Certain thiazolo compounds as acaricidal agents

Quaternary 5,6-dihydroimidazo[2,1-b]thiazolium salts and novel quaternary 6,7-dihydro-[5H]thiazolo[3,2-a]pyrimidinium and 5,6,7,8-tetrahydrothiazolo[3,2-a][1,3]diazepinium salts, their preparation and preferred use as acaricidal agents are disclosed.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The invention relates to novel 
8-substituted-6,7-dihydro[5H]thiazolo[3,2-a]pyrimidinium and 
9-substituted-5,6,7,8-tetrahydrothiazolo[3,2-a][1,3]-diazepinium salts and 
7-substituted-5,6-dihydroimidazo[2,1-b]thiazolium salts. The latter series 
of compounds have been generically disclosed as hypoglycemic agents and 
growth promotants in U.S. Pat. No. 3,954,784. It has now been found that 
all of the above salts are useful acaricidal agents and are particularly 
effective in destroying ticks and mites which tend to infect the skins of 
animals, especially sheep and cattle, and are therefore useful as 
ectoparasiticidal agents for treating such animals. 
2. Description of the Prior Art 
All stages in the life cycle of the tick tend to damage the skins of 
afflicted animals and thereby spoil the state of the skins, with the 
consequence for example, that cattle hides and sheep skins intended for 
manufacture of leather and sheep skin respectively, are reduced in 
quality. Furthermore, the ticks may facilitate the transmission of disease 
to the afflicted animal, and the general state of health and the quality 
of flesh of the animal may be detrimentally affected. 
U.S. Pat. No. 3,954,784 discloses quaternary 7-substituted 
imidazo[2,1-b]-thiazolium salts of the formula: 
##STR1## 
wherein X.sub.1.sup.- is a pharmaceutically acceptable anion, preferably 
chloride or bromide ion; R.sub.1 is alkyl having from 12 to 18 carbon 
atoms; R.sub.2 is hydrogen or alkyl having from one to three carbon atoms; 
R.sub.3 is R.sub.2, phenyl or substituted phenyl wherein said substituent 
is dimethyl or dimethoxy; R.sub.2 and R.sub.3 taken together is 
tetramethylene and R.sub.4 and R.sub.5 may be hydrogen. The preparation 
and use of these compounds as hypoglycemic agents and growth promotants is 
also disclosed therein. 
SUMMARY OF THE INVENTION 
It is an object of the invention to provide a series of compounds having 
acaricidal properties, particularly against cattle ticks, pharmaceutical 
compositions comprising such compounds and a method for protecting animals 
from acarids by treating said animals with said compounds. 
The invention therefore provides novel 
8-substituted-6,7-dihydro[5H]thiazolo[3,2-a]pyrimidinium and 
9-substituted-5,6,7,8-tetrahydrothiazolo[3,2-a][1,3]diazepinium salts of 
the formula (I): 
##STR2## 
wherein X.sup.- is a pharmaceutically acceptable anion; R.sup.1 is an 
alkyl group having from 10 to 20 carbon atoms; n is 1 or 2; each of 
R.sup.2 and R.sup.3 is selected from the group consisting of hydrogen, 
alkyl having from one to six carbon atoms, phenyl and phenyl substituted 
by up to two members which may be the same or different and are selected 
from the group consisting of fluoro, chloro, bromo, hydroxyl, alkyl having 
from one to three carbon atoms, alkoxy having from one to three carbon 
atoms, cyano, nitro, and trifluoromethyl; and R.sup.2 and R.sup.3 taken 
together form a tetramethylene group. 
It is preferred that X.sup.- is chloride, bromide or iodide ion and bromide 
ion is especially preferred. 
A preferred group of compounds are those wherein R.sup.1 is alkyl having 
from 10 to 18 and especially 15 to 17 carbon atoms; R.sup.2 is hydrogen or 
methyl and R.sup.3 is methyl, ethyl or phenyl. 
The invention also provides an acaricidal composition comprising a diluent 
or carrier and an acaricidally effective amount of a compound selected 
from those of the formulae (IV), (V) and (VI). 
##STR3## 
wherein X.sup.- and R.sup.1, R.sup.2 and R.sup.3 are as previously 
defined; with the proviso that in formula (IV) R.sup.2 is other than 
hydrogen, phenyl and said substituted phenyl and R.sup.3 is other than 
hydrogen. 
The invention further provides a method for protecting animals from acarids 
which comprises externally treating said animals with an acaricidal amount 
of a compound of the formula (IV), (V) or (VI). Particularly effective in 
providing protection from acarids by this method are compounds of formula 
(IV) wherein X.sup.- is bromide ion, R.sup.1 is alkyl having from 10 to 18 
carbon atoms, R.sup.2 is methyl and R.sup.3 is phenyl; compounds of 
formula (V) wherein X.sup.- is bromide ion, R.sup.1 is n-tetradecyl or 
n-hexadecyl, R.sup.2 is methyl and R.sup.3 is methyl or ethyl as well as 
compounds of formula (VI) wherein X.sup.- is bromide ion, R.sup.1 is 
n-pentadecyl or n-hexadecyl; R.sup.2 is hydrogen or methyl and R.sup.3 is 
methyl or phenyl. 
Particularly preferred individual novel compounds of the invention include 
the following compounds wherein the R.sup.1 substituent is a n-alkyl 
group: 
8-tetradecyl- and 8-hexadecyl-substituted derivatives of 
3-ethyl-2-methyl-6,7-dihydro-[5H]-thiazolo[3,2-a]pyrimidinium bromide; 
8-hexadecyl-2-methyl-3-phenyl-6,7-dihydro-[5H]-thiazolo[3,2-a]pyrimidinium 
bromide; 8-pentadecyl-, 8-hexadecyl- and 
8-heptadecyl-3-phenyl-6,7-dihydro-[5H]-thiazolo[3,2-a]pyrimidinium 
bromides; the 9-tetradecyl to 9-heptadecyl substituted derivatives of 
3-methyl- and 3-phenyl-5,6,7,8-tetrahydrothiazolo[3,2-a][1,3]diazepinium 
bromide; 
9-hexadecyl-2-methyl-3-phenyl-5,6,7,8-tetrahydro-thiazolo[3,2-a][1,3]diaze 
pinium bromide; and 
9-hexadecyl-2,3-tetramethylene-5,6,7,8-tetrahydrothiazolo[3,2-a][1,3]diaze 
pinium bromide. 
DETAILED DESCRIPTION OF THE INVENTION 
In the formulae used herein, the quaternary nitrogen is arbitrarily shown 
in the 7-, 8- or 9-position, but it may also be in the 4-position, the 
double bond then being to that nitrogen. There also may be resonance 
between these two structures. 
Methods for the preparation of compounds of formula (IV) are described in 
U.S. Pat. No. 3,954,784 and in the corresponding Belgian Pat. No. 820,186 
published Mar. 20, 1975. The compounds of formulae (I), (V) and (VI) can 
be readily prepared in a similar manner from compounds of formula (II): 
##STR4## 
where n, R.sup.2 and .sup.3 are as previously defined, by treatment with 
alkylating agents such as, for example, those of the formula R.sup.1 
-halogen, where halogen is Cl, Br or I, sulphates of the formula 
(R.sup.1).sub.2 SO.sub.4 or R.sup.1 HSO.sub.4 or aryl sulphonates of the 
formula R.sup.1 OSO.sub.2 Ar, where Ar is an aryl group such as, for 
example, phenyl, tolyl or xylyl, to form a quaternary salt of formula (I) 
in which X.sup.- is the corresponding anion, e.g., chloride, bromide, 
iodide, sulphate, hydrogen sulphate, benzene sulphonate or p-toluene 
sulphonate. Preferred values of X.sup.- are the above mentioned halides, 
especially bromide. Such salts can be converted to other pharmaceutically 
acceptable salts, if desired, by conventional means, see, for example, 
U.S. Pat. No. 3,954,784. Examples of such other pharmaceutically 
acceptable anions are nitrate, phosphate, acid phosphate, acetate, 
fumarate, lactate, citrate, tartarate, gluconate, p-toluenesulphonate and 
pamoate. 
Reaction with the alkylating agent may be conveniently carried out by 
dissolving or suspending the compound of formula (II) as free base in the 
alkylating agent either neat or in the presence of a suitable reaction 
inert solvent, i.e. a solvent which does not react to any appreciable 
degree with the reactants or product under the conditions of the reaction. 
Suitable reaction inert solvents can be of a varied nature, and can 
include lower alkanols such as methanol, butanol and isoamyl alcohol; 
lower alkylnitriles such as acetonitrile, propionitrile; 
di(lower)alkylketones such as acetone, diethyl ketone and methyl ethyl 
ketone; lower alkylethers such as ethyl ether, isopropyl ether and methyl 
butyl ether and N,N-dimethylformamide. Preferred solvents for this 
reaction are acetonitrile and N,N-dimethylformamide. When the reaction is 
conducted neat, it is preferred that the alkylating agent employed is a 
liquid at the reaction temperature employed. The alkylating agent is 
preferably added at room temperature and the mixture reacted at a 
temperature from about room temperature up to the reflux temperature of 
the solvent, if present, for periods up to 24 hours. Typically, when 
acetonitrile is employed as solvent the reaction mixture is held at reflux 
for 16 hours. 
On cooling the reaction mixture, if necessary to a temperature as low as 
-10.degree. C., the desired product will separate as solid which is 
filtered off and washed with a suitable non-solvent for the product, e.g. 
petroleum ether. Alternatively the solvent is removed by evaporation and 
the product washed as before. Recrystallization from a suitable solvent 
for the product e.g. ethereal acetonitrile will then normally yield the 
product in a pure state. 
The compounds of formula (II) used as starting materials are either known 
compounds or can readily be prepared by methods analogous to those 
described in the literature, e.g. by reaction of a N,N-tri or 
tetramethylenethiourea of the formula: 
##STR5## 
where n is 1 or 2, with an .alpha.-halo-aldehyde or ketone of the formula 
R.sup.2 CHZCOR.sup.3, where Z is Cl or Br. Thus the preparation of 
6,7-dihydro[5H]thiazolo[3,2-a]pyrimidines is described by Chadha and 
Pujari in Canadian J. Chem., 1969, 47, 2843, by Gakhar, Kaushal and Narang 
in Indian J. Appl. Chem., 1970, 33, 269 and in West German 
Offenlegungsschrift 1805948 while the preparation of 
5,6,7,8-tetrahydro-thiazolo[3,2-a][1,3]diazepines is described by Chadha, 
Chaudhary and Pujari in Australian J. Chem., 1969, 22, 2697, by Dhaka, 
Chadha and Pujari in Indian J. Chem., 1973, 11, 554 and in U.S. Pat. No. 
3,763,142. 
The above-mentioned .alpha.-haloaldehydes and .alpha.-haloketones are 
available either commercially or by synthetic procedures familiar to those 
skilled in the art. 
The compounds of the formulae (I), (IV), (V) and (VI) have acaricidal 
activity, particularly against all stages in the life cycle, including 
gravid female ticks, of the cattle ticks Boophilus microplus and 
Haemaphysalis longicornus. 
In one test, five freshly collected, fully engorged Boophilus microplus 
adult ticks are used for each acaricidal compound. Using a micro-pipette, 
10 micro-liters of a solution containing 10 micro-grams of the acaricidal 
compound in ethanol or acetone, is applied to the dorsal surface of each 
of the ticks. The treated ticks are placed in weighed 1 .times. 2 inch 
glass vials, weighed and stored at 26.degree. C. and 80% relative humidity 
in plastic boxes for 2 weeks. The ticks are then removed from the vials 
and the vials weighed to give the weight of eggs laid by the ticks. Any 
reduction in the egg laying of the treated ticks is calculated as a 
percentage of the eggs laid by untreated control ticks. 
The eggs are returned to the incubator for a further 3 weeks after which 
time the percentage of eggs hatching is estimated. 
The percentage effect is calculated as the overall reduction in the 
anticipated reproduction of the ticks using the weight of eggs laid and 
the percentage of eggs hatching. 
The test may be repeated using smaller amounts of the acaricidal compound 
for sufficiently active compounds. 
In another test, using a pipette 0.5 ml. of a solution containing 0.5 mg. 
of the acaricidal compound in ethanol or acetone is spread evenly on to a 
Whatman No. 1 filter paper 8 cm. .times. 6.25 cm. (50 sq. cm.) to give a 
dosage of 100 mg./m.sup.2. 
The treated paper is allowed to dry at room temperature, folded with the 
treated surface inside the two short edges sealed with a crimping machine. 
The open ended ended envelope is placed in a 1 lb. Kilner jar containing 
damp cotton wool in a plastic pot and stored in an incubator at 26.degree. 
C. for 24 hours. 20-50 Boophilus microplus larvae, which had hatched 8-14 
days previously, are placed in the envelope using a small spatula. The 
open end is then crimped to form a sealed packet. The treated paper 
containing the larvae is returned to the Kilner jar and kept for a further 
48 hours in the incubator. 20-50 larvae are placed similarly in an 
untreated paper envelope to act as controls. At the end of the 48 hours 
test period, the mortality is noted and recorded as a percentage after 
correction for any mortality among the untreated control ticks. 
The test may be repeated using smaller amounts of the acaricidal compound. 
In addition to percentage effectiveness figures, ED.sub.50 results can be 
obtained from dose response measurements using any of the aforedescribed 
tests. 
Activity against Haemaphysalis longicornus nymphs may be measured in a 
similar manner to the above larvae test. 
The activity of many of the compounds of the Examples detailed hereinafter 
against the tick Boophilus microplus has been determined. Table I shows 
the % effect for the compounds at the dose levels tested. 
TABLE I 
______________________________________ 
In Vitro Activity (topical application) vs. Adult 
Boophilus microplus % Effect 
Example 
Dose .mu.g/tick 
No. 10 8 4 2 1 0.5 
______________________________________ 
1 100 100 100 99 59 24 
2 100 100 77 67 16 
3 100 97 90 26 13 2 
4 83 100 75 12 
5 65 63 32 4 0 
6 100 98 79 43 7 
7 100 100 99 92 54 31 
8 26 
9 42 
10 72 
11 100 100 100 73 36 30 
12 100 87 38 22 19 16 
13 100 99.9 99.4 21 6 0 
14 47 
15 100 100 99.9 29 9 11 
16 33 
19 49 28 9 0 
20 100 100 99 67 29 0 
21 100 100 98 83 0 
22 57 
23 100 100 100 98 60 6 
24 100 100 97 70 48 13 
25 98 78 82 40 20 
26 99 92 61 43 12 14 
27 86 75 63 55 38 40 
28 100 83 74 52 13 
29 100 100 55 11 19 
30 100 95 56 47 13 
31 100 52 0 
32 100 95 94 66 12 0 
33 100 72 30 13 2 2 
34 32 
35 100 100 70 13 8 0 
36 26 
37 87 
38 30 
41 92 43 16 18 18 5 
42 100 100 90 50 52 6 
43 100 100 96 72 23 4 
44 100 100 93 89 63 0 
45 88 
46 95 
______________________________________ 
Thus the invention provides an acaricidal composition comprising an 
acaricidally effective amount of a compound selected from those of the 
formulae (IV), (V) and (VI) together with a diluent or carrier. The 
diluent or carrier may be a solid or a liquid, optionally together with a 
dispersing agent, emulsifying agent or wetting agent. The compositions of 
the invention include not only compositions in a suitable form for 
application but concentrated primary compositions which may be supplied to 
the user and which require dilution with a suitable quantity of water or 
other diluent prior to application. Typical compositions of the invention 
include, for example, dusting powders, dispersible powders, solutions, 
dispersions, emulsions and emulsifiable concentrations. 
A dust may be made by mixing the appropriate amount of the finely divided 
active compound with a solid pulverulent diluent or carrier such as talc, 
clay, calcite, pyrophyllite, diatomaceous earth, walnut shell flour, 
silica gel, hydrated alumina, or calcium silicate. As an alternative 
method of preparation, the diluent or carrier is mixed with a solution of 
the active compound in a volatile organic solvent such as toluene, the 
solvent being subsequently removed by evaporation. Preferably, the active 
compound will be present in the dust in an amount of from about 0.25 to 
about 4% by weight. 
Dispersible powders, of special value for spray applications, may be made 
by adding a suitable dispersing agent to the active compound, or to a dust 
containing the active compound, so that a stable aqueous dispersion of the 
active compound is formed on mixing the powder with water. The dispersible 
powders preferably contain from about 25 to 75% by weight of the active 
compound. 
Emulsifiable concentrates comprise a solution of the active compound in a 
substantially water-immiscible non-toxic organic solvent containing an 
emulsifying agent. Suitable solvents include, for example, toluene, 
xylene, petroleum oil, and alkylated naphthalenes. Preferably, the 
concentrate will contain 5-75 gms. of the active compound per 100 ml. of 
solution. The concentrates may be diluted with water prior to use to give 
a concentration of the active compound in the aqueous medium of from e.g. 
about 0.0005 to about 0.1% w/v (g/100 ml.) or approximately 5 to 1000 
p.p.m. The volatile solvents, e.g. toluene and xylene, evaporate after 
spraying to leave a deposit of the active ingredient. The made up spray or 
dip may be an emulsion or solution. 
The compositions of the invention may be applied to ground, such as that 
around dairies, in order to combat, e.g. cattle ticks thereon. However, it 
is preferred to treat animals by spraying them or passing them through 
animal dips. 
Thus the present invention also provides a method for protecting animals, 
particularly cattle, from acarids, particularly cattle ticks, which 
comprises treating the animal externally with an acaricidal amount of a 
compounds selected from those of the formulae (IV), (V) and (VI) or 
acaricidal composition as defined above. 
The compositions of the invention may also contain a pesticide, fungicide, 
additional acaricide, or the like.