Azetidine derivatives
Compounds of formula (I) are inhibitors of fatty acid amide hydrolase, (FAAH), and which are useful in the treatment of diseases or medical conditions which benefit from inhibition of FAAH activity, such as anxiety, depression pain, inflammation, and eating, sleep, neurodegenerative and movement disorders: Ar 1 is optionally substituted phenyl or optionally substituted monocyclic heteroaryl having 5 or 6 ring atoms; Ar 2 is optionally substituted phenyl, optionally substituted monocyclic heteroaryl having 5 or 6 ring atoms or optionally substituted fused bicyclic heteroaryl having 5 or 6 ring atoms in each fused ring; and Ar 3 is a divalent radical selected from optionally substituted phenylene and optionally substituted monocyclic heteroarylene radicals having 5 or 6 ring atoms.
1. A process for forming a compound of Formula (I)
comprising the step of reacting a compound of formula (IVa) with a boronic acid of formula (IVb) or a boronic ester thereof to form the compound of Formula (I)
wherein
Ar 1 is optionally substituted phenyl or optionally substituted monocyclic heteroaryl having 5 or 6 ring atoms;
Ar 2 is optionally substituted phenyl, optionally substituted monocyclic heteroaryl having 5 or 6 ring atoms or optionally substituted fused bicyclic heteroaryl having 5 or 6 ring atoms in each fused ring;
Ar 3 is a divalent radical selected from the group consisting of optionally substituted phenylene and optionally substituted monocyclic heteroarylene radicals having 5 or 6 ring atoms; and
X is I or Br.
2. The process as claimed in claim 1 , wherein the step of reacting a compound of formula (IVa) with a boronic acid of formula (IVb) or a boronic ester thereof occurs in the presence of K 2 CO 3 and tetrahydrofuran.
3. The process as claimed in claim 1 , wherein the step of reacting a compound of formula (IVa) with a boronic acid of formula (IVb) or a boronic ester thereof occurs in the presence of [1,1*-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride.
4. The process as claimed in claim 1 , wherein the compound of Formula (IVa) is formed by reaction of a compound of Formula (Va) with a compound of Formula (Vb)
5. The process as claimed in claim 1 , wherein the compound of Formula (IVa) is formed by reaction of a compound of Formula (VIa) with a compound of Formula H 2 NAr 3
Y is H or —NO 2 .
6. The process of claim 5 , wherein the reaction of a compound of Formula (VIa) with a compound of Formula H 2 NAr 3 occurs in the presence of NaH and dimethylformamide.
7. The process as claimed in claim 1 wherein Ar 1 is optionally substituted phenyl.
8. The process as claimed in claim 1 wherein Ar 2 is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, any of which being optionally substituted.
9. The process as claimed in claim 1 wherein Ar 2 is 3-pyridyl, pyrimidin-4-yl, pyrazin-2-yl or pyridazin-3-yl, any of which being optionally substituted.
10. The process as claimed in claim 1 wherein Ar 3 is an optionally substituted divalent phenylene or pyridinylene radical.
11. The process as claimed in claim 10 wherein Ar 3 is an optionally substituted divalent 1,4-phenylene or a 2,5-pyridinylene radical of formula:
wherein the bond marked with a single asterisk is attached to Ar 1 and the bond marked with a double asterisk is attached to the oxygen.
12. The process as claimed in claim 1 wherein any optional substituents in Ar 1 , Ar 2 and Ar 3 are independently selected from chloro, fluoro, bromo, cyclopropyl, methyl, mono-, di- or tri-methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, 2-methoxyethoxy, 2-benzyloxy-ethoxy, 2-hydroxy-ethoxy, mono-, di- or trifluoromethoxy, cyano, hydroxyl; —CO 2 R 1 and —SO 2 R 1 wherein R 1 is hydrogen, methyl or ethyl; tetrazolyl; —NR 2 R 3 , —CH 2 NR 2 R 3 and —C(═O)NR 2 R 3 wherein R 2 and R 3 are independently hydrogen, methyl, or ethyl.
13. The process as claimed in claim 1 wherein:
Ar 2 is 3-pyridyl, pyrimidin-4-yl, pyrazin-2-yl, or pyridazin-3-yl;
Ar 3 is an optionally substituted divalent 1,4-phenylene or a 2,5-pyridinylene radical of formula:
wherein the bond marked with a single asterisk is attached to Ar 1 and the bond marked with a double asterisk is attached to the oxygen; and
Ar 1 is optionally substituted phenyl.
14. The process as claimed in claim 13 wherein Ar 1 is phenyl, 2-fluorophenyl, 3-(2-methoxy-ethoxy)-phenyl, or 2-methoxy-5-(2-methoxy-ethoxy)-phenyl.
15. The process as claimed in claim 13 wherein Ar 2 is pyridazin-3-yl.