A novel thiazolidine derivative having the following general formula ##STR1## wherein R.sup.1 and R.sup.2 are each lower alkyl having 1 to 3 carbon atoms, or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of morpholino, piperazino, piperidino and pyrrolidino, or said heterocyclic ring substituted with 1 or 2 methyl groups, and the pharmaceutically acceptable salts thereof are useful immunomodulators.

An immunomodulator is a compound which regulates the immune response. 
Accordingly, it covers both immunostimulation and immunoinhibition. 
Certain immunomodulators are known, however, there is not known carboxy 
thiazolidine derivative having immunomodulatory action. 
This invention relates to novel thiazolidine derivatives which are useful 
immunomodulators, more especially to a thiazolidine derivative of the 
formula 
##STR2## 
wherein R.sup.1 and R.sup.2 are each lower alkyl having 1 to 3 carbon 
atoms, or R.sup.1 and R.sup.2 together with the nitrogen atom to which 
they are attached form a heterocyclic ring selected from the group 
consisting of morpholino, piperazino, piperidino and pyrrolidino, or said 
heterocyclic ring substituted with 1 or 2 methyl groups, and the 
pharmaceutically acceptable salts thereof. 
Preferred compounds of the present invention are the compounds of formula I 
wherein R.sup.1 and R.sup.2 are each alkyl having 1 or 2 carbon atoms, and 
R.sup.1 and R.sup.2 together with the nitrogen atom to which they are 
attached form pyrrolidino, morpholino, piperidino, 3,5-dimethylpiperidino 
and 4-methylpiperazino. 
The most preferred compounds of the present invention are the compounds of 
formula I wherein R.sup.1 and R.sup.2 are each methyl, and R.sup.1 and 
R.sup.2 together with the nitrogen atom to which they are attached form 
4-methylpiperazino. 
The compound of formula I may be, for example, prepared by condensing 
penicillamine with an acetylacetamide of the formula 
##STR3## 
wherein R.sup.1 and R.sup.2 are as defined above. 
This condensation may be carried out with or without a condensing agent in 
the presence or absence of a solvent, at room temperature to a refluxed 
temperature of the solvent used. 
The period of reaction time may be widely varied from tens of minutes to 
tens of hours depending upon a reaction condition such as variety and 
amount of the solvent and the condensing agent, and reaction temperature 
employed. However, the reaction is completed within several hours in many 
cases. 
Examples of the solvent are organic solvents, for example, a protic solvent 
(e.g., methyl alcohol, ethyl alcohol, or isopropyl alcohol), an aprotic 
solvent (e.g., benzene, chloroform, isopropyl ether, tetrahydrofuran, 
ethyl acetate, or dimethylformamide), or a mixture of these solvents with 
one another. 
Examples of the condensing agent are neutral capturing substances of water 
formed by condensation (e.g., magnesium sulfate or molecular sieve). 
Alternatively, the water formed by the condensation can be removed 
azeotropically without any condensing agent. 
The compounds of formula I may be converted in a conventional manner to the 
pharmaceutically acceptable salts thereof such as an alkali metal (e.g., 
sodium) salt, an alkali earth metal (e.g., calcium) salt and the like. 
The compound of formula II may be prepared, for example, by the reaction of 
diketene with a secondary amino or the formula 
##STR4## 
wherein R.sup.1 and R.sup.2 are as defined above. The compound of formula 
II prepared by the above reaction may be directly used without isolation 
as materials in the method for preparing the compounds of formula I 
described above. 
The compounds of the present invention are useful immunomodulators in 
mammals for the treatment of autoimmune diseases induced by irregular 
stimulation or inhibition of immunity, e.g., rheumatoid arthritis, 
autoimmune hemolytic anemia, lupoid hepatitis and the like. 
The compounds of the present invention are formulated for use as 
immunomodulators according to pharmaceutical practice in oral dosage forms 
such as tablets, capsules or powders, or in a subcutaneously injectable 
form in a sterile aqueous vehicle prepared in according to conventional 
pharmaceutical practice. 1-3 divided daily doses provided on a basis of 90 
to 1500 mg/70 kg/day are appropriate. 
The 50% lethal dose of each compound of the present invention in male or 
female ddY strain mice is in excess of 10,000 mg/kg of the body weight.