Positive allosteric modulators of nicotinic acetylcholine receptor

Patent metadata

Field	Value
Publication number	US-9889122-B2
Application number	US-201615370958-A
Country	US
Kind code	B2
Filing date	Dec 6, 2016
Priority date	Jul 8, 2011
Publication date	Feb 13, 2018
Grant date	Feb 13, 2018

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, said method comprising administering a therapeutically effective amount of a compound according to formula [I] to a patient in need thereof,

wherein:
R1, R2, R3, R4 and R5 are H;
R6 is methoxymethyl;
A7 is C—R7, A8 is N and A9 is C—R9;
R7, R9, R10 and R11 are selected independently of each other from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy and OR12; and

wherein R12 represents a monocyclic saturated ring moiety having 4-6 ring atoms wherein one of said ring atoms is O and the rest is C;
or a pharmaceutical acceptable salt thereof.

2. The method according to claim 1 , wherein the compound is selected from:
46: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide;
47: (1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;
48: (1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;
49: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid {(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;
or a pharmaceutical acceptable salt of any of these compounds.

3. The method according to claim 1 , wherein the compound is:
46: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide;
or a pharmaceutical acceptable salt thereof.

4. The method according to claim 1 , wherein the compound is:
47: (1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;
or a pharmaceutical acceptable salt thereof.

5. The method according to claim 1 , wherein the compound is:
48: (1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;
or a pharmaceutical acceptable salt thereof.

6. The method according to claim 1 , wherein the compound is:
49: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid {(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;
or a pharmaceutical acceptable salt thereof.

7. A method for the treatment of cognitive impairment associated with schizophrenia, said method comprising administering a therapeutically effective amount of a compound according to formula [I] to a patient in need thereof,

wherein:
R1, R2, R3, R4 and R5 are H;
R6 is methoxymethyl;
A7 is C—R7, A8 is N and A9 is C—R9;
R7, R9, R10 and R11 are selected independently of each other from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy and OR12; and

wherein R12 represents a monocyclic saturated ring moiety having 4-6 ring atoms wherein one of said ring atoms is O and the rest is C;
or a pharmaceutical acceptable salt thereof.

8. The method according to claim 7 , wherein the compound is selected from:
46: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide;
47: (1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;
48: (1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;
49: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid {(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;
or a pharmaceutical acceptable salt of any of these compounds.

9. The method according to claim 7 , wherein the compound is:
46: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide;
or a pharmaceutical acceptable salt thereof.

10. The method according to claim 7 , wherein the compound is:
47: (1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;
or a pharmaceutical acceptable salt thereof.

11. The method according to claim 7 , wherein the compound is:
48: (1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;
or a pharmaceutical acceptable salt thereof.

12. The method according to claim 7 , wherein the compound is:
49: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid {(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;
or a pharmaceutical acceptable salt thereof.

13. A method for the treatment of a cognitive disorder, said method comprising administering a therapeutically effective amount of a compound according to formula [I] to a patient in need thereof,

wherein:
R1, R2, R3, R4 and R5 are H;
R6 is methoxymethyl;
A7 is C—R7, A8 is N and A9 is C—R9;
R7, R9, R10 and R11 are selected independently of each other from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy and OR12; and

wherein R12 represents a monocyclic saturated ring moiety having 4-6 ring atoms wherein one of said ring atoms is O and the rest is C;
or a pharmaceutical acceptable salt thereof.

14. The method according to claim 13 , wherein the compound is selected from:
46: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide;
47: (1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;
48: (1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;
49: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid {(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;
or a pharmaceutical acceptable salt of any of these compounds.

15. The method according to claim 13 , wherein the compound is:
46: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide;
or a pharmaceutical acceptable salt thereof.

16. The method according to claim 13 , wherein the compound is:
47: (1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;
or a pharmaceutical acceptable salt thereof.

17. The method according to claim 13 , wherein the compound is:
48: (1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;
or a pharmaceutical acceptable salt thereof.

18. The method according to claim 13 , wherein the compound is:
49: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid {(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;
or a pharmaceutical acceptable salt thereof.

19. A method for the treatment of mild cognitive impairment, said method comprising administering a therapeutically effective amount of a compound according to formula [I] to a patient in need thereof,

wherein:
R1, R2, R3, R4 and R5 are H;
R6 is methoxymethyl;
A7 is C—R7, A8 is N and A9 is C—R9;
R7, R9, R10 and R11 are selected independently of each other from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy and OR12; and

wherein R12 represents a monocyclic saturated ring moiety having 4-6 ring atoms wherein one of said ring atoms is O and the rest is C;
or a pharmace

Assignees

• H Lundbeck As

Inventors

• Eskildsen Jorgen
• Sams Anette Graven
• Puschl Ask

Classifications

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title