Purine derivatives as CB2 receptor agonists

Patent metadata

Field	Value
Publication number	US-9505762-B2
Application number	US-201514923177-A
Country	US
Kind code	B2
Filing date	Oct 26, 2015
Priority date	May 2, 2013
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

The invention relates to a compound of formula (I)

wherein A and R 1 to R 4 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
A is CH 2 , CH 2 CH 2 , CH 2 CO or absent;
R 1 is tert-butyl, tert-butylamino, or 2,2-dimethylpropyloxy;
R 2 and R 3 , together with the nitrogen atom to which they are attached, form pyrrolidinyl, substituted pyrrolidinyl, thiazolidinyl, alkylpiperazinyl, 2-oxa-7-azaspiro[3.4]octyl, 2-oxa-6-azaspiro[3.3]heptyl, azetidinyl, substituted azetidinyl, 2,2-dioxo-2λ 6 -thia-6-azaspiro[3.3]heptyl or halo-5-azaspiro[2.4]heptyl, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one to four substituents independently selected from halogen, hydroxyl, alkyl, hydroxyalkyl, cyano, alkylcarbonylamino, alkylcarbonyloxy and haloalkyl and wherein substituted azetidinyl is azetidinyl substituted with one or two substituents selected from halogen, hydroxyl, alkyl and haloalkyl; and
R 4 is hydrogen, phenyl, halophenyl, alkylphenyl, haloalkylphenyl, pyridinyl, halopyridinyl, cycloalkyl, alkyl, alkyloxadiazolyl, oxolanyl, alkyltetrazolyl, alkoxy, alkylsulfonylphenyl, haloalkyl, alkoxyphenyl, dioxothietanyl, cycloalkyltetrazolyl, haloalkyl-1H-pyrazolyl or cycloalkylalkyltetrazolyl;
or a pharmaceutically acceptable salt or ester thereof.

2. A compound according to claim 1 , wherein A is CH 2 .

3. A compound according to claim 1 , wherein R 1 is tert.-butyl or 2,2-dimethylpropyloxy.

4. A compound according to claim 1 , wherein R 2 and R 3 , together with the nitrogen atom to which they are attached, form thiazolidinyl, substituted pyrrolidinyl or substituted azetidinyl, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from halogen, hydroxyl, hydroxyalkyl and cyano and wherein substituted azetidinyl is azetidinyl substituted with one or two substituents selected from halogen, hydroxyl and haloalkyl.

5. A compound according to claim 1 , wherein R 2 and R 3 , together with the nitrogen atom to which they are attached, form thiazolidinyl, substituted pyrrolidinyl or substituted azetidinyl, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from fluorine, hydroxyl, hydroxymethyl and cyano and wherein substituted azetidinyl is azetidinyl substituted with one or two substituents selected from fluorine, hydroxyl and trifluoromethyl.

6. A compound according to claim 1 , wherein R 2 and R 3 , together with the nitrogen atom to which they are attached, form thiazolidinyl, difluoropyrrolidinyl, hydroxypyrrolidinyl, hydroxymethylpyrrolidinyl, cyanopyrrolidinyl, difluoroazetidinyl or (hydroxyl)(trifluoromethyl)azetidinyl.

7. A compound according to claim 1 , wherein R 4 is halophenyl, haloalkylphenyl, halopyridinyl, oxolanyl, alkyl sulfonylphenyl, pyridinyl or cycloalkyltetrazolyl.

8. A compound according to claim 1 , wherein R 4 is chlorophenyl, chlorofluorophenyl, trifluoromethylphenyl, chloropyridinyl, oxolanyl, methyl sulfonylphenyl, pyridinyl or cyclopropyltetrazolyl.

9. A compound according to claim 1 selected from:
2-tert-butyl-9-[(4-chlorophenyl)methyl]-6-(3,3-difluoropyrrolidin-1-yl)purine;
2-tert-butyl-9-[(2-chlorophenyl)methyl]-6-(3,3-difluoropyrrolidin-1-yl)purine;
2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)-9-[(4-methylphenyl)methyl]purine;
2-tert-butyl-9-[(2-chloro-4-fluorophenyl)methyl]-6-(3,3-difluoropyrrolidin-1-yl)purine;
2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)-9-[[2-(trifluoromethyl)phenyl]methyl] purine;
2-tert-butyl-9-[(2-chloropyridin-3-yl)methyl]-6-(3,3-difluoropyrrolidin-1-yl)purine;
5-[[2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)purin-9-yl]methyl]-3-methyl-1,2,4-oxadiazole;
2-tert-butyl-9-(cyclohexylmethyl)-6-(3,3-difluoropyrrolidin-1-yl)purine;
2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)-9-ethylpurine;
2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)-9-propylpurine;
2-[[2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)purin-9-yl]methyl]-5-methyl-1,3,4-oxadiazole;
2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)-9-(oxolan-3-yl)purine;
2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)-9-(2-phenylethyl)purine;
2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)-9-[(1-methyltetrazol-5-yl)methyl]purine;
2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)-9-(2-methoxyethyl)purine;
3-[[2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)purin-9-yl]methyl]-4-methyl-1,2,5-oxadiazole;
2-[2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)purin-9-yl]-1-(2-chlorophenyl) ethanone;
2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)-9-[(2-methyl sulfonylphenyl)methyl] purine;
2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)-9-(3,3,3-trifluoropropyl)purine;
2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)-9-[(4-methoxyphenyl)methyl]purine;
2-tert-butyl-9-[(3-chloropyridin-2-yl)methyl]-6-(3,3-difluoropyrrolidin-1-yl)purine;
1-[2-tert-butyl-9-[(2-chlorophenyl)methyl]purin-6-yl]pyrrolidin-3-ol;
2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)-9-(2-pyridin-3-ylethyl)purine;
2-[2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)purin-9-yl]-1-pyridin-2-ylethanone;
1-[2-tert-butyl-9-[(3-chlorophenyl)methyl]purin-6-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-9-[(4-chlorophenyl)methyl]purin-6-yl]pyrrolidin-3-ol;
3-[2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)purin-9-yl]thietane 1,1-dioxide;
1-[2-tert-butyl-9-[[2-(trifluoromethyl)phenyl]methyl]purin-6-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-9-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]purin-6-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-9-[(1-methyltetrazol-5-yl)methyl]purin-6-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-9-[(4-methoxyphenyl)methyl]purin-6-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-9-[(3-chloropyridin-2-yl)methyl]purin-6-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-9-[(2-chloropyridin-3-yl)methyl]purin-6-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-9-[(2-methylsulfonylphenyl)methyl]purin-6-yl]pyrrolidin-3-ol;
1-(2-tert-butyl-9-ethylpurin-6-yl)pyrrolidin-3-ol;
1-(2-tert-butyl-9-propylpurin-6-yl)pyrrolidin-3-ol;
1-[2-tert-butyl-9-(2-methoxyethyl)purin-6-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-9-(2-phenylethyl)purin-6-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-9-[(4-methylphenyl)methyl]purin-6-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-9-(cyclohexylmethyl)purin-6-yl]pyrrolidin-3-ol;
2-tert-butyl-6-(3,3-difluoropyrrolidin-1-yl)-9-[[3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]purine;
1-[2-tert-butyl-9-[(2-chloro-4-fluorophenyl)methyl]purin-6-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-9-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]purin-6-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-9-[[3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]purin-6-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-9-(3,3,3-trifluoropropyl)purin-6-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-9-(oxolan-3-yl)purin-6-yl]pyrrolidin-3-ol;
2-[2-tert-butyl-6-(3-hydroxypyrrolidin-1-yl)purin-9-yl]-1-(2-chlorophenyl)ethanone;
N—{(S)-1-[2-tert-Butyl-9-(2-chloro-benzyl)-9H-purin-6-yl]-pyrrolidin-3-yl}-acetamide;
N—[(S)-1-[2-tert-butyl-9-[(3-chlorophenyl)methyl]purin-6-yl]pyrrolidin-3-yl]acetamide;
N—[(S)-1-[2-tert-butyl-9-[(4-chlorophenyl)methyl]purin-6-yl]pyrrolidin-3-yl]acetamide;
N—[(S)-1-[2-tert-butyl-9-[[2-(trifluoromethyl)phenyl]methyl]purin-6-yl]pyrrolidin-3-yl]acetamide;
N—[(S)-1-[2-tert-butyl-9-[(2-methylsulfonylphenyl)methyl]purin-6-yl]pyrrolidin-3-yl]acetamide;
N—[(S)-1-[2-tert-butyl-9-[(2-chloropyridin-3-yl)methyl]purin-6-yl]pyrrolidin-3-yl]acetamide;
N—[(S)-1-[2-tert-butyl-9-[(3-chloropyridin-2-yl)methyl]purin-6-yl]pyrrolidin-3-yl]acetamide
N—[(S)-1-[2-tert-butyl-9-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]purin-6-yl]pyrrolidin-3-yl]acetamide;
7-[2-tert-butyl-9-[(2-chlorophenyl)methyl]purin-6-yl]-2-oxa-7-azaspiro[3.4]octane;
7-[2-tert-butyl-9-[(3-chlorophenyl)methyl]purin-6-yl]-2-o

Assignees

• Hoffmann La Roche

Inventors

• Bendels Stefanie
• Grether Uwe
• Kimbara Atsushi
• Nettekoven Matthias
• Roever Stephan
• Rogers-Evans Mark
• Schulz-Gasch Tanja

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title