Parasiticidal pyrazoles

Details Parasiticidal pyrazoles Parasiticidal pyrazoles

2000-02-23

2001-07-31

Ramsuer, Robert W. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S275400

Reexamination Certificate

active

06268509

ABSTRACT:

This invention relates to pyrazole derivatives having parasiticidal properties. More particularly, it relates to 1-aryl-4-cyclopropylpyrazoles.
Certain pyrazole derivatives possessing, inter alia antiparasitic activity are already known. For example, EP-A-0234119 discloses 1-arylpyrazoles for the control of arthropod, plant nematode and helminth pests. 1-Arylpyrazoles are also disclosed in EP-A-0295117; in addition to having arthropodicidal, plant nematocidal and anthelmintic activity, these compounds are reported to display antiprotozoal properties. Similar profiles of activity are also displayed by the 1-arylpyrazoles disclosed in EP-A-0295118.
The present invention provides a compound of formula (I):
or a pharmaceutically, veterinarily or agriculturally acceptable salt thereof, or a pharmaceutically, veterinarily or agriculturally acceptable solvate (including hydrate) of either entity,
wherein
R
1
is 2,4,6-trisubstituted phenyl wherein the 2- and 6-substituents are each independently selected from halo and the 4-substituent is selected from C
1
to C
4
alkyl optionally substituted with one or more halo, C
1
to C
4
alkoxy optionally substituted with one or more halo, S(O)
n
C
1
to C
4
alkyl optionally substituted with one or more halo, halo and pentafluorothio; or 3,5-disubstituted pyridin-2-yl wherein the 3-substituent is halo and the 5-substituent is selected from C
1
to C
4
alkyl optionally substituted with one or more halo, C
1
to C
4
alkoxy optionally substituted with one or more halo, S(O)
n
C
1
to C
4
alkyl optionally substituted with one or more halo, halo and pentafluorothio;
R
3
is C
1
to C
4
alkyl optionally substituted with hydroxy or with one or more halo; cyano, C
1
to C
5
alkanoyl or phenyl;
R
5
is hydrogen, C
1
to C
4
alkyl, amino or halo;
R
2
and R
4
are each independently selected from hydrogen, C
1
to C
4
alkyl, fluoro, chloro and bromo or, together with the carbon atom to which they are attached, form a C
3
to C
6
cycloalkyl group;
R
6
and R
8
are each independently selected from hydrogen, C
1
to C
4
alkyl, fluoro, chloro and bromo;
or, when R
2
and R
4
do not form part of a cycloalkyl group, R
2
and R
6
, together with the carbon atoms to which they are attached, may form a C
5
to C
7
cycloalkyl group; R
7
is hydrogen, C
1
to C
4
alkyl optionally substituted with one or more halo, or C
1
to C
4
alkoxy; and
n is 0, 1 or 2.
In the above definition, unless otherwise indicated, alkyl and alkoxy groups having three or more carbon atoms and alkanoyl groups having four or more carbon atoms may be straight chain or branched chain; halo means fluoro, chloro, bromo or iodo.
The compounds of formula (I) may contain one or more chiral centres and therefore can exist as stereoisomers, i.e. as enantiomers or diastereoisomers, as well as mixtures thereof. The invention includes both the individual stereoisomers of the compounds of formula (I) together with mixtures thereof. Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation of chromatography (including HPLC) of a diastereoisomeric mixture of a compound of formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of formula (I) may be prepared from a corresponding optically pure intermediate or by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid.
Also included in the invention are radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies.
The pharmaceutically, veterinarily and agriculturally acceptable salts of the compounds of formula (I) are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulphuric and phosphoric acid, with organo-carboxylic acids, or with organo-sulphonic acids. For a review of suitable salts, see J. Pharm. Sci., 1977, 66, 1.
A preferred group of compounds of formula (I) is that wherein R
1
is 2,6-dichloro-4-trifluoromethylphenyl, 2,6-dichloro-4-pentafluorothiophenyl, 2,4,6-trichlorophenyl or 3-chloro-5-trifluoromethylpyridin-2-yl; R
3
is methyl, ethyl, prop-2-yl, 1-hydroxyethyl, 2-hydroxyprop-2-yl, difluoromethyl, dichloromethyl, trifluoromethyl, cyano, formyl, acetyl or phenyl; R
5
is hydrogen, methyl, amino or chloro; R
2
and R
4
are each independently selected from hydrogen, methyl, fluoro, chloro and bromo or, together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl or cyclopentyl group; R
6
and R
8
are each independently selected from hydrogen, methyl, chloro and bromo; or, when R
2
and R
4
do not form part of a cycloalkyl group, R
2
and R
6
, together with the carbon atoms to which they are attached, may form a cyclopentane or cyclohexane group; and R
7
is hydrogen, methyl, ethyl, trifluoromethyl, chlorodifluoromethyl, pentafluoroethyl, heptafluoropropyl or methoxy.
A more preferred group of compounds of formula (I) is that wherein R
1
is 2,6-dichloro-4-trifluoromethylphenyl, 2,6-dichloro-4-pentafluorothiophenyl or 3-chloro-5-trifluoromethylpyridin-2-yl; R
3
is cyano; R
5
is hydrogen or amino; R
2
and R
4
are the same and are hydrogen, chloro or bromo; R
6
and R
8
are hydrogen; and R
7
is hydrogen, trifluoromethyl or chlorodifluoromethyl.
Particularly preferred individual compounds of the invention include
3-cyano-4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole;
(−)-3-cyano-4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole;
3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(1-trifluoromethylcyclopropyl)pyrazole;
3-cyano-4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-pentafluorothiophenyl)pyrazole;
3-cyano-4-(2,2-dichlorocyclopropyl)-1-(2,6-dichloro-4-pentafluorothiophenyl)pyrazole;
3-cyano-4-(2,2-dichlorocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole;
4-(1-chlorodifluoromethylcyclopropyl)-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole;
1-[(3-chloro-5-trifuoromethyl)pyridin-2-yl]-3-cyano-4-(2,2-dibromocyclopropyl)pyrazole;
5-amino-3-cyano-4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole;
5-amino-3-cyano-4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-pentafluorothiophenyl)pyrazole;
5-amino-3-cyano-4-(2,2-dichlorocyclopropyl)-1-(2,6-dichloro-4-pentafluorothiophenyl)pyrazole; and
5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(1-trifluoromethylcyclopropyl)pyrazole.
In a further aspect, the present invention provides processes for the preparation of a compound of formula (I), or a pharmaceutically, veterinarily or agriculturally acceptable salt thereof, or a pharmaceutically, veterinarily or agriculturally acceptable solvate (including hydrate) of either entity, as illustrated below. It will be appreciated by persons skilled in the art that, within certain of the processes described, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates, and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent for use in the said synthetic steps. It will also be appreciated that various standard substituent or functional group interconversions and transformations within certain compounds of formula (I) will provide other compounds of formula (I). Examples are the deamination of a compound of formula (I) wherein R
5
is amino, the monodebromination of a compound of formula (I) wherein R
2
and R
4
are bromo, and the conversions of a compound of formula (I) wherein R
3
is cyano to a compound of formula (I) wherein R
3
is C
1
to C
5
alkanoyl, a compound of formula (I) wherein R
3
is C
1
to C
4
alkanoyl to a compound of formula (I) wherein R
3
is C
1
to C
4
alkyl substituted with hydroxy or with dihal

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