JPH047750B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to novel dimethyl-5,6-dihydroimidazo[2,1-b]thiazole derivatives, more specifically, compounds of the following general formula () having excellent immunomodulatory effects (In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same or different and represent a hydrogen atom or a lower alkyl group, R ₅ is a lower alkyl group, and n Xs are the same or different,
N-alkyl-3-methyl-5,6 represented by hydrogen atom, halogen atom, trifluoromethyl group, lower alkyl group, lower alkoxy group, or nitro group, where n is an integer of 0 to 5)
-dihydroimidazo[2,1-b]thiazole-
The present invention relates to a 2-carboxyanilide derivative or a salt thereof. [Prior Art] Conventionally, many compounds having an imidazothiazole skeleton have been synthesized, for example, the following formula: It has been reported that the imidazo[2,1-b]thiazole derivative (levamisole) represented by
issue). Also, the expression (In the formula, R ₉ is C ₁ to C ₃ alkylsulfonyl or

[Means for solving problems]

Under such circumstances, the present inventors synthesized various imidazo[2,1-b]thiazole derivatives and investigated their physiological activities. The present invention was completed based on the discovery that dimethyl-5,6-dihydroimidazo[2,1-b]thiazole derivatives have excellent immunomodulatory effects. That is, in the present invention, N expressed by the formula ()
-alkyl-3-methyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide derivatives and salts thereof. In the present invention, N-alkyl-3-methyl-
The salts of the 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide derivatives include pharmaceutically acceptable salts, such as hydrochlorides, sulfates, carbonates, nitrates, and hydrobromides. , phosphate,
sulfonates, acetates, oxalates, tartrates,
Examples include inorganic or organic acid salts such as citrate, malate, glutamate, and aspartate. Further, the compound of formula () and its salt of the present invention may have water of crystallization, and any of these hydrates are included within the scope of the present invention. The compound () of the present invention is produced, for example, by reacting an amide represented by the formula () with an imidazolidine-2-thione represented by the formula (), according to the following reaction formula. (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X and n have the above-mentioned meanings.) This reaction is preferably carried out in a suitable inert solvent. toluene,
xylene, acetone, methyl ethyl ketone, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, acetonitrile, ether,
Tetrahydrofuran, dioxane, chloroform, water, etc. are used. The reaction temperature is -5°C to 100°C, preferably 20°C to
80, and the compound of the present invention can be obtained in high yield and purity by reaction for 1 to 6 hours. In order to obtain the free compound of the general formula () from the hydrochloride thus obtained, a base, for example an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, ammonia, etc. It may be treated with an organic base such as pyridine or triethylamine. Also, to lead to other salts, the corresponding acids such as sulfuric acid, carbonic acid, nitric acid, hydrobromic acid, phosphoric acid, sulfonic acid, acetic acid, oxalic acid, tartaric acid, citric acid, malic acid, glumic acid, asparagine acid, etc. The above hydrochloride or free compound may be treated with an acid or the like. The compound of formula () used as a raw material in this method can be obtained by, for example, reacting diketene () with amines () to form a compound of formula () according to the following reaction formula, and then converting this into sulfuryl chloride. [Chemical Abstracts
Abstracts) 19 , 43 (1925)] or by chlorination with N-chlorosuccinimide or the like. (In the formula, _R5 ,
It is produced by the following method according to the method described in Coll., page 3394. [Effect] Next, the pharmacological effects of the compound of the present invention () and its salt will be explained. Test Example 1 Effect on in vitro plaque-forming cell response using mouse splenocytes: 1 x 10 ⁷ BALB/c mouse splenocytes were mixed with sheep red blood cells (1 x 10 ⁶ ) and the test compound (1 μg/ml). In RPMI-1640 medium containing 10% fetal bovine serum
Cultured in a CO ₂ incubator (37°C) for 5 days [Mischell, RI et al.;
[a modification of J. Exp. Med.) 126:423 (1967)], and the number of emerging plaque-forming cells was determined by the method of Jerne and Nordin [Science 140:405 (1963)]. It was measured with The results are shown in Table 1.

【table】

[Table] For levamisole to show enhancing activity, 20 μg/ml is required.
In this test, which requires a concentration of
At a low concentration of 1 μg/ml, it showed activity equal to or greater than resomisole. On the other hand, the comparative compound showed almost no activity. Test Example 2 Effect on in vitro lymphocyte blastogenesis using mouse splenocytes or thymocytes: BALB/c mouse splenocytes (1 x 10 ⁵ cells) or thymocytes (2 x 10 ⁵ cells) Mitogen (ConA: 2.5 μg/ml or LPS: 10 μg/ml) and test compound (1 μg/ml) were incubated in RPMI-1640 medium (0.2 ml) containing 5% fetal bovine serum in a CO ₂ incubator (37°C). ) and cultured for 48 hours. then
0.5 μCi of ³ H-thymidine was added and cultured for an additional 18 hours, and the radioactivity of ³ H-thymidine incorporated into the cells was measured. The results are shown in Table 2.

[Table] Compound 30 of the present invention was found to increase the uptake of ³ H-thymidine, that is, to promote the lymphocyte rejuvenation reaction. Test Example 3 Acute Toxicity: Wistar Male Larrat Group 1 Group 4
The test compound was orally administered to animals at 300 mg/Kg once a day for 4 days, and the effects on general symptoms and body weight were investigated. Compounds of the present invention include compounds 30, 31,
32, 3 and 2, and as a comparative compound, levamisole, in the formula (), R ₁ = R ₂ = R ₃ = R ₄ = R ₅ =
H, (X)n=3,4- _Cl2 (comparative compound 5) and
R ₁ = R ₂ = R ₃ = R ₄ = R ₅ = H, (X)n = 3-CF ₃
(Comparative compound 6) was used. (1) Effect on general symptoms No changes were observed in general symptoms in the groups administered with the compound of the present invention and Comparative Compound 5, but in the group administered with Comparative Compound 6, lacrimation, bleeding from the eyes, sedation,
Abnormal balance and tremor were observed. Half of the patients in the levamisole group died. (2) Effect on body weight Table 3 shows the body weights before and after administration of the test compound for 4 days.

【table】

〔effect〕

As is clear from the above test results, the compound of the present invention () has an excellent immunomodulatory effect, so it can be used as a prophylactic and therapeutic drug for immune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, collagen disease, chronic nephritis, autoimmune disease, etc. It can be used for the treatment and prevention of autoimmune diseases such as immune-mediated hemolytic anemia, immediate and delayed allergic diseases, malignant tumors, severe infections, and the like. The compounds of the present invention can be administered orally or parenterally (eg, intramuscularly, subcutaneously, intravenously, anally, or cutaneously) as such or in various dosage unit forms. The dosage forms include solid preparations such as tablets, sugar-coated tablets, film tablets, hard or soft capsules, troches, pills, granules, and powders; semi-solid preparations such as suppositories, patches, and ointments; and injections. , syrups, inhalants, emulsions, suspensions, and other liquid preparations. Although the compound of the present invention can be used alone as the above-mentioned preparation, it may also be combined with other medicinal ingredients such as non-steroidal analgesics, anti-inflammatory agents, etc. [Example] Next, reference examples and examples will be given and explained. Reference example 1 3.5 g of 3',4'-dichloro-N-methylaniline
(0.02M) and a catalytic amount of pyridine were dissolved in toluene, and 1.9g (0.022M) of diketene was slowly added dropwise at 50°C, and after the dropwise addition was completed, the mixture was heated under reflux for 3 hours.
After cooling, the organic layer was washed successively with water, 10% hydrochloric acid, water, and 5% aqueous sodium bicarbonate solution, dried, and concentrated to obtain 3',4'-dichloro-N-methylacetoacetanilide. Example 1 (i) 3',4'-dichloro-N obtained from Reference Example 1
-Methylacetoacetanilide 2.6g (0.01M)
and 1.4 g of N-chlorosuccinimide
(0.01M) was suspended in carbon tetrachloride, a catalytic amount of benzoyl peroxide was added, and the mixture was heated under reflux for 1 hour. The reaction solution was washed with water, dried and concentrated, the residue was dissolved in methyl ethyl ketone, 1.0 g (0.01 M) of imidazolidine-2-thione was added, and the mixture was heated under reflux for 3 hours. The precipitated crystals were collected, recrystallized from ethanol, and dried under reduced pressure to give 3′,4′-
Dichloro-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (compound 1) 3.4 g
(yield 89.5%). Melting point 275-276℃. (ii) 1.9 g (0.005 M) of the obtained hydrochloride was dissolved in water, and a 10% aqueous solution of caustic soda was added dropwise while stirring at room temperature. The resulting crystals were collected and purified by washing with a large amount of water. This product was dried under reduced pressure and 3',4'-dichloro-N,3-dimethyl-
1.4 g of 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide (yield
82.4%). Melting point 118-122℃. Example 2 (i) 3',5'- obtained in the same manner as Reference Example 1
Dichloro-N-methylacetoacetanilide
2.6 g (0.01 M) and 1.4 g (0.01 M) of N-chlorosuccinimide were suspended in carbon tetrachloride,
Add a catalytic amount of benzoyl peroxide,
The mixture was heated to reflux for an hour. The reaction solution was washed with water, dried, and concentrated, and the residue was dissolved in methyl ethyl ketone.
4-dimethylimidazolidine-2-thione 1.3
g (0.01M) and heated under reflux for 3 hours. The precipitated crystals were collected, recrystallized from isopropanol, and dried under reduced pressure to give 3',5'-dichloro-
N,3,6,6-tetramethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-
Carboxanilide hydrochloride (compound 2) 3.0g
(yield 75.0%). Melting point 222-230℃. (ii) 2.0 g (0.005 M) of the obtained hydrochloride was dissolved in water, and a 20% aqueous potassium carbonate solution was added dropwise to the solution while stirring at room temperature. The resulting crystals were collected and purified by washing with a large amount of water. This product was dried under reduced pressure to produce 3',5'-dichloroN,3,6,6-tetramethyl-5,6-dihydroimidazo[2,1
-b] Thiazole 2-carboxyanilide 1.5
g [yield 78.9%]. Melting point: 169℃. Example 3 N-methyl- obtained in the same manner as Reference Example 1
4′-Trifluoromethylacetoacetanilide
Dissolve 2.6g (0.01M) in diethyl ether,
1.5 g (0.011 M) of sulfuryl chloride was added dropwise at -5°C, and the mixture was stirred at -10 to -5°C for 30 minutes. This was poured into ice water, neutralized using sodium hydrogen carbonate, extracted with toluene, the organic layer was dried and concentrated, and the residue was dissolved in methyl ethyl ketone.
-dimethylimidazolidine-2-thione 1.3g
(0.01M) and heated under reflux for 3 hours. The precipitated crystals were collected, washed with acetone, and dried under reduced pressure to give N,3,6,6-tetramethyl-4'-trifluoromethyl-5,6-dihydroimidazo-[2,
1-b]-thiazole-2-carboxyanilide hydrochloride (compound 3) 3.7 g (yield 92.5%) was obtained.
Melting point 195-198℃. Example 4 2.7 g of 3',4'-dichloro-N-ethylacetoacetanilide obtained in the same manner as Reference Example 1
(0.01M) and N-chlorosuccinimide 1.4g
(0.01M) was suspended in carbon tetrachloride, a catalytic amount of benzoyl peroxide was added, and the mixture was heated under reflux for 1 hour. The reaction solution was washed with water, dried, and concentrated, the residue was dissolved in methyl ethyl ketone, and 1.3 g (0.01 M) of 4,4-dimethylimidazolidine-2-thione was added.
The mixture was heated under reflux for 3 hours. The precipitated crystals were collected, washed with acetone, and dried under reduced pressure to give 3',4'-dichloro-N-ethyl-3,6,6-trimethyl-5,
6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (compound 4)
3.3g (yield 78.6%) was obtained. Melting point 210-214℃. Example 5 3′,4′-dichloro- obtained by Reference Example 1
N-methylacetoacetanilide 2.6g (0.01M)
was chlorinated by the method of Example 2, the resulting oil was dissolved in methyl ethyl ketone, and 1.2 g (0.01 M) of 4-methylimidazolidine-2-thione was added.
The mixture was heated under reflux for 3 hours. The precipitated crystals were collected and washed with acetone to give 3',4'-dichloro-N,3,6
-trimethyl-5,6-dihydroimidazo[2,
1-b] 3.6 g (yield 92.3%) of thiazole-2-carboxyanilide hydrochloride (compound 5) was obtained.
Melting point 230-231℃. Example 6 3.2 g (0.01 M) of N-methyl 3',5'-bis(trifluoromethyl)acetoacetanilide and 1.4 g (0.01 M) of N-chlorosuccinimide obtained by the same method as in Reference Example 1 were The suspension was suspended in carbon chloride, a catalytic amount of benzoyl peroxide was added, and the mixture was heated under reflux for 1 hour. The reaction solution was washed with water, dried and concentrated, the residue was dissolved in methyl ethyl ketone, 1.3 g (0.01 M) of 3,4-dimethylimidazolidine-2-thione was added, and the mixture was heated under reflux for 3 hours.
The precipitated crystals were collected, washed with acetone and dried under reduced pressure to give N,3,5,6-tetramethyl-3',5'-
Bis(trifluoromethyl)-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (compound 6) 3.5 g (yield
74.5%). Melting point 214-218℃. Examples 7-43 The following compounds were produced in the same manner as in Reference Example 1 and Examples 1-6.

【table】

【table】

Claims (1)

[Claims] First-order general formula () (In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same or different and represent a hydrogen atom or a lower alkyl group, R ₅ is a lower alkyl group, and n Xs are the same or different,
N-alkyl-3-methyl-5,6 (represents a hydrogen atom, halogen atom, trifluoromethyl group, lower alkyl group, lower alkoxy group, or nitro group, and n represents an integer of 0 to 5)
-dihydroimidazo[2,1-b]thiazole-
2-carboxyanilide derivative or salt thereof.