group consisting of halogen, lower alkyl having from 1 to 4 carbon atoms and lower alkoxy having from 1 to 4 carbon atoms.

31. The compound of claim 29 wherein at least one of R.sup.2, R.sup.3 and R.sup.4 is selected from the group consisting of chloro and bromo.

32. The compound of claim 29 wherein at least one of R.sup.2, R.sup.3 and R.sup.4 are chloro.

33. The compound of claim 32 wherein at least two of R.sup.2, R.sup.3 and R.sup.4 are chloro.

34. The compound of claim 31 wherein at least one of R.sup.2, R.sup.3 and R.sup.4 is selected from the group consisting of chloro and bromo.

35. The compound of claim 29 wherein at least one of R.sup.2, R.sup.3 or R.sup.4 are bromo or at least two of R.sup.2, R.sup.3 or R.sup.4 are chloro.

36. The compound of claim 35 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(2-(4-bromo)thienyl)- 1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

37. The compound of claim 35 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(3-(2,5-dichloro)thie nyl-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

38. The compound of claim 35 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(2-(5-bromo)thienyl)- 1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

39. The compound of claim 35 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(2-(3-chloro)thienyl) -1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

40. The compound of claim 35 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(3-(2-chloro)thienyl- 1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

41. The compound of claim 35 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(3-(2,5-dichloro)thie nyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide.

42. The compound of claim 29 wherein at least one of R.sup.2, R.sup.3 or R.sup.4 is a lower alkyl radical having from 1 to 4 carbon atoms.

43. The compound of claim 42 wherein at least one of R.sup.2, R.sup.3 or R.sup.4 are ethyl, propyl or butyl.

44. The compound of claim 43 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(2-(5-ethyl)-thienyl) -1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

45. The compound of claim 43 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(2-(5-propyl)thienyl- 1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

46. The compound of claim 43 wherein said compound is 7-[3.alpha.,5.alpha.-Dihydroxy-2-(3.alpha.-hydroxy-5-(2-(5-butyl)thienyl-1 E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

47. A method of treating glaucoma which comprises administering topically to a mammal having glaucoma a therapeutically effective amount of a compound represented by formula II: ##STR39## wherein the hatched segments represent .alpha. bonds, the solid triangle represents .beta. bond, wavy line attachments indicate either the alpha (.alpha.) or beta (.beta.) configuration: R.sup.1 is hydrogen or a lower alkyl radical having up to six carbon atoms, Z is selected from the group consisting of O and S, X is selected from the group consisting of --OR.sup.1 and --N(R.sup.1).sub.2, Y is .dbd.O or represents hydrogen radicals, A is selected from the group consisting of --CH, and C, R.sup.2 is selected from the group consisting of hydrogen, lower alkyl or alkoxy having from 1 to 6 carbon atoms, trifluoromethyl, COR.sub.1, COCF.sub.3, SO.sub.2 NH.sub.2, NO.sub.2 and CN, R.sup.3 and R.sup.4 are selected from the group consisting of hydrogen, halogen, lower alkyl or lower alkoxy having from 1 to 6 carbon atoms, trifluoromethyl, COR.sub.1, COCF.sub.3, SO.sub.2 NH.sub.2, NO.sub.2 and CN;

provided however at least one of the R.sub.2, R.sub.3 or R.sub.4 must be halogen or alkyl.
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