Cyclopentane 1-hydroxy alkyl or alkenyl-2-one or 2-hydroxy...

Details Cyclopentane 1-hydroxy alkyl or alkenyl-2-one or 2-hydroxy... Cyclopentane 1-hydroxy alkyl or alkenyl-2-one or 2-hydroxy...

2000-09-20

2001-06-19

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S448000, C549S078000, C549S079000, C560S121000, C560S122000

Reexamination Certificate

active

06248783

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to cyclopentane 1-hydroxy alkyl or alkenyl-2-one or 2-hydroxy derivatives as therapeutic agents. These compounds are potent ocular hypotensives and are particularly suited for the management of glaucoma.
BACKGROUND OF THE INVENTION
DESCRIPTION OF RELATED ART
Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.
Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
The underlying causes of primary glaucoma are not yet known. The increased intraocular tension is due to the obstruction of aqueous humor outflow. In chronic open-angle glaucoma, the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded. In acute or chronic angle-closure glaucoma, the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupilary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm. Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe, and may plug the drainage channel with exudates. Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
Considering all types together, glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision. In cases where surgery is not indicated, topical b-adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
Certain eicosanoids and their derivatives have been reported to possess ocular hypotensive activity, and have been recommended for use in glaucoma management. Eicosanoids and derivatives include numerous biologically important compounds such as prostaglandins and their derivatives. Prostaglandins can be described as derivatives of prostanoic acid which have the following structural formula:
Various types of prostaglandins are known, depending on the structure and substituents carried on the alicyclic ring of the prostanoic acid skeleton. Further classification is based on the number of unsaturated bonds in the side chain indicated by numerical subscripts after the generic type of prostaglandin [e.g. prostaglandin E
1
(PGE
1
), prostaglandin E
2
(PGE
2
)], and on the configuration of the substituents on the alicyclic ring indicated by &agr; or &bgr; [e.g. prostaglandin F
2&agr;
(PGF
2&bgr;
)].
Prostaglandins were earlier regarded as potent ocular hypertensives, however, evidence accumulated in the last decade shows that some prostaglandins are highly effective ocular hypotensive agents, and are ideally suited for the long-term medical management of glaucoma (see, for example, Bito, L. Z.
Biological Protection with Prostaglandins
, Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z.,
Applied Pharmacology in the Medical Treatment of Glaucomas
Drance, S. M. and Neufeld, A. H. eds., New York, Grune & Stratton, 1984, pp. 477-505. Such prostaglandins include PGF
2&agr;
, PGF
1&agr;
, PGE
2
, and certain lipid-soluble esters, such as C
1
to C
2
alkyl esters, e.g. 1-isopropyl ester, of such compounds.
Although the precise mechanism is not yet known experimental results indicate that the prostaglandin-induced reduction in intraocular pressure results from increased uveoscleral outflow [Nilsson et.al.,
Invest. Ophthalmol. Vis. Sci
. (suppl), 284 (1987)].
The isopropyl ester of PGF
2&agr;
(has been shown to have significantly greater hypotensive potency than the parent compound, presumably as a result of its more effective penetration through the cornea. In 1987, this compound was described as “the most potent ocular hypotensive agent ever reported” [see, for example, Bito, L. Z.,
Arch. Ophthalmol
. 105, 1036 (1987), and Siebold et.al.,
Prodrug
5 3 (1989)].
Whereas prostaglandins appear to be devoid of significant intraocular side effects, ocular surface (conjunctival) hyperemia and foreign-body sensation have been consistently associated with the topical ocular use of such compounds, in particular PGF
2&agr;
and its prodrugs, e.g., its 1-isopropyl ester, in humans. The clinical potentials of prostaglandins in the management of conditions associated with increased ocular pressure, e.g. glaucoma are greatly limited by these side effects.
In a series of co-pending United States patent applications assigned to Allergan, Inc. prostaglandin esters with increased ocular hypotensive activity accompanied with no or substantially reduced side-cffects are disclosed. The co-pending U.S. Ser. No. 596,430 (filed Oct. 10, 1990), relates to certain 11-acyl-prostaglandins, such as 11-pivaloyl, 11-acetyl, 11-isobutyryl, 11-valeryl, and 11-isovaleryl PGF
2&agr;
. Intraocular pressure reducing 15-acyl prostaglandins are disclosed in the co-pending application U.S. Ser. No. 175,476 (filed Dec. 29, 1993). Similarly, 11,15- 9,15 and 9,11-diesters of prostaglandins, for example 11,15-dipivaloyl PGF
2&agr;
are known to have ocular hypotensive activity. See the patent application Ser. No. 385,645 (filed July 7, 1989, now U.S. Pat. No. 4,994,274), Ser. No. 584,370 (filed Sep. 18, 1990, now U.S. Pat. No. 5,028,624) and Ser. No. 585,284 (filed Sep. 18, 1990, now U.S. Pat. No. 5,034,413). The disclosures of all of these patent applications are hereby expressly incorporated by reference.
SUMMARY OF THE INVENTION
The present invention concerns a method of treating ocular hypertension which comprises administering to a mammal having ocular hypertension a therapeutically effective amount of a compound of formula I
wherein R is H or COR
3
;
R
1
is H, R
2
, phenyl, or COR
3
, wherein R
2
is C
1
-C
5
lower alkyl and R
3
is R
2
or phenyl;
Z is CH
2
or O;
Y is OH, OCOR
3
or ═O;
x is 0 or 1; and
X is C
1
-C
5
n-alkyl, C
3
-C
7
cycloalkyl, phenyl, furanyl, thienyl or substituted derivatives thereof, wherein the substituents maybe selected from the group consisting of C
1
-C
5
alkyl, halogen, CF
3
, CN, NO
2
, NR
4
2
, CO
2
R
4
and OR
4
wherein
R
4
is hydrogen or C
1
-C
5
alkyl and dotted lines represent the presence or absence of a double bond and wavy lines represent a cis or trans bond.
In a still further aspect, the present invention relates to a pharmaceutical product, comprising
a container adapted to dispense its contents in a metered form; and
an ophthalmic solution therein, as hereinabove defined.
Finally, certain of the compounds represented by the above formula, disclosed below and utilized in the method of the present invention are novel and unobvious.


REFERENCES:
patent: 4994274 (1991-02-01), Chan et al.
patent: 5028624 (1991-07-01), Chan et al.
patent: 5034413 (1991-07-01), Chan et al.
patent: 5446041 (1995-08-01), Chan et al.
Simon, Z., 1982, Timisoara Med. 27(1), 15-18.*
Bito, L.Z.,Biological Protection with Prostaglandins, “Prostaglandins and Related Compounds as Potential Ocular Therapeutic Agents”, vol. 1, Chapter 18, 1985, pp. 231-252.
Brito, L.Z.,Glaucoma, Applied Pharmacology in the Medical Tr

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