[1,2,3]triazolo[4,5-D]pyrimidine derivatives with affinity for the type-2 cannabinoid receptor
The invention relates to a compound of formula (I) wherein R 1 to R 4 and n are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.
1. A compound of formula (I)
wherein
R 1 is a ring selected from phenyl and [1,2,5]oxadiazolyl wherein said ring is substituted with one substituent selected from halosulfonyl, halosulfonylalkyl, isothiocyanatoalkyl, isothiocyanato, aminoalkyldisulfanylalkyl, hydroxyalkyldisulfanylalkyl, hydroxyalkyldisulfanyl, aminoalkyldisulfanyl, halogen, alkyl, pyridinyldisulfanylalkyl, benzotriazolylsulfonylalkyl, dihydroxyalkyldisulfanylalkyl and pyridinyldisulfanyl and optionaly further substituted with cyano;
R 2 and R 3 are independently selected from hydrogen, hydroxyl, halogen, thiohydroxyl, thiohydroxyazetidinyl, azido, isothiocyanato and alkyl disulfanyl;
provided that at least one of R 1 , R 2 and R 3 is a group comprising sulfonyl, isothiocyanato, disulfanyl, thiohydroxyl or azido;
R 4 is alkyl or phenylhaloalkyl; and
n is 0 or 1;
or a pharmaceutically acceptable salt or ester thereof.
2. The compound according to claim 1 , wherein R 1 is a ring selected from phenyl and [1,2,5]oxadiazolyl wherein said ring is substituted with one substituent selected from halosulfonyl, halosulfonylalkyl, isothiocyanatoalkyl, isothiocyanato, halogen, alkyl, hydroxyalkyldisulfanylalkyl, pyridinyldisulfanylalkyl, dihydroxyalkyldisulfanylalkyl and optionaly further substituted with cyano.
3. The compound according to claim 1 , wherein R 1 is a ring selected from phenyl and [1,2,5]oxadiazolyl wherein said ring is substituted with one substituent selected from fluorosulfonyl, fluorosulfonylmethyl, isothiocyanatomethyl, isothiocyanato, chloro, methyl, hydroxyethyldisulfanylethyl, fluorosulfonylethyl, pyridinyldisulfanylethyl, dihydroxyethyldisulfanylethyl and optionaly further substituted with cyano.
4. The compound according to claim 1 , wherein R 1 is fluorosulfonylphenyl, fluorosulfonylmethylphenyl, isothiocyanatomethylphenyl, isothiocyanatophenyl, chlorophenyl, methyl[1,2,5]oxadiazolyl, hydroxyethyldisulfanylethylphenyl, fluorosulfonylethylphenyl, pyridinyldisulfanylethylphenyl, dihydroxyethyldisulfanylethylphenyl or (fluorosulfonyl)(cyano)phenyl.
5. The compound according to claim 1 , wherein R 2 is hydrogen and R 3 is hydroxyl, thiohydroxyl, azido, isothiocyanato or methyldisulfanyl, or R 2 and R 3 are both fluoro.
6. The compound according to claim 1 , wherein R 4 is tert-butyl or phenyldifluoromethyl.
7. The compound according to claim 1 , wherein n is 1.
8. The compound according to claim 1 selected from the group consisting of:
2-({5-tert-butyl-7-[(3S)-3-hydroxypyrrolidin-1-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}methyl)benzene-1-sulfonyl fluoride;
(2-{[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]methyl}phenyl)methanesulfonyl fluoride;
[2-({5-tert-butyl-7-[(3S)-3-hydroxypyrrolidin-1-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}methyl)phenyl]methanesulfonyl fluoride;
5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-{[2-(isothiocyanatomethyl)phenyl]methyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
(3S)-1-(5-tert-butyl-3-{[2-(isothiocyanatomethyl)phenyl]methyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol;
5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-[(2-isothiocyanatophenyl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
2-{[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]methyl}benzene-1-sulfonyl fluoride;
2-{[(2-{[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]methyl}phenyl)methyl]disulfanyl}ethan-1-amine;
2-{[(2-{[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]methyl}phenyl)methyl]disulfanyl}ethan-1-ol;
2-[(2-{[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]methyl}phenyl)disulfanyl]ethan-1-ol;
2-[(2-{[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]methyl}phenyl)disulfanyl]ethan-1-amine;
2-{[2-({5-[difluoro(phenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}methyl)phenyl]disulfanyl}ethan-1-amine;
2-({[2-({5-[difluoro(phenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}methyl)phenyl]methyl}disulfanyl)ethan-1-amine;
2-({5-[difluoro(phenyl)methyl]-7-[(3S)-3-hydroxypyrrolidin-1-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}methyl)benzene-1-sulfonyl fluoride;
2-({5-[difluoro(phenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}methyl)benzene-1-sulfonyl fluoride;
[2-({5-[difluoro(phenyl)methyl]-7-[(3S)-3-hydroxypyrrolidin-1-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}methyl)phenyl]methanesulfonyl fluoride;
[2-({5-[difluoro(phenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}methyl)phenyl]methanesulfonyl fluoride;
(3S)-1-(5-[difluoro(phenyl)methyl]-3-{[2-(isothiocyanatomethyl)phenyl]methyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol;
5-[difluoro(phenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-3-{[2-(isothiocyanatomethyl)phenyl]methyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-[difluoro(phenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-3-[(2-isothiocyanatophenyl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
1-{5-tert-butyl-3-[(2-chlorophenyl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl}pyrrolidine-3-thiol;
1-{5-tert-butyl-3-[(2-chlorophenyl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl}azetidine-3-thiol;
(3S)-1-{5-tert-butyl-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl}pyrrolidine-3-thiol;
(3R)-1-{5-tert-butyl-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl}pyrrolidine-3-thiol;
(3S)-1-{5-tert-butyl-3-[(2-chlorophenyl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl}pyrrolidine-3-thiol;
(3R)-1-{5-tert-butyl-3-[(2-chlorophenyl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl}pyrrolidine-3-thiol
7-(3-azidopyrrolidin-1-yl)-5-tert-butyl-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-tert-butyl-3-[(2-chlorophenyl)methyl]-7-(3-isothiocyanatopyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-tert-butyl-7-(3-isothiocyanatopyrrolidin-1-yl)-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
7-(3-azidopyrrolidin-1-yl)-5-tert-butyl-3-[(2-chlorophenyl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-[difluoro(phenyl)methyl]-7-[3-(methyldisulfanyl)pyrrolidin-1-yl]-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-5-[difluoro(phenyl)methyl]-7-[3-(methyldisulfanyl)pyrrolidin-1-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
7-(3-azidopyrrolidin-1-yl)-5-[difluoro(phenyl)methyl]-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
7-(3-azidopyrrolidin-1-yl)-3-[(2-chlorophenyl)methyl]-5-[difluoro(phenyl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-5-[difluoro(phenyl)methyl]-7-(3-isothiocyanatopyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-[difluoro(phenyl)methyl]-7-(3-isothiocyanatopyrrolidin-1-yl)-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
2-[[5-[difluoro(phenyl)methyl]-7-[(3S)-3-hydroxypyrrolidin-1-yl]triazolo[4,5-d]pyrimidin-3-yl]methyl]benzenesulfonyl fluoride;
2-[[2-[[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]phenyl]methyldisulfanyl]ethanol;
2-[[5-[difluoro(phenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]benzenesulfonyl fluoride;
5-[difluoro(phenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-3-[[2-[2-(pyridin-2-yldisulfanyl)ethyl]phenyl]methyl]triazolo[4,5-d]pyrimidine;
2-[2-[2-[[5-[difluoro(phenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]phenyl]ethyldisulfanyl]ethanol;
2-[2-[2-[[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]phenyl]ethyldisulfanyl]ethanol;
3-[[2-[2-(benzotriazol-1-ylsulfonyl)ethyl]phenyl]methyl]-5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidine;
2-[2-[[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]phenyl]ethanesulfonyl fluoride;
5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-[[2-[2-(pyridin-2-yldisulfanyl)ethyl]phenyl]methyl]triazolo[4,5-d]pyrimidine;
2-[2-[2-[[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]phenyl]ethyldisulfanyl]ethanamine;
2-[2-[2-[[5-[difluoro(phenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]phenyl]ethyldisulfanyl]ethanamine;
3-[2-[2-[[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]phenyl]ethyldisulfanyl]propane-1,2-diol;
2-[[2-[[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]phenyl]disulfanyl]ethanol;
5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-[[2-(pyridin-2-yldisulfanyl)phenyl]methyl]triazolo[4,5-d]pyrimidine; and
2-[[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]-3-ethynylbenzenesulfonyl fluoride;
or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1 selected from the group consisting of:
2-({5-tert-butyl-7-[(3S)-3-hydroxypyrrolidin-1-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}methyl)benzene-1-sulfonyl fluoride;
(2-{[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]methyl}phenyl)methanesulfonyl fluoride;
5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-[2-(isothiocyanatomethyl)phenyl]methyl 1-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
(3S)-1-(5-tert-butyl-3-1 [2-(isothiocyanatomethyl)phenyl]methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol;
5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-[(2-isothiocyanatophenyl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
2-{[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]methyl}benzene-1-sulfonyl fluoride;
1-{5-tert-butyl-3-[(2-chlorophenyl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl}pyrrolidine-3-thiol;
(3S)-1-{5-tert-butyl-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl}pyrrolidine-3-thiol;
7-(3-azidopyrrolidin-1-yl)-5-tert-butyl-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-tert-butyl-7-(3-isothiocyanatopyrrolidin-1-yl)-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-[difluoro(phenyl)methyl]-7-[3-(methyldisulfanyl)pyrrolidin-1-yl]-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
7-(3-azidopyrrolidin-1-yl)-3-[(2-chlorophenyl)methyl]-5-[difluoro(phenyl)methyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
2-[[5-[difluoro(phenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]benzenesulfonyl fluoride;
2-[2-[2-[[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]phenyl]ethyldisulfanyl]ethanol;
2-[2-[[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]phenyl]ethanesulfonyl fluoride;
5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-[[2-[2-(pyridin-2-yldisulfanyl)ethyl]phenyl]methyl]triazolo[4,5-d]pyrimidine;
3-[2-[2-[[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]phenyl]ethyldisulfanyl]propane-1,2-diol; and
2-[[5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]-3-ethynylbenzenesulfonyl fluoride;
or a pharmaceutically acceptable salt thereof.
10. A process for the manufacture of a compound according to claim 1 comprising the reaction of a compound of formula (A)
in the presence of a compound of formula (B)
and a base, wherein R 1 to R 4 and n are as defined in claim 1 .
11. A compound manufactured according to a process of claim 10 .
12. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or ester thereof, and a therapeutically inert carrier.
13. A method for the treatment of pain, which method comprises administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or ester thereof, to a patient in need thereof.
14. The compound according to claim 4 , wherein R 2 is hydrogen and R 3 is hydroxyl, thiohydroxyl, azido, isothiocyanato or methyldisulfanyl, or R 2 and R 3 are both fluoro.
15. The compound according to claim 14 , wherein R 4 is tert-butyl or phenyldifluoromethyl.
16. The compound according to claim 15 , wherein n is 1.
17. The method of claim 13 , wherein the pain is a neuropathic pain.