Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2002-03-18
2004-01-20
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S573000, C560S121000, C562S503000
Reexamination Certificate
active
06680339
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to compounds for the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of certain 15-fluoro 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 flow of aqueous humor out of 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. Some beta-blockers have increasingly become associated with serious pulmonary side effects attributable to their effects on beta-2 receptors in pulmonary tissue. Sympathomimetics may cause tachycardia, arrhythmia and hypertension. There is therefore a continuing need for therapies which control the elevated intraocular pressure associated with glaucoma.
Prostaglandins, which are metabolite derivatives of arachidonic acid, have recently been pursued for possible efficacy in lowering IOP. 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 have been discovered including A, B, 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 effects similar to those exhibited by PGF
2&agr;
(an F-series prostaglandin):
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 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, many of 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 molecules that may activate PGF
2&agr;
receptors, yielding a more efficacious lowering of IOP, while exhibiting fewer or reduced side effects.
An agent which exhibits the same 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 PGF
2&agr;
, and methods of their use. It has now unexpectedly been discovered that the presently claimed 15-fluoro analogs of PGF
2&agr;
meet this objective. While some prostaglandins with fluorine in the omega chain are known in the art [EP 435,443 A; JP 7,070,054 A2;
Eksp. Klin. Farmakol.
, volume 57, number 2, pages 39-41 (1994) (
Chemical Abstracts
, volume 121, abstract 50656 (1994));
Izv. Akad. Nauk SSSR, Ser. Biol.
, volume 6, pages 831-7 (1989) (
Chemical Abstracts
, volume 112, abstract 30749 (1990))], the novel compounds of the present invention and their favorable therapeutic profiles in the treatment of glaucoma are neither disclosed nor suggested in that art.
SUMMARY OF THE INVENTION
The present invention is directed to compositions and methods of their use in treating IOP and ocular hypertension. In particular, the present invention provides 15-fluoro prostaglandin analogs believed to have functional PGF
2&agr;
receptor agonist activity, and methods of their use in treating glaucoma and ocular hypertension. As previously stated, the mechanism of action by which PGF
2&agr;
type prostaglandins lower IOP is not well understood. While the mechanism of action of the compounds of the present invention is not fully understood, the inventors theorize that such compounds exhibit enhanced FP receptor selectivity as a consequence of their decreased activity at the EP receptor site. While bound by no such theory, it is possible that an improved therapeutic index may result from a relative reduction of EP-mediated side-effects.
DETAILED DESCRIPTION OF THE INVENTION
It has unexpectedly been found that 15-fluoro substituted PGF
2&agr;
analogs of the present invention exhibit an improved therapeutic profile in the treatment of glaucoma and ocular hypertension when compared to natural prostaglandins and many of their known analogs. The substituted PGF
2&agr;
analogs of the 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;
- - - =single or non-cumulated double bond, with the provisos that a double bond between carbons 4 and 5 may not be of the trans configuration; and that a double bond between carbons 13 and 14 may not be of the cis configuration; R
2
, R
3
=same or different=H, alkyl, or acyl;
D, D
1
=different=H and fluorine;
X=(CH
2
)
q
or (CH
2
)
q
O; where q=1-6; and
Y=a phenyl ring 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)
m
, NR
9
, CH
2
CH
2
, CH═CH, CH
2
O, CH
2
S(O)
m
, CH═N, or CH
2
NR
9
; where m=0-2, and R
9
=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 definition, the term “pharmaceutically acceptable ester” means any ester that would be suitable for therapeutic administration to a patient by any conventional means without significant deleterious health consequences; and “ophthalmically acceptable ester” means any pharmaceutically acceptable ester that would be suitable for ophthalmic application,
Hellberg Mark R.
Klimko Peter G.
Zinke Paul W.
Alcon Manufacturing Ltd.
Copeland Barry L.
Fonda Kathleen K.
Maier Leigh C.
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