US 8,299,111 B2Granted

Compounds which modulate the CB2 receptor

AssigneeBoehringer Ingelheim International GmbH

InventorsAngela Berry, Pier Francesco Cirillo, Eugene Richard Hickey, Doris Riether, David S. Thomson, Monika Ermann, James Edward Jenkins, Innocent Mushi, Christopher Francis Palmer, Nigel Blumire

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Abstract

Compounds of formula (I) are disclosed. Compounds according to the invention bind to and are agonists, antagonists or inverse agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally useful for treating pain.

Claims9

Dependent claims

A compound of the formula

wherein:
R1 is phenyl optionally independently substituted with 1 to 3 substituents chosen from C1-C6 alkyl (which is optionally substituted with 1 to 3 halogen atoms), C1-C6 cycloalkyl, C1-C6 alkoxy (which is optionally substituted with 1 to 3 halogen atoms), C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, C1-C6 dialkylamino, C1-C6 alkylaminocarbonyl, acylamino, C1-C6 dialkylaminocarbonyl, hydroxyl, halogen, cyano, nitro, oxo, heterocyclyl, aryl and heteroaryl;
R2 and R3 are independently hydrogen or C1-C6 alkyl;
or R2 and R3 together with the carbon which they are attached to form a 3- to 6-membered cycloalkyl or heterocyclic ring;
R4 is hydrogen or methyl;
R5 is pyrazolyl optionally independently substituted with 1 to 3 substituents chosen from C1-C6 alkyl (which is optionally substituted with 1 to 3 halogen atoms or with a heterocyclyl group), C1-C6 alkoxy (which is optionally substituted with 1 to 3 halogen atoms), C1-C6 cycloalkyl, heterocyclyl, phenoxy, halogen, cyano, dimethylaminoalkyl, phenyl (which is optionally substituted with 1 to 2 halogen atoms or C1-C4 alkyl optionally substituted with halogen), thienyl (which is optionally substituted with 1 to 2 halogen atoms or C1-C4 alkyl optionally substituted with halogen), and pyridinyl (which is optionally substituted with 1 to 2 C1-C4 alkyl optionally substituted with halogen);
wherein R2 and R3, together with the carbon atom to which they are attached, do not form a cyclopropyl ring when R5 is 1-phenyl 5-pyrazolyl, and R1 is a phenyl, 4-chlorophenyl or 4-methylphenyl;
or a tautomer or pharmaceutically acceptable salt thereof.

5 more elements

A compound chosen from

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-chloro-benzenesulfonyl)-2-methyl-propionamide,
2-(4-Chloro-benzenesulfonyl)-2-methyl-N-(2-methyl-5-phenyl-2H-pyrazol-3-yl)-propionamide,
2-(4-Chloro-benzenesulfonyl)-N-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-propionamide,
2-(4-Chloro-benzenesulfonyl)-2-methyl-N-(5-methyl-2-phenyl-2H-pyrazol-3-yl)-propionamide,
2-(4-Chloro-benzenesulfonyl)-N-(2,5-dimethyl-2H-pyrazol-3-yl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-methyl-2-(4-trifluoromethyl-benzenesulfonyl)-butyramide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-chloro-2-fluoro-benzenesulfonyl)-2-methyl-propionamide,
2-(4-Bromo-benzenesulfonyl)-N-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-cyano-benzenesulfonyl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(3-fluoro-4-methyl-benzenesulfonyl)-2-methyl-propionamide,
4-(4-Trifluoromethyl-benzenesulfonyl)-tetrahydro-pyran-4-carboxylic acid (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-amide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(3-fluoro-4-methoxy-benzenesulfonyl)-2-methyl-propionamide,
N-(5-tert-Butyl-2H-pyrazol-3-yl)-2-(4-chloro-benzenesulfonyl)-2-methyl-propionamide,
1-(4-Trifluoromethyl-benzenesulfonyl)-cyclopropanecarboxylic acid (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-amide,
2-(4-Chloro-benzenesulfonyl)-N-(5-cyclohexyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-propionamide,
2-(4-Chloro-benzenesulfonyl)-N-(5-cyclopentyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-2-(toluene-4-sulfonyl)-propionamide,
2-Benzenesulfonyl-N-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-propionamide,
2-Benzenesulfonyl-2-methyl-N-(2-methyl-5-phenyl-2H-pyrazol-3-yl)-propionamide,
1-(4-Chloro-benzenesulfonyl)-cyclopropanecarboxylic acid (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-amide,
1-(4-Chloro-benzenesulfonyl)-cyclopropanecarboxylic acid (5-tert-butyl-2H-pyrazol-3-yl)-amide
1-(4-Chloro-benzenesulfonyl)-cyclopropanecarboxylic acid (2-methyl-5-phenyl-2H-pyrazol-3-yl)-amide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(3-fluoro-benzenesulfonyl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(2-fluoro-benzenesulfonyl)-2-methyl-propionamide,
N-(5-tert-Butyl-2H-pyrazol-3-yl)-2-(2-fluoro-benzenesulfonyl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(2-fluoro-4-methyl-benzenesulfonyl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-cyano-2-fluoro-benzenesulfonyl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-fluoro-benzenesulfonyl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(2,5-difluoro-benzenesulfonyl)-2-methyl-propionamide,
2-(4-Chloro-benzenesulfonyl)-N-(2,4-dimethyl-5-phenyl-2H-pyrazol-3-yl)-2-methyl-propionamide,
2-(4-Chloro-benzenesulfonyl)-N-(5-isopropyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-propionamide,
2-(2,4-Difluoro-benzenesulfonyl)-2-methyl-N-(2-methyl-5-phenyl-2H-pyrazol-3-yl)-propionamide,
N-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-2-(2,4-difluoro-benzenesulfonyl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(2,4-difluoro-benzenesulfonyl)-2-methyl-propionamide,
2-(4-Methoxy-benzenesulfonyl)-2-methyl-N-(2-methyl-5-phenyl-2H-pyrazol-3-yl)-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide,
2-(4-Methoxy-benzenesulfonyl)-2-methyl-N-(2-methyl-5-thiophen-2-yl-2H-pyrazol-3-yl)-propionamide,
2-methyl-N-(1-methyl-3-phenyl-1H-pyrazol-5-yl)-2-{[4-(methylsulfonyl)phenyl]sulfonyl}propanamide,
N-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-2-methyl-2-{[4-(methylsulfonyl)phenyl]sulfonyl}propanamide and
N-(1,4-dimethyl-3-phenyl-1H-pyrazol-5-yl)-2-[(4-methoxyphenyl)sulfonyl]-2-methylpropanamide,
N-(5-sec-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-chloro-benzenesulfonyl)-2-methyl-propionamide,
or a tautomer or pharmaceutically acceptable salt thereof.

39 more elements

A compound chosen from

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-chloro-benzenesulfonyl)-2-methyl-propionamide,
2-(4-Chloro-benzenesulfonyl)-2-methyl-N-(2-methyl-5-phenyl-2H-pyrazol-3-yl)-propionamide,
2-(4-Chloro-benzenesulfonyl)-2-methyl-N-(2-methyl-5-thiophen-2-yl-2H-pyrazol-3-yl)-propionamide,
2-(4-Chloro-benzenesulfonyl)-N-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-chloro-2-fluoro-benzenesulfonyl)-2-methyl-propionamide,
2-(4-Bromo-benzenesulfonyl)-N-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-cyano-benzenesulfonyl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(3-fluoro-4-methyl-benzenesulfonyl)-2-methyl-propionamide,
2-(4-Chloro-2-fluoro-benzenesulfonyl)-2-methyl-N-(2-methyl-5-phenyl-2H-pyrazol-3-yl)-propionamide,
4-(4-Trifluoromethyl-benzenesulfonyl)-tetrahydro-pyran-4-carboxylic acid (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-amide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(3-fluoro-4-methoxy-benzenesulfonyl)-2-methyl-propionamide,
1-(4-Trifluoromethyl-benzenesulfonyl)-cyclopropanecarboxylic acid (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-amide,
2-(4-Chloro-benzenesulfonyl)-N-(5-cyclohexyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-propionamide,
2-(4-Chloro-benzenesulfonyl)-N-(5-cyclopentyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-2-(toluene-4-sulfonyl)-propionamide,
2-Methyl-N-(2-methyl-5-phenyl-2H-pyrazol-3-yl)-2-(toluene-4-sulfonyl)-propionamide,
1-(4-Chloro-benzenesulfonyl)-cyclopropanecarboxylic acid (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-amide,
1-(4-Chloro-benzenesulfonyl)-cyclopropanecarboxylic acid (5-tert-butyl-2H-pyrazol-3-yl)-amide
1-(4-Chloro-benzenesulfonyl)-cyclopropanecarboxylic acid (2-methyl-5-phenyl-2H-pyrazol-3-yl)-amide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(3-fluoro-benzenesulfonyl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(2-fluoro-benzenesulfonyl)-2-methyl-propionamide,
N-(5-tert-Butyl-2H-pyrazol-3-yl)-2-(2-fluoro-benzenesulfonyl)-2-methyl-propionamide
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(2-fluoro-4-methyl-benzenesulfonyl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-cyano-2-fluoro-benzenesulfonyl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-fluoro-benzenesulfonyl)-2-methyl-propionamide,
2-(4-Chloro-benzenesulfonyl)-N-(2,4-dimethyl-5-phenyl-2H-pyrazol-3-yl)-2-methyl-propionamide,
2-(4-Chloro-benzenesulfonyl)-N-(5-isopropyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(2,4-difluoro-benzenesulfonyl)-2-methyl-propionamide,
2-(4-Methoxy-benzenesulfonyl)-2-methyl-N-(2-methyl-5-phenyl-2H-pyrazol-3-yl)-propionamide,
N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide,
2-(4-Methoxy-benzenesulfonyl)-2-methyl-N-(2-methyl-5-thiophen-2-yl-2H-pyrazol-3-yl)-propionamide and
N-(5-sec-Butyl-2-methyl-2H-pyrazol-3-yl)-2-(4-chloro-benzenesulfonyl)-2-methyl-propionamide,
or a tautomer or pharmaceutically acceptable salt thereof.

30 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/956,322Filed 30 Nov 2010 · division
Priority: 28 Jul 2006
Published: US 2011/0071127 A124 Mar 2011
Granted: 30 Oct 2012
Term ends: Not estimatedThe source records don’t support an estimate.

Classification71 codes

C07D 261/14
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 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…

Family

Application60/820,622Us provisional application · filed 28 Jul 2006
Application11/781,336Parent of this division · filed 23 Jul 2007
US 2011/0071127 A1Pre-grant publication · published 24 Mar 2011
US 7,935,715 B2Parent of this division
US 2008/0039464 A1Published application
US 8,299,111 B2This patent

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

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Abstract

Facts

Application

12/956,322Filed 30 Nov 2010 · division

Priority

28 Jul 2006

Published

US 2011/0071127 A124 Mar 2011

Granted

30 Oct 2012

Term ends

Not estimatedThe source records don’t support an estimate.

Classification71 codes

C07D 261/14
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 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…

Family

Application60/820,622Us provisional application · filed 28 Jul 2006

Application11/781,336Parent of this division · filed 23 Jul 2007

US 2011/0071127 A1Pre-grant publication · published 24 Mar 2011

US 7,935,715 B2Parent of this division

US 2008/0039464 A1Published application

US 8,299,111 B2This patent

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