Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders Number:6,803,385 from the United States Patent and Trademark Office (PTO) owispatent Hydroxyeicosatetraenoic acid esters and methods of their use in treating dry eye disorders are disclosed.<H Hydroxyeicosatetraenoic, disorders, Hydroxyeicosate, 6803385.html, Patent, pto, 6803385

Title: Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders

Abstract: Hydroxyeicosatetraenoic acid esters and methods of their use in treating dry eye disorders are disclosed.

Patent Number: 6,803,385 Issued on 10/12/2004 to Klimko, et al.

Inventors: Klimko; Peter G. (Fort Worth, TX); Hellberg; Mark R. (Highland Village, TX); Falck; John R. (Dallas, TX); Conrow; Raymond E. (Crowley, TX)
Assignee: Alcon, Inc. (Hunenberg, CH)

Appl. No.: 10/407,791

Filed: April 4, 2003

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
950457	Sep., 2001	6552084
694537	Oct., 2000

Current U.S. Class: 514/568 ; 514/640; 514/675; 514/710; 554/213; 554/61; 568/37; 568/671; 568/687

Field of Search: 514/568,640,675,710 554/61,213 568/687,37

References Cited [Referenced By]

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4131651	December 1978	Shah et al.
4370325	January 1983	Packman
4409205	October 1983	Shively
4421748	December 1983	Trager et al.
4744980	May 1988	Holly
4753945	June 1988	Gilbard et al.
4804539	February 1989	Guo et al.
4818537	April 1989	Guo
4868154	September 1989	Gilbard et al.
4883658	November 1989	Holly
4906467	March 1990	Schwartzman et al.
4914088	April 1990	Glonek et al.
4921644	May 1990	Lau et al.
4923700	May 1990	Kaufman
4966773	October 1990	Gressel et al.
5041434	August 1991	Lubkin
5064655	November 1991	Uster et al.
5075104	December 1991	Gressel et al.
5174988	December 1992	Mautone et al.
5278151	January 1994	Korb et al.
5290572	March 1994	MacKeen
5294607	March 1994	Glonek et al.
5306483	April 1994	Mautone
5358706	October 1994	Marlin et al.
5371108	December 1994	Korb et al.
5389383	February 1995	Huth
5403598	April 1995	Beck et al.
5403841	April 1995	Lang et al.
5455265	October 1995	Chandraratna
5578586	November 1996	Glonek et al.
5620921	April 1997	Sullivan
5696166	December 1997	Yanni et al.
5800807	September 1998	Hu et al.
6281192	August 2001	Leahy et al.
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Foreign Patent Documents


1 251 736	Mar., 1989	CA
0 097 059	Dec., 1983	EP
0 132 089	Jan., 1985	EP
WO 91/12808	Sep., 1991	WO
WO 92/04905	Apr., 1992	WO
WO 98/16240	Apr., 1998	WO

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Primary Examiner: Carr; Deborah D.
Attorney, Agent or Firm: Ryan; Patrick M.

Parent Case Text

This application is a continuation-in-part application of U.S. application Ser. No. 09/950,457, filed Sep. 10, 2001 now U.S. Pat. No. 6,552,084, which is a continuation-in-part application of U.S. application Ser. No. 09/694,537, filed Oct. 23, 2000 now abandoned, which claims the benefit of U.S. Provisional Applications, U.S. Ser. No. 60/164,386 filed Nov. 9, 1999; U.S. Ser. No. 60/164,369 filed Nov. 9, 1999, and U.S. Ser. No. 60/164,371 filed Nov. 9, 1999.

Claims

What is claimed is:

1. A composition for the treatment of dry eye in humans comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of one or more compounds of the following formula I:

wherein: R.sup.1 is CO.sub.2 R, where R is lower alkyl; A is L.sub.1 --A.sub.1 --L.sub.2, L.sub.1 --A.sub.2 --L.sub.2, L.sub.3 --A.sub.2 --L.sub.4, or L.sub.5 --A.sub.2 --L.sub.3 ; A.sub.1 is CH.sub.2 CH.sub.2 ; A.sub.2 is ##STR41## L.sub.1 is CH.sub.2 --B--D; B and D are the same or different and are CH.sub.2 CH.sub.2, CH.dbd.CH, or C.ident.C; L.sub.2 is CH.sub.2 --K--CH.sub.2 CH.sub.2 ; K is CH.sub.2 CH.sub.2, CH.dbd.CH, or C.ident.C; L.sub.3 is CH.sub.2 CH.sub.2 CH.sub.2, CH.sub.2 CH.dbd.CH, CH.sub.2 C.ident.C, CH.dbd.CHCH.sub.2, C.ident.CCH.sub.2, or CH.dbd.C.dbd.CH; L.sub.4 is X--CH.sub.2 CH.sub.2 ; X is CH.sub.2 CH.sub.2 CH.dbd.CH, CH.sub.2 CH.sub.2 C.ident.C, CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2, CH.sub.2 CH.dbd.CHCH.sub.2, CH.sub.2 C.ident.CCH.sub.2, CH.dbd.CHCH.sub.2 CH.sub.2, C.ident.CCH.sub.2 CH.sub.2, CH.sub.2 CH.dbd.C.dbd.CH, or CH.dbd.C.dbd.CHCH.sub.2 ; L.sub.5 is CH.sub.2 CH.sub.2 --B--D; and Y is C(O) (i.e. a carbonyl group) or Y is ##STR42##

wherein R.sup.9 O constitutes a free or functionally modified hydroxy group.

2. The composition of claim 1, wherein for the compound of formula I: R.sup.1 is CO.sub.2 R, where R is a C.sub.1 -C.sub.5 alkyl group; A is L.sub.1 --A.sub.1 --L.sub.2 or L.sub.1 --A.sub.2 --L.sub.2 ; A.sub.1 is CH.sub.2 CH.sub.2 ; A.sub.2 is ##STR43## L.sub.1 is CH.sub.2 --B--D; L.sub.2 is CH.sub.2 --K--CH.sub.2 CH.sub.2 ; B is C.ident.C or cis-CH.dbd.CH and D is C.ident.C or trans-CH.dbd.CH; K is cis-CH.dbd.CH; and Y is ##STR44##

3. The composition of claim 2, wherein the compound is selected from the group consisting of: ##STR45## ##STR46##

where in each case R=methyl, ethyl, n-propyl, iso-propyl, tert-butyl, or neopentyl.

4. The composition of claim 1, wherein for the compound of formula I: R.sup.1 is CO.sub.2 R, where R is a C.sub.1 -C.sub.5 alkyl group; A is L.sub.3 --A.sub.2 --L.sub.4 ; A.sub.2 is ##STR47## L.sub.3 is trans-CH.sub.2 CH.dbd.CH, trans-CH.dbd.CHCH.sub.2, or CH.sub.2 C.ident.C; L.sub.4 is X--CH.sub.2 CH.sub.2 ; X is cis-CH.sub.2 CH.sub.2 CH.dbd.CH, CH.sub.2 CH.sub.2 C.ident.C, cis-CH.sub.2 CH.dbd.CHCH.sub.2, or cis-CH.dbd.CHCH.sub.2 CH.sub.2 ; and Y is ##STR48##

5. The composition of claim 4, wherein the compound of formula I is selected from the group consisting of: ##STR49##

where in each case R=methyl, ethyl, n-propyl, iso-propyl, tert-butyl, or neopentyl.

6. The composition of claim 1, wherein for the compound of formula I: R.sup.1 is CO.sub.2 R, where R is a C.sub.1 -C.sub.5 alkyl group; A is L.sub.5 --A.sub.2 --L.sub.3 ; A.sub.2 is ##STR50## L.sub.5 is CH.sub.2 CH.sub.2 --B--D; L.sub.3 is cis-CH.sub.2 CH.dbd.CH, cis-CH.dbd.CHCH.sub.2, CH.sub.2 C.ident.C, or CH.sub.2 CH.sub.2 CH.sub.2 ; B is cis-CH.dbd.CH or C.ident.C; D is trans-CH.dbd.CH or C.ident.C; and Y is ##STR51##

7. The composition of claim 6, wherein the compound is selected from the group consisting of: ##STR52## ##STR53##

where in each case R is methyl, ethyl, n-propyl, iso-propyl, tert-butyl, or neopentyl.

8. The composition of claim 1, wherein the composition is a suitable for topical administration to the eye.

9. A method for the treatment of dry eye or other disorders requiring the wetting of the eye in mammals comprising administering to an affected eye, a pharmaceutically effective amount of one or more compounds according to formula I:

wherein: R.sup.1 is CO.sub.2 R, where R is lower alkyl; A is L.sub.1 --A.sub.1 --L.sub.2, L.sub.1 --A.sub.2 --L.sub.2, L.sub.3 --A.sub.2 --L.sub.4, or L.sub.5 --A.sub.2 --L.sub.3 ; A.sub.1 is CH.sub.2 CH.sub.2 ; A.sub.2 is ##STR54## L.sub.1 is CH.sub.2 --B--D; B and D are the same or different and are CH.sub.2 CH.sub.2, CH.dbd.CH, or C.ident.C; L.sub.2 is CH.sub.2 --K--CH.sub.2 CH.sub.2 ; K is CH.sub.2 CH.sub.2, CH.dbd.CH, or C.ident.C; L.sub.3 is CH.sub.2 CH.sub.2 CH.sub.2, CH.sub.2 CH.dbd.CH, CH.sub.2 C.ident.C, CH.dbd.CHCH.sub.2, C.ident.CCH.sub.2, or CH.dbd.C.dbd.CH; L.sub.4 is X--CH.sub.2 CH.sub.2 ; X is CH.sub.2 CH.sub.2 CH.dbd.CH, CH.sub.2 CH.sub.2 C.ident.C, CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2, CH.sub.2 CH.dbd.CHCH.sub.2, CH.sub.2 C.ident.CHCH.sub.2 ; CH.dbd.CHCH.sub.2 CH.sub.2, C.ident.CCH.sub.2 CH.sub.2, CH.sub.2 CH.dbd.C.dbd.CH, or CH.dbd.C.dbd.CHCH.sub.2 ; L.sub.5 is CH.sub.2 CH.sub.2 --B--D; and Y is C(O) (i.e. a carbonyl group) or Y is ##STR55##

wherein R.sup.9 O constitutes a free or functionally modified hydroxy group.

10. The method of claim 9, wherein the mammal is a human and the compound is administered topically.

11. The method of claim 9, wherein for the compound of formula I: R is a C.sub.1 -C.sub.5 alkyl group; A is L.sub.1 --A.sub.1 --L.sub.2 or L.sub.1 --A.sub.2 --L.sub.2 ; A.sub.1 is CH.sub.2 CH.sub.2 ; A.sub.2 is ##STR56## L.sub.1 is CH.sub.2 --B--D; L.sub.2 is CH.sub.2 --K--CH.sub.2 CH.sub.2 ; B is C.ident.C or cis-CH.dbd.CH and D is C.ident.C or trans-CH.dbd.CH; K is cis-CH.dbd.CH; and Y is ##STR57##

12. The method of claim 11, wherein the compound is selected from the group consisting of: ##STR58## ##STR59##

where in each case R=methyl, ethyl, n-propyl, iso-propyl, tert-butyl, or neopentyl.

13. The method of claim 9, wherein for the compound of formula I: R is a C.sub.1 -C.sub.5 alkyl group; A is L.sub.3 --A.sub.2 --L.sub.4 ; A.sub.2 is ##STR60## L.sub.3 is trans-CH.sub.2 CH.dbd.CH, trans-CH.dbd.CHCH.sub.2, or CH.sub.2 C.ident.C; L.sub.4 is X--CH.sub.2 CH.sub.2 ; X is cis-CH.sub.2 CH.sub.2 CH.dbd.CH, CH.sub.2 CH.sub.2 C.ident.C, cis-CH.sub.2 CH.dbd.CHCH.sub.2, or cis-CH.dbd.CHCH.sub.2 CH.sub.2 ; and Y is ##STR61##

14. The method of claim 13, wherein the compound is selected from the group consisting of: ##STR62##

where in each case R=methyl, ethyl, n-propyl, iso-propyl, tert-butyl, or neopentyl.

15. The method of claim 9, wherein for the compound of formula I: R is a C.sub.1 -C.sub.5 alkyl group; A is L.sub.5 --A.sub.2 --L.sub.3 ; A.sub.2 is ##STR63## L.sub.5 is CH.sub.2 CH.sub.2 --B--D; L.sub.3 is cis-CH.sub.2 CH.dbd.CH, cis-CH.dbd.CHCH.sub.2, CH.sub.2 C.ident.C, or CH.sub.2 CH.sub.2 CH.sub.2 ; B is cis-CH.dbd.CH or C.ident.C; D is trans-CH.dbd.CH or C.ident.C; and Y is ##STR64##

16. The method of claim 15, wherein the compound is selected from the group consisting of: ##STR65## ##STR66##

where in each case R is methyl, ethyl, n-propyl iso-propyl, tert-butyl, or neopentyl.

17. The method of claim 9 wherein the dry eye and other disorders requiring the wetting of the eye is symptoms of dry eye associated with refractive surgery.

18. A compound of formula I:

wherein: R.sup.1 is CO.sub.2 R, where R is lower alkyl; A is L.sub.1 --A.sub.1 --L.sub.2, L.sub.1 --A.sub.2 --L.sub.2, L.sub.3 --A.sub.2 -L.sub.4, or L.sub.5 --A.sub.2 --L.sub.3 ; A.sub.1 is CH.sub.2 CH.sub.2 ; A.sub.2 is ##STR67## L.sub.1 is CH.sub.2 --B--D; B and D are the same or different and are CH.sub.2 CH.sub.2, CH.dbd.CH, or C.ident.C; L.sub.2 is CH.sub.2 --K--CH.sub.2 CH.sub.2 ; K is CH.sub.2 CH.sub.2, CH.dbd.CH, or C.ident.C; L.sub.3 is CH.sub.2 CH.sub.2 CH.sub.2, CH.sub.2 CH.dbd.CH, CH.sub.2 C.ident.C, CH.dbd.CHCH.sub.2, C.ident.CCH.sub.2, or CH.dbd.C.dbd.CH; L.sub.4 is X--CH.sub.2 CH.sub.2 ; X is CH.sub.2 CH.sub.2 CH.dbd.CH, CH.sub.2 CH.sub.2 C.ident.C, CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2, CH.sub.2 CH.dbd.CHCH.sub.2, CH.sub.2 C.ident.CCH.sub.2, CH=CHCH.sub.2 CH.sub.2, C.ident.CCH.sub.2 CH.sub.2, CH.sub.2 CH.dbd.C.dbd.CH, or CH.dbd.C.dbd.CHCH.sub.2 ; L.sub.5 is CH.sub.2 CH.sub.2 --B--D; and Y is C(O) (i.e. a carbonyl group) or Y is ##STR68##

wherein R.sup.9 O constitutes a free or functionally modified hydroxy group.

19. The compound of claim 18, wherein: R is a C.sub.1 -C.sub.5 alkyl group; A is L.sub.1 --A.sub.1 --L.sub.2 or L.sub.1 --A.sub.2 --L.sub.2 ; A.sub.1 is CH.sub.2 CH.sub.2 ; A.sub.2 is ##STR69## L.sub.1 is CH.sub.2 --B--D; L.sub.2 is CH.sub.2 --K--CH.sub.2 CH.sub.2 ; B is C.ident.C or cis-CH.dbd.CH and D is C.ident.C or trans-CH.dbd.CH; K is cis-CH.dbd.CH; and Y is ##STR70##

20. The compound of claim 19, wherein the compound is selected from the group consisting of: ##STR71## ##STR72##

where in each case R=methyl, ethyl, n-propyl, iso-propyl, tert-butyl, or neopentyl.

21. The compound of claim 18, wherein: R is a C.sub.1 -C.sub.5 alkyl group; A is L.sub.3 --A.sub.2 --L.sub.4 ; A.sub.2 is ##STR73## L.sub.3 is trans-CH.sub.2 CH.dbd.CH, trans-CH.dbd.CHCH.sub.2, or CH.sub.2 C.ident.C; L.sub.4 is X--CH.sub.2 CH.sub.2 ; X is cis-CH.sub.2 CH.sub.2 CH.dbd.CH, CH.sub.2 CH.sub.2 C.ident.C, cis-CH.sub.2 CH.dbd.CHCH.sub.2, or cis-CH.dbd.CHCH.sub.2 CH.sub.2 ; and Y is ##STR74##

22. The compound of claim 21, wherein the compound is selected from the group consisting of: ##STR75##

where in each case R=methyl, ethyl, n-propyl, iso-propyl, tert-butyl, or neopentyl.

23. The compound of claim 18, wherein: R is a C.sub.1 -C.sub.5 alkyl group; A is L.sub.5 --A.sub.2 --L.sub.3 ; A.sub.2 is ##STR76## L.sub.5 is CH.sub.2 CH.sub.2 --B--D; L.sub.3 is cis-CH.sub.2 CH.dbd.CH, cis-CH.dbd.CHCH.sub.2, CH.sub.2 C.ident.C, or CH.sub.2 CH.sub.2 CH.sub.2 ; B is cis-CH.dbd.CH or C.ident.C; D is trans-CH.dbd.CH or C.ident.C; and Y is ##STR77##

24. The compound of claim 23, wherein the compound is selected from the group consisting of: ##STR78## ##STR79##

where in each case R is methyl, ethyl, n-propyl, iso-propyl, tert-butyl, or neopentyl.

Description

The present invention is directed to compositions containing hydroxyeicosatetraenoic acid analogs and methods for their use in treating dry eye.

BACKGROUND OF THE INVENTION

Dry eye, also known generically as keratoconjunctivitis sicca, is a common ophthalmological disorder affecting millions of Americans each year (Schein et. al., Prevalence of dry eye among the elderly. American J. Ophthalmology, 124:723-738, (1997)). The condition is particularly widespread among post-menopausal women due to hormonal changes following the cessation of fertility. Dry eye may afflict an individual with varying severity. In mild cases, a patient may experience burning, a feeling of dryness, and persistent irritation such as is often caused by small bodies lodging between the eyelid and the eye surface. In severe cases, vision may be substantially impaired. Other diseases, such as Sjogren's disease and cicatricial pemphigoid manifest dry eye complications.

Although it appears that dry eye may result from a number of unrelated pathogenic causes, all presentations of the complication share a common effect, that is the breakdown of the pre-ocular tear film, which results in dehydration of the exposed outer surface and many of the symptoms outlined above (Lemp, Report of the Nation Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes, The CLAO Journal, volume 21, number 4, pages 221-231 (1995)). Four events have been identified which singly or in combination are believed to result in the dry eye condition: a) decreased tear production or increased tear evaporation; b) decreased conjunctival goblet-cell density; c) increased corneal desquamation; and d) destabilization of the cornea-tear interface (Gilbard, Dry eye: pharmacological approaches, effects, and progress. The CLAO Journal, 22:141-145 (1996)). Another major problem is the decreased mucin production by the conjunctival cells and/or corneal epithelial cells of mucin, which protects and lubricates the ocular surface (Gipson and Inatomi, Mucin genes expressed by ocular surface epithelium. Progress in Retinal and Eye Research, 16:81-98 (1997)).

Practitioners have taken several approaches to the treatment of dry eye. One common approach has been to supplement and stabilize the ocular tear film using so-called artificial tears instilled throughout the day. Another approach has been the use of ocular inserts that provide a tear substitute or to stimulate endogenous tear production.

Examples of the tear substitution approach include the use of buffered, isotonic saline solutions, aqueous solutions containing water-soluble polymers that render the solutions more viscous and thus less easily shed by the eye. Tear reconstitution is also attempted by providing one or more components of the tear film such as phospholipids and oils. Examples of these treatment approaches are disclosed in U.S. Pat. No. 4,131,651 (Shah et al.), U.S. Pat. No. 4,370,325 (Packman), U.S. Pat. No. 4,409,205 (Shively), U.S. Pat. No. 4,744,980 and U.S. Pat. No. 4,883,658 (Holly), U.S. Pat. No. 4,914,088 (Glonek), U.S. Pat. No. 5,075,104 (Gressel et al.) and U.S. Pat. No. 5,294,607 (Glonek et al.).

United States Patents directed to the use of ocular inserts in the treatment of dry eye include U.S. Pat. No. 3,991,759 (Urquhart). Other semi-solid therapy has included the administration of carrageenans (U.S. Pat. No. 5,403,841, Lang) which gel upon contact with naturally occurring tear film.

Another recent approach involves the provision of lubricating substances in lieu of artificial tears. U.S. Pat. No. 4,818,537 (Guo) discloses the use of a lubricating, liposome-based composition.

Aside from the above efforts, which are directed primarily to the alleviation of symptoms associated with dry eye, methods and compositions directed to treatment of the dry eye condition have also been pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin) discloses the use of sex steroids, such as conjugated estrogens, to treat dry eye condition in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen) discloses the use of finely divided calcium ion compositions to stimulate preocular tear film; and U.S. Pat. No. 4,966,773 (Gressel et al.) discloses the use of microfine particles of one or more retinoids for ocular tissue normalization.

Although these approaches have met with some success, problems in the treatment of dry eye nevertheless remain. The use of tear substitutes, while temporarily effective, generally requires repeated application over the course of a patient's waking hours. It is not uncommon for a patient to have to apply artificial tear solution ten to twenty times over the course of the day. Such an undertaking is not only cumbersome and time consuming, but is also potentially very expensive.

The use of ocular inserts is also problematic. Aside from cost, they are often unwieldy and uncomfortable. Further, as foreign bodies introduced in the eye, they can be a source of contamination leading to infections. In situations where the insert does not itself produce and deliver a tear film, artificial tears must still be delivered on a regular and frequent basis.

In view of the foregoing, there is a clear need for an effective treatment for dry eye that is capable of alleviating symptoms, as well as treating the underlying physical and physiological deficiencies of dry eye, and that is both convenient and inexpensive to administer.

Mucins are proteins that are heavily glycosylated with glucosamine-based moieties. Mucins provide protective and lubricating effects to epithelial cells, especially those of mucosal membranes. Mucins have been shown to be secreted by vesicles and discharged on the surface of the conjunctival epithelium of human eyes (Greiner et al., Mucus Secretory Vesicles in Conjunctival Epithelial Cells of Wearers of Contact Lenses, Archives of Ophthalmology, volume 98, pages 1843-1846 (1980); and Dilly et al., Surface Changes in the Anaesthetic Conjunctiva in Man, with Special Reference to the Production of Mucus from a Non-Goblet-Cell Source, British Journal of Ophthalmology, volume 65, pages 833-842 (1981)). A number of human-derived mucins which reside in the apical and subapical corneal epithelium have been discovered and cloned (Watanabe et al., Human Corneal and conjunctival Epithelia Produce a Mucin-Like Glycoprotein for the Apical Surface, Investigative Ophthalmology and Visual Science, volume 36, number 2, pages 337-344 (1995)). Recently, Watanabe discovered a new mucin which is secreted via the cornea apical and subapical cells as well as the conjunctival epithelium of the human eye (Watanabe et al., IOVS, volume 36, number 2, pages 337-344 (1995)). These mucins provide lubrication, and additionally attract and hold moisture and sebaceous material for lubrication and the corneal refraction of light.

Mucins are also produced and secreted in other parts of the body including lung airway passages, and more specifically from goblet cells interspersed among tracheal/bronchial epithelial cells. Certain arachidonic acid metabolites have been shown to stimulate mucin production in these cells. Yanni reported the increased secretion of mucosal glycoproteins in rat lung by hydroxyeicosatetraenoic acid ("HETE") derivatives (Yanni et al, Effect of Intravenously Administered Lipoxygenase Metabolites on Rat Tracheal Mucous Gel Layer Thickness, International Archives of Allergy And Applied Immunology, volume 90, pages 307-309 (1989)). Similarly, Marom has reported the production of mucosal glycoproteins in human lung by HETE derivatives (Marom et al., Human Airway Monohydroxy--eicosatetraenoic Acid Generation and Mucus Release, Journal of Clinical Investigation, volume 72, pages 122-127 (1983)). Nowhere in the art, however, has the use of HETE derivatives been proposed to stimulate mucin production in ocular tissues as a treatment for dry eye.

The conventional treatment for dry eye, as discussed above, includes administration of artificial tears to the eye several times a day. Other agents claimed for increasing ocular mucin and/or tear production include vasoactive intestinal polypeptide (Dartt et. al., Vasoactive intestinal peptide-stimulated glycoconjugate secretion from conjunctival goblet cells. Experimental Eye Research, 63:27-34, (1996)), gefarnate (Nakmura et. al., Gefarnate stimulates secretion of mucin-like glycoproteins by corneal epithelium in vitro and protects corneal epithelium from desiccation in vivo, Experimental Eye Research, 65:569-574 (1997)), and the use of liposomes (U.S. Pat. No. 4,818,537), androgens (U.S. Pat. No. 5,620,921), melanocyte stimulating hormones (U.S. Pat. No. 4,868,154), and phosphodiesterase inhibitors (U.S. Pat. No. 4,753,945), retinoids (U.S. Pat. No. 5,455,265). However, many of these compounds or treatments suffer from a lack of specificity, efficacy and potency and none of these agents have been marketed so far as therapeutically useful products to treat dry eye and related ocular surface diseases. Of particular relevance to the present invention is the claimed use of hydroxyeicosatetraenoic acid derivatives to treat dry eye (U.S. Pat. No. 5,696,166). Thus, there remains a need for an efficacious therapy for the treatment of dry eye and related diseases.

SUMMARY OF THE INVENTION

The present invention is directed to compositions and methods for the treatment of dry eye and other disorders requiring the wetting of the eye. More specifically, the present invention discloses analogs of (5Z,8Z, 11Z, 13E)- 15-hydroxyeicosa-5,8,11,14 tetraenoic acid (15-HETE) and methods using the same for treating dry eye type disorders. The compositions are administered topically to the eye for the treatment of dry eye.

DETAILED DESCRIPTION OF THE INVENTION

It has now been discovered that certain 15-HETE analogs are useful in treating dry eye or other disorders requiring the wetting of the eye. It is believed that such analogs stimulate mucin production in human conjunctival epithelium. These compounds are of formula I:

wherein:

R.sup.1 is CO.sub.2 R, where CO.sub.2 R forms an ophthalmically acceptable ester moiety;

NR.sup.2 R.sup.3, NR.sup.5 R.sup.6 are the same or different and comprise a free or functionally modified amino group;

OR.sup.4 comprises a free or functionally modified hydroxy group;

Hal is F, Cl, Br, or I;

R.sup.20 is H, alkyl, acyl;

R.sup.21 is H or a pharmaceutically acceptable cation, or COSR.sup.21 forms a pharmaceutically acceptable thioester moiety; A is L.sub.1 --A.sub.1 --L.sub.2, L.sub.1 --A.sub.2 --L.sub.2, L.sub.3 --A.sub.2 --L.sub.4, or L.sub.5 --A.sub.2 --L.sub.3 ; A.sub.1 is CH.sub.2 CH.sub.2 ; A.sub.2 is ##STR1## L.sub.1 is CH.sub.2 --B--D; B and D are the same or different and are CH.sub.2 CH.sub.2, CH.dbd.CH, or C.ident.C; L.sub.2 is CH.sub.2 --K--CH.sub.2 CH.sub.2 ; K is CH.sub.2 CH.sub.2, CH.dbd.CH, or C.ident.C; L.sub.3 is CH.sub.2 CH.sub.2 CH.sub.2, CH.sub.2 CH.dbd.CH, CH.sub.2 C.ident.C, CH.dbd.CHCH.sub.2, C.ident.CCH.sub.2, or CH.dbd.C.dbd.CH; L.sub.4 is X--CH.sub.2 CH.sub.2 ; X is CH.sub.2 CH.sub.2 CH.dbd.CH, CH.sub.2 CH.sub.2 C.ident.C, CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2, CH.sub.2 CH.dbd.CHCH.sub.2, CH.sub.2 C.ident.CCH.sub.2, CH.dbd.CHCH.sub.2 CH.sub.2, C.ident.CCH.sub.2 CH.sub.2, CH.sub.2 CH.dbd.C.dbd.CH, or CH.dbd.C.dbd.CHCH.sub.2 ; L.sub.5 is CH.sub.2 CH.sub.2 --B--D; and Y is C(O) (i.e. a carbonyl group) or Y is ##STR2##

wherein R.sup.9 O constitutes a free or functionally modified hydroxy group.

The compounds of formula I may also be incorporated into phospholipids as glyceryl esters or sphingomyelin amides. Phospholipid sphingomyelin amides of the compounds of formula I will typically comprise a formula I compound amidated via its carbon 1 carboxylate to the amino group of the sphingomyelin backbone. The phospholipid formula I esters will comprise various phospholipids. Phospholipid esters of the compounds of formula I will typically comprise a formula I compound esterified via its carbon 1 carboxylate to the sn-1 or sn-2 position alcohol, or both, of the glycerol backbone of the phospholipid. If the sn-1 or sn-2 position of the glyceryl ester class does not contain an ester of a compound of formula I, then such carbon positions of the glycerol backbone will comprise a methylene, ether or ester moiety linked to a substituted or unsubstituted C.sub.12-30 alkyl or alkenyl (the alkenyl group containing one or more double bonds); alkyl(cycloalkyl)alkyl; alkyl(cycloalkyl); alkyl(heteroaryl); alkyl(heteroaryl)alkyl; or alkyl-M--Q; wherein the substitution is alkyl, halo, hydroxy, or functionally modified hydroxy; M is O or S; and Q is H, alkyl, alkyl(cycloalkyl)alkyl, alkyl(cycloalkyl), alkyl(heteroaryl) or alkyl(heteroaryl)alkyl. However, at least one of the sn-1 or sn-2 position alcohols of the glycerol backbone must form an ester with a compound of formula I via the carbon 1 chlorophenyl, carboxylate of the latter. Preferred phospholipid-formula I) esters will be of the phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, and phospatidylinositol type. The most preferred phospholipid-formula I esters will comprise a formula I compound esterified via its carbon 1 carboxylate to the alcohol at the sn-2 position of phosphatidylcholine, phosphatidylethanolamine or phosphatidylinositol. The phospholipid-formula I esters and sphingomyelin amides may be synthesized using various phospholipid synthetic methods known in the art; see for example, Tsai et al., Biochemistry, volume 27, page 4619 (1988); and Dennis et al., Biochemistry, volume 32, page 10185 (1993).

Included within the scope of the present invention are the individual enantiomers of the title compounds, as well as their racemic and non-racemic mixtures. The individual enantiomers can be enantioselectively synthesized from the appropriate enantiomerically pure or enriched starting material by means such as those described below. Alternatively, they may be enantioselectively synthesized from racemic/non-racemic or achiral starting materials. (Asymmetric Synthesis; J. D. Morrison and J. W. Scott, Eds.; Academic Press Publishers: New York, 1983-1985, volumes 1-5; Principles of Asymmetric Synthesis; R. E. Gawley and J. Aube, Eds.; Elsevier Publishers: Amsterdam, 1996). They may also be isolated from racemic and non-racemic mixtures by a number of known methods, e.g. by purification of a sample by chiral HPLC (A Practical Guide to Chiral Separations by HPLC; G. Subramanian, Ed.; VCH Publishers: New York, 1994; Chiral Separations by HPLC; A. M. Krstulovic, Ed.; Ellis Horwood Ltd. Publishers, 1989), or by enantioselective hydrolysis of a carboxylic acid ester sample by an enzyme (Ohno, M.; Otsuka, M. Organic Reactions, volume 37, page 1 (1989)). Those skilled in the art will appreciate that racemic and non-racemic mixtures may be obtained by several means, including without limitation, nonenantioselective synthesis, partial resolution, or even mixing samples having different enantiomeric ratios. Departures may be made from such details within the scope of the accompanying claims without departing from the principles of the invention and without sacrificing its advantages. Also included within the scope of the present invention are the individual isomers substantially free of their respective enantiomers.

As used herein, the terms "pharmaceutically acceptable salt" and "pharmaceutically acceptable ester" means any salt or ester, respectively, that would be suitable for therapeutic administration to a patient by any conventional means without significant deleterious health consequences; and "ophthalmically acceptable salt" and "ophthalmically acceptable ester" means any pharmaceutically acceptable salt or ester, respectively, that would be suitable for ophthalmic application, i.e. non-toxic and non-irritating. Preferred ophthalmically acceptable esters include lower alkyl esters, and especially methyl, ethyl, n-propyl, iso-propyl, tert-butyl, and neopentyl esters.

The term "free hydroxy group" means an OH. The term "functionally modified hydroxy group" means an OH which has been functionalized to form: an ether, in which an alkyl, aryl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl group is substituted for the hydrogen; an ester, in which an acyl group is substituted for the hydrogen; a carbamate, in which an aminocarbonyl group is substituted for the hydrogen; or a carbonate, in which an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-, alkenyloxy-, cycloalkenyloxy-, heterocycloalkenyloxy-, or alkynyloxy-carbonyl group is substituted for the hydrogen. Preferred moieties include OH, OCH.sub.2 C(O)CH.sub.3, OCH.sub.2 C(O)C.sub.2 H.sub.5, OCH.sub.3, OCH.sub.2 CH.sub.3, OC(O)CH.sub.3, and OC(O)C.sub.2 H.sub.5.

The term "free amino group" means an NH.sub.2. The term "functionally modified amino group" means an NH.sub.2 which has been functionalized to form: an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, alkynyl-, or hydroxy-amino group, wherein the appropriate group is substituted for one of the hydrogens; an aryl-, heteroaryl-, alkyl-, cycloalkyl-, heterocycloalkyl-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, or alkynyl-amino group, wherein the appropriate group is substituted for one or both of the hydrogens; an amide, in which an acyl group is substituted for one of the hydrogens; a carbamate, in which an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, or alkynyl-carbonyl group is substituted for one of the hydrogens; or a urea, in which an aminocarbonyl group is substituted for one of the hydrogens. Combinations of these substitution patterns, for example an NH.sub.2 in which one of the hydrogens is replaced by an alkyl group and the other hydrogen is replaced by an alkoxycarbonyl group, also fall under the definition of a functionally modified amino group and are included within the scope of the present invention. Preferred moieties include NH.sub.2, NHCH.sub.3, NHC.sub.2 H.sub.5, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, NHOH, and NH(OCH.sub.3).

The term "free thiol group" means an SH. The term "functionally modified thiol group" means an SH which has been functionalized to form: a thioether, where an alkyl, aryl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl group is substituted for the hydrogen; or a thioester, in which an acyl group is substituted for the hydrogen. Preferred moieties include SH, SC(O)CH.sub.3, SCH.sub.3, SC.sub.2 H.sub.5, SCH.sub.2 C(O)C.sub.2 H.sub.5, and SCH.sub.2 C(O)CH.sub.3.

The term "acyl" represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and a single bond to another carbon atom.

The term "alkyl" includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms. The alkyl groups may be interrupted by one or more heteroatoms, such as oxygen, nitrogen, or sulfur, and may be substituted with other groups, such as halogen, hydroxyl, aryl, cycloalkyl, aryloxy, or alkoxy. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl.

The term "cycloalkyl" includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings, which can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "heterocycloalkyl" refers to cycloalkyl rings that contain at least one heteroatom such as O, S, or N in the ring, and can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferred heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, piperazinyl, and tetrahydropyranyl.

The term "alkenyl" includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms with at least one carbon-carbon double bond, the chain being optionally interrupted by one or more heteroatoms. The chain hydrogens may be substituted with other groups, such as halogen. Preferred straight or branched alkeny groups include, allyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.

The term "cycloalkenyl" includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more non-aromatic rings containing a carbon-carbon double bond, which can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl, alkoxy, or lower alkyl. Preferred cycloalkenyl groups include cyclopentenyl and cyclohexenyl.

The term "heterocycloalkenyl" refers to cycloalkenyl rings which contain one or more heteroatoms such as O, N, or S in the ring, and can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferred heterocycloalkenyl groups include pyrrolidinyl, dihydropyranyl, and dihydrofuranyl.

The term "carbonyl group" represents a carbon atom double bonded to an oxygen atom, wherein the carbon atom has two free valencies.

The term "aminocarbonyl" represents a free or functionally modified amino group bonded from its nitrogen atom to the carbon atom of a carbonyl group, the carbonyl group itself being bonded to another atom through its carbon atom.

The term "lower alkyl" represents alkyl groups containing one to six carbons (C.sub.1 -C.sub.6).

The term "halogen" represents fluoro, chloro, bromo, or iodo.

The term "aryl" refers to carbon-based rings which are aromatic. The rings may be isolated, such as phenyl, or fused, such as naphthyl. The ring hydrogens may be substituted with other groups, such as lower alkyl, halogen , free or functionalized hydroxy, trihalomethyl, etc. Preferred aryl groups include phenyl, 3-(trifluoromethyl)phenyl, 3-chlorophenyl, and 4-fluorophenyl.

The term "heteroaryl" refers to aromatic hydrocarbon rings which contain at least one heteroatom such as O, S, or N in the ring. Heteroaryl rings may be isolated, with 5 to 6 ring atoms , or fused, with 8 to 10 atoms . The heteroaryl ring(s) hydrogens or heteroatoms with open valency may be substituted with other groups, such as lower alkyl or halogen. Examples of heteroaryl groups include imidazole, pyridine, indole, quinoline, furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and dihydrobenzindole.

The terms "aryloxy", "heteroaryloxy", "alkoxy", "cycloalkoxy", "heterocycloalkoxy", "alkenyloxy", "cycloalkenyloxy", "heterocycloalkenyloxy", and "alkynyloxy" represent an aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, or alkynyl group attached through an oxygen linkage.

The terms "alkoxycarbonyl", "aryloxycarbonyl", "heteroaryloxycarbonyl", "cycloalkoxycarbonyl", "heterocyloalkoxycarbonyl", "alkenyloxycarbonyl", "cycloalkenyloxycarbonyl", "heterocycloalkenyloxycarbonyl", and "alkynyloxycarbonyl" represent an alkoxy, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy, alkenyloxy, cycloalkenyloxy, heterocycloalkenyloxy, or alkynyloxy group bonded from its oxygen atom to the carbon of a carbonyl group, the carbonyl group itself being bonded to another atom through its carbon atom.

Preferred compounds of the present invention include those of formula I, wherein: R is lower alkyl; A is L.sub.1 --A.sub.1 --L.sub.2 or L.sub.1 --A.sub.2 --L.sub.2 ; A.sub.1 is CH.sub.2 CH.sub.2 ; A.sub.2 is ##STR3## L.sub.1 is CH.sub.2 --B--D; L.sub.2 is CH.sub.2 --K--CH.sub.2 CH.sub.2 ; B is C.ident.C or cis-CH.dbd.CH and D is C.ident.C or trans-CH.dbd.CH; K is cis-CH.dbd.CH; and ##STR4##

Most preferably, R is selected from the group consisting of methyl; ethyl; n-propyl; iso-propyl; tert-butyl; and neopentyl.

Other preferred compounds of the present invention include those of formula I, wherein: R is lower alkyl; A is L.sub.3 --A.sub.2 --L.sub.4 ; A.sub.2 is ##STR5## L.sub.3 is trans-CH.sub.2 CH.dbd.CH, trans-CH.dbd.CHCH.sub.2, or CH.sub.2 C.ident.C; L.sub.4 is X--CH.sub.2 CH.sub.2 ; X is cis-CH.sub.2 CH.sub.2 CH.dbd.CH, CH.sub.2 CH.sub.2 C.ident.C, cis-CH.sub.2 CH.dbd.CHCH.sub.2, or cis CH.dbd.CHCH.sub.2 CH.sub.2 ; Y is ##STR6##

Most preferably, R is selected from the group consisting of methyl; ethyl; n-propyl; iso-propyl; tert-butyl; and neopentyl.

Still other preferred compounds of the present invention include those of formula I, wherein: R is lower alkyl; A is L.sub.5 --A.sub.2 --L.sub.3 ; ##STR7## A.sub.2 is L.sub.5 is CH.sub.2 CH.sub.2 --B--D; L.sub.3 is cis-CH.sub.2 CH.dbd.CH, cis-CH.dbd.CHCH.sub.2, CH.sub.2 C.ident.C, or CH.sub.2 CH.sub.2 CH.sub.2 ; B is cis-CH.dbd.CH or C.ident.C; D is trans-CH.dbd.CH or C.ident.C; and Y is ##STR8##

Most preferably, R is selected from the group consisting of methyl; ethyl; n-propyl; iso-propyl; tert-butyl; and neopentyl.

Among the especially preferred of the foregoing compounds are those whose preparations are detailed in the following examples 1-23.

Example 1: ##STR9## ##STR10##

Compound 1a

Treatment of 1,6-hexanediol (10) with 0.9 equivalents of t-butylchlorodiphenylsilane (TBDPSCl) in the presence of imidazole and 4-(dimethylamino)pyridine (DMAP) in N,N-dimethylformamide (DMF) affords monosilyl ether 11, which is oxidized with stoichiometric N-methylmorpholine N-oxide (NMO) in the presence of a catalytic amount of tetra-n-propylammonium perruthenate (TPAP) to provide aldehyde 12. Dibromoolefination of 12 using CBr.sub.4 and PPh.sub.3 gives 13. Conversion of 13 to enynol 15 is accomplished in two steps: first, treatment of 13 with 1 equivalent of Bu.sub.3 SnH in toluene in the presence of a catalytic amount of Pd(PPh.sub.3).sub.4 to afford the corresponding cis-vinyl bromide, followed by addition of CuI, HNEt.sub.2, and chiral enantiopure propargyl alcohol 14 [for the preparation of 14, see: Midland et. al., Tetrahedron, 40:1371 (1984), which by this reference is incorporated herein]. Reduction of 15 with Na[H.sub.2 Al(OCH.sub.2 CH.sub.2 OCH.sub.3).sub.2 ] affords diene 16, which is treated with 3,4-dihydro-2H-pyran (DHP) and a catalytic amount of p-toluenesulfonic acid monohydrate (TsOH) to give ether 17. Desilylation of 17 with tetra-n-butylammonium fluoride (TBAF) yields alcohol 18, which is oxidized with TPAP/NMO to provide aldehyde 19. Condensation of 19 with Ph.sub.3 P(CH.sub.2).sub.4 CO.sub.2 H Br in the presence of KOBu.sup.t, followed by treatment of the resultant eneacid with pyridinium p-toluenesulfonate (PPTS) in warm methanol, affords 1. Reaction of 1 with (trimethylsilyl)diazomethane in THF/methanol affords methyl ester 1a.

Example 2: ##STR11## ##STR12##

Compounds 2.alpha.a and 2.beta.a

Monosilylation of (2Z)-2-buten-1,4-diol (20) with TBDPSCl provides silyl ether 21, which is reacted with diiodomethane and diethylzinc to afford cyclopropane 22. Sequential reaction with mesyl chloride and NaCN provides nitrile 23. 23 is reduced with diisobutylaluminum hydride (DIBAL-H) at low temperature, and the intermediate imine is hydrolyzed with aqueous acetic acid to afford aldehyde 24. Condensation of 24 with CBr.sub.4 and PPh.sub.3 gives dibromoolefin 25. Monoreduction of 25 using stoichiometric Bu.sub.3 SnH and catalytic Pd(PPh.sub.3).sub.4 affords an intermediate Z-vinyl bromide, which in the same pot is reacted 1-octyn-3-ol (commercially available from Aldrich Chemical Co., Milwaukee, Wis.) in the presence of CuI and diethylamine to provide enyne 27. Reduction of 27 with sodium bis(2-methoxyethyoxy)aluminum hydride yields Z, E-dienyl alcohol 28, which is converted THP ether 29 using DHP and TsOH. Desilylation of 29 with TBAF affords alcohol 30, which is extended to cyanide 31 by sequential treatment with mesyl chloride and NaCN. Conversion to aldehyde 32 effected by reduction with DIBAL-H at -78.degree. C., followed by hydrolysis of the resulting metalloenamine with aqueous acetic acid at 0.degree. C. Wittig condensation with Ph.sub.3 P(CH.sub.2).sub.4 CO.sub.2 H Br in the presence of KOBu.sup.t, followed by deprotection of the resultant eneacid with PPTS in MeOH, yields 2.alpha. and 2.beta. after separation of the two C-15 diastereomers using silica gel chromatography. Treatment of the individual diastereomers with (trimethylsilyl)diazomethane in THF/methanol affords the methyl esters 2.alpha.a and 2.beta.a.

Example 3: ##STR13## ##STR14##

Compounds 3.alpha.a and 3.beta.a

Treatment of trans-.beta.-hydromuconic acid (33) with diethyl zinc and diiodomethane affords cyclopropane 34, which is reduced to diol 35 with LiAlH.sub.4. Monosilylation with TBDPSCl provides silyl ether 36, which is oxidized to aldehyde 37 using TPAP/NMO. Reaction of 37 with CBr.sub.4 and PPh.sub.3 gives dibromoolefin 38, which is converted to Z-vinyl bromide 39 using stoichiometric Bu.sub.3 SnH in the presence of catalytic Pd(PPh.sub.3).sub.4. Sonogishira coupling of 39 with 1-octyn-3-ol in the presence of CuI Pd(PPh.sub.3).sub.2 Cl.sub.2, and HNEt.sub.2 yields enyne 40, which is reduced to the corresponding E-allyl alcohol 41 with Na[H.sub.2 Al(CH.sub.2 CH.sub.2 OCH.sub.3).sub.2 ]. Treatment of 41 with DHP and TsOH affords THP ether 42, which is desilylated to alcohol 43 with TBAF in THF. Oxidation of 43 to aldehyde 44 is achieved using TPAP/NMO. This aldehyde is reacted with Ph.sub.3 P(CH.sub.2).sub.4 CO.sub.2 H Br in the presence of KOBu.sup.t, and the intermediate eneacid is deprotected with PPTS in MeOH to afford targets 3.alpha. and 3.beta. after separation of the two C-15 diastereomers using silica gel chromatography. Treatment of the individual diastereomers with (trimethylsilyl)diazomethane in THF/methanol affords the methyl esters 3.alpha.a and 3.beta.a.

Example 4: ##STR15##

Compound 4a

Alcohol 15 is protected as its THP ether 45 by treatment with DHP and TsOH. Desilylation