Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-05-04
1998-05-05
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548500, A61K 31405, C07D40512, C07D20926
Patent
active
057475210
DESCRIPTION:
BRIEF SUMMARY
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a new N-cinnamoyl-2-methyl-5-methoxy-3-indoleacetic acid ester represented by the following general formula (I) ##STR3## wherein, R is ##STR4##
The N-cinnamoyl-2-methyl-5-methoxy-3-indoleacetic acid represented by the following general formula (II) is generally called cinmetacin and now used as an anti-inflammatory and analgesic agent.
However, the anti-inflammatory and analgesic agents which are affiliated with indoleacetic acid like indomethacin and cinmetacin involve a problem by causing a gastric ulcer and are restricted in their use owing to such an adverse reaction thereof.
Consequently, earnest study is given at a continued pace to reducing gastrointestinal trouble caused by such anti-inflammatory and analgesic agent.
As a result of researches conducted for a long time to solve a problem posed by the indoleacetic acid, the present invention is brought to completion by developing a compound represented by the above general formula (I) which makes little difference from cinmetacin in efficacy and alleviates gastrointestinal trouble substantially.
It is therefore an abject of the present invention to provide a compound represented by the above general formula (I).
Another object of the present invention is to provide a method of manufacturing the compound represented by the above general formula (I).
Still another object of the present invention is to provide a pharmaceutical preparation which contains the compound represented by the above general formula (I) as an effective component.
The invented compound represented by the formula (I) is manufactured by causing N-cinnamoyl-2-methyl-5-methoxy-3-indoleacetic acid or its reactive derivative to react upon a compound represented by the following general formula (III). When represented by a reaction formula, it is as follows ##STR5## wherein, R is ##STR6##
The synthetic reaction formulas of the invented compounds 1, 2, 3 are as follows: ##STR7##
In the above reaction schemes 1-3, reactive derivatives of cinmetacin can be used.
As the reactive derivatives of cinmetacin, an acid salt, an acid anhydride, a mixed acid anhydride, an active ester and an active amide can be taken as examples.
The acid salt includes a usual acid halide like an acid chloride, an acid bromide and an acid iodide.
As the acid anhydride, an anhydride with a lower fatty acid like an acetic anhydride can be taken as an examples.
As the active amide, an amide with hydroxybenzotriazole can be taken as an example.
Regarding a reaction in the present invention, it is desirable to produce it in usual inactive organic solvents with exert no influence thereon, such as a lower ether like dimethyl ether and diethyl ether, a cyclic ether like tetrahydrofuran and dioxane, an aromatic hydrocarbon like benzene, toluene and xylene, a halogenated hydrocarbon like chloroform and methylene chloride.
In the case where reaction is produced with a compound represented by the formula (II), it can be produced in the presence of a usual condensing agent like cyclohexylcarbodiimide.
In the case where reaction is produced with a reactive derivative of a compound represented by the formula (II) like a acid halide thereof, it is desirable to produce it in the presence of a hydroxide of alkali metals or alkaline earth metals, or a inorganic base like a carbonate and a bicarbonate, or aliphatic or aromatic organic amine like trimethyl amine, triethyl amine and pyridine as a acid receptor in order to remove halogenated hydrogen which rises as a by-product.
It is desirable to produce reaction at 10.degree. to 100.degree. C. or preferably at the temperature below the boiling point of a solvent to be used.
After reaction, it is treated by taking advantage of neutralization, extraction, washing, desiccation and concentration which are usually used in synthetic chemistry and, if necessary, purification by chromatography.
The invented compound takes effect to the same extent as the existing cinmetacin, and moreover, it is a compound excellent in great
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Cram & Hammond, "Organic Chemistry", McGraw-Hill Book Co NY., 2nd Edition, pp. 565-567, 1964.
Ghyczy et al, "Injectable pharmaceutical, etc " CA 94: 36367 e (1981).
Khanna, "Oral retard or repeat drug, etc " CA 115:35728p (1991).
Yuan et al, "Pharmacological actions, etc " CA 105:202902t (1986).
Cho Eui Hwan
Chung Sun Gan
Lee Kyou Heung
Park Si Kyung
Morris Patricia L.
Samjin Pharm. Co., Ltd.
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