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...
C549S399000, C549S401000, C549S429000, C560S129000, C562S503000
Reexamination Certificate
active
06353000
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 11-halo 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. 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 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 by some 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 ophthalmic 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)). The binding of other types of molecules with the PGF
2&agr;
receptor may lead to IOP lowering effects, but with reduced or fewer side effects than those elicited by the above mentioned PGF
2&agr;
-type analogs.
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 PGF
2&agr;
and methods of their use. It has now unexpectedly been discovered that the presently claimed 11-halo analogs of PGF
2&agr;
meet this objective. Although certain 11-halo prostaglandins are known in the art (Thierauch, et al., “Stable 9&bgr;- or 11&agr;-Halogen-15-cyclohexyl-Prostaglandins with High Affinity to the PGD
2
-Receptor,”
Prostaglandins,
35:6, 855 (June 1988); U.S. Pat. Nos. 4,870,104 and 4,983,629; and EPO 561 073 A1), the surprisingly enhanced therapeutic profiles of such compounds and the novel compounds of the present invention in the treatment of glaucoma is neither disclosed nor suggested in that art.
SUMMARY OF THE INVENTION
The present invention is directed to compositions, including certain novel compounds, and methods of their use in treating glaucoma and ocular hypertension. In particular, the present invention provides certain classes of 11-halo prostaglandins having 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 11-halo 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:
n=0 or 2;
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 forms an ophthalmically 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;
Q=halo;
one of T
1
, T
2
=H, and the other=OR
3
, wherein R
3
is as defined below; or T
1
and T
2
together=O (i.e., a carbonyl);
R
2
, R
3
=same or different=H, alkyl, or acyl;
- - -
=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;
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 and following definitions, the term “pharmaceutically acceptable ester” means any ester that would, in appropriate doses, be suitable for therapeutic administration to a patient by conventional means without significant deleterious health consequences; and “ophthalmically acceptable este
Hellberg Mark R.
Klimko Peter G.
Sallee Verney L.
Zinke Paul W.
Alcon Laboratories Inc.
Copeland Barry L.
Pryor Alton
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