JPH07116180B2 - Dithiol derivative, process for producing the same and use thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has the general formula (I): [In the formula, R ¹ represents a lower alkyl group or an allyl group, R ² represents a lower haloalkyl group, an alkenyl group, a 3-halo-2-hydroxypropyl group or (R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a phenyl group, and R ⁴ represents one or two selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkoxy group and a nitro group. A phenyl group, a heterocyclic group or a lower alkoxycarbonyl group which may be substituted with a group), a method for producing the same and a therapeutic agent for liver diseases containing the compound as an active ingredient. is there.

Conventionally, compounds in which R ¹ and R ² are the same or different and are lower alkyl groups in the dithiol derivative represented by the general formula (I) are described in JP-B-54-43506 and JP-B-56-18579. It is a known compound. Since these dithiol compounds have a liver function activating action, they have been reported to be effective as a human or animal liver function activating agent and a liver disease therapeutic agent.

According to the findings obtained by the present inventors, the dithiol derivative represented by the general formula (I) of the present invention surprisingly exhibits the above-mentioned action at an extremely low dose as compared with the compounds disclosed in the above publications. And was found to be effective as a liver function activating agent and a liver disease therapeutic agent.

The compound represented by the general formula (I) of the present invention is a novel compound which has never been described in any prior art document.

The compound represented by the general formula (I) can be prepared, for example, by the route shown below.
It can be synthesized by the A, B and C methods.

Method A; (In the formula, R ¹ and R ² are the same as described above, M is a hydrogen atom or an alkali metal atom, and X is a halogen atom.) That is, the compound represented by the general formula (I) is represented by the general formula (I
It is obtained by reacting the compound represented by V) with the compound represented by the general formula (III) in a polar solvent in the presence or absence of a base.

Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate.

Examples of the solvent include dimethylsulfoxide, dimethylformamide, diethylformamide, dimethylacetamide, hexamethylphosphoramide, N, N-dimethylethyleneurea, and the like, mixed solvents of solvents selected from these,
A mixed solution of water and the organic solvent may be mentioned.

The reaction temperature is not particularly limited, but a temperature selected from the range of 0 ° C to 80 ° C is preferable. Since this reaction is an equimolar reaction, each reaction reagent may be used in an equimolar amount, but any one of the reaction reagents may be used in excess. The reaction time varies depending on the reaction temperature and the reaction scale, but is preferably selected from the range of 1 to 24 hours.

Among the compounds represented by the general formula (IV) used in this reaction, the derivative (IVa) in which M is an alkali metal atom in the general formula (IV) is a compound represented by the general formula (V) in an alcohol solvent. Among the compounds represented by the general formula (IV), which are obtained by hydrolysis using a metal hydroxide, the derivative (IVb) in which M is a hydrogen atom can be prepared by a conventional method using the compound represented by the general formula (IVa). Obtained by treatment with an acid according to.

(In the formula, R ¹ is the same as above, M ¹ is an alkali metal atom) Method B; (In the formula, R ¹ and R ² are the same as above) That is, the compound represented by the general formula (I) is
It can be obtained by reacting the compound represented by b) with the compound represented by the general formula (VI) in the presence of a condensing agent.

Examples of the condensing agent used in this reaction include 2-chloro-1-methylpyridinium tosylate, 2-chloro-1-methylpyridinium iodide, and 2-bromo-1 iodide.
Examples include a combination of a halopyridinium salt such as -methylpyridinium and a tertiary amine such as triethylamine and tri-n-butylamine, and a combination of an azodicarboxylic acid ester such as diethyl azodicarboxylate and triphenylphosphine. Examples of the solvent used include halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and chlorobenzene; ethers such as diethyl ether, tetrahydrofuran and dioxane; nitriles such as acetonitrile. And the like and mixed solvents selected from these.

The reaction temperature is not particularly limited, but is preferably appropriately selected from room temperature to the boiling point of the solvent used.

When a combination of a halopyridinium salt and a tertiary amine is used as a condensing agent in carrying out this reaction, the tertiary amine needs to be 2 equivalents or more based on the compound represented by the general formula (IVb). . Other reaction reagents may be used in equivalent amounts, but any reaction reagent may be used in excess.

The reaction time varies depending on the reaction temperature, the reaction scale and the condensing agent used, but is appropriately selected from the range of 1 to 48 hours.

C method; (In the formula, R ¹ and R ² are the same as above, and Y represents a halogen atom.) That is, the compound represented by the general formula (I) has the general formula (V
The compound represented by the formula (I) is reacted with carbon disulfide in the presence of a base and a solvent to give a compound represented by the formula (VIII), which is isolated or unisolated and represented by the formula (V)
It is obtained by reacting with a compound represented by

The compound represented by the general formula (I) can be synthesized by the same method as a known method for producing a similar compound other than the above.

Any solvent can be used in this reaction as long as it does not inhibit the progress of this reaction, and examples thereof include the solvents mentioned in Method A.

Further, in the present invention, the polar solvent has a solvent ability even when mixed with water, so that the reaction can be carried out in a water-polar solvent system.

Examples of the base used include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and carbonates such as sodium carbonate and potassium carbonate.

The reaction temperature can be selected in the range of 0 to 100 ° C, but it is particularly preferably carried out in the range of 10 ° C to 80 ° C. The reaction time varies depending on the reaction temperature and the reaction scale,
It is appropriately selected from the range of 0.5 to 48 hours. The amount of the base used is appropriately selected from the range of 2 to 4 mol per 1 mol of the compound represented by the general formula (VI). Further, the reaction between the compound represented by the general formula (V) and the compound represented by the general formula (VIII) is an equimolar reaction, and thus they may be used in an equimolar amount, or one of them may be used in excess.

The compound represented by the general formula (I) can be obtained by treating the reaction product according to a conventional method after completion of the reaction.

Table 1 shows typical examples of the compound represented by formula (I).

Synthesis Example 1 1,1,1,3,3,3-hexafluoro-2-propyl isopropyl 1,3-dithiol-2-ylidene malonate (Compound No. 2) 2.62 g (0.010 mol) of triphenylphosphine and 1 , 1,1,
3,3,3-hexafluoro-2-propanol 1.68 g (0.01
0 mol) is dissolved in 20 ml of tetrahydrofuran (THF),
To this was added 1.74 g of azodicarboxylic acid diethyl ester (0.010
Mol) and isopropyl hydrogen 1,2-dithiol-2-ylidene malonate 2.46 g (0.010 mol)
A solution dissolved in 20 ml of THF was added dropwise at room temperature and stirred for 3 hours. After adding ice water, the mixture was extracted with chloroform, washed with 10% aqueous sodium carbonate solution and water, dried over magnesium sulfate, and concentrated to obtain a crude product, which was purified by silica gel chromatography. The obtained crystals are ether-n-
Recrystallization from hexane gave 1.31 g of the desired product. Melting point 84-85
C, Yield 37% Synthesis Example 2 1- (4-chlorophenyl) ethyl isopropyl 1,3-dithiol-2-ylidene malonate (Compound No. 38) Isopropyl potassium 1,3-dithiol-2-ylidene malonate 2.84 g (0.010 mol) and 1- (4-chlorophenyl) ethyl bromide (2.21 g, 0.010 mol) were dissolved in 10 ml of dimethyl sulfoxide, and the mixture was stirred at 50 ° C for 2 hours. After cooling, pour into ice water and extract with ethyl acetate,
After drying over magnesium sulfate, the solvent was distilled off to obtain a syrupy crude product. This was purified by silica gel chromatography and recrystallized from ethyl acetate-n-hexane to obtain 1.28 g of the desired product. Melting point 82 ° C., yield 39% Synthesis example 3 1- (2,4-dichlorophenyl) ethyl n
-Propyl 1,3-dithiol-2-ylidene malonate (Compound No. 33) n-propyl hydrogenene 1,3-dithiol-2
-Ilidene malonate 2.00 g (0.08 mol) and potassium hydroxide powder 0.52 g (0.08 mol) were added to dimethyl sulfoxide 1
It was dissolved in 0 ml and stirred at room temperature for 10 minutes. 1- (2,4
1.78 g (0.07 mol) of -dichlorophenyl) ethyl bromide was added, and the mixture was stirred at 50 ° C for 3 hours. Synthesis example 2 after completion of reaction
The same treatment as described in 1. was performed to obtain 1.07 g of the desired product.

Melting point 143 ° C., yield 31% Synthesis example 4 1- (2-methoxyphenyl) ethyl isopropyl 1,3-dithiol-2-ylidene malonate (Compound No. 46) Isopropyl hydrogenene 1,3-dithiol-2-
2.70 g (0.011 mol) of iriden malonate and 2-chloro-1-methyl-pyridinium p-toluenesulfonate
Dissolve 3.60 g (0.012 mol) in 20 ml of dichloromethane,
While cooling to 10 ° C. or lower, a solution prepared by dissolving 1.38 g (0.009 mol) of 1- (2-methoxyphenyl) ethyl alcohol and 3.46 g (0.036 mol) of triethylamine in 20 ml of dichloromethane was appropriately applied. After stirring at room temperature for 24 hours, the mixture was extracted with dichloromethane, washed with diluted hydrochloric acid, 10% aqueous sodium carbonate solution and water, dried over magnesium sulfate, concentrated and purified by silica gel chromatography. The obtained crystals were ether-n-hexane. The crystals were recrystallized to give 2.05 g of the desired product.

Melting point 105-105.5 ° C, yield 46% Synthesis Example 5 1- (2,4-dimethoxyphenyl) ethyl
Isopropyl 1,3-dithiol-2-ylidene malonate (Compound No. 49) Isopropyl hydrogenene 1,3-dithiol-2
-Ylidene malonate (2.70 g, 0.011 mol) and 2-chloro-1-methyl-pyridinium p-toluenesulfonate (3.60 g, 0.012 mol) were dissolved in 30 ml of dichloromethane and cooled to 10 ° C or lower with 1- (2 1,4-Dimethoxyphenyl) ethyl alcohol 1.64 g (0.009 mol) and triethylamine 3.46 g (0.036 mol) were added to dichloromethane 20
The solution dissolved in ml was added dropwise. After stirring under reflux for 3 hours, the mixture was cooled and post-treated in the same manner as in Synthesis Example 4 to give the desired product.
1.95 g was obtained.

Melting point 95.5-96.5 ° C, yield 48% Synthesis example 6 benzyl, isopropyl 1,3-dithiol-2-ylidene malonate (Compound No. 9) benzyl, isopropyl malonate 11.8 g (0.050 mol) and carbon disulfide 4.2 g (0.055 mol) 17.8 g (0.120 mol) of a 45% aqueous potassium hydroxide solution was added dropwise to the mixed solution of (1) under ice cooling, and the mixture was stirred at room temperature for 1 hour. Separately, 5.1 g (0.055 mol) of 1,1-dichloroethylene was dissolved in 125 ml of dimethyl sulfoxide, and the dithiolate solution prepared above was gradually added dropwise while cooling this with water. 70 hours at room temperature after dropping
The mixture was stirred at ℃ for 15 minutes and poured into ice water. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate-n-hexane to obtain 10.65 g of the desired product.

Melting point 62-64 ℃, 63% yield Synthesis of raw material Potassium isopropyl-1,3-dithiol-2-ylidene malonate Diisopropyl-1,3-dithiol-2-ylidene malonate 3.0 g (0.01 mol) , Potassium hydroxide 0.06g (0.01
(Mol) was stirred in 30 ml of isopropyl alcohol under reflux for 2 hours. After cooling to room temperature, the precipitated crystals were collected by filtration and washed well with isopropyl alcohol and ether to give the desired product (2.0 g).
Got

Melting point 241-5 ° C (decomposition), yield 70% Isopropyl hydrogen-1,3-dithiol-2
-Synthesis of iridenmalonate Dissolve 2.8 g (0.01 mol) of potassium isopropyl-1,3-dithiol-2-ylidene malonate in 50 ml of water,
10 ml of concentrated hydrochloric acid was added, and the precipitated crystals were collected by filtration, washed with water and air-dried to obtain 2.2 g of the desired product.

Melting point 165.0 to 166.0 ° C, yield 89% Even if the compound represented by the general formula (I) is continuously administered to mice or rats at a rate of 30 mg / kg / day for 2 weeks, the mice or rats show any toxic symptoms. Since it does not die and does not die, it can be seen that the toxicity is extremely low.

The compound represented by the general formula (I) is useful as a medicine for treating liver diseases. For example, it is known that various drugs such as carbon tetrachloride can be administered to healthy test animals to cause liver damage in the animals experimentally (for example, Japanese Examined Patent Publication No. 56-1).
8579) is a compound represented by the general formula (I), which is orally or parenterally (for example, injected) to experimentally prepared test animals with liver damage in various pathological models.
It was found that the administration of the drug brings about a remarkable inhibition or improvement effect on liver function. Therefore, the general formula (I)
The compound represented by is useful as a human and veterinary medicine for treating or preventing liver diseases. That is, it is an acute or chronic liver disease of humans or animals caused by various causes, such as fatty liver, alcoholic hepatitis, hepatitis, toxic liver disorder, depressive liver, cholestatic liver disorder or their terminal image. It can be used as a therapeutic agent for cirrhosis.

Therefore, the term “medicament for treating liver disease” used in the present invention refers to the treatment or treatment of liver disease utilizing a pharmacological action such as liver function activating action and liver disease prevention and therapeutic action expressed in the liver as described above. And a pharmaceutical for prevention.

The compound represented by the general formula (I) can be used as it is as a medicine for treating liver diseases, and can be used in combination with a pharmaceutically acceptable diluent and / or other pharmacologically active substance according to pharmaceutical practice. Can be formulated as a mixture,
It may also be formulated in a dosage unit form. The pharmaceutically acceptable forms include the following forms: powders, granules, tablets, dragees, capsules, pills, suspensions, solutions, emulsions, ampoules, injections, isotonic solutions and the like.

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

Here, the diluent means a material other than the compound represented by the general formula (I), and may be a solid, a semi-solid, a liquid or an ingestible capsule, and various ones can be mentioned, for example, shaping. Agents, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, flavoring agents, flavoring agents, dyes, fragrances, preservatives, solubilizing agents, solvents, coating agents , Sugar coatings, etc. However, it is not limited to this. They are also used as a mixture of one or more. Such pharmaceutically acceptable diluents may also be used in admixture with other pharmacological agents.

The medicament of the compound of the present invention may be produced by any known method. For example, the active ingredient is mixed with a diluent, for example granules, and then the composition is shaped into tablets, for example. Parenteral preparations should be sterile. It should also be isotonic with blood if necessary.

In the present invention, the compound represented by the above general formula (I) can be a drug for treating liver diseases per se.
The active ingredient is generally included in the composition in an amount of 0.01 to 100% (by weight).

In the case of a dosage unit formulation, the individual formulation parts forming the formulation may be in different forms or may be the same, for example the following forms are often adopted: tablets, Granules, pills, powders, dragees, capsules, ampoules, etc.

The medicament for treating liver disease according to the present invention can be applied to humans and animals for the prevention and treatment of liver disease by a method commonly used in the art. It is administered orally or parenterally. Oral administration includes sublingual administration. Parenteral administration includes administration by injection (including subcutaneous, intramuscular, intravenous injection, and drip).

The dose of the drug of the present invention may be an animal or a human, the sensitivity difference, age, sex, body weight, administration method, administration time, interval, medical condition, physical condition, property of pharmaceutical preparation, preparation. It varies depending on various causes such as the type of the ingredient and the type of the active ingredient.

Therefore, in some cases it may be sufficient to administer less than the lowest dose shown below, and in some cases, it may be necessary to administer more than the following upper dose.

In the case of large dose administration, it is preferable to administer in several divided doses per day.

In order to obtain effective results in animals, when orally administered as the active ingredient, 0.1 to 500 m / kg body weight per day
g, preferably in the range of 0.1-30 mg, for parenteral administration,
0.01-250 mg / kg / day, preferably 0.1-25 mg / day
Is preferred.

The dose for effective results in humans is
Considering the difference in sensitivity and the safety from the effective dose in animals, for example, the following dose ranges would be advantageous. In the case of oral administration, 0.1 to 200 mg / kg body weight per day, preferably 0.5 to
50 mg, 0.01 mg / kg body weight per day for parenteral administration
~ 100 mg, preferably 0.1-25 mg.

Examples of the present invention will be shown below.

All parts in the following examples are parts by weight. The types and proportions of the compounding ingredients can be variously changed.

Example 1 Compound 2 10 parts Heavy magnesium oxide 10 parts Lactose 80 parts are uniformly mixed to obtain a powder or fine powder to prepare a powder.

Example 2 Compound 15 10 parts Synthetic aluminum silicate 10 parts Calcium hydrogen phosphate 5 parts Lactose 75 parts A powder is prepared in accordance with Example 1.

Example 3 Compound 23 50 parts Starch 10 parts Lactose 15 parts Crystalline cellulose 20 parts Polyvinyl alcohol 5 parts Water 30 parts After uniformly kneading, crushing and granulating, drying and sieving to obtain granules.

Example 4 99 parts of the granules obtained in Example 3 are mixed with 1 part of calcium stearate and compression-molded to give tablets having a diameter of 10 mm.

Example 5 Compound 36 95 parts Polyvinyl alcohol 5 parts Water 30 parts is prepared in the same manner as in Example 3 to prepare a granule. To 90 parts of the obtained granules, 10 parts of crystalline cellulose is added and compression-molded to give tablets with a diameter of 8 mm. Further, a sugar-coated tablet is prepared by using an appropriate amount of syrup, gelatin, a mixed suspension of precipitated calcium carbonate and a pigment in the tablet.

Example 6 Compound 41 0.5 parts Nonionic surfactant 25 parts Physiological saline 97 parts is mixed by heating and sterilized to give an injection.

Example 7 A commercially available capsule container is filled with the powder obtained in Example 1 to prepare capsules.

Test Example 1 Carbon tetrachloride liver damage inhibitory effect Test method A test compound is dissolved or suspended in olive oil and orally administered to mice (6-week-old dd strain ♂) at a rate of 30 mg / kg, and 6 hours after that, tetrachloride Carbon was orally administered at a rate of 0.05 ml / kg, and 24 hours after the administration of carbon tetrachloride, the mice were sacrificed, 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-pyruvic transaminase (GPT) activity was measured according to the Reitman-Frankel method, and the activity was expressed in units of carmen (KU). The liver damage index is as follows.

Liver damage index Liver symptoms 0 Healthy liver 2 Slightly affected 4 Clearly recognized 6 Severe damage 1 Group 5 mice were used, but the average value is shown. Also GP
For the T activity above 2,100 units, no further measurement was performed, but for convenience, it was calculated as 2,100 units.

The results are shown in Table 2.

The results in Table 2 show that the compound of the present invention has an improved liver injury index and p-GPT and has a liver injury inhibitory effect as compared with the carbon tetrachloride administration group. Further, it shows excellent p-GPT activity as compared with known compounds, and it can be seen that it is useful as a liver injury inhibitor.

Claims (5)

[Claims] 1. General formula (I): [In the formula, R ¹ represents a lower alkyl group or an allyl group, R ² represents a lower haloalkyl group, an alkenyl group, a 3-halo-2-hydroxypropyl group or (R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a phenyl group, and R ⁴ represents one or two selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkoxy group and a nitro group. A phenyl group which may be substituted with a group, a heterocyclic group or a lower alkoxycarbonyl group)]. 2. General formula (II): (Wherein R ¹ represents a lower alkyl group or an allyl group, M represents a hydrogen atom or an alkali metal atom) and a compound represented by the general formula (III): R ² X (III) [wherein R ² Is a lower haloalkyl group, an alkenyl group, 3-
Halo-2-hydroxypropyl group or (R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a phenyl group, and R ⁴ represents one or two selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkoxy group and a nitro group. A phenyl group which may be substituted with a group, a heterocyclic group or a lower alkoxycarbonyl group), and X represents a halogen atom] is reacted with a compound represented by the general formula (I) : (Wherein R ¹ and R ² are the same as above). 3. General formula (IV): (Wherein R ¹ represents a lower alkyl group or an allyl group) and a compound represented by the general formula (V): R ² OH (V) [wherein R ² is a lower haloalkyl group, an alkenyl group, 3-
Halo-2-hydroxypropyl group or (R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a phenyl group, and R ⁴ represents one or two selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkoxy group and a nitro group. A phenyl group which may be substituted with a group, a heterocyclic group or a lower alkoxycarbonyl group)] is reacted in the presence of a condensing agent to give a compound of the general formula (I): (Wherein R ¹ and R ² are the same as above). 4. General formula (VI): [In the formula, R ¹ represents a lower alkyl group or an allyl group, R ² represents a lower haloalkyl group, an alkenyl group, a 3-halo-2-hydroxypropyl group or (R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a phenyl group, and R ⁴ represents one or two selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkoxy group and a nitro group. A phenyl group, a heterocyclic group or a lower alkoxycarbonyl group which may be substituted with a group) is reacted with carbon disulfide in the presence of a base, and then the reaction product is generally reacted. Formula (VII): (Wherein Y represents a halogen atom), and a compound represented by the general formula (I): (Wherein R ¹ and R ² are the same as above). 5. General formula (I): [In the formula, R ¹ represents a lower alkyl group or an allyl group, R ² represents a lower haloalkyl group, an alkenyl group, a 3-halo-2-hydroxypropyl group or (R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a phenyl group, and R ⁴ represents one or two selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkoxy group and a nitro group. A phenyl group which may be substituted with a group, a heterocyclic group or a lower alkoxycarbonyl group)] is contained as an active ingredient.