Pharmaceutical compositions and methods of use of 4-pregenen-11β-17-21-triol-3,20-dione derivatives

Patent metadata

Field	Value
Publication number	US-9717743-B2
Application number	US-201414485335-A
Country	US
Kind code	B2
Filing date	Sep 12, 2014
Priority date	Nov 11, 2011
Publication date	Aug 1, 2017
Grant date	Aug 1, 2017

Abstract

The present invention relates to pharmaceutical compositions comprising 4-pregenen-11β-17-21-triol-3,20-dione derivatives, and their use as pharmaceuticals as modulators of the glucocorticoid receptors (GR) and/or the mineralocorticoid receptors (MR). The invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat ocular conditions associated with the glucocorticoid receptors (GR) and/or the mineralocorticoid receptors (MR).

First claim

What is claimed is:

1. A method of treating an ocular condition associated with glucocorticoid and/or mineralocorticoid receptor modulation which comprises topically administering to a patient in need thereof a topical ophthalmic composition comprising a therapeutically effective amount of at least one compound selected from the group consisting of:
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl phenylacetate;
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl butyrate;
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl propionate;
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl octanoate;
(8S,9S,10R,11S,13S,14S,17R)-17-Glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl hexanoate;
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl benzoate;
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl heptanoate;
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl 2-methylpropanoate; and
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl cyclopentanecarboxylate;

and further comprising one or more vehicles selected from the group consisting of polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.

2. The method according to claim 1 wherein the ocular condition is selected from elevated intraocular pressure, glaucoma, uveitis, retinal vein occlusions, macular degeneration, diabetic retinopathy, various forms of macular edema, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, allergic conjunctivitis, retinal detachment, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis, corneal injury from chemical, radiation, or thermal burns, penetration of foreign bodies, allergy, and combinations thereof.

3. The method according to claim 1 wherein the ocular condition is selected from ocular rosacea, dry eye, blepharitis, meibomian gland dysfunction.

4. The method according to claim 1 wherein the compound is:
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl benzoate.

5. The method according to claim 1 wherein the compound is:
(8S,9S,10R,11S,13S,14S,17R)-17-Glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl hexanoate.

6. The method according to claim 1 wherein the compound is:
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl octanoate.

7. The method according to claim 1 wherein the compound is:
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl phenylacetate.

8. The method according to claim 1 wherein the compound is:
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl butyrate.

9. The method according to claim 1 wherein the compound is:
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl propionate.

10. The method according to claim 1 wherein the compound is:
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl heptanoate.

11. The method according to claim 1 wherein the compound is
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl 2-methylpropanoate.

12. The method according to claim 1 wherein the compound is
(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl cyclopentanecarboxylate.

13. The method according to claim 1 , wherein the composition further comprises one or more tonicity adjusters selected from the group consisting of sodium chloride, potassium chloride, mannitol, and glycerin.

14. The method according to claim 1 , wherein the composition further comprises one or more buffers selected from the group consisting of acetate buffers, citrate buffers, phosphate buffers, and borate buffers.

15. The method according to claim 1 , wherein the composition further comprises one or more preservatives selected from the group consisting of benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.

16. The method according to claim 1 , wherein the composition has a pH from about 4.5 to about 7.5.

17. The method according to claim 1 , wherein the composition further comprises one or more tonicity adjusters selected from the group consisting of sodium chloride, potassium chloride, mannitol, and glycerin.

18. The method according to claim 17 , wherein the composition further comprises one or more buffers selected from the group consisting of acetate buffers, citrate buffers, phosphate buffers, and borate buffers.

19. The method according to claim 18 , wherein the composition further comprises one or more preservatives selected from the group consisting of benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.

20. The method according to claim 18 , wherein the composition has a pH from about 4.5 to about 7.5.

21. The method according to claim 19 , wherein the composition has a pH from about 4.5 to about 7.5.

22. The method according to claim 1 , wherein the composition further comprises one or more vehicles selected from the group consisting of polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, and purified water; one or more tonicity adjusters selected from the group consisting of sodium chloride and potassium chloride; and one or more buffers selected from the group consisting of acetate buffers and borate buffers; and wherein the composition has a pH from about 4.5 to about 7.5.

23. The method according to claim 22 , wherein the composition further comprises one or more preservatives selected from the group consisting of benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.

24. The method according to claim 1 , wherein th

Assignees

• Allergan Inc

Inventors

• Edelman Jeffrey L
• Nehme Alissar

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/22

  for herpes viruses · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P27/14

  Decongestants or antiallergics · CPC title