JPH0430946B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (): (In the formula, R ¹ represents an alkyl group, an alkoxycarbonylalkyl group, or an alkylthioalkyl group that may be substituted with a halogen atom, and R ² represents an alkenyl group, an alkynyl group, or an alkyl group, and these are halogen atoms. ketene-S,S-acetal derivatives (which may be substituted and R ³ and R ⁴ are 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. It is something. The compound represented by the general formula () in the present invention has, for example, a liver function activating effect, and is therefore useful as a liver function activator or a therapeutic agent for liver diseases for humans or animals. Compounds represented by general formula () and formulas ( _b ), ( _c ), ( _e ), (

Compounds such as _f ) can be synthesized, for example, according to reaction routes A to E shown schematically below. Method A: (In the above formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as above.) That is, the compound represented by the general formula () is the compound represented by the general formula () and the general formula ( ) in an inert solvent in the presence of a base. B method: (In the above formula, R ¹ has the same meaning as above, R ² _a represents a haloalkenyl group having at least a halogen atom in the double bond, and R ² _b represents an alkynyl group that may have a halogen atom. , and R ³ and R ⁴ have the same meanings as above.) That is, the compound represented by the general formula ( _c ) is converted into the compound represented by the general formula ( _b ) in an inert solvent in the presence of a base.
It can be obtained by subjecting the compound represented by to a dehydrohalogenation reaction. C method: (In the above formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as above, M represents an alkali metal or ammonium, and X represents a halogen atom.) That is, represented by the general formula () The compound represented by the general formula () is prepared by reacting the compound represented by the general formula () and () in an inert solvent, and the resulting compound represented by the general formula () is isolated, or the compound represented by the general formula () is obtained without isolation. It can be obtained by reacting with a compound. D method: (In the above formula, R ¹ has the same meaning as above, R ² _c represents a haloalkyl group, R ² _d represents an alkenyl group that may be substituted with a halogen atom, and R ³ and R ⁴ represent the above-mentioned In other words, the compound represented by the general formula ( _e ) can be obtained by dehydrohalogenating the compound represented by the general formula ( _d ) in an inert solvent in the presence of a base. The amount of the base used is preferably about the same molar amount as the compound represented by the general formula ( _d ). Method E: (In the above formula, R ¹ has the same meaning as above, R ² _e represents an alkenyl group or an alkynyl group,
In addition, these may be substituted with a halogen atom, and R ³ , R ⁴ , M and X have the same meanings as above. ) That is, the compound represented by the general formula ( _f ) is obtained by reacting the general formula () and the compound represented by () in an inert solvent, and the resulting compound is the general formula ().
It can be obtained by isolating or not isolating the compound represented by and reacting it with a compound represented by general formula (). Inert solvents used in these reactions include:
Any substance that does not significantly inhibit this type of reaction may be used, such as ketones such as acetone, methyl ethyl ketone, and cyclohexanone, alcohols such as methanol, ethanol, propanol, and glycol, ethers such as tetrahydrofuran and dioxane, dimethyl sulfoxide, and dimethyl formamide. , dimethylacetamide, hexamethylphosphoramide, tetramethylene sulfone, and other aprotic polar solvents. These solvents can be used alone or as a mixture, and can also be used as a mixed solvent system with water. Examples of bases that can be used in this reaction include sodium hydroxide, potassium hydroxide,
Inorganic bases such as sodium carbonate and potassium carbonate, pyridine, trimethylamine, triethylamine,
Diethylaniline, 1,8-diazapicyclo-
Organic bases such as [5,4,0]-7-undecene can be mentioned. The reaction of the present invention is preferably carried out at a temperature below the boiling point of the solvent, and particularly preferably at an appropriately determined temperature from around room temperature to about 50°C. However, the reaction of the general formula () and the compound represented by () in Method E to obtain the compound represented by the general formula () is preferably carried out at 20°C or lower. Although the reactions of the compounds in each reaction route are equimolar reactions, one or the other may be added in slightly excess. After the reaction is completed, the target product can be collected by treating the reaction product in a conventional manner. Representative examples of compounds represented by the general formula () are shown in Table 1.

【table】

【table】

[Table] The compounds represented by the general formulas () and () used as starting materials here can be synthesized by the following reaction routes. (In the above formula, R ³ , R ⁴ and M have the same meanings as above.) (In the above formula, R ² , R ³ , R ⁴ , X and M have the same meanings as above.) The compound represented by the above general formula () has low toxicity to warm-blooded animals. The compound represented by the general formula () 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 () can be administered orally or parenterally (e.g., by injection) to test animals with liver damage in various experimentally created pathological models. It has been found that it has the effect of suppressing or improving functional decline. Therefore, the compounds represented by the general formula () are useful as human and veterinary medicines for the treatment or prevention of 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, hemorrhagic liver disease, cholestatic liver disease, or their terminal symptoms. It can be used as a treatment for certain liver cirrhosis. The compound represented by the general formula () can be used as a therapeutic agent for liver diseases as it is, or it can be formulated as a mixture with a pharmaceutically acceptable diluent and/or other pharmacologically active substances according to pharmaceutical practice. It may also be formulated in dosage unit form. Possible pharmaceutical forms include:
Powders, granules, tablets, dragees, capsules, pills, suspensions, solutions, emulsions, ampoules, injections, isotonic solutions and suppositories. When the compound of the present invention is prepared as a medicine, it includes an embodiment in which the compound represented by the general formula () is contained in a mixture with a pharmaceutically acceptable diluent. Here, the diluent means a material other than the compound represented by the general formula (), and may be solid, semi-solid, liquid, or an ingestible capsule.
Various things may be mentioned, such as excipients, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, flavoring agents, flavoring agents, pigments,
These include fragrances, preservatives, solubilizing agents, solvents, coating agents, and sugar coating agents. However, it is not limited to these. 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 () can itself be a therapeutic agent for liver diseases, the active ingredient in the composition is generally 0.01 to
100% (by weight) included. When preparing a dosage unit, the individual formulation parts forming the preparation may be in different forms or the same; for example, the following forms are often adopted: tablets, Granules, pills, powders, dragees, capsules, ampoules, etc. 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 includes injections (e.g. subcutaneous, intramuscular,
(including intravenous injection and infusion). The dosage of the medicament 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, properties of the medical condition pharmaceutical preparation, and preparation. It varies depending on various factors such as type and type of active ingredient. Therefore, in some cases, it may be sufficient to use a dose lower than the lowest dose shown below, and in some cases, 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 should be administered orally in the range of 0.1 to 500 mg per kilogram of body weight per day, preferably in the range of 0.1 to 25 mg per kilogram of body weight per day in the case of parenteral administration. 0.01～
250 mg, preferably in the range 0.1 to 25 mg is advantageous. Regarding the dosage for obtaining an effective result in humans, the following dosage range is advantageous, for example, taking into account sensitivity differences, safety, etc. from the effective dosage in animals. For oral administration, per kilogram of body weight per day
0.5 to 250 mg, preferably 0.5 to 50 mg, in the case of parenteral administration, 0.01 to 100 mg per kg of body weight per day,
Preferably it is 0.1 to 25 mg. Next, a synthesis example of the compound of the present invention will be shown. Synthesis Example 1: Isopropyl 2-isopropoxycarbonyl-3-ethylthio-3-[(Z)-2'-chlorovinyl]thioacrylate Synthesis of (Compound No. 2) 2 6.4 g of {[(Z)-2-chlorovinylthio]thiocarbonyl}malonic acid diisopropyl ester was dissolved in 25 ml of acetone, cooled with stirring, and heated to 10°C to dissolve 3.3 g of ethyl iodide. Add. 30% at the same temperature
Add 4.1 g of KOH aqueous solution dropwise to react. After the reaction,
Add 20 ml of water to the contents and extract with ethyl acetate.
After washing the ethyl acetate layer with water and drying (using anhydrous magnesium sulfate), the solvent is distilled off under reduced pressure to obtain the crude target product in the form of an oil. This is purified by column chromatography using silica gel.
Yield: 5.4g (yield: 77%). ^n20D ₌ 1.5378. NMRδ ^TMS _CDCl4
ppm: 1.30 (12H, d), 1.31 (3H, t), 2.82 (2H,
q), 5.0 (2H, m), 6.22 (1H, d, J = 6.4Hz),
6.83 (1H, d, J = 6.4Hz). Synthesis Example 2: Ethyl 2-ethoxycarbonyl-3-ethylthio-3-[(Z)-2-chlorovinyl]thioacrylate Synthesis of (compound No. 4) 4.8 diethyl malonate in a 100 ml three-necked flask
Take 2.4 g of carbon disulfide and stir. This is cooled, and 8.6 g of a 45% KOH aqueous solution is added dropwise at 10°C to react, thereby preparing a dithiolate aqueous solution. This aqueous dithiolate solution was added dropwise at 10°C to 72 ml of a dimethyl sulfoxide solution containing 2.9 g of vinylidene chloride prepared in a separate container to cause a reaction. 30 at around 20℃ after dropping
After stirring for a minute, 4.6 g of ethyl iodide was added dropwise to react. After the completion of the reaction, stirring was continued for 30 minutes, then 20 ml of ice water was added, and the mixture was extracted with a 1:1 mixed solvent of ethyl acetate/n-hexane and worked up in a conventional manner to obtain an oily crude product. This is purified by silica gel column chromatography. yield
2.5g (yield 38.5%). ^n25D ₌ 1.5538. Synthesis Example 3: Ethyl 2-ethoxycarbonyl-3-ethynylthio-3-ethylthioacrylate Synthesis of (Compound No. 16) Dissolve 4.8 g of ethyl 2-ethoxycarbonyl-3-ethylthio-3-[(Z)-2-chlorovinyl]thioacrylate in 20 ml of dimethyl sulfoxide, and add 30% potassium hydroxide aqueous solution to this. Add 3.2g and stir at 40-50°C for 1 hour to react. After the reaction is complete, cool to room temperature, add 50 ml of ice water, and stir to separate an oily substance. This is extracted with ethyl acetate/n-hexane (1:1), the organic layer is separated, washed well with water, dried, and the solvent is distilled off to obtain the desired product in the form of an oil. Yield: 1.6g (yield: 37.5%). ^n25D _{_}
1.5494. NMRδ ^TMS _CDCl3 ppm; 1.3 (9H, t), 3.04
(2H, q), 3.28 (1H, s), 4.26 (2H, q), 4.29
(2H, q). Synthesis Example 4: Isopropyl 2-isopropyloxycarbonyl-3-ethynylthio-3-n-propylthioacrylate Synthesis of (Compound No. 10) Isopropyl 2-isopropyloxycarbonyl-3-n-propylthio-3-[(E)-2-
To a solution of 2.3 g of bromovinyl thioacrylate and 50 ml of dimethyl sulfoxide, 6.7 g of a 5% aqueous potassium hydroxide solution was added dropwise at room temperature to react. After the addition was completed, the mixture was stirred for 1 hour and treated in the same manner as in Example 3 to obtain 0.7 g of oil. Yield 37.9%, n ¹⁸ _D 1.5386 NMR ^TMS _CDCl3 δppm: 1.0 (3H, t), 1.3 (12H, d, -
d), 1.6 (2H, t), 2.9 (2H, t), 3.2 (1H, S)
，
5.1 (2H, m). Synthesis Example 5: Isopropyl 2-isopropyloxycarbonyl-3-n-propylthio-3-(2,2-dibromoethyl)thioacrylate Synthesis of (Compound No. 32) Diisopropyl malonate 6.2g, carbon disulfide 2.6
g, a mixture consisting of 20 ml of dimethyl sulfoxide.
Cool to 10°C and stir. 8.6 g of a 45% potassium hydroxide aqueous solution is added dropwise to this and stirred for 30 minutes to obtain a dithiolate aqueous solution. A solution of 5.1 g of n-propyl iodide in 5 ml of dimethyl sulfoxide is added dropwise to the dithiolate solution for reaction. After stirring for 30 minutes after dropping, add 1, 1, 2
- Add 8.8 g of tribromoethane and gradually warm to 70°C. After stirring at the same temperature for 1 hour, the mixture was allowed to cool to room temperature, the contents were poured into 50 ml of ice water, and extracted with ethyl acetate. After washing with water and drying, the solvent is distilled off to obtain a crude oil, which is purified by column chromatography. Yield 5.6g (Yield 37.9
%), n ²⁵ _D 1.5426. NMRδ ^TMS _CDCl3 ppm: 1.0 (3H, t)
，
1.3 (12H, d), 1.6 (2H, m), 2.9 (2H, t), 3.9
(2H, d, J = 6.3Hz), 5.1 (2H, m), 5.7 (1H,
t, J = 6.3Hz). Synthesis Example 6: Isopropyl 2-isopropyloxycarbonyl-3-n-propylthio-3-[(E)-2-
Bromovinyl thioacrylate Synthesis of (Compound No. 38) Isopropyl 2-isopropyloxycarbonyl-3-n-propylthio-3-(2,2-dibromoethyl)thioacrylate 5.6g, tetrahydrofuran 20ml, 1,8-diazabicyclo-
A mixture of 2.1 g of [5,4,0]-7-undecene is stirred at room temperature for 1 hour to react. After the reaction is complete, tetrahydrofuran is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with dilute hydrochloric acid and water, dried, and the solvent is distilled off to obtain the crude target product. This is purified by silica gel column chromatography. Yield of oil: 2.3 g (yield: 49.2%). NMRδ ^TMS _CDCl3 ppm: 1.0 (3H, t), 1.3 (12H, d-
d), 1.6 (2H, t), 2.8 (2H, t), 5.1 (2H, m)
，
6.5 (1H, d, J = 14.2Hz), 7.1 (1H, d, J =
14.2Hz). Examples of formulations are shown below. All parts in this example are parts by weight. The types and proportions of the ingredients can be varied. Example 1 10 parts of Compound 22, 10 parts of heavy magnesium oxide, and 80 parts of lactose are uniformly mixed and made into a powder or fine granules to form a powder. Example 2 A powder was prepared according to Example 1 using 10 parts of Compound 26, 10 parts of synthetic aluminum silicate, 5 parts of calcium hydrogen phosphate, and 75 parts of lactose. Example 3 50 parts of Compound 3, 10 parts of starch, 15 parts of lactose, 20 parts of crystalline cellulose, 5 parts of polyvinyl alcohol, and 30 parts of water are uniformly mixed and kneaded, then crushed, granulated, dried, and sieved to obtain granules. Example 4 1 part of calcium stearate was mixed with 99 parts of the granules obtained in Example 3, and the mixture was compression molded to a diameter of 10 mm.
tablets. Example 5 Granules were prepared in the same manner as in Example 3 using 95 parts of Compound 6, 5 parts of polyvinyl alcohol, and 30 parts of water. 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 12 0.5 parts, nonionic surfactant 2.5 parts, and physiological saline 97 parts are mixed under heating and sterilized to prepare 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 Damage Suppressive Effect Test Method The test compound was dissolved or suspended in olive oil and orally administered to mice (6-week-old DD male) at a rate of 250 mg/Kg, and 6 hours later, carbon tetrachloride was dissolved or suspended in olive oil. carbon 0.05
The animals were orally administered at a rate of ml/Kg, sacrificed 24 hours after carbon tetrachloride administration, and the degree of liver damage was examined by visual observation. On the other hand, blood was collected at the time of slaughter, plasma was obtained by centrifugation, and plasma glutamic-pilpic transaminase (GPT) activity was determined by Reitman-Frankel (Rei).
The activity was measured according to the Tman-Frankel method, and the activity was expressed in carmen units (KU). The liver damage index is as follows. Liver damage index Liver symptoms 0 Healthy liver 2 Slightly affected 4 Obvious damage 6 Severe damage Five mice were used per group, and the average values are shown. The results are shown in Table 2.

【table】

[Table] As shown in Table 2, the compound of the present invention showed higher liver damage index and p-
It is found that it improves GPT and has the effect of suppressing liver damage.

Claims (1)

[Claims] 1 General formula (): (In the formula, R ¹ represents an alkyl group, an alkoxycarbonylalkyl group, or an alkylthioalkyl group that may be substituted with a halogen atom, and R ² represents an alkenyl group, an alkynyl group, or an alkyl group, and these groups are substituted with a halogen atom. A ketene-S,S-acetal derivative represented by (sometimes substituted with an atom, R ³ and R ⁴ represent the same or different alkyl group). 2 General formula (): (In the formula, R ¹ represents an alkyl group, an alkoxycarbonylalkyl group, or an alkylthioalkyl group that may be substituted with a halogen atom, and R ² represents an alkenyl group, an alkynyl group, or an alkyl group, and these groups are substituted with a halogen atom. A therapeutic agent for liver diseases characterized by containing as an active ingredient a ketene-S,S-acetal derivative represented by R ³ and R ⁴ which may be substituted with atoms and R 3 and R 4 are the same or different alkyl groups. . 3 General formula (): (In the formula, R ² represents an alkenyl group, an alkynyl group, or an alkyl group, and these groups may be substituted with a halogen atom, and R ³ and R ⁴ represent the same or different alkyl groups.) and ^the general formula (): R ¹ General formula () characterized by reacting the compound represented by ) in the presence of a base: A method for producing a ketene-S,S-acetal derivative represented by the formula (wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as above). 4 General formula ( _b ): (In the formula, R ¹ represents an alkyl group, alkoxycarbonylalkyl group, or alkylthioalkyl group that may be substituted with a halogen atom, and R ² _a represents a haloalkenyl group having at least a halogen atom in the double bond portion. , R ³ and R ⁴ are the same or different alkyl groups) is subjected to a dehydrohalogenation reaction in the presence of a base. General formula ( _c ): (In the formula, R ¹ , R ³ and R ⁴ have the same meanings as above, and R ² _b represents an alkynyl group that may have a halogen atom.)
A method for producing an acetal derivative. 5 General formula (): (In the formula, R ³ and R ⁴ represent the same or different alkyl groups, and M represents an alkali metal or ammonium group.) and the general formula (): R ¹
Reacting ^with a compound represented by The resulting general formula (): (In the formula, R ¹ , R ³ , R ⁴ and M have the same meanings as above.) The compound represented by the general formula (): R ² X () (in the formula, R ² represents an alkenyl group, an alkynyl group, or an alkyl group, and these groups may be substituted with a halogen atom, and X represents a halogen atom. General formula (): A method for producing a ketene-S,S-acetal derivative represented by the formula (wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as above). 6 General formula ( _d ): (In the formula, R ¹ represents an alkyl group, an alkoxycarbonylalkyl group, or an alkylthioalkyl group that may be substituted with a halogen atom, R ² _c represents a haloalkyl group, and R ³ and R ⁴ are the same or different alkyl groups. General formula ( _e ) characterized by subjecting a compound represented by (e) to a dehydrohalogenation reaction in the presence of a base: (In the formula, R ¹ , R ³ and R ⁴ have the same meanings as above, and R ² _d represents an alkenyl group which may be substituted with a halogen atom.)
Method for producing S-acetal derivative. 7 General formula (): (In the formula, R ³ and R ⁴ represent the same or different alkyl groups, and M represents an alkali metal ^or _ammonium group.) ² _e represents an alkenyl group or alkynyl group that may be substituted with a halogen atom, and X represents a halogen atom) General formula () obtained by reacting with a compound represented by: (In the formula, R ² _e , R ³ , R ⁴ and M have the same meanings as above.) The compound represented by the general formula (): R ¹ X () (in the formula , R ¹ represents an alkyl group, alkoxycarbonylalkyl group or alkylthioalkyl group which may be substituted with a halogen atom, and X represents a halogen atom). _f ): A method for producing a ketene-S,S-acetal derivative represented by the formula (wherein R ¹ , R ² _e , R ³ and R ⁴ have the same meanings as above).