Glutathione-S-lower fatty acid derivative

Details Glutathione-S-lower fatty acid derivative Glutathione-S-lower fatty acid derivative

1991-12-13

1993-12-28

Dees, Jose G.

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

530331, 562556, 562557, C07C32325

Patent

active

052741770

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a novel and useful glutathione-S-lower fatty acid derivative and a method for production thereof.


BACKGROUND ART

There are known several glutathione-S-lower fatty acid derivatives. Among them, S-(2-carboxypropyl)glutathione has been isolated from onion and garlic (Virtanen and Matikkala, 1960; Suzuki et al, 1961) but there is little information on its pharmacologic activity.
The inventors of the present invention previously found that glutathione-S-succinic acid derivatives have platelet aggregation-inhibitory, antiinflammatory, antiallergic, antitumoral and hepatic impairment-protective activities (Japanese Kokai Patent Application No. 63-8337 and Japanese Patent Application No. 1-79956No. 1-183484, No. 1-251534, No. 1-256370 and No. 2-36745).
In search of still more pharmacologically active compounds, the inventors of the present invention synthesized a variety of novel glutathione derivatives and screened them, as well as said S-(2-carboxypropyl)glutathione, for their pharmacologic activities. As a consequence, they found that S-(2-carboxypropyl)glutathione and a series of compounds which can be synthesized by reacting glutathione or an ester thereof with an .alpha., .beta.-unsaturated fatty acid, such as acrylic acid, methacrylic acid, crotonic acid, cinnamic acid, etc., or an .alpha. (or .beta.)-halogenated organic monocarboxylic acid, such as monochloroacetic acid, or an ester or amide thereof have excellent antihepatopathic efficacy. The present invention has been attained based on this finding.


DISCLOSURE OF THE INVENTION

The present invention relates to
1) a compound of the formula ##STR2## [wherein R.sub.1 is a lower alkyl group which may be substituted; R.sub.2 is a hydrogen atom; R.sub.3 is a hydrogen atom or a lower alkyl group which may be substituted; R.sub.4 is a hydroxyl group or a lower alkoxy group which may be substituted; n means 1] or a salt thereof; and,
2) a method for production thereof.
As the lower alkyl of R.sub.1, and where R.sub.3 in the above formula [I] means a lower alkyl group, such alkyl group preferably has 1 to 10 carbon atoms. This alkyl group may be straight-chain, branched or cyclic or contain a cyclic moiety. Thus, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl and benzyl may be mentioned by way of example.
Referring, further, to the above formula, where n is equal to 1 and R.sub.2 is a hydrogen atom.
Further in the formula, when R.sub.4 is a lower alkoxy group, the lower alkoxy group includes, among others, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, tert-pentyloxy, neopentyloxy, 2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy and so on. The lower alkoxy group may have a hydroxyl group or a cyclic group such as phenyl.
The above compound can occur as the free acid or as a pharmaceutically acceptable salt thereof, for instance an alkali metal salt thereof, e.g. the sodium salt, potassium salt, etc., or an alkaline earth metal salt, e.g. the calcium salt, magnesium salt and so on. Regarding the salt, any or all of the carboxyl functions available in the compound may have been converted to such salt or salts. Any of these salts can be used advantageously in the manufacture of the antihepatopathic composition of the present invention.
The compound of the present invention can be chemically synthesized as follows. The present compound is obtainable by reacting glutathione or an ester thereof with an organic monocarboxylic acid represented by the formula or an ester thereof: represented by the formula ##STR3## (wherein R.sub.3 is a hydrogen atom or a lower alkyl group which may be substituted with a group which does not react with SH group) or the formula ##STR4## (wherein X is a halogen atom and R.sub.3 is the same as previously defined)] and if necessary further esterifying the resulting compound. As the compounds represented by formula [II] are exemplified .alpha., .beta.-uns

REFERENCES:
Anal. Biochem., vol. 183, No. 1, Deterding et al, pp. 94-107, (1989).
Br. J. Ind. Med., vol. 32, No. 1, Edwards, pp. 31-38, (1975).
Biochem. J., vol. 125, No. 1, Speir et al., pp. 267-273, (1971).
Chemical Abstracts, vol. 56, No. 1, Entry No. 716f, Jan. 8, 1962.

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