Note: Descriptions are shown in the official language in which they were submitted.
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.
. ~,
'
1085297
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:
~, '
.....
"
.
'~ :
. .
~ ` ~
:
.
'` .
. '
.
1085Z~7 Jan ~-1975
- 2055B-FTR-3
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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 ;
.
:`
Jan-6-1976
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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
NH-C-NM-COOCH3
; ~ 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
2055B-FTE-5
: 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
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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~
.
.
~ - + 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
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; ~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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:
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.
.
ExamPle- S , '.
To a stirred and chilled (oC) solution of 24045 g of 2-~ ;
.
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.
~, .
.
~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.
, .
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
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.
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.
....
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. `
.~ ' ' ' .
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-
-12-
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~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.
.. .
The following examples show particularly useful formula-
tions:
. ;
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
.
.. ... : ... .; . . :
Jan-6-1976
2055E-FTE-l*
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~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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