Pyrrolidine derivatives

Patent metadata

Field	Value
Publication number	US-9226916-B2
Application number	US-201313779780-A
Country	US
Kind code	B2
Filing date	Feb 28, 2013
Priority date	Dec 15, 2009
Publication date	Jan 5, 2016
Grant date	Jan 5, 2016

Abstract

The present invention relates to compounds of formula

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

or to a pharmaceutically active salt thereof. Compounds of the invention 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 hydrogen or methyl;
R 3 is (CH 2 ) r —C(O)NH 2 or (CH 2 ) r —CN, wherein r is 1 or 2, or
is a non aromatic heterocyclic group

wherein
X is N or CH;
Y is —C(R)(R 7 )—; —N(R 7′ )—, —S(O) 2 or O;
R 6 is hydrogen, di-lower alkyl or ═O;
o and m are each independently 0, 1 or 2;
p is 0, 1 or 2;
R is hydrogen, halogen, or lower alkyl;
R 7 is hydrogen, halogen, hydroxy, lower alkyl substituted by hydroxy, cyano, or lower alkoxy;
R 7′ is hydrogen, —C(O)-lower alkyl, —C(O)O-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 halogen, lower alkoxy, lower alkyl substituted by halogen, cyano, —CH 2 O-lower alkyl, or lower alkyl, or is
—C(O)-heterocycloalkyl, heterocycloalkyl, —C(O)-heteroaryl or heteroaryl,
which heterocycloalkyl or heteroaryl groups are optionally substituted by halogen, lower alkyl, ═O, lower alkoxy, lower alkyl substituted by halogen, C(O)NH-lower alkyl, C(O)NH 2, C(O)-lower alkyl, S(O) 2 — lower alkyl or cyano;
Z is —O—
R 4 is
lower alkyl substituted by halogen,
lower alkyl substituted by hydroxy,
lower alkyl substituted by cycloalkyl,
(CH 2 ) s —O-lower alkyl, wherein s is 2 or 3,
CH(CH 3 )CH 2 —O-lower alkyl,
(CH 2 ) q CN, bicyclo[2.2.1]heptanyl,
(CH 2 ) q -cycloalkyl optionally substituted by lower alkyl, lower alkyl substituted by halogen, lower alkoxy or by halogen, or is
(CH 2 ) q -heterocycloalkyl, (CH 2 ) q -aryl, CH(lower alkyl)-aryl, CH(cycloalkyl)-aryl, or (CH 2 ) q -heteroaryl,
which heterocycloalkyl, aryl or heteroaryl rings are optionally substituted by halogen, hydroxy, lower alkyl, lower alkyl substituted by halogen, S(O) 2 -lower alkyl, cyano or by lower alkoxy;
q is 0, 1 or 2;
or a pharmaceutically active salt thereof.

2. The compound of claim 1 having formula Ia,

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 hydrogen or methyl;
R 6 is hydrogen, di-lower alkyl or ═O;
o and m are each independently 0, 1 or 2;
R 7′ is hydrogen, —C(O)-lower alkyl, —C(O)O-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 halogen, lower alkoxy, lower alkyl substituted by halogen, cyano, —CH 2 O-lower alkyl, or lower alkyl, or is
—C(O)-heterocycloalkyl, heterocycloalkyl, —C(O)-heteroaryl, or heteroaryl,
which heterocycloalkyl or heteroaryl groups are optionally substituted by halogen, lower alkyl, ═O, lower alkoxy, lower alkyl substituted by halogen, C(O)NH-lower alkyl, C(O)NH 2, C(O)-lower alkyl, S(O) 2 — lower alkyl or cyano;
Z is —O—
R 4 is
lower alkyl substituted by halogen,
lower alkyl substituted by hydroxy,
lower alkyl substituted by cycloalkyl,
(CH 2 ) s —O-lower alkyl, wherein s is 2 or 3,
CH(CH 3 )CH 2 —O-lower alkyl,
(CH 2 ) q CN, bicyclo[2.2.1]heptanyl,
(CH 2 ) q -cycloalkyl optionally substituted by lower alkyl, lower alkyl substituted by halogen, lower alkoxy or by halogen, or is
(CH 2 ) q -heterocycloalkyl, (CH 2 ) q -aryl, CH(lower alkyl)-aryl, CH(cycloalkyl)-aryl, or (CH 2 ) q -heteroaryl,
which heterocycloalkyl, aryl or heteroaryl rings are optionally substituted by halogen, hydroxy, lower alkyl, lower alkyl substituted by halogen, S(O) 2 -lower alkyl, cyano or by lower alkoxy;
q is 0, 1 or 2;
or a pharmaceutically active salt thereof.

3. The compound of claim 2 , selected from the group consisting of
rac-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester;
rac-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid cyclopentyl ester;
rac-[(3R,4S)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester;
{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester;
{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester;
rac-[(3R,4S)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid phenyl ester;
rac-[(3R,4S)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid p-tolyl ester;
rac-[(3R,4S)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-methoxy-phenyl ester; and
rac-[(3R,4S)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-chloro-phenyl ester.

4. The compound of claim 2 , selected from the group consisting of
rac-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-chloro-phenyl ester;
rac-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid phenyl ester;
rac-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid p-tolyl ester;
rac-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid p-methoxyphenyl ester;
{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid p-tolyl ester;
{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid p-tolyl ester;
{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-chlorophenyl ester;
{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-chlorophenyl ester; and
[(3R,4S)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-methoxy-phenyl ester.

5. The compound of claim 2 , selected from the group consisting of
[(3S,4R)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-methoxy-phenyl ester;
rac-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid prop-2-ynyl ester;
rac-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbo

Assignees

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

Inventors

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

Classifications

• A61K31/4025

  not condensed and containing further heterocyclic rings, e.g. cromakalim · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P25/04

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

• A61K31/497

  containing further heterocyclic rings · CPC title