JPS60132956A - S-alkylthio-l-cysteine sulfoxide compound and its preparation, drug for alleviating hyperlipemia and liver enhancing gent containing it - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R is 1-5C alkyl or aryl) and its nonpoisonous acid and salt. EXAMPLE:S-methylthio-L-cysteine sulfoxide. USE:A drug for alleviating hyperlipemia and a liver enhancing agent. Showing cholesterol-lowering action (especially LDL) on hypercholesterolemia, also showing normalizing action on transaminase of liver cell. PREPARATION:An L-cysteine shown by the formula II is reacted with an alkyl or arylthiosulfinate shown by the formula III at approximately neutrality to form an S-alkyl(or aryl)thio-L-cysteine shown by the formula IV, then this compound is oxidized with an oxidizing agent such as hydrogen peroxide, etc., to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel cysteine derivatives represented by the general formula % and their rarity.

In general 2〇), R is not a prime number 1 [75 alki/l
/ group or alkyl/l/ group.

The compound provided by the present invention (sword) has a sulfur atom of an alkyl or allyl mercaptan bonded to the 8-position of L-cysteine, one of the sulfur atoms is oxidized to a sulfoxide, and the oxidized sulfur atom has an S or R structure. It is a new cysteine derivative, and it shows excellent pharmacological action, so it is promising as a drug.In particular, this compound is effective against hypercholesterolemia (especially LDL).
) and also normalizes transaminases in liver cells, so it is useful as an antihyperlipidemic agent and a liver-strengthening agent.

The compound is used in free form or as a salt thereof.

The salt is a salt with a pharmaceutically acceptable acid, and examples of acceptable salts include acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, fumaric acid, manic acid, and malic acid.

The compound of the present invention or a salt thereof can be administered orally or parenterally as a decholesterolizing agent or a liver tonic agent.

The dosage varies depending on body weight, symptoms, etc., but is approximately 100 to 100 lOO'O'rQ.Dosage forms include injections, tablets,
It may be an oral solution, a powder, or the like, and when preparing these dosage forms, excipients, solubilizing agents, etc. can be used in a conventional manner.

This compound (g) can be produced by the following method.

NH20 (I) (N) H2 (N) (:!0OH-, CH-CH2-8-8-RNH2,0 (1) (R in the formula is an alkyl μ group of the next prime number 1 to 5 or an ary-
) represents a V group) This method uses alkyl or arylthiosulfine, cyclo(I)
[1,) is applied. S- generated here
Alkylcysteine (■) is a well-crystalline substance and can be used in the next reaction without being isolated, but the final target S-alkyl)v (or ary-/L/)thiol-L- In order to improve the purity of cisdine sulfoxide, it is preferable to return (1v) to l'li once in this step. (T51)
For oxidation, hydrogen peroxide, persulfate, thiourea, perbenzoic acid, etc. are used. Solvent 1 is water, but water-miscible solvents such as acetone, tetrahydrochloride, resotylformamide, methanol, etc. Or use as a mixed solvent. The reaction temperature tX is set to room temperature or under water cooling.

Isolation and purification of (g) from the reaction solution was carried out using conventional methods.
Precipitation of each isomer (S, R) by addition of a solvent, crystallization, frequency separation by column chromatography [purification etc.]

The explanation will be given below based on actual examples.

Fruit Tsuba 1i Example 12 g of glacial acetic acid was added to 18.8 g of dimethyl disulfide, and after cooling with water, 269 g of OA sulfuric acid was added, and 22.6 g of 30% hydrogen oxide solution was added dropwise to the mixture under ice cooling.

After brewing overnight, the upper layer was removed, and while cooling with water, sodium carbonate was gradually added to bring the pH to around 7.

After that, 15 g of L-cysteine was gradually added and stirred for 4 hours.

After standing for one night, the precipitated crystals were evaporated under reduced pressure and lightly washed with the own solvent. The obtained S-methylthio-L-cysteine was dried. Suspend 2 g of S-methylthio-L-cis9ine with 30 g of glacial acetic acid, and add 2 g of 30% hydrogen peroxide solution under ice cooling.
Ml'? c Gradually, stir for another 30 minutes at room temperature after stirring, and t'! ．． p'x The transparent liquid is concentrated under reduced pressure at 40°C or below to obtain a concentrated τ(i.
When the mixture is dissolved and left to stand, crystals of S-methylthio L-synutein wolfoxide are precipitated. Yield 0.6
g.

Synthesis yield of homologues of this compound, engineering R absorption subek)/l/
etc. are shown in Table ■.

The following experiments were conducted regarding Aoi na action and toxicity.

Example 1: For example, the transaminase (GPT) value of rat hepatocytes in which liver disease was induced with carbon tetrachloride and galac-l-samine was determined. 5Y each 0.01, 0.1 and 1. o'q/ml significantly (p 0.0) decreased to p (0,001).

Practical Example 2 Compounds NO, 1, 3 and 4 in Tablet gave the same amount of cholesterol to rats, and when examining the group 1, each substance lowered serum cholesterol in the 0.5% addition group. Yes, it significantly decreased (p<0.0-01).

However, HDL cholesterol/I/ was not reduced.

For example, the LD5Q value obtained by oral administration using mice is shown in Table ■
The compound with NO,1 was 14g/if, the compound with lJO,3 was 10g/if, and the compound with NO,4 was 16g/if.

Patent applicant Kominato Yo Yukiko Kofu is a white patent author. Patent applicant Rieko Kominato

Claims (1)

[Scope of Claims] 1 S-alkyl-L-synuteine p-fluoride compounds represented by the general formula (in the formula, R represents an alkyl group or an aryl group having 1 to 5 carbon atoms) and their pharmaceutical properties Salts with acceptable non-toxic acids. 2 L-instein and the general formula (wherein R is an alkyl group having 1 to 5 carbon atoms or ary/
A general formula (wherein R is an alkyl group having 1 to 5 carbon atoms or an aryl μ
A method for producing an S-alkylthio-L-cystine sulfoxide compound represented by the following formula. 3 general formula % formula %) (in the formula, R is an alkyl group having 1 to 5 carbon atoms or an aryμ
An anti-hyperlipidemic and liver-strengthening agent containing an S-alkylthio-μ oxide compound represented by the following formula.