Five-membered heterocyclic compounds

Details Five-membered heterocyclic compounds Five-membered heterocyclic compounds

1982-07-27

1984-08-07

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Bacterium or component thereof or substance produced by said...

424270, 544235, 548200, 548201, C07D27730, C07D41712, A61K 31425, A61K 3150

Patent

active

044643713

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to compounds of the general formula [I], ##STR6## wherein R.sup.1 is hydrogen, hydroxy, lower alkyl or lower alkoxy; ##STR7## R.sup.2 is hydrogen, benzoyl or ##STR8## R.sup.3 is hydroxy, lower alkoxy, --NHOH or ##STR9## R.sup.4 is R.sup.5 is hydrogen or halogen; ##STR10## when R.sup.3 is hydroxy or lower alkoxy, R.sup.2 is and salts thereof, said lower alkyl and lower alkoxy groups contain 1 to 6 carbon atoms.
The same shall be applied hereinafter.


BACKGROUND OF THE TECHNICAL FIELD

Thiazolidine derivatives having mercapto group are useful compounds as antihypertensive agents. It is known that particularly the compound of the formula [II], which is the basic structure of the compounds of this invention, shows an excellent antihypertensive effect (Japanese patent application No. 49657/1978). ##STR11##


DESCRIPTION OF THE INVENTION

This invention relates to novel thiazolidine derivatives.
We found that the prolongation of the activity and stability of the compound were accomplished by conversion of mercapto group and/or carboxy group of the compound of the formual [II], which shows an antihypertensive effect, into suitable derivatives shown in this invention.
Substituents of the compound [I] of this invention are as follows. Lower alkyl is alkyl group having 1 to 6 carbon atoms, for example methyl, ethyl, hexyl or isobutyl, lower alkoxy is alkoxy group having 1 to 6 carbon atoms, for example methoxy, ethoxy, t-butoxy or hexyloxy, and halogen is fluorine, chlorine or bromine.
The compounds [I] of this invention are synthesized by the following procedures.
The compound of the formula [V] is obtained by condensation of the compound of the formula [III] with the compound of the formula [IV] by the known method such as Shotten-Baumann method, mixed anhydride method, etc. ##STR12## wherein R.sup.8 is hydroxy or lower alkoxy;
The same shall be applied hereinafter.
The compound of the formula [VII] is obtained by condensation of the compound of the formula [V] with the compound of the formula [VI] by the known method such as mixed anhydride method etc. ##STR13## wherein ##STR14## R.sup.10 is hydroxy or
The same shall be applied hereinafter.
The compound of the formula [I] wherein R.sup.2 is hydrogen is obtained by hydrolysis by acid, alkaline, etc.
The compound of the formula [I] prepared by the above methods can form the conventional salts to be generally used as medicine such as sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, ammonium salt, diethylamine salt, triethanolamine salt, etc.
The compound of the formula [I] has two or more asymmetric carbon atoms, so it has the stereoisomers, which are within the limit of this invention.
Pharmacological test, acute toxicity test and examples of formulation are shown as below.


PHARMACOLOGICAL EXPERIMENT

Male spontaneously hypertensive rats (Charles River) weighing 370-430 g (37-43 weeks of age) were used.
The subject compound, suspended in 0.5% tragacanth, was given orally to the animals. Their blood pressure was measured by indirect tail-cuff method using a programmed electrosphygmomanometer.


EXPERIMENTAL RESULTS

The FIG. 1 shows the time course of the hypotensive effect in spontaneously hypertensive rats by oral administration of (2R,4R)--3--[S--4--(dipropylsulfamoyl)benzoyl]--3--mercapto--propionyl]--2 --(2-hydroxyphenyl)--4--thiazolidinecarboxylic acid (Example 1) as a representative of the compounds of this invention and of (2R,4R)--2--(2-hydroxyphenyl)--3--(3--mercaptopropionyl)--4--thiazolidinec arboxylic acid as a control compound.
The abscissa of the figure shows the time after administration and the ordinate shows the blood pressure in mmHg having decreased by the administration. In the figure, line 1 and line 2 represent the hypotensive effect by the compound of this invention at doses of 30 mg/Kg and 10 mg/Kg, respectively, line 3 that by the reference compound at a dose of 30 mg/Kg, and line 4 control (no drugs).
The compound of this invention clearly decreased the blood pressure in s

REFERENCES:
patent: 4386096 (1983-05-01), Iwao

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