KR890000381B1 - Process for preparing acylaninophenol derivatives - Google Patents

Abstract

Acylaminophenyl thiazolidinecarboxylates (I)[n=0- were prepd.. Thus, (COCl)2 was added to L-2-oxo-4-thiazolidinecarboxylic acid in MeCN/DFM and the mixt. was stirred at -10≰C, treated with 4-HOC6H4NHAc, and stirred at room temp. to give L-I (n=0) (II). (II) was an effective analgesic and had an antiinflammatory effect at an oral dose of 310mg/kg in the rat paw edema test.

Description

Method for preparing acylaminophenol derivative

The present invention relates to acylaminophenol derivatives having excellent pharmaceutical properties, methods for preparing these derivatives, and pharmaceutical compositions containing these derivatives.

British Patent No. 1,583,602 describes a class of N-acetylaminothioalkanoic acid ester derivatives of N-acetyl-para-aminophenol that have analgesic effects without overly hepatotoxic effects. The present invention relates to an acylaminophenol ester type comprising a novel ester of N-acetyl-para-aminophenol [N- (4-hydroxyphenyl) acetamide or paraacetamol], wherein the ester moiety is structurally It has been found to be completely different from the esters of the prior art and also to have analgesic effects when administered in excess without relatively hepatotoxic effect.

Derivatives of the present invention have been found to further enhance desirable pharmacological properties, such as resistance, when compared to the known derivatives. The present invention relates to compounds of the following structural formula (I).

Wherein n is an integer from 1-5, preferably n is 1.

Since the compounds of the present invention contain subtitle carbon atoms, they exist in racemic forms as well as optically active isomeric forms.

The present invention includes not only the optically active isomers of D- and L- of the compounds of the present invention but also mixtures thereof. L-isomers are preferred.

The present invention also relates to a method for preparing a compound of formula (I) by reacting 2-oxo-thiolidine-4-carboxylic acid or a reaction derivative thereof with a compound of formula (II).

Wherein n is as defined in formula (I). Suitable reaction derivatives of 2-oxo-thiazolidine-4-carboxylic acid are, for example, acyl halides, in particular acyl chlorides. The reaction is carried out in the presence of an inert solvent or diluent such as acetonitrile or dimethylformamide and the like, for example at 10 ° C. at room temperature in the presence of an acid binder such as pyridine or the like. The starting materials used in the process are known or can be prepared by known methods.

Optically active isomers of the compounds of formula (I) are, for example, L-isomers using suitable optically active starting materials such as (L) -2-oxo-thiazolidine-4-carboxylic acid or its reaction derivatives and the like. The product can be prepared directly or by decomposing the racemic mixture initially obtained according to standard methods.

In the following Examples will be described the preparation method of the compound of the present invention.

EXAMPLE

Preparation of (4-acetamido-phenyl) -2-oxo-thiazolidine-4-carboxylate

0.85 ml of oxalylchloride is added to a mixture of 10 ml of acetonitrile and 2.2 ml of dimethylformamide at −10 ° C. and the entire mixture is added to 1.3 g of (L) -2-oxo-thiazolidine-4-carboxyl. Stir for 15 minutes before combining with acid. After another 15 minutes of further heating, 3.3 g of N- (4-hydroxyphenyl) acetamide dissolved in 2.2 ml of pyridine is added dropwise at -10 ° C. The reaction mixture is allowed to warm at room temperature and stirred overnight. The resulting precipitate is filtered off, washed with tetrahydrofuran and recrystallized with acetonitrile to yield the title compound in L-isomeric form: Melting point = 204-205 ° C.

The compounds of the present invention exhibit good pharmaceutical properties, particularly analgesic activity, as shown in the following standard tests.

(1) arthritis pain testing (based on the method of A. W. Pircio et al., Eur. J. Pharmacol. 31, 207-215, 1975); And (2) Randall-Sellitto test for inflammation of rat hind paws (Arch. Int. Pharmacodyn. 61, 409-419, 1957).

As a result of testing the compound of the present invention, the test (1) showed an activity when orally administered 150-300mg / kg body weight range, and in test (2) when orally administered a 200-500mg / kg body weight range Activity was shown.

Therefore, the compounds of the present invention are used as analgesics in the treatment of pain of various etiologies. The daily dosage ranges from about 1-4 g once orally, in divided doses 2-4 times a day, or in sustained release, with a pharmaceutically acceptable diluent or carrier, the compound of formula (I) It is administered in an oral formulation containing about 250 mg-2 g.

According to the present invention for (L)-(4-acetamido-phenyl) -2-oxo-thiazolidine-4-carboxylate compound (Compound A) and known paracetamol analgesic (Compound B) The results of the tests I and II are reported in the table below.

As is known in the literature, high doses of paracetamol may cause severe liver failure and death. The compounds of formula I of the present invention have been found to exhibit significantly reduced hepatotoxicity when compared to paracetamol, such as GOT (glutamate-oxalacetate-transaminase) and GPT (glutamate-pyruvate-trans) in mouse serum. Aminase) value is demonstrated (Remmington's Pharmaceutical Sciences "(1980), 544-545 and Jungermann and Mohler," Blochemie ", Springer Verlag (1980), 555). Therefore, when oral administration of Compound A1000mg / kg of the present invention to mice did not increase the GOT and GPT values compared to the untreated control (40-80 units / 1), and none died. Conversely, when orally administered Compound B (paracetamol) at a 560 mg / kg dose, the GOT value increased to 3,800 units / 1 and the GPT value was increased to 3,000 units, and the compound was orally administered at a 1,000 mg / kg dose. Of the five test animals, two died.

Therefore, when using the compounds of the present invention, the risk of death from drug abuse (eg, suicide) can be significantly reduced compared to known paracetamol analgesics. Thus, the compounds of the present invention provide significantly "safe" drugs with reduced risk of abuse.

As described above, the present invention provides a pharmaceutical composition comprising (I) a pharmaceutical composition containing a compound of formula (I) together with a pharmaceutically acceptable diluent or carrier; II) a compound of formula I as a medicament, eg as an analgesic; And III) a method of treating pain by administering to a patient an amount of a compound of formula (I) effective to analgesic action.

Claims (1)

A method for preparing a compound of formula (I), characterized by reacting 2-oxo-thiazolidine-4-carboxylic acid or its acyl halide with a compound of formula (II):

Wherein n is an integer from 1-5.