U.S. patent application number 11/868332 was filed with the patent office on 2008-04-17 for antimicrobial [3.1.0] bicyclohexylphenyl- oxazolidinone derivatives and analogues.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Hongwu Gao, Mikhail Fedor Gordeev, Vara Prasad Venkata Nagendra Josyula, Dinesh Vinoobhai Patel, Adam Renslo.
Application Number | 20080090884 11/868332 |
Document ID | / |
Family ID | 33159819 |
Filed Date | 2008-04-17 |
United States Patent
Application |
20080090884 |
Kind Code |
A1 |
Renslo; Adam ; et
al. |
April 17, 2008 |
ANTIMICROBIAL [3.1.0] BICYCLOHEXYLPHENYL- OXAZOLIDINONE DERIVATIVES
AND ANALOGUES
Abstract
The present invention provides certain [3.1.0]bicyclic
oxazolidinone derivatives of Formula I ##STR1## I or
pharmaceutically acceptable salts or prodrugs thereof that are
antibacterial agents, pharmaceutical compositions containing them,
methods for their use, and methods for preparing these
compounds.
Inventors: |
Renslo; Adam; (Oakland,
CA) ; Gordeev; Mikhail Fedor; (Castro Valley, CA)
; Patel; Dinesh Vinoobhai; (Fremont, CA) ; Gao;
Hongwu; (Pudong New Area, CN) ; Josyula; Vara Prasad
Venkata Nagendra; (Superior Township, MI) |
Correspondence
Address: |
PFIZER INC;Steve T. Zelson
150 EAST 42ND STREET
5TH FLOOR - STOP 49
NEW YORK
NY
10017-5612
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
33159819 |
Appl. No.: |
11/868332 |
Filed: |
October 5, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10815589 |
Apr 1, 2004 |
7279494 |
|
|
11868332 |
Oct 5, 2007 |
|
|
|
60461134 |
Apr 9, 2003 |
|
|
|
Current U.S.
Class: |
514/376 ;
548/229 |
Current CPC
Class: |
A61P 31/04 20180101;
C07D 413/10 20130101; A61P 31/06 20180101; C07D 413/14
20130101 |
Class at
Publication: |
514/376 ;
548/229 |
International
Class: |
A61K 31/422 20060101
A61K031/422; A61P 31/04 20060101 A61P031/04; C07D 263/04 20060101
C07D263/04 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 30, 2004 |
EP |
04724333.2 |
Claims
1. A compound of Formula I: ##STR98## wherein A is a structure i,
ii, iii, or iv ##STR99## where the dashed line in formula iii
represents an optional double bond; n is an integer equal to 0 or
1; Y is selected from the group consisting of --SO.sub.m--, --O--
and --N(R.sup.8)--; where m is an integer equal to 0, 1, or 2; Z is
selected from the group consisting of C(.dbd.Q)R.sup.1,
--NHC(.dbd.Q)R.sup.1, C(.dbd.Q)NHR.sup.1, --NHC(.dbd.NCN)R.sup.1,
--NHC(.dbd.NNO.sub.2)R.sup.1, --SO.sub.2R.sup.1, --NH.sub.2,
--NH-het.sup.1, --O-het.sup.1, --S-het.sup.1, and -het.sup.2; Q is
oxygen or sulfur; W is selected from the group consisting of
--CH.sub.2--, --C(.dbd.O)--, --C(.dbd.NOH)--, and
--C(.dbd.NOC.sub.1-4alkyl)-; R.sup.1 is selected from the group
consisting of --H, OH, --NH.sub.2, --NHC.sub.1-4alkyl,
--C.sub.1-4alkyl, --C.sub.2-4alkenyl,
--(CH.sub.2).sub.pC(.dbd.O)C.sub.1-4alkyl, --OC.sub.1-4alkyl,
--SC.sub.1-4alkyl, --(CH.sub.2).sub.pC.sub.3-6cycloalkyl,
--CH.dbd.CH-aryl, --CH.dbd.CH-het.sup.1, --CH.sub.2C(.dbd.O)-aryl,
and --CH.sub.2C(.dbd.O)-het.sup.1; where p is an integer equal to
0, 1 or 2; R.sup.2 and R.sup.3 are independently selected from the
group consisting of --H and --F; R.sup.4 and R.sup.5 are
independently selected from the group consisting of --H, --Cl, --F,
--CH.sub.3, --NH.sub.2, and --OH; R.sup.6 and R.sup.7 are
independently selected from the group consisting of --H and
--C.sub.1-4alkyl; R.sup.8 is independently selected from the group
consisting of --H, --OH, --NR.sup.9R.sup.10, --C.sub.1-4alkyl,
--C.sub.3-6cycloalkyl, --C.sub.1-4heteroalkyl, -aryl, -het.sup.1,
--C.sub.1-4alkylNR.sup.9R.sup.10,
--(CH.sub.2).sub.pC(.dbd.O)C.sub.1-4alkyl,
--(CH.sub.2).sub.pC(.dbd.O)C.sub.1-4heteroalkyl, --C(.dbd.O)H,
--(CH.sub.2).sub.pC(.dbd.O)OR.sup.9,
--(CH.sub.2).sub.pC(.dbd.O)C.sub.1-4alkylOR.sup.9,
--(CH.sub.2).sub.pC(.dbd.O)NR.sup.9R.sup.10,
--(CH.sub.2).sub.pC(.dbd.O)NR.sup.9OR.sup.10,
--(CH.sub.2).sub.pC(.dbd.NOC.sub.1-4alkyl)H,
--(CH.sub.2).sub.pC(.dbd.NOC.sub.1-4alkyl)C.sub.1-4alkyl,
--(CH.sub.2).sub.pC(.dbd.O)het.sup.1, and
--(CH.sub.2).sub.pC(.dbd.NOC.sub.1-4alkyl)het.sup.1; where p and
het.sup.1 are as defined herein; where each R.sup.9 and R.sup.10
are independently --H, --C.sub.1-4alkyl, --C.sub.3-6cycloalkyl,
-aryl, -het.sup.1, --C(.dbd.O)C.sub.1-4alkyl, --C(.dbd.O)aryl,
--C(.dbd.O)het.sup.1, --SO.sub.2C.sub.1-4alkyl, or
--SO.sub.2NH.sub.2; and a pharmaceutically acceptable salts
thereof; with the proviso that when Y is --O-- or --SO.sub.m--,
then W is --CH.sub.2--.
2. The compound according to claim 1, wherein A is an optical
configuration of structure i, ii, or iii: ##STR100##
3. The compound according to claim 1, wherein A is an optical
configuration of structure i: ##STR101##
4. The compound of claim 3, wherein R.sup.1 is C.sub.1-4alkyl.
5. The compound of claim 3, wherein R.sup.1 is selected from the
group consisting of H, methyl, difluoromethyl, ethyl,
2-fluoroethyl, or 2,2-difluoroethyl.
6. The compound of claim 3, wherein R.sup.4 and R.sup.5 are
independently H or F.
7. The compound of claim 3, wherein R.sup.6 and R.sup.7 are H.
8. The compound of claim 3, wherein W is CH.sub.2.
9. A compound selected from the group consisting of
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}--
2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]-
phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fl-
uorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-
-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6--
yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
2,2-difluoro-N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo
[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]ethanethioamide;
methyl
exo-(1R,5S)-6-(4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolid-
in-3-yl}-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-formyl-3-azabicyclo[3.1.0]hex-6-yl]-
phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-((2S)-2,3-dihydroxypropanoyl)-3-aza-
bicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
exo-(1R,5S)-6-(4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl-
}-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxamide;
exo-(1R,5S)-6-[4-((5S)-5-{[(2,2-difluoroethanethioyl)amino]methyl}-2-oxo--
1,3-oxazolidin-3-yl)-2-fluorophenyl]-3-azabicyclo[3.1.0]hexane-3-carboxami-
de;
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]h-
ex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5--
difluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]pheny-
l}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]he-
x-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
N-[((5S)-3-{4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3--
oxazolidin-5-yl)methyl]acetamide;
N-[((5S)-3-{4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl-
}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
N-[((5S)-3-{4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-
-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]pheny-
l}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluoro-
phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluoro-
phenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-difl-
uorophenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-difl-
uorophenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)--N-ethyl-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-
-3,5-difluorophenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)--N-(2-fluoroethyl)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0-
]hex-6-yl]-3,5-difluorophenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-
-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phen-
yl}-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phen-
yl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]-
phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]-
phenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)--N-ethyl-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]-
hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-
-1,3-oxazolidine-5-carboxamide;
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-ox-
o-1,3-oxazolidine-5-carboxamide;
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}--
2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxa-
zolidine-5-carboxamide;
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]p-
henyl}-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]p-
henyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6--
yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6--
yl]phenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-
-1,3-oxazolidine-5-carboxamide;
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-N-met-
hyl-2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-
-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-N-
-methyl-2-oxo-1,3-oxazolidine-5-carboxamide;
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-
-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]-
phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;
N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5--
difluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;
N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fl-
uorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]he-
x-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6--
yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]pheny-
l}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-
-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phen-
yl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]-
phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluoro-
phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-difl-
uorophenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]p-
henyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6--
yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-5-(1H-
-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-5-
-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;
N-[((5S)-3-{3-fluoro-4-[(1S,5R,6R)-2-oxo-3-azabicyclo[3.1.0]hex-6-yl]phen-
yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
N-[((5S)-3-{3,5-difluoro-4-[(1S,5R,6R)-2-oxo-3-azabicyclo[3.1.0]hex-6-yl]-
phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
(5R)-3-{3-fluoro-4-[(1S,5R,6R)-2-oxo-3-azabicyclo[3.1.0]hex-6-yl]phenyl}--
2-oxo-1,3-oxazolidine-5-carboxamide;
(5R)-3-{3,5-difluoro-4-[(1S,5R,6R)-2-oxo-3-azabicyclo[3.1.0]hex-6-yl]phen-
yl}-2-oxo-1,3-oxazolidine-5-carboxamide;
(1S,5R,6R)-6-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3--
oxazolidin-3-yl]phenyl}-3-azabicyclo[3.1.0]hexan-2-one;
(1S,5R,6R)-6-{2,6-difluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)--
1,3-oxazolidin-3-yl]phenyl}-3-azabicyclo[3.1.0]hexan-2-one;
N-{[4-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-diflu-
orophenyl}-5-oxoisoxazol-2(5H)-yl]methyl}acetamide; and
pharmaceutically acceptable salts thereof.
10. A method for the treatment of microbial infection in a mammal
which method comprises administering to said mammal an effective
amount of the compound of claim 1.
11. The method of claim 10 wherein said compound of claim 1 is
administered to the mammal in a pharmaceutical composition orally,
parenterally, transdermally, or topically.
12. The method of claim 10 wherein said compound is administered in
an amount of from about 0.1 to about 100 mg/kg of body
weight/day.
13. The method of claim 10 wherein said compound is administered in
an amount of from about 1 to about 50 mg/kg of body weight/day.
14. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
Description
FIELD OF THE INVENTION
[0001] This invention relates to novel [3.1.0]bicyclohexyl
phenyloxazolidinone derivatives, pharmaceutical compositions
thereof, methods for their use, and methods for preparing the
bicyclic derivatives. These compounds display potent activities
against gram-positive and/or gram-negative bacteria.
BACKGROUND OF THE INVENTION
[0002] Due to ever-increasing antibiotic resistance, structurally
novel antibacterials with a new mode of action have become
increasingly important in the treatment of bacterial infections.
Effective antibacterials should exhibit potent activity against a
number of human and veterinary pathogens, including gram-positive
aerobic bacteria such as multiply-resistant staphylococci and
streptococci, anaerobic organisms such as bacteroides and
clostridia species, and acid-fast organisms such as Mycobacterium
tuberculosis and Mycobacterium avium. The present invention
provides structurally novel pharmaceutical compounds with expanded
spectrum of antibacterial activity.
[0003] Among newer antibacterial agents, oxazolidinone compounds
are the most recent synthetic class of antimicrobials active
against a number of pathogenic microorganisms. However,
oxazolidinones generally do not demonstrate useful levels of
activity against aerobic gram-negative organisms. Thus, the use of
these oxazolidinone antibacterial agents is limited to infectious
states caused by gram-positive bacteria. We have now discovered
that [3.1.0]bicyclohexylphenyl oxazolidinone derivatives and
analogues of the present invention possess enhanced
anti-gram-positive activity and/or expand the spectrum of
antimicrobial activity to include gram-negative organisms such as
Haemophilus influenza and Moraxella catarrhalis.
SUMMARY OF THE INVENTION
[0004] The present invention relates to novel [3.1.0]bicyclohexyl
phenyl-oxazolidinone derivatives that display potent activities
against gram-positive and/or gram-negative bacteria. The present
invention also relates pharmaceutical compositions, methods of use,
and methods for preparing these [3.1.0]bicyclohexyl
phenyloxazolidinone derivatives.
[0005] In one of its composition aspects, the present invention
provides a compound of Formula I ##STR2## wherein A is a structure
i, ii, iii, or iv ##STR3## where the dashed line in formula iii
represents an optional double bond; [0006] n is an integer equal to
0 or 1; [0007] Y is selected from the group consisting of
--SO.sub.m--, --O-- and --N(R.sup.8)--; where m is an integer equal
to 0, 1, or 2; [0008] Z is selected from the group consisting of
--C(.dbd.Q)R.sup.1, --NHC(.dbd.Q)R.sup.1, --C(.dbd.Q)NHR.sup.1,
--NHC(.dbd.NCN)R.sup.1, --NHC(.dbd.NNO.sub.2)R.sup.1,
--SO.sub.2R.sup.1, --NH.sub.2, --NH-het.sup.1, --O-het.sup.1,
--S-het.sup.1, and -het.sup.2; [0009] Q is oxygen or sulfur; [0010]
W is selected from the group consisting of --CH.sub.2--,
--C(.dbd.O)--, --C(.dbd.NOH)--, and --C(.dbd.NOC.sub.1-4alkyl)-;
[0011] R.sup.1 is selected from the group consisting of --H, OH,
--NH.sub.2, --NHC.sub.1-4alkyl, --C.sub.1-4alkyl,
--C.sub.2-4alkenyl, --(CH.sub.2).sub.pC(.dbd.O)C.sub.1-4alkyl,
--OC.sub.1-4alkyl, --SC.sub.1-4alkyl,
--(CH.sub.2).sub.pC.sub.3-6cycloalkyl, --CH.dbd.CH-aryl,
--CH.dbd.CH-het.sup.1, --CH.sub.2C(.dbd.O)-aryl, and
--CH.sub.2C(.dbd.O)-het.sup.1; where p is an integer equal to 0, 1
or 2; [0012] R.sup.2 and R.sup.3 are independently selected from
the group consisting of --H and --F; [0013] R.sup.4 and R.sup.5 are
independently selected from the group consisting of --H, --Cl, --F;
--CH.sub.3, --NH.sub.2, and --OH; [0014] R.sup.6 and R.sup.7 are
independently selected from the group consisting of --H and
--C.sub.1-4alkyl; [0015] R.sup.8 is independently selected from the
group consisting of --H, --OH, --NR.sup.9R.sup.10,
--C.sub.1-4alkyl, --C.sub.3-6cycloalkyl, --C.sub.1-4heteroalkyl,
-aryl, -het.sup.1, --C.sub.1-14alkylNR.sup.9R.sup.10,
--(CH.sub.2).sub.pC(.dbd.O)C.sub.1-4alkyl,
--(CH.sub.2).sub.pC(.dbd.O)C.sub.1-4heteroalkyl, --C(.dbd.O)H,
--(CH.sub.2).sub.pC(.dbd.O)OR.sup.9,
--(CH.sub.2).sub.pC(.dbd.O)C.sub.1-4alkylOR.sup.9,
--(CH.sub.2).sub.pC(.dbd.O)NR.sup.9R.sup.10,
--(CH.sub.2).sub.pC(.dbd.O)NR.sup.9OR.sup.10,
--(CH.sub.2).sub.pC(.dbd.NOC.sub.1-4alkyl)H,
--(CH.sub.2).sub.pC(.dbd.NOC.sub.1-4alkyl)C.sub.1-4alkyl,
--(CH.sub.2).sub.pC(.dbd.O)het.sup.1, and
--(CH.sub.2).sub.pC(.dbd.NOC.sub.1-4alkyl)het.sup.1; where p and
het.sup.1 are as defined herein; [0016] where each R.sup.9 and
R.sup.10 are independently --H, --C.sub.1-4alkyl,
--C.sub.3-6cycloalkyl, -aryl, -het.sup.1,
--C(.dbd.O)C.sub.1-4alkyl, --C(.dbd.O)aryl, --C(.dbd.O)het.sup.1,
--SO.sub.2C.sub.1-4alkyl, or --SO.sub.2NH.sub.2; [0017] and a
pharmaceutically acceptable salts thereof; [0018] with the proviso
that when Y is --O-- or --SO.sub.m--, then W is --CH.sub.2--.
[0019] In another of its composition aspects, the present invention
provides for pharmaceutical compositions comprising a compound of
Formula I, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
[0020] In one of its method aspects, the present invention provides
for methods for the treatment of a microbial infection in a mammal
by administering to the mammal an effective amount of the compound
of Formula I. The compound of Formula I may be administered to the
mammal in a pharmaceutical composition either orally, parenterally,
transdermally, or topically. The compound may be administered in an
amount of from about 0.1 to about 100 mg/kg of body weight/day. The
compound may also be administered in an amount of from about 1 to
about 50 mg/kg of body weight/day.
[0021] In another of its method aspects, the present invention
provides for a method for treating gram-negative microbial
infections in humans or other warm-blooded animals by administering
to the subject in need thereof a therapeutically effective amount
of a compound of Formula I, or a pharmaceutically acceptable salt
thereof. The compound of Formula I may be administered to the
mammal in a pharmaceutical composition either orally, parenterally,
transdermally, or topically. The compound of Formula I may be
administered in an amount of from about 0.1 to about 100 mg/kg of
body weight/day, or in an amount of from about 1 to about 50 mg/kg
of body weight/day.
[0022] The present invention also provides novel intermediates and
processes that are useful for preparing compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
[0023] Unless otherwise stated, the following terms used in the
specification and claims have the meanings given below:
[0024] The carbon atom content of various hydrocarbon-containing
moieties is indicated by a prefix designating the minimum and
maximum number of carbon atoms in the moiety, i.e., the prefix
C.sub.i-j indicates a moiety of the integer "i" to the integer "j"
carbon atoms, inclusive. Thus, for example, C.sub.1-7 alkyl refers
to alkyl of one to seven carbon atoms, inclusive.
[0025] The terms alkyl, alkenyl, etc. refer to both straight and
branched groups, but reference to an individual radical such as
"propyl" embraces only the straight chain radical, a branched chain
isomer such as "isopropyl" being specifically referred to. Unless
defined otherwise, the term "alkyl" refers to alkyl groups of from
1 to 6 carbon atoms and the term "alkenyl" refers to alkenyl groups
of from 2 to 6 carbon atoms. The alkyl, alkenyl, etc. group may be
optionally substituted with one, two, or three substituents, such
as, halo, hydroxy, alkoxy, amino, aryl, het.sup.1, or het.sup.2. In
addition, the functional groups on an alkyl group may optionally be
protected using protecting groups well known in the art, such as
Boc, Cbz, and the like. For examples of protecting groups and
procedures for their introduction and removal see one of the
general texts on the subject such as "Protecting Groups" by Philip
J. Kocienski (publisher: Georg Thieme Verlag Stuttgart, 1994).
Representative examples of alkyl groups include, but are not
limited to, difluoromethyl, 2-fluoroethyl, --CH.dbd.CH-aryl,
--CH.dbd.CH-het.sup.1, --CH.sub.2-phenyl, --CH.sub.2--OH,
--CH.sub.2--NHCbz, and the like.
[0026] The term "alkoxy" refers to the group --O-alkyl, where alkyl
is defined herein above.
[0027] The term "cycloalkyl" means a cyclic saturated monovalent
hydrocarbon group of three to seven carbon atoms, e.g.,
cyclopropyl, cyclohexyl, and the like. The cycloalkyl group may be
optionally substituted with one, two, or three substituents, such
as, halo, hydroxy, alkoxy, amino, aryl, het.sup.1, or het.sup.2. In
addition, the functional groups on a cycloalkyl group may
optionally be protected using protecting groups well known in the
art, such as Boc, Cbz, and the like. For examples of protecting
groups and procedures for their introduction and removal see one of
the general texts on the subject such as "Protecting Groups" by
Philip J. Kocienski (publisher: Georg Thieme Verlag: Stuttgart,
1994).
[0028] The term "heteroalkyl" means an alkyl or cycloalkyl group,
as defined above, having at least one atom replaced by a heteroatom
selected from N, O, or S(O).sub.q, where q is 0, 1 or 2. The
heteroalkyl group may be optionally substituted with one, two, or
three substituents, such as, halo, hydroxy, alkoxy, amino, thio,
aryl, het.sup.1, or het.sup.2. In addition, the functional groups
on a heteroalkyl group may optionally be protected using protecting
groups well known in the art, such as Boc, Cbz, and the like. For
examples of protecting groups and procedures for their introduction
and removal see one of the general texts on the subject such as
"Protecting Groups" by Philip J. Kocienski (publisher: Georg Thieme
Verlag: Stuttgart, 1994). In addition, the heteroalkyl group may be
optionally substituted with substituents, including
--NR.sup.aR.sup.b, --OR.sup.a, or --S(O).sub.qR.sup.c, wherein
R.sup.a is hydrogen, alkyl, cycloalkyl, optionally substituted
aryl, optionally substituted heterocyclic, or --COR (where R is
alkyl); R.sup.b is hydrogen, alkyl, --SO.sub.2R (where R is alkyl
or hydroxyalkyl), --SO.sub.2NRR' (where R and R' are independently
of each other hydrogen or alkyl), --CONR'R'' (where R' and R'' are
independently of each other hydrogen or alkyl); q is an integer
from 0 to 2; and R.sup.c is hydrogen, alkyl, cycloalkyl, optionally
substituted aryl, optionally substituted heterocyclic, or
--NR.sup.aR.sup.b where R.sup.a and R.sup.b are as defined above.
Representative examples include, but are not limited to
2-methoxyethyl (--CH.sub.2CH.sub.2OCH.sub.3), 2-hydroxyethyl
(--CH.sub.2CH.sub.2OH), 2,3-dihydroxypropanoyl
(--CH(OH)CH.sub.2OH), hydroxymethyl (--CH.sub.2OH), 2-aminoethyl
(--CH.sub.2CH.sub.2NH.sub.2), 2-dimethylaminoethyl
(--CH.sub.2CH.sub.2NHCH.sub.3), 2-morpholinoethyl, benzyloxymethyl,
and the like.
[0029] The term "halo" refers to the halogens, such as fluoro (F),
chloro (Cl), bromo (Br), or iodo (I).
[0030] Aryl refers to phenyl, biphenyl, or naphthyl, optionally
substituted with halo, --C.sub.1-4 alkyl, --OH, --OC.sub.1-4 alkyl,
--S(O).sub.qC.sub.1-4alkyl wherein q is 0, 1, or 2,
--C.sub.1-4alkylNH.sub.2, --C(.dbd.O)H, or --C.dbd.N--OR.sup.d
wherein R.sup.d is hydrogen or alkyl.
[0031] The term heterocyclic group or ring refers to an aromatic
ring or a saturated or unsaturated ring that is not aromatic of 1
to 10 carbon atoms and 1 to 4 heteroatoms selected from the group
consisting of oxygen, nitrogen, and sulfur within the ring. The
heterocyclic ring may be optionally substituted with halo,
--C.sub.1-4 alkyl, --OH, --OC.sub.1-4 alkyl,
--S(O).sub.qC.sub.1-4alkyl wherein q is 0, 1, or 2,
--C.sub.1-4alkylNH.sub.2, --C(.dbd.O)H, or --C.dbd.N--OR.sup.d
wherein R.sup.d is hydrogen or alkyl. In addition, one of the
carbon atoms of the heterocyclic ring may optionally be replaced by
>C.dbd.O or >C.dbd.S. Examples of heterocyclic rings include,
but are not limited to, azetidine, pyrrole, imidazole, pyrazole,
1,2,3-triazole, 1,3,4-triazole, oxazole, thiazole, isoxazole,
isothiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole,
1,2,3-thiadiazole, tetrazole, pyridine, pyrazine, pyrimidine,
pyridazine, indolizine, isoindole, indole, dihydroindole, indazole,
purine, quinolizine, isoquinoline, quinoline, phthalazine,
quinoxaline, quinazoline, cinnoline, pteridine, carbazole,
carboline, phenanthridine, acridine, phenanthroline, isothiazole,
phenazine, isoxazole, isoxazolinone, phenoxazine, phenothiazine,
imidazolidine, imidazoline, piperidine, piperazine, indoline,
phthalimide, 1,2,3,4-tetrahydroisoquinoline,
4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiadiazole
tetrazole, thiazolidine, thiophene, benzo[b]thiophene, morpholine,
thiomorpholine, (also referred to as thiamorpholine,), piperidine,
pyrrolidine, tetrahydrofuran, and the like.
[0032] Specifically, het.sup.1 refers to a C-linked five- (5) or
six- (6) membered heterocyclic ring, which is optionally
substituted on an available carbon atom with one or two
substituents independently selected from C.sub.1-4alkyl,
OC.sub.1-4alkyl, amino, C.sub.1-4alkylNR.sup.aR.sup.b, (where
R.sup.a and R.sup.b are as defined above) and halogen and/or on an
available nitrogen atom (provided that the ring is not thereby
quaternized) with C.sub.1-4alkyl. Representative examples of
"het.sup.1" include, but are not limited to, pyridine, thiophene,
furan, pyrazole, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl,
4-pyridazinyl, 3-pyrazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl,
4-imidazolyl, 3-isoxaz-olyl, 4-is-oxaz-olyl, 5-isoxaz-olyl,
3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl,
4-oxo-2-oxazolyl, 5-oxazolyl, 1,2,3-oxathiazole, 1,2,3-oxadiazole,
1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl,
4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole,
5-isothiazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,
2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl,
5-isopyrrolyl, 1,2,3,-oxathiazole-1-oxide, 1,2,4-oxadiazol-3-yl,
1,2,4-oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl,
1,2,4-thiadiazol-3-yl, 1,2,5-thiadiazol-3-yl,
1,2,4-thiadiazol-5-yl, 3-oxo-1,2,4-thiadiazol-5-yl,
1,3,4-thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5-yl,
1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-5-yl,
5-oxazolyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl,
1,3,4,-oxadiazole, 4-oxo-2-thiazolinyl, or
5-methyl-1,3,4-thiadiazol-2-yl, thiazoledione,
1,2,3,4-thiatriazole, or 1,2,4-dithiazolone
[0033] Specifically, het.sup.2 refers to a C-linked or N-linked
five- (5) or six- (6) membered heterocyclic ring having 1 to 4
nitrogen atoms, and optionally having one oxygen or sulfur atom,
and optionally substituted on an available carbon atom with one or
two substituents independently selected from halogen, cyano, nitro,
azido, formyl, --C.sub.1-4alkyl, --OC.sub.1-4alkyl,
--C.sub.2-4alkenyl, --OC.sub.2-4alkenyl, --C(.dbd.O)C.sub.1-4alkyl,
--C.sub.3-6cycloalkyl, --OC.sub.3-6cycloalkyl,
--C.sub.1-4heteroalkyl, --NR.sup.aR.sup.b,
--NR.sup.aC(.dbd.O)C.sub.1-4alkyl, or
--NR.sup.aC(.dbd.O)OC.sub.1-4alkyl where R.sup.a and R.sup.b are as
defined herein. Representative examples of "het.sup.2" include, but
are not limited to pyrrolyl, imidazolyl, pyrazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, and
isoxazolidinonyl group.
[0034] A C-linked heterocyclic ring is a heterocyclic group as
defined above wherein the group is attached via a carbon atom of
the heterocyclic ring.
[0035] An N-linked heterocyclic ring is a heterocyclic group as
defined above wherein the group is attached via a nitrogen atom of
the heterocyclic ring.
[0036] "Optional" or "optionally" means that the subsequently
described event or circumstance may, but need not, occur, and that
the description includes instances where the event or circumstance
occurs and instances in which it does not. For example, "aryl group
optionally mono- or di- substituted with an alkyl group" means that
the alkyl may but need not be present, and the description includes
situations where the aryl group is mono- or disubstituted with an
alkyl group and situations where the aryl group is not substituted
with the alkyl group.
[0037] Compounds that have the same molecular formula but differ in
the nature or sequence of bonding of their atoms or the arrangement
of their atoms in space are termed "isomers". Isomers that differ
in the arrangement of their atoms in space are termed
"stereoisomers".
[0038] Stereoisomers that are not mirror images of one another are
termed "diastereomers" and those that are non-superimposable mirror
images of each other are termed "enantiomers". When a compound has
an asymmetric center, for example, it is bonded to four different
groups, a pair of enantiomers is possible. An enantiomer can be
characterized by the absolute configuration of its asymmetric
center and is described by the R- and S-sequencing rules of Cahn
and Prelog, or by the manner in which the molecule rotates the
plane of polarized light and designated as dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a "racemic mixture".
[0039] The compounds of this invention may possess one or more
asymmetric centers; such compounds can therefore be produced as
individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless
indicated otherwise, the description or naming of a particular
compound in the specification and claims is intended to include
both individual enantiomers and mixtures, racemic or otherwise,
thereof. The methods for the determination of stereochemistry and
the separation of stereoisomers are well-known in the art (see
discussion in Chapter 4 of "Advanced Organic Chemistry", 4th
edition J. March, John Wiley and Sons, New York, 1992).
[0040] A "pharmaceutically acceptable carrier" means a carrier that
is useful in preparing a pharmaceutical composition that is
generally safe, non-toxic and neither biologically nor otherwise
undesirable, and includes a carrier that is acceptable for
veterinary use as well as human pharmaceutical use. "A
pharmaceutically acceptable carrier" as used in the specification
and claims includes both one and more than one such carrier.
[0041] A "pharmaceutically acceptable salt" of a compound means a
salt that is pharmaceutically acceptable and that possesses the
desired pharmacological activity of the parent compound. Such salts
include: [0042] (1) acid addition salts, formed with inorganic
acids such as hydrochloric acid, hydrobromic acid, sulfuric acid,
nitric acid, phosphoric acid, and the like; or formed with organic
acids such as acetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid,
and the like; or [0043] (2) salts formed when an acidic proton
present in the parent compound either is replaced by a metal ion,
e.g., an alkali metal ion, an alkaline earth ion, or an aluminum
ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, tromethamine, N-methylglucamine,
and the like.
[0044] "Treating" or "treatment" of a disease includes: [0045] (1)
preventing the disease, i.e. causing the clinical symptoms of the
disease not to develop in a mammal that may be exposed to or
predisposed to the disease but does not yet experience or display
symptoms of the disease, [0046] (2) inhibiting the disease, i.e.,
arresting or reducing the development of the disease or its
clinical symptoms, or [0047] (3) relieving the disease, i.e.,
causing regression of the disease or its clinical symptoms.
[0048] A "therapeutically effective amount" means the amount of a
compound that, when administered to a mammal for treating a
disease, is sufficient to effect such treatment for the disease.
The "therapeutically effective amount" will vary depending on the
compound, the disease and its severity and the age, weight, etc.,
of the mammal to be treated.
[0049] "Leaving group" has the meaning conventionally associated
with it in synthetic organic chemistry i.e., an atom or group
capable of being displaced by a nucleophile and includes halogen,
alkylsulfonyloxy, ester, or amino such as chloro, bromo, iodo,
mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy,
N,O-dimethylhydroxyl-amino, and the like.
[0050] "Pro-drugs" mean any compound that releases an active parent
drug according to a compound of the subject invention in vivo when
such prodrug is administered to a mammalian subject. Prodrugs of a
compound of the subject invention are prepared by modifying
functional groups present in a compound of the subject invention in
such a way that the modifications may be cleaved in vivo to release
the parent compound. Prodrugs include compounds of the subject
invention wherein a hydroxy, sulfhydryl or amino group in the
compound is bonded to any group that may be cleaved in vivo to
regenerate the free hydroxyl, amino, or sulfhydryl group,
respectively. Examples of prodrugs include, but are not limited to
esters (e.g., acetate, formate, and benzoate derivatives),
carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional
groups in compounds of the subject invention, and the like.
[0051] Mammal refers to human or warm-blooded animals including
livestock and companion animals.
[0052] The compounds of the present invention are generally named
according to the IUPAC or CAS nomenclature systems. Abbreviations
which are well known to one of ordinary skill in the art may be
used (e.g. "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "Ac"
for "acetyl" "h" for hour or hours and "rt" for room
temperature).
ILLUSTRATIVE EMBODIMENTS
[0053] Within the broadest definition of the present invention,
certain compounds of the compounds of formula I may be preferred.
Specific and preferred values listed below for radicals,
substituents, and ranges, are for illustration only; they do not
exclude other defined values or other values within defined ranges
for the radicals and substituents.
[0054] Specifically the term C.sub.1-4alkyl can be methyl, ethyl,
propyl, isopropyl, butyl, iso-butyl, sec-butyl, and their isomeric
forms thereof.
[0055] Specifically, C.sub.2-4alkenyl can be vinyl, propenyl,
allyl, butenyl, and their isomeric forms thereof.
[0056] Specifically, C.sub.3-6cycloalkyl can be cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, and their isomeric forms
thereof.
[0057] Specifically, C.sub.1-4heteroalkyl can be hydroxymethyl,
2-hydroxyethyl, 2-methoxyethyl, 2-morpholinoethyl.
[0058] Specifically, R.sup.1 is C.sub.1-4alkyl, optionally
substituted with one, two, or three fluoro (F) or chloro (Cl).
[0059] Specifically, R.sup.1 is --CH.sub.3, --CHF.sub.2,
--CF.sub.3, --CHCl.sub.2, --CH.sub.2CF.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CHF.sub.2, or --CH.sub.2CH.sub.2F.
[0060] Specifically, R.sup.1 is --CH.dbd.CH-aryl.
[0061] Specifically, R.sup.1 is --CH.dbd.CH-het.sup.1.
[0062] Specifically, R.sub.1 is
--CH.sub.2C(.dbd.O)C.sub.1-4alkyl.
[0063] Specifically, R.sup.4 and R.sup.5 are independently --H or
--F.
[0064] Specifically, Y is --N(R.sup.8)--.
[0065] Specifically, R.sup.8 is --C(.dbd.O)CH.sub.2OH or
--C(.dbd.O)CH(OH)CH.sub.2OH.
[0066] Specifically, Y is --SO.sub.m-- or --O--.
[0067] Specifically, Z is --C(.dbd.O)NH.sub.2.
[0068] Specifically, m is 1 or 2.
[0069] Specifically, W is --CH.sub.2--.
[0070] Specifically, R.sup.6 and R.sup.7 are --H.
[0071] Specifically, R.sup.4 and R.sup.5 are independently --H or
--F and R.sup.6 and R.sup.7 are --H.
[0072] Specifically, het.sup.1 is isoxazolyl, 1,2,5-thiadiazolyl,
or pyridyl.
[0073] Specifically, het.sup.2 is 1,2,3-triazolyl.
[0074] Specific compounds of the present invention are those
wherein structure i, ii, or iii has an optical configuration as
depicted below: ##STR4##
[0075] The dotted line within structure iii indicates an optional
double bond at that position. It will be appreciated by those
skilled in the art that compounds of the present invention may have
additional chiral centers and, as such, can be isolated in
optically active and racemic forms. The present invention
encompasses any racemic, optically active, tautomeric, or
stereoisomeric form, or mixture thereof, of a compound of the
invention.
[0076] Other specific compounds of the present invention are the
compounds of Formula II: ##STR5##
[0077] Other specific compounds of the present invention are the
compounds of Formula III: ##STR6##
[0078] Other specific compounds of the present invention are the
compounds of Formula IV: ##STR7##
[0079] Other specific compounds of the present invention are the
compounds of Formula V ##STR8##
[0080] Other specific compounds of the present invention are the
compounds of Formula VI: ##STR9##
[0081] Other specific compounds of the present invention are the
compounds of Formula VII: ##STR10##
[0082] Other specific compounds of the present invention are the
compounds of Formula VIII: ##STR11##
[0083] A particularly preferred group of compounds includes the
following: [0084]
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}--
2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; [0085]
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]-
phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; [0086]
N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fl-
uorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; [0087]
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-
-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; [0088]
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6--
yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; [0089]
2,2-difluoro-N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo-
[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]ethanethioamide;
[0090] methyl
exo-(1R,5S)-6-(4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-
-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate; [0091]
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-formyl-3-azabicyclo[3.1.0]hex-6-yl]-
phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; [0092]
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-((2S)-2,3-dihydroxypropanoyl)-3-aza-
bicyclo
[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide-
; [0093]
exo-(1R,5S)-6-(4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazol-
idin-3-yl}-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxamide;
[0094]
exo-(1R,5S)-6-[4-((5S)-5-{[(2,2-difluoroethanethioyl)amino]methyl-
}-2-oxo-1,3-oxazolidin-3-yl)-2-fluorophenyl]-3-azabicyclo[3.1.0]hexane-3-c-
arboxamide; [0095]
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-
-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; [0096]
N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5--
difluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; [0097]
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]pheny-
l}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; [0098]
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]he-
x-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; [0099]
N-[((5S)-3-{4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3--
oxazolidin-5-yl)methyl]acetamide; [0100]
N-[((5S)-3-{4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl-
}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; [0101]
N-[((5S)-3-{4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-
-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; [0102]
N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]pheny-
l}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; [0103]
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluoro-
phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide; [0104]
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluoro-
phenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide; [0105]
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-difl-
uorophenyl}-2-oxo-1,3-oxazolidine-5-carboxamide; [0106]
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-difl-
uorophenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide; [0107]
(5R)--N-ethyl-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-
-3,5-difluorophenyl}-2-oxo-1,3-oxazolidine-5-carboxamide; [0108]
(5R)--N-(2-fluoroethyl)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0-
]hex-6-yl]-3,5-difluorophenyl}-2-oxo-1,3-oxazolidine-5-carboxamide;
[0109]
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]p-
henyl}-2-oxo-1,3-oxazolidine-5-carboxamide; [0110]
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phen-
yl}-2-oxo-1,3-oxazolidine-5-carboxamide; [0111]
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phen-
yl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide; [0112]
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]-
phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide; [0113]
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]-
phenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide; [0114]
(5R)--N-ethyl-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]-
hex-6-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide; [0115]
(5R)-3-{4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-
-1,3-oxazolidine-5-carboxamide; [0116]
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-ox-
o-1,3-oxazolidine-5-carboxamide; [0117]
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}--
2-oxo-1,3-oxazolidine-5-carboxamide; [0118]
(5R)-3-{4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxa-
zolidine-5-carboxamide; [0119]
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]p-
henyl}-2-oxo-1,3-oxazolidine-5-carboxamide; [0120]
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]p-
henyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide; [0121]
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6--
yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide; [0122]
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6--
yl]phenyl}-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide; [0123]
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-
-1,3-oxazolidine-5-carboxamide; [0124]
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-N-met-
hyl-2-oxo-1,3-oxazolidine-5-carboxamide; [0125]
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-
-oxo-1,3-oxazolidine-5-carboxamide; [0126]
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-N-
-methyl-2-oxo-1,3-oxazolidine-5-carboxamide; [0127]
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-
-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide; [0128]
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]-
phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide; [0129]
N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5--
difluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide;
[0130]
N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fl-
uorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide; [0131]
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]he-
x-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide; [0132]
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6--
yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide; [0133]
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]pheny-
l}-2-oxo-1,3-oxazolidin-5-yl)methyl]propanamide; [0134]
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-
-oxo-1,3-oxazolidin-5-yl)methyl]propanamide; [0135]
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phen-
yl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one; [0136]
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]-
phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;
[0137]
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluoro-
phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;
[0138]
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-difl-
uorophenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;
[0139]
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]p-
henyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one; [0140]
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6--
yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;
[0141]
(5R)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-5-(1H-
-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one; [0142]
(5R)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-5-
-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one; [0143]
N-[((5S)-3-{3-fluoro-4-[(1S,5R,6R)-2-oxo-3-azabicyclo[3.1.0]hex-6-yl]phen-
yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; [0144]
N-[((5S)-3-{3,5-difluoro-4-[(1S,5R,6R)-2-oxo-3-azabicyclo[3.1.0]hex-6-yl]-
phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; [0145]
(5R)-3-{3-fluoro-4-[(1S,5R,6R)-2-oxo-3-azabicyclo[3.1.0]hex-6-yl]phenyl}--
2-oxo-1,3-oxazolidine-5-carboxamide; [0146]
(5R)-3-{3,5-difluoro-4-[(1S,5R,6R)-2-oxo-3-azabicyclo[3.1.0]hex-6-yl]phen-
yl}-2-oxo-1,3-oxazolidine-5-carboxamide; [0147]
(1S,5R,6R)-6-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3--
oxazolidin-3-yl]phenyl}-3-azabicyclo[3.1.0]hexan-2-one; [0148]
(1S,5R,6R)-6-{2,6-difluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)--
1,3-oxazolidin-3-yl]phenyl}-3-azabicyclo[3.1.0]hexan-2-one; [0149]
N-{[4-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-diflu-
orophenyl}-5-oxoisoxazol-2(5H)-yl]methyl}acetamide; and
pharmaceutically acceptable salts thereof.
[0150] The compounds discussed herein are named according to one of
the structures set forth below in which the ring positions are
numbered according to convention: ##STR12## [0151]
6-(4-{5-[Z.sup.2]-2-oxo-1,3-oxazolidin-3-yl}-2,6-(R.sup.4 and/or
R.sup.5)-phenyl)-3-Y-bicyclo[3.1.0]hexane-3-(R.sup.8); ##STR13##
[0152] N-[(3-{3,5-(R.sup.4 and/or
R.sup.5)-4-[3-(R.sup.8)-3-Y-bicyclo[3.1.0]hex-6-yl]-phenyl}-2-oxo-1,3-oxa-
zolidin-5-yl)(CH.sub.2).sub.n]-(Z). or [0153] 3-{3,5-(R.sup.4
and/or
R.sup.5)-4-[3-(R.sup.8)-3-Y-bicyclo[3.1.0]hex-6-yl]-phenyl}-2-oxo-1,3-oxa-
zolidin-5-(Z). General Synthetic Schemes
[0154] The compounds of this invention can be prepared in
accordance with one or more of the Schemes discussed below. Further
discussions can be found in International Publication WO 02/06278,
which is incorporated herein by reference.
[0155] The starting materials, intermediates, and final compounds
described in this invention were prepared using common procedures
and techniques that are well known to persons of ordinary skill in
organic chemistry. These compounds were prepared in accordance with
one or more of the following Schemes as described below.
[0156] It will be appreciated that some of the processes described
herein require the use of protective groups to prevent the
undesired reactivity of certain substituents. A person skilled in
organic chemistry will recognize when such protection may be
required and how such groups may be installed and subsequently
removed. For examples of protecting groups and procedures for their
introduction and removal see one of the general texts on the
subject such as "Protecting Groups" by Philip J. Kocienski
(publisher: Georg Thieme Verlag: Stuttgart, 1994).
[0157] Chiral intermediates of enantiomeric purity may be prepared
using various asymmetric reaction methodologies or, alternatively,
by resolution of the racemic mixtures. It is known that the
bicyclo[3.1.0]hexyl ring systems described herein can exist as
either endo or exo diastereomers. When products comprised of
bicyclo[3.1.0]hexyl ring systems form as mixtures, these
diastereomers can be separated by standard techniques of organic
chemistry, for example, by silica gel chromatography.
[0158] Scheme I illustrates two methods for preparing benzaldehyde
starting materials required for the preparation of the compounds of
this invention. In the first method, a substituted 5-nitrotoluene
analog is oxidized to the corresponding benzaldehyde (step 1). This
oxidation can be accomplished according to the procedure reported
by Gordeev et. al. in U.S. Pat. No. 6,239,152, incorporated herein
in its entirety.
[0159] Step 2 of Scheme I involves reduction of the nitro
substituent to an amino substituent. This reduction is generally
accomplished by reacting the nitro intermediate with iron metal.
The reaction is carried out at temperatures between 60.degree. C.
and 90.degree. C. in mixtures of water and alcohol (methanol,
ethanol, etc.) as solvent, and in the presence of ammonium
chloride. Optionally, reductions of this type are conducted by
reaction with other metals such as tin or zinc or by hydrogenation
using a palladium or platinum catalyst (see Rylander Hydrogenation
Methods; Academic Press: New York, 1985, pp. 104-116). The reaction
is run until complete, usually from about 2 hours to about 24
hours. ##STR14##
[0160] Step 3 of Scheme I involves the introduction of carbamate
protection (e.g., benzyloxycarbonyl (Cbz) or t-butoxycarbonyl
(Boc)) on the aniline formed in step 2. This is a standard
transformation that is typically carried out by reaction of the
amine with benzyl chloroformate, di-tert-butyl dicarbonate, or an
equivalent reagent (see Kocienski Protecting Groups; Georg Thieme
Verlag: Stuttgart, 1994, pp. 195-199). The reaction is typically
conducted at temperatures between 0.degree. C. and 25.degree. C. in
organic solvents such as dichloromethane in the presence of amines
such as triethylamine or pyridine and is run until substantially
complete, usually 2 hours to 16 hours. Optionally the reaction may
be performed in aqueous solutions in the presence of inorganic
bases such as sodium hydroxide or sodium bicarbonate.
[0161] A second method for preparing the benzaldehyde starting
material begins with a substituted aniline. Step A of Scheme I
involves protection of the amino group as a carbamate (e.g.,
isopropoxycarbonyl or t-butoxycarbonyl (Boc)). This is a standard
transformation that is typically carried out by reaction of the
amine with isopropyl chloroformate, di-tert-butyl dicarbonate, or
an equivalent reagent (see Kocienski Protecting Groups; Georg
Thieme Verlag: Stuttgart, 1994, pp. 195-199). The reaction is
typically conducted at temperatures between 0.degree. C. and
25.degree. C. in organic solvents such as tetrahydrofuran and using
a base such as lithium bis(trimethylsilyl) amide and is run until
complete, usually 2 hours to about 24 hours.
[0162] Step B of Scheme I illustrates the introduction of a formyl
group para to the carbamate substituent. This reaction is
accomplished by formation of the aryl lithium species and
subsequent reaction with dimethylformamide or equivalent
formylating reagent. The lithiation reaction is typically carried
out at temperatures below -50.degree. C. using strong bases such as
n-butyllithium or tert-butyllithium, optionally in the presence of
additives such as TMEDA (N,N,N',N'-tetramethylethylenediamine). The
formylating reagent may be added at temperatures below -50.degree.
C. and the reaction allowed to warm to room temperature. The
reaction is run until complete, usually 1 hours to about 3 hours.
The product of each step in Scheme I may be used as collected or
may be purified using conventional techniques such as preparative
TLC or HPLC, chromatography, precipitation, crystallization and the
like.
[0163] Scheme II illustrates the conversion of the benzaldehyde
starting materials (described in Scheme I) into
bis-hydroxymethylcyclopropane intermediates. These intermediates
can, in turn, be used to prepare bicyclo[3.1.0]hexane analogs with
various heteroatoms at the 3 position of the bicyclic ring.
[0164] Step 1 of Scheme II involves the reaction of the
benzaldehyde starting material with a phosphonate ylide. This
reaction, the Horner-Wadsworth-Emmons reaction, is well known to
those skilled in the art (for reviews, see Wadsworth in Organic
Reactions 1977, 25, pp. 73-253). The ylide is first formed by
reaction of a phosphonate (e.g. trimethyl phosphonoacetate) with a
strong base such as sodium hydride or n-butyllithium in solvents
such as dimethylformamide or tetrahydrofuran. After formation of
the ylide, it is reacted with the aldehyde in solvents such as DMSO
or DMF for about 4 hours to 20 hours at about 0.degree. C. to about
30.degree. C. to form the desired unsaturated ester product. The
product may be used as collected or may first be purified using
conventional techniques such as preparative TLC or HPLC,
chromatography, precipitation, crystallization and the like.
[0165] Step 2 of Scheme II involves reduction of the unsaturated
ester to an allylic alcohol. This is a very common reaction that
will be well known to those skilled in the art. The reduction is
carried out with reducing agents such as lithium aluminum hydride
or sodium borohydride (or an equivalent reagent). The reaction may
be conducted for about 1 hour to about 4 hours in ethereal solvents
such as tetrahydrofuran or diethyl ether at temperatures between
-40 and 25.degree. C. The product may be used as collected or may
first be purified using conventional techniques such as preparative
TLC or HPLC, chromatography, precipitation, crystallization and the
like.
[0166] Step 3 of Scheme II in involves the formation of a
diazoester. This is accomplished using glyoxylic acid chloride
p-toluenesulfonylhydrazone (prepared as described by C. J.
Blankley, F. J. Sauter and H. O. House, Organic Syntheses, Coll.
Vol. V, p. 258; John Wiley, New York (1973)). Reaction of this
reagent with the allylic alcohol may be carried out according to
the procedure described by Myers and Corey (Tetrahedron Letters,
1984, pp. 3559-3562). The product may be used as collected or may
first be purified using conventional techniques such as preparative
TLC or HPLC, chromatography, precipitation, crystallization and the
like. ##STR15##
[0167] Step 4 of Scheme II involves an intramolecular
cyclopropanation reaction. This transformation is usually
accomplished with a suitable transition metal catalyst, typically
of copper or rhodium (e.g.
bis-(N-t-butylsalicyl-aldiminato)copper(II), prepared as described
by R. G. Charles in J. Org. Chem. 1957, 22, 677). A solution of the
diazoester in toluene, dichloromethane or mixtures thereof is added
slowly using a dropping funnel or syringe pump to a refluxing
solution of the catalyst in toluene or similar solvent. The
reaction may be conducted at concentrations below 0.05M to avoid
dimerization of the diazoester and is run until substantially
complete, usually from about 12 hours to about 36 hours. The
product may be used as collected or may first be purified using
conventional techniques such as preparative TLC or HPLC,
chromatography, precipitation, crystallization and the like.
[0168] Step 5 of Scheme II involves reduction of the lactone ring
to a diol. This reduction can be accomplished using conditions
similar to those described above for step 2 of Scheme II. The
product may be used as collected or may first be purified using
conventional techniques such as preparative TLC or HPLC,
chromatography, precipitation, crystallization and the like.
[0169] Scheme III describes the preparation of
thiabicyclo[3.1.0]hexyl-substituted phenyloxazolidinones starting
from the diol intermediate described in Scheme II. Step 1 involves
conversion of the alcohol substituents into leaving groups (such as
mesylates). These transformations are well known to those skilled
in the art and may be performed with reagents such as
methanesulfonic anhydride, methanesulfonyl chloride,
p-toluenesulfonyl chloride, or equivalent reagents. The reactions
may be carried out for about 0.5 hours to about 2 hours in organic
solvents such as dichloromethane or tetrahydrofuran, and in the
presence of acid-scavenging amines such as triethylamine or
N,N-diisopropylethylamine a temperature of about 0.degree. C. to
40.degree. C. The product of this reaction may be used in the next
reaction as collected or may first be purified using conventional
techniques such as preparative TLC or HPLC, chromatography,
precipitation, crystallization and the like.
[0170] Step 2 of Scheme III describes a cyclization reaction in
which the bis-mesylate prepared in step 1 is reacted with a
nucleophilic sulfur source to form the thiabicyclo[3.1.0]hexane
ring. This reaction is generally conducted with sodium sulfide in
dipolar aprotic solvents such as dimethylsulfoxide.
[0171] Step 3 of Scheme III illustrates the construction of the
oxazolidinone ring from the aryl carbamate. Transformations of this
type are known art (see, e.g., International Publication WO
95/07271, published on 16 Mar. 1995). In step 3 the oxazolidinone
synthesis is performed with S-acetic acid
2-acetylamino-1-chloromethyl-ethyl. This reagent is prepared from
(S)-epichlorohydrin in three steps (epoxide ring opening with
benzaldehyde imine, imine hydrolysis, and peracylation with acetic
anhydride) according to the procedure described in U.S. patent
application Ser. No. 09/982,157, which is incorporated herein in
its entirety. The reaction of this reagent with aryl carbamates is
to afford the acetylaminomethyl-substituted oxazolidinone. The
reaction is performed in the presence of an organic base such as
lithium tert-butoxide, in a polar organic solvent such as
dimethylformamide, at temperatures of about 0.degree. C. to
25.degree. C. ##STR16##
[0172] Step 4 of Scheme III involves an optional oxidation of the
sulfur atom to form a sulfoxide or sulfone. These transformations
will be well known to one skilled in the art and a variety of
reagents are available (for a review see Hudlicky in Oxidations in
Organic Chemistry; American Chemical Society: Washington, 1990, pp
252-263). Sulfoxides are formed as a pair of diastereomers that are
often separable using flash column or preparative thin layer
chromatography. The oxidation to sulfoxide may be conducted with
sodium periodate in water-alcohol mixtures. Oxidation to sulfone
may be carried out with peracetic acid in aqueous tetrahydrofuran.
These reactions are typically carried out at temperatures of about
0.degree. C. to 25.degree. C.
[0173] Scheme IV describes the preparation of
azabicyclo[3.1.0]hexyl-substituted phenyloxazolidinones starting
from the diol intermediate described in Scheme II. Step 1 involves
conversion of the alcohol substituents into leaving groups (such as
mesylates). This transformation is conducted as described above for
step 1 of Scheme III.
[0174] Step 2 of Scheme IV describes a cyclization reaction in
which the bis-mesylate prepared in step 1 is reacted with a
nucleophilic amine source such as 4-methoxybenzylamine or similar
amine. This reaction is conducted neat, using the amine as solvent
and at temperatures of around 0 to 30.degree. C. The choice of
amine is important in that the subsequent deprotection step (step
4) should be facile.
[0175] Step 3 of Scheme IV involves construction of the
oxazolidinone ring. This transformation is conducted as described
above for step 3 of Scheme III. ##STR17##
[0176] Step 4 of Scheme IV involves deprotection of the tertiary
amine to reveal the free secondary azabicyclic amine. The choice of
reagent for this deprotection will depend on the amine used for
cyclization in step 2. It is understood that a person skilled in
the art will select the appropriate deprotection conditions for the
amine chosen. In this example, removal of the 4-methoxybenzylamine
group can be accomplished by hydrogenolysis. Hydrogenolysis
reactions are well known and are typically carried out using
palladium catalysts, of which several varieties are available, and
under an atmosphere of hydrogen gas. Removal of the p-methoxybenzyl
group may be conducted using palladium hydroxide on carbon as
catalyst and a solvent system of methanol, ethanol, ethyl acetate,
or mixtures thereof. These reactions are typically carried out at
temperatures of about 15.degree. C. to 35.degree. C. For analogs
lacking fluorine substitution on the aromatic ring, an alternate
procedure may be employed, involving reaction with 1-chloroethyl
chloroformate or similar reagent in the presence of amine
scavenging bases such as triethylamine and in solvents such as
dichloromethane (see Olofson et al. in J. Org. Chem. 1984, pp
2081-2082 and Yang et al. in Synlett, 1993, pp 195-196). This
alternative procedure circumvents the problem of cyclopropane
ring-opening that is sometimes encountered in the des-fluoro
aromatic analogs.
[0177] Step 5 of Scheme IV represents a coupling step in which the
free secondary amine is reacted with alkylating, acylating,
sulfonylating, or other reagents to introduce substituents
represented generically as R.sup.8. Coupling reactions of amines
are very common reactions in synthetic organic chemistry and will
be well known to those of average ability in the art. In an
illustrative example leading to a preferred structure, the amine is
reacted with benzyloxyacetyl chloride in dichloromethane and
triethylamine to form the benzyloxyacetamide.
[0178] Step 6 of Scheme IV represents an optional step or steps
that may involve a deprotection step or other reaction to further
elaborate the R.sup.8 substituent introduced in step 5. Those
skilled in the art will be able to select appropriate conditions
for removing given protecting groups or for further elaboration of
a given R.sup.8 substituent. As an illustrative example, the
benzyloxyacetamide formed in step 5 is subjected to hydrogenolysis
with a palladium catalyst to reveal the desired
hydroxyacetamide-substituted azabicyclic phenyloxazolidinone.
[0179] Scheme V describes the preparation of
oxabicyclo[3.1.0]hexyl-substituted phenyloxazolidinones starting
from the diol intermediate described in Scheme II. Conceptually
this reaction involves the conversion of one of the hydroxy
substituents into a suitable leaving group and subsequent
intramolecular displacement of the leaving group by the other
hydroxy group or its alkoxide form. A person skilled in the art
will recognize possible strategies for this cyclization including
activation of the alcohol under Mitsunobu conditions. This reaction
can be accomplished in a one-pot reaction (step 1). Initial
reaction with about two equivalents of a base such as
n-butyllithium is followed by reaction with one to two equivalents
of an activating reagent, such as, methanesulfonyl chloride.
Additional base is then added (about one equivalent) to effect
cyclization and form the oxabicyclic ring. This reaction is
typically conducted in ethereal solvent such as THF and at
temperature of about -30 to -60.degree. C. for about 1 hour to 3
hours. The product may be used as collected or may first be
purified using conventional techniques such as preparative TLC or
HPLC, chromatography, precipitation, crystallization and the like.
##STR18##
[0180] Step 2 of Scheme V involves construction of the
oxazolidinone ring. This transformation is conducted as described
above for step 3 of Scheme III.
[0181] Scheme VI describes the preparation of claimed structures in
which Y is --N(R.sup.8)-- and W is C.dbd.O, Step 1 of Scheme VI
represents a step or steps for converting the allylic alcohol
described in Scheme II to an allylic amine. This well-known
transformation may be performed by initial activation of the
hydroxy group as an alkyl or aryl sulfonate, halide, or optionally
by Mitsunobu-type activation (see Fabiano et al. Synthesis, 1987,
p. 190). These reactions are well known to those skilled in the art
and may be performed with reagents such as methanesulfonyl
chloride, p-toluenesulfonyl chloride, or with dialkyl
azodicarboxylates (for Mitsunobu reactions). Next the activated
alcohol is reacted with a nucleophilic nitrogen source. For
reactions of alkyl or aryl sulfonates this is usually accomplished
by reaction with an azide salt (e.g., sodium azide) in polar
solvents such as acetone or dimethyl sulfoxide (optionally with
added water) and at temperatures of about 50.degree. C. to
120.degree. C. For Mitsunobu activation, hydrazoic acid is commonly
employed as a nucleophilic nitrogen sources. Finally, the azide is
reduced to the amine, a transformation that can be accomplished
with a variety of inorganic reducing agents or by catalytic
hydrogenation. An alternative and selective reduction of azides is
accomplished by reaction with phosphines (Staudinger reaction).
[0182] In step 2 of Scheme VI, the allylic amine is converted to a
diazo acetamide. This conversion may be accomplished using the
procedure described by Doyle et al. (see J. Am. Chem. Soc. 1995,
117, pp 5763-5775) although other methods may also be employed.
##STR19##
[0183] Step 3 of Scheme VI describes an intramolecular
cyclopropanation reaction and may be accomplished as described
above for step 4 of Scheme II.
[0184] Step 4 of Scheme VI involves construction of the
oxazolidinone ring. This transformation is conducted as described
above for step 3 of Scheme III.
[0185] Step 5 of Scheme VI represents an optional step or steps
that may involve the introduction and further elaboration of the
R.sup.8 substituent. For example, these reactions may involve
alkylation or similar functionalization of the lactam ring nitrogen
using known processes.
[0186] Scheme VII involves an alternate route for the preparation
of analogs in which the preparation of claimed structures in which
Y is --N(R.sup.8)-- and W is C.dbd.O. The starting material for
this method is the lactone described in Scheme II. In step 1 of
Scheme VI, the lactone is reacted with a suitable amine nucleophile
such as benzyl or 4-methoxybenzylamine, opening the lactone ring to
give an amide. This is a well known reaction in organic chemistry
and may be accomplished in a variety of alcoholic or polar aprotic
solvents at temperatures from about 25.degree. C. to 100.degree.
C.
[0187] Step 2 of Scheme VII describes involves cyclization of the
amido alcohol to reform a lactam ring. These reactions are known
and are often accomplished by activating the alcohol with reagents
such as mesyl chloride (e.g., see Haddad, M. et al in J. Org. Chem.
1998, 63, 5680-5683) or by Mitsunobu-type activation (e.g., see Ma,
D. et. al. in Tet. Lett. 1998, 9067-9068).
[0188] Step 3 of Scheme VII involves construction of the
oxazolidinone ring. This transformation is conducted as described
above for step 3 of Scheme III or as described in Scheme VIII.
##STR20##
[0189] Steps 4 and 5 of Scheme VII represent an optional step or
steps that may involve removal of a substituent on the amide
nitrogen (e.g. a benzyl group) and the introduction and further
elaboration of an R.sup.8 substituent. For example, these reactions
may involve alkylation or similar functionalization of the lactam
ring nitrogen using known methods.
[0190] Scheme VIII describes a general synthesis of
aryloxazolidinone compounds substituted at C-5 of the oxazolidinone
with substituents other than simple acetylaminomethyl. In step 1 of
Scheme VIII, the aryl carbamate analogs (described in Schemes
III-VII) are reacted with (3-chloro-2-hydroxy-propyl)-carbamic acid
tert-butyl ester. This reagent is prepared from (S)-epichlorohydrin
in three steps (epoxide ring opening with benzaldehyde imine, imine
hydrolysis, and amine protection with di-tert-butyldicarbonate)
according to the procedure described in U.S. patent application
Ser. No. 09/982,157, which is incorporated herein in it entirety.
The reaction of this reagent with aryl carbamates is performed in
the presence of an organic base such as lithium tert-butoxide, in a
polar organic solvent such as dimethylformamide, at temperatures of
about 0.degree. C. to 25.degree. C.
[0191] In step 2 of Scheme VIII, the tert-butyl carbamate (Boc
group) is removed to provide the aminomethyl analog. This
transformation is conveniently accomplished with hydrochloric acid
in dioxane at a temperature in the range of about 0.degree. C. to
about 25.degree. C.; however, a person skilled in the art will
recognize other deprotection conditions that may be employed.
##STR21##
[0192] Step 3 of Scheme VIII involves acylation or thioacylation of
the amine intermediate using known art. Hence, acylations can be
performed by reaction of the amine with carboxylic acid anhydrides,
esters or acid chlorides. These transformations are usually
performed at temperatures between 0.degree. C. and 50.degree. C. in
solvents such as dichloromethane, acetonitrile, tetrahydrofuran,
dimethylformamide, methanol, or mixtures thereof. These reactions
are generally performed in the presence of acid-scavenging amines
such as triethylamine, pyridine, or potassium carbonate.
Thioacylations are accomplished by reaction of the amines from step
2 with dithioesters or thionoesters in the presence of a tertiary
amine base such as triethylamine. Preferred solvents for these
reactions include tetrahydrofuran, dichloromethane or methanol and
the reactions are conducted in a temperature range from 20.degree.
C. to 50.degree. C. Other thiocarbonyl compounds of Scheme VIII can
be prepared according to procedures disclosed in PCT International
Publication WO 98/54161, which is incorporated herein by reference
in its entirety.
[0193] Step 4 of Scheme VIII represents an optional step or steps
that may involve a deprotection step or other reaction to introduce
or further elaborate an R.sup.8 substituent in cases where Y is
--N(R.sup.8)--. In cases were Y is S, these optional steps may
constitute oxidation steps to form sulfoxide or sulfone
functionality.
[0194] Scheme IX describes the synthesis of claimed compounds that
possess a carboxamide substituent at C-5 of the oxazolidinone ring
(i.e., where Z is C(.dbd.O)NHR.sup.1). The preparation of
oxazolidinones with this particular substituent is outlined below
in steps 2-4 of Scheme IX and is further described known art in
U.S. Provisional Patent Application Ser. No. 60/359,495, which is
incorporated herein by reference in its entirety. It will be
apparent to those skilled in the art that this scheme describes a
general method that may be applied in the context of any of
bicyclic heterocycles described in Schemes III-VII to prepare
claimed structures possessing carboxamide substituent at C-5 of the
oxazolidinone ring. A person skilled in the art will also recognize
that some modifications of the synthetic protocol may be required
if certain functional groups are incompatible with the methods
described. In these cases, suitable protecting groups may be
employed to protect these functional groups from participating in
undesired reactions, see "Protecting Groups" by Philip J. Kocienski
(publisher: Georg Thieme Verlag: Stuttgart, 1994).
[0195] Step 1 of Scheme IX requires the removal of carbamate
protection from intermediates of the type described in Schemes
III-VII. The conditions employed for this reaction will depend on
the carbamate employed in a particular case. For example,
benzyloxycarbonyl (Cbz) groups can be removed using hydrogenolysis
with palladium catalysts whereas tert-butoxycarbonyl (Boc) groups
are effectively removed using hydrochloric acid in solvents such as
dioxane, although other similar reagents may also be used. These
examples are only illustrative and it is understood that other
carbamate protecting groups and deprotection conditions may be
employed.
[0196] Step 2 of Scheme IX describes the reaction of the
substituted aniline intermediate with ethyl
(2R)-2,3-epoxypropanoate, available from Acros, or similar reagent
to provide an amino alcohol. This reaction may be conducted in the
presence of a promoter such as lithium triflate and in solvents
such as acetonitrile or dioxane at temperatures of about 30.degree.
C. to 100.degree. C.
[0197] Step 3 of Scheme IX describes the formation of the
oxazolidinone ring from the amino alcohol intermediate. This type
of reaction is known in the art and is typically conducted with
reagents such carbonyldiimidazole or phosgene, with or without the
addition of acid scavenging bases such as triethylamine. The
reactions can be conducted in solvents such as acetonitrile,
dimethylformamide or dichloromethane and at temperatures of about
0.degree. C. to 50.degree. C. and are typically run for about 0.5
hours to about 48 hours, or until the reaction is complete.
##STR22##
[0198] Step 4 of Scheme IX describes the reaction of ammonia or a
primary amine with the ester bearing oxazolidinone formed in the
previous step. Reaction of the amine with the ester group provides
the desired product possessing carboxamide substitution at C-5.
These reactions may be carried out with an excess of the amine in
solvents such as methanol, tetrahydrofuran or mixtures thereof and
at temperatures of around 0.degree. C. to 50.degree. C.
[0199] Step 5 of Scheme IX represents an optional step or steps
that may involve a deprotection step and/or other reaction to
introduce or further elaborate an R.sup.8 substituent in cases
where Y is --N(R.sup.8)--. In cases were Y is S, these optional
steps may constitute oxidation steps to form sulfoxide or sulfone
functionality.
[0200] Schemes X-XII below describe general methods for the
preparation of claimed compounds in which Z is NH-het.sup.1,
O-het.sup.1, S-het.sup.1, or het.sup.2. The starting materials for
this procedure are arylcarbamates (described in Schemes III-VII)
and the conversion of these intermediates to the final compounds is
known art (see Gravestock, M. B., International Publications WO
99/64417 and WO 00/21960). The structures shown are those in which
A is structure (i); however it is understood that analogous
procedures may be employed--with some modifications of the
synthetic route--when A is structure (ii), (iii), or (iv).
[0201] Step 1 of Scheme X involves transformation of the aryl
carbamate (prepared as described in Schemes III-VII) to a
hydroxymethyl-substituted oxazolidinone. Transformations of this
type are known to those skilled in the art (see, e.g.,
International Publication WO 95/07271, published on 16 Mar. 1995).
This reaction is accomplished with R-(-)-glycidyl butyrate or a
similar glycidyl ester. The reaction is performed in the presence
of organic base such as lithium hexamethyldisilylamide in organic
solvents such as tetrahydrofuran, at temperatures of about
-78.degree. C. to 25.degree. C.
[0202] In Step 2 of Scheme X, the hydroxy group is converted to a
displaceable group (Lg) such as alkyl or aryl sulfonate, or halide.
These reactions are well known to those skilled in the art and may
be performed with reagents such as methanesulfonyl chloride,
p-toluenesulfonyl chloride, or similar reagents. The reactions may
be carried out in organic solvents such as dichloromethane or
tetrahydrofuran, and in the presence of acid-scavenging amines such
as triethylamine or N,N-diisopropylethylamine a temperature of
about 0.degree. C. to 40.degree. C. ##STR23##
[0203] In Step 3 of Scheme X, the activated hydroxy compound is
reacted with a compound of the formula HN(Pg)het.sup.1,
HOhet.sup.1, HShet.sup.1 or the corresponding metal alkoxide salts
M-N(Pg)het.sup.1, M-Ohet.sup.1, M-Shet.sup.1 where M is an alkali
metal or another metal known to promote O-alkylation (e.g., silver)
and "Pg" is a suitable protecting group. Alternatively, the
hydroxymethyl starting material may be reacted directly with
compounds of the formula HN(Pg)het.sup.1, HOhet.sup.1, HShet.sup.1
(Step A) under Mitsunobu activation using a suitable dialkyl
azodicarboxylate reagent and alkyl or aryl phosphine (see Fabiano
et. al. Synthesis, 1987, p. 190). Finally, an optional step or
steps may be required to introduce or further elaborate an R.sup.8
substituent in cases where Y is --N(R.sup.8)--. In cases were Y is
S, these optional steps may constitute oxidation steps to form
sulfoxide or sulfone functionality.
[0204] The synthesis of analogs in which Z is het.sup.2 may be
accomplished as shown in Scheme XI. Preparation of these analogs
from hydroxymethyl oxazolidinones is known art (see Gravestock, M.
B., Betts, M. J., and Griffin, D. A., International Publications WO
01/81350). In Step 1, the hydroxy group is converted to a
displaceable group (Lg) such as alkyl or aryl sulfonate, bromide,
or iodide using known art. In Step 2, this intermediate is reacted
with het.sup.2-H in the free base form or as the anion
het.sup.2-formed from the free base. An alternative method to
prepare 1,2,3-triazoles specifically involves conversion of the
hydroxy group to an azide in Step A (as described for step 1 of
Scheme VI), followed by cycloaddition with norbornadiene (Step B).
Finally, an optional step or steps may be required to introduce or
further elaborate an R.sup.8 substituent in cases where Y is
--N(R.sup.8)--. In cases were Y is S, these optional steps may
constitute oxidation steps to form sulfoxide or sulfone
functionality, ##STR24##
[0205] Scheme XII describes an alternative method for the
preparation of the analogs described in Schemes X and XI. This
method is well known in the art (see, for example, Gravestock, M.
B., International Publications WO 99/64417 and WO 00/21960;
Gravestock, M. B., Betts, M. J., and Griffin, D. A., International
Publications WO 01/81350, which are each incorporated herein in
their entirety). Reaction of aryl carbamate intermediates
(described in Schemes III-VII) with epoxides of the formula
CH.sub.2(O)CHCH.sub.2-het.sup.2,
CH.sub.2(O)CHCH.sub.2--NHhet.sup.1,
CH.sub.2(O)CHCH.sub.2--O-het.sup.1, or
CH.sub.2(O)CHCH.sub.2--S-het.sup.1 provides the desired compounds.
Finally, an optional step or steps may be required to introduce or
further elaborate an R.sup.8 substituent in cases where Y is
--N(R.sup.8)--. In cases were Y is S, these optional steps may
constitute oxidation steps to form sulfoxide or sulfone
functionality. ##STR25##
[0206] Schemes XIII-XV describe the synthesis of arylisoxazolinone
and arylisoxazoline compounds bearing bicyclic rings of the type
described in Schemes III-VII. It will be apparent to those skilled
in the art that the following schemes describe general methods to
prepare claimed structures in which A is (ii) or (iv). These
methods may be employed using any of the bicyclic heterocycles
described in Schemes III-VII. The starting materials required to
prepare these structures are aromatic aldehydes rather than amines
and therefore some modifications of the synthetic protocol will be
required. The bicyclic heterocycles can be prepared as described
above in Schemes III-VII but it is understood that suitable
protecting groups should be employed to protect and later reveal
sensitive functional groups, in particular the aromatic aldehyde
function.
[0207] Scheme XIII summarizes the synthesis of the requisite
substituted benzaldehyde intermediates. The starting materials for
this synthesis may include commercially-available terephthaldehyde
mono(diethyl acetal) or other substituted analog prepared using
known art. The aldehyde starting materials are then converted to
bicyclo[3.1.0]hexyl ring systems using the procedures described in
Schemes III-VII. A final deprotection of the acetal then reveals
the desired benzaldehyde intermediate. The removal of acetal
protection can be accomplished using various reaction conditions
that are well known in the art, (see "Protecting Groups" by Philip
J. Kocienski; publisher: Georg Thieme Verlag: Stuttgart, 1994).
##STR26##
[0208] Step 1 of Scheme XIV involves reaction of the
bicyclo[3.1.0]hexyl benzaldehyde intermediate with ethyl
diazoacetate (as described in Mahmood et al., 1998 J. Org. Chem.,
63, pgs. 3333-3336) to provide the ester aldehyde intermediate
shown. Addition of hydroxylamine, followed by warming to reflux in
aqueous methanol, yields the arylisoxazolinone (Step 2). This
intermediate is then converted to the corresponding methylacetamide
(Step 3) by reaction with N-(hydroxymethyl)acetamide acetate
(prepared as described by Barnes et al. in U.S. Pat. No. 5,284,863,
the disclosure of which is incorporated herein in its entirety) in
a polar aprotic solvent such as DMF. In step 4, an optional step or
steps may be required to introduce or further elaborate an R.sup.8
substituent in cases where Y is --N(R.sup.8)--. In cases were Y is
S, these optional steps may constitute oxidation steps to form
sulfoxide or sulfone functionality. ##STR27##
[0209] Scheme XV describes a general method for preparing
arylisoxazoline compounds bearing bicyclic heterocycles of the type
described in Schemes III-VII. In Step 1 of Scheme XV the
substituted benzaldehyde is reacted with hydroxylamine
hydrochloride in a polar protic solvent, such as methanol, in the
presence of a base, such as pyridine, to afford the oxime.
[0210] In Step 2 of Scheme XV, the oxime is oxidized with
N-chloro-succinamide (NCS) in an appropriate solvent, such as
dichloromethane, to give the oximyl chloride. In Step 3, the oximyl
chloride is reacted with an allylic compound such as allyl alcohol
or N-acetylallylamine, in the presence of a base such as
triethylamine and in a solvent such as dichloromethane, to provide
hydroxymethyl or acetamidomethyl substituted isoxazolines.
Alternatively, the oximyl chloride can be formed in situ and
directly treated with the allylic compound (a combination of steps
2 and 3). ##STR28##
[0211] Step 4 of Scheme XV represents a step or series of steps for
preparing compounds in which Z is a group other than
NH(C.dbd.O)CH.sub.3. First, the hydroxymethyl analog is elaborated
to aminomethyl using known art (as described in step 1 of Scheme
VI) and this intermediate is then converted to the desired amide or
thioamide analogs (as described in step 3 of Scheme VIII).
Alternatively, a heterocyclic substituent (for analogs where Z is
NH-het.sup.1, O-het.sup.1, S-het.sup.1, or het.sup.2) may be
introduced from hydroxymethyl or azidomethyl intermediates using
known art (as described in Schemes X-XII). In step 5, an optional
step or steps may be required to introduce or further elaborate an
R.sup.8 substituent in cases where Y is --N(R.sup.8)--. In cases
were Y is S, these optional steps may constitute oxidation steps to
form sulfoxide or sulfone functionality.
Utility and Testing
[0212] The compounds of the subject invention exhibit potent
activities against a variety of organisms, including gram positive
and/or gram negative bacteria. Accordingly, the compounds of the
subject invention have broad antibacterial activity. Thus, the
compounds of the present invention are useful antimicrobial agents
and may be effective against a number of human and veterinary
pathogens, including gram positive aerobic bacteria such as
multiply-resistant staphylococci and streptococci, gram negative
organisms such as H. influenzae and M. catarrahlis, as well as
anaerobic organisms such as bacteroides and clostridia species, and
acid-fast organisms such as Mycobacterium tuberculosis and
Mycobacterium avium. In addition the compounds of the present
invention are effective against infections in any area of the
body.
[0213] The in vitro activity of compounds of the subject invention
may be assessed by standard testing procedures such as the
determination of minimum inhibitory concentration (MIC) by agar
dilution as described in "Approved Standard. Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria that Grow
Aerobically," 3.sup.rd ed., published 1993 by the National
Committee for Clinical Laboratory standards, Villanova, Pa.,
USA.
[0214] The in vitro MICs of test compounds may be determined by a
standard agar dilution method. A stock drug solution of each analog
is prepared in a preferred solvent, usually DMSO:H.sub.2O (1:3).
Serial 2-fold dilutions of each sample are made using 1.0 mL
aliquots of sterile distilled water. To each 1.0 mL aliquot of drug
is added 9 mL of molten Mueller Hinton agar medium. The
drug-supplemented agar is mixed, poured into 15.times.100 mm petri
dishes, and allowed to solidify and dry prior to inoculation.
[0215] Vials of each of the test organisms are maintained frozen in
the vapor phase of a liquid nitrogen freezer. Test cultures are
grown overnight at 35.degree. C. on the medium appropriate for the
organism. Colonies are harvested with a sterile swab, and cell
suspensions are prepared in Trypticase Soy broth (TSB) to equal the
turbidity of a 0.5 McFarland standard. A 1:20 dilution of each
suspension is made in TSB. The plates containing the drug
supplemented agar are inoculated with a 0.001 mL drop of the cell
suspension using a Steers replicator, yielding approximately
10.sup.4 to 10.sup.5 cells per spot. The plates are incubated
overnight at 35.degree. C.
[0216] Following incubation the Minimum Inhibitory Concentration
(MIC .mu.g/mL), the lowest concentration of drug that inhibits
visible growth of the organism, is read and recorded. The data is
shown in Table I. The compounds of Example 1 to Example 20 were
tested using this method and all showed an MIC of 8 pg/mL or less
against S. aureus UC9213, 2 .mu.g/mL or less against S. pneumoniae
UC9912 and 16 .mu.g/mL or less against H. influenzae 30063, with
the exception of the compounds of examples 1 and 7 which were 32
.mu.g/mL or less and the compound of example 20 which was >64
.mu.g/mL. TABLE-US-00001 TABLE 1 Antimicrobial activity of selected
compounds. S. aureus S. pneumoniae H. influenzae UC9213 UC9912
30063 Example # MIC, .mu.g/mL MIC, .mu.g/mL MIC, .mu.g/mL linezolid
4 1 16 1 4 1 32 2 2 0.25 2 3 2 0.25 4 4 4 0.5 4 5 2 0.25 4 6 0.5
0.25 4 7 2 0.5 32 8 4 1 8 9 8 1 8 10 2 0.5 4 11 0.5 0.25 2 12 1 0.5
4 13 1 0.5 8 14 2 0.5 16 15 2 0.5 16 16 4 2 16 17 4 2 8 18 2 0.5 4
19 4 1 8 20 2 2 >64
Administration and Pharmaceutical Formulations
[0217] In general, the compounds of the subject invention will be
administered in a therapeutically effective amount by any of the
accepted modes of administration for agents that serve similar
utilities. The actual amount of the compound of the subject
invention, i.e., the active ingredient, will depend on a number of
factors, such as the severity of the disease, i.e., the infection,
to be treated, the age and relative health of the subject, the
potency of the compound used, the route and form of administration,
and other factors all of which are within the routine skill of the
attending clinician.
[0218] Toxicity and therapeutic efficacy of such compounds can be
determined by standard pharmaceutical procedures in cell cultures
or experimental animals, e.g., for determining the LD.sub.50 (the
dose lethal to 50% of the population) and the ED.sub.50 (the dose
therapeutically effective in 50% of the population). The dose ratio
between toxic and therapeutic effects is the therapeutic index and
it can be expressed as the ratio LD.sub.50/ED.sub.50. Compounds
that exhibit large therapeutic indices are preferred.
[0219] The data obtained from the cell culture assays and animal
studies can be used in formulating a range of dosage for use in
humans. The dosage of such compounds lies within a range of
circulating concentrations that include the ED.sub.50 with little
or no toxicity. The dosage may vary within this range depending
upon the dosage form employed and the route of administration
utilized. For any compound used in the method of the invention, the
therapeutically effective dose can be estimated initially from cell
culture assays. A dose may be formulated in animal models to
achieve a circulating plasma concentration range which includes the
IC.sub.50 (i.e., the concentration of the test compound which
achieves a half-maximal inhibition of symptoms) as determined in
cell culture. Such information can be used to more accurately
determine useful doses in humans. Levels in plasma may be measured,
for example, by high performance liquid chromatography.
[0220] When employed as pharmaceuticals, the compounds of the
subject invention are usually administered in the form of
pharmaceutical compositions. These compounds can be administered by
a variety of routes including oral, or parenteral, rectal,
transdermal, topical, subcutaneous, intravenous, intramuscular, and
intranasal routes. These compounds are effective as both injectable
and oral compositions. Such compositions are prepared in a manner
well known in the pharmaceutical art and comprise at least one
active compound.
[0221] This invention also includes pharmaceutical compositions
that contain, as the active ingredient, one or more of the
compounds of the subject invention above associated with
pharmaceutically acceptable carriers. In making the compositions of
this invention, the active ingredient is usually mixed with an
excipient, diluted by an excipient or enclosed within such a
carrier which can be in the form of a capsule, sachet, paper or
other container. When the excipient serves as a diluent, it can be
a solid, semi-solid, or liquid material, which acts as a vehicle,
carrier or medium for the active ingredient. Thus, the compositions
can be in the form of tablets, pills, powders, lozenges, sachets,
cachets, elixirs, suspensions, emulsions, solutions, syrups,
aerosols (as a solid or in a liquid medium), ointments containing,
for example, up to 10% by weight of the active compound, soft and
hard gelatin capsules, suppositories, sterile injectable solutions,
and sterile packaged powders.
[0222] In preparing a formulation, it may be necessary to mill the
active compound to provide the appropriate particle size prior to
combining with the other ingredients. If the active compound is
substantially insoluble, it ordinarily is milled to a particle size
of less than 200 mesh. If the active compound is substantially
water soluble, the particle size is normally adjusted by milling to
provide a substantially uniform distribution in the formulation,
e.g. about 40 mesh.
[0223] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin calcium silicate,
microcrystalline cellulose, polyvinylpyrrolidone, cellulose,
sterile water, syrup, and methylcellulose. The formulations can
additionally include: lubricating agents such as talc, magnesium
stearate, and mineral oil; wetting agents; emulsifying and
suspending agents; preserving agents such as methyl- and
propylhydroxy-benzoates; sweetening agents; and flavoring agents.
The compositions of the invention can be formulated so as to
provide quick, sustained or delayed release of the active
ingredient after administration to the patient by employing
procedures known in the art.
[0224] The quantity of active component, that is the compound
according to the subject invention, in the pharmaceutical
composition and unit dosage form thereof may be varied or adjusted
widely depending upon the particular application, the potency of
the particular compound and the desired concentration.
[0225] The compositions may be formulated in a unit dosage form,
each dosage containing from about 5 to about 100 mg, more usually
about 10 to about 30 mg, of the active ingredient. 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. The compound of the subject
invention is employed at no more than about 20 weight percent of
the pharmaceutical composition, generally no more than about 15
weight percent, with the balance being pharmaceutically inert
carrier(s).
[0226] The active compound is effective over a wide dosage range
and is generally administered in a pharmaceutically or
therapeutically effective amount. It, will be understood, however,
that the amount of the compound actually administered will be
determined by a physician, in the light of the relevant
circumstances, including the condition to be treated, the severity
of the bacterial infection being 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. In therapeutic use for treating,
or combating, bacterial infections in warm-blooded animals, the
compounds or pharmaceutical compositions thereof will be
administered orally, topically, transdermally, and/or parenterally
at a dosage to obtain and maintain a concentration, that is, an
amount, or blood-level of active component in the animal undergoing
treatment which will be antibacterially effective. Generally, such
antibacterially or therapeutically effective amount of dosage of
active component (i.e., an effective dosage) will be in the range
of about 0.1 to about 100, or about 1.0 to about 50 mg/kg of body
weight/day.
[0227] For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention. When
referring to these preformulation compositions as homogeneous, it
is meant that the active ingredient is dispersed evenly throughout
the composition so that the composition may be readily subdivided
into equally effective unit dosage forms such as tablets, pills and
capsules. This solid preformulation is then subdivided into unit
dosage forms of the type described above containing from, for
example, 0.1 to about 500 mg of the active ingredient of the
present invention.
[0228] The tablets or pills of the present invention may be coated
or otherwise compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. An enteric layer
can separate these two components. This layer serves to resist
disintegration in the stomach and to permit the inner component to
pass intact into the duodenum or to provide for delayed release. A
variety of materials can be used for such enteric layers or
coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl
alcohol, and cellulose acetate.
[0229] The liquid forms in which the novel compositions of the
present invention may be incorporated for administration orally or
by injection include aqueous solutions, suitably flavored syrups,
aqueous or oil suspensions, and flavored emulsions with edible oils
such as corn oil, cottonseed oil, sesame oil, coconut oil, or
peanut oil, as well as elixirs and similar pharmaceutical
vehicles.
[0230] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. The compositions may be
administered by the oral or nasal respiratory route for local or
systemic effect. Compositions in pharmaceutically acceptable
solvents may be nebulized by use of inert gases. Nebulized
solutions may be inhaled directly from the nebulizing device or the
nebulizing device may be attached to a facemask tent, or
intermittent positive pressure breathing machine. Solution,
suspension, or powder compositions may be administered orally or
nasally, from devices that deliver the formulation in an
appropriate manner.
[0231] Suitable formulations for use in the present invention can
be found in Remington's Pharmaceutical Sciences, Mace Publishing
Company, Philadelphia, Pa., 17th ed. (1985).
[0232] As noted above, the compounds described herein are suitable
for use in a variety of drug delivery systems described above.
Additionally, in order to enhance the in vivo serum half-life of
the administered compound, the compounds may be encapsulated,
introduced into the lumen of liposomes, prepared as a colloid, or
other conventional techniques may be employed which provide an
extended serum half-life of the compounds. A variety of methods are
available for preparing liposomes, as described in, e.g., Szoka, et
al., U.S. Pat. Nos. 4,235,871, 4,501,728 and 4,837,028 each of
which is incorporated herein by reference.
[0233] As noted above, the compounds administered to a patient are
in the form of pharmaceutical compositions described above. These
compositions may be sterilized by conventional sterilization
techniques, or may be sterile filtered. The resulting aqueous
solutions may be packaged for use as is, or lyophilized, the
lyophilized preparation being combined with a sterile aqueous
carrier prior to administration. It will be understood that use of
certain of the foregoing excipients, carriers, or stabilizers will
result in the formation of pharmaceutical salts.
[0234] The following synthetic and biological examples are offered
to illustrate this invention and are not to be construed in any way
as limiting the scope of this invention.
EXAMPLES
[0235] In the discussion above and in the examples below, the
following abbreviations have the following meanings. If an
abbreviation is not defined, it has its generally accepted meaning.
TABLE-US-00002 bm = broad multiplet bd = broad doublet bs = broad
singlet bt = broad triplet ca. = about CDI = carbodiimidazole d =
doublet dd = doublet of doublets dt = doublet of triplets DMF =
dimethylformamide DMSO = dimethyl sulfoxide eq. = equivalents g =
grams h = hours hept = heptuplet HPLC = high pressure liquid
chromatography HATU =
N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-
1-yl-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide
LiOtBu = lithium tert-butoxide m = multiplet M = molar mg =
milligram mL = milliliter mm = millimeter mmol = millimol q =
quartet s = singlet t = triplet tt = triplet of triplets TFA =
trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer
chromatography p-TLC = preparative thin layer chromatography .mu.M
= micromolar N = normality MeOH = methanol DCM = dichloromethane
HCl = hydrochloric acid ACN = acetonitrile MS = mass spectrometry
rt = room temperature EtOAc = ethyl acetate EtO = ethoxy Ac =
acetate .mu.L = microliter J = coupling constant NMR = Nuclear
magnetic resonance MHz = megahertz Hz = hertz m/z = mass to charge
ratio min = minutes Boc = tert-butoxycarbonyl CBZ =
benzyloxycarbonyl
[0236] All of the starting materials used in the synthesis of the
compounds of the present invention are known compounds, some of
which are commercially available from at least one or more of the
following companies: Aldrich, Fluka, Lancaster, Sigma, Chemservice,
Bachem, Maybridge, NovaBiochem, Alfa and TCI. Additionally, the
term "Aldrich" indicates that the compound or reagent used in the
following procedures is commercially available from Aldrich
Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee,
Wis. 53233 USA; the term "Acros" indicates that the compound or
reagent used in the following procedures is commercially available
from Acros Organics distributed by Fisher Scientific 2000 Park Lane
Drive, Pittsburgh, Pa. 15275; the term "Fluka" indicates that the
compound or reagent is commercially available from Fluka Chemical
Corp., 980 South 2nd Street, Ronkonkoma N.Y. 11779 USA; the term
"Lancaster" indicates that the compound or reagent is commercially
available from Lancaster Synthesis, Inc., P.O. Box 100 Windham,
N.H. 03087 USA; the term "Sigma" indicates that the compound or
reagent is commercially available from Sigma, P.O. Box 14508, St.
Louis Mo. 63178 USA; the term "Chemservice" indicates that the
compound or reagent is commercially available from Chemservice
Inc., Westchester, Pa., USA; the term "Bachem" indicates that the
compound or reagent is commercially available from Bachem
Bioscience Inc., 3700 Horizon Drive, Renaissance at Gulph Mills,
King of Prussia, Pa. 19406 USA; the term "Maybridge" indicates that
the compound or reagent is commercially available from Maybridge
Chemical Co. Trevillett, Tintagel, Cornwall PL34 OHW United
Kingdom; and the term "TCI" indicates that the compound or reagent
is commercially available from TCI America, 9211 North Harborgate
St., Portland, Oreg., 97203, OR, USA; the term "Alfa" indicates
that the compound or reagent is commercially available from Johnson
Matthey Catalog Company, Inc. 30 Bond Street, Ward Hill, Mass.
01835-0747; and the term "Nova Biochem" indicates that the compound
or reagent is commercially available from NovaBiochem USA, 10933
North Torrey Pines Road, P.O. Box 12087, La Jolla Calif.
92039-2087.
[0237] In the examples below, all temperatures are in degrees
Celsius (unless otherwise indicated) and the following general
procedures were used to prepare the compounds as indicated.
Example 1
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-
-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0238] ##STR29##
[0239] Lithium butoxide solution (3.0 mL of a 1.0 M THF solution,
3.0 mmol) was added to a cooled (0.degree. C.) solution of benzyl
3-fluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenylcarbamate
(0.35 g, 1.0 mmol) in DMF (0.7 mL) and MeOH (0.081 mL, 2.0 mmol).
Solid (S)-acetic acid 2-acetylamino-1-chloromethyl-ethyl ester
(0.39 g, 2.0 mmol) was then added and the solution allowed to warm
to room temperature and stirred for 20 h. Saturated aqueous
ammonium chloride (2 mL) was added, along with 10 mL of H.sub.2O
and 10 mL of brine. The solution was extracted with three portions
of dichloromethane and the combined organic phases dried
(MgSO.sub.4), filtered and concentrated. The crude residue was
purified by column chromatography (0-3% MeOH-DCM) to provide the
title compound.
[0240] Yield 0.24 g (68%).
[0241] MS (m/z): [M+H]=351
[0242] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.93 (m, 2H), 2.02 (m,
3H), 2.47 (t, J=4 Hz, 1H), 3.08-3.21 (m, 4H), 3.59-3.77 (m, 3H),
4.02 (t, J=9 Hz, 1H), 4.75-4.80 (m, 1H), 6.14 (t, J=6 Hz, 1H), 6.94
(t, J=8 Hz, 1H), 7.09 (dd, J=8, 2 Hz, 1H), 7.35 (dd, J=12, 2 Hz,
1H)
[0243] mp=177-178.degree. C.
Intermediates for the preparation of example 1 were synthesized as
follows.
I. benzyl 3-fluoro-4-formylphenylcarbamate
[0244] ##STR30##
[0245] Ammonium chloride (38 g, 0.71 mol) was added to a solution
of 2-fluoro-4-nitrobenzaldehyde (12 g, 0.071 mol, prepared as
described by Gordeev, et. al., U.S. Pat. No. 6,239,152, which is
incorporated herein by reference in its entirety) in 2:1
ethanol-H.sub.2O (300 mL). The mixture was heated to 80.degree. C.
and treated with iron metal in 6 portions over 1 hour (11.9 g
total, 0.212 mmol). After the addition was complete the reaction
mixture was stirred another hour and the warm solution filtered
with the aid of more water and ethanol. The filtrate was then
concentrated to remove ethanol and the resulting aqueous solution
extracted thrice with ethyl acetate. The combined organic phases
were washed with water, brine, and dried (MgSO.sub.4), filtered,
and concentrated to provide 9.6 g of the crude amine.
[0246] The crude amine (9.6 g, 0.069 mol) was dissolved in
dichloromethane (230 mL) and pyridine (11.1 mL, 0.138 mol) and the
solution cooled to 0.degree. C. The solution was then treated with
benzyl chloroformate (11.8 mL, 0.083 mol) dropwise and the solution
stirred at room temperature for 18 h. The reaction mixture was then
diluted with more dichloromethane and the organic solution washed
thrice with water, once with brine, and dried (MgSO.sub.4),
filtered, and concentrated. Trituration with hexane provided the
title compound as a yellow solid.
[0247] Yield 15 g (77%).
[0248] .sup.1H NMR (300 MHz, CDCl.sub.3): 5.23 (s, 2H), 6.99 (bs,
1H), 7.03 (dd, J=9, 2 Hz, 1H), 7.37-7.42 (m, 5H), 7.57 (dd, J=13, 2
Hz, 1H), 7.81 (t, J=9 Hz, 1H), 10.23 (s, 1H).
II. methyl
(2E)-3-(4-{[(benzyloxy)carbonyl]amino}-2-fluorophenyl)acrylate
[0249] ##STR31##
[0250] Sodium hydride (0.513 g of a 60% dispersion, 12.8 mmol) was
placed in a flask and washed three times with hexane. The resulting
solid was suspended in DMF (10 mL) and cooled to 0.degree. C.
Trimethyl phosphonoacetate (2.2 mL, 13.5 mmol) was added dropwise
to this suspension to give a clear homogeneous solution. After
stirring for another 15 minutes at 0.degree. C., a solution of
benzyl 3-fluoro-4-formylphenylcarbamate (3.5 g, 12.8 mmol) in DMF
(10 mL) was added dropwise. The resulting orange suspension was
allowed to warm slowly to room temperature and stirred for 16
hours. The reaction mixture was poured into 0.5 N HCl and extracted
with three portions of dichloromethane. Combined organic phases
were washed with saturated NaHCO.sub.3, H.sub.2O, brine, and dried
(MgSO.sub.4) filtered and concentrated. The resulting orange solid
was washed sequentially with hexane and then 30% ethyl
acetate-hexane to provide the title compound as a yellow-orange
solid (2.7 g). The washings were concentrated and purified by
column chromatography (0-30% ethyl acetate-hexane) to provide an
additional 0.95 g of the product.
[0251] Yield 3.66 g (87%).
[0252] .sup.1H NMR (300 MHz, d.sub.6-DMSO): 3.71 (s, 3H), 5.17 (s,
2H), 6.55 (dd, J=16.1 Hz, 1H), 7.26 (d, J=9 Hz, 1H), 7.35-7.50 (m,
6H), 7.63 (d, J=16 Hz, 1H), 7.79 (t, J=9 Hz, 1H), 10.3 (bs, 1H)
[0253] mp=157-158.degree. C.
III. benzyl
3-fluoro-4-[(1E)-3-hydroxyprop-1-enyl]phenylcarbamate
[0254] ##STR32##
[0255] A THF solution of LiAlH.sub.4 (10.2 mL of a 1.0 M solution,
10.2 mmol) was added to a cooled (-78.degree. C.) solution of
methyl
(2E)-3-(4-{[(benzyloxy)carbonyl]amino}-2-fluorophenyl)acrylate
(3.35 g, 10.2 mmol) in THF (50 mL). The solution was allowed to
warm slowly to -20.degree. C. and maintained at that temperature
for 2 hours. The reaction mixture was quenched by slow addition of
saturated NH.sub.4Cl and then treated with 30 mL of dilute citric
acid. The resulting solution was stirred for 15 minutes and then
extracted with three portions of ethyl acetate. Combined organic
phases were washed with H.sub.2O, brine and dried (MgSO.sub.4),
filtered and concentrated to give a red oil. The crude product was
purified by column chromatography (25-50% ethyl acetate-hexane) to
provide the title compound as a yellow solid.
[0256] Yield 2.14 g (70%).
[0257] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.43 (t, J=6 Hz, 1H),
4.33 (t, J=6 Hz, 2H), 5.28 (s, 2H), 6.37 (dt, J=15, 6 Hz, 1H), 6.69
(d, J=16 Hz, 1H), 6.70 (s, 1H), 6.99 (d, J=9 Hz, 1H), 7.20-7.39 (m,
7H)
[0258] mp=105-106.degree. C.
IV.
(2E)-3-(4-{[(benzyloxy)carbonyl]amino}-2-fluorophenyl)prop-2-enyl
diazoacetate
[0259] ##STR33##
[0260] Glyoxylic acid chloride p-toluenesulfonylhydrazone (2.2 g,
8.5 mmol, prepared as described by C. J. Blankley, F. J. Sauter and
H. O. House, Organic Syntheses, Coll. Vol. V, p. 258; John Wiley,
New York (1973)) was added to a suspension of benzyl
3-fluoro-4-[(1E)-3-hydroxyprop-1-enyl]phenylcarbamate (2.14 g, 7.1
mmol) in dichloromethane (55 mL). The mixture was cooled to
0.degree. C. and treated with N,N-dimethylaniline (1.0 mL, 7.81
mmol). After 30 minutes, triethylamine (4.9 mL, 35.5 mmol) was
added and the mixture stirred 30 minutes at 0.degree. C. and 15
minutes at room temperature. The reaction mixture was then
concentrated to about 15 mL and 50 mL of water added. The mixture
was extracted with two portions of diethyl ether and the combined
organic solutions washed with saturated NaHCO.sub.3, brine and
dried (MgSO.sub.4), filtered and concentrated. Purification by
column chromatography (0-25% ethyl acetate-hexane) provided the
title compound as a yellow solid.
[0261] Yield 2.30 g (88%).
[0262] .sup.1H NMR (300 MHz, CDCl.sub.3): 4.80 (s, 2H), 4.83 (s,
1H), 5.21 (s, 2H), 6.29 (dt, J=16, 6 Hz, 1H), 6.72 (d, J=16 Hz,
1H), 6.73 (s, 1H), 6.98 (d, J=8 Hz, 1H), 7.25-7.40 (m, 7H)
[0263] mp=93-96.degree. C.
V. benzyl
3-fluoro-4-[(1S,5R,6R)-2-oxo-3-oxabicyclo[3.1.0]hex-6-yl]phenylc-
arbamate
[0264] ##STR34##
[0265] A solution of
(2E)-3-(4-{[(benzyloxy)carbonyl]amino}-2-fluorophenyl)prop-2-enyl
diazoacetate (2.26 g, 6.12 mmol) in toluene (125 mL) was added
dropwise over 14 h to a refluxing solution of
bis-(N-t-butylsalicylaldiminato)copper(II) (0.254 g, 0.61 mmol,
prepared as described by R. G. Charles, J. Org. Chem. 1957, 22,
677) in 125 mL of toluene. After the addition was complete, the
reaction mixture was heated another hour at reflux, then cooled,
filtered and concentrated. The crude oil was purified by column
chromatography (0-0.5% MeOH-DCM) to provide the title compound as a
yellow solid.
[0266] Yield 1.57 g (75%).
[0267] .sup.1H NMR (300 MHz, CDCl.sub.3): 2.33-2.39 (m, 2H),
2.49-2.53 (m, 1H), 4.4 (m, 2H), 5.18 (s, 2H), 6.82 (t, J=9 Hz, 1H),
7.0 (d, J=8 Hz, 1H), 7.01 (s, 1H), 7.25-7.38 (m, 6H);
[0268] mp=141-142.degree. C.
VI. benzyl
4-[exo-(2R,3S)-2,3-bis(hydroxymethyl)cyclopropyl]-3-fluoropheny-
lcarbamate
[0269] ##STR35##
[0270] A THF solution of LiAlH.sub.4 (2.5 mL of a 1.0M solution,
2.5 mmol) was added dropwise to a solution of benzyl
3-fluoro-4-[(1S,5R,6R)-2-oxo-3-oxabicyclo[3.1.0]hex-6-yl]phenylcarbamate
(0.86 g, 2.5 mmol) in THF (20 mL) cooled at 0.degree. C. The
solution was stirred at 0.degree. C. for 1 h and then treated with
more LiAlH.sub.4 solution (1.25 mL, 1.25 mmol) and allowed to warm
to room temperature. After another hour at room temperature, the
solution was quenched by the slow addition of saturated NH.sub.4Cl
(15 mL) followed by H.sub.2O (30 mL) and saturated citric acid (10
mL). The solution was concentrated to remove THF and the resulting
aqueous solution extracted with three portions of ethyl acetate.
The combined organic phases were then washed with H.sub.2O, brine,
and dried (MgSO.sub.4), filtered and concentrated to an oil.
Purification by column chromatography (0-3% MeOH-DCM) provided the
title compound as a white foam.
[0271] Yield 0.55 g (63%).
[0272] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.65-1.72 (m, 2H), 1.90
(t, J=5 Hz, 1H), 2.72 (bs, 2H), 3.48 (m, 2H), 4.23 (m, 2H), 5.19
(s, 2H), 6.75 (s, 1H), 6.82 (t, J=8 Hz, 1H), 6.93 (dd, J=9, 2 Hz,
1H), 7.30-7.41 (m, 6H).
VII. benzyl
4-[exo-(2R,3S)-2,3-bis(methanesulfonyloxymethyl)cyclopropyl]-3-fluorophen-
ylcarbamate
[0273] ##STR36##
[0274] Methanesulfonic anhydride (1.51 g, 8.7 mmol) was added to a
cooled (0.degree. C.) solution of benzyl
4-[exo-(2R,3S)-2,3-bis(hydroxymethyl)cyclopropyl]-3-fluorophenylcarbamate
(1.0 g, 2.9 mmol) in dichloromethane (36 mL) and triethylamine
(1.61 mL, 11.6 mmol). The solution was allowed to warm to room
temperature and stirred for 2 h. The solution was then diluted with
30 mL dichloromethane and washed with two portions of saturated
NaHCO.sub.3, brine, and dried (MgSO.sub.4). The crude product was
passed through a short pad of SiO.sub.2 (eluting with ethyl
acetate) to provide the title compound as a white solid that was
used directly in the next reaction.
[0275] Yield 1.4 g (96%).
[0276] .sup.1H NMR
[0277] mp=85-95.degree. C. dec.
VIII. benzyl
3-fluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenylcarbamate
[0278] ##STR37##
[0279] Sodium sulfide (0.65 g, 8.4 mmol) was added to a solution of
benzyl
4-[exo-(2R,3S)-2,3-bis(methanesulfonyloxymethyl)cyclopropyl]-3-flu-
orophenylcarbamate (1.4 g, 2.8 mmol) in DMSO (5.5 mL). The reaction
mixture was stirred at room temperature for 2 h. The resulting
yellow suspension was then diluted with 30 mL of H.sub.2O and
extracted with three portions of diethyl ether. The combined
organic extracts were dried (MgSO.sub.4), filtered and concentrated
to provide the title compound as a white solid.
[0280] Yield 0.87 g (91%).
[0281] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.91 (m, 2H), 2.44 (m,
1H), 3.09 (d, J=11 Hz, 2H), 3.18 (d, J=11 Hz, 2H), 5.20 (s, 2H),
6.61 (s, 1H), 6.91 (t, J=8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 7.19-7.40
(m, 6H)
[0282] mp=121-122.degree. C.
Example 2
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]p-
henyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0283] ##STR38##
[0284] A solution of sodium periodate (0.087 g, 0.41 mmol) in water
(1.5 mL) was added to a suspension of
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}--
2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (0.136 g, 0.39 mmol) in
methanol (5 mL) and stirred at 4.degree. C. for 24 h. The resulting
suspension was filtered with the aid of chloroform and the filtrate
concentrated. The resulting solution was diluted with 5 mL of water
and extracted with five portions of chloroform. The combined
organic phases were dried (MgSO.sub.4) filtered and concentrated.
Purification by column chromatography (10% ACN-5% MeOH-DCM)
provided the title compound as a separable mixture of sulfoxide
diastereomers (ca. 1:1 ratio).
[0285] Yield (total for both isomers) 0.095 g (65%).
[0286] Low Rf ("syn") isomer: .sup.1H NMR (300 MHz, CD.sub.3OD):
1.95 (s, 3H), 2.24 (t, J=4 Hz, 1H), 2.58 (m, 2H), 3.10 (d, J=15 Hz,
2H), 3.33-3.38 (m, 2H), 3.54 (d, J=5 Hz, 2H), 3.78 (dd, J=6, 3 Hz,
1H), 4.11 (t, J=9 Hz, 1H), 4.74-4.81 (m, 1H), 7.03 (t, J=8 Hz, 1H),
7.19 (dd, J=9, 2 Hz, 1H), 7.46 (dd, J=13, 2 Hz, 1H)
[0287] High Rf ("anti") isomer: .sup.1H NMR (300 MHz, CD.sub.3OD):
1.95 (s, 3H), 2.31 (m, 2H), 2.74 (t, J=4 Hz, 1H), 3.24 (d, J=15 Hz,
2H), 3.46-3.55 (m, 4H), 3.78 (dd, J=6, 3 Hz, 1H), 4.11 (t, J=9 Hz,
1H), 4.75-4.81 (m, 1H), 7.06 (t, J=8 Hz, 1H), 7.20 (dd, J=8, 2 Hz,
1H), 7.44 (dd, J=13, 2 Hz, 1H).
Example 3
N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-flu-
orophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0288] ##STR39##
[0289] Peracetic acid (0.18 mL of a 32% aqueous solution, 0.856
mmol) was added to a solution of
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}--
2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (0.10 g, 0.285 mmol) in
THF (9 mL) cooled at 0.degree. C. The reaction mixture was stirred
for 2 h at room temperature, treated with more peracetic acid
(0.050 mL) and stirred another 3 h. The reaction was quenched by
the addition of saturated Na.sub.2S.sub.2O.sub.3 (2 mL) and water
(5 mL). The THF was then removed on the rotary evaporator and the
resulting solution extracted with three portions of ethyl acetate.
Combined organic extracts were then washed with dilute NaHCO.sub.3,
brine, and dried (MgSO.sub.4). The crude product was purified by
column chromatography (0-4% MeOH-DCM) to provide the title compound
as a foam.
[0290] Yield 0.089 g (82%).
[0291] MS (m/z): [M+Na]=405
[0292] .sup.1H NMR (300 MHz, d.sub.6-DMSO): 1.82 (s, 3H), 2.10 (m,
2H), 2.33 (t, J=4 Hz, 1H), 3.01 (d, J=13 Hz, 2H), 3.33-3.41 (m,
2H), 3.59 (m, 2H), 3.71 (t, J=7 Hz, 1H), 4.09 (t, J=9 Hz, 1H), 4.71
(m, 1H), 7.12 (t, J=8 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.47 (d, J=13
Hz, 1H), 8.24 (t, J=5 Hz, 1H).
Example 4
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2--
oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0293] ##STR40##
[0294] A solution of benzyl
3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenylcarbamate
(0.072 g, 0.22 mmol) in DMF (0.15 mL) and MeOH (0.018 mL, 0.44
mmol) was cooled at 0.degree. C. and treated with LiOtBu solution
(0.66 mL, 0.66 mmol) dropwise. The solution was then treated in one
portion with (S)-acetic acid 2-acetylamino-1-chloromethyl-ethyl
ester (0.085 g, 0.44 mmol). The reaction mixture was slowly warmed
to room temperature and stirred for 20 h. The solution was then
treated with 1.0 mL of saturated NH.sub.4Cl was added followed by 5
mL of water and 5 mL of brine. The mixture was extracted with three
portions of dichloromethane and the combined organic phases washed
with water, brine, and dried (MgSO.sub.4), filtered and
concentrated to an oil. Purification by column chromatography
(0.fwdarw.3% MeOH-DCM) provided the title compound.
[0295] Yield 52 mg (70%).
[0296] MS (m/z): [M+H]=335
[0297] .sup.1H NMR (300 MHz, d.sub.6-DMSO): 1.81 (m, 1H), 1.82 (s,
3H), 2.01 (m, 2H), 3.40 (t, J=5 Hz, 2H), 3.68 (d, J=8 Hz, 2H), 3.70
(m, 1H), 3.89 (d, J=8 Hz, 2H), 4.09 (t, J=9 Hz, 1H), 4.71 (m, 1H),
7.10 (t, J=9 Hz, 1H), 7.20 (dd, J=9, 2 Hz, 1H), 7.44 (dd, J=13, 2
Hz, 1H), 8.24 (t, J=6 Hz, 1H).
Intermediates for the preparation of example 4 were synthesized as
follows.
I. benzyl
3-fluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenylcarbam-
ate
[0298] ##STR41##
[0299] A solution of benzyl
4-[exo-(2R,3S)-2,3-bis(hydroxymethyl)cyclopropyl]-3-fluorophenylcarbamate
(0.18 g, 0.52 mmol,) in THF (5 mL) was cooled to -50.degree. C. An
n-BuLi solution (0.72 mL, 1.14 mmol) was added and the resulting
yellow suspension was stirred for 10 min and then methanesulfonyl
chloride (0.088 mL, 1.14 mmol) was added. This produced a
homogeneous solution that was stirred for 10 min and then treated
with more n-BuLi (0.36 mL, 0.57 mmol). The solution was allowed to
warm to -30.degree. C. over one hour and then quenched by the
addition of water and then dilute NaHCO.sub.3. THF was removed in
vacuo and the resulting aqueous solution was then extracted with
ethyl acetate three times. The combined organic phases were then
washed with brine and dried (MgSO.sub.4), filtered and
concentrated. The crude product was purified by column
chromatography (0.fwdarw.30% ethyl acetate/hexane) to provide the
title compound.
[0300] Yield 73 mg (43%).
[0301] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.89 (m, 2H), 1.98 (t,
J=4 Hz, 1H), 3.80 (d, J=8 Hz, 2H), 4.02 (d, J=8 Hz, 2H), 5.20 (s,
2H), 6.63 (bs, 1H), 6.87 (t, J=8 Hz, 1H), 6.95 (d, J=8 Hz, 1H),
7.25 (d, J=12 Hz, 1H), 7.35-7.41 (m, 5H)
[0302] mp=118-119.degree. C.
Example 5
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-y-
l]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0303] ##STR42##
[0304] A solution of
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-(2-benzyloxyacetyl)-3-azabicyclo[3.-
1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
(0.089 g, 0.185 mmol) in 2:1 methanol-dichloromethane (6 mL) was
stirred under a hydrogen atmosphere in the presence of 10% Pd/C
(0.025 g) for 1.5 h and then filtered through celite. The filtrate
was concentrated to provide the title compound.
[0305] Yield 0.069 g (95%).
[0306] .sup.1H NMR (300 MHz, d.sub.6-DMSO): 1.72 (t, J=4 Hz, 1H),
1.82 (s, 3H), 1.93 (m, 1H), 2.06 (m, 1H), 3.35-3.47 (m, 3H),
3.53-3.88 (m, 4H), 3.90-4.12 (m, 3H), 4.56 (t, J=6 Hz, 1H),
4.69-4.74 (m, 1H), 7.08 (t, J=9 Hz, 1H), 7.20 (dd, J=9, 2 Hz, 1H),
7.45 (dd, J=13, 2 Hz, 1H), 8.24 (t, J=6 Hz, 1H).
Intermediates for the preparation of example 5 were synthesized as
follows.
I. benzyl
3-fluoro-4-[exo-(1R,5S)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.0]h-
ex-6-yl]phenylcarbamate
[0307] ##STR43##
[0308]
Benzyl4-[exo-(2R,3S)-2,3-bis(methanesulfonyloxymethyl)cyclopropyl]-
-3-fluorophenylcarbamate (1.05 g, 2.1 mmol) was dissolved in
4-methoxybenzylamine (4.2 mL, 32 mmol) and stirred at room
temperature for 16 h. The resulting solution was then diluted with
125 mL of ethyl acetate and washed with 2.5% NaHCO.sub.3, dilute
aqueous HCl (32 mL of a 1 N solution diluted to 100 mL with
H.sub.2O), again with 2.5% NaHCO.sub.3, brine, and dried
(MgSO.sub.4), filtered and concentrated. The crude product was then
purified by silica gel column chromatography (gradient 0-25% ethyl
acetate-hexane-1% Et.sub.3N) to provide the title compound as a
white solid.
[0309] Yield 0.75 g (79%).
[0310] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.65 (bs, 2H), 2.44 (d,
J=9 Hz, 2H), 2.47 (m, 1H), 3.09 (d, J=9 Hz, 2H), 3.58 (s, 2H), 3.80
(s, 3H), 5.19 (s, 2H), 6.60 (bs, 1H), 6.77-6.93 (m, 4H), 7.21-7.41
(m, 8H).
II.
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-(4-methoxybenzyl)-3-azabicyclo[3-
.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0311] ##STR44##
[0312] Benzyl
3-fluoro-4-[exo-(1R,5S)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.0]hex-6-yl]p-
henylcarbamate (0.75 g, 1.7 mmol) was dissolved in DMF (1.1 mL) and
methanol (0.137 mL, 3.4 mmol), cooled at 0.degree. C. and treated
with lithium butoxide solution dropwise over 5 minutes (5.1 mL of a
1.0 M THF solution, 5.1 mmol). Solid (S)-acetic acid
2-acetylamino-1-chloromethyl-ethyl ester (0.66 g, 3.4 mmol) was
then added and the solution allowed to warm to room temperature and
stirred for 20 h. Saturated aqueous ammonium chloride (4 mL) was
added, along with 20 mL of H.sub.2O and 20 mL of brine. The
solution was extracted with three portions of dichloromethane and
the combined organic phases dried (MgSO.sub.4), filtered and
concentrated. The crude product was purified by column
chromatography (0-5% MeOH-DCM) to provide the title compound.
[0313] Yield 0.49 g (64%).
[0314] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.66 (bs, 2H), 2.02 (s,
3H), 2.44 (d, J=8 Hz, 2H), 2.50 (m, 1H), 3.10 (d, J=9 Hz, 2H),
3.51-3.78 (m, 3H), 3.56 (s, 2H), 3.80 (s, 3H), 4.00 (t, J=9 Hz,
1H), 4.72-4.79 (m, 1H), 6.20 (bs, 1H), 6.83-6.88 (m, 3H), 7.06 (dd,
J=9, 2 Hz, 1H), 7.22 (d, J=9 Hz, 2H), 7.31 (dd, J=12, 2 Hz,
1H).
III.
N-[((5S)-3-{4-[exo-(1R,5S)-3-azabicyclo[3.1.0]hex-6-yl]-3-fluoropheny-
l}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0315] ##STR45##
[0316] A solution of
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.-
0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (0.49
g, 1.08 mmol) in 1:1 ethyl acetate-methanol (50 mL) was stirred
under a hydrogen atmosphere in the presence of 20% Pd(OH).sub.2/C
(0.5 g) for 16 h and then filtered through celite. The filtrate was
concentrated to provide the title compound which was used directly
in the next reaction.
VI.
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-(2-benzyloxyacetyl)-3-azabicyclo-
[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0317] ##STR46##
[0318] A solution of
N-[((5S)-3-{4-[exo-(1R,5S)-3-azabicyclo[3.1.0]hex-6-yl]-3-fluorophenyl}-2-
-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (0.082 g, 0.25 mmol) in
dichloromethane (5 mL) and triethylamine (0.081 mL, 0.58 mmol) was
cooled to 0.degree. C. Benzyloxyacetyl chloride (0.050 mL, 0.32
mmol) was added to the solution and the mixture stirred for 1.5 h
at room temperature. More dichloromethane was added and the
solution extracted with 2.5% NaHCO.sub.3 (back extracting with more
dichloromethane). The combined organic phases were then washed with
brine and dried (MgSO.sub.4), filtered, and concentrated.
Purification by silica gel column chromatography (0-2%
MeOH--CH.sub.2Cl.sub.2) provided the title compound.
[0319] Yield 0.089 g (74% over two steps).
[0320] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.78 (bs, 1H), 1.91 (bs,
2H), 2.02 (s, 3H), 3.54-3.78 (m, 6H), 3.99-4.09 (m, 2H), 4.10 (s,
2H), 4.63 (s, 2H), 4.73-4.81 (m, 1H), 6.25 (m, 1H), 6.89 (t, J=8
Hz, 1H), 7.11 (d, J=8 Hz, 1H), 7.27-7.38 (m, 6H).
Example 6
2,2-difluoro-N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[-
3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]ethanethioamide
[0321] ##STR47##
[0322] A solution of
(5S)-5-(aminomethyl)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[-
3.1.0]hex-6-yl]phenyl}-1,3-oxazolidin-2-one (0.32 mmol) in methanol
(3 mL) and triethylamine (0.13 mL, 0.96 mmol) was treated with
difluoroacetic acid 3,3-diphenyl-1-propanol ester (0.15 g, 0.13 mL,
0.48 mmol) as a solution in 0.7 mL of dichloromethane. The mixture
was stirred at room temperature for 20 h and concentrated. The
residue was dissolved in ethyl acetate and washed with 2.5%
NaHCO.sub.3, brine, and dried (MgSO.sub.4). Purification by column
chromatography (0.fwdarw.2% MeOH--CH.sub.2Cl.sub.2) provided the
title compound.
[0323] Yield 0.113 g (75% over three steps).
[0324] .sup.1H NMR (300 MHz, d.sub.6-DMSO): 1.73 (t, J=3 Hz, 1H),
1.93 (m, 1H), 2.06 (m, 1H), 3.42 (dd, J=12, 4 Hz, 1H), 3.55 (dd,
J=11, 5 Hz, 1H), 3.65-4.09 (m, 7H), 4.16 (t, J=9 Hz, 1H), 4.56 (t,
J=5 Hz, 1H), 5.02 (m, 1H), 6.49 (t, J=55 Hz, 1H), 7.09 (t, J=9 Hz,
1H), 7.21 (dd, J=9, 2 Hz, 1H), 7.45 (dd, J=13, 2 Hz, 1H), 11.14
(bs, 1H).
Intermediates for the preparation of example 6 were synthesized as
follows.
I. tert-butyl
((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-(4-methoxyphenyl)-3-azabicyclo[3.1.0]h-
ex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methylcarbamate
[0325] ##STR48##
[0326] A solution of lithium t-butoxide (1.85 mL, 1.85 mmol) was
added to a cooled (0.degree. C.) solution of benzyl
3-fluoro-4-[exo-(1R,5S)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.0]hex-6-yl]p-
henylcarbamate (0.33 g, 0.74 mmol) and
(S)-(3-chloro-2-hydroxy-propyl)-carbamic acid tert-butyl ester
(0.20 g, 0.96 mmol, prepared according to the procedure described
in U.S. patent application Ser. No. 09/982,157, incorporated herein
in its entirety) in DMF (0.5 mL). The resulting solution was
stirred overnight and then quenched by the addition of saturated
NH.sub.4Cl, water, and brine. The solution was extracted with two
portions of dichloromethane and the combined organics washed with
water, brine, and dried (MgSO.sub.4), filtered and concentrated.
The crude product was purified by column chromatography (0-50%
ethyl acetate-hexane-1% Et.sub.3N) to provide the title
compound.
[0327] Yield 0.28 g (73%).
[0328] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.44 (s, 9H), 1.66 (m,
2H), 2.45 (d, J=8 Hz, 2H), 2.50 (t, J=3 Hz, 1H), 3.10 (d, J=9 Hz,
2H), 3.48-3.53 (m, 2H), 3.58 (s, 2H), 3.78 (m, 1H), 3.79 (s, 3H),
3.99 (t, J=9 Hz, 1H), 4.72-4.76 (m, 1H), 4.99 (bt, 1H), 6.83-6.89
(m, 3H), 7.09 (dd, J=9, 2 Hz, 1H), 7.21-7.24 (m, 2H), 7.32 (dd,
J=12, 2 Hz, 1H).
II. tert-butyl
((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-ox-
o-1,3-oxazolidin-5-yl)methylcarbamate
[0329] ##STR49##
[0330] A solution of tert-butyl
((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-(4-methoxyphenyl)-3-azabicyclo[3.1.0]h-
ex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methylcarbamate (0.275 g,
0.54 mmol) in 1:1 ethyl acetate-methanol (6 mL) was stirred under a
hydrogen atmosphere in the presence of Pd(OH).sub.2/C (0.16 g).
After 20 h the solution was filtered through celite and the
filtrate concentrated to provide 0.217 g of the title compound
which was used directly in the next reaction.
III. tert-butyl
((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-(2-benzyloxyacetyl)-3-azabicyclo[3.1.0-
]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methylcarbamate
[0331] ##STR50##
[0332] A solution of tert-butyl
((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-ox-
o-1,3-oxazolidin-5-yl)methylcarbamate (0.217 g, 0.54 mmol) in
dichloromethane (11 mL) and triethylamine (0.189 mL, 1.35 mmol) was
cooled to 0.degree. C. Benzyloxyacetyl chloride (0.10 mL, 0.65
mmol) was added to the solution and the mixture stirred for 2 h at
room temperature. More dichloromethane was added and the solution
extracted with 2.5% NaHCO.sub.3 (back extracting with more
dichloromethane). The combined organic phases were then washed with
brine and dried (MgSO.sub.4), filtered, and concentrated.
Purification by column chromatography (0.fwdarw.2%
MeOH--CH.sub.2Cl.sub.2) provided the title compound.
[0333] Yield 0.25 g (86% over two steps).
[0334] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.41 (s, 9H), 1.78 (t,
J=4 Hz, 1H), 1.91 (M, 2H), 3.49-3.66 (m, 4H), 3.75-3.84 (m, 2H),
3.70-4.09 (m, 2H), 4.10 (s, 2H), 4.64 (s, 2H), 4.75 (m, 1H), 5.04
(bt, 1H), 6.89 (t, J=8 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 7.31-7.38 (m,
6H).
VI.
(5S)-5-(aminomethyl)-3-{3-fluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyc-
lo[3.1.0]hex-6-yl]phenyl}-1,3-oxazolidin-2-one
[0335] ##STR51##
[0336] A solution of tert-butyl
((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-(2-benzyloxyacetyl)-3-azabicyclo[3.1.0-
]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methylcarbamate (0.185
g, 0.34 mmol) was dissolved in 2:1 methanol-dichloromethane (12 mL)
and stirred under a hydrogen atmosphere in the presence of 10% Pd/C
(0.09 g). After 2 h the solution was filtered through celite and
the filtrate concentrated. The residue was dissolved in dioxane (6
mL) and treated with 4 N HCl in dioxane solution (6 mL). After
stirring for 4 h the suspension was concentrated to give the title
compound as the HCl salt and this material was used directly in the
next reaction.
Example 7
methyl
exo-(1R,5S)-6-(4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-
-3-yl}-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
[0337] ##STR52##
[0338] A solution of
N-[((5S)-3-{4-[exo-(1R,5S)-3-azabicyclo[3.1.0]hex-6-yl]-3-fluorophenyl}-2-
-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (0.055 g, 0.165 mmol) was
dissolved in DMF (0.75 mL) and triethylamine (0.069 mL, 0.5 mmol),
cooled to 0.degree. C. and treated with methyl chloroformate (0.019
mL, 0.25 mmol). After 2 h, the reaction mixture was diluted with
ethyl acetate, washed with 2.5% NaHCO.sub.3 (back-extracting once)
and the combined organic extracts washed with brine and dried
(MgSO.sub.4), filtered and concentrated. The crude material was
purified by silica gel column chromatography (0-2%
methanol-dichloromethane) to provide the title compound.
[0339] Yield 0.045 g (74%).
[0340] MS (m/z): [M+H]=392
[0341] .sup.1H NMR (300 MHz, d.sub.6-DMSO): 1.73 (t, J=4 Hz, 1H),
1.82 (s, 3H), 1.95 (m, 2H), 3.20-3.48 (m, 5H), 3.58 (s, 3H),
3.61-3.73 (m, 2H), 4.09 (t, J=9 Hz, 1H), 4.69-4.74 (m, 1H) 7.08 (t,
J=9 Hz, 1H), 7.20 (dd, J=8, 2 Hz, 1H), 7.44 (dd, J=13, 2 Hz, 1H),
8.24 (t, J=6 Hz, 1H).
Example 8
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-formyl-3-azabicyclo[3.1.0]hex-6-yl]p-
henyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0342] ##STR53##
[0343] A solution of
N-[((5S)-3-{4-[exo-(1R,5S)-3-azabicyclo[3.1.0]hex-6-yl]-3-fluorophenyl}-2-
-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (0.010 g, 0.03 mmol) was
dissolved in acetic anhydride (0.25 mL) and formic acid (0.50 mL)
and stirred at room temperature. After 3 days the solution was
concentrated and the residue purified by preparative HPLC to give
the title compound.
[0344] Yield 4 mg (40%).
[0345] MS (m/z): [M+H]=362
[0346] .sup.1H NMR (300 MHz, d.sub.6-DMSO): 1.68 (t, J=4 Hz, 1H),
1.82 (s, 3H), 1.91-1.97 (m, 2H), 3.20-3.40 (m, 3H), 3.60-3.73 (m,
2H), 3.83 (d, J=10 Hz, 2H), 4.09 (t, J=9 Hz, 1H), 4.71 (m, 1H),
7.09 (t, J=8 Hz, 1H), 7.21 (dd, J=9, 2 Hz, 1H), 7.45 (dd, J=13, 2
Hz, 1H), 8.14 (s, 1H), 8.24 (t, J=6 Hz, 1H).
Example 9
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-((2S)-2,3-dihydroxypropanoyl)-3-azab-
icyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0347] ##STR54##
[0348] A solution of
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-({(4S)-2,2-dimethyl-1,3-dioxolan-4--
yl}carbonyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl-
)methyl]acetamide (8 mg, 0.017 mmol) in 1 mL of 1:1 trifluoroacetic
acid-water was stirred for 2 hours. The solution was then
concentrated and the resulting aqueous solution lyophilized. The
resulting crude product was then purified by preparative HPLC to
provide the title compound.
[0349] Yield 4 mg (50%).
[0350] MS (m/z). [M+H]=422
[0351] .sup.1H NMR (300 MHz, CD.sub.3OD): 1.82 (m, 1H), 1.95 (s,
3H), 2.03 (m, 2H), 3.50-4.14 (m, 11H), 4.33 (m, 1H), 4.78 (m, 1H),
7.04 (t, J=8 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 7.45 (dd, J=13, 2 Hz,
1H).
Intermediates for the preparation of example 9 were synthesized as
follows.
I.
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-([(4S)-2,2-dimethyl-1,3-dioxolan--
4-yl]carbonyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5--
yl)methyl]acetamide
[0352] ##STR55##
[0353] A solution of
N-[((5S)-3-{4-[exo-(1R,5S)-3-azabicyclo[3.1.0]hex-6-yl]-3-fluorophenyl}-2-
-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (0.010 g, 0.03 mmol) was
dissolved in 0.25 mL of DMF. To the solution was added a premixed
(for 15 min) solution of HATU (0.03 g, 0.075 mmol),
diisopropylethylamine (0.026 mL, 0.15 mmol) and
(S)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (0.009 g, 0.06
mmol) in 0.25 mL of DMF. After stirring overnight the solution was
diluted with ethyl acetate and washed with 2.5% NaHCO.sub.3, dilute
citric acid, 2.5% NaHCO.sub.3, brine and dried (MgSO.sub.4). The
solution was filtered and concentrated under vacuum and the residue
purified by preparative TLC (6% methanol-dichloromethane) to
provide the title compound.
[0354] Yield 8 mg (60%).
[0355] .sup.1H NMR (300 MHz, CD.sub.3OD): 1.37-1.42 (m, 6H), 1.77
(m, 1H), 1.95 (s, 3H), 2.02 (m, 2H), 3.50-3.96 (m, 7H), 4.08-4.26
(m, 4H), 4.72-4.78 (m, 1H), 7.04 (t, J=8 Hz, 1H), 7.19 (d, J=9 Hz,
1H), 7.44 (dd, J=13, 2 Hz, 1H).
Example 10
exo-(1R,5S)-6-(4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}--
2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxamide
[0356] ##STR56##
[0357] A solution of
N-[((5S)-3-{4-[exo-(1R,5S)-3-azabicyclo[3.1.0]hex-6-yl]-3-fluorophenyl}-2-
-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (5 mg, 0.015 mmol) in
dichloromethane (0.1 mL) and triethylamine (4 .mu.L, 0.03 mmol) was
treated with trimethylsilyl isocyanate in portions until the
starting material had been consumed (a total of 6 eq. added over
1.5 h). The reaction mixture was then treated with methanol and the
solution concentrated and purified by preparative HPLC to provide
the title compound.
[0358] Yield: 2 mg (40%).
[0359] MS (m/z): [M+H]=377
[0360] .sup.1H NMR (300 MHz, d.sub.6-DMSO): 1.68 (t, J=3 Hz, 1H),
1.82 (s, 3H), 1.92 (bs, 2H), 3.20-3.40 (m, 4H), 3.60 (d, J=11 Hz,
2H), 3.70 (m, 1H), 4.09 (t, J=9 Hz, 1H), 4.70 (m, 1H), 5.80 (s,
2H), 7.07 (t, J=8 Hz, 1H), 7.20 (dd, J=8, 2 Hz, 1H), 7.44 (dd,
J=13, 2 Hz, 1H), 8.24 (t, J=6 Hz, 1H).
Example 11
exo-(1R,5S)-6-[4-((5S)-5-{[(2,2-difluoroethanethioyl)amino]methyl}-2-oxo-1-
,3-oxazolidin-3-yl)-2-fluorophenyl]-3-azabicyclo[3.1.0]hexane-3-carboxamid-
e
[0361] ##STR57##
[0362] A solution of tert-butyl
((5S)-3-{4-[exo-(1R,5S)-3-(aminocarbonyl)-3-azabicyclo[3.1.0]hex-6-yl]-3--
fluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methylcarbamate (0.2 g,
0.45 mmol) was dissolved in 4 mL of dioxane and treated with a
dioxane solution of HCl (8 mL of a 4 M solution). The solution was
stirred for 4 hours at room temperature and the resulting
suspension concentrated to give an off-white solid. This material
was then dissolved in methanol (4.5 mL) and triethylamine (0.19 mL,
1.35 mmol) and treated with difluoroacetic acid
3,3-diphenyl-1-propanol ester (0.206 g, 0.68 mmol) dissolved in
0.75 mL of dichloromethane. The mixture was stirred at room
temperature for 2 h and then concentrated. The residue was
dissolved in ethyl acetate and washed with 2.5% NaHCO.sub.3, brine,
and dried (MgSO.sub.4). Purification by preparative TLC (gradient
0-5% methanol-dichloromethane/10% acetonitrile) provided the title
compound.
[0363] Yield 0.16 g (84% overall).
[0364] MS (m/z): [M+H]=429
[0365] .sup.1H NMR (300 MHz, d.sub.6-DMSO): 1.70 (m, 1H), 1.92 (bs,
2H), 3.32 (d, J=11 Hz, 2H), 3.60 (d, J=11 Hz, 2H), 3.83 (m, 1H),
3.98 (m, 2H), 4.16 (t, J=9 Hz, 1H), 5.01 (m, 1H), 5.80 (s, 2H),
6.49 (t, J=55 Hz, 1H), 7.07 (t, J=9 Hz, 1H), 7.21 (d, J=9 Hz, 1H),
7.44 (d, J=13 Hz, 1H), 11.13 (bt, 1H).
Intermediates for the preparation of example 11 were synthesized as
follows.
I. tert-butyl
((5S)-3-{4-[exo-(1R,5S)-3-(aminocarbonyl)-3-azabicyclo[3.1.0]hex-6-yl]-3--
fluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methylcarbamate
[0366] ##STR58##
[0367] A solution of tert-butyl
((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-ox-
o-1,3-oxazolidin-5-yl)methylcarbamate (0.275 g, 0.72 mmol) in
dichloromethane (15 mL) and triethylamine (0.15 mL, 1.1 mmol) was
treated with trimethylsilyl isocyanate in portions until the
starting material had been consumed (a total of 14 eq. added over
24 h). The reaction mixture was then treated with methanol and the
solution concentrated. The residue was passed through a short
column of silica gel (5% methanol-dichloromethane) to give the
title compound, which was used without further purification.
Example 12
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6--
yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0368] ##STR59##
[0369] An aqueous solution of NaIO.sub.4 (0.101 g, 0.47 mmol) was
added to a solution of
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phen-
yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (0.16 g, 0.43 mmols)
in 8 mL of MeOH--H.sub.2O (3:1) and stirred at 0.degree. C. for 20
h. The reaction mixture was filtered with the aid of chloroform and
the filtrate concentrated. Purification by column chromatography
(0-5% MeOH-10% ACN-dichloromethane) provided the title compound
which elutes first, ahead of the other sulfoxide isomer.
[0370] Yield 50 mg (30%).
[0371] MS (m/z): [M+H]=385.
[0372] HPLC (SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 5 min; 2 mL/min
rate): retention time=1.67 min.
[0373] .sup.1H NMR (300 MHz, CDCl.sub.3): 2.00 (s, 3H), 2.35 (bs,
2H), 2.62 (t, J=4.5 Hz, 1H), 3.30-(s, 4H), 3.54-3.72 (m, 3H), 3.97
(t, J=9.0 Hz, 1H), 4.72-4.80 (m, 1H), 6.01 (bs, 1H), 7.06 (d, J=10.
2 Hz, 2H).
Intermediates for the preparation of example 12 were synthesized as
follows.
I. Isopropyl 3,5-difluoro-phenylcarbamate
[0374] ##STR60##
[0375] Lithium bis(trimethylsilyl) amide (1.0 M solution in
tetrahydrofuran, 542 mL, 0.542 mol) was added to a solution of
3,5-difluoroaniline (35 g, 0.271 mol) in THF (60 mL) at 0.degree.
C. Isopropyl chloroformate (1M solution in toluene, 406 mL, 0.406
mol) was then added dropwise at 0.degree. C. and the mixture
allowed to warm to room temperature over 2 h. The reaction mixture
was diluted with ether and washed with 1N hydrochloric acid, water,
saturated aqueous sodium bicarbonate, brine and dried (MgSO.sub.4).
Solvent was removed under vacuum and the residue was triturated in
hexanes to obtain the title compound.
[0376] Yield 48 g (82%).
[0377] MS (m/z): [M+H]=216.
[0378] HPLC (SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 5 min; 2 mL/min
rate): retention time=3.04 min.
[0379] .sup.1H NMR (300 MHz, CD.sub.3OD): 1.21 (d, J=6.3 Hz, 6H),
4.96-5.04 (m, 1H), 6.71 (dd, J=7, 2 Hz, 2.1 Hz, 2H), 6.8 (tt, J=9.0
Hz, 2.1 Hz, 1H).
II. isopropyl 3,5-difluoro-4-formylphenylcarbamate
[0380] ##STR61##
[0381] n-Butyllithium (2.5M in hexane, 112 mL, 0.279 mol) was added
dropwise at -78.degree. C. to a solution of isopropyl
3,5-difluoro-phenylcarbamate (20 g, 0.093 mol) and
N,N,N,N-tetramethylethylenediamine (32 mL, 0.214 mol) in 93 mL of
THF, and stirred for 30 min. Dimethylformamide (10.8 mL, 0.140 mol)
was then added dropwise at -78.degree. C., stirred for 1 h, and
allowed to warm to -20.degree. C. The reaction was then quenched
with saturated aqueous ammonium chloride (100 mL). The reaction
mixture was extracted with ethyl acetate, the extracts washed with
brine, dried (MgSO.sub.4), and concentrated. The crude product was
triturated with hexane to provide the title compound. The combined
hexane washings were concentrated and purified by flash column
chromatography (30% ethyl acetate/hexane) to provide additional
product.
[0382] Yield=7.0 g (31%).
[0383] MS (m/z): [M+H]=244.
[0384] HPLC (SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 5 min; 2 mL/min
rate): retention time=2.72 min.
[0385] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.29, (d, J=6.3 Hz, 6H),
5.02 (hept, J=6.3 Hz, 1H). 6.85 (bs, 1H), 7.08 (d, J=10.8 hz, 2H),
10.18 (s, 1H).
III. methyl
(2E)-3-{2,6-difluoro-4-[(isopropoxycarbonyl)amino]phenyl}acrylate
[0386] ##STR62##
[0387] Sodium hydride (1.4 g of 60% dispersion, 35 mmol) was placed
in a flask and washed three times with hexane. The resulting solid
was suspended in DMF (29 mL) and cooled to 0.degree. C. Trimethyl
phosphonoacetate (5.95 mL, 36.75 mmol) was added dropwise to this
suspension to give a clear homogeneous solution. After stirring for
another 15 minutes at 0.degree. C., a solution of isopropyl
3,5-difluoro-4-formylphenylcarbamate (8.51 g, 35 mmol) in DMF (25
mL) was added dropwise. The resulting orange suspension was allowed
to warm slowly to room temperature and stirred for 16 hours. The
reaction mixture was then poured into 0.5 N HCl and extracted with
three portions of dichloromethane. Combined organic phases were
washed with saturated NaHCO.sub.3, H.sub.2O, brine, and dried
(MgSO.sub.4) filtered and concentrated. The resulting orange solid
was washed with hexane, 30% ethyl acetate-hexane, and then purified
by column chromatography (15-30% ethyl acetate-hexane) to provide
title compound.
[0388] Yield 7.8 g (75%).
[0389] MS (m/z): [M+H]=300.
[0390] HPLC (SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 5 min; 2 mL/min
rate): retention time=3.28 min.
[0391] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.28 (d, J=6.0 Hz, 6H),
3.78 (s, 3H), 5.00 (hept, J=6.3 Hz, 1H), 6.62 (d, J=16.5 Hz, 1H),
6.77 (s, 1H), 7.05 (d, J=10.8 hz, 2H), 7.69 (d, J=16. 2 Hz,
1H).
IV. isopropyl
3,5-difluoro-4-[(1E)-3-hydroxyprop-1-enyl]phenylcarbamate
[0392] ##STR63##
[0393] A solution of LiAlH.sub.4 (26 mL of a 1.0 M THF solution, 26
mmol) was added to a cooled (-78.degree. C.) solution of methyl
(2E)-3-{2,6-difluoro-4-[(isopropoxycarbonyl)amino]phenyl}acrylate
(7.77 g, 26 mmol) in THF (130 mL). The solution was allowed to warm
slowly to -20.degree. C. and maintained at that temperature for 2
hours. The reaction mixture was then quenched by slow addition of
saturated NH.sub.4Cl and then treated with 30 mL of dilute citric
acid. The resulting mixture was stirred for 15 minutes and then
extracted with three portions of ethyl acetate. Combined organic
phases were washed with H.sub.2O, brine and dried (MgSO.sub.4),
filtered and concentrated to give a red oil. The crude product was
purified by column chromatography (0-1% methanol-dichloromethane)
to afford the title compound as a yellow oil.
[0394] Yield 4.6 g (65%).
[0395] MS (m/z): [M+H]=272.
[0396] HPLC (SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 5 min; 2 mL/min
rate): retention time=2.59 min
[0397] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.27 (d, J=6.3 Hz, 6H),
4.31 (s, 2H), 4.99 (hept, J=6.3 Hz, 1H), 6.56 (s, 2H), 6.59 (s,
1H), 6.97 (d, J=10.5 Hz, 2H).
V.
(2E)-3-{2,6-difluoro-4-[(isopropoxycarbonyl)amino]phenyl}prop-2-enyl
diazoacetate
[0398] ##STR64##
[0399] Glyoxylic acid chloride p-toluenesulfonylhydrazone (4.64 g,
17.8 mmol) was added to a suspension of isopropyl
3,5-difluoro-4-[(1E)-3-hydroxyprop-1-enyl]phenylcarbamate (2.68 g,
9.89 mmol) in dichloromethane (66 mL). The mixture was cooled to
0.degree. C. and treated with N,N-dimethylaniline (2.26 mL, 17.8
mmol). After 30 minutes, triethylamine (6.89 mL, 49.5 mmol) was
added and the mixture stirred 30 minutes at 0.degree. C. and 15
minutes at room temperature. The reaction mixture was then
concentrated to ca. 15 mL and 50 mL of water added. The mixture was
extracted with two portions of diethyl ether and the combined
organic solutions washed with saturated NaHCO.sub.3, brine, and
dried (MgSO.sub.4), filtered and concentrated. Purification by
column chromatography (0-25% ethyl acetate-hexane) provided the
title compound a yellow solid.
[0400] Yield 2.44 g (73%).
[0401] MS (m/z): [M+H]=340.
[0402] HPLC (SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 5 min; 2 mL/min
rate): retention time=3.22 min.
[0403] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.28 (d, J=6.3 Hz, 6H),
4.79 (s, 2H), 4.81 (s, 1H), 4.99 (hept, J=6.3 Hz, 1H), 6.47 (dt,
J=16.2, 5.7 Hz, 1H), 6.59 (d, J=16, 2 Hz, 1H), 6.62 (s, 1H), 6.98
(d, J=10.5 Hz, 2H).
VI. isopropyl
3,5-difluoro-4-[(1S,5R,6R)-2-oxo-3-oxabicyclo[3.1.0]hex-6-yl]phenylcarbam-
ate
[0404] ##STR65##
[0405] A solution of
(2E)-3-{2,6-difluoro-4-[(isopropoxycarbonyl)amino]phenyl}
prop-2-enyl diazoacetate (2.4 g, 7.07 mmol) in 170 mL of
toluene/dichloromethane (1:2) was added dropwise over 14 h to a
refluxing solution of bis-(N-t-butylsalicylaldiminato) copper(II)
(0.147 g, 0.35 mmol) in 120 mL of toluene. After the addition was
complete, the reaction mixture was heated another hour at reflux,
then cooled, filtered and concentrated. The crude oil was purified
by column chromatography (15-40% EtOAc-hexanes) to provide the
title compound (a racemic mixture) as a yellow solid.
[0406] Yield 1.62 g (75%).
[0407] MS (m/z): [M+H]=312.
[0408] HPLC (SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 5 min; 2 mL/min
rate): retention time=2.77 min.
[0409] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.27 (d, J=6.3 Hz, 6H),
2.23 (dd, J=4.2, 3.3 Hz, 1H), 2.54 (dd, J=6.0, 3.3 Hz, 1H),
2.74-2.79 (m, 1H), 4.37-4.46 (m, 2H), 4.98 (hept, J=6.3 Hz, 1H),
6.57 (s, 1H), 6.97 (d, J=10, 2 Hz, 2H).
VII. isopropyl
4-[exo-(2R,3S)-2,3-bis(hydroxymethyl)cyclopropyl]-3,5-difluorophenylcarba-
mate
[0410] ##STR66##
[0411] A solution of LiAlH.sub.4 (5.2 mL of a 1.0 M THF solution,
5.2 mmol) was added dropwise to a solution of isopropyl
3,5-difluoro-4-[(1S,5R,6R)-2-oxo-3-oxabicyclo[3.1.0]hex-6-yl]phenylcarbam-
ate (1.61 g, 5.17 mmol) in THF (41 mL) cooled at 0.degree. C. The
solution was stirred at 0.degree. C. for 1 h and then treated with
more LiAlH.sub.4 solution (2.5 mL, 2.5 mmol) and allowed to warm to
room temperature. After another hour at room temperature, the
solution was quenched by the slow addition of saturated NH.sub.4Cl
(15 mL) followed by H.sub.2O (30 mL) and saturated citric acid (10
mL). The solution was concentrated to remove THF and the resulting
aqueous solution extracted with three portions of ethyl acetate.
The combined organic phases were then washed with H.sub.2O, brine,
and dried (MgSO.sub.4), filtered and concentrated to an oil.
Purification by column chromatography (0-3% MeOH-dichloromethane)
provided the title compound as a white solid.
[0412] Yield 1.16 g (72%).
[0413] MS (m/z): [M+H]=316.
[0414] HPLC (SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 5 min; 2 mL/min
rate): retention time=2.26 min.
[0415] .sup.1H NMR (300 MHz, CD.sub.3OD): 1.27 (d, J=6.3 Hz, 6H),
1.63-1.75 (m, 3H), 3.55-3.62 (m, 2H), 3.93 (dd, J=5.7, 11.7 Hz,
2H), 4.93 (hept, J=6.0 Hz, 1H), 7.01 (d, J=10, 2 Hz, 2H).
VIII. isopropyl
3,5-difluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenylcarbamate
[0416] ##STR67##
[0417] Methanesulfonic anhydride (0.696 g, 4.00 mmol) was added to
a suspension of isopropyl
4-[exo-(2R,3S)-2,3-bis(hydroxymethyl)cyclopropyl]-3,5-difluorophenylcarba-
mate (0.50 g, 1.6 mmol) in dichloromethane (20 mL) and
triethylamine (0.848 mL, 6.4 mmol) cooled at 0.degree. C. The
solution was stirred at 0.degree. C. for 45 minutes and then
diluted with more dichloromethane, washed with saturated
NaHCO.sub.3 solution, water, brine, dried (MgSO.sub.4) and
concentrated in an ice-cooled bath. The resulting white foam was
dissolved in DMSO (4 mL), treated with Na.sub.2S (0.375 g, 4.8
mmol) and allowed to stir overnight. The resulting suspension was
dissolved in H.sub.2O and extracted with ether thrice. The combined
organic phases were dried (MgSO.sub.4), filtered and concentrated
to provide the title compound as a yellow solid.
[0418] Yield 0.450 g (90%).
[0419] MS (m/z): [M+H]=314.
[0420] HPLC (SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 5 min; 2 mL/min
rate): retention time 3.66 min.
[0421] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.27 (d, J=6.3 Hz, 6H),
2.06 (bs, 2H), 2.18 (t, J=4, 2 Hz, 1H), 3.06-3.17 (m, 4H), 4.98 (q,
J=6.3 Hz, 1H), 6.49 (bs, 1H), 6.90 (d, J=9.9 Hz, 2H).
IX.
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]p-
henyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0422] ##STR68##
[0423] Lithium butoxide (2.07 mL of a 1.0 M THF solution, 2.07
mmol) was added to a cooled (0.degree. C.) solution of isopropyl
3,5-difluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenylcarbamate
(0.217 g, 0.69 mmol) in DMF (0.46 mL) and MeOH (0.061 mL, 1.52
mmol). Solid (S)-acetic acid 2-acetylamino-1-chloromethyl-ethyl
ester (0.267 g, 1.38 mmol) was then added and the solution allowed
to warm to room temperature and stirred for 20 h. Saturated aqueous
ammonium chloride (2 mL) was added, along with 10 mL of H.sub.2O
and 10 mL of brine. The solution was extracted with three portions
of dichloromethane and the combined organic phases dried
(MgSO.sub.4), filtered and concentrated. The crude product was
purified by column chromatography (0-1% MeOH-dichloromethane) to
provide the title compound.
[0424] Yield 0.16 g (62%).
[0425] MS (m/z): [M+H]=369
[0426] MS (ESPOS): 369 (M+1)
[0427] HPLC (SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 5 min; 2 mL/min
rate): retention time=2.70 min.
[0428] .sup.1H NMR (300 MHz, CDCl.sub.3): 2.00 (s, 3H), 2.09 (bs,
2H), 2.22 (t, J=4, 2 Hz, 1H), 3.07-3.17 (m, 4H), 3.54-3.72 (m, 3H),
3.97 (t, J=9.0 Hz, 1H), 4.71-4.80 (m, 1H), 5.94 (bs, 1H), 7.04 (d,
J=10, 2 Hz, 2H).
Example 13
N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3,5-d-
ifluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0429] ##STR69##
[0430] A solution of peracetic acid (0.24 mL, 0.99 mmol) was added
to a solution of N-[((5S)
-3-{3,5-difluoro-4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-ox-
o-1,3-oxazolidin-5-yl)methyl]acetamide (0.12 g, 0.33 mmol) in THF
(16.5 mL) and the reaction mixture allowed to stir for 20 h at room
temperature. The reaction mixture was quenched with 5 mL of
saturated Na.sub.2S.sub.2O.sub.3 and water was added. The mixture
was concentrated to remove THF and the resulting aqueous solution
extracted with ethyl acetate. The organic layer was washed with
brine and dried (MgSO.sub.4), filtered, and concentrated. The
residue was purified by pTLC (7% MeOH-dichloromethane) to provide
the title compound.
[0431] Yield 120 mg (91%).
[0432] MS (m/z): [M+H]=401
[0433] HPLC (SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 5 min; 2 mL/min
rate): retention time=1.90 min.
[0434] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.97-2.01 (m, 4H), 2.22
(t, J=4.8 Hz, 2H), 3.07 (d, J=14.1 Hz, 2H), 3.50-3.72 (m, 5H), 3.97
(t, J=9.0 Hz, 1H), 4.72-4.81 (m, 1H), 6.36 (t, J=6 Hz, 1H), 7.08
(d, J=10. 2 Hz, 2H).
Example 14
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl-
}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0435] ##STR70##
[0436] A solution of isopropyl
3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenylcarbamate
(0.063 g, 0.21 mmol) in DMF (0.14 mL) and MeOH (0.017 mL, 0.42
mmol) was cooled at 0.degree. C. and treated with LiOtBu solution
(0.64 mL, 0.64 mmol) dropwise. The solution was then treated in one
portion with (S)-acetic acid 2-acetylamino-1-chloromethyl-ethyl
ester (0.082 g, 0.42 mmol). The reaction mixture was slowly warmed
to room temperature and stirred for 20 h. The solution was then
treated with 1.0 mL of saturated NH.sub.4Cl was added followed by 5
mL of water and 5 mL of brine. The mixture was extracted with three
portions of dichloromethane and the combined organic phases washed
with water, brine, and dried (MgSO.sub.4), filtered and
concentrated to an oil. Purification by column chromatography
(0.fwdarw.2% MeOH-DCM) provided the title compound.
[0437] Yield 53 mg (71%).
[0438] MS (m/z): [M+H]=353
[0439] .sup.1H NMR (300 MHz, DMSO-d.sub.6): 1.61 (t, J=4 Hz, 1H),
1.82 (s, 3H), 2.13 (m, 2H), 3.40 (t, J=5 Hz, 2H), 3.66 (d, J=8 Hz,
2H), 3.70 (m, 1H), 3.89 (d, J=8 Hz, 2H), 4.08 (t, J=9 Hz, 1H), 4.74
(m, 1H), 7.26 (d, J=11 Hz, 2H), 8.24 (t, J=6 Hz. 1H).
Intermediates for the preparation of example 14 were synthesized as
follows.
I. isopropyl
3,5-difluoro-4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenylcarbamate
[0440] ##STR71##
[0441] A solution of isopropyl
4-[exo-(2R,3S)-2,3-bis(hydroxymethyl)cyclopropyl]-3,5-difluorophenylcarba-
mate (0.16 g, 0.51 mmol,) in THF (4.5 mL) was cooled to -50.degree.
C. An n-BuLi solution (0.58 mL, 1.6 M in hexane, 0.924 mmol) was
added and the resulting yellow suspension was stirred for 10 min
and then methanesulfonyl chloride (0.045 mL, 0.57 mmol) was added.
This produced a homogeneous solution that was stirred for 10 min
and then treated with more n-BuLi (0.41 mL, 0.57 mmol). The
solution was allowed to warm to -30.degree. C. over one hour and
then quenched by the addition of water and then dilute NaHCO.sub.3.
THF was removed in vacuo and the resulting aqueous solution was
then extracted with ethyl acetate three times. The combined organic
phases were then washed with brine and dried (MgSO.sub.4), filtered
and concentrated. The crude product was purified by column
chromatography (0-30% ethyl acetate/hexane) to provide the title
compound.
[0442] Yield 72 mg (47%).
[0443] .sup.1H NMR.
[0444] mp=125-127.degree. C.
Example 15
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-
-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0445] ##STR72##
[0446] To a solution of
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-(2-benzyloxyacetyl)-3-azabicycl-
o[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
(0.105 g, 0.21 mmol) in MeOH (7 mL) was added 10% Pd/C (0.35 g) and
the reaction mixture stirred under an H.sub.2 atmosphere for 1.5
hr. The reaction mixture was then filtered through celite and
concentrated. Purification by flash chromatography (0-3%
MeOH-dichloromethane) provided the title compound.
[0447] Yield 0.073 g (85%).
[0448] MS (m/z): [M+H].sup.+=410.4.
[0449] .sup.1H NMR (300 MHz, DMSO): 1.52 (t, J=4 Hz, 1H), 1.81 (s,
3H), 2.01-2.06 (m, 1H), 2.13-2.18 (m, 1H), 3.36-3.43 (m, 3H), 3.53
(dd, J=4.2, 10 Hz, 1H), 3.63-3.71 (m, 2H) 3.77 (d, J=12 Hz, 1H),
3.86-4.10 (m, 3H), 4.54 (br t, 1H), 4.68-4.76 (m, 1H), 7.25 (d,
J=11 Hz, 2H), 8.23 (t, J=6 Hz, 1H).
Intermediates for the preparation of example 15 were synthesized as
follows.
I. isopropyl
3,5-difluoro-4-[exo-(1R,5S)-3-azabicyclo[3.1.0]hex-6-yl]phenylcarbamate
[0450] ##STR73##
[0451] Methanesulfonic anhydride (1.325 g, 7.62 mmol) was added to
a suspension of isopropyl
4-[exo-(2R,3S)-2,3-bis(hydroxymethyl)cyclopropyl]-3,5-difluorophenylcarba-
mate (0.80 g, 2.54 mmol) in dichloromethane (50 mL) and
triethylamine (1.41 mL, 10.6 mmol) cooled at 0.degree. C. The
solution was stirred at 0.degree. C. for 1 h and then treated with
more Methanesulfonic anhydride (0.442 g, 2.54 mmol) and allowed to
warm to room temperature. After another hour at room temperature,
the reaction mixture was diluted with more dichloromethane and
washed with saturated NaHCO.sub.3 solution, water, brine, and dried
(MgSO.sub.4), filtered and concentrated. The resulting white foam
was dissolved in MeOH (50 mL), treated with NH.sub.4OH (50 mL) and
allowed to stir overnight. The mixture was then extracted with
ethyl acetate thrice. The combined organic phases were then washed
with H.sub.2O, brine, and dried (MgSO.sub.4), filtered and
concentrated to provide the title compound as an oil. This material
was used in the next step without further purification.
[0452] HPLC (SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 5 min; 2 mL/min
rate): retention time=1.96 min.
II. isopropyl
3,5-difluoro-4-[exo-(1R,5S)-3-(2-benzyloxyacetyl)-3-azabicyclo[3.1.0]hex--
6-yl]phenylcarbamate
[0453] ##STR74##
[0454] Benzyloxyacetyl chloride (0.519 mL, 3.3 mmol) was added to a
solution of isopropyl
3,5-difluoro-4-[exo-(1R,5S)-3-azabicyclo[3.1.0]hex-6-yl]phenylcarbamate
(ca. 2.5 mmol, crude) in ethyl acetate (50 mL) and 10% NaHCO.sub.3
(100 mL). This mixture was stirred vigorously for 1 hr. The aqueous
layer was maintained at basic pH and more benzyloxyacetyl chloride
(0.519 mL, 3.3 mmol) was added. When most of the starting material
had been consumed, the layers were separated and the aqueous layer
extracted with more ethyl acetate. The combined organic layers were
washed with 1 N HCl, saturated aqueous NaHCO.sub.3, water, brine,
and dried (MgSO.sub.4), filtered and concentrated. Purification by
flash chromatography (0-2% MeOH-dichloromethane) and then by pTLC
(20% EtOAc-hexanes) provided the title compound.
[0455] Yield 0.46 g (41% over 2 steps).
[0456] MS (m/z): [M+H]=445.5.
[0457] .sup.1H NMR (300 MHz, DMSO): 1.23 (d, J=6 Hz, 6H), 1.47 (t,
J=4 Hz, 1H), 1.97-2.02 (m, 1H), 2.08-2.14 (m, 1H), 3.32-3.79 (m,
4H), 4.03-4.17 (m, 2H), 4.50 (bs, 2H) 4.87 (q, J=6 Hz, 1H), 7.10
(d, J=11 Hz, 2H), 7.33 (bs, 5H), 9.91 (s, 1H).
III.
N-[((5S)-3-{3,5-difluoro-4-[exo-(1R,5S)-3-(2-benzyloxyacetyl)-3-azabi-
cyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0458] ##STR75##
[0459] Lithium butoxide solution (1.02 mL of a 1.0 M THF solution,
1.02 mmol) was added to a cooled (0.degree. C.) solution of
isopropyl
3,5-difluoro-4-[exo-(1R,5S)-3-(2-benzyloxyacetyl)-3-azabicyclo[3.1.0]hex--
6-yl]phenylcarbamate (0.150 g, 0.34 mmol) in DMF (0.23 mL) and MeOH
(0.027 mL, 0.68 mmol). Solid (S)-acetic acid
2-acetylamino-1-chloromethyl-ethyl ester (0.131 g, 0.68 mmol) was
then added and the solution stirred at room temperature for 20 h.
Saturated aqueous ammonium chloride (2 mL) was then added, along
with 10 mL of H.sub.2O and 10 mL of brine. The solution was
extracted with three portions of dichloromethane and the combined
organic phases dried (MgSO.sub.4), filtered and concentrated. The
crude product was purified by column chromatography (0-2%
MeOH-dichloromethane) to provide the title compound.
[0460] Yield 0.06 g (35%).
[0461] MS (m/z): [M+H]=500.5.
[0462] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.53 (m, 1H), 1.99 (bs,
3H), 2.07-2.11 (m, 2H), 3.49-3.76 (m, 6H), 3.93-4.07 (m, 4H), 4.60
(s, 2H) 4.75 (m, 1H), 6.01 (m, 1H), 7.06 (d, J=10 Hz, 2H),
7.33-7.35 (m, 5H).
Example 16
N-[((5S)-3-{4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-o-
xazolidin-5-yl)methyl]acetamide
[0463] ##STR76##
[0464] A solution of tert-butyl
((5S)-3-{4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxa-
zolidin-5-yl)methylcarbamate (0.068 g, 0.18 mmol) in 20%
TFA-dichloroethane (1.0 mL) was stirred at room temperature for 2
h. The reaction mixture was concentrated to provide the free amine
as a TFA salt. This material (10 mg, 0.03 mmol) was taken in
pyridine (0.05 mL, 0.6 mmol). To this solution, acetic anhydride
(0.007 mL, 0.06 mmol) was added and the mixture was stirred at room
temperature for 16 h. The reaction mixture was concentrated and the
title compound was isolated by pTLC (5% MeOH/DCM).
[0465] Yield 5 mg (56%).
[0466] MS (m/z): [M+H].sup.+=317.4.
[0467] .sup.1H NMR (300 MHz, DMSO-d.sub.6): 1.71 (s, 1H), 1.81 (s,
3H), 1.91 (s, 2H), 3.30-3.40 (m, 2H), 3.65-3.71 (m, 3H), 3.87 (d,
J=9 Hz, 2H), 4.06 (t, J=9 Hz, 1H), 4.68 (m, 1H), 7.10 (d, J=9 Hz,
2H), 7.38-7.41 (d, J=9 Hz, 2H), 8.23 (bt, 1H).
Intermediates for the preparation of example 16 were synthesized as
follows.
I. benzyl 4-formylphenylcarbamate
[0468] ##STR77##
[0469] Benzyl 4-bromophenylcarbamate (20 g, 65.3 mmol) was taken in
anhydrous THF (440 mL) and cooled to -78.degree. C. To this
solution, n-BuLi (55 mL, 137.2 mmol) was added dropwise and stirred
for 0.5 h at -78.degree. C. To this mixture, DMF (7.6 mL) was added
dropwise and the reaction was allowed to warm to room temperature
over a period of 5 h. The reaction mixture was quenched with 1 N
HCl and then concentrated to remove THF, followed by addition of
water. The mixture was extracted with three portions of ethyl
acetate. The combined organic phases were washed with H.sub.2O,
brine, and dried (MgSO.sub.4) filtered and concentrated.
Trituration with hexanes and then with 20% ethyl acetate in hexanes
afforded the title compound as a yellow solid.
[0470] Yield 8.75 g (52%).
[0471] .sup.1H NMR.
II. methyl
(2E)-3-(4-{[(benzyloxy)carbonyl]amino}phenyl)acrylate
[0472] ##STR78##
[0473] Sodium hydride (0.36 g of a 60% dispersion, 9.0 mmol) was
placed in a flask and washed three times with hexane. The resulting
solid was suspended in DMF (7 mL) and cooled to 0.degree. C.
Trimethyl phosphonoacetate (1.53 mL, 9.46 mmol) was added dropwise
to this suspension to give a clear homogeneous solution. After
stirring for another 20 minutes at 0.degree. C., a solution of
benzyl 4-formylphenyl-carbamate (2.3 g, 9.0 mmol) in DMF (7 mL) was
added dropwise. The resulting orange suspension was allowed to warm
slowly to room temperature and stirred for 15 h. The reaction
mixture was poured into 0.5 N HCl and extracted with three portions
of DCM. Combined organic phases were washed with saturated
NaHCO.sub.3, H.sub.2O, brine, and dried (MgSO.sub.4) filtered and
concentrated. Purification by silica gel column chromatography
(gradient 0-30% EtOAC/hexanes) provided the title compound.
[0474] Yield 2.5 g (89%).
[0475] .sup.1H NMR (300 MHz, CDCl.sub.3): 3.79 (s, 3H), 5.21 (s,
2H), 6.33-6.38 (d, J=16 Hz, 1H), 6.78 (s, 1H), 7.31-7.46 (m, 9H),
7.61-7.66 (d, J=16 Hz, 1H).
III. benzyl 4-[(1E)-3-hydroxyprop-1-enyl]phenylcarbamate
[0476] ##STR79##
[0477] A THF solution of LiAlH.sub.4 (6.75 mL of a 1.0 M solution,
6.75 mmol) was added to a cooled (-78.degree. C.) solution of
methyl (2E)-3-(4-{[(benzyloxy)carbonyl]amino}phenyl)acrylate (2.1
g, 6.75 mmol) in THF (34 mL). The solution was allowed to warm
slowly to -20.degree. C. and maintained at that temperature for 2
hours. The reaction mixture was quenched by slow addition of
saturated NH.sub.4Cl and then treated with dilute citric acid. The
resulting solution was stirred for 15 minutes and then extracted
with three portions of ethyl acetate. The combined organic phases
were washed with H.sub.2O, brine and dried (MgSO.sub.4), filtered
and concentrated to give an oil. The crude product was purified by
column chromatography (20-50% ethyl acetate-hexane) to provide the
title compound as a yellow solid.
[0478] Yield 1.0 g (52%).
[0479] .sup.1H NMR (300 MHz, CDCl.sub.3): 4.28-4.30 (d, J=6 Hz,
2H), 5.18 (s, 2H) 6.22-6.31 (m, 1H), 6.52-6.57 (d, J=16 Hz, 1H),
6.64 (s, 1H), 7.32-7.40 (m, 9H).
IV. (2E)-3-(4-{[(benzyloxy)carbonyl]amino}phenyl)prop-2-enyl
diazoacetate
[0480] ##STR80##
[0481] Glyoxylic acid chloride p-toluenesulfonylhydrazone (1.66 g,
6.35 mmol) was added to a suspension of benzyl
4-[(1E)-3-hydroxyprop-1-enyl]phenylcarbamate (1.0 g, 3.53 mmol) in
dichloromethane (25 mL). The mixture was cooled to 0.degree. C. and
treated with N,N-dimethylaniline (0.8 mL, 6.35 mmol). After 0.5 h,
triethylamine (2.5 mL, 17.6 mmol) was added and the mixture stirred
2 h at 0.degree. C. and warmed to room temperature. The reaction
mixture was then concentrated and water was added. The mixture was
extracted with two portions of diethyl ether and the combined
organic solutions washed with saturated NaHCO.sub.3, brine and
dried (MgSO.sub.4), filtered and concentrated. Purification by
silica gel column chromatography (gradient 0-25% EtOAc-hexane)
provided the title compound.
[0482] Yield 0.65 g (52%).
[0483] .sup.1H NMR (300 MHz, d.sub.6-DMSO): 4.72-4.74 (d, J=6 Hz,
2H), 5.13 (s, 2H), 6.18-6.28 (m, 1H), 6.56-6.62 (d, J=16 Hz, 1H),
7.32-7.45 (m, 10H), 9.85 (s, 1H).
V. benzyl
4-[(1S,5R,6R)-2-oxo-3-oxabicyclo[3.1.0]hex-6-yl]phenylcarbamate
[0484] ##STR81##
[0485] A solution of
(2E)-3-(4-{[(benzyloxy)carbonyl]amino}phenyl)prop-2-enyl
diazoacetate (0.7 g, 2.0 mmol) in dichloromethane (20 mL) was added
dropwise over 18 h to a refluxing solution of
bis-(N-t-butylsalicylaldiminato)copper(II) (0.041 g, 0.01 mmol) in
80 mL of toluene. After the addition was complete, the reaction
mixture was heated for another 2 h at reflux and stirred at room
temperature for 36 hours. Then the reaction mixture was cooled,
filtered and concentrated. The crude oil was purified by silica gel
column chromatography (gradient 0-1.5% MeOH-DCM) to provide the
title compound and its enantiomer as a racemic mixture.
[0486] Yield 0.55 g (85%).
[0487] .sup.1H NMR (300 MHz, CDCl.sub.3): 2.26-2.28 (d, J=6 Hz,
2H), 2.47 (m, 1H), 4.37-4.46 (m, 2H), 5.17 (s, 2H), 6.64 (s, 1H),
6.98-7.00 (d, J=6 Hz, 2H), 7.30-7.39 (m, 7H).
VI. benzyl
4-[exo-(2R,3S)-2,3-bis(hydroxymethyl)cyclopropyl]phenylcarbamat-
e
[0488] ##STR82##
[0489] A THF solution of LiAlH.sub.4 (2.4 mL of a 1.0M solution,
2.4 mmol) was added dropwise to a solution of benzyl
4-[(1S,5R,6R)-2-oxo-3-oxabicyclo[3.1.0]hex-6-yl]phenylcarbamate
(0.51 g, 1.58 mmol) in THF (12.5 mL) cooled at 0.degree. C. The
solution was stirred at 0.degree. C. for 1 h and at room
temperature for 1 h and then the solution was quenched by the slow
addition of saturated NH.sub.4Cl (50 mL) followed by H.sub.2O and
saturated citric acid. The solution was concentrated to remove THF
and the resulting aqueous solution extracted with three portions of
ethyl acetate. The combined organic phases were then washed with
H.sub.2O, brine, and dried (MgSO.sub.4), filtered and concentrated
to an oil. Purification by silica gel column chromatography
(gradient 0-3.5% MeOH-DCM) provided the title compound as a white
foam.
[0490] Yield 0.3 g (58%).
[0491] MS (m/z): [M+H].sup.+=350.4.
[0492] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.65-1.77 (m, 3H), 2.61
(s, 2H), 3.42-3.49 (m, 2H), 4.19-4.25 (m, 2H), 5.19 (s, 2H), 6.62
(s, 1H), 6.98 (d, J=7 Hz, 2H), 7.26-7.41 (m, 7H).
VII. benzyl
4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenylcarbamate
[0493] ##STR83##
[0494] A solution of benzyl
4-[exo-(2R,3S)-2,3-bis(hydroxymethyl)cyclopropyl]phenylcarbamate
(0.23 g, 0.7 mmol) in THF (7 mL) was cooled to -50.degree. C. The
n-BuLi solution (0.83 mL, 1.33 mmol) was added and the resulting
yellow suspension was stirred for 10 min and then methanesulfonyl
chloride (0.081 mL, 1.05 mmol) was added. This produced a
homogeneous solution that was stirred for 10 min and then treated
with more n-BuLi (0.57 mL, 0.91 mmol). The solution was allowed to
warm to -30.degree. C. over 1 h and then quenched by the addition
of water and then dilute NaHCO.sub.3. THF was removed in vacuo and
the resulting aqueous solution was then extracted with EtOAc
thrice. The combined organic phases were then washed with brine and
dried (MgSO.sub.4), filtered and concentrated. The crude product
was purified by column chromatography (0-20% EtOAc/hexanes) to give
the title compound.
[0495] Yield 80 mg (37%).
[0496] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.78-1.82 (m, 3H), 3.78
(d, J=8 Hz, 2H), 3.96 (d, J=8 Hz, 2H), 5.17 (s, 2H), 6.58 (s, 1H),
6.97 (d, J=8 Hz, 2H), 7.23-7.39 (m, 7H).
VIII. tert-butyl
((5S)-3-{4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxa-
zolidin-5-yl)methylcarbamate
[0497] ##STR84##
[0498] A solution of benzyl
4-[exo-(1R,5S)-3-oxabicyclo[3.1.0]hex-6-yl]phenylcarbamate (0.075
g, 0.24 mmol) and (S)-(3-chloro-2-hydroxy-propyl)-carbamic acid
tert-butyl ester (0.065 g, 0.31 mmol) in DMF (0.15 mL) was stirred
at 0.degree. C. The mixture was treated with LiOtBu solution (1.0 M
in THF, 0.58 mL, 0.58 mmol) dropwise. The reaction mixture was
slowly warmed to room temperature and stirred for 18 h. The
solution was then was quenched with saturated NH.sub.4Cl, followed
by addition of water and brine. The mixture was extracted with
three portions of ethyl acetate and the combined organic phases
washed with water, brine, and dried (MgSO.sub.4), filtered and
concentrated. The title compound was isolated by pTLC (5%
MeOH/DCM).
[0499] Yield 69 mg (78%).
[0500] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.31 (s, 9H), 1.73 (m,
3H), 3.35-3.41 (m, 2H), 3.65-3.70 (m, 3H), 3.85-3.90 (m, 3H),
4.60-4.63 (m, 1H), 4.93 (s, 1H), 6.92-6.96 (d, J=12 Hz, 2H),
7.26-7.30 (d, J=12 Hz, 2H).
Example 17
N-[((5S)-3-{4-[exo-(1R,5S)-3-glycoloyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-
-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0501] ##STR85##
[0502] A solution of
N-[((5S)-3-{4-[exo-(1R,5S)-3-(2-acetoxyacetyl)-3-azabicyclo[3.1.0]hex-6-y-
l]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (0.075 g, 0.18
mmol) was dissolved in THF/water (16 mL, 3:1) and treated with 0.1
M LiOH in MeOH (3.6 mL, 0.36 mmol). The mixture was stirred at room
temperature for 24 h and then concentrated to remove methanol. The
resulting aqueous solution was then extracted with ethyl acetate
thrice. The combined organic layers were washed with water, brine,
dried (MgSO.sub.4), filtered and concentrated. The title compound
was isolated by pTLC (5% MeOH/dichloromethane).
[0503] Yield 40 mg (60%).
[0504] MS (m/z): [M+H].sup.+=374.4
[0505] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.62-1.64 (t, 1H),
1.86-1.89 (m, 2H), 1.99 (s, 3H), 3.46 (s, 1H), 3.54-3.77 (m, 6H),
3.98-4.07 (m, 4H), 4.72-4.76 (m, 1H), 6.10 (m, 1H), 6.99-7.02 (d,
J=9 Hz, 2H), 7.38-7.41 (d, J=9 Hz, 2H).
Intermediates for the preparation of example 17 were synthesized as
follows.
I. benzyl
4-[exo-(1R,5S)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.0]hex-6-yl]p-
henylcarbamate
[0506] ##STR86##
[0507] A solution of benzyl
4-[exo-(2R,3S)-2,3-bis(hydroxymethyl)cyclopropyl]phenylcarbamate
(0.35 g, 1.07 mmol) in dichloromethane (13.5 mL) and triethylamine
(0.6 mL, 4.28 mmol,) was cooled to 0.degree. C. Methanesulfonic
acid anhydride (0.56 g, 3.2 mmol) was then added and the reaction
mixture stirred at 0.degree. C. for 1 hour. The solution was then
diluted with 20 mL of dichloromethane, washed with water, saturated
NaHCO.sub.3, brine, dried (MgSO.sub.4), filtered and concentrated.
The residue obtained was dissolved in 4-methoxybenzylamine (2.1 mL,
16.0 mmol) and stirred at room temperature for 18 h. The reaction
mixture was diluted with ethyl acetate and washed with dilute
NaHCO.sub.3, dilute HCl (32 mL of 1N HCl in 100 mL water), dilute
NaHCO.sub.3, brine, dried (MgSO.sub.4), filtered and concentrated.
The title compound was isolated by silica gel column chromatography
(gradient 0-25% EtOAc/hexanes/1% triethylamine).
[0508] Yield 290 mg (63%).
[0509] MS (m/z): [M+H].sup.+=429.4.
[0510] .sup.1H NMR (300 MHz, CDCl.sub.3): 2.51 (s, 1H), 2.65-2.68
(d, J=9 Hz, 2H), 3.28-3.31 (d, J=9 Hz, 2H), 3.79 (s, 2H), 4.00-4.02
(m, 5H), 5.39 (s, 2H), 6.78 (s, 1H), 7.04-7.07 (d, J=9 Hz, 2H),
7.16-7.19 (d, J=9 Hz, 2H), 7.41-7.59 (m, 9H).
II.
N-[((5S)-3-{4-[exo-(1R,5S)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.0]hex--
6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0511] ##STR87##
[0512] A solution of benzyl
4-[exo-(1R,5S)-3-(4-methoxybenzyl)-3-azabicyclo
[3.1.0]hex-6-yl]phenylcarbamate (0.35 g, 0.82 mmol) in DMF (0.15
mL) and MeOH (0.066 mL) and cooled to 10.degree. C. This mixture
was treated with LiOtBu (2.45 mL of 1M solution in THF, 2.45 mmol)
dropwise and cooled to 0.degree. C. To this mixture, (S)-acetic
acid 2-acetylamino-1-chloromethyl-ethyl ester (0.32 g, 1.63 mmol)
was added and the reaction mixture was slowly warmed to room
temperature and stirred for 18 h. The solution then was quenched
with saturated NH.sub.4Cl, followed by addition of water and brine.
The mixture was extracted with three portions of ethyl acetate and
the combined organic phases washed with water, brine, and dried
(MgSO.sub.4), filtered and concentrated. The title compound was
isolated by silica gel column chromatography (gradient 0-4%
MeOH/dichloromethane).
[0513] Yield 70 mg (20%).
[0514] MS (m/z): [M+H].sup.+=436.5.
[0515] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.98 (s, 3H), 2.31 (s,
1H), 2.44-2.47 (d, J=9 Hz, 2H), 3.07-3.10 (d, J=9 Hz, 3H),
3.57-3.75 (m, 6H), 3.78 (s, 3H), 3.96-4.02 (t, J=9 Hz, 1H),
4.71-4.73 (m, 1H), 6.20 (br t, 1H), 6.82-6.85 (d, J=9 Hz, 2H),
6.98-7.01 (d, J=9 Hz, 2H), 7.19-7.22 (d, J=9 Hz, 2H), 7.32-7.35 (d,
J=9 Hz, 2H).
III.
N-[((5S)-3-{4-[exo-(1R,5S)-3-(2-acetoxyacetyl)-3-azabicyclo[3.1.0]hex-
-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0516] ##STR88##
[0517] A solution of
N-[((5S)-3-{4-[exo-(1R,5S)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.0]hex-6-y-
l]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (0.11 g, 0.25
mmol) in dichloromethane (1.0 mL) and triethylamine (0.035 mL, 0.25
mmol) and stirred at 0.degree. C. To this, 1-chloroethyl
chloroformate (0.055 mL, 0.5 mmol) was added and the reaction
mixture stirred at 0.degree. C. for 30 min. The reaction mixture
was then concentrated, dissolved in methanol and heated at reflux
for 45 min. The reaction mixture was then concentrated and
triturated with diethyl ether to provide
N-[((5S)-3-{4-[exo-(1R,5S)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3--
oxazolidin-5-yl)methyl]acetamide as a yellow powder. This
intermediate was dissolved in dichloromethane (6.0 mL) and
triethylamine (0.1 mL, 0.75 mmol) and cooled to 0.degree. C. To
this solution, acetoxyacetyl chloride (0.04 mL, 0.36 mmol) was
added and the mixture was stirred at 0.degree. C. for 30 min. The
reaction mixture was then washed with water, brine, dried
(MgSO.sub.4), filtered and concentrated. The title compound was
isolated by pTLC (5% MeOH/dichloromethane).
[0518] Yield 75 mg (72%).
[0519] MS (m/z): [M+H].sup.+=416.4.
[0520] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.65-1.68 (br t, 1H),
1.82-1.88 (m, 2H), 1.99 (s, 3H), 2.16 (s, 3H), 3.52-3.77 (m, 6H),
3.96-4.04 (m, 2H), 4.57-4.60 (d, J=9 Hz, 2H), 4.72-4.76 (m, 1H),
6.15 (s, 1H), 6.99-7.02 (d, J=9 Hz, 2H), 7.38-7.41 (d, J=9 Hz,
2H).
Example 18
N-[((5S)-3-{4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2--
oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0521] ##STR89##
[0522] An aqueous solution of NaIO.sub.4 (0.128 g, 0.60 mmol) was
added to a solution of
N-[((5S)-3-{4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-
-oxazolidin-5-yl)methyl]acetamide (0.19 g, 0.57 mmol) in
MeOH:H.sub.2O (3:1, 10 mL) and stirred at 4.degree. C. for 20 h.
The reaction mixture was filtered with the aid of chloroform. The
filtrate was extracted with 5 additional portions of chloroform and
the combined organic layers were dried (MgSO.sub.4), filtered and
concentrated. Purification by pTLC (5% MeOH-10% ACN-DCM) provided
the title compound as two separable diastereomers.
[0523] Yield (both isomers) 0.150 g (76%).
[0524] MS (m/z): [M+H].sup.+=349.2.
[0525] HPLC (SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 5 min; 2 mL/min
rate): retention time=1.50 min.
[0526] High Rf ("anti") isomer: .sup.1H NMR (300 MHz, CD.sub.3OD):
1.95 (s, 3H), 2.23 (m, 2H), 2.59 (t, J=4. 2 Hz, 1H), 3.21 (d, J=14,
7 Hz, 2H), 3.46-3.55 (m, 4H), 3.79 (dd, J=9.0, 6.3 Hz, 1H), 4.12
(t, J=9.0 Hz, 1H), 4.72-4.80 (m, 1H), 7.12 (d, J=9.0 Hz, 2H), 7.45
(d, J=9.0 Hz, 2H).
[0527] Low Rf ("syn") isomer: .sup.1H NMR (300 MHz, CD.sub.3OD):
1.95 (s, 3H), 2.11 (t, J=4. 2 Hz, 1H), 2.52 (m, 2H), 3.04-3.09 (dd,
J=13, 2 Hz, 2H), 3.31-3.38 (m, 2H), 3.54 (d, J=5.1 Hz, 2H), 3.79
(dd, J=9.0, 6.3 Hz, 1H), 4.12 (t, J=9.0 Hz, 1H), 4.72-4.80 (m, 1H),
7.11 (d, J=9.0 Hz, 2H), 7.46 (d, J=9.0 Hz, 2H).
Intermediates for the preparation of example 18 were synthesized as
follows.
I. benzyl
4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenylcarbamate
[0528] ##STR90##
[0529] Methanesulfonic anhydride (0.92 g, 5.3 mmol) was added to a
cooled (0.degree. C.) solution of benzyl
4-[exo-(2R,3S)-2,3-bis(hydroxymethyl)cyclopropyl]phenylcarbamate
(0.577 g, 1.76 mmol) in dichloromethane (22 mL) and triethylamine
(0.98 mL, 7.05 mmol). The solution was allowed to warm to room
temperature and stirred for 2 h. The solution was then diluted with
30 mL dichloromethane and washed with two portions of saturated
NaHCO.sub.3, brine, and dried (MgSO.sub.4), filtered and
concentrated to provide the bis-mesylate. This material was
dissolved in DMSO (3.3 mL) and treated with sodium sulfide (0.39 g,
5.0 mmol). The reaction mixture was stirred at room temperature for
2 h. The resulting yellow suspension was then diluted with 30 mL of
H.sub.2O and extracted with three portions of diethyl ether. The
combined organic extracts were dried (MgSO.sub.4), filtered and
concentrated to provide the title compound as a white solid.
[0530] Yield 0.45 g (79%).
[0531] .sup.1H NMR.
II.
N-[((5S)-3-{4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo--
1,3-oxazolidin-5-yl)methyl]acetamide
[0532] ##STR91##
[0533] Lithium butoxide solution (4.1 mL of a 1.0 M THF solution,
4.1 mmol) was added to a cooled (0.degree. C.) solution of benzyl
4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]phenylcarbamate (0.44
g, 1.36 mmol) in DMF (0.91 mL) and MeOH (0.011 mL, 2.72 mmol).
Solid (S)-acetic acid 2-acetylamino-1-chloromethyl-ethyl ester
(0.53 g, 2.72 mmol) was then added and the solution allowed to warm
to room temperature and stirred for 20 h. Saturated aqueous
ammonium chloride (4 mL) was added, along with 20 mL of H.sub.2O
and 20 mL of brine. The solution was extracted with three portions
of dichloromethane and the combined organic phases washed with
water, brine, and dried (MgSO.sub.4), filtered and concentrated.
The crude residue was purified by column chromatography (0-3%
MeOH-DCM) to provide the title compound.
[0534] Yield 0.19 g (41%).
[0535] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.85 (t, J=3.6 Hz, 2H),
1.99 (s, 3H), 2.29 (t, J=3.9 Hz, 1H), 3.04-3.19 (m, 4H), 3.56 (dt,
J=15, 6.3 Hz, 1H), 3.67 (dd, J=3.3, 6.3 Hz, 1H), 3.74 (dd, J=6.9,
9.3 Hz, 1H), 4.02 (t, J=9.3 Hz, 1H), 4.69-4.78 (m, 1H), 5.96 (t,
J=6.3 Hz, 1H), 7.05 (d, J=8.7 Hz, 2H), 7.37 (d, J=8.7 Hz, 2H).
Example 19
N-[((5S)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl-
}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
[0536] ##STR92##
[0537] A solution of peracetic acid (0.12 mL, 0.58 mmol) was added
to a solution of N-[((5S)
-3-{4-[exo-(1R,5S)-3-oxido-3-thiabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-
-oxazolidin-5-yl)methyl]acetamide ("syn" isomer, 0.067 g, 0.19
mmol) in THF (6.5 mL) at 0.degree. C. and allowed to stir for 20 h.
The reaction was quenched with 5 mL saturated
Na.sub.2S.sub.2O.sub.3 and diluted with water. The solution was
concentrated to remove THF and the resulting aqueous solution
extracted with ethyl acetate. The organic layer was washed with
brine and dried (MgSO.sub.4), filtered and concentrated. The
residue was purified by pTLC (7% MeOH-DCM) to provide the title
compound.
[0538] Yield 65 mg (92%).
[0539] MS (m/z): [M+H].sup.+=401.
[0540] HPLC (SYMMETRY C.sub.18 3.5 .mu.M, 4.6.times.30 mm column;
gradient elution 2%-98% MeCN with 0.1% TFA over 5 min; 2 mL/min
rate): retention time=1.70 min.
[0541] .sup.1H NMR (300 MHz, CD.sub.3OD): 1.95 (s, 3H), 2.08 (bs,
2H), 2.17 (bs, 1H), 3.01 (d, J=14.1 Hz, 2H), 3.52-3.59 (m, 4H),
3.80 (dd, J=6.3, 9.3 Hz, 1H), 4.12 (t, J=9.0 Hz, 1H), 4.72-4.81 (m,
1H), 7.16 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H).
Example 20
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluorop-
henyl}-2-oxo-1,3-oxazolidine-5-carboxamide
[0542] ##STR93##
[0543] A solution of ethyl
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluoro-
phenyl}-2-oxo-1,3-oxazolidine-5-carboxylate (0.14 g, 0.36 mmol) in
methanol (1 mL) was treated with a solution of ammonia in methanol
(2.0 M, 4 mL) and stirred at room temperature for one hour to give
a homogeneous solution. The reaction mixture was then concentrated
and the crude product purified by column chromatography (elution
with 0.fwdarw.3% methanol in dichloromethane) to provide the title
compound.
[0544] Yield 95 mg (74%).
[0545] MS (m/z). [M+H].sup.+=355.5
[0546] .sup.1H NMR (300 MHz, d.sub.6-DMSO): 7.86 (s, 1H), 7.62 (s,
1H), 7.50 (dd, J=13, 2 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.13 (t, J=8
Hz, 1H), 5.02 (m, 1H), 4.26 (t, J=9 Hz, 1H), 3.99 (m, 1H), 3.59
(dd, J=14, 5 Hz, 2H), 3.02 (d, J=14 Hz, 2H), 2.34 (t, J=5 Hz, 1H),
2.08 (m, 2H).
Intermediates for the preparation of example 20 were synthesized as
follows.
I. benzyl
4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluor-
ophenylcarbamate
[0547] ##STR94##
[0548] An aqueous solution of peracetic acid (0.64 mL of a 32%
solution, 3.0 mmol) was added to a cooled (0.degree. C.) solution
of benzyl
4-[exo-(1R,5S)-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluorophenylcarbamate
(0.300 g, 0.88 mmol) in 20 mL of THF. After stirring at room
temperature for 3 hours, the solution was treated with saturated
Na.sub.2S.sub.2O.sub.3 and water and the THF removed on a rotary
evaporator. The resulting aqueous solution was then extracted
thrice with ethyl acetate and the combined organic extracts washed
with diluted NaHCO.sub.3, brine and dried (MgSO.sub.4), filtered
and concentrated to give an oil. Purification by column
chromatography (50% ethyl acetate-hexane) provided the title
compound as a solid.
[0549] Yield 0.31 g (95%).
[0550] mp 122-124.degree. C.
[0551] MS (m/z): [M+Na].sup.+=398
[0552] .sup.1H NMR (300 MHz, CDCl.sub.3): 7.24-7.41 (m, 6H), 6.97
(d, J=8 Hz, 1H), 6.88 (t, J=8 Hz, 1H), 6.69 (bs, 1H), 5.20 (s, 2H),
3.57 (dd, J=14, 5 Hz, 2H), 3.04 (d, J=13 Hz, 2H), 2.18 (t, J=4 Hz,
1H), 2.07 (m, 2H).
II.
4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluoroanili-
ne
[0553] ##STR95##
[0554] A solution of benzyl
4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluorophenylca-
rbamate (0.30 g, 0.80 mmol) in 2:1 methanol-dichloromethane (7.5
mL) was treated with palladium (1.2 g of 5 wt % Pd on barium
sulfate) and stirred under a hydrogen atmosphere for twenty hours.
The mixture was then filtered through celite and the filtrate
concentrated to give the title compound that was used without
further purification.
[0555] Yield 0.18 g (91%)
[0556] MS (m/z): [M+H].sup.+=242
[0557] .sup.1H NMR (300 MHz, CD.sub.3OD): 6.78 (m, 1H), 6.40 (m,
2H), 3.53 (d, J=14 Hz, 2H), 2.97 (d, J=14 Hz, 2H), 2.10 (bs, 1H),
2.00 (bs, 2H).
III. ethyl
(2R)-3-({4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-y-
l]-3-fluorophenyl}amino)-2-hydroxypropanoate
[0558] ##STR96##
[0559] Lithium triflate (0.17 g, 1.43 mmol) was added to a
suspension of
4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluoroaniline
(0.18 g, 0.75 mmol) and ethyl (2R)-2,3-epoxypropanoate (0.15 mL,
1.5 mmol) in acetonitrile (2.5 mL). The solution was heated at
60.degree. C. for 18 hours and then treated with additional lithium
triflate (70 mg) and epoxide (62 .mu.L) and stirred at 60.degree.
C. for another 20 hours. The solution was then concentrated and
purified by column chromatography (25%.fwdarw.50% ethyl
acetate-hexane) to provide the title compound.
[0560] Yield 0.14 g (52%).
[0561] MS (m/z): [M+H].sup.+=358
[0562] .sup.1H NMR (300 MHz, CDCl.sub.3): 6.76 (t, J=8 Hz, 1H),
6.38 (s, 1H), 6.35 (bs, 1H), 4.38 (q, J=4 Hz, 1H), 4.23-4.29 (m,
2H), 4.16 (m, 1H), 3.52-3.59 (m, 2H), 3.40-3.50 (m, 2H), 3.05 (s,
1H), 3.01 (d, J=15 Hz, 2H), 2.08 (m, 1H), 2.01 (m, 2H), 1.28-1.33
(m, 3H).
IV. ethyl
(5R)-3-{4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-
-3-fluorophenyl}-2-oxo-1,3-oxazolidine-5-carboxylate
[0563] ##STR97##
[0564] Phosgene (0.27 mL of a 20% toluene solution, 0.51 mmol) was
added to a cooled (0.degree. C.) solution of ethyl
(2R)-3-({4-[exo-(1R,5S)-3,3-dioxido-3-thiabicyclo[3.1.0]hex-6-yl]-3-fluor-
ophenyl}amino)-2-hydroxypropanoate (0.14 g, 0.40 mmol) and
triethylamine (0.16 mL, 1.2 mmol) in 4 mL of dichloromethane. The
reaction mixture was allowed to stir at room temperature for 2
hours and then diluted with more dichloromethane and washed with
dilute NaHCO.sub.3, brine and dried (MgSO.sub.4), filtered and
concentrated to provide the title compound that was used directly
without further purification.
[0565] Yield 0.14 g (92%).
[0566] MS (m/z): [M+H].sup.+=384.5
[0567] .sup.1H NMR (300 MHz, CDCl.sub.3): 7.42 (d, J=12 Hz, 1H),
7.19 (d, J=8 Hz, 1H), 6.97 (t, J=8 Hz, 1H), 5.05 (m, 1H), 4.22-4.37
(m, 3H), 4.10 (m, 1H), 3.58 (dd, J=14.4 Hz, 2H), 3.06 (d, J=14 Hz,
2H), 2.23 (t, J=4, 1H). 2.10 (bs, 2H), 1.37 (t, J=7 Hz, 3H).
* * * * *