Cyclic sulfur-containing compounds

Abstract: This invention relates to cyclic sulfur-containing compounds of the formula [I] and salts thereof which are useful for immunomodulator and treatment of liver diseases.

Description: This invention relates to the compounds of the formula [I] and pharmaceutically acceptable salts thereof (hereinafter called "the compound"):- wherein each of R¹ and R² (which may be the same or different) is hydrogen or C₁-C₆ alkyl, and R³ is hydrogen or C₁-C₆ alkyl; The C₁-C₆ alkyl may have a straight or a branched chain and may be exemplified by methyl, ethyl, propyl, isopropyl and hexyl. There have been various studies on cysteine derivatives. However, concerning cyclic disulfide compounds having an amino acid moiety in their chemical structure, very few studies on synthesis and application to medicines have been made. Especially, the possibility of the application to medicines has only been disclosed in US Patent 4517123. Likewise, there have been few studies on cyclic sulfide compounds having an amino acid moiety in their chemical structure, but application to medicines of these compounds is not known. One report on the chemical synthesis of 1,4-thiazepine derivatives has been published in Can.J. Chem., 49 , 3866(1971). Accordingly, the influence on pharmacological efficacy by variations of the chain length of the ring or by substitutions of radicals is almost unknown, and it is required to synthesize such cyclic compounds and study the possibility of applications to medicines. As the result of the studies on chemical synthesis and pharmacological effect of such novel compounds, we found that the compounds have excellent suppressing effect on liver disorders and immunomodulating effect. The compound represented by the formula [I] can be prepared by oxidation of the compound of the formula [II] with a generally used oxidant such as metal salt, oxygen, halogen, hydrogen peroxide or diethyl bromomalonate. When R³ is hydrogen in the compound of the formula [I], it can be easily esterized with diazomethane etc. to obtain the Compound wherein R³ is C₁-C₆ alkyl. Conversely, when R³ is C₁-C₆ alkyl in the compound of the formula [I], it can be easily hydrolyzed with sodium hydroxide etc. to obtain the Compound wherein R³ is hydrogen. The compound of the formula [I] can be converted into a pharmaceutically acceptable salt of an inorganic or organic base. Examples of the salts are sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, diethylamine salt and triethanolamine salt. The compounds of this invention have stereoisomers because of the existence of one of more asymmetric carbon atom, and these isomers are included in this invention. A liver disorder model caused by an administration of CCl₄ to a rat is widely used to examine efficacy of a compound on liver diseases. GOT and GPT values in the serum are used as an indication of a degree of liver disorder. If the value, which is raised by liver disorder, falls by an administration of a compound, the compound is judged effective on liver disorder. As the result of the experiment, whose detailed data are shown in the article of pharmacological test, using the Compound, we found that the GOT and GPT values in the group treated with the Compound is significantly decreased as compared with that in the untreated group. The experiment proves that the Compound has a suppressive effect on liver disorder. Recently, immunity has been thought to relate closely to the mechanism of development and chronicity of liver disorder. To examine influences of the Compound on the immune system, we examined the immune response of mice to sheep red blood cells which is usually used to examine immunomodulating effect. This experimental method is to examine the efficacy on the immune system according to increase or decrease of the number of haemolytic plaque-forming cells of mouse spleen cells. As shown in the pharmacological test, the Compound shows an excellent immunosuppressive effect. A compound, which has a similar chemical structure to the Compound, is disclosed in US Patent 4517123. It is generally recognized that very slight modification of the chemical structure greatly influences the efficacy of a compound. So, we examined how the modification of the chemical structure influences to the efficacy. We made a comparative test on the immunosuppressive effect of the Compound and the known compound represented by the formula [III]. As shown in the pharmacological test, the Compound shows a greater effect than the compound described in the US Patent. As the result, we found that the compound must be a new type of drug for liver diseases because the compound decreased the value of GOT and GPT in serum and suppressed the immunity. Furthermore, the Compound, which has excellent immunomodulating effect, can be used as a drug not only for liver diseases but for various immune diseases exemplified by autoimmune diseases such as rheumatoid arthritis. The Compound can be administered either orally or parenterally. Examples of dosage forms are tablet, capsule, powder, granule, injection, suppository, eye drops and percutaneous. The dosage is adjusted depending on symptom, dosage form, etc., but usual daily dosage is 1 to 5000mg in one or a few divided doses. Examples of preparations of the compounds and formulations are shown below. EXAMPLE Example 1 (4R)-Hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid (compound No.1) 1) To a solution of diethyl bromomalonate (10.5g) and triethylamine (8.5g) in methylene chloride (3.8ℓ), N-(2,2-dimethyl-3-mercaptopropionyl)-L-cysteine (9.5g) dissolved in methylene chloride (0.3ℓ ) was added dropwise under ice-salt cooling. After the addition, the reaction mixture was stirred for 30 minutes at the same temperature and for 30 minutes at room temperature. The mixture was acidified with 6N hydrochloric acid and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Separated crystals were collected by filtration to give 6.1g (65%) of the titled compound. mp 160 - 162°C (ethyl acetate) IR (KBr, cm⁻¹) 3444, 3376, 1730, 1627, 1507, 1403, 1202, 1185 [α] 25 / D : -110.8° (c=1.0, methanol) 2) By the following method, the titled compound was also obtained. To a solution of triethylamine (13.3g) in methylene chloride (0.5ℓ), N-(2,2-dimethyl-3-mercaptopropionyl)-L-cysteine (15.6g) dissolved in methylene chloride (0.5ℓ) and iodine (18.3g) dissolved in methylene chloride (0.5ℓ) were added dropwise simultaneously under ice-salt cooling. After the addition, the reaction mixture was stirred for 1 hr at the same temperature. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Separated crystals were collected by filtration to give 8.5g (55%) of the titled compound. Example 2 (4R)-Hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid methyl ester (compound No. 2) To a solution of the compound No.1 (11.0g) in methyl acetate (250ml), 3.9N hydrochloric acid in ethyl acetate (4ml) was added. Diazomethane dissolved in ether (180ml) was added to the reaction mixture under ice-salt cooling and the mixture was stirred for 10 minutes. Acetic acid (6ml) was added to the mixture and it was concentrated in vacuo. Resulting oily residue was purified by silica gel column chromatography to give 10.3g (88%) of the titled compound. mp 87.0 - 89.0°C IR (KBr, cm⁻¹ ) 3360, 1740, 1661, 1504, 1436, 1343, 1199, 615 [α] 25 / D : -100.7° (c=1.0, methanol) Example 3 (4S)-Hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid (compound No.3) By the similar procedure as Example 1 using diethyl bromomalonate (16.6g), triethylamine (13.4g) and N-(2,2-dimethyl-3-mercaptopropionyl)-D-cysteine (15.0g), 9.8g (66%) of the titled compound was obtained. mp 159.5 - 161.5°C (ethyl acetate) IR (KBr, cm⁻¹ ) 3450, 3376, 1729, 1625, 1505, 1401, 1202, 1184 [α] 25 / D : +110.2° (c=1.0, methanol) Example 4 (4R)-Hexahydro-7,7-diethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid (compound No. 4) By the similar procedure as Example 1-2) using N-[2-ethyl-2-(mercaptomethyl)butyryl]-L-cysteine (2.7g), 1.8g (67%) of the titled compound was obtained. mp 127 - 128.5 °C (ethyl acetate - hexane) IR (KBr, cm⁻¹ ) 3308, 1713, 1642, 1518, 1449, 1397, 1199, 1176 [α] 25 / D : -90.3° (c=1.0, methanol) Example 5 (formulations) 1)tablet The Compound and excipients were mixed and compressed directly to prepare the following tablet. The compound number in the formulation is the same as the above Examples (the same shall be applied hereinafter). compound No.1 100mg crystalline cellulose 20mg lactose 40mg hydroxypropylcellulose-L 5mg magnesium stearate 5mg total 170mg 2) capsule The following capsule was prepared using the compound No.1, lactose and magnesium stearate. compound No.1 5mg magnesium stearate 3mg lactose 142mg total 150mg By changing the ratio of the compound No.1 and lactose, capsules, which contains 10mg, 30mg, 50mg or 100mg of the compound No.1, were prepared. 3) granule The following granule was prepared by a usual method mixing the compound No.1, lactose and starch and using methanol solution of hydroxypropylcellulose-L as a binding agent. compound No.1 50mg lactose 55mg starch 20mg hydroxypropylcellulose-L 4mg tarc a little total 130mg PHARMACOLOGICAL TEST The rat liver disorder model caused by CCl₄ is generally used to examine the efficacy of a drug for liver diseases. We examined the efficacy of the compound on liver disorder using the rat model. Furthermore, we examined the immunomodulating effect of the Compound using immunoresponse against sheep red blood cells of mouse, which is generally used to examine the efficacy on immune system. 1) The effect on the liver disorder caused by CCl₄ . The test compound was suspended in tragacanth gum solution and administered orally to male Wistar rats ( 5 rats a group) at a dose of 300mg/kg. Thirty minutes later, CCl₄, a liver disorder inducer, was given intraperitoneally at a dose of 0.25ml/kg. Serum GOT and GPT levels were measured 24 hours after the administration of CCl₄ . To a control, 0.5% tragacanth gum solution was given. The results of the experiment with the compound No.1, a typical compound of this invention, is shown in the Table 1. Test Compound GOT GPT control 18693 10026 compound No.1 12642 6006 As shown in Table 1, the GOT and GPT values of the group given the Compound was significantly lower than that of the control. The result proved that the Compound has an excellent effect on liver disorder. 2) The effect on immune response of mice to sheep red blood cells. According to the method of Iso et. al. ( Int. J. Immunotherapy, 1 , 93 (1985)), 5 X 10⁸ sheep red blood cells were administered intraperitoneally to female BALB/c mice ( 3 to 5 mice a group ) and immunized. After immunization, the test compound suspended in 1% methyl cellulose solution was administered continuously for 4 days. Mice were killed and the number of haemolytic plaque-forming spleen cells were measured. Fifty percent suppressive dose was calculated based on the cell count. For a comparison, the similar test with the known compound of the formula[III] as identified hereinbefore described in US Patent 4517123 was performed. The results of the experiment with the compound No. 1, a typical compound of this invention, and the known compound are shown in Table 2. Test Compound 50% suppressive dose compound No.1 1.23 mg/kg known compound 7.12 mg/kg As shown in Table 2, the Compound shows excellent immunosuppressive effect and its effect is more potent than that of the known compound.

Claims: Claims for the following Contracting States : AT, BE, DE, FR, GB, IT, LU, NL, CH, LI, SE A compound of the formula [I]: wherein each of R¹ and R² (which may be the same or different) is hydrogen or C₁-C₆ alkyl, and R³ is hydrogen or C₁-C₆ alkyl; or a pharmaceutically acceptable salt of the compound of the formula [I]. Hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid or a pharmaceutically acceptable salt thereof. A pharmaceutical composition useful for the treatment of autoimmune diseases, comprising (i) a pharmaceutical carrier and (ii) a compound of the formula [I] as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, in an amount sufficient for the treatment of autoimmune diseases. A process for preparing a compound of the formula [I] or a pharmaceutically acceptable salt thereof as defined in claim 1, said process comprising oxidising a compound of the formula [II]: wherein R¹, R² and R³ are as defined in claim 1; and if necessary when R³ in the compound of the formula [II] is hydrogen, esterifying the acid to form a compound of the formula [I] where R³ is C₁-C₆ alkyl; or if necessary when R³ in the compound of the formula [II] is C₁-C₆ alkyl, hydrolyzing the ester to form a compound of the formula [I] where R³ is hydrogen. The use of a compound as claimed in claim 1 or 2 for the manufacture of a medicament for the treatment of autoimmune diseases. Claims for the following Contracting States : ES, GR A process for preparing a compound of the formula [I]: wherein each of R¹ and R² (which may be the same or different) is hydrogen or C₁-C₆ alkyl, and R³ is hydrogen or C₁-C₆ alkyl; or a pharmaceutically acceptable salt of the compound of the formula [I]; said process comprising oxidising a compound of the formula [II]: and if necessary when R³ in the compound of the formula [II] is hydrogen, esterifying the acid to form a compound of the formula [I] where R³ is C₁-C₆ alkyl; or if necessary when R³ in the compound of the formula [II] is C₁-C₆ alkyl, hydrolyzing the ester to form a compound of the formula [I] where R³ is hydrogen. A process as claimed in claim 1, wherein the compound of the formula [I] is hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid or a pharmaceutically acceptable salt thereof. A process as claimed in claim 1 or 2, wherein the oxidizing of the compound of formula [II] is effected by means of an oxidant selected from a metal salt, oxygen, a halogen, hydrogen peroxide and diethyl bromomalonate. A process for producing a pharmaceutical composition useful for the treatment of autoimmune diseases, comprising mixing (i) a pharmaceutical carrier with (ii) a compound of the formula [I] as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, in an amount sufficient for the treatment of autoimmune diseases. The use of a compound of the formula [I] or a pharmaceutically acceptable salt thereof as defined in claim 1 or 2 for the manufacture of a medicament for the treatment of autoimmune diseases.

Inventors: ISO TADASHI, KAWASHIMA YOUICHI, MITA SHIRO, MORITA TAKAKAZU KITASAKURAZUKA, ISO, TADASHI, KAWASHIMA, YOUICHI, MITA, SHIRO, MORITA, TAKAKAZU 302 KITASAKURAZUKA PARK HEIM
Applicants: SANTEN PHARMA CO LTD, SANTEN PHARMACEUTICAL CO., LTD.
Application year: 1989
Main classification: C07D285
IPC codes: C07D281, C07D285