5,6-dihydroimidazo(2,1-b)thiazole-2-carboxamide derivatives or salts thereof

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives, and more specifically to 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives having excellent immuno-modulating activities.
2. Description of the Prior Art
A number of compounds having the imidazothiazole skeleton have heretofore been synthesized. For example, an imidazo[2,1-b]thiazole derivative (levamisole) represented by the following formula: ##STR2## has been reported to have some immuno-modulating activities (German Offenlegungsschrift No. 23 40 632).
It has also been reported that certain anti-inflammatory activities are exhibited by imidazo[2,1-b]thiazole derivatives represented by the following formula: ##STR3## wherein R.sub.10 means a C.sub.1 -C.sub.3 -alkylsulfonyl or ##STR4## group, R.sub.14 and R.sub.15 being independently a hydrogen atom or a monofluorophenyl, trifluoromethylphenyl or trimethylphenyl group with a proviso that when either one of R.sub.14 and R.sub.15 is a hydrogen atom the other one is other than a hydrogen atom or being coupled to each other together with the associated nitrogen atom to form a 1-(2,3-dimethyl)pyrrolidinyl group, R.sub.11 denotes a C.sub.1 -C.sub.3 -alkyl or phenyl group, and R.sub.12 and R.sub.13 stand independently for a hydrogen atom or a C.sub.1 -C.sub.4 -alkyl group [U.S. Pat. No. 4,224,334; J. Med. Chem. 24, 604-609 (1981)]; and by 5,6-dihydroimidazo[2,1-b]-thiazole derivatives represented by the following formula: ##STR5## wherein R.sub.16 means a substituted or unsubstituted phenyl or naphthalyl group (Japanese Patent Laid-Open No. 169490/1982).
SUMMARY OF THE INVENTION
An object of this invention is to provide certain imidazo[2,1-b]thiazole derivatives having excellent immuno-modulating activities.
With the foregoing in view, the present inventors synthesized a variety of imidazo[2,1-b]thiazole derivatives and their physiological activities were investigated. As a result, it has been found that novel 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives having certain specific substituents and represented by the above general formula (I) have excellent immuno-modulating activities, leading to completion of this invention.
In one aspect of this invention, there is thus provided a 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative represented by the following general formula [I] ##STR6## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are either the same or different and mean individually a hydrogen atom or lower alkyl group, Y denotes a group of the following formula: ##STR7## wherein R.sub.5 means a lower alkyl group, X denotes a hydrogen or halogen atom or a trifluoromethyl, lower alkyl, lower alkoxy or nitro group, n stands for an integer of 0-5, and when n is greater than 1, Xs are either the same or different; ##STR8## wherein A means a lower alkylene group which may be branched, R.sub.6 denotes a hydrogen atom or a lower alkyl or cycloalkyl group, and X and n have the same meaning as defined above; ##STR9## wherein R.sub.7 means a hydrogen, chlorine, bromine or iodine atom or a lower alkyl, lower alkoxy or nitro group; or ##STR10## wherein R.sub.8 means a halogen atom or a lower alkoxy or trifluoromethyl group and R.sub.9 denotes a halogen atom or a hydroxyl, lower alkoxy or trifluoromethyl group), with a proviso that at least one of R.sub.1, R.sub.2, R.sub.3 and R.sub.4 is a methyl group when the group Y is ##STR11## or a salt thereof.
As salts of the 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives in the present invention, may be mentioned their pharmacologically acceptable salts, for example, their inorganic and organic acid salts such as hydrochlorides, sulfates, carbonates, nitrates, hydrobromides, phosphates, sulfonates, acetates, oxalates, tartrates, citrates, malates, glutamates, aspartates, etc.
The compounds (I) of this invention and their salts may contain water of crystallization. Their hydrates are all embraced within the scope of this invention.
The compounds (I) of this invention and their salts have excellent immuno-modulating activities and can hence be used, as preventive and therapeutic medicines for immunological disease, for the treatment and prevention of autoimmune diseases such as chronic rheumatoid arthritis, systemic lupus erythematodes, collagen disease, chronic nephritis and autoimmunohemolytic anemia, delayed-type and immediate-type allergic diseases, malignant tumors and serious infectious diseases by way of example.
The above and other objects, features and advantages of this invention will become apparent from the following description and the appended claims.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
The compounds (I) of this invention may be roughly divided into the following three groups (Ia)-(Ic): ##STR12## wherein Z means a group of the following formula: ##STR13## wherein R.sub.7 means a hydrogen, chlorine, bromine or iodine atom or a lower alkyl, lower alkoxy or nitro group; or ##STR14## wherein R.sub.8 means a halogen atom or a lower alkoxy or trifluoromethyl group and R.sub.9 denotes a halogen atom or a hydroxyl, lower alkoxy or trifluoromethyl group; and and R.sub.1 -R.sub.6, A, X and n have the same meaning as defined above.
The term "lower" as used herein such as "lower alkylene", "lower alkoxy" and the like means 1-5 carbon atoms.
Among the compounds (Ia), those represented by the following formula (Ia-1) are preferred: ##STR15## wherein m stands for an integer of 1-3, and R.sub.1, R.sub.3, R.sub.4, R.sub.6, X and n have the same meaning as defined above.
Of the compounds (Ia-1), particularly-preferred compounds are those having the formula (Ia-1) in which R.sub.1, R.sub.3, R.sub.4 and R.sub.6 mean individually a hydrogen atom or methyl group and X denotes a halogen atom or trifluoromethyl group.
Among the compounds (Ia-1), still preferred compounds are represented by the following formulae respectively. ##STR16## wherein R.sub.19 means a hydrogen atom or alkyl group having 1-3 carbon atoms, m stands for an integer of 1-3, and X and n have the same meaning as defined above.
Among the compounds (Ib), those represented by the following formula (Ib-1) are preferred: ##STR17## wherein R.sub.17 and R.sub.18 may be either the same or different and mean individually a hydrogen, chlorine or iodine atom or trifluoromethyl group, with a proviso that R.sub.18 is other than a trifluoromethyl group when R.sub.17 is a hydrogen atom, and R.sub.1 and R.sub.3 have the same meaning as defined above. Of these, those represented by the formula (Ib-1) in which R.sub.1 and R.sub.3 are individually a hydrogen atom or methyl group are especially preferred.
Among the compounds (Ic), those represented by the following formula (Ic-1) are preferred: ##STR18## wherein R.sub.3, R.sub.4, R.sub.5, X and n have the same meaning as defined above. Of these, particularly-preferred compounds are those represented by the formula (Ic-1) in which R.sub.3 and R.sub.4 are individually a hydrogen atom or methyl group, R.sub.5 denotes a methyl or ethyl group, and X stands for a halogen atom or trifluoromethyl group.
The compounds (I) of this invention can each be prepared, for example, by reacting an imidazolidine-2-thione represented by the following formula (III) with an amide represented by the following formula (II) in accordance with the following reaction formula: ##STR19## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and Y have the same meaning as defined above.
It is preferable to conduct the above reaction in a suitable inert solvent. As an illustrative solvent useful in the above reaction, may be mentioned benzene, toluene, xylene, acetone, methyl ethyl ketone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, ethyl ether, tetrahydrofuran, dioxane, chloroform, water or the like.
The reaction temperature may be -5.degree. C.-+100.degree. C. or preferably +20.degree. C.-+80.degree. C. By proceeding with the reaction for 1-6 hours, the compound of this invention can be obtained with high yield and high purity.
In order to obtain the corresponding compound of the general formula (I) in its free form from the thus-obtained hydrochloride, it is necessary to treat the hydrochloride with a base, for example, an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate or ammonia or an organic base such as pyridine or triethylamine. In order to derive other salts, it is required to treat the free compound with corresponding acids, for example, sulfuric acid, carbonic acid, nitric acid, hydrobromic acid, phosphoric acid, sulfonic acid, acetic acid, oxalic acid, tartaric acid, citric acid, malic acid, glutamic acid, aspartic acid and/or the like.
The compound of the formula (II), which is employed as a raw material in the above process, can be prepared, for example, in accordance with the following reaction scheme, namely, by reacting an amine (V) with a diketene (IV) to obtain a compound (VI) and then chlorinating the compound (VI) with sulfuryl chloride [Chemical Abstracts, 19, 43 (1925)], N-chlorosuccinimide or the like. ##STR20## wherein Y has the same meaning as defined above.
The other raw material (III) can be prepared, for example, in the following manner base on the process described in Org. Synth. Coll. 3, 394; ##STR21##
When the group represented by Y is ##STR22## in the compounds (I) of this invention obtained in the above manner, the following specific groups may be mentioned as preferred examples of these groups: ##STR23##
When Y stands for any one of the above exemplified groups, at least one of R.sub.1, R.sub.2, R.sub.3 and R.sub.4 means a methyl group. The methyl group is substituted to the 5- or 6-position of the imidazothiazole skeleton. The 6-substituted compound is preferred.
[EFFECTS]
Pharmacological effects of the compounds (I) of this invention and their salts will next be described.
Test 1
Effect on anti-SRBC PFC response in vitro:
In an RPMI-1640 culture medium containing 10% of fetal calf serum (FCS), 1.times.10.sup.7 spleen cells of BALB/c mouse were cultured together with sheep erythrocytes (1.times.10.sup.6) and a sample compound (0.2 or 1 .mu.g/ml) for 5 days in a CO.sub.2 incubator (37.degree. C.) in accordance with the method reported by Mischell, R. I. et al. in J. Exp. Med. 126, 423 (1967) (with some modifications). The number of resultant plaque forming cells was counted by the method proposed by Jerne and Nordin [Science 140, 405 (1963)]. Results are shown in Table 1-A-Table 1-E.
TABLE 1-A______________________________________ ##STR24## (Ia) Immune response potentiationSample activitiescompound (Control =(1 .mu.g/ml) R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 X.sub.n 100%)______________________________________Comp'd 1 H H H H CH.sub.3 3,4-Cl.sub.2 377Comp'd 30 H H CH.sub.3 CH.sub.3 CH.sub.3 3-CF.sub.3 271Comp'd 31 H H CH.sub.3 CH.sub.3 CH.sub.3 3,4-Cl.sub.2 201Comp'd 32 H H CH.sub.3 CH.sub. 3 CH.sub.3 3,5-(CF.sub.3).sub.2 199Comp'd 3 H H CH.sub.3 CH.sub.3 CH.sub.3 4-CF.sub.3 203Comp'd 2 H H CH.sub.3 CH.sub.3 CH.sub.3 3,5-Cl.sub.2 293Comp'd 4 H H CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 3,4-Cl.sub.3 177______________________________________
TABLE 1-B__________________________________________________________________________ ##STR25## (Ib) Immune repsonse potentiation activities (Control = 100%)Sample compound R.sub.1 R.sub.3 R.sub.4 R.sub.6 X.sub.n 0.2 .mu.g/ml 1 .mu.g/ml__________________________________________________________________________Comp'd 45 H H H H 4-Cl 252 302Comp'd 55 H H H H 2,4-Cl.sub.2 183 --Comp'd 56 H H H H 3,4-Cl.sub.2 239 --Comp'd 60 H H H H 3,5-Cl.sub.2 -- 190Comp'd 51 H H H CH.sub.3 2,4-Cl.sub.2 -- 267Comp'd 48 H H H CH.sub.3 3,4-Cl.sub.2 341 --Comp'd 66 H H H CH.sub.3 3-Cl 173 --Comp'd 88 H CH.sub.3 CH.sub.3 H 3-Cl -- 212Comp'd 89 H CH.sub.3 CH.sub.3 H 4-Cl -- 168Comp'd 91 H CH.sub.3 CH.sub.3 H 3,4-Cl.sub.2 220 --Comp'd 92 H CH.sub.3 CH.sub.3 H 3-CF.sub.3 361 638Comp'd 94 H CH.sub.3 CH.sub.3 CH.sub.3 3-Cl -- 181Comp'd 95 H CH.sub.3 CH.sub.3 CH.sub.3 3-CF.sub.3 186 --Comp'd 96 H CH.sub.3 CH.sub.3 CH.sub.3 3,4-Cl.sub.2 186 --Comp'd 44 H CH.sub.3 CH.sub.3 CH.sub.3 4-Cl -- 149Comp'd 49 CH.sub.3 CH.sub.3 H H 3,4-Cl.sub.2 193 --Comp'd 85 CH.sub.3 CH.sub.3 H H 3-CF.sub.3 -- 193Comp'd 87 CH.sub.3 CH.sub.3 H CH.sub.3 3-Cl 179 --__________________________________________________________________________ Note: "--" means that no measurement was conducted. ("--" will have the same meaning in the subsequent Tables.)
TABLE 1-C______________________________________ ##STR26## (Ic) Immune response potentiation activitiesSample (Control = 100%)compound R.sub.1 R.sub.4 X.sub.n 0.2 .mu.g/ml 1 .mu.g/ml______________________________________Comp'd 141 H H 3-Cl 750 842Comp'd 137 H H 3,4-I.sub.2 316 561Comp'd 142 H H 4-Cl -- 471Comp'd 140 H H 2-Cl -- 198Comp'd 144 H H 3,4-Cl.sub.2 405 663Comp'd 145 H H 3,5-Cl.sub.2 318 382Comp'd 155 H H 2-Cl, 4-CF.sub.3 208 439Comp'd 160 H CH.sub.3 3,4-Cl.sub.2 -- 896Comp'd 135 H CH.sub.3 4-Cl -- 230Comp'd 134 H CH.sub.3 3-Cl 520 --Comp'd 166 H CH.sub.3 3,5-(CF.sub.3).sub.2 339 420Comp'd 136 H CH.sub.3 3-Cl, 4-CF.sub.3 527 --Comp'd 167 H CH.sub.3 H -- 267Comp'd 138 CH.sub.3 H 3,4-Cl.sub.2 261 839Comp'd 157 CH.sub.3 H 3,4-I.sub.2 239 266______________________________________
TABLE I-D______________________________________ ##STR27## Immune respon- sive potentia- tion activities (Control =Com- 100%)pound 1 .mu.g/ 5 .mu.g/No.R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 A X.sub.n ml ml______________________________________171HH CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 H 158 --176HH HHH CH.sub.2 4-F 200 --116HH HHCH.sub.3 (CH.sub.2).sub.2 H 139 439119HH CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.2 H 611 883117HH H HCH.sub.3 (CH.sub.2).sub.2 4-Cl 675 536120HH CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.2 4-Cl 872 883179HH CH.sub.3 CH.sub.3 H (CH.sub.2).sub.2 2,4-Cl.sub.2 140 --180HH HHH (CH.sub.2).sub.2 3,4-Cl.sub.2 205 220181HH CH.sub.3 CH.sub.3 H (CH.sub.2).sub.2 3,4-Cl.sub.2 172 173182HH HHCH.sub.3 (CH.sub.2).sub.2 3,4-Cl.sub.2 172 173175HH CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.2 3,4-Cl.sub.2 505 632183HH HHH (CH.sub.2).sub.3 H 141 200______________________________________
TABLE I-E______________________________________ ##STR28## Immune re- sponsive po- tentiation activities (Control = 100%)Com- 1 5pound .mu.g/ .mu.g/No. R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 A X.sub.n ml ml______________________________________186 H H CH.sub.3 CH.sub.3 H CH.sub.2 4-NO.sub.2 -- 244172 H H CH.sub.3 CH.sub.3 H (CH.sub.2).sub.2 H 162 216173 H H CH.sub.3 CH.sub.3 H (CH.sub.2).sub.2 4-Cl -- 495188 H H CH.sub.3 CH.sub.3 H (CH.sub.2).sub. 3 H 490 373189 H H H H CH.sub.3 (CH.sub.2).sub.3 H 268 218174 H H CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.3 H -- 196______________________________________
For the sake of comparison, effects on in-vitro plaque forming cell response were also measured in the same manner with respect to the following compounds which are described in Japanese Patent Laid-Open No. 106893/1977 and J. Med. Chem., 24, 604-609 (1981). Results are shown in Table 1-F.
TABLE 1-F______________________________________ ##STR29## (VII) Immune re- sponse po- tentiation activies (Control = 100%) 0.2 1Sample .mu.g/ .mu.g/compound R.sub.1 R.sub.3 R.sub.4 X.sub.n ml ml______________________________________Comparative H H H 2-F 78 --Compound 1Comparative H H H 2,6-Cl.sub.2 82 126Compound 2Comparative H H H 2,4,6-(CH.sub.3).sub.3 -- 127Compound 3Comparative H CH.sub.3 CH.sub.3 2,4,6-(CH.sub.3).sub.3 121 132Compound 4Comparative H CH.sub.3 H 2,4,6-(CH.sub.3).sub.3 100 119Compound 5______________________________________
As apparent from Table 1-A-Table 1-F, the compounds of this invention showed activities higher than levamisole at a low concentration of 0.2, 1 or 5 .mu.g/ml in the above test in which levamisole required a concentration as high as about 20 .mu.g/ml to exhibit potentiation activities. On the other hand, the comparative compounds exhibited substantially no activities.
TEST 2
Effect on lymphocyte blstogenic response in vitro:
In an RPMI-1640 culture medium (0.2 ml) containing 5% of fetal calf serum (FCS), BALB/C mouse spleen cells (1.times.10.sup.5) or thymus cells (2.times.10.sup.5) were cultured together with mitogen (Con A: 2.5 .mu.g/ml; or LPS: 10 .mu.g/ml) and a sample compound (1 .mu.g/ml) for 48 hours in a CO.sub.2 incubator (37.degree. C.). Then, 0.5 .mu.Ci of .sup.3 H-thymidine was added, followed by further cultivation for 18 hours. The radioactivity of .sup.3 H-thymidine taken in the cells was thereafter measured. Results are summarized in Table 2.
TABLE 2______________________________________ Incorporation ratio of .sup.3 H--thymidine (Control = 100%) Spleen cellsSample compound Con A LPS Thymus cells(1 .mu.g/ml) stimulation stimulation Con A stimulation______________________________________Compound 141 131 169 --Compound 142 166 234 215Compound 144 148 197 157Compound 135 182 263 --Compound 145 133 174 --Compound 134 136 233 164Compound 48 136 -- 148Compound 91 151 -- --Compound 163 140 174 122______________________________________
The compounds of this invention apparently stimulated the incorporation of .sup.3 H-thymidine.
TEST 3
Effect on lymphocyte blastogenic response in vivo:
A group of six BALB/C mice were used. A sample compound was orally administered at a daily dose of 0.25 mg/Kg, once a day, for 5 days. On the sixth day, spleens were taken out. Spleen cells (2.times.10.sup.5) were cultured together with mitogen (Con A: 2.5 .mu.g/ml; or LPS: 10 .mu.g/ml) to investigate the lymphocyte blastogenic response. Culturing conditions were the same as those employed in Test 2 and the measurement of the lymphocyte blastogenic response was effected in accordance with the method used in Test 2. Although levamisole required its administration at a dose of 2.5 mg/Kg/day to show its effects in the present test, the compounds of this invention showed promoting activities equal to or higher than levamisole at a dose one tenth of levamisole, i.e., at a dose of 0.25 mg/Kg/day (Table 3).
TABLE 3______________________________________ Incorporation ratio of .sup.3 H--thymidine (Control: 100%)Sample compound Con A stimulation LPS stimulation______________________________________ Compound 136 240 .+-. 18 210 .+-. 9 Compound 167 155 .+-. 10 111 .+-. 9 Compound 134 310 .+-. 22 125 .+-. 9Compound 51 142 .+-. 26 118 .+-. 12Compound 49 195 .+-. 8 156 .+-. 4Compound 91 256 .+-. 17 176 .+-. 16Compound 44 155 .+-. 19 115 .+-. 6______________________________________
TEST 4
Effect on delayed-type allergic response:
A group of eight ddY mice were sensitized by injecting 2.times.10.sup.8 sheep erythrocytes subcutaneously in the back of each of the mice. On the fourth day after their sensitization, 5.times.10.sup.7 sheep erythrocytes were injected under the heel skin of one of the hind legs of each of the mice whereas a physiological saline was injected in the heel skin of the other hind leg. 24 hours later, the thickness of each paw was measured by a micrometer to determine the degree of swelling. Each sample compound was orally administered for 5 days, once a day, after passage of 2 hours from the sensitization. Results are shown in Table 4-A and 4-B. The compounds of this invention inhibited the delayed-type allergic response significantly by its oral administration at a dose of 0.1 mg/Kg/day.
TABLE 4-A______________________________________ Degree of swelling (%)Sample Dose (average value .+-.Compound (mg/Kg/day, po) standard deviation)______________________________________Control -- 29.0 .+-. 9.0Compound 134 0.1 15.6 .+-. 4.0*" 0.2 14.7 .+-. 4.82*______________________________________ *Significant at a level of P < 0.05 against Control.
TABLE 4-B______________________________________ Degree of swelling (%)Sample Dose (average value .+-.Compound (mg/Kg/day, po) standard deviation)______________________________________Control -- 24.2 .+-. 6.9Compound 44 0.1 17.1 .+-. 4.6*______________________________________ *Significant at a level of P < 0.05 against Control.
TEST 5
Effect on adjuvant arthritis:
(1) A group of eight Lewis male rats were employed. A suspension of 0.6 mg/0.1 ml of dead cells of Microbacterium tuberculosis in liquid paraffin was injected as an adjuvant in the heel skin of one of the hind legs of each of the rats, thereby inducing adjuvant arthritis. Besides, each sample compound was orally administered once a day for 20 days. On the 21.sup.st day, the paw volumes of both hind legs of each of the rats were measured to determine the degree of swelling. Results are shown in Table 5-A.
(2) A suspension of 0.6 mg/0.1 ml of dead cells of Micobacterium tuberculosis in liquid paraffin was injected as an adjuvant in the heel skin of one of the hind legs of each of eight Sprague-Dawley male rats in a group, thereby inducing adjuvant arthritis. From the 21.sup.st day after the injection of the adjuvant, each sample compound of this invention was orally administered everyday once a day. The volume of the paw of each hind leg, which was not injected with the adjuvant, was measured on the 7.sup.th and 10.sup.th days so that the degrees of swelling were determined. Results are shown in Table 5-B.
The compounds of this invention inhibited the swelling of the adjuvant non-injected legs and adjuvant-injected legs significantly when administered at a dose of 1 or 5 mg/Kg/day.
TABLE 5-A______________________________________ Degree of swelling (%) (average value .+-. standard deviation) Adjuvant AdjuvantSample Dose non-injected injectedcompound (mg/Kg/day, po) leg leg______________________________________Control -- 173.1 .+-. 25.5 309.9 .+-. 27.1Comp'd 44 1 142.6 .+-. 29.0* 285.9 .+-. 44.9Comp'd 44 5 135.1 .+-. 27.3* 274.1 .+-. 35.4*______________________________________ *Significant at a level of P < 0.05 against Control.
TABLE 5-B______________________________________ Degree of swelling (%) (average value .+-.Sample Dose standard deviation)compound (mg/Kg/day, po) 7.sup.th day 10.sup.th day______________________________________Control -- 100.5 .+-. 31.1 89.9 .+-. 28.5Comp'd 134 5 66.0 .+-. 32.8* 59.0 .+-. 27.1*______________________________________ *Significant at a level of P < 0.05 against Control.
TEST 6
Side effects and blood levels:
To each of four Wistar male rats in a group, each sample compound was orally administered at a dose of 300 mg/Kg, once a day, for 4 days to observe changes in general behaviors and at the same time, to investigate influence on body weight, liver weight and serum cholesterol level. The serum cholesterol level was measured by a Centriphichem Autoanalyzer, using a cholesterol measurement kit marketed by Baker, Inc. Compound 44 and 134 and for certain tests, Compound 2, 3, 30, 31 and 32, were all employed as compounds of this invention, while a compound represented by the general formula (X), in which R.sub.1 =R.sub.3 =R.sub.4 =H and (X).sub.n =3,4-Cl.sub.2 (Comparative Compound 6), and a compound represented along by the general formula (X), in which R.sub.1 =R.sub.3 =R.sub.4 =H and (X).sub.n =3,4-CF.sub.3 (Comparative Compound 7), were both used as comparative compounds. In certain tests, levamisole was also used as a comparative compound. The blood levels of the individual sample compounds were also compared after their single administration and after their administration for four days. Their blood levels were measured by means of a high-performance liquid chromatography.
(1) Effect on the general behaviors:
Although no changes were observed on the general behaviors in the groups administered respectively with the compounds of this invention and Comparative Compound 6, dacryorrhea, dacryohemorrhea, sedation, ataxia and tremor were observed in the group administered with Comparative Compound 7. In the group administered with levamisole, one half of the animals resulted in death.
(2) Effect on the body weight:
Body weights both before administration of the sample compounds and after their continuous administration for 4 days are shown in Table 6-A-Table 6-C.
TABLE 6-A______________________________________ Body weight, (g) (average value .+-. standard deviation) Before AfterSample Dose adminis- administrationcompound (mg/Kg/day, po) tration for 4 days______________________________________Control -- 79.0 .+-. 3.5 93.0 .+-. 3.4 Comp'd 30 300 79.0 .+-. 2.0 91.0 .+-. 0.8Control -- 91.3 .+-. 1.5 104.0 .+-. 3.7 Comp'd 31 300 91.3 .+-. 5.5 102.8 .+-. 7.8Control -- 113.3 .+-. 1.5 128.5 .+-. 3.0 Comp'd 32 300 113.8 .+-. 1.3 122.0 .+-. 6.5Comp'd 3 300 114.0 .+-. 5.7 126.0 .+-. 8.8Control -- 87.0 .+-. 5.1 102.8 .+-. 5.9Comp'd 2 300 87.3 .+-. 2.8 102.0 .+-. 1.6Comp. 300 87.3 .+-. 2.5 89.5 .+-. 3.0*Comp'd 6Control -- 93.3 .+-. 5.7 108.3 .+-. 4.9Levamisole 100 93.5 .+-. 4.7 99.5 .+-. 2.5*Control -- 111.0 .+-. 5.3 128.5 .+-. 7.0Comp. 300 110.0 .+-. 2.3 115.3 .+-. 8.2*Comp'd 7______________________________________ *Significant at a level of P < 0.05 against Control.
TABLE 6-B__________________________________________________________________________ Test 1 Test 2Sample Dose Before After Before Aftercompound (mg/Kg/day, po) administration administration administration administration__________________________________________________________________________Control -- 84.5 .+-. 3.1 100.5 .+-. 2.5 87.0 .+-. 5.1 102.8 .+-. 5.9Comp'd 44 300 84.0 .+-. 1.4 100.0 .+-. 2.9 87.0 .+-. 2.2 102.5 .+-. 3.4Comp. 300 84.3 .+-. 6.1 88.8 .+-. 6.4* 87.3 .+-. 2.5 89.5 .+-. 3.0*Comp'd 6__________________________________________________________________________ Each value indicates the average body weight (g) of 4 rats in the same group .+-. standard deviation. *Significant at a level of P < 0.05 against Control.
TABLE 6-C__________________________________________________________________________ Test 1 Test 2Sample Dose Before After Before Aftercompound (mg/Kg/day, po) administration administration administration administration__________________________________________________________________________Control -- 79.3 .+-. 1.0 97.0 .+-. 3.5 81.8 .+-. 2.6 96.0 .+-. 2.8Comp'd 134 300 79.5 .+-. 1.0 95.8 .+-. 4.2 82.0 .+-. 5.9 92.0 .+-. 5.9Comp. 300 79.3 .+-. 1.5 89.5 .+-. 3.0* -- --Comp'd 6__________________________________________________________________________ Each value indicates the average body weight (g) of 4 rats in the same group .+-. standard deviation. *Significant at a level of P < 0.05 against Control.
Although neither Compound 44 nor Compound 134 gave any effects to the body weight, Comparative Compound 6 decreased the body weight significantly against Control. Levamisole decreased the body weight significantly against Control even when administered at 100 mg/Kg/day.
(3) Effect on the liver weight:
Results are shown in Table 7-A and Table 7-B. Although Compound 1 did not give any significant effect on the liver weight compared with Control, Comparative Compound 6 increased the liver weight significantly against Control.
TABLE 7-A__________________________________________________________________________ Test 1 Test 2Sample Dose Liver weight Increase Liver weight Increasecompound (mg/Kg/day, po) (g/100 g B. W. **) (%) (g/100 g B. W.) (%)__________________________________________________________________________Control -- 4.22 .+-. 0.03 -- 4.13 .+-. 0.20 --Comp'd 44 300 4.33 .+-. 0.07 2.6 4.74 .+-. 0.65 14.8Comp. 300 5.35 .+-. 0.43* 26.8 5.71 .+-. 0.27* 38.3Comp'd 6__________________________________________________________________________ Each liver weight indicates the average value of 4 rats in the same group .+-. standard deviation. *Significant at a level of P < 0.05 against Control. **B. W. stands for "body weight".
TABLE 7-B__________________________________________________________________________ Test 1 Test 2Sample Dose Liver weight Increase Liver weight Increasecompound (mg/Kg/day, po) (g/100 g B. W.**) (%) (g/100 g B. W.) (%)__________________________________________________________________________Control -- 4.30 .+-. 0.06 -- 4.10 .+-. 0.22 --Comp'd 134 300 4.43 .+-. 0.21 3.0 4.13 .+-. 0.14 0.7Comp. 300 5.62 .+-. 0.17* 30.7 5.50 .+-. 0.44* 34.1Comp'd 6__________________________________________________________________________ Each liver weight indicates the average value of 4 rats in the same group .+-. standard deviation. *Significant at a level of P < 0.05 against Control. **B. W. stands for "body weight".
(4) Effect on the serum cholesterol level:
Test results are shown in Table 8-A and Table 8-B. Neither Compound 44 nor Compound 134 gave any significant effects to the serum cholesterol level compared with Control, Comparative Compound 6 and 7 and Levamisole increased the cholesterol level significantly against Control.
TABLE 8-A__________________________________________________________________________ Test 1 Test 2Sample Dose Cholesterol Increase Cholesterol Increasecompound (mg/Kg/day, po) (mg/dl) (%) (mg/dl) (%)__________________________________________________________________________Control -- 83.4 .+-. 7.8 -- 75.2 .+-. 6.7 -- Comp'd 44 300 81.3 .+-. 8.4 -2.5 82.6 .+-. 7.1 9.8Comp. 300 168.3 .+-. 16.1* 101.8 157.1 .+-. 21.0* 108.9Comp'd 6Control -- 63.0 .+-. 6.6 -- 63.0 .+-. 3.5 --Comp. 300 83.2 .+-. 6.2* 32.1 83.9 .+-. 5.3* 33.2Comp'd 7Control -- 73.4 .+-. 7.5 --Levamisole 100 89.0 .+-. 4.9* 21.3__________________________________________________________________________ Each cholesterol level indicates the average value of 4 rats in the same group .+-. standard deviation. *Significant at a level of P < 0.05 against Control.
TABLE 8-B__________________________________________________________________________ Test 1 Test 2Sample Dose Cholesterol Increase Cholesterol Increasecompound (mg/Kg/day, po) (mg/dl) (%) (mg/dl) (%)__________________________________________________________________________Control -- 70.6 .+-. 7.1 -- 66.2 .+-. 2.9 --Comp'd 134 300 78.5 .+-. 5.8 11.2 72.9 .+-. 6.9 10.1Comp. 300 134.5 .+-. 8.3* 90.5 138.2 .+-. 17.0* 108.8Comp'd 6__________________________________________________________________________ Each cholesterol level indicates the average value of 4 rats in the same group .+-. standard deviation. *Significant at a level of P < 0.05 against Control.
(5) Change in blood level by repeated administration:
Table 9 shows blood levels on the 1.sup.st and 2.sup.nd hours after each of a single administration and an administration for 4 days, once a day. Although the blood levels of Compounds 44 and 129 were found to be close to their blood levels after their single administration even after the administration for 4 days, the blood levels of Comparative Compounds 6 and 7 dropped remarkably by their repeated administration.
TABLE 9__________________________________________________________________________ Blood level (.mu.g/ml)Sample Dose Single administration Administration for 4 dayscompound (mg/Kg/day, po) 1 hour later 2 hours later 1 hour later 2 hours later__________________________________________________________________________ Comp'd 44 300 -- 12.98 .+-. 3.81 -- 10.48 .+-. 1.34 Comp'd 134 300 4.48 .+-. 2.32 12.15 .+-. 2.18 9.75 .+-. 4.86 7.70 .+-. 0.79Comp. 300 8.27 .+-. 2.40 4.61 .+-. 0.74 0.38 .+-. 0.33 0.16 .+-. 0.24Comp'd 6Comp. 300 8.48 .+-. 1.91 10.80 .+-. 3.53 3.03 .+-. 2.08 2.73 .+-. 1.14Comp'd 7__________________________________________________________________________ Each blood level indicates the average value of 4 rats in the same group .+-. standard deviation.
The compounds of this invention may be administered, as they are or in various dosage forms, orally or parenterally (for example, by their intramuscular, subcutaneous, intravenous, rectal or cutaneous administration). As their dosable preparation forms, they may be formed into solid preparations such as tablets, sugar-coated tablets, film-coated tablets, hard and soft capsules, troches, pills, granules and powders; semi-solid preparations such as suppositories, plasters and ointments; and liquid preparations such as injectable solutions, syrups, inhalants, emulsions and suspensions. Although the compounds of this invention may be formed into the above-described preparations without any additional pharmaceutically-effective ingredients, one or more other pharmaceutically-effective ingredients such as nonsteroid analgesic and artiphlogistic agents may also be incorporated in combination.

[EXAMPLES]
The present invention will hereinafter be described further by the following Referential Examples and Examples.
REFERENTIAL EXAMPLE 1
Dissolved in toluene were 3.5 g (0.02 mole) of 3,4-dichloro-N-methylaniline and a catalytic amount of pyridine, followed by a dropwise addition of 1.9 g (0.022 mole) of diketene at 50.degree. C. After completion of the the dropwise addition, the resultant mixture was heated under reflux for 3 hours. The reaction mixture was cooled, and its organic layer was then washed with water, water, a 10% aqueous solution of hydrochloric acid and a 5% aqueous solution of sodium hydrogencarbonate in order. The thus-washed organic solution was dried and concentrated to obtain 3',4'-dichloro-N-methylacetoacetoanilide.
EXAMPLE 1 ##STR30##
(i) Suspended in carbon tetrachloride were 2.6 g (0.01 mole) of the 3',4'-dichloro-N-methylacetoacetoanilide obtained in Referential Example 1 and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant mixture was heated under reflux for 1 hour. The reaction mixture was then washed with water, dried and concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.0 g (0.01 mole) of imidazolidine-2-thione. The mixture was then heated under reflux for 3 hours. Precipitated crystals were collected by filtration, recrystallized from ethanol and then dried under reduced pressure, thereby obtaining 3.4 g of 3',4'-dichloro-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 1) [yield: 89.5%]. Melting point: 275.degree.-276.degree. C.
(ii) Dissolved in water was 1.9 g (0.005 mole) of the thus-obtained hydrochloride, followed by a dropwise addition with stirring of a 10% aqueous solution of caustic soda at room temperature. Resultant crystals were collected by filtration and washed with a great deal of water to purify same. The thus-washed crystals were dried under reduced pressure to obtain 1.4 g of 3',4'-dichloro-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide (yield: 82.4%). Melting point: 118.degree.-122.degree. C.
EXAMPLE 2 ##STR31##
(i) Suspended in carbon tetrachloride were 1.4 g (0.01 mole) of 3',5'-dichloro-N-methylacetoacetoanilide, obtained in the same manner as in Referential Example 1, and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant mixture was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The resultant mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, recrystallized from isopropanol and then dried under reduced pressure, thereby obtaining 3.0 g of 3',5'-dichloro-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 2) [Yield: 75.0%]. Melting point: 222.degree.-230.degree. C.
(ii) Dissolved in water was 2.0 g (0.005 mole) of the above-obtained hydrochloride, followed by a dropwise addition with stirring of a 20% aqueous solution of potassium carbonate at room temperature. Resultant crystals were collected by filtration and then washed with a great deal of water for its purification. The thus-obtained crystals were dried under reduced pressure to obtain 1.5 g of 3',5'-dichloro-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide (yield: 78.9%). Melting point: 169.degree. C.
EXAMPLE 3 ##STR32##
Dissolved in diethyl ether was 2.6 g (0.01 mole) of N-methyl-4'-trifluoromethylacetoacetoanilide obtained in the same manner as in Referential Example 1, followed by a dropwise addition of 1.5 g (0.011 mole) of sulfuryl chloride at -5.degree. C. The resultant mixture was stirred at -10.degree.--5.degree. C. for 30 minutes. The reaction mixture was then poured into ice water, neutralized with sodium hydrogencarbonate and extracted with toluene. The organic layer was dried and concentrated. The residue was dissolved in methyl ethyl ketone, to which 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione was added. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, washed with acetone and then dried under reduced pressure, thereby obtaining 3.7 g of N,3,6,6-tetramethyl-4'-trifluoromethyl-5,6-dihydroimidazo-[2,1-b]-thiazole-2-carboxyanilide hydrochloride (Compound 3) [yield: 92.5%]. Melting point: 195.degree.-198.degree. C.
EXAMPLE 4 ##STR33##
Suspended in carbon tetrachloride were 2.7 g (0.01 mole) of 3',4'-dichloro-N-ethylacetoacetoanilide, obtained in the same manner as in Referential Example 1, and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant mixture was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The resultant mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, washed with acetone and then dried under reduced pressure, thereby obtaining 3.3 g of 3',4'-dichloro-N-ethyl-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 4) [yield: 78.6%]. Melting point: 210.degree.-214.degree. C.
EXAMPLE 5 ##STR34##
Following the procedure of Example 2, 2.6 g (0.01 mole) of 3',4'-dichloro-N-methylacetoacetoanilide obtained in Referential Example 1 was chlorinated. The resultant oily substance was dissolved in methyl ethyl ketone, followed by an addition of 1.2 g (0.01 mole) of 4-methylimidazolidine-2-thione. The resulting mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, followed by its washing with acetone to obtain 3.6 g of 3',4'-dichloro-N,3,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 5) [yield: 92.3%]. Melting point: 230.degree.-231.degree. C.
EXAMPLE 6 ##STR35##
Suspended in carbon tetrachloride were 3.2 g (0.01 mole) of N-methyl-3',5'-bis(trifluoromethyl)acetoacetoanilide, obtained in the same manner as in Referential Example 1, and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant mixture was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The resultant mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, washed with acetone and then dried under reduced pressure, thereby obtaining 3.5 g of N,3,5,6-tetramethyl-3',5'-bis(trifluoromethyl)-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 6) [yield: 74.5%]. Melting point: 214.degree.-218.degree. C.
EXAMPLES 7-43
The following compounds were prepared in the same manner as in Referential Example 1 and Examples 1-6.
__________________________________________________________________________No. R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 X.sub.n Appearance Melting point__________________________________________________________________________ (.degree.C.) 7 H H H H CH.sub.3 3,4-(OCH.sub.3).sub.2 Light brownish crystals 249-253 8 H H H H CH.sub.3 4-OC.sub.2 H.sub.5 White powder 205-209 9 H H H H H 3,5-(OCH.sub.3).sub.2 Light Brownish powder 222-22410 H H H H CH.sub.3 H Light brownish crystals 240-24211 H H H H CH.sub.3 4-Cl Slightly yellowish platy crystals 257-26012 H H H H CH.sub.3 3-OC.sub.3 H.sub.7 --i White powder 209-21013 H H H H CH.sub.3 3-CF.sub.3 White powder 228-23514 H H H H CH.sub.3 2-CH.sub.3, 4-Cl Yellowish granular crystals 267-27015 H H H H CH.sub.3 2-Cl, 4-CF.sub.3 Brown powder 184-19216 H H H H CH.sub.3 3-Cl Light yellow powder 210-21517 H H H H CH.sub.3 3,5-(CF.sub.3).sub.2 Light yellow powder 274-27618 H H H H CH.sub.3 4-CF.sub.3 Yellow powder 235-23919 H H H H C.sub.2 H.sub.5 3,4-Cl.sub.2 Light brownish crystals 255-25820 H H H H C.sub.2 H.sub.5 3-CF.sub.3 Light brownish crystals 232-23421 H H H H C.sub.2 H.sub.5 2-Cl, 4-CF.sub.3 Brown crystals 220-22922 H H H H C.sub.3 H.sub.7 3,4-Cl.sub.2 Milky white crystals 250-25423 H H H H C.sub.3 H.sub.7 --i 3-OC.sub.3 H.sub.7 --i White powder 187-18924 H H H H C.sub.3 H.sub.7 --i 3,4-Cl.sub.2 Milky white crystals 250-25425 H H H H C.sub.3 H.sub.7 --i 4-Cl White crystals 228-23126 H H H H C.sub.3 H.sub.7 --i 3-CF.sub.3 Light brownish crystals 197-19827 H H H H C.sub.3 H.sub.7 --i 3,5-Cl.sub.2 White powder 250-25428 CH.sub.3 H CH.sub.3 H CH.sub.3 4-F Milky white powder 195-19829 H H CH.sub.3 H CH.sub.3 3-Cl Dark yellow powder unmeasurable30 H H CH.sub.3 CH.sub.3 CH.sub.3 3-CF.sub.3 Milky white powder 202-21031 H H CH.sub.3 CH.sub.3 CH.sub.3 3,4-Cl.sub.2 Light brownish crystals 202-20632 H H CH.sub.3 CH.sub.3 CH.sub.3 3,5-(CF.sub.3).sub.2 Yellowish brown powder 168-17033 H H CH.sub.3 CH.sub.3 CH.sub.3 2-Cl, 4-CF.sub.3 Light brownish crystals 222-22434 H H CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 2-Cl, 4-CF.sub.3 Light brownish platy crystals 230-23535 H H CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 3-CF.sub.3 Yellow crystals 51-5236 H H CH.sub.3 CH.sub.3 C.sub.3 H.sub.7 3,4-Cl.sub.2 White crystals 214-21837 H H CH.sub.3 CH.sub.3 C.sub.3 H.sub.7 --i 3,4-Cl.sub.2 Milky white crystals 220-22538 H H CH.sub.3 CH.sub.3 C.sub.3 H.sub.7 --i 4-Cl White crystals 245-25039 H H CH.sub.3 CH.sub.3 C.sub.3 H.sub.7 --i 3-CF.sub.3 Light yellowish crystals unmeasurable40 H H CH.sub.3 CH.sub.3 CH.sub.3 4-NO.sub.2 Light yellowish crystals 177-18241 H H CH.sub.3 CH.sub.3 CH.sub.3 4-F Milky white powder 184-18642 H H CH.sub.3 CH.sub.3 CH.sub.3 3,5-Cl.sub.2,4-C.sub.5 H.sub.11 O Brown powder 209-21243 H H CH.sub.3 CH.sub.3 CH.sub.3 2,3,4,5,6-F.sub.5 Light yellowish powder 216-222__________________________________________________________________________
REFERENTIAL EXAMPLE 2
Dissolved in toluene was 3.1 g (0.02 mole) of 4-chloro-N-methyl-benzylamine, followed by an addition of a catalytic amount of pyridine and a further dropwise addition of 1.8 g (0.022 mole) of diketene at room temperature. After stirring the reaction mixture at room temperature for 3 hours, it was poured in water and then extracted with toluene. Subsequent to purification, N-methyl-N-(4-chlorobenzyl)acetamide was obtained in an oily form.
EXAMPLE 44 ##STR36##
(i) Suspended in carbon tetrachloride were 4.0 g (0.017 mole) of N-methyl-N-(4-chlorobenzyl)acetoacetamide obtained in Referential Example 2, 2.3 g (0.017 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and then extracted with carbon tetrachloride. The carbon tetrachloride solution was purified, dried and concentrated, thereby obtaining an oily crude product. The crude product was purified on a silica gel column (c-300, n-hexane-ethyl acetate) to obtain 3.5 g of oily N-methyl-N-(4-chlorobenzyl)-2-chloroacetamide (n.sub.D.sup.20 : 1.5336). The reaction product was then dissolved together with 1.7 g (0.013 mole) of 4,4-dimethylimidazolidine-2-thione in methyl ethyl ketone. The resultant mixture was heated under reflux for 3 hours. After cooling, the resultant precipitate was collected by filtration, washed with acetone and then recrystallized from isopropanol/isopropyl ether, thereby obtaining 4.8 g of N-(4-chlorobenzyl)-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride as (Compound 44) [melting point: 187.degree.-190.degree. C.; white crystals].
(ii) Dissolved in water was 3.9 g (0.01 mole) of the above-obtained hydrochloride. While stirring the thus-prepared aqueous solution at room temperature, a 10% aqueous solution of caustic soda was added dropwise. Resulting crystals were collected by filtration and then washed with a great deal of water to purify same. The crystals were thereafter dried under reduced pressure to obtain 3.3 g of N-(4-chlorobenzyl)-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2,1-b)thiazole-2-carboxamide (melting point: 139.degree. C.; light yellowish powdery crystals).
EXAMPLE 45 ##STR37##
Suspended in carbon tetrachloride were 2.3 g (0.01 mole) of N-(4-chlorobenzyl)acetoacetamide obtained in the same manner as in Referential Example 2, 1.3 g (0.01 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. The reaction mixture was then poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 1.0 g (0.01 mole) of imidazolidine-2-thione were suspended in methyl ethyl ketone and the resultant suspension was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration, washed with acetone and then recrystallized from isopropyl alcohol/isopropyl ether, thereby obtaining 2.8 g of N-(4-chlorobenzyl)-3-methyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 45). Melting point: 241.degree.-242.degree. C. White crystals.
EXAMPLE 46 ##STR38##
Suspended in carbon tetrachloride were 2.6 g (0.01 mole) of N-(3-trifluoromethylbenzyl)acetoacetamide obtained in the same manner as in Referential Example 2, 1.3 g (0.01 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 1.0 g (0.01 mole) of imidazolidine-2-thione were suspended in methyl ethyl ketone and the resultant suspension was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration, washed with acetone and then recrystallized from ethanol, thereby obtaining 2.5 g of 3-methyl-N-(3-trifluoromethylbenzyl)-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 46) [melting point: 210.degree.-216.degree. C.; colorless prism-like crystals].
EXAMPLE 47 ##STR39##
Suspended in carbon tetrachloride were 2.5 g (0.01 mole) of N-ethyl-N-(4-chlorobenzyl)acetoacetamide obtained in the same manner as in Referential Example 2, 1.3 g (0.01 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione were dissolved in methyl ethyl ketone and the resultant solution was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration, washed with acetone and then recrystallized from isopropanol/isopropyl ether, thereby obtaining 2.7 g of N-(4-chlorobenzyl)-N-ethyl-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 47) [melting point: 186.degree.-188.degree. C.; white crystals].
EXAMPLE 48 ##STR40##
Suspended in carbon tetrachloride were 2.6 g (0.01 mole) of N-methyl-N-(3,4-dichlorobenzyl)acetoacetamide obtained in the same manner as in Referential Example 2, 1.3 g (0.01 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 1.0 g (0.01 mole) of imidazolidine-2-thione were suspended in methyl ethyl ketone and the resultant suspension was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration, washed with acetone and then recrystallized from ethanol, thereby obtaining 3.1 g of N-(3,4-dichlorobenzyl)-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 48) [melting point: 196.degree.-198.degree. C.; light yellowish needle-like crystals].
EXAMPLE 49 ##STR41##
Suspended in carbon tetrachloride were 5.2 g (0.02 mole) of N-(3,4-dichlorobenzyl)acetoacetamide obtained in the same manner as in Referential Example 2, 2.7 g (0.02 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 2.6 g (0.02 mole) of 4,5-dimethylimidazolidine-2-thione were dissolved in methyl ethyl ketone and the resultant solution was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration and then washed and purified with a great deal of acetone, thereby obtaining N-(3,4-dichlorobenzyl)-3,5,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 49) [melting point: 148.degree.-152.degree. C.; white crystals].
EXAMPLE 50 ##STR42##
Suspended in carbon tetrachloride were 4.8 g (0.02 mole) of N-(3-chlorobenzyl)-N-methylacetamide obtained in the same manner as in Referential Example 2, 2.7 g (0.02 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. It was then poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 2.4 g (0.02 mole) of 4-methylimidazolidine-2-thione were dissolved in methyl ethyl ketone and the resultant solution was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration and then washed and purified with acetone and isopropyl ether, thereby obtaining N-(3-chlorobenzyl)-N,3,6-trimethyl-5,6-dihydroimidazo[2,1-b]-hiazole-2-carboxamide hydrochloride (Compound 50) [melting point: 41.degree.-47.degree. C.; brownish glassy matter].
EXAMPLE 51 ##STR43##
(i) Suspended in carbon tetrachloride were 5.2 g (0.02 mole) of N-(2,4-dichlorobenzyl)-N-methylacetamide obtained in the same manner as in Referential Example 2, 2.7 g (0.02 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 1.0 g (0.01 mole) of imidazolidine-2-thione were suspended in methyl ethyl ketone and the resultant suspension was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration and then washed and purified with acetone, thereby obtaining 5.3 g of N-(2,4-dichlorobenzyl)-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 51) [melting point: 251.degree.-255.degree. C.; colorless power].
(ii) Dissolved in water was 3.6 g (0.01 mole) of the thus-obtained 2-[N-methyl-N-(2,4-dichlorobenzyl)carbamoyl]-3-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride. While stirring the solution at room temperature, aqueous ammonia was added dropwise. The resultant precipitate was collected by filtration and then washed and purified with a great deal of water, thereby obtaining 3.0 g of N-(2,4-dichlorobenzyl)-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide (melting point: 55.degree.-60.degree. C.; light yellowish crystals).
EXAMPLES 52-133
The following compounds were prepared in the same manner as in Referential Example 2 and Examples 44- 51.
__________________________________________________________________________ ##STR44##CompoundNo. R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.6 A X.sub.n Appearance Melting point (.degree.C.)__________________________________________________________________________52 H H H H H CH.sub.2 H White prism-like crystals 260-27053 H H H H H CH.sub.2 2-Cl Black prism-like crystals 242-25054 H H H H H CH.sub.2 3-Cl White powder 233-23555 H H H H H CH.sub.2 2,4-Cl.sub.2 Colorless crystals 27556 H H H H H CH.sub.2 3,4-Cl.sub.2 Colorless fine 273 needle-like crystals57 H H H H H CH.sub.2 4-CH.sub.3 White powder 233-23558 H H H H H CH.sub.2 4-OCH.sub.3 Light yellowish crystals 192-19459 H H H H H CH.sub.2 4-NO.sub.2 White powder 243-24860 H H H H H CH.sub.2 3,5-Cl.sub.2 Milky white crystals 250-25361 H H H H CH.sub.3 CH.sub.2 H White prism-like crystals 187-18962 H H H H CH.sub.3 CH.sub.2 2-Cl Light yellowish powder 189-19263 H H H H CH.sub.3 CH.sub.2 4-Cl Light yellowish 126-130 prism-like crystals64 H H H H CH.sub.3 CH.sub.2 4-CH.sub.3 Light brownish crystals 195-19765* H H H H CH.sub.3 CH.sub.2 4-OCH.sub.3 White crystals 118-11966 H H H H CH.sub.3 CH.sub.2 3-Cl Yellowish brown glassy 52-58r67 H H H H CH.sub.3 CH.sub.2 3-CF.sub.3 Yellowish brown crystals 31-3468 H H H H CH.sub.3 CH.sub.2 3,5-Cl.sub.2 Milky white crystals 194-19569 H H H H CH.sub. 3 CH.sub.2 4-F Light brownish powder 173-17570 H H H H CH.sub.3 CH.sub.2 4-CF.sub.3 Milky white powder 212-21571 H H H H CH.sub.3 CH.sub.2 4-OC.sub.2 H.sub.5 Milky white powder 179-18072 H H H H CH.sub.3 CH.sub.2 4-C.sub.2 H.sub.5 Light brownish crystals 195-20073 H H H H CH.sub.3 CH.sub.2 4-NO.sub.2 Pinkish powder 236-23874 H H H H C.sub.2 H.sub.5 CH.sub.2 4-Cl White crystals 202-20575 H H H H C.sub.2 H.sub.5 CH.sub.2 3,4-Cl.sub.2 Milky white crystals 247-25076 H H H H C.sub.2 H.sub.5 CH.sub.2 3-CF.sub.3 Light brownish crystals 170-17577 H H H H n-C.sub.3 H.sub.7 CH.sub.2 3,4-Cl.sub.2 Milky white crystals 233-23778 H H H H i-C.sub.3 H.sub.7 CH.sub.2 4-Cl White crystals 225-23079 H H H H i-C.sub.3 H.sub.7 CH.sub.2 3-Cl Light brownish crystals 202-20580 H H H H i-C.sub.3 H.sub.7 CH.sub.2 3-CF.sub.3 Yellowish crystals 233-23681 H H H H i-C.sub.4 H.sub.9 CH.sub.2 4-Cl White crystals 237-23882 H H CH.sub.3 H H CH.sub.2 3-Cl Milky white powder 148-15083 CH.sub.3 H CH.sub.3 H H CH.sub.2 2,4-Cl.sub.2 White powder 170-17284 CH.sub.3 H CH.sub.3 H H CH.sub.2 4-Cl White powder 166-16785 CH.sub.3 H CH.sub.3 H H CH.sub.2 3-CF.sub.3 Light brownish glassy unmeasurable86 CH.sub.3 H CH.sub.3 H H CH.sub.2 3-Cl White crystals 171-17387 CH.sub.3 H CH.sub.3 H CH.sub.3 CH.sub.2 3-Cl Brownish glassy matter unmeasurable88 H H CH.sub.3 CH.sub.3 H CH.sub.2 3-Cl Yellowish brown powder 80-9389 H H CH.sub.3 CH.sub.3 H CH.sub.2 4-Cl Slightly brownish crystals 70-7990 H H CH.sub.3 CH.sub.3 H CH.sub.2 2,4-Cl.sub.2 White crystals 219-22291 H H CH.sub.3 CH.sub.3 H CH.sub.2 3,4-Cl.sub.2 Light yellowish crystals 107-11592 H H CH.sub.3 CH.sub.3 H CH.sub.2 3-CF.sub.3 Ocher powder 55-6393 H H CH.sub.3 CH.sub.3 H CH.sub.2 3,5-Cl.sub.2 Brown glassy matter unmeasurable94 H H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 3-Cl Brown glassy matter unmeasurable95 H H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 3-CF.sub.3 Brown syrupy matter unmeasurable96 H H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 3,4-Cl.sub.2 Light brownish glassy unmeasurable97 H H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 3,5-Cl.sub.2 Yellowish crystals unmeasurable98 H H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 4-F Ocher solid matter 155-15699 H H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 4-CF.sub.3 Milky white powder 218-220100 H H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 4-CN Pinkish powder 234-237101 H H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 2,4,6-(CH.sub.3).sub.3 White powder 228-235102 H H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 2,3,4,5,6-F.sub.5 White powder 180-181103 H H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 4-OC.sub.2 H.sub.5 Milky white powder 151-152104 H H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 4-OCH.sub.3 White crystals 165-168105 H H CH.sub.3 CH.sub. 3 CH.sub.3 CH.sub.2 4-C.sub.2 H.sub.5 Milky white powder 205-212106 H H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 4-NO.sub.2 Milky white powder 217-221107 H H CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 CH.sub.2 3,4-Cl Milky white crystals 185-187108 H H CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 CH.sub.2 3-CF.sub.3 Light brownish crystals 107-108109 H H CH.sub.3 CH.sub.3 n-C.sub.3 H.sub.7 CH.sub.2 3,4-Cl.sub.2 Milky white crystals 210-213110 H H CH.sub.3 CH.sub.3 i-C.sub.3 H.sub.7 CH.sub.2 3,4-Cl.sub.2 White crystals 235-240111 H H CH.sub.3 CH.sub.3 i-C.sub.3 H.sub.7 CH.sub.2 4-Cl White crystals 222-223112 H H H H H ##STR45## 4-Cl White crystals 208-209113 H H H H H ##STR46## 3-Cl White crystals 160-162114 H H H H H ##STR47## 3,4-Cl.sub.2 White crystals 233-236115 H H H H H (CH.sub.2).sub.2 4-Cl Milky white crystals 193-196116 H H H H CH.sub.3 (CH.sub.2).sub.2 H Colorless powder 184-185117 H H H H CH.sub.3 (CH.sub.2).sub.2 4-Cl Colorless powder 195-197118 H H H H CH.sub.3 (CH.sub.2).sub.2 4-CH.sub.3 Light yellow powder 197-198119 H H CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.2 H Light yellow powder 180-182120 H H CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.2 4-Cl Light yellow powder 193-195121 H H H H H ##STR48## 3-Cl White powder 249-256122 H H H H H ##STR49## 2-Cl White crystals 255-258123 H H H H H ##STR50## 4-Cl White crystals 240-244124 H H H H H ##STR51## 2,4-Cl.sub.2 Milky white crystals 250-253125 H H H H CH.sub.3 ##STR52## 2-Cl Milky white crystals 242-244126 H H CH.sub.3 CH.sub.3 H ##STR53## 2-Cl White crystals 212-216127 H H CH.sub.3 CH.sub.3 H ##STR54## 4-Cl Light yellowish flaky 170-172s128 H H CH.sub.3 CH.sub.3 H ##STR55## 2,4-Cl.sub.2 White crystals 240-246129 H H CH.sub.3 CH.sub.3 H ##STR56## 3-Cl Milky white crystals 119-125130 H H CH.sub.3 CH.sub.3 CH.sub.3 ##STR57## 2-Cl White crystals 255-257131 H H H H ##STR58## CH.sub.2 4-Cl White down-like crystals 215-220132 H H CH.sub.3 CH.sub. 3 ##STR59## CH.sub.2 4-Cl White down-like crystals 250-253__________________________________________________________________________ Asterisk (*) indicates that the compound is a free base.
REFERENTIAL EXAMPLE 3
Dissolved in toluene were 2.5 g (0.02 mole) of m-chloroaniline and a catalytic amount of pyridine, followed by dropwise addition of 1.9 g (0.022 mole) of diketene at 50.degree. C. After completion of the dropwise addition, the resultant mixture was heated under reflux for 3 hours. Under ice-cooling, ligroin was added, and precipitated crystals were collected by filtration and were then washed first with ligroin and then with hexane. The crystals were then dried under reduced pressure to obtain 3'-chloroacetoacetanilide.
EXAMPLE 133 ##STR60##
(i) Dissolved in diethyl ether was 2.1 g (0.01 mole) of the 3'-chloroacetanilide obtained in Referential Example 3, followed by a dropwise addition of 1.5 g (0.011 mole) of sulfuryl chloride at -5.degree. C. The resultant mixture was stirred at -10.degree.--5.degree. C. for 30 minutes. The reaction mixture was poured into ice water, neutralized with sodium hydrogencarbonate and then extracted with toluene. The organic layer was dried and concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, recrystallized from isopropanol, and then dried at 120.degree. C. under reduced pressure for 3 hours. The crystals were then suspended in methyl ethyl ketone and heated under reflux for 20 hours. The reaction mixture was cooled, and the resultant precipitate was collected by filtration, washed with acetone and then dried under reduced pressure to obtain 2.6 g of 3'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 133) [yield: 72.2%]. PMR ppm .delta.(DMSO-d.sub.6): 1.53 (6H, s, 6.6(CH.sub.3).sub.2), 2.53 (3H, s, 3,-CH.sub.3), 4.27 (2H, s, 5-CH.sub.2 --), 7.03-8.00 (4H, m, aromatic proton), 10.80 (1H, s, --NH-- ).
(ii) Dissolved in water was 1.8 g (0.005 mole) of the thus-obtained 3'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride. While stirring the aqueous solution at room temperature, a 20% aqueous solution of potassium carbonate was added dropwise. The resultant precipitate was collected by filtration and then washed and purified with a great deal of water. The precipitate was then dried under reduced pressure to obtain 1.3 g of 3'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide (melting point: 172.degree.-173.degree. C.; milky white powder).
EXAMPLE 134 ##STR61##
(i) Dissolved in diethyl ether was 2.1 g (0.01 mole) of 4'-chloroacetanilide obtained in the same manner as in Referential Example 3, followed by a dropwise addition of 1.5 g (0.011 mole) of sulfuryl chloride at -5.degree. C. The resultant mixture was stirred at -10.degree.--5.degree. C. for 30 minutes. The reaction mixture was poured in ice water, neutralized with sodium hydrogencarbonate and then extracted with toluene. The organic layer was dried and concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, washed with acetone and then dried under reduced pressure to obtain 3.4 g 4'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 134) [yield: 94.4%]. Melting point: 264.degree.-268.degree. C.
(ii) Dissolved in water was 1.8 g (0.005 mole) of the thus-obtained 4'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride. While stirring the aqueous solution at room temperature, a 10% aqueous solution of caustic soda was added dropwise. The resultant precipitate was collected by filtration and then washed and purified with a great deal of water. The precipitate was then dried under reduced pressure to obtain 1.0 g of 4'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]-thiazole-2-carboxyanilide (melting point: 235.degree.-236.degree. C.; white powder).
EXAMPLE 135 ##STR62##
(i) Dissolved in carbon tetrachloride were 2.8 g (0.01 mole) of 2'-chloro-4'-trifluoromethylacetoacetanilide obtained in the same manner as in Referential Example 3 and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant suspension was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, recrystallized from isopropyl ether-ethanol and then dried at 120.degree. C. under reduced pressure for 3 hours to obtain 2.5 g of 2'-chloro-4'-trifluoromethyl-3,6,6-trimethyl-5,6-dihydroimidazo-[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 135) [yield: 61.9%]. Melting point: 148.degree.-150.degree. C.
EXAMPLE 136 ##STR63##
Dissolved in carbon tetrachloride were 4.3 g (0.01 mole) of 3',4'-diiodoacetoacetanilide obtained in the same manner as in Referential Example 3 and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant suspension was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.2 g (0.01 mole) of 4-methylimidazolidine-2-thione. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, washed with acetone and then dried under reduced pressure to obtain 4.8 g of 3',4'-diiodo-3,6-dimethyl-5,6-dihydroimidazo-[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 136) [yield: 85.7%]. Melting point: 278.degree.-280.degree. C.
EXAMPLE 137 ##STR64##
Dissolved in carbon tetrachloride were 2.5 g (0.01 mole) of 3',4'-dichloroacetoacetanilide obtained in the same manner as in Referential Example 3 and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant suspension was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,5-dimethylimidazolidine-2-thione. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, recrystallized from isopropyl ether-ethanol, and then dried at 120.degree. C. under reduced pressure for 3 hours to obtain 2.5 g of 3',4'-dichloro-3,5,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 137) [yield: 64.1%]. Melting point: 240.degree.-245.degree. C.
EXAMPLES 138-170
The following compounds were obtained in the same manner as in Referential Example 3 and Examples 133-137.
______________________________________ ##STR65## Melting pointNo. R.sub.1 R.sub.2 X.sub.n Appearance (.degree.C.)______________________________________138 H H H Yellowish powder 207-209139 H H 2-Cl White powder 205-212140 H H 3-Cl White powder 196-198141 H H 4-Cl Yellowish powder 240-244142 H H 2,4-Cl.sub.2 White powder 245-253143 H H 3,4-Cl.sub.2 Yellowish powder 234-235144 H H 3,5-Cl.sub.2 Yellowish powder 255-259145 H H 3-Br White powder 201-204146 H H 4-NO.sub.2 Light yellowish 255-258 powder147 H H 3-I White powder 203-204148 H H 4-I White powder 270149 H H 2-CH.sub.3 White powder 241-246150 H H 4-CH.sub.3 Milky white 208-210 powder151 H H 2-OCH.sub.3 White powder 245-253152 H H 4-OCH.sub.3 White powder 210-215153 H H 3-OC.sub.3 H.sub.7i White powder 115-122154 H H 2-Cl, 4-CF.sub.3 White powder 138-142155 H H 3-Cl, 4-F Gray powder 150-154156 CH.sub.3 H 3,4-I.sub.2 Brown powder 214-215157 CH.sub.3 H 4-Cl White powder 259-264158 CH.sub.3 H 2-Cl, 4-CF.sub.3 White flaky 178-182 crystals159 H CH.sub.3 3,4-Cl.sub.2 Brown syrupy 128-136 matter160 H CH.sub.3 2,4-Cl.sub.2 Light orange 172-175 crystals161 H CH.sub.3 3,5-Cl.sub.2 Yellowish crystals 155-160162 H CH.sub.3 3,4-I.sub.2 Light brownish 266-268 crystals163 H CH.sub.3 4-I White crystals 220-225164 H CH.sub.3 3-Cl, 4-F Gray powder 251-256165 H CH.sub.3 3,5-(CF.sub.3).sub.2 Gray powder 261-265166 H CH.sub.3 H White crystals 240-245167 H CH.sub.3 4-Br White crystals 255-261168 H CH.sub.3 2,5-(OCH.sub.3).sub.2 Milky white 245-247 powder169 H CH.sub.3 2-OCH.sub.3, 5-OH Yellowish brown 279-281 powder170 H CH.sub.3 3-Cl, 4-OH Brown powder 272-273______________________________________
EXAMPLES 171-173
The following compounds were prepared in the same manner as in Referential Example 2 and Example 44.
Compound 171: ##STR66## (m.p.: 140.degree.-142.degree. C.; white powder)
Compound 172: ##STR67## (m.p.: 120.degree.-121.degree. C.; white acicular crystals)
Compound 173: ##STR68## (m.p.: 171.degree.-174.degree. C.; slightly yellow powder)
EXAMPLE 174 ##STR69## N-(n-Phenylpropyl)-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2.1-b]thiazole-2-carboxamide (Compound No. 174)
Suspended in carbon tetrachloride were 2.4 g (0.013 mole) of N-methyl-N-(3-phenylpropyl)acetoacetamide which had been obtained in the same manner as in Referential Example 1, 1.7 g (0.013 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The resultant suspension was heated under reflux for 1 hour. The reaction mixture was then poured in water, followed by extraction with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and concentrated to obtain an oily reaction product. The reaction product was purified by chromatography on a silica gel column ("C-300", n-hexane-ethyl acetate), thereby obtaining 1.9 g (0.009 mole) of N-methyl-N-(3-phenylpropyl)-2-chloroacetoacetamide as an oily substance.
Dissolved in 100 ml of methyl ethyl ketone was 1.9 g (0.009 mole) of N-methyl-N-(3-phenylpropyl)-2-chloroacetoacetamide which was obtained above, followed by an addition of 1.2 g (0.009 mole) of 4,4-dimethylimidazolidine-2-thione. The reaction mixture was heated under reflux for 3 hours. After completion of the reaction, methyl ethyl ketone was distilled off and the resulting syrup was dissolved in water. A water-insoluble oil was extracted out with ethyl acetate. The water layer was alkalinized with potassium carbonate, followed by extraction with ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate and was then concentrated. The resultant syrup was purified by chromatography on a column (silica gel "C-300", n-hexane/ethyl acetate) to obtain 1.7 g of a light brownish viscous liquid (n.sub.D.sup.20 1.5760).
EXAMPLE 175 ##STR70## N-[2-(3,4-Dichlorophenyl)ethyl]-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2.1-b]thiazole-2-carboxamide hydrochloride (Compound No. 175)
Suspended in carbon tetrachloride were 7.0 g (0.024 mole) of N-methyl-N-(3,4-dichlorophenethyl)acetoacetamide which had been obtained in the same manner as in Referential Example 1, 3.2 g (0.024 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The resultant suspension was heated under reflux for 1 hour. The reaction mixture was then poured in water, followed by extraction with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and concentrated to obtain an oily reaction product. The reaction product was purified by chromatography on a silica gel column ("C-300", n-hexane-ethyl acetate), thereby obtaining 5.6 g of N-methyl-N-(3,4-dichlorophenethyl)-2-chloroacetoacetamide as an oily substance.
Dissolved in 150 ml of methyl ethyl ketone was 5.6 g (0.017 mole) of N-methyl-N-(3,4-dichlorophenetyl)-2-chloroacetoacetamide which was obtained above, followed by an addition of 2.2 g (0.017 mole) of 4,4-dimethylimidazolidine-2-thione. The reaction mixture was heated under reflux for 3 hours. After cooling the reaction mixture, n-hexane was added to the reaction mixture, and the resulting syrup was collected and then solidified with ethyl ether. The thus-solidified reaction product was recrystallized from isopropyl alcohol/isopropyl ether to obtain 4.3 g of colorless crystalline powder. m.p. 196.degree.-198.degree. C.
EXAMPLES 176-199
The following compounds were prepared in the same manner as in Referential Example 1 and Examples 174 and 175.
__________________________________________________________________________ ##STR71##Compound Melting pointNo. R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 A X.sub.n Appearance (.degree.C.) or__________________________________________________________________________ n.sub.D.sup.20176 H H H H H CH.sub.2 4-F White powdery crystals 239-243177 H H H H H (CH.sub.2).sub.2 H White powder 191-195178 H H H H H (CH.sub.2).sub.2 2,4-Cl.sub.2 Light yellowish 229-230 powdery crystals179 H H CH.sub.3 CH.sub.3 H (CH.sub.2).sub.2 2,4-Cl.sub.2 Light yellowish 191-193 powdery crystals180 H H H H H (CH.sub.2).sub.2 3,4-Cl.sub.2 Colorless powdery crystals 222-224181 H H CH.sub.3 CH.sub.3 H (CH.sub.2).sub.2 3,4-Cl.sub.2 Colorless powdery crystals 204-205182 H H H H CH.sub.3 (CH.sub.2).sub.2 3,4-Cl.sub.2 Colorless powdery crystals 190-191183 H H H H H (CH.sub.2).sub.3 H Light yellowish 169-171 powdery crystals184 H H H H C.sub.3 H.sub.7i CH.sub.2 3,4-Cl.sub.2 Milky powdery crystals 240-242__________________________________________________________________________ ##STR72##Compound Melting pointNo. R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 A X.sub.n Appearance (.degree.C.) or__________________________________________________________________________ n.sub.D.sup.20185 H H CH.sub.3 CH.sub.3 H CH.sub.2 4-F White powder 122-125186 H H CH.sub.3 CH.sub.3 H CH.sub.2 4-NO.sub.2 Orange powder 133-139187 H H CH.sub.3 CH.sub.3 H CH.sub.2 4-OCH.sub.3 White powder 116-122188 H H CH.sub.3 CH.sub.3 H (CH.sub.2).sub.3 H Fine acicular 135-136 white crystals189 H H H H CH.sub.3 (CH.sub.2).sub.3 H Light brownish n.sub.D.sup.20 = 1.5940 viscous liquid__________________________________________________________________________
Having now fully described the invention, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the invention as set forth herein.

Number	Date	Country
60-85679	Apr 1985	JPX
60-89506	Apr 1985	JPX
60-89507	Apr 1985	JPX

Number	Name	Date	Kind
4103016	Moser	Jul 1978
4556669	Nishio	Dec 1985

5,6-dihydroimidazo(2,1-b)thiazole-2-carboxamide derivatives or salts thereof

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Continuation in Parts (1)