U.S. patent application number 12/482490 was filed with the patent office on 2009-12-17 for pyrrolidine derivatives as nk2 receptor antagonists.
Invention is credited to Caterina Bissantz, Philippe Jablonski, Henner Knust, Andreas Koblet, Anja Limberg, Matthias Nettekoven, Hasane Ratni, Claus Riemer.
Application Number | 20090312327 12/482490 |
Document ID | / |
Family ID | 40843342 |
Filed Date | 2009-12-17 |
United States Patent
Application |
20090312327 |
Kind Code |
A1 |
Bissantz; Caterina ; et
al. |
December 17, 2009 |
PYRROLIDINE DERIVATIVES AS NK2 RECEPTOR ANTAGONISTS
Abstract
The present invention relates to compounds of formula I
##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, Ar and n are as
defined herein and pharmaceutically active salts, racemic mixtures,
enantiomers, optical isomers or tautomeric forms thereof. The
compounds can be used for the treatment of depression, anxiety or
schizophrenia.
Inventors: |
Bissantz; Caterina;
(Village-Neuf, FR) ; Jablonski; Philippe;
(Steinbrunn-le-Haut, FR) ; Knust; Henner;
(Rheinfelden, DE) ; Koblet; Andreas; (Bottmingen,
CH) ; Limberg; Anja; (Basel, CH) ; Nettekoven;
Matthias; (Grenzach-Wyhlen, DE) ; Ratni; Hasane;
(Habsheim, FR) ; Riemer; Claus; (Freiburg,
DE) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.;PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
US
|
Family ID: |
40843342 |
Appl. No.: |
12/482490 |
Filed: |
June 11, 2009 |
Current U.S.
Class: |
514/236.5 ;
514/235.5; 514/249; 514/254.01; 514/326; 544/114; 544/131; 544/141;
544/353; 544/372; 546/208 |
Current CPC
Class: |
A61P 25/24 20180101;
A61P 25/18 20180101; C07D 403/12 20130101; A61P 25/22 20180101;
C07D 401/12 20130101; C07D 405/06 20130101; C07D 401/06 20130101;
A61P 43/00 20180101; C07D 403/06 20130101; C07D 405/14 20130101;
C07D 401/14 20130101; C07D 207/14 20130101; C07D 405/12 20130101;
C07D 413/10 20130101 |
Class at
Publication: |
514/236.5 ;
544/372; 514/254.01; 514/249; 544/353; 546/208; 514/326; 514/235.5;
544/141; 544/131; 544/114 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 403/06 20060101 C07D403/06; A61K 31/497 20060101
A61K031/497; A61K 31/498 20060101 A61K031/498; C07D 403/14 20060101
C07D403/14; C07D 401/06 20060101 C07D401/06; A61K 31/454 20060101
A61K031/454; C07D 413/10 20060101 C07D413/10; C07D 413/14 20060101
C07D413/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 16, 2008 |
EP |
08158326.2 |
Claims
1. A compound of formula I ##STR00225## wherein R.sup.1 is
hydrogen, halogen, cyano or lower alkyl; n is 1, 2 or 3; R.sup.2 is
hydrogen or lower alkyl; R.sup.3 is aryl- or a heteroaryl, wherein
the rings of the aryl or heteroaryl group are optionally
substituted by one or two substituents R'; R' is selected from
hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl
substituted by halogen, lower alkoxy substituted by halogen,
--S(O).sub.2-lower alkyl, CN, --NR.sup.4R.sup.5, --C(O)-lower
alkyl, heterocyclyl and heteroaryl; R.sup.4 and R.sup.5 are each
independently hydrogen, --(CO)CF.sub.3 or lower alkyl or is a non
aromatic heterocyclic group ##STR00226## wherein X is N or CH; Y is
--CH(R.sup.7)--; --N(R.sup.7')--, O or SO.sub.2 R.sup.6 is
hydrogen, lower alkyl or hydroxy; R.sup.7 is hydrogen, hydroxy,
.dbd.O, lower alkyl, lower alkoxy, --S(O).sub.2-lower alkyl,
--C(O)-lower alkyl, --C(O)CH.sub.2O-lower alkyl, --CH.sub.2CN,
--C(O)CH.sub.2CN, --C(O)-cycloalkyl wherein the cycloalkyl group is
optionally substituted by cyano, lower alkyl, one or two halogen
atoms, .dbd.O or amino, or is --C(O)O-lower alkyl, --NH-lower
alkyl, --NRC(O)O-lower alkyl, --NRC(O)-lower alkyl or
--CH.sub.2O-lower alkyl; R.sup.7' is hydrogen, lower alkyl,
--(CH.sub.2).sub.q--S(O).sub.2-lower alkyl,
--(CH.sub.2).sub.q--S(O).sub.2-cycloalkyl, --C(O)-lower alkyl,
--(CH.sub.2).sub.q-cycloalkyl, --C(O)CH.sub.2--O-lower alkyl,
--(CH.sub.2).sub.qCN, --C(O)CN, --C(O)CH.sub.2CN, lower alkyl
substituted by halogen, lower alkenyl substituted by halogen,
--C(O)-cycloalkyl wherein the cycloalkyl group is optionally
substituted by cyano, lower alkyl, one or two halogen atoms, .dbd.O
or amino, or is --C(O)O-lower alkyl or --(CH.sub.2).sub.qO-lower
alkyl and q is 0-3; or R.sup.6 and R.sup.7 together with the carbon
atoms to which they are attached form a five or six-membered non
aromatic ring or R.sup.6 and R.sup.7 together with the nitrogen and
carbon atoms to which they are attached form a five or six-membered
non aromatic ring; p is 0, 1 or 2; Ar is aryl- or heteroaryl,
wherein the rings of the aryl or heteroaryl group are optionally
substituted by one or two substituents R''; R'' is selected from
hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen,
lower alkoxy, lower alkoxy substituted by halogen,
--O--CH.sub.2-cycloalkyl, --NR.sup.4R.sup.5, --CN,
--CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl and pyrrolyl; m is 0, 1
or 2 and o is 0; and o is 0, 1 or 2 and m is 1 or a
pharmaceutically active salt, racemic mixture, enantiomer, optical
isomer or tautomeric form thereof.
2. A compound of claim 1 having formula IA ##STR00227## wherein
R.sup.1 is hydrogen or halogen; n is 1 or 2; R.sup.2 is lower alkyl
R.sup.3 is ##STR00228## R.sup.6 is hydrogen, lower alkyl or
hydroxy; R.sup.7 is hydrogen, hydroxy, .dbd.O, lower alkyl, lower
alkoxy, --S(O).sub.2-lower alkyl, --C(O)-lower alkyl,
--C(O)CH.sub.2O-lower alkyl, --CH.sub.2CN, --C(O)CH.sub.2CN,
--C(O)-cycloalkyl wherein the cycloalkyl group is optionally
substituted by cyano, lower alkyl, one or two halogen atoms, .dbd.O
or amino, or is --C(O)O-lower alkyl, --NH-lower alkyl,
--NRC(O)O-lower alkyl, --NRC(O)-lower alkyl or --CH.sub.2O-lower
alkyl; R.sup.7' is hydrogen, lower alkyl,
--(CH.sub.2).sub.q--S(O).sub.2-lower alkyl,
--(CH.sub.2).sub.q--S(O).sub.2-cycloalkyl, --C(O)-lower alkyl,
--(CH.sub.2).sub.q-cycloalkyl, --C(O)CH.sub.2--O-lower alkyl,
--(CH.sub.2).sub.qCN, --C(O)CN, --C(O)CH.sub.2CN, lower alkyl
substituted by halogen, lower alkenyl substituted by halogen,
--C(O)-cycloalkyl wherein the cycloalkyl group is optionally
substituted by cyano, lower alkyl, one or two halogen atoms, .dbd.O
or amino, or is --C(O)O-lower alkyl or --(CH.sub.2).sub.qO-lower
alkyl and q is 0-3; or R.sup.6 and R.sup.7 together with the carbon
atoms to which they are attached form a five or six-membered non
aromatic ring or R.sup.6 and R.sup.7' together with the nitrogen
and carbon atoms to which they are attached form a five or
six-membered non aromatic ring; Ar is aryl- or heteroaryl, wherein
the rings of the aryl or heteroaryl group are optionally
substituted by one or two substituents R''; and R'' is selected
from hydrogen, halogen, lower alkyl, lower alkyl substituted by
halogen, lower alkoxy, lower alkoxy substituted by halogen,
--O--CH.sub.2-cycloalkyl, --NR.sup.4R.sup.5, --CN,
--CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl and pyrrolyl; or a
pharmaceutically active salt, racemic mixture, enantiomer, optical
isomer or tautomeric form thereof.
3. A compound of claim 2, selected from the group consisting of
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-4-chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-pipe-
razine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-4-ethyl-N-methyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-N-methyl-4-trifluoromethoxy-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-3-fluoro-N-methyl-4-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-2-fluoro-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-4-dimethylamino-N-methyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-4-fluoro-3,N-dimethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-3-fluoro-4-methoxy-N-methyl-benzamide;
rac-2,2-difluoro-benzo[1,3]dioxole-5-carboxylic
acid[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-ca-
rbonyl)-pyrrolidin-3-yl]-methyl-amide; and
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-N-methyl-4-pyrrol-1-yl-benzamide.
4. A compound of claim 2, selected from the group consisting of
rac-3-chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-pipe-
razine-1-carbonyl)-pyrrolidin-3-yl]-4-fluoro-N-methyl-benzamide;
rac-3-chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-pipe-
razine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-4-fluoro-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-2-fluoro-N-methyl-5-trifluoromethyl-benzamide;
N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-((S)-4-methanesulfonyl-3-methyl-pipe-
razine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-b-
enzamide;
N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-((R)-4-methanesulfonyl-3-me-
thyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluor-
omethyl-benzamide;
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl--
benzamide;
N-{(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbo-
nyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluor-
omethyl-benzamide;
4-{(3SR,4RS)-3-(4-chloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)-
-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester; and
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromet-
hyl-benzamide.
5. A compound of claim 2, selected from the group consisting of
4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropane-
carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluorometh-
yl-benzamide;
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-3-trifluorometh-
oxy-benzamide;
4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropane-
carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-methoxy-N-methyl-benza-
mide;
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarb-
onyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-benzamide;
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-(4-fluoro-phenyl)-N-methyl-prop-
ionamide;
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrro-
lidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-isopropyl-piperidine-4-carbonyl)-py-
rrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine-4-carb-
onyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
N-{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethy-
l-benzamide; 5-chloro-pyridine-2-carboxylic
acid{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide; and
3-cyano-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanec-
arbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-benzami-
de.
6. A compound of claim 2, selected from the group consisting of
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3,3,3-trifluoro-propyl)-piperidine-
-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzami-
de;
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3,3-dimethyl-butyl)-piperidine--
4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamid-
e;
2-cyclopentyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclo-
propanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-acetamid-
e;
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(2,2-dimethyl-propyl)-piperidine--
4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamid-
e;
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-ethyl-piperidine-4-carbonyl)-pyrr-
olidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3-methylsulfanyl-propyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzam-
ide;
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3-methanesulfonyl-propyl)-pipe-
ridine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-b-
enzamide;
4-{(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(4-methoxy-3-trifluorome-
thyl-benzoyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxyli-
c acid tert-butyl ester;
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichlor-
o-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
and
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(3,3,3-trifluoro-propyl)-pi-
peridine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-
-benzamide.
7. A compound of claim 2, selected from the group consisting of
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(1-ethanesulfonyl-piperidine-4-car-
bonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
N-[(3RS,4SR)-1-(1-cyclopropanesulfonyl-piperidine-4-carbonyl)-4-(3,4-dich-
loro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzami-
de;
N-[(3RS,4SR)-1-[1-(2-cyano-ethyl)-piperidine-4-carbonyl]-4-(3,4-dichlo-
ro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide-
;
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(2-methoxy-ethyl)-piperidine-4-
-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide-
;
4-{(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-ben-
zoyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic
acid ethyl ester;
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl-
)-benzoyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide-
;
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(2-fluoro-allyl)-piperidine-4--
carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
2-cyclopentyl-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)--
4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide;
4-chloro-N-[(3S
,4R)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-py-
rrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;
4-chloro-N-{(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbon-
yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-ben-
zamide; and
4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrro-
lidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide.
8. A compound of claim 2, selected from the group consisting of
4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyclopropanesulfonyl-piper-
idine-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;
4-chloro-N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(tetrahydro-pyran-4-yl)-pi-
peridine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide-
;
4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyanomethyl-piperidine-4--
carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;
4-chloro-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,-
4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;
4-chloro-N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(2-cyano-ethyl)-piperidine-
-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide;
4-trifluoromethyl-pyridine-2-carboxylic
acid{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide;
4-chloro-N-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4--
dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;
4-trifluoromethyl-pyridine-2-carboxylic
acid{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide;
3-bromo-4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cycl-
opropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzami-
de;
4-chloro-3-cyclopropyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-me-
thyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methy-
l-benzamide;
4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropane-
carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-ethyl-N-methyl-benzami-
de; and
4-chloro-3-cyclopropyl-N-{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1--
methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-met-
hyl-benzamide.
9. A compound of claim 1 having formula IB ##STR00229## wherein
R.sup.1 is hydrogen, halogen, cyano or lower alkyl; n is 1, 2 or 3;
R' is selected from hydrogen, halogen, lower alkyl, lower alkoxy,
lower alkyl substituted by halogen, lower alkoxy substituted by
halogen, --S(O).sub.2-lower alkyl, CN, --NR.sup.4R.sup.5,
--C(O)-lower alkyl, heterocyclyl and heteroaryl; R.sup.4 and
R.sup.5 are each independently hydrogen, --(CO)CF.sub.3 or lower
alkyl Ar is aryl- or heteroaryl, wherein the rings are optionally
substituted by one or two substituents R''; and R'' is selected
from hydrogen, halogen, lower alkyl, lower alkyl substituted by
halogen, lower alkoxy, lower alkoxy substituted by halogen,
--O--CH.sub.2-cycloalkyl, --NR.sup.4R.sup.5, --CN,
--CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl and pyrrolyl; or a
pharmaceutically active salt, racemic mixture, enantiomer, optical
isomer or tautomeric form thereof.
10. A compound of claim 9, selected from the group consisting of
rac-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-pyrrolidin-3-
-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-dimethylamino-benzoyl)-pyrrol-
idin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-fluoro-benzoyl)-pyrrolidin-3--
yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-1-(3-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(2-fluoro-5-methanesulfonyl-benz-
oyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-trifluoromethyl-benzoyl)-pyrr-
olidin-3yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-trifluoromethoxy-benzoyl)-pyr-
rolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; and
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(3-methanesulfonyl-benzoyl)-pyrr-
olidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide.
11. A compound of claim 9, selected from the group consisting of
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methoxy-3-methyl-benzoyl)-pyr-
rolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(3,5-dimethyl-benzoyl)-pyrrolidi-
n-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-1-(4-acetyl-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3--
yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-4-methyl-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide;
rac-4-chloro-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrro-
lidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;
rac-3-tert-butyl-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-p-
yrrolidin-3-yl]-4-methoxy-N-methyl-benzamide;
rac-6-chloro-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrro-
lidin-3-yl]-N-methyl-nicotinamide;
rac-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-N-methyl-6-trifluoromethyl-nicotinamide; and
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl-
)-benzoyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide-
.
12. A compound of claim 1 having formula IC ##STR00230## wherein
R.sup.1 is hydrogen, halogen, cyano or lower alkyl; n is 1, 2 or 3;
R.sup.2 is hydrogen or lower alkyl; R' is selected from hydrogen,
halogen, lower alkyl, lower alkoxy, lower alkyl substituted by
halogen, lower alkoxy substituted by halogen, --S(O).sub.2-lower
alkyl, CN, --NR.sup.4R.sup.5, --C(O)-lower alkyl, heterocyclyl and
heteroaryl; R.sup.4 and R.sup.5 are each independently hydrogen,
--(CO)CF.sub.3 or lower alkyl Ar is aryl- or heteroaryl, wherein
the rings of the aryl or heteroaryl group are optionally
substituted by one or two substituents R''; and R'' is selected
from hydrogen, halogen, lower alkyl, lower alkyl substituted by
halogen, lower alkoxy, lower alkoxy substituted by halogen,
--O--CH.sub.2-cycloalkyl, --NR.sup.4R.sup.5, --CN,
--CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl and pyrrolyl; or a
pharmaceutically active salt, racemic mixture, enantiomer, optical
isomer or tautomeric form thereof.
13. A compound of claim 12, selected from the group consisting of
rac-N-[(3S,4R)-1-(benzofuran-5-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolid-
in-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(pyridine-4-carbonyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(2,6-dichloro-pyridine-4-carbony-
l)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
and
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(1,5-dimethyl-1H-pyrazole-3-carb-
onyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide.
14. A compound of formula I, having formula I-I ##STR00231##
wherein R.sup.1 is hydrogen, halogen, cyano or lower alkyl; n is 1,
2 or 3; R.sup.2 is hydrogen or lower alkyl; R.sup.3 is aryl- or
heteroaryl, wherein the rings of the aryl or heteroaryl group are
optionally substituted by one or two substituents R'; R' is
selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower
alkyl substituted by halogen, lower alkoxy substituted by halogen,
--S(O).sub.2-lower alkyl, CN, --NR.sup.4R.sup.5, and --C(O)-lower
alkyl; R.sup.4 and R.sup.5 are each independently hydrogen,
--(CO)CF.sub.3 or lower alkyl or is a non aromatic heterocyclic
group ##STR00232## wherein X is N or CH; when X is CH, Y is is
--CH(R.sup.7)--; --N(R.sup.7')--, or O; or when X is N, Y is is
--CH(R.sup.7)--; --N(R.sup.7')--, O, or SO.sub.2; R.sup.6 is
hydrogen, lower alkyl or hydroxy; R.sup.7 is hydrogen, hydroxy,
.dbd.O, lower alkyl, --S(O).sub.2-lower alkyl, --C(O)-lower alkyl,
--C(O)CH.sub.2O-lower alkyl, --CH.sub.2CN, --C(O)CH.sub.2CN,
--C(O)-cycloalkyl wherein the cycloalkyl group is optionally
substituted by cyano, lower alkyl, one or two halogen atoms, .dbd.O
or amino, or is --C(O)O-lower alkyl, --NH-lower alkyl,
--NRC(O)O-lower alkyl, --NRC(O)-lower alkyl or --CH.sub.2O-lower
alkyl; R.sup.7' is hydrogen, lower alkyl, --S(O).sub.2-lower alkyl,
--C(O)-lower alkyl, --C(O)CH.sub.2--O-lower alkyl, --CH.sub.2CN,
--C(O)CN, --C(O)CH.sub.2CN, --C(O)-cycloalkyl wherein the
cycloalkyl group is optionally substituted by cyano, lower alkyl,
one or two halogen atoms, .dbd.O or amino, or is --C(O)O-lower
alkyl or --CH.sub.2O-lower alkyl; or R.sup.6and R.sup.7 together
with the carbon atoms to which they are attached form a five or
six-membered non aromatic ring or R.sup.6and R.sup.7' together with
the nitrogen and carbon atoms to which they are attached form a
five or six-membered non aromatic ring; p is 0, 1 or 2; Ar is aryl-
or heteroaryl, wherein the rings of the aryl or heteroaryl group
are optionally substituted by one or two substituents R''; R'' is
selected from hydrogen, halogen, lower alkyl, lower alkyl
substituted by halogen, lower alkoxy, lower alkoxy substituted by
halogen, --O--CH.sub.2-cycloalkyl, --NR.sup.4R.sup.5, --CN,
--CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl and pyrrolyl; m is 0, 1
or 2 and o is 0; and o is 0, 1 or 2 and m is 1 or a
pharmaceutically active salt, racemic mixture, enantiomer, optical
isomer or tautomeric form thereof.
15. A compound of claim 14, having formula I-11 ##STR00233##
wherein R.sup.1 is hydrogen or halogen; n is 1 or 2; R.sup.2 is
lower alkyl R.sup.3 is ##STR00234## wherein R is hydrogen or lower
alkyl; R' is selected from hydrogen, halogen, lower alkyl, lower
alkoxy, lower alkyl substituted by halogen, lower alkoxy
substituted by halogen, --S(O).sub.2-lower alkyl, CN,
--NR.sup.4R.sup.5, and --C(O)-lower alkyl; R.sup.4 and R.sup.5 are
each independently hydrogen or lower alkyl; Ar is aryl- or
heteroaryl, wherein the rings of the aryl or heteroaryl group are
optionally substituted by one or two substituents R''; and R'' is
selected from hydrogen, halogen, lower alkyl, lower alkyl
substituted by halogen, lower alkoxy, lower alkoxy substituted by
halogen, --O--CH.sub.2-cycloalkyl, --NR.sup.4R.sup.5, --CN,
--CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl and pyrrolyl; or a
pharmaceutically active salt, racemic mixture, enantiomer, optical
isomer or tautomeric form thereof.
16. A compound of claim 14, having formula I-12 ##STR00235##
wherein R.sup.1 is hydrogen or halogen; n is 1 or 2; R.sup.2 is
lower alkyl R.sup.3 is ##STR00236## wherein R is hydrogen or lower
alkyl; R' is selected from hydrogen, halogen, lower alkyl, lower
alkoxy, lower alkyl substituted by halogen, lower alkoxy
substituted by halogen, --S(O).sub.2-lower alkyl, CN,
--NR.sup.4R.sup.5, and --C(O)-lower alkyl; R.sup.4 and R.sup.5 are
each independently hydrogen or lower alkyl; Ar is aryl- or
heteroaryl, wherein the rings of the aryl or heteroaryl group are
optionally substituted by one or two substituents R''; and R'' is
selected from hydrogen, halogen, lower alkyl, lower alkyl
substituted by halogen, lower alkoxy, lower alkoxy substituted by
halogen, --O--CH.sub.2-cycloalkyl, --NR.sup.4R.sup.5, --CN,
--CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl and pyrrolyl; or a
pharmaceutically active salt, racemic mixture, enantiomer, optical
isomer or tautomeric form thereof.
17. A compound of claim 14, having formula I-13 ##STR00237##
wherein R.sup.1 is hydrogen or halogen; n is 1 or 2; R.sup.2 is
lower alkyl R.sup.3 is ##STR00238## wherein R is hydrogen or lower
alkyl; R' is selected from hydrogen, halogen, lower alkyl, lower
alkoxy, lower alkyl substituted by halogen, lower alkoxy
substituted by halogen, --S(O).sub.2-lower alkyl, CN,
--NR.sup.4R.sup.5, and --C(O)-lower alkyl; R.sup.4 and R.sup.5 are
each independently hydrogen or lower alkyl; Ar is aryl- or
heteroaryl, wherein the rings of the aryl or heteroaryl group are
optionally substituted by one or two substituents R''; and R'' is
selected from hydrogen, halogen, lower alkyl, lower alkyl
substituted by halogen, lower alkoxy, lower alkoxy substituted by
halogen, --O--CH.sub.2-cycloalkyl, --NR.sup.4R.sup.5, --CN,
--CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl and pyrrolyl; or a
pharmaceutically active salt, racemic mixture, enantiomer, optical
isomer or tautomeric form thereof.
18. A compound of claim 14, having formula I-14 ##STR00239##
wherein R.sup.1 is hydrogen or halogen; n is 1 or 2; R.sup.2 is
lower alkyl R.sup.3 is ##STR00240## wherein R is hydrogen or lower
alkyl; R' is selected from hydrogen, halogen, lower alkyl, lower
alkoxy, lower alkyl substituted by halogen, lower alkoxy
substituted by halogen, --S(O).sub.2-lower alkyl, CN,
--NR.sup.4R.sup.5, and --C(O)-lower alkyl; R.sup.4 and R.sup.5 are
each independently hydrogen or lower alkyl; Ar is aryl- or
heteroaryl, wherein the rings of the aryl or heteroaryl group are
optionally substituted by one or two substituents R''; and R'' is
selected from hydrogen, halogen, lower alkyl, lower alkyl
substituted by halogen, lower alkoxy, lower alkoxy substituted by
halogen, --O--CH.sub.2-cycloalkyl, --NR.sup.4R.sup.5, --CN,
--CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl and pyrrolyl; or a
pharmaceutically active salt, racemic mixture, enantiomer, optical
isomer or tautomeric form thereof.
19. A compound of claim 14, having formula I-15 ##STR00241##
wherein R.sup.1 is hydrogen or halogen; n is 1 or 2; R.sup.2 is
lower alkyl R.sup.3 is ##STR00242## wherein R is hydrogen or lower
alkyl; R' is selected from hydrogen, halogen, lower alkyl, lower
alkoxy, lower alkyl substituted by halogen, lower alkoxy
substituted by halogen, --S(O).sub.2-lower alkyl, CN,
--NR.sup.4R.sup.5, and --C(O)-lower alkyl; R.sup.4 and R.sup.5 are
each independently hydrogen or lower alkyl; Ar is aryl- or
heteroaryl, wherein the rings of the aryl or heteroaryl group are
optionally substituted by one or two substituents R''; and R'' is
selected from hydrogen, halogen, lower alkyl, lower alkyl
substituted by halogen, lower alkoxy, lower alkoxy substituted by
halogen, --O--CH.sub.2-cycloalkyl, --NR.sup.4R.sup.5, --CN,
--CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl and pyrrolyl; or a
pharmaceutically active salt, racemic mixture, enantiomer, optical
isomer or tautomeric form thereof.
20. A compound of claim 1, having formula I-16 ##STR00243## wherein
R.sup.1 is hydrogen or halogen; n is 1 or 2; R.sup.2 is lower alkyl
R.sup.3 is ##STR00244## wherein R is hydrogen or lower alkyl; R' is
selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower
alkyl substituted by halogen, lower alkoxy substituted by halogen,
--S(O).sub.2-lower alkyl, CN, --NR.sup.4R.sup.5, and --C(O)-lower
alkyl; R.sup.4 and R.sup.5 are each independently hydrogen or lower
alkyl; Ar is aryl- or heteroaryl, wherein the rings of the aryl or
heteroaryl group are optionally substituted by one or two
substituents R''; and R'' is selected from hydrogen, halogen, lower
alkyl, lower alkyl substituted by halogen, lower alkoxy, lower
alkoxy substituted by halogen, --O--CH.sub.2-cycloalkyl,
--NR.sup.4R.sup.5, --CN, --CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl
and pyrrolyl; or a pharmaceutically active salt, racemic mixture,
enantiomer, optical isomer or tautomeric form thereof.
21. A compound of claim 1, selected from the group consisting of
rac-N-[(3S,4R)-1-(4-Methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrro-
lidin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-1-(4-Methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrro-
lidin-3-yl]-N-methyl-4-trifluoromethyl-benzamide;
rac-4-Dimethylamino-N-[(3S,4R)-1-(4-methanesulfonyl-piperazine-1-carbonyl-
)-4-phenyl-pyrrolidin-3-yl]-N-methyl-benzamide;
rac-N-[(3S,4R)-1-(4-Methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrro-
lidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-3,5-Dichloro-N-[(3S,4R)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-4-
-phenyl-pyrrolidin-3-yl]-N-methyl-benzamide;
rac-N-[(3S,4R)-4-(4-Chloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carb-
onyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(4-Chloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carb-
onyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-4-fluoro-N-methyl-benzamide; and
rac-3-Chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-pipe-
razine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide.
22. A compound of claim 1, selected from the group consisting of
rac-4-Cyano-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piper-
azine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide;
rac-3-Cyano-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piper-
azine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-3-fluoro-N-methyl-5-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-3,5-difluoro-N-methyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-3-fluoro-N-methyl-4-trifluoromethyl-benzamide;
rac-3-Chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-pipe-
razine-1-carbonyl)-pyrrolidin-3-yl]-2-fluoro-N-methyl-benzamide;
rac-Benzofuran-5-carboxylic
acid[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-ca-
rbonyl)-pyrrolidin-3-yl]-methyl-amide;
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-3,4-difluoro-N-methyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-N-methyl-4-(2,2,2-trifluoro-acetylamino)-benzam-
ide; and rac-2,3-Dihydro-benzofuran-5-carboxylic
acid[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-ca-
rbonyl)-pyrrolidin-3-yl]-methyl-amide.
23. A compound of claim 1, selected from the group consisting of
rac-Quinoxaline-6-carboxylic
acid[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-ca-
rbonyl)-pyrrolidin-3-yl]-methyl-amide;
rac-3-(Cyano-methyl-methyl)-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-metha-
nesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-N-ethyl-2-fluoro-5-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-dimethylamino-benzoyl)-pyrrol-
idin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-trifluoromethoxy-benzoyl)-pyr-
rolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
rac-4-Chloro-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide; rac-3-Methyl-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide; rac-6-Chloro-3-fluoro-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide; rac-6-Methyl-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide; and rac-6-Methoxy-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide.
24. A compound of claim 1, selected from the group consisting of
rac-5-Ethoxymethyl-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide; rac-4-Chloro-6-methyl-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide; rac-4-Methoxy-quinoline-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide; rac-4-Chloro-6-ethyl-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide; rac-5-Chloro-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide; rac-5-Cyano-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide; rac-5-Cyano-6-methoxy-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide;
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-3-fluoro-4-methoxy-N-methyl-benzamide;
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-4-cyclopropylmethoxy-N-methyl-benzamide; and
rac-2-Methoxy-pyrimidine-5-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide.
25. A compound of claim 1, selected from the group consisting of
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-6,N-dimethyl-nicotinamide;
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-2-fluoro-N-methyl-nicotinamide;
rac-6-Cyano-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrol-
idin-3-yl]-N-methyl-nicotinamide;
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-N-methyl-6-(2,2,2-trifluoro-ethoxy)-nicotinamide;
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-5,N-dimethyl-nicotinamide;
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-5-fluoro-N-methyl-nicotinamide;
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-6-fluoro-N-methyl-nicotinamide;
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-6-methoxy-N-methyl-nicotinamide;
N-{(3RS,4SR)-4-(4-Chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl--
benzamide; and
N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(4-fluoro-benzoyl)-pyrrolidin-3-yl]-4--
methoxy-N-methyl-3-trifluoromethyl-benzamide.
26. A compound of claim 1, selected from the group consisting of
N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(4-fluoro-2-methyl-benzoyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(6-cyano-pyridine-3-carbonyl)-pyrrolid-
in-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(4-isopropoxy-benzoyl)-pyrrolidin-3-yl-
]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(4-cyano-benzoyl)-pyrrolidin-3-yl]-4-m-
ethoxy-N-methyl-3-trifluoromethyl-benzamide;
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acet-
amide;
N-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbo-
nyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluor-
omethyl-benzamide; Cis-4-Hydroxy-cyclohexanecarboxylic acid
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide;
3-Cyclopropyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopr-
opanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-propionami-
de;
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbon-
yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3,3,N-trimethyl-butyramide;
and
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbo-
nyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-3,N-dimet-
hyl-butyramide.
27. A compound of claim 1, selected from the group consisting of
1-(4-Fluoro-phenyl)-cyclopentanecarboxylic acid
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide;
N-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetam-
ide;
N-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-ac-
etamide;
N-{(3RS,4SR)-4-(4-Chloro-2-methyl-phenyl)-1-[1-(1-methyl-cyclopro-
panecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-3-trifluor-
omethyl-benzamide;
N-{(3R,4S)-4-(4-Chloro-2-methyl-phenyl)-1-[1-(1-methyl-cyclopropanecarbon-
yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoro-
methyl-benzamide;
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-2-(tetrahydro-pyran-4-yl-
)-acetamide;
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-isob-
utyramide;
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(4-methoxy-cyclohexaneca-
rbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide;
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[2-(1,1-dioxo-1lambda*6*-thiomorph-
olin-4-yl)-acetyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide-
; and
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(morpholine-4-carbonyl)-pyrro-
lidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide.
28. A compound of claim 1, selected from the group consisting of
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-ca-
rbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide;
N-{(3RS,4SR)-4-(4-Chloro-phenyl)-1-[1-(3-methanesulfonyl-propyl)-piperidi-
ne-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benza-
mide;
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(4-morpholin-4-yl-benzoyl)-py-
rrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide;
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(6-morpholin-4-yl-pyridine-3-carbo-
nyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide;
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(6-methyl-pyridazine-4-carbonyl)-p-
yrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide;
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(6-morpholin-4-yl-pyridazine-3-car-
bonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide;
N-[(3RS,4RS)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichlor-
o-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide;
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl-
)-benzoyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide;
2-(4-Cyano-phenyl)-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbo-
nyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide;
N-[(3RS,4SR)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichlor-
o-phenyl)-pyrrolidin-3-yl]-2-(3,4-difluoro-phenyl)-N-methyl-acetamide;
and
N-[(3RS,4SR)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichlor-
o-phenyl)-pyrrolidin-3-yl]-2-(2,3-difluoro-phenyl)-N-methyl-acetamide.
29. A compound of claim 1, selected from the group consisting of
4-Chloro-N-[(3S,4R)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine-
-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;
4-Chloro-N-{(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbon-
yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-ben-
zamide;
4-{(3SR,4RS)-3-(4-Chloro-phenyl)-4-[(4-chloro-3-trifluoromethyl-be-
nzoyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic
acid tert-butyl ester;
2-(4-Chloro-phenyl)-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carb-
onyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide;
N-[(3RS,4SR)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichlor-
o-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-propionamide;
4-Chloro-N-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4--
dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;
4-Trifluoromethyl-pyridine-2-carboxylic acid
{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide;
6-Methyl-pyridazine-4-carboxylic acid
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide;
4-Chloro-3-cyclopropyl-N-{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl--
cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-ben-
zamide.
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropaneca-
rbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4,4,4-trifluoro-N-methyl-b-
utyramide; and
2-Cyclopropylmethoxy-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl--
cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-ace-
tamide;
30. A pharmaceutical composition comprising a compound of formula I
##STR00245## wherein R.sup.1 is hydrogen, halogen, cyano or lower
alkyl; n is 1, 2 or 3; R.sup.2 is hydrogen or lower alkyl; R.sup.3
is aryl- or a heteroaryl, wherein the rings of the aryl or
heteroaryl group are optionally substituted by one or two
substituents R'; R' is selected from hydrogen, halogen, lower
alkyl, lower alkoxy, lower alkyl substituted by halogen, lower
alkoxy substituted by halogen, --S(O).sub.2-lower alkyl, CN,
--NR.sup.4R.sup.5, --C(O)-lower alkyl, heterocyclyl and heteroaryl;
R.sup.4 and R.sup.5 are each independently hydrogen, --(CO)CF.sub.3
or lower alkyl or is a non aromatic heterocyclic group ##STR00246##
wherein X is N or CH; Y is --CH(R.sup.7)--; --N(R.sup.7')--, O or
SO.sub.2 R.sup.6 is hydrogen, lower alkyl or hydroxy; R.sup.7 is
hydrogen, hydroxy, .dbd.O, lower alkyl, lower alkoxy,
--S(O).sub.2-lower alkyl, --C(O)-lower alkyl, --C(O)CH.sub.2O-lower
alkyl, --CH.sub.2CN, --C(O)CH.sub.2CN, --C(O)-cycloalkyl wherein
the cycloalkyl group is optionally substituted by cyano, lower
alkyl, one or two halogen atoms, .dbd.O or amino, or is
--C(O)O-lower alkyl, --NH-lower alkyl, --NRC(O)O-lower alkyl,
--NRC(O)-lower alkyl or --CH.sub.2O-lower alkyl; R.sup.7' is
hydrogen, lower alkyl, --(CH.sub.2).sub.q--S(O).sub.2-lower alkyl,
--(CH.sub.2).sub.q--S(O).sub.2-cycloalkyl, --C(O)-lower alkyl,
--(CH.sub.2).sub.q-cycloalkyl, --C(O)CH.sub.2--O-lower alkyl,
--(CH.sub.2).sub.qCN, --C(O)CN, --C(O)CH.sub.2CN, lower alkyl
substituted by halogen, lower alkenyl substituted by halogen,
--C(O)-cycloalkyl wherein the cycloalkyl group is optionally
substituted by cyano, lower alkyl, one or two halogen atoms, .dbd.O
or amino, or is --C(O)O-lower alkyl or --(CH.sub.2).sub.qO-lower
alkyl and q is 0-3; or R.sup.6 and R.sup.7 together with the carbon
atoms to which they are attached form a five or six-membered non
aromatic ring or R.sup.6 and R.sup.7' together with the nitrogen
and carbon atoms to which they are attached form a five or
six-membered non aromatic ring; p is0, 1 or 2; Ar is aryl- or
heteroaryl, wherein the rings of the aryl or heteroaryl group are
optionally substituted by one or two substituents R''; R'' is
selected from hydrogen, halogen, lower alkyl, lower alkyl
substituted by halogen, lower alkoxy, lower alkoxy substituted by
halogen, --O--CH.sub.2-cycloalkyl, --NR.sup.4R.sup.5, --CN,
--CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl and pyrrolyl; m is 0, 1
or 2 and o is 0; and o is 0, 1 or 2 and m is 1 or a
pharmaceutically active salt, racemic mixture, enantiomer, optical
isomer or tautomeric form thereof and a pharmaceutically acceptable
carrier.
Description
PRIORITY TO RELATED APPLICATION(S)
[0001] This application claims the benefit of European Patent
Application No. 08158326.2, filed Jun. 16, 2008, which is hereby
incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] NK2 receptors are found in the periphery and the central
nervous system. In the periphery, the NK2 receptor is mainly found
in the smooth muscle of the gastrointestinal, respiratory and
urinary tracts. In the central nervous system, the presence of NK2
binding sites in the rat brain has been demonstrated in the
hippocampus, thalamus and the septum. The presence of NK2 binding
sites in several limbic regions suggest that NK2 receptors may
modulate emotional processes. Based on this expression pattern, the
therapeutic potential of several selective NK2 receptor antagonists
has been investigated in animal models of anxiety and
depression.
[0003] Interestingly, Saredutant (SR48968), a selective and brain
penetrant NK2 receptor antagonist was effective in exploration
based procedures sensitive to anxiolytics such as elevated plus
maze and the light/dark test in rodents. Efficacy in procedures
sensitive to anti-depressants in mouse, gerbils and marmosets is
also been documented for Saredutant. Currently Saredutant is in
clinical development for depression (Phase III).
[0004] Together these data suggest that NK2 receptor antagonists
have potential as a new class of anti-depressants and
anxiolytics.
[0005] Furthermore, NK2 receptor antagonists may be used in the
treatment of schizophrenia.
SUMMARY OF THE INVENTION
[0006] The present invention provides compounds of formula I
##STR00002##
wherein [0007] R.sup.1 is hydrogen, halogen, cyano or lower alkyl;
n is 1, 2 or 3; [0008] R.sup.2 is hydrogen or lower alkyl; [0009]
R.sup.3 is aryl- or a heteroaryl, wherein the rings of the aryl or
heteroaryl group are optionally substituted by one or two
substituents R'; [0010] R' is selected from hydrogen, halogen,
lower alkyl, lower alkoxy, lower alkyl substituted by halogen,
lower alkoxy substituted by halogen, --S(O).sub.2-lower alkyl, CN,
--NR.sup.4R.sup.5, --C(O)-lower alkyl, heterocyclyl or heteroaryl;
[0011] R.sup.4 and R.sup.5 are each independently hydrogen,
--(CO)CF.sub.3 or lower alkyl or is a non aromatic heterocyclic
group
##STR00003##
[0011] wherein [0012] X is N or CH; [0013] Y is --CH(R.sup.7)--;
--N(R.sup.7')--, O, SO.sub.2; [0014] R.sup.6 is hydrogen, lower
alkyl or hydroxy; [0015] R.sup.7 is hydrogen, hydroxy, .dbd.O,
lower alkyl, lower alkoxy, --S(O).sub.2-lower alkyl, --C(O)-lower
alkyl, --C(O)CH.sub.2O-lower alkyl, --CH.sub.2CN, --C(O)CH.sub.2CN,
--C(O)-cycloalkyl wherein the cycloalkyl group is optionally
substituted by cyano, lower alkyl, one or two halogen atoms, .dbd.O
or amino, or is --C(O)O-lower alkyl, --NH-lower alkyl,
--NRC(O)O-lower alkyl, --NRC(O)-lower alkyl or --CH.sub.2O-lower
alkyl; [0016] R.sup.7' is hydrogen, lower alkyl,
--(CH.sub.2).sub.q--S(O).sub.2-lower alkyl,
--(CH.sub.2).sub.q--S(O).sub.2-cycloalkyl, --C(O)-lower alkyl,
--(CH.sub.2).sub.q-cycloalkyl, --C(O)CH.sub.2--O-lower alkyl,
--(CH.sub.2).sub.qCN, --C(O)CN, --C(O)CH.sub.2CN, lower alkyl
substituted by halogen, lower alkenyl substituted by halogen,
--C(O)-cycloalkyl wherein the cycloalkyl group is optionally
substituted by cyano, lower alkyl, one or two halogen atoms, .dbd.O
or amino, or is --C(O)O-lower alkyl or --(CH.sub.2).sub.qO-lower
alkyl and q is 0-3; or [0017] R.sup.6 and R.sup.7 together with the
carbon atoms to which they are attached form a five or six-membered
non aromatic ring or [0018] R.sup.6 and R.sup.7' together with the
nitrogen and carbon atoms to which they are attached form a five or
six-membered non aromatic ring; [0019] p is 0, 1 or 2; [0020] Ar is
aryl- or heteroaryl, wherein the rings of the aryl or heteroaryl
group are optionally substituted by one or two substituents R'';
[0021] R'' is selected from hydrogen, halogen, lower alkyl, lower
alkyl substituted by halogen, lower alkoxy, lower alkoxy
substituted by halogen, --O--CH.sub.2-cycloalkyl,
--NR.sup.4R.sup.5, --CN, --CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl
and pyrrolyl; [0022] m is 0, 1 or 2 and o is 0; and [0023] o is 0,
1 or 2 and m is 1 or pharmaceutically active salts, racemic
mixtures, enantiomers, optical isomers or tautomeric forms
thereof.
[0024] The invention also provides pharmaceutical compositions
containing compounds of formula I and methods for the manufacture
of the compounds and compositions of the invention. The present
compounds are high potential NK-2 receptor antagonists for the
treatment of depression and anxiety. Therefore, the invention
further provides methods for the treatment of depression and
anxiety.
DETAILED DESCRIPTION OF THE INVENTION
[0025] 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. It must be noted that, as
used in the specification and the appended claims, the singular
forms "a", "an," and "the" include plural forms unless the context
clearly dictates otherwise.
[0026] As used herein, the term "lower alkyl" denotes a straight-
or branched-chain hydrocarbon group containing from 1-8 carbon
atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl,
i-butyl, t-butyl and the like. Preferred lower alkyl groups are
groups with 1-4 carbon atoms.
[0027] The term "lower alkyl substituted by halogen" denotes an
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, --CH.sub.2CH.sub.2CF.sub.3,
--CH.sub.2CF.sub.2CF.sub.3 and the like. Preferred lower alkyl
substituted by halogen groups are groups having 1-4 carbon
atoms.
[0028] The term "lower alkoxy" denotes an alkyl group as defined
above, which is attached via an oxygen atom, for example, methoxy,
ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy, 2-butoxy, t-butoxy
and the like. Preferred alkoxy groups are groups with 1-4 carbon
atoms.
[0029] The term "lower alkoxy substituted by halogen" denotes an
alkoxy group as defined above wherein at least one hydrogen atom is
replaced by halogen. Preferred lower alkoxy substituted by halogen
groups are groups having 1-4 carbon atoms.
[0030] The term "halogen" denotes chlorine, iodine, fluorine and
bromine.
[0031] The term "non aromatic heterocyclyl" denotes a saturated
cyclic ring containing from 5-7 ring atoms, wherein at least one of
the ring atoms is heteroatom, selected from N, O and S, for example
morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, and
the like. Preferred non aromatic heterocyclyl group is
piperizinyl.
[0032] 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, benzyl, naphthyl or indanyl. Preferred is the
phenyl group.
[0033] 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 contains at least one heteroatom selected
from N, O and S, for example quinoxalinyl, dihydroisoquinolinyl,
pyrazinyl, pyrazolyl, pyridinyl, pyridyl, pyrimidinyl, oxadiazolyl,
triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, furyl,
imidazolyl, benzofuranyl, dihydrobenzofuranyl and
benzo[1,3]dioxole. Preferred heteroaryl group is pyridinyl,
pyrazolyl, benzofuranyl, dihydrobenzofuranyl, benzo[1,3]dioxole,
and quinoxalinyl.
[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 salt"
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] The following groups of compounds of formula I are
preferred: Compounds of formula IA
##STR00004##
wherein [0038] R.sup.1 is hydrogen or halogen; n is 1 or 2; [0039]
R.sup.2 is lower alkyl [0040] R.sup.3 is
[0040] ##STR00005## [0041] X is N or CH; [0042] R.sup.6 is
hydrogen, lower alkyl or hydroxy; [0043] R.sup.7 is hydrogen,
hydroxy, .dbd.O, lower alkyl, lower alkoxy, --S(O).sub.2-lower
alkyl, --C(O)-lower alkyl, --C(O)CH.sub.2O-lower alkyl,
--CH.sub.2CN, --C(O)CH.sub.2CN, --C(O)-cycloalkyl wherein the
cycloalkyl group is optionally substituted by cyano, lower alkyl,
one or two halogen atoms, .dbd.O or amino, or is --C(O)O-lower
alkyl, --NH-lower alkyl, --NRC(O)O-lower alkyl, --NRC(O)-lower
alkyl or --CH.sub.2O-lower alkyl; [0044] R.sup.7' is hydrogen,
lower alkyl, --(CH.sub.2).sub.q--S(O).sub.2-lower alkyl,
--(CH.sub.2).sub.q--S(O).sub.2-cycloalkyl, --C(O)-lower alkyl,
--(CH.sub.2).sub.q-cycloalkyl, --C(O)CH.sub.2--O-lower alkyl,
--(CH.sub.2).sub.qCN, --C(O)CN, --C(O)CH.sub.2CN, lower alkyl
substituted by halogen, lower alkenyl substituted by halogen,
--C(O)-cycloalkyl wherein the cycloalkyl group is optionally
substituted by cyano, lower alkyl, one or two halogen atoms, .dbd.O
or amino, or is --C(O)O-lower alkyl or --(CH.sub.2).sub.qO-lower
alkyl and q is 0-3; or [0045] R.sup.6 and R.sup.7 together with the
carbon atoms to which they are attached form a five or six-membered
non aromatic ring or [0046] R.sup.6 and R.sup.7' together with the
nitrogen and carbon atoms to which they are attached form a five or
six-membered non aromatic ring; [0047] Ar is aryl- or heteroaryl,
wherein the rings of the aryl or heteroaryl group are optionally
substituted by one or two substituents R''; and [0048] R'' is
selected from hydrogen, halogen, lower alkyl, lower alkyl
substituted by halogen, lower alkoxy, lower alkoxy substituted by
halogen, --O--CH.sub.2-cycloalkyl, --NR.sup.4R.sup.5, --CN,
--CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl and pyrrolyl; or
pharmaceutically active salts, racemic mixtures, enantiomers,
optical isomers or tautomeric forms thereof.
[0049] Compounds of Formula IB
##STR00006##
wherein [0050] R.sup.1 is hydrogen, halogen, cyano or lower alkyl;
n is 1, 2 or 3; [0051] R' is selected from hydrogen, halogen, lower
alkyl, lower alkoxy, lower alkyl substituted by halogen, lower
alkoxy substituted by halogen, --S(O).sub.2-lower alkyl, CN,
--NR.sup.4R.sup.5, --C(O)-lower alkyl, heterocyclyl and heteroaryl;
[0052] R.sup.4 and R.sup.5 are each independently hydrogen,
--(CO)CF.sub.3 or lower alkyl [0053] Ar is aryl- or heteroaryl,
wherein the rings of the aryl or heteroaryl group are optionally
substituted by one or two substituents R''; and [0054] R'' is
selected from hydrogen, halogen, lower alkyl, lower alkyl
substituted by halogen, lower alkoxy, lower alkoxy substituted by
halogen, --O--CH.sub.2-cycloalkyl, --NR.sup.4R.sup.5, --CN,
--CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl and pyrrolyl; or
pharmaceutically active salts, racemic mixtures, enantiomers,
optical isomers or tautomeric forms thereof.
[0055] Compounds of Formula IC
##STR00007##
wherein [0056] R.sup.1 is hydrogen, halogen, cyano or lower alkyl;
n is 1, 2 or 3; [0057] R.sup.2 is hydrogen or lower alkyl; [0058]
R' is selected from hydrogen, halogen, lower alkyl, lower alkoxy,
lower alkyl substituted by halogen, lower alkoxy substituted by
halogen, --S(O).sub.2-lower alkyl, CN, --NR.sup.4R.sup.5,
--C(O)-lower alkyl, heterocyclyl and heteroaryl; [0059] R.sup.4 and
R.sup.5 are each independently hydrogen, --(CO)CF.sub.3 or lower
alkyl [0060] Ar is aryl- or heteroaryl, wherein the rings of the
aryl or heteroaryl group are optionally substituted by one or two
substituents R''; [0061] R'' is selected from hydrogen, halogen,
lower alkyl, lower alkyl substituted by halogen, lower alkoxy,
lower alkoxy substituted by halogen, --O--CH.sub.2-cycloalkyl,
--NR.sup.4R.sup.5, --CN, --CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl
and pyrrolyl; or pharmaceutically active salts, racemic mixtures,
enantiomers, optical isomers or tautomeric forms thereof.
[0062] Preferred compounds of formula IA are [0063]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
[0064]
rac-4-chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfon-
yl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide;
[0065]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-4-ethyl-N-methyl-benzamide; [0066]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-N-methyl-4-trifluoromethoxy-benzamide;
[0067]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-3-fluoro-N-methyl-4-trifluoromethyl-benzamide;
[0068]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-pipera-
zine-1-carbonyl)-pyrrolidin-3-yl]-2-fluoro-N-methyl-3-trifluoromethyl-benz-
amide; [0069]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-4-dimethylamino-N-methyl-benzamide;
[0070]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-4-fluoro-3,N-dimethyl-benzamide; [0071]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-3-fluoro-4-methoxy-N-methyl-benzamide;
[0072] rac-2,2-difluoro-benzo[1,3]dioxole-5-carboxylic
acid[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-ca-
rbonyl)-pyrrolidin-3-yl]-methyl-amide; [0073]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-N-methyl-4-pyrrol-1-yl-benzamide; [0074]
rac-3-chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-pipe-
razine-1-carbonyl)-pyrrolidin-3-yl]-4-fluoro-N-methyl-benzamide;
[0075]
rac-3-chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-pipe-
razine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-benzamide;
[0076]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-4-fluoro-N-methyl-3-trifluoromethyl-benzamide;
[0077]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-pipera-
zine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-benzamide;
[0078]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1--
carbonyl)-pyrrolidin-3-yl]-2-fluoro-N-methyl-5-trifluoromethyl-benzamide;
[0079]
N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-((S)-4-methanesulfonyl-3-meth-
yl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluorom-
ethyl-benzamide; [0080]
N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-((R)-4-methanesulfonyl-3-methyl-pipe-
razine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-b-
enzamide; [0081]
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl--
benzamide; [0082]
N-{(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piper-
idine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-be-
nzamide; [0083]
4-{(3SR,4RS)-3-(4-chloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)-
-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester; [0084]
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromet-
hyl-benzamide; [0085]
4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropane-
carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluorometh-
yl-benzamide; [0086]
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-3-trifluorometh-
oxy-benzamide; [0087]
4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropane-
carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-methoxy-N-methyl-benza-
mide; [0088]
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-benzamide;
[0089]
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropaneca-
rbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-(4-fluoro-phenyl)-N-meth-
yl-propionamide; [0090]
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; [0091]
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-isopropyl-piperidine-4-carbonyl)-py-
rrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
[0092]
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine-4-carb-
onyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
[0093]
N-{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarb-
onyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluo-
romethyl-benzamide; [0094] 5-chloro-pyridine-2-carboxylic acid
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide; [0095]
3-cyano-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanec-
arbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-benzami-
de; [0096]
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3,3,3-trifluoro-propyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluorometh-
yl-benzamide; [0097]
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3,3-dimethyl-butyl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
[0098]
2-cyclopentyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl--
cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-ace-
tamide; [0099]
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(2,2-dimethyl-propyl)-piperidine-4--
carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
[0100]
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-ethyl-piperidine-4-carbonyl)-
-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
[0101]
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3-methylsulfanyl-propyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzam-
ide; [0102]
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3-methanesulfonyl-propyl)-piperidi-
ne-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benza-
mide; [0103]
4-{(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benz-
oyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic
acid tert-butyl ester; [0104]
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; [0105]
N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichlor-
o-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
[0106]
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(3,3,3-trifluoro-propyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromet-
hyl-benzamide; [0107]
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(1-ethanesulfonyl-piperidine-4-car-
bonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
[0108]
N-[(3RS,4SR)-1-(1-cyclopropanesulfonyl-piperidine-4-carbonyl)-4-(3-
,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl--
benzamide; [0109]
N-[(3RS,4SR)-1-[1-(2-cyano-ethyl)-piperidine-4-carbonyl]-4-(3,4-dichloro--
phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
[0110]
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(2-methoxy-ethyl)-piperi-
dine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-ben-
zamide; [0111]
4-{(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benz-
oyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic
acid ethyl ester; [0112]
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl-
)-benzoyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide-
; [0113]
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(2-fluoro-allyl)-piperi-
dine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-ben-
zamide; [0114]
2-cyclopentyl-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)--
4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide; [0115]
4-chloro-N-[(3S,4R)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine-
-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;
[0116]
4-chloro-N-{(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbon-
yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-ben-
zamide; [0117]
4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrro-
lidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide; [0118]
4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyclopropanesulfonyl-piper-
idine-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;
[0119]
4-chloro-N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(tetrahydro-pyran-4-
-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-be-
nzamide; [0120]
4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyanomethyl-piperidine-4-c-
arbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;
[0121]
4-chloro-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,-
4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;
[0122]
4-chloro-N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(2-cyano-ethyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide;
[0123] 4-trifluoromethyl-pyridine-2-carboxylic acid
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide; [0124]
4-chloro-N-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4--
dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;
[0125] 4-trifluoromethyl-pyridine-2-carboxylic acid
{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide; [0126]
3-bromo-4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cycl-
opropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzami-
de; [0127]
4-chloro-3-cyclopropyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[-
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}--
N-methyl-benzamide; [0128]
4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropane-
carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-ethyl-N-methyl-benzami-
de; and [0129]
4-chloro-3-cyclopropyl-N-{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl--
cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-ben-
zamide.
[0130] Preferred compounds of formula IB are [0131]
rac-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; [0132]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-pyrrolidin-3-
-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; [0133]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-dimethylamino-benzoyl)-pyrrol-
idin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; [0134]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-fluoro-benzoyl)-pyrrolidin-3--
yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; [0135]
rac-N-[(3S,4R)-1-(3-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; [0136]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(2-fluoro-5-methanesulfonyl-benz-
oyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
[0137]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-trifluoromethyl-benzoy-
l)-pyrrolidin-3yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
[0138]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-trifluoromethoxy-benzoyl)-pyr-
rolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
[0139]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(3-methanesulfonyl-benzoyl)-pyrr-
olidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; [0140]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methoxy-3-methyl-benzoyl)-pyr-
rolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
[0141]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(3,5-dimethyl-benzoyl)-pyrrolidi-
n-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; [0142]
rac-N-[(3S,4R)-1-(4-acetyl-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3--
yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; [0143]
rac-4-methyl-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide; [0144]
rac-4-chloro-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrro-
lidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide; [0145]
rac-3-tert-butyl-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-p-
yrrolidin-3-yl]-4-methoxy-N-methyl-benzamide; [0146]
rac-6-chloro-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrro-
lidin-3-yl]-N-methyl-nicotinamide; [0147]
rac-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-N-methyl-6-trifluoromethyl-nicotinamide; and [0148]
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl-
)-benzoyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide-
.
[0149] Preferred compounds of formula IC are [0150]
rac-N-[(3S,4R)-1-(benzofuran-5-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolid-
in-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; [0151]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(pyridine-4-carbonyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; [0152]
rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(2,6-dichloro-pyridine-4-carbony-
l)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;
and [0153]
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(1,5-dimethyl-1H-pyrazole-
-3-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzami-
de.
[0154] A further embodiment of the invention are compounds of
formula I-1
##STR00008##
wherein [0155] R.sup.1 is hydrogen, halogen, cyano or lower alkyl;
n is 1, 2 or 3; [0156] R.sup.2 is hydrogen or lower alkyl; [0157]
R.sup.3 is aryl- or heteroaryl, wherein the rings of the aryl or
heteroaryl group are optionally substituted by one or two
substituents R'; [0158] R' is selected from hydrogen, halogen,
lower alkyl, lower alkoxy, lower alkyl substituted by halogen,
lower alkoxy substituted by halogen, --S(O).sub.2-lower alkyl, CN,
--NR.sup.4R.sup.5, and --C(O)-lower alkyl; [0159] R.sup.4 and
R.sup.5 are each independently hydrogen, --(CO)CF.sub.3 or lower
alkyl or is a non aromatic heterocyclic group
##STR00009##
[0159] wherein [0160] X is N or CH; [0161] when X is CH, Y is
--CH(R.sup.7)--; --N(R.sup.7')--, or O; or [0162] when X is N, Y is
--CH(R.sup.7)--; --N(R.sup.7')--, O or SO.sub.2; [0163] R.sup.6 is
hydrogen, lower alkyl or hydroxy; [0164] R.sup.7 is hydrogen,
hydroxy, .dbd.O, lower alkyl, --S(O).sub.2-lower alkyl,
--C(O)-lower alkyl, --C(O)CH.sub.2O-lower alkyl, --CH.sub.2CN,
--C(O)CH.sub.2CN, --C(O)-cycloalkyl wherein the cycloalkyl group is
optionally substituted by cyano, lower alkyl, one or two halogen
atoms, .dbd.O or amino, or is --C(O)O-lower alkyl, --NH-lower
alkyl, --NRC(O)O-lower alkyl, --NRC(O)-lower alkyl or
--CH.sub.2O-lower alkyl; and [0165] R.sup.7' is hydrogen, lower
alkyl, --S(O).sub.2-lower alkyl, --C(O)-lower alkyl,
--C(O)CH.sub.2--O-lower alkyl, --CH.sub.2CN, --C(O)CN,
--C(O)CH.sub.2CN, --C(O)-cycloalkyl wherein the cycloalkyl group is
optionally substituted by cyano, lower alkyl, one or two halogen
atoms, .dbd.O or amino, or is --C(O)O-lower alkyl or
--CH.sub.2O-lower alkyl; or [0166] R.sup.6 and R.sup.7 together
with the carbon atoms to which they are attached form a five or
six-membered non aromatic ring or [0167] R.sup.6 and
R.sup.7.varies. together with the nitrogen and carbon atoms to
which they are attached form a five or six-membered non aromatic
ring; [0168] p is 0,1 or 2; [0169] Ar is aryl- or heteroaryl,
wherein the rings of the aryl or heteroaryl group are optionally
substituted by one or two substituents R''; [0170] R'' is selected
from hydrogen, halogen, lower alkyl, lower alkyl substituted by
halogen, lower alkoxy, lower alkoxy substituted by halogen,
--O--CH.sub.2-cycloalkyl, --NR.sup.4R.sup.5, --CN,
--CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl and pyrrolyl; [0171] m is
0, 1 or 2 and o is 0; and [0172] is 0, 1 or 2 and m is 1 or
pharmaceutically active salts, racemic mixtures, enantiomers,
optical isomers or tautomeric forms thereof.
[0173] More specifically, an embodiment of the present invention
are compounds of formula I-11
##STR00010##
wherein [0174] R.sup.1 is hydrogen or halogen; n is 1 or 2; [0175]
R.sup.2 is lower alkyl [0176] R.sup.3 is
##STR00011##
[0176] wherein R is hydrogen or lower alkyl; and [0177] R' is
selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower
alkyl substituted by halogen, lower alkoxy substituted by halogen,
--S(O).sub.2-lower alkyl, CN, --NR.sup.4R.sup.5, and --C(O)-lower
alkyl; [0178] R.sup.4 and R.sup.5 are each independently hydrogen
or lower alkyl; [0179] Ar is aryl- or heteroaryl, wherein the rings
of the aryl or heteroaryl group are optionally substituted by one
or two substituents R''; [0180] R'' is selected from hydrogen,
halogen, lower alkyl, lower alkyl substituted by halogen, lower
alkoxy, lower alkoxy substituted by halogen,
--O--CH.sub.2-cycloalkyl, --NR.sup.4R.sup.5, --CN,
--CH(CH.sub.3)CN, --CH.sub.2O-lower alkyl and pyrrolyl; or
pharmaceutically active salts, racemic mixtures, enantiomers,
optical isomers or tautomeric forms thereof.
[0181] An embodiment of the present invention are further compounds
of formula I-12
##STR00012##
wherein R.sup.1, n, R and Ar are as described above for compounds
of formula I-11
[0182] An embodiment of the present invention are further compounds
of formula I-13
##STR00013##
wherein R.sup.1, n, R' and Ar are as described above for compounds
of formula I-11
[0183] An embodiment of the present invention are further compounds
of formula I-14
##STR00014##
wherein R.sup.1, n, and Ar are as described above for compounds of
formula I-11.
[0184] An embodiment of the present invention are further compounds
of formula I-15
##STR00015##
wherein R.sup.1, n, R' and Ar are as described above for compounds
of formula I-11.
[0185] An embodiment of the present invention are further compounds
of formula I-16
##STR00016##
wherein R.sup.1, n, R and Ar are as described above for compounds
of formula I-11.
[0186] The preparation of compounds of formula I of the present
invention can be carried out in sequential or convergent synthetic
routes. Syntheses of the compounds of the invention are shown in
the following scheme. The skills required for carrying out the
reaction and purification of the resulting products are known to
those skilled in the art. The substituents and indices used in the
following description of the processes have the significance given
herein before unless indicated to the contrary.
[0187] In more detail, the compounds of formula I can be
manufactured by the methods given below, by the methods given in
the examples or by analogous methods. Appropriate reaction
conditions for the individual reaction steps are known to a person
skilled in the art. The reaction sequence is not limited to the one
displayed in scheme 1, however, depending on the starting materials
and their respective reactivity the sequence of reaction steps can
be freely altered. Starting materials are either commercially
available or can be prepared by methods analogous to the methods
given below, by methods described in references cited in the
description or in the examples, or by methods known in the art.
[0188] The present compounds of formula I and their
pharmaceutically acceptable salts can be prepared by processes
described below, which process comprises [0189] a) coupling a
compound of formula VIII
##STR00017##
[0189] with a suitable carbamoyl chloride, acid chloride or
carboxylic acid to obtain a compound of formula I
##STR00018##
wherein the substituents R.sup.1, R.sup.2, R.sup.3 and Ar are as
defined above and if desired, converting the compounds obtained
into pharmaceutically acceptable acid addition salts; or [0190] b)
coupling a compound with formula XI
##STR00019##
[0190] with a corresponding aryl carboxylic acid or aryl acid
chloride, to obtain a compound of formula I
##STR00020##
wherein the substituents R.sup.1, R.sup.2, R.sup.3 and Ar are as
defined above, and if desired, converting the compounds obtained
into pharmaceutically acceptable acid addition salts.
[0191] The following schemes 1 and 2 describe the processes for
preparation of compounds of formula I in more detail. The starting
material of formula II is known compound and can be prepared
according to methods known in the art.
##STR00021## ##STR00022##
R.sup.1, R.sup.2, R.sup.3 and Ar have the same meanings as
described above.
[0192] The 3,4-disubstituted pyrrolidine IV is prepared via a
stereo specific 1,3-dipolar cycloaddition between the
2-nitrostyrene derivative II and the azomethine ylide generated in
situ from the
N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine
III in the presence of a catalytic amount of acid, such as TFA.
Reduction of the nitro moiety of IV using standard conditions for
example SnCl.sub.2.H.sub.2O yields V. The amino moiety is
subsequently alkylated to produce VI. Reaction of VI with an acid
chloride in a presence of a base, usually Et.sub.3N, or an amide
coupling with a carboxylic acid yields VII. Selective
N-debenzylation is then carried out using several known procedures
which are compatible with the substitution patterns of the aromatic
rings to afford VIII. Finally derivatives I are prepared via a
coupling with a suitable carbamoyl chloride, acid chloride or
carboxylic acide.
##STR00023## ##STR00024##
[0193] R.sup.1, R.sup.2, R.sup.3 and Ar have the same meanings as
described above.
[0194] Alternatively, the secondary amine of the intermediates VI
can be protected, for instance with a Boc group, followed by a
selective debenzylation to produce IX. Then a coupling with a
suitable carbamoyl chloride, acid chloride or carboxylic acid gives
X. Deprotection with TFA affords the free amine XI, which after
coupling with a carboxylic acid or acid chloride gives derivatives
I.
[0195] The salt formation is effected at room temperature in
accordance with methods which are known per se and which are
familiar to any person skilled in the art. Not only salts with
inorganic acids, but also salts with organic acids come into
consideration. Hydrochlorides, hydrobromides, sulphates, nitrates,
citrates, acetates, maleates, succinates, methan-sulphonates,
p-toluenesulphonates and the like are examples of such salts.
[0196] As mentioned earlier, the compounds of formula I and their
pharmaceutically usable addition salts possess valuable
pharmacological properties. Compounds of the present invention are
high potential NK-2 receptor antagonists for the treatment of
depression and anxiety. The compounds were investigated in
accordance with the tests given hereinafter.
Experimental Procedure
[0197] The compounds were investigated in accordance with the tests
given hereinafter.
[3H]SR48968 Competition Binding Assay
[0198] hNK.sub.2 receptor binding experiment were performed using
[.sup.3H]SR48968 (Catalog No. TRK398, specific activity: 27.0
Ci/mmol, Amersham, GE Healthcare UK limited, Buckinghamshire, UK)
and membrane isolated from CHO cells stably expressing recombinant
human NK2 receptor (product No. 6110510, Perkin Elmer biosignal
Inc., Shelton, Conn., USA). 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, 3 mM MnCl.sub.2, 4
.mu.g/mL Chymostatin, 0.04% BSA binding buffer at pH 7.4 to a final
assay concentration of 6.5 .mu.g protein/well. For inhibition
experiments, membranes were incubated with [.sup.3H]SR48968 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% polyethylenimine, 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
1-{2-[(R)-3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-
-3-yl]-ethyl}-4-phenyl-piperidine-4-carboxylic acid amide. 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] was the concentration
of radioligand and K.sub.D was its dissociation constant at the
receptor, derived from the saturation isotherm.
[0199] Results of some compounds of the invention are provided in
Table 1.
TABLE-US-00001 Ki NK2 Exp (.mu.M) 6 0.010709 7 0.033913 8 0.002327
9 0.086851 10 0.028806 11 0.014315 12 0.002745 13 0.0237 14
0.001172 15 0.065161 16 0.005093 17 0.09527 18 0.020671 20 0.002439
21 0.013075 22 0.004631 23 0.010176 24 0.001723 25 0.006013 26
0.009446 27 0.016243 28 0.002037 30 0.00459 31 0.014817 32 0.004574
33 0.008568 34 0.076737 35 0.028488 36 0.003591 37 0.008889 38
0.009498 39 0.068322 41 0.001449 42 0.001397 43 0.0022305 44
0.00424 45 0.002978 46 0.003259 47 0.003649 48 0.005359 49 0.002526
50 0.0063 51 0.003001 52 0.003721 53 0.002905 54 0.003811 55
0.00206 56 0.009521 57 0.001552 58 0.008517 59 0.0128 63 0.00264 65
0.0302 66 0.0498 67 0.0529 68 0.0743 69 0.0233 70 0.0397 71 0.0344
72 0.00058 73 0.0124 74 0.0013 75 0.023 76 0.096 77 0.0288 78
0.0078 80 0.04 81 0.0058 82 0.0117 83 0.0971 85 0.0821 86 0.0178 87
0.0008 88 0.0178 89 0.0233 90 0.0117 92 0.0139 94 0.0006 95 0.0022
96 0.0008 97 0.0007 98 0.0009 99 0.0009 100 0.0023 101 0.0162 102
0.0024 103 0.007 104 0.0041 105 0.0008 107 0.0006 108 0.0026 109
0.0008 110 0.0008 111 0.0007 113 0.0029 114 0.0172 115 0.023 116
0.0497 118 0.0324 119 0.0113 120 0.0008 121 0.0051 122 0.082 123
0.038 124 0.013 125 0.0679 126 0.0009 127 0.035 131 0.0001 132
0.0013 133 0.0002 134 0.0519 135 0.0854 138 0.0005 139 0.0006 140
0.0007 141 0.0007 142 0.0004 143 0.0269 144 0.0009 145 0.0011 147
0.0014 148 0.0005 150 0.0198 151 0.0067 152 0.023 153 0.0527 154
0.0005 156 0.0008 158 0.0254 159 0.0433 160 0.005 161 0.0017 162
0.0004 163 0.0037 164 0.0005 165 0.0013 166 0.0007 167 0.0936 168
0.0004 170 0.0004 171 0.0008 173 0.0017 174 0.0009 175 0.042 176
0.0006
[0200] The present invention also provides pharmaceutical
compositions containing compounds of the invention, for example,
compounds of formula I or pharmaceutically acceptable salts thereof
and a pharmaceutically acceptable carrier. Such pharmaceutical
compositions can be in the form of tablets, coated tablets,
dragees, hard and soft gelatin capsules, solutions, emulsions or
suspensions. The pharmaceutical compositions also can be in the
form of suppositories or injectable solutions.
[0201] The pharmaceutical compositions of the invention, in
addition to one or more compounds of the invention, contain a
pharmaceutically acceptable carrier. Suitable pharmaceutically
acceptable carriers include pharmaceutically inert, inorganic or
organic carriers. 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 gelatin capsules. Suitable
excipients for soft gelatin capsules are e.g. vegetable oils,
waxes, fats, semi-solid and liquid polyols etc. Suitable excipients
for the manufacture of solutions and syrups are e.g. water,
polyols, saccharose, invert sugar, glucose etc.
[0202] Suitable excipients for injection solutions are e.g. water,
alcohols, polyols, glycerol, vegetable oils etc. Suitable
excipients for suppositories are e.g. natural or hardened oils,
waxes, fats, semi-liquid or liquid polyols etc.
[0203] Moreover, the pharmaceutical compositions 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.
[0204] The dosage at which compounds of the invention can be
administered 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
0.01 mg to about 1000 mg per day and person of a compound of
general formula I should be appropriate, although the above upper
limit can also be exceeded when necessary.
EXAMPLE A
[0205] Tablets of the following composition were 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
[0206] Capsules of the following composition were manufactured:
TABLE-US-00003 mg/capsule Active substance 10 Lactose 155 Corn
starch 30 Talc 5 Capsule fill weight 200
[0207] The active substance, lactose and corn starch were firstly
mixed in a mixer and then in a comminuting machine. The mixture was
returned to the mixer, the talc was added thereto and mixed
thoroughly. The mixture was filled by machine into hard gelatin
capsules.
EXAMPLE C
[0208] Suppositories of the following composition were
manufactured:
TABLE-US-00004 mg/supp. Active substance 15 Suppository mass 1285
Total 1300
[0209] The suppository mass was melted in a glass or steel vessel,
mixed thoroughly and cooled to 45.degree. C. Thereupon, the finely
powdered active substance was added thereto and stirred until it
had dispersed completely. The mixture was poured into suppository
moulds of suitable size, left to cool. The suppositories were then
removed from the moulds and packed individually in wax paper or
metal foil.
[0210] The following Examples illustrate the present invention
without limiting it. All temperatures are given in degrees
Celsius.
Abbreviations
[0211] DMAP-=dimethyl-pyridin-4-yl-amine [0212] ES-MS=Electro Spray
Mass Spectroscopy [0213] HPLC=high-performance liquid
chromatography; [0214] MS=mass spectroscopy; [0215] RT=room
temperature [0216] TFA=trifluoroacetic acid [0217]
THF=tetrahydrofuran
General Procedure I:
[0218] To a stirred solution of a pyrrolidine intermediate VIII or
XI (1 mmol) in CH.sub.2Cl.sub.2 (15 ml) at RT were added
ethyl-diisopropyl-amine (2 mmol) and a carbamoyl chloride or acid
chloride of formula R.sup.3COCl (1.1 mmol). Stirring was continued
until completion of the reaction. The reaction mixture was then
concentrated under vacuo and purification by flash chromatography
on SiO.sub.2 or preparative HPLC yielded I.
General Procedure II:
[0219] To a stirred solution of a carboxylic acid derivative
(commercially available or known in the literature) (1 mmol) in 10
mL of CH.sub.2Cl.sub.2 was added (1.3 mmol) of EDC, (1.3 mmol) of
HOBt and Et.sub.3N (1.3 mmol). After one hour at RT, was added a
pyrrolidine intermediate of general formula VIII or XI. The mixture
was stirred at RT over night and then poured onto water and
extracted with CH.sub.2Cl.sub.2. The combined organic phases were
dried over Na.sub.2SO.sub.4 and concentrated under vacuo. Flash
chromatography or preparative HPLC afforded the title compound.
Description of pyrrolidine intermediates of formula VIII, XI
Pyrrolidine Intermediates of Formula VIII
Pyrrolidine VIII-1
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-
-3-trifluoromethyl-benzamide
##STR00025##
[0220] a)
rac-(3R,4S)-1-Benzyl-3-(3,4-dichloro-phenyl)-4-nitro-pyrrolidine
(IV-1)
[0221] 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. ES-MS m/e: 351.0 (M+H.sup.+).
b)
rac-(3,S4R)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine
(V-1)
[0222] 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 RT 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]-methyl-a-
mine (VI-1)
[0223] To a solution of
rac-(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine
(0.54 g, 1.68 mmol) in THF (5 ml) was added a solution of
K.sub.2CO.sub.3 (0.46 g, 3.36 mmol) in H.sub.2O (3 ml). After 10
minutes, ethyl chloroformate (0.18 ml, 1.85 mmol) was added and
stirring was continued at RT for an additional 2 h. The
intermediate carbamate was then extracted with Et.sub.2O, dried
over Na.sub.2SO.sub.4 and concentrated under vacuo to give viscous
oil. The oil was taken up in THF (5 ml) and a solution of borane in
THF (1M) was added (6.7 ml). The reaction mixture was then heated
at 65.degree. C. over night, cooled to RT and carefully quenched
with conc. HCl (5 ml). The mixture was then heated at 80.degree. C.
for 2 h, cooled to RT, concentrated under vacuo, diluted with
Et.sub.2O (20 ml) and neutralized with an aqueous solution of
NaHCO.sub.3. The organic phases were dried over Na.sub.2SO.sub.4
and the product purified by flash chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2AMeOH 9:1) to afford 0.29 g (51%) of
rac-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-m-
ethyl-amine_as a colorless oil. ES-MS m/e: 335.3(M+H.sup.+).
d)
rac-N-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-meth-
oxy-N-methyl-3-trifluoromethyl-benzamide (VII-1)
[0224] A solution of 4-methoxy-3-trifluoromethyl-benzoyl chloride
(commercially available) (0.88 g, 2.76 mmol) in CH.sub.2Cl.sub.2
(10 ml) was added drop wise to a stirred solution of
rac-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-ami-
ne (0.80 g, 2.38 mmol) and ethyl-diisopropyl-amine (0.61 ml, 3.58
mmol) in CH.sub.2Cl.sub.2 (10 ml). The reaction mixture was stirred
4 h, concentrated under vacuo and purification by flash
chromatography (SiO.sub.2, CH.sub.2Cl.sub.2/MeOH, 99:1) yielded
1.09 g (86%) of the title product as colorless oil. ES-MS m/e:
537.5 (M+H.sup.+).
e)
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-met-
hyl-3-trifluoromethyl-benzamide (VIII-1)
[0225] To a stirred solution of
rac-N-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methox-
y-N-methyl-3-trifluoromethyl-benzamide (1.10 g, 2.05 mmol) in
CH.sub.3CN (15 ml) at RT was added 2,2,2-trichloroethyl
chloroformate (0.56 ml, 4.10 mmol) in two portions (within 30
min.). The reaction mixture was stirred an additional 2 hours,
concentrated under vacuo, and then filtrated on silica gel
(CH.sub.2Cl.sub.2 as solvent) to afford the intermediate
rac-(3R,4S)-3-(3,4-dichloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzo-
yl)-methyl-amino]-pyrrolidine-1-carboxylic acid
2,2,2-trichloro-ethyl ester. This intermediate was then dissolved
in AcOH (10 ml) and zinc powder (300 mg) was added in 4 portions
over 3 hours. The reaction mixture was then filtered on celite,
concentrated under vacuo, taken up in CH.sub.2Cl.sub.2, and washed
with aq. NaHCO.sub.3. The organic phases were dried over
Na.sub.2SO.sub.4, and purification by flash chromatography
(SiO.sub.2, CH.sub.2Cl.sub.2/MeOH, 90:10) yielded 0.45 g (50%) of
the title product as colorless oil. ES-MS m/e: 447.1
(M+H.sup.+).
Pyrrolidine Intermediates of Formula XI
Pyrrolidine XI-1
rac-(4-Methanesulfonyl-piperazin-1-yl)-((3S,4R)-3-methylamino-4-phenyl-pyr-
rolidin-1-yl)-methanone
##STR00026##
[0226] a) rac-(3S,4R)-1-Benzyl-3-nitro-4-phenyl-pyrrolidine
(IV-1)
[0227] A solution of
N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine
(0.50 g, 2.02 mmol) in CH.sub.2Cl.sub.2 (15 ml) was added drop
wise, over a 30 minutes period, to a stirred solution of
((E)-2-nitro-vinyl)-benzene (0.30 g, 2.02 mmol) and trifluoroacetic
acid (0.17 ml, 0.2 mmol) in CH.sub.2Cl.sub.2 (10 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 0.38 g (68%) of the title compound as a colorless oil.
ES-MS m/e: 283 (M+H.sup.+).
b) rac-(3S,4R)-1-Benzyl-4-phenyl-pyrrolidin-3-ylamine (V-1)
[0228] To a stirred solution of
rac-(3S,4R)-1-benzyl-3-nitro-4-phenyl-pyrrolidine (1.0 g, 3.54
mmol) in EtOAc (50 ml) was added in one portion
SnCl.sub.2.2H.sub.2O (3.99 g, 17.70 mmol). The reaction mixture was
then heated at reflux for 2 hours, cooled down to RT and a
saturated aqueous solution of NaHCO.sub.3 (100 ml) 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 0.72 g (80%) of
rac-(3S,4R)-1-benzyl-4-phenyl-pyrrolidin-3-ylamine as a light
yellow oil. The product was then used in the next step without
further purification.
c) rac-((3S,4R)-1-Benzyl-4-phenyl-pyrrolidin-3-yl)-methyl-amine
(VI-1)
[0229] To a solution of
rac-(3S,4R)-1-benzyl-4-phenyl-pyrrolidin-3-ylamine (0.25 g, 1.0
mmol) in THF (5 ml) was added a solution of K.sub.2CO.sub.3 (0.25
g, 1.8 mmol) in H.sub.2O (2 ml). After 10 minutes, ethyl
chloroformate (0.119 g, 1.1 mmol) was added and stirring was
continued at RT for an additional 4 h. The intermediate carbamate
was then extracted with Et.sub.2O, dried over Na.sub.2SO.sub.4 and
concentrated under vacuo to give viscous oil. The oil was taken up
in THF (5 ml) and a solution of borane in THF (1M) was added (3.5
ml). The reaction mixture was then heated at 65.degree. C. over
night, cooled to RT and carefully quenched with conc. HCl (0.5 ml).
The mixture was then heated at 80.degree. C. for 2 h, cooled to RT,
concentrated under vacuo, diluted with Et.sub.2O (20 ml) and
neutralized with an aqueous solution of NaHCO.sub.3. The organic
phases were dried over Na.sub.2SO.sub.4 and the product purified by
flash chromatography (SiO.sub.2, CH.sub.2Cl.sub.2/MeOH 9:1) to
afford 0.21 g (82%) of
rac-((3S,4R)-1-benzyl-4-phenyl-pyrrolidin-3-yl)-methyl-amine as a
colorless oil.
d) rac-Methyl-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-carbamic acid
tert-butyl ester (IX-1)
[0230] To a solution of
rac-((3S,4R)-1-benzyl-4-phenyl-pyrrolidin-3-yl)-methyl-amine (2.0
g, 7.55 mmol) in CH.sub.2Cl.sub.2 (20 ml) were added Et.sub.3N
(1.84 ml, 13.3 mmol) DMAP (81 mg, 0.66 mmol) and (Boc).sub.2O (1.74
g, 7.97 mmol). Stirring was continued 1 hour; the organic phase was
washed with aq. HCl 1N, dried over Na.sub.2SO.sub.4 and the product
purified by flash chromatography (SiO.sub.2, Hx/EtOAc 4:1) to
afford 2.03 g (76%) of
((3S,4R)-1-benzyl-4-phenyl-pyrrolidin-3-yl)-methyl-carbamic acid
tert-butyl ester as a yellow oil. This intermediate was then
dissolved in MeOH (20 ml), ammonium formate (1.60 g, 0.025 mol) and
Pd/C (10%, 400 mg) was added. The reaction was stirred 2 hours, and
then filtrated on celite, concentrated under vacuo. Purification by
flash chromatography (SiO.sub.2, CH.sub.2Cl.sub.2/MeOH 9:1)
afforded 0.57 g (41%) of
rac-methyl-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-carbamic acid
tert-butyl ester as a waxy solid. ES-MS m/e: 277.1 (M+H.sup.+).
e)
rac-[(3S,4R)-1-(4-Methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrro-
lidin-3-yl]-methyl-carbamic acid tert-butyl ester (X-1)
[0231] To a solution of
rac-methyl-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-carbamic acid
tert-butyl ester (0.57 g, 2.1 mmol) in CH.sub.2Cl.sub.2 (15 ml) was
added ethyl-diisopropyl-amine (0.53 ml, 3.11 mmol) and
4-methanesulfonyl-piperazine-i-carbonyl chloride (0.56 g, 2.5
mmol). Stirring was continued over night at RT, concentrated under
vacuo and purification by flash chromatography (SiO.sub.2, EtOAc/Hx
1:1) afforded 0.64 g (66%) of
rac-[(3S,4R)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrroli-
din-3-yl]-methyl-carbamic acid tert-butyl ester as a white solid.
ES-MS m/e: 467.3 (M+H.sup.+).
4-Methanesulfonyl-piperazine-1-carbonyl chloride
[0232] To a stirred solution of carbonic acid ditrichloromethyl
ester (triphosgene) (1.81 g, 6.09 mmol) in CH.sub.2Cl.sub.2 (30 ml)
at 0.degree. C., was added a solution of
1-methanesulfonyl-piperazine (2.0 g, 12.2 mmol) and pyridine (1.08
ml, 13.4 mmol) in CH.sub.2Cl.sub.2 (5 ml) over 30 minutes. The
temperature was raised to RT, and stirring was continued over
night. The organic phase was washed with H.sub.2O, dried over
Na.sub.2SO.sub.4. Purification by flash chromatography (SiO.sub.2,
EtOAc) yielded 2.20 g (79%) of
4-methanesulfonyl-piperazine-1-carbonyl chloride as white
solid.
f)
rac-(4-Methanesulfonyl-piperazin-1-yl)-((3S,4R)-3-methylamino-4-phenyl--
pyrrolidin-1-yl)-methanone (XI-1)
[0233] To a solution of
rac-[(3S,4R)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrroli-
din-3-yl]-methyl-carbamic acid tert-butyl ester (640 mg, 1.38 mmol)
in CH.sub.2Cl.sub.2 (10 ml) was added TFA (2 ml) at RT. Stirring
was continued over night. The reaction mixture was then
concentrated under vacuo, the crude dissolved in CH.sub.2Cl.sub.2,
washed with aq. NaHCO.sub.3 and the organic phase dried over
Na.sub.2SO.sub.4. Purification by flash chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2/MeOH 95:5) yielded 0.49 g (98%) of the title
compound as a white solid. ES-MS m/e: 367.1 (M+H.sup.+).
Pyrrolidine XI-2
rac-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[(3S,4R)-4-(4-chloro-phenyl)-pyrr-
olidin-3-yl]-N-methyl-isobutyramide
##STR00027##
[0234] a)
rac-(3R,4S)-1-Benzyl-3-(4-chloro-phenyl)-4-nitro-pyrrolidine
(IV-2)
[0235] A solution of
N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine
(6.70 g, 28.2 mmol) in CH.sub.2Cl.sub.2 (100 ml) was added drop
wise, over a 30 minutes period, to a stirred solution of
1-chloro-4-((E)-2-nitro-vinyl)-benzene (4.97 g, 27.1 mmol) and
trifluoroacetic acid (0.31 g, 2.7 mmol) in CH.sub.2Cl.sub.2 (150
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 1:4) afforded 6.75 g (79%) of the title compound as a
colorless oil.
b) rac-(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylamine
(V-2)
[0236] Titanium (IV) chloride (0.36 g, 1.89 mmol) was added drop
wise to a suspension of zinc powder (0.25 g, 3.78 mmol) in THF (3
ml). This solution was heated at 68.degree. C. for one hour, then
cooled to RT before
rac-(3R,4S)-1-benzyl-3-(4-chloro-phenyl)-4-nitro-pyrrolidine (0.20
g, 0.63 mmol) in THF (2 ml) was added. The reaction mixture was
then stirred at reflux over night. The reaction was cooled to RT,
diluted with 300 ml of Et.sub.2O, washed with an aqueous solution
of NaHCO.sub.3 and the organic phases were dried over
Na.sub.2SO.sub.4. Flash chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2/MeOH, 9:1) yielded 0.10 g (57%) of
rac-(3S,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylamine as a
light yellow oil.
c)
rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-amine
(VI-2)
[0237] To a solution of
rac-(3S,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylamine (1.86
g, 6.51 mmol) in THF (20 ml) was added a solution of
K.sub.2CO.sub.3 (1.80 g, 13.02 mmol) in H.sub.2O (15 After 10
minutes, ethyl chloroformate (0.68 ml, 7.16 mmol) was added and
stirring was continued at RT for an additional 4 h. The
intermediate carbamate was then extracted with Et.sub.2O, dried
over Na.sub.2SO.sub.4 and concentrated under vacuo to give viscous
oil. The oil was taken up in THF (20 ml) and a solution of borane
in THF (1M) was added (26 ml). The reaction mixture was then heated
at 65.degree. C. over night, cooled to RT and carefully quenched
with conc. HCl (5 ml). The mixture was then heated at 80.degree. C.
for 2 h, cooled to RT, concentrated under vacuo, diluted with
Et.sub.2O (100 ml) and neutralized with an aqueous solution of
NaHCO.sub.3. The organic phases were dried over Na.sub.2SO.sub.4
and the product purified by flash chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2AMeOH 9:1) to afford 1.51 g (77%) of
rac-[(3S,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methy-
l-amine as a colorless oil.
d)
rac-[(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic
acid tert-butyl ester (IX-2)
[0238] To a solution of
rac-[(3S,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-amine
(1.19 g, 3.95 mmol) in CH.sub.2Cl.sub.2 (10 ml) were added
Et.sub.3N (1.1 ml, 7.91 mmol) DMAP (48 mg, 0.39 mmol) and
(Boc).sub.2O (1.04 g, 4.75 mmol). Stirring was continued 1 hour;
the organic phase was washed with aq. HCl 1N, dried over
Na.sub.2SO.sub.4 and the product purified by flash chromatography
(SiO.sub.2, Hx/EtOAc 4:1) to afford 1.41 g (89%) of
[(3S,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic
acid tert-butyl ester as a yellow oil. This intermediate was
dissolved in toluene (20 ml), and then chloroethyl chloroformate
(0.75 g, 5.26 mmol) was added. Stirring was continued at
110.degree. C. for 18 h, cooled to RT and MeOH (30 ml) was added.
The solution was stirred at 80.degree. C. over night, concentrated
under vacuo, taken up in EtOAc, washed with an aqueous solution of
NaHCO.sub.3 and the organic phases dried over Na.sub.2SO.sub.4.
Purification by flash chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2/MeOH 90:10) yielded 0.77 g (62%) of
rac-[(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic
acid tert-butyl ester as light brown oil. ES-MS m/e: 311.4
(M+H.sup.+).
e)
rac-[(3S,4R)-1-(4-Methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrro-
lidin-3-yl]-methyl-carbamic acid tert-butyl ester (X-2)
[0239] To a solution of
rac-[(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic
acid tert-butyl ester (0.76 g, 2.46 mmol) in CH.sub.2Cl.sub.2 (10
ml) was added ethyl-diisopropyl-amine (0.51 ml, 2.95 mmol) and
4-methanesulfonyl-piperazine-1-carbonyl chloride (0.61 g, 2.7
mmol). Stirring was continued over night at RT, concentrated under
vacuo and purification by flash chromatography (SiO.sub.2, EtOAc/Hx
1:1) afforded 0.87 g (70%) of the title compound as a white solid.
ES-MS m/e: 501.4 (M+H.sup.+).
f)
rac-[(3R,4S)-3-(4-Chloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-meth-
anesulfonyl-piperazin-1-yl)-methanone (XI-2)
[0240] To a solution of
rac-[(3S,4R)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrroli-
din-3-yl]-methyl-carbamic acid tert-butyl ester (0.86 g, 1.61 mmol)
in CH.sub.2Cl.sub.2 (12 ml) was added TFA (3 ml) at RT. Stirring
was continued over night. The reaction mixture was then
concentrated under vacuo, the crude dissolved in CH.sub.2Cl.sub.2,
washed with aq.NaHCO.sub.3 and the organic phase dried over
Na.sub.2SO.sub.4. Purification by flash chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2/MeOH 95:5) yielded 0.68 g (98%) of the title
compound as a white solid. ES-MS m/e: 401.3(M+H.sup.+).
Pyrrolidine XI-3
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-met-
hanesulfonyl-piperazin-1-yl)-methanone
##STR00028##
[0241] a)
rac-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-methyl-car-
bamic acid tert-butyl ester (IX-3)
[0242] To a solution of
rac-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-ami-
ne (described herein above) (0.28 g, 0.85 mmol) in CH.sub.2Cl.sub.2
(4 ml) were added Et.sub.3N (0.24 ml, 1.71 mmol), DMAP (10 mg,
0.081 mmol) and (Boc).sub.2O (0.223 g, 1.02 mmol). Stirring was
continued 1 hour; the organic phase was washed with aq. HCl 1N,
dried over Na.sub.2SO.sub.4 and the product purified by flash
chromatography (SiO.sub.2, Hx/EtOAc 4:1) to afford 0.28 g (75%) of
rac-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-car-
bamic acid tert-butyl ester as a colorless oil. This intermediate
was then dissolved in CH.sub.3CN (5 ml), and then
2,2,2-trichloroethyl chloroformate (0.11 ml, 0.78 mmol) was added.
The reaction mixture was stirred at RT for 2 h and concentrated
under vacuo. The crude product was then dissolved in AcOH (3 ml)
and zinc powder (80 mg) was added in two portions. After 2 hours,
the reaction mixture was filtrated on celite, the solvent
evaporated, and then the crude product was taken up in
CH.sub.2Cl.sub.2 and washed with aq. NaHCO.sub.3. The organic phase
was dried over Na.sub.2SO.sub.4 and purification by flash
chromatography (SiO.sub.2, CH.sub.2Cl.sub.2/MeOH 90:10) yielded
0.13 g (44%) of
rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic
acid tert-butyl ester as light yellow oil. ES-MS m/e: 345.20
(M+H.sup.+).
b)
rac[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester
(X-3)
[0243] To a solution of
rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic
acid tert-butyl ester (130 mg, 0.376 mmol) in CH.sub.2Cl.sub.2 (5
ml) was added ethyl-diisopropyl-amine (0.10 ml, 0.56 mmol) and
4-methanesulfonyl-piperazine-1-carbonyl chloride (94 mg, 0.41
mmol). Stirring was continued over night at RT, concentrated under
vacuo and purification by flash chromatography (SiO.sub.2, EtOAc/Hx
3:1) afforded 135 mg (66%) of the title compound as a white solid.
ES-MS m/e: 535.1 (M+H.sup.+).
c)
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4--
methanesulfonyl-piperazin-1-yl)-methanone (XI-3)
[0244] To a solution of
rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-ca-
rbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester_(130
mg, 0.24 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added TFA (1 ml) at
RT. Stirring was continued over night. The reaction mixture was
then concentrated under vacuo, the crude dissolved in
CH.sub.2Cl.sub.2, washed with aq.NaHCO.sub.3 and the organic phase
was dried over Na.sub.2SO.sub.4. Purification by flash
chromatography (SiO.sub.2, CH.sub.2Cl.sub.2/MeOH 95:5) yielded 100
mg (92%) of the title compound as light yellow oil. ES-MS m/e:
435.37 (M+H.sup.+).
Pyrrolidine XI-4
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-ethylamino-pyrrolidin-1-yl]-(4-meth-
anesulfonyl-piperazin-1-yl)-methanone
##STR00029##
[0245] a)
rac-[(3S,4R)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-e-
thyl-amine (VI-4)
[0246] To a stirred solution of acetic anhydride (0.75 ml, 7.97
mmol) in THF (10 ml) was added a solution of
rac-(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine
(described herein above) (2.00 g, 6.22 mmol) in THF (10 ml)
dropwise over 30 minutes. The reaction mixture was stirred one
additional hour, concentrated under vacuo, taken up in EtOAc,
washed with aq. NaHCO3. and then the organic phase was dried over
Na2SO4 to afford the intermediate
N-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-acetamide.
To this intermediate in THF (10 ml) at 0.degree. C., was added
portion wise LiAlH4 (0.49 g, 12.83 mmol). Stirring was continued
over night at 65.degree. C.). The reaction mixture was then heated
at 65.degree. C. over night, cooled to RT and carefully quenched
with aq. NaHCO3. The product was extracted several times with
EtOAc, the organic phases were then dried over Na.sub.2SO.sub.4 and
the product purified by flash chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2/MeOH 9:1) to afford 1.03 g (46%) of
rac-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-e-
thyl-amine as a colorless oil. ES-MS m/e: 349.10 (M+H.sup.+).
b)
rac-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid tert-butyl ester (IX-4)
[0247] To a solution of
rac-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-amin-
e (0.99 g, 2.83 mmol) in CH.sub.2Cl.sub.2 (15 ml) were added
Et.sub.3N (0.78 ml, 5.67 mmol), DMAP (3 mg, 0.28 mmol) and
(Boc).sub.2O (0.68 g, 3.11 mmol). Stirring was continued at RT over
night; the organic phase was washed with aq. HCl 1N, dried over
Na.sub.2SO.sub.4 and the product purified by flash chromatography
(SiO.sub.2, Hx/EtOAc 4:1) to afford 0.98 g (77%) of
rac-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carb-
amic acid tert-butyl ester as a colorless oil. This intermediate
was then dissolved in CH.sub.3CN (10 ml), and then
2,2,2-trichloroethyl chloroformate (0.30 ml, 2.21 mmol) was added.
The reaction mixture was stirred at RT for 2 h and concentrated
under vacuo. The crude product was then dissolved in AcOH (5 ml)
and zinc powder (300 mg) was added in two portions. After 2 hours,
the reaction mixture was filtrated on celite, the solvent
evaporated, and then the crude product was taken up in
CH.sub.2Cl.sub.2 and washed with aq. NaHCO.sub.3. The organic phase
was dried over Na.sub.2SO.sub.4 and purification by flash
chromatography (SiO.sub.2, CH.sub.2Cl.sub.2/MeOH 90:10) yielded
0.25 g (33%) of
rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid tert-butyl ester as light yellow oil. ES-MS m/e: 359.3
(M+H.sup.+).
c) rac-[(3S,4R)-4-(3
4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-
-3-yl]-ethyl-carbamic acid tert-butyl ester (X-4)
[0248] To a solution of
rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic
acid tert-butyl ester (0.25 g, 0.69 mmol) in CH.sub.2Cl.sub.2 (5
ml) was added ethyl-diisopropyl-amine (0.20 ml, 1.1 mmol) and
4-methanesulfonyl-piperazine-1-carbonyl chloride (189 mg, 0.83
mmol). Stirring was continued over night at RT, concentrated under
vacuo and purification by flash chromatography (SiO.sub.2, EtOAc)
afforded 0.37 g (97%) of the title compound as a white solid. ES-MS
m/e: 549.3 (M+H.sup.+).
d)
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-ethylamino-pyrrolidin-1-yl]-(4-m-
ethanesulfonyl-piperazin-1-yl)-methanone (XI-3)
[0249] To a solution of
rac_-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid tert-butyl ester
(0.36 g, 0.66 mmol) in CH.sub.2Cl.sub.2 (10 ml) was added TFA (2
ml) at RT. Stirring was continued over night. The reaction mixture
was then concentrated under vacuo, the crude dissolved in
CH.sub.2Cl.sub.2, washed with aq.NaHCO.sub.3 and the organic phase
was dried over Na.sub.2SO.sub.4. Purification by flash
chromatography (SiO.sub.2, CH.sub.2Cl.sub.2/MeOH 95:5) yielded 0.25
g (84%) of the title compound as light yellow oil. ES-MS m/e: 449.8
(M+H.sup.+).
Pyrrolidine XI-5
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-benzonitrile
##STR00030##
[0250] a)
rac-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrroli-
din-3-yl]-methyl-carbamic acid tert-butyl ester (X-5)
[0251] To a solution of
rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic
acid tert-butyl ester (810 mg, 2.35 mmol, described herein above)
in CH.sub.2Cl.sub.2 (20 ml) was added triethyl-amine (0.42 ml, 3.05
mmol) and 4-cyano-benzoyl chloride (466 mg, 2.81 mmol). Stirring
was continued over night at RT, concentrated under vacuo and
purification by flash chromatography (SiO.sub.2, EtOAc/Hx 2:1)
afforded 1.09 g (98%) of the title compound as a white foam. ES-MS
m/e: 474.4 (M+H.sup.+).
b)
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carb-
onyl]-benzonitrile (XI-5)
[0252] To a solution of
rac-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-carbamic acid tert-butyl ester (1.08 g, 2.28 mmol) in
CH.sub.2Cl.sub.2 (25 ml) was added TFA (5 ml) at RT. Stirring was
continued one hour. The reaction mixture was then concentrated
under vacuo, the crude dissolved in CH.sub.2Cl.sub.2, washed with
aq.NaHCO.sub.3 and the organic phase was dried over
Na.sub.2SO.sub.4. Purification by flash chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2/MeOH 95:5) yielded 0.72 g (85%) of the title
compound as light yellow foam. ES-MS m/e: 374.0 (M+H.sup.+).
EXAMPLE 1
rac-N-[(3S,4R)-1-(4-Methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrrol-
idin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide
##STR00031##
[0254] Coupling according to general procedure I: [0255]
Pyrrolidine intermediate:
rac-(4-Methanesulfonyl-piperazin-1-yl)-((3S,4R)-3-methylamino-4-phenyl-py-
rrolidin-1-yl)-methanone (XI-1), [0256] Acid chloride:
3,5-Bis-trifluoromethyl-benzoyl chloride (commercially available),
ES-MS m/e: 607.3 (M+H.sup.+).
EXAMPLE 2
rac-N-[(3S,4R)-1-(4-Methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrrol-
idin-3-yl]-N-methyl-4-trifluoromethyl-benzamide
##STR00032##
[0258] Coupling according to general procedure I: [0259]
Pyrrolidine intermediate:
rac-(4-Methanesulfonyl-piperazin-1-yl)-((3S,4R)-3-methylamino-4-phenyl-py-
rrolidin-1-yl)-methanone (XI-1), [0260] Acid chloride:
4-Trifluoromethyl-benzoyl chloride (commercially available), ES-MS
m/e: 539.5 (M+H.sup.+).
EXAMPLE 3
rac-4-Dimethylamino-N-[(3S,4R)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-
-4-phenyl-pyrrolidin-3-yl]-N-methyl-benzamide
##STR00033##
[0262] Coupling according to general procedure I: [0263]
Pyrrolidine intermediate:
rac-(4-Methanesulfonyl-piperazin-1-yl)-((3S,4R)-3-methylamino-4-phenyl-py-
rrolidin-1-yl)-methanone (XI-1), [0264] Acid chloride:
4-Dimethylamino-benzoyl chloride (commercially available), ES-MS
m/e: 514.5 (M+H.sup.+).
EXAMPLE 4
rac-N-[(3S,4R)-1-(4-Methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrrol-
idin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00034##
[0266] Coupling according to general procedure I: [0267]
Pyrrolidine intermediate:
rac-(4-Methanesulfonyl-piperazin-1-yl)-((3S,4R)-3-methylamino-4-phenyl-py-
rrolidin-1-yl)-methanone (XI-1), [0268] Acid chloride:
4-Methoxy-3-trifluoromethyl-benzoyl chloride (commercially
available), ES-MS m/e: 569.3 (M+H.sup.+).
EXAMPLE 5
rac-3,5-Dichloro-N-[(3S,4R)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-4--
phenyl-pyrrolidin-3-yl]-N-methyl-benzamide
##STR00035##
[0270] Coupling according to general procedure I: [0271]
Pyrrolidine intermediate:
rac-(4-Methanesulfonyl-piperazin-1-yl)-((3S,4R)-3-methylamino-4-phenyl-py-
rrolidin-1-yl)-methanone (XI-1), [0272] Acid chloride:
3,5-Dichloro-benzoyl chloride (commercially available), ES-MS m/e:
540.1 (M+H.sup.+).
EXAMPLE 6
rac-N-[(3S,4R)-4-(4-Chloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbo-
nyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00036##
[0274] Coupling according to general procedure I: [0275]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(4-Chloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-methan-
esulfonyl-piperazin-1-yl)-methanone (XI-2), [0276] Acid chloride:
4-Methoxy-3-trifluoromethyl-benzoyl chloride (commercially
available), ES-MS m/e: 603.3 (M+H.sup.+).
EXAMPLE 7
rac-N-[(3S,4R)-4-(4-Chloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbo-
nyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
##STR00037##
[0278] Coupling according to general procedure I: [0279]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(4-Chloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-methan-
esulfonyl-piperazin-1-yl)-methanone (XI-2), [0280] Acid chloride:
3-Trifluoromethyl-benzoyl chloride (commercially available), ES-MS
m/e: 573.1 (M+H.sup.+).
EXAMPLE 8
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00038##
[0282] Coupling according to general procedure I: [0283]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0284] Acid
chloride: 4-Methoxy-3-trifluoromethyl-benzoyl chloride
(commercially available), ES-MS m/e: 637.2 (M+H.sup.+).
EXAMPLE 9
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide
##STR00039##
[0286] Coupling according to general procedure I: [0287]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0288] Acid
chloride: Benzoyl chloride (commercially available), ES-MS m/e:
539.3 (M+H.sup.+).
EXAMPLE 10
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-4-fluoro-N-methyl-benzamide
##STR00040##
[0290] Coupling according to general procedure I: [0291]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0292] Acid
chloride: 4-Fluoro-benzoyl chloride (commercially available), ES-MS
m/e: 557.1 (M+H.sup.+).
EXAMPLE 11
rac-3-Chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piper-
azine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide
##STR00041##
[0294] Coupling according to general procedure I: [0295]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0296] Acid
chloride: 3-Chloro-benzoyl chloride (commercially available), ES-MS
m/e: 575.2 (M+H.sup.+).
EXAMPLE 12
rac-4-Chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piper-
azine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide
##STR00042##
[0298] Coupling according to general procedure I: [0299]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0300] Acid
chloride: 4-Chloro-benzoyl chloride (commercially available), ES-MS
m/e: 575.2 (M+H.sup.+).
EXAMPLE 13
rac-4-Cyano-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-pipera-
zine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide
##STR00043##
[0302] Coupling according to general procedure I: [0303]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0304] Acid
chloride: 4-Cyano-benzoyl chloride (commercially available), ES-MS
m/e: 564.3 (M+H.sup.+).
EXAMPLE 14
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-4-ethyl-N-methyl-benzamide
##STR00044##
[0306] Coupling according to general procedure I: [0307]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0308] Acid
chloride: 4-Ethyl-benzoyl chloride (commercially available), ES-MS
m/e: 567.3 (M+H.sup.+).
EXAMPLE 15
rac-3-Cyano-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-pipera-
zine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide
##STR00045##
[0310] Coupling according to general procedure I: [0311]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0312] Acid
chloride: 3-Cyano-benzoyl chloride (commercially available), ES-MS
m/e: 564.5 (M+H.sup.+).
EXAMPLE 16
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-N-methyl-4-trifluoromethoxy-benzamide
##STR00046##
[0314] Coupling according to general procedure I: [0315]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0316] Acid
chloride: 4-Trifluoromethoxy-benzoyl chloride (commercially
available), ES-MS m/e: 623.3 (M+H.sup.+).
EXAMPLE 17
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-3-fluoro-N-methyl-benzamide
##STR00047##
[0318] Coupling according to general procedure I: [0319]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0320] Acid
chloride: 3-Fluoro-benzoyl chloride (commercially available), ES-MS
m/e: 557.2 (M+H.sup.+).
EXAMPLE 18
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-3-fluoro-N-methyl-5-trifluoromethyl-benzamide
##STR00048##
[0322] Coupling according to general procedure I: [0323]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0324] Acid
chloride: 3-Fluoro-5-trifluoromethyl-benzoyl chloride (commercially
available), ES-MS m/e: 627.2 (M+H.sup.+).
EXAMPLE 19
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-3,5-difluoro-N-methyl-benzamide
##STR00049##
[0326] Coupling according to general procedure I: [0327]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0328] Acid
chloride: 3,5-Difluoro-benzoyl chloride (commercially available),
ES-MS m/e: 575.3 (M+H.sup.+).
EXAMPLE 20
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-3-fluoro-N-methyl-4-trifluoromethyl-benzamide
##STR00050##
[0330] Coupling according to general procedure I: [0331]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0332] Acid
chloride: 3-Fluoro-4-trifluoromethyl-benzoyl chloride (commercially
available), ES-MS m/e: 627.3 (M+H.sup.+).
EXAMPLE 21
rac-3-Chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piper-
azine-1-carbonyl)-pyrrolidin-3-yl]-2-fluoro-N-methyl-benzamide
##STR00051##
[0334] Coupling according to general procedure I: [0335]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0336] Acid
chloride: 3-Chloro-2-fluoro-benzoyl chloride (commercially
available), ES-MS m/e: 591.3 (M+H.sup.+).
EXAMPLE 22
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-2-fluoro-N-methyl-3-trifluoromethyl-benzamide
##STR00052##
[0338] Coupling according to general procedure I: [0339]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0340] Acid
chloride: 2-Fluoro-3-trifluoromethyl-benzoyl chloride (commercially
available), ES-MS m/e: 627.2 (M+H.sup.+).
EXAMPLE 23
rac-Benzofuran-5-carboxylic
acid[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-ca-
rbonyl)-pyrrolidin-3-yl]-methyl-amide
##STR00053##
[0342] Coupling according to general procedure I: [0343]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0344] Acid
chloride: Benzofuran-5-carbonyl chloride (commercially available),
ES-MS m/e: 579.3 (M+H.sup.+).
EXAMPLE 24
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-4-dimethylamino-N-methyl-benzamide
##STR00054##
[0346] Coupling according to general procedure I: [0347]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0348] Acid
chloride: 4-Dimethylamino-benzoyl chloride (commercially
available), ES-MS m/e: 582.2 (M+H.sup.+).
EXAMPLE 25
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-4-fluoro-3,N-dimethyl-benzamide
##STR00055##
[0350] Coupling according to general procedure I: [0351]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0352] Acid
chloride: 4-Fluoro-3-methyl-benzoyl chloride (commercially
available), ES-MS m/e: 571.3 (M+H.sup.+).
EXAMPLE 26
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-3-fluoro-4-methoxy-N-methyl-benzamide
##STR00056##
[0354] Coupling according to general procedure II: [0355]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0356] Carboxylic
acid: 3-Fluoro-4-methoxy-benzoic acid (commercially available),
ES-MS m/e: 587.1 (M+H.sup.+).
EXAMPLE 27
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-3,4-difluoro-N-methyl-benzamide
##STR00057##
[0358] Coupling according to general procedure II: [0359]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0360] Carboxylic
acid: 3,4-Difluoro-benzoic acid (commercially available), ES-MS
m/e: 575.2 (M+H.sup.+).
EXAMPLE 28
rac-2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic
acid[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-ca-
rbonyl)-pyrrolidin-3-yl]-methyl-amide
##STR00058##
[0362] Coupling according to general procedure II: [0363]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0364] Carboxylic
acid: 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid
(commercially available), ES-MS m/e: 619.3 (M+H.sup.+).
EXAMPLE 29
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-N-methyl-4-(2,2,2-trifluoro-acetylamino)-benzami-
de
##STR00059##
[0366] Coupling according to general procedure TI: [0367]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0368] Carboxylic
acid: 4-(2,2,2-Trifluoro-acetylamino)-benzoic acid (commercially
available), ES-MS m/e: 650.3 (M+H.sup.+).
EXAMPLE 30
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-N-methyl-4-pyrrol-1-yl-benzamide
##STR00060##
[0370] Coupling according to general procedure II: [0371]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0372] Carboxylic
acid: 4-Pyrrol-1-yl-benzoic acid (commercially available), ES-MS
m/e: 604.3 (M+H.sup.+).
EXAMPLE 31
rac-2,3-Dihydro-benzofuran-5-carboxylic
acid[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-ca-
rbonyl)-pyrrolidin-3-yl]-methyl-amide
##STR00061##
[0374] Coupling according to general procedure TI: [0375]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0376] Carboxylic
acid: 2,3-Dihydro-benzofuran-5-carboxylic acid (commercially
available), ES-MS m/e: 581.2 (M+H.sup.+).
EXAMPLE 32
rac-3-Chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piper-
azine-1-carbonyl)-pyrrolidin-3-yl]-4-fluoro-N-methyl-benzamide
##STR00062##
[0378] Coupling according to general procedure II: [0379]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0380] Carboxylic
acid: 3-Chloro-4-fluoro-benzoic acid (commercially available),
ES-MS m/e: 593.3 (M+H.sup.+).
EXAMPLE 33
rac-3-Chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piper-
azine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-benzamide
##STR00063##
[0382] Coupling according to general procedure II: [0383]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0384] Carboxylic
acid: 3-Chloro-4-methoxy-benzoic acid (commercially available),
ES-MS m/e: 605.3 (M+H.sup.+).
EXAMPLE 34
rac-Quinoxaline-6-carboxylic
acid[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-ca-
rbonyl)-pyrrolidin-3-yl]-methyl-amide
##STR00064##
[0386] Coupling according to general procedure II: [0387]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0388] Carboxylic
acid: Quinoxaline-6-carboxylic acid (commercially available), ES-MS
m/e: 591.3 (M+H.sup.+).
EXAMPLE 35
rac-3-(Cyano-methyl-methyl)-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methan-
esulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide
##STR00065##
[0390] Coupling according to general procedure TI: [0391]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0392] Carboxylic
acid: 3-(Cyano-methyl-methyl)-benzoic acid (commercially
available), ES-MS m/e: 592.5 (M+H.sup.+).
EXAMPLE 36
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-4-fluoro-N-methyl-3-trifluoromethyl-benzamide
##STR00066##
[0394] Coupling according to general procedure II: [0395]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0396] Carboxylic
acid: 4-Fluoro-3-trifluoromethyl-benzoic acid (commercially
available), ES-MS m/e: 625.1 (M+H.sup.+).
EXAMPLE 37
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-benzamide
##STR00067##
[0398] Coupling according to general procedure II: [0399]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0400] Carboxylic
acid: 4-Methoxy-benzoic acid (commercially available), ES-MS m/e:
569.3 (M+H.sup.+).
EXAMPLE 38
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-2-fluoro-N-methyl-5-trifluoromethyl-benzamide
##STR00068##
[0402] Coupling according to general procedure II: [0403]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-(4-me-
thanesulfonyl-piperazin-1-yl)-methanone (XI-3), [0404] Carboxylic
acid: 2-Fluoro-5-trifluoromethyl-benzoic acid (commercially
available), ES-MS m/e: 625.1 (M+H.sup.+).
EXAMPLE 39
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-N-
ethyl-4-methoxy-3-trifluoromethyl-benzamide
##STR00069##
[0406] Coupling according to general procedure I: [0407]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-ethylamino-pyrrolidin-1-yl]-(4-met-
hanesulfonyl-piperazin-1-yl)-methanone (XI-4), [0408] Acid
chloride: 4-Methoxy-3-trifluoromethyl-benzoyl chloride
(commercially available), ES-MS m/e: 650.8 (M+H.sup.+).
EXAMPLE 40
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-c-
arbonyl)-pyrrolidin-3-yl]-N-
ethyl-2-fluoro-5-trifluoromethyl-benzamide
##STR00070##
[0410] Coupling according to general procedure I: [0411]
Pyrrolidine intermediate:
rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-ethylamino-pyrrolidin-1-yl]-(4-met-
hanesulfonyl-piperazin-1-yl)-methanone (XI-4), [0412] Acid
chloride: 2-Fluoro-5-trifluoromethyl-benzoyl chloride (commercially
available), ES-MS m/e: 638.7 (M+H.sup.+).
EXAMPLE 41
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl-
]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00071##
[0414] Coupling according to general procedure I: [0415]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0416] Acid chloride:
4-Cyano-benzoyl chloride (commercially available), ES-MS m/e: 576.3
(M+H.sup.+).
EXAMPLE 42
N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-((S)-4-methanesulfonyl-3-methyl-piper-
azine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-be-
nzamide
##STR00072##
[0418] Coupling according to general procedure I: [0419]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0420] Carbamoyl chloride:
(S)-4-Methanesulfonyl-3-methyl-piperazine-1-carbonyl chloride ES-MS
m/e: 651.3 (M+H.sup.+).
(S)-4-Methanesulfonyl-3-methyl-piperazine-1-carbonyl chloride
[0421] First step: To a stirred solution of commercially available
(S)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.38 g,
12 mmol) in CH.sub.2Cl.sub.2 (25 mL) at 0.degree. C. were added
pyridine (1.91 mL, 24 mmol) and methanesulfonyl chloride (0.92 mL,
12 mmol). Stirring was continued at RT overnight, the reaction was
poured onto water and extracted with CH.sub.2Cl.sub.2. The combined
organic phases were dried on Na.sub.2SO.sub.4 and concentrated
under vacuo. The crude product was dissolved in CH.sub.2Cl.sub.2
(20 mL) and TFA (4 mL) was added. After 2 hours at RT, the
volatiles were removed under vacuo, the crude was dissolved in
CH.sub.2Cl.sub.2 and washed with aq. NaHCO.sub.3 (until pH=8). The
organic phase was dried on Na.sub.2SO.sub.4 and concentrated under
vacuo to yield 0.83 g (39%) of
(s)-1-methanesulfonyl-2-methyl-piperazine as a light yellow
oil.
[0422] Second step: To a stirred solution of carbonic acid
ditrichloromethyl ester (triphosgene) (560 mg, 1.88 mmol) in
CH.sub.2Cl.sub.2 (10 mL) at -78.degree. C., was added a solution of
(S)-1-methanesulfonyl-2-methyl-piperazine (838 mg, 4.70 mmol) and
pyridine (0.74 mL, 9.4 mmol) in CH.sub.2Cl.sub.2 (10 mL) over 1
hour. The temperature was raised to RT, and stirring was continued
over night. The organic phase was washed with H.sub.2O, dried over
Na.sub.2SO.sub.4. Concentration under vacuo and flash
chromatography (SiO.sub.2, EtOAc/H, 1:1) yielded 0.70 g (62%) of
(S)-4-methanesulfonyl-3-methyl-piperazine-1-carbonyl chloride as a
light yellow solid.
EXAMPLE 43
N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-((R)-4-methanesulfonyl-3-methyl-piper-
azine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-be-
nzamide
##STR00073##
[0424] Coupling according to general procedure I: [0425]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0426] Carbamoyl chloride:
(R)-4-Methanesulfonyl-3-methyl-piperazine-1-carbonyl chloride ES-MS
m/e: 651.3 (M+H.sup.+).
(R)-4-Methanesulfonyl-3-methyl-piperazine-1-carbonyl chloride
[0427] First step: To a stirred solution of commercially available
(R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (8.78 g,
44 mmol) in CH.sub.2Cl.sub.2 (80 mL) at 0.degree. C. were added
Et.sub.3N (12.15 mL, 88 mmol) and methanesulfonyl chloride (5.09
mL, 66 mmol). Stirring was continued at RT overnight, the reaction
was poured onto water and extracted with CH.sub.2Cl.sub.2. The
combined organic phases were dried on Na.sub.2SO.sub.4 and
concentrated under vacuo. The crude product was dissolved in
CH.sub.2Cl.sub.2 (50 mL) and TFA (15 mL) was added. After 2 hours
at RT, the volatiles were removed under vacuo, the crude was
dissolved in CH.sub.2Cl.sub.2 and washed with aq. NaHCO.sub.3
(until pH=8). The organic phase was dried on Na.sub.2SO.sub.4 and
concentrated under vacuo to yield 2.63 g (34%) of
(R)-1-methanesulfonyl-2-methyl-piperazine as a light yellow
oil.
[0428] Second step: To a stirred solution of carbonic acid
ditrichloromethyl ester (triphosgene) (1.17 g, 3.95 mmol) in
CH.sub.2Cl.sub.2 (20 mL) at -78.degree. C., was added a solution of
(R)-1-methanesulfonyl-2-methyl-piperazine (1.76 g, 9.9 mmol) and
pyridine (1.60 mL, 20 mmol) in CH.sub.2Cl.sub.2 (20 mL) over 1
hour. The temperature was raised to RT, and stirring was continued
over night. The organic phase was washed with H.sub.2O, dried over
Na.sub.2SO.sub.4. Concentration under vacuo and flash
chromatography (SiO.sub.2, EtOAc/H, 1:1) yielded 1.70 g (71%) of
(R)-4-methanesulfonyl-3-methyl-piperazine-1-carbonyl chloride as a
light yellow solid.
EXAMPLE 44
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methoxy-benzoyl)-pyrrolidin-3--
yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00074##
[0430] Coupling according to general procedure I: [0431]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0432] Acid chloride:
4-Methoxy-benzoyl chloride (commercially available), ES-MS m/e:
580.8 (M+H.sup.+).
EXAMPLE 45
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-dimethylamino-benzoyl)-pyrroli-
din-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00075##
[0434] Coupling according to general procedure I: [0435]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0436] Acid chloride:
4-Dimethylamino-benzoyl chloride (commercially available), ES-MS
m/e: 593.7 (M+H.sup.+).
EXAMPLE 46
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-fluoro-benzoyl)-pyrrolidin-3-y-
l]-4-methoxy-methyl-3-trifluoromethyl-benzamide
##STR00076##
[0438] Coupling according to general procedure I: [0439]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0440] Acid chloride:
4-Fluoro-benzoyl chloride (commercially available), ES-MS m/e:
568.7 (M+H.sup.+).
EXAMPLE 47
rac-N-[(3S,4R)-1-(3-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl-
]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00077##
[0442] Coupling according to general procedure I: [0443]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0444] Acid chloride:
3-Cyano-benzoyl chloride (commercially available), ES-MS m/e: 575.8
(M+H.sup.+).
EXAMPLE 48
rac-N-[(3S,4R)-1-(Benzofuran-5-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidi-
n-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00078##
[0446] Coupling according to general procedure I: [0447]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0448] Acid chloride:
Benzofuran-5-carbonyl chloride (commercially available), ES-MS m/e:
590.8 (M+H.sup.+).
EXAMPLE 49
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(2-fluoro-5-methanesulfonyl-benzo-
yl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00079##
[0450] Coupling according to general procedure I: [0451]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0452] Acid chloride:
2-Fluoro-5-methanesulfonyl-benzoyl chloride (commercially
available), ES-MS m/e: 646.8 (M+H.sup.+).
EXAMPLE 50
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-trifluoromethyl-benzoyl)-pyrro-
lidin-3yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00080##
[0454] Coupling according to general procedure I: [0455]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0456] Acid chloride:
4-Trifluoromethyl-benzoyl chloride (commercially available), ES-MS
m/e: 618.7 (M+H.sup.+).
EXAMPLE 51
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(pyridine-4-carbonyl)-pyrrolidin--
3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00081##
[0458] Coupling according to general procedure I: [0459]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0460] Acid chloride:
Isonicotinoyl chloride (commercially available), ES-MS m/e: 551.7
(M+H.sup.+).
EXAMPLE 52
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(2,6-dichloro-pyridine-4-carbonyl-
)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00082##
[0462] Coupling according to general procedure I: [0463]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0464] Acid chloride:
2,6-Dichloro-isonicotinoyl chloride (commercially available), ES-MS
m/e: 621.6 (M+H.sup.+).
EXAMPLE 53
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-trifluoromethoxy-benzoyl)-pyrr-
olidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00083##
[0466] Coupling according to general procedure I: [0467]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0468] Acid chloride:
4-Trifluoromethoxy-benzoyl chloride (commercially available), ES-MS
m/e: 634.5 (M+H.sup.+).
EXAMPLE 54
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(3-methanesulfonyl-benzoyl)-pyrro-
lidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00084##
[0470] Coupling according to general procedure II: [0471]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0472] Carboxylic acid:
3-Methanesulfonyl-benzoic acid (commercially available), ES-MS m/e:
628.8 (M+H.sup.+).
EXAMPLE 55
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methoxy-3-methyl-benzoyl)-pyrr-
olidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00085##
[0474] Coupling according to general procedure II: [0475]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0476] Carboxylic acid:
4-Methoxy-3-methyl-benzoic acid (commercially available), ES-MS
m/e: 594.8 (M+H.sup.+).
EXAMPLE 56
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(3,5-dimethyl-benzoyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00086##
[0478] Coupling according to general procedure II: [0479]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0480] Carboxylic acid:
3,5-Dimethyl-benzoic acid (commercially available), ES-MS m/e:
578.7 (M+H.sup.+).
EXAMPLE 57
rac-N-[(3S,4R)-1-(4-Acetyl-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-y-
l]-4-methoxy-methyl-3-trifluoromethyl-benzamide
##STR00087##
[0482] Coupling according to general procedure II: [0483]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0484] Carboxylic acid:
4-Acetyl-benzoic acid (commercially available), ES-MS m/e: 592.8
(M+H.sup.+).
EXAMPLE 58
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(1,5-dimethyl-1H-pyrazole-3-carbo-
nyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00088##
[0486] Coupling according to general procedure II: [0487]
Pyrrolidine intermediate:
rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methy-
l-3-trifluoromethyl-benzamide (VIII-1), [0488] Carboxylic acid:
1,5-Dimethyl-1H-pyrazole-3-carboxylic acid (commercially
available), ES-MS m/e: 568.7 (M+H.sup.+).
EXAMPLE 59
rac-4-Chloro-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide
##STR00089##
[0490] Coupling according to general procedure II: [0491]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0492] Carboxylic acid:
4-Chloro-pyridine-2-carboxylic acid (commercially available), ES-MS
m/e: 515.0 (M+H.sup.+).
EXAMPLE 60
rac-3-Methyl-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide
##STR00090##
[0494] Coupling according to general procedure II: [0495]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0496] Carboxylic acid:
3-Methyl-pyridine-2-carboxylic acid (commercially available), ES-MS
m/e: 495.2 (M+H.sup.+).
EXAMPLE 61
rac-6-Chloro-3-fluoro-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide
##STR00091##
[0498] Coupling according to general procedure II: [0499]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0500] Carboxylic acid:
6-Chloro-3-fluoro-pyridine-2-carboxylic acid (commercially
available), ES-MS m/e: 533.0 (M+H.sup.+).
EXAMPLE 62
rac-6-Methyl-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide
##STR00092##
[0502] Coupling according to general procedure II: [0503]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0504] Carboxylic acid:
6-Methyl-pyridine-2-carboxylic acid (commercially available), ES-MS
m/e: 493.3 (M+H.sup.+).
EXAMPLE 63
rac-4-Methyl-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide
##STR00093##
[0506] Coupling according to general procedure II: [0507]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0508] Carboxylic acid:
4-Methyl-pyridine-2-carboxylic acid (commercially available), ES-MS
m/e: 493.1 (M+H.sup.+).
EXAMPLE 64
rac-6-Methoxy-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide
##STR00094##
[0510] Coupling according to general procedure II: [0511]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0512] Carboxylic acid:
6-Methoxy-pyridine-2-carboxylic acid (commercially available),
ES-MS m/e: 509.2 (M+H.sup.+).
EXAMPLE 65
rac-5-Ethoxymethyl-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide
##STR00095##
[0514] Coupling according to general procedure II: [0515]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0516] Carboxylic acid:
5-Ethoxymethyl-pyridine-2-carboxylic acid (commercially available),
ES-MS m/e: 539.3 (M+H.sup.+).
EXAMPLE 66
rac-4-Chloro-6-methyl-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide
##STR00096##
[0518] Coupling according to general procedure II: [0519]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0520] Carboxylic acid:
4-Chloro-6-methyl-pyridine-2-carboxylic acid (commercially
available), ES-MS m/e: 529.2 (M+H.sup.+).
EXAMPLE 67
rac-4-Methoxy-quinoline-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide
##STR00097##
[0522] Coupling according to general procedure II: [0523]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0524] Carboxylic acid:
4-Methoxy-quinoline-2-carboxylic acid (commercially available),
ES-MS m/e: 559.2 (M+H.sup.+).
EXAMPLE 68
rac-4-Chloro-6-ethyl-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide
##STR00098##
[0526] Coupling according to general procedure II: [0527]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0528] Carboxylic acid:
4-Chloro-6-ethyl-pyridine-2-carboxylic acid, ES-MS m/e: 543.1
(M+H.sup.+).
EXAMPLE 69
rac-5-Chloro-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide
##STR00099##
[0530] Coupling according to general procedure II: [0531]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0532] Carboxylic acid:
5-Chloro-pyridine-2-carboxylic acid (commercially available), ES-MS
m/e: 515.0 (M+H.sup.+).
EXAMPLE 70
rac-5-Cyano-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide
##STR00100##
[0534] Coupling according to general procedure II: [0535]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0536] Carboxylic acid:
5-Cyano-pyridine-2-carboxylic acid (commercially available), ES-MS
m/e: 504.1 (M+H.sup.+).
EXAMPLE 71
rac-5-Cyano-6-methoxy-pyridine-2-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide
##STR00101##
[0538] Coupling according to general procedure II: [0539]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0540] Carboxylic acid:
5-Cyano-6-methoxy-pyridine-2-carboxylic acid (described in the
patent DE34467 13), ES-MS m/e: 534.1 (M+H.sup.+).
EXAMPLE 72
rac-4-Chloro-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrol-
idin-3-yl]-methyl-3-trifluoromethyl-benzamide
##STR00102##
[0542] Coupling according to general procedure II: [0543]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0544] Carboxylic acid:
4-Chloro-3-trifluoromethyl-benzoic acid (commercially available),
ES-MS m/e: 582.3 (M+H.sup.+).
EXAMPLE 73
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl-
]-3-fluoro-4-methoxy-N-methyl-benzamide
##STR00103##
[0546] Coupling according to general procedure II: [0547]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0548] Carboxylic acid:
3-Fluoro-4-methoxy-benzoic acid (commercially available), ES-MS
m/e: 526.1 (M+H.sup.+).
EXAMPLE 74
rac-3-tert-Butyl-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-py-
rrolidin-3-yl]-4-methoxy-N-methyl-benzamide
##STR00104##
[0550] Coupling according to general procedure II: [0551]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0552] Carboxylic acid:
3-tert-Butyl-4-methoxy-benzoic acid (described in J. Med. Chem.,
1995, 38(26), 4993), ES-MS m/e: 564.2 (M+H.sup.+).
EXAMPLE 75
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl-
]-4-cyclopropylmethoxy-N-methyl-benzamide
##STR00105##
[0554] Coupling according to general procedure II: [0555]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0556] Carboxylic acid:
4-Cyclopropylmethoxy-benzoic acid (described in patent
WO2001060813), ES-MS m/e: 548.2 (M+H.sup.+).
EXAMPLE 76
rac-2-Methoxy-pyrimidine-5-carboxylic
acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-
-methyl-amide
##STR00106##
[0558] Coupling according to general procedure II: [0559]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0560] Carboxylic acid:
2-Methoxy-pyrimidine-5-carboxylic acid (commercially available),
ES-MS m/e: 510.1 (M+H.sup.+).
EXAMPLE 77
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl-
]-6,N-dimethyl-nicotinamide
##STR00107##
[0562] Coupling according to general procedure II: [0563]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0564] Carboxylic acid: 6-Methyl-nicotinic
acid (commercially available), ES-MS m/e: 495.3 (M+H.sup.+).
EXAMPLE 78
rac-6-Chloro-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrol-
idin-3-yl]-N-methyl-nicotinamide
##STR00108##
[0566] Coupling according to general procedure II: [0567]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0568] Carboxylic acid: 6-Chloro-nicotinic
acid (commercially available), ES-MS m/e: 514.9 (M+H.sup.+).
EXAMPLE 79
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl-
]-2-fluoro-N-methyl-nicotinamide
##STR00109##
[0570] Coupling according to general procedure II: [0571]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0572] Carboxylic acid: 2-Fluoro-nicotinic
acid (commercially available), ES-MS m/e: 498.9 (M+H.sup.+).
EXAMPLE 80
rac-6-Cyano-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrroli-
din-3-yl]-N-methyl-nicotinamide
##STR00110##
[0574] Coupling according to general procedure II: [0575]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0576] Carboxylic acid: 6-Cyano-nicotinic
acid (commercially available), ES-MS m/e: 504.2 (M+H.sup.+).
EXAMPLE 81
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl-
]-N-methyl-6-trifluoromethyl-nicotinamide
##STR00111##
[0578] Coupling according to general procedure II: [0579]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0580] Carboxylic acid:
6-Trifluoromethyl-nicotinic acid (commercially available), ES-MS
m/e: 547.2 (M+H.sup.+).
EXAMPLE 82
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl-
]-N-methyl-6-(2,2,2-trifluoro-ethoxy)-nicotinamide
##STR00112##
[0582] Coupling according to general procedure II [0583]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0584] Carboxylic acid:
6-(2,2,2-Trifluoro-ethoxy)-nicotinic acid (commercially available),
ES-MS m/e: 579.2 (M+H.sup.+).
EXAMPLE 83
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl-
]-5,N-dimethyl-nicotinamide
##STR00113##
[0586] Coupling according to general procedure II: [0587]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0588] Carboxylic acid: 5-Methyl-nicotinic
acid (commercially available), ES-MS m/e: 493.2 (M+H.sup.+).
EXAMPLE 84
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl-
]-5-fluoro-N-methyl-nicotinamide
##STR00114##
[0590] Coupling according to general procedure II: [0591]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0592] Carboxylic acid: 5-Fluoro-nicotinic
acid (commercially available), ES-MS m/e: 497.3 (M+H.sup.+).
EXAMPLE 85
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl-
]-6-fluoro-N-methyl-nicotinamide
##STR00115##
[0594] Coupling according to general procedure II: [0595]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0596] Carboxylic acid: 6-Fluoro-nicotinic
acid (commercially available), ES-MS m/e: 499.2 (M+H.sup.+).
EXAMPLE 86
rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl-
]-6-methoxy-N-methyl-nicotinamide
##STR00116##
[0598] Coupling according to general procedure II: [0599]
Pyrrolidine intermediate:
rac-4-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbon-
yl]-benzonitrile (XI-5), [0600] Carboxylic acid:
6-Methoxy-nicotinic acid (commercially available), ES-MS m/e: 509.0
(M+H.sup.+).
EXAMPLE 87
N-{(3RS,4SR)-4-(4-Chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pipe-
ridine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-b-
enzamide
##STR00117##
[0601] a)
N-[(3RS,4SR)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-met-
hoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00118##
[0603] Coupling according to general procedure I: [0604]
Pyrrolidine intermediate:
[(3RS,4SR)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-amine
(XI-2c), [0605] Acide chloride:
4-Methoxy-3-(trifluoromethyl)benzoyl chloride ES-MS m/e: 503.2
(M+H.sup.+).
b)
N-[(3RS,4SR)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3--
trifluoromethyl-benzamide
##STR00119##
[0607] To a solution of
N-[(3RS,4SR)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-me-
thyl-3-trifluoromethyl-benzamide (7.44 g, 14.8 mmol) and
N,N-diisopropyl ethyl amine (3.29 ml, 19 mmol) in toluene (106 mL)
was added at ambient temperature over a period of 5 min
1-chloroethyl chloroformate (2. 10 mL, 19.2 mmol) and the reaction
mixture stirred for 3 h at this temperature. The light brown
solution was concentrated in vacuo at 45.degree. C. and the residue
was dissolved in methanol (106 mL) and stirred for 3 h at ambient
temperature. The solution was concentrated in vacuo. The residue
was diluted with an aqueous solution of hydrochloric acid (1M, 30
mL) and water (100 mL). The aqueous layer was washed twice with
TBME (50 ml). The organic layers were extracted with water (50 mL).
The combined aqueous biphasic layers were diluted with TBME (50 mL)
and basified by addition of a 32% solution of sodium hydroxide (4
mL). The aqueous layer was extracted with TBME (50 mL) and washed
with brine (30 mL). The combined organic layers were dried over
sodium sulfate. Purification by chromatography (SiO.sub.2,
dichloromethane:methanol:ammonia=95:4.5:0.5 to 90:9:1) afforded the
title compound (2.56 mg, 42%) as a brown oil. MS m/e: 413.2
[M].sup.+.
c)
N-{(3RS,4SR)-4-(4-Chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethy-
l-benzamide
[0608] To a solution of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide (200 mg, 0.484 mmol) in DMF (2 mL) was
added 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic
acid (113 mg, 0.533 mmol),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (221 mg, 0.581 mmol) and N,N-diisopropyl ethyl
amine (498 .mu.l, 2.90 mmol). The solution was stirred for 3 h at
ambient temperature. After diluting with ethyl acetate (15 mL) the
solution was washed twice with water (15 mL) and brine (10 mL). The
aqueous layers were extracted with ethl acetate (15 mL) and dried
over sodium sulfate. Purification by chromatography (SiO.sub.2,
heptane:ethyl acetate:methanol=50:50:0 to 0:90:10) afforded the
title compound (210 mg, 72%) as a light brown oil. MS m/e: 606.2
[M].sup.+.
EXAMPLE 88
N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(4-fluoro-benzoyl)-pyrrolidin-3-yl]-4-m-
ethoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00120##
[0610] To a solution of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide (200 mg, 0.484 mmol) in dichloromethane (2
mL) was added 4-fluorobenzoyl chloride (63 .mu.l, 0.533 mmol) and
N,N-diisopropyl ethyl amine (124 .mu.l, 0.727 mmol). The solution
was stirred for 3 h at ambient temperature. After diluting with
ethyl acetate (15 mL) the solution was washed twice with water (15
mL) and brine (10 mL). The aqueous layers were extracted with ethyl
acetate (15 mL) and dried over sodium sulfate. Purification by
chromatography (SiO.sub.2, heptane:ethyl acetate=50:50 to 0:100)
afforded the title compound (245 mg, 95%) as a light brown oil. MS
m/e: 535.2 [M+H].sup.+.
EXAMPLE 89
N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(4-fluoro-2-methyl-benzoyl)-pyrrolidin--
3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00121##
[0612] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(4-fluoro-2-methyl-benzoyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared
from
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide using 4-fluoro-2-methylbenzoic acid instead
of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
and was obtained as a light brown oil. MS m/e: 549.2
[M+H].sup.+.
EXAMPLE 90
N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(6-cyano-pyridine-3-carbonyl)-pyrrolidi-
n-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00122##
[0614] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(6-cyano-pyridine-3-carbonyl)-pyrrolid-
in-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was
prepared from
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide using 6-cyanonicotinic acid instead of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and
was obtained as a light brown oil. MS m/e: 543.1 [M+H].sup.+.
EXAMPLE 91
N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(4-isopropoxy-benzoyl)-pyrrolidin-3-yl]-
-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00123##
[0616] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(4-isopropoxy-benzoyl)-pyrrolidin-3-yl-
]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide using 4-isopropoxybenzoic acid instead of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and
was obtained as a light brown oil. MS m/e: 575.2 [M+H].sup.+.
EXAMPLE 92
N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(4-cyano-benzoyl)-pyrrolidin-3-yl]-4-me-
thoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00124##
[0618] In analogy to the procedure described for the synthesis of
example 88, the title compound
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(4-cyano-benzoyl)-pyrrolidin-3-yl]-4-m-
ethoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide using 4-cyanobenzoyl chloride instead of
4-fluorobenzoyl chloride and was obtained as a light brown oil. MS
m/e: 542.1 [M+H].sup.+.
EXAMPLE 93
N-{(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperi-
dine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-ben-
zamide
##STR00125##
[0619] and
EXAMPLE 94
N-{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperi-
dine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-ben-
zamide
##STR00126##
[0621]
N-{(3RS,4SR)-4-(4-Chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluorom-
ethyl-benzamide was subjected to column chromatography on chiral
phase to yield
N-{(3R,4S)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromet-
hyl-benzamide (MS(m/e): 606.2 [M].sup.+) as a colorless oil and
N-{(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piper-
idine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-be-
nzamide (MS(m/e): 606.2 [M].sup.+) as a colorless oil.
EXAMPLE 95
4-{(3SR,4RS)-3-(4-Chloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)--
methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester
##STR00127##
[0623] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
4-{(3SR,4RS)-3-(4-chloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)-
-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester was prepared from
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide using piperidine-1,4-dicarboxylic acid
mono-tert-butyl ester instead of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and
was obtained as a light brown foam. MS m/e: 624.3 [M].sup.+.
EXAMPLE 96
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluorometh-
yl-benzamide
##STR00128##
[0624] a)
[(3RS,4SR)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-met-
hyl-carbamic acid tert-butyl ester
##STR00129##
[0626] To a solution of
[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine
(Pyrrolidine VI-I, 2.85 g, 8.50 mmol) in dichloromethane (29 mL)
was added at ambient temperature triethylamine (2.4 mL, 17.0 mmol),
4-dimethylaminopyridine (0.10 g, 0.85 mmol) and
di-tert-butyl-dicarbonate (2.04 g, 9.35 mmol). The resulting
solution was stirred in a water bath for 2 h at ambient
temperature. It was diluted with water (30 mL). The organic layer
was washed with water (30 mL). The aqueous layers were extracted
twice with dichloromethane (20 mL) and the combined organic layers
were dried over sodium sulfate. Purification by chromatography
(SiO.sub.2, heptane:ethyl acetate=100:0 to 60:40) afforded the
title compound (3.52 g, 95%) as a light brown oil. MS m/e: 435.2
[M].sup.+.
b)
[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic
acid tert-butyl ester
##STR00130##
[0628] In analogy to the procedure described for the synthesis of
example 87 (step b), the title compound
[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic
acid tert-butyl ester was prepared from
[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carba-
mic acid tert-butyl ester and was obtained as a light brown oil. MS
m/e: 345.1 [M].sup.+.
c)
{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid
tert-butyl ester
##STR00131##
[0630] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid
tert-butyl ester was prepared from
[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic
acid tert-butyl ester and was obtained as a light brown foam. MS
m/e: 538.3 [M].sup.+.
d)
{4-[(3SR,4RS)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbo-
nyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone
##STR00132##
[0632] Under an atmosphere of nitrogen was added to a solution of
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid
tert-butyl ester (3.02 g, 5.61 mmol) in dichloromethane (30 mL) at
ambient temperature trifluoroacetic acid (4.3 mL, 56 mmol) and
stirred for 20 h at this temperature. The reaction mixture was
added slowly onto an aqueous solution of sodium carbonate (1M, 60
mL). The organic layer was separated and washed with brine (50 mL).
The aqueous layers were extracted with dichloromethane (30 mL) and
the combined organic layers were dried over sodium sulfate.
Purification by chromatography (SiO.sub.2, heptane:ethyl
acetate:methanol=50:50:0 to 0:90:10) afforded the title compound
(1.79 g, 73%) as a light brown oil. MS m/e: 438.3 [M].sup.+.
e)
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluorom-
ethyl-benzamide
[0633] To a solution of
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone (200 mg, 0.456
mmol) in THF (2 mL) was added N,N-diisopropyl ethyl amine (117
.mu.l, 0.684 mmol), 4-methoxy-3-(trifluoromethyl)benzoyl chloride
(131 mg, 0.547 mmol) and stirred for 4 h at ambient temperature.
The reaction mixture was diluted with ethzl acetatec (10 mL) and
was washed with an aqueous solution of sodium carbonate (1 M, 10
mL), water (10 mL) and brine (10 mL). The aqueous layers were
extracted with ethyl acetate (20 mL) and the combined organic
layers were dried over sodium sulfate. Purification by
chromatography (SiO.sub.2, heptane:ethyl acetate:methanol=50:50:0
to 0:90:10) afforded the title compound (230 mg, 79%) as a
colorless oil. MS m/e: 640.3 [M].sup.+.
EXAMPLE 97
4-Chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanec-
arbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethy-
l-benzamide
##STR00133##
[0635] To a mixture of 4-chloro-3-(trifluoromethyl)benzoic acid (31
mg, 0.14 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (27 mg, 0.14 mmol) was added at 0.degree. C. under an
atmosphere of nitrogen a solution
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone (50 mg, 0.11
mmol) in dichloromethane (1 mL). The solution was stirred for 3 d
in a thawing ice bath. The resulting solution was diluted with
dichloromethane and was washed twice with water (10 mL). The
aqueous layers were extracted with dichloromethane (10 mL) and the
combined organic layers were dried over sodium sulfate.
Purification by chromatography (SiO.sub.2, heptane:ethyl
acetate:methanol=50:50:0 to 0:90:10) afforded the title compound
(63 mg, 86%) as a light brown foam. MS m/e: 646.3 [M+H].sup.+.
EXAMPLE 98
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-3-trifluorometho-
xy-benzamide
##STR00134##
[0637] In analogy to the procedure described for the synthesis of
example 97, the title compound
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-3-trifluorometh-
oxy-benzamide was prepared from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1yl}-(1-methyl-cyclopropyl)-methanone using
4-fluoro-3-(trifluoromethyl)benzoic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown foam. MS m/e: 644.4 [M].sup.+.
EXAMPLE 99
4-Chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanec-
arbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-methoxy-N-methyl-benzam-
ide
##STR00135##
[0639] In analogy to the procedure described for the synthesis of
example 97, the title compound
4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropane-
carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-methoxy-N-methyl-benza-
mide was prepared from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
4-chloro-3-methoxybenzoic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown foam. MS m/e: 608.1 [M+H].sup.+.
EXAMPLE 100
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-benzamide
##STR00136##
[0641] In analogy to the procedure described for the synthesis of
example 96 (step e), the title compound
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-benzamide was
prepared from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-ca-
rbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
4-fluorobenzoyl chloride instead of
4-methoxy-3-(trifluoromethyl)benzoyl chloride and was obtained as a
light brown foam. MS m/e: 560.1 [M].sup.+.
EXAMPLE 101
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-aceta-
mide
##STR00137##
[0643] In analogy to the procedure described for the synthesis of
example 97, the title compound
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acet-
amide was prepared from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
4-fluorophenylacetic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown foam. MS m/e: 574.2 [M].sup.+.
EXAMPLE 102
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-(4-fluoro-phenyl)-N-methyl-propi-
onamide
##STR00138##
[0645] In analogy to the procedure described for the synthesis of
example 97, the title compound
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-(4-fluoro-phenyl)-N-methyl-prop-
ionamide was prepared from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
3-(4-fluorophenyl)propionic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown foam. MS m/e: 588.2 [M].sup.+.
EXAMPLE 103
N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl-
]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00139##
[0647] In analogy to the procedure described for the synthesis of
example 96 (step d), the title compound
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from
4-{(3SR,4RS)-3-(4-chloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)-
-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester and was obtained as a white foam. MS m/e: 524.3
[M+H].sup.+.
EXAMPLE 104
N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(1-isopropyl-piperidine-4-carbonyl)-pyr-
rolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00140##
[0649] To a solution of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (50 mg, 0.095
mmol) in dichloromethane (1 mL) was added under an atmosphere of
nitrogen acetone (70 .mu.l, 0.95 mmol) and sodium
triacetoxyborohydride (81 mg, 0.38 mmol). The reaction mixture was
stirred for 18 h at ambient temperature before it was treated with
an aqueous solution of sodium carbonate (1 M, 10 ml) and stirred
for 1 h at this temperature. It was diluted with ethyl acetate (15
mL). The aqueous layer was extracted with ethyl acetate (15 mL) and
the organic layers were washed with brine (15 mL). The combined
organic layers were dried over sodium sulfate and concentrated.
Purification by chromatography (SiO.sub.2,
dichloromethane:methanol=100:0 to 70:30) afforded the title
compound (40 mg, 73%) as a light brown oil. MS m/e: 566.3
[M].sup.+.
EXAMPLE 105
N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine-4-carbo-
nyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00141##
[0651] In analogy to the procedure described for the synthesis of
example 104, the title compound
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine-4-carb-
onyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
was prepared from
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using
cyclopropanecarboxaldehyde instead of acetone and was obtained as a
light brown oil. MS m/e: 578.2 [M].sup.+.
EXAMPLE 106
N-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pi-
peridine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-
-benzamide
##STR00142##
[0652] and
EXAMPLE 107
N-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pi-
peridine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-
-benzamide
##STR00143##
[0654]
N-{(3SR,4RS)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecar-
bonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-triflu-
oromethyl-benzamide was subjected to column chromatography on
chiral phase to yield
N-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropaneca-
rbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifl-
uoromethyl-benzamide (MS(m/e): 640.3 [M].sup.+) as a light brown
oil and
N-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethy-
l-benzamide (MS(m/e): 640.3 [M].sup.+) as a light brown oil.
EXAMPLE 108
5-Chloro-pyridine-2-carboxylic acid
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide
##STR00144##
[0656] In analogy to the procedure described for the synthesis of
example 97, the title compound 5-chloro-pyridine-2-carboxylic acid
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was prepared
from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
5-chloro-2-pyridinecarboxylic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown oil. MS m/e: 577.2 [M].sup.+.
EXAMPLE 109
3-Cyano-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropaneca-
rbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-benzamid-
e
##STR00145##
[0658] In analogy to the procedure described for the synthesis of
example 97, the title compound
3-cyano-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanec-
arbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-benzami-
de was prepared from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
3-cyano-4-fluorobenzoic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown oil. MS m/e: 585.2 [M].sup.+.
EXAMPLE 110
N-{(3RS,4SR)-4-(4-Chloro-phenyl)-1-[1-(3,3,3-trifluoro-propyl)-piperidine--
4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamid-
e
##STR00146##
[0660] In analogy to the procedure described for the synthesis of
example 104, the title compound
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3,3,3-trifluoro-propyl)-piperidine-
-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzami-
de was prepared from
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using
3,3,3-trifluoropropanal instead of acetone and was obtained as a
light brown oil. MS m/e: 620.3 [M].sup.+.
EXAMPLE 111
N-{(3RS,4SR)-4-(4-Chloro-phenyl)-1-[1-(3,3-dimethyl-butyl)-piperidine-4-ca-
rbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00147##
[0662] In analogy to the procedure described for the synthesis of
example 104, the title compound
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3,3-dimethyl-butyl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
was prepared from
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using
3,3-dimethylbutyraldehyde instead of acetone and was obtained as a
light brown oil. MS m/e: 608.2 [M].sup.+.
EXAMPLE 112
Cis-4-Hydroxy-cyclohexanecarboxylic acid
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide
##STR00148##
[0664] In analogy to the procedure described for the synthesis of
example 97, the title compound cis-4-hydroxy-cyclohexanecarboxylic
acid
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was prepared
from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
cis-4-hydroxycyclohexanecarboxylic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown oil. MS m/e: 564.4 [M].sup.+.
EXAMPLE 113
2-Cyclopentyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopro-
panecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-acetamide
##STR00149##
[0666] In analogy to the procedure described for the synthesis of
example 97, the title compound
2-cyclopentyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopr-
opanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-acetamide
was prepared from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
cyclopentylacetic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown oil. MS m/e: 548.3 [M].sup.+.
EXAMPLE 114
3-Cyclopropyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopro-
panecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-propionamid-
e
##STR00150##
[0668] In analogy to the procedure described for the synthesis of
example 97, the title compound
3-cyclopropyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopr-
opanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-propionami-
de was prepared from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
3-cyclopropylpropionic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown oil. MS m/e: 534.3 [M].sup.+.
EXAMPLE 115
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-3,3,N-trimethyl-butyramide
##STR00151##
[0670] In analogy to the procedure described for the synthesis of
example 97, the title compound
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3,3,N-trimethyl-butyramide
was prepared from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
tert-butylacetic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown oil. MS m/e: 536.3 [M].sup.+.
EXAMPLE 116
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-3,N-dimethyl-b-
utyramide
##STR00152##
[0672] In analogy to the procedure described for the synthesis of
example 97, the title compound
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-3,N-dimethyl--
butyramide was prepared from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
2-(4-fluoro-phenyl)-3-methyl-butyric acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown oil. MS m/e: 616.4
Example 117
1-(4-Fluoro-phenyl)-cyclopentanecarboxylic
acid{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide
##STR00153##
[0674] In analogy to the procedure described for the synthesis of
example 97, the title compound
1-(4-fluoro-phenyl)-cyclopentanecarboxylic
acid{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was
prepared from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
1-(4-fluoro-phenyl)-cyclopentanecarboxylic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown oil. MS m/e: 628.3 [M].sup.+.
EXAMPLE 118
N-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pi-
peridine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetami-
de
##STR00154##
[0675] and
Example 119
N-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pi-
peridine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetami-
de
##STR00155##
[0677]
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecar-
bonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methy-
l-acetamide was subjected to column chromatography on chiral phase
to yield
N-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbo-
nyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl--
acetamide (MS(m/e): 574.2 [M].sup.+) as a light brown oil and
N-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetam-
ide (MS(m/e): 574.2 [M].sup.+) as a light brown oil.
EXAMPLE 120
N-{(3RS,4SR)-4-(4-Chloro-phenyl)-1-[1-(2,2-dimethyl-propyl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00156##
[0679] In analogy to the procedure described for the synthesis of
example 104, the title compound
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(2,2-dimethyl-propyl)-piperidine-4--
carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
was prepared from
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using
trimethylacetaldehyde (75% in tert butanol) instead of acetone and
was obtained as a light brown oil. MS m/e: 594.3 [M].sup.+.
EXAMPLE 121
N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(1-ethyl-piperidine-4-carbonyl)-pyrroli-
din-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00157##
[0681] In analogy to the procedure described for the synthesis of
example 104, the title compound
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-ethyl-piperidine-4-carbonyl)-pyrrol-
idin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was
prepared from
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidi-
n-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using
acetaldehyde instead of acetone and was obtained as a light brown
oil. MS m/e: 552.2 [M].sup.+.
EXAMPLE 122
N-{(3RS,4SR)-4-(4-Chloro-2-methyl-phenyl)-1-[1-(1-methyl-cyclopropanecarbo-
nyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-3-trifluoromethyl-b-
enzamide
##STR00158##
[0682] a) 4-Chloro-2-methyl-1-((E)-2-nitro-vinyl)-benzene
##STR00159##
[0684] Under an atmosphere of nitrogen was added to a solution of
4-chloro-2-methylbenzaldehyde (10.0 g, 64.9 g) in acetic acid (70
mL) ammonium acetate (11.5 g, 149 mmol) and nitromethane (10.0 ml,
185 mmol). The solution was stirred at reflux (oil bath 140.degree.
C.) for 2 h. After cooling to ambient temperature water (70 mL) was
added and extracted twice with ethyl acetate (70 mL). The organic
layers were washed with water (70 mL) and brine (70 mL) and were
dried over sodium sulfate. The filtrated was concentrated and the
resulting solid was suspended in methanol (30 mL), at 0.degree. C.
filtered off and was washed with cold methanol (10 mL) affording
the title compound (8.30 g, 65%) as a yellow solid. MS m/e: 197.0
[M].sup.+.
b)
(3SR,4RS)-1-Benzyl-3-(4-chloro-2-methyl-phenyl)-4-nitro-pyrrolidine
##STR00160##
[0686] In analogy to the procedure described for the synthesis of
pyrrolidine intermediate VIII-1 (step a), the title compound
(3SR,4RS)-1-benzyl-3-(4-chloro-2-methyl-phenyl)-4-nitro-pyrrolidine
was prepared from 4-chloro-2-methyl-1-((E)-2-nitro-vinyl)-benzene
instead of 1,2-dichloro-4-((E)-2-nitro-vinyl)-benzene and was
obtained as a light brown oil. MS m/e: 331.1 [M+H].sup.+.
c)
(3RS,4SR)-1-Benzyl-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-ylamine
##STR00161##
[0688] In analogy to the procedure described for the synthesis of
pyrrolidine intermediate VIII-1 (step b), the title compound
(3RS,4SR)-1-benzyl-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-ylamine
was prepared from
(3SR,4RS)-1-benzyl-3-(4-chloro-2-methyl-phenyl)-4-nitro-pyrrolidine
instead of
(3SR,4RS)-1-benzyl-3-(3,4-dichloro-phenyl)-4-nitro-pyrrolidine and
was obtained as a light brown foam. MS m/e: 301.2 [M+H].sup.+.
d)
[(3RS,4SR)-1-Benzyl-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-yl]-methy-
l-amine
##STR00162##
[0690] In analogy to the procedure described for the synthesis of
pyrrolidine intermediate VIII-1 (step c), the title compound
[(3RS,4SR)-1-benzyl-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-yl]-methyl--
amine was prepared from
(3RS,4SR)-1-benzyl-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-ylamine
instead of
(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine and
was obtained as a colorless oil. MS m/e: 315.1 [M+H].sup.+.
e)
N-[(3RS,4SR)-1-Benzyl-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-yl]-4-m-
ethoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00163##
[0692] In analogy to the procedure described for the synthesis of
pyrrolidine intermediate VIII-1 (step d), the title compound
N-[(3RS,4SR)-1-benzyl-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-yl]-4-met-
hoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from
[(3RS,4SR)-1-benzyl-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-yl]-methyl--
amine instead of
[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine
and was obtained as a light yellow oil. MS m/e: 517.1
[M+H].sup.+.
f)
N-[(3RS,4SR)-4-(4-Chloro-2-methyl-phenyl)-pyrrolidin-3-yl]-4-methoxy-N--
methyl-3-trifluoromethyl-benzamide
##STR00164##
[0694] In analogy to the procedure described for the synthesis of
example 87 (step b), the title compound
N-[(3RS,4SR)-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-me-
thyl-3-trifluoromethyl-benzamide was prepared from
N-[(3RS,4SR)-1-benzyl-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-yl]-4-met-
hoxy-N-methyl-3-trifluoromethyl-benzamide instead of
N-[(3RS,4SR)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-me-
thyl-3-trifluoromethyl-benzamide and was obtained as a yellow oil.
MS m/e: 427.2 [M+H].sup.+.
g)
N-{(3RS,4SR)-4-(4-Chloro-2-methyl-phenyl)-1-[1-(1-methyl-cyclopropaneca-
rbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-3-trifluoromethy-
l-benzamide
[0695] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-{(3RS,4SR)-4-(4-chloro-2-methyl-phenyl)-1-[1-(1-methyl-cyclopropanecarb-
onyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-3-trifluoromethyl--
benzamide was prepared from
N-[(3RS,4SR)-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-me-
thyl-3-trifluoromethyl-benzamide instead of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide and was obtained as a colorless oil. MS
m/e: 606.3 [M].sup.+.
EXAMPLE 123
N-{(3R,4S)-4-(4-Chloro-2-methyl-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluorom-
ethyl-benzamide
##STR00165##
[0697] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-{(3RS,4SR)-4-(4-chloro-2-methyl-phenyl)-1-[1-(1-methyl-cyclopropanecarb-
onyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluo-
romethyl-benzamide was prepared from
N-[(3RS,4SR)-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-me-
thyl-3-trifluoromethyl-benzamide instead of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide and was obtained as a colorless oil. MS
m/e: 620.3 [M].sup.+.
EXAMPLE 124
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-2-(tetrahydro-pyran-4-yl)-
-acetamide
##STR00166##
[0699] In analogy to the procedure described for the synthesis of
example 97, the title compound
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-2-(tetrahydro-pyran-4-yl-
)-acetamide was prepared from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
tetrahydropyran-4-yl-acetic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown foam. MS m/e: 564.4 [M].sup.+.
EXAMPLE 125
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-isobu-
tyramide
##STR00167##
[0701] In analogy to the procedure described for the synthesis of
example 97, the title compound
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-
-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-isob-
utyramide was prepared from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
2-(4-fluoro-phenyl)-2-methyl-propionic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown oil. MS m/e: 602.3 [M].sup.+.
EXAMPLE 126
N-{(3RS,4SR)-4-(4-Chloro-phenyl)-1-[1-(3-methylsulfanyl-propyl)-piperidine-
-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzami-
de
##STR00168##
[0703] In analogy to the procedure described for the synthesis of
example 104, the title compound
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3-methylsulfanyl-propyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzam-
ide was prepared from
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using
3-(methylthio)propionaldehyde instead of acetone and was obtained
as a colorless oil. MS m/e: 612.1 [M].sup.+.
EXAMPLE 127
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(4-methoxy-cyclohexanecarbonyl)-pyr-
rolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide
##STR00169##
[0704] a)
N-[(3RS,4SR)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-
-(4-fluoro-phenyl)-N-methyl-acetamide
##STR00170##
[0706] In analogy to the procedure described for the synthesis of
example 97, the title compound
N-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluor-
o-phenyl)-N-methyl-acetamide was prepared from
[(3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine
using 4-fluorophenylacetic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light yellow oil. MS m/e: 471.2 [M].sup.+.
b)
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-pheny-
l)-N-methyl-acetamide
##STR00171##
[0708] In analogy to the procedure described for the synthesis of
example 87 (step b), the title compound
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-
-N-methyl-acetamide was prepared from
N-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluor-
o-phenyl)-N-methyl-acetamide and was obtained as a brown oil. MS
m/e: 381.1 [M].sup.+.
c)
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(4-methoxy-cyclohexanecarbonyl)--
pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide
[0709] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(4-methoxy-cyclohexanecarbonyl)-py-
rrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared
from
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-
-N-methyl-acetamide using 4-methoxycylcohexanecarboxylic acid
instead of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and
was obtained as a colorless oil. MS m/e: 521.3 [M].sup.+.
EXAMPLE 128
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[2-(1,1-dioxo-1lambda*6*-thiomorpho-
lin-4-yl)-acetyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide
##STR00172##
[0711] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[2-(1,1-dioxo-1lambda*6*-thiomorph-
olin-4-yl)-acetyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide
was prepared from
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-
-N-methyl-acetamide using
(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-acetic acid instead of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and
was obtained as a colorless oil. MS m/e: 556.1 [M].sup.+.
EXAMPLE 129
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(morpholine-4-carbonyl)-pyrrolidin--
3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide
##STR00173##
[0713] Coupling according to general procedure I: [0714]
Pyrrolidine intermediate:
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-
-N-methyl-acetamide, [0715] Carbamoyl chloride:
4-Morpholinecarbonyl chloride ES-MS m/e: 494.2 (M.sup.+).
EXAMPLE 130
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-car-
bonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide
##STR00174##
[0717] Coupling according to general procedure I: [0718]
Pyrrolidine intermediate:
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-
-N-methyl-acetamide, [0719] Carbamoyl chloride:
4-Methanesulfonyl-piperazine-1-carbonyl chloride ES-MS m/e: 571.1
(M.sup.+).
EXAMPLE 131
N-{(3RS,4SR)-4-(4-Chloro-phenyl)-1-[1-(3-methanesulfonyl-propyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzam-
ide
##STR00175##
[0721] To a solution of
N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3-methylsulfanyl-propyl)-piperidin-
e-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzam-
ide (80 mg, 0.13 mmol) in dichloromethane (2 mL) was added under an
atmosphere of nitrogen m-chloroperbenzoic acid (47 mg, 0.27 mmol)
and stirred for 3 d at ambient temperature. Further addition of
m-chloroperbenzoic acid (47 mg, 0.27 mmol) was followed by stirring
for 3 h at ambient temperature. After the addition of an aqueous
saturated solution of sodium bisulfite (10 mL) and water (10 mL) it
was stirred for 1 h at ambient temperature. The reaction mixture
was basified by addition of an aqueous solution of sodium carbonate
(1 M). The aqueous layer was extracted with dichloromethane (20 mL)
and the organic layers were washed with water (15 mL) and dried
over sodium sulfate. Purification by chromatography (SiO.sub.2,
heptane:(ethyl acetate:triethylamine=95:5):methanol=20:80:0 to
0:85:15) afforded the title compound (70 mg, 83%) as a light brown
oil. MS m/e: 644.2 [M].sup.+.
EXAMPLE 132
4-{(3SR,4RS)-3-(3,4-Dichloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzo-
yl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic
acid tert-butyl ester
##STR00176##
[0723] In analogy to the procedure described for the synthesis of
example 95, the title compound
4-{(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benz-
oyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic
acid tert-butyl ester was prepared from
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl--
3-trifluoromethyl-benzamide instead of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide and was obtained as a light brown oil. MS
m/e: 658.3 [M].sup.+.
EXAMPLE 133
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin--
3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00177##
[0725] In analogy to the procedure described for the synthesis of
example 103, the title compound
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared
from
4-{(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benz-
oyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic
acid tert-butyl ester instead of
4-{(3SR,4RS)-3-(4-chloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)-
-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester and was obtained as a light brown oil. MS m/e:
558.0 [M].sup.+.
EXAMPLE 134
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(4-morpholin-4-yl-benzoyl)-pyrrolid-
in-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide
##STR00178##
[0727] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(4-morpholin-4-yl-benzoyl)-pyrroli-
din-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-
-N-methyl-acetamide using 4-morpholinobenzoic acid instead of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and
was obtained as a light yellow oil. MS m/e: 570.1 [M].sup.+.
EXAMPLE 135
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(6-morpholin-4-yl-pyridine-3-carbon-
yl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide
##STR00179##
[0729] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(6-morpholin-4-yl-pyridine-3-carbo-
nyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was
prepared from
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-ph-
enyl)-N-methyl-acetamide using 6-morpholinonicotinic acid instead
of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
and was obtained as a light yellow oil. MS m/e: 571.1
[M].sup.+.
EXAMPLE 136
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(6-methyl-pyridazine-4-carbonyl)-py-
rrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide
##STR00180##
[0731] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(6-methyl-pyridazine-4-carbonyl)-p-
yrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared
from
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-
-N-methyl-acetamide using 6-methyl-pyridazine-4-carboxylic acid
instead of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and
was obtained as a light yellow oil. MS m/e: 501.1 [M].sup.+.
EXAMPLE 137
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(6-morpholin-4-yl-pyridazine-3-carb-
onyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide
##STR00181##
[0733] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(6-morpholin-4-yl-pyridazine-3-car-
bonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was
prepared from
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-
-N-methyl-acetamide using 6-morpholin-4-yl-pyridazine-3-carboxylic
acid instead of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and
was obtained as a light yellow oil. MS m/e: 572.2 [M].sup.+.
EXAMPLE 138
N-[(3RS,4SR)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-
-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00182##
[0735] In analogy to the procedure described for the synthesis of
example 105, the title compound
N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichlor-
o-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
was prepared from
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide instead of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide and was obtained
as a light brown oil. MS m/e: 612.2 [M].sup.+.
EXAMPLE 139
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(3,3,3-trifluoro-propyl)-piperid-
ine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benz-
amide
##STR00183##
[0737] In analogy to the procedure described for the synthesis of
example 105, the title compound
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(3,3,3-trifluoro-propyl)-piperi-
dine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-ben-
zamide was prepared from
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide instead of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide and was obtained
as a light brown oil. MS m/e: 645.2 [M].sup.+.
EXAMPLE 140
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(1-ethanesulfonyl-piperidine-4-carb-
onyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00184##
[0739] To a solution of
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (50 mg, 0.90
mmol) in acetone (0.5 mL) was added potassium carbonate (finely
milled) (19 mg, 0.13 mmol), ethanesulfonyl chloride (13 .mu.L, 0.13
mmol) and acetone (0.5 mL). The suspension was stirred for 18 h at
ambient temperature. It was diluted with ethyl acetatec (10 mL) and
washed with an aqueous solution of Na2CO3 (1 M, 10 mL) and brine
(10 mL). The aqueous layers were extracted with ethyl acetate (10
mL) and the combined organic layers were dried over sodium sulfate.
Purification by chromatography (SiO.sub.2, heptane:ethyl
acetate=30:70 to 0:100) afforded the title compound (44 mg, 76%) as
an off-white foam. MS m/e: 650.2 [M].sup.+.
EXAMPLE 141
N-[(3RS,4SR)-1-(1-Cyclopropanesulfonyl-piperidine-4-carbonyl)-4-(3,4-dichl-
oro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamid-
e
##STR00185##
[0741] In analogy to the procedure described for the synthesis of
example 140, the title compound
N-[(3RS,4SR)-1-(1-Cyclopropanesulfonyl-piperidine-4-carbonyl)-4-(3,4-dich-
loro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzami-
de was prepared from
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using
cyclopropanesulfonylchloride instead of ethanesulfonyl chloride and
was obtained as a off-white foam. MS m/e: 662.2 [M].sup.+.
EXAMPLE 142
N-[(3RS,4SR)-1-[1-(2-Cyano-ethyl)-piperidine-4-carbonyl]-4-(3,4-dichloro-p-
henyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00186##
[0743] To a solution of
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (50 mg, 0.090
mmol) in dichloromethane (1 mL) was added 3-bromopropionitrile (11
.mu.L, 0.13 mmol) and an aqueous saturated solution of sodium
carbonate (1000 .mu.L). The resulting suspension was stirred for 18
h at ambient temperature. After the addition of dichloromethane (1
mL) and further 3-bromopropionitrile (11 .mu.L, 0.13 mmol) it was
stirred for 6 h at 40.degree. C. After diluting with ethyl acetate
(10 mL) the mixture was washed with an aqueous solution of sodium
carbonate (10 mL) and water (10 mL). The aqueous layer was
extracted with ethyl acetate (10 mL) and the combined organic
layers were dried over sodium sulfate. Purification by
chromatography (SiO.sub.2, heptane:ethyl acetate:(ethyl
acetate:triethylamine=95:5):methanol=20:80:0:0 to 0:0:90:10)
afforded the title compound (51 mg, 93%) as an light brown foam. MS
m/e: 611.2 [M].sup.+.
EXAMPLE 143
N-[(3RS,4RS)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-
-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide
##STR00187##
[0745] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-[(3RS,4RS)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichlor-
o-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide
was prepared from
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-
-N-methyl-acetamide using
1-cyclopropylmethyl-piperidine-4-carboxylic acid instead of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and
was obtained as a colorless oil. MS m/e: 546.3 [M].sup.+.
EXAMPLE 144
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(2-methoxy-ethyl)-piperidine-4-c-
arbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00188##
[0747] In analogy to the procedure described for the synthesis of
example 104, the title compound
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(2-methoxy-ethyl)-piperidine-4--
carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
was prepared from
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide instead of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using
methoxyacetaldehyde instead of acetone and was obtained as a
colorless oil. MS m/e: 616.4 [M].sup.+.
EXAMPLE 145
4-{(3SR,4RS)-3-(3,4-Dichloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzo-
yl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic
acid ethyl ester
##STR00189##
[0749] In analogy to the procedure described for the synthesis of
example 88, the title compound
4-{(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benz-
oyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic
acid ethyl ester was prepared from
N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide instead of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide using ethyl chloroformate instead of
4-fluorobenzoyl chloride and was obtained as a light brown foam. MS
m/e: 630.3 [M].sup.+.
EXAMPLE 146
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-
-benzoyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide
##STR00190##
[0751] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl-
)-benzoyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide
was prepared from
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-
-N-methyl-acetamide using 4-(3-methyl-1,2,4-oxadiazol-5-yl)-benzoic
acid instead of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and
was obtained as a light yellow oil. MS m/e: 567.1 [M].sup.+.
EXAMPLE 147
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-
-benzoyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00191##
[0753] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl-
)-benzoyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
was prepared from
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl--
3-trifluoromethyl-benzamide using
4-(3-methyl-1,2,4-oxadiazol-5-yl)-benzoic acid instead of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and
was obtained as a light yellow oil. MS m/e: 633.1 [M].sup.+.
EXAMPLE 148
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(2-fluoro-allyl)-piperidine-4-ca-
rbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide
##STR00192##
[0755] To a solution of
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (50 mg, 0.090
mmol) in THF (1 mL) was added under an atmosphere of nitrogen
potassium bis(trimethylsilyl)amide (0.885 M in THF, 132 .mu.L,
0.116 mmol). After stirring for 15 min at ambient temperature
3-chloro-2-fluoroprop-1-ene (13 mg, 0. 13 mmol) was added und the
reaction mixture was stirred for 20 h at this temperature. It was
diluted with ethyl acetate (10 mL) and washed with an aqueous
solution of sodium carbonate (1 M, 10 mL) and brine (10 mL). The
aqueous layers were extracted with ethyl acetate (10 mL) and the
combined organic layers dried over sodium sulfate. Purification by
chromatography (SiO.sub.2, ethyl acetate:(ethyl
acetate:triethylamine=95:5):methanol=100:0:0 to 0:90:10) afforded
the title compound (26 mg, 47%) as a light brown foam. MS m/e:
616.4 [M].sup.+.
EXAMPLE 149
2-(4-Cyano-phenyl)-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbon-
yl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide
##STR00193##
[0756] a)
[(3RS,4SR)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4--
dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl
ester
##STR00194##
[0758] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro--
phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester was
prepared from
[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic
acid tert-butyl ester instead of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide using
1-cyclopropylmethyl-piperidine-4-carboxylic acid instead of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and
was obtained as a dark brown oil, which was directly used without
further characterisation.
b)
(1-Cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-
-4-methylamino-pyrrolidin-1-yl]-methanone
##STR00195##
[0760] In analogy to the procedure described for the synthesis of
example 96 (step d), the title compound
(1-Cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-
-methylamino-pyrrolidin-1-yl]-methanone was prepared from
[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro--
phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester
instead of
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid
tert-butyl ester and was obtained as a brown oil. MS m/e: 410.2
[M].sup.+.
c)
2-(4-Cyano-phenyl)-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-car-
bonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide
[0761] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
2-(4-Cyano-phenyl)-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbo-
nyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide
was prepared from
(1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-
-methylamino-pyrrolidin-1-yl]-methanone instead of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide using 4-cyanophenylacetic acid instead of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and
was obtained as a yellow oil. MS m/e: 553.2 [M].sup.+.
EXAMPLE 150
N-[(3RS,4SR)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-
-phenyl)-pyrrolidin-3-yl]-2-(3,4-difluoro-phenyl)-N-methyl-acetamide
##STR00196##
[0763] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichlor-
o-phenyl)-pyrrolidin-3-yl]-2-(3,4-difluoro-phenyl)-N-methyl-acetamide
was prepared from
(1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-
-methylamino-pyrrolidin-1-yl]-methanone instead of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide using 3,4-difluorophenylacetic acid instead
of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
and was obtained as a light yellow oil. MS m/e: 564.3
[M].sup.+.
EXAMPLE 151
2-Cyclopentyl-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-
-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide
##STR00197##
[0765] In analogy to the procedure described for the synthesis of
example 88, the title compound
2-cyclopentyl-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)--
4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide was
prepared from
(1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phen-
yl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide using cylopentylacetyl chloride instead of
4-fluorobenzoyl chloride and was obtained as a light yellow oil. MS
m/e: 520.3 [M+H].sup.+.
EXAMPLE 152
N-[(3RS,4SR)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-
-phenyl)-pyrrolidin-3-yl]-2-(2,3-difluoro-phenyl)-N-methyl-acetamide
##STR00198##
[0767] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichlor-
o-phenyl)-pyrrolidin-3-yl]-2-(2,3-difluoro-phenyl)-N-methyl-acetamide
was prepared from
(1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-
-methylamino-pyrrolidin-1-yl]-methanone instead of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide using 2,3-difluorophenylacetic acid instead
of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
and was obtained as a colorless semi-solid. MS m/e: 564.4
[M].sup.+.
EXAMPLE 153
4-Chloro-N-[(3R,4S)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine--
4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
##STR00199##
[0768] and
EXAMPLE 154
4-Chloro-N-[(3S,4R)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine--
4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
##STR00200##
[0770]
4-Chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-pi-
peridine-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
was subjected to column chromatography on chiral phase to yield
4-chloro-N-[(3R,4S)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine-
-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
(MS(m/e): 581.2 [M].sup.+) as a white foam and
4-chloro-N-[(3S,4R)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine-
-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
(MS(m/e): 581.2 [M].sup.+) as an off-white foam.
EXAMPLE 155
4-Chloro-N-{(3R,4S)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benz-
amide
##STR00201##
[0771] and
EXAMPLE 156
4-Chloro-N-{(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbony-
l)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benz-
amide
##STR00202##
[0773]
4-Chloro-N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropa-
necarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluorome-
thyl-benzamide was subjected to column chromatography on chiral
phase to yield
4-chloro-N-{(3R,4S)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropane-
carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluorometh-
yl-benzamide (MS(m/e): 610.2 [M].sup.+) as a white foam and
4-chloro-N-{(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbon-
yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-ben-
zamide (MS(m/e): 610.2 [M].sup.+) as a white foam.
EXAMPLE 157
4-{(3SR,4RS)-3-(4-Chloro-phenyl)-4-[(4-chloro-3-trifluoromethyl-benzoyl)-m-
ethyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester
##STR00203##
[0775] In analogy to the procedure described for the synthesis of
example 97, the title compound
4-{(3SR,4RS)-3-(4-chloro-phenyl)-4-[(4-chloro-3-trifluoromethyl-benzoyl)--
methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester was prepared from
4-chloro-N-[(3R,4S)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifl-
uoromethyl-benzamide instead of
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
piperidine-1,4-dicarboxylic acid mono-tert-butyl ester instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
white foam. MS m/e: 528.2 [M--BOC].sup.+.
EXAMPLE 158
2-(4-Chloro-phenyl)-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbo-
nyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide
##STR00204##
[0777] In analogy to the procedure described for the synthesis of
example 88, the title compound
2-(4-chloro-phenyl)-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carb-
onyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide
was prepared from
(1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-
-methylamino-pyrrolidin-1-yl]-methanone instead of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide using 4-chlorophenylacetyl chloride instead
of 4-fluorobenzoyl chloride and was obtained as an off-white
semi-solid. MS m/e: 562.2 [M].sup.+.
EXAMPLE 159
N-[(3RS,4SR)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-
-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-propionamide
##STR00205##
[0779] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichlor-
o-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-propionamide
was prepared from
(1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-
-methylamino-pyrrolidin-1-yl]-methanone instead of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide using 4-fluoro-alpha-methylphenyl acetic
acid instead of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and
was obtained as a colorless oil. MS m/e: 560.2 [M].sup.+.
EXAMPLE 160
4-Chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)--(piperidine
-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
##STR00206##
[0781] In analogy to the procedure described for the synthesis of
example 103, the title compound
4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrro-
lidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide was prepared from
4-{(3SR,4RS)-3-(4-chloro-phenyl)-4-[(4-chloro-3-trifluoromethyl-benzoyl)--
methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester instead of
4-{(3SR,4RS)-3-(4-chloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)-
-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid
tert-butyl ester and was obtained as a white foam. MS m/e: 528.0
[M].sup.+.
EXAMPLE 161
4-Chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyclopropanesulfonyl-piperi-
dine-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
##STR00207##
[0783] In analogy to the procedure described for the synthesis of
example 141, the title compound
4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyclopropanesulfonyl-piper-
idine-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
was prepared from
4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrro-
lidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide instead of
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide and was
obtained as a colorless oil. MS m/e: 632.3 [M].sup.+.
EXAMPLE 162
4-Chloro-N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(tetrahydro-pyran-4-yl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide
##STR00208##
[0785] In analogy to the procedure described for the synthesis of
example 104, the title compound
4-chloro-N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(tetrahydro-pyran-4-yl)-pi-
peridine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide
was prepared from
4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrro-
lidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide using
tetrahydro-4H-pyran-4-one instead of acetone and was obtained as a
white foam. MS m/e: 612.2 [M].sup.+.
EXAMPLE 163
4-Chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyanomethyl-piperidine-4-ca-
rbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
##STR00209##
[0787] To a solution of
4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrro-
lidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide (216 mg, 0.382
mmol) in DMF (1 mL) was added sodium hydride (55% dispersion in
mineral oil, 6 mg, 0.14 mmol). After stirring for 30 min at ambient
temperature iodoacetonitrile (9 .mu.l, 0.12 mmol) was added And the
suspension was stirred for 18 h at this temperature. After the
addition of further iodoacetonitrile (9 .mu.l, 0.12 mmol) the
resulting dark brown solution was stirred for further 5 h at
ambient temperature. It was diluted with ethyl acetate (10 mL) and
was washed with aqueous sodium carbonate (1 M, 10 mL) and brine (10
mL). The aqueous layers were extracted with ethyl acetate (10 mL)
and the combined organic phases were dried over sodium sulfate.
Purification by chromatography (SiO.sub.2, (ethyl
acetate:triethylamine=95:5):methanol=100:0 to 70:30) afforded the
title compound (45 mg, 88%) as a white foam. MS m/e: 567.1
[M].sup.+.
EXAMPLE 164
4-Chloro-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-
-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
##STR00210##
[0789] In analogy to the procedure described for the synthesis of
example 87 (step c), the title compound
4-chloro-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,-
4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
was prepared from
(1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-
-methylamino-pyrrolidin-1-yl]-methanone instead of
N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-tr-
ifluoromethyl-benzamide using 4-chloro-3-(trifluoromethyl)benzoic
acid instead of
1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and
was obtained as a white foam. MS m/e: 616.3 [M].sup.+.
EXAMPLE 165
4-Chloro-N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(2-cyano-ethyl)-piperidine--
4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide
##STR00211##
[0791] In analogy to the procedure described for the synthesis of
example 142, the title compound
4-chloro-N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(2-cyano-ethyl)-piperidine-
-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide
was prepared from
N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-y-
l]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide instead of
N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-
-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide and was
obtained as a colorless oil. MS m/e: 581.2 [M].sup.+.
EXAMPLE 166
4-Trifluoromethyl-pyridine-2-carboxylic acid
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide
##STR00212##
[0793] In analogy to the procedure described for the synthesis of
example 97, the title compound
4-trifluoromethyl-pyridine-2-carboxylic acid
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was prepared
from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
4-(trifluoromethyl)pyridine-2-carboxylic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown foam. MS m/e: 611.2 [M].sup.+.
EXAMPLE 167
4-Chloro-N-[(3S,4R)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-d-
ichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
##STR00213##
[0794] and
EXAMPLE 168
4-Chloro-N-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-d-
ichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
##STR00214##
[0796]
4-Chloro-N-[(3SR,4RS)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-
-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benza-
mide was subjected to column chromatography on chiral phase to
yield
4-chloro-N-[(3S,4R)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4--
dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
(MS(m/e): 616.3 [M].sup.+) as a white foam and
4-chloro-N-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4--
dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide
(MS(m/e): 616.3 [M].sup.+) as a white foam.
EXAMPLE 169
4-Trifluoromethyl-pyridine-2-carboxylic acid
{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide
##STR00215##
[0797] and
EXAMPLE 170
4-Trifluoromethyl-pyridine-2-carboxylic acid
{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide
##STR00216##
[0799] 4-Trifluoromethyl-pyridine-2-carboxylic acid
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was subjected
to column chromatography on chiral phase to yield
4-trifluoromethyl-pyridine-2-carboxylic acid
{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide (MS(m/e): 611.3
[M].sup.+) as an off-white semi-solid and
4-trifluoromethyl-pyridine-2-carboxylic acid
{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-pip-
eridine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide (MS(m/e): 611.3
[M].sup.+) as a white semi-solid.
EXAMPLE 171
3-Bromo-4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclo-
propanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzamid-
e
##STR00217##
[0801] In analogy to the procedure described for the synthesis of
example 97, the title compound
3-bromo-4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cycl-
opropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzami-
de was prepared from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
3-bromo-4-chlorobenzoic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
colorless oil. MS m/e: 656.0 [M].sup.+.
EXAMPLE 172
6-Methyl-pyridazine-4-carboxylic acid
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide
##STR00218##
[0803] In analogy to the procedure described for the synthesis of
example 97, the title compound 6-methyl-pyridazine-4-carboxylic
acid
{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-p-
iperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was prepared
from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
6-methyl-pyridazine-4-carboxylic acid instead of
4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a
light brown oil. MS m/e: 557.9 [M].sup.+.
EXAMPLE 173
4-Chloro-3-cyclopropyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-
-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-be-
nzamide
##STR00219##
[0805] To a solution of
3-bromo-4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cycl-
opropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzami-
de (78 mg, 0.12 mmol) in toluene (1 mL) and water (0.048 mL) was
added under an atmosphere of nitrogen potassium phosphate, tribasic
mono hydrate (88 mg, 0.42 mmol), tricyclohexylphosphine (4 mg,
0.014 mmol) palladium(II) acetate (2 mg, 0.009 mmol). The reaction
mixture was stirred for 18 h at 80.degree. C. under an atmosphere
of nitrogen. It was concentrated and purification by chromatography
(SiO.sub.2, ethyl acetate:methanol=100:0 to 85:15) afforded the
title compound (71 mg, 97%) as a light brown foam. MS m/e: 616.2
[M].sup.+.
EXAMPLE 174
4-Chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanec-
arbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-ethyl-N-methyl-benzamid-
e
##STR00220##
[0807] To a solution of
3-bromo-4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cycl-
opropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzami-
de (50 mg; 0.076 mmol) in THF (0.5 mL) was added under an argon
atmosphere tetrakis(triphenylphosphine)palladium (0) (5 mg; 0.04
mmol) and diethylzinc (1 M in hexane, 762 .mu.L; 0.762 mmol). The
resulting solution was stirred for 5 h at 65.degree. C. before it
was diluted with ethyl acetatec (30 mL) and washed with aqueous
sodium carbonate (saturated, 20 mL), water (20 mL) and aqueous
sodium carbonate. (saturated, 20 mL). The aqueous phases were
extracted with ethyl acetate (30 mL) and dried over sodium sulfate.
Purification by chromatography (SiO.sub.2, ethyl
acetate:methanol=100:0 to 90:10) afforded the title compound (37
mg, 47%) as a light brown foam. MS m/e: 604.2 [M].sup.+.
EXAMPLE 175
4-Chloro-3-cyclopropyl-N-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-c-
yclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benz-
amide
##STR00221##
[0808] and
EXAMPLE 176
4-Chloro-3-cyclopropyl-N-{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-c-
yclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benz-
amide
##STR00222##
[0810]
4-Chloro-3-cyclopropyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-
-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-me-
thyl-benzamide was subjected to column chromatography on chiral
phase to yield
4-chloro-3-cyclopropyl-N-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-m-
ethyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-meth-
yl-benzamide (MS(m/e): 616.5 [M].sup.+) as a light brown oil and
4-chloro-3-cyclopropyl-N-{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl--
cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-ben-
zamide (MS(m/e): 616.5 [M].sup.+) as a light brown oil.
EXAMPLE 177
N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)--
piperidine-4-carbonyl]-pyrrolidin-3-yl}-4,4,4-trifluoro-N-methyl-butyramid-
e
##STR00223##
[0812] To a solution of 4,4,4-trifluorobutyric acid (43 mg, 0.304
mmol) in NMP (1 ml) was added at ambient temperature
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (89 mg, 0.28 mmol) and N,N-diisopropyl ethyl
amine (130 .mu.l, 0.760 mmol). After stirring for 15 min a solution
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone (11 mg, 0.253
mmol) in NMP (1 mL) was added and stirred for 18 h at ambient
temperature. The reaction mixture was diluted with ethyl acetate
(15 mL) and washed with aqueous sodium carbonate (1 M, 15 mL),
water (15 mL) and brine (15 mL). The aqueous layers were extracted
with ethyl acetate (15 mL) and the combined organic layers were
dried over sodium sulfate. Purification by chromatography
(SiO.sub.2, heptane:ethyl acetate:methanol=20:80:0 to 0:85:15)
afforded the title compound (109 mg, 77%) as an off-white foam. MS
m/e: 562.2 [M].sup.+.
EXAMPLE 178
2-Cyclopropylmethoxy-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-c-
yclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-acet-
amide
##STR00224##
[0814] In analogy to the procedure described for the synthesis of
example 177, the title compound
2-cyclopropylmethoxy-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl--
cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-ace-
tamide was prepared from
{4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbony-
l]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using
Cyclopropylmethoxy-acetic acid instead of
.sup.4,4,4-trifluorobutyric acid and was obtained as an off-white
foam. MS m/e: 550.2 [M].sup.+.
* * * * *