JPH03163086A - Production of 3-methyl-5,6-dihydroimidazo(2,1-b)thiazole-2-carboxyamide derivative or salt thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (A is lower alkylene; R1 to R4 are H or lower alkyl; R5 is H, lower alkyl or cycloalkyl; X is H, halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano or nitro; n is 0-5). EXAMPLE:N-(4-Chlorobenzyl)-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2,1- b]thiazole-2-carboxamide. USE:An immunomodulator. PREPARATION:An amide [e.g. N-methyl-N-(4-chlorobenzyl)-2-chloro- acetoacetamide] shown by formula II is reacted with an imidazoline-2-thione (e.g. 4,4 dimethylimidazolidine-2-thione) shown by formula III preferably in an inert solvent such as benzene at 20-80 deg.C for 1-6 hours.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides a novel method for producing a 3-methyl-5,6-dihydroimidazo[2.1-b]thiazole-2-carbowisamide derivative; has the following general formula (I) Rs (I) (wherein A is a lower alkylene group which may be branched), which has an excellent immunomodulatory effect,
Rl% R2, R3 and R are the same or different and represent a hydrogen atom or a lower alkyl group, R is a hydrogen atom, a low toughness alkyl group or a cycloalkyl group, n X tF are the same or different and represent a hydrogen atom , a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a cyano group or a ditro group, n is an integer of 0 to 5). [
2,1-b) A method for producing a thiazole-2-carboxamide derivative or a salt thereof.

[Conventional technology]

Conventionally, many C compounds having an imidazothiazole skeleton have been synthesized. For example, it has been reported that the imidazoC2.1-b) thiazole derivative (levamisole) represented by the following formula has immunomodulatory effects (West German published patent No. 2340632).

In addition, the formula (wherein Rs represents C1 to C, alkylsulfonyl, fluorophenyl, tripleomethylphenyl or trimethylphenyl, but is not hydrogen at the same time, or RI3 and R. are the nitrogen atoms to which they are bonded) together with to form cis-dimethylpinolysine, R1. is C, to C, alkyl or phenyl, R. and RI2 independently represent hydrogen or C1 to C4 alkyl group) C2,1-b] Thiazole derivative [US Pat. No. 4,224,334, Journal of Medicinal Chemistry (J. Med, Chem.
)24. 604-609 (1981)) and the formula (wherein, RIS represents a substituted or unsubstituted phenyl group or naphthalyl group) 5,6-dihydroimidazo[2,1-b]
It has been reported that thiazole derivatives (JP-A-57-169490) have anti-inflammatory effects.

[Means for solving problems]

In such a situation, the present inventors discovered that various imidazoC
2.1-b] As a result of synthesizing thiazole derivatives and examining their physiological activities, we found that a novel 3-methyl=5,6-dihydroimidazoC2,1 represented by the above formula (1) having a specific substituent was found. -b] It was discovered that thiazole-2-carboxamide derivatives have excellent immunomodulatory effects, and the present invention was completed.

That is, the present invention provides a method for producing a 3-methyl-5,6-dihydroimidazo[2.1-b]thiazole-2-carboxamide derivative represented by formula (I) or a salt thereof.

In the present invention, the salts of the 3-methyl-5,6-dihydroimidazo C2.1-b) thiazole-2-carpoxamide derivative include pharmaceutically acceptable salts, such as hydrochloride, sulfate, carbonate, and nitrate. , hydrobromide, phosphate, sulfonate, acetate, oxalate, tartrate, citrate, malate, glutamate, aspartate, and other inorganic or organic acid salts. It will be done.

Further, the compound of formula (1) and its salt of the present invention may have crystal water, and any of these hydrates are included within the scope of the present invention.

The compound (I) of the present invention can be prepared, for example, according to the following reaction formula (
It is produced by reacting an amide represented by the formula (II) with an imidazolidine-2-thione represented by the formula (III).

Rs (I) (wherein ^, Rl, R,, R3, R4, R,, X and n
has the above-mentioned meaning) This reaction is preferably carried out in a suitable inert solvent, examples of which include benzene, toluene, xylene, acetone, methyl ethyl ketone, dimethyloleformamide, dimethylacetamide, dimethynoresulfoxide, acetonitrile, and ether. , tetrahydrofuran, dioxane, chlorophonolem, water, etc. are used.

The reaction temperature is -5°C to 100°C, preferably 20°C to 8°C.
The reaction temperature is 0°C, and the compound of the present invention can be obtained in high yield and purity in a reaction time of 1 to 6 hours.

Free general formula (I) from the hydrochloride thus obtained
To obtain the compound, a base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate,
It may be treated with an inorganic base such as sodium hydrogen carbonate or ammonia, or an organic base such as pyridine or triethylamine. In order to lead to other salts, the corresponding acids such as sulfuric acid, carbonic acid, nitric acid, hydrobromic acid, phosphoric acid, sulfonic acid,
The above hydrochloride or free compound may be treated with acetic acid, oxalic acid, tartaric acid, citric acid, malic acid, glutamic acid, aspartic acid, or the like.

The compound of formula (II) used as a raw material for this method is:
For example, Pharmaceutical Journal, 89(11), 1477-1481
(1969) etc., diketene (TV) was reacted with amines (V) according to the following reaction formula (
VI), which is then converted into sulfuryl chloride [Chemical Abstracts
Abstracts)19. 43 (1925). Same 7
4,42102t (1971)] or by chlorination with N-chlorosuccinimide or the like.

(V) 0 (wherein, ASRs,
Call. 3, p. 394 or J. Mad, Che
m, 18 (5). 447-453 (1975)
It is manufactured by the following method according to the method described in .

(Melting point: H 197-198℃) H [Effect] next, Compound (I) of the present invention and pharmacological effects of its salts Explain the results.

Test Example 1 Effect on in vitro plaque-formed cystic response using mouse pupil cells: IXIO' tile cells of BALB/c mice were injected with sheep red blood rins (1xlO') and the test compound (0, 2 or 1 μg/ 1) together with RPMI-1640 containing 10% fetal bovine serum
Cultured in a C02 incubator (37°C) for 5 days in medium [Michel. R. Ai (Michelle,
R. I) et al.: (J. Bxp. Med. 026:4
23 (1967)], the number of Braak shapes or cells that appear is determined by Jerne and Nordin (1967).
dlJordin's method [Science
ce) 140:405 (1963)]. The results are shown in Table 1-1.

Table 1-1 Rs (■) ■ Table 1-1 (Note) "1" means not measured (the same applies below).

Also, for comparison, JP-A-52-106893 and Journal of Medicinal Chemistry 10, M
ed. Chem,). 24, 604-609 (19
The following compounds described in 81) were similarly measured for their effects on plaque-shaped cartilage cell responses in vitro, and the results are shown in Tables 1-2.

Margin Table 1-2 Hrl (■) As is clear from Margin Tables 1-1 and -2 below, the compounds of the present invention exhibit immune response activity at low concentrations of 0.2 to 1 μg/mf; Comparative compounds show almost no activity.

Test Example 2 Effect on in vitro lymphocyte blastogenesis using mouse group cells: BALB/c mouse tile cells (IXIO' cells) or thymocytes (2X10-' cells) were treated with Con A (T cell mitogen). 2. 5μg/1) and test compound (
RPMI-1 containing 5% fetal bovine serum with 1 μg/d)
The cells were cultured in CD 640 medium (0.2 mf) in an incubator (37°C) for 48 hours. Next, 0.5 μCi of 3H-thymidine was added and cultured for an additional 18 hours, and the radioactivity of 3H-thymidine incorporated into the cells was measured. The results are shown in Table 2. 3H revealed by addition of the compound of the present invention
- Increased thymidine uptake was observed.

Table 2 Test Example 3 Effect on the lymphocyte rejuvenation response when the test compound was orally administered: Six BALB/c female mice were used per group. Test compound 0. 25 mg/kg was orally administered once a day for 5 days, and on the 6th day, the pancreas was removed and the tile cells (2xlO' cells) were cultured with mitogen (LPS: 10 pg/ml or Can A: 2.5 μg/mi'). Then, lymphocyte blastogenesis was investigated. The culture conditions and the measurement of lymphocyte blastogenesis were conducted according to the method of Test Example 2. The results are shown in Table 3.

Table 3 In this test, levamisole must have 2.
Although administration of 5 mg/kg/day was required, the compound of the present invention showed a promoting activity equal to or greater than that of levamisole when administered at 1/10 the dose of 0.25 mg/kg/day.

Test Example 4 Effect on delayed allergic reaction: 2 sheep red blood cells were subcutaneously placed on the back of 1 group of 8 male cldY mice.
Four days after sensitization, 5 x 107 sheep red blood cells were injected subcutaneously into the paw of one hind limb, and physiological saline was injected into the paw of the other side, and 24 hours later, both paw fluids were injected. The thickness was measured with a micrometer to determine the edema rate.The test compound was orally administered once a day for 5 days from the day of sensitization (2 hours after sensitization).

results It is shown in Table 4.

Margin below table 4 K: Significant difference from control group (P<0.05) can be.

The compound of the present invention significantly inhibited delayed allergic reactions when administered at a dose of 0.1 μ/kg/day.

Test Example 5 Effect of adjuvant on arthritis: Eight female Lewis rats were used in one group. Adjuvant arthritis was induced by intradermally injecting 0.6/0.1 - of killed Mycobacterium tuberculosis suspended in liquid paraffin as an adjuvant into one hind limb, and the test compound was administered once a day for 20
After 21 days of oral administration, the axillary volumes of both hind legs were measured,
The edema rate for each was determined.

The results are shown in Table 5. The compound of the present invention has a rating of 5 to 5/k.
The administration of 3 g/day significantly suppressed the edema of the non-azicobant-injected paws and the edema of the adjuvant-injected paws.

Test Example 6 Side effects and blood concentration: 300 mg/kg of the test compound was orally administered to a group of 4 male Wistar rats once a day for 4 days, and changes in general symptoms were observed. , body weight, liver weight,
The effect on serum cholesterol levels was investigated. Serum cholesterol was measured with a Centrificem autoanalyzer using a Baker's cholesterol measurement kit. The compounds of the present invention include Compound 1, and the comparative compounds include (
■) In the formula, R,=R. =R. =}I, (X)fi=
3 and 4Clx compounds (levamisole was used in the comparison. Blood concentrations of the test compounds were also compared after one administration and after administration for 4 days. High performance liquid chromatography was used to measure the blood concentration. It was used.

(1) Effect on general symptoms No changes were observed in general symptoms in the Compound 1 and Comparative Compound 6 administration groups, but in the Comparative Compound 7 administration group, lacrimation, lacrimation,
Bleeding from the eyes, sedation, loss of balance, and tremors were observed.

Half of the patients in the levamisole group died.

(2) Effect on body weight Table 6 shows the body weights before and after continuous administration of the test compound.

Although Compound 1 had no effect on body weight, Comparative Compound 6 significantly reduced body weight. Levamisole is 10
Administration of 0 mg/kg/day also significantly reduced body weight.

(3) Effect on liver weight The results obtained are shown in Table 7. Compound 1 had no significant effect on liver weight, whereas comparative compound 6 significantly increased liver weight.

Table 8 shows the results of the effect test on serum cholesterol level (4) below in the margin. Compound 1 had no significant effect on blood cholesterol levels, whereas comparative compounds 6 and 7 and levamisole significantly increased cholesterol levels.

Blank space below (5) Changes in blood concentration due to continuous administration Table 9 shows the blood concentrations at the 1st hour and 2nd hour after one administration and once a day for 4 days, respectively.

The blood concentration of Compound 1 was close to the blood concentration after a single administration even after 4 days of administration, but the blood concentrations of Comparative Compounds 6 and 7 were significantly reduced by continuous administration. .

The following margin [Effect] As is clear from the above test results, the compound (I) of the present invention
Because it has an excellent immunomodulatory effect, it can be used as a preventive and therapeutic drug for immune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, collagen disease, chronic nephritis, autoimmune hemolytic anemia, and other autoimmune diseases, immediate and delayed. It can be used for the treatment and prevention of type allergies, malignant tumors, severe infections, etc.

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 and anti-inflammatory agents.

〔Example〕 Next, reference examples and examples will be given and explained.

Reference example 1 4-chloro N-methyl-benzinoleamine (3.1 g
,0. 02M) was dissolved in toluene, a catalytic amount of pynodine was added, and diketene (1.8 g, 0.02M) was dissolved at room temperature.
022M) was added dropwise. After stirring the reaction solution at room temperature for 3 hours, 1 glass of water was added, and the mixture was extracted with toluene and purified to obtain an oil-like N-methyl-N-(4-chlorobenzinole)monoacetoacetamide).

Example 1 (i) N-methynole N-(4-chlorobenzyl)acetoacetamide obtained in Reference Example 1 (4, O g ,0
．． 017M), N-chlorocono\citric acid imito'' (2.
3g, 0. 017M) and a small amount of penzoinoleno-oxide were suspended in carbon tetrachloride and heated under reflux for 2 hours.

After cooling, the mixture was poured into water, extracted with carbon tetrachloride, purified, dried, and concentrated to obtain an oily crude product. This product was purified using a silica gel column (C-300, n-hexane-ethyl acetate) to obtain 3.5% of oily N-methyJLI-N-(4-chlorobenzyl)-2-chloroacetoacetamide.
g was obtained (II2′ + 1.5336).

This product and 4,4-dimethylimidazolidine-2-thiadiene (1.7 g, 0.013 M) were dissolved in methyl ethyl ketone, heated to reflux during Bwf, and after cooling, the resulting precipitate was collected by filtration, and diluted with acetone. After washing, recrystallize with isobromanol/isobrobyl ether to obtain 4.8 g of N-(4
-chlorobenzyl)-N,3,6.6-tetramethyl-
5.6-dihydroimidazo[2,1-b)thiazole-
2-carboxamide hydrochloride (compound 1) (melting point 187-
190°C, white crystals) were obtained.

(ii) Obtained hydrochloride3. 9g (0.OIM)
Dissolve it in water, add 10% caustic soda dropwise while stirring at room temperature, collect the crystals that have formed by filtration, wash with a large amount of water, and clean!
I went to a1. This material was dried under reduced pressure, and the N
-(4-chlorobenzyl)-N. 3,6.6-tetramethyl-5.6-dihydroimidazo(2.1-b)thiazole-2-carboxamide (melting point 139°C, pale yellow powder crystal) was obtained.

Example 2 N-(4-chlorobenzyl)acetoacetami Y (2.3 g, 0,
OIM) and N-chlorosuccinimide (1.3 g
%' o. OIM) and a small amount of penzoyl peroxide were suspended in carbon tetrachloride and heated under reflux for 1 hour. This was poured into water, extracted with carbon tetrachloride, washed with water, dried, and concentrated. The resulting oily substance was subjected to the next reaction without purification. The compound thus obtained and imidazolidine-2-thiamine (1.0 g, OIM) were suspended in methyl ethyl ketone and heated under reflux for 3 hours.

After cooling, the precipitate was collected by filtration, washed with acetone, and recrystallized with isopropyl alcohol/isobrobyl ether to give N-(4-chlorobenzyl)-3-methyl-5.6-
2.8 g of dihydroimidazo(2,1-b)thiazole-2-carboxami}hydrochloride (compound 2) was obtained. Melting point 2
41-242°C white crystals.

Example 3 N-(3-) fluoromethylbenzyl) acetoacetamide (2.6 g, 0
．． OIM) and N-chlorosuccinimide (1.g, 0
．． 01M) and a small amount of penzoyl peroxide were suspended in carbon tetrachloride and heated under reflux for 1 hour. After cooling, the reaction solution was poured into water, and after hitting with carbon tetrachloride, washing with water, drying,
It was concentrated, and the obtained oily oyster was subjected to the next reaction without being concentrated. The resulting compound and imidazolidine-2-thione (1.0 g, 0.01 M) were mixed with methyl ethyl ketone and heated under reflux for 3 hours. After cooling, the resulting product was filtered. After washing with acetone and recrystallizing with ethanol, 3-methyl-N-(3-
}! 2.5 g of J fluoromethylbenzyl)-5,6-dihydroimidazo(2.1-b)thiazole-2-carpoxamide hydrochloride (compound 3) (melting point 210-216°C, colorless prismatic crystals) was obtained.

Example 4 N-ethyl-N- (
4-chlorobenzyl)acetonacetamide (2.5 g
, 0. OIM) and N-chlorosuccinimide (1
．． (3 g, 0.01M) and a small amount of penzoyl peroxide were suspended in carbon tetrachloride and heated under reflux for 1 hour. After cooling, the reaction solution was poured into water, extracted with carbon tetrachloride, washed with water, dried, and concentrated. The resulting oily substance was used in the next reaction without purification. The compound thus obtained and 4,4-dimethylimidazolidine-2-thione (1.
3g, O. OIM) was dissolved in methyl ethyl ketone and heated under reflux for 3 hours. After cooling, the resulting precipitate was collected by filtration, washed with acetone, and recrystallized from isobropanol/isobrobyl ether to give N-(4-D-lobenzyl)-N-ethyl-3.6.6- }Limethyl-5.6
-dihydroimidazo[2.1-b)thiazole-2-carboxamide hydrochloride (compound 4) (melting point 178-181
t', white crystals) 2.7 g were obtained.

Example 5 N-methyl-N-(3
,4-dichlorobenzyl〉acetoacetamide (2.6
g, 0. OIM), N-chlorosuccinimide (1.3 g, 0.OIM), and a small amount of penzoyl peroxide were suspended in carbon tetrachloride, and heated under reflux for 1 hour. After cooling, the reaction solution was poured into water, extracted with carbon tetrachloride, washed with water, dried, and concentrated. The resulting oily substance was used in the next reaction without purification. The compound thus obtained and imidazolidine-2-thione (1.'
Og, 0. OIM) was suspended in methyl ethyl ketone and heated under reflux for 3 hours. After cooling, the resulting precipitate was collected by filtration, washed with acetone, and recrystallized with ethanol to obtain N-(3.4-dichlorobenzyl)-N,3-dimethyl-5.6-dihydroimidazo (2. 1-b] Thiazole-2-carpoxamide hydrochloride (compound 5) (melting point 1
>3.1 g of pale yellow microneedle crystals were obtained at 96-198°C.

Example 6 N-(3,4-dichloropenzyl)monoacetoacetamide (5.2g10.02
M) and N-chlorosuccinimide (2.7 g,0
．． 02M) and a small amount of penzoyl peroxide were suspended in carbon tetrachloride and heated under reflux for 1 hour.

After cooling, it was poured into water, extracted with carbon tetrachloride, washed with water, dried, and a-condensed, and the obtained oily substance was subjected to the next reaction without purification. The compound thus obtained and 4.
5-dimethylimidazolidine-2-thione (2.6
g, 0. 02M) was dissolved in methyl ethyl ketone and heated under reflux for 3 hours. After cooling, the precipitate is collected by filtration,
Washing and purification with a large amount of acetone resulted in N-(3,4-dichlorobenzyl>-3,5.6-trimethyl-5.6-
Dihydro pimidazo[2,1-b)thiazole-2-carboxamide hydrochloride (compound 6) (melting point 148-152°C
, white powder) was obtained.

Example 7 N-(3-chlorobenzyl)N-methyl T-cetoacetamide (4.8 g, 0
．． 02M) and N-chlorosuccinimide (2.7 g
, 0.02M) and a small amount of penzoyl peroxide were suspended in carbon tetrachloride and heated under reflux for 1 hour. This was poured into water, extracted with carbon tetrachloride, washed with water, dried, and concentrated, and the obtained oily substance was subjected to the next reaction without purification. The compound thus obtained and 4-methylimidazolidine-2-thione (2.4 g, O,
02M) was dissolved in methyl ethyl ketone and heated under reflux for 3 hours. After cooling, the precipitate was collected by filtration, washed and purified with acetone and isobrobyl ether, and N-(3-chlorobenzyl)-N,3.6-trimethyl-5,6-dihydroimidazo [2.1-b] Thiazole-2-carboxamide hydrochloride (compound 7) (melting point 41-47°C, brown glassy substance) was obtained.

Example 8 (i) N-(2,4-dichlorobenzyl)1N-methylacetoacetamide (5.2 g, 0.02M) obtained in the same manner as in Reference Example 1 and N-chlorosuccinic acid Imide (2.7 g, 0.02M) and a small amount of penzoyl peroxide were suspended in carbon tetrachloride and heated under reflux for 1 hour. After cooling, the reaction solution was poured into water, extracted with carbon tetrachloride, washed with water, dried, and concentrated, and the obtained oily substance was subjected to the next reaction without purification. The compound thus obtained and imidazolidine-2-thione (1.0g, 0.0IM) were suspended in methyl ethyl ketone and heated under reflux for 3 hours. After cooling, the resulting precipitate was collected by filtration, washed with acetone, and purified to obtain N-(2.
4-dichloropenzyl)-N. 3-dimethyl-5,6-
Dihydroimidazo[2.1-b]thiazole-2-carboxamide hydrochloride (compound 8) (melting point 251-254°C
, colorless powder) was obtained.

(ii) The obtained N-(2,4-dichloropenzyl)-
N,3-dimethyl-5,6-dihydroimidazo[2,1
-b) Thiazole carboxamide hydrochloride 3. 6g (
0. OIM) was dissolved in water, and aqueous ammonia was added dropwise while stirring at room temperature. The resulting precipitate was collected by filtration, washed and purified with a large amount of water, and 3.0 g of N-(2.4-dichlorobenzyl)-N. 3-dimethyl-5,6-dihydroimidazo[2.1-b)thiazole-2-carboxamide (melting point 55-60t: , pale yellow powder) was obtained.

Examples 9-94 The following Table 10 was prepared in the same manner as Reference Example 1 and Examples 1-8 above.
The compounds described were prepared.

The following margin Examples 95 to 99 The compounds listed in Table 11 below were produced in the same manner as in the above Reference Examples and Examples.

Below are blank spaces Example 100 Reference Example 1 and Example 1 (i) 2-chloroN-(2-phenylethyl) obtained in the same manner as in the previous step using β-7 phenethylamine in 10 ml of methyl ethyl ketone
Dissolve 2.5 g of acetoacetamide (unpurified) and 1.3 g of 4,4-dimethylimidazolidine-2-thione,
The mixture was heated to reflux for an hour. After cooling and concentrating to remove methyl ethyl ketone, the residue was dissolved in 20 parts of water.

This aqueous solution was mixed with 20 mj of a 10% aqueous sodium hydroxide solution and 20 mj of toluene! was added dropwise to the mixed solution while stirring.

The precipitated crystals were collected by filtration, washed with 20% of water, and dried to give N-(2-phenylethyl)-3.6.6-trimethyl-5.6-dihydroimidazo[2.1-b]thiazole- 2.5 g of 2-carboxamide (Compound 98, light brown powder, melting point 102-105°C) was obtained.

Further, 2.5 g of this light brown powder was dissolved in isoprobyl alcohol IO-, and then 20 g of isobrobyl ether was dissolved.
mj! was added gradually. The precipitated crystals were collected by filtration, washed with isoprobyl ether 10- and dried to give 1.1 g of Compound 98 as white needle-like crystals (corrosion point 120-121°C).
Obtained.

that's all

Claims (1)

[Claims] 1. The following general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, A represents a lower alkylene group which may be branched,
R_5 is a hydrogen atom, a lower alkyl group or a cycloalkyl group, and n X's are the same or different and represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a cyano group or a nitro group, n is an integer from 0 to 5) Amides represented by the following general formula (III) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, R_1, R_2, R_3 and R_4 are the same or General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, A, R_1, R_2, R_3, R_4, R_5
, X and n have the above-mentioned meanings) 3-methyl-5,6-dihydroimidazo [
2,1-b] Method for producing a thiazole-2-carboxamide derivative or a salt thereof.