Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-17
2003-04-08
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S412000, C514S912000, C514S913000
Reexamination Certificate
active
06545036
ABSTRACT:
BACKGROUND OF THE INVENTION
Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normal eye function. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by the majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma.
Many of the drugs formerly used to treat glaucoma proved unsatisfactory. The early methods of treating glaucoma employed pilocarpine and produced undesirable local effects that made this drug, though valuable, unsatisfactory as a first line drug. More recently, clinicians have noted that many &bgr;-adrenergic antagonists are effective in reducing intraocular pressure. While many of these agents are effective for this purpose, there exist some patients with whom this treatment is not effective or not sufficiently effective. Many of these agents also have other characteristics, e.g., membrane stabilizing activity, that become more apparent with increased doses and render them unacceptable for chronic ocular use and can also cause cardiovascular effects.
Although pilocarpine and &bgr;-adrenergic antagonists reduce intraocular pressure, none of these drugs manifests its action by inhibiting the enzyme carbonic anhydrase, and thus they do not take advantage of reducing the contribution to aqueous humor formation made by the carbonic anhydrase pathway.
Agents referred to as carbonic anhydrase inhibitors decrease the formation of aqueous humor by inhibiting the enzyme carbonic anhydrase. While such carbonic anhydrase inhibitors are now used to treat intraocular pressure by systemic and topical routes, current therapies using these agents, particularly those using systemic routes are still not without undesirable effects. Because carbonic anhydrase inhibitors have a profound effect in altering basic physiological processes, the avoidance of a systemic route of administation serves to diminish, if not entirely eliminate, those side effects caused by inhibition of carbonic anhydrase such as metabolic acidosis, vomiting, numbness, tingling, general malaise and the like. Topically effective carbonic anhydrase inhibitors are disclosed in U.S. Pat. Nos. 4,386,098; 4,416,890; 4,426,388; 4,668,697; 4,863,922; 4,797,413; 5,378,703, 5,240,923 and 5,153,192.
Prostaglandins and prostaglandin derivatives are also known to lower intraocular pressure. U.S. Pat. No. 4,883,819 to Bito descibes the use and synthesis of PGAs, PGBs and PGCs in reducing intraocular pressure. U.S. Pat. No. 4,824,857 to Goh et al. describes the use and synthesis of PGD2 and derivatives thereof in lowering intraocular pressure including derivatives wherein C-10 is replaced with nitrogen. U.S. Pat. No. 5,001,153 to Ueno et al. describes the use and synthesis of 13,14-dihydro-15-keto prostaglandins and prostaglandin derivatives to lower intraocular pressure. U.S. Pat. No. 4,599,353 describes the use of eicosanoids and eicosanoid derivatives including prostaglandins and prostaglandin inhibitors in lowering intraocular pressure.
Prostaglandin and prostaglandin derivatives lower intraocular pressure by increasing uveoscleral outflow. This is true for both the F type and A type of Pgs and hence presumably also for the B, C, D, E and J types of prostaglandins and derivatives thereof. A problem with using prostaglandin derivatives to lower intraocular pressure is that these compounds often induce an initial increase in intraocular pressure, can change the color of eye pigmentation and cause proliferation of some tissues surrounding the eye.
As can be seen, there are several current therapies for treating glaucoma and elevated intraocular pressure, but the efficacy and the side effect profiles of these agents are not ideal. Recently potassium channel blockers were found to reduce intraocular pressure in the eye and therefore provide yet one more approach to the treatment of ocular hypertension and the degenerative ocular conditions related thereto. Blockage of potassium channels can diminish fluid secretion, and under some circumstances, increase smooth muscle contraction and would be expected to lower IOP and have neuroprotective effects in the eye. (see U.S. Pat. Nos. 5,573,758 and 5,925,342; Moore, et al., Invest. Ophthalmol. Vis. Sci 38, 1997; WO 89/10757, WO94/28900, and WO 96/33719).
SUMMARY OF THE INVENTION
This invention relates to the use of potent potassium channel blockers or a formulation thereof in the treatment of glaucoma and other conditions which are related to elevated intraocular pressure in the eye of a patient. This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans. More particularly this invention relates to the treatment of glaucoma and/or ocular hypertension (elevated intraocular pressure) using indole compounds having the structural formula I:
or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof: wherein,
R
1
represents hydrogen or C
1-6
alkyl;
R
2
, R
3
a and R
3
b independently represent hydrogen, alkylsilyl, C
1-10
alkyl, C
1-10
cycloalkyl, C
4-10
heterocycloalkyl, C
4-10
heteroaryl, NH
2
, or C
6-10
aryl said alkyl, aryl or heteraryl optionally substituted with 1-3 groups of R
x
;
R
x
represents C
1-6
alkyl, halogen, CF
3
, C
1-6
alkoxy, NR
1
R
1
, or NO
2
, or NH
2
;
R
4
represents hydrogen, C
1-6
alkoxy, C
1-6
alkyl, CF
3
, or halogen;
R
5
represents hydrogen, C
1-6
alkoxy, C
1-6
alkyl, CF
3
, nitro, amino, cyano, C
1-6
alkylamino, or halogen and
R
6
represents hydrogen, halogen or C
1-6
alkyl.
This and other aspects of the invention will be realized upon inspection of the invention as a whole.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a method for decreasing elevated intraocular pressure or treating glaucoma by administration, preferably topical or intra-camaral administration, of a composition containing a potassium channel blocker of Formula I and a pharmaceutically acceptable carrier.
One embodiment of this invention is realized when R
2
is C
1-6
alkyl, C
6-10
aryl, alkylsily, or C
3-10
cycloalkyl and all other variables are as originally described.
Another embodiment of this invention is realized when R
3
b is C
1-6
alkyl, C
6-10
aryl, alkylsilyl or C
3-10
cycloalkyl and all other variables are as originally described.
A preferred embodiment of this invention is realized when R
1
is C
1-6
alkyl, R
2
and R
3
b independently are C
1-6
alkyl, C
6-10
aryl, alkylsilyl or C
3-10
cycloalkyl, R
4
is hydrogen, R
5
is C
1-6
alkoxy, C
1-6
alkyl, R
3
a is hydrogen and R
6
is halogen or C
1-6
alkyl.
A more preferred embodiment of this invention is realized when R
1
is C
1-3
alkyl, R
2
and R
3
b independently are C
1-4
alkyl, C
6-10
aryl, alkylsilyl or C
5-10
cycloalkyl, R
4
is hydrogen, R
5
is C
1-3
alkoxy, and R
6
is halogen.
Preferred compounds to be used in this invention are:
The invention is described herein in detail using the terms defined below unless otherwise specified.
The term “alkyl” refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with “branched alkyl group”.
Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused.
Alkoxy refers to C
1
-C
6
alkyl-O—, with the alkyl group optionally substituted as described herein. Said groups are those groups of the designated length in eith
Garcia Maria L.
Kaczorowski Gregory J.
McManus Owen B.
Ayler Sylvia A.
Camara Valerie J.
Daniel Mark R.
Fay Zohreh
Merck & Co. , Inc.
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