CH628350A5 - Thiazole derivatives and anthelmintic composition containing them - Google Patents

Abstract

The new derivatives of 6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole or (m-aminotetramisole) are obtained by means of a process, one of the variants of which consists in reacting the d or dl form of 6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole with a suitable acid or its functional equivalent group as acylating agent and, when the racemic form of the starting thiazole is used, in optionally resolving the dl product so as to obtain the laevorotatory form. The compounds obtained have anthelmintic properties.

Description

** ATTENTION ** start of DESC field can contain end of CLMS **.

CLAIMS 1. Form I or form dl (racemic) of the compounds of formula: (I)

wherein R is a hydrogen atom or a methyl group, or the non-toxic acid addition salts of these compounds.

2. Compound according to Claim 1, characterized in that it is in the form of a hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, acetic, lactic, tartaric or citric acid salt.

3. Anthelmintic composition, characterized in that it contains as active substance a compound of formula (I) according to claim 1 or a non-toxic acid addition salt of this compound, and a non-toxic diluent or carrier.

The present invention relates to novel 6- (m-aminophenyl) -2,3,5,64etrahydro-imidazo-p, 1-b] 4hîazole (m-aminotetramisole) derivatives, a multi-variant process for obtaining them, and pharmaceutical compositions which contain them as anthelmintic agents for warm-blooded animals.

The invention provides Form I and Form dl (racemic) of compounds of the formula:

in which R is a hydrogen atom or a methyl group, and their non-toxic acid addition salts.

Representative examples of non-toxic acid addition salts include the salts of hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, acetic, lactic, tartaric and citric acids.

R is preferably a methyl group. The I forms are more active than the dl forms.

The compounds of the invention are prepared by various methods, among which the following are mentioned: 1) The compounds can be prepared by reaction of I or dl 6- (m-aminophenyl) -2,3,5,6-tetrahydro-imidazo- [2,1-b] -thiazole (maminotetramisole) of the formula:

with an acid of formula:

or with its functional equivalent as an acylating agent, for example an acid halide, an activated ester or a mixed anhydride of the compound of formula (111).

The preferred acid halides are the acid chloride and bromide. They can be prepared by conventional methods, for example by reaction of the free acid with thionyl chloride or respectively thionyl bromide.

The activated ester of choice is the succinimidoester of formula:

This compound can also be prepared by conventional operations, for example by reaction of the free acid with the N-hydroxysuccinimide in the presence of a dehydrating agent such as dicyclohexylcarbodiimide. Another activated ester of choice is the phthalimidoester.

Suitable mixed anhydrides correspond to the formula:

in which R1 is an alkyl or alkoxy group having 1 to 6 carbon atoms, in particular a tert-butyl or isobutoxy group. They can be prepared by conventional operations, for example by reaction of the free acid with the alkanoyl chloride or respectively the corresponding alkyl chloroformate, for example pivaloyl chloride or isobutyl chloroformate, in the presence of a base such as triethylamine.

The m-aminotetramisole dl- (racemic) or 1 should be used as starting material depending on whether it is desired to obtain respectively the dl form or the form 1 of the product (I). Dl-m-aminotetramisole can be resolved into its dextrorotatory and levorotatory isomers by the methods described in the United States patents. Nos 3673205 and 3463786. In addition, the formal of the product (I) can be obtained by splitting the form dl into its dextrorotatory and levorotatory antipodes. For this purpose, the method described in British Patent No. 1402689 can be used.

Although the compounds of the invention can be prepared by reacting the compound (II) with the free acid (III), the most advantageous operation consists in using the acid in the form of its chloride.

When using the acid (III) in its free form, the reaction should generally be carried out in the presence of a dehydrating agent such as dicyclohexylcarbodiimide.

In a conventional operation involving the reaction of the compound (11) with a chloride of acid (III), the compound (II) is dissolved in an aqueous solvent such as an aqueous solution of methanol, the pH is lowered for example to By adding dilute hydrochloric acid, the mixture is cooled and the acid chloride is added cautiously. After stirring the reaction mixture at room temperature for several hours, it can be acidified with dilute hydrochloric acid and washed with a suitable solvent such as methylene chloride. After separation, the aqueous phase can be made alkaline, for example at a pH equal to 8, by adding a suitable base such as a concentrated aqueous solution of ammonia, and extracted with a suitable solvent such as methylene chloride After separation, the aqueous phase can be made alkaline, for example at a pH equal to 8, by adding a suitable base such as a concentrated aqueous solution of ammonia, and extracted with a suitable solvent such as sodium chloride. methylene.

After separation, the organic phase can be washed with water at pH

equal to 6 to remove any unreacted m-aminotetramisole, and it can be evaporated to dryness under reduced pressure leaving the desired product. If desired, the product can be purified by recrystallization from a suitable solvent such as acetone or ethyl acetate or by chromatography on silica in methylene chloride containing a small amount of methanol. If the purified product is not in a form of acceptable crystallinity, it can be taken up in ethanol, and an excess of hydrochloric gas in the ethanolic solution to be passed to convert the free base into its hydrochloride. The crystalline hydrochloride can be collected by concentrating the resulting solution under reduced pressure and, if desired, it can be recrystallized from a suitable solvent such as ethanol or isopropanol.

As an alternative, the hydrochloride of the product can be prepared directly as follows: the compound (II) is dissolved in a suitable solvent such as an aqueous solution of acetone, the pH is lowered for example to 5 by addition of dilute hydrochloric acid, the mixture is cooled and the acid chloride of compound (III) is added slowly, for example over a period of 30 min. The resulting mixture is then stirred at low temperature, eg, 10 ° C, for 2 h to 1 h and the desired hydrochloride precipitate is filtered, washed with a suitable solvent such as acetone, and dried.

2) The compounds of the invention can also be prepared by cyclization of a compound of formula:

wherein X is chlorine or bromine or a hydroxy group and Y is a hydrogen atom or a C 1 -C 4 alkanoyl group to provided that Y is a hydrogen atom when X is a group hydroxy.

The preferred alkanoyl group is the acetyl group. Y is preferably a hydrogen atom. X is preferably an atom of chlorine or bromine.

Cyclization of compounds of formula (VI), in which X is a chlorine or bromine atom and Y is a hydrogen atom or an alkanoyl group, can be carried out by heating these compounds with an excess of a base which does not hydrolyze the bond amidic, for example an aqueous solution of potassium carbonate, triethylamine or pyridine, or a dilute solution of ammonia. The operation is carried out, for example, at 30-100 C for 1 to 3 h. Chloroform is usually present in addition to the base, the chloroform phase being separated after the reaction and evaporated to dryness to give the desired product. This product is the dl (racemic) form which can optionally be resolved by a conventional operation so as to obtain form 1.

In general, compounds in the formula of which X is a chlorine or bromine atom are prepared by reacting corresponding compounds in which X is a hydroxy group or a C1-C4 alkanoyloxy group with a suitable halogenating agent, such as thionyl chloride or bromide. It is not essential to isolate the halogenated product; it can be cyclized in situ to the desired product, by reaction with the base.

Cyclization of compounds of formula (VI), in which X is a hydroxy group and Y is a hydrogen atom, can be carried out under mild dehydration conditions. Dicyclohexylcarbodiimide is a possible dehydrating agent.

The compounds of formula (VI) are generally obtained and cyclized in the form of their hydrochloric or hydrobromic acid salts.

The compounds of formula (VI) can be prepared by methods analogous to those of the prior art. A possible reaction scheme is indicated below.

3) The non-toxic acid addition salts can be prepared from the corresponding free base by conventional operations. The hydrochlorides can, for example, be prepared as described in 1 above.

The compounds of the invention can be administered alone, but they are generally administered in admixture with a non-toxic diluent or carrier, chosen having regard to the desired route of administration. For example, they can be administered orally in the form of aqueous solutions or as an admixture with animal feed or animal feed supplement. In parenteral administration, which is preferably effected subcutaneously or intramuscularly, the carrier may be an aqueous carrier such as water or isotonic saline or a non-aqueous carrier such as polyethylene glycol.

Parenteral administration of an aqueous solution is preferable and such solutions usually contain 1 to 20% by weight of the active compound.

Suitable dosages range from 0.5 to 20 mg of active ingredient per kilogram of body weight of the animal.

The compounds also work when administered dermally, the active compound being absorbed through the skin of the animal.

The compounds of the invention are particularly active against nematodes parasitizing the lungs, stomach and intestines of sheep, cattle and other domestic animals.

The invention therefore provides an anthelmintic composition containing form 1 or dl of a compound of formula (I) as defined above or of a non-toxic acid addition salt thereof, in combination with a non-toxic diluent or carrier.

The invention makes it possible to destroy helminths in an infected animal or human being, by administering to the animal or human being an anthelmintic amount of form 1 or form dl of a compound of formula ( I) as defined above, a non-toxic acid addition salt of this compound or an anthelmintic composition as defined above.

The invention is illustrated by the following examples, in which all temperatures are expressed in degrees centigrade.

Example 1: Part A: 5-Carboxy-3-methylisorhiazole acid chloride 1 g of 5-carboxy-3-methylisothiazole is refluxed with 20 ml of thionyl chloride for 1 hour. The reaction mixture is then evaporated to dryness under reduced pressure to remove the excess thionyl chloride. Toluene is then added and the mixture is again evaporated to dryness under reduced pressure to obtain 1.1 g of crude acid chloride which is used directly in the next step, without further purification.

Part B: dl-6- {m- (3-methylisothiazole-5-carboxamido) phenyl} - 2,3,5,6-tetrakydro-imidazo- [2,1-b] -thiazole It is acidified to a pH equal to 5 by adding 2N hydrochloric acid to a solution of 1.0 g of dl-6- (m-aminophenyl) -2,3,5,6 tetrahydro-imidazo- [2, Ib] -thiazole in aqueous methanol (7 ml of methanol / 3 ml of water) and cooled to 0 while maintaining it at this temperature, while adding in portions, over 10 min, the acid chloride prepared in part A (1.1 g ). The resulting mixture is stirred at 05 for 1 h, then at room temperature (255) for about 16 h. Then 5 ml of 2N hydrochloric acid are added and the solution washed with methylene chloride.

After separation, the aqueous phase is alkanilized to a pH equal to 8 by the addition of a concentrated aqueous solution of ammonia and it is extracted with methylene chloride. After separation, the organic phase is washed with water at a pH equal to 6 to remove all the uncombined imidazo [2,1-b] -thiazole used as raw material, it is dried over magnesium sulfate and evaporated to dryness under reduced pressure to obtain the desired product, namely 6-Im- (3-methylisothiazole-5-carboxymido) phenyl} -2,3,5,6-tetrahydro-imidazo- [2 , 1-b] -thiazole. The product is recrystallized from a 1: 1 mixture of acetone and ethyl acetate (yield 750 mg, melting point 168 ° C).

Analysis for C15H16N4OS2: Calculated: C 55.79 H 4.68 N 16.27% Found: C 55.21 H 4.55 N 16.20% Example 2: Part A: dl-6- {m- (isothiazole-5-carboxamido) phenyl} -2,3,5,6-tetranydro- imidazo-J2, 1-bJ-thiazole Following the procedure of part B of l Example 1, dl-6- (m- (isothiazole-5-carboxamido) pheny 2,3,5,6-tetrahydro-imidazo- [2,1-b] -thiazole, mp 170-172 ° C , from the acid chloride of 5-carboxyisothiazole and dl 6 (m-aminophenyl) -2,3,5,6-tétrahydro-imidazo- [2, 1 -b] -thiazole.

Analysis for C15H14N4OS2: Calculated: C 54.52 H 4.27 N 16.95% Found: C 53.71 H4.15 N 16.95% The acid chloride is prepared from 5-carboxyisothiazole and thionyl chloride by following a procedure identical to that of part A of Example 1.

Part B: Dl-6- (m- (isothiazole-5-carboxamidolphenyl) - 2, S, 5,6-tetrahydro-imidazo- [2,1-b] -thiazole monohydrochloride Excess hydrochloric gas is passed through a solution of dl-6- {m- (isothiazole-5-carboxamido) phenyl} -2,3,5,6-tetrahydro- imidazo- [2,1-b] -thiazole (5 g, prepared as in Part A above) in 120 ml of ethanol and the solution is concentrated under reduced pressure The desired monohydrochloride crystallizes in the solution and is isolated by filtration and recrystallized from water (yield 4.5 g; melting point 243-245 VS).

Analysis for ClsHI4N4OS2 HCl: Calculated: C 49.10 H 4.12 N 15.27% Found: C 49.26 H 4.06 N 15.87% Example 3: Dl-6- {m- (3-Methylisothiazole-5-carboxamldo) phenyl} .2,3,5,6-tetrnhya'o-imidaw- [2,1-bkthlazole monohydrochloride The above salt, melting at 275 " C is prepared as indicated in part B of Example 2 by the reaction of dl-6- {m (3-methylisothiazole-5-carboxamido) phenyl} -2,3,5,6-tetrahydro-imidazo- [2,1-b] -thiazole in ethanol with excess hydrochloric gas.

Analysis for ClH1N4OS2 HCl: Calculated: C 50.45 H 4.50 N 14.71% Found: C 50.59 H 4.70 N 14.36% Example 4: An aqueous composition which is suitable for administration by injection to humans or animals contains the following ingredients: - dl-6- (m- (3-methylisothiazole-5-carbox-amidolphenyl) -2,3 hydrochloride, 5,6-Tetrahydro-imidazo- [2, lb] -thiazole: up to 10% w / v.

- Methadioxole or polyethylene glycol 300: up to 50% by weight volume - Water: supplement to 100%.

The composition can be prepared by mixing the ingredients and can be administered in one or more doses.

Obviously, the amount of active ingredient varies depending on the dose response and the weight of the animal, but it is generally in the range of 0.5 to 20 mg / kg of body weight, for example equal to 2, 5 mg / kg.

Example 5: The administration of the compounds of the invention to animals can advantageously be carried out by incorporating these compounds into food mixtures. The typical dose used is 0.5 to 20 mg / kg of body weight per day, i.e. 250 mg to 10 g / d for cattle weighing 500 kg. Assuming that such an animal consumes 5 kg of nutritional supplement per day, this amount of active substance can be mixed with 5 kg of nutritional supplement.

The activity of the compounds in a systematic triple infection test in mice, against concurrent infection with Nematospiroides dubius, Syphacia obvelata and Hymenolepsis nana, can be determined as indicated below. Albino mice weighing 20 g are infected and treated according to the following method. Choosing the initial infection as day 0, mice are infected with 2000 H. nana eggs on day 0 and 100 N. dubius larvae on day 5, then cohabitated with a colony infected with Syphacia, for 4 d. The mice are then treated with the test compound in groups of four, once on day 14 or for three consecutive days 16, orally or subcutaneously. The mice were autopsied on day 19 and looked for worms. The results obtained were compared with those obtained in the case of the untreated infected control (12 animals per group).

For N. dubius, total counts are made and the activity is expressed by the percentage reduction. Infections by other parasites are evaluated from 0 to 3 for Syphacia and from 0 to 3 for H. nana and activity is expressed by comparing the average scores assigned to the groups. Polyethylene glycol is the conventional vehicle used in preparing test compounds for administration, while aqueous solutions are used for water soluble substances and matters insoluble in both polyethylene glycol and in water can be. incorporated in the ball mill in a 1% aqueous solution of Tween 80. The concentrations in milligrams / kg which are used can for example reach 12.5 mg / kg.

The activities of the compounds of the invention against hermit N. dubius, when using the above method, have the following values:

Dose (mg / kg) Compound Dose (mg / kg) 12.5 1 6.25 1 3.12 1 1.56 1 0.78 Product of example 1, reduction% (subcutaneous 100 95 96 76 ) Product of example 2, part A, reduction% (sub- 100 96 88 - - cutaneous route) Product of example 3, reduction% (sub- 100 100 100 82 58 cutaneous route)

Claims (3)

CLAIMS 1. Form I or form dl (racemic) of the compounds of formula: (I) wherein R is a hydrogen atom or a methyl group, or the non-toxic acid addition salts of these compounds. 2. Compound according to Claim 1, characterized in that it is in the form of a hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, acetic, lactic, tartaric or citric acid salt. 3. Anthelmintic composition, characterized in that it contains as active substance a compound of formula (I) according to claim 1 or a non-toxic acid addition salt of this compound, and a non-toxic diluent or carrier. The present invention relates to novel 6- (m-aminophenyl) -2,3,5,64etrahydro-imidazo-p, 1-b] 4hîazole (m-aminotetramisole) derivatives, a multi-variant process for obtaining them, and pharmaceutical compositions which contain them as anthelmintic agents for warm-blooded animals. The invention provides Form I and Form dl (racemic) of compounds of the formula: in which R is a hydrogen atom or a methyl group, and their non-toxic acid addition salts. Representative examples of non-toxic acid addition salts include the salts of hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, acetic, lactic, tartaric and citric acids. R is preferably a methyl group. The I forms are more active than the dl forms. The compounds of the invention are prepared by various methods, among which the following are mentioned: 1) The compounds can be prepared by reaction of I or dl 6- (m-aminophenyl) -2,3,5,6-tetrahydro-imidazo- [2,1-b] -thiazole (maminotetramisole) of the formula: with an acid of formula: or with its functional equivalent as an acylating agent, for example an acid halide, an activated ester or a mixed anhydride of the compound of formula (111). The preferred acid halides are the acid chloride and bromide. They can be prepared by conventional methods, for example by reaction of the free acid with thionyl chloride or respectively thionyl bromide. The activated ester of choice is the succinimidoester of formula: This compound can also be prepared by conventional operations, for example by reaction of the free acid with the N-hydroxysuccinimide in the presence of a dehydrating agent such as dicyclohexylcarbodiimide. Another activated ester of choice is the phthalimidoester. Suitable mixed anhydrides correspond to the formula: in which R1 is an alkyl or alkoxy group having 1 to 6 carbon atoms, in particular a tert-butyl or isobutoxy group. They can be prepared by conventional operations, for example by reaction of the free acid with the alkanoyl chloride or respectively the corresponding alkyl chloroformate, for example pivaloyl chloride or isobutyl chloroformate, in the presence of a base such as triethylamine. The m-aminotetramisole dl- (racemic) or 1 should be used as starting material depending on whether it is desired to obtain respectively the dl form or the form 1 of the product (I). Dl-m-aminotetramisole can be resolved into its dextrorotatory and levorotatory isomers by the methods described in the United States patents. Nos 3673205 and 3463786. In addition, the formal of the product (I) can be obtained by splitting the form dl into its dextrorotatory and levorotatory antipodes. For this purpose, the method described in British Patent No. 1402689 can be used. Although the compounds of the invention can be prepared by reacting the compound (II) with the free acid (III), the most advantageous operation consists in using the acid in the form of its chloride. When using the acid (III) in its free form, the reaction should generally be carried out in the presence of a dehydrating agent such as dicyclohexylcarbodiimide. In a conventional operation involving the reaction of the compound (11) with a chloride of acid (III), the compound (II) is dissolved in an aqueous solvent such as an aqueous solution of methanol, the pH is lowered for example to By adding dilute hydrochloric acid, the mixture is cooled and the acid chloride is added cautiously. After stirring the reaction mixture at room temperature for several hours, it can be acidified with dilute hydrochloric acid and washed with a suitable solvent such as methylene chloride. After separation, the aqueous phase can be made alkaline, for example at a pH equal to 8, by adding a suitable base such as a concentrated aqueous solution of ammonia, and extracted with a suitable solvent such as methylene chloride . After separation, the aqueous phase can be made alkaline, for example at a pH equal to 8, by adding a suitable base such as a concentrated aqueous solution of ammonia, and extracted with a suitable solvent such as methylene chloride . After separation, the organic phase can be washed with water at pH ** CAUTION ** end of field CLMS may contain start of DESC **.