CA1085297A - Anthelmintic therapy - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

This invention relates to methyl-6-n-propoxybenzothiazole-2-carbamate and to its use in anthelmintic preparations.
It also relates to a method for combatting helminthiasis in mammals whereby an anthelmintically effective quantity of methyl-6-n-propoxybenzothiazole-2carbamate is admini-stered to the respective mammal.

Description

1(~85Z~7 This invention relates to the compound methyl-6-n-propoxy-benzothiazole-2-carbamate, to the preparation thereof, to anthelmintic formulations containing this compound and to the use of the compound as an active anthelmintic agent in clinical and veterinary application.
Carbamate esters of benzothiaæoles of the above type have been generally described in the prior art, e.g., in Swiss Patent MoO 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 has the formula ., ' C-~N-COOCN3 According to the invention there is provided a pharma-ceutically active composition useful for combatting helminthiasis in mammals comprising as an active ingredient the compound methyl-6-n-propoxybenzothiazole-2-carbamate in combination with '~
a suitable pharmaceutically acceptable carrier. ;
The carrier is suitably a sterile carrier and the ;~ composition may be in a shaped dosage form, for example, a :: .
tablet, capsule or suppository, or in the form of an elixir -~
or a form suitable for injection.
. ~, ' The compound may be prepared according to known processes, e.g., as described in the abovementioned Swiss Patent ~o. 505,543. The preferred methods are described under items 1 to 5 below:

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1085Z~7 Jan ~-1975 SK/ch , .

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n 3 7 ~ ~-~H2 ~ZlCOOCH3 ->

II III
.,j ..
wherein Zl 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 0C and room temperature. The reactants are brought together in equi- ~ -molar proportions whereby the carbonate is added slowly over an extended period of time. After completion of the !`;`
~, 10 admixture, the reaction mixture is stirred for a longer period of time, preferably over night and the desired ;
,., , :
i product is then isolated according to techniques well- ;

-i known in the art, The purification is preferably carried ;~

1 out by recrystallization from appropriate alcohols~ Al-.. , ~. :, 15 though pyridine is the preferred solvent for this reaction other solvents such as acetonitxile and triethylamine and mixtures of acetonitrile and pyridine may also be used.
. ~ . .
~H :

n-c3s7o--~ + C=~-COC33 3 I

IV V
Z2 and Z3 represent labile groupings such as -SCH3, 0CH3 or M (CH3 ) 2 ;

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Jan-6-1976 SK/ch 3S2~7 .
The reactio~ is preferably car~ied out by stirring and heating tha reactants at reflux temperature in a suitable solvent such as ethanol, keeping the reaction mixture under an inert atmosphere, pref~rably nitrogen.

3.
,S

; ~ cyclization n~C3H7 ~
, , VI
Also this process is carried out using standard techniques.
One preferred method comprises heating the thiourea com-pound 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.
The isolation of the product is also performed according ;; to standard procedures. rme mixture is brought to room temperature, washed with aqueous ~a2C03, and a~ueous ~aCl and dried over sodium sulfate. rrhe solvent is removed by evaporation to yield the desired product.

The intramolecular cycllzation may also be accomplished by adding an aqueous solution of potassium ferricyanide to a stirred and moderately heated mixture of the thio-urea compound, sodium hydroxide and water~ After the addition of potassium ferricyanide is completed, potassium carbonate is added and stirring is continued. The _q,_ Ja~~6-1975 : L0~35;Z9'7 SK/ch :
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.
~`, . '., `~ S 4 ~ ~ ~ C~ COOC~3 ~ ~ C3~7 : The etherification is preferably carried out by heating a -~ mixture of t~e methyl-6-hydroxybenzothiaæole-2-carbamate, anhydrous potassium carbonate, n-propylbromide and a suitable solvent, e.g. acetone, at reflux temperature.
. ~ , lo The solvent is then removed by distillation, the residue taken into water and filtered. The pu~e product is ob~
- tained by recrystallization from ethanol.

5. A further process comprises reacting the corresponding benzothiazole-2-isocyanate of the formula , ~ ~ ~=C=0 X
n-c3H7~s/
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 of methanol, or benzene, at room temperature~ The pre-ferred reactive derivatives of the compound of formula X

are those wherein the group -~--C=0 is replaced by the grouping -NH-~-halogen.

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Jan-6-1975 2055B-FTE~6 SK/ch 1~85~97 .

The appropriate starting compounds in the above processes 1 to 5 may be obtained by techniques wellknown in tha art. `~
The 2-amino--benzothiazole of formula II may be obtained by cyclizing the appropriate thiouxea by heating the ~' 5 thiourea with liquid bromine in boiling chloroform or ~:
chlorobenzene. The thiourea is prepared by condensing the appropriate aniline with alkali metal isothiocyanate:
. ' :. -~ NH2 ~ ~ NH-IC-~H

n-C H ol~ J KSC~ n-C H 0 l~ IJ
3 7 "_~' (Hydrolysis) 3 7 " ~' ~ .

/CH3C1 ~ 2 , n-C3H7 S/ ,, II
':
The~-startin~ compound o~ formula VI may be obtained accor-ding to the following reaction scheme~
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~ - + Sc~-cOOcH3 )VI.
n C3 7 The starting compounds of formulae IV and V are wellknown in the art.
The following examples serve to exernplify the above des-cribed processes:

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Jan-5-1976 2055B~F'rE-7 SK/ch 1C~85Z97 ; ~xample 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-propc)x~aniline; 45025 g of methyl~ di(methylthio)-methylene~carbamate, and 250 ml absolute ethanol. This mixture is heated to boiling under an inert atmosphere of nitrogen fo~ 12 hrs. It is ~ ;
~-- then chilled and the white crystalline solid which is formed, is isolated hy filtration, washed with cold ethan ol and dried. mrp.l78-180 C0 "' .' ,;' Example 2 ;~
A solution of 26.8 ~ I-carbamethoxy-3-(p-n-propoxyphenyl)-thiourea in chloroform and 16 g.bromine is heated under reflux for 5 hr~. 'l'he solution is then brought to room temperature and washed with 100 ml of aqueous 10% Na2S03;
200 ml of aqueous 10% Na2C03; and aqueous saturated NaCl respectively. It i5 dried over anh~drous sodium sulfate and the solvent is then removed by evaporation to give 25 g of a white solid. m.p. 178-1~0 C~

~ e 3 A solution of 26~8 g 1-carbamethoxy-3-~p-n-propoxyphenyl)-thiourea and 16 g bromlne in 700 ml of chloroform is irradiated in a quartz vessel by a 450 W medium pressuxe mercury lamp until tne colour o bromine disappears. The reaction mi}~ture is thell worked up by the process descri--bed in Example 2 to give th~ desired co~poundO m.p.l78-80C .

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Jan-6-1~76 1~85Z~7 SK/ch :

ExamPle 4 To a stirred suspension of 2.1 g l-carbamethoxy-(p-n-propoxyphenyl)thiourea in a solut:ion 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 chloroformO The chloroform extracts are dried over ~ -anhydrous Na2S04 and the solvent is removed by evaporation to give the product. m.p. 178-180C.
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ExamPle- S , '.
To a stirred and chilled (oC) solution of 24045 g of 2-~ ;
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amino-6-n-propoxybenzothiazole hydrochloride in 100 ml dry pyridine is dropwise added 9.45 g. methyl chloro-formate. The mixture is then allowed to stand at room temperature for 8 hrs. It is poured in 300 g o ice-water. The solid product is separated by filtration and dried. Cr~stallisation from ethanol gave 20 g of the product. m.p.l78-180C.
, Example 6 A mixture o~ 2r24 g methyl 6~hydroxybenæothiazole-2~carbamate, 1,3 g l~br~nopropane, 2 g anhydrous ~fS'~assi~un carbonate and 50 ml anhydrous acetone is heated under reflux or 72 hours.

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~an~6-1975

2 0 5 SB --F~E--9 1085Z97 SK/ch Acetvne is then removed by distillation and the solia residue ~; is mixed with 100 ml water and filtered. Crystallisation from ,' , ethanol provid~s the desired pxoduct. m.p. 178-180Co ,~, , .
Example 7 A mixture of 11.5 g. anhydrous 6-n-propoxy-benzothiazole-.
;' 2-isocyanate, 305 g methanol and 50 ml. benzene is stirred at room temperature for 4-5 hrs, is then poured into ice- '~
water and stirred for 30 minutes. The white ~olid product is isolatPd by fil,tration and recrystallized from ethanol. ~' m.p. 178-180C. '' .. . - ~, 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 adminis- '~
tering to the host animal a prophylactic and/or thera- '~
peutic 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 anthel- ' `
mintic effect against worm types such as Ascaridae (e.g.
roundworm), Ancylostomatidal (e.g. hookworm) and Trichuris (e.g. whipworm). The anthelmintic activity of the com-pound is assessed by standard and wellknown tec,hniques such as the Modified McMaster Egg Counting Techni~le as described by H.B.Whitlock and H.McL. Gordon; J.Council _ Jan-6~1975 ~La;852~7 S~ch .. , Scientiic Industrial Re~earch (Australia) 12, p. 50, 1939 and HoB~ Whitlock J. C~uncil Scientific Research (Australia) 21; p.l77,1948. From these (and similar tests) anthel-~` mintic efficiency is assessed by determining the number of eggs in faeces passed on the days following treatment with the compound.

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From these tests it is determined that the compound of this in~ention exhibits significant anthelmintic effects when administered to a host (e.g. a horse) in the dose range of 30-100 MPK per day, either in a single day dos-ing 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, tablets, etc. as is wellknown 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 ~avourable therapeutic index. Dosages in mice and in dogs are non-lethal at 200 mg/kgO

Suitable clinical formulations containing the benzo-thiazole of this inven~ion can be admini3~ered orally in the form of tablets, cap~u]es, elixirs and the like. The active compound is compounded wi.th inert carriers such as, for example, gums, starches and sugars or may be ~ ` - 10 -~ ~an~6-1975 1~852~7 2055B-FTE-ll SK/ch .

incorporated into gelatine capsu:Les or formulated into elixirs which have the advantage of being susceptihle to manipulations in flavour by the addition of standard, natural or synthetic flavouring agents.

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Particularly useful veterinary anthelmintic formulations embodying the compound of the invention for treatment of helminthiasis can be either as a li~uid suspension ready io use or as a wettable or water-dispersible pow~er which is mixed with water prior to use. A liquid-suspension formulation may contain from 50-55% w./v. of the active compound together with a dispersing agent and stabilizing agent. `
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A typical formulation is as follows:
Active compound............... ~..... 50-55 parts weight Dispersing agent.............. ~..... l/2-2 parts weight Stabilizing agent.................. . o l~3 parts weight ' Preservative.. ~................. ~..... ..as required Water....................... ...... .... .Sufficient to make 100 volumes.
: ~ .
Suitable dispersing agents are those containing sulphonate groups, for example sodium lignin sulphonate or the sul-phonated p~enol or naphthol formaldehyde polymers. Ben-tonite may be employed as the stabilizing agent, although it is possible to use such protective colloids as carboxy methyl cellulose, sodium alginate and the like. The .~ ~

Jan-6-1976 2055B-E'T~-12 1~85Z97 SX/ch formulations can be prepared by mixing the active compound and water containing dissolved cllspersing agents very vigourously by means of suitable mechanical mlxing equip-i ment. A wettable or water-dispersible powder formulation may contain about 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-foam~ng agent, and, in some cases, a stabilizing agent may be present.
A typical formulation is as follows: ;
~. ', ' ~
Active compound...... Ø.......... 90-95 parts weight Wetting agent........ ~............ 1/2-4 parts weight Stabilizing agent.... ~........... 0-2parts weight Anti-foaming agent~............... 0~01-1 part weight Water................ 0............ 0-5 parts weight Suitable wetting agents are the non-ionic alkylphenol-- ethylene oxide adducts, such as an octylphenol or nonl-- phenol condensed with ten moles of ethylene oxider or anionic materials such as the synthetic aryl alkyl 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-foamlng agent employed may be either a silicone or such materials as ethyl hexanol, octanol and the like;
and the stabilizing agent may again be chosen from ben-tonite or the water-soluble gums. Wettable or water-~an 6-1976 2;)55B-E'TE--13 SK/ch ~8S29~

disp~rsible 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 2S ribbon blender. The powder is tirred into water by the user before application in the field.
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The following examples show particularly useful formula-tions:
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A~ Tablet formulation Grams per_1000 tablets '10 Methyl-6-n-propoxybenzothlazole- . :
2-carbamate 200.0 : .:
Lactose 90.0 , !
Dicalcium phosphate, hydrous 122.5 Polyvincylpyrolidone ' 25.0 Polyethylenglycol 1500 7.5 ; Corn Starch 50,0 Magnesium Stearate - 5.0 500.0 .~ ' ~

Mix the carbamate, the lactose and the diacalcium phos-~- 20 phate. Dissolve the polyethyleneglycol 1500 and the ; polyvincylpyrrolidone in approximately 20 ml. o~ water.
Granulate the powder blend with the water sol~tion, ~' adding additional water if necessary, to produce a damp mass. Pass,the wet granulation through a 12 mesh s~reen;
spread on trays and air dry at 35C~ Blend the dry .

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Jan-6-1976 2055E-FTE-l*
SK/ch ~08$2~7 :

granulates with the starch and the magnesium stearate.
Compress into 500 mg.tablets.

B: ~psule formulation Grams per 1000 capsules Methyl~6-n-propoxybenzothiazole-2-carbamate.................................. 200.0 Lactose.. ~........ ~..... O.................. 198.0 Magnesium Stearate......................... _2 0 400~0 Blend the ingredients and fill into hard gelatlne capsules.

C: Elixir formulation ~er 1000 ml Methyl-6-n-propoxyb~n~othiazole-2-carbamate..........O........................ 40.0 g Sodium citrate ............................ 10.0 g Sugar.....Ø............................... 500.0 g Glycerin................................... 200.0 g Compound orange spirit.n....Ø............. 10.0 ml Alcohol ................................... 100.0 "
Amaranth................................... 0.1 "
Water to total:............................ 1000.0 "

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Claims (8)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

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

2. Composition according to claim 1, wherein the pharma-ceutically acceptable carrier is sterile.

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

4. Composition according to claim 1, 2 or 3, further including at least one of a flavouring agent and a colouring agent.

5. Composition according to claim 1, in shaped dosage form.

6. Composition according to claim 5, wherein the shaped dosage form is a tablet or capsule.

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

8. Composition according to claim 1, in the form of an elixir.