Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-29
2002-06-25
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S397000, C514S326000, C514S254040, C514S386000, C548S200000, C548S311100, C546S209000, C544S367000
Reexamination Certificate
active
06410576
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATION
This application is the United States National Phase Application under 35 USC 371 of International Application PCT/JP99/04017 (not published in English) filed Jul. 27, 1999.
TECHNICAL FIELD
The present invention relates to novel thiazolidine derivatives which are useful as drugs such as chymase inhibitors.
BACKGROUND ART
Compounds having a thiazolidine ring as a main skeleton is known to be useful for various drugs, and many derivatives thereof have also been synthesized. Main synthesis studies are as follows; a study of converting 4-thiazolidinecarboxylic acid, which can be synthesized easily, into amide compounds; and a study of introducing various substituents into the nitrogen atom at the 3rd-position through a carbonyl linkage. For example, it was reported that carboxylic acid derivatives were further introduced into the amide linkage at the 4th-position through an alkylene chain (see Japanese Laid-open Patent Publication No. 49373/1981 and Japanese Laid-open Patent Publication No. 139455/1981). Many studies were also reported wherein the various substituents are introduced into the nitrogen at the 3rd-position through the carbonyl linkage. However, compounds wherein the nitrogen atom joins with the carbonyl through an alkylene chain have scarcely been studied.
There are still many unknown compounds in the compounds having a thiazolidine ring as the main skeleton, and preparation of novel compounds and a study of their pharmacological actions are very interesting subjects.
DISCLOSURE OF THE INVENTION
The present inventors studied preparation of various novel compounds derived from 4-thiazolidinecarboxylic acid. They focused attention on synthesis of novel compounds wherein 1) the carboxyl group at the 4th-position is amidated and the resulting amide moiety is substituted by substituents having a carbonyl group through an alkylene chain, and further 2) various substituents are introduced into the nitrogen atom at the 3rd-position through a carbonyl group. In particular, their efforts were focused on selection of substituents joining with the carbonyl group through an alkylene chain as the substituents introduced into the nitrogen atom at the 3rd-position through the carbonyl group. As a result, the present inventors succeeded in preparing many novel compounds as mentioned later. Studying their pharmacological actions, these novel compounds were found to have chymase inhibitory actions and to be useful as drugs. In a process of the synthesis of the above-mentioned novel thiazolidine derivatives, the present inventors succeeded also in preparing novel compounds which are useful as synthetic intermediates of the derivatives.
The present invention relates to compounds represented by the following general formula [I] and salts thereof (hereinafter referred to as “the present compounds” as far as there is no proviso), pharmaceutical compositions containing the present compound or the salt thereof as an active ingredient, and compounds which are represented by the following general formula [II] and are useful as synthetic intermediates of the present compounds and salts thereof (hereinafter referred to as “the present synthetic intermediates” as far as there is no proviso).
wherein R
1
is lower alkyl, hydroxy, lower alkoxy, lower alkoxy-lower alkyl, phenyl, phenyl-lower alkyl, phenyl-lower alkoxy, phenoxy, phenoxy-lower alkyl, amino, lower alkylamino or a nonaromatic heterocycle.
R
2
is hydrogen or lower alkyl, and R
2
can join with A
1
through carbon or sulfur to form a nonaromatic heterocycle.
R
3
is hydrogen, lower alkyl or phenyl, and R
3
can join with A
1
through carbon to form a nonaromatic heterocycle.
R
4
is hydrogen or lower alkyl.
R
5
is lower alkyl, halogeno-lower alkyl, hydroxy, lower alkoxy, phenyl, phenyl-lower alkoxy, phenoxy, carboxyl, lower alkoxy-carbonyl, phenyl-lower alkoxycarbonyl or an aromatic heterocycle.
A
1
is lower alkylene, wherein the lower alkylene can be substituted by hydroxy, lower alkoxy, phenyl, phenoxy, carboxyl, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl or an aromatic heterocycle.
A
2
is lower alkylene, wherein the lower alkylene can be substituted by phenyl.
Each nonaromatic heterocycle defined above can be substituted by lower alkyl, phenyl, phenyl-lower alkyl, amino, lower alkylamino or phenyl-lower alkylamino.
Each phenyl ring of phenyl, phenyl-lower alkyl, phenyl-lower alkoxy, phenoxy, phenoxy-lower alkyl and phenyl-lower alkoxycarbonyl defined above can be substituted by halogen, lower alkyl, hydroxy, lower alkoxy, phenyl, phenoxy, carboxyl, lower alkoxycarbonyl, amino, lower alkylamino, nitro or cyano.
Each lower alkyl moiety of lower alkylamino defined above can be substituted by phenyl, amino or lower alkylamino. The same definitions are applied hereinafter.
The groups defined above are hereinafter described in detail.
The halogen is fluorine, chlorine, bromine or iodine.
The lower alkyl is straight-chain or branched alkyl having one to six carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl or tert-butyl.
The lower alkoxy is straight-chain or branched alkoxy having one to six carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy or tert-butoxy.
The lower alkylene is straight-chain or branched alkylene having one to six carbon atoms such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, dimethylmethylene, ethylmethylene, propylmethylene, isopropylmethylene, butylmethylene, isobutylmethylene, sec-butylmethylene, tert-butylmethylene, dimethylethylene, ethylethylene, propylethylene, isopropylethylene, methyltrimethylene or propylene.
The nonaromatic heterocycle is a nonaromatic heterocycle selected from pyrrolidine, piperidine, homopiperidine, octahydroazocine, pyrroline, piperazine, imidazolidine, imidazoline, pyrazolidine, pyrazoline, oxazolidine, thiazolidine and the like.
The aromatic heterocycle is an aromatic heterocycle selected from pyrrole, indole, isoindole, imidazole, pyrazole, oxazole, isoxazole, benzoxazole, thiazole, isothiazole, benzothiazole, pyridine, quinoline, pyrazine and the like.
The lower alkylamino is mono- or di-lower alkylamino.
Nitrogen atom of the above-mentioned amino, lower alkylamino, nonaromatic heterocycle or aromatic heterocycle can be protected with a protecting group. This protecting group can be a general protecting group of nitrogen atom of amino, lower alkylamino, a nonaromatic heterocycle or an aromatic heterocycle, such as acyl, substituted lower alkyl or substituted sulfonyl.
In detail, examples of the protecting group are acyl such as formyl, lower alkanoyl, halogeno-lower alkanoyl, lower alkoxycarbonyl, halogeno-lower alkoxycarbonyl, phenylcarbonyl, phenyl-lower alkoxycarbonyl or phenoxycarbonyl, substituted alkyl such as phenyl-lower alkyl, phenyl-lower alkoxy-lower alkyl or trityl, and substituted sulfonyl such as lower alkylsulfonyl or phenylsulfonyl. Each phenyl ring of the phenylcarbonyl, the phenyl-lower alkoxycarbonyl, the phenoxycarbonyl, the phenyl-lower alkyl, the phenyl-lower alkoxy-lower alkyl, the trityl and the phenylsulfonyl can be substituted by halogen, lower alkyl, lower alkoxy or nitro.
Specific examples of the protecting group are acyl such as formyl, acetyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzoyl, benzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 2,4,6-trimethylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or phenoxycarbonyl, substituted alkyl such as benzyl, 2-nitrobenzyl, benzyloxymethyl or trityl, and substituted sulfonyl such as methanesulfonyl, benzenesulfonyl or toluenesulfonyl.
Salts in the present invention refer to any pharmaceutically acceptable salts. Examples thereof are salts with an inorganic acid such as hydrochloric acid, nitric acid or sulfuric acid, salts with an organic acid such as acetic acid, fumaric acid, maleic acid or tartaric acid, salts with
Fujimura Ken-ichi
Kobayashi Tadayuki
Matsumoto Junzo
Nishimura Kazuo
Frishauf Holtz Goodman & Chick P.C.
Patel Sudhaker B.
Santen Pharmaceutical Co. Ltd.
Shah Mukund J.
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