JPS606682A - Dithiolane derivative and its use - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention The present invention relates to the general formula (I): 1 (wherein R1 represents an alkyl group, R2 represents an alkoxycarbonyl group, and R3 and R4 each independently represent an alkylcarbonyl group) , an alkylcarbazoyl group, an alkoxycarbonyl group, a carboxyalkylcarbonyl group, or a salt thereof.) and a liver disease therapeutic agent containing the derivative as an active ingredient.

In the general formula (II), the alkyl group of R', the alkyl group moiety in the alkoxycarbonyl group of R2, and KR''
and the alkyl group moiety in the alkylcarbonyl group, alkylcarbamoyl group, alkoxycarbonyl group and carboxyalkylcarbonyl group of R4 is a lower alkyl group, such as a methyl group, an ethyl M% n-propyl group, i
-propyl group, n-butyl group, i-butyl group, S-butyl group, t-butyl group, n·-amyl group, i-amyl group,
S-amyl group, active amyl group, t-amyl group and n-
Includes hexyl group, etc.

The dithiolane derivative represented by the general formula (I) is a novel compound that has not been described in any literature and has 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.

The compound represented by the general formula (I) can be synthesized by a conventional esterification reaction in organic synthetic chemistry, as shown in the scheme below.

1 sail) O 1 (I) 0 (In the formula, R'l ■t2. R1 and R, 4 are the front IC
Same as . ) That is, it can be obtained by reacting a compound represented by the general formula (the compound represented by 11 is for the general formula) with an acid, m-halide, or ra-hydrotherm.

This reaction is preferably carried out in an organic base such as triethylamine or pyridine.

Any reaction may be used as long as it does not inhibit the reaction of the reaction, and the reaction can proceed sufficiently at a reaction temperature of 0° C. to room temperature.

Here, examples of acids, acidno-rides, and acid anhydrides include alkylcarboxylic acids, dibasic acids, halides thereof, anhydrides thereof; alkoxycarboxylic acid halides; and mono- or di-alkylcarbamic acid halides. can be used.

The compound represented by the general formula (2) can be synthesized, for example, according to the reaction route shown schematically below.

(III (In the formula, R1 and R2 are the same as above. M represents an alkali metal atom or an ammonium group.) That is, the compound represented by the general formula (n) is a compound represented by the general formula (b). It can be obtained by reacting with glyoxal in an inert solvent in the presence of.

Acids that can be used include, for example, inorganic acids such as sulfuric acid or hydrochloric acid, or organic acids such as acetic acid. can be mentioned.

Representative examples of compounds represented by the general formula (Il) are as follows.

Note 1) (t, 4H), 6.55 (s, 2H).

1 an ~ to, s (br, 2H) Note 2) a4 (br, 2H) Note 3) (8, # 8M) + '4-7 ~ 5.5 (m *
2H).

6.55 (,,2H), 9.8-10.5 (br, 2H
) The compound represented by the above general formula (1) has low toxicity to warm-blooded animals.

Compounds represented by the general formula (11) are particularly useful as therapeutic agents for liver diseases. For example, it is known that various drugs such as carbon tetrachloride may be experimentally induced to cause liver damage in healthy test animals. (For example, Special Publick Publication No. 56-1
No. 8579).

The compound represented by the general formula (11) can be administered orally or parenterally (e.g., by injection) to test animals with various experimentally created pathological models of liver damage. It has been found that it has the effect of suppressing or improving liver function.

Therefore, the compounds represented by general formula (I) are useful as human and veterinary medicines for the treatment or prevention of liver diseases. That is, 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, cholestatic liver disease, or the terminal stages thereof. It can be used as a therapeutic agent for liver cirrhosis. The compound represented by the general formula (Il) can be used as a treatment for liver diseases as it is, or can be formulated as a mixture with a pharmaceutically acceptable diluent and/or other pharmacologically active substances according to pharmaceutical practice. Medically available forms include dispersions, granules, tablets, dragees, capsules, pills, suspensions, solutions, Emulsions, ampoules, injection solutions, isotonic solutions and suppositories, etc.

When the compound of the present invention is used as a medicine, it includes an embodiment in which the compound represented by general formula (I) is contained in a mixture with a pharmaceutically acceptable diluent.

, Here, the diluent means a material other than the compound represented by general formula (I), and may be solid, semi-solid, liquid, or an ingestible capsule, and various examples include: e.g. Excipients, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, flavoring agents, flavoring agents, pigments, fragrances, preservatives, solubilizing agents, solvents , coating agents, sugar coating agents, etc. However, it is not limited to this. Alternatively, one or more of these may be used as a mixture. 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, the active ingredient is mixed with a diluent, eg, into granules, and the composition is then shaped, eg, into 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 (1) can itself be a therapeutic agent for liver diseases, the active ingredient is generally contained in the composition in an amount of 0.01 to 100% (by weight).

11 of dosage units! When used as a drug, the individual formulation parts that make up the drug have different shapes. For example, the following forms are often adopted: tablets, granules, pills, powders, dragees, capsules, ampoules, etc.

The therapeutic agents for liver diseases according to the present invention can be applied to humans and animals for the treatment of liver diseases by methods known in the art. It is administered orally or parenterally. Including oral administration and sublingual administration. Parenteral administration includes administration by injection (including subcutaneous, intramuscular, intravenous injection, and drip).

The dosage of the pharmaceutical of the present invention depends on whether the subject is an animal or a human, sensitivity differences, age, sex, body weight, administration method, administration timing, interval, medical condition, physical condition, properties of the pharmaceutical preparation, preparation It varies depending on a number of reasons, such as the type of heel, the type of active ingredient, etc.

Therefore, in some cases, it may be sufficient to administer a dose lower than the lowest dose shown below, and in other cases, it may be necessary to administer a dose exceeding the upper limit 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 kg of body weight on the same day from 10.1 to 10.1 on the day of oral administration.
500 ■, preferably in the range of α1 to 25 ■, in the case of parenteral administration, 1a on the day of 9 per 1 kg of body weight, 01 to 250 m
g, preferably in the range α1 to 25 Da, is advantageous.

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, 0.1 to 250 m9 per kg of body weight per day, preferably 0.5 to 50 mg, and in the case of parenteral administration, 0.01 to 1 oamy per kg of body weight per day, preferably is 0.1-25 mg.

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

Synthesis Example 1 Synthesis of diisopropyl 4-hydroxy-5-methylcarbonyloxy-1,3-dithiolane-2-ylidene malonate (compound 161).

1 0 Diisopropyl 4. Dissolve 8 g (24.8 mmol) of 5-dihydroxy-113-dithiolane-2-ylidene malonate in 180 m6 of chloroform, and dissolve 20 m of pyridine.
m/, then add 2539 (248 mmol) of acetic anhydride and stir in the chamber for 1 hour. Next, add ice water to the reaction mixture, shake well, and then separate the chloroform layer. After washing three times with IN-HCl and once with saturated deuterated water, drying with Mg S 04 and distilling off chloroform, the desired product having the above structure is obtained. When this is subjected to silica gel chromatography, the desired product is obtained as the oily substance of 5.4.9. Yield 38cm, nD=1.552
5゜Synthesis Example 2 Diisopropyl 4.5-bis(methylcarbonyloxy)-'*5-dithiolan-2-ylidenemalonate (
Synthesis of compound 42)
Dissolve 2 g (6.2 mmol) of dithiolane-2-ylidene malonate in 10'M pyridine and add 1.9 g of acetic anhydride.
and stir at room temperature for 3 hours.

The reaction solution was poured into ice water, and the resulting oil was extracted with chloroform. 3 times with IN-HCl, 1 time with water
After washing twice, drying (Mg5(-)4)L, chloroform is distilled off to obtain crude crystals. Recrystallized from ether-hexane, m, p, 130.0°C crystals 2.0 g
(yield 80%).

Compounds /f63-5 can be obtained in the same manner.

Synthesis Example 3 Synthesis of di-n-propyl 4,5-bis(t-methylcarbonyloxy)-1,3-dithiolane-2-ylidenemalonate (compound 166).

O di-n-propyl 4,5-dihydroxy-1゜5-dithiolane-2-ylidene malonate 20.9 (6,2
mmol) in 20ml of tetrahydrofuran and add 0
After adding 3.14 Jil (51.05 mmol) of triethylamine at the same temperature, 3.01 Jil of pivaloyl chloride was added dropwise at the same temperature for reaction.

After stirring at room temperature for 3 hours, the contents were poured into ice water.
Extract with dichloromethane. After washing with dilute hydrochloric acid and water, drying (HgS), and distilling off the solvent, 2.5 g of crystals were obtained. m, p, 107.6°C, yield 82.1%.

Compound /167 can also be obtained in the same manner.

Synthesis Example 4 Synthesis of di-n-propyl 4,5-bis(N,N-dimethylcarbamoyl 7)-1,5-dithiolan-2-ylidenemalonate (Compound 168) O 0 °G. -Propyl 4.5-dihydroxy-1゜5-
Dithiolane-2-ylidene malonate 1. Oji (5
, 1 mmol) in 5 ml of pyridine, N,N-
Dimethylcarbamoyl chloride 1. ssg was added dropwise at room temperature, and the mixture was stirred at the same temperature for 18 hours to react. The reaction mixture was poured into ice water and extracted with ethyl acetate. lN-H
After washing with Cl and water in this order and drying (Mg80+), the solvent is distilled off to obtain crude crystals. Recrystallization from a mixed solvent consisting of ether-dichloromethane-hexane 7 gives 1.38 g of the desired product (yield 96%), m, p, 129.
8℃.

Compound 169 can also be obtained in the same manner.

Synthesis Example 5 Synthesis of di-n-propyl 4,5-bis(ethoxyluponyloxy)-1,5-dithiolane-2-ylidenemalonate (compound, (610)).

0 di-n-propyl 4.5-dihydroxy-1゜3-dithiolane-2-ylidene malonate 1.0p (3,1
mmol) was dissolved in 20 d of tetrahydrofuran, and 1.57 g of triethylamine was added.

Cool with ice water. This was stirred and 1.
359 (12.4 mmol) was added dropwise to react, and the mixture was further stirred at room temperature for 3 hours to allow the reaction to proceed. The reaction mixture was poured into ice water, extracted with dichloromethane, and extracted with IN-H (
J. After washing with water, drying (Mg S 04 ) and distilling off the solvent. The obtained crude crystals are recrystallized from a mixed solvent of ether-hexane.

Yield 1.2.9 (Yield 85cm), m, p, 72.
0℃.

Compound 1611 can also be synthesized in a similar manner.

Synthesis Example 6 Synthesis of di-3-butyl 4,5-bis(2'-carboxyethylluponyloxy)-1,3-dithiolane-2-ylidenemalonate (compound At5).

〇〇 y -butyl 4,5-dihydroxy-1゜3-
1.0 g (2.85 mmol) of dithiolane was added to pyridine 5
Add succinic anhydride A57111 and stir at room temperature for 5 days and nights.The contents were poured into a trap of ice water and extracted with ethyl acetate. 1N-HCl.

After washing with water and drying (Mg5O,) L, the solvent was distilled off and 1. ．． 57.9 The desired product was obtained as a paste (yield: 100 cm).

Compounds 412 and 13*14 can also be synthesized in a similar manner.

In the following examples, all parts are M-phase parts. i The type and proportion of the gold component can be varied.

Example 1 Compound 1 10 parts Heavy q magnesium oxide 10 parts Lactose 80 parts The mixture is uniformly mixed into a powder or fine granules to form a powder.

Example 2 Compound 10 10 parts Synthetic aluminum silicate 10 parts Calcium hydrogen phosphate 5 parts Lactose 75 parts to prepare a powder according to Example 1.

Example 5 Compound 3 50 parts Starch 10 parts Lactose 15 parts Crystalline cellulose 20 parts Polyvinyl alcohol 5 parts Water 30 parts are uniformly mixed and kneaded, then crushed, granulated, dried and sieved to obtain granules.

Example 4 One part of calcium stearate was mixed with the granules 99's obtained in Example 6, and the mixture was compression molded to form tablets of 10 sizes in diameter.

Example 5 Compound 69, 5 parts Polyvinyl alcohol 5 parts Water 30 parts Granules were prepared in the same manner as in Example 3 using .

10 parts of crystalline cellulose is added to 990 parts of the obtained granules and compressed to form tablets with a diameter of 8 bars.

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 i4 0.5 parts Nonionic surfactant 2.5 parts Physiological saline! 7th part After heating and mixing, the mixture is sterilized and made into an injection.

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

Test example 1. Inhibition of Tetracarboxylic Hepatopathy - Effect Test Method The test compound was dissolved in olive oil and the temperature was cooled down to WF''!!, and it was orally administered to mice (6-week-old DD female) at a ratio of 250π9A9, and 6 hours later □ Carbon tetrachloride α05 m1
The rats were orally administered at a rate of 7 kg, and 24 hours after the administration of elemental tetrachloride, they were stratified and the degree of liver damage was examined by visual observation.

On the other hand, blood was collected at the time of sacrifice, plasma was obtained by centrifugation, and plasma glutamic birvic transaminase (GPT) activity was determined using 2-Itoman-7/Kel (Reitman-Fran).
kel) method, and the activity is measured in carmen units (K,
It is expressed as U,). The liver damage index is as follows.

Liver damage index Liver symptoms 0 Healthy liver 2 Slightly affected 4 Clearly damaged μ Severely damaged 1 group of 5 mice were used, and the average values are shown. The results are shown in Table 1.

Table 1 Effect on carbon tetrachloride liver damage As shown in Table 1, one compound of the present invention has a liver damage suppressing effect.

Procedural amendment, Patent Office Director General Sona Kyonaga 1, Indication of the case: Patent W filed on June 25, 1988
4<2r3, Relationship with the case of the person making the amendment Patent applicant address: 1-2-5-5 Nihonbashi, Chuo-ku, Totobu, date of amendment order: jJ, - “Voluntary” 7. Inner boundaries of amendment (1) Request for % forgiveness Correct the dryness on the separate sheet.

(27 specifications, #2j\, 2nd line from the bottom, 4n, 7th line from the bottom, 10'' is corrected to ``, respectively.

(3) 1R2 is in BA thin m, M3j 12th line to 7th line...
...Let that clay die. "Toruruno" represents a carboxyalkylcarbonyl group or a salt thereof, and R4 represents an alkylcarbonyl group, an alkylcarbamoyl group, an alkylcarbonyl group, a carboxyalkylcarbonyl group or a salt thereof. ” he corrected.

(4) In the table on pages 7 and 8 of the specification, Compound N
Regarding R4 of IL 6 and Flies 7, "0 1" and "Aru purple" are respectively corrected as "O 1 (CH3)3CC-".

The above (Separate Z) [Claims (1) General formula (1): (In the formula, ■ya represents an alkyl group, and R2 represents an alkoxycarbonyl group in Table I).
) A dithiolane derivative represented by

(2) General formula (1): (wherein R1 represents a furkyl group, R2 represents an alkoxycarbonyl group, 7, R3#i hydrogen atom, alkylcarbonyl-1 (, alkylcarbamoyl group, alkoxycarbonyl group, Dithiolane represented by carboxyalkylcarbonyl, 7t (-1, and l (4 represents alkylcarbonyl, furkylcarbamoyl, alkoxycarbonyl, carboxyalkylcarbonyl, and tJ, JA). A therapeutic agent for liver diseases characterized by having a derivative as a phantom ingredient.

Claims (2)

[Claims] (1) General formula (■): I (wherein R' represents an alkyl group, R1 represents an alkoxycarbonyl group, and R1 and R' each independently represent an alkylcarbonyl group, an alkylcarbamoyl group, an alkoxycarbonyl group, A dithiolane derivative represented by a carbonyl group, a carboxyalkylcarbonyl group, or a salt thereof. (2) General formula (■): 1 (wherein R1 represents an alkyl group, R2 represents an alkoxycarbonyl group, and R3 and R4 independently of each other are an alkylcarbonyl group, an alkylcarbamoyl group, an alkoxycarbonyl group, , a carboxyalkylcarbonyl group or a salt thereof) as an active ingredient.