2-oxa-5-azabicyclo[2.2.1]heptan-3-yl derivatives

Patent metadata

Field	Value
Publication number	US-9790230-B2
Application number	US-201715416485-A
Country	US
Kind code	B2
Filing date	Jan 26, 2017
Priority date	Aug 1, 2014
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

The present invention relates to compounds of formula of formula I wherein X, L and R 1 are as described herein, compositions containing compounds of formula I, methods of manufacture of compounds of formula I and methods of treating psychiatric, metabolic, cardiovascular or sleep disorders with compounds of formula I.

First claim

We claim:

1. A compound of formula I

wherein
L is a bond, —C(O)NH—, —NHC(O)—, —CH 2 NHC(O)—, CH 2 C(O)NH—, —CH 2 NH—, —NH— or —NHC(O)NH—;
R 1 is hydrogen, lower alkyl, halogen, lower alkoxy-alkyl, lower alkoxy substituted by halogen, lower alkyl substituted by halogen, phenyl or heteroaryl wherein said heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl and pyrazolyl, and wherein said phenyl or said heteroaryl are optionally substituted by one, two or three substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cycloalkyl and O—CH 2 -cycloalkyl;
X is CH or N;

or a pharmaceutically suitable acid addition salt thereof and an enantiomer, a racemic mixture or a mixture of enantiomers.

2. The compound of claim 1 , wherein R 1 is hydrogen, lower alkyl, halogen, lower alkoxy-alkyl, lower alkoxy substituted by halogen or lower alkyl substituted by halogen.

3. The compound of claim 2 , which compound is selected from the group consisting of:
(1R,3S,4R)-3-Phenyl-2-oxa-5-azabicyclo[2.2.1]heptane;
(1S,3R,4S)-3-Phenyl-2-oxa-5-azabicyclo[2.2.1]heptane;
N-Butyl-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline;
(1S,3R,4S)-3-(4-Bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane;
(1R,3S,4R)-3-(4-Bromophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane;
N-(3-Methoxypropyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline;
N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2 trifluoroethoxy)acetamide;
N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(3,3,3 trifluoropropoxy)acetamide;
N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(2,2,2 trifluoroethoxy)acetamide;
4,4,4-Trifluoro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamide;
N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(3,3,3-trifluoropropoxy)acetamide;
4,4,4-Trifluoro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamide;
(1R,3R,4R)-3-(2-Pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptane;
(1S,3S,4S)-3-(2-Pyridyl)-2-oxa-5-azabicyclo[2.2.1]heptane; and
(1R,3S,4R)-3-(2-Fluorophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane.

4. The compound of claim 1 , wherein R 1 is phenyl optionally substituted by one, two or three substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cycloalkyl or O—CH 2 -cycloalkylphenyl.

5. The compound of claim 4 , which compound is selected from the group consisting of:
3-Chloro-N-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide;
4-Chloro-N-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide;
1-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea;
1-(4-Chlorophenyl)-3-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]urea;
1-(3-Chlorophenyl)-3-[3-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]urea;
4-Chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide;
3-Chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide;
3-Chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide;
4-(Cyclopropylmethoxy)-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3 yl]phenyl]benzamide;
4-Chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide;
4-Ethoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide;
4-Ethoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]benzamide;
4-(Cyclopropylmethoxy)-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3 yl]phenyl]benzamide;
1-(4-Chlorophenyl)-3-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]urea;
N-[(4-Chlorophenyl)methyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline;
4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4-(trifluoromethyl)phenyl]methyl]aniline;
N-[(4-Fluorophenyl)methyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]aniline
4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4 (trifluoromethoxy)phenyl]methyl]aniline;
N-(4-Chlorophenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide;
N-(4-Bromophenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide,
N-(4-Fluorophenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide,
N-(4-Ethoxyphenyl)-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide,
4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[4-(trifluoromethyl)phenyl]benzamide,
4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide;
N-[(4-Chlorophenyl)methyl]-4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide;
4,4,4-Trifluoro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]butanamide;
N-(4-Bromophenyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide;
N-(4-Fluorophenyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide;
N-(4-Ethoxyphenyl)-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide;
4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide; and,
N-[(4-Chlorophenyl)methyl]-4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]benzamide.

6. The compound of claim 1 wherein R 1 is pyridinyl, pyrimidinyl, pyrazinyl or pyrazolyl, which are optionally substituted by one, two or three substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cycloalkyl and O—CH 2 -cycloalkylphenyl.

7. A compound of formula I according to claim 6 , which compounds are:
N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridin-2-amine;
6-Ethoxy-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridine-3-carboxamide;
6-Ethoxy-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridine-3-carboxamide;
N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide;
2-Cyclopropyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide;
N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyridin-2-amine;
5-Chloro-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridin-2-amine;
N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyrimidin-4-amine;
N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyrazin-2-amine;
N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyrimidin-2-amine;
5-Chloro-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyridin-2-amine;
N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide;
N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide;
N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide;
2-Cyclopropyl-N-[4-[(1R,3S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide;
N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyrazin-2-amine;
N-[4-[(1R,3S,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-5-(trifluoromethyl)pyrimidin-2-amine,
2-Ethyl-N-[4-[(1S,3R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]pyrimidine-5-carboxamide;
N-[4-[(1S,3R,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-3-yl]phenyl]-2-(trifluoromethyl)pyridin-4-amin

Assignees

• Hoffmann La Roche

Inventors

• Cecere Giuseppe
• Galley Guido
• Hu Yimin
• Norcross Roger
• Pflieger Philippe
• Shen Hong

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title