U.S. patent application number 14/336379 was filed with the patent office on 2015-06-18 for substituted oxazolidinones and their use in the field of blood coagulation.
This patent application is currently assigned to Bayer Intellectual Property GmbH. The applicant listed for this patent is BAYER INTELLECTUAL PROPERTY GMBH. Invention is credited to Thomas Lampe, Joseph Pernerstofer, Elisabeth Perzborn, Jens Pohlmann, Susanne Rohrig, Karl-Heinz Schlemmer, Alexander Straub.
Application Number | 20150166568 14/336379 |
Document ID | / |
Family ID | 7934434 |
Filed Date | 2015-06-18 |
United States Patent
Application |
20150166568 |
Kind Code |
A1 |
Straub; Alexander ; et
al. |
June 18, 2015 |
SUBSTITUTED OXAZOLIDINONES AND THEIR USE IN THE FIELD OF BLOOD
COAGULATION
Abstract
The invention relates to the field of blood coagulation. Novel
oxazolidinone derivatives of the general formula (I) ##STR00001##
processes for their preparation and their use as medicinally active
compounds for the prophylaxis and/or treatment of disorders are
described.
Inventors: |
Straub; Alexander;
(Leverkusen, DE) ; Lampe; Thomas; (Leverkusen,
DE) ; Pohlmann; Jens; (Leverkusen, DE) ;
Rohrig; Susanne; (Hilden, DE) ; Perzborn;
Elisabeth; (Wuppertal, DE) ; Schlemmer;
Karl-Heinz; (Leverkusen, DE) ; Pernerstofer;
Joseph; (Leverkusen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BAYER INTELLECTUAL PROPERTY GMBH |
Monheim |
|
DE |
|
|
Assignee: |
Bayer Intellectual Property
GmbH
Monheim
DE
|
Family ID: |
7934434 |
Appl. No.: |
14/336379 |
Filed: |
July 21, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13961264 |
Aug 7, 2013 |
8822458 |
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14336379 |
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13360107 |
Jan 27, 2012 |
8530505 |
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13961264 |
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12494879 |
Jun 30, 2009 |
8129378 |
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13360107 |
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11932082 |
Oct 31, 2007 |
7576111 |
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12494879 |
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11460529 |
Jul 27, 2006 |
7592339 |
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11932082 |
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10181051 |
Jun 24, 2002 |
7157456 |
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PCT/EP00/12492 |
Dec 11, 2000 |
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11460529 |
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Current U.S.
Class: |
514/210.02 ;
435/184; 514/210.2; 514/227.8; 514/230.5; 514/236.8; 514/253.1;
514/254.02; 514/301; 514/333; 514/367; 544/105; 544/137; 544/364;
544/369; 544/58.4; 546/114; 546/256; 548/171; 548/229 |
Current CPC
Class: |
C07D 413/14 20130101;
C07D 417/14 20130101; A61P 9/10 20180101; A61P 43/00 20180101; A61P
7/00 20180101; A61P 35/00 20180101; C07D 409/12 20130101; A61K
31/5377 20130101; A61P 9/00 20180101; C07D 495/04 20130101; A61P
19/02 20180101; C07D 413/12 20130101; C07D 333/38 20130101; C07D
498/04 20130101; C07D 413/10 20130101; A61P 7/02 20180101; A61P
7/04 20180101; A61P 25/28 20180101 |
International
Class: |
C07D 498/04 20060101
C07D498/04; C07D 413/14 20060101 C07D413/14; C07D 417/14 20060101
C07D417/14; C07D 413/12 20060101 C07D413/12; C07D 495/04 20060101
C07D495/04 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 24, 1999 |
DE |
DE 199 62 924.2 |
Claims
1. Compounds of the general formula (I) ##STR00174## in which:
R.sup.1 represents optionally benzo-fused thiophene (thienyl) which
may optionally be mono- or polysubstituted; R.sup.2 represents any
organic radical; R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are identical or different and each represents hydrogen or
represents (C.sub.1-C.sub.6)-alkyl and their pharmaceutically
acceptable salts, hydrates and prodrugs, except for compounds of
the general formula (I) in which the radical R.sup.1 is an
unsubstituted 2-thiophene radical and the radical R.sup.2 is
simultaneously a mono- or polysubstituted phenyl radical and the
radicals R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8
are each simultaneously hydrogen.
2. Compounds of the general formula (I) according to claim 1,
characterized in that R.sup.1 represents optionally benzo-fused
thiophene (thienyl) which may optionally be mono- or
polysubstituted by a radical from the group consisting of halogen;
cyano; nitro; amino; aminomethyl; (C.sub.1-C.sub.8)-alkyl which for
its part may optionally be mono- or polysubstituted by halogen;
(C.sub.3-C.sub.7)-cycloalkyl; (C.sub.1-C.sub.8)-alkoxy;
imidazolinyl; --C(.dbd.NH)NH.sub.2; carbamoyl; and mono- and
di-(C.sub.1-C.sub.4)-alkyl-aminocarbonyl, R.sup.2 represents one of
the groups below: A-, A-M-, D-M-A-, B-M-A-, B--, B-M-, B-M-B--,
D-M-B--, where: the radical "A" represents (C.sub.6-C.sub.14)-aryl,
preferably (C.sub.6-C.sub.10)-aryl, in particular phenyl or
naphthyl, very particularly preferably phenyl; the radical "B"
represents a 5- or 6-membered aromatic heterocycle which contains
up to 3 heteroatoms and/or hetero chain members, in particular up
to 2 heteroatoms and/or hetero chain members, from the group
consisting of S, N, NO (N-oxide) and O; the radical "D" represents
a saturated or partially unsaturated, mono- or bicyclic, optionally
benzo-fused 4- to 9-membered heterocycle which contains up to three
heteroatoms and/or hetero chain members from the group consisting
of S, SO, SO.sub.2, N, NO (N-oxide) and O; the radical "M"
represents --NH--, --CH.sub.2--, --CH.sub.2CH.sub.2--, --O--,
--NH--CH.sub.2--, --CH.sub.2--NH--, --OCH.sub.2--, --CH.sub.2O--,
--CONH--, --NHCO--, --COO--, --OOC--, --S--, --SO.sub.2-- or
represents a covalent bond; where the groups "A", "B" and "D"
defined above may each optionally be mono- or polysubstituted by a
radical from the group consisting of halogen; trifluoromethyl; oxo;
cyano; nitro; carbamoyl; pyridyl; (C.sub.1-C.sub.6)-alkanoyl;
(C.sub.3-C.sub.7)-cycloalkanoyl; (C.sub.6-C.sub.14)-arylcarbonyl;
(C.sub.5-C.sub.10)-heteroarylcarbonyl;
(C.sub.1-C.sub.6)-alkanoyloxymethyloxy;
(C.sub.1-C.sub.4)-hydroxy-alkylcarbonyl; --COOR.sup.27;
--SO.sub.2R.sup.27; --C(NR.sup.27R.sup.28).dbd.NR.sup.29;
--CONR.sup.28R.sup.29; --SO.sub.2NR.sup.28R.sup.29; --OR.sup.30;
--NR.sup.30R.sup.31, (C.sub.1-C.sub.6)-alkyl and
(C.sub.3-C.sub.7)-cycloalkyl, where (C.sub.1-C.sub.6)-alkyl and
(C.sub.3-C.sub.7)-cycloalkyl for their part may optionally be
substituted by a radical from the group consisting of cyano;
--OR.sup.27; --NR.sup.28R.sup.29; --CO(NH).sub.v(NR.sup.27R.sup.28)
and --C(NR.sup.27R.sup.28).dbd.NR.sup.29, where: v is either 0 or 1
and R.sup.27, R.sup.28 and R.sup.29 are identical or different and
independently of one another each represents hydrogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.4)-alkanoyl, carbamoyl, trifluoromethyl, phenyl or
pyridyl, and/or R.sup.27 and R.sup.28 or R.sup.27 and R.sup.29
together with the nitrogen atom to which they are attached form a
saturated or partially unsaturated 5- to 7-membered heterocycle
having up to three, preferably up to two, identical or different
heteroatoms from the group consisting of N, O and S, and R.sup.30
and R.sup.31 are identical or different and independently of one
another each represents hydrogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.4)-alkylsulphonyl,
(C.sub.1-C.sub.4)-hydroxyalkyl, (C.sub.1-C.sub.4)-aminoalkyl,
di-(C.sub.1-C.sub.4)-alkylamino-(C.sub.1-C.sub.4)-alkyl,
--CH.sub.2C(NR.sup.27R.sup.28).dbd.NR.sup.29 or --COR.sup.33, where
R.sup.33 represents (C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl-(C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-aminoalkyl, (C.sub.1-C.sub.4)-alkoxycarbonyl,
(C.sub.1-C.sub.4)-alkanoyl-(C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.6)-alkenyl,
(C.sub.1-C.sub.8)-alkyl, which may optionally be substituted by
phenyl or acetyl, (C.sub.6-C.sub.14)-aryl,
(C.sub.5-C.sub.10)-heteroaryl, trifluoromethyl, tetrahydrofuranyl
or butyrolactone, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are identical or different and each represents hydrogen or
represents (C.sub.1-C.sub.6)-alkyl and their pharmaceutically
acceptable salts, hydrates and prodrugs, except for compounds of
the general formula (I) in which the radical R.sup.1 is an
unsubstituted 2-thiophene radical and the radical R.sup.2 is
simultaneously a mono- or polysubstituted phenyl radical and the
radicals R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8
are each simultaneously hydrogen.
3. Compounds of the general formula (I) according to claim 1,
characterized in that R.sup.1 represents thiophene (thienyl), in
particular 2-thiophene, which may optionally be mono- or
polysubstituted by halogen, preferably chlorine or bromine, by
amino, aminomethyl or (C.sub.1-C.sub.8)-alkyl, preferably methyl,
where the (C.sub.1-C.sub.8)-alkyl radical for its part may
optionally be mono- or polysubstituted by halogen, preferably
fluorine, R.sup.2 represents one of the groups below: A-, A-M-,
D-M-A-, B-M-A-, B--, B-M-, B-M-B--, D-M-B--, where: the radical "A"
represents (C.sub.6-C.sub.14)-aryl, preferably
(C.sub.6-C.sub.10)-aryl, in particular phenyl or naphthyl, very
particularly preferably phenyl; the radical "B" represents a 5- or
6-membered aromatic heterocycle which contains up to 3 heteroatoms
and/or hetero chain members, in particular up to 2 heteroatoms
and/or hetero chain members, from the group consisting of S, N, NO
(N-oxide) and O; the radical "D" represents a saturated or
partially unsaturated 4- to 7-membered heterocycle which contains
up to three heteroatoms and/or hetero chain members from the group
consisting of S, SO, SO.sub.2, N, NO (N-oxide) and O; the radical
"M" represents --NH--, --CH.sub.2--, --CH.sub.2CH.sub.2--, --O--,
--NH--CH.sub.2--, --CH.sub.2--NH--, --OCH.sub.2--, --CH.sub.2O--,
--CONH--, --NHCO--, --COO--, --OOC--, --S-- or represents a
covalent bond; where the groups "A", "B" and "D" defined above may
in each case optionally be mono- or polysubstituted by a radical
from the group consisting of halogen; trifluoromethyl; oxo; cyano;
nitro; carbamoyl; pyridyl; (C.sub.1-C.sub.6)-alkanoyl;
(C.sub.3-C.sub.7)-cycloalkanoyl; (C.sub.6-C.sub.14)-arylcarbonyl;
(C.sub.5-C.sub.10)-heteroaryl-carbonyl;
(C.sub.1-C.sub.6)-alkanoyloxymethyloxy; --COOR.sup.27;
--SO.sub.2R.sup.27; --C(NR.sup.27R.sup.28).dbd.NR.sup.29;
--CONR.sup.28R.sup.29; --SO.sub.2NR.sup.28R.sup.29; --OR.sup.30;
--NR.sup.30R.sup.31, (C.sub.1-C.sub.6)-alkyl and
(C.sub.3-C.sub.7)-cycloalkyl, where (C.sub.1-C.sub.6)-alkyl and
(C.sub.3-C.sub.7)-cycloalkyl for their part may optionally be
substituted by a radical from the group consisting of cyano;
--OR.sup.27; --NR.sup.28R.sup.29; --CO(NH).sub.v(NR.sup.27R.sup.28)
and --C(NR.sup.27R.sup.28).dbd.NR.sup.29, where: v is either 0 or 1
and R.sup.27, R.sup.28 and R.sup.29 are identical or different and
independently of one another each represents hydrogen,
(C.sub.1-C.sub.4)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, and/or
R.sup.27 and R.sup.28 or R.sup.27 and R.sup.29 together with the
nitrogen atom to which they are attached form a saturated or
partially unsaturated 5- to 7-membered heterocycle having up to
three, preferably up to two, identical or different heteroatoms
from the group consisting of N, O and S, and R.sup.30 and R.sup.31
are identical or different and independently of one another each
represents hydrogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.4)-alkylsulphonyl,
(C.sub.1-C.sub.4)-hydroxyalkyl, (C.sub.1-C.sub.4)-aminoalkyl,
di-(C.sub.1-C.sub.4)-alkylamino-(C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkanoyl, (C.sub.6--O.sub.14)-arylcarbonyl,
(C.sub.5-C.sub.10)-heteroarylcarbonyl,
(C.sub.1-C.sub.4)-alkylaminocarbonyl or
--CH.sub.2C(NR.sup.27R.sup.28).dbd.NR.sup.29, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are identical or different
and each represents hydrogen or represents (C.sub.1-C.sub.6)-alkyl
and their pharmaceutically acceptable salts, hydrates and prodrugs,
except for compounds of the general formula (I) in which the
radical R.sup.1 is an unsubstituted 2-thiophene radical and the
radical R.sup.2 is simultaneously a mono- or polysubstituted phenyl
radical and the radicals R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each simultaneously hydrogen.
4. Compounds of the general formula (I) according to claim 1,
characterized in that R.sup.1 represents thiophene (thienyl), in
particular 2-thiophene, which may optionally be mono- or
polysubstituted by halogen, preferably chlorine or bromine, or by
(C.sub.1-C.sub.8)-alkyl, preferably methyl, where the
(C.sub.1-C.sub.8)-alkyl radical for its part may optionally be
mono- or polysubstituted by halogen, preferably fluorine, R.sup.2
represents one of the groups below: A-, A-M-, D-M-A-, B-M-A-, B--,
B-M-, B-M-B--, D-M-B--, where: the radical "A" represents phenyl or
naphthyl, in particular phenyl; the radical "B" represents a 5- or
6-membered aromatic heterocycle which contains up to 2 heteroatoms
from the group consisting of S, N, NO (N-oxide) and O; the radical
"D" represents a saturated or partially unsaturated 5- or
6-membered heterocycle which contains up to two heteroatoms and/or
hetero chain members from the group consisting of S, SO, SO.sub.2,
N, NO (N-oxide) and O; the radical "M" represents --NH--, --O--,
--NH--CH.sub.2--, --CH.sub.2--NH--, --OCH.sub.2--, --CH.sub.2O--,
--CONH--, --NHCO-- or represents a covalent bond; where the groups
"A", "B" and "D" defined above may in each case optionally be mono-
or polysubstituted by a radical from the group consisting of
halogen; trifluoromethyl; oxo; cyano; pyridyl;
(C.sub.1-C.sub.3)-alkanoyl; (C.sub.6-C.sub.10)-arylcarbonyl;
(C.sub.5-C.sub.6)-heteroarylcarbonyl;
(C.sub.1-C.sub.3)-alkanoyloxymethyloxy;
--C(NR.sup.27R.sup.28).dbd.NR.sup.29; --CONR.sup.28R.sup.29;
--SO.sub.2NR.sup.28R.sup.29; --O H; --NR.sup.30R.sup.31;
(C.sub.1-C.sub.4)-alkyl; and cyclopropyl, cyclopentyl or
cyclohexyl, where (C.sub.1-C.sub.4)-alkyl and cyclopropyl,
cyclopentyl or cyclohexyl for their part may optionally be
substituted by a radical from the group consisting of cyano; --OH;
--OCH.sub.3; --NR.sup.28R.sup.29; --CO(NH).sub.v(NR.sup.27R.sup.28)
and --C(NR.sup.27R.sup.28).dbd.NR.sup.29, where: v is either 0 or
1, preferably 0, and R.sup.27, R.sup.28 and R.sup.29 are identical
or different and independently of one another each represents
hydrogen, (C.sub.1-C.sub.4)-alkyl or else cyclopropyl, cyclopentyl
or cyclohexyl and/or R.sup.27 and R.sup.28 or R.sup.27 and R.sup.29
together with the nitrogen atom to which they are attached may form
a saturated or partially unsaturated 5- to 7-membered heterocycle
having up to two identical or different heteroatoms from the group
consisting of N, O and S, and R.sup.30 and R.sup.31 are identical
or different and independently of one another each represents
hydrogen, (C.sub.1-C.sub.4)-alkyl, cyclopropyl, cyclopentyl,
cyclohexyl, (C.sub.1-C.sub.4)-alkylsulphonyl,
(C.sub.1-C.sub.4)-hydroxyalkyl, (C.sub.1-C.sub.4)-aminoalkyl,
di-(C.sub.1-C.sub.4)-alkylamino-(C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.3)-alkanoyl or phenylcarbonyl, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are identical or different
and each represents hydrogen or represents (C.sub.1-C.sub.6)-alkyl
and their pharmaceutically acceptable salts, hydrates and prodrugs,
except for compounds of the general formula (I) in which the
radical R.sup.1 is an unsubstituted 2-thiophene radical and the
radical R.sup.2 is simultaneously a mono- or polysubstituted phenyl
radical and the radicals R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each simultaneously hydrogen.
5. Compounds of the general formula (I) according to claim 1,
characterized in that R.sup.1 represents 2-thiophene which may
optionally be substituted in the 5-position by a radical from the
group consisting of chlorine, bromine, methyl or trifluoromethyl,
R.sup.2 represents one of the groups below: A-, A-M-, D-M-A-,
B-M-A-, B--, B-M-, B-M-B--, D-M-B--, where: the radical "A"
represents phenyl or naphthyl, in particular phenyl; the radical
"B" represents a 5- or 6-membered aromatic heterocycle which
contains up to 2 heteroatoms from the group consisting of S, N, NO
(N-oxide) and O; the radical "D" represents a saturated or
partially unsaturated 5- or 6-membered heterocycle which contains a
nitrogen atom and optionally a further heteroatom and/or hetero
chain member from the group consisting of S, SO, SO.sub.2 and 0; or
contains up to two heteroatoms and/or hetero chain members from the
group consisting of S, SO, SO.sub.2 and O; the radical "M"
represents --NH--, --O--, --NH--CH.sub.2--, --CH.sub.2--NH--,
--OCH.sub.2--, --CH.sub.2O--, --CONH--, --NHCO-- or represents a
covalent bond; where the groups "A", "B" and "D" defined above may
in each case optionally be mono- or polysubstituted by a radical
from the group consisting of halogen; trifluoromethyl; oxo; cyano;
pyridyl; (C.sub.1-C.sub.3)-alkanoyl;
(C.sub.6-C.sub.10)-arylcarbonyl;
(C.sub.5-C.sub.6)-heteroarylcarbonyl;
(C.sub.1-C.sub.3)-alkanoyloxymethyloxy; --CONR.sup.28R.sup.29;
--SO.sub.2NR.sup.28R.sup.29; --OH; --NR.sup.30R.sup.31;
(C.sub.1-C.sub.4)-alkyl; and cyclopropyl, cyclopentyl or
cyclohexyl, where (C.sub.1-C.sub.4)-alkyl and cyclopropyl,
cyclopentyl or cyclohexyl for their part may optionally be
substituted by a radical from the group consisting of cyano; --OH;
--OCH.sub.3; --NR.sup.28R.sup.29; --CO(NH).sub.v(NR.sup.27R.sup.28)
and --C(NR.sup.27R.sup.28).dbd.NR.sup.29, where: v is either 0 or
1, preferably 0, and R.sup.27, R.sup.28 and R.sup.29 are identical
or different and independently of one another each represents
hydrogen, (C.sub.1-C.sub.4)-alkyl or else cyclopropyl, cyclopentyl
or cyclohexyl and/or R.sup.27 and R.sup.28 or R.sup.27 and R.sup.29
together with the nitrogen atom to which they are attached may form
a saturated or partially unsaturated 5- to 7-membered heterocycle
having up to two identical or different heteroatoms from the group
consisting of N, O and S, and R.sup.30 and R.sup.31 are identical
or different and independently of one another each represents
hydrogen, (C.sub.1-C.sub.4)-alkyl, cyclopropyl, cyclopentyl,
cyclohexyl, (C.sub.1-C.sub.4)-alkylsulphonyl,
(C.sub.1-C.sub.4)-hydroxyalkyl, (C.sub.1-C.sub.4)-aminoalkyl,
di-(C.sub.1-C.sub.4)-alkylamino-(C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.3)-alkanoyl or phenylcarbonyl, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are identical or different
and each represents hydrogen or represents (C.sub.1-C.sub.4)-alkyl
and their pharmaceutically acceptable salts, hydrates and prodrugs,
except for compounds of the general formula (I) in which the
radical R.sup.1 is an unsubstituted 2-thiophene radical and the
radical R.sup.2 is simultaneously a mono- or polysubstituted phenyl
radical and the radicals R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each simultaneously hydrogen.
6. Compounds of the general formula (I) according to claim 1,
characterized in that R.sup.1 represents 2-thiophene which is
substituted in the 5-position by a radical from the group
consisting of chlorine, bromine, methyl and trifluoromethyl,
R.sup.2 represents D-A-: where: the radical "A" represents
phenylene; the radical "D" represents a saturated 5- or 6-membered
heterocycle, which is attached to "A" via a nitrogen atom, which
has a carbonyl group directly adjacent to the linking nitrogen atom
and in which one carbon ring member may be replaced by a heteroatom
from the group consisting of S, N and O; where the group "A"
defined above may optionally be mono- or disubstituted in the meta
position with respect to the point of attachment to the
oxazolidinone, by a radical from the group consisting of fluorine,
chlorine, nitro, amino, trifluoromethyl, methyl and cyano, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 each represent
hydrogen and their pharmaceutically acceptable salts, hydrates and
prodrugs.
7. Compound according to claim 1 having the following formula
##STR00175## and its pharmaceutically acceptable salts, hydrates
and prodrugs.
8. Process for preparing substituted oxazolidinones according to
claim 1, where either according to a process alternative [A]
compounds of the general formula (II) ##STR00176## in which the
radicals R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are each as defined in claim 1 are reacted with carboxylic
acids of the general formula (III) ##STR00177## in which the
radical R.sup.1 is as defined in claim 1, or else with the
corresponding carbonyl halides, preferably carbonyl chlorides, or
else with the corresponding symmetric or mixed carboxylic
anhydrides of the carboxylic acids of the general formula (III)
defined above in inert solvents, if appropriate in the presence of
an activating or coupling agent and/or a base, to give compounds of
the general formula (I) ##STR00178## in which the radicals R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8
are each as defined in claim 1, or else according to a process
alternative [B] compounds of the general formula (IV) ##STR00179##
in which the radicals R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are each as defined in claim 1, are converted,
using a suitable selective oxidizing agent in an inert solvent,
into the corresponding epoxide of the general formula (V)
##STR00180## in which the radicals R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each as defined in claim
1, and, by reaction in an inert solvent, if appropriate in the
presence of a catalyst, with an amine of the general formula (VI)
R.sup.2--NH.sub.2 (VI), in which the radical R.sup.2 is as defined
in claim 1, the compounds of the general formula (VII) ##STR00181##
in which the radicals R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7 and R.sup.8 are each as defined in claim 1, are
initially prepared and, subsequently, in an inert solvent in the
presence of phosgene or phosgene equivalents, such as, for example,
carbonyldiimidazole (CDI), cyclized to give the compounds of the
general formula (I) ##STR00182## in which the radicals R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8
are each as defined in claim 1, where--both for process alternative
[A] and for process alternative [B]--in the case where R.sup.2
contains a 3- to 7-membered saturated or partially unsaturated
cyclic hydrocarbon radical having one or more identical or
different heteroatoms from the group consisting of N and S, an
oxidation with a selective oxidizing agent to afford the
corresponding sulphone, sulphoxide or N-oxide may follow and/or
where--both for process alternative [A] and for process alternative
[B]--in the case where the compound prepared in this manner has a
cyano group in the molecule, an amidination of this cyano group by
customary methods may follow and/or where--both for process
alternative [A] and for process alternative [B]--in the case where
the compound prepared in this manner has a BOC amino protective
group in the molecule, removal of this BOC amino protective group
by customary methods may follow and/or where--both for process
alternative [A] and for process alternative [B]--in the case where
the compound prepared in this manner has an aniline or benzylamine
radical in the molecule, a reaction of this amino group with
various reagents such as carboxylic acids, carboxylic anhydrides,
carbonyl chlorides, isocyanates, sulphonyl chlorides or alkyl
halides to give the corresponding derivatives may follow and/or
where--both for process alternative [A] and for process alternative
[B]--in the case where the compound prepared in this manner has a
phenyl ring in the molecule, a reaction with chlorosulphonic acid
and subsequent reaction with amines to give the corresponding
sulphonamides may follow.
9. Medicaments, comprising at least one compound of the general
formula (I) according to claim 1 and one or more pharmacologically
acceptable auxiliaries or excipients.
10. Use of compounds of the general formula (I) ##STR00183## in
which: R.sup.1 represents optionally benzo-fused thiophene
(thienyl) which may optionally be mono- or polysubstituted; R.sup.2
represents any organic radical; R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are identical or different and each represents
hydrogen or represents (C.sub.1-C.sub.6)-alkyl and their
pharmaceutically acceptable salts, hydrates and prodrugs, for
preparing medicaments or pharmaceutical compositions for the
prophylaxis and/or treatment of thromboembolic disorders, in
particular myocardial infarct, angina pectoris (including unstable
angina), reocclusions and restenoses after angioplasty or
aortocoronary bypass, stroke, transitory ischaemic attacks,
peripheral arterial occlusive diseases, pulmonary embolisms or deep
venous thromboses.
11. Use of compounds of the general formula (I) according to claim
10 for preparing medicaments or pharmaceutical compositions for the
prophylaxis and/or treatment of disorders which are influenced
positively by inhibition of factor Xa.
12. Use of compounds of the general formula (I) according to claim
10 for preparing medicaments or pharmaceutical compositions for the
treatment of disseminated intravascular coagulation (DIC).
13. Use of compounds of the general formula (I) according to claim
10 for preparing medicaments or pharmaceutical compositions for the
prophylaxis and/or treatment of disorders such as atherosclerosis;
arthritis; Alzheimer's disease or cancer.
14. Use of compounds of the general formula (I) according to claim
10 for preparing medicaments or pharmaceutical compositions for the
inhibition of factor Xa.
15. Method for preventing the coagulation of blood in vitro, in
particular in the case of banked blood or biological samples
containing factor Xa, characterized in that compounds of the
general formula (I) according to claim 10 are added.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/961,264, filed Aug. 7, 2013, now allowed, which is hereby
incorporated by reference herein in its entirety, which is a
continuation U.S. application Ser. No. 13/360,107, filed Jan. 27,
2012, which issued on Sep. 10, 2013 as U.S. Pat. No. 8,530,505,
which is a continuation of U.S. application Ser. No. 12/494,879,
filed Jun. 30, 2009, which issued on Mar. 6, 2012 as U.S. Pat. No.
8,129,378, which is hereby incorporated by reference herein in its
entirety, which is a continuation of U.S. application Ser. No.
11/932,082, filed Oct. 31, 2007, which issued on Aug. 18, 2009 as
U.S. Pat. No. 7,576,111, which is hereby incorporated herein by
reference in its entirety, which is a continuation application of
U.S. application Ser. No. 11/460,529 filed Jul. 27, 2006, which
issued on Sep. 22, 2009 as U.S. Pat. No. 7,592,339, which is hereby
incorporated herein by reference in its entirety, which is a
continuation of U.S. application Ser. No. 10/181,051 filed Jun. 24,
2002, which issued on Jan. 2, 2007 as U.S. Pat. No. 7,157,456,
which is hereby incorporated herein by reference in its entirety,
which is the national stage entry under 35 U.S.C. .sctn.371 of
International Application No. PCT/EP00/12492, filed Dec. 11, 2000,
which claims priority to German Application No. 199 62 924.2, filed
Dec. 24, 1999.
FIELD OF THE INVENTION
[0002] The present invention relates to the field of blood
coagulation. In particular, the present invention relates to novel
oxazolidinone derivatives, to processes for their preparation and
to their use as active compounds in medicaments.
BACKGROUND OF THE INVENTION
[0003] Blood coagulation is a protective mechanism of the organism
which helps to "seal" defects in the wall of the blood vessels
quickly and reliably. Thus, loss of blood can be avoided or kept to
a minimum. Haemostasis after injury of the blood vessels is
effected mainly by the coagulation system in which an enzymatic
cascade of complex reactions of plasma proteins is triggered.
Numerous blood coagulation factors are involved in this process,
each of which factors converts, on activation, the respectively
next inactive precursor into its active form. At the end of the
cascade comes the conversion of soluble fibrinogen into insoluble
fibrin, resulting in the formation of a blood clot. In blood
coagulation, traditionally the intrinsic and the extrinsic system,
which end in a joint reaction path, are distinguished. Here factor
Xa, which is formed from the proenzyme factor X, plays a key role,
since it connects the two coagulation paths. The activated serine
protease Xa cleaves prothrombin to thrombin. The resulting
thrombin, in turn, cleaves fibrinogen to fibrin, a
fibrous/gelatinous coagulant. In addition, thrombin is a potent
effector of platelet aggregation which likewise contributes
significantly to haemostasis.
[0004] Maintenance of normal haemostasis--between bleeding and
thrombosis--is subject to a complex regulatory mechanism.
Uncontrolled activation of the coagulant system or defective
inhibition of the activation processes may cause formation of local
thrombi or embolisms in vessels (arteries, veins, lymph vessels) or
in heart cavities. This may lead to serious disorders, such as
myocardial infarct, angina pectoris (including unstable angina),
reocclusions and restenoses after angioplasty or aortocoronary
bypass, stroke, transitory ischaemic attacks, peripheral arterial
occlusive disorders, pulmonary embolisms or deep venous thromboses;
hereinbelow, these disorders are collectively also referred to as
thromboembolic disorders. In addition, in the case of consumption
coagulopathy, hypercoagulability may--systemically--result in
disseminated intravascular coagulation.
[0005] These thromboembolic disorders are the most frequent cause
of morbidity and mortality in most industrialized countries
(Pschyrembel, Klinisches Worterbuch [clinical dictionary],
257.sup.th edition, 1994, Walter de Gruyter Verlag, page 199 ff.,
entry "Blutgerinnung" [blood coagulation]; Rompp Lexikon Chemie,
Version 1.5, 1998, Georg Thieme Verlag Stuttgart, entry
"Blutgerinnung"; Lubert Stryer, Biochemie [biochemistry], Spektrum
der Wissenschaft Verlagsgesellschaft mbH Heidelberg, 1990, page 259
ff.).
[0006] The anticoagulants, i.e. substances for inhibiting or
preventing blood coagulation, which are known from the prior art
have various, often grave disadvantages. Accordingly, in practice,
an efficient treatment method or prophylaxis of thromboembolic
disorders is very difficult and unsatisfactory.
[0007] In the therapy and prophylaxis of thromboembolic disorders,
use is firstly made of heparin, which is administered parenterally
or subcutaneously. Owing to more favourable pharmacokinetic
properties, preference is nowadays more and more given to
low-molecular-weight heparin; however, even with
low-molecular-weight heparin, it is not possible to avoid the known
disadvantages described below, which are involved in heparin
therapy. Thus, heparin is ineffective when administered orally and
has a relatively short half-life. Since heparin inhibits a
plurality of factors of the blood coagulation cascade at the same
time, the action is nonselective. Moreover, there is a high risk of
bleeding; in particular, brain haemorrhages and gastrointestinal
bleeding may occur, which may result in thrombopenia, drug-induced
alopecia or osteoporosis (Pschyrembel, Klinisches Worterbuch,
257.sup.th edition, 1994, Walter de Gruyter Verlag, page 610, entry
"Heparin"; Rompp Lexikon Chemie, Version 1.5, 1998, Georg Thieme
Verlag Stuttgart, entry "Heparin").
[0008] A second class of anticoagulants are the vitamin K
antagonists. These include, for example, 1,3-indanediones, and
especially compounds such as warfarin, phenprocoumon, dicumarol and
other coumarin derivatives which inhibit the synthesis of various
products of certain vitamin K-dependent coagulation factors in the
liver in a non-selective manner. Owing to the mechanism of action,
however, the onset of the action is very slow (latency to the onset
of action 36 to 48 hours). It is possible to administer the
compounds orally; however, owing to the high risk of bleeding and
the narrow therapeutic index, a time-consuming individual
adjustment and monitoring of the patient are required. Moreover,
other adverse effects, such as gastrointestinal disturbances, hair
loss and skin necroses, have been described (Pschyrembel,
Klinisches Worterbuch, 257.sup.th edition, 1994, Walter de Gruyter
Verlag, page 292 ff., entry "coumarin derivatives"; Ullmann's
Encyclopedia of Industrial Chemistry, 5.sup.th edition, VCH
Verlagsgesellschaft, Weinheim, 1985-1996, entry "vitamin K").
[0009] Recently, a novel therapeutic approach for the treatment and
prophylaxis of thromboembolic disorders has been described. This
novel therapeutic approach aims to inhibit factor Xa (cf.
WO-A-99/37304; WO-A-99/06371; J. Hauptmann, J. Sffirzebecher,
Thrombosis Research 1999, 93, 203; F. Al-Obeidi, J. A. Ostrem,
Factor Xa inhibitors by classical and combinatorial chemistry, DDT
1998, 3, 223; F. Al-Obeidi, J. A. Ostrem, Factor Xa inhibitors,
Exp. Opin. Ther. Patents 1999, 9, 931; B. Kaiser, Thrombin and
factor Xa inhibitors, Drugs of the Future 1998, 23, 423; A. Uzan,
Antithrombotic agents, Emerging Drugs 1998, 3, 189; B.-Y. Zhu, R.
M. Scarborough, Curr. Opin. Card. Pulm. Ren. Inv. Drugs 1999, 1
(1), 63). It has been shown that, in animal models, various both
peptidic and nonpeptidic compounds are effective as factor Xa
inhibitors.
[0010] Accordingly, it is an object of the present invention to
provide novel substances for controlling disorders, which
substances have a wide therapeutic spectrum.
[0011] In particular, they should be suitable for a more efficient
prophylaxis and/or treatment of thromboembolic disorders,
avoiding--at least to some extent--the disadvantages of the prior
art described above, where the term "thromboembolic disorders" in
the context of the present invention is to be understood as
meaning, in particular, serious disorders, such as myocardial
infarct, angina pectoris (including unstable angina), reocclusions
and restenoses after angioplasty or aortocoronary bypass, stroke,
transitory ischaemic attacks, peripheral arterial occlusive
disorders, pulmonary embolisms or deep venous thromboses.
[0012] It is another object of the present invention to provide
novel anticoagulants which inhibit the blood coagulation factor Xa
with increased selectivity, avoiding--at least to some extent--the
problems of the therapeutic methods for thromboembolic disorders
known from the prior art.
SUMMARY OF THE INVENTION
[0013] Accordingly, the present invention provides substituted
oxazolidinones of the general formula (I)
##STR00002##
in which: [0014] R.sup.1 represents optionally benzo-fused
thiophene (thienyl) which may optionally be mono- or
polysubstituted; [0015] R.sup.2 represents any organic radical;
[0016] R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
identical or different and each represents hydrogen or represents
(C.sub.1-C.sub.6)-alkyl and their pharmaceutically acceptable
salts, hydrates and prodrugs, except for compounds of the general
formula (I) in which the radical R.sup.1 is an unsubstituted
2-thiophene radical and the radical R.sup.2 is simultaneously a
mono- or polysubstituted phenyl radical and the radicals R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each
simultaneously hydrogen.
[0017] Preference is given here to compounds of the general formula
(I),
in which [0018] R.sup.1 represents optionally benzo-fused thiophene
(thienyl) which may optionally be mono- or polysubstituted by a
radical from the group consisting of halogen; cyano; nitro; amino;
aminomethyl; (C.sub.1-C.sub.8)-alkyl which for its part may
optionally be mono- or polysubstituted by halogen;
(C.sub.3-C.sub.7)-cycloalkyl; (C.sub.1-C.sub.8)-alkoxy;
imidazolinyl; --C(.dbd.NH)NH.sub.2; carbamoyl; and mono- and
di-(C.sub.1-C.sub.4)-alkyl-aminocarbonyl, [0019] R.sup.2 represents
one of the groups below: [0020] A-, [0021] A-M-, [0022] D-M-A-,
[0023] B-M-A-, [0024] B--, [0025] B-M-, [0026] B-M-B--, [0027]
D-M-B--, [0028] where: [0029] the radical "A" represents
(C.sub.6-C.sub.14)-aryl, preferably (C.sub.6-C.sub.10)-aryl, in
particular phenyl or naphthyl, very particularly preferably phenyl;
[0030] the radical "B" represents a 5- or 6-membered aromatic
heterocycle which contains up to 3 heteroatoms and/or hetero chain
members, in particular up to 2 heteroatoms and/or hetero chain
members, from the group consisting of S, N, NO (N-oxide) and O;
[0031] the radical "D" represents a saturated or partially
unsaturated, mono- or bicyclic, optionally benzo-fused 4- to
9-membered heterocycle which contains up to three heteroatoms
and/or hetero chain members from the group consisting of S, SO,
SO.sub.2, N, NO (N-oxide) and O; [0032] the radical "M" represents
--NH--, --CH.sub.2--, --CH.sub.2CH.sub.2--, --O--,
--NH--CH.sub.2--, --CH.sub.2--NH--, --OCH.sub.2--, --CH.sub.2O--,
--CONH--, --NHCO--, --COO--, --OOC--, --S--, --SO.sub.2-- or
represents a covalent bond; [0033] where [0034] the groups "A", "B"
and "D" defined above may each optionally be mono- or
polysubstituted by a radical from the group consisting of halogen;
trifluoromethyl; oxo; cyano; nitro; carbamoyl; pyridyl;
(C.sub.1-C.sub.6)-alkanoyl; (C.sub.3-C.sub.7)-cycloalkanoyl;
(C.sub.6-C.sub.14)-arylcarbonyl;
(C.sub.5-C.sub.10)-heteroarylcarbonyl;
(C.sub.1-C.sub.6)-alkanoyloxymethyloxy;
(C.sub.1-C.sub.4)-hydroxy-alkylcarbonyl; --COOR.sup.27;
--SO.sub.2R.sup.27; --C(NR.sup.27R.sup.28).dbd.NR.sup.29;
--CONR.sup.28R.sup.29; --SO.sub.2NR.sup.28R.sup.29; --OR.sup.30;
--NR.sup.30R.sup.31, (C.sub.1-C.sub.6)-alkyl and
(C.sub.3-C.sub.7)-cycloalkyl, [0035] where (C.sub.1-C.sub.6)-alkyl
and (C.sub.3-C.sub.7)-cycloalkyl for their part may optionally be
substituted by a radical from the group consisting of cyano;
--OR.sup.27; --NR.sup.28R.sup.29; --CO(NH).sub.v(NR.sup.27R.sup.28)
and --C(NR.sup.27R.sup.28).dbd.NR.sup.29, [0036] where: [0037] v is
either 0 or 1 and [0038] R.sup.27, R.sup.28 and R.sup.29 are
identical or different and independently of one another each
represents hydrogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.4)-alkanoyl,
carbamoyl, trifluoromethyl, phenyl or pyridyl, and/or [0039]
R.sup.27 and R.sup.28 or R.sup.27 and R.sup.29 together with the
nitrogen atom to which they are attached form a saturated or
partially unsaturated 5- to 7-membered heterocycle having up to
three, preferably up to two, identical or different heteroatoms
from the group consisting of N, O and S, and [0040] R.sup.30 and
R.sup.31 are identical or different and independently of one
another each represents hydrogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.4)-alkylsulphonyl,
(C.sub.1-C.sub.4)-hydroxyalkyl, (C.sub.1-C.sub.4)-aminoalkyl,
di-(C.sub.1-C.sub.4)-alkylamino-(C.sub.1-C.sub.4)-alkyl,
--CH.sub.2C(NR.sup.27R.sup.28).dbd.NR.sup.29 or --COR.sup.33,
[0041] where [0042] R.sup.33 represents (C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.4)-alkoxy-(C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl-(C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-aminoalkyl, (C.sub.1-C.sub.4)-alkoxycarbonyl,
(C.sub.1-C.sub.4)-alkanoyl-(C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.6)-alkenyl,
(C.sub.1-C.sub.8)-alkyl, which may optionally be substituted by
phenyl or acetyl, (C.sub.6-C.sub.14)-aryl,
(C.sub.5-C.sub.10)-heteroaryl, trifluoromethyl, tetrahydro-furanyl
or butyrolactone, [0043] R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are identical or different and each represents
hydrogen or represents (C.sub.1-C.sub.6)-alkyl and their
pharmaceutically acceptable salts, hydrates and prodrugs, except
for compounds of the general formula (I) in which the radical
R.sup.1 is an unsubstituted 2-thiophene radical and the radical
R.sup.2 is simultaneously a mono- or polysubstituted phenyl radical
and the radicals R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are each simultaneously hydrogen.
[0044] Preference is also given here to compounds of the general
formula (I),
in which [0045] R.sup.1 represents thiophene (thienyl), in
particular 2-thiophene, which may optionally be mono- or
polysubstituted by halogen, preferably chlorine or bromine, by
amino, aminomethyl or (C.sub.1-C.sub.8)-alkyl, preferably methyl,
where the (C.sub.1-C.sub.8)-alkyl radical for its part may
optionally be mono- or polysubstituted by halogen, preferably
fluorine, [0046] R.sup.2 represents one of the groups below: [0047]
A-, [0048] A-M-, [0049] D-M-A-, [0050] B-M-A-, [0051] B--, [0052]
B-M-, [0053] B-M-B--, [0054] D-M-B--, [0055] where: [0056] the
radical "A" represents (C.sub.6-C.sub.14)-aryl, preferably
(C.sub.6-C.sub.10)-aryl, in particular phenyl or naphthyl, very
particularly preferably phenyl; [0057] the radical "B" represents a
5- or 6-membered aromatic heterocycle which contains up to 3
heteroatoms and/or hetero chain members, in particular up to 2
heteroatoms and/or hetero chain members, from the group consisting
of S, N, NO (N-oxide) and O; [0058] the radical "D" represents a
saturated or partially unsaturated 4- to 7-membered heterocycle
which contains up to three heteroatoms and/or hetero chain members
from the group consisting of S, SO, SO.sub.2, N, NO (N-oxide) and
O; [0059] the radical "M" represents --NH--, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --O--, --NH--CH.sub.2--, --CH.sub.2--NH--,
--OCH.sub.2--, --CH.sub.2O--, --CONH--, --NHCO--, --COO--, --OOC--,
--S-- or represents a covalent bond; [0060] where [0061] the groups
"A", "B" and "D" defined above may in each case optionally be mono-
or polysubstituted by a radical from the group consisting of
halogen; trifluoromethyl; oxo; cyano; nitro; carbamoyl; pyridyl;
(C.sub.1-C.sub.6)-alkanoyl; (C.sub.3-C.sub.7)-cycloalkanoyl;
(C.sub.6-C.sub.14)-arylcarbonyl;
(C.sub.5-C.sub.10)-heteroarylcarbonyl;
(C.sub.1-C.sub.6)-alkanoyloxymethyloxy; --COOR.sup.27;
--SO.sub.2R.sup.27; --C(NR.sup.27R.sup.28).dbd.NR.sup.29;
--CONR.sup.28R.sup.29; --SO.sub.2NR.sup.28R.sup.29; --OR.sup.30;
--NR.sup.30R.sup.31, (C.sub.1-C.sub.6)-alkyl and
(C.sub.3-C.sub.7)-cycloalkyl, [0062] where (C.sub.1-C.sub.6)-alkyl
and (C.sub.3-C.sub.7)-cycloalkyl for their part may optionally be
substituted by a radical from the group consisting of cyano;
--OR.sup.27; --NR.sup.28R.sup.29; --CO(NH).sub.v(NR.sup.27R.sup.28)
and --C(NR.sup.27R.sup.28).dbd.NR.sup.29, [0063] where: [0064] v is
either 0 or 1 and [0065] R.sup.27, R.sup.28 and R.sup.29 are
identical or different and independently of one another each
represents hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.3-C.sub.7)-cycloalkyl, and/or [0066] R.sup.27 and R.sup.28
or R.sup.27 and R.sup.29 together with the nitrogen atom to which
they are attached form a saturated or partially unsaturated 5- to
7-membered heterocycle having up to three, preferably up to two,
identical or different heteroatoms from the group consisting of N,
O and S, and [0067] R.sup.30 and R.sup.31 are identical or
different and independently of one another each represents
hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.4)-alkylsulphonyl, (C.sub.1-C.sub.4)-hydroxyalkyl,
(C.sub.1-C.sub.4)-aminoalkyl,
di-(C.sub.1-C.sub.4)-alkylamino-(C.sub.1-C.sub.4)-alkyl,
--C.sub.4)-alkanoyl, (C.sub.6-C.sub.14)-arylcarbonyl,
(C.sub.5-C.sub.10)-heteroarylcarbonyl,
(C.sub.1-C.sub.4)-alkylaminocarbonyl or
--CH.sub.2C(NR.sup.27R.sup.28).dbd.NR.sup.29, [0068] R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are identical or
different and each represents hydrogen or represents
(C.sub.1-C.sub.6)-alkyl and their pharmaceutically acceptable
salts, hydrates and prodrugs, except for compounds of the general
formula (I) in which the radical R.sup.1 is an unsubstituted
2-thiophene radical and the radical R.sup.2 is simultaneously a
mono- or polysubstituted phenyl radical and the radicals R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each
simultaneously hydrogen.
[0069] Particular preference is given here to compounds of the
general formula (I),
in which [0070] R.sup.1 represents thiophene (thienyl), in
particular 2-thiophene, which may optionally be mono- or
polysubstituted by halogen, preferably chlorine or bromine, or by
(C.sub.1-C.sub.8)-alkyl, preferably methyl, where the
(C.sub.1-C.sub.8)-alkyl radical for its part may optionally be
mono- or polysubstituted by halogen, preferably fluorine, [0071]
R.sup.2 represents one of the groups below: [0072] A-, [0073] A-M-,
[0074] D-M-A-, [0075] B-M-A-, [0076] B--, [0077] B-M-, [0078]
B-M-B--, [0079] D-M-B--, [0080] where: [0081] the radical "A"
represents phenyl or naphthyl, in particular phenyl; the radical
"B" represents a 5- or 6-membered aromatic heterocycle which
contains up to 2 heteroatoms from the group consisting of S, N, NO
(N-oxide) and O; [0082] the radical "D" represents a saturated or
partially unsaturated 5- or 6-membered heterocycle which contains
up to two heteroatoms and/or hetero chain members from the group
consisting of S, SO, SO.sub.2, N, NO (N-oxide) and O; [0083] the
radical "M" represents --NH--, --O--, --NH--CH.sub.2--,
--CH.sub.2--NH--, --OCH.sub.2--, --CH.sub.2O--, --CONH--, --NHCO--
or represents a covalent bond; [0084] where [0085] the groups "A",
"B" and "D" defined above may in each case optionally be mono- or
polysubstituted by a radical from the group consisting of halogen;
trifluoromethyl; oxo; cyano; pyridyl; (C.sub.1-C.sub.3)-alkanoyl;
(C.sub.6-C.sub.10)-arylcarbonyl;
(C.sub.5-C.sub.6)-heteroarylcarbonyl;
(C.sub.1-C.sub.3)-alkanoyloxymethyloxy;
--C(NR.sup.27R.sup.28).dbd.NR.sup.29; --CONR.sup.28R.sup.29;
--SO.sub.2NR.sup.28R.sup.29; --OH; --NR.sup.30R.sup.31;
(C.sub.1-C.sub.4)-alkyl; and cyclopropyl, cyclopentyl or
cyclohexyl, [0086] where (C.sub.1-C.sub.4)-alkyl and cyclopropyl,
cyclopentyl or cyclohexyl for their part may optionally be
substituted by a radical from the group consisting of cyano; --OH;
--OCH.sub.3; --NR.sup.28R.sup.29; --CO(NH).sub.v(NR.sup.27R.sup.28)
and --C(NR.sup.27R.sup.28).dbd.NR.sup.29, [0087] where: [0088] v is
either 0 or 1, preferably 0, and [0089] R.sup.27, R.sup.28 and
R.sup.29 are identical or different and independently of one
another each represents hydrogen, (C.sub.1-C.sub.4)-alkyl or else
cyclopropyl, cyclopentyl or cyclohexyl [0090] and/or [0091]
R.sup.27 and R.sup.28 or R.sup.27 and R.sup.29 together with the
nitrogen atom to which they are attached may form a saturated or
partially unsaturated 5- to 7-membered heterocycle having up to two
identical or different heteroatoms from the group consisting of N,
O and S, and [0092] R.sup.30 and R.sup.31 are identical or
different and independently of one another each represents
hydrogen, (C.sub.1-C.sub.4)-alkyl, cyclopropyl, cyclopentyl,
cyclohexyl, (C.sub.1-C.sub.4)-alkylsulphonyl,
(C.sub.1-C.sub.4)-hydroxyalkyl, (C.sub.1-C.sub.4)-aminoalkyl,
di-(C.sub.1-C.sub.4)-alkylamino-(C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.3)-alkanoyl or phenylcarbonyl, [0093] R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are identical or
different and each represents hydrogen or represents
(C.sub.1-C.sub.6)-alkyl and their pharmaceutically acceptable
salts, hydrates and prodrugs, except for compounds of the general
formula (I) in which the radical R.sup.1 is an unsubstituted
2-thiophene radical and the radical R.sup.2 is simultaneously a
mono- or polysubstituted phenyl radical and the radicals R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each
simultaneously hydrogen.
[0094] Particular preference is given here to compounds of the
general formula (I),
in which [0095] R.sup.1 represents 2-thiophene which may optionally
be substituted in the 5-position by a radical from the group
consisting of chlorine, bromine, methyl or trifluoromethyl, [0096]
R.sup.2 represents one of the groups below: [0097] A-, [0098] A-M-,
[0099] D-M-A-, [0100] B-M-A-, [0101] B--, [0102] B-M-, [0103]
B-M-B--, [0104] D-M-B--, [0105] where: [0106] the radical "A"
represents phenyl or naphthyl, in particular phenyl; the radical
"B" represents a 5- or 6-membered aromatic heterocycle which
contains up to 2 heteroatoms from the group consisting of S, N, NO
(N-oxide) and O; [0107] the radical "D" represents a saturated or
partially unsaturated 5- or 6-membered heterocycle which contains a
nitrogen atom and optionally a further heteroatom and/or hetero
chain member from the group consisting of S, SO, SO.sub.2 and O; or
contains up to two heteroatoms and/or hetero chain members from the
group consisting of S, SO, SO.sub.2 and O; [0108] the radical "M"
represents --NH--, --O--, --NH--CH.sub.2--, --CH.sub.2--NH--,
--OCH.sub.2--, --CH.sub.2O--, --CONH--, --NHCO-- or represents a
covalent bond; [0109] where [0110] the groups "A", "B" and "D"
defined above may in each case optionally be mono- or
polysubstituted by a radical from the group consisting of halogen;
trifluoromethyl; oxo; cyano; pyridyl; (C.sub.1-C.sub.3)-alkanoyl;
(C.sub.6-C.sub.10)-arylcarbonyl;
(C.sub.5-C.sub.6)-heteroarylcarbonyl;
(C.sub.1-C.sub.3)-alkanoyloxymethyloxy; --CONR.sup.28R.sup.29;
--SO.sub.2NR.sup.28R.sup.29; --OH; --NR.sup.30R.sup.31;
(C.sub.1-C.sub.4)-alkyl; and cyclopropyl, cyclopentyl or
cyclohexyl, [0111] where (C.sub.1-C.sub.4)-alkyl and cyclopropyl,
cyclopentyl or cyclohexyl for their part may optionally be
substituted by a radical from the group consisting of cyano; --OH;
--OCH.sub.3; --NR.sup.28R.sup.29; --CO(NH).sub.v(NR.sup.27R.sup.28)
and --C(NR.sup.27R.sup.28).dbd.NR.sup.29, where: [0112] v is either
0 or 1, preferably 0, and [0113] R.sup.27, R.sup.28 and R.sup.29
are identical or different and independently of one another each
represents hydrogen, (C.sub.1-C.sub.4)-alkyl or else cyclopropyl,
cyclopentyl or cyclohexyl [0114] and/or [0115] R.sup.27 and
R.sup.28 or R.sup.27 and R.sup.29 together with the nitrogen atom
to which they are attached may form a saturated or partially
unsaturated 5- to 7-membered heterocycle having up to two identical
or different heteroatoms from the group consisting of N, O and S,
and [0116] R.sup.30 and R.sup.31 are identical or different and
independently of one another each represents hydrogen,
(C.sub.1-C.sub.4)-alkyl, cyclopropyl, cyclopentyl, cyclohexyl,
(C.sub.1-C.sub.4)-alkylsulphonyl, (C.sub.1-C.sub.4)-hydroxyalkyl,
(C.sub.1-C.sub.4)-aminoalkyl,
di-(C.sub.1-C.sub.4)-alkylamino-(C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.3)-alkanoyl or phenylcarbonyl, [0117] R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are identical or
different and each represents hydrogen or represents
(C.sub.1-C.sub.4)-alkyl and their pharmaceutically acceptable
salts, hydrates and prodrugs, except for compounds of the general
formula (I) in which the radical R.sup.1 is an unsubstituted
2-thiophene radical and the radical R.sup.2 is simultaneously a
mono- or polysubstituted phenyl radical and the radicals R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each
simultaneously hydrogen.
[0118] Very particular preference is given here to compounds of the
general formula (I), in which [0119] R.sup.1 represents 2-thiophene
which is substituted in the 5-position by a radical from the group
consisting of chlorine, bromine, methyl and trifluoromethyl, [0120]
R.sup.2 represents D-A-: [0121] where: [0122] the radical "A"
represents phenylene; [0123] the radical "D" represents a saturated
5- or 6-membered heterocycle, which is attached to "A" via a
nitrogen atom, [0124] which has a carbonyl group directly adjacent
to the linking nitrogen atom and [0125] in which one carbon ring
member may be replaced by a heteroatom from the group consisting of
S, N and O; [0126] where [0127] the group "A" defined above may
optionally be mono- or disubstituted in the meta position with
respect to the point of attachment to the oxazolidinone, by a
radical from the group consisting of fluorine, chlorine, nitro,
amino, trifluoromethyl, methyl and cyano, [0128] R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 each represent hydrogen and
their pharmaceutically acceptable salts, hydrates and prodrugs.
[0129] Very particular preference is also given here to the
compound having the following formula
##STR00003##
and to its pharmaceutically acceptable salts, hydrates and
prodrugs.
[0130] In the compounds of the general formula (I) above, the
radical [0131] R.sup.1 may in particular represent optionally
benzo-fused thiophene (thienyl) which may optionally be mono- or
polysubstituted by a radical from the group consisting of halogen;
cyano; nitro; (C.sub.1-C.sub.8)-alkyl, which for its part may
optionally be mono- or polysubstituted by halogen;
(C.sub.3-C.sub.7)-cycloalkyl; (C.sub.1-C.sub.8)-alkoxy;
imidazolinyl; --C(.dbd.NH)NH.sub.2; carbamoyl; and mono- and
di-(C.sub.1-C.sub.4)-alkylaminocarbonyl.
[0132] In the compounds of the general formula (I), the radical
[0133] R.sup.1 may preferably represent thiophene (thienyl), in
particular 2-thiophene, which may optionally be mono- or
polysubstituted by halogen, preferably chlorine or bromine, or by
(C.sub.1-C.sub.8)-alkyl, preferably methyl, where the
(C.sub.1-C.sub.8)-alkyl radical, preferably the methyl radical, may
for its part optionally be mono- or polysubstituted by halogen,
preferably fluorine.
[0134] In the compounds of the general formula (I), the radicals
[0135] R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 may
be identical or different and may represent, in particualr,
hydrogen or (C.sub.1-C.sub.6)-alkyl, preferably hydrogen or
(C.sub.1-C.sub.4)-alkyl, very particularly preferably hydrogen.
[0136] The radical R.sup.2, i.e. the organic radical, can in
particular be selected from the substituent groups listed
below:
[0137] In the compounds of the general formula (I), the radical
[0138] R.sup.2 may, in particular, represent a group of the
following formula:
[0138]
Y--X'--(CH.sub.2).sub.p--X--(CO).sub.n--(CH.sub.2).sub.o.sub.1--(-
CR.sup.9R.sup.10).sub.m--(CH.sub.2).sub.o.sub.2-- [0139] where;
[0140] m is an integer from 0 to 6, preferably from 1 to 3, [0141]
n is either 0 or 1, [0142] p is an integer from 0 to 3, preferably
either 0 or 1, [0143] o.sub.1 is an integer 0 or 1, [0144] o.sub.2
is an integer 0 or 1, [0145] R.sup.9 and R.sup.10 are identical or
different and each represents hydrogen; (C.sub.1-C.sub.4)-alkyl,
preferably methyl; (C.sub.1-C.sub.4)-alkoxy, preferably methoxy;
(C.sub.3-C.sub.7)-cycloalkyl; hydroxyl or fluorine, [0146] X and X'
are identical or different and each represents O; N--R'' or a
covalent bond, [0147] where R.sup.11 represents H;
(C.sub.1-C.sub.4)-alkyl, preferably methyl, or
(C.sub.3-C.sub.7)-cycloalkyl, [0148] Y represents a 3- to
7-membered saturated or partially unsaturated cyclic hydrocarbon
radical which optionally contains 1 to 3 identical or different
heteroatoms and/or hetero chain members from the group consisting
of N, O, S, SO and SO.sub.2, [0149] where: [0150] this radical Y
may optionally be substituted by a 5- or 6-membered aromatic or a
3- to 7-membered saturated or partially unsaturated cyclic
hydrocarbon radical which optionally contains up to 3 identical or
different heteroatoms from the group consisting of N, O and S and
where this radical may for its part optionally be substituted by a
radical from the group consisting of cyano; hydroxyl; halogen;
(C.sub.1-C.sub.4)-alkyl; --C(.dbd.NR.sup.12)NR.sup.13R.sup.13'; and
--NR.sup.14R.sup.15, [0151] where: [0152] R.sup.12 represents
hydrogen, (C.sub.1-C.sub.4)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl;
[0153] R.sup.13 and R.sup.13' are identical or different and
independently of one another each represents hydrogen,
(C.sub.1--CO-alkyl or (C.sub.3-C.sub.7)-cycloalkyl [0154] and/or
[0155] R.sup.13 and R.sup.13' together with the N atom to which
they are attached form a 5- to 7-membered heterocycle which may
optionally contain up to 2 further heteroatoms from the group
consisting of N, O and S; [0156] R.sup.14 and R.sup.15 are
identical or different and independently of one another each
represents hydrogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl or (C.sub.1-C.sub.5)-alkanoyl; [0157]
and/or [0158] this radical Y may furthermore optionally be
substituted by a radical from the group consisting of oxo; cyano;
thiono; halogen; --OR.sup.16; --NR.sup.16; --NR.sup.16R.sup.17;
--C(.dbd.NR.sup.18)NR.sup.19R.sup.19' and (C.sub.1-C.sub.4)-alkyl,
in which (C.sub.1-C.sub.4)-alkyl for its part may optionally be
substituted by a radical from the group consisting of hydroxyl;
cyano; --NR.sup.16R.sup.17 and
--C(.dbd.NR.sup.18)NR.sup.19R.sup.19', [0159] where: [0160]
R.sup.16 and R.sup.17 are identical or different and independently
of one another each represents hydrogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl or (C.sub.1-C.sub.3)-alkanoyl; [0161]
R.sup.18 represents hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.3-C.sub.7)-cycloalkyl; [0162] R.sup.19 and R.sup.19' are
identical or different and independently of one another each
represents hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.3-C.sub.7)-cycloalkyl [0163] and/or [0164] R.sup.19 and
R.sup.19' together with the N atom to which they are attached form
a 5- to 7-membered heterocycle which may optionally contain up to 2
further heteroatoms from the group consisting of N, O and S.
[0165] Particular preference is given to compounds of the general
formula (I) in which the radical [0166] R.sup.2 represents a group
of the following formula:
[0166]
Y--X'--(CH.sub.2).sub.p--X--(CO).sub.n--(CH.sub.2).sub.o.sub.1--(-
CR.sup.9R.sup.10).sub.m--(CH.sub.2).sub.o.sub.2-- [0167] where
[0168] m is an integer from 0 to 3, [0169] n is an integer 0 or 1,
[0170] P is an integer 0 or 1, [0171] o.sub.1 is an integer 0 or 1,
[0172] o.sub.2 is an integer 0 or 1, [0173] R.sup.9 and R.sup.10
are identical or different and each represents hydrogen; methyl;
methoxy; hydroxyl or fluorine, [0174] X and X' are identical or
different and each represents O; N--R'' or a covalent bond, [0175]
where R.sup.11 represents H or methyl, [0176] Y represents a 5- to
7-membered saturated cyclic hydrocarbon radical which optionally
contains 1 or 2 identical or different heteroatoms and/or hetero
chain members from the group consisting of N, O, S, SO and
SO.sub.2, in particular cyclohexyl, piperazinyl, morpholinyl,
thiomorpholinyl, diazepinyl, pyrrolidinyl and piperidinyl, [0177]
where: [0178] this radical Y may optionally be substituted by a 5-
or 6-membered aromatic or a 5- to 7-membered saturated or partially
unsaturated cyclic hydrocarbon radical which optionally contains up
to 2 identical or different heteroatoms from the group consisting
of N, O and S and [0179] where this radical for its part may be
substituted by a radical from the group consisting of cyano;
hydroxyl; fluorine; chlorine; (C.sub.1-C.sub.4)-alkyl;
--C(.dbd.NR.sup.12)NR.sup.13R.sup.13'; and --NR.sup.14R.sup.15,
[0180] where: [0181] R.sup.12 represents hydrogen, methyl, ethyl,
cyclopropyl, cyclopentyl or cyclohexyl; [0182] R.sup.13 and
R.sup.13' are identical or different and independently of one
another each represents hydrogen, methyl, ethyl, cyclopropyl,
cyclopentyl or cyclohexyl [0183] and/or [0184] R.sup.13 and
R.sup.13' together with the N atom to which they are attached form
a 5- to 7-membered heterocycle which may optionally contain up to 2
further heteroatoms from the group consisting of N, O and S, in
particular piperidinyl, piperazinyl, morpholinyl and
thiomorpholinyl; [0185] R.sup.14 and R.sup.15 are identical or
different and independently of one another each represents
hydrogen, methyl, ethyl, cyclopropyl, cyclopentyl or cyclohexyl or
else acetyl; [0186] and/or [0187] this radical Y may furthermore
optionally be substituted by a radical from the group consisting of
oxo; cyano; thiono; fluorine; chlorine; --OH; --OCH.sub.3;
.dbd.NR.sup.16; --NH.sub.2; --N(CH.sub.3).sub.2;
--C(.dbd.NR.sup.18)NR.sup.19R.sup.19' and methyl, [0188] in which
methyl for its part may optionally be substituted by a radical from
the group consisting of hydroxyl; cyano; --NR.sup.16R.sup.17 and
--C(.dbd.NR.sup.18)NR.sup.19R.sup.19', [0189] where: [0190]
R.sup.16 and R.sup.17 are identical or different and independently
of one another each represents hydrogen, methyl,
(C.sub.3-C.sub.7)-cycloalkyl or acetyl; [0191] R.sup.18 represents
hydrogen, methyl or (C.sub.3-C.sub.7)-cycloalkyl; [0192] R.sup.19
and R.sup.19' are identical or different and independently of one
another each represents hydrogen, methyl or
(C.sub.3-C.sub.7)-cyclo-alkyl [0193] and/or [0194] R.sup.19 and
R.sup.19' together with the N atom to which they are attached form
a 5- to 7-membered heterocycle which may optionally contain up to 2
further heteroatoms from the group consisting of N, O and S, in
particular piperidinyl, piperazinyl, morpholinyl and
thiomorpholinyl.
[0195] Likewise, in the compounds of the general formula (I), the
radical [0196] R.sup.2 may represent a group of the formula
below:
[0196] Z--(CO).sub.t--(CR.sup.20R.sup.21).sub.s-- [0197] where:
[0198] s is an integer from 1 to 6, [0199] t is either 0 or 1,
[0200] R.sup.20 and R.sup.2' are identical or different and each
represents hydrogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkoxy, (C.sub.3-C.sub.7)-cycloalkyl, hydroxyl or
fluorine, [0201] Z represents a radical which is selected from the
group consisting of cyano; --C(NR.sup.22R.sup.23).dbd.NR.sup.24;
--CO(NH).sub.uNR.sup.22R.sup.23; and --NR.sup.25R.sup.26, [0202]
where: [0203] u is either 0 or 1, preferably 0, and [0204]
R.sup.22, R.sup.23 and R.sup.24 are identical or different and
independently of one another each represents hydrogen,
(C.sub.1-C.sub.4)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, preferably
hydrogen or methyl, [0205] and/or [0206] R.sup.22 and R.sup.23
together with the N atom to which they are attached form a 5- to
7-membered heterocycle which may optionally contain up to 2 further
heteroatoms and/or hetero chain members from the group consisting
of N, O, S, SO and SO.sub.2; [0207] R.sup.25 and R.sup.26 are
identical or different and independently of one another each
represents hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.3-C.sub.7)-cycloalkyl, preferably hydrogen, methyl or ethyl,
where (C.sub.1-C.sub.4)-alkyl and (C.sub.3-C.sub.7)-cycloalkyl for
their part may optionally be substituted by hydroxyl or
(C.sub.1-C.sub.6)-alkoxy.
[0208] Furthermore, in the compounds of the general formula (I),
the radical [0209] R.sup.2 may represent one of the following
groups: [0210] A-, [0211] A-M-, [0212] D-M-A-, [0213] B-M-A-,
[0214] B--, [0215] B-M-, [0216] B-M-B--, [0217] D-M-B--, [0218]
where: [0219] the radical "A" represents (C.sub.6-C.sub.14)-aryl,
preferably (C.sub.6-C.sub.10)-aryl, in particular phenyl or
naphthyl, very particularly preferably phenyl; [0220] the radical
"B" represents a 5- or 6-membered aromatic heterocycle which
contains up to 3 heteroatoms and/or hetero chain members, in
particular up to 2 heteroatoms and/or hetero chain members, from
the group consisting of S, N, NO (N-oxide) and O; [0221] the
radical "D" represents a saturated or partially unsaturated 4- to
7-membered heterocycle which contains up to three heteroatoms
and/or hetero chain members from the group consisting of S, SO,
SO.sub.2, N, NO (N-oxide) and O; [0222] the radical "M" represents
--NH--, --CH.sub.2--, --CH.sub.2CH.sub.2--, --O--,
--NH--CH.sub.2--, --CH.sub.2--NH--, --OCH.sub.2--, --CH.sub.2O--,
--CONH--, --NHCO--, --COO--, --OOC--, --S-- or represents a
covalent bond; [0223] where [0224] the groups "A", "B" and "D"
defined above may in each case optionally be mono- or
polysubstituted by a radical from the group consisting of halogen;
trifluoromethyl; oxo; cyano; nitro; carbamoyl; pyridyl;
(C.sub.1-C.sub.6)-alkanoyl; (C.sub.3-C.sub.7)-cycloalkanoyl;
(C.sub.6-C.sub.14)-arylcarbonyl;
(C.sub.5-C.sub.10)-heteroarylcarbonyl;
(C.sub.1-C.sub.6)-alkanoyloxymethyloxy; --COOR.sup.27;
--SO.sub.2R.sup.27; --C(NR.sup.27R.sup.28).dbd.NR.sup.29;
--CONR.sup.28R.sup.29; --SO.sub.2NR.sup.28R.sup.29; --OR.sup.30;
--R.sup.30R.sup.31, (C.sub.1-C.sub.6)-alkyl and
(C.sub.3-C.sub.7)-cycloalkyl, [0225] where (C.sub.1-C.sub.6)-alkyl
and (C.sub.3-C.sub.7)-cycloalkyl for their part may optionally be
substituted by a radical from the group consisting of cyano;
--OR.sup.27; --NR.sup.28R.sup.29; --CO(NH).sub.v(NR.sup.27R.sup.28)
and --C(NR.sup.27R.sup.28).dbd.NR.sup.29, [0226] where: [0227] v is
either 0 or 1 and [0228] R.sup.27, R.sup.28 and R.sup.29 are
identical or different and independently of one another each
represents hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.3-C.sub.7)-cycloalkyl and/or [0229] R.sup.27 and R.sup.28 or
R.sup.27 and R.sup.29 together with the nitrogen atom to which they
are attached form a saturated or partially unsaturated 5- to
7-membered heterocycle having up to three, preferably up to two,
identical or different heteroatoms from the group consisting of N,
O and S, and [0230] R.sup.30 and R.sup.31 are identical or
different and independently of one another each represents
hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.4)-alkyl-sulphonyl, (C.sub.1-C.sub.4)-hydroxyalkyl,
(C.sub.1-C.sub.4)-aminoalkyl,
di-(C.sub.1-C.sub.4)-alkylamino-(C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkanoyl, (C.sub.6-C.sub.14)-arylcarbonyl,
(C.sub.5-C.sub.10)-heteroarylcarbonyl, (C.sub.1-C.sub.4)-alkylamino
carbonyl or --CH.sub.2C(NR.sup.27R.sup.28).dbd.NR.sup.29.
[0231] Preference is also given to compounds of the general formula
(I) in which the radical [0232] R.sup.2 represents one of the
groups below: [0233] A-, [0234] A-M-, [0235] D-M-A-, [0236] B-M-A-,
[0237] B--, [0238] B-M-, [0239] B-M-B--, [0240] D-M-B--, [0241]
where: [0242] the radical "A" represents phenyl or naphthyl, in
particular phenyl; [0243] the radical "B" represents a 5- or
6-membered aromatic heterocycle which contains up to 2 heteroatoms
from the group consisting of S, N, NO (N-oxide) and O; [0244] the
radical "D" represents a saturated or partially unsaturated 5- or
6-membered heterocycle which contains up to two heteroatoms and/or
hetero chain members from the group consisting of S, SO, SO.sub.2,
N, NO (N-oxide) and O; [0245] the radical "M" represents --NH--,
--O--, --NH--CH.sub.2--, --CH.sub.2--NH--, --OCH.sub.2--,
--CH.sub.2O--, --CONH--, --NHCO-- or represents a covalent bond;
[0246] where [0247] the groups "A", "B" and "D" defined above may
in each case optionally be mono- or polysubstituted by a radical
from the group consisting of halogen; trifluoromethyl; oxo; cyano;
pyridyl; (C.sub.1-C.sub.3)-alkanoyl;
(C.sub.6-C.sub.10)-arylcarbonyl;
(C.sub.5-C.sub.6)-heteroarylcarbonyl;
(C.sub.1-C.sub.3)-alkanoyloxymethyloxy;
--C(NR.sup.27R.sup.28).dbd.NR.sup.29; --CONR.sup.28R.sup.29;
--SO.sub.2NR.sup.28R.sup.29; --OH; --NR.sup.30R.sup.31;
(C.sub.1-C.sub.4)-alkyl; and cyclopropyl, cyclopentyl or
cyclohexyl, [0248] where (C.sub.1-C.sub.4)-alkyl and cyclopropyl,
cyclopentyl or cyclohexyl for their part may optionally be
substituted, by a radical from the group consisting of cyano; --OH;
--OCH.sub.3; --NR.sup.28R.sup.29; --CO(NH).sub.v(NR.sup.27R.sup.28)
and --C(NR.sup.27R.sup.28).dbd.NR.sup.29, [0249] where: [0250] v is
either 0 or 1, preferably 0, and [0251] R.sup.27, R.sup.28 and
R.sup.29 are identical or different and independently of one
another each represents hydrogen, (C.sub.1-C.sub.4)-alkyl or else
cyclopropyl, cyclopentyl or cyclohexyl [0252] and/or [0253]
R.sup.27 and R.sup.28 or R.sup.27 and R.sup.29 together with the
nitrogen atom to which they are attached may form a saturated or
partially unsaturated 5- to 7-membered heterocycle having up to two
identical or different heteroatoms from the group consisting of N,
O and S, and [0254] R.sup.30 and R.sup.31 are identical or
different and independently of one another each represents
hydrogen, (C.sub.1-C.sub.4)-alkyl, cyclopropyl, cyclopentyl,
cyclohexyl, (C.sub.1-C.sub.4)-alkylsulphonyl,
(C.sub.1-C.sub.4)-hydroxyalkyl, (C.sub.1-C.sub.4)-aminoalkyl,
di-(C.sub.1-C.sub.4)-alkylamino-(C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.3)-alkanoyl or phenylcarbonyl.
[0255] Likewise, in the compounds of the general formula (I), the
radical [0256] R.sup.2 may represent a group of the following
formula:
[0256] ##STR00004## [0257] where [0258] R.sup.32 represents
hydrogen or (C.sub.1-C.sub.4)-alkyl, preferably hydrogen or methyl,
and [0259] W represents S, NH or O, preferably S.
[0260] Moreover, in the compounds of the general formula (I), the
radical [0261] R.sup.2 may be a group of the formula below
##STR00005##
[0262] Finally, in the compounds of the general formula (I), the
radical [0263] R.sup.2 may be a group of the formula below
##STR00006##
[0263] DETAILED DESCRIPTION
[0264] To date, oxazolidinones have essentially only been described
as antibiotics, and in individual cases also as MAO inhibitors and
fibrinogen antagonists (review: Riedl, B., Endermann, R., Exp.
Opin. Ther. Patents 1999, 9 (5), 625), where a small
5-[acyl-aminomethyl] group (preferably 5-[acetylaminomethyl])
appears to be essential for the antibacterial activity.
[0265] Substituted aryl- and heteroarylphenyloxazolidinones in
which a mono- or polysubstituted phenyl radical may be attached to
the N atom of the oxazolidinone ring and which may have an
unsubstituted N-methyl-2-thiophenecarboxamide radical in the
5-position of the oxazolidinone ring, and their use as
antibacterial substances, are known from U.S. Pat. No. 5,929,248,
U.S. Pat. No. 5,801,246, U.S. Pat. No. 5,756,732, U.S. Pat. No.
5,654,435, U.S. Pat. No. 5,654,428 and U.S. Pat. No. 5,565,571.
[0266] In addition, benzamidine-containing oxazolidinones are known
as synthetic intermediates in the synthesis of factor Xa inhibitors
and/or fibrinogen antagonists (WO-A-99/31092, EP-A-623615).
[0267] Depending on the substitution pattern, the compounds of the
general formula (I) according to the invention may exist in
stereoisomeric forms which are either like image and mirror image
(enantiomers) or not like image and mirror image (diastereomers).
The invention relates both to the enantiomers or diastereomers and
to their respective mixtures. The racemic forms, like the
diastereomers, can be separated in a known manner into the
stereoisomerically uniform components.
[0268] Furthermore, certain compounds of the general formula (I)
can be present in tautomeric forms. This is known to the person
skilled in the art, and such compounds are likewise within the
scope of the invention.
[0269] Physiologically acceptable, i.e. pharmaceutically
compatible, salts can be salts of the compounds according to the
invention with inorganic or organic acids. Preference is given to
salts with inorganic acids, such as, for example, hydrochloric
acid, hydrobromic acid, phosphoric acid or sulphuric acid, or to
salts with organic carboxylic or sulphonic acids, such as, for
example, acetic acid, trifluoroacetic acid, propionic acid, maleic
acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic
acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid,
benzenesulphonic acid, toluenesulphonic acid or
naphthalenedisulphonic acid.
[0270] Other pharmaceutically compatible salts which may be
mentioned are salts with customary bases, such as, for example,
alkali metal salts (for example sodium or potassium salts),
alkaline earth metal salts (for example calcium or magnesium salts)
or ammonium salts, derived from ammonia or organic amines, such as,
for example, diethylamine, triethylamine, ethyldiisopropylamine,
procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine or
methylpiperidine.
[0271] According to the invention, "hydrates" are forms of the
compounds of the general formula (I) above which form a molecule
compound (solvate) in the solid or liquid state by hydration with
water. In the hydrates, the water molecules are attached through
secondary valencies by intermolecular forces, in particular
hydrogen bridges. Solid hydrates contain water as so-called crystal
water in stoichiometric ratios, where the water molecules do not
have to be equivalent with respect to their binding state. Examples
of hydrates are sesquihydrates, monohydrates, dihydrates or
trihydrates. Equally suitable are the hydrates of salts of the
compounds according to the invention.
[0272] According to the invention, "prodrugs" are forms of the
compounds of the general formula (I) above which for their part can
be biologically active or inactive, but which can be converted into
the corresponding biologically active form (for example
metabolically, solvolytically or in another way).
[0273] Halogen represents fluorine, chlorine, bromine and iodine.
Preference is given to chlorine or fluorine.
[0274] (C.sub.1-C.sub.8)-Alkyl represents a straight-chain or
branched alkyl radical having 1 to 8 carbon atoms. Examples which
may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, tert-butyl, n-pentyl and n-hexyl. The corresponding alkyl
groups with fewer carbon atoms, such as, for example,
(C.sub.1-C.sub.6)-alkyl and (C.sub.1-C.sub.4)-alkyl, are derived
analogously from this definition. In general, preference is given
to (C.sub.1-C.sub.4)-alkyl.
[0275] The meaning of the corresponding component of other more
complex substituents, such as, for example, alkylsulphonyl,
hydroxyalkyl, hydroxyalkylcarbonyl, alkoxy-alkyl,
alkoxycarbonyl-alkyl, alkanoylalkyl, aminoalkyl or alkylaminoalkyl
is likewise derived from this definition,
[0276] (C.sub.3-C.sub.7)-Cycloalkyl represents a cyclic alkyl
radical having 3 to 7 carbon atoms. Examples which may be mentioned
are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl. The corresponding cycloalkyl groups having fewer
carbon atoms, such as, for example, (C.sub.3-C.sub.5)-cycloalkyl,
are derived analogously from this definition. Preference is given
to cyclopropyl, cyclopentyl and cyclohexyl.
[0277] The meaning of the corresponding component of other more
complex substituents, such as, for example, cycloalkanoyl, is
likewise derived from this definition.
[0278] In the context of the invention, (C.sub.2-C.sub.6)-alkenyl
represents a straight-chain or branched alkenyl radical having 2 to
6 carbon atoms. Preference is given to a straight-chain or branched
alkenyl radical having 2 to 4 carbon atoms. Examples which may be
mentioned are: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.
[0279] (C.sub.1-C.sub.8)-Alkoxy represents a straight-chain or
branched alkoxy radical, having 1 to 8 carbon atoms. Examples which
may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy, n-heptoxy
and n-octoxy. The corresponding alkoxy groups having fewer carbon
atoms, such as, for example, (C.sub.1-C.sub.6)-alkoxy and
(C.sub.1-C.sub.4)-Alkoxy, are derived analogously from this
definition. In general, preference is given to
(C.sub.1-C.sub.4)-alkoxy.
[0280] The meaning of the corresponding component of other more
complex substituents, such as, for example alkoxy-alkyl,
alkoxycarbonyl-alkyl and alkoxycarbonyl, is likewise derived from
this definition.
[0281] Mono- or di-(C.sub.1-C.sub.4)-alkylaminocarbonyl represents
an amino group which is attached via a carbonyl group and which has
a straight-chain or branched or two identical or different
straight-chain or branched alkyl substitutents having in each case
1 to 4 carbon atoms. Examples which may be mentioned are:
methylamino, ethylamino, n-propylamino, isopropylamino,
t-butylamino, N,N-dimethylamino, N,N-diethylamino,
N-ethyl-N-methylamino, N-methyl-N-n-propylamino,
N-isopropyl-N-n-propylamino and N-t-butyl-N-methylamino.
[0282] (C.sub.1-C.sub.6)-Alkanoyl represents a straight-chain or
branched alkyl radical having 1 to 6 carbon atoms which carries a
doubly attached oxygen atom in the 1-position and is attached via
the 1-position. Examples which may be mentioned are: formyl,
acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl, n-hexanoyl. The
corresponding alkanoyl groups with fewer carbon atoms, such as, for
example, (C.sub.1-C.sub.5)-alkanoyl, (C.sub.1-C.sub.4)-alkanoyl and
(C.sub.1-C.sub.3)-alkanoyl, are derived analogously from this
definition. In general, preference is given to
(C.sub.1-C.sub.3)-alkanoyl.
[0283] The meaning of the corresponding component of other more
complex substituents, such as, for example, cycloalkanoyl and
alkanoylalkyl, is likewise derived from this definition.
[0284] (C.sub.3-C.sub.7)-Cycloalkanoyl represents a cycloalkyl
radical having 3 to 7 carbon atoms as defined above which is
attached via a carbonyl group.
[0285] (C.sub.1-C.sub.6)-Alkanoyloxymethyloxy represents a
straight-chain or branched alkanoyloxymethyloxy radical having 1 to
6 carbon atoms. Examples which may be mentioned are:
acetoxymethyloxy, propionoxymethyloxy, n-butyroxymethyloxy,
i-butyroxymethyloxy, pivaloyloxymethyloxy, n-hexanoyloxymethyloxy.
The corresponding alkanoyloxymethyloxy groups having fewer carbon
atoms, such as, for example,
(C.sub.1-C.sub.3)-alkanoyloxymethyloxy, are derived analogously
from this definition. In general, preference is given to
(C.sub.1-C.sub.3)-alkanoyloxymethyloxy.
[0286] (C.sub.6-C.sub.14)-Aryl represents an aromatic radical
having 6 to 14 carbon atoms. Examples which may be mentioned are:
phenyl, naphthyl, phenanthrenyl and anthracenyl. The corresponding
aryl groups with fewer carbon atoms, such as, for example,
(C.sub.6-C.sub.10)-aryl are derived analogously from this
definition. In general, preference is given to
(C.sub.6-C.sub.10)-aryl.
[0287] The meaning of the corresponding component of other more
complex substituents, such as, for example, arylcarbonyl, is
likewise derived from this definition.
[0288] (C.sub.5-C.sub.10)-Heteroaryl or a 5- to 10-membered
aromatic heterocycle having up to 3 heteroatoms and/or hetero chain
members from the group consisting of S, O, N and NO (N-oxide)
represents a mono- or bicyclic heteroaromatic which is attached via
a carbon ring atom of the heteroaromatic or, if appropriate, via a
nitrogen ring atom of the heteroaromatic. Examples which may be
mentioned are: pyridyl, pyridyl N-oxide, pyrimidyl, pyridazinyl,
pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,
thiazolyl, oxazolyl or isoxazolyl, indolinyl, indolyl,
benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl, isoquinolyl,
naphthyridinyl, quinazolinyl. The corresponding heterocycles having
a smaller ring size, such as, for example, 5- or 6-membered
aromatic heterocycles, are derived analogously from this
definition. In general, preference is given to 5- or 6-membered
aromatic heterocycles, such as, for example, pyridyl, pyridyl
N-oxide, pyrimidyl, pyridazinyl, furyl and thienyl.
[0289] The meaning of the corresponding component of other more
complex substituents, such as, for example,
(C.sub.5-C.sub.10)-heteroarylcarbonyl, is likewise derived from
this definition.
[0290] A 3- to 9-membered saturated or partially unsaturated, mono-
or bicyclic, optionally benzo-fused heterocycle having up to 3
heteroatoms and/or hetero chain members from the group consisting
of S, SO, SO.sub.2, N, NO (N-oxide) and O represents a heterocycle
which may contain one or more double bonds, which may be mono- or
bicyclic, to which a benzene ring may be fused to two adjacent
carbon ring atoms and which is attached via a carbon ring atom or a
nitrogen ring atom. Examples which may be mentioned are:
tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl,
1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl,
morpholinyl, morpholinyl N-oxide, thiomorpholinyl, azepinyl, and
1,4-diazepinyl. Preference is given to piperidinyl, morpholinyl and
pyrrolidinyl.
[0291] The corresponding cycles having a smaller ring size, such
as, for example, 5- to 7-membered cycles, are derived analogously
from this definition. The present invention also provides a process
for preparing the compounds of the general formula (I) according to
the invention where either, according to one process
alternative
[A] compounds of the general formula (II)
##STR00007## [0292] in which [0293] the radicals R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each as defined
above, [0294] are reacted with carboxylic acids of the general
formula (III)
[0294] ##STR00008## [0295] in which [0296] the radical R.sup.1 is
as defined above, [0297] or else with the corresponding carbonyl
halides, preferably carbonyl chlorides, or else with the
corresponding symmetric or mixed carboxylic anhydrides of the
carboxylic acids of the general formula (III) defined above in
inert solvents, if appropriate in the presence of an activating or
coupling agent and/or a base, to give compounds of the general
formula (I)
[0297] ##STR00009## [0298] in which [0299] the radicals R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8
are each as defined above, [0300] or else according to a process
alternative [B] compounds of the general formula (IV)
[0300] ##STR00010## [0301] in which [0302] the radicals R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each as
defined above, [0303] are converted, using a suitable selective
oxidizing agent in an inert solvent, into the corresponding epoxide
of the general formula (V)
[0303] ##STR00011## [0304] in which [0305] the radicals R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each as
defined above, [0306] and, by reaction in an inert solvent, if
appropriate in the presence of a catalyst, with an amine of the
general formula (VI)
[0306] R.sup.2--NH.sub.2 (VI), [0307] in which [0308] the radical
R.sup.2 is as defined above, [0309] the compounds of the general
formula (VII)
[0309] ##STR00012## [0310] in which [0311] the radicals R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8
are each as defined above, [0312] are initially prepared and [0313]
subsequently, in an inert solvent in the presence of phosgene or
phosgene equivalents, such as, for example, carbonyldiimidazole
(CDI), cyclized to give the compounds of the general formula
(I)
[0313] ##STR00013## [0314] in which [0315] the radicals R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8
are each as defined above, [0316] where--both for process
alternative [A] and for process alternative [B]--in the case where
R.sup.2 contains a 3- to 7-membered saturated or partially
unsaturated cyclic hydrocarbon radical having one or more identical
or different heteroatoms from the group consisting of N and S, an
oxidation with a selective oxidizing agent to afford the
corresponding sulphone, sulphoxide or N-oxide may follow [0317]
and/or [0318] where--both for process alternative [A] and for
process alternative [B]--in the case where the compound prepared in
this manner has a cyano group in the molecule, an amidination of
this cyano group by customary methods may follow [0319] and/or
[0320] where--both for process alternative [A] and for process
alternative [B]--in the case where the compound prepared in this
manner has a BOC amino protective group in the molecule, removal of
this BOC amino protective group by customary methods may follow
[0321] and/or [0322] where--both for process alternative [A] and
for process alternative [B]--in the case where the compound
prepared in this manner has an aniline or benzylamine radical in
the molecule, a reaction of this amino group with various reagents
such as carboxylic acids, carboxylic anhydrides, carbonyl
chlorides, isocyanates, sulphonyl chlorides or alkyl halides to
give the corresponding derivatives may follow [0323] and/or [0324]
where--both for process alternative [A] and for process alternative
[B]--in the case where the compound prepared in this manner has a
phenyl ring in the molecule, a reaction with chlorosulphonic acid
and subsequent reaction with amines to give the corresponding
sulphonamides may follow,
[0325] The processes according to the invention can be illustrated
in an exemplary manner by the equations below:
[A]
##STR00014## ##STR00015##
[0327] The oxidation step described above, which is optional, can
be illustrated in an exemplary manner by the equation below:
##STR00016##
[0328] Suitable solvents for the processes described above are
organic solvents which are inert under the reaction conditions.
These include halogenated hydrocarbons, such as dichloromethane,
trichloromethane, carbon tetrachloride, 1,2-dichloroethane,
trichloroethane, tetrachloroethane, 1,2-dichloroethylene or
trichloroethylene, ethers, such as diethyl ether, dioxane,
tetrahydrofuran, glycol dimethyl ether or diethylene glycol
dimethyl ether, alcohols, such as methanol, ethanol, n-propanol,
isopropanol, n-butanol or tert-butanol, hydrocarbons, such as
benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide,
dimethyl sulphoxide, acetonitrile, pyridine, hexa-methylphosphoric
triamide or water.
[0329] It is also possible to use solvent mixtures of the solvents
mentioned above.
[0330] Suitable activating or coupling agents for the processes
described above are the reagents which are customarily used for
this purpose, for example
N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide.HCl,
N,N'-dicyclohexylcarbodiimide, 1-hydroxy-1H-benzotriazole.H.sub.2O
and the like.
[0331] Suitable bases are the customary inorganic or organic bases.
These preferably include alkali metal hydroxides, such as, for
example, sodium hydroxide or potassium hydroxide, or alkali metal
carbonates, such as sodium carbonate or potassium carbonate, or
sodium methoxide or potassium methoxide or sodium ethoxide or
potassium ethoxide or potassium-tert-butoxide, or amides, such as
sodium amide, lithium bis-(trimethylsilyl)amide or lithium
diisopropylamide, or amines, such as triethylamine,
diisopropylethylamine, diisopropylamine,
4-N,N-dimethylaminopyridine or pyridine.
[0332] The base can be employed here in an amount of from 1 to 5
mol, preferably from 1 to 2 mol, based on 1 mol of the compounds of
the general formula (II).
[0333] The reactions are generally carried out in a temperature
range of from -78.degree. C. to reflux temperature, preferably in
the range from 0.degree. C. to reflux temperature.
[0334] The reactions can be carried out at atmospheric, elevated or
reduced pressure (for example in the range from 0.5 to 5 bar). In
general, the reactions are carried out at atmospheric pressure.
[0335] Suitable selective oxidizing agents, both for the
preparation of the epoxides and for the optional oxidation to give
the sulphone, sulphoxide or N-oxide, are m-chloroperbenzoic acid
(MCPBA), sodium metaperiodate, N-methylmorpholine N-oxide (NMO),
monoperoxyphthalic acid or osmium tetroxide.
[0336] With respect to the preparation of the epoxides, the
preparation conditions which are customary for this purpose are
employed.
[0337] With respect to more detailed process conditions for the
optional oxidation to give the sulphone, sulphoxide or N-oxide,
reference is made to the following literature: M. R. Barbachyn et
al., J. Med. Chem. 1996, 39, 680 and WO-A-97/10223.
[0338] Furthermore, reference is made to Examples 14 to 16 given in
the experimental part.
[0339] The optional amidation is carried out under customary
conditions. For more details, reference is made to Examples 31 to
35 and 140 to 147.
[0340] The compounds of the general formulae (II), (III), (IV) and
(VI) are known per se to the person skilled in the art or can be
prepared by customary methods. For oxazolidinones, in particular
the 5-(aminomethyl)-2-oxooxazolidines required, cf. WO-A-98/01446;
WO-A-93/23384; WO-A-97/03072; J. A. Tucker et al., J. Med. Chem.
1998, 41, 3727; S. J. Brickner et al., J. Med. Chem. 1996, 39, 673;
W. A. Gregory et al., J. Med. Chem. 1989, 32, 1673.
[0341] The compounds of the general formula (I) according to the
invention have an unforeseeable useful pharmacological activity
spectrum and are therefore particularly suitable for the
prophylaxis and/or treatment of disorders.
[0342] The compounds of the general formula (I) according to the
ivnention--including the compounds which are excluded by disclaimer
from the chemical product protection--act in particular as
anticoagulants and can therefore preferably be employed in
medicaments for the prophylaxis and/or therapy of thromboembolic
disorders. For the purpose of the present invention,
"thromboembolic disorders" include, in particular, serious
disorders such as myocardial infarct, angina pectoris (including
unstable angina), reocclusions and restenoses after angioplasty or
aortocoronary bypass, stroke, transitory ischaemic attacks,
peripheral arterial occlusion disorders, pulmonary embolisms or
deep venous thromboses.
[0343] Furthermore, the compounds of the general formula (I)
according to the invention--including the compounds which are
excluded by disclaimer from the chemical product protection--are
also suitable for treating disseminated intravascular coagulation
(DIC).
[0344] Finally, the compounds of the general formula (I) according
to the invention--including the compounds which are excluded by
disclaimer from the chemical product protection--are also suitable
for the prophylaxis and/or treatment of atherosclerosis and
arthritis, and additionally also for the prophylaxis and/or
treatment of Alzheimer's disease and cancer.
[0345] The compounds of the general formula (I) according to the
invention--including the compounds excluded by disclaimer from the
chemical product protection--act in particular as selective
inhibitors of the blood coagulation factor Xa and do not inhibit,
or only inhibit at considerably higher concentrations, other serine
proteases as well, such as thrombin, plasmin or trypsin.
[0346] In the context of the present invention, inhibitors of the
blood coagulation factor Xa in which the IC.sub.50 values for the
factor Xa inhibition are lower by a factor of 100, preferably by a
factor of 500, in particular by a factor of 1000, than the
IC.sub.50 values for the inhibition of other serine proteases, in
particular thrombin, plasmin and trypsin, are referred to as being
"selective", where with a view to the test methods for selectivity,
reference is made to the test methods of Examples A-1) a.1) and
a.2) described below.
[0347] The compounds of the general formula (I) according to the
invention--including the compounds which are excluded by disclaimer
from the chemical product protection--can furthermore be used for
preventing coagulation ex vivo, for example for banked blood or
biological samples which contain factor Xa.
[0348] The present invention thus provides oxazolidinones of the
formula (I) effecting in particular an unexpected, strong and
selective inhibition of factor Xa, and this also applies to the
compounds excluded by disclaimer from the chemical product
protection.
[0349] The present invention further provides medicaments and
pharmaceutical compositions comprising at least one compound of the
general formula (I) according to the invention together with one or
more pharmacologically acceptable auxiliaries or excipients, which
medicaments and pharmaceutical compositions can be used for the
indications mentioned above.
[0350] Furthermore, the present invention relates to a method for
the prophylaxis and/or treatment of disorders of the human or
animal body, in particular of the abovementioned disorders, using
the compounds of the general formula (I) according to the
invention--including the compounds excluded by disclaimer from the
chemical product protection.
[0351] Furthermore, the present invention also includes a method
for preventing blood coagulation in vitro, in particular in banked
blood or biological samples which contain factor Xa, which method
is characterized in that compounds of the general formula
(I)--including the compounds excluded by disclaimer from the
chemical product protection--are added.
[0352] All customary administration forms are suitable for
administration of the compounds according to the invention.
Administration is preferably carried out orally, lingually,
sublingually, buccally, rectally or parenterally (i.e. bypassing
the intestinal tract, that is intravenously, intraarterially,
intracardially, intracutaneously, subcutaneously, transdermally,
intraperitoneally or intramuscularly). Particularly suitable are
oral and intravenous administration. Very particular preference is
given to oral administration, this being a further advantage with
respect to the prior-art therapy of thromboembolic disorders.
[0353] The novel active compounds of the general formula (I) can be
converted in a known manner into the customary formulations, such
as tablets, sugar-coated tablets, pills, granules, aerosols,
syrups, emulsions, suspensions and solutions, using inert non-toxic
pharmaceutically suitable excipients or solvents. Here, the
therapeutically active compound should in each case be present in a
concentration of from about 0.1 to 95% by weight, preferably from
0.5 to 90% by weight, in particular from 1 to 85% by weight, of the
total mixture, i.e. in amounts which are sufficient in order to
achieve the dosage range indicated.
[0354] In spite of this, if appropriate, it may be necessary to
depart from the amounts mentioned, namely depending on the body
weight or on the type of administration route, on the individual
response to the medicament, on the manner of its formulation and
the time or interval at which administration takes place. Thus, in
some cases it may be adequate to manage with less than the
abovementioned minimum amount, while in other cases the upper limit
mentioned must be exceeded. In the case of the administration of
relatively large amounts, it may be advisable to divide these into
several individual administrations over the course of the day.
[0355] The formulations are prepared, for example, by extending the
active compounds with solvents and/or excipients, if appropriate
using emulsifiers and/or dispersants, it being possible, for
example if the diluent used is water, optionally to use organic
solvents as auxiliary solvents.
[0356] In general it has proved advantageous in the case of
intravenous administration to administer amounts from approximately
0.001 to 10 mg/kg, preferably approximately 0.01 to 10 mg/kg, in
particular approximately 0.1 to 8 mg/kg, of body weight to achieve
effective results.
[0357] In general, it has proved advantageous in the case of oral
administration to administer amounts from approximately 0.01 to 50
mg/kg, preferably approximately 0.1 to 10 mg/kg, in particular
approximately 0.5 to 8 mg/kg, of body weight to achieve effective
results.
[0358] In spite of this, if appropriate, it may be necessary in the
case of intravenous or oral administration to depart from the
amounts mentioned, namely depending on the body weight or on the
type of administration route, on the individual response to the
medicament, on the manner of its formulation and the time or
interval at which administration takes place. Thus, in some cases
it may be adequate to manage with less than the abovementioned
minimum amount, while in other cases the upper limit mentioned must
be exceeded. In the case of the administration of relatively large
amounts, it may be advisable to divide these over the course of the
day, namely into several individual doses or as a continuous
infusion.
[0359] Compared to the conventional preparations for treating
thromboembolic disorders, the compounds of the general formula (I)
according to the invention--including the compounds excluded by
disclaimer from the chemical product protection--are distinguished
in particular by the fact that a greater therapeutic range is
achieved by the selective inhibition of factor Xa. For the patient,
this means a lower risk of bleeding, and for the treating
physician, this means that the patient is easier to adjust.
Moreover--owing to the mechanism--the onset of action is more
rapid. Above all, however, the compounds according to the invention
permit an oral administration form, which is a further advantage of
the therapy with the compounds according to the invention.
[0360] The present invention is illustrated by the examples below;
however, these examples are not meant to restrict the invention in
any way.
EXAMPLES
A Evaluation of the Physiological Activity
[0361] 1. General Test Methods
[0362] The particularly advantageous biological properties of the
compounds according to the invention can be determined by the
following methods.
a) Test Description (In Vitro)
a.1) Determination of the Factor Xa Inhibition
[0363] The enzymatic activity of human factor Xa (FXa) was measured
using the conversion of a chromogenic substrate specific for FXa.
Factor Xa cleaves p-nitroaniline from the chromogenic substrate.
The determinations were carried out in microtitre plates as
follows.
[0364] The test substances, in various concentrations, were
dissolved in DMSO and incubated at 25.degree. C. with human FXa
(0.5 nmol/l dissolved in 50 mmol/l of tris buffer
[C,C,C-tris(hydroxymethyl)-aminomethane], 150 mmol/l of NaCl, 0.1%
BSA (bovine serum albumin), pH=8.3) for 10 minutes. Pure DMSO was
used as control. The chromogenic substrate (150 .mu.mol/l of
Pefachrome.RTM. FXa from Pentapharm) was then added. After an
incubation time of 20 minutes at 25.degree. C., the extinction at
405 nm was determined. The extinctions of the test mixtures
containing test substance were compared with the control mixtures
without test substance, and the IC.sub.50 values were calculated
from these data.
a.2) Determination of the Selectivity
[0365] To assess selective FXa inhibition, the test substances were
examined for their inhibition of other human serine proteases such
as thrombin, trypsin and plasmin. To determine the enzymatic
activity of thrombin (75 mU/ml), trypsin (500 mU/ml) and plasmin
(3.2 nmol/1), these enzymes were dissolved in tris buffer (100
mmol/l, 20 mmol/l CaCl.sub.2, pH=8.0) and incubated with test
substance or solvent for 10 minutes. The enzymatic reaction was
then started by adding the corresponding specific chromogenic
substrates (Chromozym Thrombin.RTM. from Boehringer Mannheim,
Chromozym Trypsin.RTM. from Boehringer Mannheim, Chromozym
Plasmin.RTM. from Boehringer Mannheim) and the extinction at 405 nm
was determined after 20 minutes. All determinations were carried
out at 37.degree. C. The extinctions of the test mixtures
containing test substance were compared with the control samples
without test substance, and the IC.sub.50 values were calculated
from these data.
a.3) Determination of the Anticoagulant Action
[0366] The anticoagulant action of the test substances was
determined in vitro in human plasma. To this end, human blood was
drawn off in a mixing ratio of sodium citrate/blood of 1/9 using a
0.11 molar sodium citrate solution as receiver. Immediately after
the blood had been drawn off, it was mixed thoroughly and
centrifuged at about 2000 g for 10 minutes. The supernatant was
pipetted off. The prothrombin time (PT, synonyms: thromboplastin
time, quick test) was determined in the presence of varying
concentrations of test substance or the corresponding solvent using
a commercial test kit (Neoplastin.RTM. from Boehringer Mannheim).
The test compounds were incubated with the plasma at 37.degree. C.
for 10 minutes. Coagulation was then started by addition of
thromboplastin, and the time when coagulation occurred was
determined. The concentration of test substance which effected a
doubling of the prothrombin time was determined.
b) Determination of the Antithrombotic Activity (In Vivo)
b.1) Arteriovenous Shunt Model (Rat)
[0367] Fasting male rats (strain: HSD CPB:WU) having a weight of
200-250 g were anaesthetized using a Rompun/Ketavet solution (12
mg/kg/50 mg/kg). Thrombus formation was initiated in an
arteriovenous shunt in accordance with the method described by
Christopher N. Berry et al., Br. J. Pharmacol. (1994), 113,
1209-1214. To this end, the left jugular vein and the right carotid
artery were exposed. The two vessels were connected by an
extracorporeal shunt using a polyethylene tube (PE 60) of a length
of 10 cm. In the middle, this polyethylene tube was attached to a
further polyethylene tube (PE 160) of a length of 3 cm which
contained a roughened nylon thread which had been arranged to form
a loop, to form a thrombogenic surface. The extracorporeal
circulation was maintained for 15 minutes. The shunt was then
removed and the nylon thread with the thrombus was weighed
immediately. The weight of the nylon thread on its own had been
determined before the experiment was started. Before the
extracorporeal circulation was set up, the test substances were
administered to the animals while awake either intravenously via
the tail vein or orally using a pharyngeal tube.
[0368] The results are shown in Table 1:
TABLE-US-00001 TABLE 1 Antithrombotic activity in the arteriovenous
shunt model (rat) after oral or intravenous administration Example
ED.sub.50 [mg/kg] p.o. ED.sub.50 [mg/kg] i.v. 1 10 17 6 44 3 95 3
114 3 115 3 123 3 162 3
b.2) Arterial Thrombosis Model (Rat)
[0369] Male fasting rats (strain: HSD CPB: WU) were anaesthetized
as described above. On average, the rats had a weight of about 200
g. The left carotid artery was exposed (about 2 cm). The formation
of an arterial thrombus was induced by mechanical injury to the
blood vessel in accordance with the method described by K. Meng et
al., Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119.
To this end, the exposed carotid artery was clamped from the blood
flow, cooled to -12.degree. C. in a metal trough for 2 minutes and,
to standardize the size of the thrombi, simultaneously compressed
using a weight of 200 g. The blood flow was then additionally
reduced by a clip which was placed around the carotid artery
distally from the injured section of the vessel. The proximal clamp
was removed, and the wound was closed and re-opened after 4 hours
to remove the injured section of the vessel. The section of the
vessel was opened longitudinally and the thrombus was removed from
the injured section of the vessel. The moist weight of the thrombi
was determined immediately. The test substances were administered
to the animals while awake at the beginning of the experiment,
either intravenously via the tail vein or orally using a pharyngeal
tube.
b.3) Venous Thrombosis Model (Rat)
[0370] Male fasting rats (strain: HSD CPB: WU) were anaesthetized
as described above. On average, the rats had a weight of about 200
g. The left jugular vein was exposed (about 2 cm). The formation of
a venous thrombus was induced by mechanical injury to the blood
vessel in accordance with the method described by K. Meng et al.,
Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. To
this end, the jugular vein was clamped from the blood flow, cooled
to -12.degree. C. in a metal trough for 2 minutes and, to
standardize the size of the thrombi, simultaneously compressed
using a weight of 200 g. The blood flow was re-opened and the wound
was closed. After 4 hours, the wound was re-opened to remove the
thrombi from the injured sections of the vessel. The moist weight
of the thrombi was determined immediately. The test substances were
administered to the animals while awake at the beginning of the
experiment, either intravenously via the tail vein or orally using
a pharyngeal tube.
B Preparation Examples
Starting Materials
[0371] The preparation of 3-morpholinone is described in U.S. Pat.
No. 5,349,045.
[0372] The preparation of N-(2,3-epoxypropyl)phthalimide is
described in J.-W. Chern et al. Tetrahedron Lett. 1998, 39,
8483.
[0373] The substituted anilines can be obtained by reacting, for
example, 4-fluoronitrobenzene, 2,4-difluoronitrobenzene or
4-chloronitrobenzene with the appropriate amines or amides in the
presence of a base. This can also be carried out using Pd
catalysts, such as Pd(OAc).sub.2/DPPF/NaOt-Bu (Tetrahedron Lett.
1999, 40, 2035) or copper (Renger, Synthesis 1985, 856; Aebischer
et al., Heterocycles 1998, 48, 2225). Likewise, it is possible to
initially convert halogenated aromatics without nitro group into
the corresponding amides, followed by nitration in the 4-position
(U.S. Pat. No. 3,279,880).
I. 4-(4-Morpholin-3-onyl)nitrobenzene
##STR00017##
[0374] 2 mol (202 g) of morpholin-3-one (E. Pfeil, U. Harder,
Angew. Chem. 79, 1967, 188) are dissolved in 21 of
N-methylpyrrolidone (NMP). Over a period of 2 h, 88 g (2.2 mol) of
sodium hydride (60% in paraffin) are then added a little at a time.
After the evolution of hydrogen has ceased, 282 g (2 mol) of
4-fluoronitrobenzene are added dropwise with cooling at room
temperature, over a period of 1 h, and the reaction mixture is then
stirred overnight. At 12 mbar and 76.degree. C., 1.7 l of the
liquid volume are then distilled off, the residue is poured into 21
of water and this mixture is extracted twice with in each case 1 l
of ethyl acetate. After washing of the combined organic phases with
water, the mixture is dried over sodium sulphate and the solvent is
distilled off under reduced pressure. Purification is carried out
by silica gel chromatography using hexane/ethyl acetate (1:1) and
subsequent crystallization from ethyl acetate. This gives 78 g of
product as a colourless to brownish solid, in a yield of 17.6% of
theory.
[0375] .sup.1H-NMR (300 MHz, CDCl.sub.3): 3.86 (m, 2H,
CH.sub.2CH.sub.2), 4.08 (m, 2H, CH.sub.2CH.sub.2), 4.49 (s, 2H,
CH.sub.2CO), 7.61 (d, 2H, .sup.3J=8.95 Hz, CHCH), 8.28 (d, 2H,
.sup.3J=8.95 Hz, CHCH) MS (r.I.%)=222 (74, M.sup.+.sup.+), 193
(100), 164 (28), 150 (21), 136 (61), 117 (22), 106 (24), 90 (37),
76 (38), 63 (32), 50 (25)
[0376] The following compounds were synthesized analogously: [0377]
3-fluoro-4-(4-morpholin-3-onyl)nitrobenzene [0378]
4-(N-piperidonyl)nitrobenzene [0379]
3-fluoro-4-(N-piperidonyl)nitrobenzene [0380]
4-(N-pyrrolidonyl)nitrobenzene [0381]
3-fluoro-4-(N-pyrrolidonyl)nitrobenzene II.
4-(4-Morpholin-3-onyl)aniline
##STR00018##
[0382] In an autoclave, 63 g (0.275 mol) of
4-(4-morpholin-3-onyl)nitrobenzene are dissolved in 200 ml of
tetrahydrofuran, admixed with 3.1 g of Pd/C (5% ig) and
hydrogenated at 70.degree. C. and a hydrogen pressure of 50 bar for
8 h. The catalyst is filtered off, the solvent is then distilled
off under reduced pressure and the product is purified by
crystallization from ethyl acetate. 20 g of product are obtained as
a colourless to bluish solid, in a yield of 37.6% of theory.
[0383] Purification can also be carried out by silica gel
chromatography using hexane/ethyl acetate.
[0384] .sup.1H-NMR (300 MHz, CDCl.sub.3): 3.67 (m, 2H,
CH.sub.2CH.sub.2), 3.99 (m, 2H, CH.sub.2CH.sub.2), 4.27 (s, 2H,
CH.sub.2CO), 6.68 (d, 2H, .sup.3J=8.71 Hz, CHCH), 7.03 (d, 2H,
.sup.3J=8.71 Hz, CHCH) MS (r.I.%)=192 (100, M.sup.+.sup.+), 163
(48), 133 (26), 119 (76), 106 (49), 92 (38), 67 (27), 65 (45), 52
(22), 28 (22)
[0385] The following compounds were synthesized analogously: [0386]
3-fluoro-4-(4-morpholin-3-onyl)aniline [0387]
4-(N-piperidonyl)aniline [0388] 3-fluoro-4-(N-piperidonyl)aniline
[0389] 4-(N-pyrrolidonyl)aniline [0390]
3-fluoro-4-(N-pyrrolidonyl)aniline General method for preparing
4-substituted anilines by reacting 1-fluoro-4-nitrobenzenes and
1-chloro-4-nitrobenzenes with primary or secondary amines, followed
by reduction
##STR00019##
[0391] Equimolar amounts of the fluoronitrobenzene or
chloronitrobenzene and the amine are dissolved in dimethyl
sulphoxide or acetonitrile (0.1 M to 1 M solution), and the mixture
is stirred at 100.degree. C. overnight. After cooling to RT, the
reaction mixture is diluted with ether and washed with water. The
organic phase is dried over MgSO.sub.4, filtered and concentrated.
If a precipitate forms in the reaction mixture, the precipitate is
filtered off and washed with ether or acetonitrile. If the mother
liquor also contains product, it is worked up as described using
ether and water. The crude products can be purified by silica gel
chromatography (dichloromethane/cyclohexane and
dichloromethane/ethanol mixtures).
[0392] For the subsequent reduction, the nitro compound is
dissolved in methanol, ethanol or ethanol/dichloromethane mixtures
(0.01 M to 0.5 M solution) admixed with palladium on carbon (10%)
and stirred under an atmospheric hydrogen pressure overnight. The
mixture is then filtered and concentrated. The crude product can be
purified by silica gel chromatography (dichloromethane/ethanol
mixtures) or preparative reversed-phase HPLC (acetonitrile/water
mixtures).
[0393] Alternatively, the reducing agent used can also be iron
powder. To this end, the nitro compound is dissolved in acetic acid
(0.1 M to 0.5 M solution) and, at 90.degree. C., six equivalents of
iron powder and water (0.3 to 0.5 times the volume of the acetic
acid) are added a little at a time over a period of 10-15 min.
After a further 30 min at 90.degree. C., the mixture is filtered
and the filtrate is concentrated. The residue is worked up by
extraction with ethyl acetate and 2N aqueous sodium hydroxide
solution. The organic phase is dried over magnesium sulphate,
filtered and concentrated. The crude product can be purified by
silica gel chromatography (dichloromethane/ethanol mixtures) or
preparative reversed-phase HPLC (acetonitrile/water mixtures).
[0394] The following starting materials were prepared in an
analogous manner:
III-1. tert-butyl-1-(4-aminophenyl)-L-prolinate
[0395] MS (ESI): m/z (%)=304 (M+H+MeCN, 100), 263 (M+H, 20);
[0396] HPLC (method 4): rt=2.79 min.
III-2. 1-(4-aminophenyl)-3-piperidinecarboxamide
[0397] MS (ESI): m/z (%)=220 (M+H, 100);
[0398] HPLC (method 4): rt=0.59 min.
III-3. 1-(4-aminophenyl)-4-piperidincarboxamide
[0399] MS (ESI): m/z (%)=220 (M+H, 100);
[0400] HPLC (method 4): rt=0.57 min.
III-4. 1-(4-aminophenyl)-4-piperidinone
[0401] MS (ESI): m/z (%)=191 (M+H, 100);
[0402] HPLC (method 4): rt=0.64 min.
III-5. 1-(4-aminophenyl)-L-prolinamide
[0403] MS (ESI): m/z (%)=206 (M+H, 100);
[0404] HPLC (method 4): rt=0.72 min.
III-6. [1-(4-aminophenyl)-3-piperidinyl]methanol
[0405] MS (ESI): m/z (%)=207 (M+H, 100);
[0406] HPLC (method 4): rt=0.60 min.
III-7. [1-(4-aminophenyl)-2-piperidinyl]methanol
[0407] MS (ESI): m/z (%)=207 (M+H, 100);
[0408] HPLC (method 4): rt=0.59 min.
III-8. ethyl 1-(4-aminophenyl)-2-piperidinecarboxylate
[0409] MS (ESI): m/z (%)=249 (M+H, 35), 175 (100);
[0410] HPLC (method 4): rt=2.43 min.
III-9. [1-(4-aminophenyl)-2-pyrrolidinyl]methanol
[0411] MS (ESI): m/z (%)=193 (M+H, 45);
[0412] HPLC (method 4): rt=0.79 min.
III-10.
4-(2-methylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-ybphenylamine
starting from 2-methylhexahydro-2H-pyrrolo[3,4-d]isoxazole
(Ziegler, Carl B., et al.; J. Heterocycl. Chem.; 25; 2; 1988;
719-723)
[0413] MS (ESI): m/z (%)=220 (M+H, 50), 171 (100);
[0414] HPLC (method 4): rt=0.54 min.
III-11. 4-(1-pyrrolidinyl)-3-(trilluoromethybaniline
[0415] MS (ESI): m/z (%)=231 (M+H, 100);
[0416] HPLC (method 7): rt=3.40 min.
III-12. 3-chloro-4-(1-pyrrolidinyl)aniline
[0417] MS (ESI): m/z (%)=197 (M+H, 100);
[0418] HPLC (method 4): rt=0.78 min.
III.-13. 5-amino-2-(4-morpholinyl)benzamide
[0419] MS (ESI): m/z (%)=222 (M+H, 100);
[0420] HPLC (method 4): rt=0.77 min.
III-14. 3-methoxy-4-(4-morpholinyl)aniline
[0421] MS (ESI): m/z (%)=209 (M+H, 100);
[0422] HPLC (method 4): rt=0.67 min.
III-15. 1-[5-amino-2-(4-morpholinyl)phenyl]ethanone
[0423] MS (ESI): m/z (%)=221 (M+H, 100);
[0424] HPLC (method 4): rt=0.77 min.
General method for preparing 4-substituted anilines by reacting
1-fluoro-4-nitrobenzenes with amides, followed by reduction
##STR00020##
[0425] The amide is dissolved in DMF and admixed with 1.5
equivalents of potassium tert-butoxide. The mixture is stirred at
RT for 1 h, and 1.2 equivalents of the 1-fluoro-4-nitrobenzene are
then added a little at a time. The reaction mixture is stirred at
RT overnight, diluted with ether or ethyl acetate and washed with
sat. aqu. sodium bicarbonate solution. The organic phase is dried
over magnesium sulphate, filtered and concentrated. The crude
product can be purified by silica gel chromatography
(dichloromethane/ethanol mixtures).
[0426] For the subsequent reduction, the nitro compound is
dissolved in ethanol (0.01 M to 0.5 M solution), admixed with
palladium on carbon (10%) and stirred under atmospheric hydrogen
pressure overnight. The mixture is then filtered and concentrated.
The crude product can be purified by silica gel chromatography
(dichloromethane/ethanol mixtures) or preparative reversed-phase
HPLC (acetonitrile/water mixtures).
[0427] Alternatively, the reducing agent used can also be iron
powder. To this end, the nitro compound is dissolved in acetic acid
(0.1 M to 0.5 M solution) and, at 90.degree. C., six equivalents of
iron powder and water (0.3 to 0.5 times the volume of the acetic
acid) are added a little at a time over a period of 10-15 min.
After a further 30 min at 90.degree. C., the mixture is filtered
and the filtrate is concentrated. The residue is worked up by
extraction with ethyl acetate and 2N aqueous sodium hydroxide
solution. The organic phase is dried over magnesium sulphate,
filtered and concentrated. The crude product can be purified by
silica gel chromatography (dichloromethane/ethanol mixtures) or
preparative reversed-phase HPLC (acetonitrile/water mixtures).
[0428] The following starting materials were prepared in an
analogous manner:
IV-1. 1-[4-amino-2-(trifluoromethyl)phenyl]-2-pyrrolidinone
[0429] MS (ESI): m/z (%)=245 (M+H, 100);
[0430] HPLC (method 4): rt=2.98 min
IV-2. 4-[4-amino-2-(trifluoromethyl)phenyl]-3-morpholinone
[0431] MS (ESI): m/z (%)=261 (M+H, 100);
[0432] HPLC (method 4): rt=2.54 min.
IV-3. 4-(4-amino-2-chlorophenyl)-3-morpholinone
[0433] MS (ESI): m/z (%)=227 (M+H, 100);
[0434] HPLC (method 4): rt=1.96 min.
IV-4. 4-(4-amino-2-methylphenyl)-3-morpholinone
[0435] MS (ESI): m/z (%)=207 (M+H, 100);
[0436] HPLC (method 4): rt=0.71 min.
IV-5. 5-amino-2-(3-oxo-4-morpholinyl)benzonitrile
[0437] MS (ESI): m/z (%)=218 (M+H, 100);
[0438] HPLC (method 4): rt=1.85 min.
IV-6. 1-(4-amino-2-chlorophenyl)-2-pyrrolidinone
[0439] MS (ESI): m/z (%)=211 (M+H, 100);
[0440] HPLC (method 4): rt=2.27 min.
IV-7. 4-(4-amino-2,6-dimethylphenyl)-3-morpholinone starting from
2-fluoro-1,3-dimethyl-5-nitrobenzene (Bartoli et al., J. Org. Chem.
1975, 40, 872):
[0441] MS (ESI): m/z (%)=221 (M+H, 100);
[0442] HPLC (method 4): rt=0.77 min.
IV-8. 4-(2,4-diaminophenyl)-3-morpholinone starting from
1-fluoro-2,4-dinitrobenzene:
[0443] MS (ESI): m/z (%)=208 (M+H, 100);
[0444] HPLC (method 4): rt=0.60 min.
IV-9. 4-(4-amino-2-chlorophenyl)-2-methyl-3-morpholinone starting
from 2-methyl-3-morpholinone (Pfeil, E.; Harder, U.; Angew. Chem.
1967, 79, 188):
[0445] MS (ESI): m/z (%)=241 (M+H, 100);
[0446] HPLC (method 4): rt=2.27 min.
IV-10. 4-(4-amino-2-chlorophenyl)-6-methyl-3-morpholinone starting
from 6-methyl-3-morpholinone (EP 350 002):
[0447] MS (ESI): m/z (%)=241 (M+H, 100);
[0448] HPLC (method 4): rt=2.43 min.
SYNTHESIS EXAMPLES
[0449] The Examples 1 to 13, 17 to 19 and 36 to 57 below refer to
process variant [A].
Example 1
Preparation of
5-chloro-N-{[(5S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-1,3-oxazolidin-5--
yl]methyl}-2-thiophenecarboxamide
##STR00021##
[0451]
(5S)-5-(Aminomethyl)-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolidin-
-2-one (preparation see S. J. Brickner et al., J. Med. Chem. 1996,
39, 673) (0.45 g, 1.52 mmol), 5-chlorothiophene-2-carboxylic acid
(0.25 g, 1.52 mmol) and 1-hydroxy-1H-benzotriazole hydrate (HOBT)
(0.3 g, 1.3 equivalents) are dissolved in 9.9 ml of DMF. 0.31 g
(1.98 mmol, 1.3 equivalents) of
N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI) are added,
and 0.39 g (0.53 ml, 3.05 mmol, 2 equivalents) of
diisopropylethylamine (DIEA) are added dropwise at room
temperature. The mixture is stirred at room temperature overnight.
2 g of silica gel are added, and the mixture is evaporated to
dryness under reduced pressure. The residue is chromatographed on
silica gel using a toluene/ethyl acetate gradient. This gives 0.412
g (61.5% of theory) of the target compound of melting point (m.p.)
197.degree. C.
[0452] R.sub.f (SiO.sub.2, toluene/ethyl acetate 1:1)=0.29
(starting material=0.0);
[0453] MS (DCI) 440.2 (M+H), Cl pattern;
[0454] .sup.1H-NMR (d.sub.6-DMSO, 300 MHz) 2.95 (m, 4H), 3.6 (t,
2H), 332 (m, 4H), 3.8 (dd, 1H), 4.12 (t, 1H), 4.75-4.85 (m, 1H),
7.05 (t, 1H), 7.15-7.2 (m, 3H), 7.45 (dd, 1H), 7.68 (d, 1H), 8.95
(t, 1H).
Example 2
5-Chloro-N-{[(5S)-3-(4-morpholinophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-
-2-thiophenecarboxamide
##STR00022##
[0455] is obtained analogously from benzyl
4-morpholinophenylcarbamate via the
(5S)-5-(aminomethyl)-3-(4-morpholinophenyl)-1,3-oxazolidin-2-one
intermediate (see Example 1).
[0456] M.p.: 198.degree. C.;
[0457] IC.sub.50 value=43 nM;
[0458] R.sub.f (SiO.sub.2, toluene/ethyl acetate 1:1)=0.24.
Example 3
5-Chloro-N-({(5S)-3-[3-fluoro-4-(1,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxaz-
olidin-5-yl}methyl)-2-thiophenecarboxamide
##STR00023##
[0459] is obtained analogously from
(5S)-5-(aminomethyl)-3-[3-fluoro-4-(1,4-thiazinan-4-yl)phenyl]-1,3-oxazol-
idin-2-one (preparation see M. R. Barbachyn et al., J. Med. Chem.
1996, 39, 680).
[0460] M.p.: 193.degree. C.;
[0461] Yield: 82%;
[0462] R.sub.f (SiO.sub.2, toluene/ethyl acetate 1:1)=0.47
(starting material=0.0).
Example 4
5-Bromo-N-({(5S)-3-[3-fluoro-4-(1,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazo-
lidin-5-yl}methyl)-2-thiophenecarboxamide
##STR00024##
[0463] is obtained analogously from 5-bromothiophene-2-carboxylic
acid.
[0464] M.p.: 200.degree. C.
Example 5
N-({5S)-3-[3-Fluoro-4-(1,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-y-
l}methyl)-5-methyl-2-thiophenecarboxamide
##STR00025##
[0465] is obtained analogously from 5-methylthiophene-2-carboxylic
acid.
[0466] M.p.: 167.degree. C.
Example 6
5-Chloro-N-{[(5S)-3-(6-methylthieno[2,3-b]pyridin-2-yl)-2-oxo-1,3-oxazolid-
in-5-yl]methyl}-2-thiophenecarboxamide
##STR00026##
[0467] is obtained analogously from
(5S)-5-(aminomethyl)-3-(6-methylthieno[2,3-b]pyridin-2-yl)-1,3-oxazolidin-
-2-one (preparation see EP-A-785 200).
[0468] M.p.: 247.degree. C.
Example 7
5-Chloro-N-{[(5S)-3-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2-o-
xo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide
##STR00027##
[0469] is obtained analogously from
6-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-methyl-1,3-benzothia-
zol-2(3H)-one (preparation see EP-A-738 726).
[0470] M.p.: 217.degree. C.
Example 8
5-Chloro-N-[((5S)-3-{3-fluoro-4-[4-(4-pyridinyl)piperazino]phenyl}-2-oxo-1-
,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide
##STR00028##
[0471] is obtained analogously from
(5S)-5-(aminomethyl)-3-{3-fluoro-4-[4-(4-pyridinyl)piperazino]phenyl}-1,3-
-oxazolidin-2-one (preparation analogously to J. A. Tucker et al.,
J. Med. Chem. 1998, 41, 3727).
[0472] MS (ESI) 516 (M+H), Cl pattern.
Example 9
5-Chloro-N-({(5S)-3-[3-fluoro-4-(4-methylpiperazino)phenyl]-2-oxo-4,3-oxaz-
olidin-5-yl}methyl)-2-thiophenecarboxamide
##STR00029##
[0473] is obtained analogously from
(5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-methylpiperazino)phenyl]-1,3-oxazol-
idin-2-one.
Example 10
5-Chloro-N-({(5S)-3-[3-fluoro-4-(4-tert-butoxycarbonylpiperazin-1-yl)pheny-
l]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
##STR00030##
[0474] is obtained analogously from
(5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-tert-butoxy-carbonylpiperazin-1-yl)-
phenyl]-1,3-oxazolidin-2-one (preparation see WO-A-93/23384, which
has already been cited).
[0475] M.p.: 184.degree. C.;
[0476] R.sub.f (SiO.sub.2, toluene/ethyl acetate 1:1)=0.42.
Example 11
5-Chloro-N-({(5S)-3-[3-fluoro-4-(piperazin-1-yl)phenyl]-2-oxo-1,3-oxazolid-
in-5-yl}methyl)-2-thiophenecarboxamide
##STR00031##
[0477] is obtained by reacting Example 10 with trifluoroacetic acid
in methylene chloride.
[0478] IC.sub.50 value=140 nM;
[0479] .sup.1H-NMR [d.sub.6-DMSO]: 3.01-3.25 (m, 8H), 3.5-3.65 (m,
2H), 3.7-3.9 (m, 1H), 4.05-4.2 (m, 1H), 4.75-4.9 (m, 1H), 7.05-7.25
(m, 3H), 7.5 (dd, 1H), 7.7 (d, 1H), 8.4 (broad s, 1H), 9.0 (t,
1H).
Example 12
5-Chloro-N-[((5S)-3-(2,4'-bipyridinyl-5-yl)-2-oxo-1,3-oxazolidin-5-yl)meth-
yl]-2-thiophenecarboxamide
##STR00032##
[0480] is obtained analogously from
(5S)-5-aminomethyl-3-(2,4'-bipyridinyl-5-yl)-2-oxo-1,3-oxazolidin-2-one
(preparation see EP-A-789 026).
[0481] R.sub.f (SiO.sub.2, ethyl acetate/ethanol 1:2)=0.6;
[0482] MS (ESI) 515 (M+H), Cl pattern.
Example 13
5-Chloro-N-{[(5S)-2-oxo-3-(4-piperidinophenyl)-1,3-oxazolidin-5-yl]methyl}-
-2-thiophenecarboxamide
##STR00033##
[0483] is obtained from
5-(hydroxymethyl)-3-(4-piperidinophenyl)-1,3-oxazolidin-2-one
(preparation see DE 2708236) after mesylation, reaction with
potassium phthalimide, hydrazinolysis and reaction with
5-chlorothiophene-2-carboxylic acid. R.sub.f (SiO.sub.2, ethyl
acetate/toluene 1:1)=0.31;
[0484] m.p. 205.degree. C.
Example 17
5-Chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin--
5-yl}methyl)-2-thiophenecarboxamide
##STR00034##
[0486] Analogously to the known synthesis scheme (see S. J.
Brickner et al., J. Med. Chem. 1996, 39, 673),
1-(4-aminophenyl)pyrrolidin-2-one (preparation see Reppe et al.,
Justus Liebigs Ann. Chem.; 596; 1955; 209) gives, after reaction
with benzyloxycarbonyl chloride, followed by reaction with
R-glycidyl butyrate, mesylation, reaction with potassium
phthalimide, hydrazinolysis in methanol and reaction with
5-chlorothiophene-2-carboxylic acid, finally
5-chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-
-5-yl}methyl)-2-thiophenecarboxamide. The
5-chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-
-5-yl}methyl)-2-thiophenecarboxamide obtained in this manner has an
IC.sub.50 value of 4 nM (test method for the IC.sub.50 value
according to Example A-1.a.1 described above) "determination of the
inhibition of factor Xa").
[0487] M.p.: 229.degree. C.;
[0488] R.sub.f value (SiO.sub.2, toluene/ethyl acetate 1:1)=0.05
(starting material: =0.0); MS (ESI): 442.0 (21%, M+Na, Cl pattern),
420.0 (72%, M+H, Cl pattern), 302.3 (12%), 215 (52%), 145
(100%);
[0489] .sup.1H-NMR (d.sub.6-DMSO, 300 MHz): 2.05 (m, 2H), 2.45 (m,
2H), 3.6 (t, 2H), 3.77-3.85 (m, 3H), 4.15 (t, 1H), 4.75-4.85 (m,
1H), 7.2 (d, 1H), 7.5 (d, 2H), 7.65 (d, 2H), 7.69 (d, 1H), 8.96 (t,
1H).
[0490] The individual steps of the synthesis of Example 17
described above with the respective precursors are as follows:
[0491] At -20.degree. C., 4 g (22.7 mmol) of
1-(4-aminophenyl)pyrrolidin-2-one and 3.6 ml (28.4 mmol) of
N,N-dimethylaniline in 107 ml of tetrahydrofuran are admixed slowly
with 4.27 g (25.03 mmol) of benzyl chloroformate. The mixture is
stirred at -20.degree. C. for 30 minutes and then allowed to warm
to room temperature. 0.5 l of ethyl acetate are added, and the
organic phase is washed with 0.5 l of saturated NaCl solution. The
organic phase is separated off and dried with MgSO.sub.4, and the
solvent is evaporated under reduced pressure. The residue is
triturated with diethyl ether and filtered off with suction. This
gives 5.2 g (73.8% of theory) of benzyl
4-(2-oxo-1-pyrrolidinyl)phenyl-carbamate as light-beige crystals of
melting point 174.degree. C.
[0492] At -10.degree. C. and under argon, 1.47 g (16.66 mmol) of
isoamyl alcohol in 200 ml of tetrahydrofuran are admixed dropwise
with 7.27 ml of a 2.5 M solution of n-butyllithium (BuLi) in
hexane, a further 8 ml of BuLi solution being required for the
added indicator N-benzylidenebenzylamine to change colour. The
mixture is stirred at -10.degree. C. for 10 minutes and cooled to
-78.degree. C., and a solution of 4.7 g (15.14 mmol) of benzyl
4-(2-oxo-1-pyrrolidinyl)phenylcarbamate is added slowly. Another 4
ml of n-BuLi solution are then added until the colour of the
indicator changes to pink. The mixture is stirred at -78.degree. C.
for 10 minutes, 2.62 g (18.17 mmol) of R-glycidyl butyrate are
added and the mixture is stirred at -78.degree. C. for another 30
minutes.
[0493] Overnight, the mixture is allowed to warm to room
temperature, 200 ml of water are added and the THF fraction is
evaporated under reduced pressure. The aqueous residue is extracted
with ethyl acetate and the organic phase is dried with MgSO.sub.4
and evaporated under reduced pressure. The residue is triturated
with 500 ml of diethyl ether and the precipitated crystals are
filtered off with suction under reduced pressure.
[0494] This gives 3.76 g (90% of theory) of
(5R)-5-(hydroxymethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin--
2-one of melting point 148.degree. C., with an R.sub.f value
(SiO.sub.2, toluene/ethyl acetate 1:1) of 0.04 (starting
material=0.3).
[0495] At 0.degree. C., 3.6 g (13.03 mmol) of
(5R)-5-(hydroxymethyl)-3-[4-(2-oxo-1-pynolidinyl)phenyl]-1,3-oxazolidin-2-
-one and 2.9 g (28.67 mmol) of triethylamine are initially charged
with stirring in 160 ml of dichloromethane. 1.79 g (15.64 mmol) of
methanesulphonyl chloride are added with stirring, and the mixture
is stirred at 0.degree. C. for 1.5 hours and then at room
temperature for 3 h.
[0496] The reaction mixture is washed with water and the aqueous
phase is reextracted with methylene chloride. The combined organic
extracts are dried with MgSO.sub.4 and concentrated. The residue
(1.67 g) is then dissolved in 70 ml of acetonitrile, admixed with
2.62 g (14.16 mmol) of potassium phthalimide and stirred in a
closed vessel at 180.degree. C. in a microwave oven for 45
minutes.
[0497] The mixture is filtered off from insoluble residues, the
filtrate is evaporated under reduced pressure and the residue (1.9
g) is dissolved in methanol and admixed with 0.47 g (9.37 mmol) of
hydrazine hydrate. The mixture is boiled for 2 hours, cooled,
admixed with saturated sodium bicarbonate solution and extracted
six times with a total of 21 of methylene chloride. The combined
organic extracts of the crude
(5S)-5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]--1,3-oxazolidin-2-
-one are dried with MgSO.sub.4 and concentrated under reduced
pressure.
[0498] The end product,
5-chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-
-5-yl}methyl)-2-thiophenecarboxamide, is prepared by dissolving
0.32 g (1.16 mmol) of the
(5S)-5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2--
one prepared above, 5-chlorothiophene-2-carboxylic acid (0.19 g;
1.16 mmol) and 1-hydroxy-1H-benzotriazole hydrate (HOBT) (0.23 g,
1.51 mmol) in 7.6 ml of DMF. 0.29 g (1.51 mmol) of
N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI) are added,
and 0.3 g (0.4 ml; 2.32 mmol, 2 equivalents) of
diisopropylethylamine (DIEA) are added dropwise at room
temperature. The mixture is stirred at room temperature
overnight.
[0499] The mixture is evaporated to dryness under reduced pressure
and the residue is dissolved in 3 ml of DMSO and chromatographed on
an RP-MPLC using an acetonitrile/water/0.5% TFA gradient. From the
appropriate fractions, the acetonitrile fraction is evaporated and
the precipitated compound is filtered off with suction. This gives
0.19 g (39% of theory) of the target compound.
[0500] The following compounds were prepared in an analogous
manner:
Example 18
5-Chloro-N-({(5S)-2-oxo-3-[4-(1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}m-
ethyl)-2-thiophenecarboxamide
[0501] Analogously to Example 17, 4-pyrrolidin-1-yl-aniline (Reppe
et al., Justus Liebigs Ann. Chem.; 596; 1955; 151) gives the
compound
5-chloro-N-({(5S)-2-oxo-3-[4-(1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}-
methyl)-2-thiophenecarboxamide.
[0502] IC.sub.50=40 nM;
[0503] m.p.: 216.degree. C.;
[0504] R.sub.f value (SiO.sub.2, toluene/ethyl acetate 1:1)=0.31
[starting material: =0.0].
Example 19
5-Chloro-N-({(5S)-2-oxo-3-[4-(diethylamino)phenyl]-1,3-oxazolidin-5-yl}met-
hyl)-2-thiophenecarboxamide
[0505] Analogously, N,N-diethylphenyl-1,4-diamine (U.S. Pat. No.
2,811,555; 1955) gives the compound
5-chloro-N-({(5S)-2-oxo-3-[4-(diethylamino)phenyl]-1,3-oxazolidin-5-yl}me-
thyl)-2-thiophenecarboxamide.
[0506] IC.sub.50=270 nM;
[0507] m.p.: 181.degree. C.;
[0508] R.sub.f value (SiO.sub.2, toluene/ethyl acetate 1:1)=0.25
[starting material: =0.0].
Example 36
5-Chloro-N-({(5S)-3-[2-methyl-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidi-
n-5-yl}methyl)-2-thiophenecarboxamide
[0509] starting from 2-methyl-4-(4-morpholinyl)aniline (J. E.
LuValle et al. J. Am. Chem. Soc. 1948, 70, 2223):
[0510] MS (ESI): m/z (%)=436 ([M+H].sup.+, 100), Cl pattern;
[0511] HPLC (method 1): rt (%)=3.77 (98).
[0512] IC.sub.50: 1.26 .mu.M
Example 37
5-Chloro-N-{[(5S)-3-(3-chloro-4-morpholinophenyl)-2-oxo-1,3-oxazolidin-5-y-
l]methyl}-2-thiophenecarboxamide
[0513] starting from 3-chloro-4-(4-morpholinyl)aniline (H. R.
Snyder et al. J. Pharm. Sci. 1977, 66, 1204):
[0514] MS (ESI): m/z (%)=456 ([M+H].sup.+, 100), Cl.sub.2
pattern;
[0515] HPLC (method 2): rt (%)=4.31 (100).
[0516] IC.sub.50: 33 nM
Example 38
5-Chloro-N-({(5S)-3-[4-(4-morpholinylsulphonyl)phenyl]-2-oxo-1,3-oxazolidi-
n-5-yl}methyl)-2-thiophenecarboxamide
[0517] starting from 4-(4-morpholinylsulphonyl)aniline (Adams et
al. J. Am. Chem. Soc. 1939, 61, 2342):
[0518] MS (ESI): m/z (%)=486 ([M+H].sup.+, 100), Cl pattern;
[0519] HPLC (method 3): rt (%)=4.07 (100).
[0520] IC.sub.50: 2 .mu.M
Example 39
5-Chloro-N-({(5S)-3-[4-(1-azetidinylsulphonyl)phenyl]-2-oxo-1,3-oxazolidin-
-5-yl}methyl)-2-thiophenecarboxamide
[0521] starting from 4-(1-azetidinylsulphonyl)aniline:
[0522] MS (DCI, NH.sub.3): m/z (%)=473 ([M+NH.sub.4].sup.+, 100),
Cl pattern;
[0523] HPLC (method 3): rt (%)=4.10 (100).
[0524] IC.sub.50: 0.84 .mu.M
Example 40
5-Chloro-N-[((5S)-3-{4-[(dimethylamino)sulphonyl]phenyl}-2-oxo-1,3-oxazoli-
din-5-yl)methyl]-2-thiophenecarboxamide
[0525] starting from 4-amino-N,N-dimethylbenzenesulphonamide (I. K.
Khanna et al. J. Med Chem. 1997, 40, 1619):
[0526] MS (ESI): m/z (%)=444 ([M+H].sup.+, 100), Cl pattern;
[0527] HPLC (method 3): rt (%)=4.22 (100).
[0528] IC.sub.50: 90 nM
General method for the acylation of
5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one
with carbonyl chlorides.
##STR00035##
[0529] Under argon and at room temperature, an about 0.1 molar
solution of
5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one
(from Example 45) (1.0 eq.) and absolute pyridine (about 6 eq.) in
absolute dichloromethane is added dropwise to the appropriate acid
chloride (2.5 eq.). The mixture is stirred at room temperature for
about 4 h, and about 5.5 eq of PS-trisamine (Argonaut Technologies)
are then added. The suspension is stirred gently for 2 h, diluted
with dichloromethane/DMF (3:1) and then filtered (the resin is
washed with dichloromethane/DMF) and the filtrate is concentrated.
If appropriate, the product that is obtained is purified by
preparative RP-HPLC.
[0530] The following compounds were prepared in an analogous
manner:
Example 41
N-({2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-
-thiophene-carboxamide
[0531] LC-MS (method 6): m/z (%)=386 (M+H, 100);
[0532] LC-MS: rt (%)=3.04 (100).
[0533] IC.sub.50: 1.3 .mu.M
General method for preparing acyl derivatives starting from
5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one
and carboxylic acids
##STR00036##
[0534] The appropriate carboxylic acid (about 2 eq.) and a mixture
of absolute dichloromethane/DMF (about 9:1) are added to 2.9 eq. of
resin-bonded carbodiimide (PS-carbodiimide, Argonaut Technologies).
The mixture is shaken gently at room temperature for about 15 min,
5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one
(from Example 45) (1.0 eq.) is then added and the mixture is shaken
overnight, after which the resin is filtered off (and washed with
dichloromethane), and the filtrate is concentrated. If appropriate,
the resulting product is purified by preparative RP-HPLC.
[0535] The following compounds were prepared in an analogous
manner:
Example 42
5-Methyl-N-({2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-4,3-oxazolidin-5-yl}-
methyl)-2-thiophenecarboxamide
[0536] LC-MS: m/z (%)=400 (M+H, 100);
[0537] LC-MS (method 6): rt (%)=3.23 (100).
[0538] IC.sub.50: 0.16 .mu.M
Example 43
5-Bromo-N-({2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}m-
ethyl)-2-thiophenecarboxamide
[0539] LC-MS: m/z (%)=466 (M+H, 100);
[0540] LC-MS (method 5): rt (%)=3.48 (78).
[0541] IC.sub.50: 0.014 .mu.M
Example 44
5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-
-yl}methyl)-2-thiophenecarboxamide
##STR00037##
[0542] a)
2-((2R)-2-Hydroxy-3{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-
-1H-iso-indole-1,3(2H)-dione
[0543] A suspension of
2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (A. Gutcait et
al. Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mmol) and
4-(4-aminophenyl)-3-morpholinone (5.37 g, 27.9 mmol) in
ethanol/water (9:1, 140 ml) is refluxed for 14 h (the precipitate
dissolves, after some time again formation of a precipitate). The
precipitate (desired product) is filtered off, washed three times
with diethyl ether and dried. The combined mother liquors are
concentrated under reduced pressure and, after addition of a second
portion of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione
(2.84 g, 14.0 mmol), suspended in ethanol/water (9:1, 70 ml) and
refluxed for 13 h (the precipitate dissolves, after some time again
formation of a precipitate). The precipitate (desired product) is
filtered off, washed three times with diethyl ether and dried.
Total yield: 10.14 g, 92% of theory.
[0544] MS (ESI): m/z (%)=418 ([M+Na].sup.+, 84), 396 ([M+H].sup.+,
93);
[0545] HPLC (method 3): rt (%)=3.34 (100).
b)
2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}me-
thyl)-1H-isoindole-1,3(2H)-dione
[0546] Under argon and at room temperature,
N,N'-carbonyldiimidazole (2.94 g, 18.1 mmol) and
dimethylaminopyridine (a catalytic amount) are added to a
suspension of the amino alcohol (3.58 g, 9.05 mmol) in
tetrahydrofuran (90 ml). The reaction suspension is stirred at
60.degree. C. for 12 h (the precipitate dissolves, after some time
again formation of a precipitate), admixed with a second portion of
N,N'-carbonyldiimidazole (2.94 g, 18.1 mmol) and stirred at
60.degree. C. for another 12 h. The precipitate (desired product)
is filtered off, washed with tetrahydrofuran and dried. The
filtrate is concentrated under reduced pressure and further product
is purified by flash chromatography (dichloromethane/methanol
mixtures). Total yield: 3.32 g, 87% of theory.
[0547] MS (ESI): m/z (%)=422 ([M+H].sup.+, 100);
[0548] HPLC (method 4): rt (%)=3.37 (100).
c)
5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidi-
n-5-yl}methyl)-2-thiophenecarboxamide
[0549] At room temperature, methylamine (40% strength in water,
10.2 ml, 0.142 mol) is added dropwise to a suspension of the
oxazolidinone (4.45 g, 10.6 mmol) in ethanol (102 ml). The reaction
mixture is refluxed for 1 h and concentrated under reduced
pressure. The crude product is used without further purification
for the next reaction.
[0550] Under argon and at 0.degree. C.,
5-chlorothiophene-2-carbonyl chloride (2.29 g, 12.7 mmol) is added
dropwise to a solution of the amine in pyridine (90 ml).
Ice-cooling is removed and the reaction mixture is stirred at room
temperature for 1 h and admixed with water. Dichloromethane is
added and the phases are separated, and the aqueous phase is then
extracted with dichloromethane. The combined organic phases are
dried (sodium sulphate), filtered and concentrated under reduced
pressure. The desired product is purified by flash chromatography
(dichloromethane/methanol mixtures). Total yield: 3.92 g, 86% of
theory.
[0551] M.p: 232-233.degree. C.;
[0552] .sup.1H NMR (DMSO-d.sup.6, 200 MHz): 9.05-8.90 (t, J=5.8 Hz,
1H), 7.70 (d, J=4.1 Hz, 1H), 7.56 (d, J=9.0 Hz, 2H), 7.41 (d, J=9.0
Hz, 2H), 7.20 (d, J=4.1 Hz, 1H), 4.93-4.75 (m, 1H), 4.27-4.12 (m,
3H), 4.02-3.91 (m, 2H), 3.91-3.79 (dd, J=6.1 Hz, 9.2 Hz, 1H),
3.76-3.66 (m, 2H), 3.66-3.54 (m, 2H);
[0553] MS (ESI): m/z (%)=436 ([M+11].sup.+, 100, Cl pattern);
[0554] HPLC (method 2): rt (%)=3.60 (100);
[0555] [.alpha.].sup.21.sub.D=-38.degree. (c 0.2985, DMSO); ee:
99%.
[0556] IC.sub.50: 0.7 nM
[0557] The following compounds were prepared in an analogous
manner:
Example 45
5-Methyl-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-
-yl}methyl)-2-thiophenecarboxamide
[0558] MS (ESI): m/z (%)=831 ([2M+H].sup.+, 100), 416 ([M+H].sup.+,
66);
[0559] HPLC (method 3): rt (%)=3.65 (100).
[0560] IC.sub.50: 4.2 nM
Example 46
5-Bromo-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5--
yl}methyl)-2-thiophenecarboxamide
[0561] MS (ESI): m/z (%)=480 ([M+H].sup.+, 100, Br pattern);
[0562] HPLC (method 3): rt (%)=3.87 (100).
[0563] IC.sub.50: 0.3 nM
Example 47
5-Chloro-N-{[(5S)-3-(3-isopropyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2--
oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide
##STR00038##
[0565] 200 mg (0.61 mmol) of
6-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-iso-propyl-1,3-benzo-
xazol-2(3H)-one hydrochloride (EP 738726) are suspended in 5 ml of
tetrahydrofuran and admixed with 0.26 ml (1.83 mmol) of
triethylamine and 132 mg (0.73 mmol) of
5-chlorothiophene-2-carbonyl chloride. The reaction mixture is
stirred at room temperature overnight and then concentrated. The
product is isolated by column chromatography (silica gel, methylene
chloride/ethanol=50/1 to 20/1). This gives 115 mg (43% of theory)
of the desired compound.
[0566] MS (ESI): m/z (%)=436 (M+H, 100);
[0567] HPLC (method 4): rt=3.78 min.
[0568] The following compounds were prepared in an analogous
manner:
TABLE-US-00002 Example No. Structure M.p. [.degree. C.] IC.sub.50
[.mu.M] 48 ##STR00039## 210 0.12 49 ##STR00040## 234 0.074 50
##STR00041## 195 1.15 51 ##STR00042## 212 1.19 52 ##STR00043## 160
0.19 53 ##STR00044## MS (ESI): m/z (%) = 431 ([M + H].sup.+, 100),
Cl pattern 0.74 54 ##STR00045## 221 0.13 55 ##STR00046## 256 0.04
56 ##STR00047## 218 0.004 57 ##STR00048## 226 0.58 255 ##STR00049##
228-230
[0569] Examples 20 to 30 and 58 to 139 below refer to process
variant [B], and Examples 20 and 21 describe the preparation of
precursors.
Example 20
Preparation of N-allyl-5-chloro-2-thiophenecarboxamide
##STR00050##
[0571] An ice-cooled solution of 2.63 ml (35 mmol) of allylamine in
14.2 ml of absolute pyridine and 14.2 ml of absolute THF is admixed
dropwise with 5-chloro-thiophene-2-carbonyl chloride (7.61 g, 42
mmol). Ice-cooling is removed and the mixture is stirred at room
temperature for 3 h and then concentrated under reduced pressure.
The residue is admixed with water and the solid is filtered off.
The crude product is purified by flash chromatography over silica
gel (dichloromethane).
[0572] Yield: 7.20 g (99% of theory);
[0573] MS (DCI, NH.sub.4): m/z (%)=219 (M+NH.sub.4, 100), 202 (M+H,
32);
[0574] HPLC (method 1): rt (%)=3.96 min (98.9).
Example 21
Preparation of
5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide
##STR00051##
[0576] An ice-cooled solution of 2.0 g (9.92 mmol) of
N-allyl-5-chloro-2-thiophenecarboxamide in 10 ml of dichloromethane
is admixed with meta-chloroperbenzoic acid (3.83 g, about 60%
strength). The mixture is stirred overnight, during which it is
allowed to warm to room temperature, and is then washed with 10%
sodium hydrogen sulphate solution (three times). The organic phase
is washed with saturated sodium bicarbonate solution (twice) and
with saturated sodium chloride solution, dried over magnesium
sulphate and concentrated. The product is purified by silica gel
chromatography (cyclohexane/ethyl acetate 1:1).
[0577] Yield: 837 mg (39% of theory);
[0578] MS (DCI, NH.sub.4): m/z (%)=253 (M+NH.sub.4, 100), 218 (M+H,
80);
[0579] HPLC (method 1): rt (%)=3.69 min (about 80).
General method for preparing substituted
N-(3-amino-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide
derivatives starting from
5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide
##STR00052##
[0580] At room temperature or at temperatures up to 80.degree. C.,
5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide (1.0 eq.) is
added a little at a time to a solution of the primary amine or
aniline derivative (1.5 to 2.5 eq.) in 1,4-dioxane,
1,4-dioxane/water mixtures or ethanol, ethanol/water mixtures
(about 0.3 to 1.0 mol/1). The mixture is stirred for 2 to 6 hours
and then concentrated. From the reaction mixture, the product can
be isolated by silica gel chromatography (cyclohexane/ethyl acetate
mixtures, dichloromethane/methanol mixtures or
dichloromethane/methanol/triethylamine mixtures).
[0581] The following compounds were prepared in an analogous
manner:
Example 22
N-[3-(Benzylamino)-2-hydroxypropyl]-5-chloro-2-thiophenecarboxamide
[0582] MS (ESI): m/z (%)=325 (M+H, 100);
[0583] HPLC (method 1): rt (%)=3.87 min (97.9).
Example 23
5-Chloro-N-[3-(3-cyanoanilino)-2-hydroxypropyl]-2-thiophenecarboxamide
[0584] MS (ESI): m/z (%)=336 (M+H, 100);
[0585] HPLC (method 2): rt (%)=4.04 min (100).
Example 24
5-Chloro-N-[3-(4-cyanoanilino)-2-hydroxypropyl]-2-thiophenecarboxamide
[0586] MS (ESI): m/z (%)=336 (M+H, 100);
[0587] HPLC (method 1): rt (%)=4.12 min (100).
Example 25
5-Chloro-N-{3-[4-(cyanomethyl)anilino]-2-hydroxypropyl}-2-thiophenecarboxa-
mide
[0588] MS (ESI): m/z (%)=350 (M+H, 100);
[0589] HPLC (method 4): rt (%)=3.60 min (95.4).
Example 26
5-Chloro-N-{3-[3-(cyanomethyl)anilino]-2-hydroxypropyl}-2-thiophenecarboxa-
mide
[0590] MS (ESI): m/z (%)=350 (M+H, 100);
[0591] HPLC (method 4): rt (%)=3.76 min (94.2).
Example 58
tert-Butyl
4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)ami-
no]-benzylcarbamate
[0592] starting from tert-butyl 4-aminobenzylcarbamate (Bioorg.
Med. Chem. Lett.; 1997; 1921-1926):
[0593] MS (ES-pos): m/z (%)=440 (M+H, 100), (ES-neg): m/z (%)=438
(M-H, 100);
[0594] HPLC (method 1): rt (%)=4.08 (100).
Example 59
tert-Butyl
4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)ami-
no]-phenyl-carbamate
[0595] starting from
N-tert-butyloxycarbonyl-1,4-phenylenediamine:
[0596] MS (ESI): m/z (%)=426 (M+H, 45), 370 (100);
[0597] HPLC (method 1): rt (%)=4.06 (100).
Example 60
tert-Butyl
2-hydroxy-3-{[4-(2-oxo-1-pyrrolidinyl)phenyl]amino}propyl-carba-
mate
[0598] starting from 1-(4-aminophenyl)-2-pyrrolidinone (Justus
Liebigs Ann. Chem.; 1955; 596; 204):
[0599] MS (DCI, NH.sub.3): m/z (%)=350 (M+H, 100);
[0600] HPLC (method 1): rt (%)=3.57 (97).
Example 61
5-Chloro-N-(3-{[3-fluoro-4-(3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxypro-
pyl)-2-thiophenecarboxamide
[0601] 800 mg (3.8 mmol) of
4-(4-amino-2-fluorophenyl)-3-morpholinone and 700 mg (3.22 mmol) of
5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide in 15 ml of
ethanol and 1 ml of water are heated under reflux for 6 hours. The
mixture is concentrated under reduced pressure and treated with
ethyl acetate, precipitated crystals are filtered off with suction
and the mother liquor is chromatographed giving 276 mg (17% of
theory) of the target compound.
[0602] R.sub.f (ethyl acetate): 0.25.
Example 62
(N-(3-Anilino-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide
[0603] starting from aniline:
[0604] MS (DCI, NH.sub.3): m/z (%)=311 ([M+H].sup.+, 100), Cl
pattern;
[0605] HPLC (method 3): rt (%)=3.79 (100).
Example 63
5-Chloro-N-(2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-2-th-
iophenecarboxamide
[0606] starting from 4-(4-aminophenyl)-3-morpholinone:
[0607] MS (ESI): m/z (%)=410 ([M+H].sup.+, 50), Cl pattern;
[0608] HPLC (method 3): rt (%)=3.58 (100).
Example 64
N-[3-({4-[Acetyl(cyclopropyl)amino]phenyl}amino)-2-hydroxypropyl]-5-chloro-
-2-thiophenecarboxamide
[0609] starting from N-(4-aminophenyl)-N-cyclopropylacetamide:
[0610] MS (ESI): m/z (%)=408 ([M+H].sup.+, 100), Cl pattern;
[0611] HPLC (method 3): rt (%)=3.77 (100).
Example 65
N-[3-({4-[Acetyl(methyl)amino]phenyl}amino)-2-hydroxypropyl]-5-chloro-2-th-
iophenecarboxamide
[0612] starting from N-(4-aminophenyl)-N-methylacetamide:
[0613] MS (ESI): m/z (%)=382 (M+H, 100);
[0614] HPLC (method 4): rt=3.31 min.
Example 66
5-Chloro-N-(2-hydroxy-3-{[4-(1H-1,2,3-triazol-1-yl)phenyl]amino}propyl)-2--
thiophenecarboxamide
[0615] starting from 4-(1H-1,2,3-triazol-1-yl)aniline (Bouchet et
al.; J. Chem. Soc. Perkin Trans. 2; 1974; 449):
[0616] MS (ESI): m/z (%)=378 (M+H, 100);
[0617] HPLC (method 4): rt=3.55 min.
Example 67
tert-butyl
1-{4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)-
amino]-phenyl}-L-prolinate
[0618] MS (ESI): m/z (%)=480 (M+H, 100);
[0619] HPLC (method 4): rt=3.40 min.
Example 68
1-{4-[(3-{[(5-Chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]pheny-
l}-4-piperidinecarboxamide
[0620] MS (ESI): m/z (%)=437 (M+H, 100);
[0621] HPLC (method 4): rt=2.39 min.
Example 69
1-{4-[(3-{[(5-Chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)-amino]phen-
yl}-3-piperidinecarboxamide
[0622] MS (ESI): m/z (%)=437 (M+H, 100);
[0623] HPLC (method 4): rt=2.43 min.
Example 70
5-Chloro-N-(2-hydroxy-3-{[4-(4-oxo-1-piperidinyl)phenyl]amino}propyl)-2-th-
iophenecarboxamide
[0624] MS (ESI): m/z (%)=408 (M+H, 100);
[0625] HPLC (method 4): rt=2.43 min.
Example 71
1-{4-[4(3-{[(5-Chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]phen-
yl}-L-prolinamide
[0626] MS (ESI): m/z (%)=423 (M+H, 100);
[0627] HPLC (method 4): rt=2.51 min.
Example 72
5-Chloro-N-[2-hydroxy-3-({4-[3-(hydroxymethyl)-1-piperidinyl]phenyl}-amino-
)propyl]-2-thiophenecarboxamide
[0628] MS (ESI): m/z (%)=424 (M+H, 100);
[0629] HPLC (method 4): rt=2.43 min.
Example 73
5-Chloro-N-[2-hydroxy-3-({4-[2-(hydroxymethyl)-1-piperidinyl]phenyl}-amino-
)propyl]-2-thiophenecarboxamide
[0630] MS (ESI): m/z (%)=424 (M+H, 100);
[0631] HPLC (method 4): rt=2.49 min.
Example 74
Ethyl
1-{4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)-amin-
o]phenyl}-2-piperidinecarboxylate
[0632] MS (ESI): m/z (%)=466 (M+H, 100);
[0633] HPLC (method 4): rt=3.02 min.
Example 75
5-Chloro-N-[2-hydroxy-3-({4-[2-(hydroxymethyl)-1-pyrrolidinyl]phenyl}amino-
)-propyl]-2-thiophenecarboxamide
[0634] MS (ESI): m/z (%)=410 (M+H, 100);
[0635] HPLC (method 4): rt=2.48 min.
Example 76
5-Chloro-N-(2-hydroxy-3-{[4-(2-methylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-
-yl)-phenyl]amino}propyl)-2-thiophenecarboxamide
[0636] MS (ESI): m/z (%)=437 (M+H, 100).
[0637] HPLC (method 5): rt=1.74 min.
Example 77
5-Chloro-N-(2-hydroxy-3-{[4-(1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]ami-
no}-propyl)-2-thiophenecarboxamide
[0638] MS (ESI): m/z (%)=448 (M+H, 100);
[0639] HPLC (method 4): rt=3.30 min.
Example 78
5-Chloro-N-(2-hydroxy-3-{[4-(2-oxo-1-pyrrolidinyl)-3-(trifluoromethyl)phen-
yl]-amino}propyl)-2-thiophenecarboxamide
[0640] MS (ESI): m/z (%)=462 (M+H, 100);
[0641] HPLC (method 4): rt=3.50 min.
Example 79
5-Chloro-N-(3-{[3-chloro-4-(3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxy-pr-
opyl)-2-thiophenecarboxamide
[0642] MS (ESI): m/z (%)=444 (M+H, 100);
[0643] HPLC (method 4): rt=3.26 min.
Example 80
5-Chloro-N-(2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)-3-(trifluoromethyl)pheny-
l]-amino}propyl)-2-thiophenecarboxamide
[0644] MS (ESI): m/z (%)=478 (M+H, 100);
[0645] HPLC (method 4): rt=3.37 min.
Example 81
5-Chloro-N-(2-hydroxy-3-{[3-methyl-4-(3-oxo-4-morpholinyl)phenyl]amino}-pr-
opyl)-2-thiophenecarboxamide
[0646] MS (ESI): m/z (%)=424 (M+H, 100);
[0647] HPLC (method 4): rt=2.86 min.
Example 82
5-Chloro-N-(3-{[3-cyano-4-(3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxyprop-
yl)-2-thiophenecarboxamide
[0648] MS (ESI): m/z (%)=435 (M+H, 100);
[0649] HPLC (method 4): rt=3.10 min.
Example 83
5-Chloro-N-(3-{[3-chloro-4-(1-pyrrolidinyl)phenyl]amino}-2-hydroxypropyl)--
2-thiophenecarboxamide
[0650] MS (ESI): m/z (%)=414 (M+H, 100);
[0651] HPLC (method 4): rt=2.49 min.
Example 84
5-Chloro-N-(3-{[3-chloro-4-(2-oxo-1-pyrrolidinyl)phenyl]amino}-2-hydroxypr-
opyl)-2-thiophenecarboxamide
[0652] MS (ESI): m/z (%)=428 (M+H, 100);
[0653] HPLC (method 4): rt=3.39 min.
Example 85
5-Chloro-N-(3-{([3,5-dimethyl-4-(3-oxo-4-morpholinyl)phenyl]amino}-2-hydro-
xy-propyl)-2-thiophenecarboxamide
[0654] MS (ESI): m/z (%)=438 (M+H, 100);
[0655] HPLC (method 4): rt=2.84 min.
Example 86
N-(3-{[3-(Aminocarbonyl)-4-(4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-5-
-chloro-2-thiophenecarboxamide
[0656] MS (ESI): m/z (%)=439 (M+H, 100);
[0657] HPLC (method 4): rt=2.32 min.
Example 87
5-Chloro-N-(2-hydroxy-3-{[3-methoxy-4-(4-morpholinyl)phenyl]amino}propyl)--
2-thiophenecarboxamide
[0658] MS (ESI): m/z (%)=426 (M+H, 100);
[0659] HPLC (method 4): rt=2.32 min.
Example 88
N-(3-{[3-Acetyl-4-(4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-5-chloro-2-
-thiophenecarboxamide
[0660] MS (ESI): m/z (%)=438 (M+H, 100);
[0661] HPLC (method 4): rt=2.46 min.
Example 89
N-(3-{[3-Amino-4-(3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-5-chl-
oro-2-thiophenecarboxamide
[0662] MS (ESI): m/z (%)=425 (M+H, 100);
[0663] HPLC (method 4): rt=2.45 min.
Example 90
5-Chloro-N-(3-{[3-chloro-4-(2-methyl-3-oxo-4-morpholinyl)phenyl]amino}-2-h-
ydroxypropyl)-2-thiophenecarboxamide
[0664] MS (ESI): m/z (%)=458 (M+H, 100);
[0665] HPLC (method 4): rt=3.44 min.
Example 91
5-Chloro-N-(3-{[3-chloro-4-(2-methyl-5-oxo-4-morpholinyl)phenyl]amino}-2-h-
ydroxypropyl)-2-thiophenecarboxamide
[0666] MS (ESI): m/z (%)=458 (M+H, 100);
[0667] HPLC (method 4): rt=3.48 min.
Example 91a
5-Chloro-N-[2-hydroxy-3-({4-[(3-oxo-4-morpholinyl)methyl]phenyl}amino)prop-
yl]-2-thiophenecarboxamide
[0668] starting from 4-(4-amino-benzyl)-3-morpholinone (Surrey et
al.; J. Amer. Chem. Soc.; 77; 1955; 633):
[0669] MS (ESI): m/z (%)=424 (M+H, 100);
[0670] HPLC (method 4): rt=2.66 min.
General method for preparing 3-substituted
5-chloro-N-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide
derivatives starting from substituted
N-(3-amino-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide
derivatives
##STR00053##
[0671] At room temperature, carbodiimidazole (1.2 to 1.8 eq.) or a
similar phosgene equivalent are added to a solution of the
substituted
N-(3-amino-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide
derivative (1.0 eq.) in absolute THF (about 0.1 mol/l). At room
temperature or, if appropriate, at elevated temperature (up to
70.degree. C.), the mixture is stirred for 2 to 18 h and then
concentrated under reduced pressure. The product can be purified by
silica gel chromatography (dichloromethane/methanol mixtures or
cyclohexane/ethyl acetate mixtures).
[0672] The following compounds were prepared in an analogous
manner:
Example 27
N-[(3-Benzyl-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxa-
mide
[0673] MS (DCI, m/z (%)=372 (M+Na, 100), 351 (M+H, 45);
[0674] HPLC (method 1): rt (%)=433 min (100).
Example 28
5-Chloro-N-{[3-(3-cyanophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophe-
necarboxamide
[0675] MS (DCI, NH.sub.4): m/z (%)=362 (M+H, 42), 145 (100);
[0676] HPLC (method 2): rt (%)=4.13 min (100).
Example 29
5-Chloro-N-({3-[4-(cyanomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-
-thiophenecarboxamide
[0677] MS (ESI): m/z (%)=376 (M+H, 100);
[0678] HPLC (method 4): rt=4.12 min
Example 30
5-Chloro-N-({3-[3-(cyanomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-
-thiophenecarboxamide
[0679] MS (ESI): m/z (%)=376 (M+H, 100);
[0680] HPLC (method 4): rt=4.17 min
Example 92
[0681] tert-Butyl
4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-
-yl]benzylcarbamate starting from Example 58:
[0682] MS (ESI): m/z (%)=488 (M+Na, 23), 349 (100);
[0683] HPLC (method 1): rt (%)=4.51 (98.5).
Example 93
tert-Butyl
4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-ox-
azolidin-3-yl]phenylcarbamate
[0684] starting from Example 59:
[0685] MS (ESI): m/z (%)=493 (M+Na, 70), 452 (M+H, 10), 395
(100);
[0686] HPLC (method 1): it (%)=4.41 (100).
Example 94
tert-Butyl
2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}me-
thyl-carbamate
[0687] starting from Example 60:
[0688] MS (DCI, NH.sub.3): m/z (%)=393 (M+NH.sub.4, 100);
[0689] HPLC (method 3): it (%)=3.97 (100).
Example 95
[0690]
5-Chloro-N-({3-[3-fluoro-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-o-
xazolidin-5-yl}methyl)-2-thiophenecarboxamide
##STR00054##
[0691] 260 mg (0.608 mmol) of
5-chloro-N-(3-{[3-fluoro-4-(3-oxo-4-morpholinyl)phenyl]-amino}-2-hydroxyp-
ropyl)-2-thiophenecarboxamide (from Example 61), 197 mg (1.22 mmol)
of carbonylimidazole and 7 mg of dimethylaminopyridine in 20 ml of
dioxane are boiled under reflux for 5 hours. 20 ml of acetonitrile
are then added, and the mixture is stirred in a closed vessel in a
microwave oven at 180.degree. C. for 30 minutes. The solution is
concentrated using a rotary evaporator and chromatographed on an
RP-HPLC column. This gives 53 mg (19% of theory) of the target
compound.
[0692] NMR (300 MHz, d.sub.6-DMSO): .delta.=3.6-3.7 (m, 4H), 3.85
(dd, 1H), 3.95 (m, 2H), 4.2 (m, 1H), 4.21 (s, 2H), 4.85 (m, 1H),
4.18 (s, 2H), 7.19 (d, 1H, thiophene), 7.35 (dd, 1H), 7.45 (t, 1H),
7.55 (dd, 1H), 7.67 (d, 1H, thiophene), 8.95 (t, 1H, CONH).
Example 96
5-Chloro-N-[(2-oxo-3-phenyl-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxa-
mide starting from Example 62
[0693] MS (ESI): m/z (%)=359 ([M+Na].sup.+, 71), 337 ([M+H].sup.+,
100), Cl pattern;
[0694] HPLC (method 3): rt (%)=4.39 (100).
[0695] IC.sub.50: 2 .mu.M
Example 97
5-Chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}m-
ethyl)-2-thiophenecarboxamide
[0696] starting from Example 63:
[0697] MS (ESI): m/z (%)=458 ([M+Na].sup.+, 66), 436 ([M+H].sup.+,
100), Cl pattern;
[0698] HPLC (method 3): rt (%)=3.89 (100).
[0699] IC.sub.50: 1.4 nM
Example 98
N-[(3-{4-[Acetyl(cyclopropyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methy-
l]-5-chloro-2-thiophenecarboxamide
[0700] starting from Example 64:
[0701] MS (ESI): m/z (%)=456 ([M+Na].sup.+, 55), 434 ([M+H].sup.+,
100), Cl pattern;
[0702] HPLC (method 3): rt (%)=4.05 (100).
[0703] IC.sub.50: 50 nM
Example 99
N-[(3-{4-[Acetyl)methyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5--
chloro-2-thiophenecarboxamide
[0704] MS (ESI): m/z (%)=408 (M+H, 30), 449 (M+H+MeCN, 100);
[0705] HPLC (method 4): rt=3.66 min.
Example 100
5-Chloro-N-({2-oxo-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-oxazolidin-5-yl-
}methyl)-2-thiophenecarboxamide
[0706] MS (ESI): m/z (%)=404 (M+H, 45), 445 (M+H+MeCN, 100);
[0707] HPLC (method 4): rt=3.77 min.
Example 101
Tert-butyl
1-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-
-oxazolidin-3-yl]phenyl}-L-prolinate
[0708] MS (ESI): m/z (%)=450 (M+H-56, 25), 506 (M+H, 100);
[0709] HPLC (method 4): rt=5.13 min.
Example 102
1-{4-[5-({([(5-Chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidi-
n-3-yl]phenyl}-4-piperidinecarboxamide
[0710] MS (ESI): m/z (%)=463 (M+H, 100);
[0711] HPLC (method 4): rt=2.51 min.
Example 103
1-{4-[5-({[(5-Chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-
-3-yl]phenyl}-3-piperidinecarboxamide
[0712] MS (ESI): m/z (%)=463 (M+H, 100);
[0713] HPLC (method 4): rt=2.67 min.
Example 104
5-Chloro-N-({2-oxo-3-[4-(4-oxo-1-piperidinyl)phenyl]-1,3-oxazolidin-5-yl}m-
ethyl)-2-thiophenecarboxamide
[0714] MS (ESI): m/z (%)=434 (M+H, 40), 452 (M+H+H.sub.2O, 100),
475 (M+H+MeCN, 60);
[0715] HPLC (method 4): rt=3.44 min.
Example 105
1-{4-[5-({[(5-Chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-
-3-yl]phenyl}-L-prolinamide
[0716] MS (ESI): m/z (%)=449 (M+H, 100);
[0717] HPLC (method 4): rt=3.54 min.
Example 106
5-Chloro-N-[(3-{4-[3-(hydroxymethyl)-1-piperidinyl]phenyl}-2-oxo-1,3-oxazo-
lidin-5-yl)methyl]-2-thiophenecarboxamide
[0718] MS (ESI): m/z (%)=450 (M+H, 100);
[0719] HPLC (method 5): rt=2.53 min.
Example 107
5-Chloro-N-[(3-{4-[2-(hydroxymethyl)-1-piperidinyl]phenyl}-2-oxo-1,3-oxazo-
lidin-5-yl)methyl]-2-thiophenecarboxamide
[0720] MS (ESI): m/z (%)=450 (M+H, 100);
[0721] HPLC (method 5): rt=2.32 min.
Example 108
Ethyl
1-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxaz-
olidin-3-yl]phenyl}-2-piperidinecarboxylate
[0722] MS (ESI): m/z (%)=492 (M+H, 100);
[0723] HPLC (method 5): rt=4.35 min.
Example 109
5-Chloro-N-[(3-{4-[2-(hydroxymethyl)-1-pyrrolidinyl]phenyl}-2-oxo-1,3-oxaz-
olidin-5-yl)methyl]-2-thiophenecarboxamide
[0724] MS (ESI): m/z (%)=436 (M+H, 100);
[0725] HPLC (method 4): rt=2.98 min.
Example 110
5-Chloro-N-({2-oxo-3-[4-(1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]-1,3-ox-
azolidin-5-yl}methyl)-2-thiophenecarboxamide
[0726] MS (ESI): m/z (%)=474 (M+H, 100);
[0727] HPLC (method 4): rt=4.63 min.
Example 111
5-Chloro-N-({3-[4-(2-methylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-yl)phenyl-
]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
[0728] MS (ESI): m/z (%)=463 (M+H, 100);
[0729] HPLC (method 4): rt=2.56 min.
Example 112
5-Chloro-N-({2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]--
1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
[0730] MS (ESI): m/z (%)=488 (M+H, 100);
[0731] HPLC (method 4): rt=3.64 min.
Example 113
5-Chloro-N-({3-[3-chloro-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolid-
in-5-yl}methyl)-2-thiophenecarboxamide
[0732] MS (ESI): m/z (%)=470 (M+H, 100);
[0733] HPLC (method 4): rt=3.41 min.
Example 114
5-Chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl)-3-(trifluoromethyl)phenyl]-1-
,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
[0734] MS (ESI): m/z (%)=504 (M+H, 100);
[0735] HPLC (method 4): rt=3.55 min.
Example 115
5-Chloro-N-({3-[3-methyl-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolid-
in-5-yl}methyl)-2-thiophenecarboxamide
[0736] MS (ESI): m/z (%)=450 (M+H, 100);
[0737] HPLC (method 4): rt=3.23 min,
Example 116
5-Chloro-N-({3-[3-cyano-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidi-
n-5-yl}methyl)-2-thiophenecarboxamide
[0738] MS (ESI): m/z (%)=461 (M+H, 100);
[0739] HPLC (method 4): rt=3.27 min.
Example 117
5-Chloro-N-({3-[3-chloro-4-(1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5--
yl}methyl)-2-thiophenecarboxamide
[0740] MS (ESI): m/z (%)=440 (M+H, 100);
[0741] HPLC (method 4): rt=3.72 min.
Example 118
5-Chloro-N-({3-[3-chloro-4-(2-oxo-1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazoli-
din-5-yl}methyl)-2-thiophenecarboxamide
[0742] MS (ESI): m/z (%)=454 (M+H, 100);
[0743] HPLC (method 4): rt=3.49 min.
Example 119
5-Chloro-N-({3-[3,5-dimethyl-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxaz-
olidin-5-yl}methyl)-2-thiophenecarboxamide
[0744] MS (ESI): m/z (%)=464 (M+H, 100);
[0745] HPLC (method 4): rt=3.39 min.
Example 120
N-({3-[3-(Aminocarbonyl)-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-y-
l}methyl)-5-chloro-2-thiophenecarboxamide
[0746] MS (ESI): m/z (%)=465 (M+H, 100);
[0747] HPLC (method 4): rt=3.07 min.
Example 121
5-Chloro-N-({3-[3-methoxy-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5--
yl}methyl)-2-thiophenecarboxamide
[0748] MS (ESI): m/z (%)=452 (M+H, 100);
[0749] HPLC (method 4): rt=2.86 min.
Example 122
N-({3-[3-Acetyl-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-
-5-chloro-2-thiophenecarboxamide
[0750] MS (ESI): m/z (%)=464 (M+H, 100);
[0751] HPLC (method 4): rt=3.52 min.
Example 123
N-({3-[3-Amino-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}me-
thyl)-5-chloro-2-thiophenecarboxamide
[0752] MS (ESI): m/z (%)=451 (M+H, 100);
[0753] HPLC (method 6): rt=3.16 min.
Example 124
5-Chloro-N-({3-[3-chloro-4-(2-methyl-3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-
-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
[0754] MS (ESI): m/z (%)=484 (M+H, 100);
[0755] HPLC (method 4): rt=3.59 min.
Example 125
5-Chloro-N-({3-[3-chloro-4-(2-methyl-5-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-
-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
[0756] MS (ESI): m/z (%)=484 (M+H, 100);
[0757] HPLC (method 4): rt=3.63 min.
Example 125a
5-Chloro-N-[(2-oxo-3-{4-[(3-oxo-4-morpholinyl)methyl]phenyl}-1,3-oxazolidi-
n-5-yl)methyl]-2-thiophenecarboxamide
[0758] MS (ESI): m/z (%)=450 (M+H, 100);
[0759] HPLC (method 4): rt=3.25 min.
[0760] Via epoxide opening with an amine and subsequent cyclization
to give the corresponding oxazolidinone, it was also possible to
prepare the following compounds:
TABLE-US-00003 Example No. Structure M.p. [.degree. C.] IC.sub.50
[.mu.M] 126 ##STR00055## 229Z 0.013 127 ##STR00056## 159 0.0007 128
##STR00057## 198 0.002 129 ##STR00058## 196 0.001 130 ##STR00059##
206 0.0033 130a ##STR00060## 194 131 ##STR00061## 195 0.85 132
##STR00062## 206 0.12 133 ##STR00063## 217 0.062 134 ##STR00064##
207 0.48 135 ##STR00065## 202 1.1 136 ##STR00066## 239 1.2 137
##STR00067## 219 0.044 138 ##STR00068## 95 0.42 139 ##STR00069##
217 1.7
[0761] Examples 14 to 16 below are working examples for the
optional oxidation step.
Example 14
5-Chloro-N-({(5S)-3-[3-fluoro-4-(1-oxo-1[lambda].sup.4,4-thiazinan-4-yl)ph-
enyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
##STR00070##
[0763] At 0.degree. C., 5-chloro-N-({(5
S)-3-[3-fluoro-4-(1,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}me-
thyl)-2-thiophenecarboxamide (0.1 g, 0.22 mmol) from Example 3 in
methanol (0.77 ml) is added to a solution of sodium periodate (0.05
g, 0.23 mmol) in water (0.54 ml), and the mixture is stirred at
0.degree. C. for 3 h. 1 ml of DMF is then added, and the mixture is
stirred at RT for 8 h. After addition of a further 50 mg of sodium
periodate, the mixture is once more stirred at RT overnight. The
mixture is then admixed with 50 ml of water, and the insoluble
product is filtered off with suction. Washing with water and drying
gives 60 mg (58% of theory) of crystals.
[0764] M.p.: 257.degree. C.;
[0765] R.sub.f (silica gel, toluene/ethyl acetate 1:1)=0.54
(starting material=0.46);
[0766] IC.sub.50 value=1.1 .mu.M;
[0767] MS (DCI) 489 (M+NH.sub.4), Cl pattern.
Example 15
Preparation of
5-chloro-N-({(5S)-3-[4-(1,1-dioxo-1[lambda].sup.6,4-thiazinan-4-yl)-3-flu-
orophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
##STR00071##
[0769] 5-Chloro-N-({(5
S)-3-[3-fluoro-4-(1,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}me-
thyl)-2-thiophenecarboxamide from Example 3 (0.1 g, 0.22 mmol) in
3.32 ml of a mixture of 1 part of water and 3 parts of acetone is
admixed with 80 mg (0.66 mmol) of N-methylmorpholine N-oxide (NMO)
and 0.1 ml of a 2.5% strength solution of osmium tetroxide in
2-methyl-2-propanol. The mixture is stirred at room temperature
overnight, and another 40 mg of NMO are added. The mixture is
stirred for a further night and then poured into 50 ml of water and
extracted three times with ethyl acetate. The organic phase gives,
after drying and concentrating, 23 mg and the aqueous phase, after
removal of the insoluble solid by filtration with suction, 19 mg
(in total 39% of theory) of the target compound.
[0770] M.p.: 238.degree. C.;
[0771] R.sub.f (toluene/ethyl acetate 1:1)=0.14 (starting
material=0.46);
[0772] IC.sub.50 value=210 nM;
[0773] MS (DCI): 505 (M+NH.sub.4), Cl pattern.
Example 16
5-Chloro-N-{[(5S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-1,3-oxazolidin-5-y-
l]methyl}-2-thiophenecarboxamide N-oxide
[0774] is obtained by treating
5-chloro-N-{[(5S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-1,3-oxazolidin-5--
yl]methyl}-2-thiophenecarboxamide from Example 1 with the magnesium
salt of monoperoxyphthalic acid.
[0775] MS (ESI): 456 (M+H, 21%, Cl pattern), 439 (100%).
[0776] The Examples 31 to 35 and 140 to 147 below refer to the
optional amidination step.
General method for preparing amidines and amidine derivatives
starting from cyanomethylphenyl-substituted
5-chloro-N-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide
derivatives
[0777] The cyanomethylphenyl-substituted
5-chloro-N-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide
derivative in question (1.0 eq.) is, together with triethylamine
(8.0 eq.), stirred at RT in a saturated solution of hydrogen
sulphide in pyridine (about 0.05-0.1 mol/l) for one to two days.
The reaction mixture is diluted with ethyl acetate (EtOAc) and
washed with 2 N hydrochloric acid. The organic phase is dried with
MgSO.sub.4, filtered and concentrated under reduced pressure.
[0778] The crude product is dissolved in acetone (0.01-0.1 mol/l)
and admixed with methyl iodide (40 eq.). The reaction mixture is
stirred at room temperature (RT) for 2 to 5 h and then concentrated
under reduced pressure.
[0779] The residue is dissolved in methanol (0.01-0.1 mol/l) and,
to prepare the unsubstituted amidines, admixed with ammonium
acetate (3 eq.) and ammonium chloride (2 eq.). To prepare the
substituted amidine derivatives, primary or secondary amines (1.5
eq.) and acetic acid (2 eq.) are added to the methanolic solution.
After 5-30 h, the solvent is removed under reduced pressure and the
residue is purified by chromatography over an RP8 silica gel column
(water/acetonitrile 9/1-1/1+0.1% trifluoroacetic acid).
[0780] The following compounds were prepared in an analogous
manner:
Example 31
N-({3-[4-(2-Amino-2-iminoethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-
-chloro-2-thiophenecarboxamide
[0781] MS (ESI): m/z (%)=393 (M+H, 100);
[0782] HPLC (method 4): rt=2.63 min
Example 32
5-Chloro-N-({3-[3-(4,5-dihydro-M-imidazol-2-ylmethyl)phenyl]-2-oxo-1,3-oxa-
zolidin-5-yl}methyl)-2-thiophenecarboxamide
[0783] MS (ESI): m/z (%)=419 (M+H, 100);
[0784] HPLC (method 4): rt=2.61 min
Example 33
5-Chloro-N-[(3-{3-[2-imino-2-(4-morpholinyl)ethyl]phenyl}-2-oxo-1,3-oxazol-
idin-5-yl)methyl]-2-thiophenecarboxamide
[0785] MS (ESI): m/z (%)=463 (M+H, 100);
[0786] HPLC (method 4): rt=2.70 min
Example 34
5-Chloro-N-[(3-{3-[2-imino-2-(1-pyrrolidinyl)ethyl]phenyl}-2-oxo-1,3-oxazo-
lidin-5-yl)methyl]-2-thiophenecarboxamide
[0787] MS (ESI): m/z (%)=447 (M+H, 100);
[0788] HPLC (method 4): rt=2.82 min
Example 35
N-({3-[3-(2-Amino-2-iminoethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-
-chloro-2-thiophenecarboxamide
[0789] MS (ESI): m/z (%)=393 (M+H, 100);
[0790] HPLC (method 4): rt=2.60 min
Example 140
5-Chloro-N-({3-[4-(4,5-dihydro-1H-imidazol-2-ylmethyl)phenyl]-2-oxo-1,3-ox-
azolidin-5-yl}methyl)-2-thiophenecarboxamide
[0791] MS (ESI): m/z (%)=419 (M+H, 100);
[0792] HPLC (method 4): rt=2.65 min
Example 141
5-Chloro-N-[(3-{4-[2-imino-2-(4-morpholinyl)ethyl]phenyl}-2-oxo-1,3-oxazol-
idin-5-yl)methyl]-2-thiophenecarboxamide
[0793] MS (ESI): m/z (%)=463 (M+H, 100);
[0794] HPLC (method 4): rt=2.65 min
Example 142
5-Chloro-N-[(3-{4-[2-imino-2-(1-piperidinyl)ethyl]phenyl}-2-oxo-1,3-oxazol-
idin-5-yl)methyl]-2-thiophenecarboxamide
[0795] MS (ESI): m/z (%)=461 (M+H, 100);
[0796] HPLC (method 4): rt=2.83 min
Example 143
5-Chloro-N-[(3-{4-[2-imino-2-(1-pyrrolidinyl)ethyl]phenyl}-2-oxo-1,3-oxazo-
lidin-5-yl)methyl]-2-thiophenecarboxamide
[0797] MS (ESI): m/z (%)=447 (M+H, 100);
[0798] HPLC (method 4): rt=2.76 min
Example 144
5-Chloro-N-[(3-{4-[2-(cyclopentylamino)-2-iminoethyl]phenyl}-2-oxo-1,3-oxa-
zolidin-5-yl)methyl]-2-thiophenecarboxamide
[0799] MS (ESI): m/z (%)=461 (M+H, 100);
[0800] HPLC (method 4): rt=2.89 min
Example 145
5-Chloro-N-{[3-(4-{2-imino-2-[(2,2,2-trifluoroethyl)amino]ethyl}phenyl)-2--
oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide
[0801] MS (ESI): m/z (%)=475 (M+H, 100);
[0802] HPLC (method 4): rt=2.79 min
Example 146
N-({3-[4-(2-Anilino-2-iminoethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-
-5-chloro-2-thiophenecarboxamide
[0803] MS (ESI): m/z (%)=469 (M+H, 100);
[0804] HPLC (method 4): rt=2.83 min
Example 147
5-Chloro-N-[(3-{4-[2-imino-2-(2-pyridinylamino)ethyl]phenyl}-2-oxo-1,3-oxa-
zolidin-5-yl)methyl]-2-thiophenecarboxamide
[0805] MS (ESI): m/z (%)=470 (M+H, 100);
[0806] HPLC (method 4): rt=2.84 min
[0807] Examples 148 to 151 below refer to the removal of BOC amino
protective groups:
General Method for Removing Boc Protective Groups
(Tert-Butyloxycarbonyl):
##STR00072##
[0809] Aqueous trifluoroacetic acid (TFA, about 90%) is added
dropwise to an ice-cooled solution of a tert-butyloxycarbonyl-(Boc)
protected compound in chloroform or dichloromethane (about 0.1 to
0.3 mol/1). After about 15 min, ice-cooling is removed and the
mixture is stirred at room temperature for approximately 2-3 h, and
the solution is then concentrated and dried under high vacuum. The
residue is taken up in dichloromethane or dichloromethane/methanol
and washed with saturated sodium bicarbonate or 1N sodium hydroxide
solution. The organic phase is washed with saturated sodium
chloride solution, dried over a little magnesium sulphate and
concentrated. If appropriate, purification is carried out by
crystallization from ether or ether/dichloromethane mixtures.
[0810] The following compounds were prepared in an analogous manner
from the corresponding Boc-protected precursors:
Example 148
N-({3-[4-(Aminomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-
-thiophene-carboxamide
[0811] starting from Example 92:
[0812] MS (ESI): m/z (%)=349 (M-NH.sub.2, 25), 305 (100);
[0813] HPLC (method 1): rt (%)=3.68 (98).
[0814] IC.sub.50: 2.2 .mu.M
Example 149
N-{[3-(4-Aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophe-
necarboxamide
[0815] starting from Example 93:
[0816] MS (ESI): m/z (%)=352 (M+H, 25);
[0817] HPLC (method 1): rt (%)=3.50 (100).
[0818] IC.sub.50: 2 .mu.M
[0819] An alternative enantiomerically pure synthesis of this
compound is shown in the scheme below (cf. also Delalande S.A., DE
2836305, 1979; Chem. Abstr. 90, 186926):
##STR00073##
Example 150
5-Chloro-N-({3-[4-(glycylamino)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-
-thiophenecarboxamide
[0820] starting from Example 152:
[0821] MS (ES-pos): m/z (%)=408 (100);
[0822] HPLC (method 3): rt (%)=3.56 (97).
[0823] IC.sub.50: 2 .mu.M
Example 151
5-(Aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one
[0824] starting from Example 60:
[0825] MS (ESI): m/z (%)=276 (M+H, 100);
[0826] HPLC (method 3): rt (%)=2.99 (100).
[0827] IC.sub.50: 2 .mu.M
[0828] The Examples 152 to 166 below refer to the amino group
derivatization of aniline- or benzylamine-substituted
oxazolidinones using various reagents:
Example 152
5-Chloro-N-({3-[4-(N-tert-butyloxycarbonyl-glycylamino)phenyl]-2-oxo-1,3-o-
xazolidin-5-yl}methyl)-2-thiophenecarboxamide
##STR00074##
[0830] At 0.degree. C., 754 mg (2.1 mmol) of
N-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thioph-
enecarboxamide (from Example 149) are added to a solution of 751 mg
(4.3 mmol) of Boc-glycine, 870 mg (6.4 mmol) of HOBT
(1-hydroxy-1H-benzotriazole x H.sub.2O), 1790 mg (4.7 mmol) of HBTU
[O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate] and 1.41 ml (12.9 mmol) of N-methylmorpholine
in 15 ml of DMF/CH.sub.2Cl.sub.2 (1:1). The mixture is stirred at
room temperature overnight and then diluted with water. The
precipitated solid is filtered off and dried. Yield: 894 mg (79.7%
of theory);
[0831] MS (DCI, NH.sub.3): m/z (%)=526 (M+NH.sub.4, 100);
[0832] HPLC (method 3): rt (%)=4.17 (97).
Example 153
N-[(3-{4-[(Acetylamino)methyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5--
chloro-2-thiophenecarboxamide
##STR00075##
[0834] At 0.degree. C., a mixture of 30 mg (0.082 mmol) of
N-({3-[4-(aminomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro--
2-thiophene-carboxamide (from Example 148) in 1.5 ml of absolute
THF and 1.0 ml of absolute dichloromethane, and 0.02 ml of absolute
pyridine is mixed with acetic anhydride (0.015 ml, 0.164 mmol). The
mixture is stirred at room temperature overnight. Addition of ether
and crystallization affords the product.
[0835] Yield: 30 mg (87% of theory),
[0836] MS (ESI): m/z (%)=408 (M+H, 18), 305 (85);
[0837] HPLC (method 1): rt (%)=3.78 (97).
[0838] IC.sub.50: 0.6 .mu.M
Example 154
N-{[3-(4-{[(Aminocarbonyl)amino]methyl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]--
methyl}-5-chloro-2-thiophenecarboxamide
##STR00076##
[0840] At room temperature, 0.19 ml (0.82 mmol) of
trimethylsilylisocyanate are added dropwise to a mixture of 30 mg
(0.082 mmol) of
N-({3-[4-(aminomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)--
5-chloro-2-thiophene-carboxamide (from Example 148) in 1.0 ml of
dichloromethane. The mixture is stirred overnight and, after
addition of ether, the product is then obtained by filtration.
Yield: 21.1 mg (52% of theory),
[0841] MS (ESI): m/z (%)=409 (M+H, 5), 305 (72);
[0842] HPLC (method 1): rt (%)=3.67 (83).
[0843] IC.sub.50: 1.3 .mu.M
General method for acylating
N-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thioph-
enecarboxamide with carbonyl chlorides:
##STR00077##
[0844] Under argon, an approximately 0.1 molar solution of
N-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thioph-
enecarboxamide (from Example 149) (1.0 eq.) in absolute
dichloromethane/pyridine (19:1) is added dropwise to the
appropriate acid chloride (2.5 eq.). The mixture is stirred
overnight and then admixed with about 5 eq. of PS trisamine
(Argonaut Technologies) and 2 ml of absolute dichloromethane. The
mixture is stirred gently for 1 h and then filtered off, and the
filtrate is concentrated. If appropriate, the products are purified
by preparative RP-HPLC.
[0845] The following compounds were prepared in an analogous
manner:
Example 155
N-({3-[4-(Acetylamino)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-
-thiophene-carboxamide
[0846] LC-MS: m/z (%)=394 (M+H, 100);
[0847] LC-MS (method 6): rt (%)=3.25 (100).
[0848] IC.sub.50: 1.2 .mu.M
Example 156
5-Chloro-N-[(2-oxo-3-{4-[(2-thienylcarbonyl)amino]phenyl}-1,3-oxazolidin-5-
-yl)methyl]-2-thiophenecarboxamide
[0849] LC-MS: m/z (%)=462 (M+H, 100);
[0850] LC-MS (method 6): rt (%)=3.87 (100).
[0851] IC.sub.50: 1.3 .mu.M
Example 157
5-Chloro-N-[(3-{4-[(methoxyacetyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)-
-methyl]-2-thiophenecarboxamide
[0852] LC-MS: m/z (%)=424 (M+H, 100);
[0853] LC-MS (method 6): rt (%)=3.39 (100).
[0854] IC.sub.50: 0.73 .mu.M
Example 158
N-{4-([5-({[(5-Chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidi-
n-3-yl]phenyl}-3,5-dimethyl-4-isoxazolecarboxamide
[0855] LC-MS: m/z (%)=475 (M+H, 100).
[0856] IC.sub.50: 0.46 .mu.M
Example 159
5-Chloro-N-{[3-(4-{[(3-chloropropyl)sulphonyl]amino}phenyl)-2-oxo-1,3-oxaz-
olidin-5-yl]methyl}-2-thiophenecarboxamide
##STR00078##
[0858] An ice-cooled solution of 26.4 mg (0.15 mmol) of
3-chloro-1-propanesulphonyl chloride and 0.03 ml (0.2 mmol) of
triethylamine in 3.5 ml of absolute dichloromethane is admixed with
35 mg (0.1 mmol) of
N-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]-methyl}-5-chloro-2-thiop-
hene-carboxamide (from Example 149). After 30 min, ice-cooling is
removed and the mixture is stirred at room temperature overnight,
and 150 mg (about 5.5 eq.) of PS-trisamine (Argonaut Technologies)
and 0.5 ml of dichloromethane are then added. The suspension is
stirred gently for 2 h and filtered (the resin is washed with
dichloromethane/methanol), and the filtrate is concentrated. The
product is purified by preparative RP-HPLC. Yield: 19.6 mg (40% of
theory),
[0859] LC-MS: m/z (%)=492 (M+H, 100);
[0860] LC-MS (method 5): rt (%)=3.82 (91).
[0861] IC.sub.50: 1.7 .mu.M
Example 160
5-Chloro-N-({3-[4-(1,1-dioxido-2-isothiazolidinyl)phenyl]-2-oxo-1,3-oxazol-
idin-5-yl}methyl)-2-thiophenecarboxamide
##STR00079##
[0863] A mixture of 13.5 mg (0.027 mmol) of
5-chloro-N-{[3-(4-{[(3-chloropropyl)sulphonyl]amino}phenyl)-2-oxo-1,3-oxa-
zolidin-5-yl]methyl}-2-thiophene-carboxamide (from Example 159) and
7.6 mg (0.055 mmol) of potassium carbonate in 0.2 ml of DMF is
heated at 100.degree. C. for 2 h. After cooling, the mixture is
diluted with dichloromethane and washed with water. The organic
phase is dried and concentrated. The residue is purified by
preparative thin-layer chromatography (silica gel,
dichloromethane/methanol, 95:5). Yield: 1.8 mg (14.4% of
theory),
[0864] MS (ESI): m/z (%)=456 (M+H, 15), 412 (100);
[0865] LC-MS (method 4): rt (%)=3.81 (90).
[0866] IC.sub.50: 0.14 .mu.M
Example 161
5-Chloro-N-[((5S)-3-{4-[(5-chloropentanoyl)amino]phenyl}-2-oxo-1,3-oxazoli-
din-5-yl)methyl]-2-thiophenecarboxamide
##STR00080##
[0868] 0.5 g (1.29 mmol) of
N--{[(5S)-3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2--
thiophenecarboxamide (from Example 149) is dissolved in 27 ml of
tetrahydrofuran and admixed with 0.2 g (1.29 mmol) of
5-chlorovaleryl chloride and 0.395 ml (2.83 mmol) of triethylamine.
The mixture is concentrated under reduced pressure and
chromatographed over silica gel using a toluene/ethyl
acetate=1:1->ethyl acetate gradient. This gives 315 mg (52% of
theory) of a solid.
[0869] M.p.: 211.degree. C.
Example 162
5-Chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-1-piperidinyl)phenyl]-1,3-oxazolidin-5-
-yl}-methyl)-2-thiophenecarboxamide
##STR00081##
[0871] Under inert conditions, 5 ml of DMSO are admixed with 30 mg
of NaH (60% in paraffin oil), and the mixture is heated at
75.degree. C. for 30 min, until the evolution of gas has ceased. A
solution of 290 mg (0.617 mmol) of
5-chloro-N--[((5S)-3-{4-[(5-chloropentanoyl)amino]phenyl}-2-oxo--
1,3-oxazolidin-5-yl)methyl]-2-thiophene-carboxamide (from Example
161) in 5 ml of methylene chloride is then added dropwise, and the
mixture is stirred at room temperature overnight. The reaction is
terminated and the mixture is poured into 100 ml of water and
extracted with ethyl acetate. The evaporated organic phase is
chromatographed on an RP-8 column and the product is eluted with
acetonitrile/water. This gives 20 mg (7.5% of theory) of the target
compound.
[0872] M.p.: 205.degree. C.;
[0873] NMR (300 MHz, d.sub.6-DMSO): .delta.=1.85 (m, 4H), 2.35 (m,
2H), 3.58 (m, 4H), 3.85 (m, 1H), 4.2 (t, 1H), 4.82 (m, 1H), 7.18
(d, 1H, thiophene), 7.26 (d, 2H), 7.5 (d, 2H), 2.68 (d, 1H,
thiophene), 9.0 (t, 1H, CONH).
[0874] IC.sub.50: 2.8 nM
Example 163
5-Chloro-N-[((5S)-3-{4-[(3-bromopropionyl)amino]phenyl}-2-oxo-1,3-oxazolid-
in-5-yl)methyl]-2-thiophenecarboxamide
##STR00082##
[0875] is obtained in an analogous manner from Example 149.
Example 164
5-Chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-1-azetidinyl)phenyl]-1,3-oxazolidin-5--
yl}-methyl)-2-thiophenecarboxamide
##STR00083##
[0876] is obtained in an analogous manner by cyclization of the
open-chain bromopropionyl compound from Example 163 using
NaH/DMSO.
[0877] MS (ESI): m/z (%)=406 ([M+H].sup.+, 100), Cl pattern.
[0878] IC.sub.50: 380 nM
Example 165
tert-Butyl
4-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-
-oxazolidin-3-yl]phenyl}-3,5-dioxo-1-piperazinecarboxylate
##STR00084##
[0880] A solution of 199 mg (0.85 mmol) of Boc-iminodiacetic acid,
300 mg (2.2 mmol) of HOBT, 0.66 ml (6 mmol) of N-methylmorpholine
and 647 mg (1.7 mmol) of HBTU is admixed with 300 mg (0.85 mmol) of
N-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]-methyl}-5-chloro-2-thiop-
hene-carboxamide in 6 ml of a mixture of DMF and dichloromethane
(1:1). The mixture is stirred overnight, diluted with
dichloromethane and then washed with water, saturated ammonium
chloride solution, saturated sodium bicarbonate solution, water and
saturated sodium chloride solution. The organic phase is dried over
magnesium sulphate and concentrated. The crude product is purified
by silica gel chromatography (dichloromethane/methanol 98:2).
Yield: 134 mg (29% of theory);
[0881] MS (ESI): m/z (%)=571 (M+Na, 82), 493 (100);
[0882] HPLC (method 3): rt (%)=4.39 (90).
[0883] IC.sub.50: 2 .mu.M
Example 166
N-[((5S)-3-{4-[(3R)-3-Amino-2-oxo-1-pyrrolidinyl]phenyl}-2-oxo-1,3-oxazoli-
din-5-yl)methyl]-5-chloro-2-thiophenecarboxamide
trifluoroacetate
##STR00085##
[0884]
N2-(tert-Butoxycarbonyl)-N1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbo-
nyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-D-methionineamide
[0885] 429 mg (1.72 mmol) of N-BOC-D-methionine, 605 mg (1.72 mmol)
of
N-{[(5S)-3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-t-
hiophenecarboxamide, and 527 mg (3.44 mmol) of HOBT hydrate are
dissolved in 35 ml of DMF and admixed with 660 mg (3.441 mmol) of
EDCI hydrochloride and then dropwise with 689 mg (5.334 mmol) of
N-ethyl-diisopropylamine. The mixture is stirred at room
temperature for two days. The resulting suspension is filtered off
with suction and the residue is washed with DMF. The combined
filtrates are admixed with a little silica gel, concentrated under
reduced pressure and chromatographed over silica gel using a
toluene->T10EA7 gradient. This gives 170 mg (17% of theory) of
the target compound of melting point 183.degree. C.
[0886] R.sub.f (SiO.sub.2, toluene/ethyl acetate=1:1):0.2.
[0887] .sup.1H-NMR (300 MHz, d.sub.6-DMSO): .delta.=1.4 (s, 1H,
BOC), 1.88-1.95 (m, 2H), 2.08 (s, 3H, SMe), 2.4-2.5 (m, 2H,
partially obscured by DMSO), 3.6 (m, 2H), 3.8 (m, 1H), 4.15 (m,
2H), 4.8 (m, 1H), 7.2 (1H, thiophene), 7.42 (d, part of an AB
system, 2H), 7.6 (d, part of an AB system, 2H), 7.7 (d, 1H,
thiophene), 8.95 (t, 1H, CH.sub.2NHCO), 9.93 (bs, 1H, NH).
tert-Butyl
(3R)-1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-
-2-oxo-1,3-oxazolidin-3-yl]phenyl}-2-oxo-3-pyrrolidinylcarbamate
[0888] 170 mg (0.292 mmol) of
N2-(tert-butoxycarbonyl)-N1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]am-
ino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-D-methionineamide are
dissolved in 2 ml of DMSO and admixed with 178.5 mg (0.875 mmol) of
trimethyl-sulphonium iodide and 60.4 mg (0.437 mmol) of potassium
carbonate, and the mixture is stirred at 80.degree. C. for 3.5
hours. The mixture is then concentrated under high vacuum and the
residue is washed with ethanol. 99 mg of the target compound
remain.
[0889] .sup.1H-NMR (300 MHz, d.sub.6-DMSO): .delta.=1.4 (s, 1H,
BOC), 1.88-2.05 (m, 1H), 2.3-2.4 (m, 1H), 3.7-3.8 (m, 3H), 3.8-3.9
(m, 1H), 4.1-4.25 (m, 1H), 4.25-4.45 (m, 1H), 4.75-4.95 (m, 1H),
7.15 (1H, thiophene), 7.25 (d, 1H), 7.52 (d, part of an AB system,
2H), 7.65 (d, part of an AB system, 2H), 7.65 (d, 1H, thiophene),
9.0 (broad s, 1H).
N-[((5S)-3-{4-[(3R)-3-Amino-2-oxo-1-pyrrolidinyl]phenyl}-2-oxo-1,3-oxazoli-
din-5-yl)methyl]-5-chloro-2-thiophenecarboxamide
trifluoroacetate
[0890] 97 mg (0.181 mmol) of tert-butyl
(3R)-1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-
-oxazolidin-3-yl]phenyl}-2-oxo-3-pyrrolidinylcarbamate are
suspended in 4 ml of methylene chloride, 1.5 ml of trifluoroacetic
acid are added and the mixture is stirred at room temperature for 1
hour. The mixture is then concentrated under reduced pressure and
the residue is purified on an RP-HPLC (acetonitrile/water/0.1% TFA
gradient). Evaporation of the appropriate fraction gives 29 mg (37%
of theory) of the target compound of melting point 241.degree. C.
(decomp.).
[0891] R.sub.f (SiO.sub.2, EtOH/TEA=17:1) 0.19.
[0892] .sup.1H-NMR (300 MHz, d.sub.6-DMSO): .delta.=1.92-2.2 (m,
1H), 2.4-2.55 (m, 1H, partially obscured by DMSO peak), 3.55-3.65
(m, 2H), 3.75-3.95 (m, 3H), 4.1-4.3 (m, 2H), 4.75-4.9 (m, 1H), 7.2
(1H, thiophene), 7.58 (d, part of an AB system, 2H), 7.7 (d, part
of an AB system, 2H), 7.68 (d, 1H, thiophene), 8.4 (broad s, 3H,
NH3), 8.9 (t, 1H, NHCO).
[0893] The Examples 167 to 170 below refer to the introduction of
sulphonamide groups in phenyl-substituted oxazolidinones:
General method for preparing substituted sulphonamides starting
from
5-chloro-N-[(2-oxo-3-phenyl-4,3-oxazolidin-5-yl)methyl]-2-thiophenecarbox-
amide
##STR00086##
[0894] Under argon and at 5.degree. C.,
5-chloro-N-[(2-oxo-3-phenyl-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarbox-
amide (from Example 96) is added to chlorosulphonic acid (12 eq.).
The reaction mixture is stirred at room temperature for 2 h and
then poured into ice-water. The resulting precipitate is filtered
off, washed with water and dried.
[0895] Under argon and at room temperature, the precipitate is then
dissolved in tetrahydrofuran (0.1 mol/l) and admixed with the
appropriate amine (3 eq.), triethylamine (1.1 eq.) and
dimethylaminopyridine (0.1 eq.). The reaction mixture is stirred
for 1-2 h and then concentrated under reduced pressure. The desired
product is purified by flash chromatography
(dichloromethane/methanol mixtures).
[0896] The following compounds were prepared in an analogous
manner:
Example 167
5-Chloro-N-({2-oxo-3-[4-(1-pyrrolidinylsulphonyl)phenyl]-1,3-oxazolidin-5--
yl}-methyl)-2-thiophenecarboxamide
[0897] MS (ESI): m/z (%)=492 ([M+Na].sup.+, 100), 470 ([M+H].sup.+,
68), Cl pattern;
[0898] HPLC (method 3): rt (%)=4.34 (100).
[0899] IC.sub.50: 0.5 .mu.M
Example 168
5-Chloro-N-[(3-{4-[(4-methyl-1-piperazinyl)sulphonyl]phenyl}-2-oxo-1,3-oxa-
zolidin-5-yl)methyl]-2-thiophenecarboxamide
[0900] MS (ESI): m/z (%)=499 ([M+H].sup.+, 100), Cl pattern;
[0901] HPLC (method 2): rt (%)=3.3 (100).
Example 169
5-Chloro-N-({2-oxo-3-[4-(1-piperidinylsulphonyl)phenyl]-1,3-oxazolidin-5-y-
l}-methyl)-2-thiophenecarboxamide
[0902] MS (ESI): m/z (%)=484 ([M+H].sup.+, 100), Cl pattern;
[0903] HPLC (method 2): rt (%)=4.4 (100).
Example 170
5-Chloro-N-[(3-{4-[(4-hydroxy-1-piperidinyl)sulphonyl]phenyl}-2-oxo-1,3-ox-
azolidin-5-yl)methyl]-2-thiophenecarboxamide
[0904] MS (ESI): m/z (%)=500 ([M+H].sup.+, 100), Cl pattern;
[0905] HPLC (method 3): rt (%)=3.9 (100).
Example 171
5-Chloro-N-({2-oxo-3-[4-(1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl-
)-2-thiophenecarboxamide
##STR00087##
[0907] 780 mg (1.54 mmol) of tert-butyl
1-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}-methyl)-2-oxo-1,3-oxazolid-
in-3-yl]phenyl}prolinate are dissolved in 6 ml of dichloromethane
and 9 ml of trifluoroacetic acid, and the mixture is stirred at
40.degree. C. for two days. The reaction mixture is then
concentrated and stirred with ether and 2N aqueous sodium hydroxide
solution. The aqueous phase is concentrated and stirred with ether
and 2N hydrochloric acid. The organic phase of this extraction is
dried over MgSO.sub.4, filtered and concentrated. The crude product
is chromatographed over silica gel (CH.sub.2Cl.sub.2/EtOH/conc.
aqu. NH.sub.3 sol.=100/1/0.1 to 20/1/0.1).
[0908] This gives 280 mg (40% of theory) of the product.
[0909] MS (ESI): m/z (%)=406 (M+H, 100);
[0910] HPLC (method 4): rt=3.81 min.
HPLC Parameter and LC-MS Parameter for the HPLC and LC-MS Data
Given in the Examples Above (the Unit of the Retention Time (Rt) is
Minutes:
[0911] [1] Column: Kromasil C18, L-R temperature: 30.degree. C.,
flow rate=0.75 ml min.sup.-1, eluent: A=0.01 M HClO.sub.4,
B=CH.sub.3CN, gradient:->0.5 min 98% A->4.5 min 10% A->6.5
min 10% A
[0912] [2] Column: Kromasil C18 60*2, L-R temperature: 30.degree.
C., flow rate=0.75 ml min.sup.-1, eluent: A=0.01 M H.sub.3PO.sub.4,
B=CH.sub.3CN, gradient:->0.5 min 90% A->4.5 min 10% A->6.5
min 10% A
[0913] [3] Column: Kromasil C18 60*2, L-R temperature: 30.degree.
C., flow rate=0.75 ml min.sup.-1, eluent: A=0.005 M HClO.sub.4,
B=CH.sub.3CN, gradient:->0.5 min 98% A->4.5 min 10% A->6.5
min 10% A
[0914] [4] Column: Symmetry C18 2.1.times.150 mm, column oven:
50.degree. C., flow rate=0.6 ml min.sup.-1, eluent: A=0.6 g 30%
strength HCl/l of water, B=CH.sub.3CN, gradient: 0.0 min 90%
A->4.0 min 10% A->9 min 10% A
[0915] [5] MHZ-2Q, Instrument Micromass Quattro LCZ
[0916] Column Symmetry C18, 50 mm.times.2.1 mm, 3.5 .mu.m,
temperature: 40.degree. C., flow rate=0.5 ml min.sup.-1, eluent
A=CH.sub.3CN+0.1% formic acid, eluent B=water+0.1% formic acid,
gradient: 0.0 min 10% A->4 min 90% A->6 min 90% A
[0917] [6] MHZ-2P, Instrument Micromass Platform LCZ
[0918] Column Symmetry C18, 50 mm.times.2.1 mm, 3.5 .mu.m,
temperature: 40.degree. C., flow rate=0.5 ml min.sup.-1, eluent
A=CH.sub.3CN+0.1% formic acid, eluent B=water+0.1% formic acid,
gradient: 0.0 min 10% A->4 min 90% A->6 min 90% A
[0919] [7] MHZ-7Q, Instrument Micromass Quattro LCZ
[0920] Column Symmetry C18, 50 mm.times.2.1 mm, 3.5 .mu.m,
temperature: 40.degree. C., flow rate=0.5 ml min.sup.-1, eluent
A=CH.sub.3CN+0.1% formic acid, eluent B=water+0.1% formic acid,
gradient: 0.0 min 5% A->1 min 5% A->5 min 90% A->6 min 90%
A
General Method for Preparing Oxazolidinones of the General Formula
B by Solid-Phase-Supported Synthesis
[0921] Reactions with different resin-bonded products were carried
out in a set of separated reaction vessels.
[0922]
5-(Bromomethyl)-3-(4-fluoro-3-nitrophenyl)-1,3-oxazolidin-2-one A
(prepared from epibromohydrin and 4-fluoro-3-nitrophenyl isocyanate
using LiBr/Bu.sub.3PO in xylene analogously to U.S. Pat. No.
4,128,654, Ex.2) (1.20 g, 3.75 mmol) and ethyldiisopropylamine
(DIEA, 1.91 ml, 4.13 mmol) were dissolved in DMSO (70 ml), admixed
with a secondary amine (1.1 eq., amine component 1) and reacted at
55.degree. C. for 5 h. TentaGel SAM resin (5.00 g, 0.25 mmol/g) was
added to this solution, and the mixture was reacted at 75.degree.
C. for 48 h. The resin was filtered, washed repeatedly with
methanol (MeOH), dimethylformamide (DMF), MeOH, dichloromethane
(DCM) and diethyl ether and dried. The resin (5.00 g) was suspended
in dichloromethane (80 ml), admixed with DIEA (10 eq.) and
5-chlorothiophene-2-carbonyl chloride [prepared by reacting
5-chlorothiophene-2-carboxylic acid (5 eq.) and
1-chloro-1-dimethylamino-2-methylpropene (5 eq.) in DCM (20 ml) at
room temperature for 15 minutes] and the mixture was reacted at
room temperature for 5 h. The resulting resin was filtered, washed
repeatedly with MeOH, DCM and diethyl ether and dried. The resin
was then suspended in DMF/water (v/v 9:2, 80 ml), admixed with
SnCl.sub.2*2H.sub.2O (5 eq.) and reacted at room temperature for 18
h. The resin was washed repeatedly with MeOH, DMF, water, MeOH, DCM
and diethyl ether and dried. This resin was suspended in DCM,
admixed with DIEA (10 eq.) and, at 0.degree. C., with an acid
chloride (5 eq. of acid derivative 1), and the mixture was reacted
at room temperature overnight. Prior to the reaction, carboxylic
acids were converted into the corresponding acid chlorides by
reaction with 1-dimethylamino-1-chloro-2-methylpropene (1 eq.,
based on the carboxylic acid) in DCM at room temperature for 15
min. The resin was washed repeatedly with DMF, water, DMF, MeOH,
DCM and diethyl ether and dried. If the acid derivative 1 used was
an Fmoc-protected amino acid, the Fmoc protective group was removed
in the last reaction step by reaction with piperidine/DMF (v/v,
1/4) at room temperature for 15 minutes, and the resin was washed
with DMF, MeOH, DCM and diethyl ether and dried. The products were
then removed from the solid phase using trifluoroacetic acid
(TFA)/DCM (v/v, 1/1), the resin was filtered off and the reaction
solutions were concentrated. The crude products were filtered over
silica gel (DCM/MeOH, 9:1) and evaporated, giving a set of products
B.
##STR00088##
[0923] Compounds which were prepared by solid-phase-supported
synthesis:
Example 172
N-({3-[3-Amino-4-(1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-
-5-chloro-2-thiophenecarboxamide
##STR00089##
[0925] Analogously to the general procedure for preparing the
derivatives B, 5 g (1.25 mmol) of TentaGel SAM resin were reacted
with pyrrolidine as amine derivative 1. The aniline obtained after
reduction with SnCl.sub.2*2H.sub.2O was, without any further
acylation step, removed from the solid phase and concentrated. The
crude product was partitioned between ethyl acetate and NaHCO.sub.3
solution and the organic phase was salted out using NaCl, decanted
and evaporated to dryness. This crude product was purified by
vacuum flash chromatography over silica gel (dichloromethane/ethyl
acetate, 3:1-1:2).
[0926] .sup.1H-NMR (300 MHz, CDCl.sub.3): 1.95-2.08, br, 4H;
3.15-3.30, br, 4H; 3.65-3.81, m, 2H; 3.89, ddd, 1H; 4.05, dd, 1H;
4.81, dddd, 1H; 6.46, dd, 1H; 6.72, dd, 1H; 6.90, dd, 1H; 6.99, dd,
1H; 7.03, dd, 1H; 7.29, d, 1H.
Example 173
N-[(3-{3-(.beta.-Alanylamino)-4-[(3-hydroxypropyl)amino]phenyl}-2-oxo-1,3--
oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamide
##STR00090##
[0928] Analogously to the general procedure for preparing the
derivatives B, 5 g (1.25 mmol) of TentaGel SAM resin were reacted
with azetidine as amine derivative 1 and Fmoc-.beta.-alanine as
acid derivative 1. The crude product obtained after the removal was
stirred in methanol at room temperature for 48 h and evaporated to
dryness. This crude product was purified by reversed phase HPLC
using a water/TFA/acetonitrile gradient.
[0929] .sup.1H-NMR (400 MHz, CD.sub.3OD): 2.31, tt, 2H; 3.36, t,
2H; 3.54, t, 2H; 3.62, t, 2H; 3.72, dd, 1H; 3.79, dd, 1H; 4.01, dd,
1H; 4.29, dd, 2H; 4.43, t, 2H; 4.85-4.95, m, 1H; 7.01, d, 1H;
4.48-7.55, m, 2H; 7.61, d, 1H; 7.84, d, 1H.
Example 174
N-({3-[4-(3-Amino-1-pyrrolidinyl)-3-nitrophenyl]-2-oxo-1,3-oxazolidin-5-yl-
}-methyl)-5-chloro-2-thiophenecarboxamide
##STR00091##
[0931] Analogously to the general procedure for preparing the
derivatives B, 130 mg (32.5 .mu.mol) of TentaGel SAM resin were
reacted with tert-butyl 3-pyrrolidinylcarbamate as amine derivative
1. The nitrobenzene derivative obtained after the acylation with
5-chlorothiophenecarboxylic acid was removed from the solid phase
and concentrated. This crude product was purified by reversed phase
HPLC using a water/TFA/acetonitrile gradient.
[0932] .sup.1H-NMR (400 MHz, CD.sub.3OH): 2.07-2.17, m, 1H;
2.39-2.49, m, 1H; 3.21-3.40, m, 2H; 3.45, dd, 1H; 3.50-3.60, m, 1H;
3.67, dd, 1H; 3.76, dd, 1H; 3.88-4.00, m, 2H; 4.14-4.21, t, 1H;
4.85-4.95, m, 1H; 7.01, d, 1H; 7.11, d, 1H; 7.52, d, 1H; 7.66, dd,
1H; 7.93, d, 1H.
Example 175
N-({3-[3-Amino-4-(1-piperidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)--
5-chloro-2-thiophenecarboxamide
##STR00092##
[0934] Analogously to the general procedure for preparing the
derivatives B, 130 mg (32.5 .mu.mol) of TentaGel SAM resin were
reacted with piperidine as amine derivative 1. The aniline obtained
after the reduction was, without any further acylation step,
removed from the solid phase and concentrated. This crude product
was purified by reversed phase HPLC using a water/TFA/acetonitrile
gradient.
[0935] .sup.1H-NMR (400 MHz, CD.sub.3OH): 1.65-1.75, m, 2H;
1.84-1.95, m, 4H; 3.20-3.28, m, 4H; 3.68, dd, 1H; 3.73, dd, 1H;
3.90, dd, 1H; 4.17, dd, 1H; 4.80-4.90, m, 1H; 7.00, d, 1H; 7.05,
dd, 1H; 7.30-7.38, m, 2H; 7.50, d, 1H.
Example 176
N-({3-[3-(Acetylamino)-4-(1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl-
}-methyl)-5-chloro-2-thiophenecarboxamide
##STR00093##
[0937] Analogously to the general procedure for preparing the
derivatives B, 130 mg (32.5 .mu.mol) of TentaGel SAM resin were
reacted pyrrolidine as amine derivative 1 and acetyl chloride as
acid derivative 1. The crude product was partitioned between ethyl
acetate NaHCO.sub.3 solution and the organic phase was salted out
using NaCl, decanted and evaporated to dryness. This crude product
was purified by vacuum flash chromatography over silica gel
(dichloromethane/ethyl acetate, 1:1-0:1).
[0938] .sup.1H-NMR (400 MHz, CD.sub.3OH): 1.93-2.03, br, 4H; 2.16,
s, 3H; 3.20-3.30, br, 4H; 3.70, d, 2H; 3.86, dd, 1H; 4.10, dd, 1H;
4.14, dd, 1H; 4.80-4.90, m, 1H; 7.00, d, 1H; 7.07, d, 1H; 7.31, dd,
1H; 7.51, d, 1H; 7.60, d, 1H.
[0939] The following compounds were prepared analogously to the
general procedure.
TABLE-US-00004 Ret. HPLC Example Structure time [%] 177
##STR00094## 2.62 79.7 178 ##STR00095## 2.49 33.7 179 ##STR00096##
4.63 46.7 180 ##STR00097## 3.37 44.8 181 ##STR00098## 2.16 83 182
##STR00099## 2.31 93.3 183 ##STR00100## 2.7 100 184 ##STR00101##
3.91 51 185 ##STR00102## 2.72 75.2 186 ##STR00103## 3.17 46 187
##STR00104## 4.61 50.2 188 ##STR00105## 3.89 56.6 189 ##STR00106##
3.37 52.9 190 ##STR00107## 3.6 63.9 191 ##STR00108## 2.52 70.1 192
##STR00109## 3.52 46.6 193 ##STR00110## 2.87 50.1 194 ##STR00111##
3.25 71.1 195 ##STR00112## 2.66 67 196 ##STR00113## 2.4 52.1 197
##STR00114## 3.13 48.9 198 ##STR00115## 2.67 75.5 199 ##STR00116##
2.72 65.7 200 ##STR00117## 2.71 57.3 201 ##STR00118## 2.22 100 202
##STR00119## 3.89 75.7 203 ##STR00120## 3.19 49.6 204 ##STR00121##
2.55 88.2 205 ##STR00122## 2.44 68.6 206 ##STR00123## 2.86 71.8 207
##STR00124## 2.8 63.6 208 ##STR00125## 2.41 77 209 ##STR00126##
2.56 67.9 210 ##STR00127## 3.67 78.4 211 ##STR00128## 2.54 69.8 212
##STR00129## 3.84 59.2 213 ##STR00130## 2.41 67.8 214 ##STR00131##
2.41 75.4 215 ##STR00132## 4.01 81.3 216 ##STR00133## 3.46 49.5 217
##STR00134## 4.4 60.2 218 ##STR00135## 3.79 70.9 219 ##STR00136##
4.57 51.5 220 ##STR00137## 2.68 100 221 ##STR00138## 4.53 63.5 222
##STR00139## 2.66 89.2 223 ##STR00140## 4.76 69.3 224 ##STR00141##
3.45 77.4 225 ##STR00142## 3.97 63.2 226 ##STR00143## 3.94 61.4 227
##STR00144## 4.15 66.3 228 ##STR00145## 4.41 55.1 229 ##STR00146##
2.83 41.1 230 ##STR00147## 2.7 83 231 ##STR00148## 4.39 64.2 232
##STR00149## 4.85 74.9 233 ##STR00150## 4.17 41 234 ##STR00151##
4.21 61.8 235 ##STR00152## 2.75 100 236 ##STR00153## 3.94 50 237
##STR00154## 4.65 75.8 238 ##STR00155## 4.4 75.3 239 ##STR00156##
4.24 62.2 240 ##STR00157## 4.76 75.1 241 ##STR00158## 4.17 72.5 242
##STR00159## 4.6 74.8 243 ##STR00160## 4.12 51.6 244 ##STR00161##
4.71 66.2 245 ##STR00162## 4.86 62 246 ##STR00163## 5.23 58.3 247
##STR00164## 4.17 72.4 248 ##STR00165## 3.35 59.6 249 ##STR00166##
2.41 60.3 250 ##STR00167## 3.31 65.2 251 ##STR00168## 2.86 36.5 252
##STR00169## 2.69 89.8 253 ##STR00170## 2.81 67.4 254 ##STR00171##
2.19 75.4
[0940] All products of the solid-phase-supported synthesis were
characterized by LC-MS. As standard, the following separation
system was used: HP 1100 with UV detector (208-400 mu), oven
temperature 40.degree. C., Waters-Symmetry C18 column (50
mm.times.2.1 mm, 3.5 .mu.m), mobile phase A: 99.9%
acetonitrile/0.1% formic acid, mobile phase B: 99.9% water/0.1%
formic acid; gradient:
TABLE-US-00005 Time A: % B: % flowrate 0.00 10.0 90.0 0.50 4.00
90.0 10.0 0.50 6.00 90.0 10.0 0.50 6.10 10.0 90.0 1.00 7.50 10.0
90.0 0.50
[0941] The substances were detected using a Micromass Quattro LCZ
MS, ionization: ESI positive/negative.
[0942] In the structures listed above which comprise the
radical(s)
##STR00172##
or --O, what is meant is in each case a
##STR00173##
or --OH function.
* * * * *