Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-30
2001-06-19
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S344000
Reexamination Certificate
active
06248759
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for treatment of light-injured retinal degeneration disease.
2. Related Arts
In the structure of eye, the retina exists at the ocular fundus and takes charge of the function of eye, which recognizes the presence or absence, and the shape of things in virtue of the existence of the neuroepithelial layer in the retina. In addition, the central portion of the retina is called macula lutea and one can distinguish things and feel colors by the action of the macula lutea.
The retina is destined to chronic exposure to light throughout the life. Particularly, the macula lutea, the central and most vital area of the retina, is likely to be damaged by light than the peripheral region of the retina. It has been pointed out that damage to the retina resulting from light exposure is accumulative and that the damage may promote age-related changes of retina which induce age-related macular degeneration or the like (Young, R. W.; Surv. Ophthalmol., 32: 252-269; 1988, the disclosures of which are herein incorporated by reference). It has also been described that light exposure may cause pathological conditions similar to that of age-related macular degeneration, i. e., a formation of drusen, neovascularization originated from choroidal membrane and the like. Statistically, age-related macular degeneration patients have been reported to be less likely cataract patients and more likely out-door laborers or habitants in UV-rich area.
The age-related macular degeneration is classified into the non-leakage type (dry type), which is simply called as age-related macular degeneration, and the exudative type, which is called as age-related disciform macular degeneration. In the dry type, drusen and atrophy of pigment epithelium may be observed in the macula lutea, and the vision may be damaged significantly. In the exudative type, new blood vessels originated from the choroidal membrane may develop in the macula lutea under the retina membrane, which resulting in hemorrhage, exudation and cicatrization, and further, in degeneration of the macula lutea. In the progressed stage, the visual loss becomes advanced and irreversible. At present, no effective treatment is available for the dry (non-leakage) type age-related macular degeneration. For the exudative type, it has been said that the only treatment, which might be effective, is laser photocoagulation. Recently, the effect of interferon for treatment of the exudative type was studied, but this could not necessarily be said as effective because of its side effects.
The calcium antagonists inhibit inflow of calcium ions into the vascular smooth muscle cells thereby relax the muscle to dilate the peripheral blood vessel, and thereby decrease the vascular resistance and increase the blood circulation. Clinically, they are used not only as hypotensive drugs but also as cerebral vasodilators.
In addition, in the ophthalmic field, the calcium antagonists have been attempted to use for treatment of low-tension glaucoma and it was reported that improvement of the visual field was observed in some cases. It has also been reported that the calcium antagonists increase the blood circulation in choroid, retina and optic disc (See WO97/40834, the disclosures of which are herein incorporated by reference). Based on the above actions, some calcium antagonists, for example dihydropyridine calcium antagonists such as nicardipine and pranidipine, have been concluded to be effective for treatment of ischemia-reperfusion disorder of retina (see Yasuo Hosobe, J Jpn Ophthalmol Soc 100: 665-671 (1996), and Japanese Patent Laid Open No. 10/72347, the disclosures of each of which are herein incorporated by reference).
Any efficacy of the calcium antagonists on the light-injured retinal degeneration disease, however, can not be expected from these publications. Increase in blood flow in ocular tissues such as choroid results in increase in oxygen feed to the neuroepithelial layer. It has been known, however, that light-induced retinal disorder is promoted under such condition (Jaffe, G. J. et al; Ophthalmology, 95: 1130-1141; 1988, the disclosures of which are herein incorporated by reference). It has also been described that Nimodipine, one of the dihydropyridine calcium antagonists, was not effective to light-induced retinal disorder (Li, J. et al; Research Communication in Chemical Pathology and Pharmacology, 72: 347-352; 1991, the disclosures of which are herein incorporated by reference).
SUMMARY OF THE INVENTION
After conducting extensive studies, the present inventor has surprisingly found the fact that the dihydropyridine calcium antagonists other than nimodipine have an excellent improving action on the light-induced retinal disorder and have an excellent therapeutic effect on the light-injured retinal degeneration disease. The present invention has been completed based upon such findings.
Accordingly, the present invention provides a method for treatment of light-injured retinal degeneration disease comprising administering an effective amount of a dihydropyridine calcium antagonist other than nimodipine to a subject in need of such treatment. Preferably, the dihydropyridine calcium antagonist may be a compound of the formula (I): wherein, R
1
is a halogen atom or a nitro group;
m is a number of 1 or 2;
R
2
is a lower alkyl group;
R
3
is a lower alkyl group or a group represented as —A—X
wherein
A is a saturated or unsaturated hydrocarbon residue having 2-6 carbon atoms;
X is
R
4
is a lower alkyl group; and
R
5
is a lower alkyl, cyano or amino lower alkoxy lower alkyl group or a pharmaceutically acceptable salt thereof.
More preferably, the compound of the formula (I) may be of the formula (II):
wherein each of R
2
′, R
3
′ and R
4
′ represents lower alkyl group respectively or a pharmaceutically acceptable salt thereof, and most preferably, the compound is nilvadipine.
According to the present invention, the method is useful for treatment of retinal degeneration, especially degeneration in macula lutea including age-related macular degeneration.
DETAILED DESCRIPTION OF THE INVENTION
The calcium antagonist used in the present invention is not particularly limited insofar as it belongs to dihydropyridine calcium antagonists other than nimodipine. Specific examples include, without limitation, nilvadipine, nicardipine, nitrendipine, nifedipine, felodipine, nisoldipine, iganidipine, amlodipine, pranidipine and pharmacologically acceptable salts thereof
Examples of preferred dihydropyridine calcium antagonists include compound of the following formula (I):
wherein
R
1
is a halogen atom or a nitro group;
m is a number of 1 or 2;
R
2
is a lower alkyl group;
R
3
is a lower alkyl group or a group represented by —A—X
wherein
A is a saturated or unsaturated hydrocarbon residue having 2-6 carbon atoms;
X is
R
4
is a lower alkyl group,
R
5
is a lower alkyl, cyano, or amino lower alkoxy lower alkyl group, or a pharmaceutically acceptable salt thereof.
The definitions of the terms used in the present invention are as follows:
The term “halogen” includes fluorine, chlorine, bromine, and iodine.
The term “lower alkyl” means a straight or branched-chain of saturated hydrocarbon group having 1 to 6 carbon atoms which include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and hexyl.
The term “saturated or unsaturated hydrocarbon residue having 2-6 carbon atoms” means a straight or branched-chain of C2-C6 hydrocarbon residue which is saturated or has at least one double and/or triple bonds, for example, ethylene, propylene, butylene, 2-methyl-propylene, 2-methyl-butylene, 2,2-dimethyl-propylene, vinylene, 1-propenylene, 2-methyl-1-propenylene, 1-butenylene, 1,3-pentadienylene.
The term “lower alkoxy” means a lower alkyl-O— wherein the lower alkyl is as described above.
The term “amino lower alkoxy lower alkyl group” means a lower alkyl group having an alkoxy group which comprises at least one amino group, for example, aminom
Cook Rebecca
R-Tech Ueno Ltd.
Sughrue Mion Zinn Macpeak & Seas, PLLC
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