Method of curing hepatic disease

Abstract

A method of curing or alleviating hepatic disease comprising administrating to the patient 1,3-dithiole-2-thione or 1,3-dithiolane-2-thione is disclosed. Adminstration of the compound can be made in various dosing forms, including tablets, granules, powders, capsules, suspensions, injections, and suppositories. Normal dosing amount can be determined from the range of 0.01 to 50 mg/kg/day for oral administration, and 0.002 to 10 mg/kg/day for injection or other forms of administration.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a method of curing or alleviating hepatic diseases.

2. Description of the Background

Very few therapeutic agents have been known in the art which are effective for serious hepatic diseases such as cirrhosis of the liver or the like. Only diisopropyl-1,3-dithiol-2-ylidenemalonate (generally known as Malotilate), which has an amelioration effect of liver protein metabolism, is known as a medicine effective against cirrhosis of the liver.

However, since Malotilate is known to have side effects, there has been a need for the development of a compound which is safer than Malotilate and has the same or better pharmaceutical effect. Various kinds of 1,3-dithioles and 1,3-dithiolane derivatives have been synthesized with the intention of providing such a compound. However, none of them are yet satisfactory in terms of their pharmaceutical effect and safety. Therefore, there still exists a strong need for a compound which gives both the pharmaceutical effect and is safe.

In view of this situation, the present inventors have conducted extensive screenings on a number of compounds with respect to their therapeutic effect on hepatic diseases and their safety, and as a result have found that certain cyclic sulfur-containing compounds are excellent therapeutic agents for hepatic diseases and can satisfy the requirements of therapeutic effectiveness and safety. Such a finding has led to the completion of this inention.

SUMMARY OF THE INVENTION

Accordingly an object of this invention is to provide a a method of curing or alleviating hepatic diseases such as cirrhosis, alcoholic hepatitis, virus-derived hepatitis, and the like, which comprises administrating to a patient an effective amount of a cyclic sulfur-containing compound represented by the following formula (I): ##STR1## in which the dotted line is optionally present. The groups R.sub.1 and R.sub.2 may independently be selected from hydrogen; C.sub.1-20 alkyl groups (e.g., methyl, ethyl, isobutyl, dodecyl) which are optionally substituted with halogen (i.e. F, Br, Cl, I), hydroxyl, lower alkoxy, amino, lower alkylamino, carboxyl, lower alkoxycarbonyl, cyano, C.sub.6-10 aryl (e.g. phenyl, naphthyl) or the like; C.sub.2-12 alkenyl groups (e.g. vinyl, allyl, isobutenyl, decenyl) which may optionally be substituted with halogen (i.e. F, Br, Cl, I), hydroxyl, carboxyl, C.sub.6-10 aryl (e.g. phenyl, naphthyl) or the like; C.sub.6-10 aryl (e.g. phenyl, naphthyl) groups which may optionally be substituted with halogen (i.e. F, Br, Cl, I), lower alkyl, hydroxyl, lower alkoxy, amino, lower alkylamino, carboxyl, lower alkoxycarbonyl, cyano, nitro, C.sub.6-10 aryl (e.g. phenyl, naphthyl), C.sub.6-10 aryloxy (e.g. phenoxy, naphthoxy), sulfonyl, formyl, carbamoyl, C.sub.1-6 acyl (e.g. acetyl), C.sub.7-11 aroyl (e.g. benzoyl, naphthoyl), or the like. By lower is meant C.sub.1-4 groups.

In a preferred embodiment of the invention, R.sub.1 and R.sub.2 are independently selected from hydrogen, C.sub.1-4 alkyl groups, C.sub.2-4 alkenyl groups, and C.sub.6-7 aryl groups.

In a more preferred embodiment, R.sub.1 and R.sub.2 are each hydrogen.

Other objects, features and advantages of the invention will hereinafter become more readily apparent from the following description.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The compounds shown by the above formula (I), wherein R.sub.1 and R.sub.2 are H, are known compounds. The compound with the dotted line, i.e., the compound of the following chemical structure (Ia) is 1,3-dithiole-2-thione. This compound was synthesized by R. Mayer et al [Chemische Berichte, 97, 1298 (1964)] and C. H. Chen [J. Chem. Soc., Chemical Communication, 920-921 (1976)]. ##STR2##

The compound without the dotted line in formula (I), which has the chemical structure (Ib), is 1,3-dithiolane-2-thione, and was synthesized by C. C. J. Culvenor et al [J. Chem. Soc. 1050-1052 (1946)] ##STR3##

The substituted derivatives of (I) may be prepared from appropriately substituted starting materials.

However, to the inventors' knowledge there have been no reports in the art on any pharmaceutical effects of these compounds.

Hereinafter are presented experimental examples to further illustrate the effectiveness of the invention. These examples are given for illustration of the invention and are not intended to be limiting thereof.

EXPERIMENTAL EXAMPLES

As shown in the test described below, in which hepatic disorder was experimentally induced in animals by the administration of carbon tetrachloride or galactosamine, the compound (Ia) depressed changes in the outward appearance of the liver, and (Ia) and (Ib) exhibited a remarkable suppression of GOT and GPT activities in serum. While the following experimental examples were carried out with (Ia) and (Ib), the substituted derivatives of (I) are expected to show similar therapeutic results.

EXPERIMENTAL EXAMPLE 1

Several groups of ddY male mice, each group consisting of 5 mice, aged 5 weeks and weighing approximately 25 g, were provided for the test. The mice were fasted for 16 hours and were given 0.05 ml/kg of carbon tetrachloride mixed with olive oil by oral administration to provide a dose (as a mixture of carbon tetrachloride and olive oil) of 10 ml/kg. At the same time, 1,3-dithiole-2-thione (Ia), 1,3-dithiolane-2-thione (Ib), or Malotilate, the comparative agent, each dissolved in olive oil to give the prescribed concentration, was given to each mouse in a given group. Blood was collected from each mouse at 24 hours after administration for measurement of GOT and GPT activities in serum. The results are shown in Table 1 below.

TABLE 1______________________________________ Dose GOT GPT (mg/kg p.o.) (IU/L) (IU/L)______________________________________Control Group -- 80 30Groups given only -- 12700 6340carbon tetrachlorideGroups given 0.1 5740 3880carbon tetrachloride 1 110 30and compound (Ia) 10 90 30Groups given 8 130 40carbon tetrachloride 40 90 20and compound (Ib) 200 70 20Groups given 20 8540 6260carbon tetrachloride 100 3220 2290and Malotilate 500 440 310______________________________________

Histological observations were made on the test animals to detect the presence of a liver necrosis. As a result, a centrilobular liver necrosis was found in animals of the group to which only carbon tetrachloride had been administered, while in the groups to which 100 mg/kg or more of Malotilate were given, the degree of centrilobular liver necrosis was less significant than in the group of animals to which only carbon tetrachloride had been administered. On the other hand, there was no centrilobular liver necrosis observed in animals of the groups to which 1 mg/kg or more of the compound (Ia) was administered.

EXPERIMENTAL EXAMPLE 2

Several groups of Wister male rats, each group consisting of 4 rats, age 6 weeks, were provided for the test. The rats were not fed overnight, and 1 ml/kg of carbon tetrachloride as a 20% solution in olive oil was subcutaneously injected into each rat. At the same time, a prescribed amount of 1,3-dithiole-2-thione (Ia) or Malotilate was administered orally to each rat. Blood was collected from each rat at 48 hours after administration for measurement of GOT, GPT, ALP, and LDH activities as well as TCHO and GLU concentrations in serum. The results are shown in Table 2.

TABLE 2__________________________________________________________________________ Dose GOT GPT ALP LDH TCHO GLU (mg/kg p.o.) (IU/L) (IU/L) (IU/L) (IU/L) (mg/dl) (mg/dl)__________________________________________________________________________Control Group -- 110 30 1525 2968 81 13Groups given only -- 6170 2080 3322 2203 109 10carbon tetrachlorideGroups given 0.08 5910 2020 2775 2707 105 11carbon tetrachloride 0.4 3420 1160 2622 2792 75 11and compound (Ia) 2 750 280 2075 3022 63 13 10 900 360 2262 2393 55 12Groups given 4 9040 2610 2989 4010 112 10carbon tetrachloride 20 4390 1550 2513 3195 117 11and Malotilate 100 3450 1180 2325 4204 129 11 500 900 300 1687 3765 101 13__________________________________________________________________________

EXPERIMENTAL EXAMPLE 3

Several groups of Wister male rats, each group consisting of 5 rats, age 5 weeks, were provided for the test. To each of the rats 1,3-dithiole-2-thione (Ia) or Malotilate, each dissolved in olive oil, was administered orally. Six (6) hours later 400 mg/kg of D-galactosamine was abdominally administered. Blood was collected from each rat at 24 hours after administration of D-galactosamine for measurement of GOT, GPT, ALP, and LDH activities as well as TCHO and GLU concentrations in serum. The results are shown in Table 3.

TABLE 3__________________________________________________________________________ Dose GOT GPT ALP LDH TCHO GLU (mg/kg p.o.) (IU/L) (IU/L) (IU/L) (IU/L) (mg/dl) (mg/dl)__________________________________________________________________________Control Group -- 96 28 1370 2140 77 14Groups given only -- 616 288 2117 3468 43 11D-galactosamineGroups given 2 360 156 1815 2984 35 10D-galactosamine 10 380 148 1900 2708 33 12and compound (Ia) 50 196 72 1791 2220 66 14Groups given 20 596 256 1977 3504 30 10D-galactosamine 100 268 96 1990 2604 41 12and Malotilate 500 248 76 1900 3492 56 12__________________________________________________________________________

As is evident from the above results, the administration of carbon tetrachloride or D-galactosamine brings about a significant increase in values of GOT, GPT and ALP in serum of as much as 1.5 times or much more. Also, it is shown that administration of the compounds (Ia) or (Ib), or Malotilate decreases these values almost dose dependently. Such meaningful decrease can be realized with respect to compound (Ia) at a dose of about 2 mg/kg, and with respect to Malotilate at a dose of at least 100 mg/kg or more. The LD.sub.50 value of the compound (Ia) is from 125 to 250 mg/kg (mouse; p.o.) and that of the compound (Ib) is not less than 500 mg/kg (mouse; p.o.). This evidence suggests that the compounds of formula (Ia) and (Ib) are safer than Malotilate. More specifically, from the ED.sub.50 values determined from the results shown in Table 2, the safety coefficient (LD.sub.50 /ED.sub.50) for compound (Ia) can be calculated as 260.4-520.8. On the other hand, Malotilate, which has an LD.sub.50 value of 4,000-8,000 mg/kg and an ED.sub.50 value of 118 mg/kg as determined from Table 2, has a safety coefficient (LD.sub.50 /ED.sub.50) of 33.9-67.8. Thus, it is concluded that the compound (Ia) of the present invention is 4-15 times safer than Malotilate.

As illustrated above, the compounds (Ia) and (Ib) exhibit a remarkably high liver disorder suppressing effect and safety as compared with the comparative agent Malotilate. It is expected that similar results would be obtained with the substituted derivatives of (I).

Although the amount of dosage of the compound (I) used as a hepatic disease therapeutic agent may vary depending on the body weight, age, sex of the subject, the manner by which it is administered, the conditions and significance of disease of the subject, and the like, a generally appropriate amount may be from 0.01 to 50 mg per day per kg of body weight of the subject when it is orally administered, and from 0.002 to 10 mg per day per kg of body weight when it is otherwise administered.

The hepatic disease therapeutic agent used in the method of the present invention can be prepared in various dosing forms according to conventional methods, such as tablets, granules, powders, capsules, suspensions, injections, suppositories, or the like. When it is prepared in a solid dosing form for oral administration, various additives such as a binder, disintegrator, glossing agent, coloring agent, flavor, extending agent, coating agent, sugar coating agent, and the like, are compounded as appropriate, and then formed into tablets, granules, powders, capsules, or the like according to conventional methods. When an injection is prepared using this compound (I) as a main active agent, the compound is dissolved as required in an oil or fat such as olive oil, sesame oil, or the like, and made into a liquid for subcutaneous muscle injection. Alternatively, it is possible to prepare an intravenous injection liquid or an infusion fluid by adding a surface active agent to the formulation. A suppository ca be prepared by adding coconut butter or a medium-chain fat fatty acid glycerol ester to the compound (I), and by heating and kneading the mixture before shaping it into a suppository.

Other features of the invention will become apparent in the course of the following description of the exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

FORMULATION EXAMPLES

______________________________________Example 1Tablet______________________________________1,3-dithiole-2-thione (Ia) 50 mgcrystallized cellulose 50 mglactose 50 mghydroxypropylcellulose 18 mgmagnesium stearate 2 mgTotal 170 mg______________________________________

The tablet of the above composition ca be made into a sugar coated or film coated tablet.

______________________________________Example 2Capsule______________________________________1,3-dithiole-2-thione (Ia) 50 mglight silicic acid anhydride 25 mglactose 100 mgstarch 50 mgtalc 25 mgTotal 250 mg______________________________________

The above components were filled in a No. 1 capsule.

______________________________________Example 3Granule______________________________________1,3-dithiole-2-thione (Ia) 50 mglactose 600 mgcorn starch 200 mgsodium carboxymethylcellulose 20 mghydroxypropylcellulose 130 mgTotal 1,000 mg______________________________________

The above amounts of the components were made into a granule by a conventional method.

______________________________________Example 4Powder______________________________________1,3-dithiole-2-thione (Ia) 50 mglight silicic acid anhydride 20 mgprecipitating calcium carbonate 10 mglactose 250 mgstarch 70 mgTotal 400 mg______________________________________

The above amounts of the components were made into a powder by a conventional method.

______________________________________Example 5Suppository______________________________________1,3-dithiole-2-thione (Ia) 10 mgcoconut butter 890 mgTotal 900 mg______________________________________

The above amounts of the components were made into a suppository by a conventional method.

______________________________________Example 6Injection______________________________________1,3-dithiole-2-thione (Ia) 10 mghydrogenated castor oil 80 mgpropylene glycol 60 mgdextrose 50 mg______________________________________

The above components were dissolved in distilled water for injection to make the total volume to 1 ml to prepare an injection fluid by a conventional method.

______________________________________Example 7Tablet______________________________________1,3-dithiole-2-thione (Ia) 2 mgcrystallized cellulose 74 mglactose 74 mghydroxypropylcellulose 18 mgmagnesium stearate 2 mgTotal 170 mg______________________________________

The tablet of the above composition can be made into a sugar coated or film coated tablet.

______________________________________Example 8Injection______________________________________1,3-dithiole-2-thione (Ia) 1 mgpolyoxyethylene hydrogenated 40 mgcastor oilpropylene glycol 60 mg______________________________________

The above components were dissolved in distilled water for injection to make the total volume to 1 ml to prepare an injection fluid by a conventional method.

______________________________________Example 9Tablet______________________________________1,3-dithiolane-2-thione (Ib) 50 mgcrystallized cellulose 50 mglactose 50 mghydroxypropylcellulose 18 mgmagnesium stearate 2 mgTotal 170 mg______________________________________

The tablet of the above composition can be made into a sugar coated or film coated tablet.

______________________________________Example 10Injection______________________________________1,3-dithiolane-2-thione (Ib) 10 mgpolyoxyethylene hydrogenated 40 mgcastor oilpropylene glycol 60 mg______________________________________

The above components were dissolved in distilled water for injection to make the total volume to 1 ml to prepare an injection fluid by a conventional method.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims

1. A method of curing of alleviating hepatic disease in a mammal suffering from a hepatic disease selected from the group consisting of cirrhosis, alcoholic hepatitis, and virus-derived hepatitis, comprising: administrating to said mammal a therapeutically effective amount of a cyclic sulfur-containing compound represented by the following formula (I): ##STR4## wherein the dotted line is optionally present and wherein the groups R.sub.1 and R.sub.2 are independently selected from the group consisting of hydrogen; C.sub.1-20 alkyl groups and C.sub.2-12 alkenyl groups.

2. The method according to claim 1, wherein R.sub.1 and R.sub.2 are independently selected from the group consisting of hydrogen, C.sub.1-4 alkoxy groups, and C.sub.2-4 alkenyl groups.

3. A method according to claim 1, wherein R.sub.1 and R.sub.2 are each hydrogen.

4. A method according to claim 1, wherein said compound is administered in combination with a pharmacologically acceptable carrier.

5. A method according to claim 1, wherein the mammal is a human being.

6. A method according to claim 1, wherein the compound (I) is administered orally in an amount of from 0.01 to 50 mg per day per kg of body weight of said mammal.

7. A method according to claim 1, wherein the compound (I) is administered by intramuscular injection, intravenous injection, infusion fluid, or suppository in an amount of from 0.002 to 10 mg per day per kg of body weight of said mammal.