Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-23
2001-10-30
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S503000
Reexamination Certificate
active
06310086
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel indole derivatives and pharmaceutically acceptable salts thereof which are useful as medicaments.
BACKGROUND ART
Up to this time, Timolol maleate and Isopropyl unoprostone are known as example of compounds that have been used as agents for lowering intraocular pressure.
Recently, Bunazosin hydrochloride, which has &agr;
1
-adrenoceptor blocking effect a mechanism (hereinafter referred to as &agr;
1
-blocking effect) quite different from the actions of Timolol maleate and Isopropyl Unoprostone, has been developed as an agent for the treatment of glaucoma and is attracting public attention. However, Bunazosin hydrochloride was primarily developed as an agent for the treatment of hypertension. Therefore, Bunazosin hydrochloride has potent action on the blood pressure and it is wondered that it might induce side effects such as hypotension and orthostatic hypotension.
Generally, most agents for lowering intraocular pressure are topically applied as eyedrops. Even in this case an active component distributes to all over the body via the blood flow and it is expected that it shows systemic action. Therefore, it is desired that expected systemic side effects are minimized even in topical administration.
Compounds which are absorbed into eyes immediately after the application and act for a long period are most preferable so as to act topically as much as possible.
Consequently, compounds which have potent reducing effect on intraocular pressure with less incidence of side effects such as hypotension and orthostatic hypotension, are rapidly absorbed into eyes after the installation and act for a long period are mostly recommended as agents for lowering intraocular pressure.
DISCLOSURE OF THE INVENTION
The present invention relates to an indole derivative represented by the general formula:
(wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group; Y represents a hydroxy group or a pivaloyloxy group with the proviso that Y represents a pivaloyloxy group when R represents a 2,2,2-trifluoroethyl group; and the carbon atom marked with (R) represents a carbon atom in (R) configuration) or a pharmaceutically acceptable salts thereof.
The present invention relates to a pharmaceutical composition comprising an indole derivative represented by the general formula:
(wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group; Y represents a hydroxy group or a pivaloyloxy group with the proviso that Y represents a pivaloyloxy group when R represents a 2,2,2-trifluoroethyl group; and the carbon atom marked with (R) represents a carbon atom in (R) configuration) or a pharmaceutically acceptable salt thereof.
The present invention relates to an agent for lowering intraocular pressure which comprises as the active ingredient an indole derivative represented by the general formula:
(wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group; Y represents a hydroxy group or a pivaloyloxy group; and the carbon atom marked with (R) represents a carbon atom in (R) configuration) or a pharmaceutically acceptable salt thereof.
The present invention relates to an agent for the prevention or treatment of glaucoma or ocular hypertension which comprises as the active ingredient an indole derivative represented by the general formula:
(wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group; Y represents a hydroxy group or a pivaloyloxy group; and the carbon atom marked with (R) represents a carbon atom in (R) configuration) or a pharmaceutically acceptable salt thereof.
The present invention relates to a method for the prevention or treatment of glaucoma or ocular hypertension which comprises administrating a therapeutically effective amount of an indole derivative represented by the general formula:
(wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group; Y represents a hydroxy group or a pivaloyloxy group; and the carbon atom marked with (R) represents a carbon atom in (R) configuration) or a pharmaceutically acceptable salt thereof.
The present invention relates to a use of an indole derivative represented by the general formula:
(wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group; Y represents a hydroxy group or a pivaloyloxy group; and the carbon atom marked with (R) represents a carbon atom in (R) configuration) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of glaucoma or ocular hypertension.
The present invention relates to a use of an indole derivative represented by the general formula:
(wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group; Y represents a hydroxy group or a pivaloyloxy group; and the carbon atom marked with (R) represents a carbon atom in (R) configuration) or a pharmaceutically acceptable salt thereof as an agent for the prevention or treatment of glaucoma or ocular hypertension.
Furthermore, the present invention relates a process for the manufacture of a pharmaceutical composition for the prevention or treatment of glaucoma or ocular hypertension, characterized in the use, as an essential constituent of said pharmaceutical composition, of an indole derivative represented by the general formula:
(wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group; Y represents a hydroxy group or a pivaloyloxy group; and the carbon atom marked with (R) represents a carbon atom in (R) configuration) or a pharmaceutically acceptable salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
The present inventors have studied in order to find drugs which have potent and prolonged &agr;
1
-blocking effect with less side effects such as hypotension and orthostatic hypotension and with high permeability into eyes. As a result, it has been found that (R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carboxamide (hereinafter referred to as Compound A), one of indole derivatives which were previously developed as agents for the treatment of dysuria having selective suppressive effect on urethral contractions with less affecting the blood pressure (published Japanese patent application (Kokai) No. Hei 7-330726), and (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]-amino]propyl]-1-(3-hydroxypropyl)-1H-indole-7-carboxamide (hereinafter referred to as Compound B) hydrochloride have extremely potent &agr;
1
-blocking effect, more than 70-fold stronger than Bunazosin hydrochloride, with less incidence of side effects such as hypotension and orthostatic hypotension and that these compounds are expected to act for a long period because of low excretion rate after the permeation into eyes and are useful as preferred agents for lowering intraocular pressure.
Furthermore, because Compounds A and B have poor permeability of membranes such as cornea, the present inventors have studied in order to find derivatives which have high membrane permeability and rapidly convert into the poorly membrane permeable Compound A or B after the permeation. As a result, it has been found surprisingly that pivalic acid ester derivatives represented by the general formula:
(wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group; and the carbon atom marked with (R) represents a carbon atom in (R) configuration) have extremely high membrane permeability, are rapidly converted into Compound A or B having poor membrane permeability by hydrolase after the permeation and are extremely stable in aqueous solution which is normal form of eyedrops, thereby forming the basis of the present invention.
Namely, the present inventors have found that Compounds A and B have potent &agr;
1
-blocking effect and are preferred compounds as agents for lowering intraocular pressure. However, these compounds have poor corneal permeability and their concentration in aqueous humor is fairly low when these compounds are topically applied as eyedrops. Therefore, the present inventors have extensively studied
Ajisawa Yukiyoshi
Kitazawa Makio
Miyata Hiroshi
Yamaguchi Toshiaki
Frenkel Stuart D.
Kissei Pharmaceutical Co. Ltd.
Liniak Berenato Longacre & White
Powers Fiona T.
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