IP Library › Granted Patent US 8,546,563

Granted Patent B2

US 8,546,563 · App. 12/741,260 · Granted Oct 1, 2013

Compounds which modulate the CB2 receptor

Inventors: Angela Berry (Gaylordsville, CT); Doris Riether (Newtown, CT); Renee M. Zindell (New Milford, CT); Nigel James Blumire (Didcot, GB)

Assignee: Boehringer Ingelheim International GmbH

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Quick Facts

Patent No.: US 8,546,563
App. No.: 12/741,260
Granted: Oct 1, 2013
Kind: B2

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Abstract

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

Claims (169)

1. A method of treating pain comprising administering to a patient a therapeutically effective amount of a compound of the formula (I)

wherein,

R 1 is C 1-10 alkyl, C 3-10 cycloalkyl-C 0-2 alkyl- or heterocycle-C 0-2 alkyl- wherein the heterocycle is chosen from tetrahydropyranyl, tetrahydrofuranyl, dioxanyl, thiomorpholinyl, 1,1-dioxo-1λ 6 -thiomorpholinyl, morpholinyl, piperidinyl, pyrrolidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxo-tetrahydrothiopyranyl, imidazolidinyl, pyrazolidinyl or oxetanyl, each R 1 is optionally substituted with 1 to 3 substituents chosen from halogen, C 1-5 alkyl, C 3-10 cycloalkyl, hydroxy or C 1-6 alkoxy;

R 2 is hydrogen or C 1-5 alkyl;

or R 1 and R 2 together with the N atom to which they are attached form a 3- to 6-membered heterocyclic ring optionally substituted with 1-3 substituents chosen from C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, hydroxyl, C 1-3 alkylaminocarbonyl, C 1-3 dialkylaminocarbonyl, C 1-3 alkylcarbonyl, C 1-3 alkyl sulfonyl or halogen;

R 3 is methyl, ethyl, or isopropyl;

R 4 is H or methyl;

R 3 and R 4 together with the carbon they are attached to form a 3-4 membered cycloalkyl ring;

R 5 is furanyl, pyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, imidazolyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, pyridinyl or benzothiazolyl each optionally independently substituted with 1 to 3 substituents chosen from C 1-6 alkyl, C 1-5 alkoxycarbonyl, cyano or halogen, each R 5 or it's substituents where possible are optionally partially or fully halogenated;

or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 wherein,

R 1 is C 1-5 alkyl, C 3-6 cycloalkyl-C 0-2 alkyl- or heterocycle-C 0-2 alkyl- wherein the heterocycle is chosen from tetrahydropyranyl, tetrahydrofuranyl, dioxanyl, thiomorpholinyl, 1,1-dioxo-1λ 6 -thiomorpholinyl, piperidinyl, pyrrolidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxo-tetrahydrothiopyranyl, imidazolidinyl, pyrazolidinyl, oxetanyl, or morpholinyl, each R 1 is optionally independently substituted with 1 to 3 substituents chosen from halogen, C 1-5 alkyl, C 3-6 cycloalkyl, hydroxy or C 1-6 alkoxy;

R 1 and R 2 together with the N atom to which they are attached form morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl homopiperidinyl, thiomorpholinyl, 1,1-dioxo-1λ 6 -thiomorpholinyl or piperazinyl, each optionally substituted with 1-3 substituents chosen from C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, C 1-3 alkylaminocarbonyl, C 1-3 dialkylaminocarbonyl, C 1-3 alkylcarbonyl, C 1-3 alkyl sulfonyl or halogen;

R 5 is furanyl, pyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, imidazolyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, triazolyl, pyridinyl or benzothiazolyl each R 5 substituent is further optionally substituted with 1 to 3 substituents chosen from C 1-5 alkyl, C 1-5 alkoxycarbonyl, cyano or halogen, each R 5 or it's substituents where possible are optionally partially or fully halogenated.

3. The method according to claim 2 wherein,

R 1 is C 1-5 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl, tetrahydropyranyl, tetrahydrofuranyl or morpholinyl, each optionally independently substituted with 1 to 3 substituents chosen from halogen, C 1-3 alkyl, C 3-6 cycloalkyl or C 1-3 alkoxy;

R 5 is furanyl, pyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, imidazolyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, triazolyl, pyridinyl or benzothiazolyl each R 5 substituent is further optionally substituted with 1 to 3 substituents chosen from C 1-5 alkyl, C 1-5 alkoxycarbonyl, cyano or halogen, each R 5 or it's substituents where possible are optionally partially or fully halogenated.

4. The method according to claim 3 wherein,

R 1 is C 1-5 alkyl, C 3-6 cycloalkyl, cyclohexylmethyl or tetrahydropyranyl, each optionally independently substituted with 1 to 3 substituents chosen from halogen, C 1-3 alkyl, C 3-6 cycloalkyl or C 1-4 alkoxy;

R 1 and R 2 together with the N atom to which they are attached form morpholinyl, piperidinyl, azetidinyl or pyrrolidinyl each optionally substituted with 1-3 substituents chosen from C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, C 1-3 alkylaminocarbonyl, C 1-3 dialkylaminocarbonyl, C 1-3 alkylcarbonyl, C 1-3 alkyl sulfonyl or halogen.

5. The method according to claim 4 wherein,

R 1 is C 1-5 alkyl, C 3-6 cycloalkyl or tetrahydropyranyl, each optionally independently substituted with 1 to 3 substituents chosen from halogen, C 1-3 alkyl, C 1-3 alkoxy or C 3-6 cycloalkyl.

6. A method of treating pain comprising administering to a patient a therapeutically effective amount of a compound of the formula (I),

wherein for the formula (I)

is chosen members of column A in Table I, and

is chosen members of column B in Table I:

TABLE I

or a pharmaceutically acceptable salt thereof.

7. A compound chosen from

N-(5-tert-Butyl-isoxazol-3-yl)-2-dimethylsulfamoyl-2-methyl -propionamide

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(2-methyl-piperidine -1-sulfonyl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-(isopropyl-methyl-sulfamoyl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(pyrrolidine-1-sulfonyl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-cyclopropylsulfamoyl-2-methyl-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-cyclohexylsulfamoyl-2-methyl-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(piperidine-1-sulfonyl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-cyclopentylsulfamoyl-2-methyl-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-(4-methoxy-piperidine-1-sulfonyl)-2-methyl-propionamide

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-cyclopropylsulfamoyl-2-methyl-propionamide

2-Methyl-2-(piperidine-1-sulfonyl)-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

2-(4-Methoxy-piperidine-1-sulfonyl)-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-isopropylsulfamoyl-2-methyl-propionamide

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-isopropylsulfamoyl-2-methyl-propionamide

2-Cyclopropylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

2-Cyclohexylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

2-Cyclopentylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-ethylsulfamoyl-2-methyl-propionamide

N-(4-tert-Butyl-thiazol-2-yl)-2-ethylsulfamoyl-2-methyl-propionamide

2-Ethylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

2-Ethylsulfamoyl-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-butylsulfamoyl-2-methyl-propionamide

2-Butylsulfamoyl-N-(4-tert-butyl-thiazol-2-yl)-2-methyl-propionamide

2-Butylsulfamoyl-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

2-Butylsulfamoyl-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-(2-ethoxy-ethylsulfamoyl)-2-methyl-propionamide

N-(4-tert-Butyl-thiazol-2-yl)-2-(2-ethoxy-ethylsulfamoyl)-2-methyl-propionamide

2-(2-Ethoxy-ethylsulfamoyl)-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(tetrahydro-pyran-4-ylsulfamoyl)-propionamide

N-(4-tert-Butyl-thiazol-2-yl)-2-methyl-2-(tetrahydro-pyran-4-ylsulfamoyl)-propionamide

2-Methyl-2-(tetrahydro-pyran-4-ylsulfamoyl)-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

2-Methyl-2-(tetrahydro-pyran-4-ylsulfamoyl)-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-propylsulfamoyl-propionamide

2-(2-Ethoxy-ethylsulfamoyl)-2-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-(4,4-difluoro-piperidine-1-sulfonyl)-2-methyl-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-(3,3-difluoro-azetidine-1-sulfonyl)-2-methyl-propionamide

(R)-N-(5-tert-Butyl-isoxazol-3-yl)-2-(3-fluoro-pyrrolidine-1-sulfonyl)-2-methyl-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-(butyl-methyl-sulfamoyl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-[4-(4-chloro-phenyl)-thiazol-2-yl]-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(4-tert-butyl-thiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-[4-(4-fluoro-phenyl)-thiazol-2-yl]-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(5-tert-butyl-4-methyl-thiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-propyl-isoxazol-5-yl)-propionamide

2-(Azetidine-1-sulfonyl)-N-[3-(2,2-dimethyl-propyl)-isoxazol-5-yl]-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-benzothiazol-2-yl-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(4-ethyl-pyridin-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(5-phenyl-[1,2,4]thiadiazol-3-yl)-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-thiophen-2-yl-thiazol-2-yl)-propionamide

2-(Azetidine-1-sulfonyl)-N-(5-ethyl-4-phenyl-thiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(4-cyclohexyl-thiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-trifluoromethyl-phenyl)-propionamide

2-(Azetidine-1-sulfonyl)-N-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(4-tert-butyl-phenyl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-phenethyl-propionamide

2-(Azetidine-1-sulfonyl)-N-[2-(2-chloro-phenyl)-ethyl]-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(3,3-dimethyl-butyl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(6-fluoro-benzothiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-[2-(3-chloro-phenyl)-ethyl]-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-trifluoromethyl-phenyl)-propionamide

2-(Azetidine-1-sulfonyl)-N-(3-tert-butyl-phenyl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(3-fluoro-4-trifluoromethyl-phenyl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(4-tert-butyl-5-cyano-thiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-pyridin-3-yl-thiazol-2-yl)-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-pyridin-2-yl-thiazol-2-yl)-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-pyridin-4-yl-thiazol-2-yl)-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4-trifluoromethyl-thiazol-2-yl)-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide

2-(Azetidine-1-sulfonyl)-N-(3-sec-butyl-isoxazol-5-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(3-isopropyl-isoxazol-5-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-propionamide

2-[2-(Azetidine-1-sulfonyl)-2-methyl-propionylamino]-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester

2-(Azetidine-1-sulfonyl)-N-(4,5-diphenyl-thiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(4,5-dimethyl-thiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-phenyl-isoxazol-5-yl)-propionamide

2-(Azetidine-1-sulfonyl)-N-(4-cyclopropyl-thiazol-2-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-N-(2-tert-butyl-pyridin-4-yl)-2-methyl-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(3-thiophen-2-yl-isoxazol-5-yl)-propionamide

2-(Azetidine-1-sulfonyl)-N-[4-(4-fluoro-phenyl)-5-methyl-thiazol-2-yl]-2-methyl-propionamide

N-(3-tert-Butyl-isoxazol-5-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamide

2-(Azetidine-1-sulfonyl)-2-methyl-N-(5-phenyl-4H-[1,2,4]triazol-3-yl)-propionamide

2-Methyl-2-(morpholine-4-sulfonyl)-N-(5-phenyl-4H-[1,2,4]triazol-3-yl)-propionamide

N-(5-tert-Butyl-[1,3,4]thiadiazol-2-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamide

N-(3-tert-Butyl-isothiazol-5-yl)-2-(3-fluoro-pyrrolidine-1-sulfonyl)-2-methyl-propionamide

2-(3-Fluoro-pyrrolidine-1-sulfonyl)-2-methyl-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide

N-(3-Cyclopentyl-isoxazol-5-yl)-2-(3(R)-fluoro-pyrrolidine-1-sulfonyl)-2-methyl-propionamide

2-(3-Fluoro-pyrrolidine-1-sulfonyl)-2-methyl-N-(5-phenyl-4H-[1,2,4]triazol-3-yl)-propionamide or

2-(3-Fluoro-pyrrolidine-1-sulfonyl)-2-methyl-N-(4-trifluoromethyl-thiazol-2-yl)-propionamide or a pharmaceutically acceptable salt thereof.

8. A compound chosen from

N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-methyl-2-(morpholine-4-sulfonyl)-propionamide

N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-2-(2-methyl-piperidine-1-sulfonyl)-propionamide