JPH05238978A - Cyclopentane derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound capable of exhibiting a thymulin-like activity and useful as a therapeutic agent, etc., for immunodeficiency and autoimmune diseases, etc. CONSTITUTION:A compound of formula I [R<1> and R<2> are (protected)hydroxy or (protected)sulfhydryl; X is carboxyl, lower-alkoxycarbonyl, =O, etc.; A and B are each lower alkylene], e.g. c-2,c-4-bis(benzylthiomethyl)-gamma-1- cyclopentanecarboxylic acid. Furthermore, the compound of formula I is obtained by treating e.g. a compound of formula II in a liquid ammonia in the presence of metallic sodium.

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art In recent years, a lot of researches have been conducted on diseases caused by various immune abnormalities and reduction of immune ability due to side effects of anticancer agents, and many studies on their therapeutic agents. Thymulin, which is produced in the thymus, is a peptide composed of 9 amino acids, and is known to form a complex with zinc to restore the lowered immune function. It has been suggested that it may be an effective drug for diseases (Med. Onco
& Tumor Pharmacother. 6 , 25-29, 1989). However, since thymulin is a trace substance produced in the thymus and is a biological component, it is easily decomposed by degrading enzymes in the body, and its activity is difficult to maintain. There are many problems. To solve this problem, it is preferable to use a synthetic compound that retains its activity even when administered to a living body and can be obtained in a large amount. For this purpose, lactone or lactam compounds containing two sulfur atoms in the side chain have been proposed (PCT / JP
92/00002).

[0003]

Although these compounds show excellent thymulin-like activity, it was necessary to further study related derivatives.

[0004]

[Means for Solving the Problems] PCT / JP92 / 00
The main object compound disclosed in 002 is a lactone or lactam compound containing two sulfur atoms in the side chain, but the present inventors studied a compound in which the lactone or lactam ring was replaced with a cyclopentane ring. , Found that these compounds also have excellent thymulin-like activity.

[0005]

DISCLOSURE OF THE INVENTION The present invention relates to a compound represented by the following general formula [I] and salts thereof and a therapeutic agent for an immune system disease containing them as an active ingredient.

[Chemical 3] [Wherein R ¹ and R ² are the same or different and each represents a hydroxy group or a sulfhydryl group, and the hydroxy group or the sulfhydryl group may be protected by a protecting group. X represents a carboxyl group, a lower alkoxycarbonyl group or ═O, and ═O may be in the form of acetal. A and B are the same or different and each represents a linear or branched lower alkylene. same as below. ]

The group defined above will be explained in more detail. Lower alkoxy means methoxy, ethoxy,
Propoxy, hexyloxy, isopropoxy, t-butoxy and the like are linear or branched alkoxy having 1 to 6 carbon atoms, and lower alkylene is methylene,
It represents a straight-chain or branched alkylene having 1 to 6 carbon atoms such as ethylene, trimethylene, tetramethylene, hexamethylene, (dimethyl) methylene, (diethyl) methylene.

As the protecting group, those commonly used for hydroxy groups and sulfhydryl groups can be used. For example, (substituted) such as benzyl group and p-methoxybenzyl group
Examples thereof include lower alkanoyl groups such as phenyl lower alkyl group, acetyl group and pivaloyl group, lower alkoxycarbonyl groups such as t-butoxycarbonyl group, lower alkyl groups such as tetrahydropyranyl group, trityl group, methyl group and ethyl group. Examples of acetals are dimethyl acetal, diethyl acetal, methylene acetal,
Examples thereof include ethylene acetal.

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

Taking the compounds of the Examples as examples, representative synthetic methods of the compound [I] of the present invention are shown below. a)

[Chemical 4]

B)

[Chemical 5]

C)

[Chemical 6]

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 may have stereoisomers, which are all included in the present invention. Incidentally, the naming of the configuration in the examples is based on the revised 2nd edition of the organic chemistry / biochemistry nomenclature (Nankodo 19
Issued on September 15, 1988).

The compound [I] of the present invention exhibits thymulin-like activity and is useful as a therapeutic agent for diseases caused by various immune disorders such as immunodeficiency and autoimmune diseases. Thymulin produced in the thymus is a peptide composed of 9 amino acids that forms a complex with zinc, and is known to exhibit an action to restore a reduced immune function, which may cause immunodeficiency or It has been suggested that it may be an effective drug for autoimmune diseases.

However, there are various problems in applying thymulin to clinical situations. Therefore, the present inventors, focusing on the mechanism of effect expression of thymulin, as a result of intensively researching the effect by synthesizing various novel compounds, as shown in the section of the pharmacological test described later, a sulfur atom in the side chain and It has been found that a cyclopentane derivative containing an oxygen atom has excellent thymulin-like activity and is useful as a therapeutic agent for diseases caused by various immune disorders such as immunodeficiency and autoimmune diseases. There are various diseases caused by immune disorders,
Examples thereof include rheumatoid arthritis, chronic hepatitis, anemia, systemic lupus erythematosus, primary immunodeficiency, hypoγ-globulinemia and the like, and the compound [I] of the present invention is useful for these various diseases. There is expected.

The compound [I] of the present invention is similar to thymulin.
It is considered that it forms a complex with zinc to exert its effect, but in actual clinical use, it is possible to form a complex by utilizing a trace amount of zinc existing in the body, and zinc such as zinc chloride. The salt may be co-administered.

The compound [I] of the present invention can be administered orally or parenterally. Examples of the dosage form include tablets, capsules, soft capsules, injections and the like, which can be formulated using a technique generally used as a usual formulation method. For example, tablets, capsules, soft capsules, oral agents such as granules, as necessary, lactose, starch, crystalline cellulose, bulking agents such as vegetable oil, magnesium stearate, lubricants such as talc, Hydroxypropyl cellulose, polyvinylpyrrolidone and other binders, carboxymethyl cellulose, calcium and other disintegrants, hydroxypropyl methyl cellulose, macrogol, coating agents such as silicone resins, gelatin film and other coating agents Can be used for formulation. The dose is appropriately selected depending on the symptoms, dosage form and the like, but usually 1 mg to 1000 mg, preferably 1 mg to 200 mg may be administered once or in several divided doses per day.

[0017]

【Example】

Example 1 c-2, c-4-bis (benzylthiomethyl) -r-1
-Cyclopentanecarboxylic acid (Compound 1) Under a nitrogen atmosphere, potassium tert-butoxide (30 mg) was added to a solution of benzyl mercaptan (0.1 ml) in DMF (0.5 ml), and then 3-oxa-2-oxo-7α.
-(P-toluenesulfonyloxymethyl) -1β, 5
β- [3.3.0] bicyclooctane (20 mg) D
Add MF (0.5 ml) solution at room temperature and stir at 100 ° C. for 1 hour. After cooling, the reaction solution is acidified with 1N hydrochloric acid and extracted with ether. The organic layer was concentrated under reduced pressure, and the obtained oily substance was purified by silica gel column chromatography to give the title compound 1
9 mg are obtained.

NMR (CDCl ₃ ) 1.25 (1H, m), 1.64 (1H, m), 2.1
(3H, m), 2.3-2.5 (4H, m), 2.63
(1H, dd), 2.91 (1H, m), 3.68 (2
H, s), 3.70 (2H, s), 7.2-7.3 (1
0H, m), 9.5-10.5 (1H, br)

Example 2 c-2, c-4-bis (mercaptomethyl) -r-1-
Cyclopentanecarboxylic acid (Compound 2) Under a nitrogen atmosphere, c-2, c-4-bis (benzylthiomethyl) -r-1-cyclopentanecarboxylic acid (Compound 1, 19 mg) was added to THF (1 ml) and liquid ammonia ( 10 ml), and sodium metal (50 mg) is added little by little at -78 ° C. After completion of the reaction, ammonium chloride is added and concentrated under reduced pressure. The concentrate is extracted with ether, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The resulting oily substance is purified by silica gel column chromatography,
4 mg of the title compound are obtained.

NMR (CDCl ₃ ) 1.27 (1H, m), 1.38 (1H, t), 1.5
2 (1H, t), 1.73 (1H, m), 2.1-2.
2 (3H, m), 2.41 (1H, m), 2.52 (1
H, m), 2.63 (2H, m), 2.73 (1H,
m), 3.05 (1H, m), 10.3-11.3 (1
H, br)

Example 3 c-2-benzylthiomethyl-c-4-hydroxymethyl-r-1-cyclopentanecarboxylic acid (Compound 3) Under a nitrogen atmosphere, benzyl mercaptan (0.4 ml) in DMF (0.5 ml). ) Sodium hydride solution (18m
g), and then a solution of 3-oxa-2-oxo-7α-hydroxymethyl-1β, 5β- [3.3.0] bicyclooctane (50 mg) in DMF (0.5 ml) was added at room temperature, and the mixture was added at 30 ° C. at 30 ° C. Stir for minutes. After cooling, add 1 reaction
Acidify with N hydrochloric acid and extract with ether. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 20 mg of the title compound.

NMR (CDCl ₃ ) 1.37 (1H, dt), 1.74 (1H, m), 1.
98-2.11 (2H, m), 2.24 (1H, m),
2.35 (1H, m), 2.40 (1H, m), 2.6
6 (1H, dd), 2.95 (1H, m), 3.59
(1H, dd), 3.63 (1H, dd), 3.71
(2H, s), 4-6 (1H, br), 7.2 (1
H, m), 7.3 (4H, m)

Example 4 r-2, c-4-bis (benzylthiomethyl) cyclopentanol (Compound 4) Benzyl mercaptan (0.70 ml) under nitrogen atmosphere
In DMF (5 ml) of potassium tert-butoxide (0.73 g), followed by r-2, c-4-bis (acetoxymethyl) cyclopentanol acetate (0.8
0g) in DMF (5ml) at room temperature, and add 150 ° C.
Stir for 2 hours. After cooling, dilute with ether and wash with water. The organic layer is dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 0.14 g of the title compound.

NMR (CDCl ₃ ) 1.16 (1H, dt), 1.35 (1H, m), 1.
71 (1H, d), 1.89 (2H, m), 2.09
(1H, m), 2.16 (1H, m), 2.49 (2
H, dd), 2.55 (2H, m), 3.69 (2H,
s), 3.71 (2H, m), 4.20 (1H, m),
7.2-7.3 (10H, m)

Example 5 cis-2,4-bis (benzylthiomethyl) cyclopentanone (Compound 5) Under nitrogen atmosphere, r-2, c-4-bis (benzylthiomethyl) cyclopentanol (Compound 4, 0.13 g) in methylene chloride (5 ml) was added to sodium acetate (0.
10 g) and then pyridinium chlorochromate (0.20
g) is added and the mixture is stirred at 0 ° C. for 3 hours. The reaction solution is diluted with ether and filtered through Celite. The filtrate is water, 1N hydrochloric acid,
Then, it is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 0.06 g of the title compound.

NMR (CDCl ₃ ) 1.23-1.35 (1H, m), 1.84 (1H, d)
d), 2.00 (1H, dd), 2.25-2.53
(6H, m), 2.85 (1H, dd), 3.70 (2
H, s), 3.72 (2H, s), 7.22-7.38.
(10H, m)

Example 6 Cis-2,4-bis (benzylthiomethyl) cyclopentanone Ethylene Acetate (Compound 6) Cis-2,4-bis (benzylthiomethyl) cyclopentanone (Compound 5, 58 mg), Ethylene glycol (0.5 ml) and p-toluenesulfonic acid (50 m
g) is put into benzene (10 ml) and refluxed for 2 hours while removing water produced using a dean stark apparatus. The reaction mixture is cooled, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 26 mg of the title compound.

NMR (CDCl ₃ ) 0.15-1.10 (1H, m), 1.49 (1H, d)
d), 1.68-1.73 (1H, m), 1.97-
2.04 (1H, m), 2.09-2.47 (5H,
m), 2.60 (1H, dd), 3.68 (4H,
s), 3.71-3.90 (4H, m), 7.21-
7.52 (10H, m)

Example 7 cis-2,4-bis (mercaptomethyl) cyclopentanone ethylene acetal (Compound 7) cis-2,4-bis (benzylthiomethyl) cyclopentanone ethylene acetal under a nitrogen atmosphere. (Compound 6,
26 mg) is dissolved in a mixture of THF (1 ml) and liquid ammonia (10 ml) and sodium metal (10 mg) is added in small portions at -78 ° C. After completion of the reaction, ammonium chloride is added and concentrated under reduced pressure. The concentrate is extracted with ether, the organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 6 mg of the title compound.

NMR (CDCl ₃ ) 1.11-1.23 (1H, m), 1.32 (1H,
t), 1.42 (1H, t), 1.76-1.81 (1
H, m), 2.03-2.58 (7H, m), 2.67.
-2.75 (1H, m), 3.84-3.97 (4H,
m)

Example 8 cis-2,4-bis (mercaptomethyl) cyclopentanone (Compound 8) Under nitrogen atmosphere, cis-2,4-bis (mercaptomethyl) cyclopentanone ethylene acetal (Compound 7) ,
6 mg of 2N hydrochloric acid (0.5 ml) and ether (1
ml) and stir overnight at room temperature. Ether and water are added to the reaction solution, and the organic layer is separated. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 1 mg of the title compound. _{NMR (CDCl 3) 1.20-1.23 (1H} , m), 1.40 (1H,
t), 1.48 (1H, t), 1.89-1.97 (1
H, m), 2.14-2.79 (8H, m)

Example 9 cis-2,4-bis (hydroxymethyl) cyclopentanone (Compound 9) cis-2,4-diformylcyclopentanone Ethanol acetate (0.95 g) in methanol (20 ml) Sodium borohydride (0.20 g) is added to the solution at 0 ° C., and the mixture is stirred for 20 minutes. A saturated aqueous solution of ammonium chloride is added to the reaction solution, and the mixture is concentrated under reduced pressure. The concentrate is acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 0.026 g of the title compound.

NMR (CDCl ₃ ) 1.56 (1H, m), 1.61 (2H, m), 2.0
5 (1H, dd), 2.25 (1H, m), 2.4-
2.5 (3H, m), 3.72-3.76 (3H,
m), 3.86 (1H, m)

[Formulation Example] An example of the formulation of the compound [I] of the present invention is shown below. (Tablet) Compound of the present invention 1 mg Lactose 105 mg Corn starch 38 mg Silicon dioxide 15 mg Low-substituted hydroxypropyl cellulose- 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 hydroxypropyl cellulose- 10 mg Hydroxypropyl cellulose-L 10 mg Magnesium stearate 2 mg Total 270 mg

[0036]

[Pharmacological test] The thymulin-like activity of the compound [I] of the present invention was determined by the method of J. F. Bach, etc. (Bull. Inst. Pasteu
r, 76 , 325 (1978)).

(Experimental method) Approximately 2 weeks passed after the thymectomy
The spleen of a C57BL / 6 male mouse (10 weeks old, 4 mice per group) is removed to prepare a splenocyte suspension (1 × 10 ⁸ cells / ml, Hanks' solution). To 100 μl of this preparation, 100 μl of a 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 for another 60 minutes at the same temperature. Add to this solution sheep red blood cell (1 x 1
( ⁸ cells / ml, Hanks' solution)
Incubate overnight at ° C. Then, after gently shaking and mixing, E-rosette forming cells (E-RFC) were measured. Thymulin and zinc chloride as a positive control 1:
Using the solutions prepared so that each of them had a concentration of 1 × 10 ⁻¹⁴ M at a molar ratio of 1, the same operation as for the test compound was performed.

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

The results of several examples are shown below.

[Table 1]

INDUSTRIAL APPLICABILITY The present invention provides a novel compound which exhibits excellent thymulin-like activity and is expected to be useful as a therapeutic agent for various diseases caused by various immune disorders such as immunodeficiency and autoimmune diseases.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location A61K 31/215 8413-4C C07C 323/22 7419-4H 323/53 7419-4H // C07C 31 / 135 6958-4H

Claims (4)

[Claims] 1. A compound represented by the general formula [I] and salts thereof. [Chemical 1] [Wherein R ¹ and R ² are the same or different and each represents a hydroxy group or a sulfhydryl group, and the hydroxy group or the sulfhydryl group may be protected by a protecting group. X represents a carboxyl group, a lower alkoxycarbonyl group or ═O, and ═O may be in the form of acetal. A and B are the same or different and each represents a linear or branched lower alkylene. ] 2. A therapeutic agent for immune system diseases, which comprises a compound represented by the general formula [I] or a salt thereof as an active ingredient. [Chemical 2] [Wherein R ¹ and R ² are the same or different and each represents a hydroxy group or a sulfhydryl group, and the hydroxy group or the sulfhydryl group may be protected by a protecting group. X represents a carboxyl group, a lower alkoxycarbonyl group or = O, and = O may be in the form of acetyl. A and B are the same or different and each represents a linear or branched lower alkylene. ] 3. The compound according to claim 1, wherein X is a carboxyl group, A and B are methylene, and R ¹ and R ² are sulfhydryl groups. 4. X is ═O, A and B are methylene and R
The compound according to claim 1, wherein ¹ and R ² are hydroxy groups.