U.S. patent application number 11/783341 was filed with the patent office on 2008-07-10 for pharmaceutically active pyrrolidine derivatives.
This patent application is currently assigned to APPLIED RESEARCH SYSTEM ARS HOLDING N.V.. Invention is credited to Anthony Baxter, Serge Halazy, Anna Quattropani, Alexander Scheer, Matthias Schwarz, Russell J. Thomas.
Application Number | 20080167318 11/783341 |
Document ID | / |
Family ID | 8168169 |
Filed Date | 2008-07-10 |
United States Patent
Application |
20080167318 |
Kind Code |
A1 |
Halazy; Serge ; et
al. |
July 10, 2008 |
Pharmaceutically active pyrrolidine derivatives
Abstract
The present invention is related to pyrrolidine derivatives of
formula I. Said compounds are preferably for use as
pharmaceutically active compounds. Specifically, pyrrolidine
derivatives of formula I are useful in the treatment and/or
prevention of premature labor, premature birth and dysmenorrhea. In
particular, the present invention is related to pyrrolidine
derivatives displaying a substantial modulatory, notably an
antagonist activity of the oxytocin receptor. More preferably, said
compounds are useful in the treatment and/or prevention of disease
states mediated by oxytocin, including premature labor, premature
birth and dysmenorrhea. The present invention is furthermore
related to novel pyrrolidine derivatives as well as to methods of
their preparation. ##STR00001## wherein X is selected from the
group consisting of CR.sup.6R.sup.7, NOR.sup.6, NNR.sup.6R.sup.7; A
is selected from the group consisting of --(C.dbd.O)--,
--(C.dbd.O)--O--, --C(.dbd.NH)--, --(C.dbd.O)--NH--,
--(C.dbd.S)--NH, --SO.sub.2--, --SO.sub.2NH--, --CH.sub.2--, B is
either a group --C.dbd.O)--NR.sup.8R.sup.9 or represents a
heterocyclic residue having the formula wherein Q is NR.sup.10, O
or S; n is an integer selected of 0, 1 or 2; ##STR00002## Y, Z and
E form together with the 2 carbons to which they are attached a 5-6
membered aryl or heteroaryl ring.
Inventors: |
Halazy; Serge;
(Vetraz-Monthoux, FR) ; Quattropani; Anna;
(Geneva, CH) ; Scheer; Alexander; (Versoix,
CH) ; Schwarz; Matthias; (Geneva, CH) ;
Thomas; Russell J.; (Siena, IT) ; Baxter;
Anthony; (Much Hadham, GB) |
Correspondence
Address: |
BROWDY AND NEIMARK, P.L.L.C.;624 NINTH STREET, NW
SUITE 300
WASHINGTON
DC
20001-5303
US
|
Assignee: |
APPLIED RESEARCH SYSTEM ARS HOLDING
N.V.
Curacao
NL
|
Family ID: |
8168169 |
Appl. No.: |
11/783341 |
Filed: |
April 9, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10239912 |
Feb 10, 2003 |
7211601 |
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PCT/EP01/03171 |
Mar 20, 2001 |
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11783341 |
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Current U.S.
Class: |
514/253.01 ;
514/306; 514/411; 514/423; 544/372; 546/138; 548/529; 548/537 |
Current CPC
Class: |
C07D 207/22 20130101;
A61P 25/08 20180101; A61P 9/00 20180101; C07D 405/06 20130101; C07D
403/04 20130101; A61P 15/06 20180101; A61P 37/04 20180101; A61P
43/00 20180101; C07D 409/12 20130101; A61P 15/00 20180101; A61P
25/00 20180101; A61P 13/12 20180101; C07D 405/14 20130101; A61P
15/04 20180101; A61P 15/02 20180101; C07D 417/12 20130101; A61P
31/18 20180101; C07D 405/12 20130101; A61P 7/00 20180101; A61P 9/10
20180101; A61P 1/16 20180101; C07D 401/12 20130101; A61P 25/28
20180101; C07D 403/14 20130101; C07D 403/06 20130101 |
Class at
Publication: |
514/253.01 ;
514/306; 514/411; 514/423; 544/372; 546/138; 548/529; 548/537 |
International
Class: |
A61K 31/497 20060101
A61K031/497; A61K 31/40 20060101 A61K031/40; A61K 31/403 20060101
A61K031/403; A61P 15/06 20060101 A61P015/06; C07D 209/56 20060101
C07D209/56; C07D 455/02 20060101 C07D455/02; C07D 403/02 20060101
C07D403/02; C07D 207/02 20060101 C07D207/02; A61P 15/02 20060101
A61P015/02; A61K 31/47 20060101 A61K031/47 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 27, 2000 |
EP |
00106034.2 |
Claims
1. Pyrrolidine compounds according to formula I ##STR00035## as
well as its geometrical isomers, its optically active forms as
enantiomers, diastereomers and its racemate forms, as well as
pharmaceutically acceptable salts thereof, wherein X is selected
from the group consisting of CR.sup.6R.sup.7, NOR.sup.6,
NNR.sup.6R.sup.7; m is an integer selected from the group
consisting of 0, 1, 2 and 3; A is selected from the group
consisting of --SO.sub.2--, --SO.sub.2NH--, --CH.sub.2--, B is
either a group --C.dbd.O)--NR.sup.8R.sup.9 or represents a
heterocyclic residue having the formula ##STR00036## wherein Q is
NR.sup.10, O or S; n is an integer selected of 0, 1 or 2; Y, Z and
E form together with the 2 carbons to which they are attached a 5-6
membered aryl or heteroaryl ring, R.sup.1 is selected from the
group consisting of unsubstituted or substituted
C.sub.1-C.sub.6-alkyl, unsubstituted or substituted
C.sub.2-C.sub.6-alkenyl, unsubstituted or substituted
C.sub.2-C.sub.6-alkynyl; unsubstituted or substituted aryl,
unsubstituted or substituted heteroaryl, unsubstituted or
substituted saturated or unsaturated 3-8-membered cycloalkyl,
unsubstituted or substituted C.sub.1-C.sub.6-alkyl heteroaryl, said
cycloalkyl or aryl or heteroaryl groups may be fused with 1-2
further cycloalkyl or aryl or heteroaryl group; R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are independently selected from each other from
the group consisting of hydrogen, halogen, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy; R.sup.6 and R.sup.7 are independently
selected from the group consisting of hydrogen, unsubstituted or
substituted C.sub.1-C.sub.6 alkyl, unsubstituted or substituted
C.sub.2-C.sub.6 alkenyl, unsubstituted or substituted
C.sub.2-C.sub.6 alkynyl, unsubstituted or substituted alkoxy,
unsubstituted or substituted thioalkoxy, halogen, cyano, nitro,
acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted
saturated or unsaturated 3-8-membered cycloalkyl which may contain
1 to 3 heteroatoms selected of N, O, S, unsubstituted or
substituted aryl, unsubstituted or substituted heteroaryl,
unsubstituted or substituted C.sub.1-C.sub.6-alkyl aryl,
unsubstituted or substituted C.sub.1-C.sub.6-alkyl heteroaryl;
R.sup.8, R.sup.9 and R.sup.10 are independently selected from the
group comprising or consisting of hydrogen, unsubstituted or
substituted C.sub.1-C.sub.6 alkyl, unsubstituted or substituted
C.sub.2-C.sub.6 alkenyl, unsubstituted or substituted
C.sub.2-C.sub.6 alkynyl, unsubstituted or substituted saturated or
unsaturated 3-8-membered cycloalkyl which may contain 1 to 3
heteroatoms selected of N, O, S, unsubstituted or substituted aryl,
unsubstituted or substituted heteroaryl, or each pair R.sup.6,
R.sup.7 and/or R.sup.8, R.sup.9 could form together with the N atom
to which they are attached a 3-8 membered substituted or
unsubstituted, saturated or unsaturated hetero-cyclic ring which
may contain 1-2 further heteroatoms selected from N, S and O and
which is optionally fused with an aryl, heteroaryl or 3-8 membered
saturated or unsaturated cycloalkyl ring; R.sup.11 is selected from
the group comprising or consisting of hydrogen, unsubstituted or
substituted C.sub.1-C.sub.6-alkyl, unsubstituted or substituted
alkenyl, unsubstituted or substituted alkynyl, hydroxy, mercapto,
alkoxy, thioalkoxy, aryl, heteroaryl, halogen, nitro, cyano, acyl,
acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, sulfonyl,
sulfoxy, carboxyl, primary, secondary or tertiary amino groups or
quaternary ammonium moieties, unsubstituted or substituted
saturated or unsaturated 3-8-membered cyclo-alkyl.
2. A pyrrolidine compound according to claim 1, wherein B is a
group --(C.dbd.O)--NHR.sup.9, in which R.sup.9 is selected from the
group consisting of unsubstituted or substituted C.sub.1-C.sub.6
alkyl, unsubstituted or substituted C.sub.2-C.sub.6 alkenyl,
unsubstituted or substituted C.sub.2-C.sub.6 alkynyl, unsubstituted
or substituted saturated or unsaturated 3-6-membered cycloalkyl
which optionally contains a N atom, unsubstituted or substituted
aryl, unsubstituted or substituted heteroaryl, unsubstituted or
substituted C.sub.1-C.sub.2-alkyl aryl, unsubstituted or
substituted C.sub.1-C.sub.2-alkyl heteroaryl.
3. A pyrrolidine compound according to claim 1, wherein B is a
fused heterocycle of the formula ##STR00037##
4. A pyrrolidine compound according to claim 2, wherein R.sup.9 is
a heteroaryl selected from pyridyl, pyrrolyl, furyl, thienyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
1,3,4-triazinyl, 1,2,3-triazinyl, benzo-furyl,
[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl,
benzotriazolyl, isobenzo-thienyl, 2,1,3-benzothiadiazolyl,
2,1,3-benzoxadiazolyl, benzodioxolyl, indolyl, isoindolyl,
3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl,
benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl,
quinoxalinyl, cinnolinyl, napthyridinyl, pyrido[3,4-b]pyridyl,
pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl,
tetrazolyl, 5,6,7,8-tetrahydroquinolyl,
5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,
xanthenyl, acridinyl or benzoquinolyl and whereby said heteroaryl
could be fused with a 3-8-membered cycloalkyl containing optionally
1-3 heteroatoms selected from N, O, S.
5. A pyrrolidine compound according to claim 1, wherein X is
NOR.sup.6, and R.sup.6 is selected from the group consisting of H,
unsubstituted or substituted C.sub.1-C.sub.6 alkyl, unsubstituted
or substituted C.sub.2-C.sub.6 alkenyl, unsubstituted or
substituted C.sub.2-C.sub.6 alkynyl, unsubstituted or substituted
acyl, unsubstituted or substituted aryl, unsubstituted or
substituted heteroaryl, unsubstituted or substituted saturated or
unsaturated 3-8-membered cycloalkyl, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl aryl, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl heteroaryl, said cycloalkyl or aryl or
heteroaryl groups may be fused with 1-2 further cycloalkyl or aryl
or heteroaryl groups.
6. A pyrrolidine compound according to claim 5, wherein R.sup.6 is
H, CH.sub.3, unsubstituted or substituted CH.sub.2-phenyl or allyl,
preferably H or methyl.
7. A pyrrolidine compound according to claim 1, wherein X is
CHR.sup.6, R.sup.6 is selected from the group consisting of
halogen, cyano, unsubstituted or substituted C.sub.3-C.sub.6 alkyl,
unsubstituted or substituted C.sub.2-C.sub.6 alkenyl, unsubstituted
or substituted C.sub.2-C.sub.6 alkynyl, unsubstituted or
substituted alkoxy, unsubstituted or substituted thioalkoxy, nitro,
acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted
aryl, unsubstituted or substituted heteroaryl, unsubstituted or
substituted saturated or unsaturated 3-8-membered cycloalkyl,
unsubstituted or substituted C.sub.1-C.sub.6-alkyl aryl,
unsubstituted or substituted C.sub.1-C.sub.6-alkyl heteroaryl, said
cycloalkyl or aryl or heteroaryl groups may be fused with 1-2
further cycloalkyl or aryl or heteroaryl groups.
8. A pyrrolidine compound according to claim 7, wherein R.sup.6 is
selected from the group consisting of halogen, cyano,
C.sub.3-C.sub.6 alkyl or an unsubstituted or substituted phenyl
group.
9. A pyrrolidine compound according to claim 1, wherein A is
--(C.dbd.O)--, or --(C.dbd.O)--NH--, or --SO.sub.2--.
10. A pyrrolidine compound according to claim 1, wherein R.sup.1 is
an C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, unsubstituted or
substituted C.sub.2-C.sub.6-alkynyl, aryl, heteroaryl, saturated or
unsaturated 3-8-membered cycloalkyl, C.sub.1-C.sub.6-alkyl aryl,
C.sub.1-C.sub.6-alkyl heteroaryl.
11. A pyrrolidine compound according to claim 10, wherein R.sup.1
is an C.sub.1-C.sub.6-alkyl or aryl group.
12. A pyrrolidine compound according to claim 12, wherein R.sup.1
is biphenyl.
13. A pyrrolidine compound according to claim 1, selected from the
following group:
(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-3-pyrr-
olidinone O-methyloxime
(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-([1,1'-biphenyl]-4-ylcarbonyl)--
4-(methoxy-imino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-furylm-
ethyl)-2-pyrrolidinecarboxamide
(2S,4EZ)-4-(cyanomethylene)-N-(2-furylmethyl)-1-[(2-oxo-6-pentyl-2H-pyran-
-3-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-(methoxyimi-
no)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-furylmethyl)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-
-yl)-carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-4-(cyanomethylene)-1-(diphenylace-
tyl)-2-pyrrolidinecarboxamide
(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-(diphenylacetyl)-3-pyrrolidinone
O-methyloxime
(2S)-2-[1-([1,1'-biphenyl]-4-ylcarbonyl)-4-methylene-2-pyrrolidinyl]-1H-b-
enzimidazole
(2S,4EZ)-N-allyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(diphenylacetyl)-2--
pyrrolidinecarboxamide
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N.sup.1-pentyl-N.sup.2-(6-qui-
nolinyl)-1,2-pyrrolidinedicarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(6-quinol-
inyl)-2-pyrrolidinecarboxamide
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-[4-(dimethylamino)butanoyl]-
-N-(6-quinolinyl)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(5-ethyl-1,3,4-thiadiazol-2-y-
l)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N.sup.2-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N.sup.1-(-
3-methoxyphenyl)-1,2-pyrrolidinedicarboxamide
(2S,4EZ)-1-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-{[(4-methox-
ybenzyl)oxy]-imino}-2-pyrrolidinecarboxamide
(2S)--N-(2-furylmethyl)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carb-
onyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-(diphenylacetyl)-4-(methoxyimin-
o)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-benzoyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quinolinyl)-2--
pyrrolidinecarboxamide
(2S,4EZ)-1-(4-cyanobenzoyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quino-
linyl)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(1,3-benzodioxol-5-ylmethyl)-1-([1,1'-biphenyl]-4-ylcarbonyl)--
4-(methoxyimino)-2-pyrrolidinecarboxamide
(3EZ,5S)-5-[(4-acetyl-1-piperazinyl)carbonyl]-1-acryloyl-3-pyrrolidinone
O-(3,4-dichlorobenzyl)oxime
(2S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-methylene-2-pyr-
rolidinecarboxamide
(2S,4EZ)-4-(cyanomethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-
-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-[4-(3-py-
ridinyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-phenoxypro-
pyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-
phenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(1-hydroxycyclohexyl)methyl]-4-(methoxyimino)-1-[4-(3-pyridin-
yl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1-hydroxycyclohexyl)methyl]-
-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridi-
nyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridi-
nyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(2-pyridi-
nyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4-
-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4-
-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxy-
phenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)--
1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxy-
phenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxypropyl]-4-(me-
thoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(2-naphthy-
l)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-
-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-
-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-
-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-nitroph-
enyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1'-bi-
phenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyi-
mino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyi-
mino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1'-bi-
phenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2R)-2-hydroxy-2-phenylethyl-
]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridi-
nyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridi-
nyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(2-pyridi-
nyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2R)-2-hydroxy-2-phenylethyl-
]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(3-hydroxypropyl)-4-(methoxyi-
mino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-(3-hydroxypropyl)-4-(methoxyi-
mino)-2-pyrrolidinecarboxamide
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-4-phenyl-1-piperi-
dinyl)carbonyl]-3-pyrrolidinone O-methyloxime
(3EZ,5S)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-1-[4-(4-pyridinyl-
)benzoyl]-3-pyrrolidinone O-methyloxime
(3EZ,5S)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-1-[4-(3-pyridinyl-
)benzoyl]-3-pyrrolidinone O-methyloxime
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-4-phenyl-1-piperi-
dinyl)carbonyl]-3-pyrrolidinone O-methyloxime
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-
-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-
-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-benzyl-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(-
methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-benzyl-N-(2-hydroxyethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)b-
enzoyl]-2-pyrrolidinecarboxamide
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-5-{[(3RS)-3-hydroxypiperidinyl]-
carbonyl}-3-pyrrolidinone O-methyloxime
(3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-1-[4-(4-pyridinyl)benzo-
yl]-3-pyrrolidinone O-methyloxime
(3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-1-[4-(3-pyridinyl)benzo-
yl]-3-pyrrolidinone O-methyloxime
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylsulfonyl)-5-{[(3RS)-3-hydroxypiperidinyl]-
carbonyl}-3-pyrrolidinone O-methyloxime
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxy-
methyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxy-
imino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxy-
imino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxy-
methyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-anilinoethyl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyim-
ino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-
-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-
-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-
-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-anilinoethyl)-1-([1,1'-biphenyl]-4-ylsulfonyl)-4-(methoxyim-
ino)-2-pyrrolidinecarboxamide
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-1-piperidinyl)car-
bonyl]-3-pyrrolidinone O-methyloxime
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-1-piperidinyl)car-
bonyl]-3-pyrrolidinone O-methyloxime
(2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]--
1-([1,1'-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(meth-
oxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]--
1-([1,1'-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(4-hydroxybutyl)-4-(methoxyim-
ino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-(4-hydroxybutyl)-4-(methoxyim-
ino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1R,2R)-2-(hydroxymethyl)cyc-
lohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1R,2S,3R,4S)-3-(hydroxymeth-
yl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1R,2S)-2-(hydroxymethyl)cyc-
lohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide (2S,4E and
4Z)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1,1'-
-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (2S,4E and
4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1,1'--
biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (2S,4E and
4Z)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1,1'--
biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1R,2s)-2-(hydroxymethyl)cyc-
lohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[2-hydroxy-1-(hydroxymethyl)e-
thyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]--
1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]--
1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl-
]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2RS)-3-({[(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrr-
olidinyl]-carbonyl}amino)-2-hydroxypropanoic acid
(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-([1,1'-biphenyl]-4-ylc-
arbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1RS)-2-hydroxy-1-methylethy-
l]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxy-
methyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
4-({[(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-
yl]-carbonyl}amino)butanoic acid
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-1-[(2'-methoxy[1,1'-biphenyl]-4-
-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(2-naphthyl)ethyl]-1-[(2'-methoxy[1,1'-biph-
enyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(1RS)-2-hydroxy-1-methylethyl]-4-(methoxyimino)-1-[(2'-methyl-
[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-
-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinec-
arboxamide
(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitropheny-
l)ethyl]-4-(methoxyimino)-1-[(2'-methoxy[1,1'-biphenyl]-4-yl)carbonyl]-2-p-
yrrolidinecarboxamide
(3EZ,5S)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-1-[(2'-methyl[1,1'-bipheny-
l]-4-yl)carbonyl]-3-pyrrolidinone O-methyloxime
(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]--
4-(methoxyimino)-1-[(2'-methyl[,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinec-
arboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-1-[(2'-methoxy[1,1'--
biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-1-[(2'-methyl[1,1'-bi-
phenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-1-[(2'-methyl[1,1-
'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(3-hydroxypropyl)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl-
]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(metho-
xyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-amino-2-oxoethyl)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphe-
nyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(3-hydroxy-
phenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1S,2R,3S,4R)-3-(hydroxymeth-
yl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(1R,2S,3R,4S)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-1-[(2-
'-methoxy[1,1'-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarb-
oxamide
(2S,4EZ)-N-(trans-4-hydroxycyclohexyl)-1-[(2'-methoxy[1,1'-bipheny-
l]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-1-[(2'-methoxy[1,1'-biph-
enyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-[(2'-meth-
yl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-1--
[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-1--
[(2'-methoxy[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-1-[(2'-me-
thyl[1,1'-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxami-
de
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-1-[(2'--
methoxy[1,1'-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarbox-
amide
(2S,4EZ)-N-[(2RS)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-1-[(2'-met-
hoxy[1,1'-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxami-
de
(2R,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylet-
hyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2R,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl-
[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(2'-cyano[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2--
phenyl ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(3',4'-dichloro[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydr-
oxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydr-
oxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydro-
xy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1--
[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1--
[(2'-cyano[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1--
[(3',4'-dichloro[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1--
[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1--
[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(3',4'-dichloro[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydr-
oxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydr-
oxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydro-
xy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydr-
oxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydro-
xy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)ca-
rbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)car-
bonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)c-
arbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)ca-
rbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-1--
(hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-1-(-
hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(2'-cyano[1',1'-biphenyl]-4-yl)carbonyl]-N-[(1R,2R)-2-(hydrox-
ymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(3EZ,5S)-5-(3,4-dihydro-2(1H)-isoquinolinylcarbonyl)-1-[(2',3-dimethyl[1,-
1'-biphenyl]-4-yl)carbonyl]-3-pyrrolidinone O-methyloxime
(2S,4EZ)-N-[(1R)-2-hydroxy-1-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[-
1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxy-
phenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyp-
henyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxy-
phenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyp-
henyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(1R,2S)-2-hyd-
roxy-1,2-diphenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2RS)-2-[({(2S,4EZ)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)ca-
rbonyl]pyrrolidinyl}carbonyl)amino]-3-phenylpropanoic acid
(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2',6'-dimethyl[1,1'--
biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2',3-dimethyl[1',1'--
biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
4'-{[(2S,4EZ)-2-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-4-(methoxyim-
ino)pyrrolidinyl]carbonyl}[1,1'-biphenyl]-2-carbonitrile
(3EZ,5S)-1-[(3',4'-dichloro[1,1'-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydrox-
yethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinone O-methyloxime
(3EZ,5S)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydrox-
yethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinone O-methyloxime
(3EZ,5S)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxy-
ethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinone O-methyloxime
(3EZ,5S)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-5-({4-[4-(trifluorom-
ethyl)phenyl]-1-piperazinyl}carbonyl)-3-pyrrolidinone O-methyloxime
(3EZ,5S)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-5-({4-[3-(trifluorom-
ethyl)phenyl]-1-piperazinyl}carbonyl)-3-pyrrolidinone O-methyloxime
(2S,4EZ)-4-(methoxyimino)-1-[(2'-methyl[1',1'-biphenyl]-4-yl)carbonyl]-2--
pyrrolidinecarboxamide
(2S,4EZ)-4-(methoxyimino)-N-methyl-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carb-
onyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-4-(methoxyimino)-N,N-dimethyl-1-[(2'-methyl[1,1'-biphenyl]-4-yl)-
carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2'-methyl-
[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(3S)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2'-methyl-
[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(3R)-3-hydroxy-3-phenylpropy-
l]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(3S)-3-hydroxy-3-phenylpropy-
l]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2'-(triflu-
oromethyl)[1,1'-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2'-chloro[-
1,1'-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-hydroxyphenyl)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl-
]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[2-(hydroxymethyl)phenyl]-4-(methoxyimino)-1-[(2'-methyl[1,1-b-
iphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (2S,4E and
4Z)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(-
methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-N-(-
2-phenylethyl)-2-pyrrolidinecarboxamide
14. A pyrrolidine compound according to claim 1, selected from the
following group:
(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-3-pyrr-
olidinone O-methyloxime
(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-([1,1'-biphenyl]-4-ylcarbonyl)--
4-(methoxy-imino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(6-quinoliny-
l)-2-pyrrolidinecarboxamide.
15. A pharmaceutical composition containing at least one
pyrrolidine compound according to claim 1 and a pharmaceutically
acceptable carrier, diluent or excipient thereof.
16. Process for the preparation of a pyrrolidine compound according
to claim 1, wherein the following reaction is performed
##STR00038## whereby LG is a leaving group and the substituents
R.sup.1-R.sup.9, A and X are as above defined.
17. Process for the preparation of a pyrrolidine compound according
to claim 1, wherein the following reaction is performed:
##STR00039## whereby LG is a leaving group and the substituents
R.sup.1-R.sup.5, R.sup.11, A, E, Q, X, Y and Z are as above
defined.
18. Process according to claim 17, wherein compound XV is obtained
as follows: ##STR00040##
19. A pyrrolidine compound according to claim 6, wherein R.sup.6 is
H or CH.sub.3.
20. A method for treating and/or preventing premature labor,
premature birth, and dysmenorrheal, comprising administering to a
patient in need thereof an effective amount of a pharmaceutical
composition according to claim 15.
21. The method according to claim 20 wherein the pharmaceutical
composition is administered orally to the patient.
22. A method for modulating the activity of the oxytocin receptor,
comprising administering the pharmaceutical composition of claim 15
to a patient in need thereof.
23. The method according to claim 22, wherein modulating the
activity of the oxytocin receptor blocks the oxytocin receptor or
antagonizes the binding of oxytocin to its receptor.
24. The method according to claim 33, wherein the method is used
for treating or preventing disorders mediated by the oxytocin
receptor.
25. The method according to claim 24, wherein the composition is
administered orally to the patient.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a division of application Ser. No. 10/239,912, filed
Feb. 10, 2003, which is a 371 national stage application of
PCT/EP01/03171, filed Mar. 20, 2001. The entire contents of both
applications being incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention is related to pyrrolidine derivatives.
Said compounds are preferably for use as pharmaceutically active
compounds. Specifically, pyrrolidine derivatives of formula I are
useful in the treatment and/or prevention of premature labor,
premature birth and dysmenorrhea. In particular, the present
invention is related to pyrrolidine derivatives displaying a
substantial modulatory, notably an antagonist activity of the
oxytocin receptor. More preferably, said compounds are useful in
the treatment and/or prevention of disease states mediated by
oxytocin, including premature labor, premature birth and
dysmenorrhea. The present invention is furthermore related to novel
pyrrolidine derivatives as well as to methods of their
preparation.
BACKGROUND OF THE INVENTION
[0003] Oxytocin (OT) is a peptide hormone and causes the
contraction of the uterus of mammals during labor. The
corresponding Oxytocin receptor belongs to the family of
G-protein-coupled receptors and is similar to V.sub.1a and V.sub.2
vasopressin receptors. OT receptors increase dramatically during
the course of pregnancy. The concentration of OT receptors has been
shown to correlate with spontaneous uterine activity (M. Maggi et
al. J. Clin. Endocrinol Metabol; 70; 1142, 1990). Premature labor,
though, and premature birth is undesired as it represents a major
cause of perinatal morbidity and mortality. Hence, the management
of preterm labor represents a significant problem in the field of
obstetrics.
[0004] In recent years, strong evidence has accumulated indicating
that the hormone oxytocin plays a major role in initiating labor in
mammals, notably in humans. Thereby, it is assumed that oxytocin
exerts said effect in a direct as well as an indirect way, by
contracting the uterine myometrium and by enhancing the synthesis
and release of contractile prostaglandins from the uterine
endometrium/decidua. These prostaglandins may furthermore play a
role in the cervical ripening process. This "up-regulation" of
oxytocin receptors and increased uterine sensitivity seems to be
due to trophic effects of rising plasma levels of estrogen towards
term. By down-regulating oxytocin, it is expected that both the
direct (contractile) and indirect (increased prostaglandin
synthesis) effects of oxytocin on the uterine could be blocked. An
oxytocin modulator, e.g. blocker or antagonists would likely be
more efficacious for treating preterm labor than current regimens.
Moreover, as oxytocin at term has only an effect on the uterus,
such an oxytocin modulator would have only few or no side
effect.
[0005] A further condition being related to oxytocin is
dysmenorrhea, which is characterised by cyclic pain associated with
menses during ovulatory cycles. Said pain is believed to result
from uterine contractions and ischemia, probably mediated by the
effect of prostaglandins produced in the secretory endometrium. By
blocking both the indirect and direct effects of oxytocin on the
uterus, an oxytocin antagonist is believed more efficacious for
treating dysmenorrhea than current regimens.
[0006] Some agents counteracting the action of Oxytocin (OT) are
currently used in clinical studies. Such tocolytic agents (i.e.
uterine-relaxing agents) include beta-2-adrenergic agonists,
magnesium sulfate and ethanol. The leading beta-2-adrenergic
agonists is Ritodrine, which causes a number of cardiovascular and
metabolic side effects, including tachycardia, increased renin
secretion, hyperglycemia and reactive hypoglycemia in the infant.
Further beta-32-adrenergic agonists, including terbutaline and
albuterol have side effects similar to those of ritodrine.
Magnesium sulfate at plasma concentrations above the therapeutic
range of 4 to 8 mg/dL can cause inhibition of cardiac conduction
and neuromuscular transmission, respiratory depression and cardiac
arrest, thus making this agent unsuitable when renal function is
impaired. Ethanol is as effective as ritodrine in preventing
premature labor, but it does not produce a corresponding reduction
in the incidence of fetal respiratory distress that administration
of ritodrine does.
[0007] The principal drawback to the use of peptide antagonists
including also atosiban is the problem of low oral bioavailability
resulting from intestinal degradation. Hence, they must be
administered parenterally.
[0008] The development of non-peptide ligands for peptide hormone
receptors are expected to overcome this problem. The first to
report small molecule selective oxytocin antagonists was Merck.
Apart from cyclic hexapeptides, Merck suggested indanylpiperidines
and tolylpiperazines as orally deliverable OT antagonists (Evans et
al. J. Med. Chem., 35, 3919 (1992). In WO 96/22775 and U.S. Pat.
No. 5,756,497 Merck reported benzoxazinylpiperidines or
benzoxazinones as OT receptor antagonists.
[0009] It is a purpose of this invention to provide substances
which more effectively down-regulate--up to antagonizing--the
function of OT in disease states in animals, preferably mammals,
especially in humans. It is another purpose of this invention to
provide a method of antagonizing the functions of oxytocin in
disease states of mammals. It is also an objective of the present
invention to provide small molecule chemical compounds for the
modulation, preferably the down-regulation or even antagonisation
of the Oxytocin receptor. Moreover, it is an objective of the
present invention to provide methods for preparing said small
molecule chemical compounds. It is furthermore an objective of the
present invention to provide a new category of pharmaceutical
formulations for the treatment of preterm labor and dysmenorrhea,
and/or diseases mediated by the Oxytocin receptor. It is finally an
objective of the present invention to provide a method of treating
or prevent disorders mediated by the Oxytocin receptor, like
preterm labor and dysmenorrhea by antagonising the binding of
Oxytocin to its receptor.
DESCRIPTION OF THE INVENTION
[0010] The aforementioned objectives have been met according to the
independent claims. Preferred embodiments are set out within the
dependent claims which are incorporated herewith.
[0011] The following paragraphs provide definitions of the various
chemical moieties that make up the compounds according to the
invention and are intended to apply uniformly through-out the
specification and claims unless an otherwise expressly set out
definition provides a broader definition.
[0012] "C.sub.1-C.sub.6-alkyl" refers to monovalent alkyl groups
having 1 to 6 carbon atoms. This term is exemplified by groups such
as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
tert-butyl, n-hexyl and the like.
[0013] "Aryl" refers to an unsaturated aromatic carbocyclic group
of from 6 to 14 carbon atoms having a single ring (e.g. phenyl) or
multiple condensed rings (e.g. naphthyl). Preferred aryl include
phenyl, naphthyl, phenantrenyl and the like.
[0014] "C.sub.1-C.sub.6-alkyl aryl" refers to C.sub.1-C.sub.6-alkyl
groups having an aryl substituent, including benzyl, phenethyl and
the like.
[0015] "Heteroaryl" refers to a monocyclic heteromatic, or a
bicyclic or a tricyclic fused-ring heteroaromatic group. Particular
examples of heteroaromatic groups include optionally substituted
pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl,
1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl,
isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl,
indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,
imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl,
quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl,
pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,
quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,
5,6,7,8-tetrehydroisoquinolyl, purinyl, pteridinyl, carbazolyl,
xanthenyl or benzoquinolyl.
[0016] "C.sub.1-C.sub.6-alkyl heteroaryl" refers to
C.sub.1-C.sub.6-alkyl groups having a heteroaryl substituent,
including 2-furylmethyl, 2-thienylmethyl, 2-(1H-indol-3-yl)ethyl
and the like.
[0017] "Alkenyl" refers to alkenyl groups preferably having from 2
to 6 carbon atoms and having at least 1 or 2 sites of alkenyl
unsaturation. Preferable alkenyl groups include ethenyl
(--CH.dbd.CH.sub.2), n-2-propenyl (allyl,
--CH.sub.2CH.dbd.CH.sub.2) and the like.
[0018] "Alkynyl" refers to alkynyl groups preferably having from 2
to 6 carbon atoms and having at least 1-2 sites of alkynyl
unsaturation, preferred alkynyl groups include ethynyl
(--C.ident.CH), propargyl (--CH.sub.2C.ident.CH), and the like.
[0019] "Acyl" refers to the group --C(O)R where R includes
"C.sub.1-C.sub.6-alkyl", "aryl", "heteroaryl",
"C.sub.1-C.sub.6-alkyl aryl" or "C.sub.1-C.sub.6-alkyl
heteroaryl".
[0020] "Acyloxy" refers to the group --OC(O)R where R includes
"C.sub.1-C.sub.6-alkyl", "aryl", "hetero-aryl",
"C.sub.1-C.sub.6-alkyl aryl" or "C.sub.1-C.sub.6-alkyl
heteroaryl".
[0021] "Alkoxy" refers to the group --O--R where R includes
"C.sub.1-C.sub.6-alkyl" or "aryl" or "heteroaryl" or
"C.sub.1-C.sub.6-alkyl aryl" or "C.sub.1-C.sub.6-alkyl heteroaryl".
Preferred alkoxy groups include by way of example, methoxy, ethoxy,
phenoxy and the like.
[0022] "Alkoxycarbonyl" refers to the group --C(O)OR where R
includes "C.sub.1-C.sub.6-alkyl" or "aryl" or "heteroaryl" or
"C.sub.1-C.sub.6-alkyl aryl" or "C.sub.1-C.sub.6-alkyl
heteroaryl".
[0023] "Aminocarbonyl" refers to the group --C(O)NRR' where each R,
R' includes independently hydrogen or C.sub.1-C.sub.6-alkyl or aryl
or heteroaryl or "C.sub.1-C.sub.6-alkyl aryl" or
"C.sub.1-C.sub.6-alkyl hetero-aryl".
[0024] "Acylamino" refers to the group --NR(CO)R' where each R, R'
is independently hydrogen or "C.sub.1-C.sub.6-alkyl" or "aryl" or
"heteroaryl" or "C.sub.1-C.sub.6-alkyl aryl" or
"C.sub.1-C.sub.6-alkyl heteroaryl".
[0025] "Halogen" refers to fluoro, chloro, bromo and iodo
atoms.
[0026] "Sulfonyl" refers to group "--SO.sub.2--R" wherein R is
selected from H, "aryl", "heteroaryl", "C.sub.1-C.sub.6-alkyl",
"C.sub.1-C.sub.6-alkyl" substituted with halogens e.g. an
--SO.sub.2--CF.sub.3 group, "C.sub.1-C.sub.6-alkyl aryl" or
"C.sub.1-C.sub.6-alkyl heteroaryl".
[0027] "Sulfoxy" refers to a group "--S(O)--R" wherein R is
selected from H, "C.sub.1-C.sub.6-alkyl", "C.sub.1-C.sub.6-alkyl"
substituted with halogens e.g. an --SO--CF.sub.3 group, "aryl",
"heteroaryl", "C.sub.1-C.sub.6-alkyl aryl" or
"C.sub.1-C.sub.6-alkyl heteroaryl".
[0028] "Thioalkoxy" refers to groups --S--R where R includes
"C.sub.1-C.sub.6-alkyl" or "aryl" or "heteroaryl" or
"C.sub.1-C.sub.6-alkyl aryl" or "C.sub.1-C.sub.6-alkyl heteroaryl".
Preferred thioalkoxy groups include thiomethoxy, thioethoxy, and
the like.
[0029] "Substituted or unsubstituted": Unless otherwise constrained
by the definition of the individual substituent, the above set out
groups, like "alkyl", "alkenyl", "alkynyl", "aryl" and "heteroaryl"
etc. groups can optionally be substituted with from 1 to 5
substituents selected from the group consisting of
"C.sub.1-C.sub.6-alkyl", "C.sub.1-C.sub.6-alkyl aryl",
"C.sub.1-C.sub.6-alkyl heteroaryl", "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", primary, secondary or tertiary amino
groups or quaternary ammonium moieties, "acyl", "acyloxy",
"acylamino", "aminocarbonyl", "alkoxycarbonyl", "aryl",
"heteroaryl", carboxyl, cyano, halogen, hydroxy, mercapto, nitro,
sulfoxy, sulfonyl, alkoxy, thioalkoxy, trihalomethyl and the like.
Alternatively said substitution could also comprise situations
where neighboring substituents have undergone ring closure, notably
when viccinal functional substituents are involved, thus forming
e.g. lactams, lactons, cyclic anhydrides, but also acetals,
thioacetals, animals formed by ring closure for instance in an
effort to obtain a protective group.
[0030] "Pharmaceutically acceptable salts or complexes" refers to
salts or complexes of the below-identified compounds of formula I
that retain the desired biological activity. Examples of such salts
include, but are not restricted to acid addition salts formed with
inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric
acid, phosphoric acid, nitric acid, and the like), and salts formed
with organic acids such as acetic acid, oxalic acid, tartaric acid,
succinic acid, malic acid, fumaric acid, maleic acid, ascorbic
acid, benzoic acid, tannic acid, pamoic acid, alginic acid,
polyglutamic acid, naphthalene sulfonic acid, naphthalene
disulfonic acid, and polygalacturonic acid. Said compounds can also
be administered as pharmaceutically acceptable quaternary salts
known by a person skilled in the art, which specifically include
the quartenary ammonium salt of the formula --NR, R',
R''.sup.+Z.sup.-, wherein R, R', R'' is independently hydrogen,
alkyl, or benzyl, and Z is a counterion, including chloride,
bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate,
sulfonate, phosphate, or carboxylate (such as benzoate, succinate,
acetate, glycolate, maleate, malate, fumarate, citrate, tartrate,
ascorbate, cinnamoate, mandeloate, and diphenylacetate).
[0031] "Pharmaceutically active derivative" refers to any compound
that upon administration to the recipient, is capable of providing
directly or indirectly, the activity disclosed herein.
[0032] "Enantiomeric excess" (ee) refers to the products that are
obtained by an asymmetric synthesis, i.e. a synthesis involving
non-racemic starting materials and/or reagents or a synthesis
comprising at least one enantioselective step, whereby a surplus of
one enantiomer in the order of at least about 52% ee is yielded. In
the absence of an asymmetric synthesis, racemic products are
usually obtained that do however also have the inventive set out
activity as OT-R antagonists.
[0033] Quite surprisingly, it was now found that pyrrolidine
derivatives according to formula I are suitable pharmaceutically
active agents, by effectively modulating, in particular by
effectively inhibiting the OT-R function and more specifically by
antagonising the oxytocin receptor. When the oxytocin receptor is
bound by the compounds according to formula I, oxytocin is
antagonised by being blocked from its receptor and is therefore
unable to exert its biologic or pharmacological effects. The
compounds of the present invention are therefore in particular
useful in the treatment and/or prevention of oxytocin-related
disorders of mammals and in particular of humans. These disorders
mediated by the oxytocin receptor, are primarily preterm labor and
dysmenorrhea.
[0034] The compounds according to the present invention are those
of formula I.
##STR00003##
[0035] Said formula also comprises its geometrical isomers, its
optically active forms as enantiomers, diastereomers and its
racemate forms, as well as pharmaceutically acceptable salts
thereof. Preferred pharmaceutically acceptable salts of the
compound I, are acid addition salts formed with pharmaceutically
acceptable acids like hydrochloride, hydrobromide, sulfate or
bisulfate, phosphate or hydrogen phosphate, acetate, benzoate,
succinate, fumarate, maleate, lactate, citrate, tartrate,
gluconate, methanesulfonate, benzenesulfonate, and
para-toluenesulfonate salts.
[0036] In said formula I, X is selected from the group consisting
of CR.sup.6R.sup.7, NOR.sup.6, NNR.sup.6R.sup.7.
[0037] A is selected from the group consisting of --(C.dbd.O)--,
--(C.dbd.O)--O--, --C(.dbd.NH)--, --(C.dbd.O)--NH--,
--(C.dbd.S)--NH, --SO.sub.2--, --SO.sub.2NH--, --CH.sub.2--.
[0038] B is either an amido group of the formula
--(C.dbd.O)--NR.sup.8R.sup.9 or B represents a heterocyclic residue
having the formula B
##STR00004##
wherein Q is NR.sup.10, O or S; n is an integer selected of 0, 1 or
2, preferably 0. m is an integer selected of 0, 1, 2 or 3,
preferably 0 or 1.
[0039] Y, Z and E form together with the 2 carbons to which they
are attached a 5-6 membered aryl or heteroaryl ring.
[0040] R.sup.1 is selected from the group comprising or consisting
of unsubstituted or substituted C.sub.1-C.sub.6-alkyl,
unsubstituted or substituted C.sub.2-C.sub.6-alkenyl, unsubstituted
or substituted C.sub.2-C.sub.6-alkynyl, unsubstituted or
substituted aryl, unsubstituted or substituted heteroaryl,
unsubstituted or substituted saturated or unsaturated 3-8-membered
cycloalkyl, acyl, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl aryl, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl heteroaryl, said cycloalkyl or aryl or
heteroaryl groups may be fused with 1-2 further cycloalkyl or aryl
or heteroaryl group.
[0041] R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently
selected from each other from the group consisting of hydrogen,
halogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, preferably
they are all hydrogen.
[0042] R.sup.6 and R.sup.7 are independently selected from the
group comprising or consisting of hydrogen, unsubstituted or
substituted C.sub.1-C.sub.6 alkyl, unsubstituted or substituted
C.sub.2-C.sub.6 alkenyl, unsubstituted or substituted
C.sub.2-C.sub.6 alkynyl, unsubstituted or substituted alkoxy,
unsubstituted or substituted thioalkoxy, halogen, cyano, nitro,
acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted
saturated or unsaturated 3-8-membered cycloalkyl which may contain
1 to 3 heteroatoms selected of N, O, S, unsubstituted or
substituted aryl, unsubstituted or substituted heteroaryl,
unsubstituted or substituted C.sub.1-C.sub.6-alkyl aryl,
unsubstituted or substituted C.sub.1-C.sub.6-alkyl heteroaryl.
[0043] R.sup.8, R.sup.9 and R.sup.10 are independently selected
from the group comprising or consisting of hydrogen, unsubstituted
or substituted C.sub.1-C.sub.6 alkyl, unsubstituted or substituted
C.sub.2-C.sub.6 alkenyl, unsubstituted or substituted
C.sub.2-C.sub.6 alkynyl, unsubstituted or substituted saturated or
unsaturated 3-8-membered cycloalkyl which may contain 1 to 3
heteroatoms selected of N, O, S, unsubstituted or substituted aryl,
unsubstituted or substituted heteroaryl.
[0044] Alternatively, each pair R.sup.6, R.sup.7 and/or R.sup.8,
R.sup.9 could form together with the N atom to which they are
attached a 3-8 membered substituted or unsubstituted, saturated or
unsaturated heterocyclic ring which may contain 1-2 further
heteroatoms selected from N, S and O and which is optionally fused
with an aryl, heteroaryl or 3-8 membered saturated or unsaturated
cycloalkyl ring.
[0045] R.sup.11 is selected from the group comprising or consisting
of hydrogen, unsubstituted or substituted C.sub.1-C.sub.6-alkyl,
unsubstituted or substituted alkenyl, unsubstituted or substituted
alkynyl, hydroxy, mercapto, alkoxy, thioalkoxy, aryl, heteroaryl,
halogen, nitro, cyano, acyl, acyloxy, acylamino, aminocarbonyl,
alkoxycarbonyl, sulfonyl, sulfoxy, carboxyl, primary, secondary or
tertiary amino groups or quaternary ammonium moieties,
unsubstituted or substituted saturated or unsaturated 3-8-membered
cycloalkyl.
[0046] Preferred pyrrolidine derivatives are those compounds
according to formula I wherein B is a group --(C.dbd.O)--NHR.sup.9,
in which R.sup.9 is selected from the group consisting of
unsubstituted or substituted C.sub.1-C.sub.6 alkyl, unsubstituted
or substituted alkenyl, unsubstituted or substituted alkynyl,
unsubstituted or substituted saturated or unsaturated 3-6-membered
cycloalkyl which optionally contains a N atom, unsubstituted or
substituted aryl, unsubstituted or substituted heteroaryl,
unsubstituted or substituted C.sub.1-C.sub.2-alkyl aryl,
unsubstituted or substituted C.sub.1-C.sub.2-alkyl heteroaryl.
[0047] Preferred heteroaryls are pyridyl, pyrrolyl, furyl, thienyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,
[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl,
benzotriazolyl, isobenzo-thienyl, 2,1,3-benzothiadiazolyl,
2,1,3-benzoxadiazolyl, benzodioxolyl, indolyl, isoindolyl,
3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl,
benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl,
quinoxalinyl, cinnolinyl, napthyridinyl, pyrido[3,4-b]pyridyl,
pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl,
tetrazolyl, 5,6,7,8-tetrahydroquinolyl,
5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,
xanthenyl, acridinyl or benzoquinolyl and whereby said heteroaryl
could be fused with a 3-8-membered cycloalkyl containing optionally
1-3 heteroatoms selected from N, O, S.
[0048] According to a further preferred embodiment the pyrrolidine
derivatives according to the present invention carry a residue
B.sup.1 which is a fused heterocycle of the formula
##STR00005##
[0049] Particularly preferred pyrrolidine derivatives are those
compounds according to formula I wherein X is NOR.sup.6, and
R.sup.6 is selected from the group consisting of H, unsubstituted
or substituted C.sub.1-C.sub.6 alkyl, unsubstituted or substituted
C.sub.2-C.sub.6 alkenyl, unsubstituted or substituted
C.sub.2-C.sub.6 alkynyl, unsubstituted or substituted acyl,
unsubstituted or substituted aryl, unsubstituted or substituted
heteroaryl, unsubstituted or substituted saturated or unsaturated
3-8-membered cycloalkyl, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl aryl, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl heteroaryl, said cycloalkyl or aryl or
heteroaryl groups may be fused with 1-2 further cycloalkyl or aryl
or heteroaryl groups. Particularly preferred R.sup.6 is H,
CH.sub.3, unsubstituted or substituted CH.sub.2-phenyl or
allyl.
[0050] Under no circumstances B could be a group COOR or a group
--(C.dbd.O)NR(OR), whereby R is H, alkyl or acyl. Such compounds,
notably having a group B=hydroxamic acid are described in WO
99/52868 as being potent inhibitors of metalloproteases.
[0051] Further particularly preferred pyrrolidine derivatives are
those compounds according to formula I wherein X is CHR.sup.6, and
R.sup.6 is selected from the group consisting of halogen, cyano,
unsubstituted or substituted C.sub.3-C.sub.6 alkyl, unsubstituted
or substituted C.sub.2-C.sub.6 alkenyl, unsubstituted or
substituted C.sub.2-C.sub.6 alkynyl, unsubstituted or substituted
alkoxy, unsubstituted or substituted thioalkoxy, nitro, acyl,
alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted aryl,
unsubstituted or substituted heteroaryl, unsubstituted or
substituted saturated or unsaturated 3-8-membered cycloalkyl,
unsubstituted or substituted C.sub.1-C.sub.6-alkyl aryl,
unsubstituted or substituted C.sub.1-C.sub.6-alkyl heteroaryl, said
cycloalkyl or aryl or heteroaryl groups may be fused with 1-2
further cycloalkyl or aryl or heteroaryl groups. Particularly
preferred R.sup.6 is halogen, cyano, C.sub.1-C.sub.6 alkyl or an
unsubstituted or substituted phenyl group.
[0052] According to a further preferred embodiment the pyrrolidine
derivatives have a substituent A being --(C.dbd.O)--, or
--(C.dbd.O)--NH--, or --SO.sub.2--, most preferred is
--(C.dbd.O)--.
[0053] More preferred groups R.sup.1 are substituted or
unsubstituted C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
unsubstituted or substituted C.sub.2-C.sub.6-alkynyl, aryl,
heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl and
still more preferred R.sup.1 are C.sub.1-C.sub.6-alkyl or aryl. A
particularly preferred substituent R' is biphenyl.
[0054] According to a most preferred embodiment, the pyrrolidine
derivatives according to formula I are those wherein X is
.dbd.NOR.sup.6 or .dbd.CHCl, R.sup.6 is a C.sub.1-C.sub.6-alkyl,
e.g. a methyl group, or aryl or C.sub.1-C.sub.6-alkyl aryl group, A
is --(C.dbd.O)-- and R.sup.1 is a C.sub.1-C.sub.6-alkyl or aryl or
C.sub.1-C.sub.6-alkyl aryl group. Even more preferred are those
pyrrolidine derivatives, wherein X is .dbd.NOR.sup.6, or .dbd.CHCl,
R.sup.6 is methyl, B is an amido group of the formula
--(C.dbd.O)NHR.sup.9, wherein R.sup.9 is an unsubstituted or
substituted C.sub.1-C.sub.6-alkyl aryl group, e.g. a substituted
phenylethyl group, A is --(C.dbd.O)-- and R.sup.1 is a substituted
or unsubstituted biphenyl or an acetylmethyl group.
[0055] The compounds of formula I may contain one or more
asymmetric centers and may therefore exist as enantiomers or
diasteroisomers. It is to be understood that the invention includes
both mixtures and separate individual isomers or enantiomers of the
compounds of formula I. In a particularly preferred embodiment the
pyrrolidine derivatives according to formula I are obtained in an
enantiomeric excess of at least 52% ee, preferably of at least
92-98% ee. Also E/Z isomers with regard to pyrrolidine derivatives
having residues X being .dbd.CR.sup.6R.sup.7 whereby both
R.sup.6R.sup.7 are different from each other, and/or with regard to
pyrrolidine derivatives having residues X being .dbd.NOR.sup.6 or
.dbd.NNR.sup.6R.sup.7 are comprised by the present invention.
[0056] Specific examples of compounds of formula I include the
following: [0057]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-methoxyethyl)-4-(me-
thoxyimino)-2-pyrrolidinecarboxamide [0058]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2--
hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide [0059]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyim-
ino)-2-pyrrolidinecarboxamide [0060]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-
-4-(methoxyimino)-2-pyrrolidinecarboxamide [0061]
(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-3-pyrr-
olidinone O-methyloxime [0062]
(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-([1,1'-biphenyl]-4-ylcarbonyl)--
4-(methoxy-imino)-2-pyrrolidinecarboxamide [0063]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(6-quinoliny-
l)-2-pyrrolidinecarboxamide [0064]
(2S,4EZ)-1-acetoacetyl-N-benzyl-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0065]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-
-furylmethyl)-2-pyrrolidinecarboxamide [0066]
(2S,4EZ)-1-[(4-chlorophenoxy)acetyl]-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-
-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide [0067]
(2S,4EZ)-N-allyl-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrr-
olidinecarboxamide [0068]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(2-thienylme-
thyl)-2-pyrrolidinecarboxamide [0069]
(2S,4EZ)-4-(cyanomethylene)-N-(2-furylmethyl)-1-[(2-oxo-6-pentyl-2H-pyran-
-3-yl)carbonyl]-2-pyrrolidinecarboxamide [0070]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-(methoxyimi-
no)-2-pyrrolidinecarboxamide [0071]
(2S,4EZ)-1-acetyl-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrr-
olidinecarboxamide [0072]
(2S,4EZ)-N-(2-furylmethyl)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-
-yl)carbonyl]-2-pyrrolidinecarboxamide [0073]
(2S,4EZ)-N-benzyl-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-met-
hyl-2-pyrrolidinecarboxamide [0074]
(2S,4EZ)-1-(diphenylacetyl)-4-(ethoxyimino)-N-(2-thienylmethyl)-2-pyrroli-
dinecarboxamide [0075]
(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-4-(cyanomethylene)-1-(diphenylace-
tyl)-2-pyrrolidinecarboxamide [0076]
(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-(diphenylacetyl)-3-pyrrolidinone
O-methyloxime [0077]
(2S)-2-[1-([1,1'-biphenyl]-4-ylcarbonyl)-4-methylene-2-pyrrolidinyl]-1H-b-
enzimidazole [0078]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-methox-
yethyl)-2-pyrrolidinecarboxamide [0079]
(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-(diphenylacetyl)-3-pyrrolidinone
O-allyloxime [0080]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino)ethyl]-4-(me-
thoxyimino)-2-pyrrolidinecarboxamide [0081]
(2S,4EZ)-1-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-N-(2-thienylm-
ethyl)-2-pyrrolidinecarboxamide [0082]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(3,4-dimethoxybenzyl)-4-(meth-
oxyimino)-2-pyrrolidinecarboxamide [0083]
(2S,4EZ)-1-acetoacetyl-4-(methoxyimino)-N-(1-naphthylmethyl)-2-pyrrolidin-
ecarboxamide [0084]
(2S,4EZ)-N-allyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(diphenylacetyl)-2--
pyrrolidinecarboxamide [0085]
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N.sup.1-pentyl-N.sup.2-(6-qui-
nolinyl)-1,2-pyrrolidine-dicarboxamide [0086]
(2S,4EZ)-4-(chloromethylene)-1-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phen-
ethyl]-2-pyrrolidinecarboxamide [0087]
(2S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-m-
ethylene-2-pyrrolidinecarboxamide [0088]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(6-quinol-
inyl)-2-pyrrolidinecarboxamide [0089]
(2S,4EZ)-4-benzylidene-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-2-pyr-
rolidinecarboxamide [0090] (2S,4EZ)-1
acetoacetyl-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide
[0091]
(2S,4EZ)-1-acetyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[(2RS)-2-hy-
droxy-2-phenethyl]-2-pyrrolidinecarboxamide [0092]
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N.sup.1-(3,5-dichlorophenyl)--
N.sup.2-(6-quinolinyl)-1,2-pyrrolidinedicarboxamide [0093]
(2S,4EZ)-4-(methoxyimino)-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyrrol-
idinecarboxamide [0094]
(2S,4EZ)-4-(chloromethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2-
H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide [0095]
(2S,4EZ)-1-(diphenylacetyl)-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrrol-
idinecarboxamide [0096]
(2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-(methoxyimino)-2-pyrrolidinecarbox-
amide [0097]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imi-
no}-N-[2-(diethylamino)ethyl]-2-pyrrolidinecarboxamide [0098]
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-[4-(dimethylamino)butanoyl]-
-N-(6-quinolinyl)-2-pyrrolidinecarboxamide [0099]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(5-ethyl-1,3,4-thiadiazol-2-y-
l)-4-(methoxy-imino)-2-pyrrolidinecarboxamide [0100]
(2S,4EZ)-N-benzyl-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyr-
rolidinecarboxamide [0101]
(2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-(ethoxyimino)-2-pyrrolidinecarboxa-
mide [0102]
(2S,4EZ)-N.sup.2-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N.sup.1-(-
3-methoxyphenyl)-1,2-pyrrolidinedicarboxamide [0103]
(2S,4EZ)-1-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-{[(4-methox-
ybenzyl)-oxy]imino}-2-pyrrolidinecarboxamide [0104]
(2S)--N-(2-furylmethyl)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carb-
onyl]-2-pyrrolidinecarboxamide [0105]
(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-(diphenylacetyl)-4-(methoxyimin-
o)-2-pyrrolidinecarboxamide [0106]
(2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-py-
rrolidinecarboxamide [0107]
(2S,4EZ)-1-benzoyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quinolinyl)-2--
pyrrolidinecarboxamide [0108]
(2S,4EZ)-1-acetoacetyl-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-
-pyrrolidinecarboxamide [0109]
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N.sup.2-[(2RS)-2-hydroxy-2-ph-
enethyl]-N.sup.1-pentyl-1,2-pyrrolidinedicarboxamide [0110]
(2S,4EZ)-4-[(benzyloxy)imino]-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-py-
rrolidinecarboxamide [0111]
(2S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-methylene-2-pyrrolidinecarboxamid-
e [0112]
(2S,4EZ)-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(diph-
enylacetyl)-2-pyrrolidinecarboxamide [0113]
(2S,4EZ)-1-(4-cyanobenzoyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quino-
linyl)-2-pyrrolidinecarboxamide [0114]
(2S,4EZ)-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(methoxyacety-
l)-2-pyrrolidinecarboxamide [0115]
(2S,4EZ)-N-(1,3-benzodioxol-5-ylmethyl)-1-([1,1'-biphenyl]-4-ylcarbonyl)--
4-(methoxy-imino)-2-pyrrolidinecarboxamide [0116]
(3EZ,5S)-5-[(4-acetyl-1-piperazinyl)carbonyl]-1-acryloyl-3-pyrrolidinone
O-(3,4-dichlorobenzyl)oxime [0117]
S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-methylene-2-pyrro-
lidinecarboxamide [0118]
(2S,4EZ)-4-(cyanomethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-
-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide [0119]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl-
[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0120]
(2S,4EZ)-1-([1,1'-biphenyl]-3-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethy-
l]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0121]
(2S,4EZ)-1-(4-benzoylbenzoyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methox-
yimino)-2-pyrrolidinecarboxamide [0122]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-(3-phenoxyb-
enzoyl)-2-pyrrolidinecarboxamide [0123]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-(2-phenoxyb-
enzoyl)-2-pyrrolidinecarboxamide [0124]
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[-
1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0125]
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[-
1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0126]
(2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-
-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0127]
(2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-N-methyl-1-[(2'-methyl[1,1'--
biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0128]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1S,2S,3R,4R)-3-(hydroxymeth-
yl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0129]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(trans-4-hydroxycycloh-
exyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide [0130]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1R,2R)-2-(hydroxymethyl)cyc-
lohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0131]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-phenoxypro-
pyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0132]
(2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-[4-(3-pyr-
idinyl)benzoyl]-2-pyrrolidinecarboxamide [0133]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-phenoxypro-
pyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0134]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-
phenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0135]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-
phenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0136]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1-hydroxycyclohexyl)methyl]-
-4-(methoxyimino)-2-pyrrolidinecarboxamide [0137]
(2S,4EZ)-N-[(1-hydroxycyclohexyl)methyl]-4-(methoxyimino)-1-[4-(3-pyridin-
yl)benzoyl]-2-pyrrolidinecarboxamide [0138]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1-hydroxycyclohexyl)methyl]-
-4-(methoxyimino)-2-pyrrolidinecarboxamide [0139]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-(3,4-dihydroxyphenyl-
)-2-hydroxyethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0140]
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridi-
nyl)benzoyl]-2-pyrrolidinecarboxamide [0141]
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridi-
nyl)benzoyl]-2-pyrrolidinecarboxamide [0142]
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(2-pyridi-
nyl)benzoyl]-2-pyrrolidinecarboxamide [0143]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4-
-(methoxyimino)-2-pyrrolidinecarboxamide [0144]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4-
-(methoxyimino)-2-pyrrolidinecarboxamide [0145]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxy-
phenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0146]
(2S,4EZ)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)--
1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide [0147]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxy-
phenoxy)-propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0148]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxypropyl]-4-(me-
thoxyimino)-2-pyrrolidinecarboxamide [0149]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxypropyl]-4-(me-
thoxyimino)-2-pyrrolidinecarboxamide [0150]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(2-naphthy-
l)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0151]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(4-nitroph-
enyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0152]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-
-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide [0153]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-
-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide [0154]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-
-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide [0155]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-nitroph-
enyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0156]
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1'-bi-
phenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0157]
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyi-
mino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide [0158]
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyi-
mino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide. [0159]
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1'-bi-
phenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0160]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2R)-2-hydroxy-2-phenylethyl-
]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0161]
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridi-
nyl)benzoyl]-2-pyrrolidinecarboxamide [0162]
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridi-
nyl)benzoyl]-2-pyrrolidinecarboxamide [0163]
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(2-pyridi-
nyl)benzoyl]-2-pyrrolidinecarboxamide [0164]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2R)-2-hydroxy-2-phenylethyl-
]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0165]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(3-hydroxypropyl)-4-(methoxyi-
mino)-2-pyrrolidinecarboxamide [0166]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-(3-hydroxypropyl)-4-(methoxyi-
mino)-2-pyrrolidinecarboxamide [0167]
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-4-phenyl-1-piperi-
dinyl)carbonyl]-3-pyrrolidinone O-methyloxime [0168]
(3EZ,5S)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-1-[4-(4-pyridinyl-
)benzoyl]-3-pyrrolidinone O-methyloxime [0169]
(3EZ,5S)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-1-[4-(3-pyridinyl-
)benzoyl]-3-pyrrolidinone O-methyloxime [0170]
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-4-phenyl-1-piperi-
dinyl)carbonyl]-3-pyrrolidinone O-methyloxime [0171]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-
-4-(methoxyimino)-2-pyrrolidinecarboxamide [0172]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-
-4-(methoxyimino)-2-pyrrolidinecarboxamide [0173]
(2S,4EZ)-N-benzyl-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(-
methoxyimino)-2-pyrrolidinecarboxamide [0174]
(2S,4EZ)-N-benzyl-N-(2-hydroxyethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)b-
enzoyl]-2-pyrrolidinecarboxamide [0175]
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-5-{[(3RS)-3-hydroxypiperidinyl]-
carbonyl}-3-pyrrolidinone O-methyloxime [0176]
(3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-1-[4-(4-pyridinyl)benzo-
yl]-3-pyrrolidinone O-methyloxime [0177]
(3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-1-[4-(3-pyridinyl)benzo-
yl]-3-pyrrolidinone O-methyloxime [0178]
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylsulfonyl)-5-{[(3RS)-3-hydroxypiperidinyl]-
carbonyl}-3-pyrrolidinone O-methyloxime [0179]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxy-
methyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0180]
(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxy-
imino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide [0181]
(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxy-
imino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide [0182]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxy-
methyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0183]
(2S,4EZ)-N-(2-anilinoethyl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyim-
ino)-2-pyrrolidinecarboxamide
[0184]
(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(4-pyridinyl)ben-
zoyl]-2-pyrrolidinecarboxamide [0185]
(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-
-pyrrolidinecarboxamide [0186]
(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-
-pyrrolidinecarboxamide [0187]
(2S,4EZ)-N-(2-anilinoethyl)-1-([1,1'-biphenyl]-4-ylsulfonyl)-4-(methoxyim-
ino)-2-pyrrolidinecarboxamide [0188]
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-1-piperidinyl)car-
bonyl]-3-pyrrolidinone O-methyloxime [0189]
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-1-piperidinyl)car-
bonyl]-3-pyrrolidinone [0190] O-methyloxime [0191]
(2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]--
1-([1,1'-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0192]
(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-([1,1'-biphenyl]-4-ylcarbonyl)--
4-(methoxyimino)-2-pyrrolidinecarboxamide [0193]
(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]--
1-([1,1'-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0194]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(4-hydroxybutyl)-4-(me-
thoxyimino)-2-pyrrolidinecarboxamide [0195]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-(4-hydroxybutyl)-4-(methoxyim-
ino)-2-pyrrolidinecarboxamide [0196]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1R,2R)-2-(hydroxymethyl)cyc-
lohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0197]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1R,2S,3R,4S)-3-(hydroxymeth-
yl)bicyclo-[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0198]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1R,2S)-2-(hydroxymet-
hyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0199]
(2S,4E and
4Z)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[-
1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0200]
(2S,4E and
4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1,1'--
biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0201] (2S,4E and
4Z)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1,1'--
biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0202]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1R,2S)-2-(hydroxymethyl)cyc-
lohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0203]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[2-hydroxy-1-(hydroxymethyl)e-
thyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0204]
(2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]--
1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0205]
(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-
-2-yl]-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarb-
oxamide [0206]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl-
]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0207]
(2RS)-3-({[(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrr-
olidinyl]-carbonyl}amino)-2-hydroxypropanoic acid [0208]
(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-([1,1'-biphenyl]-4-ylc-
arbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide [0209]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1RS)-2-hydroxy-1-methylethy-
l]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0210]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxy-
methyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0211]
4-({[(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyr-
rolidinyl]carbonyl}-amino)butanoic acid [0212]
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-1-[(2'-methoxy[1,1'-biphenyl]-4-
-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0213]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(2-naphthyl)ethyl]-1-[(2'-methoxy[1,1'-biph-
enyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0214]
(2S,4EZ)-N-[(1RS)-2-hydroxy-1-methylethyl]-4-(methoxyimino)-1-[(2'-methyl-
[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0215]
(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-
-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinec-
arboxamide [0216]
(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-
-(methoxyimino)-1-[(2'-methoxy[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidine-
carboxamide [0217]
(3EZ,5S)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-1-[(2'-methyl[1,1'-bipheny-
l]-4-yl)carbonyl]-3-pyrrolidinone O-methyloxime [0218]
(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]--
4-(methoxyimino)-1-[(2'-methyl[1',1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidin-
ecarboxamide [0219]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-1-[(2'-methoxy[1,1'-biphenyl]--
4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0220]
(2S,4EZ)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-1-[(2'-methyl[1',1'-b-
iphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0221]
(2S,4EZ)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-1-[(2'-methyl[1,1-
'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0222]
(2S,4EZ)-N-(3-hydroxypropyl)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl-
]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0223]
(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(metho-
xyimino)-2-pyrrolidinecarboxamide [0224]
(2S,4EZ)-N-(2-amino-2-oxoethyl)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphe-
nyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0225]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(3-hydroxy-
phenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0226]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1S,2R,3S,4R)-3-(hydroxymeth-
yl)-bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0227]
(2S,4EZ)-N-[(1R,2S,3R,4S)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl-
]-1-[(2'-methoxy[1,1'-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolid-
inecarboxamide [0228]
(2S,4EZ)-N-(trans-4-hydroxycyclohexyl)-1-[(2'-methoxy[1,1'-biphenyl]-4-yl-
)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0229]
(2S,4EZ)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-1-[(2'-methoxy[1,1'-biph-
enyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0230]
(2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-[(2'-meth-
yl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0231]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-1--
[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0232]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-1--
[(2'-methoxy[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0233]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-1-[(2'-me-
thyl[1',1'-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxam-
ide [0234]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-
-1-[(2'-methoxy[1,1'-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidi-
necarboxamide [0235]
(2S,4EZ)-N-[(2RS)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-1-[(2'-methoxy[-
1,1'-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0236]
(2R,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phe-
nylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0237]
(2R,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl-
[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0238]
(2S,4EZ)-1-[(2'-cyano[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2--
phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0239]
(2S,4EZ)-1-[(3',4'-dichloro[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydr-
oxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0240]
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydr-
oxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0241]
(2S,4EZ)-1-[(2',3-dimethyl[1',1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydr-
oxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0242]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1--
[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0243]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1--
[(2'-cyano[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0244]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1--
[(3',4'-dichloro[,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0245]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyim-
ino)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxa-
mide [0246]
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1--
[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0247]
(2S,4EZ)-1-[(3',4'-dichloro[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-
-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxa-
mide [0248]
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydr-
oxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0249]
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)--
2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxam-
ide [0250]
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2-
RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidineca-
rboxamide [0251]
(2S,4EZ)-1-[(2',3-dimethyl[1',1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydr-
oxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0252]
(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-[(2',6'-dimethyl[1,1'-biphenyl]--
4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0253]
(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)car-
bonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0254]
(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)c-
arbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0255]
(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)ca-
rbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0256]
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-1--
(hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0257]
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-1-(-
hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0258]
(2S,4EZ)-1-[(2'-cyano[1,1'-biphenyl]-4-yl)carbonyl]-N-[(1R,2R)-2-(hydroxy-
methyl)-cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0259]
(3EZ,5S)-5-(3,4-dihydro-2(1H)-isoquinolinylcarbonyl)-1-[(2',3-dimethyl[1,-
1'-biphenyl]-4-yl)carbonyl]-3-pyrrolidinone O-methyloxime [0260]
(2S,4EZ)-N-[(1R)-2-hydroxy-1-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[-
1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0261]
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxy-
phenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0262]
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyp-
henyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0263]
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxy-
phenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0264]
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyp-
henyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0265]
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(1R,2S)-2-hyd-
roxy-1,2-diphenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0266]
(2RS)-2-[({(2S,4EZ)-4-(methoxyimino)-1-[(2'-methyl[1,1-biphenyl]-4-yl)car-
bonyl]-pyrrolidinyl}carbonyl)amino]-3-phenylpropanoic acid [0267]
(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2',6'-dimethyl[1,1'--
biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0268]
(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2',3-dimethyl[1,1'-b-
iphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0269]
4'-{[(2S,4EZ)-2-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-4-(methoxyim-
ino)-pyrrolidinyl]carbonyl}[1,1'-biphenyl]-2-carbonitrile [0270]
(3EZ,5S)-1-[(3',4'-dichloro[1,1'-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydrox-
yethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinone O-methyloxime
[0271]
(3EZ,5S)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydrox-
yethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinone O-methyloxime
[0272]
(3EZ,5S)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxy-
ethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinone O-methyloxime [0273]
(3EZ,5S)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-5-({4-[4-(trifluorom-
ethyl)phenyl]-1-piperazinyl}carbonyl)-3-pyrrolidinone O-methyloxime
[0274]
(3EZ,5S)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-5-({4-[3-(trifluorom-
ethyl)phenyl]-1-piperazinyl}carbonyl)-3-pyrrolidinone O-methyloxime
[0275]
(2S,4EZ)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-p-
yrrolidinecarboxamide [0276]
(2S,4EZ)-4-(methoxyimino)-N-methyl-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carb-
onyl]-2-pyrrolidinecarboxamide [0277]
(2S,4EZ)-4-(methoxyimino)-N,N-dimethyl-1-[(2'-methyl[1,1'-biphenyl]-4-yl)-
carbonyl]-2-pyrrolidinecarboxamide [0278]
(2S,4EZ)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2'-methyl-
[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0279]
(2S,4EZ)-N-[(3S)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2'-methyl-
[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0280]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(3R)-3-hydroxy-3-phenylpropy-
l]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0281]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(3S)-3-hydroxy-3-phenylpropy-
l]-4-(methoxyimino)-2-pyrrolidinecarboxamide [0282]
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2'-(triflu-
oro-methyl)[1,1'-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxamide
[0283]
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2'-chloro[-
1,1'-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxamide [0284]
(2S,4EZ)-N-(2-hydroxyphenyl)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl-
]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0285]
(2S,4EZ)-N-[2-(hydroxymethyl)phenyl]-4-(methoxyimino)-1-[(2'-methyl[1,1'--
biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0286]
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0287] (2S,4E
and
4Z)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(-
methoxyimino)-2-pyrrolidinecarboxamide [0288]
(2S,4EZ)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-N-(-
2-phenylethyl)-2-pyrrolidinecarboxamide
[0289] Thereby, the most preferred compounds are those which are
selected from the group consisting of: [0290]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2--
hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide [0291]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyim-
ino)-2-pyrrolidinecarboxamide [0292]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-
-4-(methoxyimino)-2-pyrrolidinecarboxamide [0293]
(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-3-pyrr-
olidinone O-methyloxime [0294]
(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-([1,1'-biphenyl]-4-ylcarbonyl)--
4-(methoxyimino)-2-pyrrolidinecarboxamide [0295]
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino(,N-(6-quinoliny-
l)-2-pyrrolidinecarboxamide [0296]
(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide [0297]
(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0298] A further aspect of the present invention is related to the
use of the pyrrolidine derivatives according to formula I for the
preparation of pharmaceutical compositions for the treatment and/or
prevention of premature labor, premature birth, for stopping labor
prior to cesarean delivery and dysmenorrhea. Preferably, the
compounds according to formula I are suitable for the modulation of
the OT function, thus specifically allowing the treatment and/or
prevention of disorders which are mediated by the oxytocin
receptor. Said treatment involves the modulation--notably the down
regulation or the antagonisation--of the oxytocin receptor.
[0299] More specifically, the compounds of the present invention
are useful for the treatment of preterm labor, premature birth,
dysmenorrhea and for stopping labor prior to cesarean delivery.
[0300] Still a further aspect of the present invention is related
to the actually novel pyrrolidine compounds of formula I. Some very
few compounds have actually been disclosed prior to the filing of
the present application, without any medical use though. Said known
compounds of formula I are those, wherein
[0301] X is (.dbd.CH.sub.2), A is --(C.dbd.O)--O--, R.sup.1 is a
t-butyl group and B is --(C.dbd.O)--NMe.sub.2 (Tetrahedron 53(2),
539, 1997); --(C.dbd.O)--NHMe (WO 95/47718);
--(C.dbd.O)--NH--CH(Me)--(C.dbd.O)--NH--CH(Me)--COOH (WO 95/47718);
or --(C.dbd.O)--NH--CH(COOCH.sub.2-Ph)--CH.sub.2--COOPh
(Tetrahedron 48(31), 6529, 1992).
[0302] X is (.dbd.CHR.sup.6) with R.sup.6 being cyclohexylmethyl, A
is --(C.dbd.O)--O--, R.sup.1 is a t-butyl group and is
--(C.dbd.O)--NH-t-butyl (Biorg. Chem. Lett. 3(8), 1485, 1993).
[0303] X is C.sub.1-C.sub.20 alkylidene, A is --(C.dbd.O)--O--,
R.sup.1 is a t-butyl and B is
##STR00006##
wherein R is C.sub.1-C.sub.12 alkyl and Hal is Cl, Br, J. Said
compounds are disclosed in DE-1,932,823 as intermediates.
[0304] X is C.sub.1-C.sub.20 alkylidene, A-R.sup.1 is a protective
group and B is
##STR00007##
with R being H or C.sub.1-C.sub.12 alkyl (GB-1,118,306)
[0305] Hence, the novel compounds are those of the formula I,
wherein the above mentioned known compounds are excluded.
[0306] Still a further object of the present invention is a process
for preparing the pyrrolidine derivatives according to formula
I.
[0307] The pyrrolidine derivatives exemplified in this invention
can be prepared from readily available starting materials using the
following general methods and procedures. It will be appreciated
that where typical or preferred experimental conditions (i.e.
reaction temperatures, time, moles of reagents, solvents, etc.) are
given, other experimental conditions can also be used unless
otherwise stated. Optimum reaction conditions may vary with the
particular reactants or solvents used, but such conditions can be
determined by one skilled in the art by routine optimisation
procedures.
[0308] Generally, the pyrrolidine derivatives according to the
general formula I could be obtained by several processes, using
both solution-phase and solid-phase chemistry protocols. Depending
on the nature of A, B, and X, certain processes will, in some
instances, be preferred over others, and it is assumed that the
choice of the most suitable process will be known to the
practitioner skilled in the art.
[0309] According to one process, pyrrolidine derivatives according
to the general formula I, whereby the substituent B is
C(O)--NR.sup.8R.sup.9, with R.sup.8 and R.sup.9 being defined as
above, are prepared from the corresponding suitably N-protected
4-substituted pyrrolidine derivatives II, whereby the substituent X
is as above defined, by solution-phase chemistry protocols such as
described in the Examples and shown in Scheme 1, below. The
suitably N-protected 4-substituted pyrrolidine derivatives II are
first reacted with primary or secondary amines III, whereby the
substituents R.sup.8 and R.sup.9 are as above defined, using
conditions and methods well known to those skilled in the art to
prepare an amide from an amine and a carboxylic acid or a
carboxylic acid derivative, using standard peptide coupling agents,
such as e.g. DIC, EDC, TBTU, DECP, or others, to yield compounds of
formula IV. Removal of the N-protecting group using the appropriate
deprotection agents produces derivatives of formula V. These can be
treated with acylating agents of general formula VI, whereby the
substituent R.sup.1 is as above defined, while LG could be any
appropriate leaving group. Preferred acylating agents VI are acid
chlorides (VIa), used in conjunction with a tertiary amine base, or
carboxylic acids (VIb), used in conjunction with a peptide coupling
agent, e.g. from the above mentioned group, to yield the products
of general formula I, with B being defined as C(O)N.sup.8R.sup.9
(Ia).
##STR00008##
[0310] Other derivatives of formula I are prepared using known
modifications to the Scheme 1 reaction sequence. Compounds of
formula I wherein A is different from the carbonyl functionality
are prepared by replacing formula VI compounds with compounds
containing the appropriate functional groups, e.g. sulfonyl
chlorides, isocyanates, isothiocyanates, chloroformates,
substituted alkyl halides, or others to yield sulfonamide, urea,
thiourea, carbamate, substituted alkyl derivatives, or others,
respectively.
[0311] Compounds of formula II, whereby the substituent X is
CR.sup.6R.sup.7, and R.sup.6 and R.sup.7 are as above defined, can
be prepared from compounds of general formula VII by Wittig-type
reactions with anions of phosphoranes such as VIIIa and/or of
phosphonates such as VIIb, followed by saponification of the ester
function using standard synthetic techniques, as hereinafter
described in the Examples and shown in Scheme 2.
##STR00009##
[0312] Compounds of general formula VII can be prepared from
commercially available, suitably N-protected 4-hydroxyproline X, by
a reaction sequence consisting of oxidation and esterification,
using standard synthetic techniques as hereinafter described in the
Examples and shown in Scheme 3.
##STR00010##
[0313] Compounds of formula II, wherein the substituent X is
NOR.sup.6 or NNR.sup.6R.sup.7, and R.sup.6 and R.sup.7 are as above
defined, can be prepared from compounds of general formula XI by
reaction with substituted hydroxylamines XIIa and/or substituted
hydrazines and/or hydrazides XIIb using standard synthetic
techniques as hereinafter described in the Examples and shown in
Scheme 4.
##STR00011##
[0314] Compounds of formula XIIa are commercially available or
prepared by standard synthetic techniques as hereinafter described
in the Examples. Compounds of formula II with X.dbd.S are
accessible from the corresponding suitably protected
ketopyrrolidine intermediates VII through standard functional group
interconversion methods well known to the person skilled in the
art, such as, e.g., by treatment with Lawesson's reagent or others
(Pedersen, B. S. et al.; Bull. Soc. Chim. Belg. 1978, 87, 223),
followed by saponification.
[0315] According to another process, pyrrolidine derivatives
according to the general formula I, whereby the substituent B is a
heterocyclic residue B1 as above defined, and the substituents are
as above defined, are prepared from the corresponding suitably
N-protected 4-substituted pyrrolidine derivatives II, whereby the
substituent X is as above defined, by solution-phase chemistry
protocols such as described in the Examples and shown in Scheme 5,
below. The starting suitably N-protected 4-substituted pyrrolidine
derivatives II are first reacted with ortho-substituted primary
anilines of general formula XIII, whereby the substituents Q, Z, E,
Y, and R.sup.11 are as above defined, using standard peptide
coupling agents, such as DIC, EDC, TBTU, DECP, or others, followed
by exposure to dilute weak acid, such as acetic acid, in a suitable
organic solvent, such as DCM, to promote cyclisation yielding
compounds of formula XIV. Removal of the N-protecting group using
the appropriate deprotection agents produces cyclic derivatives of
formula XV. These can be treated with acylating agents of general
formula VI, whereby the substituent R.sup.1 is as above defined,
while LG could be any appropriate leaving group. Preferred
acylating agents VI are acid chlorides (VIa), used in conjunction
with a tertiary amine base, or carboxylic acids (VIb), used in
conjunction with a peptide coupling agent, e.g. from the
abovementioned group, to yield the products of general formula I,
with B being defined as B1 (Ib).
##STR00012##
[0316] Other derivatives of formula I are prepared using known
modifications to the Scheme 5 reaction sequence. Compounds of
formula I wherein A is different from the carbonyl functionality
are prepared by replacing formula VI with compounds containing the
appropriate functional groups, e.g. sulfonyl chlorides,
isocyanates, isothiocyanates, chloroformates, substituted alkyl
halides, or others to yield sulfonamide, urea, thiourea, carbamate,
substituted alkyl derivatives, or others, respectively.
[0317] According to another general process, summarized in Scheme
6, pyrrolidine derivatives according to the general formula I,
whereby the substituents A, B, X, and R.sup.1 are as above defined,
are prepared from compounds of formula XVI, using the synthetic
techniques as outlined in Schemes 2 and 4. As further shown in
Scheme 6, compounds of formula XVI are accessible either from XI,
following, e.g., the synthetic methodologies introduced in Schemes
1 and 5, or from Ic through hydrolysis of the methyloxime moiety,
e.g. under mild hydrolysis conditions as described hereinafter in
the Examples. This present synthetic strategy is most preferred
when X is NOH or NNR.sup.6R.sup.7, whereby the substituents R.sup.6
and R.sup.7 are as above defined.
##STR00013##
[0318] According to yet another process, pyrrolidine derivatives
according to the general formula I, whereby the substituents A, B,
X, and R.sup.1 are as above defined, are prepared from the
corresponding suitably N-protected 4-substituted pyrrolidine
derivatives II, whereby the substituent X is above defined, by a
solid-phase protocol such as described in the examples and shown in
Scheme 7, below. The N-Boc-protected 4-substituted pyrrolidine
derivative II is reacted e.g. with Kaiser oxime resin using
standard carbodiimide-mediated coupling conditions well known to
the practitioner skilled in the art, followed by Boc-deprotection
with dilute TFA in DCM, or with BF.sub.3.OEt.sub.2 in dilute HOAc
in DCM, to give compound XIX. The latter compound can be treated
with acylating agents of general formula VI, whereby the
substituent R.sup.1 is as above defined, while LG could be any
appropriate leaving group. Preferred acylating agents VI are acid
chlorides (VIa), used in conjunction with a tertiary amine base, or
carboxylic acids (VIb), used in conjunction with a peptide coupling
agent, e.g. DIC or EDC, to yield products of general formula
XX.
[0319] Compounds of formula I wherein A is different from the
carbonyl functionality are prepared by replacing formula VI with
compounds containing the appropriate functional groups, e.g.
sulfonyl chlorides, isocyanates, isothiocyanates, chloroformates,
substituted alkyl halides, or others to yield sulfonamide, urea,
thiourea, carbamate, substituted alkyl derivatives, or
others-respectively.
[0320] In order to obtain the final compounds of general formula I,
the linkage to the resin is cleaved by prolonged treatment with
amines of general formulae III or XIII and low percentages of a
weak acid, such as HOAc. The cycles within the below Scheme 7
illustrate the resign beads to which the corresponding compounds
are linked during the solid phase synthesis. Other derivatives of
formula I are prepared using known modifications to, or variations
of, the Scheme 7 reaction sequence. Further to the above mentioned
Kaiser oxime resin, other suitable reagents, notably resins, known
to a person skilled in the art, could be employed for the
solid-phase synthesis of compounds of general formula I.
##STR00014## ##STR00015##
[0321] The reaction sequences outlined in the above Schemes
provides enantiomerically pure compounds of formula I, if
enantiomerically pure starting materials are used. (R) as well as
(S) enantiomers can be obtained depending upon whether (R) or (S)
forms of commercially available compounds of formulas II, III, VI,
and/or X were used as the starting materials.
[0322] However, the reaction sequences outlined in the above
Schemes usually provide mixtures of (E) and (Z) isomers with
respect to the substituents on the exocyclic double bond of the
pyrrolidine ring. In all cases studied, these (E)/(Z)-isomers could
be separated by standard chromatography techniques well known to
the person skilled in the art, such as by reversed phase
high-pressure liquid chromatography (HPLC) or silica gel flash
chromatography (FC). The assignment of the absolute configuration
of the exocyclic double bond was performed using NMR-techniques
well described in the literature as will be known to the
practitioner skilled in the art (for configurationnal assignments
of e.g. oxime functionalities, see e.g. E. Breitmaier, W. Voelter
Carbon-13 NMR Spectroscopy, 3rd Ed, VCH, 1987, p. 240).
[0323] According to a further general process, compounds of formula
I can be converted to alter-native compounds of formula I,
employing suitable interconversion techniques such as hereinafter
described in the Examples.
[0324] If the above set out general synthetic methods are not
applicable for obtaining compounds according to formula I and/or
necessary intermediates for the synthesis of compounds of formula
I, suitable methods of preparation known by a person skilled on the
art should be used. In general, the synthesis pathways for any
individual compound of formula I will depend on the specific
substitutents of each molecule and upon the ready availability of
intermediates necessary; again such factors being appreciated by
those of ordinary skill in the art. For all the protection,
de-protection methods, see Philip J. Kocienski, in "Protecting
Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and,
Theodora W. Greene and Peter G. M. Wuts in "Protective Groups in
Organic Synthesis", Wiley-Interscience, 1991.
[0325] Compounds of this invention can be isolated in association
with solvent molecules by crystallization from evaporation of an
appropriate solvent. The pharmaceutically acceptable acid addition
salts of the compounds of formula I, which contain a basic center,
may be prepared in a conventional manner. For example, a solution
of the free base may be treated with a suitable acid, either neat
or in a suitable solution, and the resulting salt isolated either
by filtration or by evaporation under vacuum of the reaction
solvent. Pharmaceutically acceptable base addition salts may be
obtained in an analogous manner by treating a solution of compound
of formula I with a suitable base. Both types of salt may be formed
or interconverted using ion-exchange resin techniques.
[0326] If the above set out general synthetic methods are not
applicable for the obtention of compounds of formula I, suitable
methods of preparation known by a person skilled in the art should
be used.
[0327] A final aspect of the present invention is related to the
use of the compounds according to formula I for the modulation of
the Oxytocin receptor, the use of said compounds for the
preparation of pharmaceutical compositions for the modulation of
the oxytocin receptor as well as the formulations containing the
active compounds according to formula I. Said modulation of the
oxytocin receptor is viewed as a suitable approach for the
treatment of preterm labor, premature birth and dysmenorrhea.
Hence, the compounds of the present invention are suitable for the
treatment of preterm labor, premature birth and dysmenorrhea.
[0328] When employed as pharmaceuticals, the pyrrolidine
derivatives of the present invention are typically administered in
the form of a pharmaceutical composition. Hence, pharmaceutical
compositions comprising a compound of formula I and a
pharmaceutically acceptable carrier, diluent or excipient therefore
are also within the scope of the present invention. A person
skilled in the art is aware of a whole variety of such carrier,
diluent or excipient compounds suitable to formulate a
pharmaceutical composition. Also, the present invention provides
compounds for use as a medicament. In particular, the invention
provides the compounds of formula I for use as antagonists of the
oxytocin receptor, for the treatment or prevention of disorders
mediated by the oxytocin receptor in mammals, notably of humans,
either alone or in combination with other medicaments, e.g. in
combination with a further OT antagonist.
[0329] The compounds of the invention, together with a
conventionally employed adjuvant, carrier, diluent or excipient may
be placed into the form of pharmaceutical compositions and unit
dosages thereof, and in such form may be employed as solids, such
as tablets or filled capsules, or liquids such as solutions,
suspensions, emulsions, elixirs, or capsules filled with the same,
all for oral use, or in the form of sterile injectable solutions
for parenteral (including subcutaneous use). Such pharmaceutical
compositions and unit dosage forms thereof may comprise ingredients
in conventional proportions, with or without additional active
compounds or principles, and such unit dosage forms may contain any
suitable effective amount of the active ingredient commensurate
with the intended daily dosage range to be employed.
[0330] When employed as pharmaceuticals, the pyrrolidine
derivatives of this invention are typically administered in the
form of a pharmaceutical composition. Such compositions can be
prepared in a manner well known in the pharmaceutical art and
comprise at least one active compound. Generally, the compounds of
this invention are administered in a pharmaceutically effective
amount. The amount of the compound actually administered will
typically be determined by a physician, in the light of the
relevant circumstances, including the condition to be treated, the
chosen route of administration, the actual compound administered,
the age, weight, and response of the individual patient, the
severity of the patient's symptoms, and the like.
[0331] The pharmaceutical compositions of these inventions can be
administered by a variety of routes including oral, rectal,
transdermal, subcutaneous, intravenous, intramuscular, and
intranasal. Depending on the intended route of delivery, the
compounds are preferably formulated as either injectable or oral
compositions. The compositions for oral administration can take the
form of bulk liquid solutions or suspensions, or bulk powders. More
commonly, however, the compositions are presented in unit dosage
forms to facilitate accurate dosing. The term "unit dosage forms"
refers to physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, in association with a suitable
pharmaceutical excipient. Typical unit dosage forms include
prefilled, premeasured ampoules or syringes of the liquid
compositions or pills, tablets, capsules or the like in the case of
solid compositions. In such compositions, the pyrrolidine compound
is usually a minor component (from about 0.1 to about 50% by weight
or preferably from about 1 to about 40% by weight) with the
remainder being various vehicles or carriers and processing aids
helpful for forming the desired dosing form.
[0332] Liquid forms suitable for oral administration may include a
suitable aqueous or nonaqueous vehicle with buffers, suspending and
dispensing agents, colorants, flavors and the like. Solid forms may
include, for example, any of the following ingredients, or
compounds of a similar nature: a binder such as microcrystalline
cellulose, gum tragacanth or gelatine; an excipient such as starch
or lactose, a disintegrating agent such as alginic acid, Primogel,
or corn starch; a lubricant such as magnesium stearate; a glidant
such as colloidal silicon dioxide; a sweetening agent such as
sucrose or saccharin; or a flavoring agent such as peppermint,
methyl salicylate, or orange flavoring.
[0333] Injectable compositions are typically based upon injectable
sterile saline or phosphate-buffered saline or other injectable
carriers known in the art. As above mentioned, the pyrrolidine
derivatives of formula I in such compositions is typically a minor
component, frequently ranging between 0.05 to 10% by weight with
the remainder being the injectable carrier and the like.
[0334] The above described components for orally administered or
injectable compositions are merely representative. Further
materials as well as processing techniques and the like are set out
in Part 8 of Remington's Pharmaceutical Sciences, 17.sup.th
Edition, 1985, Marck Publishing Company, Easton, Pa., which is
incorporated herein be reference.
[0335] The compounds of this invention can also be administered in
sustained release forms or from sustained release drug delivery
systems. A description of representative sustained release
materials can also be found in the incorporated materials in
Remington's Pharmaceutical Sciences.
[0336] In the following the present invention shall be illustrated
by means of some examples which are not construed to be viewed as
limiting the scope of the invention. The HPLC, NMR and MS data
provided in the examples described below were obtained as followed.
The following abbreviations are hereinafter used in the
accompanying examples: min (minute), hr (hour), g (gram), mmol
(millimole), m.p. (melting point), eq (equivalents), mL
(milliliter), .mu.L (microliters), mL (milliliters), ACN
(Acetonitrile), CDCl.sub.3 (deuterated chloroform), cHex
(Cyclohexanes), DCM (Dichloromethane), DECP
(Diethylcyanophosphonate), DIC (Diisopropyl carbodiimide), DMAP
(4-Dimethylaminopyridine) DMF (Dimethylformamide), DMSO
(Dimethylsulfoxide), DMSO-d.sub.6 (deuterated dimethylsulfoxide),
EDC (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide), EtOAc (Ethyl
acetate), Et.sub.2O (Diethyl ether), HOBt (1-Hydroxybenzotriazole),
K.sub.2CO.sub.3 (potassium carbonate), NaH (Sodium hydride),
NaHCO.sub.3 (Sodium bicarbonate), nBuLi (n Butyllithium), TBTU
(O-Benzotriazolyl-N,N,N',N'-tetramethyluronium-tetrafluoroborate),
TEA (Triethyl amine), TFA (Trifluoro-acetic acid), THF
(Tetrahydrofuran), MgSO.sub.4 (Magnesium sulfate), PetEther
(Petroleum ether), rt (room temperature).
EXAMPLES
Intermediate 1:
(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid
[0337] Commercial
(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic
acid (30 g, 0.13 mol) was dissolved in acetone (1500 ml). A
mechanical stirrer was placed in the flask and the solution stirred
vigorously. A freshly made solution of 8N chromic acid was prepared
by dissolving chromium trioxide (66.7 g, 0.667 mol) in water (40
ml), adding concentrated sulphuric acid (53.3 ml) and adding enough
water to bring the solution volume to 115 ml. The 8N chromic acid
solution (1-15 ml) was then added dropwise over a period of 30
minutes with continued vigorous stirring, the reaction's exotherm
being maintained at the optimal temperature of 25.degree. C. by the
use of an ice bath. After the complete addition of the chromic
acid, the reaction mixture was stirred for a further 15
minutes--maintaining the optimal temperature of 25.degree. C. The
reaction mixture was then quenched by the addition of methanol (20
ml). Exotherm controlled by the use of an ice bath and, if
necessary, direct addition of a small amount of crushed ice to the
reaction mixture itself. The reaction mixture was filtered through
a Celite pad and then concentrated in vacuo. The resulting acidic
solution was then extracted with ethyl acetate (3.times.300 ml) and
the combined organic layers washed with brine (2.times.100 ml).
Organics then dried with magnesium sulfate and concentrated in
vacuo. Crude product recrystallised from ethyl acetate to give the
white crystalline product,
(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid
(22.55 g, 76%). The antipodal intermediate,
(2R)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid,
was made according to the same protocol, starting from commercial
(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic
acid.
[0338] 1H NMR (360 MHz, CDCl3); 1.4 (m, 9H), 2.5-3.0 (m, 2H),
3.7-3.9 (m, 2H), 4.75 (dd, 1H)
Intermediate 2: 1-tert-butyl 2-methyl
(2S)-4-oxo-1,2-pyrrolidinedicarboxylate
[0339] A solution of
(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (1
g, 4.3 mmol) in a 1:1 mixture of methanol and toluene (60 ml) was
made. Trimethylsilyl diazomethane (6.5 ml of a 2M solution in
hexanes, 13 mmol) was then added dropwise to the stirred solution
at room temperature under nitrogen. After completion of the
evolution of nitrogen gas, the resulting yellow solution was
evaporated in vacuo, and the residue filtered through a pad of
silica gel, eluting with ethyl acetate. Removal of solvent from the
filtrate gave a yellow oil (1.05 g, near quantitative yield).
[0340] .sup.1H NMR (400 MHz, CDCl.sub.3); 1.4 (m, 9H), 2.5 (m, 1H),
2.8-2.9 (m, 1H) 3.7 (s, 3H), 3.9 (m, 2H), 4.6-4.8 (m, 1H).
Intermediate 3: 1-tert-butyl 2-methyl
(2S,4EZ)-4-(chloromethylene)-1,2-pyrrolidinedicarboxylate
[0341] Chloromethyltriphenylphosphonium iodide (270 mg, 0.62 mmol)
was added to a solution of potassium tert-butoxide (67 mg, 0.59
mmol) in anhydrous diethyl ether (5 ml) under nitrogen and the
resulting bright yellow mixture stirred for 30 minutes at ambient
temperature. The reaction was then cooled to 0.degree. C. and a
solution of 1-tert-butyl 2-methyl
(2S)-4-oxo-1,2-pyrrolidinedicarboxylate (100 mg, 0.41 mmol in 2 ml
anhydrous diethyl ether) was added dropwise. The reaction was then
warmed to room temperature and stirred for 30 minutes before adding
saturated aqueous ammonium chloride solution (0.5 ml). The organic
layer was removed in vacuo, and the aqueous washed with diethyl
ether (3.times.5 ml). The combined organic layers were dried with
brine and magnesium sulfate before filtering and removal of
solvent. The desired product was isolated by silica gel
chromatography, eluting with 15% ethyl acetate in hexanes to give
105 mg (93% yield) as a off-white wax.
[0342] .sup.1H NMR (400 MHz, CDCl.sub.3); 1.4 (9H, m), 2.6-2.75 (m,
1H), 2.8-3.0 (m, 1H), 3.65 (s, 3H), 4.1 (m, 2H), 4.4-4.5 (m, 1H)
5.9-6.0 (m, 1H).
Intermediate 4: 1-tert-butyl 2-methyl
(2S)-4-methylene-1,2-pyrrolidinedicarboxylate
[0343] Methyltriphenylphosphonium bromide (22 g, 61.6 mmol) was
added to a solution of potassium tert-butoxide (6.5 g, 57.6 mmol)
in anhydrous diethyl ether (450 ml) at 0.degree. C. under nitrogen
and the resulting bright yellow mixture stirred for 30 minutes. A
solution of 1-tert-butyl 2-methyl
(2S)-4-oxo-1,2-pyrrolidinedicarboxylate (10 g, 41.1 mmol in 150 ml
anhydrous diethyl ether) was added slowly to the reaction mixture,
which was then warmed at 35.degree. C. for 3 h. Saturated aqueous
ammonium chloride solution (0.5 ml) was then added. The organic
layer was removed, and the aqueous washed with diethyl ether
(3.times.5 ml). The combined organic layers were dried with brine
and magnesium sulfate before filtering and removal of solvent.
Silica gel chromatography, eluting with 15% ethyl acetate in
hexanes gave the desired product 6.9 g (70% yield) as a off-white
wax.
[0344] .sup.1H NMR (400 MHz, CDCl.sub.3); 1.4 (9H, m), 2.5 (m, 1H),
2.8 (m, 1H), 3.65 (s, 3H), 4.0 (m, 2H), 4.3-4.5 (m, 1H), 4.9 (m,
2H).
Intermediate 5: 1-tert-butyl 2-methyl
(2S,4EZ)-4-(cyanomethylene)-1,2-pyrrolidinedicarboxylate
[0345] Diethyl cyanomethyl phosphonate (0.86 ml, 4.4 mmol) was
dissolved in dry THF (50 ml) and the solution cooled to 0.degree.
C. Sodium hydride (205 mg of a 60% suspension in parrafin oil, 5.1
mmol) was then added cautiously and the reaction stirred for 30
min. The reaction mixture was then cooled to -78.degree. C. and a
solution of 1-tert-butyl 2-methyl
(2S)-4-oxo-1,2-pyrrolidinedicarboxylate (1.0 g, 4.1 mmol) in dry
THF (5 ml) was added dropwise. The reaction was then allowed to
reach room temperature. Saturated aqueous ammonium chloride
solution (15 ml) was then added, followed by ethyl acetate (100
ml). (The organic layer was removed, and the aqueous washed with
ethyl acetate (3.times.5 ml). The combined organic layers were
dried with brine and magnesium sulfate before filtering and removal
of solvent. Silica gel chromatography, eluting with 35% ethyl
acetate in hexanes gave the desired compound (860 mg, 80%) as an
off-white wax.
[0346] .sup.1H NMR (360 MHz, CDCl.sub.3); 1.4 (m, 9H), 2.7-3.0 (m,
1H), 3.1-3.3 (m, 1H), 3.7 (m, 3H), 4.2-4.4 (m, 2H), 4.5-4.7 (m,
1H), 5.4 (m, 1H).
Intermediate 6: 1-tert-butyl 2-methyl
(2S,4EZ)-4-benzylidene-1,2-pyrrolidinedicarboxylate
[0347] Potassium tert-butoxide (6.1 g, 54 mmol) was added
portionwise to a solution of benzyl-triphenylphosphonium chloride
(22.45 g, 58 mmol) in anhydrous dichloromethane (400 ml) and the
reaction stirred at ambient temperature for 1 h. The solution was
then cooled to 0.degree. C. and a solution of 1-tert-butyl 2-methyl
(2S)-4-oxo-1,2-pyrrolidinedicarboxylate (9.36 g, 38.5 mmol) in dry
dichloromethane (30 ml) was added dropwise. After stirring for a
further 1 h at 0.degree. C. the reaction was stirred for a further
3 h at ambient temperature. Saturated aqueous ammonium chloride
solution (30 ml) was then added. The organic layer was removed, and
the aqueous washed with dichloromethane (3.times.20 ml). The
combined organic layers were dried with brine and magnesium sulfate
before filtering and removal of solvent. Silica gel chromatography,
eluting with 30% ether in hexanes gave the desired product 8.65 g
(71% yield) as a pale yellow wax.
[0348] .sup.1H NMR (400 MHz, CDCl.sub.3);1.5 (m, 9H), 2.8-3.0 (m,
1H), 3.2 (m, 1H), 3.7 (m, 3H), 4.2-4.4 (m, 2H), 4.5-4.6 (m, 1H),
6.3-6.4 (m, 1H), 7.1-7.5 (m, 5H).
Intermediate 7:
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxyli-
c acid
[0349] A solution was made containing
(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid
(5.0 g, 21 mmol) and O-methylhydroxylamine hydrochloride (2.7 g,
32.8 mmol) in chloroform (100 ml) containing triethyl-amine (5.5 g,
55 mmol). The reaction mixture was then stirred at ambient
temperature over-night, prior to removal of solvent. The resultant
crude reaction mixture was dissolved in ethyl acetate (150 ml) and
washed rapidly with 1N HCl (40 ml). The acidic layer was then
extracted with ethyl acetate (3.times.20 ml) and the combined
organic layers washed with brine before drying over magnesium
sulfate, filtering and removal of solvent in vacuo. The desired
product (5.3 g, 94%) was isolated as a pale yellow oil.
[0350] .sup.1H NMR (400 MHz, CDCl.sub.3); 1.45 (m, 9H), 2.8-3.2 (m,
2H), 3.9 (s, 3H), 4.2 (m, 2H), 4.5-4.7 (m, 1H).
Intermediate 8:
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic
acid
[0351] A solution was made containing
(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidine-carboxylic acid
(5.0 g, 22 mmol) and O-ethylhydroxylamine hydrochloride (6.4 g,
65.5 mmol) in a 1:1 mixture of pyridine and ethanol (100 ml). The
reaction was heated to reflux for 2.5 h before cooling and removal
of solvent. The residue was dissolved in ethyl acetate and washed
rapidly with 1.3N HCl (40 ml). The acidic layer was then extracted
with ethyl acetate (3.times.20 ml) and the combined organic layers
washed with brine before drying over magnesium sulfate, filtering
and removal of solvent in vacuo. The desired product (5.5 g, 93%)
was isolated as a pale yellow oil.
[0352] .sup.1H NMR (400 MHz, DMSO); 1.3 (t, 3H), 1.55 (m, 9H),
2.9-2.7 (m, 1H), 3.4-3.1 (m, 1H), 4.1-4.3 (m, 4H), 4.6 (m, 1H),
12-13.5 (br, 1H).
Intermediate 9:
(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidine-carbox-
ylic acid
[0353] A solution was made containing
(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidine-carboxylic acid
(5.0 g, 22 mmol) and O-allylhydroxylamine hydrochloride monohydrate
(7.2 g, 65.5 mmol) in a 1:1 mixture of pyridine and ethanol (100
ml). The reaction was heated to reflux for 2.5 h before cooling and
removal of solvent. The residue was dissolved in ethyl acetate and
washed rapidly with 1.3N HCl (40 ml). The acidic layer was then
extracted with ethyl acetate (3.times.20 ml) and the combined
organic layers washed with brine before drying over magnesium
sulfate, filtering and removal of solvent in vacuo. The desired
product (5.9 g, 94%) was isolated as a pale yellow oil.
[0354] .sup.1H NMR (400 MHz, CDCl.sub.3); 1.5 (m, 9H), 2.8-3.2 (m,
2H), 4.2 (m, 2H), 4.5-4.7 (m, 3H), 5.25 (m, 2H), 5.9 (m, 1H), 11.1
(broad S, 1H).
Intermediate 10: 1-[(aminooxy)methyl]-4-methoxybenzene
[0355] A solution was made of Boc hydroxylamine (2.0 g, 17.1 mmol)
in dry THF (60 ml). Sodium hydride (1.1 g of a 60% suspension in
paraffin oil, 25.7 mmol) was then added and the suspension stirred.
A catalytic amount of KI was then added to the reaction prior to
the cautious addition of 4-methoxybenzyl chloride (3.2 g, 20.4
mmol). The reaction was then allowed to stir overnight before
removal of solvent in vacuo. The residue was taken up with diethyl
ether (100 ml) and HCl gas bubbled in for 20 minutes, causing the
start of precipitation of the product. The flask was stoppered and
left to stand overnight. The product was then filtered off as a
off-white wax (39-52% yield according to varying batches).
[0356] .sup.1H NMR (400 MHz, D.sub.2O);3.8 (s, 3H), 5 (s, 2H), 7.0
(d, 2H), 7.4 (d, 2H).
Intermediate 11:
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrol-
idine-carboxylic acid
[0357] The same method as employed in the preparation of
Intermediate 7, but starting from
(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid
(Intermediate 1) and 1-[(aminooxy)methyl]-4-methoxy-benzene
(Intermediate 10) gave the title compound as a gum in a 85%
yield.
[0358] .sup.1H NMR (400 MHz, DMSO); 1.5 (m, 9H), 2.7-2.9 (m, 1H)
3.9 (s, 3H), 4.2 (m, 3H), 4.6 (m, 1H), 5.15 (s, 2H), 7.1 (d, 2H),
7.45 (d, 2H).
Intermediate 12: 2-aminoethyl acetate TFA-salt
[0359] A solution was made containing ethanolamine (36.5 ml, 0.6
mol) in chloroform (1000 ml). The Boc.sub.2O (13.1 g, 60 mmol)
dissolved in chloroform (600 ml) was slowly added dropwise at
0.degree. C. over a 6-hours period (the temperature was maintained
all over this period). The reaction was allowed to reach room
temperature and was stirred overnight. The organic layer was washed
with water (2.times.500 ml), brine and dried over magnesium sulfate
before being concentrated in vacuo. The desired product (9.5 g,
>95%) was isolated as a colourless oil and was used without
further purification. A solution was made containing the
Boc-ethanolamine (1.92 g, 12 mmol) with potassium carbonate (5 g,
36 mmol) in DCM (40 ml). Acetyl chloride (30 ml, 0.42 mol) was
added and the reaction stirred for 6 hours at room temperature. The
excess of acetyl chloride was removed in vacuo and the crude
dissolved in DCM (100 ml). The organic layer was washed with water
(50 ml), brine and dried over magnesium sulfate before being
concentrated in vacuo. The desired product (1.86 g, 77%) was
isolated as a colourless oil and was used without further
purification. A solution was made containing the O-acyl,
Boc-ethanolamine (1.65 g, 8.1 mmol) in DCM (20 ml) and TFA (20 ml)
was added. After one hour at room temperature, the solvent was
removed in vacuo. The crude was concentrated from methanol (2-3
times) and from DCM (2-3 times) to give the expected compound (1.75
g, quant.) as an oil used without further purification.
[0360] .sup.1H NMR (400 MHz, D.sub.2O); 2.0 (m, 9H), 3.1-3.2 (m,
2H), 4.15-4.25 (m, 2H).
Intermediate 13: 2'-methyl[1,1'-biphenyl]-4-carboxylic acid
[0361] To a mixture of 4-bromobenzoic acid (30 g, 0.15 mol),
2-methylphenylboronic acid (24 g, 0.15 mol), sodium carbonate (250
g) in toluene (500 mL) and water (500 mL) was added
tetrakistriphenylphosphine palladium(0) (9 g, 0.0074 mol) under
nitrogen atmosphere. The reaction mixture was refluxed for 10 h.
After this time, 100 ml of 10% NaOH were added to the reaction
mixture, the aqueous layer was separated and washed with toluene
(2.times.200 mL). Acidification of the aqueous layer with 3N HCl
solution gave a solid product, which was filtered, washed with
water and dried. The crude product was then crystallised from
toluene to yield 2'-methyl[1,1'-biphenyl]-4-carboxylic acid (20 g,
62.5%). Conversely, the product could also be obtained from
1-bromo-2-methylbenzene and 4-carboxybenzeneboronic acid, using
analogous conditions.
[0362] .sup.1H NMR (300 MHz, DMSO); 2.2 (s, 3H), 7.2-7.4 (m, 4H),
7.43 (d, J=9 Hz, 2H), 7.99 (d, J=9 Hz, 2H), 13 (b, 1H).
[0363] Similarly, using the appropriate commercial boronic acids
and arylbromides, the following, related 1,1'-biphenyl
intermediates 13 may be obtained:
[0364] 4'-methyl[1',1'-biphenyl]-4-carboxylic acid;
2',3-dimethyl[1,1'-biphenyl]-4-carboxylic acid;
2',6'-dimethyl[1,1'-biphenyl]-4-carboxylic acid;
2-methyl[1,1'-biphenyl]-4-carboxylic acid;
3-methyl[1,1'-biphenyl]-4-carboxylic acid;
2,2'-dimethyl[1,1'-biphenyl]-4-carboxylic acid;
2'-methoxy[1,1'-biphenyl]-4-carboxylic acid;
3'-methoxy[1,1'-biphenyl]-4-carboxylic acid;
4'-methoxy[1,1'-biphenyl]-4-carboxylic acid;
2'-chloro[1,1'-biphenyl]-4-carboxylic acid;
3'-chloro[1,1'-biphenyl]-4-carboxylic acid;
4'-chloro[1,1'-biphenyl]-4-carboxylic acid;
3',4'-dichloro[1,1'-biphenyl]-4-carboxylic acid;
2'-(trifluoromethyl)[1,1'-biphenyl]-4-carboxylic acid;
3'-(trifluoromethyl)[1,1'-biphenyl]-4-carboxylic acid;
2'-cyano[1,1'-biphenyl]-4-carboxylic acid;
2',4'-difluoro[1,1'-biphenyl]-4-carboxylic acid;
4-(2-pyridinyl)benzoic acid; 4-(3-pyridinyl)benzoic acid;
4-(4-pyridinyl)benzoic acid; 4-(5-pyrimidinyl)benzoic acid.
Intermediate 14: 4-(3-methyl-2-pyridinyl)benzoic acid
[0365] A mixture of 2-bromo-3-methylpyridine (22.5 g, 0.1312 mol),
4-(hydroxymethyl)phenyl-boronic acid (25 g, 0.164 mol),
Pd(PPh.sub.3).sub.4 (9.5 g, 0.0082 mol), and sodium carbonate (200
g in 500 ml of water) in toluene (750 ml) were refluxed under
nitrogen atmosphere for 15 h. Separated the toluene layer and
distilled under reduced pressure to give a residue. The residue was
then purified by column chromatography to yield
[4-(3-methyl-2-pyridinyl)-phenyl]methanol (12 g, 47%).
[0366] To a solution of [4-(3-methyl-2-pyridinyl)phenyl]methanol
(12 g, 0.06 mol) in dry DMF (150 mL) was added pyridiniumdichromate
(91 g, 0.24 mol) and stirred at RT for 3 days. The reaction mixture
was poured into water and extracted with ethyl acetate (250 mL).
The organic layer was washed with water, brine, dried and
concentrated. The crude was purified by column chromatography over
silica gel to give 4-(3-methyl-2-pyridinyl)benzoic acid (3 g, 25%)
as white solid.
[0367] .sup.1H NMR (300 MHz, DMSO); 2.3 (s, 3H), 7.33 (dd, J=7.5
Hz, 5 Hz, 1H), 7.67 (d, J=8 Hz, 2H), 7.75 (d, J=7.5 Hz, 1H), 8.01
(d, J=8 Hz, 2H), 8.50 (d, J=5 Hz, 1H), 13 (b, 1H).
Intermediate 15: 4-(1-oxido-3-pyridinyl)benzoic acid
[0368] To a mixture of 4-tolylboronic acid (38 g, 0.28 mol),
3-bromopyridine (44 g, 0.28 mol), Na.sub.2CO.sub.3 (200 g) in
toluene (500 ml) and water (500 ml) was added Pd(PPh.sub.3).sub.4
(16 g, 0.014 mol), and refluxed for 16 h. The reaction mixture was
cooled, and the separated organic layer was washed with water and
brine, and dried. The solvent was removed to give
4-(3-pyridyl)toluene (42 g, 90%).
[0369] To a mixture of 4-(3-pyridyl)toluene (35 g, 0.207 mol) in
pyridine (400 ml) and water (400 ml) was added KMnO.sub.4 (163 g,
1.03 mol) in portions and refluxed for 12 h. The reaction mixture
was filtered through celite and acidified with conc. HCl. The
product was washed with water and dried to give
4-(3-pyridyl)benzoic acid (32 g, 76%) as a white solid. To a
mixture of 4-(3-pyridyl)benzoic acid (22 g, 0.11 mol) in THF
(2.51), mCPBA (152 g, 0.44 mol, 50%) was added and stirred at RT
for 12 h. The solid was filtered, and washed with THF to give
4-(1-oxido-3-pyridinyl)benzoic acid (20 g, 86%).
[0370] .sup.1H NMR (300 MHz, DMSO); 7.5-7.8 (m, 5H), 7.9 (d, J=8
Hz, 2H), 8.33 (d, J=5 Hz, 2H).
[0371] Similarly, starting from 4-tolylboronic acid (45 g, 0.33
mol) and 2-bromopyridine (52 g, 0.33 mol), the related intermediate
4-(1-oxido-2-pyridinyl)benzoic acid was obtained.
Example 1
General Procedure for the Saponification of the Olefin-Type Proline
Methyl Esters, Such as Intermediates 3-6
[0372] A solution of sodium hydroxide (4.5 g, 112 mmol) in water
(70 ml) was added to the relevant proline olefin methyl ester (66
mmol) in 3:1 dioxane:water (500 ml) and the reaction stirred for 3
h. The reaction mixture was then washed with diethyl ether
(2.times.50 ml), and the aqueous phase acidified to pH 2 (0.1N HCl)
and extracted into ethyl acetate. The ethyl acetate layer was then
dried over magnesium sulfate, filtered and the solvent was then
removed in vacuo to give the desired product in near quantitative
yields as an oil which was used without further purification.
Example 2
General Protocol for the Solution-Phase Synthesis of Oximether
Pyrrolidine Derivatives of General Formula Ia (Scheme 1)
Method A: e.g.
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-methoxyethyl)-4-(methoxyim-
ino)-2-pyrrolidinecarboxamide
a) Protocol for the Formation of the Amide Bond
[0373] A solution was made containing the central building block,
e.g.
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic
acid (Intermediate 7) (1.5 g, 5.8 mmol), an amine or an amine salt,
e.g. 2-methoxy-ethylamine (0.51 ml, 5.81 mmol) and DMAP (780 mg,
5.8 mmol) in DCM (30 ml). At 0.degree. C., EDC (1.1 g, 5.8 mmol)
was slowly added portion-wise. The reaction was slowly allowed to
reach room temperature and was stirred overnight. The DCM was
evaporated and the crude purified by column chromatography using
EtOAc (100%) to collect the desired product, e.g. tert-butyl
(2S,4EZ)-2-{[(2-meth-oxyethyl)amino]carbonyl}-4-(methoxyimino)-1-pyrrolid-
inecarboxylate (1.5 g, 80%) as a colourless oil.
[0374] .sup.1H NMR (400 MHz, CDCl.sub.3); 1.25 (m, 9H), 2.5-2.9 (m,
2H), 3.1 (s, 3H), 3.2-3.3 (m, 4H), 3.65 (s, 3H), 3.8-4.4 (m, 3H),
6.7 (s broad, 1H).
b) Protocol for the N-Deprotection Step
[0375] A solution was made containing the amide compounds from the
previous step, e.g. tert-butyl
(2S,4EZ)-2-{[(2-methoxyethyl)amino]carbonyl}-4-(methoxyimino)-1-pyrrolidi-
ne-carboxylate (1.5 g, 0.4 mmol), in anhydrous ether (35 ml). HCl
gas was bubbled slowly through the reaction and the deprotection
was followed by TLC. After approximately 20 minutes, the ether was
evaporated. The product was concentrated in vacuo from DCM (2-3
times) to remove the HCl. The desired product, e.g.
(2S,4EZ)-N-(2-methoxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(1.2 g, quant.) was isolated as a yellow oil and used without
further purification.
c) Protocol for the N-Capping Step
[0376] A solution was made containing the free NH-compound from the
previous step, e.g. (2S
4EZ)-N-(2-methoxyethyl)-4-(ethoxyimino)-2-pyrrolidinecarboxamide
(940 mg, 3.7 mmol), a carboxylic acid, e.g.
[1,1'-biphenyl]-4-carboxylic acid (740 mg, 3.7 mmol) and DMAP (960
mg, 7.8 mmol) in DCM (30 ml). At 0.degree. C., EDC (715 mg, 3.7
mmol) was slowly added portionwise. The reaction was slowly allowed
to reach room temperature and was stirred overnight. The DCM was
evaporated and the crude purified by column chromatography using
EtOAc (100%) to collect the desired product, e.g.
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-methoxyethyl)-4-(methoxyim-
ino)-2-pyrrolidinecarboxamide as a mixture of two isomers as an
off-white solid.
[0377] 1H NMR (400 MHz, CDCl3); 2.75-2.85 (m, 1H), 3.1-3.3 (m, 4H),
3.4-3.5 (m, 4H), 3.8 (m, 3H), 4.1-4.3 (m, 2H), 5.1 (m, 1H), 6.9 (m,
1H), 7.2-7.7 (m, 10H). M.sup.+(APCI.sup.+); 396.
Method B: e.g. (2S,4E and
4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2-methyl[1,1'-b-
iphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
a) Protocol for the Formation of the Amide Bond
[0378] To a solution of the central building block, e.g.
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic
acid (Intermediate 7) (24.2 mmol, 6.24 g) in dry THF (125 ml) at
-25.degree. C. was added NMM (2.5 eq, 60.4 mmol, 6.64 ml) followed
by isobutylchloroformate (1.05 eq, 25.4 mmol, 3.3 ml). The
resulting mixture was stirred at -25.degree. C. for 30 min and an
amine or an amine salt, e.g. (S)-2-amino-1-phenylethanol (1.51 eq,
36.5 mmol, 5 g) was then added. The mixture was allowed to
gradually warm to rt. After 16 h, the solvents were removed. The
residue was dissolved in AcOEt, washed twice with NH.sub.4Cl
saturated solution, then twice with 10% NaHCO.sub.3 solution. The
organic layer was dried over Na.sub.2SO.sub.4, filtrated and
concentrated to afford the desired product, e.g. tert-butyl
(2S,4EZ)-2-({[(2S)-2-hydroxy-2-phenylethyl]amino}carbonyl)-4-(methoxyimin-
o)-1-pyrrolidine-carboxylate (8.76 g, 96%) as a pale yellow oil in
88.5% purity by HPLC.
[0379] .sup.1H NMR (CDCl.sub.3: 300 MHz) .delta. 1.44 (s, 9H,
N-Boc), 3.23-2.85 (m, 4H), 3.72 (m, 1H), 3.85 (s, 3H, O--CH.sub.3),
4.10 (m, 2H), 4.49 (m, 1H), 4.83 (m, 1H), 7.34 (m, 5H, Ar--H);
[M+Na.sup.+] (ESI.sup.+): 400.
b) Protocol for the N-Deprotection Step
[0380] A solution was made containing the amide compounds from the
previous step, e.g. tert-butyl
(2S,4EZ)-2-({[(ZS)-2-hydroxy-2-phenylethyl]amino}carbonyl)-4-(methoxyimin-
o)-1-pyrrolidinecarboxylate (2.64 g, 7 mmol), in anhydrous DCM (35
ml). At 0.degree. C., HCl gas was bubbled slowly through the
reaction and the deprotection was followed by TLC. After
approximately 20 minutes, the DCM was evaporated. The product was
concentrated in vacuo from DCM (2-3 times) to remove the HCl. The
desired product, e.g.
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinec-
arboxamide (1.94 g, quant.) was isolated as a yellow solid and used
without further purification.
c) Protocol for the N-Capping Step
[0381] To a suspension of 4-(2-methylphenyl)benzoic acid (1.49 g, 7
mmol.) in 35 ml DCM, was added oxalyl chloride and DMF (3 ml) under
ice cooling. The mixture was stirred for 2 h at rt. The solvent was
removed affording the corresponding acyl chloride as a yellow
solid. It was dissolved in DCM (30 mL) and added slowly on a
0.degree. C. solution containing the free NH-compound from the
previous step, e.g.
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinec-
arboxamide (1.94 g, 7 mmol), and triethylamine (5 eq, 35 mmol, 4.9
ml) in dry DCM (35 ml). The reaction mixture was stirred overnight
at r.t. Pol-trisamine was added (2.12 g, 3.45 mmol/g) in order to
scavenge excess of acyl chloride. The mixture was shaken 3 h,
filtered and the resulting solution was washed with NH.sub.4Cl sat,
brine, and dried over Na.sub.2SO.sub.4. After filtration and
evaporation of the solvents, the resulting dark oil (3.26 g) was
purified by flash chromatography (Biotage system, column 40M, 90 g
SiO.sub.2, with gradients of DCM and MeOH as eluent), affording
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[-
1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide. Separation
of the E/Z-isomers was achieved by several chromatographies,
affording
(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (230 mg,
colorless powder, 98.7% purity by HPLC) and
(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (266 mg,
colorless powder, 98.3% purity by HPLC).
[0382]
(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-me-
thyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide: M.p.
74.degree. C.; IR (neat) v 3318, 2932, 1613, 1538, 1416, 1239,
1047, 848 cm.sup.-1; .sup.1H NMR (300 MHz, CDCl.sub.3): 2.27 (s,
3H, ArCH.sub.3), 2.89 (dd, J=6, 12 Hz, 1H),3.18 (br d, J=12 Hz,
1H), 3H), 3.27 (m, 1H), 3.76 (m, 1H), 3.88 (s, 3H, NOCH.sub.3),
4.28 (d, J=10 Hz, 1H), 4.47 (d, J=10 Hz, 1H), 4.59 (br s, 1H), 4.88
(m, 1H), 5.20 (m, 1H), 7.03-7.42 (m, 1H, H arom.), 7.45-7.54 (m,
2H, H arom.); M.sup.+(APCI.sup.+): 472; M.sup.-(APCI.sup.-): 470.
Analysis calculated for C.sub.28H.sub.29N.sub.3O.sub.4 0.3H.sub.2O:
C, 70.51; H, 6.26; N, 8.81. Found: C, 70.53; H. 6.30; N, 8.87.
[0383]
(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-me-
thyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide: M.p.
78.degree. C.; IR (neat) v 3318, 2938, 1622, 1538, 1416, 1233,
1045, 852 cm.sup.-1; .sup.1H NMR (300 MHz, CDCl.sub.3): 2.28 (s,
3H, ArCH.sub.3), 2.69 (dd, J=6, 10 Hz, 1H), 3.02-3.22 (m, 2H), 3.25
(br s, 1H), 3.60 (m, 1H), 3.86 (s, 3H, NOCH.sub.3), 4.14 (m, 2H),
4.71 (m, 1H), 4.96 (m, 1H), 7.03-7.42 (m, 1H, H arom.), 7.45-7.54
(m, 2H, H arom.); M.sup.+(APCI.sup.+): 472; M.sup.-(APCI.sup.-):
470. Analysis calculated for C.sub.28H.sub.29N.sub.3O.sub.4
0.9H.sub.2O: C, 68.95; H, 6.36; N, 8.61. Found: C, 68.87; H, 6.25;
N, 8.77.
d) E/Z-Isomerisation
[0384] The pure E-isomer was isomerized to a mixture of the
E/Z-isomers by the following procedure: the E-isomer was dissolved
in dioxane/water 3:1 mixture. NaOH (1.7 eq; 0.52 mL of, NaOH 1.6N)
was added and the resulting solution was stirred 2 h at r.t. The
mixture was neutralised with HCl 0.1 N and lyophilised. The
components of the resulting E/Z-mixture were separated and purified
by flash chromatography using same conditions as described
above.
Example 3
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino)ethyl]-4-{[(4-
-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide
[0385] Following the general method as outlined in, Example 2,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, [1,1'-biphenyl]-4-carboxylic acid, and
N.sup.1,N.sup.1-diethyl-1,2-ethanediamine the title compound was
obtained after column chromatography as an off-white solid as a
mixture of E/Z-isomers.
[0386] 1H NMR (400 MHz, CDCl3); 1.05-1.15 (m, 6H), 2.7-2.8 (m, 1H),
2.9-3.2 (m, 6H), 3.4 (m, 1H), 3.6 (s, 3H), 4.0-4.1 (m, 1H), 4.3-4.4
(m, 1H), 3.75 (m, 1H), 3.8 (m, 2H), 6.65 (m, 2H), 7.0-7.1 (m, 2H),
7.2-7.3 (m, 3H), 7.35-7.45 (m, 6H), 8.8 (sibr, 0.5H).
M.sup.+(APCI.sup.+); 543.
Example 4
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2-h-
ydroxy-2-phenethyl]-2-pyrrolidinecarboxamide
[0387] Following the general method as outlined in Example 2,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, [1,1'-biphenyl]-4-carboxylic acid, and
(1RS)-2-amino-1-phenylethanol, the title compound was obtained
after column chromatography as a mixture of E/Z-isomers as an
off-white solid. The two isomers could be separated by another
flash chromatographic purification step.
[0388]
(2S,4E)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2R-
S)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide: 1H NMR (400
MHz, CDCl3); 2.6-2.7 (m, 1H), 2.8-3.0 (m, 3H), 3.2 (m, 1H), 3.4-3.6
(m, 1H), 3.9 (m, 1H), 4.15 (t, 1H), 4.6 (m, 1H), 4.85 (m, 1H), 5.75
(s, 1H), 7.0-7.4 (m, 14H). M.sup.+(APCI.sup.+); 461.
[0389]
(2S,4Z)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2R-
S)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide: 1H NMR (400
MHz, CDCl3); 2.5-2.6 (m, 1H), 2.7-2.9 (m, 1H), 3.0 (m, 1H), 3.1-3.4
(m, 1H), 3.4-3.6 (m, 1H), 3.9-4.0 (m, 1H), 4.2-4.4 (m, 2H), 4.6 (m,
1H), 4.8-4.9 (m, 1H), 5.75 (s, 1H), 7.0-7.5 (m, 14H).
M.sup.+(APCI.sup.+); 461.
Example 5
(2S,4EZ)-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-4-(methoxyimino)-2-p-
yrrolidinecarboxamide
[0390] Following the general method as outlined in Example 2,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, diphenylacetic acid, and
N.sup.1,N.sup.1-diethyl-1,2-ethanediamine the title compound was
obtained after column chromatography as an off-white solid as a
mixture of E/Z-isomers.
[0391] 1H NMR (400 MHz, CDCl3); 0.9 (t, 3H), 1.0 (m, 3H), 2.6-3.1
(m, 7H), 3.15 (m, 1H), 3.4 (m, 1H), 3.75 (s, 3H), 3.95 (t, 1H),
4.4-4.7 (m, 4H), 5.1 (m, 1H), 7.0-7.3 (m, 10H), 9.1 (m, 1H).
M.sup.+(APCI.sup.+); 451.
Example 6
(2S,4EZ)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacetyl)-2--
pyrrolidinecarboxamide
[0392] Following the general method as outlined in Example 2,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, phenoxyacetic acid, and 9-ethyl-9H-carbazol-3-amine the
title compound was obtained after column chromatography as an
off-white solid as a mixture of E/Z-isomers. The isomers were then
separated using column chromatography.
[0393]
(2S,4E)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacet-
yl)-2-pyrrolidinecarboxamide: 1H NMR (360 MHz, CDCl.sub.3); 1.2 (m,
6H), 2.7 (m, 1H), 3.35 (d, 1H), 4.1 (m, 4H), 4.3 (d, 1H), 4.45 (d,
1H), 4.7 (m, 2H), 5.15 (d, 1H), 6.9-7.3 (m, 10H), 7.9 (d, 1H), 8.15
(m, 1H), 9.0 (br s, 1H). M.sup.+(APCI.sup.+); 499.
[0394]
(2S,4Z)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacet-
yl)-2-pyrrolidinecarboxamide: 1H NMR (360 MHz, CDCl.sub.3); 1.2 (m,
6H), 2.7 (m, 1H), 3.2 (m, 1H), 4.1 (m, 4H), 4.35 (m, 2H), 4.7 (m,
2H), 5.1 (m, 1H), 6.9-7.3 (m, 10H), 7.9 (d, 1H), 8.15 (m, 1H), 9.0
(br s, 1H). M.sup.+(APCI.sup.+); 499.
Example 7
(2S,4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1-[(2-oxo-6-pentyl--
2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0395] Following the general method as outlined in Example 2,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2-oxo-6-pentyl-2H-pyran-3-carboxylic acid, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained after
column chromatography as an off-white solid as a mixture of
E/Z-isomers. The isomers were separated by column
chromatography.
[0396]
(2S,4E)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1-[(2-oxo-6-p-
entyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide: 1H NMR (360
MHz, CDCl.sub.3); 0.8 (m, 6H), 1.2 (m. 6H), 2.5 (m, 2H), 3.0 (m,
1H), 3.3 (m, 1H), 3.8 (s, 3H), 4.2 (m, 3H), 4.45 (m, 1H), 5.3 (m,
1H), 6.1 (d, 1H), 7.1 (m, 1H), 7.2 (m, 1H), 7.3 (d, 1H), 7.35 (m,
1H), 7.55 (m, 1H), 7.65 (m, 1H), 8.0 (d, 1H), 8.5 (m, 1H), 9.1 (br
S, 1H). M.sup.+(ES.sup.+); 543.
[0397]
(2S,4Z)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1-[(2-oxo-6-p-
entyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide: 1H NMR (360
MHz, CDCl.sub.3); 0.8 (m, 6H), 1.2 (m. 6H), 2.5 (m, 2H), 3.05 (m,
1H), 3.25 (m, 1H), 3.75 (s, 3H), 4.1 (m, 3H), 4.45 (d, 1H), 5.3 (d,
1H), 6.1 (d, 1H), 7.1 (t, 1H), 7.2 (m, 1H), 7.3 (m, 1H), 7.4 (m,
1H), 7.6 (m, 1H), 7.7 (m, 1H), 8.0 (d, 1H), 8.45 (m, 1H), 9.1 (m,
1H). M.sup.+(ES.sup.+); 543.
Example 8
(2S,4EZ)-4-[(allyloxy)imino]-1-benzoyl-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrr-
olidinecarboxamide
[0398] Following the general method as outlined in Example 2,
starting from
(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidineca-
rboxylic acid, benzoic acid, and 9-ethyl-9H-carbazol-3-amine the
title compound was obtained after column chromatography as an
off-white solid as a mixture of E/Z-isomers.
[0399] 1H NMR (360 MHz, CDCl.sub.3); 1.2 (m, 3H), 2.8 (m, 1H), 3.35
(m, 1H), 4.2 (m, 4H), 4.4 (m, 3H), 5.2 (m, 2H), 5.35 (m, 1H), 5.85
(m, 1H), 7.0-7.5 (m, 5H), 7.9 (m, 3H), 8.1 (m, 2H), 8.3 (m, 1H),
9.2 (br s, 1H). M.sup.+(APCI.sup.+); 481.
Example 9
General Protocol for the Solution-Phase Synthesis of Oximether
Pyrrolidine Derivatives of General Formula I Containing Additional
Reactive Groups;
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyim-
ino)-2-pyrrolidinecarboxamide
a) Protocol for the Formation of the Amide Bond
[0400] A solution was made containing the central building block,
e.g.
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic
acid (Intermediate 7) (575 mg, 2.2 mmol), the amine or amine salt
containing the suitably protected reactive group, e.g. 2-aminoethyl
acetate (Intermediate 12) (480 mg, 2.2 mmol) and DMAP (870 mg, 7.1
mmol) in DCM (20 ml). At 0.degree. C., EDC (427 mg, 2.2 mmol) was
slowly added portion-wise. The reaction was slowly allowed to reach
room temperature and was stirred overnight. The DCM was evaporated
and the crude purified by column chromatography using EtOAc/Hexane:
55/45 to collect the desired amide compound, e.g. tert-butyl
(2S,4EZ)-2-({[2-(acetyloxy)ethyl]-amino}carbonyl)-4-(methoxyimino)-1-pyrr-
olidinecarboxylate (373 mg, 49%) as an oil.
[0401] 1H NMR (400 MHz, CDCl3); 1.7 (m, 9H), 2.1-2.2 (m, 3H),
2.8-3.3 (m, 2H), 3.7-3.8 (m, 2H), 4.0-4.1 (m, 3H), 4.2-4.8 (m, 5H),
7.3 (s broad, 1H).
b) Protocol for the N-Deprotection Step
[0402] A solution was made containing the Boc-protected compound
from the previous step, e.g. tert-butyl
(2S,4EZ)-2-({[2-(acetyloxy)ethyl]amino}carbonyl)-4-(methoxyimino)-1-pyrro-
lidinecarboxylate (373 mg, 1.2 mmol) in anhydrous ether (40 ml).
HCl gas was bubbled slowly through the reaction and the
deprotection was followed by TLC. After approximately 20 minutes,
the ether was evaporated. The product was concentrated in vacuo
from DCM (2-3 times) to remove the HCl. The desired free NH
product, e.g.
2-({[(2S,4EZ)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)ethyl
acetate (300 mg, quant.) was isolated as a yellow oil and used
without further purification.
[0403] 1H NMR (400 MHz, D.sub.2O); 1.75 (s, 3H), 2.55-2.65 (m, 1H),
2.8-3.3 (m, 3H), 3.45-3.55 (m, 3H), 3.8-4.0 (m, 4H), 4.25-4.35 (m,
1H).
c) Protocol for the N-Capping Step
[0404] A solution was made containing the amine-hydrochloride from
the previous step, e.g.
2-({[(2S,4EZ)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)ethyl
acetate (560 mg, 2 mmol) and an acid chloride, e.g.
[1,1'-biphenyl]-4-carbonyl chloride (433 mg, 2 mmol) in DCM (20
ml). Triethylamine (0.7 ml, 5 mmol) was added and the reaction
stirred overnight at room temperature. The DCM was evaporated and
the crude purified by column chromatography using EtOAc (100%) to
collect the desired amide compound, e.g.
2-({[(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-
yl]carbonyl}amino)ethyl acetate (457 mg, 54%) as an oil.
[0405] 1H NMR (400 MHz, CDCl3); 1.9 (s, 3H), 2.7-2.8 (m, 1H),
3.2-3.6 (m, 3H), 3.75-3.85 (m, 3H), 4.0-4.4 (m, 4H), 5.15-5.25 (m,
1H), 7.2-7.6 (m, 9H).
d) Protocol for the Deprotection of the Reactive Group
[0406] A solution was made containing the side-chain protected
compound from the previous step, e.g.
2-({[(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-
yl]carbonyl}amino)ethyl acetate (450 mg, 10.6 mmol) in THF (10 ml).
An aqueous solution (10 ml) of sodium hydroxide (75 mg, 19 mmol)
with methanol (5 ml) was added and the reaction stirred at room
temperature for three hours. The solvent was removed in vacuo and
the crude purified by column chromatography using THF (100%) to
give the expected final product, e.g.
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyim-
ino)-2-pyrrolidinecarboxamide (300 mg, 75%) as a white solid.
[0407] 1H NMR (400 MHz, CDCl3); 2.85-3.0 (m, 1H), 3.3-3.6 (m, 3H),
3.7-3.8 (2H), 3.85-3.95 (m, 3H), 4.2-4.5 (m, 2H), 5.15-5.25 (m,
1H), 7.2-7.9 (m, 9H). M.sup.+(APCI.sup.+); 382.
Example 10
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]--
4-(methoxyimino)-2-pyrrolidinecarboxamide
[0408] Following the general method as outlined in Example 9,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
2-amino-1-phenylethyl acetate, the title compound was obtained
after column chromatography as a mixture of E/Z-isomers as an
off-white solid. The two isomers could be separated by another
flash chromatographic purification step.
[0409]
(2S,4E)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phene-
thyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide: 1H NMR (400 MHz,
CDCl3); 2.75-2.9 (m, 1H), 3.1-3.25 (m, 2H), 3.35-3.6 (m, 1H),
3.7-3.8 (m, 1H), 3.75 (s, 3H), 4.1-4.3 (m, 2H), 4.8 (m, 1H), 5.1
(dd, 1H), 7.1-7.6 (m, 15H). M.sup.+(APCI.sup.+); 458.
[0410]
(2S,4Z)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phene-
thyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide: 1H-NMR (400 MHz,
CDCl3); 2.7-2.85 (m, 1H), 3.05-3.25 (m, 2H), 3.35 (m, 1H), 3.65-3.8
(m, 1H), 3.8 (s, 3H), 4.15-4.25 (d, 1H), 4.25-4.4 (m, 1H), 4.75 (m,
1H), 5.1 (dd, 1H), 7.15-7.6 (m, 15H). M.sup.+(APCI.sup.+); 458.
Example 11
General Protocol for the Solution-Phase Synthesis of Oximether
Pyrrolidine Derivatives of General Formula Ib (Scheme 5);
(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-([1'-biphenyl]-4-ylcarbonyl)-3-pyrrol-
idinone O-methyloxime
a) Protocol for the Formation of the Amide Bond
[0411] A solution was prepared containing the central building
block, e.g.
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic
acid (Intermediate 7) (2.1 g, 8.1 mmol), an ortho-substituted
aromatic amine or amine salt, e.g. 1,2-benzenediamine (0.88 g, 8.1
mmol) and DMAP (1.59 g, 13.0 mmol). in dry dichloromethane (30 ml).
This solution was cooled to 0.degree. C. and treated with EDC (1.56
g, 8.2 mmol) before warming to room temperature and stirring for 2
days. The solvent was removed in vacuo and the product purified by
silica gel chromatography, eluting with a gradient of 30-80% ethyl
acetate in hexane to give the desired anilide product, e.g.
tert-butyl
(2S,4EZ)-2-[(2-aminoanilino)carbonyl]-4-(methoxyimino)-1-pyrrolidinecarbo-
xylate 2.8 g, 97% as a colourless foam.
[0412] 1H NMR (360 MHz, CDCl3); 1.7, (m, 9H), 2.5-3.5 (br, 4H), 3.4
(m, 1H), 4.0 (m, 3H), 4.2-4.4 (m, 2H), 4.9 (m, 1H), 6.9-7.5 (m,
4H), 8.5 (br, 1H).
b) Protocol for the Formation of the Fused Heterocyclic Ring
[0413] A solution of the anilide compound from the previous step,
e.g. tert-butyl
(2S,4EZ)-2-[(2-aminoanilino)carbonyl]-4-(methoxyimino)-1-pyrrolidinecarbo-
xylate (0.8 g, 2.3 mmol) in dichloromethane (30 ml) and acetic acid
(3 ml) was stirred at room temperature for 3 days. Saturated
aqueous sodium bicarbonate (7 ml) was added to the reaction, the
organic phase collected and dried over magnesium sulfate before
filtering and removal of solvent in vacuo to give the desired
product, e.g. tert-butyl
(2S,4EZ)-2-(1H-benzimidazol-2-yl)-4-(methoxy-imino)-1-pyrrolidinecarboxyl-
ate (740 mg, 97%) as an off-white foam.
[0414] 1H NMR (360 MHz, CDCl3); 1.5 (m, 9H), 3.1 (m, 1H), 3.8 (m,
3H) 3.9-4.3 (m, 3H), 5.3 (m, 1H), 7.1-7.6 (m, 4H), 10-10.5 (br,
1H).
c) Protocol for the N-Deprotection Step
[0415] Hydrogen chloride gas was bubbled into a solution of the
fused heterocyclic product from the previous step, e.g. tert-butyl
(2S,4EZ)-2-(1H-benzimidazol-2-yl)-4-(methoxyimino)-1-pyrrolidinecarboxyla-
te (740 mg, 2.2 mmol) in dry DCM (20 ml) for 30 min. The solvent
was removed in vacuo to give the desired product, e.g.
(3EZ,5S)-5-(1H-benzimidazol-2-yl)-3-pyrrolidinone O-methyloxime
(0.58 g, 99%), as a brown amorphous powder which was used without
further purification.
d) Protocol for the N-Capping Step
[0416] A solution of the free NH product from the previous step,
e.g. (3EZ,5S)-5-(1H-benzimidazol-2-yl)-3-pyrrolidinone
O-methyloxime (0.58 g, 2.2 mmol) in dry dichloromethane (25 ml) was
treated with an acid chloride, e.g. [1,1'-biphenyl]-4-carbonyl
chloride (0.48 g, 2.2 mmol) and triethylamine (0.9 ml, 6.6 mmol).
The resulting solution was then stirred for 3 h at room temp before
removal of solvent in vacuo and the desired isomers were isolated
by flash chromatography on silica gel, eluting with a gradient of
ethyl acetate (10-80%) in hexane to give the two isomers (120 mg of
the less polar and 400 mg of the more polar) of the desired
product, e.g. (3E,5S) and
(3Z,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-3-pyrro-
lidinone O-methyloxime, as off-white powders.
[0417]
(3E,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-3-
-pyrrolidinone O-methyloxime: 1H NMR (360 MHz, CDCl3); 3.2, (m,
1H), 3.8 (s, 3H), 4.0 (m, 1H), 4.3 (m, 2H), 6.0 (m, 1H), 6.0 (m,
1H), 7.2-7.7 (m, 13H), 10-11 (br, 1H). M.sup.+(APCI.sup.+);
411.
[0418]
(3Z,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-3-
-pyrrolidinone O-methyloxime: 1H NMR (360 MHz, CDCl3); 3.1, (m,
1H), 3.8 (s, 3H), 3.9 (m, 1H), 4.3 (m, 2H), 6.0 (m, 1H), 6.0 (m,
1H), 7.2-7.7 (m, 13H), 10-11 (br, 1H). M.sup.+(APCI.sup.+);
411.
Example 12
(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)-carbo-
nyl]-3-pyrrolidinone O-methyloxime
[0419] Following the general method as outlined in Example 11,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
1,2-benzenediamine, the title compound was obtained in 91% purity
by HPLC. MS(ESI+): m/z=425.
Example 13
(3EZ,5S)-5-(1-methyl-1H-benzimidazol-2-yl)-1-[(2'-methyl[1,1'-biphenyl]-4--
yl)carbonyl]-3-pyrrolidinone O-methyloxime
[0420] Following the general method as outlined in Example 11,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
N-methyl-1,2-benzenediamine, the title compound was obtained in 83%
purity by HPLC. MS(ESI+): m/z=439.
Example 14
(3EZ,5S)-5-(7-hydroxy-1H-benzimidazol-2-yl)-1-[(2'-methyl[1,1'-biphenyl]-4-
-yl)carbonyl]-3-pyrrolidinone O-methyloxime
[0421] Following the general method as outlined in Example 11,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
2,3-diaminophenol, the title compound was obtained in 91% purity by
HPLC. MS(ESI+): m/z=441.
Example 15
(3EZ,5S)-5-(3,4-dihydro-2-quinazolinyl)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)-
carbonyl]-3-pyrrolidinone O-methyloxime
[0422] Following the general method as outlined in Example 11,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
2-(aminomethyl)aniline, the title compound was obtained in 77%
purity by HPLC. MS(ESI+): m/z=439.
Example 16
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-5-(1-methyl-1H-benzimidazol-2-yl-
)-3-pyrrolidinone O-methyloxime
[0423] Following the general method as outlined in Example 11,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
N.sup.1-methyl-1,2-benzenediamine, the title compound was obtained
in 88% purity by HPLC. MS(ESI+): m/z=425.
Example 17
General Protocol for the Solution-Phase Synthesis of Oxime or
Hydrazone Pyrrolidine Derivatives of General Formula I (Scheme 6);
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(hydroxyimino)-N-[(2RS)-2-hyd-
roxy-2-phenethyl]-2-pyrrolidinecarboxamide
a) Protocol for the Hydrolysis of the Oximether Group.
[0424] The starting oximether compounds, e.g.
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-
-4-(methoxyimino)-2-pyrrolidinecarboxamide, were obtained following
the general methods as outlined, e.g., in Example 2, 11 or 22. A
solution containing the oximether compound was prepared, e.g.
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-
-4-(methoxyimino)-2-pyrrolidinecarboxamide (64 mg, 0.14 mmol),
paraformaldehyde powder (95%, 42 mg, 1.41 mmol) and Amberlyst.RTM.
15 (30 mg) in acetone containing 10% of water (2 mL). The reaction
was stirred 4 h at 60.degree. C. Insoluble materials were filtered
off and washed with a small amount of acetone. The filtrate was
concentrated and the residue was diluted with DCM (15 mL). The
organic solution was washed with brine (10 mL), dried over
Na2SO.sub.4, and concentrated. The desired ketocarbonyl product,
e.g.
(2S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-
-oxo-2-pyrrolidinecarboxamide (56 mg, 92%) was isolated as a yellow
oil and used without further purification.
b) Protocol for the Formation of Oxime and/or Hydrazone
Compounds
[0425] A solution was made containing the keto-pyrrolidine
derivative from the previous step, e.g.
(2S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy(2-phenethyl]-4-o-
xo-2-pyrrolidinecarboxamide (46 mg, 0.11 mmol) and hydroxylamine
hydrochloride (12 mg, 0.17 mmol) in chloroform (1 ml) containing
triethylamine (29 mg, 0.29 mmol). The reaction mixture was then
stirred at ambient temperature for one day, prior to removal of
solvent. The resultant crude reaction mixture was purified by
column chromatography using DCM/MeOH (25:1) to collect the desired
product, e.g.
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(hydroxy-imino)-N-[(2RS)-2-hy-
droxy-2-phenethyl]-2-pyrrolidinecarboxamide as a mixture of two
isomers as an off-white solid (46 mg, 96% yield).
[0426] .sup.1H NMR (300 MHz, CDCl.sub.3); 2.6-3.3 (m, 4H), 4.0-4.7
(m, 4H), 4.9 (m, 1H), 5.5 (m, 1H), 7.1-7.5 (m, 8H), 7.6-7.8 (m,
5H), 8.1 (m, 1H), 10.9 (m, 1H). M.sup.+(APCI.sup.+); 444.
Example 18
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(dimethylhydrazono)-N-[(2RS)-2-
-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide
[0427] Following the general method as outlined in Example 17,
starting from
(2S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenyleth-
yl]-4-oxo-2-pyrrolidinecarboxamide and N,N-dimethylhydrazine, the
resultant crude reaction mixture was purified by column
chromatography using DCM/MeOH (30:1) to collect the desired
product, e.g.
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(dimethylhydrazono)-N-[(2RS)--
2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide as a mixture of
two isomers as a light yellow oil in 56% yield (90.2% purity by
HPLC).
[0428] .sup.1H NMR (300 MHz, CDCl.sub.3); 2.35-2.55 (br s, 3H),
2.40-2.60 (m, 1H), 2.75-3.55 (m, 5H), 3.55-3.82 (m, 1H), 3.90-4.4
(m, 2H), 4.83 (m, 1H), 4.93-5.35 (m, 1H), 7.18-7.49 (m, 9H),
7.49-7.68 (m, 5H). M.sup.+(APCI.sup.+); 471. M.sup.-(APCI.sup.-);
469.
Example 19
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl-
]-4-(methylhydrazono)-2-pyrrolidinecarboxamide
[0429] Following the general method as outlined in Example 17,
starting from
(2S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenyleth-
yl]-4-oxo-2-pyrrolidinecarboxamide and N-methylhydrazine, the
resultant crude reaction mixture was purified by column
chromatography using DCM/MeOH (30:1) to collect the desired
product, e.g.
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethy-
l]-4-(methylhydrazono)-2-pyrrolidinecarboxamide as a mixture of two
isomers as a colorless solid in 57% yield (95.2% purity by
HPLC).
[0430] .sup.1H NMR (300 MHz, CDCl.sub.3); 2.45-2.70 (m, 1H), 2.85
(br s, 3H, NNHCH.sub.3), 2.85-3.5 (m, 2H), 3.51-4.4 (m, 4H), 4.84
(br s, 1H, NNHMe), 4.95-5.35 (m, 1H), 7.18-7.67 (m, 14H).
M.sup.+(APCI.sup.+); 457. M.sup.-(APCI.sup.-); 455.
Example 20
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-hydrazono-N-[(2RS)-2-hydroxy-2-
-phenylethyl]-2-pyrrolidinecarboxamide
[0431] Following the general method as outlined in Example 17,
starting from
(2S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenyleth-
yl]-4-oxo-2-pyrrolidinecarboxamide and hydrazine hydrate (4% in
EtOH), the resultant crude reaction mixture was purified by column
chromatography using DCM/MeOH (30:1) to collect the desired
product, e.g.
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-hydrazono-N-[(2RS)-2-hydroxy--
2-phenylethyl]-2-pyrrolidinecarboxamide as a mixture of two isomers
as a colorless solid in 63% yield (95.3% purity by HPLC).
[0432] .sup.1H NMR (300 MHz, DMSO-d.sub.6, 80.degree. C.); 2.55
(dd, J=9.8; 17.6 Hz, 1H), 2.73 (dd, J=9.8; 18.2 Hz, 1H), 3.28 (m,
2H), 4.12 (m, 2H), 4.61 (m, 1H), 4.85 (m, 1H), 5.15 (m, 1H), 5.70
(br s, 2H, NH.sub.2N.dbd.c), 7.17-7.43 (m, 6H), 7.44-7.60 (m, 4H),
7.66-7.77 (m, 5H). M.sup.+(APCI.sup.+); 443. M.sup.-(APCI.sup.-);
441.
Example 21
(2S,4EZ)-4-(acetylhydrazono)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-h-
ydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide
[0433] A hydrazono pyrrolidine derivative obtained by the general
method outlined in Example 17, e.g.
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-hydrazono-N-[(2RS)-2-hydroxy--
2-phenylethyl]-2-pyrrolidinecarboxamide (51 mg, 0.11 mmol) was
dissolved in pyridine (1 mL). Acetic anhydride (3 eq, 32 .mu.l,
0.35 mmol) was added, and the mixture was stirred overnight. The
solvent was evaporated and the resultant crude reaction mixture was
purified by column chromatography using DCM/MeOH (20:1) to collect
the desired product, e.g.
(2S,4EZ)-4-(acetylhydrazono)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2--
hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide as a mixture of two
isomers as a colorless solid in 73% yield (98.4% purity by
HPLC).
[0434] .sup.1H NMR (300 MHz, DMSO-d.sub.6, 80.degree. C.); 1.99 (br
s, 3H, CH.sub.3CON), 2.7-3.4 (m, 5H), 4.26 (m, 2H), 4.63 (m, 1H),
4.89 (m, 1H), 5.15 (m, 1H), 7.18-7.44 (m, 6H), 7.45-7.62 (m, 4H),
7.66-7.85 (m, 5H), 9.97 (br s, 1H, MeCONHN, major isomer), 10.04
(br s, 1H, MeCONHN, minor isomer). M.sup.+(ESI.sup.+); 485.
M.sup.-(ESI.sup.-); 483.
Example 22
General Protocol for the Solid-Phase Synthesis of Pyrrolidine
Derivatives of General Formula I
a) Loading Step
[0435] Kaiser oxime resin (16.5 g, loading 1.57 mmol/g) was added
to a solution of the relevant pyrrolidine carboxylic acid building
block (51.8 mmol) and diisopropylcarbodiimide (8.1 ml, 51.8 mmol)
in dry dichloromethane (150 ml). The resulting suspension was
shaken overnight before filtering at the pump and washing
sequentially with DMF, DCM and finally diethyl ether before drying
at room temperature in vacuo.
b) N-Deprotection Step
[0436] The resin obtained in the loading step was shaken with a 20%
solution of trifluoroacetic acid in dichloromethane (200 ml) for 30
minutes prior to filtering at the pump and washing sequentially
with aliquots of DMF, DCM and finally diethyl ether before drying
at room temperature in vacuo.
c) N-Capping Step
[0437] The resin from the previous step was transferred into a
96-well filter-plate (approx. 50 mg of dry resin/well) and each
well treated with an N-reactive derivatising agent, e.g. with
either of the following solutions:
[0438] a) an acid chloride (0.165 mmol) and diisopropylethylamine
(0.165 mmol) in dry dichloromethane (1 ml), overnight
[0439] b) an acid (0.165 mmol) and DIC (0.165 mmol) in, depending
on the solubility of the carboxylic acid, dry dichloromethane or
NMP (1 ml) overnight.
[0440] c) an isocyanate (0.165 mmol) in dry THF (1 ml);
overnight
[0441] d) a sulfonyl chloride (0.165 mmol) and
diisopropylethylamine (0.165 mmol) in NMP (1 ml), overnight.
[0442] e) a benzyl(alkyl)bromide (0.165 mmol) and
diisopropylethylamine (0.165 mmol) in NMP (1 ml), overnight.
[0443] f) a vinyl ketone (0.165 mmol) in THF, overnight
[0444] g) diketene (0.165 mmol) in THF, overnight
[0445] The plate was then sealed and shaken overnight at ambient
temperature. The resins were then filtered, washing the resin
sequentially with aliquots of DMF, DCM and finally diethyl ether
before drying at room temperature in vacuo.
d) Cleavage Step
[0446] A solution of amine (0.05 mmol) in 2% AcOH in
dichloromethane (1 ml) was added to each well containing the resin,
from the previous step. The plate was then sealed and shaken for
two days at ambient temperature. The wells were then filtered into
a collection plate and the solvent removed in a vacuum centrifuge
to yield 2-3 mg of the corresponding products, generally obtained
as oils. The products were characterised by LC (205 nm) and mass
spectrometry (ES+). All of the following examples were identified
based on the observation of the correct molecular ion in the mass
spectrum, and were shown to be at least 40% pure (usually 60-95%
pure) by LC.
Example 23
(2S,4EZ)-N.sup.2-(2-hydroxyethyl)-4-(methoxyimino)-N.sup.1-pentyl-1,2-pyrr-
olidinedicarboxamide
[0447] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 1-isocyanatopentane, and 2-aminoethanol the title
compound was obtained in 100% purity by LC/MS. MS(ESI+):
m/z=315.2.
Example 24
(2S,4EZ)-4-benzylidene-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino-
)-ethyl]-2-pyrrolidinecarboxamide
[0448] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxyl-
ic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in
90% purity by LC/MS. MS(ESI+): m/z=482.4.
Example 25
(2S,4EZ)-4-[(allyloxy)imino]-1-(4-cyanobenzoyl)-N-[2-(1H-pyrrol-1-yl)pheny-
l]-2-pyrrolidinecarboxamide
[0449] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 4-cyanobenzoyl chloride, and
2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in
51% purity by LC/MS. MS(ESI+): m/z=454.4.
Example 26
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(2-furylmethyl)-1-[(2-oxo-6--
pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0450] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl
chloride, and 2-furylmethylamine the title compound was obtained in
92% purity by LC/MS. MS(ESI.sup.+): m/z=574.4.
Example 27
(2S,4EZ)-4-(methoxyimino)-N.sup.1-(3-methoxyphenyl)-N.sup.2-(2-thienylmeth-
yl)-1,2-pyrrolidinedicarboxamide
[0451] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic-acid, 1-isocyanato-3-methoxy-benzene, and
2-thienylmethylamine the title compound was obtained in 79% purity
by LC/MS. MS(ESI+): m/z=403.2.
Example 28
(2S,4EZ)-2-{[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]carbonyl}-4-(met-
hoxyimino)-N-pentyl-1-pyrrolidinecarboxamide
[0452] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 1-isocyanatopentane, and
1-(1,3-benzodioxol-5-ylmethyl)piperazine the title compound was
obtained in 72% purity by LC/MS. MS(ESI+): m/z=474.4.
Example 29
(2S,4EZ)-4-[(benzyloxy)imino]-1-(4-cyanobenzoyl)-N-(2-furylmethyl)-2-pyrro-
lidinecarboxamide
[0453] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 4-cyanobenzoyl chloride, and 2-furylmethylamine the
title compound was obtained in 49% purity by LC/MS. MS(ESI+):
m/z=443.4.
Example 30
(2S,4EZ)-4-[(benzyloxy)imino]-N-[.sup.2-(diethylamino)ethyl]-1-(4-phenoxyb-
enzoyl)-2-pyrrolidinecarboxamide
[0454] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 4-phenoxybenzoyl chloride, and
N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in
86% purity by LC/MS. MS(ESI+): m/z=529.6.
Example 31
4-[((2S,4EZ)-4-[(benzyloxy)imino]-2-{[4-(3,4-dichlorophenyl)-1-piperazinyl-
]-carbonyl}pyrrolidinyl)carbonyl]benzonitrile
[0455] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 4-cyanobenzoyl chloride, and
1-(3,4-dichlorophenyl)piperazine the title compound was obtained in
43% purity by LC/MS. MS(ESI+): m/z=576.6.
Example 32
(2S,4EZ)-4-(methoxyimino)-N.sup.1-pentyl-N.sup.2-[2-(1H-pyrrol-1-yl)phenyl-
]-1,2-pyrrolidinedicarboxamide
[0456] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 1-isocyanatopentane, and 2-(1H-pyrrol-1-yl)phenylamine
the title compound was obtained in 74% purity by LC/MS. MS(ESI+):
m/z=412.2.
Example 33
(2S,4EZ)-1-acryloyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(2-furylmethyl)-2-
-pyrrolidinecarboxamide
[0457] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, acryloyl chloride, and
2-furylmethylamine the title compound was obtained in 74% purity by
LC/MS. MS(ESI+): m/z=436.8.
Example 34
(2S,4EZ)-4-(tert-butoxyimino)-N.sup.2-cyclopropyl-N.sup.1-(3,5-dichlorophe-
nyl)-1,2-pyrrolidinedicarboxamide
[0458] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinec-
arboxylic acid, 1,3-dichloro-5-iso-cyanatobenzene, and
cyclopropylamine the title compound was obtained in 48% purity by
LC/MS. MS(ESI+): m/z=427.6.
Example 35
(2S,4EZ)-4-[(allyloxy)imino]-N-[2-(diethylamino)ethyl]-1-[(2-oxo-6-pentyl--
2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0459] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in
93% purity by LC/MS. MS(ESI+): m/z=475.4.
Example 36
(2S,4EZ)-N.sup.2-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-N.sup.1-(3-
-methylphenyl)-1,2-pyrrolidinedicarboxamide
[0460] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 1-isocyanato-3-methylbenzene, and
(1RS)-2-amino-1-phenylethanol the title compound was obtained in
100% purity by LC/MS. MS(ESI+): m/z=411.2.
Example 37
(2S,4EZ)-1-[(benzoylamino)carbonyl]-N-benzyl-4-[(benzyloxy)imino]-N-methyl-
-2-pyrrolidinecarboxamide
[0461] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, benzoyl isocyanate, and N-benzyl-N-methylamine the
title compound was obtained in 40% purity by LC/MS. MS(ESI+):
m/z=485.4.
Example 38
(2S,4EZ)-1-(4-cyanobenzoyl)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)--
2-pyrrolidinecarboxamide
[0462] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-cyanobenzoyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 72%
purity by LC/MS. MS(ESI+): m/z=480.4.
Example 39
(2S,4EZ)-4-(methoxyimino)-N.sup.1-(3-methylphenyl)-N.sup.2-(2-thienylmethy-
l)-1,2-pyrrolidinedicarboxamide
[0463] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 1-isocyanato-3-methylbenzene, and 2-thienylmethylamine
the title compound was obtained in 98% purity by LC/MS. MS(ESI+):
m/z=387.2.
Example 40
(2S,4EZ)-4-(tert-butoxyimino)-N-(2-methoxyethyl)-1-[(2-oxo-6-pentyl-2H-pyr-
an-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0464] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinec-
arboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
2-methoxyethylamine the title compound was obtained in 75% purity
by LC/MS. MS(ESI+): m/z=450.2.
Example 41
(3EZ,5S)-5-{[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]carbonyl}-1-benz-
oyl-3-pyrrolidinone O-(3,4-dichlorobenzyl)oxime
[0465] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, benzoyl chloride, and
1-(1,3-benzodioxol-5-ylmethyl)piperazine the title compound was
obtained in 71% purity by LC/MS. MS(ESI+): m/z=609.8.
Example 42
tert-butyl
3-[({(2S,4EZ)-4-(ethoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)-
carbonyl]pyrrolidinyl}carbonyl)amino]-1-azetidinecarboxylate
[0466] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
tert-butyl 3-amino-1-azetidinecarboxylate the title compound was
obtained in 100% purity by LC/MS. MS(ESI+): m/z=519.6.
Example 43
(2S,4EZ)-4-{[(4-methoxybenzyl)oxy]imino}-N-(3-methylphenyl)-2-(4-morpholin-
ylcarbonyl)-1-pyrrolidinecarboxamide
[0467] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, 1-isocyanato-3-methylbenzene, and
morpholine the title compound was obtained in 41% purity by LC/MS.
MS(ESI+): m/z=467.4.
Example 44
(2S,4EZ)-N.sup.2-cyclopropyl-4-{[(4-methoxybenzyl)oxy]imino}-N.sup.1-penty-
l-1,2-pyrrolidinedicarboxamide
[0468] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, 1-isocyanatopentane, and
cyclopropylamine the title compound was obtained in 75% purity by
LC/MS. MS(ESI+): m/z=417.2.
Example 45
(3EZ,5S)-5-{[4-(3,4-dichlorophenyl)-1-piperazinyl]carbonyl}-1-[(2-oxo-6-pe-
ntyl-2H-pyran-3-yl)carbonyl]-3-pyrrolidinone O-benzyloxime
[0469] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
1-(3,4-dichlorophenyl)piperazine the title compound was obtained in
47% purity by LC/MS. MS(ESI+): m/z=639.8.
Example 46
(2S,4EZ)-4-(tert-butoxyimino)-N-[2-(1H-pyrrol-1-yl)phenyl]-2-pyrrolidineca-
rboxamide
[0470] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinec-
arboxylic acid, and 2-(1H-pyrrol-1-yl)phenylamine the title
compound was obtained in 83% purity by LC/MS. MS(ESI+):
m/z=341.2.
Example 47
1-({(2S,4EZ)-4-(chloromethylene)-1-[(4-chlorophenoxy)acetyl]pyrrolidinyl}--
carbonyl)-4-(3,4-dichlorophenyl)piperazine
[0471] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, (4-chlorophenoxy)acetyl chloride, and
1-(3,4-dichlorophenyl)piperazine the title compound was obtained in
64% purity by LC/MS. MS(ESI+): m/z=543.6.
Example 48
(2S,4EZ)-4-[(benzyloxy)imino]-N-(4,6-dimethoxy-2-pyrimidinyl)-1-[(2-oxo-6--
pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0472] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
4,6-dimethoxy-2-pyrimidinamine the title compound was obtained in
62% purity by LC/MS. MS(ESI+): m/z=564.6.
Example 49
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-[4-(dimethylamino)butanoyl]--
N-(1-naphthylmethyl-2-pyrrolidinecarboxamide
[0473] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, 4-(dimethylamino)butanoyl chloride,
and 1-naphthylmethylamine the title compound was obtained in 62%
purity by LC/MS. MS(ESI+): m/z=555.6.
Example 50
(2S)--N.sup.2-(2,1,3-benzothiadiazol-4-yl)-N.sup.1-(3,5-dichlorophenyl)-4--
oxo-1,2-pyrrolidinedicarboxamide
[0474] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxy-carbonyl)-4-oxoproline,
1,3-dichloro-5-isocyanatobenzene, and 2,1,3-benzothiadiazol-4-amine
the title compound was obtained in 47% purity by LC/MS. MS(ESI+):
m/z=450.6.
Example 51
(2S,4EZ)-N-benzyl-4-(chloromethylene)-N-methyl-1-(4-phenoxybenzoyl)-2-pyrr-
olidinecarboxamide
[0475] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, 4-phenoxybenzoyl chloride, and
N-benzyl-N-methylamine the title compound was obtained in 61%
purity by LC/MS. MS(ESI+): m/z=461.4.
Example 52
(2S,4EZ)-N.sup.2-(9-ethyl-9H-carbazol-3-yl)-4-{[(4-methoxybenzyl)oxy]imino-
}-N.sup.1-(3-methylphenyl)-1,2-pyrrolidinedicarboxamide
[0476] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, 1-isocyanato-3-methylbenzene, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 72%
purity by LC/MS. MS(ESI+): m/z=590.8.
Example 53
(2S)--N-(tert-butyl)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl-
]-2-pyrrolidinecarboxamide
[0477] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxy-carbonyl)-4-methyleneproline,
2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and tert-butylamine
the title compound was obtained in 100% purity by LC/MS. MS(ESI+):
m/z=375.4.
Example 54
(2S,4EZ)-4-benzylidene-1-[4-(dimethylamino)butanoyl]-N-(6-quinolinyl)-2-py-
rrolidinecarboxamide
[0478] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxyl-
ic acid, 4-(dimethylamino)butanoyl chloride, and 6-quinolinamine
the title compound was obtained in 71% purity by LC/MS. MS(ESI+):
m/z=443.6.
Example 55
(2S)-1-[4-(dimethylamino)butanoyl]-N-(9-ethyl-9H-carbazol-3-yl)-4-methylen-
e-2-pyrrolidinecarboxamide
[0479] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline,
4-(dimethylamino)butanoyl chloride, and 9-ethyl-9H-carbazol-3-amine
the title compound was obtained in 51% purity by LC/MS. MS(ESI+):
m/z=433.6.
Example 56
(2S,4EZ)-N-(1,3-benzodioxol-5-ylmethyl)-4-[(benzyloxy)imino]-1-(4-cyanoben-
zoyl)-2-pyrrolidinecarboxamide
[0480] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 4-cyanobenzoyl chloride, and
1,3-benzodioxol-5-ylmethylamine the title compound was obtained in
51% purity by LC/MS. MS(ESI+): m/z=497.6.
Example 57
(2S)-1-({1-[4-(dimethylamino)butanoyl]-4-methylene-2-pyrrolidinyl}carbonyl-
)-3-azetidinol
[0481] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxy-carbonyl)-4-methyleneproline,
4-(dimethylamino)butanoyl chloride, and 3-azetidinol the title
compound was obtained in 100% purity by LC/MS. MS(ESI+):
m/z=296.4.
Example 58
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imin-
o}-N-[2-(1H-pyrrol-1-yl)phenyl]-2-pyrrolidinecarboxamide
[0482] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, [1,1'-biphenyl]-4-carbonyl chloride,
and 2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained
in 54% purity by LC/MS. MS(ESI+): m/z=623.6.
Example 59
(2S,4EZ)-4-benzylidene-1-[(4-chlorophenoxy)acetyl]-N-(3,47-dimethoxy-benzy-
l)-2-pyrrolidinecarboxamide
[0483] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxyl-
ic acid, (4-chlorophenoxy)acetyl chloride, and
3,4-dimethoxybenzylamine the title compound was obtained in 49%
purity by LC/MS. MS(ESI+): m/z=521.6.
Example 60
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(diphenylacetyl)-N-(2-thieny-
lmethyl)-2-pyrrolidinecarboxamide
[0484] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and
2-thienylmethylamine the title compound was obtained in 51% purity
by LC/MS. MS(ESI+): m/z=592.6.
Example 61
(2S,4EZ)-N-(3,4-dimethoxybenzyl)-1-(diphenylacetyl)-4-(methoxyimino)-2-pyr-
rolidinecarboxamide
[0485] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, diphenylacetyl chloride, and 3,4-dimethoxybenzylamine
the title compound was obtained in 74% purity by LC/MS. MS(ESI+):
m/z=502.6.
Example 62
(2S,4EZ)-N.sup.1-(3,5-dichlorophenyl)-4-(ethoxyimino)-N.sup.2-[2-(1H-pyrro-
l-1-yl)phenyl]-1,2-pyrrolidinedicarboxamide
[0486] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, 1,3-dichloro-5-isocyanato-benzene, and
2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in
54% purity by LC/MS. MS(ESI+): m/z=500.6.
Example 63
(2S,4EZ)-N.sup.2-(1,3-benzodioxol-5-ylmethyl)-4-{[(4-methoxybenzyl)-oxy]im-
ino}-N.sup.1-pentyl-1,2-pyrrolidinedicarboxamide
[0487] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, 1-isocyanatopentane, and
1,3-benzodioxol-5-ylmethylamine the title compound was obtained in
63% purity by LC/MS. MS(ESI+): m/z=511.4.
Example 64
(2S,4EZ)-N-benzyl-4-[(benzyloxy)imino]-1-(diphenylacetyl)-N-methyl-2-pyrro-
lidinecarboxamide
[0488] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, diphenylacetyl chloride, and N-benzyl-N-methylamine
the title compound was obtained in 42% purity by LC/MS. MS(ESI+):
m/z=532.4.
Example 65
(2S,4EZ)-N-(2,13-benzothiadiazol-4-yl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4--
(methoxyimino)-2-pyrrolidinecarboxamide
[0489] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
2,1,3-benzothiadiazol-4-amine the title compound was obtained in
66% purity by LC/MS. MS(ESI+): m/z=472.4.
Example 66
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(6-quinolinyl-
)-2-pyrrolidinecarboxamide
[0490] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
6-quinolinamine the title compound was obtained in 79% purity by
LC/MS. MS(ESI+): m/z=465.4.
Example 67
(2S,4EZ)-1-acetoacetyl-N-benzyl-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0491] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2,4-oxetanedione, and benzylamine the title compound
was obtained in 45% purity by LC/MS. MS(ESI+): m/z=332.2.
Example 68
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-furyl-m-
ethyl)-2-pyrrolidinecarboxamide
[0492] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
2-furylmethylamine the title compound was obtained in 70% purity by
LC/MS. MS(ESI+): m/z=421.4.
Example 69
(2S,4EZ)-1-[(4-chlorophenoxy)acetyl]-4-{[(3,4-dichlorobenzyl)oxy]imino}-N--
[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide
[0493] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, (4-chlorophenoxy)acetyl chloride, and
(1RS)-2-amino-1-phenylethanol the title compound was obtained in
62% purity by LC/MS. MS(ESI+): m/z=590.8.
Example 70
(2S,4EZ)-N-allyl-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrro-
lidinecarboxamide
[0494] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and allylamine the
title compound was obtained in 87% purity by LC/MS. MS(ESI+):
m/z=378.2.
Example 71
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(2-thienyl-me-
thyl)-2-pyrrolidinecarboxamide
[0495] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
2-thienylmethylamine the title compound was obtained in 78% purity
by LC/MS. MS(ESI+): m/z=434.4.
Example 72
(2S,4EZ)-4-(cyanomethylene)-N-(2-furylmethyl)-1-[(2-oxo-6-pentyl-2H-pyran--
3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0496] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecar-
boxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
2-furylmethylamine the title compound was obtained in 34% purity by
LC/MS. MS(ESI+): m/z=424.4.
Example 73
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-(methoxy-imi-
no)-2-pyrrolidinecarboxamide
[0497] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
2-furylmethylamine the title compound was obtained in 75% purity by
LC/MS. MS(ESI+): m/z=418.4.
Example 74
(2S,4EZ)-1-acetyl-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrro-
lidinecarboxamide
[0498] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, acetyl chloride, and cyclopropylamine
the title compound was obtained in 52% purity by LC/MS. MS(ESI+):
m/z=384.4.
Example 75
(2S,4EZ)-N-(2-furylmethyl)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3--
yl)carbonyl]-2-pyrrolidinecarboxamide
[0499] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
2-furylmethylamine the title compound was obtained in 62% purity by
LC/MS. MS(ESI+): m/z=430.4.
Example 76
(2S,4EZ)-N-benzyl-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-meth-
yl-2-pyrrolidinecarboxamide
[0500] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
N-benzyl-N-methylamine the title compound was obtained in 67%
purity by LC/MS. MS(ESI+): m/z=442.4.
Example 77
(2S,4EZ)-1-(diphenylacetyl)-4-(ethoxyimino)-N-(2-thienylmethyl)-2-pyrrolid-
inecarboxamide
[0501] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, diphenylacetyl chloride, and 2-thienylmethylamine the
title compound was obtained in 74% purity by LC/MS. MS(ESI+):
m/z=462.4.
Example 78
(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-4-(cyanomethylene)-1-(diphenylacet-
yl)-2-pyrrolidinecarboxamide
[0502] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecar-
boxylic acid, diphenylacetyl chloride, and
2,1,3-benzothiadiazol-4-amine the title compound was obtained in
42% purity by LC/MS. MS(ESI+): m/z=480.4.
Example 79
(2S)-1-(diphenylacetyl)-N-(1-naphthylmethyl)-4-oxo-2-pyrrolidinecarboxamid-
e
[0503] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-oxoproline, diphenylacetyl
chloride, and 1-naphthylmethylamine the title compound was obtained
in 60% purity by LC/MS. MS(ESI+): m/z=463.4.
Example 80
(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-(diphenylacetyl)-3-pyrrolidinone
O-methyloxime
[0504] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, diphenylacetyl chloride, and 1,2-benzenediamine the
title compound was obtained in 72% purity by LC/MS. MS(ESI+):
m/z=425.4.
Example 81
(2S)-2-[1-([1,1'-biphenyl]-4-ylcarbonyl)-4-methylene-2-pyrrolidinyl]-1H-be-
nzimidazole
[0505] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxy-carbonyl)-4-methyleneproline,
[1,1'-biphenyl]-4-carbonyl chloride, and 1,2-benzenediamine the
title compound was obtained in 73% purity by LC/MS. MS(ESI+):
m/z=380.4.
Example 82
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-methoxy-
ethyl)-2-pyrrolidinecarboxamide
[0506] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
2-methoxyethylamine the title compound was obtained in 55% purity
by LC/MS. MS(ESI+): m/z=399.6.
Example 83
(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-(diphenylacetyl)-3-pyrrolidinone
O-allyloxime
[0507] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, diphenylacetyl chloride, and 1,2-benzenediamine the
title compound was obtained in 63% purity by LC/MS. MS(ESI+):
m/z=451.4.
Example 84
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino)ethyl]-4-(met-
hoxyimino)-2-pyrrolidinecarboxamide
[0508] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in
90% purity by LC/MS. MS(ESI+): m/z=437.4.
Example 85
(2S,4EZ)-1-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-N-(2-thienylme-
thyl)-2-pyrrolidinecarboxamide
[0509] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, diphenyl-acetyl chloride, and
2-thienylmethylamine the title compound was obtained in 63% purity
by LC/MS. MS(ESI+): m/z=554.4.
Example 86
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(3,4-dimethoxybenzyl)-4-(metho-
xyimino)-2-pyrrolidinecarboxamide
[0510] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
3,4-dimethoxybenzylamine the title compound was obtained in 58%
purity by LC/MS. MS(ESI+): m/z=488.4.
Example 87
(2S,4EZ)-1-acetoacetyl-4-(methoxyimino)-N-(1-naphthylmethyl)-2-pyrrolidine-
carboxamide
[0511] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2,4-oxetanedione, and 1-naphthylmethylamine the title
compound was obtained in 40% purity by LC/MS. MS(ESI+):
m/z=382.2.
Example 88
(2S,4EZ)-N-allyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(diphenylacetyl)-2-p-
yrrolidinecarboxamide
[0512] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, diphenyl-acetyl chloride, and
allylamine the title compound was obtained in 54% purity by LC/MS.
MS(ESI+): m/z=536.6.
Example 89
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N.sup.1-pentyl-N.sup.2-(6-quin-
olinyl)-1,2-pyrrolidinedicarboxamide
[0513] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, 1-isocyanatopentane, and
6-quinolinamine the title compound was obtained in 54% purity by
LC/MS. MS(ESI+): m/z=542.6.
Example 90
(2S,4EZ)-4-(chloromethylene)-1-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phene-
thyl]-2-pyrrolidinecarboxamide
[0514] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, diphenylacetyl chloride, and
(1RS)-2-amino-1-phenylethanol the title compound was obtained in
87% purity by LC/MS. MS(ESI+): m/z=475.4.
Example 91
(2S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-me-
thylene-2-pyrrolidinecarboxamide
[0515] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline,
[1,1'-biphenyl]-4-carbonyl chloride, and 2-amino-1-phenyl-ethanol
the title compound was obtained in 74% purity by LC/MS. MS(ESI+):
m/z=427.4.
Example 92
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(6-quinoli-
nyl)-2-pyrrolidinecarboxamide
[0516] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
6-quinolinamine the title compound was obtained in 73% purity by
LC/MS. MS(ESI+): m/z=468.4.
Example 93
(2S,4EZ)-4-benzylidene-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-2-pyrr-
olidinecarboxamide
[0517] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxyl-
ic acid, diphenylacetyl chloride, and
N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in
71% purity by LC/MS. MS(ESI+): m/z=496.4.
Example 94
(2S,4EZ)-1-acetoacetyl-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinec-
arboxamide
[0518] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2,4-oxetanedione, and 2-thienylmethylamine the title
compound was obtained in 42% purity by LC/MS. MS(ESI+):
m/z=338.2.
Example 95
(2S,4EZ)-1-acetyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(2-hydroxy-2-phenyl-
ethyl)-2-pyrrolidinecarboxamide
[0519] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, acetyl chloride, and
(1RS)-2-amino-1-phenylethanol the title compound was obtained in
48% purity by LC/MS. MS(ESI+): m/z=464.6.
Example 96
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N.sup.1-(3,5-dichlorophenyl)-N-
.sup.2-(6-quinolinyl)-1,2-pyrrolidinedicarboxamide
[0520] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, 1,3-dichloro-5-isocyanatobenzene, and
6-quinolinamine the title compound was obtained in 66% purity by
LC/MS. MS(ESI+): m/z=617.2.
Example 97
(2S,4EZ)-4-(methoxyimino)-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyrroli-
dinecarboxamide
[0521] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, phenoxyacetyl chloride, and 1-naphthylmethylamine the
title compound was obtained in 99% purity by LC/MS. MS(ESI+):
m/z=432.2.
Example 98
(2S,4EZ)-4-(chloromethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-
-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0522] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
3,4-dimethoxybenzylamine the title compound was obtained in 51%
purity by LC/MS. MS(ESI+): m/z=503.4.
Example 99
(2S,4EZ)-1-(diphenylacetyl)-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrroli-
dinecarboxamide
[0523] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, diphenylacetyl chloride, and 2-thienylmethylamine the
title compound was obtained in 88% purity by LC/MS. MS(ESI+):
m/z=448.4.
Example 100
(2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-(methoxyimino)-2-pyrrolidinecarboxa-
mide
[0524] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, diphenylacetyl chloride, and benzylamine the title
compound was obtained in 82% purity by LC/MS. MS(ESI+):
m/z=442.4.
Example 101
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]-imi-
no}-N-[2-(diethylamino)ethyl]-2-pyrrolidinecarboxamide
[0525] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, [1,1'-biphenyl]-4-carbonyl chloride,
and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained
in 74% purity by LC/MS. MS(ESI+): m/z=581.6.
Example 102
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-[4-(dimethylamino)butanoyl]--
N-(6-quinolinyl)-2-pyrrolidinecarboxamide
[0526] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, 4-(dimethylamino)butanoyl chloride,
and 6-quinolinamine the title compound was obtained in 95% purity
by LC/MS. MS(ESI+): m/z=542.6.
Example 103
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(5-ethyl-1,3,4-thiadiazol-2-yl-
)-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0527] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
5-ethyl-1,3,4-thiadiazol-2-amine the title compound was obtained in
89% purity by LC/MS. MS(ESI+): m/z=450.2.
Example 104
(2S,4EZ)-N-benzyl-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrr-
olidinecarboxamide
[0528] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and benzylamine
the title compound was obtained in 72% purity by LC/MS. MS(ESI+):
m/z=428.2.
Example 105
(2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-(ethoxyimino)-2-pyrrolidinecarboxam-
ide
[0529] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, diphenylacetyl chloride, and benzylamine the title
compound was obtained in 53% purity by LC/MS. MS(ESI+):
m/z=456.4.
Example 106
(2S
4EZ)-N.sup.2-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N.sup.1-(3-
-methoxyphenyl)-1,2-pyrrolidinedicarboxamide
[0530] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, 1-isocyanato-3-methoxybenzene, and
cyclopropylamine the title compound was obtained in 45% purity by
LC/MS. MS(ESI+): m/z=491.6.
Example 107
(2S,4EZ)-1-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-{[(4-methoxy-
benzyl)oxy]imino}-2-pyrrolidinecarboxamide
[0531] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, diphenyl-acetyl chloride, and
(1RS)-2-amino-1-phenylethanol the title compound was obtained in
66% purity by LC/MS. MS(ESI+): m/z=578.4.
Example 108
(2S)--N-(2-furylmethyl)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbo-
nyl]-2-pyrrolidinecarboxamide
[0532] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline,
2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
2-furyl-methylamine the title compound was obtained in 43% purity
by LC/MS. MS(ESI+): m/z=399.2.
Example 109
(2S,4EZ)-N-(2,13-benzothiadiazol-4-yl)-1-(diphenylacetyl)-4-(methoxy-imino-
)-2-pyrrolidinecarboxamide
[0533] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, diphenylacetyl chloride, and
2,1,3-benzothiadiazol-4-amine the title compound was obtained in
69% purity by LC/MS. MS(ESI+): m/z=486.4.
Example 110
(2S)--N1-(3,5-dichlorophenyl)-N2-(3,4-dimethoxybenzyl)-4-oxo-1,2-pyrrolidi-
nedicarboxamide
[0534] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxy-carbonyl)-4-oxoproline,
1,3-dichloro-5-isocyanatobenzene, and 3,4-dimethoxybenzylamine the
title compound was obtained in 48% purity by LC/MS. MS(ESI+):
m/z=466.6.
Example 111
(2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyr-
rolidinecarboxamide
[0535] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, diphenyl-acetyl chloride, and
benzylamine the title compound was obtained in 60% purity by LC/MS.
MS(ESI+): m/z=548.4.
Example 112
(2S,4EZ)-1-benzoyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quinolinyl)-2-p-
yrrolidinecarboxamide
[0536] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, benzoyl chloride, and 6-quinolinamine
the title compound was obtained in 67% purity by LC/MS. MS(ESI+):
m/z=533.6.
Example 113
(2S,4EZ)-1-acetoacetyl-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-2--
pyrrolidinecarboxamide
[0537] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, 2,4-oxetanedione, and
cyclopropylamine the title compound was obtained in 76% purity by
LC/MS. MS(ESI+): m/z=426.6.
Example 114
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N.sup.2-[(2RS)-2-hydroxy-2-phe-
nethyl]-N.sup.1-pentyl-1,2-pyrrolidinedicarboxamide
[0538] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, 1-isocyanatopentane, and
(1RS)-2-amino-1-phenylethanol the title compound was obtained in
47% purity by LC/MS. MS(ESI+): m/z=535.6.
Example 115
(2S,4EZ)-4-[(benzyloxy)imino]-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyr-
rolidinecarboxamide
[0539] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, phenoxyacetyl chloride, and 1-naphthylmethylamine
the title compound was obtained in 74% purity by LC/MS. MS(ESI+):
m/z=508.4.
Example 116
(2S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-methylene-N-(6-quinolinyl)-2-pyrro-
lidinecarboxamide
[0540] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxy-carbonyl)-4-methyleneproline,
[1,1'-biphenyl]-4-carbonyl chloride, and 6-quinolinamine the title
compound was obtained in 88% purity by LC/MS. MS(ESI+):
m/z=434.2.
Example 117
(2S,4EZ)-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(diphenyl-acet-
yl)-2-pyrrolidinecarboxamide
[0541] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, diphenyl-acetyl chloride, and
cyclopropylamine the title compound was obtained in 49% purity by
LC/MS. MS(ESI+): m/z=536.6.
Example 118
(2S,4EZ)-1-(4-cyanobenzoyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quinol-
inyl)-2-pyrrolidinecarboxamide
[0542] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, 4-cyanobenzoyl chloride, and
6-quinolinamine the title compound was obtained in 52% purity by
LC/MS. MS(ESI+): m/z=558.6.
Example 119
(2S)-4-oxo-1-(phenoxyacetyl)-N-[2-(1H-pyrrol-1-yl)phenyl]-2-1)pyrrolidinec-
arboxamide
[0543] Following, the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-oxoproline, phenoxyacetyl
chloride, and 2-(1H-pyrrol-1-yl)phenylamine the title compound was
obtained in 42% purity by LC/MS. MS(ESI+): m/z=404.2.
Example 120
(2S,4EZ)-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(methoxy-acety-
l)-2-pyrrolidinecarboxamide
[0544] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, methoxyacetyl chloride, and
cyclopropylamine the title compound was obtained in 54% purity by
LC/MS. MS(ESI+): m/z=414.6.
Example 121
(2S,4EZ)-N-(1,3-benzodioxol-5-ylmethyl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-
-(methoxyimino)-2-pyrrolidinecarboxamide
[0545] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
1,3-benzodioxol-5-ylmethylamine the title compound was obtained in
64% purity by LC/MS. MS(ESI+): m/z=472.4.
Example 122
(3EZ,5S)-5-[(4-acetyl-1-piperazinyl)carbonyl]-1-acryloyl-3-pyrrolidinone
O-(3,4-dichlorobenzyl)oxime
[0546] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, acryloyl chloride, and
1-acetylpiperazine the title compound was obtained in 79% purity by
LC/MS. MS(ESI+): m/z=467.6.
Example 123
(2S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-methylene-2-pyrr-
olidinecarboxamide
[0547] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline,
[1,1'-biphenyl]-4-carbonyl chloride, and 2-furylmethylamine the
title compound was obtained in 94% purity by, LC/MS. MS(ESI+):
m/z=387.2.
Example 124
(2S,4EZ)-4-(cyanomethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H--
pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0548] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecar-
boxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
3,4-dimethoxybenzylamine the title compound was obtained in 65%
purity by LC/MS. MS(ESI+): m/z=494.4.
Example 125
(2S,4EZ)-1-[(benzoylamino)carbonyl]-4-(cyanomethylene)-N-(9-ethyl-9H-carba-
zol-3-yl)-2-pyrrolidinecarboxamide
[0549] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecar-
boxylic acid, benzoyl isocyanate, and 9-ethyl-9H-carbazol-3-amine
the title compound was obtained in 74% purity by LC/MS. MS(ESI+):
m/z=492.4.
Example 126
(2S,4EZ)-1-benzoyl-N-[2-(diethylamino)ethyl]-4-(methoxyimino)-2-pyrrolidin-
ecarboxamide
[0550] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, benzoyl chloride, and N1,N1-diethyl-1,2-ethanediamine
the title compound was obtained in 80% purity by LC/MS. MS(ESI+):
m/z=361.2.
Example 127
(2S,4EZ)-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-4-(ethoxyimino)-2-py-
rrolidinecarboxamide
[0551] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, diphenylacetyl chloride, and
N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in
50% purity by LC/MS. MS(ESI+): m/z=465.4.
Example 128
(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-4-[(benzyloxy)imino]-1-(4-cyanoben-
zoyl)-2-pyrrolidinecarboxamide
[0552] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 4-cyanobenzoyl chloride, and
2,1,3-benzothiadiazol-4-amine the title compound was obtained in
55% purity by LC/MS. MS(ESI+): m/z=497.4.
Example 129
(2EZ)-[5-(1H-benzimidazol-2-yl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-3-pyrroli-
dinylidene]ethanenitrile
[0553] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecar-
boxylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
1,2-benzenediamine the title compound was obtained in 70% purity by
LC/MS. MS(ESI+): m/z=405.2.
Example 130
(2S,4EZ)-4-(chloromethylene)-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacetyl-
)-2-pyrrolidinecarboxamide
[0554] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, phenoxyacetyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 63%
purity by LC/MS. MS(ESI+): m/z=488.6.
Example 131
(2S)--N.sup.2-(9-ethyl-9H-carbazol-3-yl)-N.sup.1-(3-methoxyphenyl)-4-methy-
lene-1,2-pyrrolidinedicarboxamide
[0555] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline,
1-isocyanato-3-methoxybenzene, and 9-ethyl-9H-carbazol-3-amine the
title compound was obtained in 47% purity by LC/MS. MS(ESI+):
m/z=469.4.
Example 132
(2S,4EZ)-4-(cyanomethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarb-
oxamide
[0556] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecar-
boxylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound
was obtained in 36% purity by LC/MS. MS(ESI+): m/z=345.2.
Example 133
(2S,4EZ)-1-(4-cyanobenzoyl)-N-[2-(diethylamino)ethyl]-4-(methoxyimino)-2-p-
yrrolidinecarboxamide
[0557] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-cyanobenzoyl chloride, and
N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in
58% purity by LC/MS. MS(ESI+): m/z=386.2.
Example 134
4-{[(2S,4EZ)-2-(1H-benzimidazol-2-yl)-4-(cyanomethylene)pyrrolidinyl]-carb-
onyl}benzonitrile
[0558] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecar-
boxylic acid, 4-cyanobenzoyl chloride, and 1,2-benzenediamine the
title compound was obtained in 84% purity by LC/MS. MS(ESI+):
m/z=354.2.
Example 135
(2S,4EZ)-4-[(allyloxy)imino]-1-[4-(dimethylamino)butanoyl]-N-(9-ethyl-9H-c-
arbazol-3-yl)-2-pyrrolidinecarboxamide
[0559] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidineca-
rboxylic acid, 4-(dimethylamino)-butanoyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 40%
purity by LC/MS. MS(ESI+): m/z=490.4.
Example 136
(2S,4EZ)-4-benzylidene-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxami-
de
[0560] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxyl-
ic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was
obtained in 53% purity by LC/MS. MS(ESI+): m/z=396.2.
Example 137
(2S,4EZ)-4-benzylidene-1-[4-(dimethylamino)butanoyl]-N-(9-ethyl-9H-carbazo-
l-3-yl)-2-pyrrolidinecarboxamide
[0561] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxyl-
ic acid, 4-(dimethylamino)butanoyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 74%
purity by LC/MS. MS(ESI+): m/z=509.4.
Example 138
(2S,4EZ)-4-(chloromethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecar-
boxamide
[0562] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound
was obtained in 73% purity by LC/MS. MS(ESI+): m/z=354.4.
Example 139
(2S)--N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrrolidinecarboxamide
[0563] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 71%
purity by LC/MS. MS(ESI+): m/z=320.2.
Example 140
(2S,4EZ)-4-(cyanomethylene)-N-(9-ethyl-9H-carbazol-3-yl)-1-(4-phenoxybenzo-
yl)-2-pyrrolidinecarboxamide
[0564] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecar-
boxylic acid, 4-phenoxybenzoyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 37%
purity by LC/MS. MS(ESI+): m/z=541.4.
Example 141
N-{[(2S,4EZ)-2-(1H-benzimidazol-2-yl)-4-(chloromethylene)pyrrolidinyl]-car-
bonyl}benzamide
[0565] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, benzoyl isocyanate, and 1,2-benzenediamine the title
compound was obtained in 51% purity by LC/MS. MS(ESI+):
m/z=381.4.
Example 142
(2S)--N.sup.1-(3,5-dichlorophenyl)-N.sup.2-(9-ethyl-9H-carbazol-3-yl)-4-me-
thylene-1,2-pyrrolidinedicarboxamide
[0566] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline,
1,3-dichloro-5-isocyanatobenzene, and 9-ethyl-9H-carbazol-3-amine
the title compound was obtained in 40% purity by LC/MS. MS(ESI+):
m/z=507.6.
Example 143
(2S)-1-(diphenylacetyl)-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrroli-
dinecarboxamide
[0567] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline,
diphenylacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title
compound was obtained in 42% purity by LC/MS. MS(ESI+):
m/z=514.4.
Example 144
(2S,4EZ)-1-benzoyl-4-(chloromethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrr-
olidinecarboxamide
[0568] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, benzoyl chloride, and 9-ethyl-9H-carbazol-3-amine
the title compound was obtained in 48% purity by LC/MS. MS(ESI+):
m/z=458.4.
Example 145
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(cyanomethylene)-N-(9-ethyl-9H-
-carbazol-3-yl)-2-pyrrolidinecarboxamide
[0569] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecar-
boxylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 32%
purity by LC/MS. MS(ESI+): m/z=525.4.
Example 146
(2S,4EZ)-4-(cyanomethylene)-N-(9-ethyl-9H-carbazol-3-yl)-1-(3-oxobutyl)-2--
pyrrolidinecarboxamide
[0570] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecar-
boxylic acid, 3-buten-2-one, and 9-ethyl-9H-carbazol-3-amine the
title compound was obtained in 59% purity by LC/MS. MS(ESI+):
m/z=415.2.
Example 147
(2S)-1-[(4-chlorophenoxy)acetyl]-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene--
2-pyrrolidinecarboxamide
[0571] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline,
(4-chlorophenoxy)acetyl chloride, and 9-ethyl-9H-carbazol-3-amine
the title compound was obtained in 100% purity by LC/MS. MS(ESI+):
m/z=488.4.
Example 148
(2S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(9-ethyl-9H-carbazol-3-yl)-4-methy-
lene-2-pyrrolidinecarboxamide
[0572] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline,
[1,1'-biphenyl]-4-carbonyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 46%
purity by LC/MS. MS(ESI+): m/z=500.4.
Example 149
2-[(2S,4EZ)-4-(chloromethylene)pyrrolidinyl]-1H-benzimidazole
[0573] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, and 1,2-benzenediamine the title compound was
obtained in 43% purity by LC/MS. MS(ESI+): m/z=234.4.
Example 150
(2S,4EZ)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxa-
mide
[0574] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was
obtained in 91% purity by LC/MS. MS(ESI+): m/z=365.2.
Example 151
(2S)-1-benzoyl-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrrolidinecarbo-
xamide
[0575] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, benzoyl
chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was
obtained in 52% purity by LC/MS. MS(ESI+): m/z=424.2.
Example 152
(2S,4EZ)-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-4-{[(4-methoxybenzyl-
)oxy]imino}-2-pyrrolidinecarboxamide
[0576] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, diphenylacetyl chloride, and
N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in
56% purity by LC/MS. MS(ESI+): m/z=557.4.
Example 144153
(2S,4EZ)-1-benzoyl-N-(2-furylmethyl)-4-{[(4-methoxybenzyl)oxy]-imino}-2-py-
rrolidinecarboxamide
[0577] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, benzoyl chloride, and 2-furylmethylamine
the title compound was obtained in 40% purity by LC/MS. MS(ESI+):
m/z=448.2.
Example 154
(2S,4EZ)-4-(tert-butoxyimino)-N-[2-(diethylamino)ethyl]-1-(diphenyl-acetyl-
)-2-pyrrolidinecarboxamide
[0578] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinec-
arboxylic acid, diphenylacetyl chloride, and
N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in
80% purity by LC/MS. MS(ESI+): m/z=493.4.
Example 155
(2S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(3,4-dimethoxybenzyl)-4-methylene--
2-pyrrolidinecarboxamide
[0579] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline,
[1,1'-biphenyl]-4-carbonyl chloride, and 3,4-dimethoxybenzyl-amine
the title compound was obtained in 72% purity by LC/MS. MS(ESI+):
m/z=457.2.
Example 156
(2S,4EZ)-4-(cyanomethylene)-N.sup.1-(3,5-dichlorophenyl)-N.sup.2-(9-ethyl--
9H-carbazol-3-yl)-1,2-pyrrolidinedicarboxamide
[0580] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecar-
boxylic acid, 1,3-dichloro-5-isocyanatobenzene, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 60%
purity by LC/MS. MS(ESI+): m/z=532.8.
Example 157
(2S,4EZ)-4-[(allyloxy)imino]-N.sup.2-(9-ethyl-9H-carbazol-3-yl)-N.sup.1-ph-
enyl-1,2-pyrrolidinedicarboxamide
[0581] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, isocyanato-benzene, and 9-ethyl-9H-carbazol-3-amine
the title compound was obtained in 67% purity by LC/MS. MS(ESI+):
m/z=496.4.
Example 158
(2S)--N.sup.2-(9-ethyl-9H-carbazol-3-yl)-4-methylene-N.sup.1-phenyl-1,2-py-
rrolidinedicarboxamide
[0582] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline,
isocyanatobenzene, and 9-ethyl-9H-carbazol-3-amine the title
compound was obtained in 66% purity by LC/MS. MS(ESI+):
m/z=439.2.
Example 159
(2S,4EZ)-N.sup.2-(2,1,3-benzothiadiazol-4-yl)-N.sup.1-(3,5-dichlorophenyl)-
-4-(methoxyimino)-1,2-pyrrolidinedicarboxamide
[0583] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 1,3-dichloro-5-isocyanatobenzene, and
2,1,3-benzothiadiazol-4-amine the title compound was obtained in
55% purity by LC/MS. MS(ESI+): m/z=479.6.
Example 160
(2EZ)-[5-(1H-benzimidazol-2-yl)-1-(4-phenoxybenzoyl)-3-pyrrolidinylidene]e-
thanenitrile
[0584] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecar-
boxylic acid, 4-phenoxybenzoyl chloride, and 1,2-benzenediamine the
title compound was obtained in 90% purity by LC/MS. MS(ESI+):
m/z=421.2.
Example 161
(2S,4EZ)-4-(tert-butoxyimino)-1-(2-ethoxy-1-naphthoyl)-N-(9-ethyl-9H-carba-
zol-3-yl)-2-pyrrolidinecarboxamide
[0585] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinec-
arboxylic acid, 2-ethoxy-1-naphthoyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 47%
purity by LC/MS. MS(ESI+): m/z=591.4.
Example 162
(2S,4EZ)-1-benzoyl-N-[2-(diethylamino)ethyl]-4-(ethoxyimino)-2-pyrrolidine-
carboxamide
[0586] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, benzoyl chloride, and N1,N1-diethyl-1,2-ethanediamine
the title compound was obtained in 84% purity by LC/MS. MS(ESI+):
m/z=375.2.
Example 163
(2S,4EZ)-N.sup.2-(2,1,3-benzothiadiazol-4-yl)-4-[(benzyloxy)imino]-N.sup.1-
-phenyl-1,2-pyrrolidinedicarboxamide
[0587] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, isocyanatobenzene, and
2,1,3-benzothiadiazol-4-amine the title compound was obtained in
57% purity by LC/MS. MS(ESI+): m/z=487.4.
Example 164
(2S,4EZ)-1-(4-cyanobenzoyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(1-naphth-
ylmethyl)-2-pyrrolidinecarboxamide
[0588] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, 4-cyanobenzoyl chloride, and
1-naphthylmethylamine the title compound was obtained in 39% purity
by LC/MS. MS(ESI+): m/z=571.6.
Example 165
(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-benzoyl-4-{[(4-methoxybenzyl)-ox-
y]imino}-2-pyrrolidinecarboxamide
[0589] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, benzoyl chloride, and
2,1,3-benzothiadiazol-4-amine the title compound was obtained in
61% purity by LC/MS. MS(ESI+): m/z=502.4.
Example 166
(2S,4EZ)-4-[(allyloxy)imino]-N-(2,1,3-benzothiadiazol-4-yl)-1-(diphenylace-
tyl)-2-pyrrolidinecarboxamide
[0590] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, diphenylacetyl chloride, and
2,1,3-benzothiadiazol-4-amine the title compound was obtained in
46% purity by LC/MS. MS(ESI+): m/z=512.4.
Example 167
(2S,4EZ)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-[(2-oxo-6-pentyl-2-
H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0591] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 75%
purity by LC/MS. MS(ESI+): m/z=557.4.
Example 168
(2S,4EZ)-1-benzoyl-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolid-
inecarboxamide
[0592] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, benzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the
title compound was obtained in 74% purity by LC/MS. MS(ESI+):
m/z=469.4.
Example 169
(2S,4EZ)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-(methoxyacetyl)-2--
pyrrolidinecarboxamide
[0593] Following the general method as outlined in Example 22,
starting from
(2S,5,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarb-
oxylic acid, methoxyacetyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 88%
purity by LC/MS. MS(ESI+): m/z=437.2.
Example 170
(2S,4EZ)-4-[(benzyloxy)imino]-N.sup.2-(9-ethyl-9H-carbazol-3-yl)-N.sup.1-p-
entyl-1,2-pyrrolidinedicarboxamide
[0594] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 1-isocyanato-pentane, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 63%
purity by LC/MS. MS(ESI+): m/z=540.4.
Example 171
(3EZ,5S)-1-benzoyl-5-{[4-(3,4-dichlorophenyl)-1-piperazinyl]carbonyl}-3-py-
rrolidinone O-ethyloxime
[0595] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, benzoyl chloride, and 1-(3,4-dichlorophenyl)piperazine
the title compound was obtained in 51% purity by LC/MS. MS(ESI+):
m/z=489.6.
Example 172
(2S,4EZ)-4-[(allyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-[(2-oxo-6-pent-
yl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0596] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 48%
purity by LC/MS. MS(ESI+): m/z=569.4.
Example 173
(2S,4EZ)-4-{[(4-methoxybenzyl)oxy]imino}-N-(2-methoxyethyl)-2-pyrrolidinec-
arboxamide
[0597] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, and 2-methoxyethylamine the title
compound was obtained in 52% purity by LC/MS. MS(ESI+):
m/z=322.2.
Example 174
(2S,4EZ)-4-[(allyloxy)imino]-N-(3,4-dimethoxybenzyl)-1-(diphenylacetyl)-2--
pyrrolidinecarboxamide
[0598] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, diphenylacetyl chloride, and
3,4-dimethoxybenzylamine the title compound was obtained in 63%
purity by LC/MS. MS(ESI+): m/z=528.4.
Example 175
(2S,4EZ)-4-[(allyloxy)imino]-1-(4-cyanobenzoyl)-N-(9-ethyl-9H-carbazol-3-y-
l)-2-pyrrolidinecarboxamide
[0599] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 4-cyanobenzoyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in
43%.purity by LC/MS. MS(ESI+): m/z=506.4.
Example 176
(2S,4EZ)-4-{[(4-methoxybenzyl)oxy]imino}-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)-
carbonyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide
[0600] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl
chloride, and 6-quinolinamine the title compound was obtained in
61% purity by LC/MS. MS(ESI+): m/z=583.4.
Example 177
(2S,4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-2-pyrrolidinecarbox-
amide
[0601] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was
obtained in 46% purity by LC/MS. MS(ESI+): m/z=351.2.
Example 178
(2S,4EZ)-N.sup.2-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-N.sup.1-(3-me-
thoxyphenyl)-1,2-pyrrolidinedicarboxamide
[0602] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 1-isocyanato-3-methoxybenzene, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 100%
purity by LC/MS. MS(ESI+): m/z=500.4.
Example 179
(2S,4EZ)-4-(ethoxyimino)-N.sup.2-(9-ethyl-9H-carbazol-3-yl)-N-(3-methoxy-p-
henyl)-1,2-pyrrolidinedicarboxamide
[0603] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, 1-isocyanato-3-methoxy-benzene, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 60%
purity by LC/MS. MS(ESI+): m/z 514.4.
Example 180
(2S,4EZ)-1-[(4-chlorophenoxy)acetyl]-4-(ethoxyimino)-N-(9-ethyl-9H-carbazo-
l-3-yl)-2-pyrrolidinecarboxamide
[0604] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, (4-chlorophenoxy)acetyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 100%
purity by LC/MS. MS(ESI+): m/z=533.4.
Example 181
(2S,4EZ)-4-[(allyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-(4-phenoxybenz-
oyl)-2-pyrrolidinecarboxamide
[0605] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 4-phenoxybenzoyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 63%
purity by LC/MS. MS(ESI+): m/z=573.4.
Example 182
(2S,4EZ)-N.sup.1-benzoyl-N.sup.2-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimin-
o)-1,2-pyrrolidinedicarboxamide
[0606] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, benzoyl isocyanate, and 9-ethyl-9H-carbazol-3-amine the
title compound was obtained in 59% purity by LC/MS. MS(ESI+):
m/z=498.4.
Example 183
(2S,4EZ)-4-[(benzyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-[(2-oxo-6-pen-
tyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0607] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 93%
purity by LC/MS. MS(ESI+): m/z=619.6.
Example 184
(2S,4EZ)-1-acetyl-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidi-
necarboxamide
[0608] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, acetyl chloride, and 9-ethyl-9H-carbazol-3-amine the
title compound was obtained in 87% purity by LC/MS. MS(ESI+):
m/z=407.2.
Example 185
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(ethoxyimino)-N-(9-ethyl-9H-ca-
rbazol-3-yl)-2-pyrrolidinecarboxamide
[0609] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 70%
purity by LC/MS. MS(ESI+): m/z=545.4.
Example 186
(2S,4EZ)-1-acetyl-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-2-pyrrolid-
inecarboxamide
[0610] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, acetyl chloride, and 9-ethyl-9H-carbazol-3-amine the
title compound was obtained in 69% purity by LC/MS. MS(ESI+):
m/z=393.2.
Example 187
(2S,4EZ)-1-(diphenylacetyl)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxy-imino)-
-2-pyrrolidinecarboxamide
[0611] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, diphenylacetyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 77%
purity by LC/MS. MS(ESI+): m/z=545.4.
Example 188
(2S,4EZ)-4-[(allyloxy)imino]-N.sup.1-benzoyl-N.sup.2-(9-ethyl-9H-carbazol--
3-yl)-1,2-pyrrolidinedicarboxamide
[0612] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidineca-
rboxylic acid, benzoyl isocyanate, and 9-ethyl-9H-carbazol-3-amine
the title compound was obtained in 63% purity by LC/MS. MS(ESI+):
m/z=524.4.
Example 189
(2S,4EZ)-N.sup.2-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-N.sup.1-(3-me-
thyl-phenyl)-1,2-pyrrolidinedicarboxamide
[0613] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 1-isocyanato-3-methylbenzene, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 89%
purity by LC/MS. MS(ESI+): m/z=484.4.
Example 190
(2S,4EZ)-4-{[(4-methoxybenzyl)oxy]imino}-N.sup.1-pentyl-N.sup.2-(2-thienyl-
-methyl)-1,2-pyrrolidinedicarboxamide
[0614] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, 1-isocyanatopentane, and
2-thienylmethylamine the title compound was obtained in 86% purity
by LC/MS. MS(ESI+): m/z=473.2.
Example 191
(2S,4EZ)-4-(ethoxyimino)-1-(methoxyacetyl)-N-(6-quinolinyl)-2-pyrrolidinec-
arboxamide
[0615] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, methoxyacetyl chloride, and 6-quinolinamine the title
compound was obtained in 81% purity by LC/MS. MS(ESI+):
m/z=371.2.
Example 192
(2S,4EZ)-4-[(allyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecar-
boxamide
[0616] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound
was obtained in 80% purity by LC/MS. MS(ESI+): m/z=377.2.
Example 193
(2S,4EZ)-4-[(benzyloxy)imino]-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N-
-(6-quinolinyl)-2-pyrrolidinecarboxamide
[0617] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
6-quinolinamine the title compound, was obtained in 48% purity by
LC/MS. MS(ESI+): m/z=553.4.
Example 194
(2S,4EZ)-4-[(allyloxy)imino]-N-[2-(diethylamino)ethyl]-2-pyrrolidinecarbox-
amide
[0618] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, and N1,N1-diethyl-1,2-ethanediamine the title
compound was obtained in 78% purity by LC/MS. MS(ESI+):
m/z=283.0.
Example 195
(2S,4EZ)-1-[4-(dimethylamino)butanoyl]-N-(9-ethyl-9H-carbazol-3-yl)-4-(met-
hoxyimino)-2-pyrrolidinecarboxamide
[0619] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(dimethylamino)-butanoyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 42%
purity by LC/MS. MS(ESI+): m/z=464.2.
Example 196
(2S)-2-[(3-hydroxy-1-azetidinyl)carbonyl]-N-(3-methoxyphenyl)-4-oxo-1-pyrr-
olidinecarboxamide
[0620] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-oxoproline,
1-isocyanato-3-methoxybenzene, and 3-azetidinol the title compound
was obtained in 87% purity by LC/MS. MS(ESI+): m/z=334.2.
Example 197
(2S,4EZ)-4-[(benzyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacety-
l)-2-pyrrolidinecarboxamide
[0621] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, phenoxyacetyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 65%
purity by LC/MS. MS(ESI+): m/z=561.4.
Example 198
(2S)--N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-
-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0622] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline,
2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 70%
purity by LC/MS. MS(ESI+): m/z=512.4.
Example 199
(2S,4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-1-(methoxyacetyl)-4-(methoxy-imino)--
2-pyrrolidinecarboxamide
[0623] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, methoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine
the title compound was obtained in 73% purity by LC/MS. MS(ESI+):
m/z=423.4.
Example 200
(2S,4EZ)-N.sup.2-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-N.sup.1-penty-
l-1,2-pyrrolidinedicarboxamide
[0624] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 1-isocyanatopentane, and 9-ethyl-9H-carbazol-3-amine
the title compound was obtained in 81% purity by LC/MS. MS(ESI+):
m/z=464.2.
Example 201
(2S,4EZ)-4-(ethoxyimino)-N.sup.1-pentyl-N.sup.2-[2-(1H-pyrrol-1-yl)phenyl]-
-1,2-pyrrolidinedicarboxamide
[0625] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, 1-isocyanatopentane, and 2-(1H-pyrrol-1-yl)phenylamine
the title compound was obtained in 83% purity by LC/MS. MS(ESI+):
m/z=426.2.
Example 202
(2S,4EZ)-4-[(allyloxy)imino]-N-(2-methoxyethyl)-2-pyrrolidinecarboxamide
[0626] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, and 2-methoxyethyl-amine the title compound was
obtained in 100% purity by LC/MS. MS(ESI+): m/z=242.0.
Example 203
(2S,4EZ)-4-(tert-butoxyimino)-N.sup.2-(2-methoxyethyl)-N.sup.1-(3-methoxyp-
henyl)-1,2-pyrrolidinedicarboxamide
[0627] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinec-
arboxylic acid, 1-isocyanato-3-methoxybenzene, and
2-methoxyethylamine the title compound was obtained in 76% purity
by LC/MS. MS(ESI+): m/z=407.2.
Example 204
(2S,4EZ)-4-[(allyloxy)imino]-N.sup.2-(2-methoxyethyl)-N.sup.1-(3-methylphe-
nyl)-1,2-pyrrolidinedicarboxamide
[0628] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 1-isocyanato-3-methyl-benzene, and
2-methoxyethylamine the title compound was obtained in 85% purity
by LC/MS. MS(ESI+): m/z=375.2.
Example 205
(2S,4EZ)-1-benzoyl-4-benzylidene-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidin-
ecarboxamide
[0629] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxyl-
ic acid, benzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the
title compound was obtained in 81% purity by LC/MS. MS(ESI+):
m/z=500.4.
Example 206
(2S,4EZ)-N.sup.2-benzyl-4-benzylidene-N.sup.2-methyl-N.sup.1-(3-methylphen-
yl)-1,2-pyrrolidinedicarboxamide
[0630] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxyl-
ic acid, 1-isocyanato-3-methylbenzene, and N-benzyl-N-methylamine
the title compound was obtained in 68% purity by LC/MS. MS(ESI+):
m/z=440.2.
Example 207
(2S,4EZ)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-(4-phenoxybenzoyl)-
-2-pyrrolidinecarboxamide
[0631] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, 4-phenoxybenzoyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 99%
purity by LC/MS. MS(ESI+): m/z=561.4.
Example 208
(2S,4EZ)-4-(ethoxyimino)-N.sup.2-(9-ethyl-9H-carbazol-3-yl)-N.sup.1-(3-met-
hyl-phenyl)-1,2-pyrrolidinedicarboxamide
[0632] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, 1-isocyanato-3-methylbenzene, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 80%
purity by LC/MS. MS(ESI+): m/z=498.4.
Example 209
(2S,4EZ)-4-(methoxyimino)-1-(phenoxyacetyl)-N-(6-quinolinyl)-2-pyrrolidine-
carboxamide
[0633] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, phenoxyacetyl chloride, and 6-quinolinamine the title
compound was obtained in 100% purity by LC/MS. MS(ESI+):
m/z=419.2.
Example 210
(2S,4EZ)-4-(tert-butoxyimino)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2-
H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0634] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinec-
arboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
3,4-dimethoxybenzylamine the title compound was obtained in 63%
purity by LC/MS. MS(ESI+): m/z=542.4.
Example 211
(2S,4EZ)-4-(tert-butoxyimino)-N-cyclopropyl-1-(phenoxyacetyl)-2-pyrrolidin-
ecarboxamide
[0635] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinec-
arboxylic acid, phenoxyacetyl chloride, and cyclopropylamine the
title compound was obtained in 73% purity by LC/MS. MS(ESI+):
m/z=374.2.
Example 212
(2S,4EZ)-4-[(benzyloxy)imino]-N-(tert-butyl)-1-(phenoxyacetyl)-2-pyrrolidi-
necarboxamide
[0636] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, phenoxyacetyl chloride, and tert-butylamine the
title compound was obtained in 100% purity by LC/MS. MS(ESI+):
m/z=424.2.
Example 213
(2S,4EZ)-N-(4,6-dimethoxy-2-pyrimidinyl)-4-(ethoxyimino)-1-(4-phenoxybenzo-
yl)-2-pyrrolidinecarboxamide
[0637] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, 4-phenoxybenzoyl chloride, and
4,6-dimethoxy-2-pyrimidinamine the title compound was obtained in
79% purity by LC/MS. MS(ESI+): m/z=506.4.
Example 214
(4ZE)-4-[(allyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacetyl)-2-
-pyrrolidinecarboxamide
[0638] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, phenoxyacetyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 63%
purity by LC/MS. MS(ESI+): m/z=511.4.
Example 215
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(9-ethyl-9H-carbazol-3-yl)-4-(-
methoxyimino)-2-pyrrolidinecarboxamide
[0639] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 66%
purity by LC/MS. MS(ESI+): m/z=531.4.
Example 216
(3EZ,5S)-1-[4-(dimethylamino)butanoyl]-5-(1-piperidinylcarbonyl)-3-pyrroli-
dinone O-methyloxime
[0640] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(dimethylamino)butanoyl chloride, and piperidine the
title compound was obtained in 100% purity by LC/MS. MS(ESI+):
m/z=339.2.
Example 217
(2S,4EZ)-1-acetoacetyl-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-2-pyr-
rolidinecarboxamide
[0641] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2,4-oxetanedione, and 9-ethyl-9H-carbazol-3-amine the
title compound was obtained in 42% purity by LC/MS. MS(ESI+):
m/z=435.2.
Example 218
(2S,4EZ)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N-(6--
quinolinyl)-2-pyrrolidinecarboxamide
[0642] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
6-quinolinamine the title compound was obtained in 57% purity by
LC/MS. MS(ESI+): m/z=477.2.
Example 219
(2S,4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-4-{[(4-methoxybenzyl)oxy]imino}-1-[(-
2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0643] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl
chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was
obtained in 57% purity by LC/MS. MS(ESI+): m/z=649.4.
Example 220
(2S,4EZ)-N.sup.2-allyl-N.sup.1-benzoyl-4-(methoxyimino)-1,2-pyrrolidinedic-
arboxamide
[0644] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, benzoyl isocyanate, and allylamine the title compound
was obtained in 49% purity by LC/MS. MS(ESI+): m/z=345.0.
Example 221
(2S,4EZ)-4-[(benzyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-(methoxy-acet-
yl)-2-pyrrolidinecarboxamide
[0645] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, methoxyacetyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 46%
purity by LC/MS. MS(ESI+): m/z=499.2.
Example 222
(2S,4EZ)-N.sup.1-(3,5-dichlorophenyl)-N.sup.2-(9-ethyl-9H-carbazol-3-yl)-4-
-(methoxyimino)-1,2-pyrrolidinedicarboxamide
[0646] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 1,3-dichloro-5-isocyanatobenzene, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 42%
purity by LC/MS. MS(ESI+): m/z=538.2.
Example 223
(2S,4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1-(4-phenoxybenzoyl-
)-2-pyrrolidinecarboxamide
[0647] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-phenoxybenzoyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 43%
purity by LC/MS. MS(ESI+): m/z=547.2.
Example 224
(2S,4EZ)-N-(3,5-dichlorophenyl)-4-(ethoxyimino)-N.sup.2-(9-ethyl-9H-carbaz-
ol-3-yl)-1,2-pyrrolidinedicarboxamide
[0648] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, 1,3-dichloro-5-isocyanato-benzene, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 43%
purity by LC/MS. MS(ESI+): m/z=552.6.
Example 225
(3EZ,5S)-5-{[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]carbonyl}-1-[(2--
oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-3-pyrrolidinone
O-(tert-butyl)oxime
[0649] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinec-
arboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
1-(1,3-benzodioxol-5-ylmethyl)piperazine the title compound was
obtained in 59% purity by LC/MS. MS(ESI+): m/z=595.4.
Example 226
(2S,4EZ)-4-benzylidene-N-(9-ethyl-9H-carbazol-3-yl)-1-[(2-oxo-6-pentyl-2H--
pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0650] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxyl-
ic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 47%
purity by LC/MS. MS(ESI+): m/z=588.4.
Example 227
(2S,4EZ)-4-[(allyloxy)imino]-1-benzoyl-N-(6-quinolinyl)-2-pyrrolidinecarbo-
xamide
[0651] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, benzoyl chloride, and 6-quinolinamine the title
compound was obtained in 83% purity by LC/MS. MS(ESI+):
m/z=415.2.
Example 228
(2S,4EZ)-4-[(allyloxy)imino]-1-(methoxyacetyl)-N-(6-quinolinyl)-2-pyrrolid-
inecarboxamide
[0652] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, methoxyacetyl chloride, and 6-quinolinamine the
title compound was obtained in 71% purity by LC/MS. MS(ESI+):
m/z=383.0.
Example 229
(2S,4EZ)-4-[(allyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-(methoxyacetyl-
)-2-pyrrolidinecarboxamide
[0653] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, methoxyacetyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 74%
purity by LC/MS. MS(ESI+): m/z=449.2.
Example 230
(2S,4EZ)-4-[(allyloxy)imino]-1-(2-ethoxy-1-naphthoyl)-N-(9-ethyl-9H-carbaz-
ol-3-yl)-2-pyrrolidinecarboxamide
[0654] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 2-ethoxy-1-naphthoyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 60%
purity by LC/MS. MS(ESI+): m/z=575.4.
Example 231
(2S,4EZ)-4-[(allyloxy)imino]-1-[(4-chlorophenoxy)acetyl]-N-(9-ethyl-9H-car-
bazol-3-yl)-2-pyrrolidinecarboxamide
[0655] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, (4-chlorophenoxy)acetyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 78%
purity by LC/MS. MS(ESI+): m/z=545.4.
Example 232
(2S,4EZ)-4-[(allyloxy)imino]-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(9-ethyl-9-
H-carbazol-3-yl)-2-pyrrolidinecarboxamide
[0656] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 51%
purity by LC/MS. MS(ESI+): m/z=557.2.
Example 233
(2S,4EZ)-4-[(allyloxy)imino]-1-(diphenylacetyl)-N-(9-ethyl-9H-carbazol-3-y-
l)-2-pyrrolidinecarboxamide
[0657] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, diphenylacetyl chloride, and
9-ethyl-9H-carbazol-3-amine the title compound was obtained in 43%
purity by LC/MS. MS(ESI+): m/z=571.2.
Example 234
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(tert-butyl)-4-(chloromethylen-
e)-2-pyrrolidinecarboxamide
[0658] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
tert-butylamine the title compound was obtained in 80% purity by
LC/MS. MS(ESI+): m/z=397.6.
Example 235
tert-butyl
3-[({4-methylene-1-[(pentylamino)carbonyl]-2-pyrrolidinyl}carbo-
nyl)amino]-1-azetidinecarboxylate
[0659] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxy-carbonyl)-4-methyleneproline,
1-isocyanatopentane, and tert-butyl 3-amino-1-azetidine-carboxylate
the title compound was obtained in 75% purity by LC/MS. MS(ESI+):
m/z=395.2.
Example 236
(3EZ,5S)-1-acetyl-5-[(4-acetyl-1-piperazinyl)carbonyl]-3-pyrrolidinone
O-(3,4-dichlorobenzyl)oxime
[0660] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, acetyl chloride, and
1-acetylpiperazine the title compound was obtained in 85% purity by
LC/MS. MS(ESI+): m/z=455.2.
Example 237
(2S,4EZ)-N.sup.2-benzyl-4-(methoxyimino)-N.sup.1-pentyl-1,2-pyrrolidinedic-
arboxamide
[0661] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 1-isocyanatopentane, and benzylamine the title compound
was obtained in 100% purity by LC/MS. MS(ESI+): m/z=361.0.
Example 238
(2S,4EZ)-1-acetyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(1-naphthyl-methyl)-
-2-pyrrolidinecarboxamide
[0662] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, acetyl chloride, and
1-naphthylmethylamine the title compound was obtained in 60% purity
by LC/MS. MS(ESI+): m/z=484.2.
Example 239
(2S,4EZ)-4-(tert-butoxyimino)-N-cyclopropyl-1-[(2-oxo-6-pentyl-2H-pyran-3--
yl)carbonyl]-2-pyrrolidinecarboxamide
[0663] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinec-
arboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
cyclopropylamine the title compound was obtained in 75% purity by
LC/MS. MS(ESI+): m/z=432.2.
Example 240
(2S,4EZ)-4-{[(4-methoxybenzyl)oxy]imino}-1-(4-phenoxybenzoyl)-N-[2-(1H-pyr-
rol-1-yl)phenyl]-2-pyrrolidinecarboxamide
[0664] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, 4-phenoxybenzoyl chloride, and
2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in
55% purity by LC/MS. MS(ESI+): m/z=601.4.
Example 241
(2S)--N-(1,3-benzodioxol-5-ylmethyl)-4-oxo-2-pyrrolidinecarboxamide
[0665] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-oxoproline, and
1,3-benzodioxol-5-ylmethylamine the title compound was obtained in
71% purity by LC/MS. MS(ESI+): m/z=263.0.
Example 242
(2S,4EZ)-N-(1,3-benzodioxol-5-ylmethyl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-
-(chloromethylene)-2-pyrrolidinecarboxamide
[0666] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
1,3-benzodioxol-5-ylmethylamine the title compound was obtained in
63% purity by LC/MS. MS(ESI+): m/z=475.6.
Example 243
(2S,4EZ)-N-(3,4-dimethoxybenzyl)-4-(ethoxyimino)-1-[(2-oxo-6-pentyl-2H-pyr-
an-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0667] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
3,4-dimethoxybenzylamine the title compound was obtained in 41%
purity by LC/MS. MS(ESI+): m/z=514.2.
Example 244
(2S)-2-[(3-hydroxy-1-azetidinyl)carbonyl]-N-(3-methylphenyl)-4-oxo-1-pyrro-
lidinecarboxamide
[0668] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-oxoproline,
1-isocyanato-3-methylbenzene, and 3-azetidinol the title compound
was obtained in 73% purity by LC/MS. MS(ESI+): m/z=318.0.
Example 245
(2S,4EZ)-4-[(benzyloxy)imino]-N-[(2RS)-2-hydroxy-2-phenethyl]-1-[(2-oxo-6--
pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide
[0669] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinec-
arboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
(1RS)-2-amino-1-phenylethanol the title compound was obtained in
55% purity by LC/MS. MS(ESI+): m/z=546.2.
Example 246
(2S,4EZ)-4-[(allyloxy)imino]-N.sup.2-(3,4-dimethoxybenzyl)-N.sup.1-(3-meth-
oxy-phenyl)-1,2-pyrrolidinedicarboxamide
[0670] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidineca-
rboxylic acid, 1-isocyanato-3-methoxybenzene, and
3,4-dimethoxybenzylamine the title compound was obtained in 97%
purity by LC/MS. MS(ESI+): m/z=483.2.
Example 247
(2S,4EZ)-4-[(allyloxy)imino]-1-(4-cyanobenzoyl)-N-(2-methoxyethyl)-2-pyrro-
lidinecarboxamide
[0671] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidineca-
rboxylic acid, 4-cyanobenzoyl chloride, and 2-methoxyethylamine the
title compound was obtained in 44% purity by LC/MS. MS(ESI+):
m/z=371.0.
Example 248
(2S,4EZ)-N-benzyl-1-(methoxyacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrr-
olidinecarboxamide
[0672] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, methoxyacetyl chloride, and benzylamine
the title compound was obtained in 49% purity by LC/MS. MS(ESI+):
m/z=426.2.
Example 249
(2S,4EZ)-1-benzoyl-4-(chloromethylene)-N-(2-furylmethyl)-2-pyrrolidinecarb-
oxamide
[0673] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, benzoyl chloride, and 2-furylmethylamine the title
compound was obtained in 73% purity by LC/MS. MS(ESI+):
m/z=345.6.
Example 250
(2S)-1-acetyl-4-methylene-N-(6-quinolinyl)-2-pyrrolidinecarboxamide
[0674] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, acetyl
chloride, and 6-quinolinamine the title compound was obtained in
87% purity by LC/MS. MS(ESI+): m/z=296.0.
Example 251
(2S,4EZ)-1-acetyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(2-furylmethyl)-2-p-
yrrolidinecarboxamide
[0675] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, acetyl chloride, and
2-furylmethylamine the title compound was obtained in 199% purity
by LC/MS. MS(ESI+): m/z=424.6.
Example 252
(2S)--N.sup.1-(3,5-dichlorophenyl)-4-methylene-N.sup.2-(6-quinolinyl)-1,2--
pyrrolidinedicarboxamide
[0676] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxy-carbonyl)-4-methyleneproline,
1,3-dichloro-5-isocyanatobenzene, and 6-quinolinamine the title
compound was obtained in 65% purity by LC/MS. MS(ESI+):
m/z=441.0.
Example 253
(3EZ,5S)-1-(diphenylacetyl)-5-(1-piperidinylcarbonyl)-3-pyrrolidinone
O-(4-methoxybenzyl)oxime
[0677] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, diphenyl-acetyl chloride, and piperidine
the title compound was obtained in 87% purity by LC/MS. MS(ESI+):
m/z=526.4.
Example 254
(2S,4EZ)-4-(chloromethylene)-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyrr-
olidinecarboxamide
[0678] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, phenoxyacetyl chloride, and 1-naphthylmethylamine
the title compound was obtained in 75% purity by LC/MS. MS(ESI+):
m/z=435.6.
Example 255
(2S,4EZ)-4-[(allyloxy)imino]-N-benzoyl-2-(4-morpholinylcarbonyl)-1-pyrroli-
dinecarboxamide
[0679] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidineca-
rboxylic acid, benzoyl isocyanate, and morpholine the title
compound was obtained in 46% purity by LC/MS. MS(ESI+):
m/z=401.2.
Example 256
(2S,4EZ)-N.sup.1-benzoyl-4-(chloromethylene)-N.sup.2-cyclopropyl-1,2-pyrro-
lidinedicarboxamide
[0680] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, benzoyl isocyanate, and cyclopropylamine the title
compound was obtained in 76% purity by LC/MS. MS(ESI+):
m/z=348.6.
Example: 257
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(methoxyacetyl)-N-(1-naphthy-
lmethyl)-2-pyrrolidinecarboxamide
[0681] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, methoxyacetyl chloride, and
1-naphthylmethylamine the title compound was obtained in 91% purity
by LC/MS. MS(ESI+): m/z=514.8.
Example 258
(2S,4EZ)-1-benzoyl-N-benzyl-4-(chloromethylene)-N-methyl-2-pyrrolidinecarb-
oxamide
[0682] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidineca-
rboxylic acid, benzoyl chloride, and N-benzyl-N-methylamine the
title compound was obtained in 62% purity by LC/MS. MS(ESI+):
m/z=369.4.
Example 259
(2S)--N.sup.2-(2-furylmethyl)-N.sup.1-(3-methoxyphenyl)-4-methylene-1,2-py-
rrolidinedicarboxamide
[0683] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline,
1-isocyanato-3-methoxybenzene, and 2-furylmethylamine the title
compound was obtained in 95% purity by LC/MS. MS(ESI+):
m/z=356.0.
Example 260
(3EZ,5S)-5-[(4-benzhydryl-1-piperazinylcarbonyl]-1-(phenoxyacetyl)-3-pyrro-
lidinone O-ethyloxime
[0684] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, phenoxyacetyl chloride, and 1-benzhydrylpiperazine the
title compound was obtained in 67% purity by LC/MS. MS(ESI+):
m/z=541.2.
Example 261
(3EZ,5S)-1-benzoyl-5-(4-morpholinylcarbonyl)-3-pyrrolidinone
O-(3,4-dichlorobenzyl)-oxime
[0685] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, benzoyl chloride, and morpholine the
title compound was obtained in 69% purity by LC/MS. MS(ESI+):
m/z=476.2.
Example 262
(2S)--N.sup.1-(3-methoxyphenyl)-4-methylene-N.sup.2-(1-naphthylmethyl)-1,2-
-pyrrolidinedicarboxamide
[0686] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxy-carbonyl)-4-methyleneproline,
1-isocyanato-3-methoxybenzene, and 1-naphthylmethyl-amine the title
compound was obtained in 55% purity by LC/MS. MS(ESI+):
m/z=416.3.
Example 263
N.sup.2-(2-methoxyethyl)-4-methylene-N.sup.1-(3-methylphenyl)-1,2-pyrrolid-
inedicarboxamide
[0687] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline,
1-isocyanato-3-methylbenzene, and 2-methoxyethylamine the title
compound was obtained in 85% purity by LC/MS. MS(ESI+):
m/z=318.0.
Example 264
(2S,4EZ)-N-allyl-4-{[(4-methoxybenzyl)oxy]imino}-1-(phenoxyacetyl)-2-pyrro-
lidinecarboxamide
[0688] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, phenoxy-acetyl chloride, and allylamine
the title compound was obtained in 72% purity by LC/MS. MS(ESI+):
m/z=438.2.
Example 265
(2S,4EZ)-1-benzoyl-4-(cyanomethylene)-N-(1-naphthylmethyl)-2-pyrrolidineca-
rboxamide
[0689] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecar-
boxylic acid, benzoyl chloride, and 1-naphthylmethylamine the title
compound was obtained in 43% purity by LC/MS. MS(ESI+):
m/z=396.0.
Example 266
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-[2-oxo-6-pentyl-2H-pyran-3-y-
l)carbonyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide
[0690] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}--
2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl
chloride, and 6-quinolinamine the title compound was obtained in
70% purity by LC/MS. MS(ESI+): m/z=621.2.
Example 267
(2S,4EZ)-N-[2-(diethylamino)ethyl]-1-[4-(dimethylamino)butanoyl]-4-{[(4-me-
thoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide
[0691] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-p-
yrrolidinecarboxylic acid, 4-(dimethylamino)butanoyl chloride, and
N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in
100% purity by LC/MS. MS(ESI+): m/z=476.2.
Example 268
(2S,4EZ)-4-[(allyloxy)imino]-1-[4-(dimethylamino)butanoyl]-N-(1-naphthylme-
thyl)-2-pyrrolidinecarboxamide
[0692] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidineca-
rboxylic acid, 4-(dimethylamino)butanoyl chloride, and
1-naphthylmethylamine the title compound was obtained in 85% purity
by LC/MS. MS(ESI+): m/z=437.2.
Example 269
(2S,4EZ)-N-[2-(diethylamino)ethyl]-4-(ethoxyimino)-2-pyrrolidinecarboxamid-
e
[0693] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, and N1,N1-diethyl-1,2-ethanediamine the title compound
was obtained in 70% purity by LC/MS. MS(ESI+): m/z=271.0.
Example 270
(2S)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N-(6-quinoliny-
l)-2-pyrrolidinecarboxamide
[0694] Following the general method as outlined in Example 22,
starting from 1-(tert-butoxycarbonyl)-4-methyleneproline,
2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinamine
the title compound was obtained in 48% purity by LC/MS. MS(ESI+):
m/z=446.2.
Example 271
(2S,4EZ)-1-acryloyl-N-allyl-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0695] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, acryloyl chloride, and allylamine the title compound
was obtained in 81% purity by LC/MS. MS(ESI+): m/z=252.0.
Example 273
tert-butyl
3-({[(2S,4EZ)-1-acetyl-4-benzylidenepyrrolidinyl]carbonyl}-amin-
o)-1-azetidinecarboxylate
[0696] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxyl-
ic acid, acetyl chloride, and tert-butyl
3-amino-1-azetidinecarboxylate the title compound was obtained in
81% purity by LC/MS. MS(ESI+): m/z=400.2.
Example 273
(2S,4EZ)-4-[(allyloxy)imino]-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N--
(6-quinolinyl)-2-pyrrolidinecarboxamide
[0697] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidineca-
rboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and
6-quinolinamine the title compound was obtained in 67% purity by
LC/MS. MS(ESI+): m/z=503.2.
Example 274
(2S,4EZ)-4-(ethoxyimino)-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyrrolid-
inecarboxamide
[0698] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarbox-
ylic acid, phenoxyacetyl chloride, and 1-naphthylmethylamine the
title compound was obtained in 85% purity by LC/MS. MS(ESI+):
m/z=446.3.
Example 275
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[-
1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0699] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(1RS)-2-amino-1-phenylethanol, the title compound was obtained in
96.4% purity by HPLC. MS(ESI+): m/z=472.
Example 276
(2S,4EZ)-1-([1,1'-biphenyl]-3-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenyl-ethy-
l]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0700] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-3-carboxylic acid, and
(1RS)-2-amino-1-phenylethanol, the title compound was obtained in
72% purity by HPLC. MS(ESI+): m/z=458.
Example 277
(2S,4EZ)-1-(4-benzoylbenzoyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxy-
imino)-2-pyrrolidinecarboxamide
[0701] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-benzoylbenzoic acid, and
(1RS)-2-amino-1-phenylethanol, the title compound was obtained in
93% purity by HPLC. MS(ESI+): m/z=486.
Example 278
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-(3-phenoxybe-
nzoyl)-2-pyrrolidinecarboxamide
[0702] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 3-phenoxybenzoic acid, and
(1RS)-2-amino-1-phenylethanol, the title compound was obtained in
94% purity by HPLC. MS(ESI+): m/z=474.
Example 279
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-(2-phenoxybe-
nzoyl)-2-pyrrolidinecarboxamide
[0703] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2-phenoxybenzoic acid, and
(1RS)-2-amino-1-phenylethanol, the title compound was obtained in
92% purity by HPLC. MS(ESI+): m/z=474.
Example 280
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0704] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(1S)-2-amino-1-phenylethanol, the title compound was obtained in
98% purity by HPLC. MS(ESI+): m/z=472.
Example 281
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0705] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(1R)-2-amino-1-phenylethanol, the title compound was obtained in
84% purity by HPLC. MS(ESI+): m/z=472.
Example 282
(2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]--
4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0706] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
2-aminoethanol, the title compound was obtained in 75% purity by
HPLC. MS(ESI+): m/z=396.
Example 283
(2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-N-methyl-1-[(2'-methyl-[1,1'--
biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0707] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
2-(methylamino)ethanol, the title compound was obtained in 78%
purity by HPLC. MS(ESI+): m/z=410.
Example 284
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1S,2S,3R,4R)-3-(hydroxymethy-
l)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0708] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
[(1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the title
compound was obtained in 79% purity by HPLC. MS(ESI+): m/z=498.
Example 285
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(trans-4-hydroxycyclohexyl)-4--
(methoxyimino)-2-pyrrolidinecarboxamide
[0709] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
trans-4-aminocyclohexanol, the title compound was obtained in 62%
purity by HPLC. MS(ESI+): m/z=436.
Example 286
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1R,2R)-2-(hydroxymethyl)cycl-
ohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0710] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
[(1R,2R)-2-aminocyclohexyl]methanol, the title compound was
obtained in 65% purity by HPLC. MS(ESI+): m/z=450.
Example 287
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-phenoxyprop-
yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0711] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained
in 68% purity by HPLC. MS(ESI+): m/z=488.
Example 288
(2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-[4-(3-pyri-
dinyl)benzoyl]-2-pyrrolidinecarboxamide
[0712] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(3-pyridinyl)benzoic acid, and
(2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained
in 76% purity by HPLC. MS(ESI+): m/z=489.
Example 289
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-phenoxyprop-
yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0713] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
(2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained
in 78% purity by HPLC. MS(ESI+): m/z=524.
Example 290
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(4-hydroxyp-
henyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0714] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was
obtained in 63% purity by HPLC. MS(ESI+): m/z=474.
Example 291
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-hydroxyp-
henyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0715] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
4-[(RS)-2-amino-1-hydroxyethyl]phenol, the title compound was
obtained in 72% purity by HPLC. MS(ESI+): m/z=510.
Example 292
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1-hydroxycyclohexyl)-methyl]-
-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0716] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
1-(aminomethyl)cyclohexanol, the title compound was obtained in 65%
purity by HPLC. MS(ESI+): m/z=450.
Example 293
(2S,4EZ)-N-[(1-hydroxycyclohexyl)methyl]-4-(methoxyimino)-1-[4-(3-pyridiny-
l)benzoyl]-2-pyrrolidinecarboxamide
[0717] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(3-pyridinyl)benzoic acid, and
1-(aminomethyl)cyclohexanol, the title compound was obtained in 69%
purity by HPLC. MS(ESI+): m/z=451.
Example 294
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1-hydroxycyclohexyl)methyl]--
4-(methoxyimino)-2-pyrrolidinecarboxamide
[0718] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
1-(aminomethyl)cyclohexanol, the title compound was obtained in 66%
purity by HPLC. MS(ESI+): m/z=486.
Example 295
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-(3,4-dihydroxy-phenyl-
)-2-hydroxyethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0719] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
4-[(1RS)-2-amino-1-hydroxyethyl]-1,2-benzenediol, the title
compound was obtained in 66% purity by HPLC. MS(ESI+): m/z=490.
Example 296
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridin-
yl)benzoyl]-2-pyrrolidinecarboxamide
[0720] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(4-pyridinyl)benzoic acid, and
(1S)-2-amino-1-phenylethanol, the title compound was obtained in
65% purity by HPLC. MS(ESI+): m/z=459.
Example 297
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridin-
yl)benzoyl]-2-pyrrolidinecarboxamide
[0721] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(3-pyridinyl)benzoic acid, and
(1S)-2-amino-1-phenylethanol, the title compound was obtained in
73% purity by HPLC. MS(ESI+): m/z=459.
Example 298
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(2-pyridin-
yl)benzoyl]-2-pyrrolidinecarboxamide
[0722] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(2-pyridinyl)benzoic acid, and
(1S)-2-amino-1-phenylethanol, the title compound was obtained in
69% purity by HPLC. MS(ESI+): m/z=459.
Example 299
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4--
(methoxyimino)-2-pyrrolidinecarboxamide
[0723] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(2RS)-3-amino-1,2-propanediol, the title compound was obtained in
73% purity by HPLC. MS(ESI+): m/z=412.
Example 300
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4--
(methoxyimino)-2-pyrrolidinecarboxamide
[0724] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
(2RS)-3-amino-1,2-propanediol, the title compound was obtained in
64% purity by HPLC. MS(ESI+): m/z=448.
Example 301
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxyp-
henoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0725] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound
was obtained in 81% purity by HPLC. MS(ESI+): m/z=518.
Example 302
(2S,4EZ)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxy-imino)--
1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
[0726] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(3-pyridinyl)benzoic acid, and
(2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound
was obtained in 63% purity by HPLC. MS(ESI+): m/z=519.
Example 303
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxyp-
henoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0727] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
(2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound
was obtained in 69% purity by HPLC. MS(ESI+): m/z=554.
Example 304
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxypropyl]-4-(met-
hoxyimino)-2-pyrrolidinecarboxamide
[0728] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(2RS)-1-amino-2-propanol, the title compound was obtained in 82%
purity by HPLC. MS(ESI+): m/z=396.
Example 305
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxypropyl]-4-(met-
hoxyimino)-2-pyrrolidinecarboxamide
[0729] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
(2RS)-1-amino-2-propanol, the title compound was obtained in 75%
purity by HPLC. MS(ESI+): m/z=432.
Example 306
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(2
naphthyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0730] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
(1RS)-2-amino-1-(2-naphthyl)ethanol, the title compound was
obtained in 77% purity by HPLC. MS(ESI+): m/z=544.
Example 307
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(4-nitrophe-
nyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0731] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was
obtained in 84% purity by HPLC. MS(ESI+): m/z=503.
Example 308
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4--
(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
[0732] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(4-pyridinyl)benzoic acid, and
(1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was
obtained in 89% purity by HPLC. MS(ESI+): m/z=504.
Example 309
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4--
(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
[0733] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(3-pyridinyl)benzoic acid, and
(1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was
obtained in 72% purity by HPLC. MS(ESI+): m/z=504.
Example 310
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4--
(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
[0734] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(2-pyridinyl)benzoic acid, and
(1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was
obtained in 63% purity by HPLC. MS(ESI+): m/z=504.
Example 311
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-nitrophe-
nyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0735] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
(1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was
obtained in 79% purity by HPLC. MS(ESI+): m/z=539.
Example 312
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1'-bip-
henyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0736] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
N-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl)acetamide, the
title compound was obtained in 79% purity by HPLC. MS(ESI+):
m/z=545.
Example 313
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyim-
ino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
[0737] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(4-pyridinyl)benzoic acid, and
N-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl)acetamide, the
title compound was obtained in 62% purity by HPLC. MS(ESI+):
m/z=546.
Example 314
(2S,4EZ)-N-[(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl]-4-(methoxyim-
ino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
[0738] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(3-pyridinyl)benzoic acid, and
N-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl)acetamide, the
title compound was obtained in 66% purity by HPLC. MS(ESI+):
m/z=546.
Example 315
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1'-bip-
henyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0739] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
N-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl)acetamide, the
title compound was obtained in 62% purity by HPLC. MS(ESI+):
m/z=581.
Example 316
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]-
-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0740] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(1R)-2-amino-1-phenylethanol, the title compound was obtained in
84% purity by HPLC. MS(ESI+): m/z=458.
Example 317
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridin-
yl)benzoyl]-2-pyrrolidinecarboxamide
[0741] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(4-pyridinyl)benzoic acid, and
(1R)-2-amino-1-phenylethanol, the title compound was obtained in
66% purity by HPLC. MS(ESI+): m/z=459.
Example 318
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridin-
yl)benzoyl]-2-pyrrolidinecarboxamide
[0742] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(3-pyridinyl)benzoic acid, and
(1R)-2-amino-1-phenylethanol, the title compound was obtained in
76% purity by HPLC. MS(ESI+): m/z=459.
Example 319
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(2-pyridin-
yl)benzoyl]-2-pyrrolidinecarboxamide
[0743] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(2-pyridinyl)benzoic acid, and
(1R)-2-amino-1-phenylethanol, the title compound was obtained in
65% purity by HPLC. MS(ESI+): m/z=459.
Example 320
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(2R)-2-hydroxy-2-phenyl-ethyl-
]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0744] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
(1R)-2-amino-1-phenylethanol, the title compound was obtained in
87% purity by HPLC. MS(ESI+): m/z=494.
Example 321
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(3-hydroxypropyl)-4-(methoxyim-
ino)-2-pyrrolidinecarboxamide
[0745] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
3-amino-1-propanol, the title compound was obtained in 81% purity
by HPLC. MS(ESI+): m/z=395.
Example 322
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-(3-hydroxypropyl)-4-(methoxyim-
ino)-2-pyrrolidinecarboxamide
[0746] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
3-amino-1-propanol, the title compound was obtained in 64% purity
by HPLC. MS(ESI+): m/z=432.
Example 323
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-4-phenyl-1-piperid-
inyl)carbonyl]-3-pyrrolidinone O-methyloxime
[0747] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
4-phenyl-4-piperidinol, the title compound was obtained in 74%
purity by HPLC. MS(ESI+): m/z=498.
Example 324
(3EZ,5S)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-1-[4-(4-pyridinyl)-
benzoyl]-3-pyrrolidinone O-methyloxime
[0748] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(4-pyridinyl)benzoic acid, and
4-phenyl-4-piperidinol, the title compound was obtained in 78%
purity by HPLC. MS(ESI+): m/z=499.
Example 325
(3EZ,5S)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-1-[4-(3-pyridinyl)-
benzoyl]-3-pyrrolidinone O-methyloxime
[0749] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(3-pyridinyl)benzoic acid, and
4-phenyl-4-piperidinol, the title compound was obtained in 79%
purity by HPLC. MS(ESI+): m/z=499.
Example 326
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-4-phenyl-1-piperid-
inyl)carbonyl]-3-pyrrolidinone O-methyloxime
[0750] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
4-phenyl-4-piperidinol, the title compound was obtained in 84%
purity by HPLC. MS(ESI+): m/z=534.
Example 327
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxycyclohexyl]--
4-(methoxyimino)-2-pyrrolidinecarboxamide
[0751] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(1S,2S)-2-aminocyclohexanol, the title compound was obtained in 84%
purity by HPLC. MS(ESI+): m/z=436.
Example 328
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxycyclohexyl]--
4-(methoxyimino)-2-pyrrolidinecarboxamide
[0752] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
(1S,2S)-2-aminocyclohexanol, the title compound was obtained in 61%
purity by HPLC. MS(ESI+): m/z=472.
Example 329
(2S,4EZ)-N-benzyl-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(m-
ethoxyimino)-2-pyrrolidinecarboxamide
[0753] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
2-(benzylamino)ethanol, the title compound was obtained in 74%
purity by HPLC. MS(ESI+): m/z=472.
Example 330
(2S,4EZ)-N-benzyl-N-(2-hydroxyethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)-b-
enzoyl]-2-pyrrolidinecarboxamide
[0754] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(3-pyridinyl)benzoic acid, and
2-(benzylamino)ethanol, the title compound was obtained in 82%
purity by HPLC. MS(ESI+): m/z=473.
Example 331
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-5-{[(3RS)-3-hydroxypiperidinyl]--
carbonyl}-3-pyrrolidinone O-methyloxime
[0755] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(3RS)-3-piperidinol, the title compound was obtained in 78% purity
by HPLC. MS(ESI+): m/z=422.
Example 332
(3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-1-[4-(4-pyridinyl)-benzo-
yl]-3-pyrrolidinone O-methyloxime
[0756] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(4-pyridinyl)benzoic acid, and (3RS)-3-piperidinol,
the title compound was obtained in 91% purity by HPLC. MS(ESI+):
m/z=423.
Example 333
(3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-1-[4-(3-pyridinyl)-benzo-
yl]-3-pyrrolidinone O-methyloxime
[0757] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(3-pyridinyl)benzoic acid, and (3RS)-3-piperidinol,
the title compound was obtained in 84% purity by HPLC. MS(ESI+):
m/z=423.
Example 334
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylsulfonyl)-5-{[(3RS)-3-hydroxypiperidinyl]--
carbonyl}-3-pyrrolidinone O-methyl oxime
[0758] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
(3RS)-3-piperidinol, the title compound was obtained in 79% purity
by HPLC. MS(ESI+): m/z=458.
Example 335
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxym-
ethyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0759] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound was
obtained in 88% purity by HPLC. MS(ESI+): m/z=488.
Example 336
(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyi-
mino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
[0760] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(4-pyridinyl)benzoic acid, and
(1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound was
obtained in 64% purity by HPLC. MS(ESI+): m/z=489.
Example 337
(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyi-
mino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
[0761] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(3-pyridinyl)benzoic acid, and
(1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound was
obtained in 93% purity by HPLC. MS(ESI+): m/z=489.
Example 338
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxym-
ethyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0762] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
(1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound was
obtained in 82% purity by HPLC. MS(ESI+): m/z=524.
Example 339
(2S,4EZ)-N-(2-anilinoethyl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxy-im-
ino)-2-pyrrolidinecarboxamide
[0763] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
N.sup.1-phenyl-1,2-ethanediamine, the title compound was obtained
in 93% purity by HPLC. MS(ESI+): m/z=457.
Example 340
(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2--
pyrrolidinecarboxamide
[0764] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(4-pyridinyl)benzoic acid, and
N.sup.1-phenyl-1,2-ethanediamine, the title compound was obtained
in 85% purity by HPLC. MS(ESI+): m/z=458.
Example 341
(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2--
pyrrolidinecarboxamide
[0765] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(3-pyridinyl)benzoic acid, and
N.sup.1-phenyl-1,2-ethanediamine, the title compound was obtained
in 85% purity by HPLC. MS(ESI+): m/z=458.
Example 342
(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2--
pyrrolidinecarboxamide
[0766] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 4-(2-pyridinyl)benzoic acid, and
N.sup.1-phenyl-1,2-ethanediamine, the title compound was obtained
in 67% purity by HPLC. MS(ESI+): m/z=458.
Example 343
(2S,4EZ)-N-(2-anilinoethyl)-1-([1,1'-biphenyl]-4-ylsulfonyl)-4-(methoxy-im-
ino)-2-pyrrolidinecarboxamide
[0767] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
N.sup.1-phenyl-1,2-ethanediamine, the title compound was obtained
in 73% purity by HPLC. MS(ESI+): m/z=493.
Example 344
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-1-piperidinyl)-car-
bonyl]-3-pyrrolidinone O-methyloxime
[0768] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and 4-piperidinol,
the title compound was obtained in 86% purity by HPLC. MS(ESI+):
m/z=422.
Example 345
(3EZ,5S)-1-([1,1'-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-1-piperidinyl)-car-
bonyl]-3-pyrrolidinone O-methyloxime
[0769] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and 4-piperidinol,
the title compound was obtained in 68% purity by HPLC. MS(ESI+):
m/z=458.
Example 346
(2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-
-([1,1'-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0770] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the
title compound was obtained in 79% purity by HPLC. MS(ESI+):
m/z=509.
Example 347
(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(metho-
xyimino)-2-pyrrolidinecarboxamide
[0771] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
3-aminopropanamide, the title compound was obtained in 71% purity
by HPLC. MS(ESI+): m/z=409.
Example 348
(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-
-([1,1'-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0772] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
(1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the
title compound was obtained in 83% purity by HPLC. MS(ESI+):
m/z=509.
Example 349
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(4-hydroxybutyl)-4-(methoxyimi-
no)-2-pyrrolidinecarboxamide
[0773] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
4-amino-1-butanol, the title compound was obtained in 68% purity by
HPLC. MS(ESI+): m/z=410.
Example 350
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-(4-hydroxybutyl)-4-(methoxy-im-
ino)-2-pyrrolidinecarboxamide
[0774] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
4-amino-1-butanol, the title compound was obtained in 78% purity by
HPLC. MS(ESI+): m/z=446.
Example 351
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1R,2R)-2-(hydroxymethyl)-cyc-
lohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0775] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
[(1R,2R)-2-aminocyclohexyl]methanol, the title compound was
obtained in 40% purity by HPLC. MS(ESI+): m/z=486.
Example 352
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1R,2S,3R,4S)-3-(hydroxymethy-
l)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0776] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
[(1S,2R,3S,4R)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the title
compound was obtained in 58% purity by HPLC. MS(ESI+): m/z=498.
Example 353
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylsulfonyl)-N-[(1R,2S)-2-(hydroxymethyl)-cyc-
lohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0777] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-sulfonyl chloride, and
[(1S,2R)-2-aminocyclohexyl]methanol, the title compound was
obtained in 41% purity by HPLC. MS(ESI+): m/z=486.
Example 354
(2S,4E and
4Z)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-m-
ethyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0778] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(1RS)-2-amino-1-phenylethanol, the title compounds were obtained as
a mixture of E/Z-isomers of the oxime functionality. Separation of
the isomers by flash chromatography yielded
(2S,4E)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[-
1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide in 98.9%
purity and
(2S,4Z)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[-
1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide in 99.9%
purity by HPLC. MS(ESI+): m/z=472.
Example 355
(2S,4E and
4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-me-
thyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0779] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(1S)-2-amino-1-phenylethanol, the title compounds were obtained as
a mixture of E/Z-isomers of the oxime functionality. Separation of
the isomers by flash chromatography yielded
(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide in 98.9%
purity and
(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide in 99.8%
purity by HPLC. MS(ESI+): m/z=472.
Example 356
(2S,4E and
4Z)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-me-
thyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0780] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(1R)-2-amino-1-phenylethanol, the title compounds were obtained as
a mixture of E/Z-isomers of the oxime functionality. Separation of
the isomers by flash chromatography yielded
(2S,4E)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide in 99.7%
purity and
(2S,4Z)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide in 99.7%
purity by HPLC. MS(ESI+): m/z=472.
Example 357
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1R,2S)-2-(hydroxymethyl)-cyc-
lohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0781] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
[(1S,2R)-2-aminocyclohexyl]methanol, the title compound was
obtained in 63% purity by HPLC. MS(ESI+): m/z=450.
Example 358
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[2-hydroxy-1-(hydroxymethyl)-e-
thyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0782] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
2-amino-1,3-propanediol, the title compound was obtained in 61%
purity by HPLC. MS(ESI+): m/z=412.
Example 359
(2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-
-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0783] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the
title compound was obtained in 68% purity by HPLC. MS(ESI+):
m/z=473.
Example 360
(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-
-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0784] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the
title compound was obtained in 78% purity by HPLC. MS(ESI+):
m/z=473.
Example 361
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenyl-ethyl-
]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0785] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(1S)-2-amino-1-phenylethanol, the title compound was obtained in
87,% purity by HPLC. MS(ESI+): m/z=458.
Example 362
(2RS)-3-({[(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-pyrr-
olidinyl]carbonyl}amino)-2-hydroxypropanoic acid
[0786] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(2RS)-3-amino-2-hydroxypropanoic acid, the title compound was
obtained in 44% purity by HPLC. MS(ESI+): m/z=426.
Example 363
(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-([1,1'-biphenyl]-4-ylca-
rbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0787] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(1S,2R)-2-aminocyclohexanecarboxamide, the title compound was
obtained in 89% purity by HPLC. MS(ESI+): m/z=463.
Example 364
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1RS)-2-hydroxy-1-methyl-ethy-
l]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0788] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(2RS)-2-amino-1-propanol, the title compound was obtained in 81%
purity by HPLC. MS(ESI+): m/z=396.
Example 365
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxym-
ethyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0789] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, the title
compound was obtained in 70% purity by HPLC. MS(ESI+): m/z=533.
Example 366
4-({[(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidiny-
l]carbonyl}amino)butanoic acid
[0790] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
4-aminobutanoic acid, the title compound was obtained in 57% purity
by HPLC. MS(ESI+): m/z=424.
Example 367
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-1-[(2'-methoxy[1,1'-biphenyl]-4--
yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0791] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methoxy[1,1'-biphenyl]-4-carboxylic acid, and
(1S)-2-amino-1-phenylethanol, the title compound was obtained in
90% purity by HPLC. MS(ESI+): m/z=488.
Example 368
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(2-naphthyl)ethyl]-1-[(2'-methoxy[1,1'-biphe-
nyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0792] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methoxy[1,1'-biphenyl]-4-carboxylic acid, and
(1RS)-2-amino-1-(2-naphthyl)ethanol, the title compound was
obtained in 67% purity by HPLC. MS(ESI+): m/z=538.
Example 369
(2S,4EZ)-N-[(1RS)-2-hydroxy-1-methylethyl]-4-(methoxyimino)-1-[(2'-methyl[-
1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0793] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(2RS)-2-amino-1-propanol, the title compound was obtained in 88%
purity by HPLC. MS(ESI+): m/z=410.
Example 370
(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4--
(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidineca-
rboxamide
[0794] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, the title
compound was obtained in 74% purity by HPLC. MS(ESI+): m/z=547.
Example 371
(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4--
(methoxyimino)-1-[(2'-methoxy[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinec-
arboxamide
[0795] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methoxy[1,1'-biphenyl]-4-carboxylic acid, and
(1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, the title
compound was obtained in 61% purity by HPLC. MS(ESI+): m/z=563.
Example 372
(3EZ,5S)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-1-[(2'-methyl[1,1'-biphenyl-
]-4-yl)carbonyl]-3-pyrrolidinone O-methyloxime
[0796] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
4-piperidinol, the title compound was obtained in 86% purity by
HPLC. MS(ESI+): m/z=436.
Example 373
(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-4-
-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinec-
arboxamide
[0797] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the
title compound was obtained in 55% purity by HPLC. MS(ESI+):
m/z=487.
Example 374
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-1-[(2'-methoxy[1,1'-biphenyl]-4-
-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0798] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methoxy[1,1'-biphenyl]-4-carboxylic acid, and
(1RS)-2-amino-1-phenylethanol, the title compound was obtained in
82% purity by HPLC. MS(ESI+): m/z=488.
Example 375
(2S,4EZ)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-1-[(2'-methyl[1,1'-bip-
henyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0799] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(2RS)-1-amino-2-propanol, the title compound was obtained in 90%
purity by HPLC. MS(ESI+): m/z=410.
Example 376
(2S,4EZ)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-1-[(2'-methyl-[1,1-
'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0800] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(2RS)-3-amino-1,2-propanediol, the title compound was obtained in
67% purity by HPLC. MS(ESI+): m/z=426.
Example 377
(2S,4EZ)-N-(3-hydroxypropyl)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-
-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0801] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
3-amino-1-propanol, the title compound was obtained in 90% purity
by HPLC. MS(ESI+): m/z=410.
Example 378
(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methox-
yimino)-2-pyrrolidinecarboxamide
[0802] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
2-aminoacetamide, the title compound was obtained in 82% purity by
HPLC. MS(ESI+): m/z 395.
Example 379
(2S,4EZ)-N-(2-amino-2-oxoethyl)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphen-
yl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0803] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
2-aminoacetamide, the title compound was obtained in 92% purity by
HPLC. MS(ESI+): m/z=409.
Example 380
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(3-hydroxyp-
henyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0804] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was
obtained in 88% purity by HPLC. MS(ESI+): m/z=504.
Example 381
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(1S,2R,3S,4R)-3-(hydroxymethy-
l)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0805] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
[(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the title
compound was obtained in 64% purity by HPLC. MS(ESI+): m/z=462.
Example 382
(2S,4EZ)-N-[(1R,2S,3R,4S)-3-(hydroxymethylbicyclo[2.2.1]hept-2-yl]-1-[(2'--
methoxy[1,1'-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarbox-
amide
[0806] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methoxy[1,1'-biphenyl]-4-carboxylic acid, and
[(1S,2R,3S,4R)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the title
compound was obtained in 56% purity by HPLC. MS(ESI+): m/z=492.
Example 383
(2S,4EZ)-N-(trans-4-hydroxycyclohexyl)-1-[(2'-methoxy[1,1'-biphenyl]-4-yl)-
carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0807] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methoxy[1,1'-biphenyl]-4-carboxylic acid, and
trans-4-aminocyclohexanol, the title compound was obtained in 61%
purity by HPLC. MS(ESI+): m/z=466.
Example 384
(2S,4EZ)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-1-[(2'-methoxy[1,1'-biphe-
nyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0808] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methoxy[1,1'-biphenyl]-4-carboxylic acid, and
[(1R,2R)-2-aminocyclohexyl]methanol the title compound was obtained
in 68% purity by HPLC. MS(ESI+): m/z=480.
Example 385
(2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-[(2'-methy-
l[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0809] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained
in 80% purity by HPLC. MS(ESI+): m/z=502.
Example 386
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxy-imino)-1--
[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0810] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was
obtained in 76% purity by HPLC. MS(ESI+): m/z=488.
Example 387
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxy-imino)-1--
[(2'-methoxy[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0811] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methoxy[1,1'-biphenyl]-4-carboxylic acid, and
4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was
obtained in 90% purity by HPLC. MS(ESI+): m/z=504.
Example 388
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-1-[(2'-met-
hyl[1,1'-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamid-
e
[0812] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
4-[(1RS)-2-amino-1-hydroxyethyl]-2-methoxyphenol, the title
compound was obtained in 67% purity by HPLC. MS(ESI+): m/z=518.
Example 389
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-1-[(2'-met-
hoxy[1,1'-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxami-
de
[0813] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methoxy[1,1'-biphenyl]-4-carboxylic acid, and
4-[(1RS)-2-amino-1-hydroxyethyl]-2-methoxyphenol, the title
compound was obtained in 87% purity by HPLC. MS(ESI+): m/z=534.
Example 390
(2S,4EZ)-N-[(2RS)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-1-[(2'-methoxy[1-
,1'-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0814] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methoxy[1,1'-biphenyl]-4-carboxylic acid, and
4-[(1RS)-2-amino-1-hydroxyethyl]-1,2-benzenediol, the title
compound was obtained in 69% purity by HPLC. MS(ESI+): m/z=520.
Example 391
(2R,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenyl-ethy-
l]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0815] Following the general method as outlined in Example 22,
starting from
(2R,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(1RS)-2-amino-1-phenylethanol, the title compound was obtained in
90% purity by HPLC. MS(ESI+): m/z=456.
Example 392
(2R,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[-
1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0816] Following the general method as outlined in Example 22,
starting from
(2R,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(1RS)-2-amino-1-phenylethanol, the title compound was obtained in
94% purity by HPLC. MS(ESI+): m/z=472.
Example 393
(2S,4EZ)-1-[(2'-cyano[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-p-
henylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0817] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-cyano[1,1'-biphenyl]-4-carboxylic acid, and
(1RS)-2-amino-1-phenylethanol, the title compound was obtained in
86% purity by HPLC. MS(ESI+): m/z=483.
Example 394
(2S,4EZ)-1-[(3',4'-dichloro[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydro-
xy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0818] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 3',4'-dichloro[1,1'-biphenyl]-4-carboxylic acid, and
(1RS)-2-amino-1-phenylethanol, the title compound was obtained in
89% purity by HPLC. MS(ESI+): m/z=527.
Example 395
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydro-
xy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0819] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',6'-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
(1RS)-2-amino-1-phenylethanol, the title compound was obtained in
95% purity by HPLC. MS(ESI+): m/z=486.
Example 396
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydrox-
y-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0820] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',3-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
(1RS)-2-amino-1-phenylethanol, the title compound was obtained in
83% purity by HPLC. MS(ESI+): m/z=486.
Example 397
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxy-imino)-1--
[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0821] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was
obtained in 70% purity by HPLC. MS(ESI+): m/z=488.
Example 398
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxy-imino)-1--
[(2'-cyano[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0822] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-cyano[1,1'-biphenyl]-4-carboxylic acid, and
3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was
obtained in 86% purity by HPLC. MS(ESI+): m/z=499.
Example 399
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxy-imino)-1--
[(3',4'-dichloro[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0823] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 3',4'-dichloro[1,1'-biphenyl]-4-carboxylic acid, and
3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was
obtained in 91% purity by HPLC. MS(ESI+): m/z=543.
Example 400
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxy-imino)-1--
[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0824] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',6'-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was
obtained in 87% purity by HPLC. MS(ESI+): m/z=502.
Example 401
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxy-imino)-1--
[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0825] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',3-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was
obtained in 91% purity by HPLC. MS(ESI+): m/z=502.
Example 402
(2S,4EZ)-1-[(3',4'-dichloro[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydro-
xy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0826] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 3',4'-dichloro[1,1'-biphenyl]-4-carboxylic acid, and
4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was
obtained in 86% purity by HPLC. MS(ESI+): m/z=543.
Example 403
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydro-
xy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0827] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',6'-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was
obtained in 89% purity by HPLC. MS(ESI+): m/z=502.
Example 404
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydrox-
y-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0828] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',3-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was
obtained in 90% purity by HPLC. MS(ESI+): m/z=502.
Example 405
(2S,4EZ)-1-[(2',6'-dimethyl[111'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydro-
xy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0829] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',6'-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
(2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound
was obtained in 87% purity by HPLC. MS(ESI+): m/z=546.
Example 406
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydrox-
y-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0830] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',3-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
(2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound
was obtained in 77% purity by HPLC. MS(ESI+): m/z=546.
Example 407
(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)car-
bonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0831] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',6'-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
2-aminoacetamide, the title compound was obtained in 88% purity by
HPLC. MS(ESI+): m/z=423.
Example 408
(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carb-
onyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0832] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',3-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
2-aminoacetamide, the title compound was obtained in 85% purity by
HPLC. MS(ESI+): m/z=423.
Example 409
(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)ca-
rbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0833] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',6'-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
3-aminopropionamide, the title compound was obtained in 87% purity
by HPLC. MS(ESI+): m/z=437.
Example 410
(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)car-
bonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0834] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',3-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
3-aminopropionamide, the title compound was obtained in 87% purity
by HPLC. MS(ESI+): -m/z=437.
Example 411
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-1-(-
hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0835] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',6'-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
2-amino-1,3-propanediol, the title compound was obtained in 70%
purity by HPLC. MS(ESI+): m/z=440.
Example 412
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-1-(h-
ydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0836] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',3-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
2-amino-1,3-propanediol, the title compound was obtained in 68%
purity by HPLC. MS(ESI+): m/z=440.
Example 413
(2S,4EZ)-1-[(2'-cyano[1,1'-biphenyl]-4-yl)carbonyl]-N-[(1R,2R)-2-(hydroxym-
ethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0837] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-cyano[1,1'-biphenyl]-4-carboxylic acid, and
[(1R,2R)-2-aminocyclohexyl]methanol, the title compound was
obtained in 78% purity by HPLC. MS(ESI+): m/z=475.
Example 414
(3EZ,5S)-5-(3,4-dihydro-2(1H)-isoquinolinylcarbonyl)-1-[(2',3-dimethyl[1,1-
'-biphenyl]-4-yl)carbonyl]-3-pyrrolidinone O-methyloxime
[0838] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',3-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
1,2,3,4-tetrahydroisoquinoline, the title compound was obtained in
77% purity by HPLC. MS(ESI+): m/z=482.
Example 415
(2S,4EZ)-N-[(1R)-2-hydroxy-1-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0839] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(2R)-2-amino-2-phenylethanol, the title compound was obtained in
91% purity by HPLC. MS(ESI+): m/z=472.
Example 416
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyp-
henyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0840] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',6'-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
4-(2-aminoethyl)phenol, the title compound was obtained in 87%
purity by HPLC. MS(ESI+): m/z=486.
Example 417
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyph-
enyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0841] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',3-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
4-(2-aminoethyl)phenol, the title compound was obtained in 83%
purity by HPLC. MS(ESI+): m/z=486.
Example 418
(2S,4EZ)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyp-
henyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0842] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',6'-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
3-(2-aminoethyl)phenol, the title compound was obtained in 81%
purity by HPLC. MS(ESI+): m/z=486.
Example 419
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyph-
enyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0843] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',3-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
3-(2-aminoethyl)phenol, the title compound was obtained in 89%
purity by HPLC. MS(ESI+): m/z=486.
Example 420
(2S,4EZ)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-N-[(1R,2S)-2-hydr-
oxy-1,2-diphenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0844] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',3-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
(1S,2R)-2-amino-1,2-diphenylethanol, the title compound was
obtained in 73% purity by HPLC. MS(ESI+): m/z=562.
Example 421
(2RS)-2-[({(2S,4EZ)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)car-
bonyl]pyrrolidinyl}carbonyl)amino]-3-phenylpropanoic acid
[0845] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
DL-phenylalanine, the title compound was obtained in 62% purity by
HPLC. MS(ESI+): m/z=500.
Example 422
(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2',6'-dimethyl[1,1'-b-
iphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0846] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',6'-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
(1S,2R)-2-aminocyclohexanecarboxamide, the title compound was
obtained in 92% purity by HPLC. MS(ESI+): m/z=491.
Example 423
(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2',3-dimethyl[1,1'-bi-
phenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0847] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',3-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
(1S,2R)-2-aminocyclohexanecarboxamide, the title compound was
obtained in 91% purity by HPLC. MS(ESI+): m/z=491.
Example 424
4'-{[(2S,4EZ)-2-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-4-(methoxyimi-
no)pyrrolidinyl]carbonyl}[1,1'-biphenyl]-2-carbonitrile
[0848] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-cyano[1,1'-biphenyl]-4-carboxylic acid, and
2-(1-piperazinyl)ethanol, the title compound was obtained in 89%
purity by HPLC. MS(ESI+): m/z=476.
Example 425
(3EZ,5S)-1-[(3',4'-dichloro[1,1'-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxy-
ethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinone O-methyloxime
[0849] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 3',4'-dichloro[1,1'-biphenyl]-4-carboxylic acid, and
2-(1-piperazinyl)ethanol, the title compound was obtained in 86%
purity by HPLC. MS(ESI+): m/z=520.
Example 426
(3EZ,5S)-1-[(2',6'-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxy-
ethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinone O-methyloxime
[0850] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',6'-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
2-(1-piperazinyl)ethanol, the title compound was obtained in
79%.purity by HPLC. MS(ESI+): m/z=479.
Example 427
(3EZ,5S)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxye-
thyl)-1-piperazinyl]carbonyl}-3-pyrrolidinone O-methyloxime
[0851] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2',3-dimethyl[1,1'-biphenyl]-4-carboxylic acid, and
2-(1-piperazinyl)ethanol, the title compound was obtained in 86%
purity by HPLC. MS(ESI+): m/z=479.
Example 428
(3EZ,5S)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-5-({4-[4-(trifluorome-
thyl)phenyl]-1-piperazinyl}carbonyl)-3-pyrrolidinone
O-methyloxime
[0852] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
1-[4-(trifluoromethyl)phenyl]piperazine, the title compound was
obtained in 89% purity by HPLC. MS(ESI+): m/z=565.
Example 429
(3EZ,5S)-1-[(2'-methyl[,1'-biphenyl]-4-yl)carbonyl]-5-({4-[3-(trifluoromet-
hyl)phenyl]-1-piperazinyl}carbonyl)-3-pyrrolidinone
O-methyloxime
[0853] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
1-[3-(trifluoromethyl)phenyl]piperazine, the title compound was
obtained in 88% purity by HPLC. MS(ESI+): m/z=565.
Example 430
(2S,4EZ)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-py-
rrolidinecarboxamide
[0854] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and ammonia
(0.5M in dioxane), the title compound was obtained in 88% purity by
HPLC. MS(ESI+): m/z=352.
Example 431
(2S,4EZ)-4-(methoxyimino)-N-methyl-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbo-
nyl]-2-pyrrolidinecarboxamide
[0855] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
methylamine (2M in methanol), the title compound was obtained in
96% purity by HPLC. MS(ESI+): m/z=366.
Example 432
(2S,4EZ)-4-(methoxyimino)-N,N-dimethyl-1-[(2'-methyl[1,1'-biphenyl]-4-yl)c-
arbonyl]-2-pyrrolidinecarboxamide
[0856] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
dimethylamine (5.6M in ethanol), the title compound was obtained in
94% purity by HPLC. MS(ESI+): m/z=380.
Example 433
(2S,4EZ)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2'-methyl[-
1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0857] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(1R)-3-amino-1-phenyl-1-propanol, the title compound was obtained
in 94% purity by HPLC. MS(ESI+): m/z=486.
Example 434
(2S,4EZ)-N-[(3S)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2'-methyl[-
1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0858] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(1S)-3-amino-1-phenyl-1-propanol, the title compound was obtained
in 91% purity by HPLC. MS(ESI+): m/z=486.
Example 435
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(3R)-3-hydroxy-3-phenyl-propy-
l]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0859] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(1R)-3-amino-1-phenyl-1-propanol, the title compound was obtained
in 94% purity by HPLC. MS(ESI+): m/z=472.
Example 436
(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(3S)-3-hydroxy-3-phenyl-propy-
l]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0860] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(1S)-3-amino-1-phenyl-1-propanol, the title compound was obtained
in 93% purity by HPLC. MS(ESI+): m/z=472.
Example 437
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2'-(trifluo-
romethyl)[1,1'-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxamide
[0861] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-(trifluoromethyl)[1,1'-biphenyl]-4-carboxylic acid,
and (1S)-2-amino-1-phenylethanol, the title compound was obtained
in 87% purity by HPLC. MS(ESI+): m/z=526.
Example 438
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2'-chloro[1-
,1'-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxamide
[0862] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-chloro[1,1'-biphenyl]-4-carboxylic acid, and
(1S)-2-amino-1-phenylethanol, the title compound was obtained in
89% purity by HPLC. MS(ESI+): m/z=492.
Example 439
(2S,4EZ)-N-(2-hydroxyphenyl)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-
-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0863] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
2-aminophenol, the title compound was obtained in 88% purity by
HPLC. MS(ESI+): m/z=444.
Example 440
(2S,4EZ)-N-[2-(hydroxymethyl)phenyl]-4-(methoxyimino)-1-[(2'-methyl-[1,1'--
biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0864] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2'-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(2-aminophenyl)methanol, the title compound was obtained in 86%
purity by HPLC. MS(ESI+): m/z=458.
Example 441
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2-methyl[1,-
1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
[0865] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2-methyl[1,1'-biphenyl]-4-carboxylic acid, and
(1S)-2-amino-1-phenylethanol, the title compound was obtained in
95% purity by HPLC. MS(ESI+): m/z=472.
Example 442
(2S,4E and
4Z)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenyl-
ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
[0866] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, [1,1'-biphenyl]-4-carbonyl chloride, and
(1S)-2-amino-1-phenylethanol, the title compounds were obtained as
a mixture of E/Z-isomers of the oxime functionality. Separation of
the isomers by flash chromatography yielded
(2S,4E)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-
-4-(methoxyimino)-2-pyrrolidinecarboxamide in 98.8% purity and
(2S,4Z)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-
-4-(methoxyimino)-2-pyrrolidinecarboxamide in 97.4% purity by HPLC.
MS(ESI+): m/z=458.
Example 443
(2S,4EZ)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-N-(2-
-phenylethyl)-2-pyrrolidinecarboxamide
[0867] Following the general method as outlined in Example 22,
starting from
(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbo-
xylic acid, 2-methyl[1,1'-biphenyl]-4-carboxylic acid, and
2-phenylethanamine, the title compound was obtained in 89% purity
by HPLC. MS(ESI+): m/z=456.
Example 444
Preparation of a Pharmaceutical Formulation
[0868] The following formulation examples illustrate representative
pharmaceutical compositions according to the present invention
being not restricted thereto.
Formulation 1--Tablets
[0869] A pyrrolidine compound of formula I is admixed as a dry
powder with a dry gelatin binder in an approximate 1:2 weight
ration. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg
of active pyrrolidine compound per tablet) in a tablet press.
Formulation 2--Capsules
[0870] A pyrrolidine compound of formula I is admixed as a dry
powder with a starch diluent in an approximate 1:1 weight ratio.
The mixture is filled into 250 mg capsules (125 mg of active
pyrrolidine compound per capsule).
Formulation 3--Liquid
[0871] A pyrrolidine compound of formula I (1250 mg), sucrose (1.75
g) and xanthan gum (4 mg) are blended, passed through a No. 0.10
mesh U.S. sieve, and then mixed with a previously prepared solution
of microcrystalline cellulose and sodium carboxymethyl cellulose
(11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color
are diluted with water and added with stirring. Sufficient water is
then added to produce a total volume of 5 mL.
Formulation 4--Tablets
[0872] A pyrrolidine compound of formula I is admixed as a dry
powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 450-900 mg tablets (150-300
mg of active pyrrolidine compound) in a tablet press.
Formulation 5--Injection
[0873] A pyrrolidine compound of formula I is dissolved in a
buffered sterile saline injectable aqueous medium to a
concentration of approximately 5 mg/ml.
Example 445
Biological Assays
a) In Vitro Binding Assay (SPA)
[0874] Membranes from HEK293EBNA cells expressing the hOT receptor
were resuspended in buffer containing 50 mM Tris-HCl, pH 7.4, 5 mM
MgCl2 and 0.1% BSA (w/v). The membranes (2-4 .mu.g) were mixed with
0.1 mg wheat-germ aglutinin (WGA) SPA bead (type A) and increasing
concentrations of [.sup.125I]-OVTA (for saturation binding
experiments) or 0.2 nM [.sup.125I]-OVTA (for competition binding
experiments). Non specific binding was deter-mined in the presence
of, 1 .mu.M Oxytocin. The total assay volume was 100 .mu.l. The
plates were incubated at room temperature for 30 min and counted on
a Mibrobeta plate counter. The competition binding data were
analysed using the iterative, nonlinear, curve-fitting program,
Prism.
b) Biological Results--Discussion
[0875] The binding affinities to the oxytocin receptor of the
pyrrolidine derivatives claimed in the formula I were assessed
using the above described in vitro biological assay. Representative
values for some example compounds are given in Table 1 below. The
values refer to the binding capacity of the example compounds
according to formula I to the Oxytocin receptor. From the values
shown in Table 1 it can be derived that said test compounds
according to formula I do show a significant binding to the
Oxytocin receptor.
TABLE-US-00001 TABLE 1 Binding affinity human OT-R Structure
IUPAC-Name IC.sub.50 (.mu.M) ##STR00016##
(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide 0.13
##STR00017##
(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide 0.07
##STR00018##
(3Z,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-3-pyrro-
lidinone O-methyloxime 0.63 ##STR00019##
(2S,4Z)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2-h-
ydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide 0.35 ##STR00020##
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-(3-phenoxyb-
enzoyl)-2-pyrrolidinecarboxamide 2.3 ##STR00021##
(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2',3-dimethyl[1,1'-biphenyl]-4-yl)ca-
rbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide 0.54 ##STR00022##
(2S,4EZ)-1-[(2'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-N-[(2S)-2-hydroxy-2--
phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide 0.17
##STR00023##
(2S,4EZ)-N-(3-hydroxypropyl)-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl-
]-4-yl)carbonyl]-2-pyrrolidinecarboxamide 0.37 ##STR00024##
(3EZ,5S)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-1-[(2'-methyl[1,1'-bipheny-
l]-4-yl)carbonyl]-3-pyrrolidinone O-methyloxime 0.30 ##STR00025##
(2S,4EZ)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-1-[(2'-methoxy[1,1'-biph-
enyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
0.55
[0876] According to a preferred embodiment, the compounds display
binding affinities (K.sub.i (.mu.M)) of less 0.40 .mu.M, more
preferred of less than 0.1 .mu.M.
c) Functional Assay No. 1: Inhibition of Ca.sup.2+-Mobilization by
FLIPR
[0877] Preparing the plates: FLIPR-plates were pre-coated with PLL
10 .mu.g/ml+0.1% gelatine for 30 min up to 2 days at 37.degree. C.
(for HEK-cells). The cells were plated out into 96-well plates
(60000 cells/well).
[0878] Labelling with fluo-4: 50 kg fluo-4 were dissolved in 20
.mu.l pluronic acid (20% in DMSO). The dissolved fluo-4 was then
diluted in 10 ml DMEM-F12 medium without FCS. The medium was
removed from the plates, followed by one wash with DMEM-F12 medium.
Now, 100 .mu.l of the DMEM-F12 medium containing fluo-4 were added
and the cells incubated for 1-1.5 h (CHO-cells), and 1.5-2 h
(HEK-cells).
[0879] Buffer: 145 mM NaCl, 5 mM KCl, 1 mM MgCl.sub.2, 10 mM Hepes,
10 mM Glucose, EGTA. Adjust to pH 7.4.
[0880] Preparation of agonists and antagonists: A minimum of 80
.mu.l/well of agonists and antagonists (5.times.) in the above
buffer (1.times.) were prepared (96-well plates).
[0881] The activities of the pyrrolidine derivatives according to
formula I were assessed using the above described in vitro
biological assay. Representative values for some example compounds
are given in Table 2 below. The values refer to the capacity of the
example compounds according to formula I to effectively antagonize
oxytocin-induced intracellular Ca.sup.2+-mobilization mediated by
the Oxytocin receptor. From the values shown in Table 2 it can be
derived that said example test compounds according to formula I do
exhibit a significant activity as Oxytocin receptor
antagonists.
TABLE-US-00002 TABLE 2 Inhibition of Ca.sup.2+- mobilization,
hOT-R, Structure IUPAC Name IC.sub.50 (.mu.M) ##STR00026##
(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide 0.07
##STR00027##
(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide 0.03
##STR00028##
(2S,4EZ)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2'-methyl-
[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide 0.32
##STR00029##
(3Z,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1'-biphenyl]-4-ylcarbonyl)-3-pyrro-
lidinone O-methyloxime 0.4 ##STR00030##
(2S,4Z)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimi-
no)-2-pyrrolidinecarboxamide 0.65
d) Functional Assay No. 2: Inhibition of IP3-Synthesis in
HEK/EBNA-OTR Cells
[0882] Stimulation of the cells: HEK/EBNA OTR (rat or human) cells
were plated out into costar 12-well plates, and equilibrated for
15-24 h with [.sup.3H]-inositol in medium without inositol
supplement, with 1% FCS (0.5 ml/well). 4 .mu.Ci/ml were used. After
this, the medium containing the label was aspirated. Then was added
DMEM (without FCS, inositol), 20 mM Hepes, 1 mg/ml BSA containing
10 mM LiCl (freshly prepared), for 10-15 min at 37.degree. C. The
agonists and antagonists were added for the time required (15-45
min), followed by aspiration of the medium. The reaction was
stopped with 1 ml STOP-solution (0.4 M perchloric acid), and let
sit for 5-10 min at RT (not longer). Then, 0.8 ml were transferred
into tubes containing 0.4 ml of neutralizing solution (0.72 M
KOH/0.6M KHCO.sub.3), and the tubes vortexed and kept in the cold
at least for 2 h. At this stage, samples could be kept over a
prolonged period of time.
[0883] Separation of IP's: The samples were spun in a table top
centrifuge at 3000-4000 rpm for 15 min. 1 ml of the supernatant was
transferred to new tubes containing 2.5 ml H.sub.2O. Packed resin
(0.8 ml) was equilibrated with 20 ml H.sub.2O, and the whole
samples poured onto the columns. To discard free inositol, two
washes with 10 ml H.sub.2O were carried out.
[0884] Elution of total IP's: The elution was achieved using 3 ml
1M ammonium formate/0.1M formic acid. The eluant was collected in
scintillation counting tubes, followed by addition of 7 ml of
scintillation liquid. Mixing and counting concluded the
operation.
[0885] The activities of the pyrrolidine derivatives claimed in the
formula I were assessed using the above described in vitro
biological assay. Representative values for some example compounds
are given in Table 3 below. The values refer to the capacity of the
example compounds according to formula I to effectively antagonize
oxytocin-induced IP3-synthesis mediated by the Oxytocin receptor.
From the values shown in Table 3 it can be derived that said
example test compounds according to formula I do exhibit a
significant activity as Oxytocin receptor antagonists.
TABLE-US-00003 TABLE 3 Inhibition of IP3- synthesis, ratOT-R
Structure IUPAC Name IC.sub.50 (.mu.M) ##STR00031##
(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide 0.33
##STR00032##
(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide 0.03
##STR00033##
(2S,4Z)-1-([1,1'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl-
]-4-(methoxyimino)-2-pyrrolidinecarboxamide 0.35
e) In Vivo Model for Inhibition of Uterine Contractions
[0886] Non-pregnant Charles River CD(SD) BR female rats (9-10 weeks
old, 200-250 g) were treated at 18 and 24 hours before the
experiment with 250 .mu.g/kg, i.p. diethylstilbestrol (DES). For
the assay, the animal was anaesthetised by urethane (1.75 g/kg,
i.p.) and placed on an homeothermic operating table. The trachea
was isolated and cannulated with a suitable polyethylene (PE)
tubing. A midline incision at the hypogastrium level was made and
one uterine horn exposed, its cephalic end cannulated with a PE240
tubing and, after filling the internal cavity with 0.2 ml of
sterile physiological saline, connected to a "Gemini"
amplifying/recording system via a P23ID Gould Statham pressure
transducer. For the i.v. route of administration of the test
compounds, one jugular vein was isolated and cannulated with a PE60
tubing connected to a butterfly needle to allow the administration
by a dispensing syringe. In the case of intraduodenal
administration of the test compounds, the duodenum was isolated and
similarly cannulated through a small incision in its wall. One
carotid artery was also isolated and cannulated with PE60 catheter
and connected to a suitable syringe for blood sample collection
(see below). After a stabilization period, the same dose of
oxytocin was repeatedly injected intravenously at 30-min intervals.
When comparable contractile responses of the uterus to the selected
dose of oxytocin were obtained, the dose of the test or reference
compound was administered. Further injections of the same dose of
oxytocin were then made for a suitable time after treatment to
assess inhibitory effects of the compounds under study. The
contractile response of the uterus to oxytocin was quantified by
measuring the intrauterine pressure and the number of contractions.
The effect of the reference and test compounds were evaluated by
comparing pre- and post-treatment pressure values. In addition, at
2, 30, 90 and 210 minutes after test compound administration, a
0.5-ml blood sample was withdrawn from the cannulated carotid
artery of each experimental animal. Plasma was obtained by standard
laboratory procedure and the resulting samples were stored at
-20.degree. C.
[0887] The activities of the pyrrolidine derivatives claimed in the
formula I were assessed using the above described in vivo
biological assay. Representative values for one example compound
are given in Table 4 below. The values refer to the capacity of the
example compound according to formula I to effectively antagonize
oxytocin-induced uterine contractions in the rat. From the values
shown in Table 4 it can be derived that said example test compound
according to formula I does exhibit a significant activity as
tocolytic, i.e. uterine-relaxing, agent.
TABLE-US-00004 TABLE 4 Route of % Reduction of administration/
Uterine Dose Structure IUPAC Name Vehicle Contraction (mg/kg)
##STR00034##
(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1-
,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
intravenous;PEG 400/saline50:50;5 ml/kg infusion -23.8 .+-.
4.1-27.6 .+-. 4.6-50.4 .+-. 5.8-65.6 .+-. 6.4 -76.5 .+-. 4.24 0.3 1
31030
* * * * *