Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1994-03-10
2001-08-28
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S913000
Reexamination Certificate
active
06281208
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a therapeutic agent for glaucoma which comprises administering 2-phenyl-3-oxo-2H-1,4-benzothiazine derivative by systemic and/or topical route.
Glaucoma is an intractable eye disease caused by an elevation of intraocular pressure with various factors and a patient of glaucoma has a risk of losing his eyesight, and various medical treatments have been proposed. U.S. Pat. No. 4,786,635 discloses the use of 2-phenyl-3-oxo-2H-1,4-benzothiazine derivatives. It is described therein that these compounds have a unique structure and are useful as a therapeutic agent for circulatory diseases, since they have a calcium antagonistic effect and a blood platelet coagulation-inhibiting effect. However, any effect of these compounds on eyes has not been known.
The present inventors decided to make investigations on other effects of these compounds particularly in the ophthalmologic field.
SUMMARY OF THE INVENTION
A primary object of the present invention is to utilize the compounds in the ophthalmologic field.
Another object of the present invention is to provide a therapeutic agent for glaucoma.
Another object of the present invention is to provide a method for treating glaucoma.
These and other objects of the present invention will be apparent from the following description and Examples.
After investigations on the effects of these compounds on eyes, the inventors have found that they have an excellent effect of lowering the intraocular pressure and are useful as a therapeutic agent for glaucoma.
The present invention relates to a therapeutic agent for glaucoma which comprises, as active ingredient, a compound of the following formula (I) or its salt (hereinafter referred to as the compound of the present invention):
wherein R
1
represents one or more groups selected from the group consisting of a hydrogen atom, lower alkyl groups, halogen atoms, a nitro group, a hydroxyl group, lower alkoxy groups, lower alkanoyloxy groups, an amino group, lower alkylamino groups and lower alkoxycarbonyl groups, R
2
represents a hydrogen atom, a lower alkyl group or a cycloalkyl group having 3 to 6 carbon atoms, R
3
represents one or more groups selected from the group consisting of a hydrogen-atom, lower alkyl groups, a hydroxyl group, lower alkoxy groups, halogen atoms, a nitro group, lower alkylenedioxy groups, lower alkanoyl groups, lower alkanoyloxy groups, an amino group, lower alkylamino groups, lower alkanoylamino groups and lower alkoxycarbonyloxy groups, or a group of —(CH
2
)
b
—, R
4
represents a hydrogen atom or a lower alkyl group, A and B may be the same or different from each other and each represents a lower alkylene group having 1 to 6 carbon atoms, and n represents 3 or 4, and pharmaceutically acceptable excipients.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the above general formula (I), the lower alkyl groups include those having 1 to 6 carbon atoms such as methyl, ethyl, propyl and hexyl groups; the halogen atoms include fluorine, chlorine, bromine, etc.; the lower alkoxy groups include those having 1to 6 carbon atoms such as methoxy, ethoxy, propoxy and hexyloxy groups; the lower alkanoyloxy groups are those having 2 to 6 carbon atoms such as acetyloxy, propionyloxy and hexanoyloxy groups; the cycloalkyl groups having 3 to 6 carbon atoms include cyclopropyl and cyclohexyl groups, etc.; the lower alkylenedioxy groups include those having an alkylene group having 1 to 6 carbon atoms between two oxygen atoms such as methylenedioxy and ethylenedioxy groups; and the lower alkanoyl groups include those having 2 to 6 carbon atoms such as acetyl, propionyl and hexanoyl groups.
In this connection, it is preferable that R
1
represents a hydrogen atom or one lower alkoxy group, more preferably one lower alkoxy group, R
2
represents a lower alkyl group, R
3
represents one lower alkylenedioxy group and R
4
represents a lower alkyl group. Specifically, the compound represented by the following formula (II) and its salt is the most preferred:
wherein R
11
represents a lower alkoxy group, R
12
represents a lower alkyl group, R
14
represents a lower alkyl group, A
1
and B
1
may be the same or different from each other and each represents a lower alkylene group having 1 to 6 carbon atoms, and m represents 1 to 6.
The salts of these compounds are not particularly limited as long as they are suitable as pharmaceuticals such as hydrochloride, sulfate, phosphate, lactate, maleate, fumarate, oxalate, methanesulfonate and p-toluenesulfonate. These compounds have stereoisomers, which are also included in the present invention.
Examples of the compounds represented by the formula [I] include, 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1, 4-benzothiazine fumarate, 3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate, 3,4-dihydro-2-[2-[4-[N-[2-(4-methoxyphenoxy)ethyl]-N-methylamino]butoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate, 3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4,5-trimethoxy)phenoxy]ethyl]lamino]propoxy]phenyl]-4-methyl-3-oxo-2H,-1,4-benzothiazine oxalate, 3,4-dihydro-2-[4-[3-N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate, 3,4-dihydro-2-[5-methoxy-2-[2-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]ethoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazineoxolate, 3,4-dihydro-2-[5-chloro-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxyl]-phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate, 3,4-dihydro-2-[2-[4-[N-[2-[(5-indanyloxy)ethyl]-N-methylamino]butoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate, 3,4-dihydro-2-[5-methyl-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]-phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate, 3,4-dihydro-2-[[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]-5-nitrophenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate, their stereoisomers and optical isomers.
Although the compounds of the present invention are useful as an effective therapeutic agent for circulatory diseases, the effect of them on eyes has never been known.
After investigations made for the purpose of using these compounds in the field of ophthalmology, the inventors have found that they have an excellent effect of lowering the intraocular pressure and, therefore, they are useful as a therapeutic agent for glaucoma.
To evaluate the utility of the compounds of the present invention for the treatment of glaucoma, the effect of them on rabbits having a high intraocular pressure provoked by chymotrypsin was examined.
The detailed data will be described below with reference to the physiological tests. When the compound of the present invention was given by instillation or oral administration, the intraocular pressure was reduced to indicate that this compound is useful as a therapeutic agent for glaucoma.
The therapeutic agent for glaucoma of the present invention can be used as either an agent for topical application such as eye drops or eye ointment or a systemic one such as tablets, capsules, granules and powders. Further they can be used in combination.
The dose of the compound of the present invention can be suitably determined depending on the symptoms, age, dosage form, etc. In the topical application, a solution or an ointment having a concentration of 0.1 to 5%, more preferably 0.1 to 2%, is applied once
Mita Shiro
Shirasawa Eiichi
Burns Doane , Swecker, Mathis LLP
Fay Zohreh
Santen Pharmaceutical Co. Ltd.
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