Heterocyclic-substituted oxoalkanoic acid derivatives

Details Heterocyclic-substituted oxoalkanoic acid derivatives Heterocyclic-substituted oxoalkanoic acid derivatives

1981-08-28

1983-05-31

Bond, Robert T.

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

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

424270, 546112, 546121, 548154, A61K 31425, A61K 31435, C07D47104, C07D51304

Patent

active

043860923

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a novel and therapeutically valuable heterocyclic-substituted oxoalkanoic acid derivative.


DISCLOSURE OF INVENTION

The heterocyclic-substituted acid derivatives of the present invention are represented by the formula: ##STR2## wherein R.sup.1 is hydrogen, lower alkyl, phenyl which may be substituted by at least one substituent selected from halogen, lower alkyl, lower alkoxy, mono- or di-lower alkyl aminosubstituted lower alkoxy, lower alkylthio, lower alkylsulfinyl, amino, nitro and cyano at any position(s) on the nucleus, thienyl or furyl, each of R.sup.2 and R.sup.3 is hydrogen or lower alkyl, A is lower alkylene, X is sulfur or vinylene, Y is nitrogen or methine which may be substituted by lower alkyl, and Z is carbonyl or direct bond.
In this specification, halogen means chlorine, bromine, fluorine, etc., lower alkyl means the one having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl or butyl, lower alkoxy means the one having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy or butoxy, lower alkylene means the one having 1 to 4 carbon atoms such as methylene, ethylene, trimethylene, propylene, ethylidene or propylidene.
The compounds of formula (I) can be prepared by one of the following Methods (1) to (3):
Method (1): The compounds of formula (I) wherein Z is carbonyl, namely the compounds of formula: ##STR3## wherein R.sup.4 is hydrogen or lower alkyl and other symbols are as defined above, can be prepared by subjecting a compound of the formula: ##STR4## wherein each symbol is as defined above, to condensation reaction with a compound of the formula: ##STR5## wherein R.sup.2 is as defined above.
The reaction is carried out in a suitable solvent (methanol, ethanol, tetrahydrofuran, dioxane, benzene, toluene, etc., or a mixture thereof) in the presence of a basic catalyst (potassium ethoxide, sodium ethoxide, sodium methoxide, sodium hydride, etc.) at 30.degree. to 100.degree. C. for 30 minutes to 3 hours.
Method (2): The compounds of formula (I) wherein Z is direct bond, namely the compounds of the formula: ##STR6## wherein each symbol is as defined above, can be prepared by subjecting a compound of the formula: ##STR7## wherein each symbol is as defined above, to condensation reaction with a compound of the formula:
The reaction is carried out in a suitable solvent (acetone, benzene, toluene, xylene, methylene chloride, chloroform, dichloroethane, dioxane, etc., or a mixture thereof) in the presence of a deacidifying agent (pyridine, triethylamine, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium acetate, etc.) at 30.degree. to 150.degree. C. for 30 minutes to 5 hours.
Method (3): The carboxylic acid derivatives of formula (I) wherein R.sup.2 is hydrogen can be prepared by hydrolyzing a compound of the formula (II) or (V) in a conventional manner.
The carboxylic acid derivatives can be converted into, for example, sodium salt, potassium salt, carcium salt and aluminium salt according to a conventional manner.
The compounds of formula (I) and salts thereof have potent immunomodulatory activities and very low toxicities as shown, for example, by the following pharmacological experiments:


TEST METHODS

(I) Activity for potentiating production of rosette forming cells
As test animals, 6-week old female C57L/6-strain mice were used by dividing them into groups of 6 members. The sensitization was made by the intraperitoneal administration of the antigen; 5.times.10.sup.8 sheep red blood cells. The test compounds were orally administered to the animals at the day of sensitization and the next day. Seven days after sensitization, the number of rosette forming cells in the spleen and thymus was measured in a usual manner. The results are shown in Table 1.
It can be understood that the compounds of the present invention have immunopotentiating activities since the increase of the number of rosette forming cells can be observed in the groups treated with the compounds of the present invention as apparently shown in

REFERENCES:
patent: 4267339 (1981-05-01), Tedeschi

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