IE43095B1 - Novel anthelmintic therapy - Google Patents

Abstract

To prepare 6-n-propoxybenzothiazole-2-methylcarbamates, 2-amino-6-n-propoxybenzothiazole is reacted with a compound ZCOOCH3, in which Z denotes an easily substitutable reactive group. This compound has an anthelmintic action.

Description

This invention relates to a novel benzothiazole derivative, to processes for its production and to its use ase an active anthelmintic agent in clinical and veterinary application.

According to the present invention there is provided the compound methyl-6-n-propoxy-benzothiazole-2-carbonate and pharmaceutically active compositions useful in combatting helminthiasis in mammals comprising said compound as active ingredient in combination with a suitable pharmaceutically acceptable carrier.

The invention also includes a process for preparing a pharmaceutically active composition useful for combatting helminthiasis in mammals, characterised in that methyl-6-n-propoxybenzothiazole-2-carbamate is admixed with a suitable pharmaceutically acceptable carrier and a method of combatting helminthiasis in mammals other than humans characterised in administering an aftthelmintically effective quantity of methyl-6-n-prOpoxybenzothiazole-2-carbamate.

Carbamate esters of benzothiazoles of the above type have been generally described in the prior art, e.g. in Swiss Patent No. 505.543, as herbicides or fungicides but the pharmaceutical activity, e.g. as an anthelmintic, has not been disclosed in the prior art.

Methyl-6-n-propoxybenzothiazole-2-carbamate which has the formula has, to our knowledge, never heretobefore been specifically disclosed and, accordingly, it is a novel compound.

The compound may be prepared according to known processes, e.g. as described in the abovementioned Swiss Patent No. 505.543.

The preferred methods are described under items 1 to 5 below:-21.

II +Z1COOCH3 III wherein Z^ is a reactive grouping such as halogen or an easily removable carbon containing residue.

Preferably the process is carried out in a basic solvent such as pyridine at a temperature between o°C and room temperature. The reactants are brought together in equimolar proportions whereby the reactant COOCH3 Is added slowly over an extended period of time. After completion of the admixture, the reaction mixture is stirred for a longer period of time, preferably over night and the desired product is then isolated according to techniques wellknown in the art. The purification is preferably carried out by recrystallization from appropriate alcohols. Al15 though pyridine is the preferred solvent for this reaction other solvents such as acetonitrile and triethylamine and mixtures of acetonitrile and pyridine may also be used.

Z2 and represent labile -SCH3, OCH3 or N(CH3)2. groupings such as -> I -3005 The reaction is preferably carried out by stirring and heating the reactants at reflux temperature in a suitable solvent such as ethanol, keeping the reaction mixture under an inert atmosphere, preferably nitrogen. 3.

Also this process is carried Out using standard techniques One preferred method comprises heating the thiourea compound in a suitable solvent such as chloroform at reflux temperature in the presence of bromine. Instead of heating, one may also irradiate the reaction mixture.

• I The isolation of the product is also performed according to standard procedures. The mixture is brought to room temperature, washed with aqueous Na2CO3, and aqueous NaCl and dried over sodium sulfate. The solvent is removed by evaporation to yield the desired product.

The intramolecular cyclization may also be accomplished by adding an aqueous solution of potassium ferricyanide to a stirred and moderately heated mixture of the thiourea compound, sodium hydroxide and water. After the addition of potassium ferricyanide is completed, potassium carbonate is added and stirring is continued. The -44309 reaction mixture is then extracted with a suitable solvent preferably chloroform. The extracts are dried over sodium sulfate and the solvent is evaporated to yield the desired product n-Propylation of methyl-6-hydroxybenzothiazole-2-carbamate, e.g 5 as follows :- The etherification is preferably carried out by heating a mixture of the methyl-6-hydroxybenzothiazole-2-carbamate, anhydrous potassium carbonate, n-propylbromide and a suitable solvent, e.g. acetone, at reflux temperature.

The solvent is then removed by distillation, and the residue is taken into water and filtered. The pure product is obtained by recrystallization from ethanol.

. A further process comprises reacting the corresponding benzothiazole-2-isocyanate of the formula or a reactive derivative thereof with methanol. The reaction is preferably carried out by stirring a mixture of the anhydrous reactants in a solvent such as an excess 20 of methanol, or benzene, at room temperature. The preferred reactive derivatives of the compound of formula X are those wherein the group -N=C=O is replaced by the grouping -NH-^-halogen. -509S The appropriate starting compounds in the above processes 1 to 5 may be obtained by techniques wellknown in the art. The 2-amino-benzothiazole of formula II may be obtained by cyclizing the appropriate thiourea by heating the thiourea with liquid bromine in boiling chloroform or chlorobenzene. The thiourea is prepared by condensing the appropriate aniline with alkali metal isothiocyanates n-C3H7°.

VIII KSCN (Hydrolysis) n-C3H?O IX S ΝΗ-ϋ?-ΝΗ„ Br2/CH3C1 .II The starting compOuhd of formula VI may be'obtained according to the following reaction schemes nh2 · + SCN-COOCHg--^VI. n_C3H7°~^ The starting compounds in the art.

The following examples cribed processes: of formulae IV and V are wellknown serve to exemplify the above des-64309$ Example 1 In a round bottom 1 liter flask equipped with a reflux condenser, a magnetic stirrer and a heating mantle is placed 45.75g of 2-mercapto-4-propoxyaniline; 45.25 g of methyl-N-[di (methylthio)-methylene]carbamate, and 250 ml absolute ethanol. This mixture is heated to boiling under an inert atmosphere of nitrogen for 12 hrs. It is then chilled and the white crystalline solid which is formed, is isolated by filtration, washed with cold ethanol and dried. m.p.l78~18O°c.

Example 2 A solution of 26.8 g l-carb«methoxy-3-(p-n-propoxyphenyl)thiourea in chloroform and 16 g.bromine is heated under reflux for 5 hrs. The solution is then brought to room temperature and washed with 100 ml of aqueous 10% Na2S03; 200 ml of aqueous 10% Na2CO3; and aqueous saturated NaCl respectively. It is dried over anhydrous sodium sulfate and the solvent is then removed hy evaporation to give 25 g of a white solid. m.p. 178-18O°C.

Example 3 A solution of 26.8 g l-carbamethoxy-3-(p-n-propoxyphenyl)thiourea and 16 g bromine in 700 ml of chloroform is irradiated in a quartz vessel by a 450 W medium pressure mercury lamp until the colour of bromine disappears. The reaction mixture is then worked up by the process described in Example 2 to give the desired compound, m.p.178' 180°C. -7330® 5 Example 4 To a stirred suspension of 2.1 g l-carbomiethoxy-(p-npropoxyphenyl)thiourea in a solution of 2.4 g sodium hydroxide in 35 ml of water, in an Erlenmeyer flask at 64° (by water bath) is added a solution of 8,8 g potassium ferricyanide in 20 ml water. The stirring is continued for 2 additional hrs. Potassium carbonate, 6 g. is then added to this reaction mixture and stirring is continued for another 2 hr. period. It is then extracted by 2 x 50 ml chloroform. The chloroform extracts are dried over anhydrous Na^O^ and the solvent is removed by evaporation to give the product. m.p. 178-18O°C.

Example 5 To a stirred and chilled (0°C) solution of 24.45 g of 2-. amino-5-n-propoxybenzothiazole .hydrochloride in 100 ml dry pyridine is dropwise added 9.45 g. methyl chloroformate. The mixture is then allowed to stand at room temperature for 8 hrs. It is poured into 300g of ice.... water. The solid product is separated by filtration and dried, crystallisation from ethanol gave 20 g of the product. ' m.p,178-18O°C.

Example 6 A mixture of 2,24 g methyl 6-hydroxybenzothiazole-2-carbamate, 1,3 g 1-bromopropane, 2 g anhydrous potassium carbonate and 50 ml anhydrous acetone is heated under reflux for 72 hours. -843095 Acetone is then removed by distillation and the solid residue is mixed with 100 ml water and filtered. Crystallisation from ethanol provides the desired product, m.p. 178°-18O°C.

Example 7 A mixture of 11.5 g. anhydrous 6-n-propoxy-benzothiazole2-isocyanate, 3.5 g methanol and 50 ml. benzene is stirred at room temperature for 4-5 hrs, and is then ncurtd into icewater and stirred for 30 minutes. The white solid product is isolated by filtration and recrystallized from ethanol, m.p. 178-18O°C.

Methyl-6-n~propoxybenzothiazole-2-carbamate is useful in combatting nematodes, i.e. in treating humans and animals susceptible to or suffering from an infestation of the gastrointestinal tract with parasitic worms, by administering to the host animal a prophylactic and/or therapeutic amount of the compound which combines a high degree of anthelmintic activity toward the parasites with a low toxicity toward the host. The compound is particularly unique and therefore quite valuable since it is effective against the three most prevalent nematodes known to infest mammals, i.e. the compound exhibits an effective anthelmintic effect against worm types such as Ascaridae (e.g. roundworm), Ancylostomatidal (e.g. hookworm) and Trichuris (e.g. whipworm). The anthelmintic activity of the compound is assessed by standard and wellknown techniques such as the Modified McMaster Egg Counting Technique as described by H.B.Whitlock and H.McL. Gordon; J.Council - 9 09 S Scientific Industrial Research (Australia) 12, p. 50, 1939 and H.B. Whitlock J„ Council Scientific Research (Australia) 21? p.177,1948. From these (and similar tests) anthelmintic efficiency, is assessed by determining the number of eggs in faeces passed on the days following treatment with the compound.

From these tests it is determined that the compound of this invention exhibits significant anthelmintic effects when administered to a host (e.g. a horse) ih the dose range of 30-100 MFK per day, either in a single day dosing or in dosing over several days according to techniques wellknown in the art. The compound of this invention may be administered in suspensions, capsules, feed additive preparation or in shaped dosage form, for example, tablet or suppositories as is well known to those skilled in the clinical and veterinary arts. In addition the compound may also be used as injectible anthelmintic preparations. For this purpose the active ingredient is admixed with suitable sterile, carriers such as sterile water and isotonic saline solution.

The compound has low toxicity and, therefore, shows a favourable therapeutic index. Dosages in mice and in dogs are non-lethal at 200 mg/kgo Suitable clinical formulations containing the benzothiazole of this invention can be administered orally in the form of tablets, capsules, θ* elixirs. The active compound is compounded with inert carriers such as, for example, gums, starches and sugars or may be incorporated into gelatine capsules or formulated into elixirs which have the advantage of being susceptible to manipulations in flavour and/or colour by the additieii of standard natural or synthetic flavouring and/or colouring agents 5 Particularly useful veterinary anthelmintic formulations embodying the compound of the invention for treatment of helminthiasis can be either as a liquid suspension ready to use or as a wettable or water-dispersible powder which is mixed with water prior to use. A liquid-suspension formulation may contain from 50-55 grains per 100 ml- of the active compound together with a dispersing agent and stabilizing agent.

A typical formulation is as follows: Active compound......................50-55 grams Dispersing agent.....................1/2-2 grams Stabilizing agent Preservative.....

Water............ 1-3 x ° grams as required Sufficient to make 100 «1.

Suitable dispersing agents are those containing sulphonate 20 groups, for example sodium lignin sulphonate or the sulphonated phenol or naphthol formaldehyde polymers. Bentonite may be employed as the stabilizing agent, although it is possible to use such protective colloids as carboxy methyl or cellulose, sodium alginate . The -11I formulations can be prepared by mixing the active compound and water containing dissolved dispersing agents very vigourously by means of suitable mechanical mixing equipment. A wettable or water-dispersible powder formulation may contain 90-95% w./w. of the active compound together with a wetting agent and dispersing agent. A diluent such as kaolin can also be added if a concentration below about 98% w./w. is required. An anti-foaming agent, and, in some cases, a stabilizing agent may be present.

A typical formulation is as follows: Active compound..................

Wetting agent....................

Stabilizing agent................

Anti-foaming agent...............

Water............................ 90-95 parts weight 1/2-4 parts weight 0-2parts weight 0.01-1 part weight 0-5 parts weight Suitable wetting agents are the non-ionic alkylphenolethylene oxide adducts, such as an octylphenol or nonylphenol condensed with ten moles of ethylene oxide, or anionic materials such as the synthetic alkyl aryl sulphonates, examples of which are sodium dodecyl benzene sulphonates, or sodium dibutyl napthalene sulphonate.

In general, about 1% w./w. wetting agent is required. The anti-foaming agent employed may be either a silicone or such materials as ethyl hexanol, or octanol; and the stabilizing agent may again be chosen from bentonite or the water-soluble gums. Wettable or water-1243095 dispersible powder formulations are prepared by careful and adequate mixing of the active compound with other ingredients with or without the addition of some water using typical powder blending equipment such as a ribbon blender. The powder is stirred into water by the user before application in the field.

The following examples show particularly useful formulations : A, Tablet formulation Methy1-6-n-propoxybenzothiazole2-carbamate Lactose Dicalcium phosphate, hydrous Polyvinylpyrolidone Polyethyleneglycol 1500 Corn Starch Magnesium Stearate Grams per 1000 tablets 200.0 90.0 122.5 .0 7.5 50.0 .0 500.0 Mix the carbamate, the lactose and the diacalcium phosphate. Dissolve the polyethyleneglycol 1500 and the polyvincylpyrrolidone in approximately 20 ml. of water. Granulate the powder blend with the water solqtion, adding additiona). water if necessary, to produce a damp mass. Pass the wet granulation through a 12 mesh screen; spread on trays and air dry at 35°C. Blend the dry -13granulates with the starch and the magnesium stearate Compress into 500 mg.tablets.

B: Capsule formulation Grams per 1000 capsules Methyl-6-n-propoxybenZothiazole-2carbamate........................... 200.0 Lactose................ 198.0 Magnesium Stearate.·......... 2.0 400.0 Blend the ingredients and fill into hard gelatine capsules C: Elixir formulation per 1000 ml Mefchyl-6-n-propoxybenZothiazole-2carbamate.......................... 40.0 g Sodium citrate ................ 10.0 g Sugar.............................. 500.0 g Glycerin........................... 200.0 g Compound orange spirit............. 10.0 ml Alcohol ................ 100.0 .Amaranth....... 0.1 Water to total·..................... 1000.0 11

Claims (11)

1. What we claim is:

1. Pharmaceutically active composition useful for combatting helminthiasis in mammals comprising as an active ingredient the compound methyl-6-n-propoxybensothiazole5 2-carbamate in combination with a suitable pharmaceutically acceptable carrier.

2. Composition according to claim 1 wherein the pharmaceutically acceptable carrier is sterile.

3. Composition according to claim 2, wherein the sterile 10 carrier is a carrier suitable for injections.

4. Composition according to any one of claims 1 to 3, characterised in that in addition to the active ingredient and the pharmaceutically acceptable carrier are added flavouring and/or colouring agents. 15 5. Composition according to any one of claims 1 to 4, in shaped dosage form. G. Composition according to claim 5, wherein the shaped dosage form is a tablet or capsule.

5. 7. Composition according to claim 5, wherein the shaped 20 dosage form is a suppository.

6. 8. Composition according to claim 1 in the form of an elixir. -159. Methyl-6-n-propoxybenzothiazole -2-carbamate.

7. 10. Process for preparing methyl-6-n-propoxybenzothiazole 2-carbamate, characterised in that a) the compound of the formula is reacted with a compound of the general formula 2 1 C00CH 3 wherein Z^ represents an easily replaceable group; b) the compound of the formula n-C 3 H 7O is reacted with a compound of the general formula Ζ» ° > H C=N-COCH. wherein Z^ and Z 3 represent labile groupings capable of being eliminated together with one hydrogen atom under the reaction conditions applied; -1643095 c) the compound of the formula is subjected to an intramolecular condensation; d) the compound of the formula is subjected to an n-propylation. e) the compound of the formula or a reactive derivative thereof is reacted with 10 ’ methanol.

8. 11. Process according to claim 10, characterised in that Z^ is halogen.

9. 12. Process according to claim lo, characterised in that Z 2 and represents one of the groupings “SCHg, 15 0CII 3 and -N(CH ) 2 -17300 3

10. 13. Process for preparing a pharmaceutically active composition useful for combatting helminthiasis in mammalsj characterised in that methy1-6-n-propoxybenzothiazole-2-carbamate is admixed with a suitable pharmaceutically acceptable carrier.

11. 14. & method of combatting helminthiasis in mammals other than humans characterised in administering an anthelmintically · effective quantity of methy1-6-n-propoxybenzothiazole-2-carbamate.