N-aryl-1,2,3-triazole compounds for pharmaceutical and veterinary application

Compounds of formula (I): ##STR1## wherein the substituents are as defined herein, are antiparasitic agents.

This invention relates to nitrogen-containing heterocyclic substances 
having parasiticidal properties, in particular to 
N-aryl/heteroaryl-substituted heterocycles. 
International Patent Application publication number WO98/24767 and European 
Patent Application publication number EP 0 846 686 A1 disclose certain 
1-N-arylpyrazole substances with a 4-cyclopropyl moiety and a 
4-heterocyclyl moiety respectively, as having antiparasitic properties. 
According to the present invention, there is provided a compound of formula 
(I): 
##STR2## 
wherein A is N or CR.sup.5, B is N or CR.sup.6, 
wherein R.sup.5 and R.sup.6 are each independently selected from H, 
C.sub.1-4 alkyl optionally substituted by one or more halo, CN and halo, 
or when A and B are CR.sup.5 and CR.sup.6, respectively, they can be taken 
together to form a fused benzo- or pyridino-ring, 
which fused ring is optionally substituted by one or two halo substituents 
and, when the pyridino-fused ring is present, optionally bears an oxide 
substituent on the nitrogen of said pyridino-ring, 
R.sup.1 is a 5-membered heteroaryl group selected from furan-2-yl, 
furan-3-yl, thien-2-yl, thien-3-yl and isoxazol-5-yl, each of which is 
optionally substituted by one or two substituents independently selected 
from halo, C.sub.1-4 alkyl optionally substituted by one or more halo, and 
(C.sub.1-4 alkyl optionally substituted by one or more halo)S(O).sub.n, 
or R.sup.1 is a group of formula (II): 
##STR3## 
wherein R.sup.7 is H, C.sub.1-4 alkyl optionally substituted by one or 
more halo, or C.sub.1-4 alkoxy optionally substituted by one or more halo, 
R.sup.8 and R.sup.9 are either each independently selected from H, chloro, 
fluoro, bromo and 
C.sub.1-4 alkyl optionally substituted by one or more halo, or, when taken 
together with the carbon atom to which they are attached, form a C.sub.3-6 
cycloalkyl group, 
R.sup.10 and R.sup.11 are either each independently selected from H, 
chloro, fluoro, bromo and C.sub.1-4 alkyl optionally substituted by one or 
more halo, or, when R.sup.8 and R.sup.9 taken together do not form part of 
a cycloalkyl group, R.sup.10 and R.sup.11 together with the carbon atom to 
which they are attached, form a C.sub.5-7 cycloalkyl group, 
E is N or CR.sup.2, wherein 
R.sup.2 is H, NH.sub.2, halo, NHCH.sub.2 (phenyl optionally substituted by 
C.sub.1-4 alkoxy), CO.sub.2 (C.sub.1-4 alkyl optionally substituted by one 
or more halo) or S(O).sub.n (C.sub.1-4 alkyl optionally substituted by one 
or more halo), 
X is N or CR.sup.12, wherein 
R.sup.12 is halo, 
R.sup.3 is halo, 
R.sup.4 is C.sub.1-4 alkyl optionally substituted by one or more halo, 
C.sub.1-4 alkoxy optionally substituted by one or more halo, S(O).sub.n 
(C.sub.1-4 alkyl optionally substituted by one or more halo), halo or 
SF.sub.5, and 
n is 0, 1 or 2, 
with the provisos that (i) when B is N, then A and/or E is also N, and (ii) 
when E is N then A and/or B is also N, 
or a pharmaceutically-, agriculturally- or veterinarily-acceptable salt 
thereof, or solvate of any such compound or salt (hereinafter referred to 
as "the substances of the invention"). 
Alkyl groups may be straight or branched where the number of carbon atoms 
allows. S(O).sub.n alkyl and alkoxy groups incorporate such alkyl 
moieties. Halo means fluoro, chloro, bromo or iodo. 
Pharmaceutically-, agriculturally or veterinarily-acceptable salts are 
well-known in the art and include, for example those mentioned by Berge et 
al in J.Pharm.Sci., 66, 1-19 (1977). Suitable acid addition salts are 
formed from acids which form non-toxic salts and include the 
hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate, bisulphate, 
phosphate, hydrogenphosphate, acetate, gluconate, lactate, salicylate, 
citrate, tartrate, ascorbate, succinate, maleate, fumarate, formate, 
benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate and 
p-toluenesulphonate salts. 
Solvates (e.g. hydrates) are generally well-known in the art and can be 
prepared by standard methods. 
Preferably the "ABNEC" ring moiety in the compound of formula (I) above is 
a pyrrol-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, imidazol-1-yl or 
indol-1-yl moiety. 
Preferably R.sup.5 is H, C.sub.1-4 alkyl optionally substituted by one or 
more halo, CN, or when B is CR.sup.6, together with the carbon atom to 
which it is attached and CR.sup.6, is a benzo- or pyridino-ring, which 
benzo- or pyridino-ring is optionally substituted by one or two halo 
groups, and, when the pyridino-ring is present, oxide on the nitrogen of 
said pyridino-ring. More preferably R.sup.5 is H, CN, CH.sub.3 or 
CF.sub.3, or when B is CR.sup.6, together with the carbon atom to which it 
is attached and CR.sup.6, is a benzo- or pyridino-ring, which benzo- or 
pyridino-ring is optionally substituted by one or two fluoro groups, and, 
when the pyridino-ring is present, oxide on the nitrogen of said 
pyridino-ring. Most preferably R.sup.5 is H, CH.sub.3 or CN. 
Preferably R.sup.6 is H, halo, C.sub.1-4 alkyl optionally substituted by 
one or more halo, or when A is CR.sup.5, together with the carbon atom to 
which it is attached and CR.sup.5, is a benzo- or pyridino-ring, which 
benzo- or pyridino-ring is optionally substituted by one or two halo 
groups, and, when the pyridino-ring is present, oxide on the nitrogen of 
said pyridino-ring. More preferably R.sup.6 is H, halo, CH.sub.3 or 
CF.sub.3, or when A is CR.sup.5, together with the carbon atom to which it 
is attached and CR.sup.5, is a benzo- or pyridino-ring, which benzo- or 
pyridino-ring is optionally substituted by one or two fluoro groups, and, 
when the pyridino-ring is present, oxide on the nitrogen of said 
pyridino-ring. Most preferably, R.sup.6 is H, Cl, Br or CH.sub.3. 
Preferably R.sup.1 is a furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl or 
isoxazol-5-yl group, each optionally substituted by one or two 
substituents independently selected from halo, C.sub.1-4 alkyl optionally 
substituted by one or more halo, and (C.sub.1-4 alkyl optionally 
substituted by one or more halo)S(O).sub.n, 
or R.sup.1 is a group of formula (II): 
##STR4## 
wherein R.sup.7 is H or C.sub.1-4 alkyl optionally substituted by one or 
more halo, 
R.sup.8 and R.sup.9 are each independently selected from H, chloro, fluoro 
or bromo, and R.sup.10 and R.sup.11 are both H. 
More preferably R.sup.1 is furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl 
or isoxazol-5-yl group, each optionally substituted by one or two 
substituents independently selected from fluoro, chloro, bromo, CF.sub.3 
and CH.sub.3, 
or R.sup.1 is a group of formula (II): 
##STR5## 
wherein R.sup.7 is H, CH.sub.3 or CF.sub.3, R.sup.8 and R.sup.9 are each 
independently selected from H, chloro, fluoro or bromo, and R.sup.10 and 
R.sup.11 are both H. 
Most preferably, R.sup.1 is 3-bromisoxazol-5-yl, 2,2-dibromocyclopropyl, 
2,2-dichlorocyclopropyl or 1-trifluoromethylcyclopropyl. 
Preferably R.sup.2 is H, NH.sub.2, halo or NHCH.sub.2 (phenyl optionally 
substituted by C.sub.1-4 alkoxy). 
More preferably R.sup.2 is H, NH.sub.2,F, Cl or Br. 
Most preferably R.sup.2 is H or NH.sub.2. 
Preferably X is C--F, C--Cl or C--Br. 
More preferably X is C--Cl. 
Preferably R.sup.3 is chloro. 
Preferably R.sup.4 is methyl optionally substituted by one or more halo, 
methoxy optionally substituted by one or more halo, S(O).sub.n (methyl 
optionally substituted by one or more halo), halo or SF.sub.5. 
More preferably R.sup.4 is CF.sub.3, OCF.sub.3, SCF.sub.3 or SF.sub.5. 
The most preferred substances are those of the Examples below, and the 
salts and solvates thereof. 
The compounds of the formula (I) may possess one or more asymmetric centres 
and so exist in two or more stereoisomeric forms. The present invention 
includes all the individual stereoisomers of the compounds of formula (I), 
salts, solvates and mixtures thereof. 
Separation of diastereomers may be achieved by conventional techniques, 
e.g. by fractional crystallisation, chromatography such as H.P.L.C. of a 
stereoisomeric mixture of a compound of formula (I) or a suitable salt or 
derivative thereof. An individual enantiomer of a compound of formula (I) 
may also be prepared from a corresponding optically pure intermediate or 
by resolution, such as by H.P.L.C. of the corresponding racemate using a 
suitable chiral support or by fractional crystallisation of the 
diastereomeric salts formed by reaction of the corresponding racemate with 
a suitably optically active acid or base. 
The substances provided by the invention can be prepared by adaptation of 
methods disclosed in the art, specifically in the art relating to 
antiparasitic pyrazoles, such as in copending International Patent 
Application publication number WO98/24767 and European Patent Application 
publication number EP 0 846 686 A1, for instance by the methods 
specifically described in the Examples and Preparations section below, and 
suitable adaptation thereof. The synthetic chemist skilled in the art will 
be aware of many transformations that can be used to construct the 
substances of the invention.

Exemplary synthetic methods are described below. In these methods the 
definitions for the various groups and substituents are as given above for 
compounds of formula (I), unless specified otherwise. 
Method 1 
Compounds of the formula (I) wherein R.sup.1 is a group of formula (II): 
##STR6## 
can be made from the corresponding olefinic compound of formula (III) or 
(IV) below by a reaction which is formally regarded as a carbene transfer 
or insertion reaction of a "R.sup.8 R.sup.9 C:" or "R.sup.10 R.sup.11 C:" 
moiety as required. 
##STR7## 
Compounds of formulae (III) and (IV) can be made by conventional methods, 
for example by adaptation of the methods described for the corresponding 
pyrazole-4-olefins in International Patent Application publication number 
WO97/07102, which is herein incorporated by reference. 
The carbene transfer/insertion reactions can be carried out by the methods 
described in various texts known in the art, such as "Carbenes, Nitrenes 
and Arynes" by T L Gilchrist and C W Rees, published by Nelson (1973), and 
"Advanced Organic Chemistry" by J March, 3rd edition, published by 
Wiley-Interscience (1985) (e.g. section 5-49 on pp 768-774), both of which 
are herein incorporated by reference. The "R.sup.8 R.sup.9 C:" and 
"R.sup.10 R.sup.11 C:" moieties may be generated from suitable precursors 
known in the art. 
Method 2 
Compounds of formula (I) wherein R.sup.1 is a 5-membered heteroaryl group 
selected from furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl and 
isoxazol-5-yl, each of which is optionally substituted by one or two 
substituents independently selected from halo, CH.sub.3 CF.sub.3, and 
CF.sub.3 S(O).sub.n, can be prepared by cross-coupling reactions, for 
example palladium-catalysed cross-coupling, of compounds of the formula 
(V): 
##STR8## 
with boronic acids of the formula ArB(OH).sub.2, where Ar is a 5-membered 
heteroaryl group selected from furan-2-yl, furan-3-yl, thien-2-yl, 
thien-3-yl and isoxazol-5-yl, each of which is optionally substituted by 
one or two substituents independently selected from halo, CH.sub.3, 
CF.sub.3, and CF.sub.3 S(O).sub.n. The reaction is carried out using a 
suitable palladium (0) species such as Pd(PPh.sub.3).sub.4, in a suitable 
solvent or solvent system such as N,N-dimethylformamide (DMF), 
ethanol/toluene/water, diglyme/water or dioxane/water, and using a 
suitable base such as NaHCO.sub.3 or K.sub.2 CO.sub.3. The general 
palladium-catalysed cross coupling chemistry is described by A R Martin 
and Y Yang in Acta Chemica Scandinavica (1993), 47, 221-230. 
Intermediates of formula (V) above can be made by reaction of compounds of 
formula (VI): 
##STR9## 
with an iodinating or brominating species such as N-iodo- or 
N-bromosuccinimide in a suitable solvent such as acetonitrile. 
Compounds of formula (VI) can be made by conventional methods and by 
suitable adaptation of the methods described later in the Examples and 
Preparations section. 
Boronic acids of the formula ArB(OH).sub.2, where Ar is as defined above, 
can be made by conventional methods. 
Method 3 
Compounds of formula (I) where R.sup.1 is 3-bromoisoxazol-5-yl can be made 
by reaction of compounds of the formula (VII): 
##STR10## 
with dibromoformaldoxime and a suitable base such as KHCO.sub.3, in a 
suitable solvent or solvent system such as water/ethyl acetate. 
Compounds of formula (VII) can be made by conventional methods and those 
described in the Examples and Preparations section and suitable adaptation 
thereof, and also as described for the corresponding pyrazole-4-alkynes in 
International Patent Application publication no. WO 97/07102,herein 
incorporated by reference. 
Method 4 
Compounds of the formula (I) where R.sup.1 is 3-(iodo, bromo, or 
chloro)furan-2-yl can be made according to the reaction sequence shown 
below: 
##STR11## 
Compounds of formula (IX) can be made by oxidation of olefins of formula 
(III) or (IV) above where R.sup.7 is H, with a suitable oxidising regime 
such as with osmium tetroxide/N-methylmorpholine oxide (NMMO)/sodium 
metaperiodate. The reaction is carried out in a suitable solvent or 
solvent system such as acetone/water. 
Compounds of formula (X) can be made by reaction of aldehydes (IX) with the 
lithium salt of propiolaldehyde diethyl acetal. Preferably the lithium 
salt of propiolaldehyde diethyl acetal is prepared in situ from 
propiolaldehyde diethyl acetal and a suitable lithiating agent such as 
n-butyllithium. The reaction is preferably carried out in an ether solvent 
such as tetrahydrofuran, and preferably under an inert atmosphere such as 
under dry nitrogen. 
Compounds of formula (XI) where Y is chloro, bromo or iodo, can be made by 
reaction of compounds of formula (X) with an acid such as aqueous 
hydro(chloric, bromic or iodic) acid. The reaction can be carried out in a 
suitable solvent such as dioxane. The cyclisation reaction is derived from 
those described by Obrecht in Helv.Chim.Acta, vol.72 (1989) 447. 
Method 5 
Compounds of the formula (I) where R.sup.1 is 5-(iodo, bromo or 
chloro)thien-2-yl can be made by reacting the corresponding compound of 
formula (I) where R.sup.1 is thien-2-yl (preparable by Method 2) with an 
iodinating, brominating or chlorinating species respectively such as the 
corresponding N-(iodo, bromo, or chloro)succinimide in a suitable solvent 
such as acetonitrile. 
Method 6 
Compounds of the formula (I) where R.sup.1 is 
5-trifluoromethylsulphenylthien-2-yl can be made by reacting the 
corresponding compound of formula (I) where R.sup.1 is thien-2-yl 
(preparable by Method 2) with trifluoromethylsulphenyl chloride and 
stannic chloride in a suitable solvent such as dichloromethane. 
Method 7 
Compounds of the formula (I) where R.sup.1 is 3-(iodo, bromo, or 
chloro)4-(iodo, bromo, or chloro)-isoxazol-5-yl can be made by reacting 
the corresponding compound of formula (I) where R.sup.1 is 3-(iodo, bromo, 
or chloro)-isoxazol-5-yl (preparable by Methods above) with an iodinating, 
brominating or chlorinating species respectively such as the corresponding 
N-(iodo, bromo, or chloro)succinimide in a suitable solvent such as 
acetonitrile. 
Method 8 
Compounds of the formula (I) where R.sup.1 is 2-trifluoromethylfuran-3-yl 
can be made by reacting the corresponding compound of formula (I) where 
R.sup.1 is furan-3-yl (preparable by Method 2) with CF.sub.3 --Z where Z 
is a suitable leaving group such as Br, I, Cl, etc. with sodium dithionite 
and disodium hydrogen phosphate in a suitable solvent such as DMF, under 
elevated pressure such as 1.37 bar to 3.1 bar (20 to 45 p.s.i.). This type 
of reaction is described in J.Chem.Soc., Perkin Transactions 2, (1990) 
2293. 
CF.sub.3 --Z compounds can be made by conventional methods. 
Method 9 
Compounds of the formula (I) where R.sup.1 is 2-(chloro or bromo)furan-3-yl 
can be made by reacting the corresponding compound of formula (I) where 
R.sup.1 is furan-3-yl (preparable by Method 1) with chlorinating or 
brominating agents such as N-(chloro or bromo)succinimide, as appropriate, 
in a suitable solvent such as acetonitrile. 
Method 10 
Compounds of the formula (I) where R.sup.1 is 
2-trifluoromethylsulphenylfuran-3-yl can be made by reacting the 
corresponding compound of formula (I) where R.sup.1 is furan-3-yl 
(preparable by Method 2) with with trifluoromethylsulphenyl chloride and 
stannic chloride in a suitable solvent such as dichloromethane. 
Method 11 
Compounds of the formula (I) where E is CH can be made by reacting the 
corresponding compound where E is CNH.sub.2 with a suitable alkyl nitrite 
such as t-butyl nitrite, in a suitable solvent such as tetrahydroftiran 
(THF). 
Method 12 
Compounds of the formula (I) where E is C-halo can be made by reacting 
reacting the corresponding compound where E is CNH.sub.2 with a suitable 
alkyl nitrite such as t-butyl nitrite, and a halide source such as iodine, 
tribromomethane or CuCl.sub.2, in a suitable solvent such as 
tetrahydrofuran (THF). 
Method 13 
Compounds of the formula (I) where E is C--C.sub.1-6 alkyl and R.sup.1, Ar, 
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as defined before for 
compounds of formula (I), can be made by reacting the corresponding 
compound where E is C-iodo with a lithiating species such as 
n-butyllithium, to make the corresponding 5-lithiated pyrazole, followed 
by reaction with an alkylating species (C.sub.1-6 alkyl-Z) where Z is a 
suitable leaving group such as iodide or bromide. 
The substances of the invention may be separated and purified by 
conventional methods. 
It will be apparent to those skilled in the art that sensitive functional 
groups may need to be protected and deprotected during synthesis of 
substances of the invention. This may be achieved by conventional 
techniques, for example as described in "Protective Groups in Organic 
Synthesis" by T W Greene and P G M Wuts, John Wiley and Sons Inc., 1991. 
The substances of the invention are useful because they possess 
parasiticidal activity in humans, animals and plants. They are 
particularly useful in the treatment of ectoparasites. 
With regard to the use of the substances of the invention in humans, there 
is provided: 
a) a pharmaceutical formulation comprising a substance of the invention in 
admixture with a pharmaceutically acceptable adjuvant, diluent or carrier 
which may be adapted for topical administration; 
b) a substance of the invention, for use as a medicament; 
c) the use of a substance of the invention in the manufacture of a 
parasiticidal medicament; and 
d) a method of treating a parasitic infestation in a patient which 
comprises administering an effective amount of a substance of the 
invention to the patient. 
With regard to the use of the substances of the invention in non-human 
animals, the substances may be administered alone or in a formulation 
appropriate to the specific use envisaged and to the particular species of 
host animal being treated and the parasite involved. The methods by which 
the substances may be administered include oral administration by capsule, 
bolus, tablet or drench, or as a pour-on or spot-on formulation, or 
alternatively, they can be administered by injection (e.g. subcutaneously, 
intramuscularly or intravenously), dip, spray, mousse, shampoo, powder, or 
as an implant. 
Such formulations are prepared in a conventional manner in accordance with 
standard veterinary practice. Thus capsules, boluses or tablets may be 
prepared by mixing the active substance with a suitable finely divided 
diluent or carrier additionally containing a disintegrating agent and/or 
binder such as starch, lactose, talc, magnesium stearate etc. Oral 
drenches are prepared by dissolving or suspending the active ingredient in 
a suitable medium. Injectable formulations may be prepared in the form of 
a sterile solution which may contain other substances, for example, enough 
salts or glucose to make the solution isotonic with blood. Acceptable 
liquid carriers include the vegetable oils such as sesame oil and the 
like, glycerides such as triacetin and the like, esters such as benzyl 
benzoate, isopropyl myristate and fatty acid derivatives of propylene 
glycol and the like, as well as organic solvents such as pyrrolidone, 
glycerol formal and the like. The formulations are prepared by dissolving 
or suspending the active ingredient in the liquid carrier such that the 
final formulation contains from, for instance, 0.01 to 10% by weight of 
the active ingredient. 
These formulations will vary with regard to the weight of active substance 
contained therein depending on the species of host animal to be treated, 
the severity and type of infection and the body weight of the host. For 
parenteral, topical (e.g. using pour-on or spot-on, dip, spray, mousse, 
shampoo or powder to deliver the compound) and oral administration, 
typical dose ranges of the active ingredient are 0.01-100 mg per kg of 
body weight of the animal. Preferably the range is 0.1 to 10 mg per kg. 
As an alternative the substances of the invention may be administered with 
the animal feedstuff and for this purpose a concentrated feed additive or 
premix may be prepared for mixing with the normal animal feed. 
The substances of the invention have utility in the control of arthropod, 
plant nematode, helminth or protozoan pests. The substances of the 
invention may, in particular, be used in the field of veterinary medicine 
and livestock husbandry and in the maintenance of public health against 
arthropods, helminths or protozoa which are parasitic internally or 
externally upon vertebrates, particularly warm-blooded vertebrates, for 
example man and domestic animals, e.g. cattle, sheep, goats, equines, 
swine, poultry, dogs, cats and fish, for example Acarina, including ticks 
(e.g. Ixodes spp., Boophilus spp. e.g. Boophilus microplus, Amblyomma 
spp., Hyalomma spp., Rhipicephalus spp. e.g. Rhipicephalus appendiculatus, 
Haemaphysalis spp., Dermacentor spp., Ornithodorus spp. (e.g. Ornithodorus 
moubata and mites (e.g. Damalinia spp., Dermahyssus gallinae, Sarcoptes 
spp. e.g. Sarcoptes scabiei, Psoroptes spp., Chorioptes spp., Demodex 
spp., Eutrombicula spp.,) Diptera (e.g. Aedes spp., Anopheles spp., Musca 
spp., Hypoderma spp., Gastrophilus spp., Simulium spp.); Hemiptera (e.g. 
Triatoma spp.); Phthiraptera (e.g. Damalinia spp., Linoqnathus spp.) 
Siphonaptera (e.g. Ctenocephalides spp.); Dictyoptera (e.g. Periplaneta 
spp., Blatella spp.); Hymenoptera (e.g. Monomorium pharaonis); for example 
against infections of the gastrointestinal tract caused by parasitic 
nematode worms, for example members of the family Trichostrongylidae, 
Nippostronylus brasiliensis, Trichinella spiralis, Haemonchzs contortus, 
Trichostronylus colubriformis, Nematodirus battus, Ostertagia 
circumcincta, Trichostrongylus axei, Cooperia spp. and Hymenolepis nana, 
in the control and treatment of protozoal diseases caused by, for example 
Eimeria spp. e.g. Eimeria tenella, Eimeria acervulina, Eimeria brunetti, 
Eimeria maxima, Eimeria necatrix, Eimeria bovis, Eimeria zuerni and 
Eimeria ovinoidalis; Trypanosoma cruzi, Leishmania spp., Plasmodium spp., 
Babesia spp., Trichomonadidae spp., Histomonas spp., Giardia spp., 
Toxoplasma spp., Entamoeba histolytica and Theileria spp.; in the 
protection of stored products, for example cereals, including grain and 
flour, groundnuts, animal foodstuffs, timber and household goods, e.g. 
carpets and textiles, against attack by arthropods, more especially 
beetles, including weevils, moths and mites, for example Ephestia spp. 
(flour moths), Anthrenus spp. (carpet beetles), Tribolium spp. (flour 
beetles), Sitophilus spp. (grain weevils) and Acarus spp. (mites), in the 
control of cockroaches, ants and termites and similar arthropod pests in 
infested domestic and industrial premises and in the control of mosquito 
larvae in waterways, wells, reservoirs or other running or standing water; 
for the treatment of foundations, structure and soil in the prevention of 
the attack on buildings by termites, for example, Reticulitermes spp., 
Heterotermes spp., Coptoterms spp.; in agriculture, against adults, larvae 
and eggs of Lepidoptera (butterflies and moths), e.g. Heliothis spp. such 
as Heliothis virescens (tobacco budworm), Heliothis armioera and Heliothis 
zea, Spodoptera spp. such as S. exempta, S. littoralis (Egyptian cotton 
worm), S. eridania (southern army worm), Mamestra configurata (bertha army 
worm); Earias spp. e.g. E. insulana (Egyptian bollworm), Pectinophora spp. 
e.g. Pectinophora gossypiella (pink bollworm), Ostrinia spp. such as O. 
nubilalis (European cornborer), Trichoplusia ni (cabbage looper), Pieris 
spp. (cabbage worms), Laphyqma spp. (army worms), Agrotis and Amathes spp. 
(cutworms), Wiseana spp. (porina moth), Chilo spp. (rice stem borer), 
Tryporyza spp. and Diatraea spp. (sugar cane borers and rice borers), 
Sparganothis pilleriana (grape berry moth), Cydia pomnonella (codling 
moth), Archips spp. (fruit tree tortrix moths), Plutella xylostella 
(diamond black moth); against adult and larvae of Coleoptera (beetles) 
e.g. Hypothenemus hampei (coffee berry borer), Hylesinus spp. (bark 
beetles), Anthonomus grandis (cotton boll weevil), Acalymma spp. (cucumber 
beetles), Lema spp., Psylliodes spp., Leptinotarsa decemlineata (Colorado 
potato beetle), Diabrotica spp. (corn rootworms), Gonocephalum spp. (false 
wire worms), Agriotes spp. (wireworms), Dermolepida and Heteronychus spp. 
(white grubs), Phaedon cochleariae (mustard beetle), Lissorhoptrus 
oryzophilus (rice water weevil), Melioethes spp. (pollen beetles), 
Ceutorhynchus spp., Rhynchophorus and Cosmopolites spp. (root weevils); 
against Hemiptera e.g. Psylla spp., Bemisia spp., Trialeurodes spp., Aphis 
spp., Myzus spp., Megoura viciae, Phylloxera spp., Adelges spp., Phorodon 
humuli (hop damson aphid), Aeneolamia spp., Nephotettix spp. (rice leaf 
hoppers), Empoasca spp., Nilaparvata spp., Perkinsiella spp., Pyrilla 
spp., Aonidiella spp. (red scales), Coccus spp., Pseucoccus spp., 
Helopeltis spp. (mosquito bugs), Lygus spp., Dysdercus spp., Oxycarenus 
spp., Nezara spp.; Nymenoptera e.g. Athalia spp. and Cephus spp. (saw 
flies), Atta spp. (leaf cutting ants); Diptera e.g. Hylemyia spp. (root 
flies), Atherigona spp. and Chlorops spp. (shoot flies), Phytomyza spp. 
(leaf miners), Ceratitis spp. (fruit flies); Thysanoptera such as Thrips 
tabaci: Orthoptera such as Locusta and Schistocerca spp. (locusts) and 
crickets e.g. Gryllus spp. and Acheta spp.; Collembola e.g. Sminthurus 
spp. and Onychiurus spp. (springtails), Isoptera e.g. Odontotermes spp. 
(termites), Dermnaptera e.g. Forficula spp. (earwigs) and also other 
arthropods of agricultural significance such as Acari (mites) e.g. 
Tetranychus spp., Panonychus spp. and Bryobia spp. (spider mites), 
Eriophyes spp. (gall mites), Polyphacotarsonemus spp.; Blaniulus spp. 
(millipedes), Scutigerella spp. (symphilids), Oniscus spp. (woodlice) and 
Triops spp. (crustacea); nematodes which attack plants and trees of 
importance to agriculture, forestry and horticulture either directly or by 
spreading bacterial, viral, mycoplasma or fungal diseases of the plants, 
root-knot nematodes such as Meliodogyne spp. (e.g. M. incognita); cyst 
nematodes such as Globodera spp. (e.g. G. rostochiensis); Heterodera spp. 
(e.g. H. avenae); Radopholus spp. (e.g. R. similis); lesion nematodes such 
as Pratylenchus spp. (e.g. P. pratensis); Belonoliamus spp. (e.g. B. 
gracilis); Tylenchulus spp. (e.g. T. semipenetrans); Rotylenchulus spp. 
(e.g. R. reniformis); Rotylenchus spp. (e.g. R. robustus); Helicotylenchus 
spp. (e.g. H. multicinctus); Hemicycliophora spp. (e.g. H. gracilis); 
Criconemoides spp. (e.g. C. similis); Trichodorus spp. (e.g. T. 
primitivus); dagger nematodes such as Xiphinema spp. (e.g. X 
diversicaudatum), Longidorus spp. (e.g. L. elongatus); Hoplolaimus spp. 
(e.g. H. coronatus); Aphelenchoides spp. (e.g. A. ritzema-bosi, A. 
besseyi); stem and bulb eelworms such as Ditylenchus spp. (e.g. D. 
dipsaci). 
The substances of the invention also have utility in the control of 
arthropod or nematode pests of plants. The active substance is generally 
applied to the locus in which arthropod or nematode infestation is to be 
controlled at a rate of about 0.005 kg to about 25 kg of active compound 
per hectare of locus treated, preferably 0.02 to 2 kg/ha. Under ideal 
conditions, depending on the pest to be controlled, the lower rate may 
offer adequate protection. On the other hand, adverse weather conditions, 
resistance of the pest and other factors may require that the active 
ingredient be used in higher proportions. For foliar application, a rate 
of 0.01 to 1 kg/ha may be used. 
When the pest is soil-borne, the formulation containing the active 
substance is distributed evenly over the area to be treated in any 
convenient manner. Application may be made, if desired, to the field or 
crop-growing area generally or in close proximity to the seed or plant to 
be protected from attack. The active substance can be washed into the soil 
by spraying with water over the area or can be left to the natural action 
of rainfall. During or after application, the formulation can, if desired, 
be distributed mechanically in the soil, for example by ploughing or 
disking. Application can be prior to planting, at planting, after planting 
but before sprouting has taken place or after sprouting. 
The substances of the invention may be applied in solid or liquid 
compositions to the soil principally to control those nematodes dwelling 
therein but also to the foliage principally to control those nematodes 
attacking the aerial parts of the plants (e.g. Aphelenchoides spp. and 
Ditylenchus spp. listed above). 
The substances of the invention are of value in controlling pests which 
feed on parts of the plant remote from the point of application, e.g. leaf 
feeding insects are killed by the subject substances applied to roots. In 
addition the substances may reduce attacks on the plant by means of 
antifeeding or repellent effects. 
The substances of the invention are of particular value in the protection 
of field, forage, plantation, glasshouse, orchard and vineyard crops, or 
ornamentals and of plantation and forest trees, for example, cereals (such 
as maize, wheat, rice, sorghum), cotton, tobacco, vegetables and salads 
(such as beans, cole crops, curcurbits, lettuce, onions, tomatoes and 
peppers), field crops (such as potato, sugar beet, ground nuts, soyabean, 
oil seed rape), sugar cane, grassland and forage (such as maize, sorghum, 
lucerne), plantations (such as of tea, coffee, cocoa, banana, oil palm, 
coconut, rubber, spices), orchards and groves (such as of stone and pip 
fruit, citrus, kiwifruit, avocado, mango, olives and walnuts), vineyards, 
ornamental plants, flowers and shrubs under glass and in gardens and 
parks, forest trees (both deciduous and evergreen) in forests, plantations 
and nurseries. 
They are also valuable in the protection of timber (standing, felled, 
converted, stored or structural) from attack by sawflies (e.g. Urocerus) 
or beetles (e.g. scolytids, platypodids, lyctids, bostrychids, 
cerambycids, anobiuds), or termites, for example, Reticulitermes spp., 
Heterotermes spp., Coptotermes spp. 
They have applications in the protection of stored products such as grains, 
fruits, nuts, spices and tobacco, whether whole, milled or compounded into 
products, from moth, beetle and mite attack. Also protected are stored 
animal products such as skins, hair, wool and feathers in natural or 
converted form (e.g. as carpets or textiles) from moth and beetle attack; 
also stored meat and fish from beetle, mite and fly attack. 
The substances of the invention are of value in the control of arthropods, 
helminths or protozoa which are injurious to, or spread or act as vectors 
of diseases in man and other animals, e.g. domestic animals, such as those 
hereinbefore mentioned, and more especially in the control of ticks, 
mites, lice, fleas, midges and biting, nuisance and myiasis flies. The 
substances of the invention are also useful in controlling arthropods, 
helminths or protozoa which are present, for example, inside domestic host 
animals or which feed in or on the skin or suck the blood of the animal, 
for which purpose they may be administered orally, parenterally, 
percutaneously or topically. 
According to a further aspect of the invention, there is provided a 
parasiticidal formulation comprising a substance of the invention, in 
admixture with a compatible adjuvant, diluent or carrier. Preferably, the 
formulation is adapted for topical administration. 
The invention further provides a substance of the invention for use as a 
parasiticide; and a method of treating a parasitic infestation at a locus, 
which comprises treatment of the locus with an effective amount of a 
substance of the invention. Preferably, the locus is the skin or fur of an 
animal, or a plant surface or the soil around the plant to be treated. 
The invention further provides: 
the processes described herein for preparing the compounds of formula (I) 
and salts and solvates thereof; 
pharmaceutical, veterinary or agricultural parasiticidal formulations 
comprising a compound of formula (I), or a pharmaceutically-, 
agriculturally- or veterinarily-acceptable salt and/or solvate thereof, in 
admixture with a compatible adjuvant, diluent or carrier; 
compounds of formula (I), and pharmaceutically- or veterinarily-acceptable 
salts and/or solvates, 
and formulations thereof, for use as a medicament; 
the use of a compound of formula (I), or pharmaceutically- or 
veterinarily-acceptable salt therof, or formulation thereof, in the 
manufacture of a medicament for the treatment of a parasitic infestation; 
a method of killing or harming a parasite at a locus; and 
any novel intermediates described herein. 
It is to be appreciated that reference to treatment herein includes 
prophylaxis as well as the alleviation of established symptoms of a 
condition, such as a parasitic infection. 
Test for Insecticidal Activity 
Adult flies (Stomoxys calcitrans) are collected and anaesthetized using 
CO.sub.2, 1 .mu.l of an acetone solution containing the test substance is 
applied directly to the thorax of the fly. The flies are then placed 
carefully into a 50 ml tube covered with damp gauze to recover from the 
CO.sub.2. Negative controls have 1 .mu.l of acetone dispensed onto them. 
Mortality is assessed 24 hours after dosing. The table below illustrates 
the in vivo activity of a selection of the substances of the invention 
against such flies. Dosages required to produce 100% mortality are 
expressed in .mu.g/fly. 
______________________________________ 
Example No. 
Dosage 
______________________________________ 
1 0.005 
2 0.01 
3 0.005 
4 0.05 
6 0.01 
______________________________________ 
Test for Acaricidal Activity 
A dose of 10 .mu.g/cm.sup.2 is created by evenly pipetting 0.5 ml of a 1 
mg/ml solution of the test compound in a suitable solvent such as acetone 
or ethanol onto a Whatman No. 1 (Trade Mark) filter paper cut to a size of 
8.times.6.25 cm. When dry, the paper is folded in half, sealed on two 
sides using a crimping device and placed in a Kilner jar containing a 
cotton wool pad dampened with water. The jar is then sealed and placed at 
25.degree. C. for 24 hours. Next, approximately 50 Boophilus microplus 
larvae are introduced into the treated paper envelope which is then 
crimped along the third side to effect a complete seal. The paper envelope 
is returned to the Kilner jar, which is sealed and placed at 25.degree. C. 
for a further 48 hours. The papers are then removed and mortality 
assessed. Negative controls are provided by treating an appropriately cut 
filter paper with 0.5 ml of solvent only and following the same procedure. 
Activity at other doses is obtained by varying the concentration of the 
test solution. The table below illustrates the in vivo activity of a 
selection of the compounds of the invention against Boophilus microplus 
larvae. Dosages are expressed in .mu.g/cm.sup.2. 
______________________________________ 
Example No. Dosage/% Mortality 
______________________________________ 
1 0.5 90% 
2 1 100% 
3 0.5 100% 
______________________________________ 
The invention is illustrated by the following Examples. In the Examples and 
Preparations, melting points were determined using a Gallenkamp melting 
point apparatus and are uncorrected. Nuclear magnetic resonance (NMR) data 
were obtained using a Bruker AC300 or AM300 and are quoted in parts per 
million using solvent or tetramethylsilane as reference. Mass spectral 
(MS) data were obtained on a Finnigan Mat. TSQ 7000 or a Fisons 
Instruments Trio 1000. The calculated and observed ions quoted refer to 
the isotopic composition of lowest mass. HPLC purification was performed 
on a 21.times.250 mm Dynamax.TM. 5 .mu.ODS reverse-phase column eluted at 
10 ml/minute with acetonitrile: 0.005M aqueous heptanesulphonic acid: 
methanol (50:40:10). Fractions were processed by evaporation of the 
non-aqueous components followed by partition between ether and saturated 
aqueous sodium hydrogen carbonate solution. The organic layer was then 
separated, dried and evaporated. 
EXAMPLES 
Example 1 
4-(2,2-Dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-1,2,3-t 
riazole 
To a solution of the title compound of Preparation 2 (210 mg) in bromoforrn 
(4 ml) and dichloromethane (2 ml) was added sodium hydroxide (200 mg in 
water (0.2 ml)) and benzyltriethylammonium chloride (10 mg), the mixture 
was stirred vigourously for 16 hours at room temperature. Further 
equivalents of sodium hydroxide (200 mg in water (0.2 ml)) and 
benzyltriethylammonium chloride (10 mg) were added to the reaction, which 
was stirred for a further 4 days. The reaction was diluted with water (100 
ml) and extracted with dichloromethane (100 ml), the organic layer was 
separated, evaporated to dryness and purified by column chromatography on 
silica gel (5 g) eluted with dichloromethane:hexane (3:1) to give the 
title compound as a yellow crystaline solid, m.p. 156-158.degree. C. 
.delta.(CDCl.sub.3): 7.76 (2H,s), 7.20 (1H,s), 2.88 (1H,dd), 2.20 (1H,dd), 
1.94 (1H,dd). MS (thermospray): M/Z [M+NH.sub.4 ] 497.9;C.sub.12 H.sub.6 
Br.sub.2 Cl.sub.2 F.sub.3 N.sub.3 +NH.sub.4 requires 498.0. 
Example 2 
4-(2,2-Dichlorocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-1,2,3- 
triazole 
To a solution of the title compound of Preparation 2 (200 mg) in toluene (5 
ml) was added phenyl(trichloromethyl)mercury (309 mg). The mixture was 
heated to 70.degree. C. for 6 hours and then left to stir for 16 hours at 
room temperature. A further mole equivalent of 
phenyl(trichloromethyl)mercury (309 mg) was added, the reaction was heated 
to 100.degree. C. for 8 hours and then left to stir for 16 hours at room 
temperature. The reaction was diluted with water (100 ml) and extracted 
with dichloromethane (100 ml), the organic fraction was separated, 
evaporated to dryness and purified by column chromatography on silica gel 
(20 g) eluted with dichloromethane to give the title compound as a pale 
yellow crystaline solid, m.p. 134-136.degree. C. 
.delta.(CDCl.sub.3): 7.78 (2H,s), 7.18 (1H,s), 3.03 (1H,t), 2.20 (2H,d). MS 
(thermospray): M/Z [M+NH.sub.4 ] 407.2;C.sub.12 H.sub.6 Cl.sub.4 F.sub.3 
N.sub.3 +NH.sub.4 requires 407.0. 
Example 3 
3-Cyano4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)p 
yrrole 
To a solution of the title compound of Preparation 5 (200 mg) in bromoform 
(1 ml), dichloromethane (0.5 ml) and ethanol (0.1 ml) was added sodium 
hydroxide (100 mg in H.sub.2 O (0.1 ml)) and benzyltriethylammonium 
chloride (5 mg), the mixture was stirred vigourously for 3 days at room 
temperature. The reaction was diluted with water (100 ml) and extracted 
with ether (100 ml), the organic fraction was separated, dried over 
MgSO.sub.4, filtered, evaporated to dryness and purified by reverse phase 
HPLC on C18 silica using acetonitrile:water:methanol (60:30:10) as eluent, 
to give the title compound as a colourless gum-like solid. 
.delta.(CDCl.sub.3): 7.78 (2H,s), 7.18 (1H,s), 6.56 (1H,s), 2.88 (1H,dd), 
2.24 (1H,dd), 1.94 (1H,dd). Ms (thermospray): M/Z [M+NH.sub.4 ] 
517.9;C.sub.15 H.sub.7 Br.sub.2 Cl.sub.2 F.sub.3 N.sub.2 +NH.sub.4 
requires 517.9. 
Example 4 
3-(2,2-Dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)indole 
To a solution of the title compound of Preparation 7 (200 mg) in bromoform 
(4 ml) and dichloromethane (2 ml) was added sodium hydroxide (200 mg in 
H.sub.2 O (0.2 ml)) and benzyltriethylammonium chloride (10 mg). The 
mixture was stirred vigourously for 16 hours at room temperature. The 
reaction was diluted with water (100 ml) and extracted with 
dichloromethane (100 ml), the organic fraction was separated, dried over 
MgSO.sub.4, filtered and evaporated to dryness. The residue was purified 
by column chromatography on silica gel (20 g) eluted with 
dichloromethane:hexane (1:5) to give the title compound as a colourless 
gum-like solid. .delta.(CDCl.sub.3): 7.72-7.90 (3H,m), 7.20-7.30 (2H,m), 
6.92 (1H,d), 6.84 (1H,s), 3.02 (1H,dd), 2.12 (1H,dd), 1.94 (1H,dd). M/Z 
[M+NH.sub.4 ] 545.8;C.sub.18 H.sub.10 Br.sub.2 Cl.sub.2 F.sub.3 N+NH.sub.4 
requires 546.0. 
Example 5 
3-(2,2-Dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-6-fluor 
oindole 
To a solution of the title compound of Preparation 10 (20 g) in bromoform 
(80 ml), dichloromethane (400 ml) and ethanol (20 ml) was added sodium 
hydroxide (40 g in H.sub.2 O (40 ml)) and benzyltriethylammonium chloride 
(0.80 g). The mixture was heated under reflux for 6 hours and then stirred 
for a further 48 hours at room temperature. The reaction was diluted with 
water (1000 ml) and extracted with dichloromethane (1000 ml), the organic 
fraction was separated, dried over MgSO.sub.4, filtered and evaporated to 
dryness. The residue was purified by column chromatography on silica gel 
(1 kg) eluted with dichloromethane to give the title compound as a 
colourless gum-like solid. .delta.(CDCl.sub.3): 7.70-8.00 (3H,m), 
6.98-7.16 (1H,m), 6.80-6.94 (1H,m), 6.50-6.70 (1H,m), 2.98 (1H,dd), 2.24 
(1H,dd), 1.94 (1H,dd). 
Example 6 
3-(2,2-Dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-1,2,4-t 
riazole 
To a solution of the title compound of Preparation 13 (600 mg) in bromoform 
(20 ml) and dichloromethane (20 ml) was added sodium hydroxide (400 mg in 
0.4 ml H.sub.2 O) and benzyltriethylammonium chloride (100 mg), the 
mixture was stirred vigourously for 3 days at room temperature. The 
reaction was diluted with water (100 ml) and extracted with 
dichloromethane (100 ml), the organic fraction was separated, dried over 
MgSO.sub.4, filtered, evaporated to dryness and purified by column 
chromatography on silica gel (20 g) eluted with dichloromethane to give 
the title compound as a yellow gum-like solid. 
.delta.(CDCl.sub.3): 8.18 (1H,s), 7.76 (2H,s), 3.10 (1H,dd), 2.42 (1H,dd), 
2.10 (1H,dd). MS (thermospray): M/Z [M+H] 478.3;C.sub.12 H.sub.6 Br.sub.2 
Cl.sub.2 F.sub.3 N.sub.3 +H requires 477.8. 
Example 7 
4-(3-Bromoisoxazol-5-yl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-1,2,3-tri 
azole 
To a rapidly stirred solution of the compound of Preparation 14 (1.06 g) in 
ethyl acetate (25 ml) and water (2.5 ml) was added potassium hydrogen 
carbonate (0.658 g) and dibromoformaldoxime (0.703 g) respectively. The 
reaction was left stirring at room temperature overnight. A further 0.703 
g of dibromoformaldoxime was added and the reaction stirred for a further 
5 hours. The solvent was evaporated by rotary evaporation in vacuo and the 
reaction mixture dissolved in methylene chloride (60 ml) and washed with 
water (2.times.50 ml). The organics were separated, dried (MgSO.sub.4), 
filtered, evaporated to dryness and purified by column chromatography on 
silica gel (100 g) eluted with hexane:ethyl acetate (95:5) to give the 
title compound as a pale yellow solid. 
.delta.(CDCl.sub.3): 8.20 (1H,s), 7.85(2H,s), 6.97(1H,s). 
Example 8 
3-(3-Bromoisoxazol-5-yl)-1-(2,6-dichloro-4-trifluoromethylphenyl)indole 
To a rapidly stirred solution of the title compound of Preparation 15 (1.0 
g) in ethyl acetate (25 ml) and water (2.5 ml) was added potassium 
hydrogen carbonate (0.54 g) and dibromoformaldoxime (1.4 g) respectively. 
The reaction was left stirring at room temperature overnight. The solvent 
was evaporated by rotary evaporation in vacuo and the reaction mixture 
dissolved in methylene chloride (50 ml) and washed with water (2.times.50 
ml). The organics were separated, dried (Na.sub.2 SO.sub.4), filtered, 
evaporated to dryness and purified by column chromatography on silica gel 
(50 g) eluted with hexane followed by dichloromethane to give the title 
compound as a white solid (284 mg). 
.delta.(CDCl.sub.3): 8.0 (1H,d), 7.8(2H,s), 7.7(1H,s), 7.3-7.5 (2H,m), 7.0 
(1H,d), 6.6 (1H,s). 
PREATIONS 
Preparation 1 
1-(2,6-Dichloro-4-trifluoromethylphenyl)-4-iodo-1,2,3-triazole 
To a solution of 
1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trimethylsilyl-1,2,3-triazole 
(EP-400842-A1; 1.00 g) in tetrahydrofuran (20 ml) was added silver 
trifluoroacetate (623 mg) and iodine (716 mg) at -78.degree. C. under an 
atmosphere of nitrogen. The reaction was allowed to warm to room 
temperature over 1 hour and then left to stir for a further 16 hours. The 
reaction was filtered and the filtrate diluted with water (100 ml) and 
extracted with ether (100 ml), the organic fraction was separarted, dried 
over MgSO.sub.4, filtered and evaporated to dryness. The residue was 
purified by column chromatography (silica, 100 g) eluted with 
dichloromethane:hexane (2:1) to give the title compound as a pale yellow 
crystalline material, m.p. 194-195.degree. C. 
Preparation 2 
1-(2,6-Dichloro-4-trifluoromethylphenyl)-4-ethenyl-1,2,3-triazole 
To a solution of the title compound of Preparation 1 (500 mg) in 
dimethylformamide (50 ml) was added tributylvinyltin (715 .mu.l) and 
tetrakis(triphenylphosphine)palladium (0) (50 mg). The reaction was heated 
to 100.degree. C. under nitrogen for 1 hr, diluted with water (100 ml) and 
extracted with ether (100 ml), the organic fraction was separated were 
dried over MgSO.sub.4, filtered and evaporated to dryness. The residue was 
purified by column chromatography (silica, 50 g) eluted with 
dichloromethane:hexane (3:1) to give the title compound as a white 
crystaline material, m.p. 109-111.degree. C. 
Preparation 3 
2-Amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-iodopyrrole 
To a solution of 
2-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-cyanopyrrole (EP-372982 
A2) in acetonitrile (20 ml) was added N-iodosuccinimide (703 mg). The 
reaction was stirred at room temperature for 30 minutes, diluted with 
water (100 ml) and extracted with ether (100 ml). The organic fraction was 
separated, dried over MgSO.sub.4, filtered and evaporated to dryness, the 
residue was purified by column chromatography (silica, 20 g) eluted with 
dichloromethane:hexane (7:3) to give the title compound as a yellow 
crystaline material, m.p. 130-132.degree. C. 
Preparation 4 
4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-iodopyrrole 
To a solution of the title compound of Preparation 3 in tetrahydrofuran 
(120 ml) was added tert-butyl nitrite (4 ml). The reaction was refluxed 
for 1 hr and then evaporated to dryness, the residue was purified by 
column chromatography on silica gel (500 g) eluted with 
dichloromethane:hexane (7:3) to give the title compound as a pale yellow 
crystaline material, m.p. 118-120.degree. C. 
Preparation 5 
3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethenylpyrrole 
To a solution of the title compound of Preparation 4 (2.50 g) in 
dimethylformamide (100 ml) was added tributylvinyltin (5 ml) and 
tetrakis(triphenylphosphine) palladium (0) (300 mg). The reaction was 
heated to 100.degree. C. under nitrogen for 1 hr, and the mixture was 
evaporated to dryness. The residue was purified by column chromatography 
on silica gel (500 g) eluted with dichloromethane:hexane (7:3) to give the 
title compound as a white crystalline solid, m.p. 55-60 .degree. C. 
Preparation 6 
1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-formylindole 
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (10 g) in 
dimethylformamide (10 ml) was added 3-formylindole (623 mg) and potassium 
carbonate (593 mg), the mixture was heated at 90.degree. C. for 1.5 hrs. 
The reaction was cooled to room temperature and diluted with water (200 
ml) and extracted with ether (200 ml). The organic fraction was separated 
and evaporated to dryness to give the title compound as a pale yellow 
crystaline material, m.p. 167-169.degree. C. 
Preparation 7 
1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-ethenylindole 
To a solution of methyltriphenylphosphonium bromide (714 mg) in 
tetrahydrofuran (20 ml) was added n-butyl lithium (0.8 ml, 2.5M in 
hexanes) under nitrogen at 0.degree. C. After 10 minutes the title 
compound of Preparation 6 (700 mg) was added. The reaction was stirred for 
a further 1 hr and then poured into an iced solution of 10% ammonium 
chloride (50 ml), extracted with ether (100 ml), washed with brine (50 
ml), dried over MgSO.sub.4, filtered and evaporated an oil. The residue 
was purified by column chromatography on silica gel (10 g) eluted with 
dichloromethane:hexane (7:3) to give the title compound as a pale yellow 
crystalline material, m.p. 85-87.degree. C. 
Preparation 8 
1-(2,6-Dichloro-4-trifluoromethylphenyl)-6-fluoroindole 
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (34.5 g) in 
dimethylformamide (250 ml) was added 6-fluoroindole (34.5 g) and potassium 
carbonate (20.4 g). The mixture was heated at 90.degree. C. for 6 hours 
and then left to stir for 16 hours at room temperature. The reaction was 
diluted with water (1000 ml) and extracted with hexane (1000 ml). The 
organic fraction was separated and evaporated to dryness to give the title 
compound as a colourless liquid. 
.delta.(CDCl.sub.3): 7.80 (2H,s), 7.62 (1H,dd), 7.20 (1H,d), 6.96 (1H,dt), 
6.76 (1H,d), 6.62 (1H,dd). 
Preparation 9 
3-Bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-6-fluoroindole 
To a solution of the title compound of Preparation 8 (37.8 g) in 
N,N-dimethylformamide (200 ml) was added bromine (6.8 ml) in 
N,N-dimethylformamide (200 ml) dropwise over 10 minutes, and the reaction 
was stirred at room temperature for 1 hour. The reaction was diluted with 
a solution of ammonia (10 ml) and sodium metabisulphite (2.0 g) in water 
(1000 ml), and extracted with hexane (2.times.500 ml), dried over 
MgSO.sub.4, filtered and evaporated to give the title compound as a 
colourless oil. 
.delta.(CDCl.sub.3): 7.80 (2H,s), 7.60 (1H,dd), 7.22 (1H,s), 7.08 (1H,dt), 
6.64 (1H,dd). 
Preparation 10 
1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-ethenyl-6-fluoroindole 
To a solution of the title compound of Preparation 9 (44.3 g) in 
dimethylformamide (400 ml) was added tributylvinyltin (35 ml) and 
tetrakis(triphenylphosphine)palladium (0) (2.7 g). The reaction was heated 
to 70.degree. C. for 24 hrs under an atmosphere of nitrogen and then left 
to stir at room temperature for a further 4 days, after which 
tetrakis(triphenylphosphine)palladium(0) (2.5 g) was added and the 
reaction heated to 70.degree. C. for 24 hrs. The reaction mixture was 
evaporated to dryness and the residue was purified by column 
chromatography on silica gel (1 kg), eluted with hexane to give the title 
compound as a colourless oil. 
.delta.(CDCl.sub.3): 7.74 (1H,dd), 7.80 (2H,s), 7.22 (1H,s), 7.02 (1H,dt), 
6.80 (1H,dd), 6.60 (1H,dd), 5.80 (1H,d), 5.30 (1H,d). 
Preparation 11 
3-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-1,2,4-triazole; 
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-1,2,4-triazole (60:40 
mixture) 
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (1.0 g) in 
dimethylformamide (5 ml) was added 3-amino-1,2,4-triazole (360 mg) and 
potassium carbonate (296 mg), the mixture was heated at 100.degree. C. for 
2 hrs. The reaction was cooled to room temperature, diluted with water 
(100 ml) and extracted with ether (100 ml). The organic extracts were 
evaporated to dryness to give the title compounds as pale yellow crystals. 
Preparation 12 
1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-iodo-1,2,4-triazole 
To a solution of the title compounds of Preparation 11 (600 mg) in 
diuodomethane (4 ml) was added t-butyl nitrite (2 ml), and the reaction 
was stirred at room temperature for 1 hr, then diluted with water (100 
ml), extracted with ether (100 ml), dried over MgSO.sub.4, filtered and 
evaporated to an oil. The residue was purified by column chromatography 
(silica, 100 g) eluted with dichloromethane:hexane (10:1) to give 
exclusively the title compound as yellow crystals, m.p. 130-132.degree. C. 
Preparation 13 
1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-ethenyl-1,2,4-triazole 
To a solution of the title compound of Preperation 12 (204 mg) in 
N,N-dimethylformamide (3 ml) was added tributylvinyltin (291 ul) and 
tetrakis(triphenylphosphine)palladium (0) (5 mg). The reaction was heated 
to 90.degree. C. under nitrogen for 5 hrs, evaporated to dryness and the 
residue was purified by column chromatography on silica gel (10 g) eluted 
with dichloromethane to give the title compound as a white crystals, m.p. 
97-99.degree. C. 
Preparation 14 
1-(2,6-Dichloro-4-trifluoromethylphenyl)-4-ethynyl-1,2,3-triazole 
To a solution of the title compound of Preparation 1 (25.02 g), 
trimethylsilylacetylene (260 ml) and diisopropylamine (230 ml) in 
tetrahydrofuran, (700 ml) was added copper (I) iodide (0.465 g) and 
PdCl.sub.2 (PPh.sub.3).sub.2 (0.865 g). The reaction mixture was heated to 
reflux for 5 hours, evaporated to dryness and purified using column 
chromatography on silica gel (350 g) eluted with dichloromethane to give a 
brown oil. The resulting material was dissolved in tetrahydrofuran (500 
ml), cooled to -78.degree. C. and tetrabutylammonium fluoride (90.7 ml) 
was added dropwise. After the addition was complete the reaction was 
allowed to warm to room temperature, the mixture was diluted with water 
(250 ml), extracted with methylene chloride (400ml), dried (MgSO.sub.4), 
filtered, evaporated to dryness and purified by column chromatography on 
silica gel (400 g) eluted with dichloromethane:hexane (90:10). 
Recystallisation of the material in hexane yielded the title compound as a 
light brown solid. 
.delta.(CDCl.sub.3): 7.93 (1H,s), 7.82 (2H,s), 3.38 (1H,s). 
Preparation 15 
1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-ethynylindole 
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (4.79 g) in 
dimethylformamide (25 ml) was added 3-ethynylindole (2.9 g) and potassium 
carbonate (2.84 g), the mixture was heated at 90.degree. C. for 3 hours 
under an atmosphere of nitrogen and then left to stir overnight at room 
temperature. The reaction was diluted with water (100 ml) and extracted 
with hexane (2.times.100 ml). The organic fractions were separated, 
combined, evaporated to dryness and purified by column chromatography on 
silica gel (300 g) eluted with hexane:ethylacetate (97:3) to give the 
title compound as a white solid (1.3 g), m.p. 120-122.degree. C. 
.delta.(CDCl.sub.3): 6.9-7.8 (7H,m), 3.3 (3H,s).