12-Aryl prostaglandin analogs

• US 7,091,231 B2
• Filed: 12/10/2004
• Issued: 08/15/2006
• Est. Priority Date: 12/10/2004
• Status: Active Grant

• Current Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Original Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Inventors: Donde, Yariv, Nguyen, Jeremiah H.
• Primary Examiner(s): Saeed, Kamal A.
• Assistant Examiner(s): Barker, Michael P.
• Application Number:
  US11/009,298
• Publication Number:
  US 20060148894A1
• Time in Patent Office: 613 Days
• Field of Search: 514/381, 514/507, 514/513, 514/563, 514/570, 560/121, 548/250, 562/503, 564/161, 564/170, 564/189
• US Class Current: 514/381
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 405/00 Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
• CPC Class Codes: C07C 59/56 containing halogen
• CPC Class Codes: C07C 59/90 containing singly bound oxygen-containing groups

Abstract

Compounds comprising

are disclosed, wherein Y, A, X, R, D, and n are as described.

A compound comprising a prostaglandin EP₂ selective agonist wherein the ω-chain comprises a substituted phenyl, wherein at least one substituent consists of hydrocarbyl or non-linear hydroxyhydrocarbyl is also disclosed herein.

Methods, compositions, and medicaments related thereto are also disclosed.

Claims

1. A compound of the formula

2. The compound of claim 1 wherein n is 0.

3. The compound of claim 1 wherein R has from 6 to 9 carbon atoms and a cyclic structure.

4. The compound of claim 3 wherein R is a 1-hydroxyhydrocarbyl moiety.

5. The compound of claim 1 wherein R has from 1 to 5 carbon atoms.

6. The compound of claim 5 wherein R consists of t-butyl.

7. The compound of claim 1 of the formula

8. The compound of claim 1 of the formula

9. The compound of claim 4 of the formula

10. The compound of claim 4 of the formula

11. The compound of claim 1 of the formula

12. The compound of claim 11 of the formula

13. The compound of claim 11 of the formula

14. The compound of claim 13 of the formula

15. The compound of claim 13 of the formula

16. The compound of claim 15 of the formula

17. The compound of claim 12 of the formula

18. The compound of claim 11 of the formula

19. The compound of claim 11 selected from the group consisting of

(Z)-7-{(1R,2S,3R)-2-[4-(Cyclohexyl-hydroxy-methyl)-phenyl]-3-hydroxy-5-oxo-cyclopentyl}-hept-5-enoic acid methyl ester;

(Z)-7-{(1R,2S,3R)-2-[4-(Cyclohexyl-hydroxy-methyl)-phenyl]-3-hydroxy-5-oxo-cyclopentyl}-hept-5-enoic acid;

7-{(1R,2S,3R)-2-[4-(Cyclohexyl-hydroxy-methyl)-phenyl]-3-hydroxy-5-oxo-cyclopentyl}-heptanoic acid methyl ester;

7-{(1R,2S,3R)-2-[4-(Cyclohexyl-hydroxy-methyl)-phenyl]-3-hydroxy-5-oxo-cyclopentyl]-heptanoic acid;

(Z)-7-((1R,2S,3R)-3-Hydroxy-2-{4-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-5-oxo-cyclopentyl)-hept-5-enoic acid methyl ester;

(Z)-7-((1R,2S,3R)-3-Hydroxy-2-{4-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-5-oxo-cyclopentyl)-hept-5-enoic acid;

7-((1R,2S,3R}3-Hydroxy-2-{4-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-5-oxo-cyclopentyl)-heptanoic acid methyl ester;

7-((1R,2S,3R)-3-Hydroxy-2-{4-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-5-oxo-cyclopentyl)-heptanoic acid;

(Z)-7-[(1R,2S,3R)-2-(4-tert-Butyl-phenyl)-3-hydroxy-5-oxo-cyclopentyl]-hept-5-enoic acid methyl ester;

(Z)-7-[(1R,2S,3R)-2-(4-tert-Butyl-phenyl)-3-hydroxy-5-oxo-cyclopentyl]-hept-5-enoic acid;

7-[(1R,2S,3R)-2-(4-tert-Butyl-phenyl)-3-hydroxy-5-oxo-cyclopentyl]-heptanoic acid methyl ester;

7-[(1R,2S,3R)-2-(4-tert-Butyl-phenyl)-3-hydroxy-5-oxo-cyclopentyl]-heptanoic acid;

(Z)-7-{(1R,2S,3R}3-Hydroxy-2-[4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-5-oxo-cyclopentyl}-hept-5-enoic acid methyl ester;

(Z)-7-{(1R,2S,3R)-3-Hydroxy-2-[4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-5-oxo-cyclopentyl}-hept-5-enoic acid;

7-{(1R,2S,3R)-3-Hydroxy-2-[4 (2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-5-oxo-cyclopentyl}-heptanoic acid methyl ester;

7-{(1R,2S,3R)-3-Hydroxy-2-[4-(2-hydroxy-1,1-dimethylethyl)-phenyl]-5-oxo-cyclopentyl}-heptanoic acid;

(Z)-7-{(1R,2S,3R)-3-Hydroxy-2-[4-(1-hydroxy-cyclobutyl)-phenyl]-5-oxo-cyclopentyl}-hept-5-enoic acid methyl ester;

7-{(1R,2S,3R)-3-Hydroxy-2-[4-(1-hydroxy-cyclobutyl)-phenyl]-5-oxo-cyclopentyl}-heptanoic acid methyl ester;

7-{(1R,2S,3R)-3-Hydroxy-2-[4-(1-hydroxy-cyclobutyl)-phenyl]-5-oxo-cyclopentyl}-heptanoic acid;

(Z)-7-((1R,2S,3R)-3-Hydroxy-2-{3-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-5-oxo-cyclopentyl)-hept-5-enoic acid methyl ester;

(Z)-7-((1R,2S,3R)-3-Hydroxy-2-{3-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-5-oxo-cyclopentyl)-hept-5-enoic acid;

7-((1R,2S,3R)-3-Hydroxy-2-{3-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-5-oxo-cyclopentyl)-heptanoic acid methyl ester;

7-((1R,2S,3R)-3-Hydroxy-2-{3[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-5-oxo-cyclopentyl)-heptanoic acid;

(Z)-7-((1R,2S,3R)-3-Hydroxy-2-{3-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-5-oxo-cyclopentyl)-hept-5-enoic acid (2-hydroxy-ethyl)-amide;

(Z)-7-((1R,2S,3R)-3-Hydroxy-2-{3-[hydroxy-(1-propyl-cyclobutyl)-methyl)-phenyl}-5-oxo-cyclopentyl)-hept-5-enoic acid ethyl amide;

(Z)-7-((1R,2S,3R)-3-Hydroxy-2-{3-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-5-oxo-cyclopentyl)-hept-5-enoic acid ethyl amide;

(Z)-7-{(1R,2S,3R,5R)-5-Chloro-2-[4-(cyclohexyl-hydroxy-methyl)-phenyl]-3-hydroxy-cyclopentyl}-hept-5-enoic acid methyl ester;

(Z)-7-{(1R,2S,3R,5R)-5-Chloro-2-[4-(cyclohexyl-hydroxy-methyl)-phenyl]-3-hydroxy-cyclopentyl}-hept-5-enoic acid;

(Z)-7-{(1R,2S,3R,5R)-5-Chloro-2-[4-(cyclohexyl-hydroxy-methyl)-phenyl]-3-hydroxy-cyclopentyl}-hept-5-enoic acid isopropyl ester;

7-{(1R,2S,3R,5R)-5-Chloro-2-[4-(cyclohexyl-hydroxy-methyl)-phenyl]-3-hydroxy-cyclopentyl}-heptanoic acid methyl ester;

7-[(1R,2S,3R,5R)-5-Chloro-2-(4-cyclohexylmethyl-phenyl)-3-hydroxy-cyclopentyl]-heptanoic acid methyl ester;

7-{(1R,2S,3R,5R)-5-Chloro-2-[4-(cyclohexyl-hydroxy-methyl)-phenyl]-3-hydroxy-cyclopentyl}-heptanoic acid;

7-[(1R,2S,3R,5R)-5-Chloro-2-(4-cyclohexylmethyl-phenyl)-3-hydroxy-cyclopentyl]-heptanoic acid;

(Z)-7-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-{3-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-cyclopentyl)-hept-5-enoic acid methyl ester;

(Z)-7-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-{3-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-cyclopentyl)-hept-5-enoic acid;

7-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-{3-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-cyclopentyl)-heptanoic acid methyl ester;

7-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-{3-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-cyclopentyl)-heptanoic acid;

(Z)-7-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-{4-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-cyclopentyl)-hept-5-enoic acid methyl ester;

(Z)-7-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-{4-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-cyclopentyl)-hept-5-enoic acid;

7-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-{4-[hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-cyclopentyl)-heptanoic acid methyl ester;

7-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-{4-hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-cyclopentyl)-heptanoic acid;

(Z)-7-[(1R,2S,3R,5R)-2-(4-tert-Butyl-phenyl)-5-chloro-3-hydroxy-cyclopentyl]-hept-5-enoic acid methyl ester;

(Z)-7-[(1R,2S,3R,5R)-2-(4-tert-Butyl-phenyl)-5-chloro-3-hydroxy-cyclopentyl]-hept-5-enoic acid;

7-[(1R,2S,3R,5R)-2-(4-tert-Butyl-phenyl)-5-chloro-3-hydroxy-cyclopentyl]-heptanoic acid methyl ester;

7-[(1R,2S,3R,5R)-2-(4-tert-Butyl-phenyl)-5-chloro-3-hydroxy-cyclopentyl]-heptanoic acid;

(Z)-7-[(1R,2S,3R,5R)-2-(4-tert-Butyl-phenyl)-5-chloro-3-hydroxy-cyclopentyl]-hept-5-enoic acid isopropyl ester;

(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-cyclobutyl)-phenyl]-cyclopentyl}-hept-5-enoic acid methyl ester;

(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-cyclobutyl)-phenyl]-cyclopentyl}-hept-5-enoic acid;

7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-cyclobutyl)-phenyl]-cyclopentyl}-heptanoic acid methyl ester;

7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-cyclobutyl)-phenyl]-cyclopentyl}-heptanoic acid;

(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(2-hydroxy-1,1-dimethylethyl)-phenyl]-cyclopentyl}-hept-5-enoic acid methyl ester;

(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[(4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-cyclopentyl}-hept-5-enoic acid;

7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-cyclopentyl}-heptanoic acid methyl ester;

7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-cyclopentyl}-heptanoic acid;

7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-cyclopentyl}-heptanoic acid isopropyl ester;

(Z)-7-[(1R,2S,3R)-3-Hydroxy-2-(4-hydroxymethyl-phenyl)-5-oxo-cyclopentyl]-hept-5-enoic acid methyl ester;

(Z)-7-[(1R,2S,3R)-3-Hydroxy-2-(4-hydroxymethyl-phenyl)-5-oxo-cyclopentyl]-hept-5-enoic acid;

7-[(1R,2S,3R)-3-Hydroxy-2-(4-hydroxymethyl-phenyl)-5-oxo-cyclopentyl]-heptanoic acid methyl ester;

7-((1R,2S,3R)-3-Hydroxy-5-oxo-2-p-tolyl-cyclopentyl)-heptanoic acid methyl ester;

7-[(1R,2S,3R)-3-Hydroxy-2-(4-hydroxymethyl-phenyl)-5-oxo-cyclopentyl]-heptanoic acid;

(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(4-hydroxymethyl-phenyl)-cyclopentyl]-hept-5-enoic acid methyl ester;

(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(4-hydroxymethyl-phenyl)-cyclopentyl]-hept-5-enoic acid;

7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(4-hydroxymethyl-phenyl)-cyclopentyl]-heptanoic acid methyl ester;

7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(4-hydroxymethyl-phenyl)-cyclopentyl]-heptanoic acid;

(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-2-methyl-propyl)-phenyl]-cyclopentyl}-hept-5-enoic acid methyl ester;

(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-2,2-dimethyl-propyl)-phenyl]-cyclopentyl}-hept-5-enoic acid methyl ester;

(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-2-methyl-propyl)-phenyl]-cyclopentyl}-hept-5-enoic acid;

(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-2,2-dimethyl-propyl)-phenyl]-cyclopentyl}-hept-5-enoic acid;

7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-2-methyl-propyl)-phenyl]-cyclopentyl}-heptanoic acid methyl ester;

7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-2,2-dimethyl-propyl)-phenyl]-cyclopentyl}-heptanoic acid methyl ester;

7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-2-methyl-propyl)-phenyl]-cyclopentyl}-heptanoic acid;

7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-2,2-dimethyl-propyl)-phenyl]-cyclopentyl}-heptanoic acid;

(4-{(1R,2S,3R,5R)-5-Chloro-2-[4-(cyclohexyl-hydroxy-methyl)-phenyl]-3-hydroxy-cyclopentyl}-but-2-enyloxy)-acetic acid methyl ester;

(4-{(1R,2S,3R,5R)-5-Chloro-2-[4-(cyclohexyl-hydroxy-methyl)-phenyl]-3-hydroxy-cyclopentyl}-but-2-ynyloxy)-acetic acid;

((Z)-4-{(1R,2S,3R,5R)-5-Chloro-2-[4-(cyclohexyl-hydroxy-methyl)-phenyl]-3-hydroxy-cyclopentyl}-but-2-enyloxy)-acetic acid methyl ester;

((Z)-4-{(1R,2S,3R,5R)-5-Chloro-2-[4-(cyclohexyl-hydroxy-methyl)-phenyl]-3-hydroxy-cyclopentyl}-but-2-enyloxy)-acetic acid;

(4-{(1R,2S,3R,5R)-5-Chloro-2-[(4-(cyclohexyl-hydroxy-methyl)-phenyl]-3-hydroxy-cyclopentyl}-butoxy)-acetic acid methyl ester;

(4-{(1R,2S,3R,5R)-5-Chloro-2-[4-(cyclohexyl-hydroxy-methyl)-phenyl]-3-hydroxy-cyclopentyl}-butoxy)-acetic acid;

[3-((1R,2S,3R)-3-Hydroxy-2-{3-[(S)-hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-5-oxo-cyclopentylmethyl)-phenoxy]-acetic acid methyl ester;

[3-((1R,2S,3R)-3-Hydroxy-2-{3-[(S)-hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-5-oxo-cyclopentylmethyl)-phenoxy]-acetic acid;

[3-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-{3-[(S)-hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-cyclopentylmethyl)-phenoxy]-acetic acid methyl ester;

[3-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-{3-[(S)-hydroxy-(1-propyl-cyclobutyl)-methyl]-phenyl}-cyclopentylmethyl)-phenoxy]-acetic acid;

(Z)-7-[(1R,2S,3R)-3-Hydroxy-2-(1-hydroxy-indan-5-yl)-5-oxo-cyclopentyl]-hept-5-enoic acid methyl ester;

(Z)-7-[(1R,2S,3R)-3-Hydroxy-2-(1-hydroxy-indan-5-yl)-5-oxo-cyclopentyl]-hept-5-enoic acid;

(Z)-7-[(1R,2S,3R)-3-Hydroxy-5-oxo-2-(1-oxo-indan-5-yl)-cyclopentyl]-hept-5-enoic acid methyl ester;

(Z)-7-[(1R,2S,3R)-3-Hydroxy-5-oxo-2-(1-oxo-indan-5-yl)-cyclopentyl]-hept-5-enoic acid;

7-[(1R,2S,3R)-3-Hydroxy-2-(1-hydroxy-indan-5-yl)-5-oxo-cyclopentyl]-heptanoic acid methyl ester;

7-((1R,2S,3R)-3-Hydroxy-2-indan-5-yl-5-oxo-cyclopentyl)-heptanoic acid methyl ester;

7-[(1R,2S,3R)-3-Hydroxy-2-(1-hydroxy-indan-5-yl)-5-oxo-cyclopentyl]-heptanoic acid;

7-((1R,2S,3R)-3-Hydroxy-2-indan-5-yl-5-oxo cyclopentyl)-heptanoic acid;

(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(1-hydroxy-indan-5-yl)-cyclopentyl]-hept-5-enoic acid methyl ester;

(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(1-hydroxy-indan-5-yl)-cyclopentyl]-hept-5-enoic acid;

(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(1-hydroxy-indan-5-yl)-cyclopentyl]-hept-5-enoic acid isopropyl ester;

7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(1-hydroxy-indan-5-yl)-cyclopentyl]-heptanoic acid methyl ester;

7-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-indan-5-yl-cyclopentyl)-heptanoic acid methyl ester;

7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(1-hydroxy-indan-5-yl)-cyclopentyl]-heptanoic acid;

7-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-indan-5-yl-cyclopentyl)-heptanoic acid;

7-[(1R,2S,3R)-5-Fluoro-3-hydroxy-2-(1-hydroxy-indan-5-yl)-cyclopentyl]-heptanoic acid methyl ester;

7-[(1R,2S,3R)-5-Fluoro-3-hydroxy-2-(1-hydroxy-indan-5-yl)-cyclopentyl]-heptanoic acid;

(Z)-7-[(1R,2S,3R)-5-Fluoro-3-hydroxy-2-(1-hydroxy-indan-5-yl)-cyclopentyl]-hept-5-enoic acid methyl ester;

or

(Z)-7-[(1R,2S,3R)-5-Fluoro-3-hydroxy-2-(1-hydroxy-indan-5-yl)-cyclopentyl]-hept-5-enoic acid.

20. The compound of claim 14 of the formula

21. The compound of claim 12 of the formula

22. The compound of claim 20 of the formula

23. The compound of claim 20 of the formula

24. The compound of claim 21 of the formula

25. The compound of claim 16 of the formula

26. The compound of claim 16 of the formula

27. The compound of claim 1 of the formula

28. The compound of claim 27 wherein A is —

(CH₂)₆—

, cis —

CH₂CH≡

CH—

(CH₂)₃—

, or —

CH₂C≡

C—

(CH₂)₃—

.

29. The compound of claim 28 of the formula

30. The compound of claim 29 of the formula

31. The compound of claim 5 wherein R is 1-hydroxyalkyl having from 1 to 5 carbon atoms.

32. The compound of claim 31 of the formula

33. The compound of claim 1 wherein Y is selected from the group consisting of CO₂(R³), CH₂OH, P(O)(OH)₂, SO₂N(R³)₂, SO₂NHR³, and tetrazolyl-R³;

wherein R³ is independently H, C₁–

C₆ alkyl, phenyl, or biphenyl.

34. The compound of claim 1 wherein R is 2-hydroxyhydrocarbyl.

35. The compound of claim 34 of the formula

36. The compound of claim 35 wherein R⁴ and R⁵ are methyl.

37. The compound of claim 36 of the formula

38. The compound of claim 1 wherein A is —

(CH₂)_m—

Ar—

(CH₂)_o—

wherein Ar is phenyl, the sum of m and o is from 1 to 4, and wherein one CH₂ may be substituted with S or O.

39. The compound of claim 38 wherein A is —

CH₂—

Ar—

O—

CH₂—

.

40. The compound of claim 39 of the formula

41. The compound of claim 29 of the formula

42. The compound of claim 31 of the formula

43. The compound of claim 42 of the formula

44. The compound of claim 37 of the formula

45. A method of treating glaucoma or reducing intraocular pressure comprising administering a compound of claim 1 to a mammal in need thereof.

46. A liquid composition having a compound of claim 1 wherein said liquid is ophthalmically acceptable.