US 6,506,747 B1Granted

Substituted 1-(4-aminophenyl)pyrazoles and their use as anti-inflammatory agents

AssigneeBoehringer Ingelheim Pharmaceuticals, Inc.

InventorsRajashekhar Betageri, Charles L. Cywin, Karl Hargrave, Mary Ann Hoermann, Thomas M. Kirrane, Thomas M. Parks, Usha R. Patel, John R. Proudfoot, Rajiv Sharma, Sanxing Sun, Xiao-Jun Wang

Life of this patent

Estimating the term…

Abstract

1-(4-aminophenyl)pyrazoles optionally substituted on the 3- and 5-positions of the pyrazole ring and on the amino group at the 4-position of the phenyl ring are disclosed and described, which pyrazoles inhibit IL-2 production in T-lymphocytes.

Claims15

Dependent claims

A compound of formula I′

wherein:
R1′ is aryl or heterocyclyl connected to the pyrazole in any position that makes a stable bond, optionally substituted with halogen, C1-4 alkyl, C1-4 alkenyl, CN, Me2N, CO2Me, OMe, aryl, heterocyclyl or R5 (hereinafter defined);
R2 is H, halogen, or methyl;
R3 is CF3, halogen, CN, C1-8 alkyl or branched alkyl or C1-8 alkenyl or branched alkenyl or C3-8 cycloalkyl optionally substituted with OH, CN or methoxy;
C1-8 alkoxy, C1-4 alkyloxyalkyl, C1-8 alkylthio, C1-4 alaylthioalkyl, C1-8 dialkylamino C1-4 dialkylaminoalkyl, CO2R5 where R5 is C1-4 alkyl or C1-4alkenyl optionally substituted with carbocyclyl or heterocyclyl;
aryl or heterocyclyl connected to the pyrazole in any position that makes a stable bond, optionally substituted with halogen, C1-4 alkyl, C1-4 alkenyl, CN, Me2N, CO2Me, OMe, aryl, heterocyclyl or R5;
L is —NHC(O)—, —NHC(O)O—, —NHC(O)C(O)—, —NHC(S)—, —NH—, —NHC(O)NH, NHC(S)NH, NECH2, —NHCH(R6)—, where R6 is H, CN, C1-6 alkyl, C1-6 alkyloxyoalyl C1-6 alkythioalkyl, C1-6 alkylsnylalkyl, C1-6 alkylsulfonylalkyl, C3-6 cycloalkyl, or heterocyclyl or aryl optionally substituted with a halogen, C1-4 alkyl, CN, Me2N, CO2Me or OMe, or —NHC(R6)-lower alkyl;
R4 is C1-8 alkyl, C1-8 alkyloxy, C1-8 akylthio, C1-8 alkylamino, C1-4 alkoxyayl, C1-4 allthioalkl, C1-4 alkylarninoll, C1-4 dialkylaminoalkyl, carbocyclyl or heterocyclyl, optionally substituted with one or more halogen, —CN, —NO2, SO2NH2, or R7 where R7 is phenyl, heterocyclyl, C3-6 cycloalkyl, C1-6 alkyl, C2-6 alkenyl, C1-6 alkyloxyalkyl, C1-6 alkylthioalkyl, C1-6 alkylsulfinylalkyl, C1-6 alkylsulfonylalkyl or C2-6 alkynyl, optionally substituted with halogen, OH, alkyloxy, CN, COO-lower alkyl, —CONH-lower alkyl, —CON(lower alkyl)2, dialkylamino, phenyl or heterocylcyl;
CO2R7, —N(R7)2, —NH(R7), —C(O)R7, —OR7, S(O)nR7 where n is 0, 1 or 2, —SO2NHR7, or —SO2N(R7)2,
wherein heterocyclyl refers to unsubstituted heterocycle radicals, those radicals that are partially or fully halogenated and those radicals substituted with alkyl, hydroxyl, nitro, —COOH, —CO (lower alkoxy), —CO (lower alkyl), amino, alkylamino, dialkylamino, alkoxy, —NCHO, —NCO (lower alkyl), —NSO2—Ph(halo)0.3, Ph, —O—Ph, naphthyl, —O-naphthyl, pyrrolyl, pyrrolyl substituted with lower alkyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl wherein heterocycle means benzimidazolyl, furyl;
imidazolyl, imidazolinyl, imidazolidinyl, quinolinyl, isoquinolinyl, indolyl, oxazolyl, pyridyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinoxolyl, piperidinyl, morpholinyl, thiomorpholinyl, furyl, thienyl, thiazolyl, β-carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl, benzoxazolyl, oxopiperidinyl, oxopyrroldinyl, oxoazepinyl, azepinyl, isoxazolyl, tetrahydropyranyl, tetrahydrofuranyl, thiadiazolyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl.

8 more elements

A compound of formula I″

wherein:
R1 and R3 are the same or different and each is CF3, halogen, CN, C1-8 alkyl or branched alkyl or C1-8 alkenyl or branched alkrenyl or C3-8 cycloalkyl optionally substituted with OH, CN or methoxy;
C1-8 alkoxy, C1-4 alkyloxyalkyl, C1-8 alkylthio, C1-4 alkylthioalkyl, C1-8 dialkylamino, C1-4 dialkylaminoalkyl, CO2R5 where R5 is C1-4 alkryl or C1-4 alkenyl optionally substituted with carbocyclyl or heterocyclyl;
aryl or heterocyclyl connected to the pyrazole in any position that makes a stable bond, optionally substituted with halogen, C1-4 alkyl, C1-4 alkenyl, CN, Me2N, CO2Me, OMe, aryl, heterocyclyl or R5;
R2 is H, halogen, or methyl;
and
R4′ is aryl, heterocyclyl or cycloalkyl,
wherein heterocyclyl refers to unsubstituted heterocycle radicals, those radicals that are partially or fully halogenated and those radicals substituted with alkyl, hydroxyl, nitro, —COOH, —CO (Gower alkoxy), —CO (lower alkyl), amino, alkylamino, dialkylamino, alkoxy, —NCHO, —NCO (lower alkyl), —NSO2—Ph(halo)0-3, Ph, —O—Ph, naphthyl, —O-naphthyl, pyrrolyl, pyrrolyl substituted with lower alkyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl wherein heterocycle means benz imidazolyl, furyl;
imidazolyl, imidazolinyl, imidazolidinyl, quinolinyl, isoquinolinyl, indolyl, oxazolyl, pyridyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinoxolyl, piperidinyl, morpholinyl, thiomorpholinyl, furyl, thienyl, thiazolyl, β-carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl, benzoxazolyl, oxopiperidinyl, oxopyrroldinyl, oxoazepinyl, azepinyl, isoxazolyl, tetrahydropyranyl, tetrahydrofiuranyl, thiadiazoly, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, and
with the proviso thai compounds of Formula I″ in which R1 is CN, R2 is H, R3 is 4-methylsulfonylphenyl and R4 is either 4-methylaminophenyl or 4-ethylaminophenyl are excluded.

7 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/324,933Filed 3 Jun 1999 · us provisional application
Priority: 5 Jun 1998
Granted: 14 Jan 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07D 231/14
Having two or three double bonds between ring members or between ring members and non-ring members: with hetero atoms or with carbon atoms having…

Family

Application60/088,154Us provisional application · filed 5 Jun 1998
US 6,506,747 B1This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound of formula I′

wherein:
R1′ is aryl or heterocyclyl connected to the pyrazole in any position that makes a stable bond, optionally substituted with halogen, C1-4 alkyl, C1-4 alkenyl, CN, Me2N, CO2Me, OMe, aryl, heterocyclyl or R5 (hereinafter defined);
R2 is H, halogen, or methyl;
R3 is CF3, halogen, CN, C1-8 alkyl or branched alkyl or C1-8 alkenyl or branched alkenyl or C3-8 cycloalkyl optionally substituted with OH, CN or methoxy;
C1-8 alkoxy, C1-4 alkyloxyalkyl, C1-8 alkylthio, C1-4 alaylthioalkyl, C1-8 dialkylamino C1-4 dialkylaminoalkyl, CO2R5 where R5 is C1-4 alkyl or C1-4alkenyl optionally substituted with carbocyclyl or heterocyclyl;
aryl or heterocyclyl connected to the pyrazole in any position that makes a stable bond, optionally substituted with halogen, C1-4 alkyl, C1-4 alkenyl, CN, Me2N, CO2Me, OMe, aryl, heterocyclyl or R5;
L is —NHC(O)—, —NHC(O)O—, —NHC(O)C(O)—, —NHC(S)—, —NH—, —NHC(O)NH, NHC(S)NH, NECH2, —NHCH(R6)—, where R6 is H, CN, C1-6 alkyl, C1-6 alkyloxyoalyl C1-6 alkythioalkyl, C1-6 alkylsnylalkyl, C1-6 alkylsulfonylalkyl, C3-6 cycloalkyl, or heterocyclyl or aryl optionally substituted with a halogen, C1-4 alkyl, CN, Me2N, CO2Me or OMe, or —NHC(R6)-lower alkyl;
R4 is C1-8 alkyl, C1-8 alkyloxy, C1-8 akylthio, C1-8 alkylamino, C1-4 alkoxyayl, C1-4 allthioalkl, C1-4 alkylarninoll, C1-4 dialkylaminoalkyl, carbocyclyl or heterocyclyl, optionally substituted with one or more halogen, —CN, —NO2, SO2NH2, or R7 where R7 is phenyl, heterocyclyl, C3-6 cycloalkyl, C1-6 alkyl, C2-6 alkenyl, C1-6 alkyloxyalkyl, C1-6 alkylthioalkyl, C1-6 alkylsulfinylalkyl, C1-6 alkylsulfonylalkyl or C2-6 alkynyl, optionally substituted with halogen, OH, alkyloxy, CN, COO-lower alkyl, —CONH-lower alkyl, —CON(lower alkyl)2, dialkylamino, phenyl or heterocylcyl;
CO2R7, —N(R7)2, —NH(R7), —C(O)R7, —OR7, S(O)nR7 where n is 0, 1 or 2, —SO2NHR7, or —SO2N(R7)2,
wherein heterocyclyl refers to unsubstituted heterocycle radicals, those radicals that are partially or fully halogenated and those radicals substituted with alkyl, hydroxyl, nitro, —COOH, —CO (lower alkoxy), —CO (lower alkyl), amino, alkylamino, dialkylamino, alkoxy, —NCHO, —NCO (lower alkyl), —NSO2—Ph(halo)0.3, Ph, —O—Ph, naphthyl, —O-naphthyl, pyrrolyl, pyrrolyl substituted with lower alkyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl wherein heterocycle means benzimidazolyl, furyl;
imidazolyl, imidazolinyl, imidazolidinyl, quinolinyl, isoquinolinyl, indolyl, oxazolyl, pyridyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinoxolyl, piperidinyl, morpholinyl, thiomorpholinyl, furyl, thienyl, thiazolyl, β-carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl, benzoxazolyl, oxopiperidinyl, oxopyrroldinyl, oxoazepinyl, azepinyl, isoxazolyl, tetrahydropyranyl, tetrahydrofuranyl, thiadiazolyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl.

8 more elements

Facts

Application

09/324,933Filed 3 Jun 1999 · us provisional application

Priority

5 Jun 1998

Granted

14 Jan 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07D 231/14
Having two or three double bonds between ring members or between ring members and non-ring members: with hetero atoms or with carbon atoms having…