JPH0684362B2 - Cyclic sulfur-containing compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION "Industrial field of application" The present invention relates to a novel compound having an effect of suppressing liver damage, an immunomodulatory effect and the like.

“Prior Art” Although much research has been conducted on cysteine derivatives, almost no research has been conducted on the synthesis of cyclic disulfide compounds containing an amino acid as a part of their structure and their applicability as pharmaceuticals. In particular, its applicability as a medicine was only slightly as described in JP-B-61-43350.

On the other hand, research on a cyclic sulfide compound containing an amino acid as a part of its structure has not been conducted much, and
Can.J.Chem., 49 , 3866 (1971) describes a method for synthesizing a 1,4-thiazepine derivative, and its application as a medicine has not been known.

"Problems to be Solved by the Invention and Means for Solving the Problems" There have been almost no studies on the synthesis and availability of medicinal agents of cyclic sulfides and disulfide derivatives containing an amino acid as a part of the structure. Little was known about the effect on the effect of changing the size of the compound or introducing a substituent. Therefore,
It was necessary to synthesize these derivatives and study their potential utility as pharmaceuticals.

As a result of synthesizing these novel compounds and examining their effects, the present inventors have found that they have an excellent liver damage inhibitory action and immunomodulatory action.

"Structure of the Invention" The present invention relates to a compound represented by the following general formula [I] and salts thereof (hereinafter referred to as the present compound).

[In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or a lower alkyl group.

R ³ represents a hydrogen atom or a lower alkyl group.

X represents S, SO, SO ₂ or SS.

m represents 0 or 1.

n represents 1 or 2.

However, when m is 0, n is 2, and X is S, SO or SO.
_When showing ₂ , m and n do not show 1 at the same time. When the definition shown above is explained in more detail, the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, and hexyl.

This compound can be synthesized, for example, by the following methods A to C.

[A] A compound represented by the formula [II] is used as a general oxidizing agent. The present compound represented by the general formula [I-1] can be obtained by oxidation with (for example, metal salt, oxygen, halogen, hydrogen peroxide, diethyl brommalonate, etc.).

[B] The disulfide compound represented by the general formula [I-1] and an appropriate reagent such as phosphine (for example, tris (diethylamino) phosphine) are used to extract one sulfur atom to give the general formula [I-2]. The present compound represented by can be obtained.

[C] The sulfide compound represented by the general formula [I-2] is converted into a general oxidizing agent (for example, organic peroxide, halide, periodate, nitrogen oxide, hydrogen peroxide, ozone,
The present compound represented by the general formula [I-3] (wherein l represents 1 or 2) can be obtained by oxidation with a metal oxide, singlet oxygen, air, an electrode, etc.).

[D] Of the present compounds represented by the general formula [I], the compound in which R ³ is a hydrogen atom can be easily esterified with, for example, diazomethane or the like, and a compound in which R ³ is a lower alkyl group can be obtained.

On the other hand, a compound in which R ³ is a lower alkyl group can be easily hydrolyzed with, for example, sodium hydroxide, and R ³
A compound having a hydrogen atom is obtained.

The compound of the formula [I] can be optionally formed into a salt with a pharmaceutically acceptable inorganic or organic base. Examples of salts include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, diethylamine salt, triethanolamine salt and the like. The compound of the present invention is 1
Stereoisomers exist because they have one or more asymmetric carbon atoms, and both and isomers are included in the scope of the present invention.

Heretofore, almost no research has been conducted on cyclic disulfide compounds and sulfide compounds containing an amino acid as a part of the structure. Therefore, the present inventors synthesized various novel compounds in order to investigate changes in ring size, position of sulfur atom, introduction effect of substituents, etc., and examined their usefulness as therapeutic agents for liver diseases and immunomodulators. did.

As a method for investigating whether a certain compound is useful as a therapeutic drug for liver disease, a method using a carbon tetrachloride liver injury model is widely used. This model causes liver damage by administering carbon tetrachloride to rats, and GOT and GPT levels in serum are used as indicators of the damage. If these values increased due to liver damage are decreased by administration of the compound, it is judged to be effective against liver damage. Therefore, as a result of conducting an experiment using this compound, detailed data will be described in the section of the pharmacological test.However, compared with the group to which this compound was not administered, this compound-administered group showed significant GOT and GPT in serum. The value is decreasing. From this, it was clarified that this compound has a liver damage suppressing effect.

In recent years, it is considered that the immunological mechanism is deeply involved in the mechanism of onset and chronicity of liver disease. Therefore, the effect of the present compound on the immune system was examined by using an immune response to mouse sheep erythrocytes, which is often used to examine the immunomodulatory action.
This method uses the number of hemolytic plaque-forming cells of mouse splenocytes as an index, and examines the effect on the immune system by the degree of increase or decrease. As described in the section of pharmacological test, this compound showed an excellent immunosuppressive effect.

A compound having a chemical structure similar to this compound is Japanese Patent Publication No. Sho 61
-43350, it is generally accepted that slight differences in the chemical structure of organic compounds have a large effect on the effect. Therefore, in order to investigate how the difference in chemical structure affects the effect and to prove the usefulness of the present compound, the immunosuppressive effect of the compound described in the publication (shown by the following formula [III]) When a comparative test was conducted, the compound showed a far superior effect as compared with the compounds described in the publications, as shown in the section of pharmacological test.

From the above results, it was found that the present compound reduces serum GOT and GPT levels and also has an immunosuppressive effect, and can be a new type of excellent liver disease therapeutic agent. Furthermore, since the compound has an excellent immunomodulatory action, it can be used as a therapeutic agent for various diseases related to immunity other than liver disease, for example, autoimmune diseases such as rheumatoid arthritis. .

The compound may be administered orally or parenterally, and its dosage form includes tablets, capsules, powders, granules, suppositories, injections, transdermal absorption agents, eye drops and the like. The dose is determined according to symptoms, dosage form, etc., but usually 1 to 5000 mg daily
Can be administered once or in several divided doses.

The production examples and formulation examples of the present compound are shown below as Examples.

Examples Example 1 (4R) -hexahydro-7,7-dimethyl-6-oxo-
1,2,5-Dithiazosine-4-carboxylic acid (Compound 1) (i) To a solution of diethyl brommalonate (10.5 g) and triethylamine (8.5 g) in methylene chloride (3.8 l) was added N 2.
-(2,2-Dimethyl-3-mercaptopropionyl)-
A solution of L-cysteine (9.5 g) in methylene chloride (0.3 l) was added dropwise under cooling with a cryogen. At the same temperature for 30 minutes after completion of dropping, at room temperature
Stir for 30 minutes. The reaction mixture is acidified with 6N hydrochloric acid and washed with saturated saline. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The precipitated crystals are collected to give 6.1 g (65%) of the title compound.

Melting point: 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) (ii) As an alternative method, the title compound was synthesized by the following method, and the same physical property values as (i) were obtained.

A solution of triethylamine (13.3 g) in methylene chloride (0.5 l) was added with N- (2,2-dimethyl-3-mercaptopropionyl) -L-cysteine (15.6 g) in methylene chloride (0.5 l).
l) Solution and a solution of iodine (18.3 g) in methylene chloride (0.5 l) are simultaneously added dropwise under cooling with a cryogen. After the end of dropping, 1 at the same temperature
Stir for hours. The organic layer is washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were taken,
8.5 g (55%) of the title compound are obtained.

Example 2 (4R) -Hexahydro-7,7-dimethyl-6-oxo-
1,2,5-Dithiazosine-4-carboxylic acid methyl ester (Compound 2) To a solution of Compound 1 (11.0 g) in methyl acetate (250 ml) was added 3.9 N hydrochloric acid / ethyl acetate solution (4 ml). The diazomethane / ether solution (180 ml) is added under cooling with a freezing medium, and the mixture is stirred for 10 minutes. Add 6 ml of acetic acid and evaporate the solvent under reduced pressure. The obtained oily substance was purified by silica gel column chromatography to give the title compound 1
Obtain 0.3 g (88%).

Melting point: 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 Hexahydro-3,3-dimethyl-4-oxo-1,2,5-dithiazocine-6-carboxylic acid (Compound 3) Using diethyl brommalonate (25.0 g), triethylamine (20.2 g) and N- (2-mercapto-2-methylpropionyl) -DL-homocysteine (22.6 g) in the same manner as in Example 1, the title compound 31.3 g Get (70%).

Melting point: 210.5-212 ° C (ethanol-water) IR (KBr, cm ^-1 ): 3348,1701,1653,1520,1238,1213,1186,
1109,674 Example 4 Hexahydro-3,3-dimethyl-4-oxo-1,2,5-dithiazocine-6-carboxylic acid methyl ester (Compound 4) Compound 3 (28.0 g) was treated in the same manner as in Example 2. Is performed to obtain 27.0 g (91%) of the title compound.

Melting point: 110-112 ° C (benzene-hexane) IR (KBr, cm ^-1 ): 3340,1728,1644,1520,1296,1239,1212,
685 Example 5 Hexahydro-2,2-dimethyl-4-oxo-1,4-thiazepine-5-carboxylic acid methyl ester (Compound 5) Compound 4 (12.0 g) was dissolved in 1200 ml of anhydrous tetrahydrofuran, and [tris (diethylamino ) Phosphine] (5
Anhydrous tetrahydrofuran (240 ml) solution of 9.5 g) at 50 ° C
Add dropwise with heating and stirring. After completion of dropping, the mixture was stirred at the same temperature for 2 hours and the solvent was distilled off under reduced pressure to obtain 5.8 g (55%) of the title compound.

Melting point: 172-174 ° C (ethyl acetate) IR (KBr, cm ^-1 ): 3320,1738,1647,1509,1431,1224,1188,
1172 Example 6 Hexahydro-2,2-dimethyl-3-oxo-1,4-thiazepine-5-carboxylic acid (Compound 6) To a methanol solution of Compound 5 (200 mg) was added 1N while stirring with ice cooling.
Sodium hydroxide solution (3 ml) is added and the mixture is stirred at the same temperature for 2 hours. After distilling off methanol under reduced pressure, the mixture was acidified with 1N hydrochloric acid under ice cooling and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the title compound (110 mg).
Get (59%).

Melting point: 263-265 ° C. (decomposition) (ethanol) IR (KBr, cm ⁻¹ ): 3372,1735,1609,1509,1235,1173 Example 7 (4s) -hexahydro-7,7-dimethyl-6-oxo −
1,2,5-Dithiazosine-4-carboxylic acid (Compound 7) Diethyl brommalonate (16.6 g), triethylamine (13.4 g), N- (2,2-dimethyl-3-mercaptopropionyl) -D-cysteine (15.0 g) Example 1 using g)
The same operation is performed to obtain 9.8 g (66%) of the title compound.

Melting point: 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 8 Hexahydro-2,2-dimethyl-3-oxo-1,4-thiazepine-5-carboxylic acid S-oxide (compound 8) To a solution of compound 6 (200 mg) in methylene chloride under ice-cooling and stirring 8
Add 0% metachloroperbenzoic acid (220 mg). After stirring for 2 hours at the same temperature, the precipitated crystals are separated. The oily substance obtained by concentrating the liquid under reduced pressure is purified by silica gel column chromatography to obtain 162 mg (75%) of the title compound.

IR (KBr, cm ^-1 ): 3370,1730,1610,1055 Example 9 Hexahydro-2,2-dimethyl-3-oxo-1,4-thiazepine-5-carboxylic acid S-dioxide (Compound 9) Compound 6 (200 mg) in methanol solution under ice-cooled stirring 30
Add% hydrogen peroxide solution (250 mg). After stirring at the same temperature for 3 hours, the solvent is distilled off under reduced pressure. The oily substance obtained is purified by silica gel column chromatography to give 169 mg (73%) of the title compound.
To get

IR (KBr, cm ^-1 ): 3373,1733,1609,1310,1140 Example 10 (4r) -hexahydro-7,7-diethyl-6-oxo-
1,2,5-Dithiazosine-4-carboxylic acid (Compound 10) Using N- [2-ethyl-2- (mercaptomethyl) butyryl] -L-cysteine (2.7 g), Example 1- (i
Operate as in i) to give 1.8 g (67%) of the title compound.

Melting point: 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 11 (formulation example) 1) Tablet This compound was mixed with a excipient and directly compressed to give the following tablet. In addition, the compound number shows the number described in the above-mentioned Examples (hereinafter the same).

Compound 1 100 mg Crystalline cellulose 20 mg Lactose 40 mg Hydroxypropyl cellulose-L 5 mg Magnesium stearate 5 mg 170 mg 2) Capsule Preparation Compound 1, lactose and magnesium stearate were used to prepare the following capsule preparations.

Compound 1 5 mg Magnesium stearate 3 mg Lactose 142 mg 150 mg By changing the mixing ratio of compound 1 and lactose, capsules containing 10 mg / capsule, 30 mg / capsule, 50 mg / capsule, 100 mg / capsule were prepared.

3) Granules Compound 1, lactose and potato starch were mixed and the following granules were prepared by a conventional method using a methanol solution of hydroxypropyl cellulose-L as a binder.

Compound 1 50mg Lactose 55mg Potato starch 20mg Hydroxypropylcellulose-L 4mg Talc Trace 130mg Compound 3 and mannitol are mixed and made into a granule by an ordinary method using an aqueous solution of polyvinylpyrrolidone K-30 as a binder. : Eudragit RL
And triacetin were used as a plasticizer) by a conventional method to prepare the following coated granules.

Compound 3 30 mg Mannitol 46.5 mg Polyvinylpyrrolidone K-30 7 mg Eudragit RL 15 mg Triacetin 1.5 mg 100 mg Pharmacological test A rat carbon tetrachloride liver injury model is generally used as an index for examining the usefulness of a drug for treating liver diseases. Therefore, the effect of the present compound on liver damage was examined using this model. Furthermore, the immunomodulatory effect of the present compound was examined using a method of immune response to mouse sheep erythrocytes, which is often used to examine the effect on the immune system.

1) Effect on rat carbon tetrachloride liver injury model The test drug was suspended in a tragacanth gum solution and orally administered to male Wistar rats (5 rats per group) so that the drug amount would be 300 mg / Kg, and after 30 minutes liver damage. Carbon tetrachloride, an inducer (0.25 ml / K
g) was administered intraperitoneally. The GOT and GPT values of the serum collected 24 hours after carbon tetrachloride administration were measured. As a control, a 0.5% tragacanth gum solution was used. Table 1 shows the results using Compound 1 as a representative example of this compound.

As shown in Table 1, GOT and GPT levels were significantly decreased in the administration of the present compound as compared with the control, showing that the present compound has an excellent effect on liver damage. There is.

2) Effect on mouse anti-sheep erythrocyte immune response According to the method of Iso et al. (Int. J. Immunotherapy, 1 , 93 (1985)), 5 × 10 ⁸ BALB / C female mice (3 to 5 mice per group) were obtained.
One sheep red blood cell was intraperitoneally administered for immunization, and a drug suspended in a 1% methylcellulose solution was administered for 4 consecutive days from the immunization day. On day 4 of immunization, the mice were sacrificed and the number of hemolytic plaque-forming cells in splenocytes was measured. The 50% inhibitory dose was determined using this value as an index. As a known compound, JP-B-61-43 represented by the formula [III] described in "Constitution of Invention"
The same test was conducted using the compound described in No. 350.

The results of using Compound 1 as a representative example of this compound are shown in Table 2 together with examples of known compounds.

As shown in Table 2, this compound showed an excellent immunosuppressive effect, and it was further found that the effect was far stronger than that of known compounds.

[Effect of the Invention] As described above, the present compound reduces GOT and GPT levels in serum, exhibits an excellent immunosuppressive action, and is useful as a liver disease therapeutic agent and immunomodulator.

Claims (3)

[Claims] 1. A compound represented by the following general formula [I] and salts thereof. [In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or a lower alkyl group. R ³ represents a hydrogen atom or a lower alkyl group. X represents S, SO, SO ₂ or SS. m represents 0 or 1. n represents 1 or 2. However, when m is 0, n is 2, and X is S, SO or SO.
_When showing ₂ , m and n do not show 1 at the same time. ] 2. A therapeutic agent for liver diseases, which comprises the compound according to claim 1 as a main component. 3. An immunomodulator comprising the compound according to claim 1 as a main component.