Positive allosteric modulators of nicotinic acetylcholine receptor

Patent metadata

Field	Value
Publication number	US-9549919-B2
Application number	US-201514704038-A
Country	US
Kind code	B2
Filing date	May 5, 2015
Priority date	Jul 8, 2011
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

The present invention relates to compounds useful in therapy, to compositions comprising said compounds, and to methods of treating diseases comprising administration of said compounds. The compounds referred to are positive allosteric modulators (PAMs) of the nicotinic acetylcholine α7 receptor.

First claim

The invention claimed is:

1. A method for the treatment of schizophrenia comprising administering a therapeutically effective amount of a compound to a patient in need thereof, wherein the compound is selected from the group consisting of:
21: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-2-hydroxy-1-(6-propoxy-pyridin-3-yl)-ethyl]-amide;
26: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-2-hydroxy-1-(6-isopropoxy-pyridin-3-yl)-ethyl]-amide;
31: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(2,2,2-d 3 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
33: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
36: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(1,1-d 2 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
38: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(1,1,2,2,2-d 5 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide; and
40: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-cyclobutoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
or is a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-2-hydroxy-1-(6-propoxy-pyridin-3-yl)-ethyl]-amide.

3. The method of claim 1 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-2-hydroxy-1-(6-isopropoxy-pyridin-3-yl)-ethyl]-amide.

4. The method of claim 1 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(2,2,2-d 3 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide.

5. The method of claim 1 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide.

6. A method for the treatment of cognitive impairment associated with schizophrenia comprising administering a therapeutically effective amount of a compound to a patient in need thereof, wherein the compound is selected from the group consisting of:
21: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-2-hydroxy-1-(6-propoxy-pyridin-3-yl)-ethyl]-amide;
26: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-2-hydroxy-1-(6-isopropoxy-pyridin-3-yl)-ethyl]-amide;
31: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(2,2,2-d 3 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
33: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
36: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(1,1-d 2 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
38: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(1,1,2,2,2-d 5 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide; and
40: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-cyclobutoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
or is a pharmaceutically acceptable salt thereof.

7. The method of claim 6 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-2-hydroxy-1-(6-isopropoxy-pyridin-3-yl)-ethyl]-amide.

8. The method of claim 6 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(2,2,2-d 3 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide.

9. The method of claim 6 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide.

10. The method of claim 6 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(1,1-d 2 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide.

11. A method for treating a cognitive disorder comprising administering a therapeutically effective amount of a compound to a patient in need thereof, wherein the compound is selected from the group consisting of:
21: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-2-hydroxy-1-(6-propoxy-pyridin-3-yl)-ethyl]-amide;
26: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-2-hydroxy-1-(6-isopropoxy-pyridin-3-yl)-ethyl]-amide;
31: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(2,2,2-d 3 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
33: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
36: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(1,1-d 2 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
38: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(1,1,2,2,2-d 5 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide; and
40: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-cyclobutoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
or is a pharmaceutically acceptable salt thereof.

12. The method of claim 11 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(2,2,2-d 3 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide.

13. The method of claim 11 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide.

14. The method of claim 11 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(1,1-d 2 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide.

15. The method of claim 11 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(1,1,2,2,2-d 5 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide.

16. A method for the treatment of mild cognitive impairment comprising administering a therapeutically effective amount of a compound to a patient in need thereof, wherein the compound is selected from the group consisting of:
21: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-2-hydroxy-1-(6-propoxy-pyridin-3-yl)-ethyl]-amide;
26: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-2-hydroxy-1-(6-isopropoxy-pyridin-3-yl)-ethyl]-amide;
31: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(2,2,2-d 3 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
33: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
36: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(1,1-d 2 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
38: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(1,1,2,2,2-d 5 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide; and
40: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-cyclobutoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;
or is a pharmaceutically acceptable salt thereof.

17. The method of claim 16 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide.

18. The method of claim 16 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(1,1-d 2 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide.

19. The method of claim 16 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-(1,1,2,2,2-d 5 )-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide.

20. The method of claim 16 wherein the compound is (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-cyclobutoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide.

21. The method of claim 1 wherein the method further comprises the administration of a therapeutically effective amount of a second compound wherein the second compound is selected from the group consisting of: an acetylcholinesterase inhibitor, a glutamate receptor antagonist, a dopamine transport inhibitor, a noradrenaline transport inhibitor, a D2 antagonist, a D2 partial agonist, a PDE10 antagonist, a 5-HT2A antagonist, a 5-HT6 antagonist, a KCNQ antagonist, lithium, a sodium channel blocker, and a GABA signaling enhancer.

22. The method of claim 6 wherein the method further comprises the administration of a therapeutically effective amount of a second compound whe

Assignees

• H Lundbeck As

Inventors

• Eskildsen Jorgen
• Sams Anette Graven
• Puschl Ask

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title