JPS6168464A - Thiocarbonylmalonic acid ester derivative, its preparation and its use - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is (halogen-substituted) alkenyl, alkynyl or alkyl; R<2> and R3 are alkyl]. EXAMPLE:2{[(Z)-2-chlorovinylthio]thiocarbonyl} malonic acid diisopropyl ester. USE:Remedy for hepatopathy. Useful for the remedy of jecur adiposum, hepatitis, toxic hepatopathy, hepatocirrhosis, etc. PREPARATION:The compound of formula I can be prepared by (1) reacting the compound of formula II (M is alkali metal or ammonium) with the compound of formula R<1>X (X is halogen) in an inert solvent, (2) if necessary, separating the resultant compound of formula III from the system, and (3) subjecting the compound of formula III to dealkalization reaction in the presence of an acid.

Description

Detailed Description of the Invention The present invention relates to the general formula (I): (wherein R1 each represents an alkenyl group, an alkynyl group, or an alkyl group which may be substituted with a halogen atom, R1 and R3 represent the same or different alkyl groups), a method for producing the same, and a therapeutic agent for liver diseases containing the compound as an active ingredient.

The compound represented by the general formula fI) in Fudo 8A has, for example, a liver function-enhancing effect and is therefore useful as a liver function-enhancing agent and a therapeutic agent for liver diseases in humans or animals.

In the general formula (RI), the alkyl groups of RI, 几2 and R'' are, for example, methyl group, ethyl group, n-propylene
so-propyl group% n-butyl group, 1so-butyl M
s 5ec-butyl group, tert-butyl it,
Includes n-7 mil group, 15o-amyl group, □n-hexyl group, and the like.

The alkenyl group of 几1 is a lower alkenyl group such as vinyl group, allyl group, n-buty/-2-yl group, 2-methyl-3
-buten-2-yl group, 5-penten-2-yl M, 2
-Mef-2-propenylts, 2-)f-nyl group, 3-
Methyl-2-butenyl group, 3-methyl-5-butenyl t
s,'-methyl-5-butenyl group, etc. are all included.

The alkynyl group of 几1 is a lower alkynyl group such as an ethynyl group, a propargyl group, 2-methyl-3-butene-2-
yl-5,2-7'thynyl Tss3-butyn-2-yl group, 1-benthyl-3-yl &, 5-butynyl group, 4-
Includes pentyn-2-yl group, 4-hexyn-2-yl group, and the like.

The compound represented by the general formula (1) can be synthesized, for example, according to the reaction route shown schematically below.

(n) - (In the above formula, Bt each represents an alkenyl group, an alkynyl group, or an alkyl group that may be substituted with a halogen atom, R1 and R1 are the same or p, or each alkyl group, M represents an alkali metal or ammonium &, and X represents a halogen atom. A compound represented by 'C' is reacted in an inert solvent, and the resulting compound represented by the general formula (good) is subjected to a dealkalization reaction in the presence of an acid in an inert solvent, with or without isolation. This can be obtained by

The inert solvent used in this reaction may be any solvent as long as it does not significantly inhibit this type of reaction, but in particular, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, dimethylacetamide, hexamethylphosphoramide, sulfolane Aprotic polar solvents such as (tetrahydrothio7ene-1°1-dioxide) are preferred.

These solvents can be used alone or as a mixture, or can be used in a mixed solvent system with water.

Examples of acids that can be used in this reaction include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid.

Since the reaction of the present invention is an exothermic reaction, it is desirable to carry out the reaction at an appropriately determined temperature within the low temperature range, for example around 20°C.

Although this reaction is an equimolar reaction, there is no problem in adding a slight excess of either one.

After the reaction is completed, the target product can be collected by treating the reaction product in a conventional manner.

The compound represented by the general formula (n) used here as a starting material can be synthesized by the following reaction route.

fI[) (wherein R'', 1%$ and M have the same meanings as above) Representative examples of the compound represented by general formula (1) are shown below.

Here, the compound represented by the general formula (I) is a tautomer with the general formula (1): (in the formula, %R'.V and R1 have the same meanings as above) in a solution, for example, an aqueous solution. It exists as.

That is, in the acidic to neutral range, it exists as a compound represented by the general formula (1), and in the alkaline range,
It exists as a compound represented by the general formula (■f) and its anionic form.

The compound represented by the above general formula (I) has low toxicity to warm-blooded animals.

The compound represented by general formula (1) is particularly useful as a therapeutic agent for liver diseases. It is known that various drugs, such as carbon tetrachloride, can be administered to healthy test animals to experimentally induce liver damage in the animals.

The compound represented by the general formula (1) can be administered orally or parenterally (for example, by injection) to test animals with various experimentally created pathological models of liver damage. It has been found that the compound represented by the general formula (I) has a remarkable effect of inhibiting or improving the decline in liver function, and therefore, the compound represented by the general formula (I) is useful as a human and veterinary drug for treating or preventing liver diseases. In other words, acute or chronic liver diseases in humans and animals caused by various causes, such as fatty liver, alcoholic hepatitis, hepatitis, toxic liver disease, congestive liver disease, biliary stasis liver disease, and the terminal stage thereof, cirrhosis. It can be taken as a therapeutic agent. The compound represented by general formula (I) can be used as a therapeutic agent for liver diseases as it is or as a mixture with a pharmaceutically acceptable diluent and/or other chemical substances according to pharmaceutical practice. The composition may be formulated or may be assembled into dosage unit form. Forms that can be taken as pharmaceuticals include the following forms: dispersion, granules, tablets, sugar-coated tablets, capsules, tablets, 8I suspensions, solutions, emulsions, ampoules,
such as injection solutions, isotonic solutions and suppositories.

When preparing the compounds of the present invention as a medicament, a compound of the general formula CI+ is included in all eight formulations containing the compound in admixture with a pharmaceutically acceptable diluent.

Here, the diluent refers to a material other than the compound represented by the general formula (1), and may be solid, semi-solid, liquid, or an ingestible capsule, and includes various types: for example, excipients. agents, fillers, binders, wetting agents, disintegrants,
These include surfactants, lubricants, dispersants, buffers, flavoring agents, flavoring agents, pigments, fragrances, preservatives, solubilizing agents, solvents, coating agents, sugar coating agents, etc. However, they are not limited to these, and they may be conveniently used as a mixture of one or more of them. Such pharmaceutically acceptable diluents may also be used in mixtures with other pharmacologically active substances.

A medicament based on the compound of the present invention may be produced by any known method. For example, by mixing the active ingredient with a diluent,
IIIJ, for example into granules, and then the composition is formed into, for example, tablets. Parenterally administered preparations should be sterile. It should also be made isotonic with blood if necessary.

In the present invention, since the compound represented by the above general formula (I) can itself be a therapeutic agent for liver diseases, the active ingredient in the composition is generally number 1 to 100 (Mfk
)included.

In the case of dosage-specific formulations, the individual formulation parts forming the formulation may be in mutually different forms or may be the same; for example, the following forms are often employed: Tablets, granules, pills, powders, sugar-coated, capsules, amprunates.

The therapeutic agent for liver diseases according to the present invention can be applied to humans and animals for the treatment of liver diseases by methods commonly used in the field. It is administered orally or parenterally. Oral administration includes sublingual administration. Parenteral administration is by injection (
Examples include subcutaneous, intramuscular, intravenous injection, and infusion).

The dosage of the drug of the present invention is determined based on whether the subject is an animal or a human, sensitivity differences, age, sex, body weight, administration method, administration timing, interval, medical condition, properties of the medical condition drug preparation, and preparation. It varies depending on various factors such as type and type of active ingredient.

Therefore, there may be cases in which a dose lower than the lowest dose shown below is sufficient, but if the dose is exceeded, it may be necessary to administer a dose exceeding the upper limit dose shown below.

In addition, in the case of large-dose administration, it is preferable to divide the administration into several times a day.

In order to obtain effective results in animals, the active ingredient must be administered per 1 rf of body weight per day (L1-50
0 capes, preferably in the range 11 to 25 IIP, and in the case of parenteral administration, a range of L01 to 250 capes, preferably 111 to 25 capes per day per gram of body weight.

The dosage required to obtain effective results in humans is
Considering the effective dosage in animals, sensitivity differences, safety, etc., the following dosage ranges are advantageous, for example. In the case of oral administration, 1 kg body weight per day (15 to 250 q, preferably 15 to 50 q), in the case of parenteral administration, 1 kg per body weight per day.
001 to 100"v per day, preferably (11 to 25 capes).

Next, a synthesis example of the compound of the present invention will be shown.

Synthesis Example 1 21 ((Z)-2-chlorovinylthio]thiocarbonyl)diisoglobil malonate ester Cisoglobil malonate ja8F (cL1 model) and carbon disulfide Blf) mixture is cooled to 10°0 and stirred. . 24 pf of potassium hydroxide aqueous solution (Hydroxide Licum 141 dissolved in 10 ml of water) was added dropwise to this solution, keeping the reaction temperature below 20 degrees, and after MT, stirring for another 20 minutes resulted in 2.
゜2-bis(isopropoxycarbonyl)ethylene-1
, an aqueous solution of potassium 1-dithiolate is obtained.

Vinylidene chloride 10! and dimethyl sulfoxide 250m
Separate mixture of /! I4 and cooled to 15°C!. The previously obtained aqueous dithiolate solution was added dropwise to this solution and allowed to react. At this time, the reaction solution was sufficiently stirred so that the degree of one reaction did not exceed 20°C. Be careful to
Stir at 0°C for 1 hour, then add 200ml of cold water to the reaction mixture.
Add rnt and transfer contents to a separatory funnel. After washing twice with 50 ml of ethyl acetate, the aqueous layer is separated and discarded, followed by acidification with 1N hydrochloric acid to separate an oil. This is extracted with ethyl acetate, washed with water, dried, and the solvent is distilled off under reduced pressure to obtain the target thiocarbonyl malonic acid ester 271 as an oil (yield: 85%).

4.9 (+I(,s), 17 (2I-L m), &47 (IH, d, J=7.3±), 7.4 s
(IH, d, J=7.s±).

Examples of formulations are shown below; all parts in these examples are heavy parts. The types and proportions of the ingredients can be varied.

Example 1 Compound 2 10 parts heavy magnesium oxide 10 parts lactose
80 parts are mixed uniformly and made into a powder or fine granules.

Example 2 Compound 1 1 part synthetic silicified aluminum 10 parts calcium hydrogen oxide
5 parts lactose 75
According to Example 1, a powder was prepared using 1.5 parts.

Example 5 Compound 5 50 parts starch
10th part milk @
15 parts crystalline cellulose 20
1 part polyvinyl alcohol 5 parts water
After uniformly mixing and kneading 30 parts, the mixture is crushed, granulated, dried, and sieved to obtain granules.

Example 4 99 parts of the granules obtained in Example 3 were mixed with 1 part of calcium stearate and compressed to form tablets with a diameter of 10H.

Example 5 Compound 5 95 parts polyvinyl alcohol 5 parts water
Granules were prepared in the same manner as in Example 3 using 30 parts.

10 parts of crystalline cellulose is added to 90 parts of the obtained granules and compressed to form tablets with a diameter of 8 mm.

Further, appropriate amounts of syrup gelatin, a mixed suspension of precipitated calcium carbonate, and a coloring agent are added to the tablets to form sugar-coated tablets.

Example 6 Compound 4 [L5 parts nonionic surfactant 2-5 parts physiological saline
97 parts were mixed under heating and sterilized to form an injection.

Example 7 The powder obtained in Example 1 is filled into a commercially available capsule container to form a capsule.

Examples of biological tests are shown below.

Test example 1. Carbon tetrachloride liver injury inhibitory effect test method The test compound was dissolved or suspended in olive oil and orally administered to mice (6 withdrawal DD strain) at a rate of 250 caps/immediately. [It was orally administered at a rate of 1LO5rrt/D, and 24 hours after administration of carbon tetrachloride, it was sacrificed and the degree of liver damage was examined by observation.

On the other hand, blood was collected at the time of sacrifice, plasma was obtained by centrifugation, and plasma glutamic-bilvic transaminase-a (GPT) activity was determined using Reitman-7 Rankel (几eitman-
The activity was measured according to the Franke I method and expressed in carmen units (K, U,). The liver damage index is as follows.

Liver damage index Liver symptoms 0 Healthy liver 2 Slightly affected 4 Obvious damage 6 Severe damage 1 Group of 5m mice were used, and the average values are shown. The results are shown in Table 2.

Table 2 Effect on Carbon Tetrachloride Liver Damage As shown in Table 2, the compound of the present invention improved the liver damage index and p-op'r compared to the group administered with carbon tetrachloride alone, and had a suppressive effect on liver damage. It is known that Qin Dynasty.

(1 other person) Procedural amendment November 7, 1981 B 3 Person who corrects Relationship with 11 parts Patent applicant 5. Date of FiIif, II Decree →→−→１−←−→ “Spontaneous” 6. Fin positive object 7.? 1 positive content

Claims (3)

[Claims] (1) General formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 each represents an alkenyl group, an alkynyl group, or an alkyl group that may be substituted with a halogen atom. , R^2 and R^3 represent the same or different alkyl groups.) A thiocarbonyl malonic acid ester derivative represented by: (2) General formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 each represents an alkenyl group, an alkynyl group, or an alkyl group that may be substituted with a halogen atom. , R^2 and R^3 represent the same or different alkyl groups.) A therapeutic agent for liver diseases characterized by containing a thiocarbonyl malonic acid ester derivative represented by the following as an active ingredient. (3) General formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^2 and R^3 represent the same or different alkyl groups, and M represents an alkali metal or ammonium group. ) and the compound represented by the general formula (III): R^1 represents a halogen atom.) The general formula (IV) obtained by reacting the compound represented by
: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, R^1, R^2, R^3 and M have the same meanings as above.) General formula (I) characterized by a dealkalization reaction in the presence of an acid without separation: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1, R^2 and R ^3 represents the same meaning as above.) A method for producing a thiocarbonyl malonic acid ester derivative represented by: