5-HT3 receptor antagonists

Patent metadata

Field	Value
Publication number	US-10125145-B2
Application number	US-201715599239-A
Country	US
Kind code	B2
Filing date	May 18, 2017
Priority date	Jul 17, 2012
Publication date	Nov 13, 2018
Grant date	Nov 13, 2018

Abstract

The present invention provides 5-HT3 receptor antagonists of Formula (I):

which are useful for the treatment of diseases treatable by inhibition of 5-HT3 receptor such as emesis, pain, drug addiction, neurodegenerative and psychiatric disorders, and GI disorders. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

First claim

What is claimed is:

1. A compound of Formula (I):

wherein:
Z is O or NR a where R a is hydrogen or C 1-6 alkyl;
R 1 is a ring of the formula (a)-(h) below:

R 2 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl;
each R 3 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or halo and can be present on any carbon atom in the rings;
R 4 is pyridinyl or pyrazolyl each optionally substituted with one or two substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, cyano, or halo;
one of X 1 , X 2 , X 3 , and X 4 is N and the others are CR 5 ;
each R 5 is independently hydrogen, C 1-6 alkyl, halo, hydroxy, or cyano provided that at least one of R 5 is hydrogen;
X 5 is N or CR 6 where R 6 is hydrogen, C 1-6 alkyl, or halo;
or a pharmaceutically acceptable salt thereof or N-oxide thereof.

2. The compound or pharmaceutically acceptable salt of claim 1 wherein R 1 is a ring of formula (a) or (d).

3. The compound or pharmaceutically acceptable salt of claim 1 wherein R 1 is a ring of formula (e), (f), or (g).

4. The compound or pharmaceutically acceptable salt of claim 1 wherein R 1 is a ring of formula (e).

5. The compound or pharmaceutically acceptable salt of claim 1 wherein each R 3 is hydrogen.

6. The compound or pharmaceutically acceptable salt of claim 1 wherein R 2 is hydrogen and each R 3 is hydrogen.

7. The compound or pharmaceutically acceptable salt of claim 1 wherein each R 3 is independently hydrogen or methyl and R 2 is C 1-6 alkyl.

8. The compound or pharmaceutically acceptable salt of claim 1 wherein R 2 is methyl and each R 3 is hydrogen.

9. The compound or pharmaceutically acceptable salt of claim 8 wherein X 1 is N and X 2 , X 3 , and X 4 are CR 5 .

10. A compound claim 1 selected from:
N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide;
N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide;
5-fluoro-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide;
5-fluoro-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide;
or a pharmaceutically acceptable salt of each above mentioned compound.

11. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

12. A method of treating a disease selected from the group consisting of: emesis, migraine, drug addiction, anxiety, depression, eating disorders, schizophrenia, cognitive dysfunction associated with schizophrenia, congnitive dysfuntion associated with Parkinson's disease, Huntington's Chorea, presenile dementia, Alzheimer's disease, substance abuse, autism spectrum disorders, pain, dyspepsia, gastroesophagal reflux disease, and irritable bowel syndrome, the method comprising:
administrating to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Hitchcock Stephen
• Monenschein Holger
• Reichard Holly
• Sun Huikai
• Kikuchi Shota
• Macklin Todd
• Hopkins Maria

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

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

• A61P39/02

  Antidotes · CPC title

• A61P39/00

  General protective or antinoxious agents · CPC title