Pyrrolidine compounds

Patent metadata

Field	Value
Publication number	US-9346786-B2
Application number	US-201313798583-A
Country	US
Kind code	B2
Filing date	Mar 13, 2013
Priority date	Dec 18, 2009
Publication date	May 24, 2016
Grant date	May 24, 2016

Abstract

The present application relates to compounds of formula

wherein R 1 , R 2 , R 3 , R 4 , and n are defined herein

or to a pharmaceutically active salt thereof. The present compounds are high potential NK-3 receptor antagonists for the treatment of depression, pain, psychosis, Parkinson's disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).

First claim

The invention claimed is:

1. A compound of formula I

wherein
R 1 is hydrogen, halogen, cyano, lower alkyl or lower alkyl substituted by halogen;
n is 1, 2 or 3, wherein when n is 2 or 3, each R 1 is the same or different;
R 2 is C 2-7 -alkyl or C 3-6 -cycloalkyl;
R 3 is the group

wherein
X is CH or N;
R 5 is hydrogen, —C(O)-lower alkyl, —C(O)O-lower alkyl, S(O) 2 -lower alkyl, —C(O)CH 2 O-lower alkyl, —C(O)—CH 2 —CN, or is
—C(O)-cycloalkyl, cycloalkyl, or —CH 2 -cycloalkyl,
wherein the cycloalkyl groups are optionally substituted by lower alkyl, —CH 2 —O-lower alkyl, lower alkoxy, CF 3 , halogen or cyano, or is
—C(O)-heterocycloalkyl, heterocycloalkyl, —C(O)-heteroaryl, heteroaryl, —C(O)-aryl, or aryl,
which heterocycloalkyl, heteroaryl or aryl groups are optionally substituted by halogen, lower alkyl, ═O, lower alkoxy, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy, —C(O)—CH 2 —N(di-lower alkyl), C(O)NH-lower alkyl, C(O)NH 2 , —O—C(O)-lower alkyl, C(O)-lower alkyl, S(O) 2 -lower alkyl or cyano;

R 4 is aryl, which is optionally substituted by halogen, hydroxy, lower alkyl, lower alkyl substituted by halogen, S(O) 2 -lower alkyl, cyano or by lower alkoxy;
or a pharmaceutically active salt thereof.

2. The compound of claim 1 , wherein R 4 is aryl substituted by halogen.

3. The compound of claim 2 , wherein aryl is phenyl.

4. The compound of claim 1 , having formula Ia

wherein
R 1 is halogen;
n is 1, 2 or 3, wherein when n is 2 or 3, each halogen is the same or different;
R 2 is C 2-7 -alkyl or C 3-6 -cycloalkyl;
R 3 is the group

wherein
R 5 is hydrogen, —C(O)-lower alkyl, —C(O)O-lower alkyl, S(O) 2 -lower alkyl, —C(O)—CH 2 —CN, or is
—C(O)-cycloalkyl,
wherein the cycloalkyl groups are optionally substituted by lower alkyl, —CH 2 —O-lower alkyl, lower alkoxy, CF 3 , halogen or cyano, or is
—C(O)-heterocycloalkyl, —C(O)-heteroaryl, heteroaryl, or —C(O)-aryl,
which heterocycloalkyl, heteroaryl or aryl groups are optionally substituted by halogen, lower alkyl, ═O, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy, —C(O)—CH 2 —N(di-lower alkyl), C(O)NH 2 , —O—C(O)-lower alkyl, C(O)-lower alkyl, S(O) 2 -lower alkyl or cyano;

R 4 is aryl, which is optionally substituted by halogen,
or a pharmaceutically active salt thereof.

5. The compound of claim 1 , selected from the group consisting of
rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester;
rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-isopropyl-carbamic acid 4-fluoro-phenyl ester;
rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-isobutyl-carbamic acid 4-fluoro-phenyl ester;
rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-cyclopropyl-carbamic acid 4-fluoro-phenyl ester;
{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester;
{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester;
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester;
[(3R,4S)-1-(5′-Acetyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
[(3R,4S)-4-(4-Chloro-phenyl)-1-(4′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
[(3R,4S)-4-(4-Chloro-phenyl)-1-(5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester; and
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester.

6. The compound of claim 1 , selected from the group consisting of
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester;
[(3S,4R)-1-(5′-Acetyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
[(3S,4R)-4-(4-Chloro-phenyl)-1-(4′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester;
[(3R,4S)-4-(4-Chloro-phenyl)-1-(5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
[(3R,4S)-4-(4-Chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-isopropyl-carbamic acid 4-fluoro-phenyl ester; and
[(3S,4R)-1-(5′-Acetyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-isopropyl-carbamic acid 4-fluoro-phenyl ester.

7. The compound of claim 1 , selected from the group consisting of
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-isopropyl-carbamic acid 4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-isopropyl-carbamic acid 4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-isopropyl-carbamic acid 4-fluoro-phenyl ester;
[(3R,4S)-4-(4-Chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-isopropyl-carbamic acid 4-fluoro-phenyl ester;
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-cyclopropyl-carbamic acid 4-fluoro-phenyl ester;
[(3S,4R)-1-(5′-Acetyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-cyclopropyl-carbamic acid 4-fluoro-phenyl ester;
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5′-tr

Assignees

• Hoffmann La Roche

Inventors

• Knust Henner
• Koblet Andreas
• Nettekoven Matthias
• Ratni Hasane
• Riemer Claus
• Vifian Walter

Classifications

• A61P25/16

  Anti-Parkinson drugs · CPC title

• C07D207/14

  Nitrogen atoms not forming part of a nitro radical · CPC title

• A61P25/24

  Antidepressants · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title