JPH05239045A - Lactone or lactam compound - Google Patents

Abstract

PURPOSE:To provide a new compound having excellent thymulin-like activity, thus useful as a medicine for diseases due to various kinds of immunological dysfunction such as immunodeficiencies and autoimmune diseases. CONSTITUTION:The objective compound of formula I (X is O or NR<8>; Z is A-OR<6> or COOR<7>; R<1> and R<2> are each H or lower alkyl; R<3> and R<4> are each H, lower alkyl or COOR<7>; R<5> and R<6> are each H, lower alkyl, lower alkanoyl, benzyl, trityl, tetrahydropyranyl, etc.; R<7> is H or lower alkyl; R<8> is H, lower alkyl, lower alkoxy, benzyl, etc.), e.g. 4-(1-benzyloxy-1-methylethyl)-2-methylene-4- butanolide. The compound of the formula I can be obtained by addition reaction between a compound of formula II and a thiol compound of formula R<5>SH in the presence of a catalyst (e.g. n-butyllithium).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD 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, and a synthetic intermediate thereof.

[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
Although the main object compound disclosed in 002 is a lactone or lactam compound containing two sulfur atoms in the side chain, the present inventors have found out about a lactone or lactam compound containing one sulfur atom in the side chain. Researched. as a result,
It has been found that a lactone or lactam compound further containing an oxygen atom or a carboxy group in the side chain has excellent thymulin-like activity.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a compound represented by the following general formula [I] and salts thereof, a therapeutic agent for immune system diseases containing them as an active ingredient, and a general formula [I] as a synthetic intermediate thereof.
I] and a salt thereof.

[Chemical 4] [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 and R ⁴ are the same or different and each represents a hydrogen atom, a lower alkyl group, a carboxyl group or a lower alkoxycarbonyl group.
Z represents -A-O-R ⁶ or -COOR ^7. R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkanoyl group, a phenyl lower alkyl group, a phenylcarbonyl group, a trityl group or a tetrahydropyranyl group, and the phenyl lower alkyl group. Group and phenyl ring of phenylcarbonyl group are lower alkyl group, lower alkoxy group, halogen atom,
It may be substituted with a carboxy group or a lower alkoxycarbonyl group. R ⁷ represents a hydrogen atom or a lower alkyl group. X represents an oxygen atom or NR ⁸ . R ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a phenyl lower alkyl group or a phenyl lower alkoxy group, and the lower alkyl group is a carboxyl group, a lower alkoxycarbonyl group, an amino group, a lower alkylamino group, a lower alkoxycarbonyl group. It may be substituted with an amino group or a phenyl lower alkylamino group, and the phenyl ring of the phenyl lower alkyl group, phenyl lower alkoxy group and phenyl lower alkylamino group is a lower alkyl group, a lower alkoxy group, a halogen atom, a carboxy group. Alternatively, it may be substituted with a lower alkoxycarbonyl group. A represents a linear or branched lower alkylene. same as below. ]

[0006] To describe the group defined above in more detail, lower alkyl means straight chain or branched alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, hexyl, isopropyl, t-butyl and the like. Indicates
The lower alkenyl refers to a linear or branched alkenyl having 1 to 6 carbon atoms containing a double bond such as vinyl, allyl and hexenyl, and the lower alkanoyl refers to acetyl, propionyl, hexanoyl, isopropionyl, A linear or branched alkanoyl having 2 to 6 carbon atoms such as pivaloyl is shown, and lower alkoxy is
Methoxy, ethoxy, propoxy, hexyloxy, isopropoxy, t-butoxy and the like linear or branched alkoxy having 1 to 6 carbon atoms, lower alkylene is methylene, ethylene, trimethylene, tetramethylene, Hexamethylene, (dimethyl) methylene,
(Diethyl) methylene and the like are linear or branched alkylene having 1 to 6 carbon atoms, and the halogen atom is fluorine, chlorine, bromine or iodine.

The salts include sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, hydrochloride salt,
Examples thereof include pharmaceutically acceptable salts such as sulfate, phosphate, lactate, maleate, fumarate and oxalate.

A representative synthetic method of the compound [I] of the present invention is shown below.

[Chemical 5] As represented by the above reaction scheme, it is a method by an addition reaction of a compound represented by the formula [II] and a thiol compound represented by the formula [III]. This addition reaction can be carried out under the conditions used for the addition reaction to the double bond of the thiol compound and is not particularly limited, but it proceeds smoothly when a catalyst such as n-butyllithium is used.

When X is an oxygen atom, that is, a lactone compound, it can also be obtained by a method of ring-closing the compound of the formula [IV].

[Chemical 6] [In the formula, R ⁹ represents an amino group or a lower alkoxy group. same as below. ]

In these reactions, when R ⁵ is used as a protecting group for SH group and R ⁶ is used as a protecting group for OH group, a commonly used method for removing the protecting group for SH group or OH group is used. Can be used to remove at any desired stage. On the contrary, when the resulting compound is an SH or OH compound, the group defined by R ⁵ or R ⁶ (however, excluding a hydrogen atom) may be bonded by a commonly used method. When X represents NR ⁸ and R ⁸ is used as a protective group for NH group, it can be removed at a desired stage by using a commonly used method for removing protective group for NH group. Further, when R ⁸ contains an amino group having a protecting group, it can be removed at a desired stage by using a usual method for removing a protecting group. When the obtained compound contains an ester group, it can be hydrolyzed into a carboxylic acid derivative by a usual method.

Next, a typical synthetic route of the compound represented by the formula [II] which is a synthetic intermediate is shown below. 1) Lactone compound a)

[Chemical 7]

B)

[Chemical 8]

C)

[Chemical 9] [In the formula, R ¹⁰ represents a halogen atom, and R ¹¹ represents a lower alkyl group. R ¹² and R ¹³ are R ¹ and R ² or R ^{3 respectively.}
And R ⁴ . same as below. ]

In the above reaction, the compound of the formula [VII] may or may not be isolated.

Further, the compound represented by the formula [VII] is also converted into the compound [I] of the present invention by directly reacting the thiol compound represented by the formula [III] without leading to the compound represented by the formula [VIII]. be able to.

2) Lactam compound a)

[Chemical 10]

B)

[Chemical 11]

C)

[Chemical 12]

The compound of the formula [XVII] is preferably isolated and subjected to the next reaction when it is easy to isolate, but when it is not easy to isolate, it is subjected to the next reaction without being particularly isolated. be able to.

The compound obtained by the above method can be converted into the salts as described above by a conventional method.

The compounds [I] and [II] of the present invention may have optical isomers and geometric isomers, all of which are included in the present invention.

The nomenclature of compounds in the present invention follows the following figures.

[Chemical 13]

In the names of the following compounds, cis,
The term "trans" means that the substituents at the 2-position and the 4-position have a cis-trans relationship, respectively, and when there is no indication, it means a mixture of cis-trans or the relationship thereof is not specified.

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 to be described later, with a sulfur atom in the side chain. It has been found that a lactone or lactam compound containing an oxygen atom or a carboxyl group exhibits excellent thymrin-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, such as rheumatoid arthritis, chronic hepatitis, anemia, systemic lupus erythematosus, primary immunodeficiency, hypoγ-globulinemia, etc., and the compound of the present invention [I ] Are expected to be useful against these various diseases.

The compound [I] of the present invention is the same as thymurin.
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.

[0028]

【Example】

Example 1 4- (1-benzyloxy-1-methylethyl) -2-
Methylene-4-butanolide (Compound 1-1) Under a nitrogen atmosphere, zinc dust (2.75 g) in THF (30 m
l) A small amount of iodine was added to the suspension, and then T of 2-benzyloxy-2-methylpropionaldehyde (3.00 g).
Add HF (15 ml) solution and stir at 55-60 ° C.
A solution of 2-bromomethylacrylic acid methyl ester (3.42 g) in THF (15 ml) was added dropwise to this reaction solution, and the mixture was refluxed. The reaction mixture is further stirred at 55-60 ° C for 1 hr, filtered through Celite, and concentrated under reduced pressure. Ethyl acetate is added to the concentrate, which is washed with 1N hydrochloric acid, water, and saturated brine, the organic layer is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 3.29 g (79%) of the title compound. _{NMR (CDCl 3) 1.32 (6H} , s), 2.91 (1H, m), 3.0
8 (1H, d), 4.43 (1H, dd), 4.51
(2H, s), 5.62 (1H, t), 6.21 (1
H, t), 7.30 (5H, m)

By replacing the raw materials and operating in the same manner as in Example 1, the following compound is obtained. 4- (4-methoxybenzyloxymethyl) -2-methylene-4-butanolide (Compound 1-2) 4-methoxymethyl-2-methylene-4-butanolide (Compound 1-3) 4- (4- Benzyloxybutyl) -2-methylene-
4-Butanolide (Compound 1-4)

Example 2 4-Carboxy-2-methylene-4-butanolide (Compound 2-1) Glyoxylic acid monohydrate (2.22 g), 2-bromomethylacrylic acid (2.69 g), tin chloride ( II)
(2.84 g) and Amberlyst 15 (2.40 g).
g) is added to a mixed solution of THF (25 ml) and water (6 ml), and the mixture is stirred under reflux for 2 hours. The reaction solution is cooled, filtered, and concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to obtain 0.43 g (20%) of the title compound. mp 83.2-87.8 ° C NMR (CDCl ₃ ) 3.09 (1H, m), 3.35 (1H, m), 5.2
7 (1H, dd) 5.78 (1H, t), 6.36 (1
H, t)

Example 3 4-Ethoxycarbonyl-2-methylene-4-butanelactam (Compound 3-1) In a nitrogen atmosphere, zinc powder (1.08 g, activated with hydrochloric acid) suspended in THF (10 ml). 2-Bromomethylacrylic acid ethyl ester (2.
90 g) is added dropwise at 26 ° C. or lower, and after completion of the addition, ultrasonic waves are irradiated for 5 minutes. This prepared solution is added to a solution of glyoxylic acid (1.11 g) in THF (20 ml) at room temperature under a nitrogen atmosphere and stirred for 1 hour. 2N hydrochloric acid and saturated saline are added to the reaction solution, and the mixture is extracted with methylene chloride. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. P-Toluenesulfonic acid (0.2
9 g) and toluene (50 ml) are added, and the mixture is stirred at 60 ° C. for 2.5 hours and concentrated under reduced pressure. The oily substance obtained is purified by silica gel column chromatography to give 0.65 g of the title compound.
(25%) is obtained. _{NMR (CDCl 3) 1.31 (3H} , t), 3.02 (1H, m), 3.2
7 (1H, m), 4.27 (2H, dd), 4.96
(1H, dd), 5.73 (1H, t), 6.32 (1
H, t)

Example 4 N-benzyl-4- (1-benzyloxy-1-methylethyl) -2-methylene-4-butanelactam (Compound 4-1) Zinc dust (1.83 g) was added under a nitrogen atmosphere. THF (30m
l) N- (2-benzyloxy-2-methylpropylidene) benzylamine (3.00 g) and a small amount of iodine are added to the suspension and stirred. The reaction solution is heated to 55-60 ° C., a solution of 2-bromomethylacrylic acid methyl ester (2.28 g) in THF (10 ml) is added dropwise, and the mixture is refluxed. After completion of dropping, the mixture is stirred at 55-60 ° C for additional 30 minutes, cooled, saturated aqueous ammonium chloride solution is added, and the mixture is filtered through Celite. The filtrate is concentrated under reduced pressure, ethyl acetate is added to the concentrate, the mixture is washed with 1N hydrochloric acid, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily substance obtained is purified by silica gel column chromatography to obtain 1.81 g (48%) of the title compound. NMR (CDCl ₃ ) 1.17 (3H, s), 1.22 (3H, s), 2.5
9 (1H, m), 2.76 (1H, m), 3.63 (1
H, dd), 4.41 (2H, s), 4.45 (1H,
d), 5.23 (1H, d), 5.35 (1H, m),
6.04 (1H, t), 6.95-7.40 (10H,
m)

By replacing the raw materials and operating in the same manner as in Example 4, the following compound is obtained. · N-benzyl-4-benzyloxymethyl-2-methylene-4-butane lactam (Compound _{4-2) NMR (CDCl 3) 2.58} (1H, m), 2.79 (1H, m), 3. Four
3 (2H, d), 3.66 (1H, m), 4.21 (1
H, d), 4.40 (1H, d), 4.43 (1H,
d), 5.02 (1H, d), 5.36 (1H, m),
6.06 (1H, m), 7.20-7.40 (10H,
m)

N-benzyl-4-methoxymethyl-2
-Methylene-4-butanelactam (Compound 4-3)

N-benzyl-4- (4-methoxybenzyloxymethyl) -2-methylene-4-butanelactam (compound 4-4)

N-benzyl-4- (4-benzyloxybutyl) -2-methylene-4-butanelactam (compound 4-5)

N-isopropyl-4-benzyloxymethyl-2-methylene-4-butanelactam (compound 4
-6)

4-benzyloxymethyl-N-ethoxycarbonylmethyl-2-methylene-4-butanelactam (compound 4-7)

4-benzyloxymethyl-N- (5-
tert-Butoxycarbonylaminopentyl) -2-methylene-4-butanelactam (Compound 4-8)

4-benzyloxymethyl-N- (4-
Methoxycarbonylbenzyl) -2-methylene-4-butanelactam (Compound 4-9)

4-benzyloxymethyl-N-methoxy-2-methylene-4-butanelactam (compound 4-1
0)

4-benzyloxymethyl-N-benzyloxy-2-methylene-4-butanelactam (compound 4-11)

4-benzyloxymethyl-N- (4-
Methoxybenzyl) -2-methylene-4-butanelactam (Compound 4-12)

Example 5 N-benzyl-4-carboxy-2-methylene-4-butanelactam (Compound 5-1) In a nitrogen atmosphere, zinc dust (0.47 g) in THF (20 m
l) To the suspension, a solution of 2-bromomethylacrylic acid methyl ester (2.28 g) in THF (10 ml) was added dropwise at room temperature, and ultrasonic waves were applied for 5 minutes. N-
Crystals of (carboxymethylidene) benzylamine sodium salt (1.33 g) are added little by little, and the mixture is further stirred at room temperature for 30 minutes. 2N hydrochloric acid is added to the reaction solution, and the mixture is extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.45 g, 8
7%). mp 144.0-146.2 ° C. (decomposition) (ethyl acetate) NMR (CDCl ₃ ) 2.86 (1H, m), 3.05 (1H, m), 4.0
6 (1H, dd), 4.07 (1H, d), 5.28
(1H, d), 5.45 (1H, t), 6.14 (1
H, t), 7.2-7.3 (2H, m), 7.3-7.
4 (3H, m)

Example 6 cis-4- (1-benzyloxy-1-methylethyl)
2- (4-Methoxybenzylthiomethyl) -4-butanolide (Compound 6-1) Under a nitrogen atmosphere, a solution of 4-methoxybenzylmercaptan (1.98 ml) in THF (15 ml) was added with -78.
N-butyllithium (1.6 N / n-hexane,
0.08 ml), then 4- (1-benzyloxy-1)
-Methylethyl) -2-methylene-4-butanolide (Compound 1-1, 3.00 g) in THF (5 ml) was added dropwise, and the mixture was stirred for 10 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was returned to 0 ° C., acidified with 1N hydrochloric acid and returned to room temperature. Ethyl acetate is added to the reaction solution, the organic layer is washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oily matter was purified by silica gel column chromatography to give 4.32 g (8%) of the title compound.
9%). NMR (CDCl ₃ ) 1.28 (3H, s), 1.34 (3H, s), 2.0
7 (1H, m), 2.34 (1H, m), 2.54 (1
H, dd), 2.78 (1H, m), 2.92 (1H,
dd), 3.67 (2H, s), 3.79 (3H,
s), 4.29 (1H, dd), 4.51 (2H,
s), 6.83 (2H, d), 7.20 (2H, d),
7.30 (5H, m)

The following compounds were obtained in the same manner as in Example 6 except that the raw materials were changed. * 4- (4-methoxybenzyloxymethyl) -2-
(4-Methoxybenzylthiomethyl) -4-butanolide (Compound 6-2)

4-methoxymethyl-2- (4-methoxybenzylthiomethyl) -4-butanolide (compound 6-
3)

.4- (4-benzyloxybutyl) -2
-(4-Methoxybenzylthiomethyl) -4-butanolide (Compound 6-4)

4- (1-benzyloxy-1-methylethyl) -2-benzylthiomethyl-4-butanolide (compound 6-5)

4- (1-benzyloxy-1-methylethyl) -2-methylthiomethyl-4-butanolide (compound 6-6)

Example 7 cis-4- (1-hydroxy-1-methylethyl) -2
-Mercaptomethyl-4-butanolide (Compound 7-1) 1) cis-4- (1-benzyloxy-1-methylethyl) -2- (4-methoxybenzylthiomethyl) -4-
A solution of butanolide (Compound 6-1, 463 mg) in methanol (15 ml) was passed through ammonia gas for 30 minutes under ice-cooling and left overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the resulting oily substance is purified by silica gel column chromatography to give 5-benzyloxy-4-hydroxy-2- (4-methoxybenzylthiomethyl) -5-methylpentanamide (406 mg, 84) %).

2) Under a nitrogen atmosphere, a solution of the amide (406 mg) obtained above in THF (5 ml) was added to liquid ammonia (30 ml), and sodium metal (98 mg) was added in small portions while stirring at -78 ° C. After the reaction,
Ammonium chloride is added and ammonia is distilled off. Then, the mixture is concentrated under reduced pressure, 1N hydrochloric acid and ethyl acetate are added to the concentrate, and the organic layer is separated. The organic layer is washed with water and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The resulting oily substance is purified by silica gel column chromatography,
21 mg (11%) of the title compound are obtained. Also, 75 mg (41%) was obtained as a mixture of cis and trans. NMR (CDCl ₃ ) 1.21 (3H, s), 1.35 (3H, s), 1.6
3 (1H, t), 1.70 (1H, br, s), 2.2
3 (1H, dt), 2.33 (1H, m), 2.86
(2H, m), 2.98 (1H, m), 4.25 (1
H, dd)

By replacing the raw materials and operating in the same manner as in Example 7, the following compound is obtained.・ 4-Hydroxymethyl-2-mercaptomethyl-4-
Butanolide (Compound 7-2)

4- (4-hydroxybutyl) -2-mercaptomethyl-4-butanolide (Compound 7-3)

Example 8 cis-2-acetylthiomethyl-4-carboxy-4-
Butanolide (Compound 8-1) and trans-2-Acetylthiomethyl-4-carboxy-4-butanolide (Compound 8-2) Under a nitrogen atmosphere, 4-carboxy-2-methylene-4-butanolide (Compound 2-1, To a mixed solution of 111 mg) and thioacetic acid (2 ml) was added potassium tert-butoxide (4.5 mg) at room temperature, and the mixture was stirred for 30 minutes. The reaction solution is concentrated under reduced pressure, and the resulting oily matter is purified by silica gel column chromatography to obtain 82 mg (48%) of the title compound in the cis form and 52 mg (31%) of the trans form.

Cis-form: mp 127.6-128.8 ° C NMR (CDCl ₃ ) 2.13 (1H, m), 2.79 (1H, m), 2.9
6-3.03 (1H, m), 3.15 (1H, dd),
3.36 (1H, dd), 4.86 (1H, dd)

Trans form: mp 122.5-125.1 ° C NMR (CDCl ₃ ) 2.38 (2H, m), 2.57 (1H, m), 3.0
0-3.08 (1H, m), 3.14 (1H, dd),
3.36 (1H, dd), 4.96 (1H, dd)

Example 9 cis-2-mercaptomethyl-4-carboxy-4-butanolide (Compound 9-1) Under a nitrogen atmosphere, cis-2-acetylthiomethyl-4-carboxy-4-butanolide (Compound 8-1). , 67 mg)
Is added to 1N aqueous ammonia (1.0 ml), and the mixture is stirred at room temperature for 10 minutes. The reaction mixture is neutralized with 1N hydrochloric acid (1 ml) under ice cooling and extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The oily substance obtained is purified by silica gel column chromatography to give 41 m of the title compound.
g (75%) are obtained. NMR (CDCl ₃ ) 1.62 (1H, dd), 2.40 (1H, m), 2.
80-3.06 (4H, m), 4.92 (1H, dd)

By replacing the raw materials and operating in the same manner as in Example 9, the following compound is obtained.・ Trans-2-mercaptomethyl-4-carboxy-
4-butanolide (compound 9-2) mp 100.6-106.3 ° C NMR (CDCl ₃ ) 1.58 (1H, dd), 2.58 (1H, m), 2.
67 (1H, m), 2.81 (1H, m), 2.96
(1H, m), 3.03-3.15 (1H, m), 5.
01 (1H, dd)

Example 10 cis-N-benzyl-4- (1-benzyloxy-1-)
Methylethyl) -2-benzylthiomethyl-4-butanelactam (Compound 10-1) and trans-N-benzyl-4- (1-benzyloxy-1-methylethyl)
2-Benzylthiomethyl-4-butanelactam (Compound 10-2) Benzyl mercaptan (0.62 ml) under nitrogen atmosphere
N-Butyllithium (1.6 N / n-hexane, 0.30 ml) was added to a THF (10 ml) solution of the above at −78 ° C. and stirred for 10 minutes, and then N-benzyl-4- (1-benzyloxy-1). -Methylethyl) -2-methylene-4
TH of butanelactam (Compound 4-1, 1.60 g)
Add the F (5 ml) solution dropwise and stir for an additional 10 minutes.
A saturated aqueous solution of ammonium chloride is added to the reaction solution, and the mixture is returned to room temperature, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography to obtain 1.07 g (49%) of the cis form of the title compound and 0.38 g (17%) of the trans form.
%).

Cis isomer: NMR (CDCl ₃ ) 1.16 (3H, s), 1.18 (3H, s), 1.4
2 (1H, m), 2.17 (1H, m), 2.64 (2
H, m), 3.04 (1H, m), 3.64 (1H,
t), 3.74 (1H, d), 3.78 (1H, d),
4.36 (1H, d), 4.38 (1H, d), 4.4
3 (1H, d), 5.01 (1H, d), 6.90-
7.40 (15H, m)

Trans form: NMR (CDCl ₃ ) 1.17 (3H, s), 1.21 (3H, s), 1.8
5 (1H, m), 1.98 (1H, m), 2.56 (2
H, dd), 2.80 (1H, dd), 3.02 (1
H, dd), 3.45 (1H, dd), 3.75 (2
H, s), 4.29 (1H, d), 4.38 (2H,
s), 5.15 (1H, d), 6.95-7.38 (1
5H, m)

The following compounds were obtained in the same manner as in Example 10 except that the raw materials were changed. N-benzyl-4-benzyloxymethyl-2-benzylthiomethyl-4-butanelactam (compound 10-
3) IR (film, cm ⁻¹ ) 3028, 2915, 2863, 1684, 1495,
1453, 1360, 1248, 1115, 1028,
737,700

N-benzyl-4-benzyloxymethyl-2- (4-methoxybenzylthiomethyl) -4-
Butanelactam (Compound 10-4)

N-benzyl-4-benzyloxymethyl-2-methylthiomethyl-4-butanelactam (compound 10-5)

4-benzyloxymethyl-2-benzylthiomethyl-N-isopropyl-4-butanelactam (Compound 10-6)

4-benzyloxymethyl-2-benzylthiomethyl-N-ethoxycarbonylmethyl-4-butanelactam (compound 10-7)

4-benzyloxymethyl-2-benzylthiomethyl-N- (5-tert-butoxycarbonylaminopentyl) -4-butanelactam (compound 10-
8)

4-benzyloxymethyl-2-benzylthiomethyl-N- (4-methoxycarbonylbenzyl) -4-butanelactam (Compound 10-9)

4-benzyloxymethyl-2-benzylthiomethyl-N-methoxy-4-butanelactam (compound 10-10)

4-benzyloxymethyl-2-benzylthiomethyl-N-benzyloxy-4-butanelactam (Compound 10-11)

4-benzyloxymethyl-2-benzylthiomethyl-N- (4-methoxybenzyl) -4-butanelactam (Compound 10-12)

N-benzyl-2-benzylthiomethyl-4-methoxymethyl-4-butanelactam (compound 1
0-13)

N-benzyl-2-benzylthiomethyl-4- (4-methoxybenzyloxymethyl) -4-butanelactam (compound 10-14)

N-benzyl-2-benzylthiomethyl-4- (4-benzyloxybutyl) -4-butanelactam (compound 10-15)

Example 11 cis-4- (1-hydroxy-1-methylethyl) -2
-Mercaptomethyl-4-butanelactam (Compound 11
-1) Under nitrogen atmosphere, cis-N-benzyl-4- (1-benzyloxy-1-methylethyl) -2-benzylthiomethyl-4-butanelactam (Compound 10-1, 300 m
g) in THF (5 ml) with liquid ammonia (30 m
1), and sodium metal (100 mg) is added in small portions with stirring at -78 ° C. After completion of the reaction, ammonium chloride is added and ammonia is distilled off. Then, the mixture is concentrated under reduced pressure, 1N hydrochloric acid is added to the concentrate, and the mixture is extracted with chloroform. The organic layer is washed with water and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography to give the title compound 22
Obtain mg (11%). Also, 45 mg (22%) was obtained as a mixture of cis and trans. NMR (CDCl ₃ ) 1.20 (3H, s), 1.25 (3H, s), 1.5
5 (1H, t), 1.79 (1H, br, s), 1.8
4 (1H, m), 2.25 (1H, m), 2.75-
2.91 (3H, m), 3.57 (1H, dd), 6.
22 (1H, br, s)

The following compounds were obtained in the same manner as in Example 11 except that the raw materials were changed. Cis-4-hydroxymethyl-2-mercaptomethyl-4-butane lactam (compound 11-2) mp 57.5-65.4 ℃ (ethyl _{acetate) NMR (CDCl 3) 1.54 (} 1H, dd), 1.75 (1H, m), 2.
34 (1H, m), 2.53 (1H, br, s), 2.
73-2.92 (3H, m), 3.53 (1H, m),
3.79 (2H, m), 6.40 (1H, br, s)

Trans-4-hydroxymethyl-2-
Mercaptomethyl-4-butanelactam (Compound 11-
3) mp 92.2-94.9 ° C (isopropyl ether-
Ethyl acetate - ethanol - _{Le) NMR (CDCl 3) 1.51 (} 1H, dd), 2.07 (1H, m), 2.
21 (1H, m,), 2.62 (1H, br, s),
2.71-2.90 (3H, m), 3.52 (1H, d
d), 3.70 (1H, dd), 3.77 (1H,
m), 6.50 (1H, br, s)

4- (4-hydroxybutyl) -2-mercaptomethyl-4-butanelactam (compound 11-
4)

Example 12 N-benzyl-2-benzylthiomethyl-4-carboxy-4-butanelactam (Compound 12-1) Benzyl mercaptan (0.30 ml) under a nitrogen atmosphere.
In THF (6 ml) at 0 ° C. with n-butyllithium (1.6 N / n-hexane, 1.35 ml) then N.
-Benzyl-4-carboxy-2-methylene-4-butanelactam (Compound 4-1, 0.50 g) in THF (4
ml) solution is added dropwise and stirred for 30 minutes. The reaction solution is further stirred at room temperature for 1 hour, poured into water and washed with ether.
The aqueous layer is acidified with 2N hydrochloric acid and extracted with ether. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound 0.81 g (quantitative, cis: trans = 24: 76). NMR (CDCl ₃ ) 2.02 and 2.03 (1H, dt), 2.32 and 2.51 (1H, dt), 2.61 (1H, dd),
2.72 and 2.79 (1H, m), 3.01 (1
H, dd), 3.74 (2H, s), 3.94 (1H,
dd), 4.01 (1H, d), 4.4-5.1 (1
H, br), 5.13 and 5.18 (1H, d),
7.2-7.3 (10H, m)

Example 13 cis-4-carboxy-2-mercaptomethyl-4-butanelactam (Compound 13-1) N-benzyl-2-benzylthiomethyl-4-carboxy-4-butanelactam ( Compound 12-
A solution of 1,675 mg) in THF (5 ml) is added to liquid ammonia (20 ml) and sodium metal (250 mg) is added in small portions with stirring. After completion of the reaction, ammonium chloride is added and ammonia is distilled off. Then, the mixture is concentrated under reduced pressure, 1N hydrochloric acid is added to the concentrate, and the mixture is extracted with ethyl acetate.
The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid is recrystallized from ethyl acetate to obtain 122 mg (37%, a small amount of trans isomer) of the title compound. NMR (CDCl ₃ ) 2.11 (1H, dt), 2.66 (1H, dt),
2.7-2.8 (3H, m), 4.24 (1H, t)

Example 14 2-Acetylthiomethyl-N-benzyl-4-carboxy-4-butanelactam (Compound 14-1) N-benzyl-4-carboxy-2-methylene-4-butanelactam under a nitrogen atmosphere. (Compound 5-1, 75m
A mixture of g) and thioacetic acid (1.0 ml) is heated at 80 ° C. for 1 hour. The reaction solution is concentrated under reduced pressure and then purified by silica gel column chromatography to obtain 83 mg (83%, mixture of cis: trans = 75: 25) of the title compound. NMR (CDCl ₃ ) 1.91 and 2.01 (1H, dt), 2.33 and 2.35 (3H, s), 2.52 (1H, dt),
2.84 and 3.03 (1H, m), 3.12 and 3.15 (1H, dd), 3.36 and 3.39 (1
H, dd), 3.95 (1H, dd), 4.04 (1
H, d), 5.15 and 5.20 (1H, d), 7.
21 (2H, m), 7.28-7.35 (3H, m),
8.84 (1H, br, s)

The following compounds were obtained in the same manner as in Example 14 except that the raw materials were changed. -2-benzoylthiomethyl-N-benzyl-4-carboxy-4-butanelactam (Compound 14-2)

[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

[0086]

[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.

[0090]

[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 indication location A61K 31/40 ABB 7252-4C C07D 207/26 7019-4C 207/28 7019-4C (72) Invention Person Masataka Morishita 6-16-16-8 Shintaka, Yodogawa-ku, Osaka-shi

Claims (7)

[Claims] 1. A compound represented by the general formula [I] and salts thereof. [Chemical 1] [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 and R ⁴ are the same or different and each represents a hydrogen atom, a lower alkyl group, a carboxyl group or a lower alkoxycarbonyl group.
Z represents -A-O-R ⁶ or -COOR ^7. R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkanoyl group, a phenyl lower alkyl group, a phenylcarbonyl group, a trityl group or a tetrahydropyranyl group, and the phenyl lower alkyl group. Group and phenyl ring of phenylcarbonyl group are lower alkyl group, lower alkoxy group, halogen atom,
It may be substituted with a carboxy group or a lower alkoxycarbonyl group. R ⁷ represents a hydrogen atom or a lower alkyl group. X represents an oxygen atom or NR ⁸ . R ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a phenyl lower alkyl group or a phenyl lower alkoxy group, and the lower alkyl group is a carboxyl group, a lower alkoxycarbonyl group, an amino group, a lower alkylamino group, a lower alkoxycarbonyl group. It may be substituted with an amino group or a phenyl lower alkylamino group, and the phenyl ring of the phenyl lower alkyl group, phenyl lower alkoxy group and phenyl lower alkylamino group is a lower alkyl group, a lower alkoxy group, a halogen atom, a carboxy group. Alternatively, it may be substituted with a lower alkoxycarbonyl group. A represents a linear or branched lower alkylene. ] 2. A compound represented by the general formula [II] and salts thereof. [Chemical 2] [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 and R ⁴ are the same or different and each represents a hydrogen atom, a lower alkyl group, a carboxyl group or a lower alkoxycarbonyl group.
Z represents -A-O-R ⁶ or -COOR ^7. R ⁶ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkanoyl group, a phenyl lower alkyl group, a phenylcarbonyl group, a trityl group or a tetrahydropyranyl group, and the phenyl ring of the phenyl lower alkyl group and the phenylcarbonyl group is It may be substituted with a lower alkyl group, a lower alkoxy group, a halogen atom, a carboxy group or a lower alkoxycarbonyl group. R ⁷ represents a hydrogen atom or a lower alkyl group. X is an oxygen atom or NR
⁸ is shown. R ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a phenyl lower alkyl group or a phenyl lower alkoxy group, and the lower alkyl group is a carboxyl group, a lower alkoxycarbonyl group, an amino group, a lower alkylamino group, a lower alkoxycarbonyl group. It may be substituted with an amino group or a phenyl lower alkylamino group, and the phenyl ring of the phenyl lower alkyl group, phenyl lower alkoxy group and phenyl lower alkylamino group is a lower alkyl group, a lower alkoxy group, a halogen atom, a carboxy group. Alternatively, it may be substituted with a lower alkoxycarbonyl group. A represents a linear or branched lower alkylene. ] 3. 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 3] [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 and R ⁴ are the same or different and each represents a hydrogen atom, a lower alkyl group, a carboxyl group or a lower alkoxycarbonyl group.
Z represents -A-O-R ⁶ or -COOR ^7. R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkanoyl group, a phenyl lower alkyl group, a phenylcarbonyl group, a trityl group or a tetrahydropyranyl group, and the phenyl lower alkyl group. Group and phenyl ring of phenylcarbonyl group are lower alkyl group, lower alkoxy group, halogen atom,
It may be substituted with a carboxy group or a lower alkoxycarbonyl group. R ⁷ represents a hydrogen atom or a lower alkyl group. X represents an oxygen atom or NR ⁸ . R ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a phenyl lower alkyl group or a phenyl lower alkoxy group, and the lower alkyl group is a carboxyl group, a lower alkoxycarbonyl group, an amino group, a lower alkylamino group, a lower alkoxycarbonyl group. It may be substituted with an amino group or a phenyl lower alkylamino group, and the phenyl ring of the phenyl lower alkyl group, phenyl lower alkoxy group and phenyl lower alkylamino group is a lower alkyl group, a lower alkoxy group, a halogen atom, a carboxy group. Alternatively, it may be substituted with a lower alkoxycarbonyl group. A represents a linear or branched lower alkylene. ] 4. X is an oxygen atom, Z is —A—O—R ⁶ ,
The compound according to claim ¹ , wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen atoms. 5. X is an oxygen atom, Z is --COOR ⁷ , and R
The compound according to claim ¹ , wherein ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁷ are hydrogen atoms. 6. X is NR ⁸ , Z is —A—O—R ⁶ , and R
The compound according to claim ¹ , wherein ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁸ are hydrogen atoms. 7. X is NR ⁸ , Z is —COOR ⁷ , and R
The compound according to claim ¹ , wherein ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ and R ⁸ are hydrogen atoms.