BE825260A - IMIDAZO (2,1-B) THIAZOLES AND THEIR PREPARATION - Google Patents

Description

       

  "Imidazo (2, l-b) thiazoles and their preparation" <EMI ID = 1.1>

  
Pharmaceutical preparations containing such compounds.

  
There are several known hypoglycaemic drugs for

  
 <EMI ID = 2.1>

  
fasting blood in untreated or glucose-treated animals, but they do not work in this way in animals that have been

  
 <EMI ID = 3.1>

  
have a pancreatic reserve of insulin, as in nori-diabetics or moderate diabetics, whose disease began in adulthood, requiring a daily insulin dose of less than 10 units. On the other hand, these compounds do not act in patients suffering from severe diabetes and in cases of diabetes of the juvenile type or, of the type of the beginning of growth. In addition, they cannot be used in patients with a tendency to ketosis or ketoacidosis. They can cause severe hypoglycemia with the acute neurologic state of hemiparesis and coma. These compounds do not have direct insulin-like activity.

  
Phenformin and certain other biguanides are more effective than arylsulfonylureas because they also produce hypoglycemia in subjects who have undergone pancreatectomy or in cases of severe diabetes caused by alloxan. The di-

  
 <EMI ID = 4.1>

  
en = 135) is achieved with phenformin in animals with a baseline blood glucose concentration of
250-300 mg / 100 ml. However, some activity (& average =

  
90) is still achieved at a starting concentration of up to 380 mg / 100 ml. However, the therapeutic dose of phenformin is close to the toxic dose in humans and it can produce anorexia, nausea, vomiting and by <EMI ID = 5.1>

  
more stable a labile diabetic patient and this is one of the main clinical applications. Other applications are in cases of diabetes in early maturity, accompanied by obesity, or in cases of failure of arylsulfonylureas.

  
It is therefore necessary to be able to have available a new non-toxic, anti-diabetic drug exhibiting a mechanism of action of the type of insulin, acting orally on the most severe diabetes, as for example in the case of juvenile diabetes or early growth diabetes.

  
It has now been found that, surprisingly, certain imidazo (2,1-b) thiazoles provide improved properties compared to known drugs.

  
Some of the compounds according to the present invention have an average statistical antihyperglycemic activity, which is stronger than that of phenformin and they are particularly effective in the treatment of severe diabetes in rats. When the starting blood glucose concentration is greater than 380 mg / 100 ml, the LA value may rise to a figure over 230 with an A% value of 55. Under conditions

  
 <EMI ID = 6.1>

  
of 50 and 10%. The duration of activity is longer than that of phenformin (5 hours) and the product is still active after 24 hours. There are no glucosuria, antidiuretic or other activities, as unwanted side effects.

  
 <EMI ID = 7.1>

  
imidazo (2,1-b) thiadiazoles in normal beings is very weak

  
 <EMI ID = 8.1>

  
thus a possible hypoglycemic coma.

  
The present invention therefore relates to imidazo (2,1-b) thiazoles of general formula (I):

  

 <EMI ID = 9.1>


  
in which at least one of the substituents A, B, C and D represents

  
 <EMI ID = 10.1>

  
where n has a value of 0 to 2, R denotes an alkyl (straight or branched), aryl, aralkyl or alicyclic radical, a hydrogen atom, an inorganic cation, for example sodium or calcium, or

  
 <EMI ID = 11.1>

  
hydrogen or hydroxyalkyl, alkyl, alkylamino (optionally substituted), alkylcarbalkoxy or alkylcarboxy radicals

  
 <EMI ID = 12.1>

  
whether or not it is a cyclic amine, a hydroxylamine or a hydrazine group, X represents a halogen atom or else a hydroxy, mercapto, alkoxy, aryloxy or aralkoxy radicel, or else

  
 <EMI ID = 13.1>

  
or branched), aryl, aralkyl or heterocyclic, the substituents A, B, C and D not representing one of the preceding groups denote a hydrogen atom or an alkyl radical (straight or branched).

  
 <EMI ID = 14.1>

  
physiologically acceptable quaternary ammonium or acid addition salts of the above compounds, all excluding:

  
 <EMI ID = 15.1>

  

 <EMI ID = 16.1>


  
in which A 'denotes a COOR "radical, R" denotes a hydrogen atom, a hydroxyalkylammonium cation, an inorganic cation or a lower alkyl group, or else A' denotes a ra-

  
 <EMI ID = 17.1>

  
nyl optionally substituted, C 'denotes methyl, tertiary butyl or an optionally substituted phenyl group, and D' denotes hydrogen or an alkyl group.

  
The alkyl radical advantageously contains from 1 to 8 carbon atoms, the aryl radical is preferably a phenyl, diphenyl or naphthyle radical, substituted or not. The heterocyclic radical is preferably chosen from substituted or unsubstituted imidazoJyle, pyridyl, thienyl or furyl radicals. As acids suitable in the preparation of the acid addition salts, there may be mentioned hydrochloric, hydrobromic, nitric, sulfuric and phosphoric acids. However, some organic acids can also be used. As preferred esters in the preparation of quaternary ammonium salts, there may be mentioned the esters of sulfuric, hydrochloric, hydrobromic acids and of certain aromatic sulfuric acids.

  
The two compounds which have been excluded above as chemicals have been described by Ochiai, Ber. 69, 1650
(1936). However, no pharmaceutical activity has been reported for these compounds so that they remain encompassed within the scope of the present invention as drugs whose pharmaceutical activity is proposed here for the first time.

  
The compounds of the general formula can be prepared
(I) by various methods. A process for preparing compounds of general formula (I) comprises the condensation of an α-halocarbonyl derivative of general formula (II):

  

 <EMI ID = 18.1>


  
in which C and D have the meaning given above, Y denotes a halogen atom, and the carbonyl group can be

  
 <EMI ID = 19.1>

  
 <EMI ID = 20.1>

  

 <EMI ID = 21.1>


  
in which A and B have the preceding meaning, to thereby form a thiocarbonyl derivative of the general formula (IV):

  

 <EMI ID = 22.1>


  
in which A, B, C and D have the meaning given above and, if the carbonyl group of the halocarbonyl derivative of the general formula (II) has been protected, the application to the compound obtained, of an acid separation reaction, the thiocarbonyl derivative of general formula (IV) being converted into the compound of general formula (I) with a suitable reagent by cyclization and dehydration by methods known per se.

  
 <EMI ID = 23.1>

  
General mules (II) and (III) is preferably carried out in a suitable inert solvent. As suitable solvents, there may be mentioned, by way of example, alcohols, such as methanol, ethanol, isopropanol, butanol, or aprotic solvents, for example acetonitrile, dimethylformamide (DMF) , dimethyl sulfoxide (DMSO), etc.

  
The condensation reaction is carried out at temperatures which vary between room temperature and the boiling point of the solvent.

  
The reaction can be carried out in any suitable medium, for example in an alkaline, neutral or acidic medium. In the case where the reaction is carried out in an alkaline medium, a metal hydride or alkoxide is used, and the main reaction product is the thiocarbonyl derivative of the general formula (IV). When the reaction is carried out in a medium

  
at room temperature, the main reaction product is the corresponding halhydrate salt of the thiocarbonyl derivative of the general formula (IV). However, in the case where the condensation reaction is carried out in a neutral medium at a temperature of <EMI ID = 24.1>

  
 <EMI ID = 25.1>

  
are carried out directly and the desired compound of general formula (I) is obtained.

  
The thiocarbonyl derivative of the general formula (IV) is not always isolated, as has been pointed out above. In many cases, the final compound of general formula (I) is obtained directly. Sometimes the cycle is closed but the dehydration reaction must be carried out. In the case where an intermediate compound is isolated, the cyclization and / or the dehydration reaction can be carried out by various methods. According to a preferred process, the base of the thiocarbonyl derivative of general formula (IV) or the hydroxydihydrothiazole derivative is treated under reflux in phosphorus oxychloride or sulfuric acid. Another method is to reflux a

  
 <EMI ID = 26.1>

  
suitable, for example butanol.

  
The reaction time for cyclization and dehydration can vary widely, that is, it can be between 10 minutes and 24 hours depending on the substituents and the reaction conditions.

  
The thiocarbonyl derivatives of the general formula (IV) are new compounds except as regards 2-thioacea-

  
 <EMI ID = 27.1>

  
therefore also these new compounds.

  
Another method of preparing compounds of general formula (I) comprises the condensation of an α-halocarbonyl derivative of general formula (V):

  

 <EMI ID = 28.1>


  
in which A and B have the meaning given above and Y denotes a halogen atom, with a 2-aminothiazole derivative of the general formula (VI)

  

 <EMI ID = 29.1>


  
in which C and D have the meaning given above.

  
 <EMI ID = 30.1> <EMI ID = 31.1>

  
takes between a few minutes and several days depending on the substituents and the reaction conditions.

  
Most of the compounds corresponding to formulas (II), (III), (V) and (VI) are known. Those which are new can easily be prepared by methods analogous to those by which the known compounds are prepared.

  
 <EMI ID = 32.1>

  
dant to general formula (I) can be introduced either directly during one of the preceding processes, or through the conversion of a compound of general formula (I) into another compound by methods known per se .

  
This is how, for example, we can introduce the ra-

  
 <EMI ID = 33.1>

  
 <EMI ID = 34.1>

  
the best way by transformation of the carbalkbxy function, for example by reduction to hydroxymethyl, halogenation to chloromethyl and aminolysis with a primary, secondary orcy- amine

  
 <EMI ID = 35.1>

  
a suitable acid chloride of the hydroxymethyl function

  
 <EMI ID = 36.1>

  
suitable metal coolate or phenate gives the desired ether (X =

  
 <EMI ID = 37.1>

  
from the ester or via the acid chloride, and the cyano group can be obtained from the amide.

  
The compounds of general formula (I), in which the dotted line denotes 2 hydrogen atoms, can be prepared by reduction of a thiocarbonyl derivative of the general formula.

  
 <EMI ID = 38.1>

  
cool from the general formula (Vil):

  

 <EMI ID = 39.1>
 

  
 <EMI ID = 40.1>

  
inert and adding to the solution obtained a solution of '

  
 <EMI ID = 41.1>

  
As suitable solvents, there may be mentioned in particular ethanol, acetonitrile, etc.

  
Acid addition salts of compounds of general formula (I) are obtained by methods known per se, for example by dissolving the base in a suitable solvent (par.

  
example of alcohols, ethyl acetate, acetonitrile, etc.) and then addition of the selected acid at a temperature of

  
 <EMI ID = 42.1>

  
Quaternary ammonium salts of compounds of general formula (I) can also be prepared by methods known per se, for example by reacting the base with a suitable ester of the desired acid, for example butyl bromide, methyl sulfate, methyl p-toluenesulfonate, etc., with a suitable solvent or without a solvent.

  
The present invention also encompasses pharmaceutical compositions containing, as active substance, at least one imidazo (2, 1-b) thiazole of general formula (I). These novel compositions are preferably administered orally. However, if desired, they can be administered in any other suitable form, for example by injection, in the form of suppositories, etc.

  
The new compositions according to the present invention <EMI ID = 43.1>

  
fairs, etc: These compositions are prepared in a traditional way.

  
 <EMI ID = 44.1>

  
Of course, these compositions should include

  
 <EMI ID = 45.1>

  
posed according to the present invention. These doses may vary

  
 <EMI ID = 46.1>

  
invention. These doses vary depending on the compound used, the

  
 <EMI ID = 47.1>

  
the drug is administered and the manner in which it is administered.

  
The present invention also encompasses a method of reducing blood sugar levels in patients with diabetes, wherein said patients are administered a composition comprising a therapeutically effective dose of a compound of the general formula (I).

  
The present invention will be further illustrated by

  
Following examples which are given without any limiting intention. All temperatures are given in [deg.] C. - Melting points are uncorrected points. The solvents shown in parentheses after the melting points are those in which the substances have been recrystallized.

Example 1

  
158 g of 2-mercapto-4 (5) -carbomethoxy-imidazole are suspended, [prepared as described in JACS. 71, 644-647
(1949)] in 1.5 l of dry methanol containing 1 mole of sodium methoxide, and then slowly added to the suspension 169 g of bromoacetaldehyde dimethyl acetal. After refluxing the suspension for 16 hours, 1.5 l of benzene are added thereto and the methanol is evaporated off. 2- [4 (5) -carbomethoxyimidazolyl] thioacetaldehyde dimethyl acetal precipitates after extraction of the precipitate with isopropanol and evaporation of the solvent, 228 g of a substance is obtained which is dissolved in 1.2 1 of. a so- <EMI ID = 48.1> ', <1>, 3-dihydrothiazole .--

  
The above substance is treated under reflux for 2 hours in 1.4 l of phosphorus oxychloride. The solvent is separated by vacuum distillation; water and chloroform are added to the residue and then sodium bicarbonate is added until a pH of 7.5 is obtained. The chloroform layer is washed with water and the aqueous phase is extracted with chloroform. The dried chloroform solution is evaporated and the residue is crystallized to obtain 84 g of 6-carbomethoxy-imidazo (2, 1-b) -

  
 <EMI ID = 49.1>

Example 2

  
The 6-carbomethoxy-imidazo (2,1-b) thiazole prepared as described in Example 1 is added to an isopropanol solution containing dry HCl until a pH of 2 is obtained after dissolution of the substance. . The solvent is evaporated and the residue, which is 6-carbomethoxyimidazo (2,1-b) thiazole hydrochloride, is crystallized from absolute alcohol; melting point of
182-185 [deg.] C ..

Example 3

  
A solution of 15 g of 2-aminothiazole and 31.4 g of ethyl bromoacetate in 200 ml of acetonitrile is stirred for 2 hours at room temperature. After reflux of the solution

  
for 3 hours, it is decolorized and the solvent is evaporated off in vacuo. The residue obtained is dissolved in water, neutralized with sodium bicarbonate and extracted with chloroform. The solvent is dried and evaporated. The residue is then dissolved in acetone, then concentrated nitric acid is dropped into the solution dropwise until a pH of 4.5 is obtained. Crystallization of 32 g of ethyl imidazo (2,1-b) thiazole-6-acetate nitrate is obtained; melting point 102-
106 [deg.] (Acetone).

Example 4

  
A solution of 4.25 g of ethyl imidazo (2,1-b) thiazole-6-acetate base (obtained <EMI ID = 50.1> is refluxed for 2 hours).

  
 <EMI ID = 51.1>

  
of 8 g of barium hydroxide octahydrate in 200 ml of water. Sulfuric acid is then allowed to drop dropwise into the solution until complete precipitation of the sulfate is obtained.

  
 <EMI ID = 52.1>

  
After separation of the precipitate by filtration, the solution is washed with chloroform and concentrated to a quarter of the initial volume to obtain 3.2 g of imidazo (2,1-b) thiazole-6-acetic acid; melting point of 193-195 [deg.] ..

Example 5

  
Refluxed for 12 hours, a solution of

  
 <EMI ID = 53.1>

  
melting point of 198-200 [deg.]. The mother liquor is evaporated and the residue dissolved in chloroform. After washing with alkaline water and drying, the solvent is evaporated off and the remainder is dissolved in ether. A solution of dry HCl in isopropanol is added to the pH of 3 to obtain 10.2 g of hydrochloride.

  
 <EMI ID = 54.1>

  
of 175-178 [deg.] (absolute ethanol).

  
 <EMI ID = 55.1>

  
18.6 g of 2-mercap- are stirred at room temperature

  
 <EMI ID = 56.1> <EMI ID = 57.1>

  
mp 123-124 [deg.] (ethyl acetate).

  
13 g of the preceding compound are treated under reflux in 130 ml of phosphorus oxychloride; after evaporation of the solvent in vacuo, the remainder is dissolved in ice-water and neutralized with sodium carbonate to obtain, after filtration,

  
7 g of 5-methyl-6-carboethoxy-imidazo (2, 1-b) thiazole; melting point 102-103 [deg.] (hexane).

Example 7

  
(a) The same reaction as that described by Ochiai [Ber., 69 ,. 1650 (1936) j, i.e. 2-mercapto-4 (5) -carboethoxy-5 (4) -methyl-imidazole is reacted with chloroacetone at room temperature to obtain 2-thioacetonyl-4 (5) -carboethoxy-5 (4) -methyl-imidazole. This imidazole derivative is reacted with phosphorus oxychloride <EMI ID = 58.1>

  
the; melting point of 141-142 [deg.].

  
(b) A solution of 11.4 g of 2-amino-4-methyl-thiazole and 21 g of ethyl α-bromoethylglyoxalate in 200 ml of ethyl α-bromoethylglyoxalate in 200 ml is refluxed in a nitrogen atmosphere for 5 hours. acetonitrile, then left to stand overnight at room temperature. After decolorization and evaporation of the solvent, the remainder is dissolved in water and the resulting solution is neutralized with sodium carbonate. We obtain a precipitate of <EMI ID = 59.1>

  
it is separated by filtration; mp 141-142 [deg.] (ethyl acetate).

Example 8

  
(a) A solution of 15.8 g of 2-mercapto-4 (5) -carbomethoxy-imidazole and 10.17 g <EMI ID = 60.1> is refluxed for 20 hours.

  
solution and ether is added to form, after filtration,

  
 <EMI ID = 61.1>

  
fusion of 169-174 [deg.] (acetic acid).

  
 <EMI ID = 62.1>

  
a nitrogen atmosphere a solution of 15; 8 g of 2-mercapto-4 (5) -

  
 <EMI ID = 63.1> 0 &#65533; &#65533; &#65533; &#65533; *, &#65533; &#65533; &#65533; &#65533; &#65533;

  
 <EMI ID = 64.1>

  
 <EMI ID = 65.1>

  
2 hours the base which has a melting point of 106.5-107.5 [deg.] And which was obtained from the hydrochloride. The solution is then concentrated in vacuo and ice water is added to the residue. After neutralization with sodium bicarbonate, the aqueous solution is extracted with chloroform. The solvent is then evaporated off to form 17 g of 3-methyl-6-carbomethoxy-imidazo (2, 1-b) thiazole; melting point 170-173 [deg.] (isopropanol).

Example 9

  
5 g of 3-methyl-6-carbomethoxy-imidazo (2,1-b) thiazole obtained as described in Example 8, with stirring at room temperature, are dissolved in 100 ml of acetonitrile containing 10

  
 <EMI ID = 66.1>

  
3-methyl-6-carbomethoxy-imidazo (2, 1-b) thiazolium crystallize and are separated by filtration. The filtrate is then evaporated and the remainder is dissolved in water, then the aqueous solution obtained is extracted with chloroform. The water is separated off by vacuum distillation and the residue obtained is continuously extracted with chloroform. After concentration, ether is added to give an additional 2.5 g of the above quaternary salt, mp 179-180 [deg.] (Decomp.).

Example 10

  
Refluxed for 2 hours in 500 ml of a 10% aqueous solution of NaOH, 100 g of 3-methyl-6-carbomethoxy-imidazo (2,1-b) thiazole (obtained as described in Example 8 ). Acetic acid is dropped dropwise into the solution until a pH of 5. The solution is then cooled to obtain, after filtration, 71 g of 3-methylimidazo (2, lb) thiazole acid. -6-carboxylic; melting point 245-
2470.

Example 11

  
It is refluxed in 10 ml of ethanol, 1 g of acid

  
 <EMI ID = 67.1> <EMI ID = 68.1>

  
 <EMI ID = 69.1>

  
te tion, melting point 196-197 [deg.].

Example 12

  
It is refluxed in 10 ml of ethanol, 1 g of acid

  
 <EMI ID = 70.1>

  
written in Example 10, and a solution of 0.49 g of 2-amino-2-methyl-1-propanol in 5 ml of ethanol is added. After cooling, a precipitation of 1 g of 2'-methyl-l'-propanol-2'-ammonium 3-methyl-imidazo (2,1-b) thiazole-6-carboxylate is obtained, which is separated by filtration. , melting point 235-238 [deg.].

Example 13

  
Refluxed in 25 ml of ethanol, 1 g of 3-methyl-imidazo (2,1-b) thiazole-6-carboxylic acid obtained as described in Example 10, and a solution of 0, 55 g of triethylamine in 5 ml of ethanol. Ether is added to the cooled solution until an oily layer appears. the solvent is then evaporated off to obtain oily triethylammonium 3-methyl-imidazo (2,1-b) thiazole-6-carboxylate.

Example 14

  
It is refluxed in 25 ml of ethanol, 1 g of acid

  
 <EMI ID = 71.1>

  
written in Example 10, and a solution of 0.56 g of dimethylaminopropylamine in 2 ml of ethanol is added. The solvent is then evaporated to obtain 1.5 g of water-soluble, oily 3-methyl-imidazo (2,1-b) thiazole6-carboxylate.

Example 15

  
0.41 g of methyl ester hydrochloride is dissolved

  
 <EMI ID = 72.1>

  
sodium bicarbonate to pH 7 and a rapid extraction is then carried out with 2 times 10 ml of chloroform. A boiling solution of 1 g of 3-methyl-imidazo (2,1-b) thiazole-6-carboxylic acid obtained as described in Example 10 in 25 ml of ethanol is added to the preceding extract. After drying over sodium sulfate, the solvent is evaporated off to obtain 1.2 g of methylammonium 3-methyl-imidazo (2,1-b) thiazole-6-carboxylate-ethanoate.

  
 <EMI ID = 73.1>

  
 <EMI ID = 74.1>

  
flow for 3 hours. After evaporation of the solvent under vacuum, the residue obtained, which is 3-methyl chloride hydrochloride

  
 <EMI ID = 75.1>

  
 <EMI ID = 76.1>

  
The solvent is separated and the residue obtained is dissolved in water.

  
 <EMI ID = 77.1>

  
 <EMI ID = 78.1>

  
fusion of 117-119 [deg.].

  
 <EMI ID = 79.1>

  
 <EMI ID = 80.1>

Example 18-

  
In a manner analogous to that described in Example

  
 <EMI ID = 81.1>

  
thiazole, melting point 96-98 [deg.] (reaction time between acyl chloride and alcohol is about 24 hours).

Example 19

  
 <EMI ID = 82.1>

  
 <EMI ID = 83.1>

  
thiazole, melting point 79-83 [deg.].

  
 <EMI ID = 84.1>

  
In a manner analogous to that described in Example
16, 4.2 g of-3-methyl-6-carboisobutoxy-imidazo (2,1-b) thiazole, with a melting point of 80.5-81.5 [deg.] (Hexane) are prepared.

Example 21

  
In a manner analogous to that described in Example

  
 <EMI ID = 85.1>

  
 <EMI ID = 86.1>

  
 <EMI ID = 87.1>

  
thiazol-6-carboxyl and secondary butanol is about 14 hours).

  
 <EMI ID = 88.1>

  
 <EMI ID = 89.1>

  
The solvent is then removed and the residue is neutralized with an aqueous solution of sodium carbonate, followed by extraction with chloroform. The solvent is then separated off and an oil is obtained. The oily residue is dissolved in ethyl acetate and concentrated nitric acid is added dropwise until the pH is equal to 3. 6 g of 3-methyl-6 nitrate are obtained. -

  
 <EMI ID = 90.1>

Example 25

  
In a manner analogous to that described in Example

  
 <EMI ID = 91.1>

  
 <EMI ID = 92.1>

  
 <EMI ID = 93.1>

  
tion of diethylamine).

Example 26

  
(a) 48 g of 3-methyl- <EMI ID = 94.1> are dropped dropwise

  
Example 8, suspended in 400 ml of dry tetrahydrofuran
(THF), in a suspension of 12 g of LiAlH. in 150 ml of dry THF. The reaction temperature is maintained at 25-30 [deg.]. At the end of the reaction, the suspension is maintained for 1 hour at room temperature and the excess LiAlH is destroyed. by addition of ethyl acetate and water.

  
 <EMI ID = 95.1> thiazole, prepared as described in Example 8, in 250 ml of dry THF. The suspension is stirred for 2 hours at room temperature and then 25 ml of water is slowly added. The suspension is then filtered and the filtrate is concentrated to obtain

  
 <EMI ID = 96.1>

  
 <EMI ID = 97.1>

  
It is refluxed for 2 hours in 100 ml of

  
 <EMI ID = 98.1>

  
prepared as described, in one of the procedures of Example 26. The solution was then cooled and 50 ml of ether was added to obtain

  
 <EMI ID = 99.1>

  
 <EMI ID = 100.1>

Example 2 8

  
3.4 g of hydrochloride are introduced with stirring

  
 <EMI ID = 101.1>

  
written in Example 27, in a cooled solution of 3.5 g of sodium phenate in 100 ml of THF. After about 1 hour, the sodium chloride which precipitates is filtered off, the solvent is evaporated and: acidic water is added to the residue. The aqueous solution is extracted at pH 3-6 with chloroform. The pH is then raised to 7-7.5 and the aqueous solution is extracted again with chloroform. The extract is dried and the solvent is then evaporated to obtain 4 g of 3-methyl-6-phenoxymethyl-

  
 <EMI ID = 102.1>

  
ethyl ketone).

Example 29

  
Slowly added 3.4 g of 3-methyl-6-chloromethyl-

  
 <EMI ID = 103.1>

  
Stirring is continued for 1 hour at room temperature and for another hour at 40-50 [deg.]. We filter the sus- <EMI ID = 104.1> <EMI ID = 105.1>

  
 <EMI ID = 106.1>

  
5-6 with water and, after drying, it is evaporated. Ethyl acetate is added to the residue to form 4.5 g of 3-methyl6-morpholinomethyl-imidazo (2,1-b) thiazole, mp 203-204 [deg.] (Methyl ethyl ketone)

Example 30

  
A solution of 5 g of

  
 <EMI ID = 107.1>

  
dry chloroform, at 35 [deg.], in a solution of 15 ml of butyroyl chloride and 12 ml of pyridine in 75 ml of dry chloroform. The resulting solution was stirred for 1 hour at room temperature and then filtered. The filtrate was concentrated by evaporation. The rest obtained is dissolved in absolute ethanol and a stream of dry hydrochloric acid is bubbled through the solution to obtain 4.5 g of 3-methyl-6-butyroxymethylimidazo (2,1-b) thiazole hydrochloride, with a melting point of 126-128 [deg.].

Example 31

  
A solution of 5 g of 3-methyl-6-hydroxymethyl-imidazo (2,1-b) thiazole in 100 ml of dry chloroform is dropped at room temperature in a solution of 20 ml of p-chlorobenzoyl chloride and 12 ml of pyridine in 75 ml of dry chloroform. The solution is stirred for 30 minutes at room temperature and filtered. The filtrate is concentrated in vacuo, the resulting residue is dissolved in isopropanol and bubbled. a stream of dry hydrochloric acid in the solution to obtain 6 g of 3-methyl-6-p-chlorobenzoyloxymethyl-imidazo (2,1-b) thiazole hydrochloride, with a melting point of 198-199 [deg. ].

Example 32

  
15.8 g of 2-mercapto-4 (5) -carbomethoxy-imidazole are suspended in a solution of 15.8 g of bromomethyl

  
ethyl ketone (which is prepared by bromination of methyl ethyl ketone in the presence of one equivalent of potassium chlorate in

  
some water ; melting point 75-80 [deg.] / 60 mm Hg; 103-105 [deg.] / 150

  
mm Hg) in 100 ml of absolute ethanol. The resulting suspension is stirred for 1 hour and then allowed to stand overnight at room temperature. The solvent is then evaporated off.

  
 <EMI ID = 108.1>

  
a 5% aqueous solution of sodium carbonate until a pH of 6.5 is obtained. The solution is extracted with chloroform and then the chloroform is evaporated to obtain 23 g of 4 (5) -carbo-

  
 <EMI ID = 109.1>

  
treat this compound at reflux for 5 hours in 230 ml of phosphorus oxychloride. The solvent is then evaporated off, ice water is added to the residue and the solution is neutralized with

  
 <EMI ID = 110.1>

  
 <EMI ID = 111.1>

  
ethyl) ,.

  
 <EMI ID = 112.1>

  
 <EMI ID = 113.1>

  
thoxyimidazole in a solution of 16.5 g of bromomethyl propyl ketone (which is prepared by bromination of methyl propyl ketone in the presence of one equivalent of potassium chlorate in water; boiling point 88- 94 [deg.] / 50 mm Hg) in 100 ml of absolute ethanol. The suspension is then stirred for 2 hours at room temperature and the resulting solution is allowed to stand overnight. The solvent is then evaporated off. The residue obtained is dissolved in water and then neutralized with a 5% aqueous solution of sodium carbonate. The solution is then extracted with chloroform and the chloroform is evaporated to obtain

  
 <EMI ID = 114.1>

  
 <EMI ID = 115.1>

  
'- This oil is refluxed for 3 hours in

  
 <EMI ID = 116.1>

  
vacuum, ice water is added and the resulting solution is neutralized with sodium carbonate, then extracted with chlorofor-

  
 <EMI ID = 117.1>

  
 <EMI ID = 118.1>

  
(absolute ethanol).

  
 <EMI ID = 119.1>

  
 <EMI ID = 120.1> <EMI ID = 121.1>

  
 <EMI ID = 122.1>

  
acétcnylthio) -imidazole precipitates and is separated by filtration. After neutralization of the salt, 19 g of the free base are obtained; melting point 110-111 [deg.] (ether).

  
The aforementioned base is refluxed for 12 hours in 190 ml of phosphorus oxychloride (the cyclization reaction is not complete and a certain amount of the starting material can be found at the end of the reaction). The solvent is evaporated off in vacuo, the remainder is dissolved in ice-water and the resulting solution is neutralized with sodium carbonate, then extracted with chloroform. The remainder obtained after evaporation of the solvent is chromatographed on neutral aluminum oxide and eluted with a mixture (20/80) of chloroform and petroleum ether.

  
 <EMI ID = 123.1>

  
imidazo (2,1-b) thiazole, melting point 134-135 [deg.].

Example 35

  
Stirred for 2.5 hours at room temperature a solution of 15.8 g of 2-mercapto-4 (5) -carbomethoxy-imidazole and 22 g of LJ-bromo-acetophenone [which is prepared as described in Zhuk.Obshch.Khim 33, 1135 (1963)] in 100 ml of absolute ethanol. 30 g of hydrobromide are separated by filtration

  
 <EMI ID = 124.1>

  
The free base, crystallized in acetone, is treated under reflux for 5 hours in 250 ml of phosphorus oxychloride. The solvent is evaporated off in vacuo. The residue obtained is dissolved in iced water, the solution is neutralized with sodium bicarbonate until a pH of 6 is obtained and then extracted with chloroform. The extract was dried and the solvent evaporated to give 21 g of 3-phenyl-6-carbomethoxy-imi-.

  
 <EMI ID = 125.1>

Example 36

  
Stirred for 2 hours at room temperature, a solution of 15.8 g of 2-mercapto-4 (5) -carbomethoxy-imidazole

  
 <EMI ID = 126.1>

  
bromination of 17 g of p-chloroacetophenone in dioxane / ether, 1/2) in 150 ml of absolute ethanol. We then add 200 ml <EMI ID = 127.1>

  
(p-chloro-phenacylthio) -imidazole.

  
30 g of the free base obtained from the aforesaid hydrobromide are treated at reflux for 10 hours in 250 ml of phosphorus oxychloride. The solvent is then evaporated in vacuo, chloroform and ice are added to the residue and sodium carbonate is slowly added to the solution until the pH is 7. The layer is separated with chloroform, dried and evaporated to obtain. 17 g of 3-p-chlorophenyl-6-carbomethoxy-imidazo (2, lb) thiazole, mp 229-230 [deg.] (Decomposition) (methanol).

Example 37

  
A solution of 15.8 g of 2-mercapto-4 (5) -carbomethoxy-imidazole and 29.7 g of 'W-bromo-p-phenyl-acetophenone (which we prepare by

  
 <EMI ID = 128.1>

  
in 400 ml of absolute ethanol and 250 ml of dry methylene chloride. 37 g of 4 (5) -carbomethoxy-2- (pphenylphenacylthio) -imidazole hydrobromide are obtained.

  
29 g of the free base obtained from this hydrobromide are treated under reflux for 7 hours in 300 ml of phosphorus oxychloride. The solution is then treated as described in Example 36 to form 22 g of 3-p-phenyl-phenyl-6carbomethoxy-imidazo (2, 1-b) thiazole, melting point 186-
188 [deg.] (Acetonitrile).

Example 38

  
Stirred for 2 hours at room temperature,

  
a solution of 15.8 g of 2-mercapto-4 (5) -carbomethoxy-imidazole

  
 <EMI ID = 129.1>

  
J.O.C., 11, 21 (1946)] in 150 ml of absolute ethanol. We obtain
25 g of 4 (5) -carbomethoxy-2-naphtacylthio-imidazole hydrobromide. This salt is neutralized to obtain 21 g of the free base, with a melting point of 162-163.5 [deg.] (Absolute ethanol). The base is refluxed for at least 36 hours in 200 ml of phosphorus oxychloride and the solution is then treated in a manner similar to that described in Example 36 to give

  
 <EMI ID = 130.1>

  
with a melting point of 187-188 [deg.].

  
:at 8.......

  
 <EMI ID = 131.1>

  
15.8 g of 2-mercapto-4 (5) -carbo- are suspended

  
 <EMI ID = 132.1>

  
furyl ketone (which is prepared by bromination of methyl-α-furyl ketone in dioxane / ether) in 150 ml of absolute ethanol and then the solution is stirred for 2 hours at room temperature to obtain 26 g of the hydrobromide. 4 (5) -carbomethoxy-2-
(a-furacylthio) -imidazole. After neutralization, 20 g of the free base are obtained, with a melting point of 139-141 [deg.] (Ethyl acetate).

  
The base is refluxed for 12 hours in 200 ml of phosphorus oxychloride. The solvent is then evaporated off in vacuo, the remainder dissolved in water and the 3- (2'-furyl) -6-carbomethoxy-imidazo (2,1-b) thiazole hydrochloride is filtered off. After neutralization, the free base is obtained, with a melting point of 169-170 [deg.] (Methyl ethyl ketone).

Example 40

  
15.8 g of 2-mercapto-4 (5) -carbomethoxy-imidazole are suspended in a solution of 20.5 g of W-bromomethyla-thienyl-ketone (which is prepared by bromination of methyl-athenyl- ketone in dioxane / ether) in 150 ml of absolute ethanol. The suspension was then stirred for 2 hours and then allowed to stand overnight at room temperature to obtain 26 g of 4 (5) -carbomethoxy-2- (α-thienacylthio) -imidazole hydrobromide.

  
The salt is dissolved in water, the solution is neutralized with sodium carbonate and extracted with chloroform. The extract is evaporated to obtain 22 g of the free base, melting point 125-126 [deg.] (Ethyl acetate).

  
The base is refluxed for 10 hours in 200 ml of phosphorus oxychloride. The solvent is then evaporated off in vacuo. The remainder is dissolved in ice water, the resulting solution is neutralized with sodium carbonate and extracted with chloroform. The solvent is evaporated to obtain 17.5 g of 3-

  
 <EMI ID = 133.1>

  
melting point of 161.5-163.0 [deg.] (absolute ethanol).

Example 41

  
15.8 g of ambient 2-mercapto-4 (5) -carbomethoxy-imi- <EMI ID = 134.1> are dissolved. The solvent is evaporated off, water and chloroform are added to the residue and the resulting solution is neutralized with sodium carbonate. After extraction with chloroform, drying, de-

  
 <EMI ID = 135.1>

  
 <EMI ID = 136.1>

  
This compound is refluxed for 2 hours in
360 ml of phosphorus oxychloride. The solvent is evaporated off and water and chloroform are added to the residue. The solution is neutralized with sodium carbonate and then extracted with

  
 <EMI ID = 137.1>

  
 <EMI ID = 138.1>

  
mp 187..189 [deg.] (ethyl acetate).

Example 42

  
Stirred for 24 hours at room temperature

  
a solution of 15.8 g of 2-mercapto-4 (5) -carbomethoxy-imidazole and 20.9 g of ethyl bromoacetoacetate in 250 ml of acetonitrile. After decolorization, the solvent is evaporated off and the mixture is dissolved. remains in a mixture of chloroform and water; sodium carbonate is then added until a pH of 7.5 is obtained. The aqueous phase is extracted several times with chloroform and the chloroform phase is sometimes extracted with water. The chloroform extracts are combined, dried, then the solvent is

  
 <EMI ID = 139.1>

  
ethyl thioacetoacetate.

  
The oil is refluxed for 15 minutes in 180 ml of phosphorus oxychloride. The solvent is evaporated off in vacuo, the residue is dissolved in water and the resulting solution is neutralized with sodium bicarbonate, then extracted with chloroform. The extract is dried with chloroform, the solvent is evaporated off and the residue obtained is dissolved in a mixture of benzene-ether. The solution is concentrated to form 14 g of 6-carbomethoxy-imi-

  
 <EMI ID = 140.1>

  
152-154 [deg.].

Example 43

  
Stirred for 24 hours at room temperature, a solution of 15.8 g of 2-mercapto-4 (5) -carbomethoxy-imidazole <EMI ID = 141.1>

  
4 mm Hg) in 100 ml of absolute ethanol. We separate by filtration

  
 <EMI ID = 142.1>

  
and the residue is dissolved in a mixture of water-chloroform. The solution is neutralized with sodium carbonate and extracted with chloroform. The chloroform is evaporated to obtain 11 g of

  
 <EMI ID = 143.1>

  
 <EMI ID = 144.1>

  
The compound is refluxed for 4 hours in
110 ml of phosphorus oxychloride. The solvent is evaporated off. The remainder obtained is dissolved in ice water and the solution is neutralized with sodium carbonate to give 10.5 g of 2-

  
 <EMI ID = 145.1>

  
sion of 155-156 [deg.] (methyl ethyl ketone):

Example 44

  
Stirred for 2 hours at room temperature a

  
 <EMI ID = 146.1>

  
15.1 g of α-bromoethyl methyl ketone (which is prepared in a manner analogous to that described in Example 32; boiling point 87-88 [deg.] / 150 mm Hg) in 120 ml of absolute ethanol, then left to stand overnight. The solution is then evaporated, the residue obtained is dissolved in water and the solution is neutralized with sodium carbonate, then extracted with chloroform. The chloroform is evaporated to give 23 g of 4 (5) -carbomé

  
 <EMI ID = 147.1>

  
This compound is refluxed for 3 hours in
230 ml of phosphorus oxychloride. The solvent is evaporated off, the remainder is dissolved in ice-water and the solution is neutralized with sodium carbonate to obtain 17 g of 2,3-dimethyl-6-carbomethoxy-imidazo (2,1-b) thiazole, with a melting point of 180-181 [deg.] (absolute ethanol).

Example 45

  
The following is carried out: for 2 hours at room temperature a suspension of 15.8 g of 2-mercapto-4 (5) -carbomethoxy-imidazole in a solution of 16.5 g of a-bromopropyl methyl ketone
(which is prepared in a manner analogous to that described in Example 33; boiling point 76-82 [deg.] / 50 mm Hg) in <EMI ID = 148.1>

  
the water. The solution is neutralized with sodium carbonate and extracted with chloroform. The extract is evaporated to obtain

  
 <EMI ID = 149.1>

  
melting point 105-106 [deg.] .. '.

  
The compound is refluxed for 2.5 hours in 200 ml of phosphorus oxychloride. The solution is evaporated, the remainder is dissolved in ice-water, the solution obtained is neutralized with sodium carbonate and extracted with chloroform. The solvent is evaporated off to obtain an oil which,

  
 <EMI ID = 150.1>

  
2-isoamyl-3-methyl-6-carboethoxy-imidazo (2,1-b) thiazole

Example 46

  
Stirred for 1 hour at room temperature, a solution of 15.8 g of 2-mercapto-4 (5) -carbomethoxy-imidazole and

  
23.4 g of α-bromobenzyl methyl ketone in 150 ml of absolute ethanol. The solvent is separated off by distillation and the remainder is dissolved in water. The solution is neutralized with sodium carbonate and the solution is removed. chloroform extract. The extract is dried and the chloroform is evaporated to give 38.5 g of an oil which is

  
 <EMI ID = 151.1>

  
The oil is refluxed for 1 hour in 200 ml of phosphorus oxychloride and the solvent is then evaporated in vacuo. The remainder is dissolved in ice water and sodium bicarbonate is added to the resulting solution until the pH is 7.5. The solution is extracted with chloroform. The extract is dried and evaporated to form 17 g of 2-phenyl-3-methyl-6-carbomethoxyimidazo (2,1-b) thiazole, with a melting point of 155-157 [deg.] (Acetate d ' ethyl).

Example 47

  
A solution of 15.8 g of 2-mercapto-4 (5) -carbomethoxy-imidazole and 17.7 g of a-bro- <EMI ID = 152.1> is heated at 80 ° C. for 1 hour.

  
in water. The resulting solution is neutralized with sodium carbonate and extracted with chloroform. the extract is dried, the solvent is evaporated and the remainder is chromatographed on an alumina column to obtain 14.5 g of 2-carbomethoxy-imidazo
(2,1-b) -5,6,7,8-tetrahydro-benzothiazole, with a melting point of
97-99 [deg.] (Ether / petroleum ether mixture).

Example 48

  
0.5 g of NaBH4 is slowly introduced into a stirred solution of 5.5 g of 4 (5) -carbomethoxy-2-acetonylthio-imidazole
(which is prepared as described in Example 8b) in 60 ml of methanol. The temperature is maintained at 5-10 [deg.]. The solution is stirred for 1 hour at this temperature, then the solvent is evaporated off. Water is added to the remainder and the solution is neutralized.

  
 <EMI ID = 153.1>

  
Bomethoxy-2 - (&#65533; -hydroxypropylthio) -imidazole, melting point 153-154 [deg.].

  
This compound is refluxed for 2 hours in

  
55 ml of phosphorus oxychloride, and the residue obtained after evaporation of the solvent is dissolved in ice water. The solution obtained is neutralized with sodium carbonate and extracted with chloroform. The extract is evaporated to give 3.2 g of 3-methyl-6-carbomethoxy-imidazo (2,1-b) -2,3-dihydrothiazole, with a melting point of 94-95 [deg.] ( ether).

Example 49

  
Reflux for 2 hours in 25 ml of 10% NaOH, 4.5 g of 2,3-dimethyl-6-carbomethoxy-imidazo (2,1-b) thiazole (prepared as described in Example 44) . The resulting solution is cooled to 40 [deg.] And acetic acid is allowed to drop into the solution dropwise until the pH is 5. The solution is then cooled to obtain, after filtration, 4.1. g of 2,3-dimethyl-imidazo (2,1-b) thiazole-6-carboxylic acid, melting point 260-261 [deg.].

Example 50

  
Refluxed for 2 hours in 5 ml of 10% NaOH, 1.5 g of 2-ethyl-3-methyl-6carbomethoxy-imidazo (2,1-b) thiazole (obtained as described in Example 45) . We treat the solution obtained in the same way as according to 1

  
 <EMI ID = 154.1>

  
carboxylic, with a melting point of 243-245 [deg.] C.

Example 51

  
Refluxed in 50 ml of ethanol, 2.1 g of 2-ethyl-3-methyl-imidazo (2,1-b) thiazole-6-carboxylic acid, obtained as described in Example 50, and a solution of 1.2 g of 2-amino-2- (hydroxymethyl) -1,3-propanediol in 10 ml of ethanol is added. The solvent is then evaporated off to give 3 g of 2 '- (hydroxymethyl) - 2-ethyl-3-methyl-imidazo (2,1-b) thiazole-6-carboxylate.

  
 <EMI ID = 155.1>

  
(isopropanol).

Example 52

  
 <EMI ID = 156.1>

  
 <EMI ID = 157.1>

  
as described in Example 50, and a solution of 0.75 g of triethanolamine in 5 ml of ethanol is added to the solution. The solvent is then evaporated off and. an oily salt is obtained which is triethanolammonium 2-ethyl-3-methyl-imidazo (2,1-b) thiazole-6-carboxylate.

Example 53

  
 <EMI ID = 158.1>

  
thiazole-6-carboxylic acid (prepared as described in Example 49) to a solution of 3.3 phosphorus pentachloride in 70 ml of dry methylene and the resulting solution is refluxed for 3 hours. After evaporating the solvent in vacuo, the residue is dissolved in 100 ml of absolute ethanol and the solution is then treated under reflux for 24 hours. The solvent is then evaporated off and the residue is dissolved in water, then the sodium is neutralized.

  
 <EMI ID = 159.1>

  
ration to dryness, 2.1 g of 2,3-dimethyl-6-carbo-

  
 <EMI ID = 160.1>

  
(acetone),

Example 54

  
 <EMI ID = 161.1>

  
 <EMI ID = 162.1>

  
 <EMI ID = 163.1>

  
 <EMI ID = 164.1>

  
100,000 tablets are prepared using the following substances:

  

 <EMI ID = 165.1>


  
The tablets are prepared as follows. Substances A and B are granulated together. Then, compound C is added which gives a wet granulated mixture. This mixture is dried and then ground. The compounds D are then introduced into the preceding mixture and the tablets are prepared from the final mixture obtained.

Example 56

  
100,000 long-acting tablets are prepared using the following substances:

  

 <EMI ID = 166.1>


  
The tablets are prepared as follows. Substances A and B are granulated together. The resulting mixture is dried and then ground. The ground mixture is mixed with the substances C. The tablets are prepared from the mixture thus obtained.

  
 <EMI ID = 167.1>

  
Some of the new compounds according to the present invention were tested on diabetic rats treated with alloxan (blood glucose concentration of 250-450 mg /
100 ml). In the trial, a dose of
200 mg / kg and then a sensitivity-dose curve was established.

  
The concentration of glucose in the blood was determined initially, then after 5 and after 24 hours following oral administration. In some cases, a time-sensitivity curve was determined at 0-3-5-8-24 hours.

  
The influence of the products on hyperglycemic glucose-treated rats and on normal rats during oral administration or administration into the peritoneum, was also determined for certain compounds. The concentration of glucose in the urine was also checked, and in many cases general pharmacological "screening" was followed.

  
Results are shown in Tables I-V, where

  
 <EMI ID = 168.1>

  
of blood (mg / 100 ml) during "n" experiments at the specified time.

  
quée and:

  

 <EMI ID = 169.1>


  
formula in which C is the mean concentration of glucose in the starting blood

  
All the compounds are compounds of formula I and the substituents A, B, C and D are those which have been presented for this same formula.

  
 <EMI ID = 170.1>

  
Diabetic rats, treated with alloxan
 <EMI ID = 171.1>
  <EMI ID = 172.1>

  

 <EMI ID = 173.1>

TABLE II

  
Diabetic rats, treated with glucose

  

 <EMI ID = 174.1>

TABLE III

  
Normal rats

  

 <EMI ID = 175.1>


  
I.P. = in the peritoneum <EMI ID = 176.1>

  

 <EMI ID = 177.1>

TABLE V

  
 <EMI ID = 178.1>

  
 <EMI ID = 179.1>

  

 <EMI ID = 180.1>
 

  
 <EMI ID = 181.1>

  
 <EMI ID = 182.1>

  

 <EMI ID = 183.1>


  
 <EMI ID = 184.1>

  
 <EMI ID = 185.1>

  
 <EMI ID = 186.1>

  
 <EMI ID = 187.1>

  
inorganic ion, for example sodium or calcium, or an ion

E "

  
 <EMI ID = 188.1>

  
hydrogen or hydroxyalkyl, alkyl, alkylamino (optionally substituted), alkylcarbalkoxy or alkylcarboxy radicals iden-

  
 <EMI ID = 189.1>

  
or not, a cyclic amine or a hydroxylamine or hydrazine group; X denotes a halogen atom or else a hydroxy, mercapto, alkoxy, aryloxy or aralkoxy radical, or else a.grou-

  
 <EMI ID = 190.1>

  
 <EMI ID = 191.1>

  
do not denote one of the preceding groups represent a hydrogen atom or an alkyl (straight or branched), aryl, aralkyl or heterocyclic radical: C and D can form, with the bond which unites them, a cycloaliphatic radical; the dashed line denotes either 2 hydrogen atoms or a C = C bond; as well as the quaternary ammonium salts and the pharmacologically acceptable acid addition salts of the above compounds, excluding 2-carbomethyl-3,5-dimethyl6-carboethoxy-imidazo (2,1- b) thiazole and 3,5-dimethyl-6-carboethoxy-imidazo (2,1-b) thiazole, except when the latter two compounds are used as purely pharmaceutical compounds.

  
 <EMI ID = 192.1>


    

Claims (1)

according to Claim 1, characterized in that the alkyl radical preferably contains from 1 to 8 carbon atoms, the radical <EMI ID = 193.1> <EMI ID = 194.1> titled or not. 3. Imidazo (2,1-b) thiazoles according to claim 1, characterized in that they more particularly correspond to formula (Ia): <EMI ID = 195.1> in which A ′ represents COOR ″, R ″ denoting a hydrogen atom, a hydroxyalkylammonium cation or an inorganic cation, or else a lower alkyl group, A ′ possibly representing <EMI ID = 196.1> optionally substituted nyl; C 'denotes methyl, tertiary butyl or an optionally substituted phenyl group; and D 'denotes hydrogen or an alkyl group. 4. Imidazo (2, 1-b) thiazoles according to any one of the preceding claims, characterized in that they consist of one of the following compounds: 6-carbomethoxy-imida- <EMI ID = 197.1> <EMI ID = 198.1> phenyl-imidazo (2,1-b) thiazole, 5-methyl-6-carboethoxy-imidazo (2,1-b) thiazole, 3-methyl-6-carbomethoxy-imidazo (2, lb) thiazole, 3-methyl-6-carbomethoxy-imidazo (2,1-b) thiazolium methyl iodide, 3-methyl-imidazo (2,1-b) thiazol-6carboxylic acid, 3-methyl-6-carboethoxy-imidazo (2,1-b) thiazole, 3-methyl-6-carbopropoxy-imidazo (2 , 1-b) thiazole, 3-methyl-6-carboisopropoxy-imidazo (2,1-b) thiazole, 3-methyl-6-carbobutoxy-imidazo (2,1-b) thiazole, 3-methyl- 6-carboisobutoxy-imidazo (2, lb) thiazole, 3-methyl-6-sec-carbobutoxy-imidazo (2,1-b) thiazole, 3-methyl-6-carbooctanoxy-imidazo (2,1-b) thiazole, 3-methyl-6carbocyclohexanoxy-imidazo (2,1-b) thiazole, 3-methyl-6-ethylcarboxamide-imidazo (2,1-b) thiazole, 3-methyl-6-diethylcarboxa- <EMI ID = 199.1> zo (2,1-b) thiazole, 3-methyl-6-chloromethyl-imidazo (2,1-b) thia- <EMI ID = 200.1> <EMI ID = 201.1> methoxy-imidazo (2,1-b) thiazole, 3- (2'-furyl) -6-carbom6thoxy- <EMI ID = 202.1> <EMI ID = 203.1> <EMI ID = 204.1> the general formula 00 as defined in claim 1, excluding 2-carbomethyl-3,5-dimethyl-6-carboethoxy-imidazo (2,1-b) thiazole and 3,5-dimethyl-6-carboethdxy-imidazo (2, i-b) thiazole, characterized in that an a-halocarbonyl derivative of the general formula (II) <EMI ID = 205.1> wherein C and D have the meaning given in claim 1, Y denotes a halogen, and the carbonyl group may be protected by an easily separable group, is condensed with a 2-mercapto-imidazole derivative of the general formula ( III) <EMI ID = 206.1> wherein A and B have the meaning given in claim 1, to form a thiocarbonyl derivative of general formula (IV): <EMI ID = 207.1> wherein A, B, C and D have the meanings given in claim 1, and, if the carbonyl group of the halocarbonyl derivative of the general formula (II) has been protected, applying to the compound obtained a reaction of acid separation, the thiocarbonyl derivative of general formula (IV) being converted into the compound of general formula (I) with an appropriate reagent by cyclization and dehydration using methods known per se. 6. Process for preparing imidazo (2,1-b) thiazoles of general formula (I) as defined in claim 1, .caractérisé in that an α-halocarbonyl derivative of general formula (V): <EMI ID = 208.1> in which A and B have the meaning given in claim 1 and Y denotes a halogen atom, is condensed with a 2-amino-thiazole derivative of the general formula (VI): <EMI ID = 209.1> wherein C and D have the meanings given in claim 1. 7. Process for preparing imidazo (2, lb) thiazoles of general formula (I) as defined in claim 1, in which at least one of the substituents A, B, C and D denotes a radical (CH2 ) 2COOR, in which R denotes an inorganic cation <EMI ID = 210.1> in which E, E 'and E "may denote identical or different hydrogen or hydroxyalkyl, alkyl, alkylamino (optionally substituted), alkylcarbalkoxy or alkylcarboxy radicals, characterized in that the acid imidazo (2,1-b) The corresponding carboxylic thiazole is dissolved in an inert solvent and a solution of the appropriate base is added to the resulting solution. 8. A method according to any one of claims <EMI ID = 211.1> obtained is converted into another compound (I) by a method known per se. 9. A process according to any one of claims 5 to 8, characterized in that the acid addition salts of the compounds corresponding to the general formula (I) are prepared by reacting such a compound with the appropriate acid corresponding. 10. A process according to any one of claims 5 to 8, characterized in that the quaternary ammonium salt of a compound of the general formula (I) is prepared by reacting such a compound with an appropriate ester of l. desired acid. 11. Pharmaceutical compositions for reducing blood sugar level in patients suffering from diabetes, characterized in that they contain, as active substance, <EMI ID = 212.1> line (I), these compositions being in the form of tablets, lozenges, capsules, ampoules, powders, granules, solutions, suspensions, emulsions, injections, suppositories, etc., and possible <EMI ID = 213.1> appropriate agents, as well as optionally other desirable therapeutic compounds. 12. Thiocarbonyl derivatives, characterized in that they correspond to general formula (IV): <EMI ID = 214.1> wherein A, B, C and D have the meaning given in claim 1, excluding 2-thioacetonyl-4 (5) -carboethoxy-5 (4) -methyl-imidazole. 13. Derivatives according to claim 12, characterized in that they consist of the compounds of the group below: <EMI ID = 215.1> taldehyde, 2- [4 (5) -carboethoxy-5 (4) methylimidazolyl] -thioacetaldehyde diethyl acetal, 4 (5) -carbomethoxy-2-acetonylthio- <EMI ID = 216.1> 4 (5) -carbomethoxy-2-phenacylthio-imidazole, 4 (5) -carbomethoxy2- (p-phloro-phenacylthio) -imidazole, 4 (5) -carbomethoxy-2- (pphenyl-phenacylthio) -imidazole, 4 (5) -carbomethoxy-2-naphtacylthio-imidazole, 4 (5) -carbomethoxy-2-furacylthio-imidazole, 4 (5) -carbomethoxy-2-thienacylthio-imidazole, a-oxo- [4 (5 ) Ethyl) -carbomethoxy-2-imidazolyl] -thiopropionate, ethyl [4 (5) -carbomethoxy-2-imidazolyl] -thioacetoacetate, 4 (5) -carbomé <EMI ID = 217.1> (a-methyl-acetonylthio) -imidazole, 4 (5) -carbomethoxy-2- (aethyl-acetonylthio) -imidazole and 4 (5) -carbomethoxy-2- (a-phenylacetonylthio) -imidazole. 14. New compounds, characterized in that they correspond to the general formula (VII): <EMI ID = 218.1> in which X denotes a hydroxy or carbalkoxy radical, and A, B, C and D have the meaning given in claim 1. <EMI ID = 219.1> corresponding to general formula (I), as described above, in particular in the Examples given, and / or as obtained by a process according to any one of Claims 5 to 10. 17. The thiocarbonyl derivatives corresponding to the general formula (IV), as described above, in particular in the Examples given. 18. The compounds corresponding to general formula (VII), as described above, in particular in the Examples given. 19. A method for reducing the blood sugar level in patients suffering from diabetes, characterized in that these patients are administered a composition comprising a therapeutically effective dose of a compound of the general formula (I ) or a composition according to claim 11.