Title of Invention	"1-ARYL-4-CYCLOPROPYLPYRAZOLE COMPOUNDS"
Abstract	Compounds of formula (I) or pharmaceutically veterinarily or agriculturally acceptable sails thereof, or pharmaceutically, veterinarily or agriculturally acceptable solvates of either entity, wherein R1 is 2,4,6-trisubsituted phenyl or 3,5-disubstituted pyridin-2-yl; R3 is C1-C4 alkyl optionally substituted with hydroxy or with one or more halo; cyano, C1 to C5 alkanoyl or phenyl R5 is hydrogen, C1 to C4 alkyl, amino or halo; R2 and R4 are each independently selected from hydrogen, C, to C„ alkyl, fluoro, chloro and bromo or, together with the carbon atom to which they are attached, form a C3 to C6 cycloalkyl group; R6 and R8 are each independently selected from hydrogeri, C1 to C4 alkyl, fluoro, chloro and bromo; or; when R2 and R4 do not form part of a cycloalkyl group, R2 and R6; together with the carbon atoms to which they are attached, may form a C5 to C7 cycloalkyl group; and R7 is hydrogen, C1 to C4 alkyl optionally substituted with one 01 more halo; or C1 to C4 alkoxy; are parasiticidal agents,

Title of Invention

"1-ARYL-4-CYCLOPROPYLPYRAZOLE COMPOUNDS"

Abstract

Compounds of formula (I) or pharmaceutically veterinarily or agriculturally acceptable sails thereof, or pharmaceutically, veterinarily or agriculturally acceptable solvates of either entity, wherein R1 is 2,4,6-trisubsituted phenyl or 3,5-disubstituted pyridin-2-yl; R3 is C1-C4 alkyl optionally substituted with hydroxy or with one or more halo; cyano, C1 to C5 alkanoyl or phenyl R5 is hydrogen, C1 to C4 alkyl, amino or halo; R2 and R4 are each independently selected from hydrogen, C, to C„ alkyl, fluoro, chloro and bromo or, together with the carbon atom to which they are attached, form a C3 to C6 cycloalkyl group; R6 and R8 are each independently selected from hydrogeri, C1 to C4 alkyl, fluoro, chloro and bromo; or; when R2 and R4 do not form part of a cycloalkyl group, R2 and R6; together with the carbon atoms to which they are attached, may form a C5 to C7 cycloalkyl group; and R7 is hydrogen, C1 to C4 alkyl optionally substituted with one 01 more halo; or C1 to C4 alkoxy; are parasiticidal agents,

Full Text	NA WE CLAIM : 1. 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I): (Formula Removed) or a veterinarily or agriculturally acceptable salt thereof, or a veterinarily or agriculturally acceptable solvate of either entity as herein described, wherein R1 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 C1 to C4 alkyl optionally substituted with one or more halo, C1 to C4 alkoxy optionally substituted with one or more halo, S(O)nC1 to C4 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 C1 to C4 alkyl optionally substituted with one or more halo, C1 to C4 alkoxy optionally substituted with one or more halo, S(O)nC1 to C4 alkyl optionally substituted with one or more halo, halo and pentafluorothio; R3 is C1 to C4 alkyl optionally substituted with hydroxy or with one or more halo; cyano, C1 to C5 alkanoyl or phenyl; R5 is hydrogen, C1 to C4 alkyl, amino or halo; R2 and R4 are each independently selected from hydrogen, C1 to C4 alkyl, fluoro, chloro and bromo or, together with the carbon atom to which they are attached, form a C3 to C6 cycloalkyl group; R6 and R8 are each independently selected from hydrogen, C1 to C4 alkyl, fluoro, chioro and bromo; or, when R2and R4 do not form part of a cycloalkyl group, R2 and R6, together with the carbon atoms to which they are attached, may form a C5 to C7 cycloalkyl group; R7 is hydrogen, C1 to C4 alkyl optionally substituted with one or more halo, or C1 to C4 alkoxy; and n is 0, 1 or 2. 2. 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I) as claimed in claim 1 wherein R1 is 2,6-dichloro-4-trifluoromethylphenyl, 2,6-dichloro-4-pentafluorothiophenyl, 2,4,6- trichlorophenyl or 3-chloro- 5-trifluoromethylpyridin-2-yl; R3 is methyl, ethyl, prop-2-yl, 1- hydroxyethyl, 2-hydroxyprop-2-yl, difluoromethyl, dichloromethyl, trifluoromethyl, cyano, formyl, acetyl or phenyl; R5 is hydrogen, methyl, amino or chioro; R2 and R4 are each independently selected from hydrogen, methyl, fluoro, chioro and bromo or, together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl or cyclopentyl group; R6 and R8 are each independently selected from hydrogen, methyl, chioro and bromo; or, when R2 and R4 do not form part of a cycloalkyl group, R2 and R6, together with the carbon atoms to which they are attached, may form a cyclopentane or cyclohexane group; and R7 is hydrogen, methyl, ethyl, trifluoromethyl, chlorodifluoromethyl, pentafluoroethyl, heptafluoropropyl or methoxy. 3. 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I) as claimed in claim 2 wherein R1 is 2,6-dichloro-4-trifluoromethylphenyl, 2,6-dichloro-4-pentafluorothiophenyl or 3-chloro-5- trifluoromethylpyridin-2-yl; R3 is cyano; R5 is hydrogen or amino; R2 and R4 are the same and are hydrogen, chioro or bromo; R6 and R8 are hydrogen; and R7 is hydrogen, trifluoromethyl or chiorodifluoromethyl. 4. 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I) as claimed in claim 3 wherein the compound of formula (I) is selected from 3-cyano-4-(2,2-dibromocyclopropyl)-1 -(2,6-dichloro-4-trifluoromethylphenyl)pyrazole; (-)-3-cyano-4-(2,2~dibromocyclopropyl)-l-(2,6-dichloro-4-triflu orome thylphenyl) pyrazole; 3-cyano-l-(2,6-dichloro-4-trifluoromethylphenyl)-4-(l-triflu oromethylcy clopr opyl) pyrazole; 3 -cyano-4 - (2,2 -dibromocyclopropyl) -1 - (2,6 -dichloro-4-pentafluorothiophenyl)pyrazole; 3-cyano-4-(2,2-dichlorocyclopropyl)-l-(2,6-dichloro-4-triflu or omethylphenyl) pyrazole; 4-(l-chlorodifluoromethylcyclopropyl)-3-cyano-l-(2, 6-dichloro-4 -triflu or ome thylphenyl) pyrazole; l-[(3-chloro-5-trifluoromethyl)pyridin-2-yl]-3-cyano-4-(2,2-dibromocyclopropyl)pyrazole; 5-amino-3-cyano-4-(2,2-dibromocyclopropyl)-l-(2,6-dichloro-4-trifluoromethylphenyl) pyrazole; 5-amino-3-cyano-4-(2,2-dibromocyclopropyl)-l-(2,6-dichloro-4-pentafluorothiophenyl) pyrazole; 5-amino-3-cyano-4-(2,2-dichlorocyclopropyl)-l-(2,6-dichloro-4-pentafluorothiophenyl)pyrazole; and 5-amino-3-cyano-l-(2,6-dichloro-4-trifluoromethylphenyl)-4-(l-trifluoromethylcyclopropyl) pyrazole. 5. A veterinary or agricultural formulation comprising 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I) or a veterinarily or agriculturally acceptable salt thereof, or a veterinarily or agriculturally acceptable solvate of either entity, together with a veterinarily or agriculturally acceptable diluent or carrier, wherein the formulation contains from 0.01 to 10% by weight of the active ingredient. 6. A veterinary or agricultural formulation as claimed in claim 5, which is adapted for topical administration. 7. 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I), or a veterinarily or agriculturally acceptable salt thereof, or a veterinarily or agriculturally acceptable solvate of either entity, or a veterinarily or agriculturally acceptable formulation containing any of the foregoing, for use as a parasiticide. 8. A process for the preparation of 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I) as claimed in claim 1: (Formula Removed) or a veterinarily or agriculturally acceptable salt thereof, or a veterinarily or agriculturally acceptable solvate of either entity, wherein R1 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 C1 to C4 alkyl optionally substituted with one or more halo, C1 to C4 alkoxy optionally substituted with one or more halo, S(O)nC1 to C4 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 C1 to C4 alkyl optionally substituted with one or more halo, C1 to C4 alkoxy optionally substituted with one or more halo, S(O)nC1 to C4 alkyl optionally substituted with one or more halo, halo and pentafluorothio; R3 is C1 to C4 alkyl optionally substituted with hydroxy or with one or more halo; cyano, C1 to C5 alkanoyl or phenyl; R5 is hydrogen, C1 to C4 alkyl, amino or halo; R2 and R4 are each independently selected from hydrogen, C1 to C4 alkyl, fluoro, chloro and bromo or, together with the carbon atom to which they are attached, form a C3 to C6 cycloalkyl group: R6 and R8 are each independently selected from hydrogen, C1 to C4 alkyl, fluoro, chloro and bromo; or, when R2 and R4 do not form part of a cycloalkyl group, R2 and R6 together with the carbon atoms to which they are attached, may Form a C5 to C7 cycloalkyl group; R7 is hydrogen, C1 to C4 alkyl optionally substituted with one or more halo, or C1 to C4 alkoxy; and n is 0, 1 or 2; which comprises treatment of a compound of formula (II): (Formula Removed) wherein R1, R3, R5, R6, R7 and R8 are as previously defined for formula (I), when R2 and R4 are either both chloro or both bromo, (i) with chloroform or bromoform in the presence of a base and a catalyst as herein described, or (ii) with an aryltrichloromethyl or aryltribromomethyl mercury derivative under thermolysis conditions; and the reaction is conducted at from 60°C to about 75°C temperature, followed by formation of a veterinarily or agriculturally acceptable salt of the required product or a veterinarily or agriculturally acceptable solvate of either entity. 9. A process as claimed in claim 8 wherein in (i) the base is a concentrated aqueous solution of an alkali metal hydroxide and the reaction is conducted under phase transfer catalysis conditions using a quaternary ammonium salt as catalyst in a suitable solvent at from about room temperature to about the reflux temperature of the reaction medium; in (ii) the reagent is either phenyltrichloromethylmercury or phenyltribromomethylmercury and the reaction is conducted in a suitable solvent at from about 60°C to about 75°C. 10. A process as claimed in claim 9, wherein in (i) the base is a concentrated aqueous solution of sodium hydroxide, the catalyst is benzyltriethylammonium chloride and the solvent is dichloromethane optionally in the presence of a small amount of ethanol; in (ii) the solvent in toluene, xylene or a mixture thereof. 11. 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I) as defined in claim 1 substantially as hereinbefore described with reference to the foregoing examples. 12. A process for the preparation of 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I) substantially as herein described with reference to the foregoing examples. .

Full Text

NA

WE CLAIM :
1. 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I):
(Formula Removed)
or a veterinarily or agriculturally acceptable salt thereof, or a veterinarily or agriculturally acceptable solvate of either entity as herein described, wherein
R1 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 C1 to C4 alkyl optionally substituted with one or more halo, C1 to C4 alkoxy optionally substituted with one or more halo, S(O)nC1 to C4 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 C1 to C4 alkyl optionally substituted with one or more halo, C1 to C4 alkoxy optionally substituted with one or more halo, S(O)nC1 to C4 alkyl optionally substituted with one or more halo, halo and pentafluorothio;
R3 is C1 to C4 alkyl optionally substituted with hydroxy or with one or more halo; cyano, C1 to C5 alkanoyl or phenyl;
R5 is hydrogen, C1 to C4 alkyl, amino or halo;
R2 and R4 are each independently selected from hydrogen, C1 to C4 alkyl, fluoro, chloro and bromo or, together with the carbon atom to which they are attached, form a C3 to C6 cycloalkyl group;
R6 and R8 are each independently selected from hydrogen, C1 to C4
alkyl, fluoro, chioro and bromo;
or, when R2and R4 do not form part of a cycloalkyl group, R2 and R6, together with the carbon atoms to which they are attached, may form a C5 to C7 cycloalkyl group;
R7 is hydrogen, C1 to C4 alkyl optionally substituted with one or more halo, or C1 to C4 alkoxy; and n is 0, 1 or 2.
2. 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I) as
claimed in claim 1 wherein R1 is 2,6-dichloro-4-trifluoromethylphenyl,
2,6-dichloro-4-pentafluorothiophenyl, 2,4,6- trichlorophenyl or 3-chloro-
5-trifluoromethylpyridin-2-yl; R3 is methyl, ethyl, prop-2-yl, 1-
hydroxyethyl, 2-hydroxyprop-2-yl, difluoromethyl, dichloromethyl,
trifluoromethyl, cyano, formyl, acetyl or phenyl; R5 is hydrogen, methyl,
amino or chioro; R2 and R4 are each independently selected from
hydrogen, methyl, fluoro, chioro and bromo or, together with the carbon
atom to which they are attached, form a cyclopropyl, cyclobutyl or
cyclopentyl group; R6 and R8 are each independently selected from
hydrogen, methyl, chioro and bromo; or, when R2 and R4 do not form
part of a cycloalkyl group, R2 and R6, together with the carbon atoms to
which they are attached, may form a cyclopentane or cyclohexane group;
and R7 is hydrogen, methyl, ethyl, trifluoromethyl, chlorodifluoromethyl,
pentafluoroethyl, heptafluoropropyl or methoxy.
3. 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I) as
claimed in claim 2 wherein R1 is 2,6-dichloro-4-trifluoromethylphenyl,
2,6-dichloro-4-pentafluorothiophenyl or 3-chloro-5-
trifluoromethylpyridin-2-yl; R3 is cyano; R5 is hydrogen or amino; R2 and
R4 are the same and are hydrogen, chioro or bromo; R6 and R8 are
hydrogen; and R7 is hydrogen, trifluoromethyl or chiorodifluoromethyl.
4. 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I) as
claimed in claim 3 wherein the compound of formula (I) is selected from
3-cyano-4-(2,2-dibromocyclopropyl)-1 -(2,6-dichloro-4-trifluoromethylphenyl)pyrazole;
(-)-3-cyano-4-(2,2~dibromocyclopropyl)-l-(2,6-dichloro-4-triflu orome thylphenyl) pyrazole;
3-cyano-l-(2,6-dichloro-4-trifluoromethylphenyl)-4-(l-triflu oromethylcy clopr opyl) pyrazole;
3 -cyano-4 - (2,2 -dibromocyclopropyl) -1 - (2,6 -dichloro-4-pentafluorothiophenyl)pyrazole;
3-cyano-4-(2,2-dichlorocyclopropyl)-l-(2,6-dichloro-4-triflu or omethylphenyl) pyrazole;
4-(l-chlorodifluoromethylcyclopropyl)-3-cyano-l-(2, 6-dichloro-4 -triflu or ome thylphenyl) pyrazole;
l-[(3-chloro-5-trifluoromethyl)pyridin-2-yl]-3-cyano-4-(2,2-dibromocyclopropyl)pyrazole;
5-amino-3-cyano-4-(2,2-dibromocyclopropyl)-l-(2,6-dichloro-4-trifluoromethylphenyl) pyrazole;
5-amino-3-cyano-4-(2,2-dibromocyclopropyl)-l-(2,6-dichloro-4-pentafluorothiophenyl) pyrazole;
5-amino-3-cyano-4-(2,2-dichlorocyclopropyl)-l-(2,6-dichloro-4-pentafluorothiophenyl)pyrazole; and
5-amino-3-cyano-l-(2,6-dichloro-4-trifluoromethylphenyl)-4-(l-trifluoromethylcyclopropyl) pyrazole.
5. A veterinary or agricultural formulation comprising 1-Aryl - 4 -
cyclopropylpyrazole compounds of formula (I) or a veterinarily or
agriculturally acceptable salt thereof, or a veterinarily or agriculturally
acceptable solvate of either entity, together with a veterinarily or
agriculturally acceptable diluent or carrier, wherein the formulation
contains from 0.01 to 10% by weight of the active ingredient.
6. A veterinary or agricultural formulation as claimed in claim 5, which is adapted for topical administration.
7. 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I), or a veterinarily or agriculturally acceptable salt thereof, or a veterinarily or agriculturally acceptable solvate of either entity, or a veterinarily or agriculturally acceptable formulation containing any of the foregoing, for use as a parasiticide.
8. A process for the preparation of 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I) as claimed in claim 1:
(Formula Removed)
or a veterinarily or agriculturally acceptable salt thereof, or a veterinarily or agriculturally acceptable solvate of either entity, wherein
R1 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 C1 to C4 alkyl optionally substituted with one or more halo, C1 to C4 alkoxy optionally substituted with one or more halo, S(O)nC1 to C4 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 C1 to C4 alkyl optionally substituted with one or more halo, C1 to C4 alkoxy optionally substituted with one or
more halo, S(O)nC1 to C4 alkyl optionally substituted with one or more halo, halo and pentafluorothio;
R3 is C1 to C4 alkyl optionally substituted with hydroxy or with one or more halo; cyano, C1 to C5 alkanoyl or phenyl;
R5 is hydrogen, C1 to C4 alkyl, amino or halo;
R2 and R4 are each independently selected from hydrogen, C1 to C4 alkyl, fluoro, chloro and bromo or, together with the carbon atom to which they are attached, form a C3 to C6 cycloalkyl group:
R6 and R8 are each independently selected from hydrogen, C1 to C4 alkyl, fluoro, chloro and bromo;
or, when R2 and R4 do not form part of a cycloalkyl group, R2 and R6 together with the carbon atoms to which they are attached, may Form a C5 to C7 cycloalkyl group;
R7 is hydrogen, C1 to C4 alkyl optionally substituted with one or more halo, or C1 to C4 alkoxy;
and n is 0, 1 or 2;
which comprises treatment of a compound of formula (II):
(Formula Removed)
wherein R1, R3, R5, R6, R7 and R8 are as previously defined for formula (I),
when R2 and R4 are either both chloro or both bromo, (i) with chloroform or bromoform in the presence of a base and a catalyst as herein described, or
(ii) with an aryltrichloromethyl or aryltribromomethyl mercury derivative under thermolysis conditions; and the reaction is conducted at from 60°C to about 75°C temperature,
followed by formation of a veterinarily or agriculturally acceptable salt of the required product or a veterinarily or agriculturally acceptable solvate of either entity.
9. A process as claimed in claim 8 wherein in
(i) the base is a concentrated aqueous solution of an alkali metal hydroxide and the reaction is conducted under phase transfer catalysis conditions using a quaternary ammonium salt as catalyst in a suitable solvent at from about room temperature to about the reflux temperature of the reaction medium; in
(ii) the reagent is either phenyltrichloromethylmercury or phenyltribromomethylmercury and the reaction is conducted in a suitable solvent at from about 60°C to about 75°C.
10. A process as claimed in claim 9, wherein in
(i) the base is a concentrated aqueous solution of sodium hydroxide,
the catalyst is benzyltriethylammonium chloride and the solvent is
dichloromethane optionally in the presence of a small amount of ethanol;
in
(ii) the solvent in toluene, xylene or a mixture thereof.
11. 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I) as
defined in claim 1 substantially as hereinbefore described with reference
to the foregoing examples.
12. A process for the preparation of 1-Aryl - 4 - cyclopropylpyrazole compounds of formula (I) substantially as herein described with reference to the foregoing examples. .

Documents:

3450-del-1997-abstract.pdf

3450-del-1997-assignment.pdf

3450-DEL-1997-Claims-(27-07-2011).pdf

3450-del-1997-claims.pdf

3450-DEL-1997-Correspondence Others-(27-07-2011).pdf

3450-del-1997-correspondence-others.pdf

3450-del-1997-correspondence-po.pdf

3450-del-1997-description (complete).pdf

3450-del-1997-form-1.pdf

3450-del-1997-form-13.pdf

3450-del-1997-form-18.pdf

3450-del-1997-form-2.pdf

3450-del-1997-form-3.pdf

3450-del-1997-form-4.pdf

3450-del-1997-form-5.pdf

3450-del-1997-form-6.pdf

3450-del-1997-gpa.pdf

3450-del-1997-petition-137.pdf

3450-del-1997-petition-138.pdf

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Patent Number

253903

Indian Patent Application Number

3450/DEL/1997

PG Journal Number

36/2012

Publication Date

07-Sep-2012

Grant Date

31-Aug-2012

Date of Filing

01-Dec-1997

Name of Patentee

PFIZER INC.,

Applicant Address

235 EAST 42nd STREET, NEW YORK, NEW YORK 10017, USA

Inventors:

#	Inventor's Name	Inventor's Address
1	BERNARD JOSEPH BANKS	PFIZER RESEARCH, RAMSGATE ROAD, SANDWICH, KENT, CT13 9NJ, UNITED KINGDOM

PCT International Classification Number

A61K 31/44

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	9625290.3	1996-12-05	U.K.