BACKGROUND OF THE INVENTION 
This invention relates to novel isoxazole carboxamides of 
6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[ 2,1-b]thiazole 
(m-aminotetramisole), to processes for their preparation, and to their use 
for controlling helminths in warm-blooded animals. 
British patent specification No. 1,365,515 discloses 
6-amino-phenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazoles useful in the 
treatment of gastrointestinal nematodes in warm-blooded animals. 
U.S. Pat. No. 3,673,205 discloses dl or 
1-6-(m-amino-phenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole and their 
use as anthelmintics. 
U.S. Pat. No. 3,274,209 discloses 
dl-2,3,5,6-tetrahydro-6-phenyl-imidazo[2,1-b]thiazole and its use as an 
anthelmintic. 
SUMMARY OF THE INVENTION 
The present invention discloses the l- and dl (racemic)- forms of the 
compounds of the formula: 
##STR1## 
and the pharmaceutically acceptable addition salts thereof, wherein R is 
hydrogen or methyl. 
Also disclosed is an anthelmintic composition useful for the treatment of 
helminth infections comprising a compound of formula (I) together with a 
pharmaceutically acceptable diluent or carrier. 
In addition there is disclosed a method of treating helminth infections in 
an infected host comprising administering to said host an anthelmintic 
amount of a compound of formula (I). 
Further disclosed is a veterinary composition comprising an anthelmintic 
concentration of a compound of formula (I) in an animal feed. 
Typical pharmaceutically acceptable acid addition salts include the 
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, acetate, 
lactate, tartrate and citrate salts. 
R is preferably methyl. 
The preferred compounds are 1- and dl-{6- 
m-(5-methyl-isoxazole-3-carboxamido)phenyl}-2,3,5,6-tetrahydroimidazo[2,1- 
b]thiazole. 
We have found that the compounds of this invention are significantly more 
active than other closely related 
6-{m-(isoxazolecarboxamido)phenyl}-2,3,5,6-tetrahydroimidazo[2,1-b]thiazol 
es, including the analogous 5-ethylisoxazole-3-carboxamido- and 
5-phenylisoxazole-3-carboxamido- compounds, and positional isomers such as 
the 3-methylisoxazole-5-carboxamido compound. 
The l- forms are the most preferred forms of the compounds of the 
invention. 
DETAILED DESCRIPTION OF THE INVENTION 
The compounds may be prepared by a number of routes, including the 
following: 
(1) The compounds may be prepared by reacting 
6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole 
(m-aminotetramisole) of the formula: 
##STR2## 
with an acid of the formula: 
##STR3## 
or with its functional equivalent as an acylating agent, e.g. an acid 
halide, "activated" ester or mixed anhydride of the compound of the 
formula (III). 
The preferred acid halides are the acid chloride and bromide. They may be 
prepared by conventional procedures, e.g. by reacting the free acid with, 
respectively, thionyl chloride or bromide. 
The preferred "activated" ester is the succinimido ester of the formula: 
##STR4## 
This may again be prepared by conventional procedures, e.g. by reacting 
the free acid with N-hydroxysuccinimide in the presence of a dehydrating 
agent, e.g. dicyclohexylcarboniimide. Another preferred activated ester is 
the phthalimido ester. 
Suitable mixed anhydrides have the formula: 
##STR5## 
wherein R.sup.1 is a C.sub.1 -C.sub.6 alkyl or C.sub.1 -C.sub.6 alkoxy 
group, most preferably a t-butyl or iso-butoxy group. They may be prepared 
by conventional procedures, e.g. by reacting the free acid with the 
appropriate alkanoyl chloride or alkyl chloroformate, respectively, e.g. 
pivaloyl chloride or iso-butyl chloroformate, in the presence of a base 
such as triethylamine. 
dl-(Racemic) or l-m-aminotetramisole should be used as the starting 
material according to whether the dl or l- form, respectively, of the 
product (I) is required. dl-m-Aminotetramisole may be resolved into its d- 
and l- isomers by using the method described in U.S. Pat. Nos. 3,673,205 
and 3,463,786. Further, the l- form of the product (I) may be obtained by 
resolution of the dl- form into its dextro and laevo antipodes. For this 
purpose, the procedure described in British Pat. No. 1,402,689 is 
possible. 
Although the compounds of the invention may be prepared by reacting the 
compound (II) with the free acid (III), it is most preferred to use the 
acid in the form of its acid chloride. 
When the free acid form (III) is used, the reaction should generally be 
carried out in the presence of a dehydrating agent such as 
dicyclohexylcarbodiimide. 
In a typical procedure involving the reaction of compound (II) with an acid 
chloride of compound (III), compound (II) is dissolved in an aqueous 
solvent, e.g. aqueous methanol, the pH lowered to e.g. 5 with dilute 
hydrochloride acid, the mixture cooled, and the acid chloride carefully 
added. After stirring the reaction mixture at room temperature for several 
hours, it may be acidified with dilute hydrochloric acid and washed with a 
suitable solvent, e.g. methylene chloride. After separation, the aqueous 
phase may be basified to e.g. pH 8 with a suitable base, e.g. concentrated 
aqueous ammonia, and extracted with a suitable solvent, e.g. methylene 
chloride. After separation, the organic phase may be washed with water at 
pH 6 to remove any unreacted m-aminotetramisole, and evaporated to dryness 
under reduced pressure to leave the desired product. If necessary, the 
product may be purified by recrystallization from a suitable solvent, e.g. 
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 an acceptably crystalline form, then it may be taken up in ethanol, 
and excess hydrogen chloride gas passed through the ethanolic solution to 
convert the free base into its hydrochloride salt form. The crystalline 
hydrochloride may be recovered by concentrating the resulting solution 
under reduced pressure, and, if necessary, may be recrystallized from a 
suitable solvent, e.g. ethanol or isopropanol. 
Alternatively, the hydrochloride salt of the product may be directly 
prepared in the following manner. Compound (II) is dissolved in a suitable 
solvent, e.g. aqueous acetone, the pH lowered to e.g. 5 with dilute 
hydrochloric acid, the mixture cooled, and the acid chloride of compound 
(III) slowly added, e.g. over a period of 30 minutes. The resulting 
mixture is then stirred at low temperature e.g. 10.degree. C, for 1/2-1 
hour, and the precipitate of the desired hydrochloride salt filtered, 
washed with a suitable solvent, e.g. acetone, and dried. 
(2) dl-(racemic) forms of the compounds of the invention may also be 
prepared by cyclizing a compound of the formula: 
##STR6## 
wherein X is chlorine, bromine or hydroxy, and Y is hydrogen or C.sub.1 
-C.sub.4 alkanoyl, with the proviso that when X is hydroxy Y is hydrogen. 
The preferred alkanoyl group is acetyl. 
Y is preferably hydrogen. 
X is preferably chlorine or bromine. 
The cyclization of the compounds of the formula (VI) in which X is Cl or Br 
and Y is H or alkanoyl may be carried out by heating them with excess of a 
base which does not hydrolyze the amide linkage, e.g. aqueous potassium 
carbonate, aqueous triethylamine, aqueous pyridine, or dilute ammonia 
solution. Typical conditions are 30.degree.-100.degree. C for 1 to 3 
hours. Typically, chloroform is present in addition to the base, the 
chloroform layer being separated after reaction and evaporated to dryness 
to yield the desired product. Again, the l-form may be prepared by 
resolution of the dl-product in a conventional manner. 
Generally the compounds in which X is Cl or Br are prepared by the reaction 
of the corresponding compounds in which X is OH or C.sub.1 -C.sub.4 
alkanoyloxy with a suitable halogenating agent, e.g. thionyl chloride or 
bromide. It is not essential to isolate the halogenated product -- this 
may be cyclized in situ to the desired product by reaction with the base. 
The cyclization of the compounds of the formula (VI) in which X is hydroxy 
and Y is H may be carried out under mild dehydrating conditions. 
Dicyclohexylcarbodiimide is a possible dehydrating agent. 
The compounds of the formula (VI) will often be obtained and cyclized in 
the form of their hydrochloride or hydrobromide salts. 
The compounds of the formula (VI) may be prepared by methods analogous to 
those of the prior art. The following is a typical route: 
##STR7## 
(3) The pharmaceutically acceptable acid addition salts may be prepared 
from the corresponding free base by conventional procedures. The 
hydrochloride salts may for example be prepared as described in (1) above. 
The compounds of the invention can be administered alone, but will 
generally be administered in admixture with a non-toxic diluent or carrier 
selected with regard to the intended route of administration. For example, 
they may be administered orally as aqueous solutions or in admixture with 
an animal feedstuff or animal feed supplement. In parenteral 
administration, which is preferably carried out subcutaneously or 
intramuscularly, the carrier may be aqueous such as water or isotonic 
saline or non-aqueous such as polyethylene glycol 300. 
Parenteral administration of an aqueous solution is preferred, and such 
solutions will typically contain 1 to 20% by weight of the active 
compound. 
Suitable dose levels are from 0.5 to 20 mg. of the active ingredient per 
kg. of body weight of the animal. 
The compounds are also active when administered dermally, the active 
compound being absorbed through the skin of the animal. 
The compounds of the invention are particularly active against nematodes 
occurring in the lungs, stomachs and intestines of sheep, cattle and other 
domestic animals.

The following examples, in which all temperatures are given in .degree. C, 
illustrate the invention: 
EXAMPLE 1 
Part A 
Acid Chloride of 3-Carboxy-5-methylisoxazole 
3-Carboxy-5-methylisoxazole (14.6 g) was refluxed with thionyl chloride 
(100 ml) for 1 hour. The reaction mixture was then evaporated to dryness 
under reduced pressure to remove excess thionyl chloride. Toluene was then 
added and the mixture again evaporated to dryness under reduced pressure 
to leave the crude acid chloride (16 g), which was used directly in the 
next stage without further purification. 
Part B 
dl-6-{m-(5-Methylisoxazole-3-carboxamido)phenyl}-2,3,5,6-tetrahydroimidazo[ 
2,1-b]thiazole 
A solution of dl-6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole 
(1.0g) in aqueous methanol (7 ml methanol/3 ml water) acidified to pH5 
with 2N hydrochloric acid was cooled to 0.degree. and maintained at this 
temperature while the acid chloride prepared in Part A (1.3g) was added 
portionwise over a period of 10 minutes. The resulting mixture was stirred 
at 0.degree. for 1 hour, and then overnight at room temperature 
(25.degree.). 2N Hydrochloric acid (5 ml) was then added and the solution 
washed with methylene chloride. After separation, the aqueous layer was 
basified to pH8 by the addition of concentrated aqueous ammonia, and 
extracted with methylene chloride. After separation, the organic phase was 
washed with water at pH6 to remove any unreacted imidazo[2,1-b] thiazole 
starting material, dried (MgSO.sub.4), and evaporated to dryness under 
reduced pressure to leave the desired product, 
dl-6-{m-(5-methylisoxazole-3-carboxamido)phenyl}-2,3,5,6-tetrahydroimidazo 
[2,1-b]thiazole. The product was recrystallized from acetone (yield 0.7 g, 
m.p. 122.degree.-124.degree.). 
Analysis %: Found: C, 57.95; H, 4.90; N, 16.76. Required for C.sub.16 
H.sub.16 N.sub.4 O.sub.2 S: C, 58.51; H, 4.91; N, 17.06. 
Part C 
Monohydrochloride salt of 
dl-6-{m-(5-methylisoxazole-3-carboxamido)phenyl}-2,3,5,6-tetrahydroimidazo 
[2,1-b]thiazole 
Excess hydrogen chloride gas was passed through 
dl-6-{m-(5-methylisoxazole-3-carboxamido)phenyl}-2,3,5,6-tetrahydroimidazo 
[2,1-b]thiazole (10 g, prepared as in Part B) in ethanol (150 ml), and the 
solution was then concentrated under reduced pressure. The desired 
monohydrochloride salt crystallized out of solution, and was filtered off 
and recrystallized from methanol (yield 9.3g, m.p. 
259.degree.-261.degree.). 
Analysis %: Found: C, 52.30; H, 4.73; N, 15.48. Calculated for C.sub.16 
H.sub.16 N.sub.4 O.sub.2 S.HCl: C, 52.66; H, 4.69; N, 15.35. 
Recrystallization of the monohydrochloride from methanol/ether (1:1) 
yielded the monohydrochloride monohydrate, m.p. 115.degree.-120.degree. 
(d.). 
Analysis %: Found: C, 51.06; H, 5.09; H, 14.12. Calculated for C.sub.16 
H.sub.16 N.sub.4 O.sub.2 S.HCl.H.sub.2 O: C, 50.19; H, 5.00; N, 14.63. 
EXAMPLE 2 
dl-6-{m-(isoxazole-3-carboxamido)phenyl}-2,3,5,6-tetrahydroimidazo[2,1-b]th 
iazole 
By a procedure similar to that of Example 1 Part B, 
dl-6-{m-(isoxazole-3-carboxamido)phenyl}-2,3,5,6-tetrahydroimidazo[2,1-b]t 
hiazole, m.p. 114.degree.-115.degree., was prepared from the acid chloride 
of 3-carboxyisoxazole and 
dl-6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole. 
Analysis %: Found: C, 57.60; H, 4.55; N, 17.19. Calculated for C.sub.15 
H.sub.14 N.sub.4 O.sub.2 S; C, 57.32; H, 4.46; N, 17.83. 
The acid chloride was prepared as in Example 1 Part A, starting from the 
corresponding free acid and thionyl chloride. 
EXAMPLE 3 
Monohydrochloride monohydrate of 
dl-6-{m-Isoxazole-3-carboxamido)phenyl}-2,3,5,6-tetrahydroimidazo[2,1-b]th 
iazole 
The above compound was prepared similarly to Example 1 Part C by passing 
excess hydrogen chloride gas through a solution of the product of Example 
2 in ethanol. 
Analysis %: Found: C, 48.21; H, 4.46; N, 14.95. Calculated C.sub.15 
H.sub.14 N.sub.4 O.sub.2 S.HCl.H.sub.2 O: C, 48.85; H, 4.61; N, 15.20. 
EXAMPLE 4 
1-6-{m-(5-Methylisoxazole-3-carboxamido)phenyl}-2,3,5,6-tetrahydroimidazo[2 
,1-b]thiazole 
By a procedure similar to that of Example 1 Part B, 
1-6-{m-(5-methylisoxazole-3-carboxamido)phenyl}-2,3,5,6-tetrahydroimidazo[ 
2,1-b]thiazole, m.p. 120.degree., was prepared from the acid chloride of 
3-carboxy-5-methylisoxazole and 
1-6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole. 
Analysis %: Found: C, 57.94; H, 4.98; N, 16.78. Calculated for C.sub.16 
H.sub.16 N.sub.4 O.sub.2 S: C, 58.52; H, 4.91; N, 17.06. Optical rotation 
[.alpha.].sub.D.sup.26 - 79.7.degree.. 
EXAMPLE 5 
Part A 
Preparation of 3'-acetyl-5-methyl-3-isoxazolecarboxanilide. 
1/4 hydrate 
##STR8## 
A solution of 5-methyl-3-isoxazolecarbonyl chloride (14.5 g) in acetone (30 
ml) was added to a solution of m-aminoacetophenone (13.8 g) in acetone 
(280 ml) in the presence of anhydrous potassium carbonate (21.0 g). The 
mixture was stirred for 1/2hour, and then diluted with water. The 
precipitated product was filtered, washed with water and dried. Yield = 
20.5 g (83%), m.p. 188.degree.-190.degree.. 
Analysis %: Found: C, 62.77; H, 5.00; N, 10.89. Calculated for C.sub.13 
H.sub.12 N.sub.2 O.sub.3.1/4H.sub.2 O: C, 62.77; H, 5.03; N, 11.26. 
Part B 
Preparation of 3'-bromoacetyl-5-methyl-3-isoxazolecarboxanilide. 
1/2 hydrate 
##STR9## 
A solution of bromine (12.5 g) in chloroform (60 ml) was added to a slurry 
of 3'-acetyl-5-methyl-3-isoxazolecarboxanilide. 1/4 hydrate (19 g) in 
chloroform (190 ml). The mixture was stirred for 1/2 hour and diluted with 
diethyl ether. The product was filtered and dried. Yield 21.0 g = (84%,) 
m.p. 172.degree.-174.degree.. 
Analysis %: Found: C, 46.63; H, 3.57; N, 7.99. Calculated for C.sub.13 
H.sub.11 BrN.sub.2 O.sub.3.1/2H.sub.2 O: C, 46.90; H, 3.61; N, 8.43. 
Part C 
Preparation of 
3'-[2-(2-imino-3-thiazolidinyl)acetyl]-5-methyl-3-isoxazolecarbocanilide 
hydrobromide 
##STR10## 
A solution of 3'-bromoacetyl-5-methyl-3-isoxazolecarboxanilide. 1/2 hydrate 
(20 g) in acetone (400 ml) was added to a stirred solution of 
2-amino-2-thiazoline (6.5 g) in acetone (400 ml). The mixture was stirred 
for 1/2 hour, and the product filtered, washed with acetone and dried. 
Yield 25.9 g (95%), m.p. 275.degree.-277.degree.. 
Analysis %: Found: C, 45.18; H, 4.00; N, 13.17. Calculated for C.sub.16 
H.sub.16 N.sub.4 O.sub.3 S.HBr: C, 45.17; H, 4.13; N, 12.88. 
Part D 
Preparation of 
3'-[1-hydroxy-2-(2-imino-3-thiazolidinyl)ethyl]-5-methyl-3-isoxazolecarbox 
anilide hydrochloride 
##STR11## 
Sodium borohydride (11.5 g) was added to a stirred slurry of 
3'-[2-(2-imino-3-thiazolidinyl)acetyl]-5-methyl-3-isoxazolecarboxanilide 
hydrobromide (23.0 g) in industrial methylated spirits (230 ml). The 
mixture was stirred for 1/2 hour, diluted with water and filtered. The 
crude product obtained was dissolved in acetone (240 ml) and a solution of 
hydrogen chloride in acetone added to it. The solid obtained was filtered, 
washed with acetone and dried. Yield 15.0 g (90%), m.p. 
206.degree.-208.degree.. 
Analysis %: Found: C, 50.19; H, 5.17; N, 15.04. Calculated for C.sub.16 
H.sub.18 N.sub.4 O.sub.3 S.HCl: C, 50.20; H, 4.96; N, 14.64. 
Part E 
Preparation of 
dl-6-{m-(5-methylisoxazole-3-carboxamido)phenyl}-2,3,5,6-tetrahydroimidazo 
[2,1-b]thiazole monohydrochloride monohydrate 
##STR12## 
3'-[1-Hydroxy-2-(2-imino-3-thiazolidinyl)ethyl]-5-methyl-3-isoxazolecarboxa 
nilide hydrochloride (3.8 g) was added to stirred thionyl chloride (12 ml) 
at 5.degree.. The mixture was stirred at 5.degree.-10.degree. for 1/2 
hour, and the solution evaporated to dryness at 25.degree. under vacuum. 
The resulting residue was stirred at 60.degree. with a mixture of 
chloroform and aqueous potassium carbonate solution for 1 hour. The 
chloroform layer was separated and evaporated to dryness. The solid 
obtained was dissolved in acetone (200 ml) and a solution of hydrochloric 
acid in acetone added to it. The product was filtered, washed with acetone 
and dried. Yield = 2.6 g (68%). The product was shown by n.m.r. and i.r. 
to be identical with the product of Example 1, Part C. 
EXAMPLE 6 
Preparation of 
dl-6-{m-(5-methylisoxazole-3-carboxamido)phenyl}-2,3,5,6-tetrahydroimidazo 
[2,1-b]thiazole monohydrochloride monohydrate 
dl-6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (14.5 g) was 
stirred in acetone (100 ml) and water (25 ml) and 2.5N HCl (27 ml) added 
to give a clear solution of pH approximately 5. 
This solution was stirred and cooled to 5.degree. and a solution of 
5-methyl-3-isoxazolecarbonyl chloride (14.5 g) in acetone (30 ml) added 
over 1/2 hour at 5.degree.-10.degree.. The resulting mixture was stirred 
at 10.degree. for 1/2 hour and the precipitated solid filtered, washed 
with acetone and dried. Yield = 21 g (87.5%), m.p. 118.degree.-121.degree. 
(d). N.M.R., I.R. and T.L.C. analyses showed the product to be identical 
with the product of Example 1 Part C. 
EXAMPLE 7 
An aqueous composition suitable for administration by injection to human or 
non-human animals is as follows: 
__________________________________________________________________________ 
Monohydrochloride salt of dl-6-{m-(5-methylisoxazole- 
3-carboxamido)-phenyl}2,3,5,6-tetrahydroimidazo 
up to 10% w/v 
[2,1-b]thiazole 
Methadioxole or Polyethylene Glycol 300 
up to 50% w/v 
Water balance to 100% 
__________________________________________________________________________ 
The composition may be prepared by mixing the ingredients together, and may 
be administered in one or more doses. 
Obviously the amount of the active ingredient will vary according to the 
dose response and weight of the animal but will generally be in the range 
of 0.5 to 20 mg per kg. of body weight, typically 2.5 mg/kg. 
EXAMPLE 8 
Administration of the compounds of the invention to animals may 
conveniently be carried out by incorporating them into feed mixtures. The 
typical dose used will be 0.5 to 20 mg/kg of body weight per day, i.e. 250 
mg to 10 gm per day for 500 kg. cattle. Assuming such an animal consumes 5 
kg. of feed supplement per day, then the said quantity of the active 
material may be mixed with 5 kg. of feed supplement. 
EXAMPLE 9 
The activity of the compounds in a triple infection mouse screen against a 
concurrent infection of Nematospiroides dubius, Syphacia obvelata and 
Hymenolepsis nana may be determined as follows. Albino mice, 20 grams in 
weight, are infected and treated according to the following procedure. 
Taking the initial infection as day 0, mice are infected with 2,000 H. 
nana ova on day 0 and 100 N. dubius larvae on day 5 and then exposed to a 
Syphacia infected colony for 4 days. The mice are then treated with test 
compound in groups of four either once on day 14 or on three consecutive 
days 14-16 by the oral or subcutaneous route. The mice are autopsied on 
day 19 examined for the presence of worms. The results obtained are 
compared with those from an untreated infected control (12 per group). For 
N. dubius total counts are carried out and activity is expressed as a 
percentage reduction. Infections of the other parasites are graded, 
Syphacia (0-3) and H. nana (0-3) and activity is expressed by comparing 
group mean grades. Polyethylene glycol is the standard vehicle used in the 
preparation of the test compounds for dosing, although aqueous solutions 
are used for water-soluble substances, and materials insoluble in both 
polyethylene glycol and water may be ball-milled in aqueous 1% Tween 80. 
The mg/kg. levels used may be for example up to 12.5 mg/kg. 
The activities of the compounds of the invention against the helminth N. 
dubius using the above method was found to be as follows: 
______________________________________ 
Dose (mg/kg) 
Compound 12.5 6.25 3.12 1.56 0.78 0.39 
______________________________________ 
Product of Example 
1 Part B 
% Clearance (s.c.) 
100% 99% 72% -- -- -- 
Product of Examples 
1 Part C, 
5 and 6, % Clearance (s.c.) 
-- 99% 79% 68% -- -- 
Product of Examples 
1 Part C, 
5 and 6, % Clearance (oral) 
-- -- 100% 98% 56% 31% 
Product of Example 
2 % Clearance (s.c.) 
100% 89% 65% 39% -- -- 
Product of Example 
3 % Clearance (s.c.) 
96% 88% 100% -- -- -- 
Product of Example 
4 % Clearance (s.c.) 
100% 100% 100% -- -- -- 
______________________________________