Certain heteroaryl triazapentadienes with acaricidal properties and their preparation are described.

BACKGROUND OF THE INVENTION 
All stages in the life cycle of ticks tend to damage the skins of afflicted 
animals and thereby spoil the state of the skins with the consequence that 
cattle hides and sheep skins intended for the manufacture of leather and 
sheep skin 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. 
Belgian Pat. No. 816,760 describes certain 5-(substituted 
phenyl)-3-(alkyl)-1-(alkyl)-1,3,5-triazapenta-1,4-dienes as broad spectrum 
parasiticides. 
We have now found that certain 5-(substituted 
phenyl)-3-methyl-1-(heteroaryl)-triazapenta-1,4-dienes have particularly 
useful acaricidal properties, and are thus very useful in destroying one 
or more stages in the life cycle of ticks which tend to infest the skins 
of animals such as cattle. They may also have insecticidal properties, 
particularly against plant insects such as pea aphids (hemiptera). 
SUMMARY OF THE INVENTION 
This invention is concerned with triazapentadienes of the formula: 
##STR1## 
wherein R.sup.1 is a C.sub.1 -C.sub.4 alkyl group; 
R.sup.2 is a hydrogen atom, a halogen atom or a C.sub.1 -C.sub.4 alkyl 
group; 
R.sup.3 is a monocyclic or bicyclic heteroaryl group attached to the 
adjacent nitrogen atom by a carbon atom of said group; and 
R.sup.4 is a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group; 
and the acid addition salts of the compounds of the formula (I) which form 
such salts. 
DETAILED DESCRIPTION OF THE INVENTION 
In this specification the term "halogen" means fluorine, chlorine, bromine 
or iodine. 
Alkyl groups containing three or more carbon atoms may be straight or 
branched chain. The preferred alkyl groups contain 1 or 2 carbon atoms. 
R.sup.1 is preferably a methyl group. 
R.sup.2 is preferably a methyl group or a chlorine atom. 
R.sup.2 is most preferably methyl. 
Generally, the preferred heteroaryl groups within the scope of R.sup.3 are 
those including at least one ring nitrogen atom, such as quinolyl, 
isoquinolyl, pyridyl, pyrimidinyl, quinazolinyl, quinoxalinyl, tetrazolyl, 
thiazolyl, benzothiazolyl, 4,5,6,7-tetrahydrobenzothiazolyl, thiadiazolyl, 
indazolyl, oxazolyl, benzoxazolyl, pyridazinyl and pyrazinyl. However, 
benzothienyl is also a preferred heteroaryl group within the scope of 
R.sup.3. 
The heteroaryl group represented by R.sup.3 may be substituted or 
unsubstituted. Preferred substituents are C.sub.1 -C.sub.6 alkyl, C.sub.1 
-C.sub.6 alkoxy, di(C.sub.1 -C.sub.4 alkoxy) methyl, (C.sub.1 -C.sub.4 
alkoxy) carbonyl, halogen, trifluoromethyl, phenyl, and C.sub.2 -C.sub.5 
alkanoyl. Preferred alkoxy groups contain 1 or 2 carbon atoms and 
preferred alkanoyl groups 2 or 3 carbon atoms. 
The more preferred heteroaryl groups are quinolyl, isoquinolyl, pyridyl, 
quinoxalinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, tetrazolyl, 
thiazolyl, benzothiazolyl, 4,5,6,7-tetrahydrobenzothiazolyl and 
benzothienyl optionally containing one or two substituents selected from 
C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, phenyl, di(C.sub.1 
-C.sub.4 alkoxy) methyl, (C.sub.1 -C.sub.4 alkoxy)carbonyl and halogen. 
The most preferred heteroaryl groups are thiazolyl, pyridyl, quinolyl, 
pyrazinyl, pyridazinyl, quinoxalinyl, benzothiazolyl and benzothienyla 
optionally containing one or two substituents selected from halogen, 
C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 alkoxy. 
R.sup.4 is preferably a hydrogen atom. 
The preferred individual compounds are as follows: 
5-(2,5-dimethylphenyl)-3-methyl-1-(2-thiazolyl)-1,3,5-triazapenta-1,4-diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(2-pyridyl)-1,3,5-triazapenta-1,4-diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(3-quinolyl)-1,3,5-triazapenta-1,4-diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(3-ethyl-6-methyl-pyrid-2-yl)-1,3,5-triaz 
apenta-1,4-diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(3-ethyl-pyrid-2-yl)-1,3,5-triazapenta-1, 
4-diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(3-methyl-pyrid-2-yl)-1,3,5-triazapenta-1 
,4-diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(2,5-dimethyl-pyrid-3-yl)-1,3,5-triazapen 
ta-1,4-diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(2-chloro-pyrid-3-yl)-1,3,5-triazapenta-1 
,4-diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(2-pyrazinyl)-1,3,5-triazapenta-1,4-diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(6-methoxy-pyridazin-3-yl)-1,3,5-triazape 
nta-1,4-diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(6-quinolyl)-1,3,5-triazapenta-1,4-diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(6-quinoxalinyl)-1,3,5-triazapenta-1,4-di 
ene 
5-(2,4-dimethylphenyl)-3-methyl-1-(3,6-dimethyl-pyrid-2-yl)-1,3,5-triazapen 
ta-1,4-diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(3,5-dimethyl-pyrid-2-yl)-1,3,5-triazapen 
ta-1,4-diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(3-n-propyl-pyrid-2-yl)-1,3,5-triazapenta 
-1,4-diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(3-n-butyl-pyrid-2-yl)-1,3,5-triazapenta- 
1,4-diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(6-benzothiazolyl)-1,3,5-triazapenta-1,4- 
diene 
5-(2,4-dimethylphenyl)-3-methyl-1-(6-benzothienyl)-1,3,5-triazapenta-1,4-di 
ene 
5-(2,4-dimethylphenyl)-3-methyl-1-(3,4-dimethyl-pyrid-2-yl)-1,3,5-triazapen 
ta-1,4-diene. 
The compounds of the invention may be prepared via a number of routes, 
including the following: 
(1) Compounds in which R.sup.4 is hydrogen may be prepared by reacting a 
formamidine of the formula: 
##STR2## 
with an isonitrile of the formula R.sup.3.NC. R.sup.1, R.sup.2 and R.sup.3 
are as defined for formula (I). 
The reaction may be effected in the presence of a suitable catalyst, most 
preferably finely divided copper metal or a cuprous catalyst such as 
cuprous oxide or cuprous chloride in a trace amount, a typical reaction 
temperature being 50.degree. to 80.degree. C. Increased reaction 
temperatures are not generally recommended because they tend to increase 
the formation of by-products due to the reaction of one molecule of 
compound (II) with another such molecule. The reaction may be effected in 
the presence of a suitable inert organic solvent, such as benzene or 
toluene. 
Generally, long reaction times are necessary unless finely divided copper 
metal is used as the catalyst. 
Typically, the product is recovered by evaporation of the reaction mixture 
in vacuo to leave an oil which may, if necessary, be purified by a 
conventional procedure such as treatment with neutral alumina in 
40.degree.-60.degree. petroleum ether. The purified oil may crystallise on 
standing to give crystals of the desired product of the formula (I). 
The isonitriles of the formula R.sup.3.NC and the formamidines of the 
formula (II) are either known compounds or may be prepared by procedures 
analogous to those of the prior art. Methods for the preparation of 
formamidines falling within the formula (II) are described for example in 
British Patent Specifications Nos. 964,640, 1,039,930 and 1,327,936. 
(2) The following route, in which R.sup.4 may be hydrogen or C.sub.1 
-C.sub.4 alkyl, is also possible: 
an imidate of the formula: 
##STR3## 
wherein R.sup.1 and R.sup.2 are as defined for formula (I) and R.sup.5 is 
a C.sub.1 -C.sub.4 alkyl group, is reacted with an amidine of the formula: 
##STR4## 
wherein R.sup.3 and R.sup.4 are as defined for formula (I). 
(3) Compounds of the formula (I) in which R.sup.4 is a hydrogen atom or a 
C.sub.1 -C.sub.4 alkyl group may be prepared by reacting an amidine of the 
formula: 
##STR5## 
wherein R.sup.3 and R.sup.4 are as defined for formula (I), with an 
isonitrile of the formula: 
##STR6## 
wherein R.sup.1 and R.sup.2 are as defined for formula (I). 
The reaction and isolation of the product may be carried out in a similar 
manner to method (1) above, although in this case it is generally possible 
to use reaction temperature of above 80.degree. C. without substantially 
increasing the formation of by-products, reaction generally being 
substantially complete within 4-8 hours at 100.degree. C. except when 
using finely divided copper metal as the catalyst in which case the 
reaction is generally complete in 1-2 hours. 
This is a preferred route. The starting materials of the formula (IV) are 
either known compounds or may be obtained in a conventional manner, e.g. 
as follows: 
##STR7## 
(4) The compounds of the formula (I) in which R.sup.4 is a hydrogen atom or 
a C.sub.1 -C.sub.4 alkyl group may also be prepared by reacting a 
formamidine of the formula: 
##STR8## 
wherein R.sup.1 and R.sup.2 are as defined for formula (I), with an 
imidate of the formula: 
##STR9## 
wherein R.sup.3 and R.sup.4 are as defined for formula (I) and R.sup.6 is 
a C.sub.1 -C.sub.4 alkyl group. R.sup.6 is preferably an ethyl group. 
The reaction is typically carried out by heating the reactants together for 
several hours, e.g. at 40.degree.-100.degree. C. for 2-4 hours. 
Alternatively a solvent, e.g. iso-octane, may be used. The product 
typically crystallises on cooling and may be purified by crystallisation 
from e.g. hexane, cyclohexane or mixed solvents, e.g. methylene 
chloride/hexane. Treatment with decolouring carbon during crystallisation 
may be beneficial. 
This is a preferred route. 
The imidates of the formula (VI) are either known compounds or may be 
obtained in a conventional manner, e.g. as follows: 
##STR10## 
(5) The acid-addition salts of the compounds of the formula (I) which form 
such salts may be made in a conventional manner, e.g. by mixing a solution 
of the free base in a suitable solvent, e.g. diethyl ether, with a 
solution of the appropriate acid in a suitable solvent, e.g. diethyl 
ether, and recovering the salt as a precipitate. 
The compounds of the formula (I) have acaricidal activity, particularly 
against all stages in the life cycle, including gravid female ticks, of 
the cattle ticks Boophilus microplus, Haemaphysalis longicornus, 
Phipicephalus appendiculatus and Boophilus decoloratus. 
In one test, five freshly collected, fully engorged Boophilus microplus 
adult female 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" glass vials, weighed and stored at 26.degree. C. and 80%+R.H. 
in plastic boxes for two 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 reduction in the anticipated reproduction of the ticks is 
calculated using the weight of eggs laid and the percentage of eggs 
hatching. 
The test may be repeated using smaller amounts of the acaricidal compound. 
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. c.m.) 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 and two short edges sealed with a crimping machine. 
The open 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 hour 
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 afore-described 
tests. 
Activity against Haemaphysalis longicornus nymphs may be measured in a 
similar manner to the above larvae test. 
The activity of certain of the compounds of the Examples detailed 
hereinafter against the tick Boophilus microplus is set out in the 
following Table: 
TABLE 
______________________________________ 
Boophilus Microplus (in vitro) 
Adult (Topical) 
% 
Larva (Contact) Reduction 
Compound 
Dose Dose in Egg 
No. (mg/m.sup.2) 
% Kill (.mu.g/tick) 
Hatch 
______________________________________ 
1 100 100 10 100 
and 90 12.5 100 2 99 
2 100 100 10 99 
and 91 6.25 100 4 93 
3 100 100 10 99 
12.5 94 2 96 
4 100 100 10 100 
12.5 100 2 97 
5 100 100 10 100 
12.5 100 4 88 
6 100 100 10 100 
6.25 100 4 86 
7 100 100 10 89 
12.5 100 
8 100 100 10 90 
25 100 
9 100 100 10 53 
25 86 
10 100 100 10 92 
25 89 
11 100 100 10 92 
6.25 100 
12 100 78 -- -- 
13 100 31 8 68 
14 100 100 10 100 
3.13 90 4 97 
15 100 100 10 100 
3.13 100 4 83 
16 100 100 10 100 
and 92 3.13 98 2 95 
17 100 100 10 100 
6.25 100 2 67 
18 100 56 10 100 
and 76 4 99 
20 100 100 10 29 
12.5 100 
21 100 86 10 58 
22 100 90 10 99 
4 97 
23 100 100 10 85 
12.5 100 
24 100 100 10 100 
12.5 83 2 90 
25 100 100 10 100 
12.5 88 2 91 
26 100 100 10 100 
25 98 8 98 
27 100 85 10 53 
28 100 100 10 100 
50 98 2 99 
29 100 100 2 20 
50 82 
30 100 100 10 78 
25 92 
31 100 100 10 94 
6.25 83 
32 100 17 10 59 
33 100 33 10 100 
4 98 
34 100 100 10 93 
35 100 100 10 13 
25 83 
36 100 100 10 16 
37 100 32 10 100 
4 90 
38 100 100 10 72 
6.25 94 
39 100 100 10 96 
12.5 98 
40 100 14 8 100 
4 81 
41 100 100 10 100 
42 100 100 10 25 
12.5 100 
43 100 97 10 100 
12.5 100 
44 100 100 10 97 
6.25 84 
45 100 100 10 100 
6.25 100 
46 100 100 10 22 
47 100 100 10 28 
48 100 92 10 100 
8 91 
50 100 100 10 95 
25 100 8 94 
51 100 100 10 93 
52 100 100 10 18 
50 100 
54 100 80 10 55 
55 100 100 10 26 
12.5 100 
56 100 100 10 85 
25 73 
57 100 80 10 89 
58 100 97 10 96 
25 79 
59 100 100 10 66 
25 68 
60 100 94 10 28 
25 88 
62 100 98 10 88 
50 60 
63 100 100 10 7 
12.5 100 
65 100 100 10 100 
12.5 76 1 97 
66 100 100 10 100 
-- -- 1 90 
67 100 84 10 98 
-- -- 4 58 
68 100 69 10 100 
-- -- 4 84 
69 100 24 10 99 
70 100 100 10 100 
3.12 95 1 31 
71 100 85 10 89 
-- -- 4 57 
72 100 100 10 99 
1.56 73 2 22 
73 100 100 10 91 
12.5 100 2 69 
74 100 66 10 99 
-- -- 4 52 
77 100 100 10 100 
12.5 89 2 71 
78 100 91 10 100 
2 97 
79 100 100 10 100 
50 33 1 83 
80 100 59 10 100 
2 98 
83 100 85 10 100 
1 97 
______________________________________ 
Thus the invention also provides an acaricidal composition comprising a 
compound of the formula (I) together with a diluent or carrier. The 
diluent or carrier may be a solid or a liquid, optionally together with an 
antioxidant, 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, 
dispersions, emulsions and emulsifiable concentrates. 
A dust may be made by mixing the appropriate amount of the finely divided 
active compound with a solid pulverent 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 benzene, the 
solvent being subsequently removed by evaporation. Typically, the active 
compound will be present in the dust in an amount of from 0.25 to about 4% 
by weight. 
Dispersible powders 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 typical concentration of the active compound in the aqueous medium of 
from e.g. about 0.001 to about 0.1% w/v (g/100 ml.), or approximately 10 
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 will generally be an emulsion. 
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 
compound of the formula (I) or acaricidal composition as defined above. 
The compositions of the invention may also contain a pesticide, fungicide, 
additional acaricide, or the like.