IP Library Granted Patent US 10,383,871
Granted Patent B2
US 10,383,871 · App. 15/278,386 · Granted Aug 20, 2019

Azetidine derivatives

Inventors: Stephen Roughley (Great Abington, Cambridge, GB); Steven Walls (Great Abington, Cambridge, GB); Terance Hart (Great Abington, Cambridge, GB); Rachel Parsons (Great Abington, Cambridge, GB); Paul Brough (Great Abington, Cambridge, GB); Christopher Graham (Great Abington, Cambridge, GB); Alba Macias (Great Abington, Cambridge, GB)
Assignee: Vernalis (R&D) Ltd.
A61K31/506A61K31/397A61K31/4427A61K31/4439A61K31/495A61K31/497A61K31/501C07D205/04C07D401/12C07D401/14C07D413/14
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Quick Facts
Patent No.
US 10,383,871
App. No.
15/278,386
Granted
Aug 20, 2019
Kind
B2
Abstract

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.

Claims (48)

1. A method of treatment of a disease or medical condition which benefits from inhibition of FAAH activity, wherein the disease or condition is selected from vomiting, nausea, depression, anxiety, spinal cord injury, and schizophrenia, comprising administering to a subject suffering such disease or condition an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

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; and

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.

2. The method as claimed in claim 1 wherein Ar 1 is optionally substituted phenyl.

3. The method as claimed in claim 1 wherein Ar 2 is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, any of which being optionally substituted.

4. The method 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.

5. The method as claimed in claim 1 wherein Ar 3 is an optionally substituted divalent phenylene or pyridinylene radical.

6. The method as claimed in claim 5 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.

7. The method 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 tri-fluoromethoxy, 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.

8. The method 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.

9. The method as claimed in claim 8 wherein Ar 1 is phenyl, 2-fluorophenyl, 3-(2-methoxy-ethoxy)-phenyl, or 2-methoxy-5-(2-methoxy-ethoxy)-phenyl.

10. The method as claimed in claim 8 wherein Ar 2 is pyridazin-3-yl.

11. The method as claimed in claim 1 , wherein the compound is selected from the group consisting of

3-(biphenyl-4-yloxy)-azetidine-1-carboxylic acid phenylamide,

3-(biphenyl-4-yloxy)-azetidine-1-carboxylic acid (3-fluoro-phenyl)-amide,

3-(biphenyl-4-yloxy)-azetidine-1-carboxylic acid (2-fluoro-phenyl)-amide,

3-(biphenyl-4-yloxy)-azetidine-1-carboxylic acid pyridin-3-ylamide,

3{-5-[3-(2-methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylic acid pyrimidin-4-ylamide,

3{-5-[3-(2-methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylic acid pyrazin-2-ylamide,

3{-5-[3-(2-ethoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylic acid pyridazin-3-ylamide,

3{-5-[3-(2-ethoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylic acid pyridin-3-ylamide,

3{-5-[3-(2-benzyloxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylic acid pyridazin-3-ylamide,

3-{5-[3-(2-hydroxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylic acid pyridazin-3-ylamide,

3-{5-[2-methoxy-5-(2-methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylic acid pyridazin-3-ylamide,

3-[5-(2,5-dimethoxy-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid pyridazin-3-ylamide,

3-(5-phenyl-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridazin-3-ylamide,

3-[5-(2,6-difluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid pyridazin-3-ylamide,

3-{5-[2-chloro-5-(2-methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylic acid pyridazin-3-ylamide,

3-[5-(2-fluoro-phenyl]-pyridin-2-yloxy]-azetidine-1-carboxylic acid pyrazin-2-ylamide,

3-[5-(2-methoxy-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid pyridazin-3-ylamine,

3-[5-(2-fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid pyridazin-3-ylamide,

3-[5-(2-fluoro-3-methoxy-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid pyridazin-3-ylamide,

3-[5-(2-fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid (6-methyl-pyridazin-3-yl)-amide,

3-[5-(2-fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid (6-methoxy-pyridazin-3-yl)-amide,

3-[5-(2-fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid (5-methyl-[1,3,4]oxadiazol-2-yl)-amide,

3-[5-(2-fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid pyridazin-4-ylamide,

3-[5-(2-fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid (5-methyl-pyridazin-3-yl)-amide,

3-[5-(2-fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid (4-methyl-pyridazin-3-yl)-amide,

or a pharmaceutically salt thereof.

12. The method of claim 1 , wherein the disease or condition is selected from vomiting and nausea.

13. The method of claim 1 , wherein the disease or condition is selected from depression, anxiety, spinal cord injury, and schizophrenia.

Assignments (4)
CHANGE OF NAME Recorded Jan 24, 2022
From: VERNALIS DEVELOPMENT LIMITED
To: LIGAND UK DEVELOPMENT LIMITED
Reel/Frame 058738/0271 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 24, 2022
From: VERNALIS (R&D) LIMITED
To: VERNALIS DEVELOPMENT LIMITED
Reel/Frame 058822/0570 →
CHANGE OF ADDRESS FOR ASSIGNEE Recorded Jul 31, 2019
From: VERNALIS (R&D) LIMITED
To: VERNALIS (R&D) LTD.
Reel/Frame 049917/0662 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 5, 2017
From: ROUGHLEY, STEPHEN; WALLS, STEVEN; PARSONS, RACHEL; BROUGH, PAUL; GRAHAM, CHRISTOPHER; MACIAS, ALBA
To: VERNALIS (R&D) LTD.
Reel/Frame 041857/0163 →
Priority Claims (2)
GB 0804006.5 · Apr 5, 2008 · national
GB 0821694.7 · Nov 27, 2008 · national
Continuity (4)
Continuation 14641783 · Mar 9, 2015
Continuation 13866059 · Apr 19, 2013
Division 12920181
Related Publication 20170196864A1 · Jul 13, 2017
Cited By (1)
US 12,246,014