JP3157341B2 - Tetrahydrothiopyran derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention provides a novel compound useful as a therapeutic agent for various immune disorders such as immunodeficiency and autoimmune diseases.

[0002]

2. Description of the Related Art In recent years, studies on various immunological disorders and a decrease in immunity due to side effects of anticancer drugs have been actively conducted, and many studies have been conducted on therapeutic agents therefor. Thymulin, which is produced in the thymus, is a peptide consisting of 9 amino acids. It is known to form a complex with zinc and to restore the reduced immune function. It has been suggested that it may be an effective drug for diseases (Med. Oncol. & Tumor Ph.
armacother. 6 , 25-29, 1989).

[0003] However, thymulin is a trace substance produced in the thymus and is a biological component, so it is easily decomposed by degrading enzymes in the living body and its activity is hardly maintained. There are many problems to do. In order to solve this problem, a synthetic compound which maintains its activity and can be obtained in large quantities is desired. As such a synthetic compound, a lactone or lactam compound containing two sulfur atoms in a side chain has been proposed (PCT / J
P92 / 000002 patent application).

[0004]

Although these compounds exhibit an excellent thymulin-like activity, there is a need for further studies such as compounds having different ring structures.

[0005]

Means for Solving the Problems The present inventors have proposed PCT /
Focusing on the lactone compound containing two sulfur atoms in the side chain described in the JP 92/000002 patent application, a 6-membered tetrahydrothiopyran derivative having one sulfur atom incorporated into the ring structure is disclosed. As a result of conducting research on the creation and examining the effect, a novel tetrahydrothiopyran derivative having excellent thymulin-like activity was successfully obtained.

[0006]

DISCLOSURE OF THE INVENTION The present invention relates to a compound represented by the following general formula [I] and salts thereof.

Wherein R ¹ represents a hydrogen atom or a lower alkyl group. R ² represents a hydrogen atom or a protecting group for a thiol group. R ³ represents a hydroxy group or an ester residue. same as below. ]

The thiol group-protecting group includes, for example, a thiol group such as a lower alkyl group, a lower alkenyl group, a lower alkanoyl group, a phenyl lower alkyl group, a phenylcarbonyl group, a phenyl lower alkylcarbonyl group, a trityl group and a tetrahydropyranyl group. The phenyl ring of the phenyl lower alkyl group, the phenyl carbonyl group and the phenyl lower alkyl carbonyl group is a lower alkyl group, a lower alkoxy group, a halogen atom, a carboxy group, a lower alkoxy carbonyl group and the like. It may be substituted.

The ester residue means a group which can be converted to a carboxylic acid by hydrolysis or the like, for example, a lower alkoxy group, a lower alkenyloxy group, a phenyl lower alkoxy group, an N-succinimidooxy group and the like. May be substituted with a lower alkyl group, a lower alkoxy group, a halogen atom, a carboxy group, a lower alkoxycarbonyl group or the like.

The groups defined above are described in more detail. Lower alkyl refers to straight-chain or branched alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, hexyl, isopropyl and t-butyl. Indicates that
Lower alkenyl refers to straight-chain or branched alkenyl having 2 to 6 carbon atoms containing a double bond such as vinyl, allyl and hexenyl, and lower alkanoyl refers to acetyl, propionyl, hexanoyl, isopropionyl, A straight-chain or branched alkanoyl having 2 to 6 carbon atoms such as pivaloyl;
Methoxy, ethoxy, propoxy, hexyloxy, isopropoxy, t-butoxy, etc., represents a straight-chain or branched alkoxy having 1 to 6 carbon atoms, and a halogen atom represents fluorine, chlorine, bromine, iodine. , Lower alkylene means methylene, ethylene, trimethylene, tetramethylene, hexamethylene, (dimethyl) methylene,
(Diethyl) represents a straight or branched alkylene having 1 to 6 carbon atoms such as methylene.

The salts include pharmaceutically acceptable salts such as sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt and the like.

A typical method for synthesizing the compound [I] of the present invention is as follows:
The following are a), b) and c). a)

Embedded image

As described above, PCT / JP92 / 000
The compound [III] of the present invention having a carboxyl group at the 3-position and an SH group at the 5-position is obtained by alkali-treating a lactone compound [II] containing two sulfur atoms in the side chain described in the Patent Application No. 02. Can be

B)

Embedded image [In the formula, X represents a reactive group such as a hydroxy group, a halogen atom, an alkanoyloxy group, an alkylsulfonyl group, or an arylsulfonyl group, and R ⁴ represents a reactive group such as a methanesulfonyl group. ]

In b), a diol compound [IV] is dehydrated to give a desired derivative (compound [V]), which is then closed with sodium hydrosulfide or the like to form a carboxyl group at the 3-position and an SH group at the 5-position. This is a method for obtaining invention compound [III].

C)

Embedded image c) is a method for obtaining the compound of the present invention by reducing the compound represented by the formula [VI] to give a hydroxy form (compound [VII]) and then reacting with R ² SH.

In the above methods a to c, when R ² is a protecting group for a thiol group, it can be appropriately attached or detached at a desired stage by a known method depending on the nature of the group.
Also, when R ³ is an ester residue, a desired compound can be obtained at an appropriate stage using a known method.

The compound obtained by the above method can be converted into the above-mentioned salts by a conventional method.

The compound [I] of the present invention includes optical isomers and geometric isomers, all of which are included in the present invention.
When an optically active raw material is used, an optically active substance is obtained. When a racemic form is used as a raw material, the optically active substance can be optically resolved using an optical resolving agent or the like.

The term "cis or trans" in the specification means that -COR ³ and -SR ² have a relationship of cis or trans, and when there is no indication, a mixture of cis and trans or a mixture thereof. Indicates that the relationship is not specified.

The compound [I] of the present invention is a novel tetrahydrothiopyran derivative.
One SH group and one carboxyl group. That is, the basic structure is represented by the following formula [VIII], the SH group may be protected by a commonly used protecting group for a thiol group, and the -COOH moiety may be in the form of an ester. .

Embedded image

The compound [I] of the present invention exhibits excellent thymulin-like activity as shown in the pharmacological test described below, and is useful as a therapeutic agent for various immunological disorders such as immunodeficiency and autoimmune diseases. Be expected.

There are various types of immunological disorders, such as rheumatoid arthritis, chronic hepatitis, anemia, systemic lupus erythematosus, primary immunodeficiency, AIDS, cancer, hypoγ-globulinemia, etc. Invention compound [I] is expected to be useful for those various diseases.

The compound [I] of the present invention exhibits an effect even when used alone, but exhibits a more effective effect in the presence of zinc, like thymulin. Zinc can be supplied by the combined administration of a zinc salt such as zinc chloride, but can also be supplied by using a trace amount of zinc present in a living body.

The compound [I] of the present invention can be administered orally or parenterally. Examples of the dosage form include tablets, capsules, soft capsules, and injections, which can be formulated using a technique widely used as a usual formulation method. For example, oral preparations such as tablets, capsules, soft capsules, and granules may be used, if necessary, in lactose, starch, crystalline cellulose, bulking agents such as vegetable oils, lubricating agents such as magnesium stearate, talc, and hydroxypropyl. It can be formulated using a binder such as cellulose and polyvinylpyrrolidone, a disintegrant such as calcium carboxymethylcellulose, a coating agent such as hydroxypropylmethylcellulose, macrogol, a silicone resin, and a film agent such as a gelatin film. The dose is appropriately selected depending on the condition, dosage form, etc., but usually 1 mg to 1000 mg, preferably 1 mg to 200 mg, may be administered once or several times a day.

[0025]

【Example】

Example 1 cis-3-ethoxycarbonyl-5-mercaptotetrahydrothiopyran (Compound 1-1)

Trans-2,4-bis (mercaptomethyl) -4-butanolide (150 mg) in THF (4 m
l) 1N aqueous solution of sodium hydroxide (0.8 ml)
And stirred at room temperature for 30 minutes. The reaction solution is acidified by adding 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography to obtain crude cis-3-carboxy-5-mercaptotetrahydrothiopyran.

This crude product is dissolved in ethanol (3 ml), 1 drop of concentrated sulfuric acid is added, and the mixture is refluxed for 2 hours. After cooling the reaction solution, an aqueous solution of sodium hydrogen carbonate is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 72 mg (77%) of the title compound (Compound 1-1).

IR (film, cm ^-1 ) 2979, 29
25, 2558, 1728, 1447, 1421, 13
69, 1300, 1256, 1174, 1112, 10
26,711

By operating in the same manner as in Example 1, the following compound is obtained. -Trans-3-ethoxycarbonyl-5-mercaptotetrahydrothiopyran (compound 1-2)-trans-3-ethoxycarbonyl-5-mercapto-4-methyltetrahydrothiopyran (compound 1-3)

Example 2 cis-3-carboxy-5-mercaptotetrahydrothiopyran (compound 2-1)

Cis-3-ethoxycarbonyl-5-mercaptotetrahydrothiopyran (compounds 1-1 and 140
mg) in THF (6 ml), 2N sodium hydroxide solution (1.4 ml) was added, and the mixture was stirred at room temperature for 30 minutes.
The reaction solution is acidified by adding 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography to give the title compound (Compound 2-
1) Obtain 72 mg (60%).

Mp 126.3-127.0 ° C. (n-
Hexane-ethyl acetate) IR (KBr, cm ^-1 ) 1699, 1418, 130
1,1272,1238,1200,1111,105
1,933,830,708,657

By operating in the same manner as in Example 2, the following compound is obtained. Trans-3-carboxy-5-mercaptotetrahydrothiopyran (compound 2-2) mp 111.3-112.4 ° C. (n-hexane-ethyl acetate) IR (KBr, cm ⁻¹ ) 2547, 1698, 144
5,1405,1322,1287,1236,121
3,1135,916,850,788,715 trans-3-carboxy-5-mercapto-4-methyltetrahydrothiopyran (compound 2-3)

Example 3 (3S, 5S) -5-Acetylthio-3-tert-butoxycarbonyltetrahydrothiopyran (Compound 3-1)

1) Under ice cooling, (4S) -5-chloro-4-
Mesyl chloride (11.5 g) was added dropwise to a solution of tert-butyl hydroxy-2-hydroxymethylpentanoate (10.0 g) and triethylamine (12.7 g) in methylene chloride (100 ml), and the mixture was stirred for 20 minutes. After the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate, water and then with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil is dissolved in benzene (130 ml), 1,8-diazabicyclo [5.4.0] undec-7-ene (7.0 g) is added, and the mixture is stirred at room temperature for 2 hours. Water is added to the reaction solution, and extracted with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography to obtain 11.1 g (89%) of (4S) -5-chloro-4-mesyloxy-2-methylenepentanoic acid tert-butyl ester as an oil.

[Α] ²⁰ _D −1.6 ° (c = 1.0, chloroform) IR (film, cm ⁻¹ ) 2978, 2938, 170
7,1633,1367,1255,1175,96
0,916,849,798

2) (4S) -5-chloro-4-mesyloxy-2-methylenepentanoic acid tert-butyl ester (5.0 g) in dimethylformamide (80 ml)
To the mixture was added sodium bisulfide hydrate (4.0 g) under ice cooling, and the mixture was stirred for 3.5 hours. Water is added to the reaction solution, and extracted with diethyl ether. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil is dissolved in ethanol (60 ml), potassium thioacetate (2.9 g) is added, and the mixture is refluxed for 10 minutes. Water is added to the reaction solution, and extracted with diethyl ether. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to obtain 0.3 g of the title compound (compound 3-1).
7 g (8%) are obtained.

IR (film, cm ^-1 ) 2977, 29
31, 1724, 1694, 1450, 1423, 13
92, 1368, 1298, 1259, 1151, 95
3,848

By operating in the same manner as in Example 3, the following compound is obtained. -(3S, 5S) -5-benzoylthio-3-tert-butoxycarbonyltetrahydrothiopyran (compound 3-
2) IR (film, cm ^-1 ) 2975, 1719, 165
4,1580,1449,1367,1314,126
0,1207,1149,910,846,773,6
87 · 5-acetylthio-3-isopropoxycarbonyltetrahydrothiopyran (compound 3-3) IR (film, cm ⁻¹ ) 2912, 1724, 168
6,1257,1181,1110

Example 4 (3S, 5S) -5-Acetylthio-3-carboxytetrahydrothiopyran (Compound 4-1)

Under a nitrogen atmosphere, trifluoroacetic acid (1 ml) was added to a solution of (3S, 5S) -5-acetylthio-3-tert-butoxycarbonyltetrahydrothiopyran (compound 3-1, 120 mg) in methylene chloride (2 ml). Stir at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, and the obtained oil is purified by silica gel column chromatography to obtain the title compound (Compound 4-1).

By following the same procedure as in Example 4, the following compound is obtained. · (3S, 5S) -5-benzoylthio-3-carboxytetrahydrothiopyran (compound 4-2) · 5-acetylthio-3-carboxytetrahydrothiopyran (compound 4-3)

Example 5 (3S, 5S) -3-carboxy-5-mercaptotetrahydrothiopyran (compound 5-1)

(3S, 5S) -5-acetylthio-3-
Carboxytetrahydrothiopyran (compounds 4-1 and 1
30 mg) was added to 1N aqueous ammonia (2 ml) and stirred at room temperature for 30 minutes. The reaction solution is acidified with 1N hydrochloric acid under ice-cooling, saturated brine is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain the title compound (compound 5-1).

Example 6 4-acetylthio-2-ethoxycarbonyltetrahydrothiopyran (compound 6-1)

1) Under a nitrogen atmosphere, sodium borohydride (1.1 g) was added to a solution of 2-ethoxycarbonyl-4-oxotetrahydrothiopyran (5.0 g) in ethanol (50 ml) while cooling with ice. Stir for hours.
Under ice cooling, a saturated aqueous ammonium chloride solution was added to the reaction solution,
Stir at room temperature for 20 minutes. After the solvent is concentrated under reduced pressure, it is extracted with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 2-ethoxycarbonyl-4-hydroxytetrahydrothiopyran.

2) Under a nitrogen atmosphere, 2-ethoxycarbonyl-4-hydroxytetrahydrothiopyran (3.2
g) and triphenylphosphine (6.6 g)
To a solution of F (20 ml) was added diethyl azodicarboxylate (4.4 g) in THF (8 m
l) and a solution of thioacetic acid (1.9 g) in THF (7 ml) are added and stirred for 30 minutes. The reaction solution is concentrated under reduced pressure, and the obtained oil is purified by silica gel column chromatography to obtain the title compound (Compound 6-1).

By following the same procedure as in Example 6, the following compound is obtained. • 4-acetylthio-3-ethoxycarbonyltetrahydrothiopyran (compound 6-2) • 5-acetylthio-4-ethoxycarbonyltetrahydrothiopyran (compound 6-3) • 3-acetylthio-2-ethoxycarbonyltetrahydrothiopyran (compound) 6-4) 3-Acetylthio-2-ethoxycarbonyl-4-methyltetrahydrothiopyran (Compound 6-5) 3-Acetylthio-2-ethoxycarbonyl-6-methyltetrahydrothiopyran (Compound 6-6)

Example 7 2-carboxy-4-mercaptotetrahydrothiopyran (compound 7-1)

Under a nitrogen atmosphere, 4-acetylthio-2-ethoxycarbonyltetrahydrothiopyran (3.4 g)
4N sodium hydroxide solution (8.6 ml) was added to a solution of the above in ethanol (9 ml) while cooling with ice, and the mixture was stirred for 1 hour. After adding 6N hydrochloric acid to the reaction mixture, the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give the title compound (compound 7-
Obtain 1).

By operating in the same manner as in Example 7, the following compound is obtained. 3-carboxy-4-mercaptotetrahydrothiopyran (compound 7-2) 4-carboxy-5-mercaptotetrahydrothiopyran (compound 7-3) 2-carboxy-3-mercaptotetrahydrothiopyran (compound 7-4) ) 2-carboxy-3-mercapto-4-methyltetrahydrothiopyran (compound 7-5) 2-carboxy-3-mercapto-6-methyltetrahydrothiopyran (compound 7-6)

[Formulation Example] An example of the formulation of the compound [I] of the present invention is shown below.

(Tablets) Compound of the present invention 1 mg Lactose 105 mg Corn starch 38 mg Silicon dioxide 15 mg Low-substituted hydroxypropylcellulose 5 mg Hydroxypropyl cellulose-L 5 mg Magnesium stearate 1 mg Total 170 mg

Compound of the present invention 5 mg Lactose 155 mg Corn starch 58 mg Silicon dioxide 30 mg Low-substituted hydroxypropylcellulose 10 mg Hydroxypropylcellulose-L 10 mg Magnesium stearate 2 mg Total 270 mg

[0055]

[0056]

【The invention's effect】

"Pharmacological test" The thymulin-like activity of the compound [I] of the present invention was determined by J.I. F. Bach et al. (Bull. Inst. Pasteur, 76 , 325 (1
978)).

(Experimental Method) About 2 weeks have passed since the thyme was removed
The spleen of a C57BL / 6 male mouse (10 weeks old, 4 mice per group) is removed, and a spleen cell suspension (1 × 10 ⁸ cells / ml, Hanks' solution) is prepared. To 100 μl of this preparation, 100 μl of a solution of the test compound and zinc chloride dissolved in Hanks 'solution at a molar ratio of 1: 1 was added, and the mixture was incubated at 37 ° C. for 30 minutes, and then azathioprine (50 μg / ml, Hanks' solution)
Add 50 μl and incubate at the same temperature for another 60 minutes. Add this solution to a sheep red blood cell (1 x 1
( ⁸ cells / ml, Hanks' solution) and mix.
Incubate overnight at 0 ° C. Then, after shaking gently, E-rosette-forming cells (E-RFC) were measured. Thymulin and zinc chloride as positive controls:
The same operation as in the case of the test compound was performed using the solutions prepared so that the concentration was 1 × 10 ⁻¹⁴ M at a molar ratio of 1.

(Results) Thymulin-like activity was determined by the following equation.

Among the compounds of the present invention, as a representative example of the compound having the basic structure of the formula [VIII], the thymulin-like activity of the compound 2-2 was measured to be 50% or more at a concentration of 10 ^-10 M or less. Was.

Continued on the front page (72) Inventor Masataka Morishita 6-16-16-806 Shindaka, Yodogawa-ku, Osaka-shi (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 335/02 A61K 31/382 A61P 37 / 02 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A compound represented by the following general formula [I] and a salt thereof . Embedded image [In the formula, R ¹ represents a hydrogen atom or a lower alkyl group.
R ² represents a hydrogen atom or a protecting group for a thiol group. R ³
Is a hydroxy group, a lower alkoxy group, a lower alkenyl
Xy group, phenyl lower alkoxy group or N-succin
Indicates an imidooxy group . ] 2. The compound according to claim ¹ , wherein R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a hydrogen atom, a lower alkanoyl group or a phenylcarbonyl group, and R ³ represents a hydroxy group or a lower alkoxy group. And that
Salt . 3. The compound according to claim ¹ , wherein R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a hydrogen atom, and R ³ represents a hydroxy group, and a salt thereof . 4. A 3-carboxy-5-mercaptotetrahydrothiopyran and a salt thereof .