Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-02
2002-03-05
Pryor, Alton (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S305000, C514S306000, C514S307000, C514S309000, C514S310000, C514S412000, C514S416000, C514S432000, C514S443000, C514S456000, C514S461000, C514S463000, C514S464000, C514S465000, C514S467000, C546S290000, C546S134000, C548S452000, C548S469000, C548S470000, C548S482000, C549S049000, C549S051000, C549S057000, C549S078000, C549S398000, C549S399000
Reexamination Certificate
active
06353014
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel compounds and methods for the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of certain 15-ketal analogs of F 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. Moreover, some 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 the elevated intraocular pressure associated with glaucoma.
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 similar IOP lowering mechanisms to those exhibited by PGF
2&agr;
, an F-series prostaglandin of the following formula:
The relationship of PGF
2&agr;
, receptor activation and IOP lowering effects is not well understood. It is believed that PGF
2&agr;
receptor activation leads to increased outflow of aqueous humor. Regardless of mechanism, PGF
2&agr;
and certain of its analogs have been shown to lower IOP (Giuffre,
The Effects of Prostaglandin F
2&agr;
the Human Eye, Graefe's Archive Ophthalmology
, volume 222, pages 139-141 (1985); and Kerstetter et al.,
Prostaglandin F
2&agr;
-1-
Isopropylester Lowers Intraocular Pressure Without Decreasing Aqueous Humor Flow, American Journal of Ophthalmology
, volume 105, pages 30-34 (1988)). Thus, it has been of interest in the field to develop synthetic PGF
2&agr;
analogs with IOP lowering efficacy.
Synthetic PGF
2&agr;
-type analogs have been pursued in the art (
Graefe's Archive Ophthalmology
, volume 229, pages 411-413 (1991)). Though PGF
2&agr;
-type molecules lower IOP, these types of molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing. Such effects include an initial increase in IOP, breakdown of the blood aqueous barrier and conjunctival hyperemia (Alm,
The Potential of Prostaglandin Derivatives in Glaucoma Therapy, Current Opinion in Ophthalmology
, volume 4, No. 11, pages 44-50 (1993)). Based on the foregoing, a need exists for the development of compounds that may activate the PGF
2&agr;
receptors, yielding a more efficacious lowering of IOP, while exhibiting fewer or reduced side effects.
An agent which exhibits comparable 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 PGF
2&agr;
, and methods of their use. It has unexpectedly been found that the presently claimed 15-ketal analogs of PGF
2&agr;
meet this objective. Although etiproston, a 15-ketal prostaglandin and certain analogs thereof are known in the art (U.S. Pat. No. 4,088,775 and Skuballa, et al., “15-,15-ketals of Natural Prostaglandins and Prostaglandin Analogues Synthesis and Biological Activities,”
J. Med. Chem,
21(5):443 (1978)), they are known primarily for their luteolytic properties. See, e.g.
The Merck Index
(Eleventh Ed.) p. 608, monograph no. 3827 (1989). Etiproston was also disclosed in U.S. Pat. No. 5,480,900 as one of many prostaglandin analogs which in combination with a clonidine derivative would be useful for treating glaucoma. In addition, U.S. Pat. No. 4,870,104 discloses 11-halo prostaglandins which may have an ethylenedioxymethylene group at the 15 position. The novel compositions and the methods of use claimed in this application, however, are neither disclosed nor suggested in the foregoing art.
SUMMARY OF THE INVENTION
The present invention is directed to novel compounds, ophthalmic compositions and methods of their use in treating glaucoma and ocular hypertension. In particular, the present invention provides certain classes of 15-ketal prostaglandins believed to have functional PGF
2&agr;
receptor agonist activity, and methods of their use in treating glaucoma and ocular hypertension.
DETAILED DESCRIPTION OF THE INVENTION
It has unexpectedly been found that the 15 -ketal substituted PGF
2&agr;
analogs of the present invention exhibit an improved therapeutic profile in the treatment of glaucoma and ocular hypertension when compared natural prostaglandins and some of their known analogs. The substituted PGF
2&agr;
analogs useful in the methods and compositions of the Ad present invention have the following formula I:
wherein:
R
1
=CO
2
R, CONR
4
R
5
, CH
2
OR
6
, or CH
2
NR
7
R
8
, where:
R=H or cationic salt moiety, or CO
2
R=pharmaceutically acceptable ester moiety; R
4
, R
5
=same or different=H or alkyl; R
6
=H, acyl, or alkyl; R
7
, R
8
=same or different=H, acyl, or alkyl; with the proviso that if one of R
7
, R
8
=acyl, then the other=H or alkyl;
n=0 or 2;
R
2
=H, alkyl, or acyl;
R
3
=H, halo, or OR
9
; where R
9
=H, alkyl, or acyl;
- - - -
=single or non-cumulated double bond, with the provisos that if a double bond is present between carbons 4 and 5, it is of the cis configuration; and that if a double bond is present between carbons 13 and 14, it is of the trans configuration;
X=(CH
2
)
m
or (CH
2
)
m
O, where m=1-6; and
Y=phenyl, optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, or hydroxy; or
X—Y=(CH
2
)
p
Y
1
; where p=0-6; and
wherein:
W=CH
2
, O, S(O)
q
, NR
10
, CH
2
CH
2
, CH═CH, CH
2
O, CH
2
S(O)
q
, CH═N, or CH
2
NR
9
,
where q=0-2, and R
10
=H, alkyl, or acyl;
Z=H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, or hydroxy; and
- - - -
=single or double bond.
For purposes of the foregoing and following definitions, the term “pharmaceutically acceptable ester” means an
Hellberg Mark R.
Klimko Peter G.
Sallee Verney L.
Alcon Laboratories Inc.
Copeland Barry L.
Pryor Alton
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