Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-02-04
2003-04-08
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S573000, C514S913000
Reexamination Certificate
active
06545045
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of certain analogs of E series prostaglandins to treat glaucoma and ocular hypertension.
Glaucoma is a progressive disease which leads to optic nerve damage and, ultimately, total loss of vision. The causes of this disease have been the subject of extensive studies for many years, but are still not fully understood. The principal symptom of and/or risk factor for the disease is elevated intraocular pressure or ocular hypertension due to excess aqueous humor in the anterior chamber of the eye.
The causes of aqueous humor accumulation in the anterior chamber are not fully understood. It is known that elevated intraocular pressure (“IOP”) can be at least partially controlled by administering drugs which either reduce the production of aqueous humor within the eye, such as beta-blockers and carbonic anhydrase inhibitors, or increase the outflow of aqueous humor from the eye, such as miotics and sympathomimetics.
Most types of drugs conventionally used to treat glaucoma have potentially serious side effects. Miotics such as pilocarpine can cause blurring of vision and other visual side effects, which may lead either to decreased patient compliance or to termination of therapy. Systemically administered carbonic anhydrase inhibitors can also cause serious side effects such as nausea, dyspepsia, fatigue, and metabolic acidosis, which side effects can affect patient compliance and/or necessitate the termination of treatment. Another type of drug, beta-blockers have increasingly become associated with serious pulmonary side effects attributable to their effects on beta-2 receptors in pulmonary tissue. Sympathomimetics, on the other hand, may cause tachycardia, arrhythmia and hypertension. Recently, certain prostaglandins and prostaglandin derivatives have been described in the art as being useful in reducing intraocular pressure. Typically, however, prostaglandin therapy for the treatment of elevated intraocular pressure is attended by undesirable side-effects, such as irritation and hyperemia of varying severity and duration. There is therefore a continuing need for therapies which control elevated intraocular pressure associated with glaucoma without the degree of undesirable side-effects attendant to most conventional therapies.
Prostaglandins are metabolite derivatives of arachidonic acid. Arachidonic acid in the body is converted to prostaglandin G
2
, which is subsequently converted to prostaglandin H
2
. Other naturally occurring prostaglandins are derivatives of prostaglandin H
2
. A number of different types of prostaglandins are known in the art including A, B, C, D, E, F, G, I and J-Series prostaglandins (EP 0 561 073 A1). Of interest in the present invention are compounds which are believed to exhibit IOP lowering mechanisms similar to those exhibited by PGE
2
(an E-series prostaglandin):
The relationship between EP receptor activation and IOP lowering effects is also not well understood. There are currently four recognized subtypes of the EP receptor (EP
1
, EP
2
, EP
3
, and EP
4
; J. Lipid Mediators Cell Signaling
, volume 14, pages 83-87 (1996)). It is known in the art that ligands capable of EP
2
receptor activation, such as PGE
2
and synthetic analogs (
Journal of Ocular Pharmacology
, volume 4, number 1, pages 13-18 (1988);
Journal of Ocular Pharmacology and Therapeutics
, volume 11, number 3, pages 447-454 (1995);
Journal of Lipid Mediators
, volume 6, pages 545-53 (1993); Woodward, U.S. Pat. No. 5,698,598; Woodward, U.S. Pat. No. 5,462,968), or EP
3
receptor activation (
Journal of Lipid Mediators
, volume 7, pages 545-553 (1993);
Investigative Ophthalmology and Visual Science
, volume 31, number 12, pages 2560-2567 (1990)) lower IOP. However, some of these molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing, including an initial increase in IOP, photophobia, and eye ache (see for example
Journal of Ocular Pharmacology
, volume 4, number 1, pages 13-18 (1988)).
Based on the foregoing, a need exists for the development of molecules that may activate the PGE receptors, yielding a more efficacious lowering of IOP, while exhibiting fewer or reduced side effects.
An agent which exhibits comparable or improved efficacy, but with reduced side effects when compared to other agents, is said to have an improved therapeutic profile. It is an object of this invention to provide a class of IOP lowering agents with an improved therapeutic profile over PGE
2
, and methods of their use. It has now unexpectedly been discovered that the presently claimed prostanoids meet this objective. Although certain analogs of prostaglandin E
2
have been disclosed as ocular hypotensives in U.S. Pat. Nos. 5,057,621; 5,698,598; 5,462,968; and 4,822,891, and by Woodward el al.,
J. Lipid Mediators
, 6:545 (1993), the presently claimed compounds of this invention are neither disclosed, claimed, nor suggested in that art. Furthermore, certain compounds of the claimed invention in combination with prostaglandin FP receptor agonists (EP 603800 A1) or with clonidine derivatives (U.S. Pat. No. 5,811,443) have been claimed for treating glaucoma.
SUMMARY OF THE INVENTION
The present invention is directed to novel compositions, and methods of use in treating ocular disorders in mammals, and especially in humans. More specifically, and in preferred embodiments, the present invention encompasses compositions containing certain prostaglandin E receptor agonists and methods for treating glaucoma and ocular hypertension.
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Griffin Brenda W.
Klimko Peter G.
Sharif Najam A.
Alcon Manufacturing Ltd.
Copeland Barry
Fay Zohreh
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