US 6,444,696 B1Granted

Pyrazole derivatives P38 MAP kinase inhibitors

AssigneeSyntex (U.S.A.) Inc.

InventorsDavid Michael Goldstein, Sharada Shenvi Labadie, David Mark Rotstein, Eric Brian Sjogren, Francisco Xavier Talamas

Life of this patent

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Abstract

The present invention relates to certain pyrazole derivatives of Formula (I): that are p-38 MAP kinase inhibitors, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.

Claims29

Dependent claims

A compound selected from the group of compounds represented by Formula (I):

wherein:
R1 is hydrogen or acyl;
R2 is hydrogen or alkyl;
A is an aryl ring;
B is a heteroaryl ring;
R3 is selected from the group consisting of:
(c) optionally substituted heterocyclyl;
(d) optionally substituted aryl or heteroaryl;
(f) heteroalkenyl;
(g) heteroalkynyl;
(h) heteroalkoxy;
(i) heteroalkylamino;
(j) optionally substituted heterocyclylalkyl;
(k) optionally substituted heterocyclylalkenyl;
(l) optionally substituted heterocyclylalkynyl;
(m) optionally substituted cycloalkoxy, cycloalkylalkyloxy, heterocyclylalkoxy, or heterocyclyloxy;
(n) optionally substituted heterocyclylalkylamino;
(o) optionally substituted heterocyclylalkylcarbonyl;
(p) heteroalkylcarbonyl;
(q) optionally substituted cycloalkylamino;
(t) —Y-(alkylene)-R9 where:
Y is a single bond, —O—, —NH— or —S(O)n— (where n is an integer from 0 to 2);
and R9 is cyano, optionally substituted heteroaryl, —COOH, —COR10, —COOR11, —CONR12R13, —SO2R14, —SO2NR15, R16, —NHSO2R17 or —NHSO2NR18R19, where R10 is alkyl or optionally substituted heterocycle, R11 is alkyl, and R12, R13, R14, R15, R16, R17, R18 and R19 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(u) —C(═NR20)(NR21R22) where R20, R21 and R22 independently represented hydrogen, alkyl or hydroxy, or R20 and R21 (together are —(CH2)n— where n is 2 or 3 and R22 is hydrogen or alkyl;
(v) —NHC(X)NR23R24 where X is —O— or —S—, and R23 and R24 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(w) —CONR25R26 where R25 and R26 independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R25 and R26 together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring;
(y) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino;
(z) arylaminoalkylene or geteroarylaminoalkylene;
(aa) Z-alkylene-NR30R31 or Z-alkylene-OR32 where Z is —NH—, —N(alkyl)- or —O—, and R30, R31 and R32 are independently of each other, hydrogen, alkyl or heteroalkyl;
(bb) —OC(O)-alkylene-CO2H or —OC(O)—NR′R″ (where R′ and R″ are independently hydrogen or alkyl;
(cc) heteroarylalkenylene or heteroarylalkynylene;
(dd) X-(alkylene)CH[(CR′R″)mOR40][(CR′R″)nOR40] where:
X is —O—, —NH—, —NR— (where R is alkyl), —S(O)p— (where p is an integer from 0 to 2);
R40 is acyl, C(O)OR41 (where R41 is hydrogen, alkyl, or cycloalkyl);
C(O)ONR41R42 (where R41 is as defined above and R42 are as is hydrogen or alkyl);
or C(O)NR41R42 (where R41 and R42 aredefined above);
R′ and R″, independently, are hydrogen or alkyl;
and m and n, independently, are an integer from 0 to 3 provided that m and n are not both zero;
(ee) X-(alkylene)-CH(OH)CH2NHR50 where:
X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)n— (where n is an integer from 0 to 2);
and
R50 is C(O)OR51 and C(O)NR51R52 (where R51 is hydrogen, alkyl, or cycloalkyl and R52 is hydrogen or alkyl);
and
(ff) X-(alkylene)-CH(NR50)—CH2OH where:
X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)n— (where n is an integer from 0 to 2);
and
R50 is C(O)OR51 and C(O)NR51R52 (where R51 is hydrogen, alkyl, or cycloalkyl and R52 is hydrogen or alkyl);
and
R4 is selected from the group consisting of:
(a) hydrogen;
(a) halo;
(b) alkyl;
(c) alkoxy;
and
(d) hydroxy;
R5 is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl;
(d) haloalkyl;
(e) thioalkyl;
(f) hydroxy;
(g) amino;
(h) alkylamino;
(i) dialkylamino;
(j) heteroalkyl;
(k) optionally substituted heterocyclo;
(l) optionally substituted heterocyclylalkyl;
(m) optionally substituted heterocyclylalkoxy;
(n) alkylsulfonyl;
(o) aminosulfonyl, mono-alkylaminosulfonyl or dialkylaminosulfonyl;
(p) heteroalkyl;
and
(q) carboxy;
R6 is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl;
and
(d) alkoxy;
and
prodrugs, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.

79 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/909,966Filed 19 Jul 2001 · division
Priority: 5 May 1998
Published: US 2002/0103245 A11 Aug 2002
Granted: 3 Sep 2002
Term ends: Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07D 231/38
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 11/06
Drugs for disorders of the respiratory system: antiasthmatics

Family

Application60/084,250Us provisional application · filed 5 May 1998
Application60/122,140Us provisional application · filed 2 Mar 1999
Application60/130,369Us provisional application · filed 21 Apr 1999
Application09/305,737Parent of this continuation-in-part · filed 5 May 1999
Application09/401,141Parent of this division · filed 22 Sep 1999
US 6,316,466 B1Parent of this division
Application09/401,141Parent of this continuation-in-part
US 2002/0103245 A1Published application
US 6,376,527 B1Related patent
US 6,444,696 B1This patent

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

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Abstract

A compound selected from the group of compounds represented by Formula (I):

wherein:
R1 is hydrogen or acyl;
R2 is hydrogen or alkyl;
A is an aryl ring;
B is a heteroaryl ring;
R3 is selected from the group consisting of:
(c) optionally substituted heterocyclyl;
(d) optionally substituted aryl or heteroaryl;
(f) heteroalkenyl;
(g) heteroalkynyl;
(h) heteroalkoxy;
(i) heteroalkylamino;
(j) optionally substituted heterocyclylalkyl;
(k) optionally substituted heterocyclylalkenyl;
(l) optionally substituted heterocyclylalkynyl;
(m) optionally substituted cycloalkoxy, cycloalkylalkyloxy, heterocyclylalkoxy, or heterocyclyloxy;
(n) optionally substituted heterocyclylalkylamino;
(o) optionally substituted heterocyclylalkylcarbonyl;
(p) heteroalkylcarbonyl;
(q) optionally substituted cycloalkylamino;
(t) —Y-(alkylene)-R9 where:
Y is a single bond, —O—, —NH— or —S(O)n— (where n is an integer from 0 to 2);
and R9 is cyano, optionally substituted heteroaryl, —COOH, —COR10, —COOR11, —CONR12R13, —SO2R14, —SO2NR15, R16, —NHSO2R17 or —NHSO2NR18R19, where R10 is alkyl or optionally substituted heterocycle, R11 is alkyl, and R12, R13, R14, R15, R16, R17, R18 and R19 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(u) —C(═NR20)(NR21R22) where R20, R21 and R22 independently represented hydrogen, alkyl or hydroxy, or R20 and R21 (together are —(CH2)n— where n is 2 or 3 and R22 is hydrogen or alkyl;
(v) —NHC(X)NR23R24 where X is —O— or —S—, and R23 and R24 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(w) —CONR25R26 where R25 and R26 independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R25 and R26 together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring;
(y) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino;
(z) arylaminoalkylene or geteroarylaminoalkylene;
(aa) Z-alkylene-NR30R31 or Z-alkylene-OR32 where Z is —NH—, —N(alkyl)- or —O—, and R30, R31 and R32 are independently of each other, hydrogen, alkyl or heteroalkyl;
(bb) —OC(O)-alkylene-CO2H or —OC(O)—NR′R″ (where R′ and R″ are independently hydrogen or alkyl;
(cc) heteroarylalkenylene or heteroarylalkynylene;
(dd) X-(alkylene)CH[(CR′R″)mOR40][(CR′R″)nOR40] where:
X is —O—, —NH—, —NR— (where R is alkyl), —S(O)p— (where p is an integer from 0 to 2);
R40 is acyl, C(O)OR41 (where R41 is hydrogen, alkyl, or cycloalkyl);
C(O)ONR41R42 (where R41 is as defined above and R42 are as is hydrogen or alkyl);
or C(O)NR41R42 (where R41 and R42 aredefined above);
R′ and R″, independently, are hydrogen or alkyl;
and m and n, independently, are an integer from 0 to 3 provided that m and n are not both zero;
(ee) X-(alkylene)-CH(OH)CH2NHR50 where:
X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)n— (where n is an integer from 0 to 2);
and
R50 is C(O)OR51 and C(O)NR51R52 (where R51 is hydrogen, alkyl, or cycloalkyl and R52 is hydrogen or alkyl);
and
(ff) X-(alkylene)-CH(NR50)—CH2OH where:
X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)n— (where n is an integer from 0 to 2);
and
R50 is C(O)OR51 and C(O)NR51R52 (where R51 is hydrogen, alkyl, or cycloalkyl and R52 is hydrogen or alkyl);
and
R4 is selected from the group consisting of:
(a) hydrogen;
(a) halo;
(b) alkyl;
(c) alkoxy;
and
(d) hydroxy;
R5 is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl;
(d) haloalkyl;
(e) thioalkyl;
(f) hydroxy;
(g) amino;
(h) alkylamino;
(i) dialkylamino;
(j) heteroalkyl;
(k) optionally substituted heterocyclo;
(l) optionally substituted heterocyclylalkyl;
(m) optionally substituted heterocyclylalkoxy;
(n) alkylsulfonyl;
(o) aminosulfonyl, mono-alkylaminosulfonyl or dialkylaminosulfonyl;
(p) heteroalkyl;
and
(q) carboxy;
R6 is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl;
and
(d) alkoxy;
and
prodrugs, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.

79 more elements

Facts

Application

09/909,966Filed 19 Jul 2001 · division

Priority

5 May 1998

Published

US 2002/0103245 A11 Aug 2002

Granted

3 Sep 2002

Term ends

Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07D 231/38
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 11/06
Drugs for disorders of the respiratory system: antiasthmatics

Family

Application60/084,250Us provisional application · filed 5 May 1998

Application60/122,140Us provisional application · filed 2 Mar 1999

Application60/130,369Us provisional application · filed 21 Apr 1999

Application09/305,737Parent of this continuation-in-part · filed 5 May 1999

Application09/401,141Parent of this division · filed 22 Sep 1999

US 6,316,466 B1Parent of this division

Application09/401,141Parent of this continuation-in-part

US 2002/0103245 A1Published application

US 6,376,527 B1Related patent

US 6,444,696 B1This patent

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