U.S. patent application number 10/483905 was filed with the patent office on 2004-12-02 for oxazolidinone derivatives as pontential antimicrobials.
Invention is credited to Arora, Sudershan R., Das, Biswajit, Mehta, Anita, Rao, Ajjarapu Venkata Subramanya Raja, Rattan, Ashok, Ray, Abhijit, Rudra, Sonali, Srinivas, Akella Satya Surya Visweswara.
Application Number | 20040242591 10/483905 |
Document ID | / |
Family ID | 11097070 |
Filed Date | 2004-12-02 |
United States Patent
Application |
20040242591 |
Kind Code |
A1 |
Mehta, Anita ; et
al. |
December 2, 2004 |
Oxazolidinone derivatives as pontential antimicrobials
Abstract
The present invention relates to certain substituted phenyl
oxazolidinones and to processes for the synthesis of the same. This
invention also relates to pharmaceutical compositions containing
the compounds of the present invention as antimicrobials. The
compounds are useful antimicrobial agents, effective against a
number of human and veterinary pathogens, including gram-positive
aerobic bacteria such as multiply-resistant staphylococci,
streptococci and enterococci as well as anaerobic organisms such as
Bacteroides spp. and Clostridium spp. species, and acid fast
organisms such as Mycobacterium tuberculosis, Mycobacterium avium
and Mycobacterium spp.
Inventors: |
Mehta, Anita; (Buffalo
Grove, IL) ; Rudra, Sonali; (New Delhi, IN) ;
Rao, Ajjarapu Venkata Subramanya Raja; (Gurgaon, IN)
; Das, Biswajit; (New Delhi, IN) ; Ray,
Abhijit; (Elkridge, MD) ; Srinivas, Akella Satya
Surya Visweswara; (Sarror Nagar, IN) ; Arora,
Sudershan R.; (Gurgaon, IN) ; Rattan, Ashok;
(New Delhi, IN) |
Correspondence
Address: |
Jayadeep R deshmukh
Ranbaxy Pharmaceuticals Inc
Suite 2100
600 College Road East
Princeton
NJ
08540
US
|
Family ID: |
11097070 |
Appl. No.: |
10/483905 |
Filed: |
July 13, 2004 |
PCT Filed: |
January 21, 2002 |
PCT NO: |
PCT/IB02/00167 |
Current U.S.
Class: |
514/254.02 ;
514/326; 544/369; 546/209 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 413/14 20130101; C07D 413/12 20130101; A61P 31/04 20180101;
C07D 413/10 20130101 |
Class at
Publication: |
514/254.02 ;
514/326; 544/369; 546/209 |
International
Class: |
C07D 413/14; A61K
031/496 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 16, 2001 |
WO |
PCT/IB01/01262 |
Claims
1. A compound having the structure of Formula I, 15and its
pharmaceutically acceptable salts, enantiomers, diastereomers,
N-oxide, polymorphs, pharmaceutically acceptable solvates, prodrugs
or metabolites, wherein ring D is a five membered heterocyclic
ring; ring C is four to eight membered in size or larger which has
either two or three carbon atoms between each nitrogen atoms or
ring C is a bridged bicyclic system and is optionally substituted
by the substituents Y and Z independently selected from alkyl
groups, cycloakyl groups, fluoro group, carboxylic groups and
corresponding esters or amides; Q.sub.1 is selected from O, S,
NR.sub.11; Q.sub.2 is selected from N or C; G, J, L are
independently selected from H, C.sub.1-6 alkyl, F, Cl, Br, I, --CN,
COR.sub.5, COOR.sub.5, N(R.sub.6, R.sub.7), NHCOC(R.sub.5, R.sub.8,
R.sub.9), --NHCOOR.sub.5, CON(R.sub.6, R.sub.7), CH.sub.2NO.sub.2,
NO.sub.2, CH.sub.2R.sub.8, CHR.sub.9, --CH.dbd.N--OR.sub.10,
--C.dbd.CH--R.sub.5, OR.sub.5, SR.sub.5,
--C(R.sub.9).dbd.C(R.sub.9)NO.su- b.2, C.sub.1-12 alkyl substituted
with one or more of F, Cl, Br, I, OR.sub.4, SR.sub.4; wherein
R.sub.5 is selected from H, C.sub.1-12 alkyl, C.sub.3-12
cycloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with one
or more of F, Cl, Br, I or OH, aryl, heteroaryl; R.sub.6 and
R.sub.7, are independently selected from H, optionally substituted
C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy; R.sub.8
and R.sub.9 are independently selected from H, C.sub.1-6 alkyl, F,
Cl, Br, I, C.sub.1-12 alkyl substituted with one or more of F, Cl,
Br, I, OR.sub.5, SR.sub.5, N(R.sub.6, R.sub.7); R.sub.10=H,
optionally substituted C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkyl, aryl, heteroaryl; except when W
is C.dbd.O, Q.sub.1=S, Q.sub.2=C, and G, J, L=H; R.sub.1 is
selected from the group consisting of --NHC(.dbd.O)R.sub.2,
N(R.sub.3, R.sub.4), --NR.sub.2C(.dbd.S)R.sub.3,
--NR.sub.2C(.dbd.S)SR.sub.3, wherein R.sub.2 is hydrogen,
C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl substituted with one or more of F, Cl, Br, I or OH;
R.sub.3, R.sub.4 are independently selected from hydrogen,
C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl substituted with one or more of F, Cl, Br, I or OH;
U and V are independently selected from hydrogen, optionally
substituted C.sub.1-6 alkyl, F, Cl, Br, C.sub.1-12 alkyl
substituted with one or more of F, Cl, Br, I; X is selected from C,
CH, CH--S, CH--O and N; Y and Z are independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl and C.sub.0-3
bridging groups; W is selected from the group CH.sub.2, CO,
CH.sub.2NH, --NHCH.sub.2, --CH.sub.2NHCH.sub.2,
--CH.sub.2--N(R.sub.11)CH.sub.2--, CH.sub.2(R.sub.11)N--,
CH(R.sub.11), S, CH.sub.2(CO), NH, O, N(R.sub.11), (CO)CH.sub.2,
N(R.sub.11)CON(R.sub.11), N(R.sub.11)C(.dbd.S)N(R.sub.11),
SO.sub.2, SO, wherein R.sub.11 is hydrogen, optionally substituted
C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkylcarboxy,
aryl, heteroaryl; n is an integer ranging from 0 to 3.
2. The compound of Formula I according to claim 1 wherein ring C is
four to eight membered in size or the larger size which have either
two or three carbon atoms between each nitrogen atom, comprising of
16or ring C is bridged to form a bicyclic system as shown below,
17ring C is optionally substituted by Y and Z, independently
selected from alkyl groups, cycloalkyl groups, fluoro group,
carboxylic and corresponding esters, amides, substituted alkyls or
bridging alkyl groups which are as shown below: 18the five or six
membered ring C (when X is --CH--(NHR), or >CCH.sub.2(NHR--) is
selected from the group consisting of the following rings, 19and
the bicyclic bridged ring C is selected from the group consisting
of the following rings, 20
3. The compound of Formula I according to claim 1 wherein ring D is
selected from the group consisting of furanyl, thienyl, pyrrolyl
and pyrazolyl.
4. The compound of Formula I according to claim 1 wherein
Q.sub.1=NR.sub.11 and Q.sub.2=N shown as Formula II below 21
5. The compound of Formula II according to claim 4 selected from
the group consisting of:
(S)-N-[[3-[3-Fluoro-[N-1-[4-{3-pyrazolecarbonyl-(4-nitro)}-
]piperazinyl]phenyl-]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{3-pyrazolecarbonyl-(5-nitro)}]piperazinyl]-
phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
6. The compound of Formula I according to claim 1 wherein
Q.sub.1=NR.sub.11 and Q.sub.2=C shown as Formula III below, 22
7. The compound of Formula III according to claim 6 selected from
the group consisting of:
(S)-N-[[-[3-Fluoro-4-[N-1-[4-{2-pyrrole-(1-methyl-5--
nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-pyrrole-(5-nitro)methyl}]piperazinyl]phe-
nyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
8. The compound of Formula I according to claim 1 wherein Q.sub.1=S
and Q.sub.2=C shown as Formula IV below, 23
9. The compound of Formula IV according to claim 8 selected from
the group consisting of:
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophen-(4-nitro)methyl--
}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(5-nitro)}]homopiperazinyl]p-
henyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[-
4-[1-{2-thiophenyl-(5-nitro)}-1-ethyl]piperazinyl]phenyl]-2-oxo-5-oxazolid-
inyl]methyl]-acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[2-methyl-4-{2-thiophen-
oyl-(5-nitro)}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-(3-Fluoro-4-[4-{N-ethyl-2-thiophenoyl-(5-nitro)}-aminopiperidin-
e-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1,{3-{[N-methyl)[N-{2-thiophenoyl(5-nitro)}]amin-
o pyrrolidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
10. The compound of Formula I according to claim 1 wherein
Q.sub.1=O and Q.sub.2=C shown as Formula V below, 24
11. The compound of Formula V according to claim 10 selected from
the group consisting of:
(S)-N-[[3-[3-Fluoro-4-[N-1-[-4-{2-furoyl-(3-methyl)}-
]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furoyl-(3-methyl-5-nitro)}]piperazinyl]p-
henyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[-
4-[1-{2-furyl-(5-nitro)}]ethyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]me-
thyl]-acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]p-
iperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-difluoroacetamide,
(S)-N-[[3-[-Fluoro-4-[4-[N-2-furyl-(5-nitro)methyl}-aminopiperidine-1-yl]-
phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
12. A compound selected from the group consisting of:
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-(2-furyl-carbonylmethyl)]piperazinyl]phenyl-
]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-(2--
thiophenoyl-methyl)]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetam-
ide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl{5-(4-chloro-2-nitro-)-phenyl}m-
ethyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophen-(4-bromo-5-nitro)methyl}]pipera-
zinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl-(3-methyl-5-nitro)methyl-}]piperaz-
inyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[(3-[3-Fluoro-4-[N-1-[4-{2-thiophene-(4-cyano-5-nitro)methyl}]piper-
azinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl-(5-(4-chloro)phenyl)methyl}]pipera-
zinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl],
(S)-N-[[3-[3-Fluoro-4-[N-1-[4--
{3-furyl(5-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]a-
cetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-(4-bromo)phenyl)methyl}-
]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-methyl)methyl}]piperazinyl]pheny-
l]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-(3-Fluoro-4-[N-1-[4-{2-
-pyrrole-(1-methyl-4-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidiny-
l]methyl]acetamide,
(S)-N-[[3-(3-Fluoro-4-N-1-[4-{2-pyrrole-(1-methyl-5-ni-
tro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-pyrrole-(5-nitro)methyl}]piperazinyl]phe-
nyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4--
{2-thiophen-(4-nitro-)methyl-}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]me-
thyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl-(5-methoxy)methyl}]-
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl-{5-O-(2-nitro-4-fluoro-phenyloxy)}-
methyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-chloro)methyl}]piperazinyl]pheny-
l]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{3-
-furyl(2-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]ace-
tamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophen-(4-dimethylamino-5-nitro-
)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophene-(4-morpholino-5-nitro)methyl}]-
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl-(5-methylsulphonyl-)methyl-}]piper-
azinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-(4-nitro)-phenyl)-methyl}]pipera-
zinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-(3-nitro-)phenyl-)methyl}]pipera-
zinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[2-furyl(5-(2-nitro)-phenyl)methyl}]piperaziny-
l]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4[N-1-
-[4-{2-Furyl-4-bromo-(5-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolid-
inyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4[N-1-4-{2-Furyl-(4-isopropyl)m-
ethyl}]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4[N-1-[4-{2-Furyl-4-isopropyl-(5-nitro)methyl}]pipera-
zinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-[2-furoyl-(5-methoxy)methyl]piperazinyl]phe-
nyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4--
{2-thiophenoyl-(5-acetamido)}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]met-
hyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{3-pyrazolecarbonyl-(4-nitro)-
}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{3-pyrazolecarbonyl(5-nitro)}]piperazinyl]p-
henyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-4-
-{2-thiophenoyl-(5-tert-butoxy-carboxamido)}]piperazinyl]phenyl]-2-oxo-5-o-
xazolidinyl]methyl}acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-
(5-trifuoroacetamido)}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl],
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl(5-amino)}]piperazinyl]phenyl-
]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2--
furoyl{5-(4-chloro-2-nitro-)-phenyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidi-
nyl]methyl],
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furoyl-(3-methyl)}]piperazin-
yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-
-1-[4-{2-furoyl-(3-methyl-5-nitro)}]piperazinyl]phenyl]-2-oxo-5-oxazolidin-
yl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(4-dimet-
hylamino-5-nitro)}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetam-
ide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-Furoyl-(5-nitro)acrylic}]piperazinyl-
]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide,
(S)-N-[[3-[3-Fluoro-4-[N--
1-[4-{2-thiophenoyl-(5-nitro)acrylic}]piperazinyl]phenyl]-2-oxo-5-oxazolid-
inyl]methyl]-acetamide, Iodide
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-N-methyl-4-{2-
-furyl-(5-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]ac-
etamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-nitro)methyl}]piperaziny-
l]phenyl]-2-oxo-5-oxazolidinyl]methyl]-fluoroacetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophen(5-nitro)methyl}]piperazinyl]phe-
nyl]-2-oxo-5-oxazolidinyl]methyl]fluoroacetamide,
(S)-N-[[3-[3-Fluoro-4-[N-
-1-[4-{2-thiophen(5-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl-
]methyl]difluoroacetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-nitro)-
methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]difluoroacetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-nitro)methyl}]piperazinyl]phenyl-
]-2-oxo-5-oxazolidinyl]methyl]monochloroacetamide,
(S)-N-[[3-[3-Fluoro-4-[- N-1-[4-[2-thiophenyl-5-nitro)methyl}],
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-[2-th-
iophenyl-4-bromo-(5-nitro)methyl}]piperazinyl]-phenyl]2-oxo-5-oxazolidinyl-
]methyl]monochloroacetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1[4-[2-thiophenyl-(5-
-nitro)methyl}]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]-2-chloropro-
pionamide,
(S)-N-[[3-[3-Fluoro-4-[N-1[4-[2-Furyl-(5-nitro)methyl}]piperazi-
nyl]-phenyl]2-oxo-5-oxazolidinyl]methyl]-2-chloropropionamide,
(S)-N-[[3-[3-Fluoro-4-[N-1[4-[2-thiophenyl-4-bromo-(5-nitro)methyl}]piper-
azinyl]-phenyl]2-oxo-5-oxazolidinyl]methyl]-2-chloropropionamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]homopiperazinyl]p-
henyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-{-
4-(3-furoyl)}homopiperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide-
,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(5-nitro)}]homopiperazinyl]-
phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-[[3-[3-Fluoro-4-[N-1-[4-
-{2-furoyl(5-nitro)}]homopiperazinyl]phenyl)-2-oxo-5-oxazolidinyl]methyl]a-
cetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-{2-methyl-4-(t-butoxycarbonyl)}pipera-
zinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[2-methyl-4-{2-thiophen-(5-nitro)methyl}]piper-
azinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[2-methyl-4-{2-furyl(5-nitro)methyl}]-piperazi-
nyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[-
N-1-[2-methyl-4-{2-furoyl(5-nitro)}]-piperazinyl]phenyl]-2-oxo-5-oxazolidi-
nyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[2-methyl-4-{2-thiophenoy-
l-(5-nitro)}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-{2-furoyl-}]-piperazinyl]pheny-
l]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6--
dimethyl-4-{2-furyl-(5-formyl)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolid-
inyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-{2-furyl-
-(5-nitro)methyl-}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetami-
de,
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-{2-furyl-(5-hydroxymethyl)m-
ethyl-}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-{2-furyl-(aldoxime)methyl-}]pi-
perazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-(2-thienylacetyl)]-piperazinyl-
]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-
-[2,6-dimethyl-4-{2-furyl-(5-cyano)methyl-}]piperazinyl]phenyl]-2-oxo-5-ox-
azolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[3-methyl-4-{2-thi-
enylacetyl-}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[3-methyl-4-{2-furoyl-(5-nitro)}]-piperazinyl]-
phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1--
[3-methyl-4-{2-thienoyl-(5-nitro)}]-piperazinyl]phenyl-2-oxo-5-oxazolidiny-
l]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{3-methyl-2-furyl-(5-for-
myl)methyl-}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[4-{N-acetyl-N-2-furyl-(5-nitro)methyl-}]aminopiper-
idine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[{3-methyl-4-(N-methyl-N-thiophenacetyl-)}aminopipe-
ridine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[[3-methyl-4-{N-methyl-2-furoyl(5-nitro)}]aminopipe-
ridine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[[3-methyl-4-{N-methyl-2-thienoyl-(5-nitro)}]aminop-
iperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[{3-methyl-4-(N-methyl-N-2-furoyl)}-aminopiperidine-
-1-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[[-
3-methyl-4-{N-methyl-N-2-furyl(5-nitro)}]aminopiperidine-1-yl]phenyl]-2-ox-
o-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[[3-methyl-4-{N-m-
ethyl-N-2-thienyl-(5-nitro)}]aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolid-
inyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl-2-thienoyl-(5-nit-
ro)}-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl-2-furoyl-(5-nitro)}aminopiperidine-1-yl-
]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[4-{-
N-ethyl-N-2-furoyl}-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]meth-
yl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl-N-2-thiophenacetyl}-aminop-
iperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl-N-2-thiophenyl-(5-nitro)methyl}aminopip-
eridine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[4-{N-thienyl-(5-nitro)methyl}-aminopiperidine-1-yl-
]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[4-{-
2-furyl-(5-nitro)methylene}-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidi-
nyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[4-{N-2-furyl-(5-nitro)methyl}-
-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[4-{N-methyl-N-2-pyrrole-(5-nitro)methyl}aminopiper-
idine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[4-{N-methyl-N-2-furyl-(5-acetoxymethyl)methyl}amin-
opiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[4-{N-methyl-N-2-furoyl-(5-nitro)}-aminopiperidine--
1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1,3-[N-methyl[N-{2-thiophenyl-(5-nitro)methyl}]a-
minopyrodinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1,{3-[[N-methyl)[N-{2-thiophenoyl(5-nitro)}]amin-
opyrrolidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-{[3-[3-Fluoro-4[N-1[3-{(N-methyl)[N-2-furoyl(5-nitro)}]aminopryroli-
dinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1[4-{N-methyl)-N-2-furyl-(5-nitro)-methyl}]amino-
methylpiperidine-1-yl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[4-N-1(N-methyl){N-2-thiophenyl-(5-nitro)-methyl}]a-
minomethylpiperidine-1-yl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-{N-1[4-N-methyl)-N-2-furoyl(5-Nitro)-methyl}]aminom-
ethylpiperidine-1-yl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(S)-N-[[3-{3-Fluoro-4-(3-oxopiperidin-1-yl)-phenyl}-2-oxo-5-oxazolidinyl]-
methyl]acetamide,
(S)-N-[3-{3-Fluoro-4-[N-1-[3-N-methyl]-N-2-furyl(5-nitro-
)methyl}]aminopiperidinyl]-phenyl]2-oxo-5-oxazolidinyl]methyl]acetamidezol-
idinyl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[3-{2-furyl-(5-nitro)--
methylene}aminomethyl]-3-azabiyclo(3.1.0)hexane]phenyl]-2-oxo-5-oxazolidin-
yl]methyl]acetamide,
(S)-N-[[3-[3-Fluoro-4[N-1[3N-2-furyl-(5-nitro)methyl}-
-aminomethyl]-3-azabicyclo[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methy-
l]acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-[1-{2-thiophenyl-(5-nitro)}-1-e-
thyl]]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-[1-{2-furyl-(5-nitro)}-1-ethyl]]piperazinyl-
]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide,
(S)-N-[[3-[3-Fluoro-4-[N--
1-[4-{2-thiophene-(4-(4-t-butoxycarbonyl)piperazinyl-5-nitro)methyl}]piper-
azinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophene-(4N-piperazinyl-5-nitro)methyl-
}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide,
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophene-(4-(4-methyl)piperazinyl-5-nit-
ro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide,
13. A pharmaceutical composition comprising the compound of claim 1
or 12 and a pharmaceutical acceptable carrier, diluent, excipient
or solvate.
14. A pharmaceutical composition comprising a pharmaceutically
effective amount of a compound according to claims 1 or 12, or a
physiologically acceptable acid additional salt thereof with a
pharmaceutically acceptable carrier for treating microbial
infections.
15. A method of treating or preventing microbial infection in a
mammal comprising administering to said mammal the pharmaceutical
composition according to claim 14.
16. A process for preparing a compound of Formula I, 25and its
pharmaceutically acceptable salts, enantiomers, diastereomers,
N-oxide, polymorphs, pharmaceutically acceptable solvates prodrugs
or metabolites, wherein ring D is a five membered heterocyclic
ring; ring C is four to eight membered in size or larger which has
either two or three carbon atoms between each nitrogen atoms or
ring C is a bridged bicyclic system and is optionally substituted
by the substients Y and Z independently selected from alkyl groups,
cycloakyl groups, fluoro group, carboxylic groups and corresponding
esters or amides; Q.sub.1 is selected from O, S, NR.sub.11; Q.sub.2
is selected from N or C; G, J, L are independently selected from H,
C.sub.1-6 alkyl, F, Cl, Br, I, N, --CN, COR.sub.5, COOR.sub.5,
N(R.sub.6, R.sub.7), NHCOC(R.sub.5, R.sub.8, R.sub.9),
--NHCOOR.sub.5, CON(R.sub.6, R.sub.7), CH.sub.2NO.sub.2, NO.sub.2,
CH.sub.2R.sub.8, CHR.sub.9, --CH.dbd.N--OR.sub.10,
--C.dbd.CH--R.sub.5, OR.sub.5, SR.sub.5,
--C(R.sub.9).dbd.C(R.sub.9)NO.sub.2, C.sub.1-12 alkyl substituted
with one or more of F, Cl, Br, I, OR.sub.4, SR.sub.4; wherein
R.sub.5 is selected from H, C.sub.1-12 alkyl, C.sub.3-12
cycloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with one
or more of F, Cl, Br, I or OH, aryl, heteroaryl; R.sub.6 and
R.sub.7, are independently selected from H, optionally substituted
C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy; R.sub.8
and R.sub.9 are independently selected form H, C.sub.1-6 alkyl, F,
Cl, Br, I, C.sub.1-12 alkyl substituted with one or more of F, Cl,
Br, I, OR.sub.5, SR.sub.5, N(R.sub.6, R.sub.7); R.sub.10=H,
optionally substituted C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkyl, aryl, heteroaryl; except when W
is C.dbd.O, Q.sub.1=S, Q.sub.2=C, and G, J, L=H; R.sub.1 is
selected from the group consisting of --NHC(.dbd.O)R.sub.2,
N(R.sub.3, R.sub.4), --NR.sub.2C(.dbd.S)R.sub.3,
--NR.sub.2C(.dbd.S)SR.sub.3, wherein R.sub.2 is hydrogen,
C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl substituted with one or more of F, Cl, Br, I or OH;
R.sub.3, R.sub.4 are independently selected from hydrogen,
C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl substituted with one or more of F, Cl, Br, I or OH;
U and V are independently selected from hydrogen, optionally
substituted C.sub.1-6 alkyl, F, Cl, Br, C.sub.1-12 alkyl
substituted with one or more of F, Cl, Br, I, X is selected from C,
CH, CH--S, CH--O and N; Y and Z are independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl and C.sub.0-3
bridging groups; W is selected from the group CH.sub.2, CO,
CH.sub.2NH, --NHCH.sub.2, --CH.sub.2NHCH.sub.2,
--CH.sub.2--N(R.sub.11)CH.sub.2--, CH.sub.2(R.sub.11)N--,
CH(R.sub.11), S, CH.sub.2(CO), NH, O, N(R.sub.11), (CO)CH.sub.2,
N(R.sub.11)CON(R.sub.11), N(R.sub.11)C(.dbd.S)N(R.sub.11),
SO.sub.2, SO, wherein R.sub.11 is hydrogen, optionally substituted
C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkylcarboxy,
aryl, heteroaryl; n is an integer ranging from 0 to 3; which
comprises reacting an amine compound of Formula VI 26with a
heterocyclic compound of Formula VII 27wherein Q.sub.1, Q.sub.2, G,
J, L, W, X Y, Z, U, V, R.sub.1 and n are the same as defined above
and M.sub.1 in amine of Formula VI is defined as NH,
CH(NHR.sub.13), CH--CH.sub.2NHR.sub.13, CCH.sub.2NHR.sub.13 wherein
R.sub.13 is H, methyl, ethyl, isopropyl, acetyl, cyclopropyl,
alkoxy or acetyl; R.sub.12 is a suitable leaving group or suitable
functional group.
17. The process according to claim 16 wherein the suitable leaving
group R.sub.12 is selected from the group comprising of fluoro
alkyl, chloro alkyl, bromo alkyl SCH.sub.3, --SO.sub.2CH.sub.3,
--SO.sub.2CF.sub.3 and OC.sub.6H.sub.5.
18. The process according to claim 16 wherein the suitable
functional group is carboxaldehyde or carboxylic acid.
19. The process according to claim 16 for preparing a compound of
Formula I wherein reaction of compounds of Formula VI and VII is
carried out in a suitable solvent selected from the group
consisting of N,N-dimethylformamide, dimethylacetamide,
dimethylsulfoxide, ethanol and ethylene glycol.
20. The process according to claim 19 wherein the reaction is
carried out in the presence of a base selected from the group
consisting of triethylamine, diisopropylamine, potassium carbonate
and sodium carbonate.
21. The process according to claim 16 for preparing a compound of
Formula I wherein a compound of Formula VII is a heterocyclic
aldehyde.
22. The process according to claim 16 wherein the reductive
amination of the compound of Formula VI with the heterocyclic
aldehyde of Formula VII is performed with a reducing agent selected
from the group consisting of sodium triacetoxyborohydride and
sodium cyanoborohydride to give a compound of Formula I wherein
W=CH.sub.2.
23. The process according to claim 16 wherein the compound of
Formula VII is a heterocyclic carboxylic acid.
24. The process according to claim 16 wherein the reaction of amine
of Formula VI with carboxylic acid of Formula VII is carried out in
the presence of a suitable condensing agent.
25. The process according to claim 24 wherein the suitable
condensing agent is selected from the group consisting of
1,3-dicyclohexylcarbodiimi- de (DCC) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDC).
26. The process according to claim 16 for preparing a compound of
Formula I wherein the compounds of Formula I having carbonyl link
are prepared by reacting heteroaromatic compound of Formula VII
with a compound of Formula VI is in the presence of triphosgene and
phosgene.
27. The process according to claim 22 wherein compound of Formula
VII is N-methyl pyrrole.
28. The process according to claim 16 for preparing a compound of
Formula I wherein W=CO comprising reacting 3-bromothiophene
(Formula VII) and amine of Formula VI with carbon monoxide.
29. The process according to claim 16 for preparing a compound of
Formula I 28when G=R.sub.15 shown as Formula IX 29wherein R.sub.15
is a subset of G comprising of amine and acetamide, comprising
converting compound of Formula VIII (Formula I, when G=R.sub.14
wherein R=.sub.14 is also a subset of G comprising carbamate) 30to
a compound of Formula IX (Formula I, when G=R.sub.15).
30. The process according to claim 16 for preparing a compound of
Formula I when G=NHCOCF.sub.3, Q.sub.1=S, Q.sub.2=C, G=J=L=H, W=CO,
X=N, Y=Z=H, n=1, U=H, V=F, R.sub.1=NHCOCH.sub.3) shown as Formula
XI 31comprising reacting compound of Formula X with trifluoroacetic
acid. 32
31. The process according to claim 16 for preparing a compound of
Formula I when G=NH.sub.2, Q.sub.1=S, Q.sub.2=C, G=J=L=H, W=CO,
X=N, Y=Z=H, n=1, U=H, V=F, R.sub.1=NHCOCH.sub.3) shown as Formula
XII 33comprising reacting compound of Formula X 34with
trifluoroacetic acid followed by potassium carbonate in a suitable
solvent.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to certain substituted phenyl
oxazolidinones and to processes for the synthesis of the same. This
invention also relates to pharmaceutical compositions containing
the compounds of the present invention as antimicrobials The
compounds are useful antimicrobial agents, effective against a
number of human and veterinary pathogens, including gram-positive
aerobic bacteria such as multiply-resistant staphylococci,
streptococci and enterococci as well as anaerobic organisms such as
Bacteroides spp. and Clostridium spp. species, and acid fast
organisms such as Mycobacterium tuberculosis, Mycobacterium avium
and Mycobacterium spp,
BACKGROUND OF THE INVENTION
[0002] Increasing antibacterial resistance in gram positive
bacteria has presented a formidable treatment problem. The
enterococci, although traditionally non virulent pathogens, have
been shown, when associated with Vancomycin resistance, to have an
attributable mortality of approximately 40%. Staphylococcus aureus,
the traditional pathogen of post operative wounds, has been
resistant to Penicillin due to production of penicillinases. This
resistance was overcome by the development of various penicillinase
stable .beta. lactams. But the pathogen responded by synthesizing a
modified target penicillin binding protein-2' leading to less
affinity for .beta. lactam antibiotics and a phenotype known as
Methicillin Resistant S. aureus (MRSA). These strains, till
recently were susceptible to Vancomycin, which inspite of its
various drawbacks, has become the drug of choice for MRSA
infections. Streptococcus pneumoniae is a major pathogen causing
pneumonia, sinusitis and meningitis. Until very recently it was
highly susceptible to penicillin. Recently though, different PBP 2'
strains with different susceptibility to penicillin have been
reported from across the globe.
[0003] Oxazolidinones are a new class of synthetic antimicrobial
agents which kill Gram positive pathogens by inhibiting a very
early stage of protein synthesis. Oxazolidinones Inhibit the
formation of ribosomal initiation complex involving 30S and 50S
ribosomes leading to prevention of initiation complex formation.
Due to their novel mechanism of action, these compounds are active
against pathogens resistant to other clinically useful
antibiotics.
[0004] WO93/23384 application discloses phenyloxazolidinones
containing a substituted diazine moiety and their uses as
antimicrobials.
[0005] WO93/09103 application discloses substituted aryl and
heteroaryl-phenyl-oxazolidinones useful as antibacterial
agents.
[0006] WO90/02744 application discloses
5-indolinyl-5.beta.-amidomethyloxa- zolidinones, 3-(fused ring
substituted)phenyl-5.beta.-amidomethyloxazolidi- nones which are
useful as antibacterial agents.
[0007] European Patent Publication 352,781 discloses phenyl and
pyridyl substituted phenyl oxazolidinones.
[0008] European Patent Application 312,000 discloses phenylmethyl
and pyridinylmethyl substituted phenyl oxazolidinones.
[0009] U.S. Pat. No. 5,254,577 discloses nitrogen heteroaromatic
rings attached to phenyloxazolidinone.
[0010] U.S. Pat. Nos. 5,547,950 and 5,700,799 also disclose the
phenyl piperazinyl oxazolidinones.
[0011] Other references disclosing various phenyloxazolidinones
include U.S. Pat. Nos. 4,801,600 and 4,921,869; Gregory W. A., et
al., J. Med. Chem., 32, 1673-81 (1989); Gregory W. A., et al., J.
Med. Chem., 33, 2569-78 (1990); Wang C., et al., Tetrahedron, 45,
1323-26 (1989); Britteili, et al., J. Med. Chem., 35, 1156 (1992);
and Bio-organic and Medicinal Chemistry Letters, 9, pp. 2679-2684,
1999; Antibacterial & Antifungal Drug Discovery &
Development Summit, Strategic Research Institute, Jun. 28-29, 2001,
Amsterdam, The Netherlands; Posters No. 1822, 1823, 1824, 1825,
1826, 1827, 1828, 1829, 1830, 1831, 1832, 1833, and 1834, 40.sup.th
Interscience Conference on Antimicrobial Agents and Chemotherapy,
Sep. 17-20, 2000, Toronto, Canada.
SUMMARY OF THE INVENTION
[0012] The objective of this Invention is to synthesize, identify
and profile oxazolidinone molecules which have good activity
against multiply resistant gram positive pathogens like MRSA, VRE
and PRSP. Some of these molecules have activity against MDR-TB and
MAI strains, while others have significant activity against
important anaerobic bacteria.
[0013] The compounds of the present invention are related by their
substituted phenyloxazolidinone ring structure in the compounds
disclosed to the publications described above except that the
subject compounds have a diazine moiety attached to the
phenyloxazolidinone which is further substituted by heterocyclic,
aryl, substituted aryl, heteroaroamatic ring therefore the
compounds are unique and have superior antibacterial activity.
[0014] Another object of the present invention is to provide
processes for the novel phenyloxazolidinones derivatives that
exhibit significantly greater antibacterial activity, than
available with the present compounds against multiply resistant
gram positive pathogens like MRSA, VRE and PRSP , MDR-TB and MAI
strains, in order to provide safe and effective treatment of
bacterial infections.
[0015] In order to achieve the above-mentioned objectives and in
accordance with the purpose of the invention as embodied and
broadly described herein, there is provided a process for the
synthesis of novel phenyloxazolidinone derivatives represented by
Formula I, 1
[0016] wherein
[0017] ring C is four to eight membered in size or larger which has
either two or three carbon atoms between each nitrogen atoms or
ring C is a bridged bicyclic system and is optionally substituted
by the substituents Y and Z independently selected from alkyl
groups, cycloakyl groups, fluoro group, carboxylic groups and
corresponding esters or amides;
[0018] D is a five membered heterocyclic ring; the preferred
heterocyclic rings are furanyl, thienyl, pyrrolyl and
pyrazolyl;
[0019] Q.sub.1 is selected from O, S, NR.sub.11;
[0020] Q.sub.2 is selected from N or O;
[0021] G, J, L are independently selected from H, C.sub.1-6 alkyl,
F, Cl, Br, I, --CN, COR.sub.5, COOR.sub.5, N(R.sub.6, R.sub.7),
NHCOC(R.sub.8, R.sub.9), --NHCOOR.sub.5, CON(R.sub.6, R.sub.7),
CH.sub.2NO.sub.2, NO.sub.2, CH.sub.2R.sub.8, CHR.sub.9,
--CH.dbd.N--OR.sub.10, --C.dbd.CH--R.sub.5, OR.sub.5, SR.sub.5,
--C(R.sub.9).dbd.C(R.sub.9)NO.su- b.2, C.sub.1-12 alkyl substituted
with one or more of F, Cl, Br, I, OR.sub.4, SR.sub.4; wherein
R.sub.5 is selected from H, C.sub.1-12 alkyl, C.sub.3-12
cycloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with one
or more of F, Cl, Br, I or OH, aryl, heteroaryl; R.sub.6 and
R.sub.7, are independently selected from H, optionally substituted
C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy; R.sub.8
and R.sub.9 are independently selected from H, C.sub.1-6 alkyl, F,
Cl, Br, I, C.sub.1-12 alkyl substituted with one or more of F, Cl,
Br, I, OR.sub.5, SR.sub.4, N(R.sub.6, R.sub.7); R.sub.10=H,
optionally substituted C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkyl, aryl, heteroaryl; except when W
is C.dbd.O, Q.sub.1=S, Q.sub.2=C, and G, J, L=H;
[0022] R.sub.1 is selected from the group consisting of
--NHC(.dbd.O)R.sub.2, N(R.sub.3, R.sub.4),
--NR.sub.2C(.dbd.S)R.sub.3, --NR.sub.2C(.dbd.S)SR.sub.3, wherein
R.sub.2 is hydrogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with one or more of
F, Cl, Br, I or OH: R.sub.3, R.sub.4 are independently selected
from hydrogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6
alkoxy, C.sub.1-6 alkyl substituted with one or more of F, Cl, Br,
I or OH; preferably R.sub.1 is of the formula --NH(C.dbd.O)X
wherein X is CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3, CH.sub.2Cl,
CHCl.sub.2, CCl.sub.3;
[0023] U and V are independently selected from hydrogen, optionally
substituted C.sub.1-6 alkyl, F, Cl, Br, C.sub.1-12 alkyl
substituted with one or more of F, Cl, Br, I, preferably U and V
are hydrogen or fluoro;
[0024] X is selected from C, CH, CH--S, CH--O and N;
[0025] Y and Z are independently selected from hydrogen, C.sub.1-6
alkyl, C.sub.3-12 cycloalkyl and C.sub.0-3 bridging groups;
[0026] W is selected from the group CH.sub.2, CO, CH.sub.2NH,
--NHCH.sub.2, --CH.sub.2 NHCH.sub.2,
--CH.sub.2--N(R.sub.11)CH.sub.2--, CH.sub.2(R.sub.11)N--,
CH(R.sub.11), S, CH.sub.2(CO), NH, O, N(R.sub.11), (CO)CH.sub.2,
N(R.sub.11)CON(R.sub.11), N(R.sub.11)C(.dbd.S)N(R.sub.11),
SO.sub.2, SO, wherein R.sub.11 is hydrogen, optionally substituted
C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkylcarboxy,
aryl, heteroaryl; and,
[0027] n is an integer in the range from 0 to 3.
[0028] Preferred compounds of Formula I have R.sub.1 as acetamide
or halogen substituted acetamide and the most preferred compounds
in this series would be prepared as the optically pure enantiomers
having the (S)-configuration according to the Cahn-Ingold-Prelog
notation at C.sub.5 of the oxazolidinone ring. The (S)-enantiomer
of this series of compounds is preferred since it has two times
more antibacterial activity than the corresponding racemic
compound. The scope of the Individual isomers end mixture of
enantiomers of the structural Formula I are also covered in this
invention.
[0029] In the more preferred compounds represented by Formula I
ring C may be four to eight membered in size and the larger rings
may have either two or three carbons between each nitrogen atom,
for example: 2
[0030] The ring C may be bridged to form a bicyclic system as shown
below: 3
[0031] Ring C is optionally substituted by Y and Z with alkyl
groups, cycloalkyl groups, fluoro group, carboxylic and
corresponding esters, amides, substituted alkyls or bridging alkyl
groups are as shown below. 4
[0032] When ring C is five or six membered in size and X is
--CH--(NHR), or >CCH.sub.2NHR--, the following rings are
preferred ones wherein R.sub.11 is the same as defined earlier.
5
[0033] In addition to the above, ring C also includes the following
structures: 6
[0034] Still more preferred compounds of Formula I when
Q.sub.1=NR.sub.11, and Q.sub.2=N is represented by Formula II
wherein rings C and D are the same as defined before; 7
[0035] R.sub.1 is selected from the group consisting of
--NHC(.dbd.O)R.sub.2; --N(R.sub.3, R.sub.4);
--NR.sub.2C(.dbd.S)R.sub.3; --NR.sub.2C(.dbd.S)SR.sub.3 wherein
R.sub.2, R.sub.3, R.sub.4 are independently hydrogen, C.sub.1-12
alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl
substituted with one or more of F, Cl, Br, I, OH, preferably
R.sub.1 is of the formula --NH(C.dbd.O)X wherein X is CH.sub.3,
CH.sub.2F, CHF.sub.2, CF.sub.3, CH.sub.2Cl, CHCl.sub.2,
CCl.sub.3;
[0036] U and V are independently selected from hydrogen, optionally
substituted C.sub.1-6 alkyl, F, Cl, Br, C.sub.1-12 alkyl
substituted with one or more of F, Cl, Br, I; preferably U and V
are hydrogen or fluoro;
[0037] Y and Z are independently selected from hydrogen, C.sub.1-6
alkyl, C.sub.3-12 cycloalkyl C.sub.0-3 bridging group;
[0038] X is selected from C, CH, CH--S, CH--O, and N;
[0039] W is independently selected from the group CH.sub.2, CO,
CH.sub.2NH, --NHCH.sub.2, --CH.sub.2NHCH.sub.2,
--CH.sub.2--N(R.sub.11)CH- .sub.2, CH.sub.2(R.sub.11)N--,
CH(R.sub.11), S, CH.sub.2(CO), NH, O, N(R.sub.11), (CO)CH.sub.2,
N(R.sub.11)CON(R.sub.11), N(R.sub.11)C(.dbd.S)N(R.sub.11),
SO.sub.2, SO, wherein R.sub.11 is hydrogen, optionally substituted
C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkylcarboxy,
aryl, heteroaryl;
[0040] G, J, L are independently selected from H, C.sub.1-6 alkyl,
F, Cl, Br, I, --CN, COR.sub.5, COOR.sub.5, N(R.sub.6, R.sub.7),
NHCOC(R8, R9), NHCOOR.sub.5, CON(R.sub.6, R.sub.7),
CH.sub.2NO.sub.2, NO.sub.2, CH.sub.2R.sub.8, CHR.sub.9,
--CH.dbd.N--OR.sub.10, --C.dbd.CH--R.sub.5, OR.sub.5, SR.sub.5,
--C(R.sub.9).dbd.C(R.sub.9)NO.sub.2, C.sub.1-12 alkyl substituted
with one or more of F, Cl, Br, I, OR.sub.4, SR.sub.4, wherein
R.sub.5 is selected from H, C.sub.1-12 alkyl, C.sub.3-12
cycloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with one
or more F, Cl, Br, I or OH, aryl, heteroaryl; R.sub.6 and R.sub.7,
are independently selected from H, optionally substituted
C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy; R.sub.8
and R.sub.9 are independently selected from H, C.sub.1-6 alkyl, F,
Cl, Br, I, C.sub.1-12 alkyl substituted with one or more of F, Cl,
Br, I, OR.sub.5, SR.sub.4, N(R.sub.6, R.sub.7); R.sub.10=H,
optionally substituted C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkyl, aryl, heteroaryl;
[0041] n is an integer in the range from 0 to 3;
[0042] more preferred G, J and L substitutions are nitro, aldehydes
and halides;
[0043] preferably W is selected from the groups consisting of
CH.sub.2, C(.dbd.O), C(.dbd.O)--C(.dbd.O), CH.sub.2NH,
--NHCH.sub.2, --CH.sub.2NHCH.sub.2,
--CH.sub.2--N(CH.sub.3)CH.sub.2--, CH.sub.2(CH.sub.3)N--,
CH(CH.sub.3), S and CH.sub.2(C.dbd.O), --NH. The preferred
compounds of Formula II are as follows:
[0044]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{3-pyrazolecarbonyl-(4-nitro)}]pipera-
zinyl]phenyl-]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0045]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{3-pyrazolecarbonyl-(5-nitro)}]pipera-
zinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0046] Still more preferred compounds of Formula I when
Q=NR.sub.11, and Q.sub.2=carbon is represented by Formula III 8
[0047] wherein
[0048] rings C and D are the same as defined before;
[0049] R.sub.1 is selected from the group consisting of
--NHC(.dbd.O)R.sub.2; --N(R.sub.3, R.sub.4);
--NR.sub.2C(.dbd.S)R.sub.3; --NR.sub.2C(.dbd.S)SR.sub.3 wherein
R.sub.2, R.sub.3, R.sub.4 are independently hydrogen, C.sub.1-12
alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl
substituted one or more F, Cl, Br, I, OH; preferably R.sub.1 is of
the formula --NH(C.dbd.O)X wherein X is CH.sub.3, CH.sub.2F,
CHF.sub.2, CF.sub.3, CH.sub.2Cl, CHCl.sub.2, CCl.sub.3;
[0050] U and V are independently selected from hydrogen, optionally
substituted C.sub.1-6 alkyl, F, Cl, Br, C.sub.1-12 alkyl
substituted with one or more of F, Cl, Br, I; preferably U and V
are hydrogen and fluoro;
[0051] Y and Z are independently selected from hydrogen, C.sub.1-6
alkyl, C.sub.3-12 cycloalkyl, C.sub.0-3 bridging group.
[0052] X is selected from C, CH, CH--S, CH--O, and N;
[0053] W is independently selected from CH.sub.2, CO, CH.sub.2NH,
--NHCH.sub.2, --CH.sub.2NHCH.sub.2,
--CH.sub.2--N(R.sub.11)CH.sub.2--, CH.sub.2(R.sub.11)N--,
CH(R.sub.11), S, CH.sub.2(CO), NH, O, N(R.sub.11), (CO)CH.sub.2,
N(R.sub.11)CON(R.sub.11), N(R.sub.11)C(.dbd.S)N(R.sub.11),
SO.sub.2, SO, wherein R.sub.11 is hydrogen, optionally substituted
C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkylcarboxy,
aryl, heteroaryl;
[0054] G, J, L are independently selected from H, C.sub.1-6 alkyl,
F, Cl, Br, I, --CN, COR.sub.5, COOR.sub.5, N(R.sub.6, R.sub.7),
NHCOC(R.sub.8, R.sub.9), NHCOOR.sub.5, CON(R.sub.6, R.sub.7),
CH.sub.2NO.sub.2, NO.sub.2, CH.sub.2R.sub.8, CHR.sub.9,
--CH.dbd.N--OR.sub.10, --C.dbd.CH--R.sub.5, OR.sub.5, SR.sub.5,
--C(R.sub.9).dbd.C(R.sub.9)NO.su- b.2, C.sub.1-12 alkyl substituted
with one or more F, Cl, Br, I, OR.sub.4, SR.sub.4; wherein R.sub.5
is selected from H, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with one or more F,
Cl, Br, I or OH, aryl, heteroaryl; R.sub.6 and R.sub.7, are
independently selected from H, optionally substituted C.sub.1-12
alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy; R.sub.8 and R.sub.9
are independently selected from H, C.sub.1-6 alkyl, F, Cl, Br, I,
C.sub.1-12 alkyl substituted with one or more of F, Cl, Br, I,
OR.sub.5, SR.sub.4, N(R.sub.6, R.sub.7); R.sub.10=H, optionally
substituted C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6
alkoxy, C.sub.1-6 alkyl, aryl, heteroaryl;
[0055] n is an integer in the range from 0 to 3;
[0056] more preferred G, J and L substitutions are nitro, aldehydes
and halides.
[0057] Preferably W is selected from the groups consisting of
CH.sub.2, C(.dbd.O), C(.dbd.O)--C(.dbd.O), CH.sub.2NH,
--NHCH.sub.2, --CH.sub.2NHCH.sub.2,
--CH.sub.2--N(CH.sub.3)CH.sub.2--, CH.sub.2(CH.sub.3)N--,
CH(CH.sub.3), S and CH.sub.2(C.dbd.O), --NH. The preferred
compounds of Formula III are as follows:
[0058]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-pyrrole-(1-methyl-5-nitro)methyl}]-
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0059]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-pyrrole-(5-nitro)methyl}]piperazin-
yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0060] Still more preferred compounds of Formula I is represented
by Formula IV with Q.sub.1=sulphur and Q.sub.2=carbon of Formula I,
9
[0061] wherein
[0062] rings C and D are the same as defined before;
[0063] R.sub.1 is selected from the group consisting of
--NHC(.dbd.O)R.sub.2, --N(R.sub.3, R.sub.4),
--NR.sub.2C(.dbd.S)R.sub.3, --NR.sub.2C(.dbd.S)SR.sub.3 wherein
R.sub.2, R.sub.3, R.sub.4 are independently hydrogen, C.sub.1-12
alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl
substituted one or more of F, Cl, Br, I, OH; preferably R.sub.1 is
of the formula --NH(C.dbd.O)X wherein X is CH.sub.3, CH.sub.2F,
CHF.sub.2, CF.sub.3, CH.sub.2Cl, CHCl.sub.2, CCl.sub.3;
[0064] U and V are independently selected from hydrogen, optionally
substituted C.sub.1-6 alkyl, F, Cl, Br, C.sub.1-12 alkyl
substituted with one or more F, Cl, Br, I; preferably U and V are
hydrogen and fluoro;
[0065] Y and Z are independently selected from hydrogen, C.sub.1-6
alkyl, C.sub.3-12 cycloalkyl C.sub.0-3 bridging group;
[0066] X is selected from C, CH, CH--S, CH--O, and N;
[0067] W is Independently selected from CH.sub.2, CO, CH.sub.2NH,
--NHCH.sub.2, --CH.sub.2NHCH.sub.2,
--CH.sub.2--N(R.sub.11)CH.sub.2--, CH.sub.2(R.sub.11)N--,
CH(R.sub.11), S, CH.sub.2(CO), NH, O, N(R.sub.11), (CO)CH.sub.2,
N(R.sub.11)CON(R.sub.11), N(R.sub.11)C(.dbd.S)N(R.sub.11),
SO.sub.2, SO, wherein R.sub.11 is hydrogen, optionally substituted
C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkylcarboxy,
aryl, heteroaryl;
[0068] G, J, L are independently selected from H, C.sub.1-6 alkyl,
F, Cl, Br, I, --CN, COR.sub.5, COOR.sub.5, N(R.sub.6, R.sub.7),
NHCOC(R.sub.8, R.sub.9), NHCOOR.sub.5, CON(R.sub.6, R.sub.7),
CH.sub.2NO.sub.2, NO.sub.2, CH.sub.2R.sub.8, CHR.sub.9,
--CH.dbd.N--OR.sub.10, --C.dbd.CH--R.sub.5, OR.sub.5, SR.sub.5,
--C(R.sub.9).dbd.C(R.sub.9)NO.su- b.2, C.sub.1-12 alkyl substituted
with one or more F, Cl, Br, I, OR.sub.4, SR.sub.4; wherein R.sub.5
is selected from H, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with one or more of
F, Cl, Br, I or OH, aryl, heteroaryl; R.sub.6 and R.sub.7, are
independently selected from H, optionally substituted C.sub.1-12
alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy; R.sub.8 and R.sub.9
are independently selected from H, C.sub.1-6 alkyl, F, Cl, Br, I,
C.sub.1-12 alkyl substituted with one or more of F, Cl, Br, I,
OR.sub.5, SR.sub.4, N(R.sub.6, R.sub.7); R.sub.10 is H, optionally
substituted C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6
alkoxy, aryl, heteroaryl; except when W=(C.dbd.O), Q.sub.1=S,
Q.sub.2=C, and G, J, L=H;
[0069] n is an integer in the range from 0 to 3.
[0070] More preferred G, J and L substitutions are nitro, aldehydes
and halides.
[0071] Preferably W is selected from the groups consisting of
CH.sub.2, C(.dbd.O), C(.dbd.O)--C(.dbd.O), CH.sub.2NH,
--NHCH.sub.2, --CH.sub.2NHCH.sub.2,
--CH.sub.2--N(CH.sub.3)CH.sub.2--, CH.sub.2(CH.sub.3)N--,
CH(CH.sub.3), S and CH.sub.2(C.dbd.O), --NH. The preferred
compounds of Formula IV are as follows:
[0072]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophen-(4-nitro-)methyl-}]pipera-
zinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0073]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(5-nitro)}]homopiperaz-
inyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0074]
(S)-N-[[4-[3-Fluoro-4-[N-1-[4-[1-{2-thiophenyl-(5-nitro)}-ethyl]]pi-
perazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide
[0075]
(S)-N-[[3-[3-Fluoro-4-[N-1-[2-methyl-4-{2-thiophenoyl-(5-nitro)}]-p-
iperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0076]
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl-2-thiophenoyl-(5-nitro)}-aminopip-
eridine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0077]
(S)-N-[[3-[3-Fluoro-4-[N-1,{3-{[N-methyl)[N-{24-chlorophenoyl-(5-ni-
tro)}]aminopyrrolidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
[0078] Still more preferred compounds of Formula I is represented
by Formula V with Q.sub.1=O, Q.sub.2=C of Formula II, 10
[0079] wherein
[0080] rings C and D are the same as defined before;
[0081] R.sub.1 is selected from the group consisting of
--NHC(.dbd.O)R.sub.2, --N(R.sub.3, R.sub.4),
--NR.sub.2C(.dbd.S)R.sub.3, NR.sub.2C(.dbd.S)SR.sub.3 wherein
R.sub.2, R.sub.3, R.sub.4 are independently selected from the group
consisting of hydrogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted one or more F, Cl,
Br, I, OH, preferably R.sub.1 is of the formula --NH(C.dbd.O)X
wherein X is CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3, CH.sub.2Cl,
CHCl.sub.2, CCl.sub.3;
[0082] U and V are independently selected from hydrogen, optionally
substituted C.sub.1-6 alkyl, F, Cl, Br, C.sub.1-12 alkyl
substituted with one or more of F, Cl, Br, I; preferably U and V
are hydrogen and fluoro;
[0083] Y and Z are independently selected from hydrogen, C.sub.1-6
alkyl, C.sub.3-12 cycloalkyl, C.sub.0-3 bridging group;
[0084] X is selected from C, CH, CH--S, CH--O, and N;
[0085] W is Independently selected from the group consisting of
CH.sub.2, CO, CH.sub.2NH, --NHCH.sub.2, --CH.sub.2NHCH.sub.2,
--CH.sub.2--N(R.sub.11)CH.sub.2--, CH.sub.2(R.sub.11)N--,
CH(R.sub.11), S, CH.sub.2(CO), NH, O, N(R.sub.11), (CO)CH.sub.2,
N(R.sub.11)CON(R.sub.11), N(R.sub.11)C(.dbd.S)N(R.sub.11),
SO.sub.2, SO, wherein R.sub.11 is hydrogen, optionally substituted
C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkylcarboxy,
aryl, heteroaryl;
[0086] G, J, L are independently selected from H, C.sub.1-6 alkyl,
F, Cl, Br, I, --CN, COR.sub.5, COOR.sub.5, N(R.sub.6, R.sub.7),
NHCOC(R.sub.8, R.sub.9), NHCOOR.sub.5, CON(R.sub.6, R.sub.7),
CH.sub.2NO.sub.2, NO.sub.2, CH.sub.2R.sub.8, CHR.sub.9,
--CH.dbd.N--OR.sub.10, --C.dbd.CH--R.sub.5, OR.sub.5, SR.sub.5,
--C(R.sub.9).dbd.C(R.sub.9)NO.su- b.2, C.sub.1-12 alkyl substituted
with one or more F, Cl, Br, I, OR.sub.4, SR.sub.4; wherein R.sub.5
is selected from H, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with one or more of
F, Cl, Br, I or OH, aryl, heteroaryl; R.sub.6 and R.sub.7, are
independently selected from H, optionally substituted C.sub.1-12
alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy; R.sub.8 and R.sub.9
are independently selected from H, C.sub.1-6 alkyl, F, Cl, Br, I,
C.sub.1-12 alkyl substituted with one or more of F, Cl, Br, I,
OR.sub.5, SR.sub.4, N(R.sub.6, R.sub.7); R.sub.10=H, optionally
substituted C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.1-6
alkoxy, C.sub.1-6 alkyl, aryl, heteroaryl;
[0087] n is an integer in the range from 0 to 3.
[0088] More preferred G, J and L substitutions are nitro, aldehydes
and halides.
[0089] Preferably W is selected from the groups consisting of
CH.sub.2, C(.dbd.O), C(.dbd.O)--C(.dbd.O), CH.sub.2NH,
--NHCH.sub.2, --CH.sub.2NHCH.sub.2,
--CH.sub.2--N(CH.sub.3)CH.sub.2--, CH.sub.2(CH.sub.3)N--,
CH(CH.sub.3), S and CH.sub.2(C.dbd.O), --NH. The preferred
compounds of Formula V are as follows:
[0090]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furoyl-(3-methyl)}]piperazinyl]phe-
nyl-2-oxo-5-oxazolidinyl]methyl]acetamide,
[0091]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furoyl-(3-methyl-5-nitro)}]piperaz-
inyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
[0092]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-[1-{2-furyl-(5-nitro)}-1-ethyl]]piper-
azinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
[0093]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-nitro)methyl}]piperazinyl]-
phenyl]-2-oxo-5-oxazolidinyl]methyl]-difluoroacetamide,
[0094]
(S)-N-[[3-[3-Fluoro-4-[4-{N-2-furyl-(5-nitro)methyl}-aminopiperidin-
e-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
[0095] The compounds of the present invention are useful as
antimicrobial agents, effective against a number of human and
veterinary pathogens, particularly aerobic Gram-positive bacteria,
including multiply-antibiotic resistant staphylococci and
streptococci, as well as anaerobic organisms such as Mycobacterium
tuberculosis and other mycobacterium species.
[0096] For preparing pharmaceutical compositions from the compounds
described by this invention, inert, pharmaceutically acceptable
carriers can be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules, capsules, cachets,
suppositories, and ointments. A solid carrier can be one or more
substances which may also act as diluents, flavouring agents,
solubilizers, lubricants, suspending agents, binders, or tablets
disintegrating agents; it can also be as finely divided solid which
is in admixture with the finely divided active compound. For the
preparation of tablets, the active compound is mixed with carrier
having the necessary binding properties in suitable proportions and
compacted in the shape and size desired. The powders and tablets
preferably contain from about 5 to about 70 percent of the active
ingredient. Suitable solid carriers are lactose, pectin, dextrin,
starch, gelatin, tragacanth, low melting wax, cocoa butter, and the
like. The term "preparation" is intended to include the formulation
of the active compound with encapsulating material as carrier
providing a capsule in which the active component (with or without
other carriers) is surrounded by carrier, which is thus in
association with it. Similarly, capsules can be used as solid
dosage forms suitable for oral administration.
[0097] Liquid form preparations include solutions, suspensions, and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection. Such solutions are
prepared so as to be acceptable to biological systems (isotonicity,
pH, etc.). Liquid preparations can also be formulated in solution
in aqueous polyethylene glycol solution. Aqueous solutions suitable
for oral use can be prepared by dissolving the active component in
water and adding suitable colorants, flavours, stabilizing, and
thickening agents as desired. Aqueous suspension suitable for oral
use can be made by dispersing the finely divided active component
in water with viscous material, i.e., natural or synthetic gums,
resins, methyl cellulose, sodium carboxymethyl cellulose, and other
well-known suspending agents.
[0098] Ointment preparations contain heavy metal salts of a
compound of Formula I with a physiologically acceptable carrier.
The carrier is desirably a conventional water-dispersible
hydrophilic or oil-in-water carrier, particularly a conventional
semi-soft or cream-like water dispersible or water soluble,
oil-in-water emulsion infected surface with a minimum of
discomfort. Suitable compositions may be prepared by merely
incorporating or homogeneously admixing finely divided compounds
with the hydrophilic carrier or base or ointment.
[0099] Preferably, the pharmaceutical preparation is in unit dosage
form. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete capsules, powders in vials or ampoules, and ointments
capsule, cachet, tablet, gel, or cream itself or it can be the
appropriate number of any of these packaged forms.
[0100] In order to achieve the above mentioned objects in
accordance with the purpose of the invention as embodied and
broadly described herein, there are provided processes for the
synthesis of compounds of Formulae I, II, III, IV and V.
Pharmaceutically acceptable non-toxic acid addition salts of the
compounds of the present invention of Formulae I, II, III, IV and V
may be formed with inorganic or organic acids, by methods well
known in the art.
[0101] The present invention also includes within its scope
prodrugs of the compounds of Formulae I, II, III, IV and V. In
general, such prodrugs will be functional derivatives of these
compounds which readily get converted in vivo into defined
compounds. Conventional procedures for the selection and
preparation of suitable prodrugs are known.
[0102] The invention also includes pharmaceutically acceptable
salts, the enantiomers, diastereomers, N-oxides, polymorphs,
pharmaceutically acceptable solvates, prodrugs, metabolites in
combination with pharmaceutically acceptable carrier and optionally
included excipient.
[0103] Other objects and advantages of the invention will be set
forth in the description which follows, and in part will be
apparent from the description, or may be learned by the practice of
the invention. The objects and the advantages of the invention may
be realized and obtained by means of the mechanism and combination
pointed out in the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
[0104] The compounds of the present invention may be prepared by
following the reaction sequences as depicted in the schemes in the
accompanied drawings of which description is defined below
[0105] Mainly seventeen different amines of Formula VI identified
as seventeen is different cores, namely
[0106]
(S)-N-[[3-[3-Fluoro-4-(N-piperazinyl)phenyl-2-oxo-5-oxazolidinyl]me-
thyl]acetamide (Core I)
[0107]
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl-
]methyl]-fluoroacetamide (Core II);
[0108]
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl-
]methyl]-difluoroacetamide (Core III)
[0109]
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl-
]methyl]monochloroacetamide (Core IV)
[0110]
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)-phenyl]2-oxo-5-oxazolidinyl-
]methyl]-2-chloropropionamide (Core V)
[0111]
(S)-N-[[3-[3-[3-Fluoro-4-(N-1-homopiperazinyl)phenyl]-2-oxo-5-oxazo-
lidinyl]methyl]acetamide (Core VI);
[0112]
(S)-N-[[3-[3-Fluoro-4-{N-1-(2-methyl)piperazinyl}phenyl]2-oxo-5-oxa-
zolidinyl]methyl]acetamide (Core VII);
[0113]
(S)-N-[[3-[3-Fluoro-4-[N-1-{2,6-dimethyl-}-piperazinyl]phenyl]-2-ox-
o-5-oxazolidinyl]-methyl]acetamide (Core VII);
[0114]
(S)-N-[[3-[3-Fluoro-4-[N-1-{3-methyl-}-piperazinyl]phenyl]-2-oxo-5--
oxazolidinyl]methyl]acetamide (Core IX);
[0115]
(S)-N-[[3-[3-Fluoro-4-[{3-methyl-4-(N-methyl-)}-aminopiperidine-1-y-
l]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Core X);
[0116]
(S)-N-[[3-[3-Fluoro-4-[{N-ethyl}-aminopiperidine-1-yl]phenyl]-2-oxo-
-5-oxazolidinyl]methyl]acetamide (Core XI);
[0117]
(S)-N-[[3-[3-Fluoro-4-(4-aminopiperidine-1-yl)phenyl]-2-oxo-5-oxazo-
lidinyl]methyl]acetamide (Core XII);
[0118]
(S)-N-[[4-[3-Fluoro-4-[4-{N-methyl-}-aminopiperidine-1-yl]phenyl]-2-
-oxo-5-oxazolidinyl]methyl]acetamide (Core XIII);
[0119]
(S)-N-[[3-[3-Fluoro-4-[N-1,3-[N-methylaminopyrodinyl]phenyl]]-2-oxo-
-5-oxazolidinyl]methyl]acetamide (Core XIV);
[0120]
(S)-N-[[3-[3-Fluoro-4-[N-1(4-N-methyl)-]aminomethyl]piperidine-1-yl-
]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Core XV);
[0121]
(S)-N[3-[3-[Fluoro-4-(N-1-(3-N-methyl)-aminopiperidinyl}-phenyl]2-o-
xo-5-oxazolidinyl]methyl]acetamide (Core XVI);
[0122]
(S)-N-[[3-[3-Fluoro-4-{N-1-(N-aminomethyl)-3-azabicyclo[3.1.0]-hexa-
ne}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Core XVII)
[0123] were used for analoguing purposes.
[0124] Key intermediate amines for the analogue preparation of
compounds of Formula I are represented by Formula VI, 11
[0125] wherein
[0126] M.sub.1 is NH, NHR.sub.13, --CH.sub.2NHR.sub.13,
>C--CH.sub.2NHR.sub.13, wherein R.sub.13 is H, ethyl, methyl,
isopropyl, acetyl, cyolopropyl, alkoxy, or acetyl and n, R.sub.1 U,
V, Y and Z are as defined for Formula I.
[0127] Some amines of Formula VI are already known in the
literature and if they have been made for the first time or by a
different procedure or variation of known procedure they are
described in detail in the experimental section.
[0128] Optically pure amines of Formula VI could be obtained either
by one of asymmetric syntheses methods known in the art or
alternatively by resolution from a racemic mixture by selective
crystallization of a salt prepared, with an appropriate optically
active acid such as dibenzoyl tartrate or 10-camphorsulfonic acid,
followed by treatment with base to afford the optically pure
amine.
[0129] Scheme-I
[0130] The compounds of the present invention represented by
general Formula I may be prepared by the reaction sequence shown in
Scheme I. 12
[0131] In Scheme I, the heteroaromatic group with the corresponding
appendage can be introduced on the nitrogen atom of ring C of
compounds of Formula VI by one of the methods described below to
give the compounds of Formula I.
[0132] Amine of the structure of Formula VI wherein Y, Z, U, V,
R.sub.1 and n are the same as defined for Formula I and M.sub.1 is
the same as defined earlier, is reacted with a heteroaromatic
compound of Formula VII wherein Q.sub.1, Q.sub.2, J, L and G are
the same as defined for Formula I earlier; R.sub.12 is a suitable
leaving group well known to one of ordinary skill in the art such
as fluoro, chloro, bromo, SCH.sub.3, --SO.sub.2CH.sub.3,
--SO.sub.2CF.sub.3, Tosyl or OC.sub.6H.sub.5 etc
[0133] For the preparation of compounds of Formula I wherein W is
equal to CH.sub.2, corresponding aldehyde can be used through a
process of reductive amination and is attached to amine of Formula
VI.
[0134] Similarly, for the preparation of compound of Formula I
wherein W is equal to C.dbd.O corresponding acid can be used and
the amine of Formula VI can be acylated through activated esters in
the presence of condensing agents such as
1,3-dicyclohexycarbodiimide (DCC) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC).
Other methods of acylatlon known in the art can also be
employed.
[0135] Alternatively, the compounds of Formula I (W=CO) having
carbonyl link can also be made by reacting heteroaromatic compound
of the Formula VII such as N-methyl pyrrole with the intermediate
amine of Formula VI in the presence of triphosgene or phosgene.
Carbonyl linkers may also be introduced between heteroaromatic
compound of Formula VII such as 3-bromothiophene and amine of
Formula VI with carbon monoxide and the catalyst such as
Pd(PPh.sub.3).sub.2Cl.sub.2. Extended chain pyroles having
dicarbonyl linkers can also be obtained from treatment with oxalyl
chloride and amine of the Formula VI.
[0136] The reduction of the carbonyl linkers (W=CO) using the
standard reducing agents results in the formation of methylene
linkers (W=CH.sub.2),
[0137] Preparation of the compound of Formula I is accomplished as
exemplified below by three methods A, B and C as shown in Scheme
I:
[0138] Method A:
[0139] Amine of Formula VI is reacted with a heteroaromatic
compound of Formula VII having R.sub.12 as a suitable leaving group
defined earlier for Scheme I, R.sub.1, Q.sub.1, O.sub.2, G, J and L
are the same as defined for Formula I.
[0140] The reaction is carried out in a suitable solvent such as
dimethylformamide, dimethylacetamide, ethanol or ethylene glycol at
a suitable temperature in the range of -70.degree. C. to
180.degree. C. to afford compounds of Formula I. The presence of a
suitable base such as triethylamine, diisopropyl amine, potassium
carbonate, sodium bicarbonate is useful in some cases to improve
the yield of the reaction,
[0141] Method B:
[0142] Reductive alkylation of the amine intermediate of Formula
VI, with the corresponding heterocyclic aldehydes of the Formula
VII, such as furaldehyde (Q.sub.1=O, Q.sub.2=C; G, J, L=H; R.sub.12
is CHO) using known reducing agents well known to one of ordinary
skill in the art such as sodium triacetoxyborohydride or sodium
cyanoborohydride gave the products of Formula I wherein W=CH.sub.2,
as shown in the Scheme I.
[0143] Method C:
[0144] Acylation of intermediate amines of Formula VI with
heterocyclic acid of Formula VII, such as 2-furmic acid (Q.sub.1=O;
Q.sub.2=C; G, J, L=H; R.sub.12=COOH) yield compound of Formula I,
wherein W=CO, as shown in the Scheme I wherein U, V, Y, Z, X, W,
Q.sub.1, Q.sub.2, G, J, L and are the are as defined earlier.
[0145] The reduction of the carbonyl linkers using the standard
reducing agents results in the formation of methylene linkers.
[0146] Scheme II
[0147] The compounds prepared by following the methods of Scheme I
represented by Formula VIII (Formula I, when G=R.sub.14) were
further used as starting compounds for further dervatisation as
shown in Scheme II 13
[0148] wherein R.sub.1, U, V, Y, Z, X, W, Q.sub.1, Q.sub.2, J, L
and n are the same as defined earlier. The group R.sub.14 (for
example carbamate) is a subset of G in Formula I represented by
Formula VIII, was transformed by carrying out one to three steps
into final compounds of Formula IX, (Formula I when G=R.sub.15).
The transformed group R.sub.15 (for example amine, acetamide etc.),
is also a subset of G group.
[0149] Scheme IIA
[0150] The following compounds are exemplified in Scheme IIA 14
[0151] in which
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl(5-trfluoroace-
tamido)}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
represented by Formula XI (Formula I, G=NHCOCF.sub.3, Q.sub.1=S,
Q.sub.2=C, G=J=L=H, W=CO, X=N, Y=Z=H, n=1 U=H, V=F,
R.sub.1=--NHCOCH.sub.3) was prepared by treating the Boc derivative
of Formula X with trifluoroacetic acid for extended time.
[0152]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(5-amino)}]piperazinyl-
]phenyl]-2-oxo-5-oxazolidinyl]methyl)acetamide represented by
Formula XII (Formula I G=NH.sub.2, Q.sub.1=S, Q.sub.2=C, G=J=L=H,
W=CO, X=N, Y=Z=H, n=1, U=H, V=F, R.sub.1=--NHCOCH.sub.3) was
prepared by treating the Boc derivative of Formula X with
trifluoroacetic acid followed by neutralization with potassium
carbonate in acetone as shown in Scheme IIA.
[0153] The transformations effected are described in the
experimental section. In the above synthetic methods where specific
acids, bases, solvents, catalysts, oxidising agents, reducing
agents etc. are mentioned, it is to be understood that the other
acids, bases, solvents, catalysts, oxidising agents; reducing
agents etc. may be used. Similarly, the reaction temperature and
duration of the reaction may be adjusted according to the need.
[0154] An illustrative list of particular compounds according to
the invention and capable of being produced by the above mentioned
schemes include:
[0155]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-(2-furyl-carbonylmethyl)]piperazinyl]-
phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
1),
[0156]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-(2-thiophenoyl-methyl}]piperazinyl]ph-
enyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No. 2),
[0157]
(S)-N-([3-[3-Fluoro-4-[N-1-{2-furyl-{5-(4-chloro-2-nitro)-phenyl}me-
thyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 3),
[0158]
(S)-N-[[3-[3-Fluoro-4-[-1-[4-{2-thiophen-(4-bromo-5-nitro)methyl]pi-
perazinyl]phenyl)-2-oxo-5-oxazolidinyl]methyl]-acetamide. (Compound
No. 4),
[0159]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl-(3-methyl-5-nitro)methyl-}]--
piperazinyl]phenyl-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 5),
[0160]
(S)-N-[[3-[3-Fluoro-4-[N-1-[2-thiophene-(4-cyano-5-nitro)methyl}]pi-
perazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide. (Compound
No. 6),
[0161]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-(4-chloro)phenyl)methyl}]--
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 7),
[0162]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{3-furyl(5-nitro)methyl}]piperazinyl]-
phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
8),
[0163]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-(4-bromo)phenyl)methyl}]pi-
perazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 9),
[0164]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl-(5-methyl)methyl}]piperaziny-
l]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
10),
[0165]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-pyrrole-(1-methyl-4-nitro)methyl}]-
piperazinyl]phenyl-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 11),
[0166]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-pyrrole-(1-methyl-5-nitro)methyl}]-
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 12),
[0167]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-pyrrole-(5-nitro)methyl}]piperazin-
yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
13),
[0168]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophen-(4-nitro-)methyl-}]pipera-
zinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
14),
[0169]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl-(5-methoxy)methyl}]piperazin-
yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
15),
[0170]
(S)-N-[[3-[3-Fluoro-4-[N-1[4-[2-furyl{5-O-(2-nitro-4-fluoro-phenylo-
xy)}methyl]]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 16),
[0171]
(S)-N-[[3-[3-Fluoro-4-[N-1[4-{2-furyl(5-chloro)methyl}]piperazinyl]-
phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
17),
[0172]
(S)-N-[[3-[3-Fluoro-4-[N-1[4-{3-furyl(2-nitro)methyl}]piperazinyl]p-
henyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
18),
[0173]
(S)-N-[[3-[3-Fluoro-[N-1-[4-{2-thiophen-(4-dimethylamino-5-nitro)me-
thyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
(Compound No. 19),
[0174]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophene-(4-morpholino-5-nitro)me-
thyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
(Compound No. 20),
[0175]
(S)-N-[[-[3-Fluoro-4-[N-1-[4-{2-furyl-(5-methylsulphonyl-)methyl-}]-
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
(Compound No. 21),
[0176]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4{-2-furyl(5-(4-nitro)-phenyl)-methyl}]-
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 22),
[0177]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-(3-nitro-)phenyl)methyl}]--
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 23),
[0178]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-(2-nitro)-phenyl)-methyl}]-
-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 24),
[0179]
(S)-N-[[3-[3-Fluoro-4[N-1-[4-{2-Furyl-4-bromo-(nitro)methyl}]pipera-
zinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No
25),
[0180]
(S)-N-[[3-[3-Fluoro-4[N-1-[4-{2-Furyl-(4-isopropyl)methyl}]piperazi-
nyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
26),
[0181]
(S)-N-[[3-[3-Fluoro-4[N-1-[4-{2-Furyl-4-isopropyl-(5-nitro)methyl}]-
piperazinyl]-Phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 27),
[0182]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furoyl-(5-methoxy)methyl}]piperazi-
nyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
28),
[0183]
(S)-N-[[3-[3-Fluoro-1-[N-1-[4-{2-thiophenoyl-(5-acetamido)}]piperaz-
inyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
29),
[0184]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{3-pyrazolecarbonyl-(4-nitro)}]pipera-
zinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
30),
[0185]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{3-pyrazolecarbonyl](5-nitro)}]pipera-
zinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
31),
[0186]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(5-tert-butoxycarboxam-
ido)}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 32),
[0187]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(5-trifluoroacetamido)-
}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 33),
[0188]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(5-amino)}]piperazinyl-
]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
34),
[0189]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furoyl{5-(4-chloro-2-nitro-)
-phenyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 35),
[0190]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furoyl-(3-methyl)}]piperazinyl]phe-
nyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No. 36),
[0191]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furoyl-(3-methyl-5-nitro)}]piperaz-
inyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
37),
[0192]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-4-dimethylamino-5-nitr-
o)}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
(Compound No. 38),
[0193]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-Furoyl-(5-nitro)acylic}]piperaziny-
l]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide. (Compound No.
39),
[0194]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(5-nitro)acrylic}]pipe-
razinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide. (Compound
No. 40),
[0195] Iodide
(S)-N-[[3-[3-Fluoro-4[N-1[4-N-methyl-4-{2-furyl(5-nitro)meth-
yl}]piperinyl]-phenyl]-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 41),
[0196]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-nitro)methyl}]piperinyl]ph-
enyl]-2-oxo-5-oxazolidinyl]methyl]-fluoroacetamide. (Compound No.
42),
[0197]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophen(5-nitro)methyl}]piperazin-
yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]fluoroacetamide. (Compound
No. 43),
[0198]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophen(5-nitro)methyl}]piperazin-
yl]phenyl]oxo-5-oxazolidinyl]methyl]difluoroacetamide (Compound No.
44),
[0199]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-nitro)methyl}]piperazinyl]-
phenyl]-2-oxo-5-oxazolidinyl]methyl]-difluoroacetamide. (Compound
No. 45),
[0200]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-nitro)methyl}]piperazinyl]-
phenyl-2-oxo-5-oxazolidinyl]methyl]monochloroacetamide. (Compound
No. 46),
[0201]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-[2-thiophenyl-5-nitro)methyl}](Compou-
nd No. 47),
[0202]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-[2-thiophenyl-4-bromo-(5-nitro)methyl-
}]piperazinyl-phenyl]2-oxo-5-oxazolidinyl]methyl]monochloroacetamide.
(Compound No. 48),
[0203]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-[2-thiophenyl-(5-nitro)methyl}]pipera-
zinyl]-phenyl]2-oxo-5-oxazolidinyl]methyl]-2-chloropropionamide.
(Compound No. 49),
[0204]
(S)-N-[[3-[3-Fluoro-4-[N-1-[2-Furyl-(5-nitro)methyl}]piperazinyl]-p-
henyl]2-oxo-5-oxazolidinyl]methyl]-2-chloropropionamide. (Compound
No 50),
[0205]
(S)-N-[(3-[3-Fluoro-4-[N-1-[2-thiophenyl-4-bromo-(5-nitro)methyl}]p-
iperazinyl]-phenyl]2-oxo-5-oxazolidinyl]methyl]-2-chloropropionamide.
(Compound No. 51),
[0206]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-nitro)methyl}]homopiperazi-
nyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
52),
[0207]
(S)-N-[[3-[3-Fluoro-4-[N-1-{4-(3-furoyl)}homopiperazinyl]phenyl]-2--
oxo-5-oxazolidinyl]methyl]acetamide. (Compound No. 53),
[0208]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(5-nitro)}]homopiperaz-
inyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
54),
[0209]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furoyl-(5-nitro)}]homopiperazinyl]-
phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
55),
[0210]
(S)-N-[[3-[-3-Fluoro-4-[N-1-{2-methyl-4-(t-butoxycarbonyl)}piperazi-
nyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
56),
[0211]
(S)-N-[g3-[3-Fluoro-4-[N-1-[2-methyl-4-{2-thiophen-(5-nitro)methyl}-
]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 57),
[0212]
(S)-N-[[3-[3-Fluoro-4-[N-1-[2-methyl-4-{2-furyl(5-nitro)methyl}]-pi-
perazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 58),
[0213]
(S)-N-[[3-[3-Fluoro-4-[N-1-[2-methyl-4-{2furoyl-(5-nitro)}]-piperaz-
inyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
59),
[0214]
(S)-N-[[3-[3-Fluoro-4-[N-1-[2-methyl-4-{2-thiophenoyl-(5-nitro)}]-p-
iperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 60),
[0215]
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-{2-furoyl-}]-piperazinyl-
]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
61),
[0216]
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-{2-furyl-(5-formyl)methy-
l-}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
(Compound No. 62),
[0217]
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-{2-furyl-(5-nitro)methyl-
-}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 63),
[0218]
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-{2-furyl-(5-hydroxymethy-
l)methyl-}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 64),
[0219]
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-{2-furyl-(aldoxime)methy-
l-}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 65),
[0220]
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-(2-thienylacetyl)]-piper-
azinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
66),
[0221]
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-{2-furyl-(5-cyano)methyl-
-}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl acetamide.
(Compound No. 67),
[0222]
(S)-N-[[3-[3-Fluoro-4-[N-1-[3-methyl-4-{2-thienylacetyl-}]-piperazi-
nyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
68),
[0223]
(S)-N-[[3-[3-Fluoro-4-[N-1-[3-methyl-4-{2-furoyl-(5-nitro)}]-pipera-
zinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
69),
[0224]
(S)-N-[[3-[3-Fluoro-4-[N-1-[3-methyl-4-{2-thienoyl-(5-nitro)}]-pipe-
razinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 70),
[0225]
(S)-N-[[3-[3-Fluoro-4-[N-1-{4-[3-methyl-2-furyl-(5-formyl)methyl-}]-
-piperazinyl]phenyl-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 71),
[0226]
(S)-N-[[3-[3-Fluoro-4-[4-{N-acetyl-N-2-furyl-(5-nitro)methyl-}]amin-
opiperidine-1-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 72),
[0227]
(S)-N-[[3-[3-Fluoro-4-[{3-methyl-4-(N-methyl-N-thiophenacetyl-}-ami-
nopiperidine-1-yl]phenyl]-2-oxo-56-oxazolidinyl]methyl]acetamide.
(Compound No. 73),
[0228]
(S)-N-[[3-[3-Fluoro-4-[[3-methyl-4-{N-methyl-2-furoyl-(5-nitro)}]-a-
minopiperidine-1-y]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 74),
[0229]
(S)-N-[[3-[3-Fluoro-4-[[3-methyl-4-{N-methyl-2-thienoyl-(5-nitro)}]-
-aminopiperidine-1-yl]phenyl-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 75),
[0230]
(S)-N-[[3-[3-Fluoro-4-[{3-methyl-4-(N-methyl-N-2-furoyl)}-aminopipe-
ridine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 76),
[0231]
(S)-N-[[3-[3-Fluoro-4-[[3-methyl-4-{N-methyl-N-2-furyl-(5-nitro)}]a-
minopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 77).
[0232]
(S)-N-[[3-[3-Fluoro-4-[[3-methyl-4-{N-methyl-N-2-thienyl-(5-nitro)}-
]-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 78),
[0233]
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl-2-thienoyl-(5-nitro)}aminopiperid-
ine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 79),
[0234]
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl-2-furoyl-(5-nitro)}aminopiperidin-
e-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
80),
[0235]
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl-N-2-furoyl}-aminopiperidine-1-yl]-
phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
81),
[0236]
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl-N-2-thiophenacetyl}-aminopiperidi-
ne-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide. (Compound
No. 82),
[0237]
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl-N-2-thiophenyl-(5-nitro)methyl}-a-
minopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 83),
[0238]
(S)-N-[[3-[3-Fluoro-4-[4-{N-thienyl-(5-nitro)methyl}-aminopiperidin-
e-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
84),
[0239]
(S)-N-[[3-[3-Fluoro-4-[4-{2-furyl-(5-nitro)methylene]-aminopiperidi-
ne-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 85),
[0240]
(S)-N-[[3-[3-Fluoro-4-[4-{N-2-furyl-(5-nitro)methyl}-aminopiperidin-
e-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
86),
[0241]
(S)-N-[[3-[3-Fluoro-4-[4-{N-methyl-N-2-pyrrole-(5-nitro)methyl}-ami-
nopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 87),
[0242]
(S)-N-[[3-[3-Fluoro-4-[4-{N-methyl-N-2-furyl-(5-acetoxymethyl)methy-
l}-aminopiperidine-1-yl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 88),
[0243]
(S)-N-[[3-[3-Fluoro-4-[4-{N-methyl-N-2-furoyl-(5-nitro)}-aminopiper-
idine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 89),
[0244]
(S)-N-[[3-[3-Fluoro-4-[N-1,3-[N-methyl[N-{2-thiophenyl(5-nitro)meth-
yl}]aminopyrodinyl]phenyl]]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 90),
[0245]
(S)-N-[[3-[3-Fluoro-4-[N-1,{3-{[N-methyl)[N-.ident.2-thiophenoyl(5--
nitro)}]aminopyrrolidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 91),
[0246]
(S)-N-[[3-[3-Fluoro-4[N-1,[3{(N-methyl)[N-2-furoyl(5-nitro)}]aminop-
ryrolidinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 92),
[0247]
(S)-N-[[3-[3-Fluoro-4-[N-1[4-{N-methyl)-N-2-furyl-(5-nitro)-methyl}-
]aminomethylpiperidine-1-yl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide-
. (Compound No. 93),
[0248]
(S)-N-[[3-[3-Fluoro-4[4N-1-(N-methyl){N-2-thiophenyl-(5-nitro)-meth-
yl}]aminomethylpiperidine-1-yl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetam-
ide. (Compound No. 94),
[0249]
(S)-N-[[3-[3-Fluoro-4-N-1-[4-N-methyl[N-2-furoyl(5-nitro)methyl}]am-
inomethylpiperidine-1-yl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 95),
[0250]
(S)-N-[[3-{3-Fluoro-4-(3-oxo-piperidin-1-yl)-phenyl}-2-oxo-5-oxazol-
idinyl]methyl]acetamide. (Compound No. 96),
[0251]
(S)-N-[[3-[3-Fluoro-4-[N-1-3-N-methyl]-N-2-furyl(5-nitro)methyl}]am-
inopiperidinyl]-phenyl]2-oxo-5-oxazolidinyl]methyl]acetamidezolidinyl]meth-
yl]acetamide. (Compound No. 97),
[0252]
(S)-N-[[3-[3-Fluoro-4[N-1-[3-{2-furyl-(5-nitro)-methylene}aminometh-
yl]-3-azabiyclo(3.1.0)hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide-
. (Compound No 98),
[0253]
(S)-N-[[3-[3-Fluoro-4[N-1-[3-{N-2-furyl-(5-nitro)methyl}-aminomethy-
l]-3-azabicyclo[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide-
. (Compound No. 99),
[0254]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-[1-{2-thiophenyl-(5-nitro)}-1-ethyl]p-
iperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
(Compound No. 100),
[0255]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-[1-{2-furyl-(5-nitro)}-1-ethyl]pipera-
zinyl]phenyl]-2 oxo-5-oxazolidinyl]methyl]3-acetamide. (Compound
No. 101),
[0256]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophene-(4-(4-t-butoxycarbonyl)p-
iperazinyl-5-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl-
]-acetamide. (Compound No. 102),
[0257]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophene-(4-N-piperazinyl-5-nitro-
)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
(Compound No. 103),
[0258]
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophene-(4-(4-methyl)piperazinyl-
-5-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamid-
e. (Compound No. 104),
[0259] Pharmacological Testing
[0260] The compounds of the invention display antibacterial
activity when tested by the agar incorporation method. The
following minimum inhibitory concentrations (.mu.g/ml) were
obtained for representative compounds of the invention which are
given below in the following tables.
[0261] Guide to Table Abbreviations:
[0262] 1) S.aureus ATCC 25923--Staphylococus aureus ATCC 25923
[0263] 2) MRSA 15187--Methicillin Resistant Staphylococcus
aureus
[0264] 3) Ent. faecalis ATCC 29212--Enterococcus faecalis ATCC
29212
[0265] 4) Ent. faecium 8A--Enterococcus faecium 6A Van.RTM.,
Cipro.RTM.
[0266] 5) Strep. pne. ATCC 6303--Streptococcus pneumoniae ATCC
6303
[0267] 6) Strep.pyog. ATCC 19615--Streptococcus pyogenes
[0268] 7) S. epidermidis--Staphylococcus epidermidis ATCC 12228
In Vitro (MIC) (.mu.l/ml)
[0269]
1 Compound S.aureus MRSA MRSA MRSA E.faecalis VRE S.pyogenes S.
pneum S. pneum No. 25923 15187 562 33 29212 6A 19615 6303 AB 34 2 8
8 4 4 8 8 2 2 8 4 2 1 1 2 2 2 4 4 4 5 2 2 2 0.254 2 4 0.5 1 1 6 2 2
2 2 4 8 1 1 1 8 8 8 4 4 8 4 4 8 16 11 4 4 4 4 4 4 2 2 4 12 4 4 4 4
4 4 2 8 8 13 4 2 4 4 4 4 1 4 4 14 0.25 0.25 0.25 0.25 4 2 0.5 2 1
15 4 4 4 4 4 4 2 2 2 18 8 4 4 4 4 4 1 1 2 19 4 4 8 8 4 4 2 2 2 25 2
1 2 2 2 2 0.5 2 2 29 8 4 4 4 4 4 0.5 0.5 1 31 >8 >8 >8
>8 4 4 1 1 1 34 8 8 4 8 4 4 1 4 4 35 1 1 1 1 0.5 1 1 1 1 36 2 2
2 2 2 1 1 0.5 1 37 0.5 0.5 0.5 0.5 0.25 0.5 <0.06 0.25 0.125 38
8 4 4 4 4 4 2 2 2 39 0.5 0.5 0.25 0.25 0.5 <0.125 <0.125 0.5
4 40 0.5 0.25 1 0.5 1 0.5 0.5 1 1 42 4 2 2 4 4 4 0.5 1 2 45 2 1 2 2
2 2 0.5 0.5 2 46 2 2 2 2 2 2 0.5 0.5 1 47 4 4 4 4 4 4 1 2 4 48 4 4
4 4 2 2 16 16 16 51 8 8 8 8 8 8 16 16 16 52 2 2 1 2 2 2 1 1 4 54 1
0.5 0.5 0.5 1 0.5 0.25 8 8 55 2 0.5 1 2 0.25 0.25 4 8 8 58 4 4 2 4
4 4 4 8 16 59 2 1 1 1 1 2 8 8 8 60 0.25 <0.125 <0.125
<0.125 1 1 0.5 4 4 61 4 4 4 4 4 4 2 2 2 63 16 8 8 8 8 8 16 16 16
66 8 8 8 8 8 8 16 16 16 68 4 4 4 4 4 4 2 4 4 69 1 1 0.5 1 0.5 0.5 2
8 8 70 <0.25 0.5 <0.25 <0.25 2 1 <0.25 4 4 71 4 2 2 4
>8 >8 >8 >8 >8 74 <0.5 <0.5 <0.5 1 1 1 8 8
8 79 0.5 0.5 0.5 0.5 2 2 0.5 4 4 80 1 1 0.5 1 1 1 2 4 4 83 4 4 4 4
4 4 8 8 8 84 2 2 2 2 1 2 1 2 2 85 4 4 4 4 >8 >8 2 4 4 86 1 1
1 1 0.5 0.5 <0.25 2 2 90 4 2 2 4 4 4 2 4 4 93 2 1 1 1 2 4 1 4 4
91 <0.25 <0.25 <0.25 <0.25 0.5 1 <0.25 1 1 92 1 0.5
<0.25 0.5 <0.25 <0.25 1 1 1 94 4 2 2 2 4 4 4 4 8 95 1 1
0.5 1 <0.25 0.5 -- -- -- 96 16 16 8 16 8 8 4 4 4 99 >8 >8
>8 >8 >8 8 2 4 4 100 0.5 0.5 0.5 0.5 0.5 0.5 2 2 2 101 1 1
1 1 0.125 0.25 0.06 1 2
[0270] The in vitro antibacterial activity of the compounds were
demonstrated by the agar incorporation method (NCCLS M 7 and M
100-S8 documents). Briefly, the compounds were dissolved in DMSO
and doubling dilution of the compounds were incorporated into
Mueller Hinton agar before solidification. Inoculum was prepared by
suspending 4 to 5 colonies into 5 ml of normal saline solution and
adjusting the turbidity to 0.5 Macfarland turbidity standard tables
(1.5.times.10.sup.8 CFU/ml), after appropriate dilutions, 10.sup.4
CFU/spot was transfered into the surface of dried plate and
incubated for 18 hours (24 hours for MRSN studies). The
concentration showing no growth of the inoculated culture was
recorded as the MIC. Appropriate ATCC standard strains were
simultaneously tested and result recorded only when the MIC's
against standard antibiotics were within the acceptable range.
[0271] The compounds of the present invention represented by
general Formula I may be prepared by the method of reaction in
Scheme I. Key intermediate amines of Formula VI for the analogue
preparation were prepared by the synthetic procedures described
below, from commercially available reagents. The compounds of
Formula I were made by either Method A, B, or C.
[0272] Amines already known in the literature are given by
reference and if they have been made by a different procedure they
are described in detail.
[0273] Mainly following seventeen different amines of Formula VI
were identified as different cores, namely
[0274]
(S)-N-[[3-[3-Fluoro-4-(N-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]m-
ethyl]acetamide (Core I);
[0275]
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl-
]methyl]-fluoroacetamide (Core II),
[0276]
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl-
]methyl]difluoroacetamide (Core III),
[0277]
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl-
]methyl]monochloroacetamide (Core IV),
[0278]
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl-
]methyl]-2-chloropropionamide (Core V),
[0279]
(S)-N-[[3-[3-Fluoro-4-(N-1-homopiperazinyl)phenyl]-2-oxo-5-oxazolid-
inyl]-methyl]acetamide (core VI),
[0280]
(S)-N-[[3-[3-Fluoro-4-{N-1-(2-methyl)piperazinyl}phenyl]-2-oxo-5-ox-
azolidinyl]methyl]acetamide (Core VII),
[0281]
(S)-N-[[3-[3-Fluoro-4-[N-1-{2,6-dimethyl-}-piperazinyl]phenyl]-2-ox-
o-5-oxazolidinyl]-methyl]acetamide (Core VIII),
[0282]
(S)-N-[[3-[3-Fluoro-4-[N-1-{3-methyl-}-piperazinyl]phenyl]-2-oxo-5--
oxazolidinyl]methyl]acetamide (Core IX),
[0283]
(S)-N-[[3-[3-Fluoro-4-[{3-methyl-4-(N-methyl-)]aminopiperidine-1-yl-
]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Core X),
[0284]
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl}-aminopiperidine-1-yl]phenyl]-2-o-
xo-5-oxazolidinyl]methyl]acetamide (Core XI),
[0285]
(S)-N-[[3-[3-Fluoro-4-(4-aminopiperidine-1-yl)phenyl]-2-oxo-5-oxazo-
lidinyl]methyl]acetamide (Core XII),
[0286]
(S)-N-[[3-[3-Fluoro-4-[4-{N-methyl-}-aminopiperidine-1-yl]phenyl]-2-
-oxo-5-oxazolidinyl]methyl]acetamide (Core XIII),
[0287]
(S)-N-[[3-[3-Fluoro-4-[N-1,3-[N-methylaminopyrodinyl]phenyl]]-2-oxo-
-5-oxazolidinyl]methyl]acetamide (Core XIV),
[0288]
(S)-N-[[3-[3-Fluoro-4-[N-1(4-N-methyl)-]aminomethylpiperidine-1-yl]-
-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Core XVI),
[0289]
(S)-N-[[3-[3-[3-Fluoro-4-{N-1-(3-N-methyl)-aminopiperidinyl}-phenyl-
]2-oxo-5-oxazolidinyl]methyl]acetamide (Core XVI),
[0290]
(S)-N-[[3-[3-Fluoro-4-{N-1-(N-aminomethyl)-3-azabicyclo[3.1.0]-hexa-
ne}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Core XVII)
[0291] The mentioned cores were used for the synthesis of compounds
of this invention.
[0292] Most of the compounds were characterized using NMR, IR and
were purified by chromatography. Crude products were subjected to
column chromatographic purification using silica gel (100-200 or
60-120 mesh) as stationary phase.
[0293] The examples mentioned below demonstrate the general
synthetic procedure as well as the specific method for the
preparation of the preferred compound. The examples are given to
illustrate the details of the invention and should not be
constrained to limit the scope of the present invention.
EXAMPLE 1
Analogues of
(S)-N-[[3-[3-Fluoro-4-(N-piperazinyl)phenyl]-2-oxo-5-oxazolid-
inyl]methyl]acetamide (Core I)
[0294] The heteroaromatic group with the corresponding appendage
can be introduced on the nitrogen atom of ring C of compounds of
Formula I by one of the methods described below:
[0295] Method A:
[0296] General Procedure.
[0297] Amine of structure of Formula VI is reacted with a
heteroaromatic compounds of Formula VII having corresponding
R.sub.12 appendages such as--CH.sub.2R.sub.13, --COR.sub.13 or
--CH(CH.sub.3)R.sub.13 wherein R.sub.13 is a suitable leaving group
well known to one of ordinary skill in the art such as fluoro,
chloro, bromo, SCH.sub.3, --SO.sub.2CH.sub.3, --SO.sub.2CF.sub.3,
Tos or OC.sub.6H.sub.5 etc.
[0298] The reaction is done in a suitable solvent such as
dimethylformamide, dimethylacetamide, ethanol or ethylene glycol at
a suitable temperature in the range of -78.degree. C. to
180.degree. C. to afford compounds of Formula II. The presence of a
suitable base such as triethylamine, diisopropyl amine, potassium
carbonate, sodium bicarbonate is useful in some cases to improve
the yield of the reaction,
[0299] The following compounds were made using this method:
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-(2-furylcarbonylmethyl)]piper-
inyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
1)
[0300] To the mixture of
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2--
oxo-5-oxazolidinyl]methyl-]-acetamide (prepared by following the
method described in U.S. Pat. No. 5,700,799; 0.57 mmol) and
2-chloroacetylfuran (0.13 g, 0.86 mmol) (prepared by following the
method described in J. Am. Chem. Soc., 57, 909-912, 1935) in
dimethyl formamide (10 mL), potassium carbonate (0.24 g, 1.72 mmol)
was added and stirred for 1 hr. The reaction mixture was then
diluted with water and extracted with ethyl acetate. The combined
organic layers were dried over anhydrous sodium sulphate and
evaporated in vacuo. The crude product was purified by column
chromatography (MeOH/CHCl.sub.3) to get the title compound (0.1
g).
[0301] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.62 (s, 1H), 7.5 (d,
1H), 7.38 (s, 1H), 7.06 (m, 1H), 6.96 (t, 1H), 6.67 (s, 1H), 6.01
(m, 1H), 4.77 (m, 1H), 4.03 (t, 1H), 3.85-3.5 (m, 5H), 3.2 (m, 4H),
2.89 (m, 4H), 2.03 (s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-(2-thiophenoylmethyl)}piperaz-
inyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
2)
[0302] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
2-chloroacetylthiophene using Method A
[0303] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.94 (d, 1H), 7.63 (d,
1H), 7.39 (d, 1H), 7.12 (m, 1H), 7.05 (m 1H), 6.93 (t, 1H), 6.08
(m, 1H), 4.75 (m, 1H), 4.01 (t, 1H), 3.8-3.4 (m, 5H), 3.14 (m, 4H),
2.79 (m, 4H), 2.01 (s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl{5-(4-chloro-2-nitro--
)-phenyl}methyl}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamid-
e. (Compound No. 3)
[0304] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-(4-chloro-2-nitro)phenyl-2-chloromethyl-furan using Method A
[0305] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.68 (m, 2H), 7.55 (d,
1H), 7.44 (d, 1H), 7.02 (m, 1H), 6.92 (t, 1H), 6.62 (d, 1H), 6.38
(d, 1H), 6.07 (t, 1H), 4.77 (m, 1H), 4.01 (t, 1H), 3.9-3.97 (m,
6H), 3.10 (m, 4H), 2.71 (m, 4H), 2.01 (s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophen-(4-bromo-5-nitro)-
methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
(Compound No. 4)
[0306] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
4-bromo-5-nitro-2-chloromethylthiophene (prepared by following the
method described in J. Med. Chem. 2000, 43, 2258-2265) using Method
A.
[0307] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.47 (m, 1H), 7.1-6.6
(m, 3H), 6.05 (m, 1H), 4.77 (m, 1H), 4.1-2.5 (m, 4H), 2.03 (s,
3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl-(3-methyl-5-nitro)me-
thyl}]piperazinyl]phenyl-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 5)
[0308] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
3-methyl-5-nitro-2-chloromethylfuran using Method A.
[0309] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.46 (dd, 1H), 7.18 (s,
1H), 7.04 (dd, 1H), 6.93 (t, 1H), 6.06 (m, 1H), 4.77 (m, 1H),
4.1-3.5 (m, 6H), 3.22 (m, 4H), 2.91 (m, 4H), 2.21 (s, 3H), 2.02 (s,
3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophene-(4-cyano-5-nitro-
)methyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
(Compound No. 6)
[0310] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
4-cyano-5-nitro-2-chloromethylthiophene using Method A.
[0311] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.44 (m, 1H), 7.2-6.7
(m, 3H), 6.04 (m, 1H), 4.76 (m, 1H), 4.1-2.6 (m, 14H), 2.02 (s,
3H).
[0312] M+1=503.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-[1-{2-thiophenyl-(5-nitro)}-1-
-ethyl]]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
(Compound No. 100)
[0313] To a mixture of
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-ox-
o-5-oxazolidinyl]methyl]-acetamide (0.65 g, 1.93 mmol) in
tetrahydrofuran (20 mL), triethylamine (0.8 mL, 5.8 mmol) was added
and the resultant mixture cooled to 0.degree. C.
5-nitro-2-(.alpha.-methylsulfonate)ethylth- iophene (0.885 g, 2.9
mmol) dissolved in tetrahydrofuran (10 mL) was added and the
reaction mixture stirred at room temperature for 24 hrs. It was
then diluted with ethylacetate and washed with saturated sodium
bicarbonate solution, water and brine solution. The organic layer
was dried over anhydrous sodium sulphate and evaporated in vacuo.
The residue was purified by silica gel column chromatography using
dichloromethane-methanol as eluents (Yield=0.612 g).
[0314] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 2.02 (s, 3H), 2.69-2.72
(m, 6H), 3.01-3.06 (q, 2H), 3.12-3.14 (br s, 4H), 3.63-3.77 (m,
3H), 4.00-4.06 (q, 1H), 4.76 (br s, 1H), 6.13 (s, 1H), 6.8-6.81 (d,
1H), 6.93-6.96 (t, 1H), 7.04-7.07 (t, 1H), 7.42-7.46 (dd, 1H),
7.76-7.78 (d, 1H).
Preparation of
5-nitro-2-(.alpha.-Trifluoromethylsulfonate)ethylthiophene
[0315] (a) 5-nitro-2-(.alpha.-hydroxy)ethylthiophene:
5-nitro-2-acetylthiophene (0.85 g, 4.97 mmol; Synthesis, 1992,
849-851) was taken in 25 ml of tetrahydrofuran and cooled to
0.degree. C. Sodium borohydride (0.19 g, 4.97 mmol) was added to
the above, followed by 25 ml of water. The reaction mixture was
allowed to come to room temperature and stirring was further
continued for about 3 hrs The reaction mixture was then diluted
with ethyl acetate and washed with water and brine solution. The
combined organic layers were dried over anhydrous sodium sulphate
and then concentrated in vacuo (Yield=652 mg).
[0316] .sup.1HNMR (CDCl.sub.3) ppm: 1.60-1.66 (d, 3H), 2.41 (br s,
1H), 5.11-5.13 (d, 1H), 6.88-6.9 (d, 1H), 7.79-7.81 (d, 1H).
[0317] (b)
5-nitro-2-(.alpha.-Trifluoromethylsulfonate)ethylthiophene:
5-nitro-2-(.alpha.-hydroxy)ethylthiophene (650 mg, 3.76 mmol) was
taken in 10 ml of dichloromethane and cooled to 0.degree. C.
Triflic anhydride (0.95 ml, 5.64 mmol) was added at 0.degree. C.
and the reaction mixture was allowed to come to room temperature
and stirring was further continued for about 3 hrs. The reaction
mixture further diluted with dichloromethane and washed with sodium
bicarbonate solution, water and brine solution. The combined
organic layers were dried over anhydrous sodium sulphate and then
concentrated in vacuo. The crude product obtained was used for the
next reaction without further purification (Yield=940 mg).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-[1-{2-furyl-(5-nitro)}1-ethyl-
]]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
(Compound No. 101)
[0318] To a mixture of
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-ox-
o-5-oxazolidinyl]methyl]-acetamide (0.25 g, 0.744 mmol) in
tetrahydrofuran (20 mL), triethylamine (0.3 mL, 2.23214 mmol) was
added and the resultant mixture was cooled to 0.degree. C. To it,
5-nitro-2-(.alpha.-Triflurometh- ylsulfonate)ethylfuran (0.43 g,
1049 mmol) dissolved in tetrahydrofuran (10 mL) was added and the
reaction mixture stirred at room temperature for 24 hrs. It was
then diluted with ethyl acetate and washed with saturated sodium
bicarbonate solution, water and bone solution. The organic layer
was dried over sodium sulphate and evaporated in vacuo. The residue
was purified by silica gel column chromatography using
dichloromethane-methanol as eluents (Yield 0.2 g, m.p.:
144-46.degree. C.).
[0319] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 2.015 (s, 3H), 2.68-2.7
(d, 4H), 2.80-2.82 (m, 2H), 2.84-2.89 (t, 2H), 3.07-3.1 (s, 4H),
3.46-3.7 (m, 3H), 4.01 (t, 1H), 4.7 (br s, 1H), 5.29 (s, 1H), 6.05
(br s, 1H), 6.37 (s, 1H), 6.89-6.91 (t, 1H), 7.04-7.07 (d, 1H),
7.4-7.45 (d, 1H).
Preparation of
5-nitro-2-(.alpha.-Trifluoromethylsulfonate)ethylfuran
[0320] (a) 5-nitro-2-acetylfuran: 58 ml of acetic anhydride was
cooled to -30.degree. C. and 23.1 ml of fuming HNO.sub.3 was added
to acetic anhydride dropwise at -30.degree. C. In another flask, 10
g of 2-acetyl furan was dissolved in 21.6 ml of acetic anhydride
and added to the nitration mixture at -30.degree. C. dropwise. The
reaction mixture was stirred at -30 to -0.degree. C. for about 4
hours and then was poured over ice and neurtralized with 40% NaOH
solution (up to pH -6). The reaction mixture was then extracted the
with ethyl acetate (3.times.100 ml). To the ethyl acetate layer 10
ml of pyridine was added and further kept for 1 hour. This mixture
was then washed with saturated citric acid solution, water and
brine solution. The combined organic layers were dried over
anhydrous sodium sulphate and evaporated in vacuo. The residue was
purified by silica gel column chromatography using hexane-ethyl
acetate mixture as eluent (Yield: 625 mg).
[0321] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 2.39 (s, 3H), 726d 7.28
(s, 1H), 7.35-7.38 (s, 1H)
[0322] (b) 5-nitro-24-(.alpha.-hydroxy)ethylfuran:
5-nitro-2-acetylfuran (1 g, 6.45 mmol) was taken in 25 ml of
tetrahydrofuran and cooled to 0.degree. C. Sodium borohydride was
added to the above, followed by 25 ml of water. The reaction
mixture was allowed to come to room temperature and stirring was
further continued for about 3 hrs. The reaction mixture was then
diluted with ethyl acetate and washed with water and brine
solution. The combined organic layers were dried over anhydrous
sodium sulphate and then concentrated in vacuo. The crude product
obtained was used for the next reaction without further
purification (Yield=625 mg).
[0323] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 1.60 (d, 3H), 4.99 (q,
1H), 6.50-6.51 (d, 1H), 7.27-7.28 (d, 1H).
[0324] (c) 5-nitro-2-(.alpha.-trifluoromethylsulfonate)ethylfuran:
To a mixture of 5-nitro-2-(.alpha.-hydroxy)ethylfuran (400 mg,
2.5477 mmoles) and dichloromethane (10 ml), triethylamine (0.7 m,
5.0955 m.moles) was added arid the reaction mixture cooled to
0.degree. C. Triflic anhydride (0.6 ml, 3.8216 m.moles) was added
at 0.degree. C. and then the reaction mixture was allowed to stir
at room temperature for another 6 hours. The reaction mixture was
further diluted with dichloromethane and washed with sodium
bicarbonate solution, water and brine solution dried. The combined
organic layers were dried over sodium sulphate and evaporated in
vacuo. The crude product obtained was used for the next reaction
without further purification (Yield=410 mg).
[0325] Method B
[0326] General Procedure:
[0327] Reductive alkylation of the amine intermediate of Formula
VI, with the corresponding heterocyclic aldehydes of the Formula
VII, using known reducing agents weld known to one of ordinary
skill in the art such as sodium triacetoxyborohydride or sodium
cyanoborohydride gave the products of Formula I wherein
W=CH.sub.2.
[0328] The following compounds were made using this method:
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-(4-chloro)phenyl)m-
ethyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 7)
[0329] To a mixture of
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-ox-
o-5-oxazolidinyl]methyl]-acetamide (1.14 mmol) and
5-(4-chloro)phenyl-2-fu- rfuraldehyde (1.37 mmol) in
tetrahydrofuran, freshly activated molecular sieves were added and
stirred for 45 min. Then, sodium triacetoxyborohydride (0.29 g,
1.37 mmol) was added and stirred for 1-17 hrs. It was then filtered
and filterate evaporated in vacuo. The crude product was purified
by column chromatography (1%, 2% MeOH/CHCl.sub.3) to get the title
compound (0.126 g)
[0330] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.7-7.3 (m, 5H), 7.04
(m, 1H), 6.92 (t, 1H), 6.58 (d, 1H), 6.32 (d, 1H), 5.95 (m, 1H),
4.74 (m, 1H), 4.01 (t, 1H), 3.8-3.5 (m, 5H), 3.11 (m, 4H), 2.74 (m,
4H), 2.01 (s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{3-furyl(5-nitro)methyl}]pipe-
razinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 8)
[0331] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-nitro-3-furfuraldehyde (prepared by following method described in
J. Am. Chem. Soc., 1933, 55, 2903-2909) using Method B.
[0332] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.6-7.3 (m, 3H), 7.07
(m, 1H), 6.92 (t, 1H), 6.06 (m, 1H), 4.76 (m, 1H), 4.41 (m, 1H),
4.0 (m, 2H), 3.8-2.8 (m, 9H), 2.65 (m, 2H), 2.01 (s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-(4-bromo)phenyl)me-
thyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 9)
[0333] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-(4-bromo)phenyl-2-furfuraldehyde using Method B.
[0334] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.6-7.3 (m, 5H), 7.06
(m, 1H), 6.92 (t, 1H), 6.60 (d, 1H), 6.4 (d, 1H), 6.00 (m, 1H),
4.75 (m, 1H), 4.0 (t, 1H), 3.8-3.5 (m, 5H), 3.2-2.6 (m, 8H), 2.0
(s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-[2-furyl(5-methyl)methyl}]pip-
erazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 10)
[0335] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-methyl-2-furfuraldehyde using Method B.
[0336] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.39 (dd, 1H), 7.03 (m,
1H), 6.92 (t, 1H), 6.11 (d, 1H), 6.02 (m, 1H), 5.9 (d, 1H), 4.76
(m, 1H), 4.00 (t, 1H), 3.8-3.4 (m, 5H), 3.11 (m, 4H), 2.67 (m, 4H)
2.28 (s, 3H), 2.01 (s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-pyrrole-(1-methyl-4-nitro)-
methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 11)
[0337] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
1-methyl-4-nitro-pyrrole-2-aldehyde using Method B.
[0338] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.48 (s, 1H), 7.4 (dd,
1H), 7.05 (m, 1H), 6.89 (t, 1H), 6.6 (s, 1H), 6.24 (t, 1H), 4.75
(m, 1H), 4.0 (t, 1H), 3.8-3.5 (m, 6H), 3.45 (s, 2H), 3.02 (m, 4H),
2.59 (m, 4H), 2.01 (s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-[1-[4-{2-pyrrole-(1-methyl-5-nitro-
)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 12)
[0339] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
1-methyl-5-nitro-pyrrole-2-aldehyde using Method B.
[0340] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.42 (dd, 1H), 7.16 (d,
1H), 7.05 (m, 1H), 6.9 (t, 1H), 6.1 (d, 1H), 5.97 (m, 1H), 4.75 (m,
1H), 4.04 (m, 4H), 3.8-3.4 (m, 5H), 3.04 (m, 4H), 2.6 (m, 4H), 2.01
(s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-pyrrole-(5-nitro)methyl}]p-
iperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 13)
[0341] The title compound was prepared by reacting
(S)-N-[[3-[-Fluoro-4-(N-
-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-nitro-pyrrole-2-aldehyde (Bull. Soc. Chim. France, 1963, 484-487)
using Method B.
[0342] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.42 (dd, 1H), 7.06 (m,
2H), 6.91 (t, 1H), 6.37 (m, 1H), 6.16 (d, 1H), 4.77 (m, 1H), 4.01
(t, 1H), 3.76 (t, 1H), 3.65 (m, 5H), 3.08 (m, 4H), 2.68 (m, 4H),
2.02 (s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophen-(4-nitro-)methyl}-
]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 14)
[0343] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
4-nitro-2-thiophenaldehyde using Method B.
[0344] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 8.24 (s, 1H), 7.53 (s,
1H), 7.44 (dd, 1H), 7.06 (d, 1H), 6.93 (t, 1H), 6.14 (t, 1H), 4.76
(m, 1H), 4.2-3.4 (m, 6H), 3.14 (m, 4H), 2.75 (m, 4H), 1.93 (s,
3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl-(5-methoxy)methyl}]p-
iperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 15)
[0345] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-methoxy-2-furaldehyde (Khlm. Geterosikl. Soedin, 1982, (6),
747-50) using Method B.
[0346] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.43 (dd, 1H), 7.03 (m,
1H), 6.91 (t, 1H), 6.1 (m, 2H), 5.06 (d, 1H), 4.8 (m, 1H), 3.97 (t,
1H), 3.8-3.4 (m, 8H), 3.08 (m, 4H), 2.66 (m, 4H), 2.01 (s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-[2-furyl{5-O-(2-nitro-4-fluor-
ophenyloxy)}methyl]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamid-
e. (Compound No. 16)
[0347] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-piperazinylphenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-O-(2-nitro-4-fluoro)-phenyloxy-2-furaldehyde (Chem. Pharm. Bull.
28(9), 2846-2849, 1980) using Method B.
[0348] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.8 (d, 1H, Ar--H), 7.7
(d, 1H, Ar--H), 7.1-7.4 (m, 4H, Ar--H), 6.2 (d, 1H, Ar H), 6.0 (t,
1H, NH) 5.6 (d, 1H, Ar--H), 4.7 (m, 1H, CH), 4.0 (t, 1H, CH),
3.4-3.6 (m, 5H, CH.sub.2), 3.1 (m, 4H, CH.sub.2), 2.6 (m, 4H,
CH.sub.2), 2.0 (s, 3H, CH.sub.3).
[0349] IR: 1748, 1654 cm.sup.-1.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-chloro)methyl}]pip-
erazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 17)
[0350] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-piperazinyl]phenyl]-2-oxo-65-oxazolidinyl]methyl]acetamide and
5-chloro-2-furaldehyde using Method B.
[0351] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.8 (d, 1H, Ar--H), 7.6
(m, 1H, Ar--H), 7.4 (m, 1H, Ar--H), 6.4 (m, 1H, Ar--H), 6.0 (m, 1H,
Ar--H), 4.7 (m, 1H, CH), 4.0 (m, 2H, CH.sub.2), 3.8 (m, 4H,
CH.sub.2), 3.6 (m, 4H, CH.sub.2), 3.4 (m, 4H, CH.sub.2), 2.0 (s,
3H, CH.sub.3).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{3-furyl(2-nitro)methyl}]pipe-
razinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 18)
[0352] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
2-nitro-3-furaldehyde (J. Org. Chem. 1989, 54, 5094-5100) using
Method B.
[0353] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.3-7.5 (m, 2H, Ar--H),
7.1 (d, 1H, Ar--H), 6.9 (t, 1H, Ar--H), 6.8 (d, 1H, Ar--H), 6.0 (t,
1H, NH), 4.7 (m, 1H, CH), 4.0 (t, I1H, CH), 3.9 (s, 2H, CH.sub.2),
3.6-3.8 (m, 3H, CH.sub.2), 3.1 (m, 4H, CH.sub.2), 2.8 (m, 4H,
CH.sub.2), 2.0 (s, 3H, CH.sub.3).
[0354] IR: 1743, 1654 cm.sup.-1.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophen-(4-dimethylamino--
5-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]]acetamide-
. (Compound No. 19)
[0355] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
4-dimethylamino-6-nitro-2-thiophenaldehyde (J. Med. Chem., 2000,
43, 2258-65) using Method B.
[0356] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.44 (dd, 1H), 7.06 (m,
1H), 6.93 (t, 1H), 6.56 (s, 1H), 6.15 (t, 1H), 4.76 (m, 1H), 4.02
(t, 1H), 3.5-3.9 (m, 5H), 3.11 (m, 10H), 2.71 (m, 4H), 2.02 (s,
3H).
[0357] M+1=521; m.p=135.degree. C.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophene-(4-morpholino-5--
nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
(Compound No. 20)
[0358] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
4-morpholino-5-nitro-2-thiophenaldehyde (prepared by following the
method as described in J. Med. Chem., 2000, 43, 2258-65, wherein
instead of dimethylamine hydrochloride, morpholine was used) using
Method B.
[0359] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.44 (m, 1H), 7.06 (m,
1H), 6.93 (t, 1H), 6.60 (s, 1H), 5.09 (t, 1H), 4.75 (m, 1H),
3.5-4.1 (m, 10H), 3.39 (m, 4H), 3.11 (m, 4H), 2.73 (m, 4H), 2.02
(s, 3H).
[0360] M+1=663; m.p.=188-191.degree. C.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl-(5-methylsulphonyl)m-
ethyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 21)
[0361] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-methylsulphonyl-2-furaldehyde (prepared by following the method
as described in Chem. Abs. 71:101697d) using Method B.
[0362] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.42 (m, 1H), 7.13 (d,
1H), 7.05 (m, 1H), 6.94 (t, 1H), 6.42 (d, 1H), 6.09 (m, 1H), 4.76
(m, 1H), 4.01 (t, 1H), 3.3-3.8 (m, 5H), 3.17 (s, 3H), 3.09 (m, 4H),
2.7 (m, 4H), 2.04 (s, 3H).
[0363] M+1=495.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-(4-nitro)phenyl)me-
thyl}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 22)
[0364] The title compound was prepared with
(S)-N-[[3-[3-Fluoro-4-[N-1-pip-
erazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-(4-nitro)phenyl-2-furaldehyde using Method B.
[0365] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 8.23 (d, 2H), 7.79 (d,
2H), 7.42 (dd, 1H), 7.06 (m, 1H), 6.92 (t, 1H), 6.83 (d, 1H), 6.41
(d, 1H), 6.06 (t, 1H), 4.74 (m, 1H), 3.97 (t, 1H), 3.4-3.48 (m,
5H), 3.12 (m, 4H), 2.75 (m, 4H), 2.08 (s, 3H).
[0366] M+1=538.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl-(5-(3-nitro-)phenyl)-
methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 23)
[0367] The title compound was prepared by reacting
(S)-N-a[3-[3-Fluoro-4-[-
N-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-(3-nitro)phenyl-2-furaldehyde using Method B.
[0368] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 8.49 (s, 1H), 8.08 (d,
1H), 7.96 (d, 1H.sub.1), 7.54 (t, 1H), 7.42 (dd, 1H), 7.04 (m, 1H),
6.94 (m, 1H), 6.76 (d, 1H), 6.39 (d, 1H), 6.02 (t, 1H), 4.75 (m,
1H), 4.01 (t, 1H), 3.9-3.4 (m, 1H), 3.12 (m, 4H), 2.74 (m, 1H),
2.01 (s, 3H).
[0369] M+1=538.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl-(5-(2-nitro)-phenyl)-
methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 24)
[0370] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-(2-nitro)phenyl-2-furaldehyde using Method B.
[0371] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.7 (m, 2H), 7.58 (t,
1H), 7.41 (m, 2H), 7.03 (m, 1H), 6.94 (t, 1H), 6.61 (d, 1H), 6.36
(d, 1H), 5.99 (t, 1H), 4.75 (m, 1H), 4.00 (t, 1H), 3.8-3.25 (m,
5H), 3.11 (m, 4H), 2.71 (m, 4H), 2.01 (s, 3H).
[0372] M+1=538.
Preparation of
(S)-N-[[3-[3-Fluoro-4[N-1-[4-{2-Furyl-4-bromo-(5-nitro)meth-
yl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 25)
[0373] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
4-bromo-5-nitro-2-furaldehyde using Method B.
[0374] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.45 (d, 1H, Ar--H), 7.1
(d, 1H, Ar--H), 6.9 (m, 1H, Ar--H), 6.65 (s, 1H, Ar--H), 6.0 (m,
1H, NH), 4.76 (m, 1H, CH), 4.0 (m, 1H, CH), 3.8-3.6 (m, 6H,
CH.sub.2), 3.1 (m, 4H, CH.sub.2), 2.8 (m, 4H, CH.sub.2) 2.0 (s, 3H,
CH.sub.3).
Preparation of
(S)-N-[[3-[3-Fluoro-4[N-1-[4-{2-Furyl-(4-isopropyl)methyl}]-
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 26)
[0375] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro
4-[N-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 4-Isopropyl-2-furaldehyde (J. Org Chem., 1976, 41, 2835-2846)
using Method B.
[0376] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.4 (d, 1H, Ar--H), 7.2
(d, 1H, Ar--H), 7.0 (m, 1H, Ar--H), 6.9 (m, 1H, Ar--H), 6.2 (m, 2H,
Ar--H, and NH), 4.77 (m, H, CH) 4.0 (m, 1H, CH), 3.8-3.6 (m, 6H
CH.sub.2) 2.8 (m, 4H, CH.sub.2). 2.0 (s, 3H, CH.sub.3.
Preparation of
(S)-N-[[3-[3-Fluoro-4[N-1-[4-{2-Furyl-(4-isopropyl-5-nitro)-
methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 27)
[0377] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
4-isopropyl-5-nitro-2-furaldehyde using Method B.
[0378] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.45 (d, 1H, Ar--H), 7.1
(m, 1H, Ar--H), 6.9 (m, 1H, Ar--H), 6.5 (s, 1H, Ar--H), 6.0 (m, 1H,
NH), 4.77 (m, 1H, CH), 4.5 (m, 1H, CH), 4.0 (m, 3H, CH.sub.2) 3.8
(m, 3H, CH.sub.2), 3.2 (m, 4H, CH.sub.2), 2.8 (m, 4H, CH.sub.2),
2.0 (s, 3H, CH.sub.3).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophene-(4-N-(4-t-butoxy-
carbonyl)piperazinyl-5-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidi-
nyl]methyl]-acetamide. (Compound No. 102)
[0379] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
4-N-(4t-butoxycarbonyl)piperazinyl-5-nitro-2-thiophenaldehyde (J.
Med. Chem, 2000, 43, 2268-2265, wherein instead of dimethyl amine
hydrochloride, 1-(t-butoxycarbonyl)-piperazine was used) using
Method B.
[0380] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 1.25-1.33 (s, 9H), 2.023
(s, 3H), 2.724 (s, 4H), 3.105 (s, 4H), 3.36-3.52 (d, 4H), 3.60-54.0
(m, 9H), 4.75 (br s, 1H), 6.0 (br s, 1H), 6.592 (s, 1H), 6.937 (t,
1H), 7.0503 (d, 1H), 7.4 (dd, 1H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophene-44-N-piperazinyl-
]-5-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamid-
e. (Compound No. 103)
[0381] To a mixture of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophene-(4-N-pip-
erazinyl-5-nitro)methyl}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
-acetamide (0.15 g) in dichloromethane (20 mL) at 0.degree. C. was
added trifluoroacetic acid (2 ml). The resultant mixture was
allowed to come to room temperature and was further stirred for 3
hours. It was then diluted with ethyl acetate (20 ml) and sodium
carbonate (300 mg) was added and the mixture stirred for another
for 10 min. The reaction mixture was filtered and the filterate
evaporated in vacuo to give the title compound (Yield: 0.118
g).
[0382] .sup.1HNMR (CDCl.sub.3+DMSO) .delta.ppm: 1.96 (s, 3H), 2.59
(s, 4H), 2.88 (s, 4H), 3.16 (s, 4H), 3.35-3.36 (br s, 4H),
3.55-3.63 (m, 6H), 4.77 (br s, 1H), 6.68 (s, 1H0, 6.97 (s, 1H),
7.07-7.1 (d, 1H), 7.47 (s, 1H), 8.09 (br s, 1H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophene-(4-N-methyl)pipe-
razinyl-5-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-a-
cetamide. (Compound No. 104)
[0383] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyleacetamide and
4-N-(4-methyl)piperazinyl-5-nitro-2-thiophenaldehyde (prepared by
following the method as described in J. Med. Chem., 2000, 43,
2258-2265), wherein 1-methyl-piperazine was used instead of
dimethyl amine hydrochloride, using Method B.
[0384] .sup.1HNMR (CDCl.sub.3) ppm: 2.02 (s, 3H), 2.32 (s, 3H),
2.39 557 (d, 4H), 2.65-52.8 (m, 4H), 3.44-3.47 (s, 4H), 3.60 (m,
3H), 3.9-3.95 (t, 2H), 4.05 (t, 1H), 4.77 (bs, 1H), 6.99 (bs, 1H),
6.59 (s, 1H), 691-6.97 (t, 1H), 7.05-7.07 (d, 1H), 7.43-7.47 (d,
1H).
[0385] Method C:
[0386] General Procedure:
[0387] Preparation of compound of Formula I wherein W is equal to
C.dbd.O corresponding acid of Formula VII can be used and the amine
of Formula VI can be acylated through activated esters in the
presence of condensing agents such as 1,3-dicyclohexylcarbodiimide
(DCC) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC), along with 1-hydroxybenzotriazole (HOBT).
Other methods of acylation can also be employed.
[0388] The following compounds were used using this method:
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furoyl-(5-methoxy)methyl}]-
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 28)
[0389] To a mixture of
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-ox-
o-5-oxazolidinyl]methyl]-acetamide (1.14 mmol) and
5-methoxy-2-furoic acid (0.16 g, 1.14 mmol) and dry
dimethylformamide (10 mL) at 5.degree. C., N-methylmorpholine (0.14
g, 1.37 mmol) and 1-hydroxybenzo-triazole (0.17 g. 1.14 mmol) were
added and stirred for 15 min. Next,
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.22
g, 1.14 mmol) was added to the above. The reaction mixture was
allowed to come to room temperature and stirred for further 18
hours. It was then diluted with water and extracted with ethyl
acetate (3.times.20 ml). The organic layers were dried over
anhydrous sodium sulphate and evaporated in vacuo. The crude
product was purified by column chromatography (3%
MeOH/CH.sub.2Cl.sub.2) to get 0.37 g of product. The product was
then digested with ether and filtered to yield 0.25 g of the title
compound.
[0390] .sup.1HNMR (CDCl.sub.3) .delta.ppm; 7.43 (d, 1H), 7.04 (m,
2H), 6.92 (t, 1H), 6.03 (m, 1H), 5.31 (m, 1H), 4.76 (m, 1H), 3.91
(m, 7H), 3.8-3.51 (m, 3H), 3.09 (m, 4H), 2.02 (s, 3H),
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(5-acetamido)}-
]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 29)
[0391] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-acetamido-2-thiophenoic acid using Method C.
[0392] .sup.1HNMR (CDCl.sub.3+DMSO) .delta.ppm: 10.81 (s, 1H),
7.69-6,60 (m, 6H), 4.75 (m, 1H), 4.01-3.57 (m, 8H), 3.08 (m, 4H),
2.17 (s, 3H), 1.98 (s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{3-pyrazolecarbonyl-(4-nitro)-
}]piperazinyl]phenyl-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 30)
[0393] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
4-nitro-pyrazole-3-carboxylic acid using Method C.
[0394] .sup.1HNMR (CDCl.sub.3+DMSO) .delta.ppm: 8.3-6.6 (m, 6H),
4.74 (m, 1H), 4.1-2.1 (m, 12H+DMSO), 1.99 (s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{3-pyrazolecarbonyl-(5-nitro)-
}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 31)
[0395] The title compound was prepared by reacting
(S)-N-[[-[3-Fluoro-4-(N-
-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-nitro-pyrazole-8-carboxylic acid using Method C.
[0396] .sup.1HNMR (CDCl.sub.3+DMSO) .delta.ppm: 8.04 (t, 1H), 7.5
(dd, 1H), 7.13 (m, 2H), 6.9 (t, 1H), 4.78 (m, 1H), 4.1-3.25 (m,
8H), 3.13 (m, 4H+DMSO), 1.97 (s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(5-tert-butoxy-
carboxamido)}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 32)
[0397] The title compound was prepared with
(S)-N-[[3-[3-Fluoro-4-(N-1-pip-
erazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-tert-butoxycarboxamido-2-thiophenoic acid using Method C.
[0398] .sup.1HNMR (CDCl.sub.3)ppm: 7.5-6.75 (m, 4H), 6.46 (m, 1H),
6.16 (t, 1H), 4.76 (m, 1H), 4.2-3.25 (m, 8H), 3.07 (m, 4H), 2.02
(s, 3H), 1.53 (s, 9H).
Preparation of 5-tert-butoxycarboxamido-2-thiophenoic acid
[0399] (a) Ethyl
5-bis-tert-butoxycarboxamidothiophone-2-carboxylate:
[0400] To a mixture of ethyl 6-amino-thiophene-2-carboxylate (2.06
g, 12 mmol) in dry tetrahydrofuran at 5.degree. C., sodium hydride
(60% w/w, 0.58 g) was added and stirred for 10 minutes. Next,
di-t-butoxypyrocarbonate (3.15 g, 14.5 mmol) was added and the
reaction mixture stirred for 17 hrs. It was then diluted with ethyl
acetate (200 ml) and washed with water. The organic layers were
dried over anydrous sodium sulphate and evaporated in vacuo. The
crude product was purified by column chromatography to yield 2.3 g
of product.
[0401] .sup.1HNMR (DMSO) .delta.ppm: 7.63 (d, 1H), 6.97 (d, 1H),
4.29 (q, 2H), 1.43 (s, 18H), 1.39 (t, 3H);
[0402] M+1=394.
[0403] (b) 5-tert-butoxycarboxamido-2-thiophenoic acid:
[0404] To ethyl
5-bis-tert-butoxycarboxamido-thiophene-2-carboxylate (0.27 g, 1
mmol) in tetrahydrofuran (15 ml), a solution of lithium hydroxide
hydrate (0.1 g, 2.4 mmol) in water (5 mL) was added and the
reaction mixture stirred for 24 hours. Another 0.1 g of lithium
hydroxide hydrate was added and the reaction mixture stirred for
further 3 days. It was then acidified with saturated citric acid
solution to pH=3. The mixture was extracted with ethyl acetate
(3.times.30 ml). The organic layers were washed with water and
brine solution, dried over anhydrous sodium sulphate and evaporated
in vacuo. The product was digested with hexanes and filtered. The
filtered solid was further digested with ether and filtered again.
The filterate was evaporated to get the title compound.
[0405] .sup.1HNMR (DMSO) .delta.ppm: 12.16 (br, 1H), 10.91 (s, 1H),
7.46 (d, 1H), 6.52 (d, 1H), 1.48 (s, 9H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(5-trifluoroac-
etamido)}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 33)
[0406] A mixture of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl(5-tert-bu-
toxycarboxamido)}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamid-
e (Compound No. 32) (0.25 g) and 20% trifluoroacetic acid (10 ml)
in dichloromethane was kept at 4-10.degree. C. for 24 hours. The
reaction mixture was then evaporated in vacuo and cooled to get the
title compound.
[0407] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 12.96 (s, 1H), 8.25 (m,
1H), 7.5-6.8 (m, 5H), 4.7 (m, 1H), 3.03 (m, 4H), 1.83 (m, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl(5-amino)}]pipe-
razinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 34)
[0408] Compound No. 32 was treated with 20% trifluoroacetic acid in
dichloromethane for 3 hrs and evaporated. The residue was then
taken in acetone and treated with potassium carbonate (10 eq.),
stirred for 15 min and filtered, Filterate was evaporated in vacuo.
The residue was digested with ether and decanted to give the title
compound along with potassium salt of trifluoroacetic acid.
[0409] .sup.1HNMR (DMSO) .delta.ppm : 8.26 (m, 1H), 7.47 (m, 1H),
7.3-6.8 (m, 3H), 6.29 (s, 2H), 5.83 (m, 1H), 4.7 (m, 1H), 4.05 (m,
1H), 3.7 (m, 4H), 2.9 (m, 4H), 1.8 (m, 3H).
Preparation of
(S)-N-[[3-3-Fluoro-4-[N-1-[4-{2-furoyl{5-(4-chloro-2-nitro--
)phenyl}}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 35)
[0410] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-(4-chloro-2-nitro)-2-furoic acid using Method C
[0411] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 8-6.5 (m,
9H+CDCl.sub.3), 4.78 (m, 1H), 4.1-3.5 (m, 8H), 3.13 (m, 4H), 2.0
(s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furoyl-(3-methyl)}]piperaz-
inyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
36)
[0412] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl-2-oxo-5-oxazolidinyl]methyl]acetamide and
3-methyl-2-furoic acid using Method C.
[0413] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.49 (dd, 1H), 7.34 (s,
1H), 7.06 (m, 1H), 6.97 (t, 1H), 6.34 (s, 1H), 6.06 (m, 1H), 4.76
(m, 1H), 4.1-3.75 (m, 8H), 3.11 (m, 4H), 2.29 (s, 3H), 2.02 (s,
3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furoyl-(3-methyl-5-nitro)}-
]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 37)
[0414] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
3-methyl-5-nitro-2-furoic acid using Method C.
[0415] .sup.1HNMR (CDCl.sub.3) ppm: 7.55 (dd, 1H), 7.22 (s, 2H),
7.1 (dd, 1H), 6.23 (t, 1H), 4.79 (m, 1H), 4.1-3.2 (m, 12H), 2.36
(s, 3H), 2.03 (s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(4-dimethylami-
no-5-nitro)}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
(Compound No. 38)
[0416] The title compound was prepared reacting
(S)-N-[[3-[3-Fluoro-4-(N-1-
-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
4-dimethylamino-5-nitro-2-thiophenoic acid using Method C
[0417] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.45 (m, 1H), 7.09 (m,
1H), 6.92 (m, 2H), 5.99 (m, 1H), 4.76 (m, 1H), 4.02 (t, 1H),
3.9-3.4 (m, 9H), 3.1 (m, 10H), 2.04 (s, 3H).
[0418] M+1=535.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-Furoyl-(5-nitro)acrylic]pi-
perazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide. (Compound
No. 39)
[0419] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
5-nitro-2-furoylacrlic acid (J. Med. Chem., 16, 72-78, 1973) using
Method C.
[0420] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.6 (d, 1H, Ar--H), 7.4
(m, 1H, Ar--H), 7.2 (m, 3H, Ar--H), 6.8 (d, 1H, Ar--H), 6.0 (m, 1H,
NH), 4.7 (m, 1H, CH), 4.0 (m, 4H, CH.sub.2), 3.8 (m, 4H, CH.sub.2),
3.4 (m, 4H, CH.sub.2), 2.0 (s, 3H, CH.sub.3).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(5-nitro)acryl-
ic}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
(Compound No. 40)
[0421] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
2-thiophenoyl-5-nitroacrylic acid using Method C.
[0422] .sup.1HNMR (CDCl.sub.3) .delta.ppm 7.9 (d, 1H, Ar--H), 7.8
(d, 1H, Ar--H), 7.6 (d, 1H, Ar--H), 7.2 (m, 1H, Ar--H), 7.0 (m, 2H,
Ar--H), 6.9 (d, 1H, Ar--H), 6.0 (m, 1H, NH), 4.78 (m, 1H, CH),
3.8-3.6 (m, 8H, CH.sub.2), 3.2 (m, 4H, CH.sub.2), 2.0 (s, 3H,
CH.sub.3).
Preparation of Iodide
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-N-methyl-4-{2-furyl(5--
nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 41)
[0423] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4[N-
-1-[4-N-methyl-4-{2-furyl(5-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxaz-
olidinyl]methyl]acetamide and Iodomethane.
[0424] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 8.1 (m, 1H, NH), 8.0 (m,
1H, Ar--H), 7.5 (m, 1H, Ar--H), 7.4 (d, 1H, Ar--H), 7.2 (m, 2H,
Ar--H), 5.0 (m, 2H, CH.sub.2), 4.7 (m, 1H, CH.sub.2), 4.1 (t, 1H,
CH), 3.3-3.6 (m, 3H, CH.sub.2), 3.2 (broad, s, CH.sub.3), 3.0 (m,
4H, CH.sub.2) 2.8 (m, 4H, CH.sub.2), 1.9 (s, 3H, CH.sub.3).
EXAMPLE 2
Analogues of
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-oxo-5-oxazol-
idinyl]methyl]-fluoroacetamide (Core II)
Preparation of
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-oxo-5-oxaz-
olidinyl]methyl]fluoroacetamide (Core II)
[0425] (a)
(S)-N-[[3-[3-Fluoro-4-[N-1-(4-tert-butoxycarbonyl)piperazinyl]p-
henyl]-2-oxo-5-oxazolidinyl]methyl]fluoroacetamide:
[0426] To a mixture of
(S)-N-[[3-[3-Fluoro-4-[N-1-(4-tert-butoxycarbonyl)p-
iperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methylamine (1 g, 2.5 mmol;
U.S. Pat. No. 5,700,799) and dry dimethylformamide (20 mL) at
5.degree. C. were added fluoroacetic acid (0.2 g, 2.5 mmol),
N-methylmorpholine (0.33 g, 3 mmol) and 1-hydroxybenzotriazole
(0.38 g, 2.8 mmol), and stirred the reaction mixture for 15 min.
Then, 1-(3-dimethylaminopropyl)-3-ethycarbod- imide hydrochloride
(EDC) (0.48 g, 2.5 mmol) was added to the above, and it was further
stirred for 20 hrs at room temperature. Water was added to the
reaction mixture and it was then extracted with ethyl acetate. The
combined organic layer were dried over anhydrous sodium sulphate
and evaporated in vacuo. The crude product was purified by column
chromatography to yield 0.38 g of product.
[0427] .sup.1HNMR (CDCl.sub.3) ppm: 7.45 (dd, 1H), 7.08 (m, 1H),
6.91 (m, 2H), 4.8 (d and m, 3H), 4.06 (t, 1H), 3.9-3.3 (m, 8H),
2.98 (m, 4H), 1.48 (s, 9H).
[0428] M+1=455.
[0429] (b)
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-oxo-5-oxazolid-
inyl]methyl]-fluoroacetamide
[0430] To a mixture of
(S)-N-[[3-[3-Fluoro-4-(N-1-(4-tert-butoxycarbonyl)p-
iperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]fluoroacetamide
(0.25 g, 0.55 mmol) and dichloromethane (4 mL), trifluoroacetic
acid (1 mL) was added and stirred for 2 hrs. The solvent was
evaporated and to the reaction mixture was added acetone (10
mL),and potassium carbonate (0.5 g). This was further stirred for
15 min. The separated solid was filtered and the filtrate was
evaporated in vacuo. The residue was used as such in subsequent
step without further purification.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-nitro)methyl}]pipe-
razinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-fluoroacetamide.
(Compound No. 42)
[0431] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-fluoroacetamide
and 5-nitro-2-furaldehyde using Method B.
[0432] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.5-6.5 (m, 6H), 5-4.6
(m, 3H), 4.1-3.5 (m, 6H), 3.08 (m, 4H), 2.72 (m, 4H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophen(5-nitro)methyl}]p-
iperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]fluoroacetamide.
(Compound No. 43)
[0433] The title compound was prepared with
(S)-N-[[3-[3-Fluoro-4-(N-1-pip-
erazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-fluoroacetamide and
5-nitro-2-thiophenaldehyde using Method B.
[0434] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.81 (d, 1H), 7.43 (dd,
1H), 7.06 (m, 1H), 6.94 (m, 2H), 6.81 (m, 1H), 4.5-5 (m, 3H),
4.2-3.5 (m, 6H), 3.13 (s, 4H), 2.77 (s, 4H).
EXAMPLE 3
Analogues of
(S)-N-[[3-[-Fluoro-4-(N-1-piperazinyl)phenyl]2-oxo-5-oxazolid-
inyl]methyl]difluoroacetamide (Core III)
[0435] Preparation of
(S)-N-H3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-oxo--
5-oxazolidinyl]methyl]difluoroacetamide (Core III) was similar to
the method used for the synthesis of
(S)-N-[[3-[3-Fluoro-4-[N-1-piperazinyl)p-
henyl]-2-oxo-5-oxazolidinyl]methyl]-fluoroacetamide (Core II)
except using difluoroacetic acid instead of fluoroacetic acid.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophen(5-nitro)methyl}]p-
iperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]difluoroacetamide.
(Compound No. 44)
[0436] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]difluoroacetamide
and 5-nitro-2-thiophenaldehyde using Method B.
[0437] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.8 (d, 1H), 7.42 (dd,
1H), 7.05 (m, 1H), 6.9 (m, 3H), 5.93 (t, 1H), 4.8 (m, 1H), 4.08 (t,
1H), 3.9-3.5 (m, 6H), 3.12 (m, 4H), 2.73 (m, 4H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-nitro)methyl}]pipe-
razinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]difluoroacetamide.
(Compound No. 45)
[0438] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-difluoroacetamide
and 5-nitro-2-furaldehyde using Method B.
[0439] .sup.1HNMR (CDCl.sub.3) ppm. 7.5-6.75 (N, 5H+CHCl.sub.3 in
CDCl.sub.3), 6.51 (m, 1H), 594 (t, 1H), 4.81 (m, 1H), 4.2-3.3 (m,
6H), 3.1 (m, 4H), 2.7 (m, 4H).
EXAMPLE 4
Analogues of
(S)-N-[[3-[3-Fluoro-4-[4-(N-1-piperazinyl)phenyl]-2-oxo-5-oxa-
zolidinyl]-methyl]monochloroacetamide (Core IV)
[0440] Preparation of
(S)-N[[3-[3-Fluoro-4(N-1-piperazinyl)-phenyl]-2-oxo--
5-oxazolidinyl]methyl]monochloroacetamide (Core IV) was similar to
the synthesis of
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)-phenyl]]-2-oxo-5-oxa-
zolidinyl]-methyl]fluoro-acetamide (core II) using chloroacetic
acid instead of fluoroacetic acid.
Preparation of
(S)-N-[[3-[3-Fluoro-4[N-1-[4-{2-furyl(5-nitro)methyl}]piper-
azinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]monochloroacetamide.
(Compound No. 46)
[0441] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4[N-
-1-]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]monochloroacetamide
and 5-nitro-2-furaldehyde using Method B.
[0442] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.6 (d, 2H, Ar--H), 6.8
(7.3 (m, 4H, Ar--H), 6.6 (broad s, 1H, Ar--H), 4.7 (m, 1H, CH), 4.0
(m, 3H, CH.sub.2Cl, CH) 3.8 (m, 5H, CH.sub.2) 3.4 (m, 4H,
CH.sub.2), 2.8 (m, 4H, CH.sub.2), 2.0 (s, 3H, CH.sub.3).
[0443] IR: 1749, 1678 cm.sup.-1.
Preparation of
(S)-N-[[3-[3-Fluoro-4[N-1[4-[2-thiophenyl-(5-nitro)methyl}]-
piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]monochloroacetamide.
(Compound No. 47)
[0444] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-piperazinyl]-phenyl]2-oxo-5-oxazolidinyl]methyl]monochloroacetamide
and 5-nitro-2-thiophene aldehyde using Method B.
[0445] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.8 (d, 1H, Ar--H), 7.4
(d, 1H, Ar--H), 7.0 (m, 2H, Ar--H), 6.9 (m, 2H, Ar--H), 4.79 (m,
1H, CH) 4.0 (m, 3H, CH.sub.2), 3.6-3.8 (m, 5H, CH.sub.2), 3.2 (m,
2H, CH.sub.2), 2.8 (m, 2H, CH.sub.2), 2.0 (s, 3H, CH.sub.3).
Preparation of
(S)-N-[[3-[3-Fluoro-4[N-1[4-[2-thiophenyl-(4-bromo-5-nitro)-
methyl]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]monochloroacetamid-
e. (Compound No. 48)
[0446] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-piperazinyl]-phenyl]2-oxo-5-oxazolidinyl]methyl]monochloroacetamide
and 4-bromo-5-nitro-2-thiophene aldehyde using Method B.
[0447] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.46 (d, 1H, Ar--H), 7.0
(m, 2H, Ar--H), 6.9 (m, 2H, Ar--H and NH), 4.79 (m, 1H, CH), 4.1
(m, 3H, CH.sub.2), 3.8 (m, 5H, CH.sub.2), 3.2 (m, 4H, CH.sub.2),
2.8 (m, 4H, CH.sub.2).
EXAMPLE 5
Analogues of
(S)-N-[[3-[3-Fluoro-4(N-1-piperazinyl)-phenyl]2-oxo-5-oxazoli-
dinyl]methyl]-2-chloropropionamide (Core V)
[0448] Preparation of
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-oxo-
-5-oxazolidinyl]methyl]-2-chloropropionamide (Core V) was similar
to the synthesis of
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)-phenyl]-2-oxo-5-oxaz-
olidinyl]-methyl]-fluoroacetamide (core II) except using
2-chloropropionic acid instead of fluoroacetic acid.
Preparation of
(S)-N-[[3-[3-Fluoro-4[N-1[4-[2-thiophenyl-(5-nitro)methyl]]-
piperazinyl]-phenyl]2-oxo-5-oxazolidinyl]methyl]-2-chloropropionamide.
(Compound No. 49)
[0449] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4(N-
-1-piperazinyl)-phenyl]2-oxo-5-oxazolidinyl]methyl]-2-chloropropionamide
and 5-nitro-2-thiophene aldehyde using Method B.
[0450] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.8 (d, 1H, Ar--H), 7.4
(d, 1H, Ar--H), 7.1 (m, 2H, Ar--H), 6.9 (m, 2H, Ar--H, NH), 4.8 (m,
1H, CH), 4.4 (m, 1H, CH), 4.0 (m, 1H, CH), 3.8-3.6 (m, 5H,
CH.sub.2), 3.2 (m, 2H, CH.sub.2), 2.8 (m, 2H, CH.sub.2), 1.8 (d,
3H, CH.sub.3).
[0451] IR 1752, 1658 cm.sup.-1.
Preparation of
(S)-N-[[3-[3-Fluoro-4[N-1[4-[2-Furyl-(5-nitro)methyl]]piper-
azinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]-2-chloropropionamide.
(Compound No. 50)
[0452] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-piperazinyl]-phenyl]2-oxo-5-oxazolidinyl]methyl]-2-chloropropionamide
and 5-nitro-2-furfural using Method B.
[0453] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.6 (d, 1H, Ar--H), 7.4
(d, 2H, Ar--H, NH), 7.1 (m, 2H, Ar--H), 6.9 (m, 1H, NH), 6.6 (broad
s, 1H, Ar--H), 4.8 (m, 1H, CH), 4.4 (m, 1H, CH), 4.0 (m, 1H, CH),
3.8-3.6 (m, 5H, CH.sub.2), 3.2 (m, 2H, CH.sub.2), 2.8 (m, 2H,
CH.sub.2), 1.8 (d, 3H, CH.sub.3).
[0454] IR 1745, 1663 cm.sup.-1.
Preparation of
(S)-N-[[3-[3-Fluoro-4[N-1[4-[2-thiophenyl-(4-bromo-5-nitro)-
methyl]piperazinyl]-phenyl]2-oxo-5-oxazolidinyl]methyl]-2-chloropropionami-
de. (Compound No. 51)
[0455] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-piperazinyl]-phenyl]2-oxo-5-oxazolidinyl]methyl]-2-chloropropionamide
and 4-bromo-5-nitro-2-thiophene carboxaldehyde using Method B.
[0456] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.46 (d, 1H, Ar--H),
7.05-6.9 (m, 3H, Ar--H), 4.78 (m, 1H, CH), 4.4 (m, 1H, CH), 4.0 (m,
1H, CH), 3.8 (m, 4H, CH.sub.2), 3.6 (m, 2H, CH), 3.11 (m, 4H,
CH.sub.2), 2.75 (m, 4H, CH.sub.2), 1.8 (m, 3H, CH.sub.3).
EXAMPLE 6
Analogues of
(S)-N-[[3-[3-Fluoro-4-(N-1-homopiperazinyl)phenyl]-2-oxo-5-ox-
azolidinyl]methyl]acetamide.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furyl(5-nitro)methyl}]homo-
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 52)
[0457] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-homopiperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 5-nitro-2-chloromethylfuran using Method A.
[0458] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.43 (d, 1H), 7.25-6.75
(m, 2H), 6.58 (s, 1H), 6.15 (m, 1H), 4.81 (m, 1H), 4.25-3.0 (m,
10H), 2.9 (m, 4H), 2.1 (s, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-{4-(3-furoyl)}homopiperazinyl]ph-
enyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No. 53)
[0459] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-homopiperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 3-furoic acid using Method C.
[0460] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.8-7.25 (m,
3H+CHCl.sub.3 in CDCl.sub.3), 7.05 (m, 1H), 6.93 (t, 1H), 6.56 (m,
1H), 6.11 (m, 1H), 4.8 (m, 1H), 4.2-3.1 (m, 12H), 2.07 (m, 5H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-thiophenoyl-(5-nitro)}]hom-
opiperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 54)
[0461] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-homopiperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 5-nitro-2-thiophenoic acid using Method C.
[0462] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.79 (m, 1H), 7.4 (m,
1H), 7.01 (m, 2H), 6.88 (t, 1H), 6.12 (m, 1H), 4.77 (m, 1H),
4.1-3.25 (m, 12H), 2.03 (s, 5H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{2-furoyl-(5-nitro)}]homopipe-
razinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 55)
[0463] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
N-1-homopiperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 5-nitro-2-furoic acid using Method C.
[0464] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.5-6.75 (N, 5H+CHCl3 in
CDCl.sub.3), 5.99 (m, 1H), 4.76 (m, 1H), 4.1-3.25 (m, 12H), 2.2 (m,
2H), 2.03 (s, 3H).
EXAMPLE 7
Analogues of
(S)-N-[[3-[3-Fluoro-4-[N-1-(2-methyl)piperazinyl}phenyl]-2-ox-
o-5-oxazolidinyl]methyl]acetamide
Preparation of
(S)-N-[[3-[3-Fluoro-4-{N-1-(2-methyl)piperazinyl}phenyl]-2--
oxo-5-oxazolidinyl]methyl]acetamide
[0465] (a) Preparation of
2-methyl-4-tert-butoxycarbonylpiperazine.
[0466] To a solution of 2-methylpiperazine (5 g, 0.05 mol) in water
(30 ml),and tetrahydrofuran (60 mL), tert-butoxydicarbonate (4.35
g, 0.02 mol) were added and stirred for 2 days. The reaction
mixture was subjected to vacuum until all the tetrahydrofuran was
removed. The aqueous phase was then extracted with ethyl acetate
(3.times.250 mL). The combined organic layer were washed with
saturated sodium chloride solution, dried over anhydrous sodium
sulphate and evaporated in vacuo to yield 3.2 g of the title
compound.
[0467] .sup.1HNMR (CDCl.sub.3) .delta.ppm 3.92 (br s, 2H), 2.96
(dd, 1H), 2.71 (m, 3H), 2.39 (m, 1H), 1.46 (s, 9H), 1.03 (d,
3H).
[0468] M+1=201.
[0469] (b) Preparation of
1-(2-fluoro-4-nitrophenyl)-2-methyl-4-tert-butox-
ycarbonyl-piperazine
[0470] To a mixture of 2-methyl-4tert-butoxycarbonylpiperazine (A,
1 g, 0.005 mol) and DMSO (20 mL), 3,4-difluornitrobenzene (0.79 g,
0.005 mol), and potassium carbonate (3.45 g, 0.025 mol), were added
and the reaction mixture heated to 120.degree. C. for 8 hrs. It was
then diluted with ethyl acetate and washed with water (3.times.)
and brine solution. Combined organic layer were dried over
anhydrous sodium sulphate and evaporated in vacuo to get a
semisolid . This was further purified by column chromatography
using 6-10% Hexane ethyl acetate as eluent to yield 0.98 g
compound.
[0471] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.93 (m, 2H), 6.89 (t,
1H), 3.98 (m, 2H), 3.8 (d, 1H), 3.4 (m, 2H), 3.15 (m, 2H), 1.49 (s,
9H), 1.1 (d, 3H).
[0472] (c) Preparation of
3-Fluoro-4-{N-1-(2-methyl-4-tert-butoxycarbonyl)-
piperazinyl}-aniline.
[0473] To a solution of
1-(2-fluoro-4-nitrophenyl]2-methyl-4-tert-butoxyca-
rbonylpiperazine (B, 23 g) and methanol (1 00 mL), 10%
palladium/carbon (5 g) was added and shaken in a Parr hydrogenation
apparatus under 40 psi of hydrogen gas for 3 hrs. Then the reaction
mixture was filtered over celite and the filtrate evaporated in
vacuo to yield 17.2 g of the final product.
[0474] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 6.88 (t, 1H), 6.4 (m,
2H), 4-2.75 (m, 9H), 1.46 (s, 9H), 0.85 (d, 3H).
[0475] M+1=311.
[0476] (d) Preparation of
N-Benyloxycarbonyl-3fluoro-4-{N-1-(2-methyl-4-te-
rt-butoxylcarbonyl)-piperazinyl}aniline.
[0477] To a mixture of
3-Fluoro-4-{N-1-(2-methyl-4-tert-butoxycarbonyl)pip-
erazinyl)aniline (C, 17 g, 0.055 mol) and THF (200 ml) at 5.degree.
C., sodium bicarbonate (23 g, 0.274 mol), was added.
Benzylchloroformate (11.22 g, 0.066 mol) was added dropwise to the
above. The reaction mixture was allowed to come to room temperature
and was further stirred for 18 hrs. It was then filtered and
evaporated in vacuo. The residue was dissolved in ethyl acetate and
washed with saturated sodium bicarbonate solution, water and brine
water. The combined organic layer were dried over anhydrous sodium
sulphate and evaporated in vacuo to give 27 g of final product.
[0478] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.33 (m, 6H), 6.97 (m,
2H), 6.78 (m, 1H), 5.17 (s, 2H), 3.8-2.7 (m, 7H), 1.47 (s, 9H),
0.88 (d, 3H).
[0479] M+444, M+2=445.
[0480] (e) Preparation of
(R)-[N-3-[3-Fluoro-4-[N-1-(2-methyl-4-tert-butox-
ycarbonyl)-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methanol
[0481] To a solution of
N-Benzyloxycarbonyl-3-fluoro-4-(N-1-(2-methyl-4-te-
rt-butoxylcarbonyl)-piperazinyl}-aniline (D, 25 g, 0.0056 mol) in
dry tetrahydrofuran (150 mL), at 78.degree. C., butyl lithium (49.2
mL, 15% sol. In hexane, 0.112 mol) was added under positive
pressure of nitrogen. The reaction mixture was stirred at
-78.degree. C. for 1.5 hrs. R-gycidyl butyrate (9.71 g, 0.067 mol)
was added to the above and the reaction mixture was stirred at
-78.degree. C. for 1 hr further the reaction mixture was allowed to
come to room temperature and stirred for further 18 hrs. 100 mL of
saturated ammonium chloride solution was added to the above and the
reaction mixture extracted with ethyl acetate. The combined organic
layers was washed with water and brine solution, dried over
anhydrous sodium sulphate and evaporated in vacuo. The crude
product was purified by column chromatography using 3%
(MeOH/CHCl.sub.3) as eluent to yield 8.8 g of final product.
[0482] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.33 (m, 1H), 7.16 (m,
1H), 6.99 (t, 1H), 4.75 (m, 1H), 4.1-3.75 (m, 1H), 1.49 (s, 9H),
0.92 (d, 3H).
[0483] M+1=410.
[0484] (f) Preparation of
(R)-[N-[3[3-Fluoro-4-[N-1-(2-methyl-4-tert-butox-
ycarbonyl)-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl
methanesulfonate.
[0485] To a solution of
(R)-[N-[3-[3-Fluoro-4-[N-1-(2-methyl-4-tert-butoxy-
carbonyl)piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methanol (E, 6.5
g, 0.016 mol) in dichloromethane (200 mL) 5.degree. C.,
triethylamine (2.4 g, 0.024 mol) and methanesulfonylchloride (2.66
g, 0.024 mol) were added and the reaction mixture was stirred for
17 hr. The reaction mixture was then diluted with dichloromethane
and washed with saturated sodium bicarbonate solution and brine
water. The combined organic layer was dried over ahydrous sodium
sulphate arid evaporated in vacuo to yield 6.5 g of product.
[0486] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.38 (m, 2H), 7.11 (m,
1H), 4.91 (m, 1H), 4.75-2.5 (m, 14H), 1.48 (s, 9H), 0.76 (m,
3H).
[0487] M+1=488.
[0488] (g) Preparation of
(R)-[N-[3-[3-Fluoro-4-[N-1-(2-methyl-4-tert-buto-
xycarbonyl)-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methylazide.
[0489] To a solution of
(R)-[N-[3-[3-Fluoro-4-[N-1-(2-methyl-4-tert-butoxy-
carbonyl)piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl
methanesulfonate compound (F, 6.5 g, 0.013 mol) in
dimethylformamide (200 mL), sodium azide (4.33 g, 0.067 mol) was
added and the reaction mixture heated to 80.degree. C. for 7 hrs.
The solid was filtered off and the filterate evaporated in vacuo.
The residue was dissolved in chloroform and washed with water and
brine solution. The combined organic layer was dried over anhydrous
sodium sulphate and evaporated in vacuo to yield 6 g of the
product.
[0490] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.38 (m, 1H), 7.13 (m,
1H), 7.01 (m, 1H), 4.77 (m, 1H), 4.25-3 (m, 11H), 1.47 (s, 9H),
0.76 (d, 3H).
[0491] (h) Preparation of
(S)-[N-3-[3-Fluoro-4-[N-1-(2-methyl-4-tert-butox-
ycarbonyl)-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methylamine.
[0492] To a solution of
(R)[N-3[3-Fluoro-4-[N-1-(2-methyl-4-tert-butoxycar-
bonyl)piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methylazide (G, 6 g)
in methanol (100 mL), 10% palladium/carbon (0.6 g) was added and
the reaction mixture shaken in a Parr hydrogenation apparatus under
40 psi hydrogen pressure for 9 hrs. The reaction was filtered over
celite and the filterate evaporated in vacuo to yield 5 g of
product. The crude product was used in further next reaction
without further purification.
[0493] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.44 (m, 1H), 7.14 (m,
1H), 7.00 (m, 1H), 4.67 (m, 1H), 4.25-2.75 (m, 11H), 1.48 (s, 9H),
0.79 (d, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-(2-methyl-4-tert-butoxycarbonyl)-
piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 56)
[0494] To a solution of
(S)-[N-[3-[3-Fluoro-4-[N-1-(2-methyl-4-tert-butoxy-
carbonyl)piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methylamine (H, 5
g, 0.0122 mol) in dichloromethane (150 mL), pyrdine (1.94 g. 0.025
mol) and acetic anhydride (2.5 g, 0.025 mol) were added and the
reaction mixture was stirred at room temperature for 17 hrs. The
reaction mixture was diluted with dichloromethane and washed with
saturated sodium bicarbonate solution and brine water. The combined
organic layer was dried over anhydrous sodium sulphate and
evaporated in vacuo. The residue obtained was purified by column
chromatography to yield 3.5 g of final product.
[0495] .sup.1HNMR (CDCl.sub.3) ppm: 7.4 (d, 1H), 7.07 (d, 1H), 6.99
(t, 1H), 6.18 (m, 1H), 4.76 (m, 1H), 4.06 (t, 1H), 3.9-2.6 (m,
10H), 2.01 (s, 3H), 0.89 (d, 3H).
[0496] HPLC: 84% purity.
[0497] (j) Preparation of
(S)-N-[[3-[3-Fluoro-4-{N-1-(2-methyl)piperazinyl-
}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0498] To a solution of
(S)-N-[[3-[3-Fluoro-4-[N-1-(2-methyl-4-tert-butoxy-
carbonyl)piperazinyl]phenyl]-oxo-5-oxazolidinyl]methyl]acetamide
(I, 0.5 g, 1.11 mmol) in dichloromethane (8 mL), trifluoroacetic
acid (2 mL) was added and stirred for 2 hrs. The reaction mixture
was then evaporated and dried in vacuo. The residue was taken in
acetone (10 mL), potassium carbonate (0.78 g, 5.55 mmol) was added
to it and stirred for 15 minutes. Then the reaction mixture was
filtered and the filterate evaporated in vacuo to yield the product
in quantitative yield. This product was used as such in next step
without further characterization.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[2-methyl-4-{2-thiophen-(5-nitro-
)methyl}]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 57)
[0499] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-{-
N-1-(2-methyl]piperazinylphenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 5-nitro-2-thiophene aldehyde using Method B.
[0500] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.8 (s, 1H), 7.39 (dd,
1H), 7.06 (m, 2H), 6.89 (m, 1H), 6.02 (m, 1H), 4.76 (m, 1H), 4.03
(t, 1H), 3.8-2.25 (m, 12H), 2.02 (s, 3H), 0.96 (d, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[2-methyl-4-{2-furyl(5-nitro)met-
hyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 58)
[0501] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-{-
N-1-(2-methyl)piperazinyl}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 5-nitro-2-furaldehyde using Method B.
[0502] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.6-6.8 (m, 4H), 6.5 (s,
1H), 6.06 (m, 1H), 4.76 (m, 1H), 4.02 (t, 1H), 4.8-2.25 (m, 12H),
2.0 (s, 3H), 0.92 (d, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-[N-1-[2-methyl-4-{2-furoyl-(5-nitr-
o)}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 59)
[0503] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-{-
N-1-(2-methyl)piperazinyl}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 5-nitro-2-furoic acid using Method C.
[0504] .sup.1HNMR (CDCl.sub.3) .delta.ppm; 7.7-6.8 (m, 5H+CHCl3),
6.16 (m, 1H), 4.79 (m, 1H), 4.2-2.8 (m, 11H), 2.03 (s, 3H), 1.00
(d, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-[N-1-[2-ethyl-4-{2-thiophenoyl-(5--
nitro)}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 60)
[0505] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-N-
-1-(2-methyl)piperazinyl}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 5-nitro-2-thiophenoic acid using Method C.
[0506] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.84 (d, 1H), 7.47 (dd,
1H), 7.21 (d, 1H), 7.11 (d, 1H), 7.04 (t, 1H), 5.97 (m, 1H), 4.75
(m, 1H), 4.2-2.75 (m, 11H), 2.02 (s, 3H), 0.96 (d, 3H).
EXAMPLE 8
Analogues of
(S)-N-[[3-[3-Fluoro-4-[N-1-{2,6-dimethyl-}-piperazinyl]phenyl-
]-2-oxo-5-oxazolidinyl]methyl]acetamide (Core VIII)
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-{2-furoyl-}]pipe-
razinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 61)
[0507] The title compound was prepared by reacting
(S)-N-[[3-[3-fluoro-4-[-
N-1-[2,6-methyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 2-furoyl chloride using Method A.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-{2furyl-(5-formy-
l)methyl-}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 62)
[0508] The title compound was prepared by reacting
(S)-N-[[3-[3-fluoro-4-[-
N-1-[2,6-dimethyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamid-
e and 5-formyl-2-chloromethylfuran using Method A.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-{2-furyl-(5-nitr-
o)methyl-}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 63)
[0509] The title compound was prepared by reacting
(S)-N-[[3-[3-fluoro-4-[-
N-1-[2,6-dimethyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamid-
e and 5-nitro-furaldehyde using Method B.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-{2-furyl-(5-hydr-
oxymethyl)methyl-}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetam-
ide. (Compound No. 64)
[0510] The title compound was prepared with
(S)-N-[[3-[3-fluoro-4-[N-1-[2,-
6-dimethyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 5-hydroxymethyl furan 2-carboxaldehyde using Method B.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-dimethyl-4-{2-furyl(aldoxim-
e)methyl-}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 65)
[0511] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-[2,6-dimethyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamid-
e and 5-aldoxime-2-chloromethylfuran using Method A.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6-diethyl-4-(2thienylacetyl)]-
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 66)
[0512] The title compound was prepared reacting
(S)-N-[[3-[3-fluoro-4-[N-1-
-[2,6-dimethyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and thiophene-2-acetyl chloride using Method A.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[2,6.dimethyl-4-{2-furyl-(5-cyan-
o)methyl-}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 67)
[0513] The title compound was prepared by reacting
(S)-N-[[3-[3-fluoro-4-[- N-1-cyano-2-chlomomethylfuran using Method
A
EXAMPLE 9
Analogues of
(3)-N-[[3-[3-Fluoro-4-[N-1-{3-methyl-}-piperazinyl]phenyl]-2--
oxo-5-oxazolidinyl]methyl]acetamide (Core IX)
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[3-methyl-4-{2-thiophenacetyl-}]-
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 68)
[0514] The title compound was prepared by reacting
(S)-N-[[3-[3-fluoro-4-[-
N-1-[3-methyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and thiophene-2-acetyl chloride using Method A.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[3-dimethyl-4-{2-furoyl-(5-nitro-
)}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 69)
[0515] The title compound was prepared by reacting
(S)-N-[[3-[3-fluoro-4-[-
N-1-[3-methyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 5-nitro furan 2-carboxaldehyde using Method B.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[3-methyl-4-{2-thienoyl-(5-nitro-
)}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 70)
[0516] The title compound was prepared by reacting
(S)-N-[[-[3-fluoro-4-[N-
-1-[3-methyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 5-nitro-thiophene-2-carboxaldehyde using Method B
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[4-{3-methyl-2-furyl-(5-formyl)m-
ethyl-}]-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 71)
[0517] The title compound was prepared by reacting
(S)-N-[[3-[3-fluoro-4-[-
N-1-[3-methyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 5-formyl-2-chloromethylfuran using Method A Preparation of
(S)-N-[[3-[3-Fluoro-4-[4-{N-acetyl-N-2-Furyl-(5-nitro)methyl}]aminopiperi-
dine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound
No. 72)
[0518] The title compound was prepared by acetylation of
(S)-N-[[3-[3-Fluoro-4-[4-{N-2-furyl-(5-nitro)methyl}-aminopiperidine-1-yl-
]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide with acetic
anhydride and pyridine.
[0519] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.45 (d, 1H), 7.28, 6.96
(m, 3H), 6.52 (bs, 1H), 6.00 (bs, 1H), 4.77 (bs, 1H), 4.57 (s, 2H),
4.07-3.43 (m, 5H), 2.80 (t, 2H), 2.49 (s, 3H), 2.04 (s, 5H),
1.91-1.87 (m, 3H).
EXAMPLE 10
Analogues of
(S)-N-[[3-[3-Fluoro-4-[{3-methyl-4-(N-methyl-}]aminopiperidin-
e-1-yl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide (Core X)
Preparation of
(S)-N-{3-[4-[3-methyl,4-(N-methyl)aminopiperidin-1-yl]-3-fl-
uorophenyl]-2-oxo-5-oxazolidin-5-yl}methyl acetamide.
[0520] N-(2-methylmethacryl)benzylamine: To a solution of
benzylamine (43.6 ml, 406.8 mmol) in methanol (50 ml) was added
methyl methacrylate (64.52 ml, 644.4 mmol). The reaction mixture
was refluxed for 32 hours. Solvent was evaporated under reduced
pressure and the residue was purified through column chromatography
using hexane:ethylacetate (5%) as eluent to give 67 gm of the
desired product as oil.
[0521] .sup.1HNMR (CDCl.sub.3): 7.248 (s, 6H), 3.776 (s, 2H), 3.674
(s, 3H), 2.834 (m, 1H), 2.615&2.686 (m, 2H), 1.676 (d, 3H).
[0522]
N,N'-[2-Carboethoxyethyl,methyl-(2-methyl)propionate]benzylamine: A
mixture of N-(2-methylmethacryl)benzylamine methacrylate derivative
(64 gm, 309.1 mmol) and ethylacrylate (35.6 gm, 352.4 mmol) was
heated at 80.degree. C. for 12 hours. The reaction mixture was
heated for further 5 hours. Ethylacrylate was removed under reduced
pressure and the residue was purified by column chromatography
using hexane:ethylacetate (1%) as eluent (Yield-63 gms)
[0523] .sup.1HNMR (CDCl.sub.3): 7.34-7.22 (bs, 5H), 4.07 (dd, 2H)
3.65 (s, 3H), 3.52 (q, 2H), 2.79-2.66 (m, 4H), 2.45-2.36 (m, 3H),
1.25 (t, 3H).
[0524] N-Benzyl-4-methylpiperidin-4-one: To a hot solution of
benzene (590 ml) was added sodium hydride (20 gms, mmol). After 5
minutes ethyl alcohol (0.3 ml) was added. The reaction mixture was
heated at 80-90.degree. C. for 10 to 15 min then benzlamine
derivative (59 gms) was added dropwise. Reaction mixture was then
refluxed for 5 hrs. at 90.degree. C.
[0525] Reaction mixture was cooled down to room temperature and
water was added slowly to decompose sodium hydride followed by
addition of conc. hydrochloric acid. The aqueous layer was then
separated and refluxed at 100.degree. C. for 6.8 hours. The aqueous
solution was then added to solid potassium carbonate and extracted
with ethyl acetate. Ethyl acetate layer was washed with water and
dried over anhydrous sodium sulphate and solvent was removed to
give 8.5 gms of product.
[0526] .sup.1HNMR (CDCl.sub.3): 7.36-7.26 (bs, 5H), 3.60 (s, 2H),
3.11-3.05 (m, 2H), 2.66-2.58 (m, 2H), 2.45-2.37 (m, 2H), 0.99 (d,
3H).
[0527] N-Benzyl 3-methylpiperidine-4-oxime: To a solution of
N-benzylpiperidin-4-one derivative 18.5 gms) in pyridine (75ml) was
added hydroxlamine hydrochloride (6.93 gms). The reaction mixture
was stirred at room temperature for 1 hour then at 60.degree. C.
for 2 hr. Pyridine was removed under reduced pressure and the
residue was digested with isopropyl alcohol and filtered.
Yield-17.5 gms as white solid.
[0528] m.p. 221.degree. C.
[0529] .sup.1HNMR (CDCl.sub.3): 13.50 (bs, 1H), 7.60-7.47 (m, 5H),
4.15 (s, 2H), 3.54-3.43 (m, 2H), 2.79-2.43 (m, 4H), 1.08 (d,
3H).
[0530] N-Benzyl-3-methyl-4-aminopiperidine: To a solution of the
oxime derivative (35 gm) in methanolic ammonia (250 ml) was added
Raney Ni (3.5 gms). The whole reaction mixture was hydrogenated at
45 psi for 6 hours. The reaction mixture was filtered through
celite bed and washed with methanol. Solvent was removed to give 25
gms of product.
[0531] .sup.1HNMR (CDCl.sub.3): 7.43-7.31 (bs, 5H), 3.74 (bs, 2H),
3.61 (s, 2H), 2.44-2.08 (m, 7H), 0.99 (bs, 3H).
[0532] N-Benzyl-3-methyl-4-(t-butyloxycarbonyl)aminopiperidine: To
a solution of 4-aminopiperidine derivative (8.0 gm, 39.2 mmol) in
dichloromethane (75 ml) was added triethylamine (6.2 ml) followed
by addition of BOC-anhydride (dropwise, 10.7 ml, mmol) at 0.degree.
C. The reaction mixture was then stirred overnight at room
temperature. The reaction mixture was washed with water 3 to 4
times. The organic layer was then separated and dried over
anhydrous sodium sulphate and evaporated in vacuo. The residue was
then dried to give desired product in 10.7 gms as oil.
[0533] .sup.1HNMR (CDCl.sub.3): 7.35 (s, 6H), 2.85 (s, 2H),
2.85-2.82 (m, 2H), 2.40-2.02 (bs, 2H), 2.06-1.90 (m, 4H), 1.44 (s,
9H), 0.90 (d, 3H).
[0534] N-(t-butyloxy)amino-3-methylpiperidine: To a solution of
N-benzylpiperidine derivative (22 gms, 72.3 mmol) in methanol (100
ml) was added dry ammonium formate (6.8 gms, 108.5 mmol) and Pd/C
(10%, 3.3 gm). The reaction mixture was then refluxed for 6 to 8
hr. at 80.degree. C. The reaction mixture was filtered through
celite bed using methanol. Solvent was evaporated under reduced
pressure. Residue was dried to give 15.0 gms of desired
product.
[0535] .sup.1HNMR (CDCl.sub.3): 3.80 (bs, 1H), 3.08 (m, 1H), 2.86
(m, 2H), 2.66-2.61 (m, 2H), 199-1.95 (m, 1H), 1.67-1.45 (m, 2H),
1.45 (s, 9H), 0.91 (d, 3H).
[0536]
1-[4-(N-t-Butyloxycarbonylamino-3-methyl)piperidin1-1-yl]-3-fluoro]-
nitrobenzene: To a solution of aminopiperidine derivative (15 gm,
70 mmol) in acetonitrile (120 ml) was added diisopropylethyl amine
followed by the addition of 1,2-difluoro-4-nitrobenzene. The
reaction mixture was refluxed for 5 to 6 hours. Thereafter,
acetonitrile was evaporated from reaction mixture. The residue was
dissolved in ethyl acetate, washed with water 3 to 4 times. The
combined organic layers were dried over sodium sulphate and
evaporated in vacuo to give 24 gms (97%) of the desired
product.
[0537] .sup.1HNMR (CDCl.sub.3): 7.97-7.87 (m, 2H), 6.92-6.86 (t,
1H), 3.86 (bs, 1H), 3.67 (t, 1H), 3.35 (m, 1H), 3.20-3.16 (m, 1H),
2.94 (t, 1H), 2.63 (t, 1H), 2.03-1.84 (m, 1H), 1.68-1.57 (m, 1H),
1.45 (s, 9H), 1.01 (d, 3H).
[0538] The following compounds were also prepared:
[0539] 1-[[3-methyl
4-(N-t-butyloxycarbonyl,N-methyl)amino]piperidin-1-yl]-
-3-fluoro]-nitrobenzene,
[0540] 1-[[3-methyl
4-(N-t-butyloxycarbonyl,N-methyl)amino]piperidin-1-yl]-
-3-fluoro]-aniline,
[0541] 1-{N-Carbobenzyloxy-[3-methyl
4-(N-t-butyloxycarbonyl,N-methyl)amin-
o]piperidin-1-yl]-3-fluoro]-aniline,
[0542] (S)-(N)-{3-[4-[3-methyl
4-(N-t-butyloxycarbonyl,N-methyl)amino]pipe-
ridin-1-yl]-3-fluorophenyl]-2-oxo-5-oxazolidin-5-yl}methanol,
[0543] (S)-(N)-{3-[4-[3-methyl
4-(N-t-butyloxycarbonyl,N-methyl)amino]pipe-
ridin-1-yl]-3-fluorophenyl]2-oxo-5-oxazolidin-5yl}methyl
methanesulfonate,
[0544] (S)-(N)-{3-[4-[3-methyl
4-(N-t-butyloxycarbonyl,N-methyl)amino]pipe-
ridin-1-yl]-3-fluorophenyl]2-oxo-5-oxazolidin-5-yl}methyl
azide,
[0545] (S)-(N)-{3-[4-[3-methyl
4-(N-t-butyloxycarbonyl,N-methyl)amino]pipe-
ridin-1-yl]-3-fluorophenyl]-2-oxo-5-oxazolidin-5-yl}methyl
amine,
[0546] (S)-(N)-{3-[4-[3-methyl
4-(N-t-butyloxycarbonyl,N-methyl)amino]pipe-
ridin-1-yl]-3-fluorophenyl]-2-oxo-5-oxazolidin-5-yl}methyl
acetamide,
[0547] (S)-(N)-{3-[4-[3-methyl
4-(N-methyl)amino]piperidin-1-yl]-3-fluorop-
henyl]2-oxo-5-oxazolidin-5yl}methyl acetamide,
Preparation of
(S)-N-[[3-[3-Fluoro-4-[{3-methyl-4-(N-methyl-N-thiophenacet-
yl)}-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 73)
[0548] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
{3-methyl-4-(N-methyl-)}-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl-
]methyl]acetamide and thiophene-2-acetyl chloride by method A.
[0549] .sup.1HNMR (CDCl.sub.3) ppm: 7.44-6.91 (m, 6H), 6.05 (bs,
1H), 4.77 (bs, 1H), 4.50-4.25 (m, 1H), 4.06-2.88 (m, 15H), 2.04 (s,
4H), 1.15 (s, 1H), 1.14 (d, 1H), 0.85-0.77 (m, 2H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[[3-methyl-4-{N-methyl-2-furoyl(5-nit-
ro)}]aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 74)
[0550] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
[3-methyl-4-{N-methyl-}]-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl-
]methyl]acetamide and 5-nitro-2-furoyl chloride by using Method
A.
[0551] .sup.1HNMR (CDCl.sub.3) ppm: 7.48-7.06 (m, 4H), 6.22 (bs,
1H), 4.78 (bs, 1H), 3.03-4.02 (9H), 3.00-2.10 (m, 2H), 2.02 (s,
3H), 1.74 (bs, 4H), 0.80 (m, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[[3-methyl-4-{N-methyl-2-thienoyl-(5--
nitro)}]-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamid-
e. (Compound No. 75)
[0552] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
[3-methyl-4-{N-methyl-}]-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl-
]methyl]acetamide and 5-nitro-2-thiophenoyl chloride by using
Method A.
[0553] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.87-6.85 (m, 6H), 4.70
(bs, 1H), 3.94 (t, 1H), 3.74 (t, 1H), 3.55 (s, 2H), 3.50-2.50 (m,
12H), 1.94 (s, 3H), 0.75 (bs, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[{3-methyl-4-(N-methyl-N-2-furoyl)}am-
inopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 76)
[0554] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
[3-methyl-4-{N-methyl-}]-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl-
]methyl]acetamide and 2-furoyl chloride by using Method A.
[0555] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.46 (bs, 1H), 7.38 (m,
1H), 6.93 (d, 2H), 6.49 (bs, 1H), 6.02 (bs, 1H), 4.77 (bs, 1H),
4.52-4.25 (m, 1H), 3.99 (t, 1H), 3.77-3.49 (m, 5H), 3.20&3.16
(s, 3H), 2.99 (d, 1H), 2.82 (t, 1H), 2.65-2.17 (m, 4H), 2.02 (s,
3H), 0.87 (t, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[[3-methyl-4-{N-methyl-N-2-furyl(5-ni-
tro)}]-aminopiperidine-1-yl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 77).
[0556] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
[3-methyl-4-{N-methyl}]-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]acetamide and 5-nitrofuraldehyde by using Method B.
[0557] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.39 (d, 1H), 7.06-6.88
(m, 2H), 6.48 (t, 1H), 6.17 (bs, 1H), 4.76 (bs, 1H), 4.01-3.25 (m,
8H), 2.60 (t, 1H), 2.33 (s, 4H), 2.01 (m, 1H), 1.84 (s, 5H), 1.66
(m, 3H), 0.88 (t, 2H), 0.8 (t, 1H).
Preparation of (S)-N-[[3-[3-Fluoro-4-[[3-methyl
4-{N-methyl-N-2-thienyl-(5-
-nitro)}]-aminopiperidine-1-yl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamid-
e. (Compound No. 78)
[0558] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[- [3-methyl
4-{N-methyl-}]-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl-
]methyl]acetamide and 5-nitro thiophene 2-aldehyde by using the
Method B.
EXAMPLE 11
Analogues of
(S)-N-[[3-[3-Fluoro-4-[4-(N-ethyl)-aminopiperidine-1-yl
phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Core XI)
[0559] The preparation of
(S)-N-[[3-[3-Fluoro-4-[4-(N-ethyl)-aminopiperidi-
ne-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Core XI) is
similar to the synthesis of
(S)-N-[[3-[3-Fluoro-4-4-(N-methyl)-aminopiperidine-1--
yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Core XIII).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl-2-thienoyl-(5-nitro)}amin-
opiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 79)
[0560] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
4-{N-ethyl}-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]aceta-
mide and 5-nitro-2-thienoyl chloride by using Method A.
[0561] .sup.1HNMR (CDCl.sub.3) .delta.ppm; 7.45 (d, 1H), 7.45 (d,
1H), 7.23 (d, 1H), 7.07-6.97 (m, 2H), 4.92 (bs, 1H), 3.98 (t, 1H),
3.98-3.47 (m, 9H), 2.76 (bs, 1H), 2.15 (m, 2H), 2.01 (s, 4H), 1.88
(d, 2H), 1.41 (bs, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl-2furoyl-(5-nitro)}aminopi-
peridine-(1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 80)
[0562] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
4-{N-ethyl-}aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]aceta-
mide and 5-nitro-2-furoyl chloride by using the Method A.
[0563] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 8.01-6.96 (m, 5H), 6.05
(bs, 1H), 5.29 (s, 1H), 4.91 (m, 1H), 4.75 (bs, 1H), 4.27-3.99 (m,
1H), 3.77-3.49 (m, 7H), 2.95-2.32 (m, 3H), 2.02 (bs, 4H), 1.25 (bs,
3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl-N-2-furoyl}-aminopiperidi- ne-77
1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (Compound No.
81)
[0564] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
4-{N-ethyl)aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetam-
ide and 2-furoylchloride using Method A.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl-N-2-thiophenacetyl}aminop-
iperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 82)
[0565] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
4-{N-ethyl}-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]aceta-
mide and thiophene-2-acetyl chloride by using Method A.
[0566] .sup.1HNMR (CDCl.sub.3) ppm: 7.46-6.92 (m, 6H), 6.18 (bs,
1H), 4.76 (bs, 1H), 4.58 (bs, 1H), 4.01-3.35 (m, 10H), 2.75-2.50
(m, 2H), 2.02 (s, 3H), 1.97-1.75 (m, 3H), 1.45 (m, 1H), 1.20 (s,
3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[4-{N-ethyl-N-2-thiophenyl-4-(nitro)m-
ethyl}]aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 33)
[0567] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
4-{N-ethyl-)methyl}-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]meth-
yl]acetamide and 5-nitro thiophene-2-aldehyde by using the Method
B.
[0568] .sup.1HNMR (CDCl.sub.3) ppm: 7.79 (d, 1H), 7.43 (dd, 1H),
7.05 (dd, 1H), 6.92 (t, 1H), 6.83 (d, 1H), 6.05 (t, 1H), 4.75 (bs,
1H), 4.01 (t, 1H), 3.75 (s, 2H), 3.84-3.44 (m, 5H), 2.71-2.60 (m,
5H), 1.75-1.90 (m, 4H), 1.97 (s, 3H), 1.07 (t, 3H).
EXAMPLE 12
Analogues of
(S)-N-[[3-[3-Fluoro-4-(4-aminopiperidine-1-yl)phenyl]-2-oxo-5-
-oxazolidinyl]methyl]acetamide (Core XII)
[0569] The title core XII is prepared by following the procedure as
given in WO 95/25106.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[4-{N-thienyl-(5-nitro)methyl}aminopi-
peridine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 84)
[0570] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(-
4-aminopiperidine-1-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 5-nitro-thiophene-2-aldehyde by using Method B.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[4-{2-furyl-(5-nitro)methylene}aminop-
iperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 85)
[0571] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
4-aminopiperidine-1-yl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 5-nitro-2-furaldehyde.
[0572] .sup.1HNMR (CDCl.sub.3) ppm: 8.2 (s, 1H, CH), 7.8 (t, 1H,
NH), 7.6 (m, 1H, Ar--H), 7.4 (m, 1H, Ar--H), 6.8-7.0 (m, 2H,
Ar--H), 4.7 (m, 1H, CH), 4.0 (t, 1H, CH), 3.4-3.8 (m, 7H,
CH.sub.2), 2.0 (s, 3H, CH.sub.3), 2.0 (m, 2H, CH.sub.2), 1.9 (m,
2H, CH.sub.2).
[0573] IR: 1748, 1656 cm.sup.-1.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[4-{N-2-furyl-(5-nitro)methyl}aminopi-
peridine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 86)
[0574] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-(- 4-aminopiperidine-1-yl)
phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide and
5-nitro-2-furaldehyde by using Method B.
[0575] .sup.1HNMR (CDCl.sub.3) ppm: 7.41-6.45 (m, 4H), 6.48 (bs,
1H), 6.11 (bs, 1H), 4.75 (bs, 1H), 4.04-3.97 (m, 1H), 3.95 (s, 2H),
3.76-3.57 (m, 3H), 3.40-3.37 (m, 2H), 2.75-2.67 (m, 3H), 2.01 (bs,
3H), 1.74 (bs, 3H), 1.66-1.55 (m, 2H).
EXAMPLE 13
Analogues of
(S)-N-[[3-[3-Fluoro-4-[4-{N-methyl-}-aminopiperidine-1-yl]phe-
nyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Core XIII)
Preparation of
(S)-N-[[3-[3-Fluoro-4-[4-{N-methyl-N-2-pyrrole-(5-nitro)met-
hyl}-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 87)
[0576] The title compound was prepared by reacting Core XIII and
5-nitro-pyrrole-2-aldehyde using Method B.
[0577] .sup.1HNMR (CDCl.sub.3) ppm: 7.41 (d, 1H), 7.06 (d, 1H),
6.92 (t, 1H), 6.17-6.12 (m, 2H), 4.77-4.73 (m, 1H), 4.05-3.46 (m,
7H), 2.69-2.62 (t, 4H), 2.33 (s, 3H), 2.09 (s, 2H), 2.04 (s, 3H),
2.02-1.81 (m, 3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[4-{N-methyl-N-2-furyl-(5-acetoxymeth-
yl)methyl}-aminopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetam-
ide. (Compound No. 88)
[0578] The title compound was prepared by reacting Core XIII and
5-acetoxypyrrol-2-aldehyde using Method A.
[0579] .sup.1HNMR (CDCl.sub.3) ppm 7.40 (d, 1H), 7.05 (d, 1H), 6.90
(t, 1H), 6.39 (bs, 1H), 6.09 (bs, H), 5.01 (s, 2H), 4.75 (bs, 1H),
4.02-3.96 (m, 3H), 3.75-3.46 (m, 5H), 2.90 (bs, 1H), 2.71-2.63 (t,
2H), 2.54 (s, 3H), 2.03 (s, 3H), 1.90 (s, 3H), 1.95-1.87 (m,
3H).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[4-{N-methyl-N-2-furoyl-(5-nitro)}ami-
nopiperidine-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 89)
[0580] The title compound was prepared from Core XIII and
5-nitro-2-furoyl chloride using Method A.
[0581] .sup.1HNMR (CDCl.sub.3) ppm: 7.87-6.91 (m, 6H), 4.76 (bs,
1H).
EXAMPLE 14
Analogues of
(S)-N-[[3-[3-Fluoro-4[N-1,3-[N-methylaminopyrolidinyl]phenyl]-
-2-oxo-5-oxazolidinyl]methyl]acetamide (Core XIV)
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1-[3-[N-methyl[N-{2-thiophenyl(5-n-
itro)methyl}]aminopyrodinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 90)
[0582] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4[N-
-1,3-[N-methylaminopyrodinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
(WO 95/25106) and 5-nitro-2-thiophenecarboxaldehyde using Method
B.
[0583] .sup.1HNMR (CDCl.sub.3) ppm: 7.8 (d, 1H, Ar--H), 7.5 (d, 1H,
Ar--H), 7.0 (m, 2H, Ar--H), 6.8 (t, 1H, Ar--H), 6.4 (t-1H, NH), 4.7
(m, 1H, CH), 4.0 (t, 1H, CH), 3.4-3.8 (m, 9H, CH.sub.2), 2.4 (s,
3H, CH.sub.3), 2.3 (m, 1H, CH), 2.1 (m, 1H, CH), 2.0 (s, 3H,
CH.sub.3).
[0584] IR: 1746, 1650 cm.sup.-1.
Preparation of
(S)-N-[[3-[3-Fluoro-4-[N-1[3-{(N-methyl)-N-{2-thiophenoyl(5-
-nitro)}]aminopyrrolidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 91)
[0585] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-aminopyrrolidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and 5-nitro-2-thiophenoic acid using Method C.
[0586] .sup.1HNMR (CDCl.sub.3) ppm: 7.8 (d, 1H, Ar--H), 7.5 (d, 1H,
Ar--H), 7.2 (m, 1H, Ar--H), 7.0 (d, 1H, Ar--H) 6.8 (t, 1H, Ar--H),
6.0 (t, 1H, NH), 4.70 (m, 1H, CH) 4.0 (m, 1H, CH), 3.6-3.8 (m, 8H,
CH), 3.2 (broad s, 3H, CH.sub.3), 2.5 (m, 1H, CH), 2.4 (m, 1H, CH),
2.0 (s, 3H, CH.sub.3).
[0587] IR: 1746, 1622 cm.sup.-1.
Preparation of
(S)-N-[[3-3-Fluoro-4-[N-1[3-[(N-methyl)-N-2-furoyl-(5-nitro-
)}]aminopryrolidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 92)
[0588] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4-[-
N-1-aminopryrolidinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
and 5-nitro-2-furoic acid using Method C.
[0589] .sup.1HNMR (CDCl.sub.3) ppm: 7.5 (d, 1H, Ar--H), 7.4 (m, 1H,
Ar--H), 7.0 (m, 2H, Ar--H), 6.8 (t, 1H, Ar--H), 6.0 (t, 1H, NH),
4.7 (m, 1H, CH), 4.0 (t, 1H, CH), 3.4-3.8 (m, 8H, CH.sub.2), 2.6
(m, 1H, CH), 2.4 (m, 1H, CH), 2.0 (s, 1H, CH.sub.3).
EXAMPLE 15
Analogues of
(S)-N-[[3-[3-Fluoro-4-[N-1-(4-N-methyl)-]aminomethylpiperidin-
e-1-yl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Core XV)
Preparation of
(S)-N-[[(3-[3-Fluoro-4-[N-1[4-{N-methyl-N-2-furyl-(5-nitro)-
methyl}]aminomethyl]piperidine-1-yl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]a-
cetamide. (Compound No. 93)
[0590] The title compound was prepared by reacting
(S)-N-[[(3-[3-Fluoro-4--
[N-1-(4-N-methyl)-]aminomethyl]piperidine-1-yl]-phenyl]-2-oxo-5-oxazolidin-
yl]methyl]acetamide and 5-nitro-2-furaldehyde using Method B.
Synthesis of
(S)-N-[[3-[3-Fluoro-4-[N-1[4-N-methyl)-]aminomethylpiperidine-1-yl]-pheny-
l]-2-oxo-5-oxazolidinyl]methyl]acetamide is similar to the
synthesis of
(S)-N-[[3-[3-Fluoro-4-(N-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methy-
l-]-acetamide (Core I, U.S. Pat. No. 5,700,799) except that instead
of piperazine, 4-(aminomethyl)piperidine was used.
[0591] .sup.1HNMR (CDCl.sub.3) ppm: 7.6 (d, 1H, Ar--H), 7.5 (d, 1H,
Ar--H), 7.0 (d, 1H, Ar--H), 6.9 (t, 1H, Ar--H), 6.6 (d, 1H, Ar--H),
6.0 (t, 1H, OH), 4.7 (m, 1H, CH), 4.0 (t, 1H, CH), 3.3.8 (m, 6H,
CH), 2.8 (t, 2H, CH.sub.2), 2.4 (m, 5N, CH.sub.2, CH.sub.2), 2.0
(s, 3H, CH.sub.3), 1.8 (m, 3H, CH.sub.2), 1.4 (m, 2H,
CH.sub.2).
Preparation of
(S)-N-[[3-[3-Fluoro-4-[4-N-1-(N-methyl){N-2-thiophenyl-(5-n-
itro)-methyl}]aminomethylpiperidine
1-yl]-phenyl]-2-oxo-5-oxazolidinyl]met- hyl]acetamide. (Compound
No. 94)
[0592] The title compound was prepared by reacting
(S)-N-[[3-[3-Fluoro-4[4-
-N-1(N-methyl)]aminomethylpiperidine-1-yl]-phenyl]-2-oxo-5-oxazolidinyl]me-
thyl]acetamide and 5-nitro-2-thiophenecarboxyaldehyde using Method
B.
Preparation of
(s)-N-[[3-[3-Fluoro-4-{N-1[4-N-methyl)-N-2-furoyl(5-Nitro)}-
]aminomethylpiperidine-1-yl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide-
. (Compound No. 95)
[0593] The title compound was prepared by reacting
(s)-N-[[3-[3-Fluoro-4-{-
N-1[4-N-methyl]aminomethyl]piperidine-1-yl]-phenyl]-2-oxo-5-oxazolidinyl]m-
ethyl]acetamide and 5-nitro-2-furoicacid using Method C.
[0594] .sup.1HNMR (CDCl.sub.3) ppm: 7.6 (m, 1H, Ar--H), 7.5 (m, 1H,
Ar--H), 7.4 (m, 1H, Ar--H), 7.1 (d, 1H, Ar--H), 7.0 (t, 1H, Ar--H),
6.0 (t, 1H, NH), 4.7 (m, 1H, CH), 4.0 (t, H, CH), 3.4-3.8 (m, 10H,
CH.sub.2), 3.1 (m, 1H, CH), 2.6 (t, 2H, CH.sub.2), 2.0 (s, 3H,
CH.sub.3), 1.6 (m, 5H, CH.sub.2).
Preparation of
(S)-N-[[3-{3-Fluoro-4-(3-oxo-piperidin-1-yl)-phenyl}-2-oxo--
5-oxazolidinyl]methyl]acetamide. (Compound No. 96)
[0595] .sup.1HNMR (CDCl.sub.3) ppm: 7.6 (d, 1H, Ar--H), 7.0 (d, 1H,
Ar--H), 6.8 (m, 1H, Ar--H), 6.0 (t, 1H, NH), 4.7 (m, 1H, CH), 4.0
(t, 1H, CH), 3.4-3.6 (m, 5H, CH.sub.2), 3.2 (m, 2H, CH.sub.2) 2.0
(s, 3H, CH.sub.3), 1.9 (m, 2H, CH.sub.2), 1.8 (m, 2H,
CH.sub.2).
[0596] IR: 1748, 1660.
EXAMPLE 16
Analogues of
(S)-N-[[3-[3-[3-Fluoro-4-[N-1-[3-N-methyl]-aminopiperidinyl]p-
henyl]2-oxo-5-oxazolidinyl]methyl]acetamide (Core XVI)
Preparation of
(S)-N-[[3-[3-[3-Fluoro-4-[N-1-[3-[N-methyl-N-2-furyl(5-nitr-
o)methyl}]aminopiperidinyl]-phenyl]]2-oxo-5-oxazolidinyl]methyl]acetamide.
(Compound No. 97)
[0597] The title compound was prepared by reacting
(S)-N[3-{3-Fluoro-4-[N--
1-[3-N-methyl]-aminopiperidinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetami-
de (WO 95/25106) and 5-nitro-2-furaldehyde using Method B.
[0598] .sup.1HNMR (CDCl.sub.3) ppm: 7.6 (d, 1H, Ar--H), 7.2 (m, 1H,
Ar--H), 7.0 (m, 1H, Ar--H), 6.9 (m, 1H, Ar--H), 6.6 (d, 1H, Ar--H),
6.0 (t, 1H, NH), 4.7 (m, 1H, CH), 4.0 (t, 1H, CH), 3.6-3.8 (m, 5H,
CH.sub.2) 3.2 (m, 4H, CH.sub.2) 2.5 (s, 3H, CH.sub.3) 2.0 (s, 3H,
CH.sub.3), 1.9 (m, 2H, CH.sub.2) 1.8 (m, 2H, CH.sub.2).
[0599] IR: 1749, 1659 cm.sup.-1.
EXAMPLE 17
Analogues of
(S)-N-[[3-[3-Fluoro-4-{N-1-(N-aminomethyl)-3-azabicyclo-3.1.0-
]-hexane]-phenyl]-2-oxo-5-oxaolidinyl]methyl]acetamide (Core
XVII)
Preparation of
(S)-N-[[3-[3-Fluoro-4-(N-1-(N-tert-butytloxycarbonylaminome-
thyl)-3-azabicyclo[3.1.0]hexane)-phenyl]-2-oxo-5-oxazolidinyl]methyl]aceta-
mide
[0600] (a) Preparation of
N-(tert-butytloxycarbonylaminomethyl)-3-azabicyc-
lo[3.1.0]-hexane.
[0601] The title compound was prepared by following the procedure
as described in U.S. Pat. No. 5,164,402.
[0602] (b) Preparation of
11-[(N-tert-butytloxycarbonylaminomethyl)-3-azab-
icyclo[3.1.0]hexane]-2-fluoro-4-nitrophenyl
[0603] To
N-(tert-butytloxycarbonylaminomethyl)-3-azabicyclo[3.1.0]hexane.
(A, 15 g, 70.75 mmol) in acetonitrile (100 mL),
3,4-difluornitrobenzene (11.24 g, 70.75 mmol), and
ethyldiisopropylamine (10.04 g, 77.8 mmol), were added and the
reaction mixture heated to 60.degree. C. for 6 hrs. The solution
was cooled to ambient temperature and concentrated to yield 22.2 g
of title compound.
[0604] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.9 (m, 2H), 6.89 (t,
1H), 3.4-3.8 (m, 6H), 1.6 (m, 1H), 1.5 (s, 9H), 0.8 (m, 1H), 0.6
(m, 1H).
[0605] c) Preparation of
1-[4-(N-tert-butytloxycarbonylaminomethyl)-3-azab-
icyclo[3.1.0]hexane]-3-fluoro aniline.
[0606] To a solution of
1-[4-(N-tert-butytloxycarbonylaminomethyl)-3-azabi-
cyclo[3.1.0]hexane]-2-fluoro-3-nitrophenyl (B, 26 g) in methanol
(100 mL), 10% palladium/carbon (2.6 g) was added and shaken in a
Parr hydrogenation apparatus under 40 psi of hydrogen gas for 3
hrs. Then, the reaction mixture was filtered over celite and the
filtrate evaporated in vacuo to yield 24 gm of the final
product.
[0607] .sup.1HNMR (CDCl.sub.3) ppm: 6.4-6.8 (m, 3H), 4.6 (brs, 1H,
NH), 3-3.8 (m, 8H), 1.5 (s, 10H), 0.9 (m, 1H), 0.6 (m, 1H).
[0608] d) Preparation of
1-[N-benzyloxycarbonyl-4-(N-tert-butyloxycarbonyl-
-aminomethyl)-3-azabicyclo-[3.1.0]hexane]-3-fluoro aniline.
[0609] To a solution of
1-[4-(N-tert-butytoxycarbonylaminomethyl)-3-azabic-
yclo[3.1.0]hexane]-3-fluoro aniline (C, 24 g, 74.7 mmols).) in
tetrahydrofuran (200 ml) cooled to 5.degree. C., sodium bicarbonate
(25 g, 298 mmol) was added and then benzylchloroformate (36 mL) was
added dropwise. The reaction mixture was stirred for 18 hrs. at
room temperature and then filtered. The filtrate was evaporated in
vacuo. The residue was dissolved in ethyl acetate and washed with
saturated sodium bicarbonate solution, water and brine water. The
organic layer was dried over anhydrous sodium sulphate and
evaporated in vacuo to give 33 g of final product.
[0610] .sup.1HNMR (CDCl.sub.3) .delta.ppm: 7.6 (m, 6H), 7.4 (m,
1H), 6.8 (m, 1H), 6.6 (t, 1H), 5.2 (s, 2H), 4.6 (brs, 1H, NH),
3.6-3.8 (m, 4H), 1.6 (m, 1H), 1.5 (s, 9H) 0.8 (m, 1H), 0.6 (m,
1H).
[0611] e) Preparation of
(R)-N[3-[3-Fluoro-4[N-1-(N-tert-butytloxycarbonyl-
aminomethyl)-3-azabicyclo[3.1.0]hexane]phenyl-2-Oxo-5-Oxazolidinyl]methano-
l
[0612] To a solution of 1-[N
benzyloxycarbonyl-4(N-tert-butytloxycarbonyla-
minomethyl)-3-azabicyclo[3.1.0]hexane]-3-fluoro aniline. (D, 25.5
g,) in dry tetrahydrofuran (150 mL), cooled to -78.degree. C.,
butyl lithium (28.6 mL, 15% sol. in hexane) was added under +ve
pressure of nitrogen. The reaction mixture was stirred at
-78.degree. C. for 1.5 hrs. Then R-glycidyl butyrate (9.51 g) was
added and the reaction mixture was stirred at -78.degree. C. for 1
hr and then at room temperature for 18 hrs. To it, 100 mL of
saturated ammonium chloride solution was added and the reaction
mixture extracted with ethyl acetate. The combined organic layers
were washed with water and brine water, dried over anhydrous sodium
sulphate and evaporated in vacuo. The crude product (.about.28 g)
was purified by column chromatography (3% MeOH/CHCl.sub.3) to yield
9 g of final product.
[0613] .sup.1HNMR (CDCl.sub.3) ppm: 7.4 (m, 1H), 7.0 (m, 1H), 6.6
(t, 1H), 4.7 (m, 1H), 4.0 (m, 1H), 3.8 (m, 3H), 3.4-3.6 (m, 3H),
1.6 (m, 1H), 1.5 (s, 9H), 0.8 (m, 1H), 0.7 (m, 1H).
[0614] (f) Preparation of
(R)-N[3-[3-Fluoro-4[N-1-(N-tert-butytloxycarbony-
lamino-methyl)-3-azabicyclo[3.1.0]hexane]phenyl}-2-Oxo-5-Oxazolidinyl]meth-
ylsulfonate.
[0615] To a solution of
(S)-N[3-[3-Fluoro-4[N-1-(N-tert-butytloxycarbonyla-
minomethyl)-3-azabicyclo[3.1.0]hexane]phenyl-2-Oxo-5-Oxazolidinyl]methanol
(E, 1.5 g, 3.562 mmol) in dichloromethane (20 mL) at 5.degree. C.,
triethylamine 5 (0.6 ml, 4.275 mmol) and methanesulfonylchloride
(0.33 ml, 4.275 mmol) were added and the reaction mixture was
stirred for 17 hr. Then the reaction mixture was diluted with
dichloromethane and washed with saturated sodium bicarbonate
solution and brine. The organic layer was dried over ahydrous
sodium sulphate and evaporated in vacuo to yield 1.45 g of
product.
[0616] .sup.1HNMR (CDCl.sub.3) ppm: 7.3 (m, 1H), 7.0 (m, 1H), 6.6
(t, 1H), 4.8 (m, 1H), 4.5 (m, 2H) 4.0 (t, 1H), 3.9 (t, 1H), 3.6-3.8
(m, 2H), 3.2-3.4 (m, 4H), 3.0 (s, 3H), 1.6 (m, 1H), 1.5 (s, 9H),
0.8 (m, 1H), 0.6 (m, 1H).
[0617] (g) Preparation of
(R)-N[3-[3-Fluoro-4[N-1-(N-tert-butytloxycarbony-
laminomethyl)-3-azabicyclo[3.1.0]hexane]phenyl]2-Oxo-5-Oxazolidinyl]methyl-
azide.
[0618] To a solution of
(S)-N[3-[3-Fluoro-4[N-1-(N-tert-butytloxycarbonyla-
minomethyl)-3-azabicyclo[3.1.0]hexane]phenyl}-2-oxo-5-Oxazolidinyl]methyls-
ulfonate.
[0619] (F, 1.4 gm, 2.8 mmol) in dimethylformamide (20 mL), sodium
aide (0.547 g, 8.41 mmol) was added and the reaction mixture heated
to 80.degree. C. for 7 hrs. The solid was filtered off and the
filterate evaporated in vacuo. The residue was dissolved in
chloroform and washed with water and brine solution. The organic
layer was dried over anhydrous sodium sulphate and evaporated in
vacuo to yield 1 g of the product.
[0620] .sup.1HNMR (CDCl.sub.3) ppm: 7.2 (m, 1H), 7.0 (m, 1H), 6.5
(t, 1H), 4.8 (m, 1H), 4.0 (t, 1H), 3.6-3.8 (m, 5H), 3.4-3.6 (m,
4H), 1.5 (s, 9H), 1.4 (m, 1H), 0.8 (m, 1H), 0.6 (m, 1H).
[0621] (h) Preparation of
(S)-N[3-[3-Fluoro-4[N-1-(N-tert-butytloxycarbony-
lamino-methyl)-3-azabicyclo[3.1.0]hexane]phenyl}-2-Oxo-5-Oxazolidinyl]meth-
ylamine.
[0622] To a solution of
(S)-N[3-[3-Fluoro-4[N-1-(N-tert-butytloxycarbonyla-
minomethyl)-3-azabicyclo[3.1.0]hexane]phenyl]-2-Oxo-5-Oxazolidinyl]methyla-
zide (G, 15 g) in methanol (100 mL), 10% palladium/carbon (1.5 g)
was added and the reaction mixture shaken in a Parr hydrogenation
apparatus under 40 psi hydrogen pressure for 9 hrs. The reaction
was filtered over celite and the filterate evaporated in vacuo to
yield 13 g of product. The product was used as such in next step
without further purification.
[0623] .sup.1HNMR (CDCl.sub.3) ppm: 7.2 (m, 1H), 7.0 (m, 1H), 6.6
(t, 1H), 4.6 (m, 1H), 4.0 (m, 1H), 3.7-3.8 (m, 3H), 3.0-3.6 (m,
6H), 1.5 (s, 10H), 0.8 (m, 1H), 0.6 (m, 1H).
[0624] (i) Preparation of
(S)-N[3-[3-Fluoro-4[N-1-(N-tert-butytloxycarbony-
lamino-methyl)-3-azabicyclo[3.1.0]hexane]phenyl}-2-Oxo-5-Oxazolidinyl]meth-
yl]acetamide.
[0625] To a solution of
(S)-N[3-[3-Fluoro-4[N-1-(N-tert-butytloxycarbonyla-
minomethyl)-3-azabicyclo[3.1.0]hexane]phenyl}-2-Oxo-5-Oxazolidinyl]methyla-
mine (H, 14 g, 33.5 mmol) in dichloromethane (150 mL),
triethylamine (6.98 ml) and acetic anhydride (4.12 ml) were added
and the reaction mixture was stirred at room temperature for 17
hrs. Then the reaction mixture was diluted with dichloromethane and
washed with saturated sodium bicarbonate solution and brine water.
The organic layer was dried over anhydrous sodium sulphate and
evaporated in vacuo. The residue was purified by column
chromatography to yield 10 g of final product.
[0626] .sup.1HNMR (CDCl.sub.3) ppm: 7.4 (m, 1H), 7.0 (m, 1H), 6.0
(m, 1H), 4.7 (m, 1H), 4.68 (br s, 1H), 4.06 (t, 1H), 3.5-3.7 (m,
5H), 3.0-3.5 (m, 4H), 2.0 (s, 3H), 1.5 (s, 10H), 0.8 (m, 1H), 0.67
(m, 1H).
[0627] (j)
(S)-N[3-[3-Fluoro-4[N-1-(aminomethyl)-3-azabicyclo[3.1.0]hexane- ]
of phenyl}-2-oxo-5-oxazolidinyl]methylacetamide.
[0628] To a solution of
(S)-N[3-[3-Fluoro-4-[N-1-(N-tert-butytoxycarbonyla-
minomethyl)-3-azabicyclo[3.1.0]hexane]phenyl)-2-Oxo-5-Oxazolidinyl]methyl]-
acetamide (I, 0.6 g,) in dichloromethane (8 mL), trifluoroacetic
acid (2 mL) was added and stirred for 2 hrs. Then the reaction
mixture was evaporated and dried in vacuo. To the residue in
acetone (10 mL), potassium carbonate (0.78 g, 5.55 mmol) was added
and stirred for 15 minutes. Then the reaction mixture was filtered
and the filterate evaporated in vacuo to yield the product in
quantitative yield. This product was used as such in next step
without further characterization.
Preparation of
(S)-N-[[3-[3-Fluoro-4[N-1-[3-{2-furyl-(5-nitro)methylene}am-
inomethyl]-3-azabiyclo(3.1.0)hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]ac-
etamide. (Compound No. 98)
[0629] The title compound was prepared with
(S)-N[3-[3-Fluoro-4[N-1-(amino- methyl)-3-azabicyclo[3.1.0]hexane]
of phenyl}-2-oxo-5-oxazolidinyl]methyl]- acetamide and
5-nitro-2-furaldehyde.
[0630] .sup.1HNMR (CDCl.sub.3) ppm: 8.2 (s, 1H, CH), 7.4 (m, 2H,
Ar--H), 7.0 (m, 2H, Ar--H), 6.4 (m, 1H, Ar--H), 6.0 (t, 1H, NH),
4.7 (m, 1H, CH), 3.4-3.8 (m, 1H, CH.sub.2), 2.0 (s, 3H, CH.sub.3),
1.6 (m, 1H, CH), 0.8 (m, 1H, CH), 0.6 (m, 1H, CH).
[0631] IR: 1745, 1659 cm.sup.-.
Preparation of
(S)-N-[[3-[3-Fluoro-4[N-1-[3-{N-2-furyl-(5-nitro)methyl}ami-
nomethyl]-3-azabicyclo[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]ac-
etamide. (Compound No. 94)
[0632] The title compound was prepared with
(S)-N-[[3-[3-Fluoro-4[N-1-(ami-
nomethyl)-3-azabicyclo[3.1.0]hexane]phenyl}2-oxo-5-oxazolidinyl]methyl]ace-
tamide and 5-nitro-2-furaldehyde using Method B.
[0633] .sup.1HNMR (CDCl.sub.3) ppm: 7.4 (m, 2H, Ar--H), 7.0 (d, 1H,
Ar--H), 6.7 (t, 1H, Ar--H), 6.5 (d, 1H, Ar--H), 6.0 (t, 1H, NH),
4.7 (m, 1H, CH), 3.4-4.0 (m, 8H, CH.sub.2) 3.2 (m, 2H, CH.sub.2)
3.0 (d, 2H, CH), 2.8 (d, 1H, CH.sub.2) 2.0 (s, 3H, CH.sub.3) 1.4
(m, 1H, CH), 0.8 (m, 1H, CH), 0.6 (m, 1H, CH).
* * * * *