U.S. patent application number 12/964769 was filed with the patent office on 2011-06-23 for pyrrolidine compounds.
Invention is credited to Henner Knust, Andreas Koblet, Matthias Nettekoven, Hasane Ratni, Claus Riemer, Walter Vifian.
Application Number | 20110152233 12/964769 |
Document ID | / |
Family ID | 43480770 |
Filed Date | 2011-06-23 |
United States Patent
Application |
20110152233 |
Kind Code |
A1 |
Knust; Henner ; et
al. |
June 23, 2011 |
PYRROLIDINE COMPOUNDS
Abstract
The present application relates to compounds of formula
##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.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).
Inventors: |
Knust; Henner; (Rheinfelden,
DE) ; Koblet; Andreas; (Bottmingen, CH) ;
Nettekoven; Matthias; (Grenzach-Wyhlen, DE) ; Ratni;
Hasane; (Habsheim, FR) ; Riemer; Claus;
(Freiburg, DE) ; Vifian; Walter; (Gelterkinden,
CH) |
Family ID: |
43480770 |
Appl. No.: |
12/964769 |
Filed: |
December 10, 2010 |
Current U.S.
Class: |
514/210.02 ;
514/252.03; 514/255.05; 514/275; 514/316; 514/318; 514/326;
540/200; 544/238; 544/297; 544/405; 546/187; 546/194; 546/208 |
Current CPC
Class: |
A61P 25/22 20180101;
C07D 401/06 20130101; A61P 25/00 20180101; A61P 25/24 20180101;
C07D 207/14 20130101; A61P 29/00 20180101; A61P 25/18 20180101;
C07D 405/14 20130101; A61P 25/16 20180101; A61P 25/28 20180101;
C07D 401/14 20130101 |
Class at
Publication: |
514/210.02 ;
514/252.03; 514/255.05; 514/275; 514/316; 514/318; 514/326;
540/200; 544/238; 544/297; 544/405; 546/187; 546/194; 546/208 |
International
Class: |
A61K 31/397 20060101
A61K031/397; A61K 31/501 20060101 A61K031/501; A61K 31/4965
20060101 A61K031/4965; A61K 31/506 20060101 A61K031/506; A61K
31/4545 20060101 A61K031/4545; C07D 405/14 20060101 C07D405/14;
C07D 401/14 20060101 C07D401/14; C07D 401/08 20060101
C07D401/08 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 18, 2009 |
EP |
09179797.7 |
Claims
1. A compound of formula I ##STR00196## wherein R.sup.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.sup.1 is
the same or different; R.sup.2 is C.sub.2-7-alkyl or
C.sub.3-6-cycloalkyl; R.sup.3 is the group ##STR00197## wherein X
is CH or N; R.sup.5 is hydrogen, --C(O)-lower alkyl, --C(O)O-lower
alkyl, S(O).sub.2-lower alkyl, --C(O)CH.sub.2O-lower alkyl,
--C(O)--CH.sub.2--CN, or is --C(O)-cycloalkyl, cycloalkyl, or
--CH.sub.2-cycloalkyl, wherein the cycloalkyl groups are optionally
substituted by lower alkyl, --CH.sub.2--O-lower alkyl, lower
alkoxy, CF.sub.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, .dbd.O, lower
alkoxy, lower alkyl substituted by halogen, lower alkyl substituted
by hydroxy, --C(O)--CH.sub.2--N(di-lower alkyl), C(O)NH-lower
alkyl, C(O)NH.sub.2, --O--C(O)-lower alkyl, C(O)-lower alkyl,
S(O).sub.2-lower alkyl or cyano; R.sup.4 is aryl, which is
optionally substituted by halogen, hydroxy, lower alkyl, lower
alkyl substituted by halogen, S(O).sub.2-lower alkyl, cyano or by
lower alkoxy; or a pharmaceutically active salt thereof.
2. The compound of claim 1, wherein R.sup.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 ##STR00198## wherein
R.sup.1 is halogen; n is 1, 2 or 3, wherein when n is 2 or 3, each
halogen is the same or different; R.sup.2 is C.sub.2-7-alkyl or
C.sub.3-6-cycloalkyl; R.sup.3 is the group ##STR00199## wherein
R.sup.5 is hydrogen, --C(O)-lower alkyl, --C(O)O-lower alkyl,
S(O).sub.2-lower alkyl, --C(O)--CH.sub.2--CN, or is
--C(O)-cycloalkyl, wherein the cycloalkyl groups are optionally
substituted by lower alkyl, --CH.sub.2--O-lower alkyl, lower
alkoxy, CF.sub.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, .dbd.O, lower alkyl
substituted by halogen, lower alkyl substituted by hydroxy,
--C(O)--CH.sub.2--N(di-lower alkyl), C(O)NH.sub.2, --O--C(O)-lower
alkyl, C(O)-lower alkyl, S(O).sub.2-lower alkyl or cyano; R.sup.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)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbon-
yl)-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-c-
arbonyl]-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-car-
bonyl]-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-c-
arbonyl]-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-c-
arbonyl]-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-car-
bonyl]-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-c-
arbonyl]-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']bipy-
ridinyl-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']bipy-
ridinyl-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-c-
arbonyl]-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-car-
bonyl]-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']bipy-
ridinyl-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']bipy-
ridinyl-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'-trifluoromethyl-3,4,5,6-tetrahydro-2H--
[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-cyclopropyl-carbamic
acid 4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-cyclopropyl-carbamic acid 4-fluoro-phenyl
ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperidine-4-car-
bonyl]-pyrrolidin-3-yl}-cyclopropyl-carbamic acid 4-fluoro-phenyl
ester;
[(3R,4S)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipy-
ridinyl-4-carbonyl)-pyrrolidin-3-yl]-cyclopropyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; and
[(3S,4R)-1-(5'-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester.
8. The compound of claim 1, selected from the group consisting of
Ethyl-[(3S,4R)-4-(4-fluoro-phenyl)-1-(5'-methanesulfonyl-3,4,5,6-tetrahyd-
ro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester;
4-{(3R,4S)-3-(4-Chloro-3-fluoro-phenyl)-4-[ethyl-(4-fluoro-phenoxy-
carbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic
acid tert-butyl ester;
[(3S,4R)-4-(4-Chloro-3-fluoro-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-3-fluoro-phenyl)-1-(5'-chloro-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-3-fluoro-phenyl)-1-(5'-trifluoromethyl-3,4,5,6-tetra-
hydro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester;
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(6'-cyano-3,4,5,6-tetrahydro-2H-[-
1,3']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl-
)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-4-(4-Chloro-3-fluoro-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-3-fluoro-phenyl)-1-(5'-fluoro-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-3-fluoro-phenyl)-1-(5'-methyl-3,4,5,6-tetrahydro-2H--
[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; and
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester.
9. The compound of claim 1, selected from the group consisting of
[(3S,4R)-1-(5'-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-4-(3,4-Difluoro-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)-1-(6'-Cyano-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-4-carbonyl)--
4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(3,4-Difluoro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-1-(4'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-car-
bonyl)-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H-[1,2'-
]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(5'-methyl-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-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piper-
idine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-1-[1-(6-Cyano-pyridazin-3-yl)-piperidine-4-carbonyl]-4-(3-
,4-difluoro-phenyl)-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-ca-
rbonyl)-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester; and
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester.
10. The compound of claim 1, selected from the group consisting of
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperid-
ine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-1-[1-(5-Cyano-pyrazin-2-yl)-piperidine-4-carbonyl]-4-(3,4-
-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(5'-methanesulfonyl-3,4,5,-
6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carba-
mic acid 4-fluoro-phenyl ester;
[(3S,4R)-4-(3,4-Difluoro-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-3-fluoro-phenyl)-1-[1-(3-methyl-oxetane-3-carbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(3,3-difluoro-cyclobutanecarbo-
nyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(1-cyclobutanecarbonyl-piperidine-
-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester;
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-trifluoromethyl-cyclobutane-
carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(3-fluoro-cyclobutanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(2,2-difluoro-cyclopropanecarb-
onyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-trifluoromethyl-cyclopropan-
ecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester; and
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-cyano-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester.
11. The compound of claim 1, selected from the group consisting of
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(2,2-dimethyl-tetrahydro-pyran-
-4-carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(5-trifluoromethyl-pyridine-2--
carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(5-fluoro-pyridine-2-carbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(4-cyano-benzoyl)-piperidine-4-
-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester;
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(4-fluoro-benzoyl)-piperidine--
4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester;
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(5-trifluoromethyl-pyrazine-2--
carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(6-cyano-pyridine-3-carbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-1-(1-Acetyl-piperidine-4-carbonyl)-4-(4-chloro-3-fluoro-phenyl)--
pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(1-methanesulfonyl-piperidine-4-c-
arbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester;
[(3S,4R)-1-(1-Acetyl-piperidine-4-carbonyl)-4-(4-chloro-phenyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[5'-(1-hydroxy-1-methyl-ethyl)-3,-
4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl]-pyrrolidin-3-yl}-ethyl-c-
arbamic acid 4-fluoro-phenyl ester; and
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-methyl-oxetane-3-carbonyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 2-fluoro-phenyl
ester.
12. The compound of claim 1, selected from the group consisting of
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-cyano-cyclopropanecarbonyl)-piperidi-
ne-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 2-fluoro-phenyl
ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-trifluoromethyl-pyridine-2-carbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
2-fluoro-phenyl ester;
[(3S,4R)-4-(4-Chloro-phenyl)-1-(1-cyclobutanecarbonyl-piperidine-4-carbon-
yl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-methyl-oxetane-3-carbonyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-fluoro-cyclobutanecarbonyl)-piperidi-
ne-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3,3-difluoro-cyclobutanecarbonyl)-pipe-
ridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-methoxy-cyclobutanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-trifluoromethyl-cyclobutanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2-cyano-acetyl)-piperidine-4-carbonyl]-
-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-cyano-cyclopropanecarbonyl)-piperidi-
ne-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-trifluoromethyl-cyclopropanecarbonyl-
)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2,2-difluoro-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; and
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(tetrahydro-pyran-4-carbonyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester.
13. The compound of claim 1, selected from the group consisting of
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2,2-dimethyl-tetrahydro-pyran-4-carbon-
yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-methoxymethyl-cyclopropanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2,2-dimethyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-trifluoromethyl-pyridine-2-ca-
rbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-fluoro-pyridine-2-carbonyl)-piperidi-
ne-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(6-oxo-piperidine-3-carbonyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-isopropyl-6-oxo-piperidine-3-carbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(1-isopropyl-6-oxo-piperidine-3-c-
arbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester;
{(3S,4R)-4-(3,4-Difluoro-phenyl)-1-[1-((S)-4-oxo-azetidine-2-carbonyl)-pi-
peridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(3,4-Difluoro-phenyl)-1-[1-(6-oxo-piperidine-3-carbonyl-
)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[5'-(1-hydroxy-ethyl)-3,4,5,6-tetrahydro-2-
H-[1,2']bipyridinyl-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester;
[(3S,4R)-1-(5'-Carbamoyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbon-
yl)-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester; and
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-chloro-3,4,5,6-tetrahydro-2H-[1,2']bip-
yridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester.
14. The compound of claim 1, selected from the group consisting of
[(3S,4R)-1-(5'-Carbamoyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbon-
yl)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H-[1,2'-
]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-1-(5'-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-4-(3,4-Dichloro-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)-1-(5'-Carbamoyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbon-
yl)-4-(3,4-dichloro-phenyl)-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-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H--
[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-1-(5'-chloro-3,4,5,6-tetrahydro-2H--
[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-1-(5'-trifluoromethyl-3,4,5,6-tetra-
hydro-2H-[1,2']bipyridinyl-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-(3-chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester;
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-((S)-4-oxo-azetidine-2-carbonyl)-piperi-
dine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester;
[(3S,4R)-1-[5'-(2-Diethylamino-acetyl)-3,4,5,6-tetrahydro-2H-[1,2'-
]bipyridinyl-4-carbonyl]-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbam-
ic acid 4-fluoro-phenyl ester, and acetic acid
4-{(3R,4S)-3-(4-chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-amino]-
-pyrrolidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl
ester.
15. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of formula I ##STR00200## wherein
R.sup.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.sup.1 is the same or different; R.sup.2 is C.sub.2-7-alkyl
or C.sub.3-6-cycloalkyl; R.sup.3 is the group ##STR00201## wherein
X is CH or N; R.sup.5 is hydrogen, --C(O)-lower alkyl,
--C(O)O-lower alkyl, S(O).sub.2-lower alkyl, --C(O)CH.sub.2O-lower
alkyl, --C(O)--CH.sub.2--CN, or is --C(O)-cycloalkyl, cycloalkyl,
or --CH.sub.2-cycloalkyl, wherein the cycloalkyl groups are
optionally substituted by lower alkyl, --CH.sub.2--O-lower alkyl,
lower alkoxy, CF.sub.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, .dbd.O, lower alkoxy, lower alkyl substituted by
halogen, lower alkyl substituted by hydroxy,
--C(O)--CH.sub.2--N(di-lower alkyl), C(O)NH-lower alkyl,
C(O)NH.sub.2, --O--C(O)-lower alkyl, C(O)-lower alkyl,
S(O).sub.2-lower alkyl or cyano; R.sup.4 is aryl, which is
optionally substituted by halogen, hydroxy, lower alkyl, lower
alkyl substituted by halogen, S(O).sub.2-lower alkyl, cyano or by
lower alkoxy; or a pharmaceutically active salt thereof and a
pharmaceutically acceptable carrier.
Description
PRIORITY TO RELATED APPLICATION(S)
[0001] This application claims the benefit of European Patent
Application No. 09179797.7, filed Dec. 18, 2009, which is hereby
incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] The three main mammalian tachykinins, substance P(SP),
neurokinin A (NKA) and neurokinin B (NKB) belong to the family of
neuropeptides sharing the common COOH-terminal pentapeptide
sequence of Phe-X-Gly-Leu-Met-NH.sub.2. As neurotransmitters, these
peptides exert their biological activity via three distinct
neurokinin (NK) receptors termed as NK-1, NK-2 and NK-3. SP binds
preferentially to the NK-1 receptor, NKA to the NK-2 and NKB to the
NK-3 receptor.
[0003] The NK-3 receptor is characterized by a predominant
expression in CNS and its involvement in the modulation of the
central monoaminergic system has been shown. These properties make
the NK-3 receptor a potential target for central nervous system
disorders such as anxiety, depression, bipolar disorders,
Parkinson's disease, schizophrenia and pain (Neurosci. Letters,
2000, 283, 185-188; Exp. Opin. Ther. Patents 2000, 10, 939-960;
Neuroscience, 1996, 74, 403-414; Neuropeptides, 1998, 32,
481-488).
[0004] Schizophrenia is one of the major neuropsychiatric
disorders, characterized by severe and chronic mental impairment.
This devastating disease affects about 1% of the world's
population. Symptoms begin in early adulthood and are followed by a
period of interpersonal and social dysfunction. Schizophrenia
manifests as auditory and visual hallucinations, paranoia,
delusions (positive symptoms), blunted affect, depression,
anhedonia, poverty of speech, memory and attention deficits as well
as social withdrawal (negative symptoms).
[0005] For decades scientists and clinicians have made efforts with
the aim of discovering an ideal agent for the pharmacological
treatment of schizophrenia. However, the complexity of the
disorders, due to a wide array of symptoms, has hampered those
efforts. There are no specific focal characteristics for the
diagnosis of schizophrenia and no single symptom is consistently
present in all patients. Consequently, the diagnosis of
schizophrenia as a single disorder or as a variety of different
disorders has been discussed but not yet resolved. The major
difficulty in the development of a new drug for schizophrenia is
the lack of knowledge about the cause and nature of this disease.
Some neurochemical hypotheses have been proposed on the basis of
pharmacological studies to rationalize the development of a
corresponding therapy: the dopamine, the serotonin and the
glutamate hypotheses. But taking into account the complexity of
schizophrenia, an appropriate multireceptor affinity profile might
be required for efficacy against positive and negative signs and
symptoms. Furthermore, an ideal drug against schizophrenia would
preferably have a low dosage allowing once-per-day dosage, due to
the low adherence of schizophrenic patients.
[0006] In recent years clinical studies with selective NK1 and NK2
receptor antagonists appeared in the literature showing results for
the treatment of emesis, depression, anxiety, pain and migraine
(NK1) and asthma (NK2 and NK1). The most exciting data were
produced in the treatment of chemotherapy-induced emesis, nausea
and depression with NK1 and in asthma with NK2-receptor
antagonists. In contrast, no clinical data on NK3 receptor
antagonists have appeared in the literature until 2000. Osanetant
(SR 142,801) from Sanofi-Synthelabo was the first identified potent
and selective non-peptide antagonist described for the NK3
tachykinin receptor for the potential treatment of schizophrenia,
which was reported in the literature (Current Opinion in
Investigational Drugs, 2001, 2(7), 950-956 and Psychiatric
Disorders Study 4, Schizophrenia, June 2003, Decision Recources,
Inc., Waltham, Mass.). The proposed drug SR 142,801 has been shown
in a phase II trial as active on positive symptoms of
schizophrenia, such as altered behaviour, delusion, hallucinations,
extreme emotions, excited motor activity and incoherent speech, but
inactive in the treatment of negative symptoms, which are
depression, anhedonia, social isolation or memory and attention
deficits.
[0007] The neurokinin-3 receptor antagonists have been described as
useful in pain or inflammation, as well as in schizophrenia, Exp.
Opinion. Ther. Patents (2000), 10(6), 939-960 and Current Opinion
in Investigational Drugs, 2001, 2(7), 950-956 956 and Psychiatric
Disorders Study 4, Schizophrenia, June 2003, Decision Recources,
Inc., Waltham, Mass.).
SUMMARY OF THE INVENTION
[0008] The present application provides compounds of formula
##STR00002##
wherein [0009] R.sup.1 is hydrogen, halogen, cyano, lower alkyl or
lower alkyl substituted by halogen; [0010] n is 1, 2 or 3, wherein
when n is 2 or 3, each R.sup.1 is the same or different; [0011]
R.sup.2 is C.sub.2-7-alkyl or C.sub.3-6-cycloalkyl; [0012] R.sup.3
is the group
##STR00003##
[0012] wherein [0013] X is CH or N; [0014] R.sup.5 is hydrogen,
--C(O)-lower alkyl, --C(O)O-lower alkyl, S(O).sub.2-lower alkyl,
--C(O)CH.sub.2O-lower alkyl, --C(O)--CH.sub.2--CN, or is [0015]
--C(O)-cycloalkyl, cycloalkyl, or --CH.sub.2-cycloalkyl, [0016]
wherein the cycloalkyl groups are optionally substituted by lower
alkyl, --CH.sub.2--O-lower alkyl, lower alkoxy, CF.sub.3, halogen
or cyano, or is [0017] --C(O)-heterocycloalkyl, heterocycloalkyl,
--C(O)-heteroaryl, heteroaryl, --C(O)-aryl or aryl, [0018] which
heterocycloalkyl, heteroaryl or aryl groups are optionally
substituted by halogen, lower alkyl, .dbd.O, lower alkoxy, lower
alkyl substituted by halogen, lower alkyl substituted by hydroxy,
--C(O)--CH.sub.2--N(di-lower alkyl), C(O)NH-lower alkyl,
C(O)NH.sub.2, --O--C(O)-lower alkyl, C(O)-lower alkyl,
S(O).sub.2-lower alkyl or cyano; [0019] R.sup.4 is aryl, which is
optionally substituted by halogen, hydroxy, lower alkyl, lower
alkyl substituted by halogen, S(O).sub.2-lower alkyl, cyano or
lower alkoxy; or to a pharmaceutically active salt thereof.
[0020] The invention includes all stereoisomeric forms, including
individual diastereoisomers and enantiomers of the compound of
formula (I) as well as racemic and non-racemic mixtures
thereof.
[0021] The present invention provides novel compounds of formula I,
their manufacture, pharmaceutical compositions containing them and
methods for producing such compositions.
[0022] The present compounds are high potential NK-3 receptor
antagonists for the treatment of depression, pain, bipolar
disorders, psychosis, Parkinson's disease, schizophrenia, anxiety
and attention deficit hyperactivity disorder (ADHD).
[0023] The preferred indications using the compounds of the present
invention are depression, psychosis, Parkinson's disease,
schizophrenia, anxiety and attention deficit hyperactivity disorder
(ADHD).
DETAILED DESCRIPTION OF THE INVENTION
[0024] The following definitions of the general terms used in the
present description apply irrespective of whether the terms in
question appear alone or in combination.
[0025] As used herein, the terms "lower alkyl" and
"C.sub.2-7-alkyl" denote a straight- or branched-chain hydrocarbon
group containing from 2-7 carbon atoms, for example, ethyl, propyl,
isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower
alkyl groups are groups with 2-4 carbon atoms.
[0026] As used herein, the term "lower alkoxy" denotes a lower
alkyl group as defined above which is connected with an oxygen
atom.
[0027] The term "lower alkyl substituted by halogen" denotes a
lower alkyl group as defined above, wherein at least one hydrogen
atom is replaced by halogen, for example --CF.sub.3, --CHF.sub.2,
--CH.sub.2F, --CH.sub.2CF.sub.3, --C(CH.sub.3).sub.2CF.sub.3,
--CH(CH.sub.3)CH.sub.2CF.sub.3, --CH(CH.sub.3)CF.sub.3,
--CH.sub.2CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CF.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CF.sub.2CF.sub.3,
--CH.sub.2CF.sub.2CF.sub.3 and the like. Preferred lower alkyl
substituted by halogen groups are groups having 1-5 carbon
atoms.
[0028] The term "halogen" denotes chlorine, iodine, fluorine and
bromine.
[0029] The term "lower alkyl substituted by hydroxy" denotes a
lower alkyl group as defined above, wherein at least one hydrogen
atom is replaced by a hydroxyl group.
[0030] The term "cycloalkyl" denotes a saturated carbon ring
containing from 3-6 carbon atoms, for example, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
[0031] The term "aryl" denotes a cyclic aromatic hydrocarbon
radical consisting of one or more fused rings containing 6-14
carbon atoms in which at least one ring is aromatic in nature, for
example phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl or
indanyl. Preferred is the phenyl group.
[0032] The term "heteroaryl" denotes a cyclic aromatic radical
consisting of one or more fused rings containing 5-14 ring atoms,
preferably containing 5-10 ring atoms, in which at least one ring
is aromatic in nature, and which contains at least one heteroatom,
selected from N, O and S, for example quinoxalinyl,
dihydroisoquinolinyl, pyrazinyl, pyrazolyl,
2,4-dihydro-pyrazol-3-one, pyridinyl, isoxazolyl, benzo[1,3]dioxol,
[1.3.4]thiadiazol, pyridazinyl, pyrimidinyl, benzotriazol-5-yl,
benzoimidazol-5-yl, [1,3,4]-oxadiazol-2-yl, [1,2,4]triazol-1-yl,
[1,6]naphthyridin-2-yl, imidazo[4,5-b]pyridine-6-yl, tetrazolyl,
thiazolyl, thiadiazolyl, thienyl, furyl, imidazol-1-yl, or
benzofuranyl. Preferred heteroaryl group is pyridine-2, 3 or
4-yl.
[0033] The term "heterocycloalkyl" denotes a cyclic nonaromatic
ring, containing one or two heteroatoms selected from N, S and O,
for example the following groups: tetrahydropyranyl,
1,1-dioxo-hexahydro-1.lamda..sup.6-thiopyranyl,
1,1-dioxo-tetrahydro-1.lamda..sup.6-thiophenyl, oxetanyl,
morpholinyl, [1,4]diazepam-1-yl, piperazinyl, pyrrolidinyl,
piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,
piperidin-4-yl or 1,1-dioxo-.lamda..sup.6-thiomorpholinyl.
[0034] "Pharmaceutically acceptable," such as pharmaceutically
acceptable carrier, excipient, etc., means pharmacologically
acceptable and substantially non-toxic to the subject to which the
particular compound is administered.
[0035] The term "pharmaceutically acceptable acid addition salts"
embraces salts with inorganic and organic acids, such as
hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid,
citric acid, formic acid, fumaric acid, maleic acid, acetic acid,
succinic acid, tartaric acid, methanesulfonic acid,
p-toluenesulfonic acid and the like.
[0036] "Therapeutically effective amount" means an amount that is
effective to prevent, alleviate or ameliorate symptoms of disease
or prolong the survival of the subject being treated.
[0037] One embodiment of the invention provides compounds of
formula Ia
##STR00004##
wherein [0038] R.sup.1 is halogen; [0039] n is 1, 2 or 3, wherein
when n is 2 or 3, each halogen is the same or different; [0040]
R.sup.2 is C.sub.2-7-alkyl or C.sub.3-6-cycloalkyl; [0041] R.sup.3
is the group
##STR00005##
[0041] wherein [0042] R.sup.5 is hydrogen, --C(O)-lower alkyl,
--C(O)O-lower alkyl, S(O).sub.2-lower alkyl, --C(O)--CH.sub.2--CN,
or is --C(O)-cycloalkyl, [0043] wherein the cycloalkyl groups are
optionally substituted by lower alkyl, --CH.sub.2--O-lower alkyl,
lower alkoxy, CF.sub.3, halogen or cyano, or is [0044]
--C(O)-heterocycloalkyl, --C(O)-heteroaryl, heteroaryl,
--C(O)-aryl, [0045] which heterocycloalkyl, heteroaryl or aryl
groups are optionally substituted by halogen, lower alkyl, .dbd.O,
lower alkyl substituted by halogen, lower alkyl substituted by
hydroxy, --C(O)--CH.sub.2--N(di-lower alkyl), C(O)NH.sub.2,
--O--C(O)-lower alkyl, C(O)-lower alkyl, S(O).sub.2-lower alkyl or
cyano; [0046] R.sup.4 is aryl, which is optionally substituted by
halogen, or a pharmaceutically active salt thereof.
[0047] A preferred aryl group is phenyl.
[0048] The following compounds are encompassed by the present
invention: [0049]
rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropaneca-
rbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0050]
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; [0051]
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; [0052]
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; [0053]
{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0054]
{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0055]
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0056]
[(3R,4S)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-ca-
rbonyl)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0057]
[(3R,4S)-4-(4-Chloro-phenyl)-1-(4'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipy-
ridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0058]
[(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; [0059]
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperidine-4-car-
bonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester;
[0060]
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0061]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperid-
ine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0062]
[(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; [0063]
[(3S,4R)-4-(4-Chloro-phenyl)-1-(4'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipy-
ridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0064]
[(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; [0065]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperidine-4-car-
bonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester;
[0066]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0067]
[(3R,4S)-4-(4-Chloro-phenyl)-1-(5'-trifluoromethyl-3,4,5,6-tetrahy-
dro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0068]
[(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; [0069]
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipy-
ridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0070]
[(3R,4S)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipy-
ridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0071]
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipy-
ridinyl-4-carbonyl)-pyrrolidin-3-yl]-isopropyl-carbamic acid
4-fluoro-phenyl ester; [0072]
[(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; [0073]
[(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; [0074]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-isopropyl-carbamic acid 4-fluoro-phenyl
ester; [0075]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-isopropyl-carbamic acid
4-fluoro-phenyl ester; [0076]
[(3R,4S)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipy-
ridinyl-4-carbonyl)-pyrrolidin-3-yl]-isopropyl-carbamic acid
4-fluoro-phenyl ester; [0077]
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipy-
ridinyl-4-carbonyl)-pyrrolidin-3-yl]-cyclopropyl-carbamic acid
4-fluoro-phenyl ester; [0078]
[(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; [0079]
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H--
[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-cyclopropyl-carbamic
acid 4-fluoro-phenyl ester; [0080]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-cyclopropyl-carbamic acid 4-fluoro-phenyl
ester; [0081]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-cyclopropyl-carbamic acid
4-fluoro-phenyl ester; [0082]
[(3R,4S)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipy-
ridinyl-4-carbonyl)-pyrrolidin-3-yl]-cyclopropyl-carbamic acid
4-fluoro-phenyl ester; [0083]
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0084]
[(3S,4R)-1-(5'-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0085]
Ethyl-[(3S,4R)-4-(4-fluoro-phenyl)-1-(5'-methanesulfonyl-3,4,5,6-tetrahyd-
ro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-carbamic acid
4-fluoro-phenyl ester; [0086]
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0087]
4-{(3R,4S)-3-(4-Chloro-3-fluoro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbony-
l)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester; [0088]
[(3S,4R)-4-(4-Chloro-3-fluoro-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; [0089]
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(5'-chloro-3,4,5,6-tetrahydro-2H--
[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0090]
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(5'-trifluoromethyl-3,4,5,6-tetra-
hydro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0091]
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(6'-cyano-3,4,5,6-tetrahydro-2H-[-
1,3']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0092]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl-
)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0093]
[(3S,4R)-4-(4-Chloro-3-fluoro-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; [0094]
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H--
[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0095]
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(5'-methyl-3,4,5,6-tetrahydro-2H--
[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0096]
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0097]
[(3S,4R)-1-(5'-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0098]
[(3S,4R)-4-(3,4-Difluoro-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; [0099]
[(3S,4R)-1-(6'-Cyano-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-4-carbonyl)--
4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0100]
{(3S,4R)-4-(3,4-Difluoro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0101]
[(3S,4R)-1-(4'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0102]
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H-[1,2'-
]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0103]
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(5'-methyl-3,4,5,6-tetrahydro-2H-[1,2'-
]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0104]
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester; [0105]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piper-
idine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0106]
[(3S,4R)-1-[1-(6-Cyano-pyridazin-3-yl)-piperidine-4-carbonyl]-4-(3,4-difl-
uoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0107]
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-ca-
rbonyl)-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0108]
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0109]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperid-
ine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0110]
[(3S,4R)-1-[1-(5-Cyano-pyrazin-2-yl)-piperidine-4-carbonyl]-4-(3,4-difluo-
ro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0111]
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(5'-methanesulfonyl-3,4,5,-
6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carba-
mic acid 4-fluoro-phenyl ester; [0112]
[(3S,4R)-4-(3,4-Difluoro-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; [0113]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(3-methyl-oxetane-3-carbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0114]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(3,3-difluoro-cyclobutanecarbo-
nyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0115]
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(1-cyclobutanecarbonyl-piperidine-
-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0116]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-trifluoromethyl-cycl-
obutanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0117]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(3-fluoro-cyclobutanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0118]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(2,2-difluoro-cyclopropanecarb-
onyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0119]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-trifluoromethyl-cyclopropan-
ecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0120]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-cyano-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0121]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(2,2-dimethyl-tetrahydro-pyran-
-4-carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0122]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(5-trifluoromethyl-pyridine-2--
carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0123]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(5-fluoro-pyridine-2-carbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0124]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(4-cyano-benzoyl)-piperidine-4-
-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0125]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(4-fluoro-benzoyl)-pipe-
ridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0126]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(5-trifluoromethyl-pyrazine-2--
carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0127]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(6-cyano-pyridine-3-carbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0128]
[(3S,4R)-1-(1-Acetyl-piperidine-4-carbonyl)-4-(4-chloro-3-fluoro-phenyl)--
pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester; [0129]
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(1-methanesulfonyl-piperidine-4-c-
arbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0130]
[(3S,4R)-1-(1-Acetyl-piperidine-4-carbonyl)-4-(4-chloro-phenyl)-py-
rrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester; [0131]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[5'-(1-hydroxy-1-methyl-ethyl)-3,-
4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl]-pyrrolidin-3-yl}-ethyl-c-
arbamic acid 4-fluoro-phenyl ester; [0132]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-methyl-oxetane-3-carbonyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 2-fluoro-phenyl
ester; [0133]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-cyano-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
2-fluoro-phenyl ester; [0134]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-trifluoromethyl-pyridine-2-carbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
2-fluoro-phenyl ester; [0135]
[(3S,4R)-4-(4-Chloro-phenyl)-1-(1-cyclobutanecarbonyl-piperidine-4-carbon-
yl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
[0136]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-methyl-oxetane-3-carbonyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0137]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-fluoro-cyclobutanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0138]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3,3-difluoro-cyclobutanecarbonyl)-pipe-
ridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0139]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-methoxy-cyclobutanecarbonyl)-piperid-
ine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0140]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-trifluoromethyl-cyclobutanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0141]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2-cyano-acetyl)-piperidine-4-carbonyl]-
-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester;
[0142]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-cyano-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0143]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-trifluoromethyl-cyclopropanecarbonyl-
)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0144]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2,2-difluoro-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0145]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(tetrahydro-pyran-4-carbonyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0146]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2,2-dimethyl-tetrahydro-pyran-4-
-carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0147]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-methoxymethyl-cyclopropanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0148]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2,2-dimethyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0149]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-trifluoromethyl-pyridine-2-carbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0150]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-fluoro-pyridine-2-carbonyl)-piperidi-
ne-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0151]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(6-oxo-piperidine-3-carbonyl)-pi-
peridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0152]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-isopropyl-6-oxo-piperidine-3-carbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0153]
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(1-isopropyl-6-oxo-piperidine-3-c-
arbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0154]
{(3S,4R)-4-(3,4-Difluoro-phenyl)-1-[1-((S)-4-oxo-azetidine-2-carbo-
nyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0155]
{(3S,4R)-4-(3,4-Difluoro-phenyl)-1-[1-(6-oxo-piperidine-3-carbonyl)-piper-
idine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0156]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[5'-(1-hydroxy-ethyl)-3,4,5,6-tetrahydro-2-
H-[1,2']bipyridinyl-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0157]
[(3S,4R)-1-(5'-Carbamoyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbon-
yl)-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0158]
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-chloro-3,4,5,6-tetrahydro-2H-[1,2']bip-
yridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0159]
[(3S,4R)-1-(5'-Carbamoyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbon-
yl)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0160]
[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H-[1,2'-
]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0161]
[(3S,4R)-1-(5'-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0162]
[(3S,4R)-4-(3,4-Dichloro-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; [0163]
[(3S,4R)-1-(5'-Carbamoyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbon-
yl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0164]
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0165]
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H--
[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0166]
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-1-(5'-chloro-3,4,5,6-tetrahydro-2H--
[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0167]
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-1-(5'-trifluoromethyl-3,4,5,6-tetra-
hydro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0168]
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(3-chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0169]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-((S)-4-oxo-azetidine-2-carbonyl)-piperi-
dine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0170]
[(3S,4R)-1-[5'-(2-Diethylamino-acetyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyri-
dinyl-4-carbonyl]-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester; and [0171] acetic acid
4-{(3R,4S)-3-(4-chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-amino]-
-pyrrolidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl
ester.
[0172] In one embodiment the invention provides the following
compounds [0173]
rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropaneca-
rbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0174]
{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0175]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0176]
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-ca-
rbonyl)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0177]
[(3S,4R)-4-(4-Chloro-phenyl)-1-(4'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipy-
ridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0178]
[(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; [0179]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperidine-4-car-
bonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester;
[0180]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0181]
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-trifluoromethyl-3,4,5,6-tetrahy-
dro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0182]
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipy-
ridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0183]
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0184]
Ethyl-[(3S,4R)-4-(4-fluoro-phenyl)-1-(5'-methanesulfonyl-3,4,5,6-tetrahyd-
ro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-carbamic acid
4-fluoro-phenyl ester; [0185]
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0186]
4-{(3R,4S)-3-(4-Chloro-3-fluoro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbony-
l)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester; [0187]
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(5'-trifluoromethyl-3,4,5,6-tetra-
hydro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0188]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl-
)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0189]
[(3S,4R)-4-(4-Chloro-3-fluoro-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; [0190]
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H--
[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0191]
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(5'-methyl-3,4,5,6-tetrahydro-2H--
[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0192]
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0193]
[(3S,4R)-1-(5'-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0194]
[(3S,4R)-4-(3,4-Difluoro-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; [0195]
[(3S,4R)-1-(6'-Cyano-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-4-carbonyl)--
4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0196]
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H-[1,2'-
]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0197]
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(5'-methyl-3,4,5,6-tetrahydro-2H-[1,2'-
]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0198]
[(3S,4R)-1-[1-(6-Cyano-pyridazin-3-yl)-piperidine-4-carbonyl]-4-(3,4-difl-
uoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0199]
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-ca-
rbonyl)-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0200]
[(3S,4R)-1-[1-(5-Cyano-pyrazin-2-yl)-piperidine-4-carbonyl]-4-(3,4-difluo-
ro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0201]
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(5'-methanesulfonyl-3,4,5,6-tet-
rahydro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0202]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(3-methyl-oxetane-3-carbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0203]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(3,3-difluoro-cyclobutanecarbo-
nyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0204]
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(1-cyclobutanecarbonyl-piperidine-
-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0205]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-trifluoromethyl-cycl-
obutanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0206]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(3-fluoro-cyclobutanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0207]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(2,2-difluoro-cyclopropanecarb-
onyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0208]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-trifluoromethyl-cyclopropan-
ecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0209]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-cyano-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0210]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(2,2-dimethyl-tetrahydro-pyran-
-4-carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0211]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(5-fluoro-pyridine-2-carbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0212]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(4-fluoro-benzoyl)-piperidine--
4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0213]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(5-trifluoromethyl-pyra-
zine-2-carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0214]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(6-cyano-pyridine-3-carbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0215]
[(3S,4R)-1-(1-Acetyl-piperidine-4-carbonyl)-4-(4-chloro-3-fluoro-phenyl)--
pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester; [0216]
[(3S,4R)-1-(1-Acetyl-piperidine-4-carbonyl)-4-(4-chloro-phenyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester; [0217]
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[5'-(1-hydroxy-1-methyl-ethyl)-3,-
4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl]-pyrrolidin-3-yl}-ethyl-c-
arbamic acid 4-fluoro-phenyl ester; [0218]
[(3S,4R)-4-(4-Chloro-phenyl)-1-(1-cyclobutanecarbonyl-piperidine-4-carbon-
yl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester;
[0219]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-methyl-oxetane-3-carbonyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0220]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-fluoro-cyclobutanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0221]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3,3-difluoro-cyclobutanecarbonyl)-pipe-
ridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0222]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-methoxy-cyclobutanecarbonyl)-piperid-
ine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0223]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-trifluoromethyl-cyclobutanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0224]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2-cyano-acetyl)-piperidine-4-carbonyl]-
-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester; [0225]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-cyano-cyclopropanecarbonyl)-piperidi-
ne-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0226]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-trifluoromethyl-cyclopropanec-
arbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0227]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2,2-difluoro-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0228]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(tetrahydro-pyran-4-carbonyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0229]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2,2-dimethyl-tetrahydro-pyran-4-
-carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0230]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-methoxymethyl-cyclopropanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0231]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2,2-dimethyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester; [0232]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-fluoro-pyridine-2-carbonyl)-piperidi-
ne-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester; [0233]
{(3S,4R)-4-(4-Chloro-phenyl)-1-[5'-(1-hydroxy-ethyl)-3,4,5,6-tetra-
hydro-2H-[1,2']bipyridinyl-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0234]
[(3S,4R)-1-(5'-Carbamoyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbon-
yl)-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0235]
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-chloro-3,4,5,6-tetrahydro-2H-[1,2']bip-
yridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0236]
[(3S,4R)-1-(5'-Carbamoyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbon-
yl)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0237]
[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H-[1,2'-
]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0238]
[(3S,4R)-1-(5'-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0239]
[(3S,4R)-4-(3,4-Dichloro-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; [0240]
[(3S,4R)-1-(5'-Carbamoyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbon-
yl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0241]
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0242]
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H--
[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0243]
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-1-(5'-chloro-3,4,5,6-tetrahydro-2H--
[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; [0244]
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-1-(5'-trifluoromethyl-3,4,5,6-tetra-
hydro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester; [0245]
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(3-chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester; and [0246] Acetic acid
4-{(3R,4S)-3-(4-chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-amino]-
-pyrrolidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl
ester.
[0247] An embodiment of the invention provides compounds of
formula
##STR00006##
wherein R.sup.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.sup.1 is the same or different; R.sup.2 is
C.sub.2-7-alkyl or C.sub.3-6-cycloalkyl; R.sup.3 is a non aromatic
heterocyclic group
##STR00007##
wherein
X is CH;
Y is --N(R.sup.7)--;
[0248] R.sup.6 is hydrogen; o and m are each independently 0, 1 or
2; p is 0 or 1; R.sup.7' is hydrogen, --C(O)-lower alkyl,
--C(O)O-lower alkyl, S(O).sub.2-lower alkyl, --C(O)CH.sub.2O-lower
alkyl, or is cycloalkyl, --CH.sub.2-cycloalkyl or
--C(O)-cycloalkyl, wherein the cycloalkyl groups are optionally
substituted by lower alkyl, CF.sub.3, halogen or cyano, or is
--C(O)-heterocycloalkyl, heterocycloalkyl, heteroaryl,
--C(O)-heteroaryl, --C(O)-aryl, or aryl, which heterocycloalkyl,
heteroaryl or aryl groups are optionally substituted by halogen,
lower alkyl, lower alkoxy, lower alkyl substituted by halogen,
C(O)NH-lower alkyl, C(O)NH.sub.2, C(O)-lower alkyl,
S(O).sub.2-lower alkyl or cyano;
Z is --O--;
[0249] R.sup.4 is (CH.sub.2).sub.q-aryl or is
(CH.sub.2).sub.q-heteroaryl, which aryl or heteroaryl rings are
optionally substituted by halogen, hydroxy, lower alkyl, lower
alkyl substituted by halogen, S(O).sub.2-lower alkyl, cyano or by
lower alkoxy; q is 0 or 1; or to a pharmaceutically active salt
thereof.
[0250] The present compounds of formula I and their
pharmaceutically acceptable salts can be prepared by processes
described below, which process comprises
a) coupling a compound of formula II
##STR00008##
with a suitable carbamoyl chloride, acid chloride or carboxylic
acid to afford a compound of formula I
##STR00009##
wherein the substituents R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
as defined above and if desired, converting the compounds obtained
into pharmaceutically acceptable acid addition salts; or b)
coupling a compound with formula III
##STR00010##
with a corresponding chloroformate, acid anhydride or a mixture of
triphosgene and corresponding alcohol or amine to afford a compound
of formula I
##STR00011##
wherein the substituents R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
as defined above and if desired, converting the compounds obtained
into pharmaceutically acceptable acid addition salts.
[0251] The following schemes 1 and 2 describe the processes for the
preparation of compounds of formula I in more detail. The starting
material of formula II is a known compound and can be prepared
according to methods known in the art.
##STR00012##
[0252] According to scheme 1, the 3,4-disubstituted pyrrolidine VI
is prepared via a stereo specific 1,3-dipolar cycloaddition between
the 2-nitrostyrene compound IV and the azomethine ylide generated
in situ from the
N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine V
in the presence of a catalytic amount of acid, such as TFA.
Reduction of the nitro moiety of VI using standard conditions for
example SnCl.sub.2.H.sub.2O yields VII. The amino moiety of VII is
subsequently alkylated to produce VIII. Reaction of VIII with an
acid anhydride, chloroformate or a mixture of triphosgene and an
alcohol or amine in the presence of a base affords IX. Selective
N-debenzylation is then carried out using several known procedures
which are compatible with the substitution patterns of the aromatic
rings to afford II. Finally, compounds I are prepared via a
coupling with a suitable carbamoyl chloride, acid chloride or
carboxylic acide. Alternatively, pyrrolidine II is coupled with the
corresponding acid to afford a compound of formula IA which can be
deprotected to afford the piperidine of formula IB which might be
further derivatised to obtain final compounds of formula I.
##STR00013##
[0253] According to scheme 2, the secondary amine of the
intermediates VII can be protected, for instance with a Boc group
to afford a compound of formula X, followed by a selective
debenzylation to produce XI. Then a coupling with a suitable
carbamoyl chloride, acid chloride or carboxylic acid gives XII.
Deprotection with TFA affords the free amine XIII, which after
reaction with an acid anhydride, chloroformate or a mixture of
triphosgene and an alcohol or amine in the presence of a base
affords compounds of formula I.
Example 1
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
##STR00014##
[0254] a)
rac-(3R,4S)-1-Benzyl-3-(3,4-dichloro-phenyl)-4-nitro-pyrrolidine
[0255] A solution of
N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine
(32.50 g, 0.135 mol) in CH.sub.2Cl.sub.2 (70 mL) was added drop
wise, over a 30 minutes period, to a stirred solution of
1,2-dichloro-4-((E)-2-nitro-vinyl)-benzene (19.60 g, 0.09 mol) and
trifluoroacetic acid (1.54 mL, 0.013 mol) in CH.sub.2Cl.sub.2 (160
mL) at 0.degree. C. The ice bath was removed, and the solution was
stirred at 25.degree. C. for an additional 48 h. It was then
concentrated and purification by flash chromatography (SiO.sub.2,
EtOAc/H 1:6) afforded 25.0 g (79%) of the title compound as a
yellow oil. MS m/e: 351.0 (M+H.sup.+).
b)
rac-(3S,4R)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine
[0256] To a stirred solution of
rac-(3R,4S)-1-benzyl-3-(3,4-dichloro-phenyl)-4-nitro-pyrrolidine
(11.60 g, 33.0 mmol) in EtOAc (200 mL) was added in one portion
SnCl.sub.2.2H.sub.2O (37.26 g, 0.165 mol). The reaction mixture was
then heated at reflux for 4 hours, cooled down to ambient
temperature and a saturated aqueous solution of NaHCO.sub.3 was
added. The salts were filtered off and the product extracted with
EtOAc. The organic phases were then dried over Na.sub.2SO.sub.4,
and concentration under vacuum gave 5.7 g (54%) of
rac-(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine
as a yellow oil. The product was then used in the next step without
further purification. ES-MS m/e: 321.2 (M+H.sup.+).
c)
rac-(3S,4R)-[1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-carbamic
acid tert-butyl ester
[0257] To a solution of
rac-(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine
(30.64 g, 0.095 mol) in dichloromethane (300 mL) was added
N,N-diisopropylamine (32.65 mL, 0.191 mol) and
4-dimethylaminopyridine (1.17 g, 0.01 mol). The reaction mixture
was cooled to 0.degree. C. and di-tert-butyl-dicarbonate (24.98 g,
0.114 mol) was added. After stirring for 2 h at 0.degree. C. and at
ambient temperature for 18 h it was concentrated. Purification by
flash chromatography (SiO.sub.2, EtOAc/Heptane 1:3) afforded 5.82 g
(14%) of the title compound as a light yellow solid. ES-MS m/e:
421.1 (M+H.sup.+).
d) rac-(3S,4R)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-carbamic
acid tert-butyl ester
[0258] To a solution of
rac-(3S,4R)-[1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-carbamic
acid tert-butyl ester (5.59 g, 0.013 mol) and N,N-diisopropylamine
(6.81 mL, 0.017 mol) in toluene (60 mL) was added at ambient
temperature 1-chloroethyl formate (1.88 mL, 0.017 mol) and the
reaction mixture was stirred for 24 h. It was concentrated and the
resulting residue was diluted in methanol (60 mL) and stirred for 3
h at ambient temperature. Concentration afforded the crude title
compound (6.59 g, 67% purity) as a light brown solid which was
directly used without further purification.
e)
rac-(3S,4R)-{4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl
ester
[0259] To a solution of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
(4.48 g, 0.02 mol) in DMF (40 ml) was added
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (9.54 g, 0.03 mol). After stirring for 10 min
at ambient temperature N,N-diisopropyl ethyl amine (19.82 ml, 0.116
mol) and a solution of
rac-(3S,4R)-[4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-carbamic acid
tert-butyl ester (6.39 g, 67% purity, 0.013 mol) in DMF (45 ml)
were added and the reaction mixture was stirred for 19 h at this
temperature. It was diluted with ethyl acetate (80 mL) and the
organic layer was washed with water (80 mL), aqueous sodium
carbonate (1M, 40 mL) and brine (40 mL). The aqueous layers were
extracted with ethyl acetate (160 mL). the combined organic layers
were dried over sodium sulfate and concentrated. Purification by
flash chromatography (SiO.sub.2, EtOAc/methanol 100:0 to 80:20)
afforded 5.84 g (87%) of the title compound as a light brown foam.
ES-MS m/e: 524.1 (M+H.sup.+).
f)
rac-(3S,4R)-[3-Amino-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-met-
hyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
[0260] To a solution of
rac-(3S,4R)-{4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl
ester (5.747 g, 0.011 mol) in dichloromethane (55 mL) was added
trifluoroacetic acid (8.39 mL, 0.110 mol) and the reaction mixture
was stirred for 4 h at ambient temperature. The reaction mixture
was basified by addition of aqueous sodium carbonate (1M, 10 mL).
The organic layers were washed with water (8 mL) and the aqueous
layers were extracted with dichloromethane (10 mL). The combined
org. layers were dried over sodium sulfate and concentration
afforded 4.30 g (92%) of the title compound as a light brown foam.
ES-MS m/e: 524.2 (M+H.sup.+).
g)
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-ethylamino-pyrrolidin-1-yl]-[1-(-
1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
[0261] To a solution of
rac-(3S,4R)-[3-Amino-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methy-
l-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (50 mg, 0.12
mmol) in ethanol (0.3 mL) were added acetaldehyde (10 uL, 0.18
mmol) and sodiumcyanoborohydride (15 mg, 0.24 mmol) and the
reaction mixture was stirred at ambient temperature for 3 h. It was
concentrated and the residue separated between water and
ethylacetate. The organic layer was dried over sodium sulfate and
concentrated. Purification by chromatography (SiO.sub.2,
dichloromethane:methanol=100:0 to 95:5) afforded the title compound
(30 mg, 56%) as a light yellow oil. MS m/e: 452.3 [M].sup.+.
h)
rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
[0262] To a solution of
rac-[(3R,4S)-3-(3,4-dichloro-phenyl)-4-ethylamino-pyrrolidin-1-yl]-[1-(1--
methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (25 mg, 0.06
mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine
(10 uL, 0.06 mmol). It was cooled to 0.degree. C. and
4-fluorophenyl chloroformate (8 uL, 0.06 mmol) was added and the
reaction mixture was stirred for 30 min at this temperature and
then 2 h at ambient temperature. Concentration and purification by
chromatography (SiO.sub.2, ethyl acetate) afforded the title
compound (17 mg, 52%) as a colorless foam. MS m/e: 590.4
[M].sup.+.
Example 2
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
##STR00015##
[0263] a)
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-isopropylamino-pyrrolidin-
-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
[0264] To a solution of
rac-(3S,4R)-[3-Amino-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methy-
l-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (120 mg, 0.28
mmol) in dichloromethane (1 mL) were added acetone (21 uL, 0.28
mmol) and sodiumtriacetoxy-borohydride (72 mg, 0.34 mmol) and
acetic acid (16 uL, 0.28 mmol) and the reaction mixture was stirred
at ambient temperature for 3 h. It was diluted with dichloromethane
and washed with aqueous sodiumhydrogenecarbonate (1M). The organic
layer was dried over sodium sulfate and concentrated affording the
title compound (95 mg, 72%) as a light yellow foam. MS m/e: 466.3
[M].sup.+.
b)
rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-isopropyl-carbamic acid
4-fluoro-phenyl ester
[0265] In analogy to the procedure described for the synthesis of
example 1 (step h), the title compound
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 was prepared from
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-isopropylamino-pyrrolidin-1-yl]-[1-
-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone instead
of
rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbo-
nyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
4-fluorophenyl chloroformate and was obtained as a colorless foam.
MS m/e: 604.3 [M].sup.+.
Example 3
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
##STR00016##
[0266] a)
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-isobutylamino-pyrrolidin--
1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
[0267] To a solution of
rac-(3S,4R)-[3-Amino-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methy-
l-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (150 mg, 0.35
mmol) in dichloromethane (1 mL) were added isobutylaldehyde (39 uL,
0.42 mmol) and sodiumcyanoborohydride (27 mg, 0.42 mmol) and acetic
acid (51 uL, 0.88 mmol) and the reaction mixture was stirred at
ambient temperature for 3 h. It was diluted with dichloromethane
and washed with aqueous sodiumhydrogenecarbonate (1M). The organic
layer was dried over sodium sulfate and concentrated affording the
title compound (140 mg, 82%) as a light yellow oil. MS m/e: 480.3
[M].sup.+.
b)
rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-isobutyl-carbamic acid
4-fluoro-phenyl ester
[0268] In analogy to the procedure described for the synthesis of
example 1 (step h), the title compound
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 was prepared from
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-isobutylamino-pyrrolidin-1-yl]-[1--
(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone instead
of
rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbo-
nyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
4-fluorophenyl chloroformate and was obtained as a colorless foam.
MS m/e: 618.5 [M].sup.+.
Example 4
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
##STR00017##
[0269] a)
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-cyclopropylamino-pyrrolid-
in-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
[0270] To a solution of
rac-(3S,4R)-[3-Amino-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methy-
l-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (150 mg, 0.35
mmol) in dichloromethane (1 mL) were added
((1-ethoxycyclopropyl)oxy)trimethylsilan (62 uL, 0.35 mmol) and
sodiumtrisacetoxyborohydride (90 mg, 0.42 mmol) and acetic acid (20
uL, 0.35 mmol) and the reaction mixture was stirred at ambient
temperature for 20 h. It was diluted with dichloromethane and
washed with aqueous sodiumhydrogenecarbonate (1M). The organic
layer was dried over sodium sulfate and concentrated. Purification
by chromatography (SiO.sub.2, dichloromethane:methanol=100:0 to
95:5) afforded the title compound (30 mg, 18%) as a light yellow
oil. MS m/e: 464.3 [M].sup.+.
b)
rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-cyclopropyl-carbamic
acid 4-fluoro-phenyl ester
[0271] In analogy to the procedure described for the synthesis of
example 1 (step h), the title compound
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 was prepared from
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-cyclopropylamino-pyrrolidin-1-yl]--
[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
instead of
rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbo-
nyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
4-fluorophenyl chloroformate and was obtained as a colorless foam.
MS m/e: 602.3 [M].sup.+.
Example 5
{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pipe-
ridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00018##
[0272] Example 6
[0273]
{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00019##
[0274]
rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecar-
bonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester was subjected to column chromatography on
chiral phase to yield
{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester (MS (m/e): 590.3 [M].sup.+) as a colorless
foam
{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester (MS (m/e): 590.3 [M].sup.+) as a colorless
foam.
Example 7
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-ca-
rbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00020##
[0275] a)
rac-(3R,4S)-1-benzyl-3-(4-chloro-phenyl)-4-nitro-pyrrolidine
##STR00021##
[0277] In analogy to the procedure described for the synthesis of
rac-(3R,4S)-1-Benzyl-3-(3,4-dichloro-phenyl)-4-nitro-pyrrolidine
(example 1, step a) the title compound was prepared from
(E)-1-chloro-4-(2-nitrovinyl)benzene and
N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine as
light yellow viscous oil. MS m/e: 317.1 [M+H].sup.+.
b)
rac-(3S,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylamine
##STR00022##
[0279] In anaolgy to the procedure descrive for the synthesis of
rac-(3S,4R)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine
(example 1, step b) the title compound was prepared from
rac-(3R,4S)-1-benzyl-3-(4-chloro-phenyl)-4-nitro-pyrrolidine
through reduction with SnCl.sub.2 as brown oil. MS m/e: 287.1
[M+H].sup.+.
c)
rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbam-
ic acid 4-fluoro-her
##STR00023##
[0281] A mixture of 2.14 g (7.09 mmol)
rac-(3S,4R)-1-benzyl-4-(4-chlorophenyl)-pyrrolidin-3-amine, 540 uL
(9.5 mmol) acetaldehyde, 609 uL (10.6 mmol) acetic acid and 2.25 g
(10.6 mmol) sodium triacetoxyborohydride was stirred at 20.degree.
C. over night. Water and Na.sub.2CO.sub.3 aq. was added and the
mixture was extracted with ethyl acetate. The combined organic
layers were dried with Na.sub.2SO.sub.4 and evaporated to dryness.
the residue was taken up in 60 mL DCM. 1.15 g DIPEA (8.86 mmol) and
43.3 mg DMAP (354 .mu.mol) was added. The brownish solution was
cooled with an ice-bath. A solution of 1.48 g (8.51 mmol)
4-fluorophenyl chloroformate in 15 mL DCM was added drop-wise and
the mixture was stirred at 0-5.degree. C. for 1 h. Na.sub.2CO.sub.3
aq. was added and the mixture was extracted with DCM. The combined
organic layers were washed with brine, dried with Na.sub.2SO.sub.4
and evaporated to dryness. The residue was purified by flash column
chromatography on silica eluting with a gradient formed from TBDME
and heptane to yield after evaporation of the product containing
fractions 1.62 g (50%) of the title compound as yellow oil. MS m/e:
453.3 [M+H].sup.+.
d)
rac-4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)--
amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester
##STR00024##
[0283] A mixture of 1.62 g (3.58 mmol) rac-4-fluorophenyl
(3S,4R)-1-benzyl-4-(4-chlorophenyl)pyrrolidin-3-yl(ethyl)carbamate
and 624 mg (4.83 mmol) DIPEA in 25 mL toluene was cooled to
0-5.degree. C. 690 mg (4.83 mmol) 1-chloroethyl chloroformate was
added and the mixture was stirred over night at ambient temperature
and evaported to dryness. The residue was dried under high vacuum
at 60-70.degree. C. to yield
rac-[(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester. The residue was dissolved in 25 mL
methanol, stirred for 90 min and evaporated to dryness. The residue
was taken up in 25 mL DMF and 2.5 g (19.3 mmol) DIPEA was added. A
solution of 738 mg (3.22 mmol)
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid and 1.35 g
(3.54 mmol) HATU in 25 mL DMF was added and the mixture was stirred
for 30 min at room temperature and evaporated under high vacuum.
The residue was dissolved in ethyl acetate and washed with 10%
aq.Na.sub.2CO.sub.3 and brine. The aqueous layers were extracted
with ethyl acetate and the combined organic layers were dried over
Na.sub.2SO.sub.4, filtered off and concentrated under vacuum. The
residue was purified by column chromatography over silica eluting
with a gradient formed from ethyl acetate and heptane to yield
after evaporation of the product containing fractions 1.8 g (97%)
of the title compound as light brown foam. MS m/e: 574.2
[M+H].sup.+.
e)
4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-amin-
o]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl
ester
##STR00025##
[0285]
rac-4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbon-
yl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester was subjected to separation by chiral HPLC eluting
with i-propanol/heptane. After evaporation of the product
containing fractions the title compound was obtained as yellow
viscous oil. MS m/e: 474.3 [M-Boc].sup.+. And
4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-amino]--
pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl
ester
##STR00026##
[0287]
rac-4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbon-
yl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester was subjected to separation by chiral HPLC eluting
with i-propanol/heptane. After evaporation of the product
containing fractions the title compound was obtained as yellow
viscous oil. MS m/e: 474.3 [M-Boc].sup.+.
f)
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-
-ethyl-carbamic acid 4-fluoro-phenyl ester
##STR00027##
[0289] A mixture of 804 mg (1.4 mmol)
4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-amino]-
-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl
ester and 1.6 g (14 mmol) TFA in 25 mL DCM was stirred for 5 h at
room temperature. Water and 2N NaOH aq. was added and the mixture
was extracted with DCM. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered off and evaporated to yield 577 mg (87%)
of the title compound as yellow foam. MS m/e: 474.3
[M+H].sup.+.
g)
{(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
[0290] A mixture of 94.7 mg (0.2 mmol)
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester, 83.7 mg (0.3 mmol)
2-chloropyrimidine-5-carbonitrile and 129 mg (1 mmol) DIPEA in 2.5
mL DMF was shaken a for 22 h at 65.degree. C. The mixture was
subjected to preparative HPLC purification on reversed phase
eluting with a gradient formed from acetonitrile, water and
NEt.sub.3. The product containing fraction were evaporated to
access 58 mg (51%) of the title compound as off-white solid. MS
m/e: 577.3 [M+H].sup.+.
Example 8
[(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
##STR00028##
[0292] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
1-(6-bromopyridin-3-yl)ethanone as off-white solid. MS m/e: 593.4
[M+H].sup.+.
Example 9
[(3R,4S)-4-(4-Chloro-phenyl)-1-(4'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyr-
idinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00029##
[0294] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
2-bromoisonicotinonitrile as off-white solid. MS m/e: 576.3
[M+H].sup.+.
Example 10
[(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
##STR00030##
[0296] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
2-bromo-5-(methylsulfonyl)pyridine as off-white solid. MS m/e:
629.3 [M+H].sup.+.
Example 11
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperidine-4-carb-
onyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00031##
[0298] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
5-bromopyrazine-2-carbonitrile as off-white solid. MS m/e: 577.3
[M+H].sup.+.
Example 12
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperidine-4-ca-
rbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00032##
[0300] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
6-chloropyridazine-3-carbonitrile as off-white solid. MS m/e: 577.3
[M+H].sup.+.
Example 13
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-ca-
rbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00033##
[0301] a)
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester
##STR00034##
[0303] In analogy to the procedure described for the synthesis of
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester the title compound was
prepared from
4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-a-
mino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester through cleavage of the protecting group with TFA.
The title compound was obtained as yellow foam. MS m/e: 474.3
[M+H].sup.+.
b)
{(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
[0304] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from)
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
6-chloropyridazine-3-carbonitrile as off-white solid. MS m/e: 577.3
[M+H].sup.+.
Example 14
[(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
##STR00035##
[0306] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from)
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
1-(6-bromopyridin-3-yl)ethanone as off-white solid. MS m/e: 593.4
[M+H].sup.+.
Example 15
[(3S,4R)-4-(4-Chloro-phenyl)-1-(4'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyr-
idinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00036##
[0308] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from)
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
2-bromoisonicotinonitrile as off-white solid. MS m/e: 576.3
[M+H].sup.+.
Example 16
[(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
##STR00037##
[0310] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from)
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
2-bromo-5-(methylsulfonyl)pyridine as off-white solid. MS m/e:
629.3 [M+H].sup.+.
Example 17
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperidine-4-carb-
onyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00038##
[0312] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from)
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
5-bromopyrazine-2-carbonitrile as off-white solid. MS m/e: 577.3
[M+H].sup.+.
Example 18
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperidine-4-ca-
rbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00039##
[0314] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
6-chloropyridazine-3-carbonitrile as off-white solid. MS m/e: 577.3
[M+H].sup.+.
Example 19
[(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
##STR00040##
[0315] and
Example 20
[(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
##STR00041##
[0316] a)
rac-[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-trifluoromethyl-3,4,5,6-t-
etrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester
[0317] A mixture of 125 mg (0.456 mmol)
rac-[(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester, 198 mg (0.547 mmol)
1-(5-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxylic acid,
208 mg (0.547 mmol) HATU and 353 mg (2.73 mmol) DIPEA in 10 mL DMF
and stirred for 1 h ar room temperature. The mixture was
concentrated and DMF and DIPEA was added and subjected to
purification by preparative HPLC on reversed phase eluting with a
gradient formed from acetonitrile, water and NEt.sub.3. The product
containing fractions were evaporated to yield 187 mg (66%) of the
title compound as light brown viscous oil. MS m/e: 619.4
[M+H].sup.+.
[0318] The racemic material was subjected to separation on
CHIRALPAK AD eluting with i-propanol/heptane.
[(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 was obtained as light yellow solid. MS m/e:
619.4 [M+H].sup.+ and
[(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 was obtained as light yellow solid. MS m/e:
619.4 [M+H].sup.+
Example 21
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyr-
idinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00042##
[0320] In analogy to the procedure described for the synthesis of
[(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 the title compound was prepared from
rac-[(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(5-cyanopyridin-2-yl)piperidine-4-carboxylic acid with subsequent
separation via chiral chromatography on Chiralpak AD as off-white
solid. MS m/e: 576.3 [M+H].sup.+
Example 22
[(3R,4S)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyr-
idinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00043##
[0322] In analogy to the procedure described for the synthesis of
[(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 the title compound was prepared from
rac-[(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(5-cyanopyridin-2-yl)piperidine-4-carboxylic acid with subsequent
separation via chiral chromatography on Chiralpak AD as off-white
solid. MS m/e: 576.3 [M+H].sup.+
Example 23
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyr-
idinyl-4-carbonyl)-pyrrolidin-3-yl]-isopropyl-carbamic acid
4-fluoro-phenyl ester
##STR00044##
[0323] a)
rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-isopr-
opyl-carbamic acid 4-fluoro-phenyl ester
##STR00045##
[0325] A mixture of 3.1 g (10.8 mmol)
rac-(3S,4R)-1-benzyl-4-(4-chlorophenyl)pyrrolidin-3-amine, 785 mg
(13.5 mmol) acetone, 974 mg (16.2 mmol) acetic acid and 3.44 g
(16.2 mmol) sodium triacteoxyborohydride in 50 mL THF was stirred
for 4 h at room temperature. Water and Na.sub.2CO.sub.3 aq. was
added and the mixture was extracted with ethyl acetate. The organic
layer was washed with brine, dried with Na.sub.2SO.sub.4, filtered
off and evaporated to dryness. The residue was dissolved in 50 mL
DCM and 1.75 g (13.5 mmol) DIPEA and 13.2 mg (0.1 mmol) DMAP was
added. The mixture was cooled to 0-5.degree. C. and 2.08 g (11.9
mmol) 4-fluorophenyl chloroformate in 20 mL DCM was added. The
mixture was stirred at room temperature over night and evaporated
to dryness. The residue was purified by flash column chromatography
on silica eluting with a gradient formed from TBME and heptane. The
product containing fractions were evaporated to yield 3.1 g (61%)
of the title compound as light yellow viscous oil. MS m/e: 467.2
[M+H].sup.+
b)
4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-isopropyl--
amino]-pyrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester
##STR00046##
[0326] and
4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-isopropyl-ami-
no]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl
ester
##STR00047##
[0328] In analogy to the procedure described for the synthesis of
rac-4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-am-
ino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester the title compounds were prepared from
rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-isopropyl-carb-
amic acid 4-fluoro-phenyl ester by cleavage of the benzyl group and
subsequent coupling with
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. The resulting
rac-4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-isopropy-
l-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester was subjected to separation by chiral HPLC on
CHIRALPAK AD eluting with i-propanol/heptane. After evaporation of
the product containing fractions
4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-is-
opropyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester was obtained as yellow viscous oil. MS m/e: 588.3
[M+H].sup.+.
4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-isopropyl-am-
ino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester was obtained as yellow viscous oil. MS m/e: 588.3
[M+H].sup.+.
c)
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-
-isopropyl-carbamic acid 4-fluoro-phenyl ester
##STR00048##
[0330] In analogy to the procedure described for the synthesis of
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester the title compound was
prepared from
4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-isoprop-
yl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester through cleavage of the protecting group with TFA.
The title compound was obtained as off-white foam. MS m/e: 488.3
[M+H].sup.+.
d)
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bi-
pyridinyl-4-carbonyl)-pyrrolidin-3-yl]-isopropyl-carbamic acid
4-fluoro-phenyl ester
[0331] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-i-
sopropyl-carbamic acid 4-fluoro-phenyl ester and
6-bromonicotinonitrile as off-white solid. MS m/e: 590.4
[M+H].sup.+.
Example 24
[(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
##STR00049##
[0333] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-i-
sopropyl-carbamic acid 4-fluoro-phenyl ester and
1-(6-bromopyridin-3-yl)ethanone as off-white solid. MS m/e: 607.3
[M+H].sup.+.
Example 25
[(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
##STR00050##
[0335] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-i-
sopropyl-carbamic acid 4-fluoro-phenyl ester and
2-bromo-5-(trifluoromethyl)pyridine as off-white solid. MS m/e:
633.4 [M+H].sup.+.
Example 26
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperidine-4-ca-
rbonyl]-pyrrolidin-3-yl}-isopropyl-carbamic acid 4-fluoro-phenyl
ester
##STR00051##
[0337] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-i-
sopropyl-carbamic acid 4-fluoro-phenyl ester and
6-chloropyridazine-3-carbonitrile as light brown solid. MS m/e:
591.3 [M+H].sup.+.
Example 27
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperidine-4-carb-
onyl]-pyrrolidin-3-yl}-isopropyl-carbamic acid 4-fluoro-phenyl
ester
##STR00052##
[0339] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-i-
sopropyl-carbamic acid 4-fluoro-phenyl ester and
5-chloropyrazine-2-carbonitrile as light brown solid. MS m/e: 591.3
[M+H].sup.+.
Example 28
[(3R,4S)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyr-
idinyl-4-carbonyl)-pyrrolidin-3-yl]-isopropyl-carbamic acid
4-fluoro-phenyl ester
##STR00053##
[0340] a)
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-isopropyl-carbamic acid 4-fluoro-phenyl ester
##STR00054##
[0342] In analogy to the procedure described for the synthesis of
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester the title compound was
prepared from
4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-isoprop-
yl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester through cleavage of the protecting group with TFA.
The title compound was obtained as off-white foam. MS m/e: 488.3
[M+H].sup.+.
b)
[(3R,4S)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bi-
pyridinyl-4-carbonyl)-pyrrolidin-3-yl]-isopropyl-carbamic acid
4-fluoro-phenyl ester
[0343] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-i-
sopropyl-carbamic acid 4-fluoro-phenyl ester and
6-bromonicotinonitrile as off-white solid. MS m/e: 590.2
[M+H].sup.+.
Example 29
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyr-
idinyl-4-carbonyl)-pyrrolidin-3-yl]-cyclopropyl-carbamic acid
4-fluoro-phenyl ester
##STR00055##
[0344] a)
rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-cyclo-
propyl-amine
##STR00056##
[0346] A mixture of 3.75 g (13.1 mmol)
rac-(3S,4R)-1-benzyl-4-(4-chlorophenyl)pyrrolidin-3-amine, 3.14 g
(52 mmol) acetic acid and 2.62 g (15 mmol) (1-ethoxycyclopropoxy)
trimethylsilane in 15 mL methanol was stirred 1 h at room
temperature and 3 h at reflux and evaporated to dryness. The
residue was taken up in 35 mL THF and added to a mixture formed
from 989 mg (26 mmol) sodium borohydride in 15 mL THF which was
treated at 0-5.degree. C. with 3.7 g (26 mmol) boron trifluoride
etherate and stirred 1 h. The mixture was stirred at room
temperature over night, water and 4N NaOH aq. was added and
extracted with ethyl acetate. The organic layer were washed with
brine, dried with Na.sub.2SO.sub.4, filtered off and evaporated to
dryness. The residue was purified with flash column chromatography
on silica eluting with a gradient formed from DCM, methanol and
NEt.sub.3. The product containing fractions were evaporated to
yield 2.27 g (53%) of the title compound as light brown oil. MS
m/e: 327.1 [M+H].sup.+.
b)
rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-cyclopropyl--
carbamic acid 4-fluoro-phenyl ester
##STR00057##
[0348] A mixture of 2.27 g (6.94 mmol)
rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-cyclopropyl-am-
ine, 987 mg (7.64 mmol) DIPEA, 8.48 mg (0.07 mmol) DMAP and 1.27 g
(7.29 mmol) 4-fluorophenyl chloroformate in 40 mL DCM at 0.degree.
C. was stirred at room temperature over night and evaporated to
dryness. the residue was purified by column chromatography on
silica eluting with a gradient formed from TBME and heptane. The
product containing fractions were evaporated to yield 1.64 g (51%)
of the title compound as colorless viscous oil. MS m/e: 465.1
[M+H].sup.+.
c)
4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbonyl-
)-amino]-pyrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester
##STR00058##
[0349] and
4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbonyl)-a-
mino]-pyrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester
##STR00059##
[0351] In analogy to the procedure described for the synthesis of
rac-4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-am-
ino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester the title compounds were prepared from
rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-cyclopropyl-ca-
rbamic acid 4-fluoro-phenyl ester by cleavage of the benzyl group
and subsequent coupling with
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. The resulting
rac-4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbon-
yl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester was subjected to separation by chiral HPLC on
CHIRALPAK AD eluting with i-propanol/heptane. After evaporation of
the product containing fractions
4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxy-
carbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic
acid tert-butyl ester was obtained as light brown foam. MS m/e:
586.3 [M+H].sup.+.
4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbonyl)--
amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester was obtained as yellow viscous oil. MS m/e: 586.3
[M+H].sup.+.
d)
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-
-cyclopropyl-carbamic acid 4-fluoro-phenyl ester
##STR00060##
[0353] In analogy to the procedure described for the synthesis of
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester the title compound was
prepared from
4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbo-
nyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester through cleavage of the protecting group with TFA.
The title compound was obtained as light yellow foam. MS m/e: 486.4
[M+H].sup.+.
e)
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bi-
pyridinyl-4-carbonyl)-pyrrolidin-3-yl]-cyclopropyl-carbamic acid
4-fluoro-phenyl ester
[0354] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-c-
yclopropyl-carbamic acid 4-fluoro-phenyl ester and
6-bromonicotinonitrile as off-white solid. MS m/e: 588.2
[M+H].sup.+.
Example 30
[(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
##STR00061##
[0356] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-c-
yclopropyl-carbamic acid 4-fluoro-phenyl ester and
1-(6-bromopyridin-3-yl)ethanone as off-white solid. MS m/e: 605.3
[M+H].sup.+.
Example 31
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[-
1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-cyclopropyl-carbamic
acid 4-fluoro-phenyl ester
##STR00062##
[0358] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-c-
yclopropyl-carbamic acid 4-fluoro-phenyl ester and
2-bromo-5-(trifluoromethyl)pyridine as off-white solid. MS m/e:
631.4 [M+H].sup.+.
Example 32
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperidine-4-ca-
rbonyl]-pyrrolidin-3-yl}-cyclopropyl-carbamic acid 4-fluoro-phenyl
ester
##STR00063##
[0360] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-c-
yclopropyl-carbamic acid 4-fluoro-phenyl ester and
6-chloropyridazine-3-carbonitrile as off-white solid. MS m/e: 589.3
[M+H].sup.+.
Example 33
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperidine-4-carb-
onyl]-pyrrolidin-3-yl}-cyclopropyl-carbamic acid 4-fluoro-phenyl
ester
##STR00064##
[0362] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-c-
yclopropyl-carbamic acid 4-fluoro-phenyl ester and
5-chloropyrazine-2-carbonitrile as pink solid. MS m/e: 589.3
[M+H].sup.+.
Example 34
[(3R,4S)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyr-
idinyl-4-carbonyl)-pyrrolidin-3-yl]-cyclopropyl-carbamic acid
4-fluoro-phenyl ester
##STR00065##
[0363] a)
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-cyclopropyl-carbamic acid 4-fluoro-phenyl ester
##STR00066##
[0365] In analogy to the procedure described for the synthesis of
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester the title compound was
prepared from
4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbo-
nyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester through cleavage of the protecting group with TFA.
The title compound was obtained as light yellow foam. MS m/e: 486.4
[M+H].sup.+.
b)
[(3R,4S)-4-(4-Chloro-phenyl)-1-(5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bi-
pyridinyl-4-carbonyl)-pyrrolidin-3-yl]-cyclopropyl-carbamic acid
4-fluoro-phenyl ester
[0366] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
the title compound was prepared from
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-c-
yclopropyl-carbamic acid 4-fluoro-phenyl ester and
6-bromonicotinonitrile as off-white solid. MS m/e: 588.2
[M+H].sup.+.
Example 35
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-4-
-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00067##
[0367] a)
rac-(3S,4R)-1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylamine
##STR00068##
[0369] In analogy to the procedure described for the synthsis of
rac-(3S,4R)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine
(example 1, step a & b) the title compound was prepared from
N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine
and 1-Fluoro-4-((E)-2-nitro-vinyl)-benzene subsequently reducing
the NO.sub.2-function with tin chloride. MS m/e: 271.4
[M+H].sup.+.
b)
rac-[(3S,4R)-1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-amine
##STR00069##
[0371] A mixture of 38 g (141 mmol)
rac-(3S,4R)-1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylamine, 7.12
g (162 mmol) acetaldehyde, 12.1 mL acetic acid and 44.7 g (211
mmol) sodium triacetoxyborohydride in 400 mL THF was stirred for 3
h at 0.degree. C. and then warmed to room temperature. Water,
Na.sub.2CO.sub.3 aq. and ethyl acetate was added. The organic layer
was washed with brine, dried with Na.sub.2SO.sub.4, filtered and
evaporated to dryness. The residue was purified by column
chromatograpghy on silica eluting with a gradient formed from ethyl
acetate, heptane and NEt.sub.3. The product containing fractions
were evaporated to yield 18.5 g (44%) of the title compound as
brown oil. MS m/e: 299.4 [M+H].sup.+.
c)
rac-[(3S,4R)-1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbam-
ic acid 4-fluoro-phenyl ester
##STR00070##
[0373] In anolgy to the procedure described for the synthesis 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 (example 1, step h) the title compound was
prepared from
rac-[(3S,4R)-1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-ami-
ne and 4-fluorophenyl chloroformate as light brown viscous oil. MS
m/e: 437.3 [M+H].sup.+.
d)
[(3S,4R)-1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00071##
[0375]
rac-[(3S,4R)-1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-ca-
rbamic acid 4-fluoro-phenyl ester was subjected to separation by
column chromatography on Chiralpak AD eluting with hexane and
i-propanol. The product containing fractions were evaporated to
yield the title compound as light brown viscous oil. MS m/e: 437.3
[M+H].sup.+.
and
[(3R,4S)-1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00072##
[0377]
rac-[(3S,4R)-1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-ca-
rbamic acid 4-fluoro-phenyl ester was subjected to separation by
column chromatography on Chiralpak AD eluting with hexane and
i-propanol. The product containing fractions were evaporated to
yield the title compound as light brown viscous oil. MS m/e: 437.3
[M+H].sup.+.
e) Ethyl-[(3S,4R)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic
acid 4-fluoro-phenyl ester
##STR00073##
[0379] In analogy to the procedure described for the synthesis of
rac-(3S,4R)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-carbamic acid
tert-butyl ester (example 1, step d) the title compound was
prepared from
[(3S,4R)-1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester through cleavage of the benzyl
protecting group as brown foam. MS m/e: 347.1 [M+H].sup.+.
f)
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl-
)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
[0380] A mixture of 125 mg (0.36 mmol)
ethyl-[(3S,4R)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid
4-fluoro-phenyl ester, 137 mg (0.36 mmol) HATU, 63 uL (0.36 mmol)
DIPEA and 69.4 mg (0.3 mmol)
5'-cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid
in 4 mL DMF was shaken for 2 h at room temperature. The mixture was
subjected to purification by preparative HPLC on reversed phase
eluting with a gradient formed from acetonitrile, water and
NEt.sub.3. The product containing fractions were evaporated to
yield 106 mg (63%) of the title compound as off-white solid. MS
m/e: 560.2 [M+H].sup.+.
Example 36
[(3S,4R)-1-(5'-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00074##
[0382] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35) the title compound was prepared
from ethyl-[(3S,4R)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic
acid 4-fluoro-phenyl ester and
1-(5-chloropyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 569.3
[M+H].sup.+.
Example 37
Ethyl-[(3S,4R)-4-(4-fluoro-phenyl)-1-(5'-methanesulfonyl-3,4,5,6-tetrahydr-
o-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-carbamic acid
4-fluoro-phenyl ester
##STR00075##
[0383] a)
4-[(3S,4R)-3-[Ethyl-(4-fluoro-phenoxycarbonyl)-amino]-4-(4-fluor-
o-phenyl)-pyrrolidine-1-carbonyl]-piperidine-1-carboxylic acid
tert-butyl ester
##STR00076##
[0385] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35) the title compound was prepared
from ethyl-[(3S,4R)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic
acid 4-fluoro-phenyl ester and
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. MS m/e: 558.4
[M+H].sup.+.
b)
Ethyl-[(3S,4R)-4-(4-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-
-3-yl]-carbamic acid 4-fluoro-phenyl ester
##STR00077##
[0387] In analogy to the procedure described for the synthesis of
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester (example 7, step f) the
title compound was prepared from
4-[(3S,4R)-3-[Ethyl-(4-fluoro-phenoxycarbonyl)-amino]-4-(4-fluoro-phenyl)-
-pyrrolidine-1-carbonyl]-piperidine-1-carboxylic acid tert-butyl
ester through cleavage of the Boc-group with TFA. MS m/e: 458.4
[M+H].sup.+.
c)
Ethyl-[(3S,4R)-4-(4-fluoro-phenyl)-1-(5'-methanesulfonyl-3,4,5,6-tetrah-
ydro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-carbamic
acid 4-fluoro-phenyl ester
[0388] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
(example 7, step g) the title compound was prepared from
ethyl-[(3S,4R)-4-(4-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-
-yl]-carbamic acid 4-fluoro-phenyl ester and
2-bromo-5-(methylsulfonyl)pyridine. MS m/e: 613.2 [M+H].sup.+.
Example 38
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00078##
[0390] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
(example 7, step g) the title compound was prepared from
ethyl-[(3S,4R)-4-(4-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-
-yl]-carbamic acid 4-fluoro-phenyl ester and
1-(6-bromopyridin-3-yl)ethanone. MS m/e: 577.3 [M+H].sup.+.
Example 39
4-{(3R,4S)-3-(4-Chloro-3-fluoro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl-
)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester
##STR00079##
[0391] a) (4-Chloro-3-fluoro-phenyl)-propynoic acid ethyl ester
##STR00080##
[0393] To a mixture of 4-chloro-3-fluoroiodobenzene (74.27 g, 284
mmol) and cesium carbonate (185.0 g, 568 mmol) in tetrahydrofuran
(730 mL) was added under an argon atmosphere cuprous iodide (2.16
g, 11.4 mmol) and bis(triphenylphosphine)palladium (II) chloride
(3.98 g, 5.7 mmol). Ethyl propiolate (57.0 g, 575 mmol) was added
dropwise over a period of 20 min. The resulting dark brown
suspension was stirred for 38 h at 35.degree. C., then filtrated
over Hyflo.RTM. and the residue was washed with tetrahydrofuran
(285 ml). The filtrate was evaporated and purification of the
residue by chromatography (SiO.sub.2, heptane: ethyl acetate=90:10)
afforded the title compound (57.1 g, 89%) as a yellow liquid. MS
m/e: 226.0 [M].sup.+.
b)
1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxyl-
ic acid
##STR00081##
[0395] To a solution of (4-chloro-3-fluoro-phenyl)-propynoic acid
ethyl ester (57.08 g, 252 mmol) in dichloromethane (240 mL) was
added trifluoroacetic acid (1.9 mL, 25.2 mmol). The reaction
mixture was cooled with a water bath at ambient temperature and a
solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine
(93.43 g, 378 mmol) in dichloromethane (185 mL) was added dropwise
over a period of 3 h. After stirring for 20 h at ambient
temperature further
N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (15.6 g, 63.0
mmol) in dichloromethane (30 mL) was added and stirring was
continued for another 4 h. The solvent was removed and the residue
was dissolved in dioxane (540 mL). After addition of water (270 mL)
and aqueous sodium hydroxide (32%, 64.8 ml, 700 mmol), it was
stirred for 44 h at ambient temperature. After concentration the
resulting residue was diluted with water (225 mL) and extracted
with tert-butylmethylether (225 mL). The organic layer was washed
with water (225 mL) and the aqueous layer was cooled to 5.degree.
C. and set to pH=1.5 with aqueous hydrogen chloride (25%, 112 mL).
After stirring for 1 h at 5.degree. C., the resulting solid was
filtered and washed with water (795 mL) and ethanol (225 mL).
Drying gave a light yellow solid which was stirred with ethanol (4
L) for 1 h at 85.degree. C. The resulting suspension was filtered
and the filtrate was concentrated. Trituration with
tert-butylmethylether (2 L) afforded the title compound (62.34 g,
67%) as an off-white solid. MS m/e: 330.1 [M-H].sup.-.
c)
(3R,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidine-3-carboxylic
acid
##STR00082##
[0397] An autoclave was charged under argon in a glove box (O.sub.2
content <2 ppm) with
1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic
acid (1.00 g, 3.01 mmol), [Ru(OAc).sub.2((S)-2-furyl-MeOBIPHEP)]
(9.18 mg, 0.012 mmol)
(2-furyl-MeOBIPHEP=(6,6'-dimethoxybiphenyl-2,2'-diyl)bis(di-2-furylphosph-
ine) and methanol (30 mL). The asymmetric hydrogenation was run for
20 h at 30.degree. C. under 40 bar of hydrogen. After the pressure
was released, the grey suspension was evaporated to dryness to
yield the crude title compound. MS m/e: 332.1 [M-H].
d)
(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidine-3-carboxylic
acid
##STR00083##
[0399] A mixture of 48.8 g (146 mmol)
(3R,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidine-3-carboxylic
acid and 15.6 mL sulfuric acid in 400 mL methanol was heated to
reflux for 21 h and evaporated. the residue was diluted with
ice-water and extracted with ethyl acetate. the combined organic
layers were washed with brine, dried with Na.sub.2SO.sub.4,
filtered and evaporated to dryness. The residue was purified by
column chromatography on silica eluting with ethyl acetate and
heptane. The intermediate was dissolved in 500 mL methanol and 4.06
mL sodium methoxide (5.4N in methanol) was added and stirred at
room temperature overnight. Another 31.3 ml, sodium methoxide (5.4N
in methanol) was added and stirred for 1 h at room temperature.
Water was added and the mixture was stirred for 2 h at room
temperature. After evaporation of methanol, water was added and th
pH was adjusted to 6-7 with acetic acid. The product precipitated
and the mixture was decanted. The organic layer from the extraction
with THF and ethyl acetate was washed with brine, dried with
Na.sub.2SO.sub.4, filtered and evaporated to dryness. The residue
was washed with hexane and diethyl ether and filtered to yield
after drying 44 g (49%) of the title compound as colorless solid.
MS m/e: 334.3 [M+H].sup.+.
e)
[(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-carbami-
c acid tert-butyl ester
##STR00084##
[0401] A mixture of 44 g (132 mmol)
(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidine-3-carboxylic
acid, 25.3 mL (145 mmol) DIPEA and 45.3 g (165 mmol)
diphenylphosphoryl azide in 600 mL tert.-butanol was heated to
reflux for 16 h. After cooling to room temperature the mixture was
evaporated to dryness. The residue was adsorbed on isolute HM-N and
purified by column chromatography on silica eluting with a gradient
formed from heptane and ethyl acetate. The product containing
fraction were evaporated to yield 25 g (47%) of the title compound
as light brown solid. MS m/e: 405.4 [M+H].sup.+.
f)
(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-ylamine
##STR00085##
[0403] In analogy to the procedure described for the synthesis of
rac-(3S,4R)-[3-Amino-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methy-
l-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (example 1, step
f) the title compound was prepared from
[(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic
acid tert-butyl ester through cleavage of the Boc-group with TFA.
MS m/e: 305.2 [M+H].sup.+.
g)
[(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-c-
arbamic acid 4-fluoro-phenyl ester
##STR00086##
[0405] In analogy to the procedure described for the synthesis 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 (example 1, step g & h) the title
compound was prepared from
(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-ylamine
through reductive amination with acetaldehyde followed by reaction
with 4-fluorophenyl chloroformate to yield the title compound as
light brown oil. MS m/e: 471.2 [M+H].sup.+.
h)
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00087##
[0407] In analogy to the procedure described for the synthesis of
rac-(3S,4R)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-carbamic acid
tert-butyl ester (example 1, step d) the title compound was
prepared from
[(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-car-
bamic acid 4-fluoro-phenyl ester through cleavage of the
benzyl-group as brown foam which was used in the consecutive step
without further purification. MS m/e: 381.3 [M+H].sup.+.
i)
4-{(3R,4S)-3-(4-Chloro-3-fluoro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbo-
nyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester
[0408] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35) the title compound was prepared
from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. MS m/e: 592.4
[M+H].sup.+.
Example 40
[(3S,4R)-4-(4-Chloro-3-fluoro-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
##STR00088##
[0409] a)
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)--
pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester
##STR00089##
[0411] In analogy to the procedure described for the synthesis of
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester (example 7, step f) the
title compound was prepared from
4-{(3R,4S)-3-(4-Chloro-3-fluoro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbony-
l)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester through cleavage of the Boc-group with TFA. MS
m/e: 492.2 [M+H].sup.+.
b)
[(3S,4R)-4-(4-Chloro-3-fluoro-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
[0412] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
(example 7, step g) the title compound was prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
1-(5-cyanopyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 594.3
[M+H].sup.+.
Example 41
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(5'-chloro-3,4,5,6-tetrahydro-2H-[-
1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00090##
[0414] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
1-(5-chloropyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 603.2
[M+H].sup.+.
Example 42
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(5'-trifluoromethyl-3,4,5,6-tetrah-
ydro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00091##
[0416] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
1-(5-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxylic acid. MS
m/e: 637.3 [M+H].sup.+.
Example 43
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(6'-cyano-3,4,5,6-tetrahydro-2H-[1-
,3']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00092##
[0418] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
1-(5-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxylic acid. MS
m/e: 594.3 [M+H].sup.+.
Example 44
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00093##
[0420] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
1-(1-methylcyclopropanecarbonyl)piperidine-4-carboxylic acid. MS
m/e: 574.5 [M+H].sup.+.
Example 45
[(3S,4R)-4-(4-Chloro-3-fluoro-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
##STR00094##
[0422] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
1-(4-cyanopyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 594.3
[M+H].sup.+.
Example 46
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H-[-
1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00095##
[0424] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
1-(5-fluoropyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 587.2
[M+H].sup.+.
Example 47
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(5'-methyl-3,4,5,6-tetrahydro-2H-[-
1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00096##
[0426] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
1-(5-methylpyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 583.2
[M+H].sup.+.
Example 48
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-4-
-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00097##
[0427] a) (3,4-Difluoro-phenyl)-propynoic acid ethyl ester
##STR00098##
[0429] In analogy to the procedure described for the synthesis of
(4-Chloro-3-fluoro-phenyl)-propyonic acid ethyl ester (example 39,
step a) the title compound was prepared from
3,4-difluoroiodobenzene and ethyl propionate as yellow liquid. MS
m/e: 210 [M+H].sup.+.
b)
1-Benzyl-4-(3,4-difluoro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic
acid
##STR00099##
[0431] In analogy to the procedure described for the synthesis of
1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic
acid (example 39, step b) the title compound was prepared from
(3,4-Difluoro-phenyl)-propynoic acid ethyl ester and
N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine. MS m/e:
314.1 [M-H].sup.-.
c)
(3R,4R)-1-Benzyl-4-(3,4-difluoro-phenyl)-pyrrolidine-3-carboxylic
acid
##STR00100##
[0433] In analogy to the procedure described for the synthesis of
(3R,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidine-3-carboxylic
acid (example 39, step c) the title compound was prepared from
1-Benzyl-4-(3,4-difluoro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic
acid through asymmetric hydrogenation.
d)
(3S,4R)-1-Benzyl-4-(3,4-difluoro-phenyl)-pyrrolidine-3-carboxylic
acid
##STR00101##
[0435] In analogy to the procedure described for the synthesis of
(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidine-3-carboxylic
acid (example 39, step d) the title compound was prepared from
(3R,4R)-1-Benzyl-4-(3,4-difluoro-phenyl)-pyrrolidine-3-carboxylic
acid as white solid. MS m/e: 318.1 [M+H].sup.+.
e)
[(3S,4R)-1-Benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic
acid tert-butyl ester
##STR00102##
[0437] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic
acid tert-butyl ester (example 39, step e) the title compound was
prepared from
(3S,4R)-1-Benzyl-4-(3,4-difluoro-phenyl)-pyrrolidine-3-carboxylic
acid as off-white solid. MS m/e: 389.3 [M+H].sup.+.
f)
(3S,4R)-1-Benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-ylamine
##STR00103##
[0439] In analogy to the procedure described for the synthesis of
(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-ylamine
(example 39, step f) the title compound was prepared from
[(3S,4R)-1-Benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic
acid tert-butyl ester as brown oil. MS m/e: 289.2 [M+H].sup.+.
g)
[(3S,4R)-1-Benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbam-
ic acid 4-fluoro-phenyl ester
##STR00104##
[0441] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-car-
bamic acid 4-fluoro-phenyl ester (exymple 39, step g) the title
compound was prepared from
(3S,4R)-1-Benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-ylamine as
light yellow oil. MS m/e: 455.3 [M+H].sup.+.
h) [(3S,4R)-4-(3,4-Difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00105##
[0443] In analogy to the procedure described for the synthesis of
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester (example 39, step h) the title compound
was prepared from
[(3S,4R)-1-Benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester as brown foam. MS m/e: 365.3
[M+H].sup.+.
i)
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl-
)-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
[0444] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35) the title compound was prepared
from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(5-cyanopyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 578.3
[M+H].sup.+.
Example 49
[(3S,4R)-1-(5'-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00106##
[0446] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35) the title compound was prepared
from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(5-chloropyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 587.2
[M+H].sup.+.
Example 50
[(3S,4R)-4-(3,4-Difluoro-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
##STR00107##
[0448] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(5-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxylic acid. MS
m/e: 612.4 [M+H].sup.+.
Example 51
[(3S,4R)-1-(6'-Cyano-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-4-carbonyl)-4-
-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00108##
[0450] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(6-cyanopyridin-3-yl)piperidine-4-carboxylic acid. MS m/e: 578.3
[M+H].sup.+.
Example 52
{(3S,4R)-4-(3,4-Difluoro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pipe-
ridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00109##
[0452] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(1-methylcyclopropanecarbonyl)piperidine-4-carboxylic acid. MS
m/e: 558.3 [M+H].sup.+.
Example 53
[(3S,4R)-1-(4'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-4-
-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00110##
[0454] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(4-cyanopyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 578.4
[M+H].sup.+.
Example 54
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H-[1,2']-
bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00111##
[0456] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(5-fluoropyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 571.4
[M+H].sup.+.
Example 55
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(5'-methyl-3,4,5,6-tetrahydro-2H-[1,2']-
bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00112##
[0458] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(5-methylpyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 567.4
[M+H].sup.+.
Example 56
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-
-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester
##STR00113##
[0459] a)
4-{(3R,4S)-3-(4-Chloro-3-fluoro-phenyl)-4-[ethyl-(4-fluoro-pheno-
xycarbonyl)-amino]-pyrolidine-1-carbonyl}-piperidine-1-carboxylic
acid tert-butyl ester
##STR00114##
[0461] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. MS m/e: 592.4
[M+H].sup.+.
b)
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrroli-
din-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester
[0462] In analogy to the procedure described for the synthesis of
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester (example 7, step f) the
title compound was prepared from
4-{(3R,4S)-3-(4-Chloro-3-fluoro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbony-
l)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester through cleavage of the Boc-group with TFA. MS
m/e: 492.2 [M+H].sup.+.
Example 57
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperi-
dine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00115##
[0464] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
(example 7, step g) the title compound was prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
6-chloropyridazine-3-carbonitrile in acetonitrile as off-white
solid after purification over silica. MS m/e: 595.4
[M+H].sup.+.
Example 58
[(3S,4R)-1-[1-(6-Cyano-pyridazin-3-yl)-piperidine-4-carbonyl]-4-(3,4-diflu-
oro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00116##
[0465] a)
4-{(3R,4S)-3-(3,4-Difluoro-phenyl)-4-[ethyl-(4-fluoro-phenoxycar-
bonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester
##STR00117##
[0467] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. MS m/e: 576.3
[M+H].sup.+.
b)
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-
-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester
##STR00118##
[0469] In analogy to the procedure described for the synthesis of
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester (example 7, step f) the
title compound was prepared from
4-{(3R,4S)-3-(3,4-Difluoro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-am-
ino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester through cleavage of the Boc-group with TFA. MS
m/e: 492.2 [M+H].sup.+.
c)
[(3S,4R)-1-[1-(6-Cyano-pyridazin-3-yl)-piperidine-4-carbonyl]-4-(3,4-di-
fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester
[0470] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
(example 7, step g) the title compound was prepared from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-ethyl-carbamic acid 4-fluoro-phenyl ester and
6-chloropyridazine-3-carbonitrile in acetonitrile as off-white
solid after purification over silica. MS m/e: 579.4
[M+H].sup.+.
Example 59
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00119##
[0472] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
(example 7, step g) the title compound was prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
1-(6-bromopyridin-3-yl)ethanone in acetonitrile as off-white solid
after purification over silica. MS m/e: 611.3 [M+H].sup.+.
Example 60
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00120##
[0474] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
(example 7, step g) the title compound was prepared from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-ethyl-carbamic acid 4-fluoro-phenyl ester and
1-(6-bromopyridin-3-yl)ethanone in acetonitrile as off-white solid
after purification over silica. MS m/e: 595.4 [M+H].sup.+.
Example 61
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(5-cyano-pyrazin-2-yl)-piperidi-
ne-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00121##
[0476] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
(example 7, step g) the title compound was prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
5-bromopyrazine-2-carbonitrile in acetonitrile as dark brown solid
after purification over silica. MS m/e: 595.4 [M+H].sup.+.
Example 62
[(3S,4R)-1-[1-(5-Cyano-pyrazin-2-yl)-piperidine-4-carbonyl]-4-(3,4-difluor-
o-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00122##
[0478] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
(example 7, step g) the title compound was prepared from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-ethyl-carbamic acid 4-fluoro-phenyl ester and
5-bromopyrazine-2-carbonitrile in acetonitrile as dark brown solid
after purification over silica. MS m/e: 579.4 [M+H].sup.+.
Example 63
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(5'-methanesulfonyl-3,4,5,6-tetrah-
ydro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00123##
[0480] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
(example 7, step g) the title compound was prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
2-bromo-5-(methylsulfonyl)pyridine in acetonitrile as off-white
solid after purification over silica. MS m/e: 647.4
[M+H].sup.+.
Example 64
[(3S,4R)-4-(3,4-Difluoro-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
##STR00124##
[0482] In analogy to the procedure described for the synthesis of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
(example 7, step g) the title compound was prepared from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-ethyl-carbamic acid 4-fluoro-phenyl ester and
2-bromo-5-(methylsulfonyl)pyridine in acetonitrile as dark brown
solid after purification over silica. MS m/e: 631.4
[M+H].sup.+.
Example 65
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(3-methyl-oxetane-3-carbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00125##
[0484] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
3-methyloxetane-3-carboxylic acid. MS m/e: 590.3 [M+H].sup.+.
Example 66
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(3,3-difluoro-cyclobutanecarbon-
yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00126##
[0486] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
3,3-difluorocyclobutanecarboxylic acid. MS m/e: 610.2
[M+H].sup.+.
Example 67
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(1-cyclobutanecarbonyl-piperidine--
4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00127##
[0488] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
cyclobutanecarboxylic acid. MS m/e: 574.5 [M+H].sup.+.
Example 68
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-trifluoromethyl-cyclobutanec-
arbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00128##
[0490] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
1-(trifluoromethyl)cyclobutanecarboxylic acid. MS m/e: 642.3
[M+H].sup.+.
Example 69
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(3-fluoro-cyclobutanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00129##
[0492] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
3-fluorocyclobutanecarboxylic acid. MS m/e: 592.4 [M+H].sup.+.
Example 70
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(2,2-difluoro-cyclopropanecarbo-
nyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00130##
[0494] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
2,2-difluorocyclopropanecarboxylic acid. MS m/e: 596.3
[M+H].sup.+.
Example 71
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-trifluoromethyl-cyclopropane-
carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00131##
[0496] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
1-(trifluoromethyl)cyclopropanecarboxylic acid. MS m/e: 628.4
[M+H].sup.+.
Example 72
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(1-cyano-cyclopropanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00132##
[0498] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
1-cyanocyclopropanecarboxylic acid. MS m/e: 585.3 [M+H].sup.+.
Example 73
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(2,2-dimethyl-tetrahydro-pyran--
4-carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00133##
[0500] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
2,2-dimethyltetrahydro-2H-pyran-4-carboxylic acid. MS m/e: 632.5
[M+H].sup.+.
Example 74
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(5-trifluoromethyl-pyridine-2-c-
arbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00134##
[0502] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
5-(trifluoromethyl)picolinic acid. MS m/e: 665.2 [M+H].sup.+.
Example 75
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(5-fluoro-pyridine-2-carbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00135##
[0504] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
5-fluoropicolinic acid. MS m/e: 615.2 [M+H].sup.+.
Example 76
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(4-cyano-benzoyl)-piperidine-4--
carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00136##
[0506] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
4-cyanobenzoic acid. MS m/e: 621.4 [M+H].sup.+.
Example 77
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(4-fluoro-benzoyl)-piperidine-4-
-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00137##
[0508] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
4-fluorobenzoic acid. MS m/e: 614.2 [M+H].sup.+.
Example 78
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(5-trifluoromethyl-pyrazine-2-c-
arbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00138##
[0510] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
5-(trifluoromethyl)pyrazine-2-carboxylic acid. MS m/e: 666.2
[M+H].sup.+.
Example 79
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[1-(6-cyano-pyridine-3-carbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00139##
[0512] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and
6-cyanonicotinic acid. MS m/e: 622.4 [M+H].sup.+.
Example 80
[(3S,4R)-1-(1-Acetyl-piperidine-4-carbonyl)-4-(4-chloro-3-fluoro-phenyl)-p-
yrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester
##STR00140##
[0514] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and acetic acid.
MS m/e: 534.2 [M+H].sup.+.
Example 81
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(1-methanesulfonyl-piperidine-4-ca-
rbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00141##
[0516] A mixture of 32 mg (0.065 mmol)
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester, 57 uL (0.325
mmol) DIPEA and 11.2 mg (0.097 mmol) mesyl chloride in 1.5 mL DMF
was shaken for 90 min at room temperature. The mixture was
subjected to purification by preparative HPLC on reversed phase
eluting with a gradient formed from acetonitrile, water and
NEt.sub.3. The product containing fractions were evaporated to
yield 16 mg (43%) of the title compound as off-white solid. MS m/e:
570.4 [M+H].sup.+.
Example 82
[(3S,4R)-1-(1-Acetyl-piperidine-4-carbonyl)-4-(4-chloro-phenyl)-pyrrolidin-
-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester
##STR00142##
[0517] a)
[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-car-
bamic acid 4-fluoro-phenyl ester
##STR00143##
[0519] The title compound was prepared from
rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester (example 7, c) through chiral column
chromatography on Chiralpak AD. MS m/e: 453.3 [M+H].sup.+.
b) [(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00144##
[0521] In analogy to the procedure described for the synthesis of
d) rac-(3S,4R)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-carbamic
acid tert-butyl ester (example 1, d) the title compound was
prepared from
[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester as light brown foam which was used crude
in the subsequent step. MS m/e: 363.2 [M+H].sup.+.
c)
[(3S,4R)-1-(1-Acetyl-piperidine-4-carbonyl)-4-(4-chloro-phenyl)-pyrroli-
din-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester
[0522] In analogy to the procedure described for the synthesis of
[(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 (example 20) the title compound was prepared
from [(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and 1-acetylpiperidine-4-carboxylic
acid. MS m/e: 516.2 [M+H].sup.+.
Example 83
{(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-[5'-(1-hydroxy-1-methyl-ethyl)-3,4-
,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl]-pyrrolidin-3-yl}-ethyl-ca-
rbamic acid 4-fluoro-phenyl ester
##STR00145##
[0524] A mixture of 142 mg (0.23 mmol)
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 59) and 0.097 mL (0.29 mmol)
methylmagnesium iodide (3M) in 5 mL was stirred from 0.degree. to
15.degree. C. during 90 min and quenched at 0.degree. C. with
NH.sub.4Cl (aq.). The mixture was extracted with ethyl acetate and
the combined organic layers were dried with Na.sub.2SO.sub.4 and
evaporated. The residue was subjected to preparative HPLC on
reversed phase eluting with a gradient formed from acetonitrile,
water and NEt.sub.3. The product containing fractions were
evaporated to yield 19 mg (13%) of the title compound as white
solid. MS m/e: 627.2 [M+H].sup.+.
Example 84
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-methyl-oxetane-3-carbonyl)-piperidine-
-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 2-fluoro-phenyl
ester
##STR00146##
[0525] a)
rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-
-carbamic acid 2-fluoro-phenyl ester
##STR00147##
[0527] In analogy to the procedure described for the synthesis of
rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester (example 7, c) the title compound was
prepared from
rac-(3S,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylamine
through reductive amination with acetaldehyde and subsequent
reaction with 2-fluorophenyl chloroformate as light yellow oil. MS
m/e: 453.1 [M+H].sup.+.
b)
[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 2-fluoro-phenyl ester
##STR00148##
[0529] The title compound was prepared from
rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 2-fluoro-phenyl ester through chiral column chromatography on
Chiralpak AD. MS m/e: 453.1 [M+H].sup.+.
c) [(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 2-fluoro-phenyl ester
##STR00149##
[0531] In analogy to the procedure described for the synthesis of
d) rac-(3S,4R)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-carbamic
acid tert-butyl ester (example 1, d) the title compound was
prepared from
[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 2-fluoro-phenyl ester as light brown foam which was used crude
in the subsequent step. MS m/e: 363.3 [M+H].sup.+.
d)
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-
-ethyl-carbamic acid 2-fluoro-phenyl ester
##STR00150##
[0533] In analogy to the procedure described for the synthesis of
[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester (example 7, f) the title
compound was prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
2-fluoro-phenyl ester and
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (coupling
according to example 7, d) and subsequent removal of the
Boc-protecting group (example 7, e) as light yellow foam. MS m/e:
474.2 [M+H].sup.+.
e)
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-methyl-oxetane-3-carbonyl)-piperid-
ine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
2-fluoro-phenyl ester
[0534] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 2-fluoro-phenyl ester and
1-(1-methylcyclopropanecarbonyl)piperidine-4-carboxylic acid. MS
m/e: 572.2 [M+H].sup.+.
Example 85
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-cyano-cyclopropanecarbonyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 2-fluoro-phenyl
ester
##STR00151##
[0536] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 2-fluoro-phenyl ester and
1-cyanocyclopropanecarboxylic acid. MS m/e: 567.3 [M+H].sup.+.
Example 86
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-trifluoromethyl-pyridine-2-carbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
2-fluoro-phenyl ester
##STR00152##
[0538] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 2-fluoro-phenyl ester and
5-(trifluoromethyl)picolinic acid. MS m/e: 647.7 [M+H].sup.+.
Example 87
[(3S,4R)-4-(4-Chloro-phenyl)-1-(1-cyclobutanecarbonyl-piperidine-4-carbony-
l)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester
##STR00153##
[0540] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and cyclobutanecarboxylic
acid. MS m/e: 556.2 [M+H].sup.+.
Example 88
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-methyl-oxetane-3-carbonyl)-piperidine-
-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00154##
[0542] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
3-methyloxetane-3-carboxylic acid. MS m/e: 572.2 [M+H].sup.+.
Example 89
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-fluoro-cyclobutanecarbonyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00155##
[0544] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
3-fluorocyclobutanecarboxylic acid. MS m/e: 574.2 [M+H].sup.+.
Example 90
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3,3-difluoro-cyclobutanecarbonyl)-piper-
idine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00156##
[0546] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
3,3-difluorocyclobutanecarboxylic acid. MS m/e: 592.3
[M+H].sup.+.
Example 91
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(3-methoxy-cyclobutanecarbonyl)-piperidi-
ne-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00157##
[0548] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
3-methoxycyclobutanecarboxylic acid. MS m/e: 586.2 [M+H].sup.+.
Example 92
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-trifluoromethyl-cyclobutanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00158##
[0550] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
1-(trifluoromethyl)cyclobutanecarboxylic acid. MS m/e: 624.1
[M+H].sup.+.
Example 93
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2-cyano-acetyl)-piperidine-4-carbonyl]--
pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
##STR00159##
[0552] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and 2-cyanoacetic acid. MS
m/e: 541.3 [M+H].sup.+.
Example 94
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-cyano-cyclopropanecarbonyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00160##
[0554] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
1-cyanocyclopropanecarboxylic acid. MS m/e: 567.3 [M+H].sup.+.
Example 95
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-trifluoromethyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00161##
[0556] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
1-(trifluoromethyl)cyclopropanecarboxylic acid. MS m/e: 610.2
[M+H].sup.+.
Example 96
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2,2-difluoro-cyclopropanecarbonyl)-pipe-
ridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00162##
[0558] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
2,2-difluorocyclopropanecarboxylic acid. MS m/e: 578.3
[M+H].sup.+.
Example 97
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(tetrahydro-pyran-4-carbonyl)-piperidine-
-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00163##
[0560] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
tetrahydro-2H-pyran-4-carboxylic acid. MS m/e: 586.3
[M+H].sup.+.
Example 98
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2,2-dimethyl-tetrahydro-pyran-4-carbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00164##
[0562] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
2,2-dimethyltetrahydro-2H-pyran-4-carboxylic acid. MS m/e: 614.2
[M+H].sup.+.
Example 99
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-methoxymethyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00165##
[0564] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
1-(methoxymethyl)cyclopropanecarboxylic acid. MS m/e: 586.3
[M+H].sup.+.
Example 100
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(2,2-dimethyl-cyclopropanecarbonyl)-pipe-
ridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00166##
[0566] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
2,2-dimethylcyclopropanecarboxylic acid. MS m/e: 570.2
[M+H].sup.+.
Example 101
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-trifluoromethyl-pyridine-2-carbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00167##
[0568] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
5-(trifluoromethyl)picolinic acid. MS m/e: 647.3 [M+H].sup.+.
Example 102
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(5-fluoro-pyridine-2-carbonyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00168##
[0570] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and 5-fluoropicolinic
acid. MS m/e: 597.2 [M+H].sup.+.
Example 103
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(6-oxo-piperidine-3-carbonyl)-piperidine-
-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00169##
[0572] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
6-oxopiperidine-3-carboxylic acid. MS m/e: 599.2 [M+H].sup.+.
Example 104
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-isopropyl-6-oxo-piperidine-3-carbonyl-
)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00170##
[0574] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-e-
thyl-carbamic acid 4-fluoro-phenyl ester and
1-isopropyl-6-oxopiperidine-3-carboxylic acid. MS m/e: 641.4
[M+H].sup.+.
Example 105
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(1-isopropyl-6-oxo-piperidine-3-ca-
rbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl
ester
##STR00171##
[0576] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester (example 39, h) and
1-isopropyl-6-oxopiperidine-3-carboxylic acid. MS m/e: 548.3
[M+H].sup.+.
Example 106
{(3S,4R)-4-(3,4-Difluoro-phenyl)-1-[1-((S)-4-oxo-azetidine-2-carbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00172##
[0578] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-ethyl-carbamic acid 4-fluoro-phenyl ester (example 58, b) and
(S)-4-oxoazetidine-2-carboxylic acid. MS m/e: 573.2
[M+H].sup.+.
Example 107
{(3S,4R)-4-(3,4-Difluoro-phenyl)-1-[1-(6-oxo-piperidine-3-carbonyl)-piperi-
dine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00173##
[0580] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3,4-Difluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-ethyl-carbamic acid 4-fluoro-phenyl ester (example 58, b) and
6-oxopiperidine-3-carboxylic acid. MS m/e: 601.3 [M+H].sup.+.
Example 108
{(3S,4R)-4-(4-Chloro-phenyl)-1-[5'-(1-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-
-[1,2']bipyridinyl-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00174##
[0582] A mixture of 62 mg (0.1.5 mmol)
[(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 (example 14) and 3.95 mg (0.105 mmol) sodium
borohydride in 2 mL THF/0.2 mL MeOH was stirred at room temperature
for 45 minutes. Water was added and the mixture was extracted with
ethyl acetate. The combined organic layers were dried with
Na.sub.2SO.sub.4, filtered and evaporated to dryness to yield 58 mg
(93%) of the title compound as off-white solid. MS m/e: 595.2
[M+H].sup.+.
Example 109
[(3S,4R)-1-(5'-Carbamoyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbony-
l)-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00175##
[0584] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester (example 39, h) and
1-[5-(aminocarbonyl)pyridine-2-yl]piperidine-4-carboxylic acid. MS
m/e: 612.3 [M+H].sup.+.
Example 110
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-chloro-3,4,5,6-tetrahydro-2H-[1,2']bipy-
ridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00176##
[0585] a)
[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-carbamic
acid tert-butyl ester
##STR00177##
[0587] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-Benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic
acid tert-butyl ester (example 48, e) the title compound was
prepared following the sequence as described in example 48, b to e
starting from ethyl 3-(4-chlorophenyl)propiolate and
N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine as off-white
solid. MS m/e: 387.3 [M+H].sup.+.
b)
[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid tert-butyl ester
##STR00178##
[0589] A mixture of 4.2 g (10.9 mmol)
[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-carbamic
acid tert-butyl ester, 521 mg (13 mmol) NaH (60%) and 2.54 g (16.3
mmol) iodoethane in 40 mL DMF was stirred for 1 h at 60.degree. C.
and evaporated to dryness. The residue was taken up in ethyl
acetate and water and extracted further with ethyl acetate. The
combined organic layers were washed with brine, dried with
Na.sub.2SO.sub.4, filtered and evaporated to dryness. The residue
was purified by column chromatography on silica eluting with a
gradient formed from ethyl acetate and heptane to yield after
evaporation of the product containing fractions 2.5 g (55%) of the
title compound as light yellow viscous oil. MS m/e: 415.3
[M+H].sup.+.
c) [(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00179##
[0591] In analogy to the procedure described for
rac-(3S,4R)-[3-Amino-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methy-
l-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (example 1, f)
the Boc protecting group was removed. The liberated amine was
reacted to the respective carbamate in analogy to the procedure
described for the synthesis 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 (example 1, h). The benzyl protecting group
was removed in analogy to the procedure described for
rac-(3S,4R)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-carbamic acid
tert-butyl ester (example 1, d) to yield the title compound as
amorphous crude brown foam. MS m/e: 363.3 [M+H].sup.+.
d)
[(3S,4R)-4-(4-Chloro-phenyl)-1-(5'-chloro-3,4,5,6-tetrahydro-2H-[1,2]bi-
pyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
[0592] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester and
1-(5-chloropyridine-2-yl)piperidine-4-carboxylic acid. MS m/e:
585.2 [M+H].sup.+.
Example 111
[(3S,4R)-1-(5'-Carbamoyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbony-
l)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00180##
[0594] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester and
1-[5-(aminocarbonyl)pyridine-2-yl]piperidine-4-carboxylic acid. MS
m/e: 594.3 [M+H].sup.+.
Example 112
[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H-[1,2']-
bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00181##
[0595] a)
[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00182##
[0597] In analogy to the procedure described for the synthesis of
[(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 110, c) the title compound was
prepared following the same sequence of transformations described
in example 110 starting from ethyl 3-(3,4-dichlorophenyl)propiolate
and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine as
amorphous crude brown foam.
b)
[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H-[1,-
2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
[0598] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(5-fluoropyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 603.2
[M+H].sup.+.
Example 113
[(3S,4R)-1-(5'-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00183##
[0600] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(5-chloropyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 619.3
[M+H].sup.+.
Example 114
[(3S,4R)-4-(3,4-Dichloro-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
##STR00184##
[0602] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(5-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxylic acid. MS
m/e: 653.2 [M+H].sup.+.
Example 115
[(3S,4R)-1-(5'-Carbamoyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbony-
l)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00185##
[0604] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(5-carbamoylpyridin-2-yl)piperidine-4-carboxylic acid. MS m/e:
628.4 [M+H].sup.+.
Example 116
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00186##
[0605] a)
4-{(3R,4S)-3-(3,4-Dichloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycar-
bonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester
##STR00187##
[0607] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. MS m/e: 608.0
[M+H].sup.+.
b) [(3
S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-1-4-carb-
onyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
[0608] After removal of the Boc-protecting group under acidic
conditions, in analogy to the procedure described for the synthesis
of
{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester
(example 7, g) the title compound was prepared from
[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-ethyl-carbamic acid 4-fluoro-phenyl ester and
5-acetyl-2-bromopyridine as off-white foam. MS m/e: 627.3
[M+H].sup.+.
Example 117
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2H-[-
1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00188##
[0609] a)
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-car-
bamic acid 4-fluoro-phenyl ester
##STR00189##
[0611] In analogy to the procedure described for the synthesis of
[(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 110, c) the title compound was
prepared following the same sequence of transformations described
in example 110 starting from (3-Chloro-4-fluoro-phenyl)-propynoic
acid ethyl ester (prepared in analogy to
(4-Chloro-3-fluoro-phenyl)-propynoic acid ethyl ester (example 39,
step a)) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine
as amorphous crude brown solid.
b)
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-1-(5'-fluoro-3,4,5,6-tetrahydro-2-
H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester
[0612] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(5-fluoropyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 587.1
[M+H].sup.+.
Example 118
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-1-(5'-chloro-3,4,5,6-tetrahydro-2H-[-
1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00190##
[0614] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(5-chloropyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 603.2
[M+H].sup.+.
Example 119
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-1-(5'-trifluoromethyl-3,4,5,6-tetrah-
ydro-2H-[1,2']bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00191##
[0616] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(5-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxylic acid. MS
m/e: 637.3 [M+H].sup.+.
Example 120
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(3-chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00192##
[0618] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
prepared from
[(3S,4R)-4-(3-Chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and
1-(5-acetylpyridin-2-yl)piperidine-4-carboxylic acid. MS m/e: 611.3
[M+H].sup.+.
Example 121
{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-((S)-4-oxo-azetidine-2-carbonyl)-piperid-
ine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid
4-fluoro-phenyl ester
##STR00193##
[0620] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the title compound was
from [(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester and (S)-4-oxoazetidine-2-carboxylic
acid. MS m/e: 571.2 [M+H].sup.+.
Example 122
[(3S,4R)-1-[5'-(2-Diethylamino-acetyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrid-
inyl-4-carbonyl]-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid 4-fluoro-phenyl ester
##STR00194##
[0622] A mixture of 0.17 g (0.285 mmol)
[(3S,4R)-1-(5'-Acetyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)-
-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 38) and 84.3 mg (0.295 mmol)
5,5-dibromobarbituric acid in 10 mL dioxane was heated to
85.degree. C. for 40 h. At room temperature 0.216 g (2.95 mmol)
diethylamine was added and heated to 45.degree. C. for 2 h and
evaporated. the residue was taken up in methanol and subjected to
preparative HPLC on reversed phase eluting with a gradient formed
from acetonitrile, water and NEt.sub.3. The product containing
fractions were evaporated to yield 49 mg (26%) of the title
compound as light brown solid. MS m/e: 648.3 [M+H].sup.+.
Example 123
Acetic acid
4-{(3R,4S)-3-(4-chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-amino]-
-pyrrolidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl
ester
##STR00195##
[0624] In analogy to the procedure described for the synthesis of
[(3S,4R)-1-(5'-Cyano-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carbonyl)--
4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester (example 35, step f) the intermediate was
prepared from
[(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid
4-fluoro-phenyl ester and
1-(5-hydroxypyridin-2-yl)piperidine-4-carboxylic acid. Afterwards,
acetyl chloride was added and stirring was continued for 30 min at
room temperature. The mixture was directly subjected to preparative
HPLC on reversed phase eluting with a gradient formed from
acetonitrile, water and NEt.sub.3. The product containing fractions
were evaporated to yield the title compound as off-white solid. MS
m/e: 608.2 [M+H].sup.+.
Experimental Procedure
[0625] The compounds were investigated in accordance with the tests
given hereinafter
[.sup.3H]SR142801 Competition Binding Assay
[0626] hNK3 receptor binding experiment were performed using
[.sup.3H]SR142801 (Catalog No. TRK1035, specific activity: 74.0
Ci/mmol, Amersham, GE Healthcare UK limited, Buckinghamshire, UK)
and membrane isolated from HEK293 cells transiently expressing
recombinant human NK3 receptor. After thawing, the membrane
homogenates were centrifuged at 48,000.times.g for 10 min at
4.degree. C., the pellets were resuspended in the 50 mM Tris-HCl, 4
mM MnCl.sub.2, 1 .mu.M phosphoramidon, 0.1% BSA binding buffer at
pH 7.4 to a final assay concentration of 5 .mu.g protein/well. For
inhibition experiments, membranes were incubated with
[.sup.3H]SR142801 at a concentration equal to K.sub.D value of
radioligand and 10 concentrations of the inhibitory compound
(0.0003-10 .mu.M) (in a total reaction volume of 500 .mu.l) for 75
min at room temperature (RT). At the end of the incubation,
membranes were filtered onto unitfilter (96-well white microplate
with bonded GF/C filter preincubated 1 h in 0.3% PEI+0.3% BSA,
Packard BioScience, Meriden, Conn.) with a Filtermate 196 harvester
(Packard BioScience) and washed 4 times with ice-cold 50 mM
Tris-HCl, pH 7.4 buffer. Nonspecific binding was measured in the
presence of 10 .mu.M SB222200 for both radioligands. The
radioactivity on the filter was counted (5 min) on a Packard
Top-count microplate scintillation counter with quenching
correction after addition of 45 .mu.l of microscint 40 (Canberra
Packard S. A., Zurich, Switzerland) and shaking for 1 h. Inhibition
curves were fitted according to the Hill equation:
y=100/(1+(x/IC.sub.50).sup.nH), where n.sub.H=slope factor using
Excel-fit 4 software (Microsoft). IC.sub.50 values were derived
from the inhibition curve and the affinity constant (K.sub.i)
values were calculated using the Cheng-Prussoff equation
K.sub.i=IC.sub.50/(1+[L]/K.sub.D) where [L] is the concentration of
radioligand and K.sub.D is its dissociation constant at the
receptor, derived from the saturation isotherm. All experiments
were performed in duplicate and the mean.+-.standard error (SEM) of
the individual K.sub.i values was calculated.
[0627] The results of all specific compounds with a hNK-3 receptor
affinity in .mu.M were shown in the following table 1.
TABLE-US-00001 TABLE 1 Example Data K.sub.i [.mu.M] 1 0.001 2 0.046
3 0.276 4 0.01 5 0.002 6 0.062 7 0.089 8 0.055 9 0.138 10 0.065 11
0.036 12 0.023 13 0.008 14 0.003 15 0.008 16 0.002 17 0.002 18
0.002 19 0.088 20 0.003 21 0.002 22 0.025 23 0.021 24 0.062 25
0.112 26 0.046 27 0.047 28 0.05 29 0.012 30 0.035 31 0.057 32 0.052
33 0.048 34 0.116 35 0.004 36 0.01 37 0.008 38 0.007 39 0.004 40
0.0007 41 0.0006 42 0.002 43 0.0003 44 0.002 45 0.003 46 0.001 47
0.002 48 0.002 49 0.005 50 0.009 51 0.002 52 0.015 53 0.016 54
0.007 55 0.009 56 0.267 57 0.0007 58 0.005 59 0.0005 60 0.004 61
0.0008 62 0.006 63 0.0007 64 0.005 65 0.003 66 0.001 67 0.002 68
0.002 69 0.002 70 0.004 71 0.004 72 0.002 73 0.003 74 0.012 75
0.003 76 0.017 77 0.004 78 0.005 79 0.008 80 0.002 81 0.029 82
0.0082 83 0.0038 84 0.0298 85 0.0233 86 0.0707 87 0.0021 88 0.0056
89 0.0033 90 0.0024 91 0.0065 92 0.0066 93 0.0071 94 0.0078 95
0.0061 96 0.0034 97 0.0044 98 0.0047 99 0.0047 100 0.0036 101
0.0425 102 0.0082 103 0.0326 104 0.0176 105 0.0312 106 0.066 107
0.1312 108 0.0047 109 0.0017 110 0.0048 111 0.0074 112 0.0008 113
0.0005 114 0.0016 115 0.0009 116 0.0005 117 0.0033 118 0.0018 119
0.0037 120 0.0017 121 0.0169 122 0.0696 123 0.006
[0628] The compounds of formula I as well as their pharmaceutically
usable acid addition salts can be used as medicaments, e.g. in the
form of pharmaceutical preparations. The pharmaceutical
preparations can be administered orally, e.g. in the form of
tablets, coated tablets, dragees, hard and soft gelatine capsules,
solutions, emulsions or suspensions. The administration can,
however, also be effected rectally, e.g. in the form of
suppositories, or parenterally, e.g. in the form of injection
solutions.
[0629] The compounds of formula I and their pharmaceutically usable
acid addition salts can be processed with pharmaceutically inert,
inorganic or organic excipients for the production of tablets,
coated tablets, dragees and hard gelatine capsules. Lactose, corn
starch or derivatives thereof, talc, stearic acid or its salts etc
can be used as such excipients e.g. for tablets, dragees and hard
gelatine capsules.
[0630] Suitable excipients for soft gelatine capsules are e.g.
vegetable oils, waxes, fats, semi-solid and liquid polyols etc.
[0631] Suitable excipients for the manufacture of solutions and
syrups are e.g. water, polyols, saccharose, invert sugar, glucose
etc.
[0632] Suitable excipients for injection solutions are e.g. water,
alcohols, polyols, glycerol, vegetable oils etc.
[0633] Suitable excipients for suppositories are e.g. natural or
hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
[0634] Moreover, the pharmaceutical preparations can contain
preservatives, solubilizers, stabilizers, wetting agents,
emulsifiers, sweeteners, colorants, flavorants, salts for varying
the osmotic pressure, buffers, masking agents or antioxidants. They
can also contain still other therapeutically valuable
substances.
[0635] The dosage can vary within wide limits and will, of course,
be fitted to the individual requirements in each particular case.
In general, in the case of oral administration a daily dosage of
about 10 to 1000 mg per person of a compound of general formula I
should be appropriate, although the above upper limit can also be
exceeded when necessary.
Example A
[0636] Tablets of the following composition are manufactured in the
usual manner:
TABLE-US-00002 mg/tablet Active substance 5 Lactose 45 Corn starch
15 Microcrystalline cellulose 34 Magnesium stearate 1 Tablet weight
100
Example B
[0637] Capsules of the following composition are manufactured:
TABLE-US-00003 mg/capsule Active substance 10 Lactose 155 Corn
starch 30 Talc 5 Capsule fill weight 200
[0638] The active substance, lactose and corn starch are firstly
mixed in a mixer and then in a comminuting machine. The mixture is
returned to the mixer, the talc is added thereto and mixed
thoroughly. The mixture is filled by machine into hard gelantine
capsules.
Example C
[0639] Suppositories of the following composition are
manufactured:
TABLE-US-00004 mg/supp. Active substance 15 Suppository mass 1285
Total 1300
[0640] The suppository mass is melted in a glass or steel vessel,
mixed thoroughly and cooled to 45.degree. C. Thereupon, the finely
powdered active substance is added thereto and stirred until it has
dispersed completely. The mixture is poured into suppository moulds
of suitable size, left to cool, the suppositories are then removed
from the moulds and packed individually in wax paper or metal
foil.
* * * * *