Thiazolidine derivatives

Details Thiazolidine derivatives Thiazolidine derivatives

1993-03-04

1995-01-31

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548146, 548200, 548201, C07D37704, A61K 31425

Patent

active

053859227

DESCRIPTION:

BRIEF SUMMARY
The invention relates to novel thiazolidine derivatives having the formula 1, and their salts, in which formula group of the general formula 2, 1-6C-alkyl, 1-6C-alkoxy, 4-8C-cycloalkyl, 4-8C-cycloalkoxy, F, Cl, Br, NO.sub.2, nitroxy-2-6C-alkoxy, nitroxy-4-8C-cycloalkoxy, nitroxy-1-2C-alkyl-4-8C-cycloalkyl-1-2C-alkoxy or a group ##STR1## wherein W represents a bond or a group --OCH.sub.2 --, nitroxy-4-8C-cycloalkyl, ##STR2## wherein Z represents an oxygen atom or an imino group and nitroxy-4-8C-cycloalkyl, nitroxy-1-2C-alkyl-4-8C-cycloalkyl-1-2C-alkyl or 4-nitroxy-2,6-dioxabicyclo[3.3.0]oct-8-yl, and nitroxy-4-8C-cycloalkyl, phenyl or 1-4C-alkylphenyl.
It has been found that these novel thiazolidine derivatives have outstanding properties as medicaments. The novel thiazolidine derivatives may be used, optionally symptomatically, in the treatment of pathological processes in mammals, especially man, where it is necessary, for example. or
By virtue of their pharmacological characteristics, the novel thiazolidine derivatives can be used in the case of (especially portal hypertension), bowel syndrome, or
The invention thus also relates to a medicament for the treatment of the above-mentioned disorders which contains, as active substance, a thiazolidine derivative having the formula 1 described above, or a salt thereof. The novel thiazolidine derivatives all contain one or more organic nitrate ester groups. Organic nitrate esters, such as glyceryl trinitrate and isosorbide dinitrate, have already been used medicinally for more than 100 years, and 50 years respectively, as vasodilators in, inter alia, angina pectoris. With regard to the manner in which vasodilation is effected by nitrate esters, it is postulated, inter alia, that this is caused, inter alia, by nitric oxide NO. It is known that endogenous NO can be liberated from endothelium cells on an intact vessel wall by specific mediators such as acetylcholine, bradykinin, serotonin, histamine and the like. This endogenous NO, which is also termed endothelium derived relaxing factor (EDRF), is alleged, in turn, to stimulate the enzyme guanylate cyclase in the adjacent smooth muscle cells. As a result, inter alia, of the increased concentrations of cyclic GMP, the existing balance in the vessel wall tension is disturbed, which, via a cascade of reactions, ultimately leads to relaxation of the smooth muscle cells in the vessel wall.
Organic nitrate esters are able to give rise to vasodilation even if the endothelial cell layer has been damaged or removed, which effect could be explained by direct formation of NO from these nitrate esters. It is alleged that sulphhydryl-containing endogenous compounds such as the amino acid cysteine play a role in this process, which presumably proceeds enzymatically. It is postulated that the pharmacodynamic effects of nitrate esters decrease in the course of time as a result of depletion of the said sulphhydryl compounds if treatment with nitrate esters is continued without a break. This phenomenon, which incidentally is reversible by temporarily stopping therapy, is termed nitrate tolerance.
Moreover, in the literature reference is made to the possibility that --SNO compounds instead of NO lead to relaxation. NO is then converted to RSNO by means of endogenous sulphhydryl compounds RSH. In this case also it is alleged that depletion or RSH can lead to nitrate tolerance.
Various approaches are described in the literature in order to prevent nitrate tolerance. Thus, it is alleged that the addition of high dosage (1-3 grams) of N-acetylcysteine to a glyceryl trinitrate therapy does not lead to tolerance but scientific opinions are divided in this regard. Moreover, in a U.S. patent application Ser. No. 89/02611 (WO 89/12627), hybrid compounds of angiotensin converting enzyme (ACE) inhibitors (agents which lower the blood pressure, such as captopril, which contains a --SH group) and NO are described. The S-ni-trosocaptopril described in this literature reference does indeed have an ACE-inhibiting effect comparable to that of capto

REFERENCES:
Fernandez, J. Med. Chem. 26 1317(1983).
Chemical Abstracts, vol. 107, No. 19, pp. 725, Abstract 176023b, Nov. 9, 1987.

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