Title of Invention

OXAZOLIDINONES AND THEIR USE

Abstract SUBSTITUTED OXAZOLIDINONES AND THEIR USE The invetion relates to the field of blood coagulation. Novel oxazolidinone derivatives of the general formula (I) process for their preparation and their use as medicianally active compounds for the prophylaxis and/or treatment of disorders are described.
Full Text FORM 2
THE PATENTS ACT 1970 [39 OF 1970]
86
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"OXAZOLIDINONES AND THEIR USE"
BAYER HEALTHCARE AG, a body corporate organized under the laws of Germany of 51368 Leverkusen, Germany,
The following specification particularly describes the invention and the manner in which it is to be performed:


The present invention relates to the field of blood coagulation. In particular, the
present invention relates to novel oxazolidinone derivatives, to processes for their
5 preparation and to their use as active compounds in medicaments.
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
10 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
15 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
20 fibrous/gelatinous coagulant. In addition, thrombin is a potent effector of platelet
aggregation which likewise contributes significantly to haemostasis.
Maintenance of normal haemostasis - between bleeding and thrombosis - is subject to . a complex regulatory mechanism. Uncontrolled activation of the coagulant system or
25 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,
30 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.
35 These thromboembolic disorders are the most frequent" cause of morbidity and
mortality in most industrialized countries (Pschyrembel, Klinisches Worterbuch



[clinical dictionary], 257th edition, 1994, Walter de Gruyter Verlag, page 199 ff.,
entry "Blutgerinnung" [blood coagulation]; R6rPPP Lexikon Chemie, Version 1.5,
1998, Georg Thieme Verlag Stuttgart, entry "Blutgerinnung"; Lubert Stryer,
Biochemie [biochemistry], Spektrum der Wisenschaft Verlagsgesellschaft mbH
5 Heidelberg, 1990, page 259 ff.).
The anticoagulants, i.e. substances for inhibiting or preventing blood coagulation,
which are known from the prior an have various, often grave disadvantages.
Accordingly, in practice, an efficient treatment method or prophylaxis of
10 thromboembolic disorders is very difficult and unsatisfactory.
In the therapy and prophylaxis of thromboembolic disorders, use is firstly made of heparin, which is administered parenterally of subcutaneously. Owing to more favourable pharmacokinetic properties, preference is nowadays more and more given
15 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,
20 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, 257th edition, 1994, Walter de Gruyter Verlag, page 610, entry "Heparin"; Rornpp Lexikon Chemie, Version 1.5, 1998, Georg Thieme Verlag Stuttgart, entry "Heparin").
25
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 coumafin derivatives which inhibit the synthesis of various products of certain vitamin K-dependent coagulation factors in
30 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
35 gastrointestinal disturbances, hair loss and skin necroses, have been described
(Pschyrembel, Klinisches Worterbuch, 257th edition, 1994, Walter de Gruyter Verlag,
3-3



ax
0 R1 . represents 2-thiophenc which is substituted in the 5-position by a radical from the group consisting of chlorine, bromine, methyl and trifluoromethyl,
R2 represents D-A-:
where:
the radical "A" represents phonylene;
the radical "D" represents a saturated 5~ or 6-membered heterocyclic,
which is attached to "A" via a nitrogen atom.
which has a carbonyl group directly adjacent In 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 0;
where
the group "A" defined above may optionally be mono- or disubstituted in the metaposition
with respect to the point of attachment to the oxazolidinone, by a radical fromthe group
consisting of fluorine, chlorine, nitro. amino, trilhioroinethyl, methyl andeyano,
R3; R4, R5, R6 R.7and R8each represent hydrogen
and their pharmaeeuticaily acceptable salts, hydrates. liydrates of sails.
except for compounds of the general formula (1) in which the radical R is an unsubstituted 2-thiopbene radical and the radical R" is simultaneously a mono- or polysubstituted phenyl radical and the radicals R~", R4, R5, R6, R7 and R are each simultaneously hydrogen.
Preference is given here to compounds of the. general formula (I),
in which
R represents optionally benzo-fused thiophenc (thienyl) which may optionally be mono- or polysubstituted by a radical from the group consisting of halogen; cyano; nitro; amino; aminomethyl; (C7-C8)-alkyl which for its part may optionally be mono- or polysubstituted bv halogen; (C3-C7)-eyeloalkyl:




(C1-C-8)-alkoxy; imidazolinyl; -C(=NH)NH2; carbamoyl; and mono- and di-(C1-C-4)-alkyl-aminocarbonyI,
R2 represents one of the groups below:
5 A-,
A-M-,
D-M-A-,
B-M-A-,
B-,
10 B-M",
B-M"B-, D-M-B-,
where:
15 the radical "A" represents ( 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
20 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,SO2,N,NO (N-oxide)and G,
25 the radical "M" represents -NH-, -CH2-, -CH2CH2-, -O-, -NH-CH2-,
-CH2-NH-, -OCHr, -CH2CK -CONH-, -NHCO-, -COO-, -OOC-, -S-, -S02- or represents a covalent bond;
where
30 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; (Cr C6)-alkanoyl; (C3-C7)-cycloalkanoyl; (C6-C14)-arylcarbonyl; (C5-C10)-heteroarylcarbonyl; (C1-C6)-alkanoyloxymethyloxy; (C1-C4)hydroxy-
35 alkylcarbonyl; -COOR27; -S02R27; -C(NR27R28)=NR29; -CONR28R29;
-SO2NR28R29; -OR30; -NR30R31, (CrC6)-alkyl and (C3-C7)-cycloalkyl,








where (C1-C6)-aIkyI and (C3-C7)-cycloalkyl for their part may optionally be substituted by a radical from the group consisting of cyano; -OR27; -NR28R29; -CO(NH)v(NR27R28) and
-C(NR27R28)=NR29,
where:
v is either 0 or 1 and
10
R27, R28 and R29 are identical or different and independently of one
another each represents hydrogen, (C1-C4)-alkyI1 (C3-C7)-
cycloalkyl, (C1-C4)-alkanoyl, carbamoyl, trifluoromethyl,
phenyl or pyridyl,
15 and/or
R27 and R28 or R27 and R29 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
20 two, identical or different heteroatoms from the group
consisting of N, O and S, and
R30 and R31 are identical or different and independently of one another
each represents hydrogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl,
25 (CrC4)alkylsuIphonyI, (C1-C4)-hydroxyaikyl, (CrC4)-
aminoalkyl, di-(C 1 -C4)-alkylamino-(C 1 -C4)-alkyl,
-CH2C(NR27R2S)=NR29 or -COR33,

where
30
.33
R33 represents (CrC6)-alkoxy, (C1-C4)-aIkoxy-(CI-C4)-
alkyl, (C1-C4)-aIkoxycarbonyl-(CI-C4)-alkyI, (CrC4>
aminoalkyl, (C1-C4)~alkoxycarbonyl, (C1-C4)-alkanoyl-
(Ci-C4)-alkyl, (C3-C7)-cycloalkylT (C1-C6)-alkenyl,
35 (Ct-Cg^alkyl, which may optionally be substituted by
7-






phenyl or acetyl, (C6-CI4)-aryl, (C5-C10)-heteroaryI, trifluoromethyl, tetrahydrofuranyl or butyrolactone,
R3, R4, R5, R6, R7 and R8 are identical or different and each represents hydrogen or represents (C1-C6)-alkyl
and their pharmaceutically acceptable salts, hydrates and prodrugs,

1
except for compounds of the general formula (I) in which the radical R is an
10 unsubstituted 2-thiophene radical and the radical R2 is simultaneously a mono- or
polysubstituted phenyl radical and the radicals R3, R4; R5, Rs, R7 and R8 are each
simultaneously hydrogen.

15
Preference is also given here to compounds of the general formula (I),
in which
R1 represents thiophene (thienyl), in particular 2-thiophene, which may
optionally be mono- or polysubstituted by halogen, preferably chlorine or
20 bromine, by amino, aminomethyl or (C1-C8)-alkyl, preferably methyl, where
the (C1-C8)-alkyl radical for its part may optionally be mono- or
polysubstituted by halogen, preferably fluorine,
R2 represents one of the groups below:
25 A-,
A-M-,
D-M-A-,
B-M-A-,
B-,
30 B-M-,
B-M-B-,
D-M-B-,

35

where:

5


the radical "A" represents (C6-C14)-aryl preferably (C6-C1o)-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
5 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, S02, N, NO
10 (N-oxide) and O;
the radical "M" represents -NH-, -CH2-, -CH2CH2-, -0~, -NH-CH2-, -CH2-NH-, -OCH2-, -CH20-, -CONH-, -NHCO-, -COO-, -OOC-, -S-or represents a covalent bond;
15 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; (C1-C6)-alkanoyl; (C3-C7)-cycloalkanoyl; (C6-C14)-
20 arylcarbonyl; (C5-C1o)-heteroarylcarbonyl; (C1-C6)-
alkanoyloxymethyloxy; -COOR27; -S02R27; -C(NR27R28)=NR29;
-CONR28R29; -S02NR28R29; -OR30; -NR30R31, (C1C6)-alkyl and (C3-
C7)-cycloaIkyl,
25 where (C1-C6)-alkyl and (C3-C7)-cycloalkyl for their part may
optionally be substituted by a radical from the group consisting of cyano; -OR27; -NR28R29; -CO(NH)v(NR27R28) and
-C(NR27R28)=NR29,
30 where:
v is either 0 or 1 and
R27, R28 and R29 are identical or different and independently of one
35 another each represents hydrogen, (C1-C4)-alkyl or (C3-C7)-
cycloalkyl,
9



and/or
R27 and R28 or R27 and R29 together with the nitrogen atom to which
they are attached form a saturated or partially unsaturated 5- to
5 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
R30 and R31 are identical or different and independently of one another 10each represents hydrogen,
alkylsulphonyl, aminoalkyl, (Ci-C4)~
alkanoyl,
15
R3, R4, R5, R6, R7 and Rs are identical or different and each represents hydrogen or represents (Ci-C6)-alkyl
and their phannaceutically acceptable salts, hydrates and prodrugs,
20
except for compounds of the general formula (I) in which the radical R1 is an unsubstituted 2-thiophene radical and the radical R is simultaneously a mono- or polysubstituted phenyl radical and the radicals R3, R4, R5, R6, R7 and Rs are each simultaneously hydrogen.
25
Particular preference is given here to compounds of the general formula (I),
in which - ,;J
30 R1 represents thiophene (thienyl), in particular 2-thiophene, which may
optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, or by (Ci-Cg)-alkyl, preferably methyl, where the (Ci-Cg)-alkyl radical for its part may optionally be mono- or polysubstituted by halogen, preferably fluorine,

35

R2 represents one of the groups below;

10


A-,
A-M-,
D-M-A-,
B-M-A-,
5 B-,
B-M-,
B-M-B-,
D-M-B-,
10 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;
15 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, SO2, N, NO
(N-oxide) and O;
the radical "M" represents -NH-, -O-, -NH-CH2-, -CH2-NH-, -OCHz-,
20 -CH2O-, -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
25 consisting of halogen; trifluoromethyl; oxo; cyano; pyridyl; (C1-C3)-
alkanoyl; (C6-Cio)-arylcarbonyI; (C5-C6)-heteroarylcarbonyl; (C1-C3)-
alkanoyloxymethyloxy; -C(NR27R28)=NR29; -CONR28R29;
-S02NR28R29; -OH; -NR30R31; (C1-C4)-alkyl; and cyclopropyl, cyclopentyl or cyclohexyl, 30
where (C1-C4)-alkyl and cyclopropyl, cyclopentyl or cyclohexyl for their part may optionally be substituted by a radical from the group consisting of cyano; -OH; -OCH3; -NR28R29; -CO(NH)v(NR27R28) and -C(NR27R28)=NR29, 35
where:
1)





v is either 0 or 1, preferably 0, and
R27, R28 and R29 are identical or different and independently of
5 one another each represents hydrogen, (C1-G4)-alkyl or
else cyclopropyl, cyclopentyl or cyclohexyl and/or
R27 and R28 or R27 and R29 together with the nitrogen atom to which
10 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
15 R30 and R31 are identical or different and independently of one another
each represents hydrogen, (Ci-GO-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C1-C4)-alkylsulphonyl, (C1-C4)-hydroxyalkyl, (C1-C4)-aminoalkyl, di-(C1-C4)-alkylamino-(C1-C4)-alkyl, (C1C3)-alkanoyl or phenylcarbonyl,

20
25
30

R3, R4, R5, R6, R7 and Rs are identical or different and each represents hydrogen or represents (C1-C6)-alkyl
and their pharmaceutically acceptable salts, hydrates and prodrugs,
except for compounds of the general formula (I) in which the radical R is an unsubstituted 2-thiophene radical and the radical R2 is simultaneously a mono- or polysubstituted phenyl radical and the radicals R3, R4, R5, R6, R7 and R8 are each simultaneously hydrogen.
Particular preference is given here to compounds of the general formula (I),
in which







R1 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,
5 R2 represents one of the groups below:
A-,
A-M-,
D-M-A-,
B-M-A-,
10 B-,
B-M-,
B-M-P-,
D-M-B-,
15 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;
20 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, SO2 and O; or contains up to two heteroatoms and/or hetero chain members from the group consisting of S, SO, SOx
25 and O;
the radical "M" represents -NH-, -O-, -NH-CH2-, -CH2-NH-, -OCH2-, -CH2O-, -CONH-, -NHCO- or represents a covalent bond;
where
30 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; (C1-C3)-alkanoyl; (C6-C10)-aryIcarbonyl; (C5-C6)-hetefoarylcarbonyl; (C1-C3)-alkanoyloxymethyloxy; -CONR28R29; -S02NR28R29; -OH; -NR30R31;
35 (C1-C4)-alkyl; and cyclopropyl, cyclopentyl or cyclohexyl,




may, in particular, represent a group of the following formula:
Y-X-(CH2),-X-(CO)n-(CH2)1-(CR9R10)m-(CH3)02-
where
m is an integer from 0 to 6, preferably from 1 to 3,
n is either 0 or 1,
p is an integer from 0 to 3, preferably either 0 or 1,
o{ is an integer 0 or J,
o2 is an integer 0 or 1,
R9 and R10 are identical or different and each represents hydrogen; (C1-C4)-alkyl, preferably methyl; (C1-C4)-alkoxy, preferably methoxy; (C3-C7)-cycloalkyl; hydroxyl or fluorine,
X and X" are identical or different and each represents O; N-R11 or a covalent bond,
where R11 represents H; (C1-C4)-aIkyI, preferably methyl, or (C3-C7)-cycloalkyl,
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 $O2,
where:
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; (C1-C4)-alkyl; -C(=NR12)NR13R!3"; and-NRI4R!5,
where:
R12 represents hydrogen, (C1-C4)-alkyl or (C3-C7)-cycloalkyl;
R13 and R13 are identical or different and independently of one another each represents hydrogen, (C1-C4)-alkyl or (C3-C7)-cycloalkyl
and/or
R13 and R13 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;
R14 and R15 are identical or different and independently of one another each represents hydrogen, (C1-C4)-alkyI, (C3-C7)-cyc]oalky) or (C1-C5)-alkanoyl;
and/or
this radical Y may furthermore optionally be substituted by a radical from the group consisting of oxo; cyano; thiono; halogen; -OR16; =NR16; -NR16R17; -C(=NR18)NRI9R19" and (C1C4)-alkyl,
in which (C1-C4)-alkyi for its part may optionally be substituted by a radical from the group consisting of hydroxyl; cyano; -NR16R17 and -C(=NR18)NR19R19",


18






where:
R16 and R17 are identical or different and independently of one another each represents hydrogen, (C1-C4)-alkyl, (C3-C7)-cycIoalkyI or (C1-C3)-alkanoyl;
R18 represents hydrogen, (C1-C4)-alkyl or (C3-C7)-cycloalkyl;
10
R19 and R19 are identical or different and independently of one
another each represents hydrogen, (C1-C4)-aIkyI or (C3-
C7)-cycloalkyl
and/or
15 R19 and R19 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, 0 and S.
20 Particular preference is given to compounds of the general fonnula (I) in which the
radical
R2 represents a group of the following fonnula:
25 Y-X"-(CH2)p-X-(CO)n-(CH2)Ol-(CR9Rl0)m-(CH2)o2-
where
m is an integer from 0 to 3, 30
n is an integer 0 or 1,
p is an integer 0 or 1,
35 01 is an integer 0 or 1,





19 —
02 is an integer 0 or 1,
R9 and R10 are identical or different and each represents hydrogen; methyl;
5
X and X" are identical or different and each represents O; N-R11 or a covalent
bond,
where R1" represents H or methyl,
10
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 SO2, in particular cyclohexyl, piperazinyl, morpholinyl,
15 thiomorpholinyl, diazepinyl, pyrrolidinyl and piperidinyl,
where:
this radical Y may optionally be substituted by a 5- or 6-membered
20 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
where this radical for its pan may be substituted by a radical from the
25 group consisting of cyano; hydroxyl; fluorine; chlorine; (C1-C4)-alkyl;
-C(=NR12)NR13R13"; and -NR14R15,
where:
30 R12 represents hydrogen, methyl, ethyl, cyclopropyl, cyclopentyl or
cyclohexyl;
R13 and R13 are identical or different and independently of one
another each represents hydrogen, methyl, ethyl, cyclopropyl,
35 cyclopentyl or cyclohexyl
and/or








R13 and R13" 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
5 and S, in particular piperidinyl, piperazinyl, morpholinyl and
thiomorpholinyl;
R14and R15 are identical or different and independently of one another
each represents hydrogen, methyl, ethyl, cyclopropyl,
. 10 cyclopentyl or cyclohexyi or else acetyl;
and/or
this radical Y may furthermore optionally be substituted by a
15 radical from the group consisting of oxo; cyano; thiono;
fluorine; chlorine; -OH; -OCH3; =NR16; -NH2; -N(CH3)2; -C(=NR18)NR19R19" and methyl,
in which methyl for its part may optionally be substituted by a
20 radical from the group consisting of hydroxyl; cyano; -NR16R17
and-C(=NRI8)NR19R19",
where:
25 R16 and R17 are identical or different and independently of one
another each represents hydrogen, methyl, (C3-C7)-cycloalkyl or acetyl;

30


R18 reprsents hydrogen, methyl or (C3-C7)-cycloalkyl;
R19 and R19" are identical or different and independently of one another each represents hydrogen, methyl or {C3-C7)-cycloalkyl and/or



35

21




-2*-=—=
R19 and R19" 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
5 piperidinyl, piperazinyl, morpholinyl and thio-
morpholinyl.
Likewise, in the compounds of the general formula (I), the radical
10 R2 may represent a group of the formula below:
Z-(CO)r(CR20R2I)s-
where; 15
s is an integer from 1 to 6,
t is either 0 or 1,
20 R20 and R21 are identical or different and each represents hydrogen, (C1-C4)-
alkyl, (C1-C4)-alkoxy, (C3-C7)-cycIoaIkyl, hydroxyl or fluorine,
Z represents a radical which is selected from the group consisting of cyano; -C(NR22R23)=NR24; -CO(NH)uNR22R23; and-NR25R26,
25
where:
u is either 0 or 1, preferably 0, and
30 R22, R23 and R24 are identical or different and independently of one
another each represents hydrogen, (C1-C4)-alkyI or (C3-C7)-cycloalkyl, preferably hydrogen or methyl, and/or
35 R22 and R23 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 SO2;
R25 and R26 are identical or different and independently of one another
5 each represents hydrogen, (C1-C4)-aIkyl or (C3-C7)-cycloalkyl,
preferably hydrogen, methyl or ethyl, where (C1-C4)-alkyl and (C3-C7)-cycloalkyl for their part may optionally be substituted by hydroxy! or (C1-C6)-alkoxy.
10 Furthermore, in the compounds of the general formula (I), the radical
R2 may represent one of the following groups:
A-,
A-M-,
15 D-M-A-,
B-M-A-,
B-,
B-M-,
B-M-B-,
20 D-M-B-,
where:
the radical "A" represents (C6-C14)-aryl, preferably (C6-C10)-aryl, in particular
25 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;
30 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, S02, N, NO (N-oxide)
and O;
the radical "M" represents -NH-, -CH2-, -CH2CB2-, -0-, -NH-CH2->
35 -CH2-NH-, -OCH2-, -CH20-, -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; (C1-C6)-alkanoyI; (C3-C7)-cycloalkanoyI; (C6-C14)-arylcarbonyl; (C5-C1o)-heteroarylcarbonyl; (C1-C6)-alkanoyloxymethyloxy; -COOR27; -S02R27; -C(NR27R28)=NR29; -CONR28R29; -S02NR28R29; -OR30; -NR30R31 (CrC6)-aIkyl and (C3-C7)-cycloalkyl,
10
where (C1-C6)-alkyl and (C3-C7)-cycloalkyl for their part may optionally be substituted by a radical from the group consisting of cyano; -OR ; -NR R ; -CO(NH)v(NR27R2s) and -C(NR27R28)=NR29,
15 where:
v is either 0 or 1 and
R27, R28 and R29 are identical ov different and independently of one another
20 each represents hydrogen, (C1-C4)-alkyl or (C3-C7)-cycloalkyl
and/or
R27 and R28 or R27 and R29 together with the nitrogen atom to which they are
attached form a saturated or partially unsaturated 5- to 7-membered
25 heterocycle having up to three, preferably up to two, identical or
different heteroatoms from the group consisting of N, O and S, and
R30 and R31 are identical or different and independently of one another each
represents hydrogen, (C1-C4)-aIkyl, (C3-C7)-cycloalkyl, (C1C4)-alkyl-
30 sulphonyl, (C1-C4)-hydroxyaIkyl, (C1C4)-aminoalkyl, di-(C1-C4)-
alkylamino-(C1-C4)-alkyl, (C1C4)-aIkanoyl, (C6-C14)-aryIcarbonyI,
(C5-C10)-heteroarylcarbonyl, (C1-C4)-alkylaminocarbonyl or
-CH2C(NR27R28)=NR29.
35 Preference is also given to compounds of the general formula (I) in which the radical



Infi-A ^4-P3-T6it;i!Hi Countries


-24-
R2 represents one of the groups below: A-, A-M-, D-M-A-, B-M-A-, B-, B-M-, B-M-B-, D-M-B-,

10
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)
15 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, S02l N, NO (N-oxide) and O;
20 the radical "M" represents -NH-, -O-, -NH-CH2-, -CH2-NH-, -OCH2-,
-CH20-, -CONH-, -NHCO- or represents a covalent bond;
where
the groups "A", "B" and "D" defined above may in each case optionally be
25 mono- or polysubstituted by a radical from the group consisting of halogen;
trifluoromethyl; oxo; cyano; pyridyl; (C1-C3)-alkanoyl; (C6-C10)-arylcarbonyl;
(C5-C6)-heteroarylcarbonyl; (C1-C3)-alkanoyloxymethyloxy;
-C(NR27R28)=NR29; -CONR28R29; -S02NR28R29; -OH; -NR30R31; (C1-C4)-alkyl; and cyclopropyl, cyclopentyl or cyclohexyl,
30
where (C1-C4)-alkyI and cyclopropyl, cyclopentyl or cyclohexyl for their part may optionally be substituted by a radical from the group consisting of cyano; OH; -OCH3; -NR28R29; -CO(NH)v(NR27R28) and -C(NR27R28)=NR29,
35 where:







v is either 0 or 1, preferably 0, and
R27, R28 and R29 are identical or different and independently of one another
each represents hydrogen, (C1-C4)-alkyl or else cyclopropyl,
5 cyclopentyl or cyclohexyl
and/or
R27 and R28 or R27 and R29 together with the nitrogen atom to which they are
attached may form a saturated or partially unsaturated 5- to 7-
10 membered heterocycle having up to two identical or different
heteroatoms from the group consisting of N, O and S, and
R30 and R31 are identical or different and independently of one another each
represents, hydrogen, (C1-C4)-alkyl, cyclopropyl, cyclopentyl,
15 cyclohexyl, (C1-C4)-alkyIsulphonyI, (C1-C4)-hydroxyalkyl, (C1-C4)-
aminoalkyl, di-(C1-C4)-alkylaminO-(C1-C4)-alkyl, (C1-C3)-alkanoyI or phenylcarbonyl.

20

Likewise, in the compounds of the general formula (I), the radical R2 may represent a group of the following formula:






25
30

R32 represents hydrogen or (C1-C4)-alkyl, preferably hydrogen or methyl, and
W represents S, NH or O, preferably S.
Moreover, in the compounds of the general formula (I), the radical
R2 may be a group of the formula below

26



where (C1-C4)-alkyl and cyclopropyl, cyclopentyl or cyclohexyl for their part may optionally be substituted by a radical from the group consisting of cyano; -OH; -OCH3; -NR28R29;-CO(NH)v(NR27R28) and -C(NR27R28)=NR29, 5
where:
v is either 0 or 1, preferably 0, and
10 R27, R28 and R29 are identical or different and independently of one
another each represents hydrogen, (C1-C4)-alkyl or else cyclopropyl, cyclopentyl or cyclohexyl and/or
15 R27 and R28 or R27 and R29 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
20
R30 and R31 are identical or different and independently of one another each represents hydrogen, (C1-C4)-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C1-C4)-alkylsulphonyl, (C1-C4)-hydroxyalkyl, (C1-C4)-aminoalkyl, di-(C1-C4)-aIkylarnino-
25 (C1-C4)-alkyl, (C1-C3)-alkanoyl or phenylcarbonyl,
R3, R4, R5, R6, R7 and R8 are identical or different and each represents hydrogen or represents (C1-C4)-alkyl
30 and their pharmaceutically acceptable salts, hydrates and prodrugs,
except for compounds of the general formula (I) in which the radical R1 is an
unsubstituted 2-thiophene radical and the radical R2 is simultaneously a mono- or
polysubstituted phenyl radical and the radicals R3, R4, R5, R6, R7 and R8 are each
35 simultaneously hydrogen.





--14-
Very particular preference is given here to compounds of the general formula (I),
in which
5 R1 represents 2-thiophene which is substituted in the 5-position by a radical from
the group consisting of chlorine, bromine, methyl and trifluoromethyl,
R2 represents D-A-:
10 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
15 atom and
in which one carbon ring member may be replaced by a heteroatom
from the group consisting of S, N and O;
where
20 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,
25 R3, R4, R5, R6, R7 and R8 each represent hydrogen
and their pharmaceutically acceptable salts, hydrates and prodrugs.
Very particular preference is also given here to the compound having the following
30 formula
/










NW

and to its pharmaceutically acceptable salts, hydrates and prodrugs.
In the compounds of the general formula (I) above, the radical 5
R1 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; (C1-C8)-alkyl, which for its part may
optionally be mono- or polysubstituted by halogen; (C3-C7)-cycIoalkyl;
10 (C1-C8)-alkoxy; imidazolinyl; -C(=NH)NH2; carbamoyl; and mono- and di-
(C1-C4)-alkylaminocarbonyI.
In the compounds of the general formula (I), the radical
15 R1 may preferably represent thiophene (thienyl), in particular 2-thiophene, which
may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, or by (C1-C8)-alkyl, preferably methyl, where the (C1-C8)-alkyl radical, preferably the methyl radical, may for its part optionally be mono- or polysubstituted by halogen, preferably fluorine.
20
In the compounds of the general formula (I), the radicals

R3, R4, R5, R6, R7 and R8 may be identical or different and may represent, in
particualr, hydrogen or (C1-C6)-alkyl, preferably hydrogen or (C1-C4)-alkyl,
25 very particularly preferably hydrogen.
The radical R2, i.e. the organic radical, can in particular be selected from the substituent groups listed below:
30 In the compounds of the general formula (I), the radical

6



5 Finally, in the compounds of the general formula (I), the radical
R2 may be a group of the formula below


10
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-
15 aminomethyl] group (preferably 5-[acetylarninoinethyl]) appears to be essential for
the antibacterial activity.
Substituted aryl- and heteroarylphenyloxazolidinones in which a mono- or
polysubstituted phenyl radical may be attached to the N atom of the oxazolidinone
20 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. Patents US-A-5 929 248, US-A-5 801 246, US-A-5 756 732, US-A-5 654 435, US-A-5 654 428 and US-A-5 565 571.
25 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).
Depending on the substitution pattern, the compounds of the general formula (I)
30 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





27
(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.
5 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.
Physiologically acceptable, i.e. pharmaceutically compatible, salts can be salts of the
10 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
15 acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid,
benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
Other pharmaceutically compatible salts which may be mentioned are salts with
customary bases, such as, for example, alkali metal salts (for example sodium or
20 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, dibenzylarnine, N-methylmorpholine, dihydroabietylamine or methylpiperidine.
25 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
30 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.
According to the invention, "prodrugs" are forms of the compounds of the general
35 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).
Halogen represents fluorine, chlorine, bromine and iodine. Preference is given to
5 chlorine or fluorine.
(C1-C8)-Alkvl represents a straight-chain or branched alkyl radical having 1 to S 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
10 fewer carbon atoms, such as, for example, (C1-C6)-aIkyI and (C1-C4)-alkyl, are derived
analogously from this definition. In genera], preference is given to (C1-C4)-alkyl
The meaning of the corresponding component of other more complex substituents,
such as, for example, alkvlsulphonyl. hvdroxvalkvl. hvdroxyalkvlcarbonvl, alkoxy-
15 alkyl, alkoxvcarbonvl-alkvl alkanoylalkyl, aminoalkvl or alkylaminoalkyl is likewise
derived from this definition.
(C3-C7)-CvcloaIkvl represents a cyclic alkyl radical having 3 to 7 carbon atoms.
Examples which may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl,
20 cyclohexyl or cycloheptyl. The corresponding cycloalkyl groups having fewer carbon
atoms, such as, for example, (C3-C5)-cycloalkyl, are derived analogously from this definition. Preference is given to cyclopropyl, cyclopentyl and cyclohexyl.
The meaning of the corresponding component of other more complex substituents,
25 such as, for example, cvcloalkanoyl, is likewise derived from this definition.
In the context of the invention, (C2-C6)-alkenvl 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
30 mentioned are; vinyl, allyl, isopropenyl and n-but-2-en-l-yI.
(C1-C8)-Alkoxv 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
35 n-octoxy. The corresponding alkoxy groups having fewer carbon atoms, such as, for







example, (C1-C6)-alkoxy and (C1-C4)-Alkoxy, are derived analogously from this definition. In general, preference is given to (C1-C4)-alkoxy.
The meaning of the corresponding component of other more complex substituents,
5 such as, for example alkoxy-alkyl. alkoxvcaibonvl-alkvl and alkoxycarbonyl. is
likewise derived from this definition.
Mono- or di-(C1-C4)-alkylaminocarbonvl represents an amino group which is attached via a carbonyl group and which has a straight-chain or branched or two identical or
10 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.
15
(C1-C6)-Alkanovl 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
20 groups with fewer carbon atoms, such as, for example, (C1-C5)-alkanoyl,
(C1-C4)-alkanoyl and (C1-C3)-alkanoylr are derived analogously from this definition. In general, preference is given to (C1-C3)-alkanoyl.
The meaning of the corresponding component of other more complex substituents,
25 such as, for example, cvcloalkanoyl and alkanovlalkvl. is likewise derived from this
definition.
(C3-C7)-Cycloalkanovl represents a cycloalkyl radical having 3 to 7 carbon atoms .as, defined above which is attached via a carbonyl group.
30
(C1-C6)-AlkanovloxymethvIoxv represents a straight-chain or branched alkanoyloxymethyioxy radical having 1 to 6 carbon atoms. Examples which may be mentioned are: acetoxymethyloxy, propionoxymethyloxy, n-butyroxymethyloxy, i-butyroxymethyloxy, pivaloyloxymethyloxy, n-hexanoyloxymethyloxy. The
35 corresponding alkanoyloxymethyioxy groups having fewer carbon atoms, such as, for

30


example, (CrC3)-aIkanoyIoxymethyloxy, are derived analogously from this definition, In general, preference is given to (C1-C3)-alkanoyloxymethyloxy.
(C6-C14)-Aryl represents an aromatic radical having 6 to 14 carbon atoms. Examples
5 which may be mentioned are: phenyl, naphthyl, phenanthrenyl and anthracenyl. The
corresponding aryl groups with fewer carbon atoms, such as, for example, (C6-C1o)-aryl are derived analogously from this definition. In general, preference is given to (C6-C10)-aryl
10 The meaning of the corresponding component of other more complex substituents,
such as, for example, arylcarbonyl. is likewise derived from this definition.
(C5-C10)-Heteroarvl 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
15 (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, thiazotyl, oxazolyl or isoxazolyl, indolizinyl, indolyl, benzofbjthienyl, benzo[b]fuiyl,
20 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.
25
The meaning of the corresponding component of other more complex substituents, such as, for example, (C5-C10)-heteroarvlcarbonyl is likewise derived from this definition.
30 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. SO2, N. NO (N-oxide) and Q 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
35 which is attached via a carbon ring atom or a mtrogen 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, 1,4-diazepinyl and cyclohexyi. Preference is given to piperidinyl, morpholinyl and pyrrolidinyl.
5 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
10 alternative
[A] compounds of the general formula (II)

O
R R8
15
in which
the radicals R2, R3, R4, R5, R6 and R7 are each as defined above,
20 are reacted with carboxylic acids of the general formula (HI)

HO^.R1 (HI),


25

in which
the radical R1 is as defined above,

32-




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 (HI) 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)


(D,

10 in which
the radicals R\ R2, R3, R4, R5, R6, R7 and R8 are each as defined
above,

15 or else according to a process alternative
[B] compounds of the general formula (IV)


R3 R6 R7 Q

20
in which
the radicals R1, R3, R4, R5, R6, R7 and R8 are each as defined above,
25 are converted, using a suitable selective oxidizing agent in an inert solvent,
into the corresponding epoxide of the general formula (V)
33








R3 R6 B7 ft


in which
the radicals R1, R3, R4, R5, R6, R7 and R8 are each as defined above,
and, by reaction in an inert solvent, if appropriate in the presence of a catalyst, with an amine of the general formula (VI)

10
R2-NH2 (VI),
in which
15 the radical R2 is as defined above,


the compounds of the general formula (VII) R4 R3 R6 R7 ft
20
in which

25

the radicals R1, R2, R3, R4, R5, R6, R7 and R8 are each as defined above,
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
30 give the compounds of the general formula (I)




~?A~-



in which
5 the radicals R1, R2, R3, R4, R5, R6, R7 and R8 are each as defined
above,
where - both for process alternative [A] and for process alternative [B] - in
the case where R2 contains a 3- to 7-membered saturated or partially
10 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
15 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
20 follow
and/or
where - both for process alternative [A] and for process alternative [B] - in the
25 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
30





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

10

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 iicid and subsequent reaction with amines to give the corresponding sulphonamides may follow.

15 The processes according to the invention can be illustrated in an exemplary manner
by the equations below:












The oxidation step described above, which is optional, can be illustrated in an
5 exemplary manner by the equation below:

Suitable solvents for the processes described above are organic solvents which are
10 inert under the reaction conditions. These include halogenated hydrocarbons, such as
dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane,
trichloroethane, tetrachloroethane, 1,2-dichIoroethyIene 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,
15 n-butanol or tert-butanol, hydrocarbons, such as benzene, xylene, toluene, hexane or
cyclohexane, dimethylformamide, dimethyl sulphoxide, acetonitrile, pyridine, hexa-methylphosphoric triamide or water.
It is also possible to use solvent mixtures of the solvents mentioned above.
20





37
Suitable activating or coupling agents for the processes described above are the reagents which are customarily used for this purpose, for example N"-(3-dimemyIaminopropyI)-N-ethylcarbodiimide . HO, N,N"-dicyclohexylcarbo-diimide, 1-hydroxy-lH-benzotriazole • H20 and the like. 5
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
10 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-dimethylamino-pyridine or pyridine.
15 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).
The reactions are generally carried out in a temperature range of from -78°C to reflux temperature, preferably in the range from 0°C to reflux temperature. 20
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,
25 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.
30 With respect to the preparation of the epoxides, the preparation conditions which are
customary for this purpose are employed.
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:
35 M. R. Barbachyn et al., J. Med. Chem. 1996,39, 680 and WO-A-97/10223.





Furthermore, reference is made to Examples 14 to 16 given in the experimental part.
The optional amidation is carried out under customary conditions. For more details, reference is made to Examples 31 to 35 and 140 to 147. 5
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 etal., J.Med,
10 Chem. 1998, 41, 3727; S.J.Brickner etal., J.Med Chem. 1996, 39, 673;
W. A. Gregory et al., J. Med. Chem. 1989,32,1673.
The compounds of the general formula (I) according to the invention have an
unforeseeabte useful pharmacological activity spectrum and are therefore parrkttlarYy
15 suitable for the prophylaxis and/or treatment of disorders.
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
20 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
25 occlusion disorders, pulmonary embolisms or deep venous thromboses.
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
30 coagulation (DIC).
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
35 atherosclerosis and arthritis, and additionally also for the prophylaxis and/or
treatment of Alzheimer"s disease and cancer.
39


4frA-34^l2i-froreign Lountrfes


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
5 inhibit, or only inhibit at considerably higher concentrations, other serine proteases as
well, such as thrombin, plasmin or trypsin.
In the context of the present invention, inhibitors of the blood coagulation factor Xa in which the IC50 values for the factor Xa inhibition are lower by a factor of 100,
10 preferably by a factor of 500, in particular by a factor of 1000, than the IC50 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-l) a.l) and a.2) described below.
15
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,
20
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,
25
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
30 the indications mentioned above.
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
35 to the invention - including the compounds excluded by disclaimer from the chemical
product protection.




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
5 formula (I) - including the compounds excluded by disclaimer from the chemical
product protection - are added.
All customary administration forms are suitable for administration of the compounds according to the invention. Administration is preferably carried out orally, lingually,
10 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
15 disorders.
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-
20 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.
25
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
30 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.
35 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.
In general it has proved advantageous in the case of intravenous administration to
5 administer amounts from approximately 0,001 to 10 mg/kg, preferably approximately
0.01 to 10 mg/kg, in particular approximately 0.1 to 8mg/kg, of body weight to
achieve effective results.
In general, it has proved advantageous in the case of oral administration to administer
10 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.
In spite of this, if appropriate, it may be necessary in the case of intravenous or oral
15 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 mininum amount, while in other cases the upper limit
20 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.
Compared to the conventional preparations for treating thromboembolic disorders,
25 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.
30 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.
35 The present invention is illustrated by the examples below; however, these examples
are not meant to restrict the invention in any way.





-"42- "
Examples
A Evaluation of the physiological activity
5 1. General test methods
The particularly advantageous biological properties of the compounds according to the invention can be determined by the following methods.
10 a) Test description (in vitro)
a.l) Determination of the factor Xa inhibition
The enzymatic activity of human factor Xa (FXa) was measured using the conversion
15 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.
The test substances, in various concentrations, were dissolved in DMSO and
20 incubated at 25°C with human FXa (0.5 nmol/l dissolved in 50 mmol/1 of tris buffer
[C,C,C-tris(hydroxymethyl)-aminomethane], 150 mmol/1 of NaCI, 0.1% BSA
(bovine serum albumin), pH = 8.3) for 10 minutes. Pure DMSO was used as control.
The chromogenic substrate (150 /imol/1 of Pefachrome® FXa from Pentapharm) was
then added. After an incubation time of 20 minutes at 25°C, the extinction at 405 nm
25 was determined. The extinctions of the test mixtures containing test substance were
compared with the control mixtures without test substance, and the IC5o values were
calculated from these data.
- ^
a.2) Determination of the selectivity
30
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/l), these enzymes were dissolved in tris buffer (100 mmol/1,
35 20 mmol/1 CaCl2, pH = 8.0) and incubated with test substance or solvent for 10
minutes. The enzymatic reaction was then started by adding the corresponding





removed and the nylon thread with the thrombus was weighed immediately. The weight of the nylon thread on its own had been detennined 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.




specific chromogenic substrates (Chromozym Thrombin® from Boehringer
Mannheim, Chromozym Trypsin® from Boehringer Mannheim, Chromozym
Plasmin® from Boehringer Mannheim) and the extinction at 405 nm was determined
after 20 minutes. All determinations were carried out at 37°C. The extinctions of the
5 test mixtures containing test substance were compared with the control samples
without test substance, and the IC50 values were calculated from these data.
a3) Determination of the anticoagulant action
10 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
15 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® from Boehringer Mannheim). The test compounds were incubated with the plasma at 37°C for 10 minutes. Coagulation was then started by addition of thromboplastin, and the time when coagulation occurred
20 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)
25 b.l) Arteriovenous shunt model (rat)
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
30 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
35 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



LfrA-3+i23=Fb15i"gn countries
45-
The results are shown in Table 1:
Table 1: Antithrombotic activity in the arteriovenous shunt model (rat) after oral or intravenous administration


Example ED56 [mg/kfi] p.o. ED50 [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)
Male fasting rats (strain: HSD CPB: WU) were anaesthetized as described above. On
10 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°C in a metal
15 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 ofthe
20 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.
25





b.3) Venous thrombosis model (rat)
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
5 (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°C in a metal trough for 2 minutes and, to standardize the size of the thrombi, simultaneously compressed
10 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
15 tube.





B Preparation Examples Starting materials
5 The preparation of 3-morphoIinone is described in US 5 349 045.
The preparation of N-(2,3-epoxypropyI)phthalimide is described in J.-W. Chcm et al. Tetrahedron Lett. 1998,39,8483.
10 The substituted anilines can be obtained by reacting, for example, 4-fluoronitro-
benzene, 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)2/DPPF/NaOt-Bu (Tetrahedron Lett 1999,40,2035) or copper (Kenger, Synthesis 1985.856; Aebischer et a]., Heterocycles 1998,48,2225).
15 Likewise, it is possible to initially convert halogenated aromatics without nitro group
into the corresponding amides, followed by nitration in the 4-position (US3279880).
I. 4-(4-Morpholin-3-onyl)nitrobenzene

NO,

rV°
20 O
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
25 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°C, 1,71 of the liquid volume are then distilled off, the residue is poured into 2 1 of water and this mixture is extracted twice with in each case 11 of ethyl acetate. After washing of the combined organic phases with water, the mixture is dried over sodium sulphate and
30 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









10
15

from ethyl acetate. This gives 78 g of product as a colourless to brownish solid, in a
yield of 17.6% of theory.
"H-NMR (300 MHz, CDC13): 3,86 (m, 2 H, CH2CH2), 4.08 (m, 2 H, CH2C#2), 4.49
(s, 2H, CH2CO), 7.61 (d, 2H, 3/=8.95 Hz, CHCH), 8.28 (d, 2H, 37=8.95Hz,
CHCtf)
MS (r.L%) = 222 (74, M+), 193 (100), 164 (28), 150 (21), 136 (61), 117 (22), 106
(24), 90 (37), 76 (38), 63 (32), 50 (25)
The following compounds were synthesized analogously: 3-fluoro-4-(4-morpholin-3-onyl)nitrobenzene 4-(N-piperidonyl)nitrobenzene 3-fluoro-4-(N-piperidonyl)nitrobenzene 4-(N-pyrrolidonyl)nitrobenzene 3-fluoro-4-(N-pyrrolidonyl)nitrobenzene
II. 4-(4-Morpholin-3-onyI)aniline


In an autoclave, 63 g (0.275 mol) of 4-(4-morpholin-3-onyl)nitrobenzene are
20 dissolved in 200 ml of tetrahydrofuran, admixed with 3.1 g of Pd/C (5%ig) and
hydrogenated at 70°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. 25
Purification can also be carried out by silica gel chromatography using hexane/ethyl acetate.
]H-NMR (300 MHz, CDC13): 3.67 (m, 2 H, CH2CH2), 3.99 (m, 2 H, CH2CH2), 4.27
(s, 2H, CH2CO), 6.68 (d, 2H, 3/=8.71 Hz, CHCH), 7.03 (d, 2 H, 3/=8.71 Hz,
30 CHCH)









10

MS (r.L%) = 192 (100, M+), 163 (48), 133 (26), 119 (76), 106 (49), 92 (38), 67 (27), 65 (45), 52 (22), 28 (22)
The following compounds were synthesized analogously: 3-fluoro-4-(4-morpholin-3-onyl)aniIine 4-(N-piperidonyI)aniline 3-fluoro-4-(N-piperidonyl)aniline 4-(N-pyrrolidonyl)aniline 3-fluoro-4-(N-pyrrolidonyl)aniline
General method for preparing 4-substituted anilines by reacting l-fluoro-4-nitrobenzenes and l-chloro-4-nitrobenzenes with primary or secondary amines, followed by reduction







15 X = F.CI
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°C overnight. After cooling to RT, the reaction mixture is
20 diluted with ether and washed with water. The organic phase is dried over MgSO4,
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-
25 and dichloromethane/ethanol mixtures).
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
30 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).





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°C, six
equivalents of iron powder and water (0.3 to 0.5 times the volume of the acetic acid)
5 are added a little at a time over a period of 10-15 rnin. After a further 30 min at 90°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
10 preparative reversed-phase HPLC (acetonitrile/water mixtures).
The following starting materials were prepared in an analogous manner:
III-l. tert-butv1-1-(4-aminophesyl)-L-proIinate
15 MS (ESI): m/z (%) = 304 (M+H+MeCN, 100), 263 (M+H, 20);
HPLC (method 4): rt = 2.79 min.
III-2. l-(4-aminoDhenvl)"3-piperidinecarboxamide
MS (ESI): m/z (%) = 220 (M+H, 100);
20 HPLC (method 4): rt = 0.59 min.
1H-3. l-(4-aminophenvl)-4-piperidincarboxamide
MS (ESI): m/z (%) = 220 (M+H, 100); HPLC (method 4)-. rt = 0.57 min. 25
III-4. l-(4-aminophenvl)-4-piperidinone MS (ESI): m/z (%) = 191 (M+H, 100); HPLC (method 4): n = 0.64 min.
30 III-5. l-(4-aminophenvl)-L-prolinamide
MS (ESI): m/z (%) = 206 (M+H, 100); HPLC (method 4); rt = 0.72 min.
III-6. [1-(4-anninophenvl)-3-piperidinvl]methanol
35 MS (ESI): m/z (%) s 207 (M+H, 100);
HPLC (method 4): rt - 0.60 min.




III-7. [1-(4-aminophenvl)-2-Diperidinvl1methanol
MS (ESI): m/z (%) = 207 (M+H, 100); HPLC (method 4): rt = 0.59 min. 5
III-8. ethvl l-(4-aminophenvl)-2-piperiduiecarboxylate
MS (ESI): m/z (%) = 249 (M+H, 35), 175 (100); HPLC (method 4): rt = 2.43 min.
10 III-9, [1-(4-aminophenvI)-2-pvrroIidinynmethanol
MS (ESI): m/z (%) = 193 (M+H, 45); HPLC (method 4): rt = 0.79 min.
111-10. 4-(2-methvlhexahvdro-5H-Pvrrolor3.4:d]isoxazol-5-vl)phenviamine
15 starting from 2-methylhexahydro-2H-pyrrolo[3,4-d]isoxazoIe (Ziegler, Carl B., et al.;
J. Heterocycl Chem.; 25; 2; 1988; 719-723) MS (ESI): m/z (%) = 220 (M+H, 50), 171 (100); HPLC (method 4): rt = 0.54 min.
20 III-11. 4-(l-pvrrolidinvI)-3-(trifluoromethvl)aniline
MS (ESI): m/z (%) = 231 (M-fH, 100); HPLC (method 7): rt = 3.40 min.
III-12. 3-chloro-4-(l-pvrrolidinyl)aniIine
25 MS (ESI): m/z (%) = 197 (M+H, 100);
HPLC (method 4); rt = 0.78 min.
111,-13. 5-amino-2-(4-morpholinvl)benzamide
MS (ESI): m/z (%) = 222 (M+H, 100);
30 HPLC (method 4): rt = 0.77 min.
111-14. 3-methoxv-4-(4-morDholinvI)aniline
MS (ESI): m/z (%) = 209 (M+H, 100); HPLC (method 4): rt = 0.67 min. 35
111-15. l-f5-aminO-2-(4-morpholinvl)phenvIlethanone







MS (ESI): m/z (%) = 221 (M+H, 100); HPLC (method 4): rt = 0.77 min,

General method for preparing 4-substituted anilines by reacting l-fluoro-4-
5 nitrobenzenes with amides, followed by reduction
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 l-fluoro-4-
10 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).
15
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
20 (dichloromethane/ethanol mixtures) or preparative reversed-phase HPLC
(acetonitrile/water mixtures).
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°C; six
25 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°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
30 can be purified by silica gel chromatography (dichloromethane/ethanol mixtures) or
preparative reversed-phase HPLC (acetonitrile/water mixtures).





The following starting materials were prepared in an analogous manner:
IV-1, l-[4-amino-2-(trifluoromethyl)phenyl]-2-PvrroIidinone
MS (ESI): m/z (%) = 245 (M+H, 100);
5 HPLC (method 4): rt = 2.98 min
IV-2. 4-[4-amino-2-(trifluoromethyl)phenvl]-3-morpholinone
MS (ESI): m/z (%) = 261 (M+H, 100); HPLC (method 4): it = 2.54 min. 10
IV-3. 4-(4-amino-2-chlorophenyl)"3-morpholinone
MS (ESI): m/z (%) = 227 (M+H, 100); HPLC (method 4): rt = 1.96 min.
15 IV-4. 4-(4-amino-2-methylphenvl)-3-morpholinone
MS (ESI): m/z (%) = 207 (M+H, 100); HPLC (method 4): rt = 0.71 min.
IV-5. 5-amino-2-(3-oxo-4-morpholinvl)benzoilitrile
20 MS (ESI): m/z (%) = 218 (M+H, 100);
HPLC (method 4): rt = 1.85 min.
IV-6. l-(4-ajnino-2-chlorophenvl)-2-pvrrolidinone
MS (ESI): m/z (%) = 211 (M+H, 100);
25 HPLC (method 4): rt = 2,27 min.
IV-7. 4-(4-aniino-2.6-dimethvlphenvl)-3-morpholinone
starting from 2-fluoro-l,3-dimethyl-5-nitrobenzene (Bartoli et al., J. Org. Cherry
1975,40, 872):
30 MS (ESI): m/z (%) = 221 (M+H, 100);
HPLC (method 4): rt = 0.77 min.
IV-8. 4-(2,4-diaminophenvI)-3-_morpholinone
starting from l-fluoro-2,4-drnitrobenzene:
35 MS (ESI): m/z (%) = 208 (M+H, 100);
HPLC (method 4): rt = 0.60 min.





IV-9. 4-(4-amino-2-chlorophenyl)-2-methvl-3-morpholinone
starting from 2-methyl-3-morpholinone (Pfeil, E.; Harder, U.; Angew. Chem. 1967,
79,188):
5 MS (ESI): m/z (%) = 241 (M+H, 100);
HPLC (method 4); rt = 2.27 min.
IV-10. 4-(4-amino-2-chloropheny)-6-methvl-3-morphollone
starting from 6-methyl-3-morpholinone (EP 350 002):
10 MS (ESI): m/z (%) = 241 (M+H, 100);
HPLC (method 4): rt - 2.43 min.





Synthesis Examples
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-morpholinophenyI)-2-oxo-l,3-oxazolidin-5-yI]methyl}-2-thiophenecarboxamide

10
(5S)-5-(Aminomethyl)-3-(3-fluoro-4-morpholinophenyl)-lt3-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
15 1-hydroxy-lH-benzotriazole hydrate (HOBT) (0.3 g7 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 (EDO) 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
20 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°C. Rf (Si02, toluene/ethyl acetate 1:1) = 0.29 (starting material = 0.0);
25 MS (DCI) 440.2 (M+H), CI pattern;
"H-NMR (D6VDMSO, 300 MHz) 2.95 (m, 4H), 3.6 (t, 2H), 3.72 (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).




LftA-34 122^FefektQ-Countries





Example 2
5-Chloro-N-{[(5S)-3-(4-morphoIinophenyl)-2-oxo-13-oxazoIidin-5-yl]methyl}-2-thiophenecarboxamide



is obtained analogously from benzyl 4-morpholinophenylcarbamate via the (5S)-5-
(aminomethyI)-3-(3-fluorc-4-morpholinophenyl)-l,3-oxazolidin-2-one intermediate
(see Example 1).
M.p.: 198°C;
10 IC50 value = 43 nM;
Rf (Si02, toluene/ethyl acetate 1:1) = 0.24.
Example 3
15 5-Chloro-N-({(5S)-3-[3-fluoro-4-(l,4-thiazinan-4-yI)phenyl]-2-oxo-l,3-oxazoIi-
din-5-yl}methyl)-2-thiophcnecarboxamide




is obtained analogously from (5S)-5-(aminomethyl)-3-[3-fluoro-4-(l,4-thiazinan-4-
20 yl)phenyl]-l,3-oxazolidin-2-one (preparation see M. R. Barbachyn et ah, J, Med.
Chem. 1996,39, 680). M.p.: 193°C; Yield: 82%; Rf (Si02, toluene/ethyl acetate 1:1) = 0.47 (starting material =0.0).
25





Example 4
5-Bromo-N-({(5S)-3-[3-fluoro-4-(l,4-thiazinan-4-yl)phenyI]-2-oxo-l,3-oxazolidin-5-yI}methyl)-2-thiophenecarboxamide



is obtained analogously from 5-bromothiophene-2-carboxylic acid. M.p.: 200°C.
10 Example 5

15

N-({(5S)-3-[3-Fluoro-4-(l,4-thia2inan-4-yl)phenyl]-2-oxo-13-oxazolidin-5-yl}methyI)-5-methyI-2-thiophenecarboxamide

Fv Q
S\J*-\J~\ 1 CH.






Example 6
5-ChIoro-N-{[(5S)-3-(6-methylthieno[2r3-b]pyrldin-2-yl)-2-oxo-l73-oxazoIidin-5. yl]methyl}-2-thiopheriecarboxarnide

is obtained analogously from (5S)-5-(aminomethyl)-3-(6--niethylthieno[213-b]pyridin-2-yl)-l,3-oxazolidin-2-one (preparation see EP-A-785 200). M.p.: 247°C.
Example 7
5-Chloro-N-{[(5S)-3-(3-methyl-2-oxo-2,3-dihydro-l,3-benzothiazol-6-yI)-2-oxo-l,3-oxazolidin-5-yI]methyl}-2-thiophenecarboxomide

is obtained analogously from 6-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazoIidin-3-yl]-3-methyl-l,3-benzothiazoI-2(3H)-one (preparation see EP-A-738 726). M.p.:217°C.




Example 8
5-Chloro-N.[((5S)-3-{3-fluoro-4-[4-(4-pyridinyl)piperazino]phenyl}-2-oxo-l,3-oxazoIidin-5-yI)methyI]-2-thiophenecarboxamide
5

o
is obtained analogously from (5S)-5-(aminomethyl)-3-{3-fluoro-4-[4-(4-
pyridinyl)piperazino]phenyl}-l,3-oxazolidin-2-one (preparation analogously to J. A.
Tucker et al., J. Med. Chem. 1998, 41, 3727).
10 MS (EST) 516 (M+H),C1 pattern.
Example 9
5-Chloro-N-({(5S)-3-[3-fluoro-4-(4-methylpiperazino)phenyI3-2-oxo-l,3-oxazoli-
15 dm-5-yl}methyI)-2-thiophenecarboxamide

O is obtained analogously from (5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-methylpiperazino)phenyl]-l73-oxazolidin-2-one.

20






Example 10
5-Chloro-N-({(5S)-3-[3-fluoro-4-(4-tert-butoxycarbonyIpiperazin-l-yI)phenyI]-2-oxo-l^-oxazoIidin-5-yI}methyl)-2-thiophenecarboxamide
5




a o"
is obtained analogously from (5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-tert-butoxy-
carbonylpiperazin-l-yl)phenyl]-l,3-oxazoIidin-2-one (preparation see
WO-A-93/23384, which has already been cited).
10 M.p.: 184°C;
Rf(Si02, toluene/ethyl acetate 1:1) = 0.42.
Example 11
15 5-Chloro-N-({(5S)-3-[3-fluoro-4-(piperazin-l-yl)phenyl]-2-oxo-l,3-oxazoIidin-5-
yl}methyl)-2-thiophenecarboxamide


C! O"

is obtained by reacting Example 12 with trifluoroacetic acid in methylene chloride.
20 IC5o value = 140 nM;








4H-NMR [d6-DMSO]: 3.01-3.25 (m, SH), 3.5-3.65 (m, 2H), 3.7-3.9 (m, IH), 4.05-4.2 (m, IH), 4.75-4.9 (m, IH), 7.05-7.25 (m, 3H), 7.5 (dd, IH), 7.7 (d, IH), 8.4 (broad s, IH), 9.0 (t, IH).
Example 12
5-Chloro-N-[((5S)-3-(2?4-bipyiridinyl-5-yI)-2-oxo-1,3-oxazolidin-5-yI)methyl]-2-thiophenecarboxamide

10
15


is obtained analogously from (5S)-5-aminomethyl-3-(2,4-bipyridinyl-5-yI)-2-oxo-l,3-oxazolidin-2-one (preparation see EP-A-789 026). Rf (Si02, ethyl acetate/ethanol 1:2) = 0.6; MS (ESI) 515 (M+H), C\ pattern.
Example 13
5-Chloro-N-{[(5S)-2-oxo-3-(4-piperidinophenyl)-l,3-oxazolidin-5-yl3methyI}-2-thiophenecarboxamide

20





■-^62-
is obtained from 5-(hydroxymethyl)-3-(4-piperidinophenyl)-13-o\azolidin-2-one
(preparation see DE 2708236) after mesylation, reaction with potassium phthalimide,
hydrazinolysis and reaction with 5-chIorothiophene-2-carboxylic acid.
Rf (Si02, ethyl acetate/toluene 1:1) = 0,31;
5 m.p. 205°C.
Example 17
S-Chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-l-pyrroIidinyl)phenyl]-l^-oxazolidin-5-
10 yl}methyI)-2-thiophenecarboxamide


Analogously to the known synthesis scheme (see S.J Brickner et al., J. Med. Chem. 1996, 39, 673), l-(4-aminophenyl)pytrolidin-2-one (preparation see Reppe et al.,
15 Justus Liebigs Ann. Chem.; 596; 1955; 209) gives, after reaction with
benzyloxycarbonyl chloride, followed by reaction with i?-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- l-pyrrolidinyl)phenyl]-1,3-oxazolidhv5-yl }methyl)-2-thio-
20 phenecarboxamide. The 5-chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-l-pyrrolidinyI)-
phenyl]-l,3-oxazoIidin-5-yl}methyl)-2-thiophenecarboxamide obtained in this
manner has an IC50 value of 4 nM (test method for the IC50 value according to
Example A-l.a.1 described above) "determination of the inhibition of factor Xa").
M.p.:229°C; v
25 Rf value (SiO2, toluene/ethyl acetate 1:1) = 0.05 (starting material: = 0.0);
MS (ESI): 442.0 (21%, M+Na, CI pattern), 420.0 (72%, M+H, CI pattern), 302.3 (12%), 215(52%), 145 (100%);
"H-NMR (d6-DMSO, 300 MHz): 2.05 (m,2H), 2.45 (m,2H), 3.6 (t,2H), 3.77-3.85 (m,3H), 4.15(t,lH), 4.75-4.85 (m,lH), 7.2 (d,lH), 7.5 (d,2H), 7,65 (d,2H), 7.69
30 (d,iH),8.96(t,lH).














The following compounds were prepared in an analogous manner
Example 18
5
yI}methyI)-2-thiophenecarboxamide
Analogously to Example 17, 4-pyrroIidin-l-yl-aniIine (Reppe et al., Justus Liebigs
Ann. Chem.; 596; 1955; 151) gives the compound 5-chloro-N-({(5S)-2-oxo-3-[4-(l-
10 pyrrolidinyl)phenyl]-l,3-oxazolidin-5-yI}methyI)-2-thiophenecarboxamide.
IC5o=40 nM; m.p.: 216°C; Rf value (Si02, toluene/ethyl acetate 1:1) = 0.31 [starting material: = 0.0].
15 Example 19
5-Chloro-N-({(5S)-2-oxo-3-[4-(diethyIamino)phenyl]-l,3-oxazoIidin-5-yl}methyl)-2-thiophenecarboxamide
20 Analogously, N,N-diethyipheny]-l,4-diamine (US-A-2 811 555; 1955) gives the
compound 5-chloro-N-({(5S)-2-oxo-3-[4-(diethylamino)phenyl]-l,3-oxazolidin-5-
yl }methyl)-2-thiophenecarboxamide.
IC50=270 nM;
m.p.: 181°C;
25 Rf value (Si02, toluene/ethyl acetate 1:1) = 0.25 [starting material: = 0.0].
Example 36
5-Chloro-N-({(5S)-3-2-methyI-4-(4-morpholinyI)phenyl]-2-oxo-l,3-oxazoIidin-5-
30 yI}methyI)-2-thiophenecarboxamide
starting from 2-methyI-4-(4-morpholinyl)aniIine (J.EXuValle et al. J.Am.Chem.Soc. 1948, 70, 2223):
MS (ESI): m/z {%) = 436 ([M+H]+, 100), CI pattern;
HPLC (method 1): it (%) = 3.77 (98).
35 IC50: 1-26 fiM




Le^i M 172-Foreign CosHtries

Example 37
5-Chloro-N-{[(55)-3-(3-chIoro-4-morphoIinophenyI)-2-oxo-l,3-oxazolidin-5-yI]methyI}-2-thiophenecarboxamide
5 starting from 3-chloro-4-(4-morpholinyl)aniline (H.R.Snyder et al J.Pharm.Scl
1977,66,1204):
MS (ESI): m/z (%) = 456 ([M+H]+, 100), Cl2 pattern; HPLC (method 2): rt (%) = 4.31 (100). IC50: 33 nM 10
Example 38
5-Chloro-N-({(55)-3-[4-(4-morphoIinylsuIphonyl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)-2-thiophenecerboxamide
15 starting from 4-(4-morphoIinylsulphony])aniline (Adams et al J.Am.Chem.Soc.
1939,61,2342):
MS (ESI): m/z (%) = 486 ([M+H]+, 100), CI pattern;
HPLC (method 3): rt (%) - 4.07 (100).
IC50: 2 fiM 20
Example 39
S-Chloro-N-({(5S)-3-[4-(l-a2etidinylsulphonyl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
25 starting from 4-(l-azetidinylsulphonyl)aniIine:
MS (DCI, NH3): m/z (%) = 473 ([M+NH4]+, 100), CI pattern;
HPLC (method 3): rt (%) = 4.10 (100).
IC50:0.84pM
30 Example 40
5-Chloro-N-[((S5)-3-{4-[(dimethylainino)suIphonyl]phenyl}-2-oxo-l,3-oxazoIidin-5-yl)methyl]-2-thiophenecarboxamide
starting from 4-amino-N,N-dimethyIben2enesulphonamide (I.K.Khanna el al
35 JMed.Chem. 1997,40, 1619):
MS (ESI): m/z (%) = 444 ([M-4-H]+ 100), CI pattern;





HPLC (method 3): rt (%) = 4.22 (100). IC50:90nM
General method for the acylation of 5-(aminomethyl)-3-[4-(2-oxo-l-pyrro-
5 IidinyI)phenyl]-l,3-oxazolidin-2-one with carbonyl chlorides.



Under argon and at room temperature, an about 0.1 molar solution of 5-
10 (aminomethyl)-3-[4-(2-oxo-l-pyrroIidinyl)phenyl]-l,3-oxazoIidin-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
15 for 2h, 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.

20

The following compounds were prepared in an analogous manner: Example 41

N-({2-oxo-3-[4-(2-oxo-l-pyrrolidinyi)phenyl]-l,3-oxazoIidin-5-yl}methyl)-2-thiophene-carboxamide
25 LC-MS (method 6): m/z (%) = 386 (M+H, 100);
LC-MS;rt(%) = 3.04 (100). IC50: 1.3 fiM







General method for preparing acyl derivatives starting from 5-(aminomethyl)-3-[4-(2-oxo-l-pyrroIidinyl)phenyI]-l,3-oxazoIidin*2-one and carboxylic adds

5 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-carbodnmide, Argonaut Technologies), The mixture is shaken gently at room temperature for about 15 min, 5-(aminomethyl)-3-[4-(2-oxo-l-pyrrolidinyl)phenyl]-l,3-oxazo!idin-2-one (from Example 45) (1.0 eq.) is then added and the mixture is
10 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.

15

The following compounds were prepared in an analogous manner Example 42

5-MethyI-N-({2-oxo-3-[4-(2-oxo-l-pyrrolidinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
20 LC-MS: m/z (%) = 400 (M+H, 100);
LC-MS (method 6): it (%) = 3.23 (100). IC50:0.16/iM

25

Example 43
5-Bromo-N-({2-oxo-3-[4-(2-oxo-l-pyrroIidinyI)phenyl]-lT3-oxazoIidin-5-yl}methyl)-2-thiophenecarboxamide
LC-MS : m/z (%) = 466 (M+H, 100); LC-MS (method 5): n (%) = 3.48 (78).








Example 44
5 5-Chloro-^V-({(55)-2-oxo-3-[4-(3-oxo-4-morphoIinyI)phenyI]-l^-oxa2olidin-5-
yI}methyI)-2-thiophenecarboxainide
10
a) 2-((2R)-2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyI)-1h-iso-
15 indole-l,3(2H)-dione:
A suspension of 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,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-oxiranylmethyI]-lH-isoindole-
5 l,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.
MS (ESI): m/z (%) = 418 ([M+Na]+, 84), 396 ([M+H]+, 93);
10 HPLC (method 3): rt (%) = 3.34 (100).
b) 2-({(55)-2-Oxo-3-[4-(3-oxo-4-morpholinyI)phenyl]-l,3-oxazolidin-5-yI}me-
thyl)-lH-isoindole-1,3(2H)-dione:
15 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°C for 12 h (the precipitate dissolves, after some time again formation of a precipitate), admixed with a second portion of N,N"-
20 carbonyldiimidazole (2.94 g, 18.1 mmol) and stirred at 60°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,
25 MS (ESI): m/z (%) = 422 (EM+H]+ 100);
HPLC (method 4): rt (%) = 3.37 (100).
c) S-Chloro-N-({(55)-2-oxo-3-[4-(3-oxo-4-morphoIinyI)phenyl]-lr3-oxazolidin-5-
yl}methyI)-2-thiophenecarboxamide:
30
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. 35
7/



Under argon and at 0°C, 5-chlorothiophene-2-carbonyI 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
5 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 gt 86% of theory. M.p: 232-233°C;
10 lH NMR (DMSO-d6, 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, / = 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); MS (ESI): m/z (%) = 436 ([M+H]+ 100, CI pattern);
15 HPLC (method 2): rt (%) = 3.60 (100);
[a]21D = -38° (c 0.2985, DMSO); ee: 99%. IC50: 0.7 nM
The following compounds were prepared in an analogous manner: 20
Example 45
5-MethyI-N-({(55)-2-oxo-3-[4-(3-oxo-4-morphoIinyl)phenyI}-l,3-oxazolidin-5-yI}methyl)-2-thiophenecarboxamide
25 MS (ESI): m/z (%) = 831 ([2M+H]+, 100), 416 ([M+H]+, 66);
HPLC (method 3): rt (%) = 3.65 (100). IC50:4.2nM
Example 46
30
5-Bromo-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl }methyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 480 ([M+H]+ 100, Br pattern);
HPLC (method 3): rt (%) = 3.87 (100).
35 IC50: 0.3 nM




Example 47
5-ChIoro-N-{[(5S)-3-(3-isopropyl-2-oxo-2,3-dihydro-l,3-benzoxazoI-6-yl)-2-oxo-l,3-oxazolidin-5-yI]methyI}-2-thiophenecarboxatnide

200 mg (0.61 mmol) of 6-[(5S)-5-(aminomethyl)-2-oxo-lT3-oxazolidin-3-yl]-3-isO" pfopyI-l»3-benzoxa2oI-2(3H)-one hydrochloride (EP 738726) are suspended in 5 ml of tetrahydrofuran and admixed with 0,26 ml (1.83 mmol) of tnethylamine and
10 132 mg (0.73 mmol) of 5-chlorothiophene-2-carboriyl 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. MS (ESI): m/z (%) = 436 (M+H, 100);
15 HPLC (method 4): rt = 3.78 min.
The following compounds were prepared in an analogous manner:







Example No. Structure M.p. [°Cj IC5o {uM}
48 0 S-^C|Chira" 0 210 0.12
49 O CJwal 234 0.074
50 • Ctwai 195 1.15
51 ° 0 212 1.19
52 O Cm 160 0.19
53 O Cnirai MS (ESI): m/z (%) = 431
(IM+H)+, 100), CI pattern 0.74

/
,/
/
/
/

/
74







Example No. Structure M-P- [°C] 1C50 [uM]
54 O CJiiraJ
4
N O
from 5-amino-2-pyrrolidino-benzonitrile (Grell, W., Hurnaus, R.; Griss, G., Sauter, R.; Rupprecht, E. et al; J.MedChem.1998, 41; 5219) 221 0.13
55 0
from 3-(4-amino-phenyl)-oxazoIidin-2-one (Artico, M. et al.; Farmaco Ed.Sci. 1969,24; 179) 256 0.04
56 Q CWnU 218 0.004
51 O Chital
0 i 226 0.58
255 228-230
/
/
/ /"


-75-


5

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-aIIyI-5-chIoro-2-thiophenecarboxamide
o

10 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
15 purified by flash chromatography over silica gel (dichloromethane).
Yield: 7.20 g (99% of theory);
MS (DCI, NH4): m/z (%) = 219 (M+NH4, 100), 202 (M+H, 32); HPLC (method 1): rt (%) = 3.96 min (98.9).
20 Example 21
Preparation of 5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide

25
An ice-cooled solution of 2,0 g (9.92 mmol) of N-aIlyI-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
30 10% sodium hydrogen sulphate solution (three times). The organic phase is washed
with saturated sodium bicarbonate solution (twice) and with saturated sodium




Le A34 I22^ercrgTreountrics

chloride solution, dried over magnesium sulphate and concentrated. The product is purified by silica gel chromatography (cyclohexane/ethyl acetate 1:1). Yield: 837 mg (39% of theory);
MS (DCI, NHi): m/z (%) =253 (M+NH4,100), 218 (M+H, 80);
5 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-iV-{2-oxiranylmethyl)-2-thiophenecarboxamide
10
At room temperature or at temperatures up to 80°C, 5-chloro-N-(2-oxiranyImethyI)-2-thiophenecarboxamide (1.0 eq.) is added a little at a time to a solution of the
15 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
20 mixtures).
The following compounds were prepared in an analogous manner
Example 22 25
iV-[3-(Benzylamino)-2-hydroxypropyl3-5-chloro-2-thiophenecarboxamide
MS (ESI): m/z (%) = 325 (M+H, 100); HPLC (method 1): rt (%) = 3.87 min (97.9).
30 Example 23
5-Chloro-N-[3-(3-cyanoanilino)-2-hydroxypropyl]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 336 (M+H, 100); HPLC (method 2); rt (%) = 4.04 min (100).





Example 24
5-Chloro-iV-[3-(4-cyanoaniIino)-2-hydroxypropyI]-2-thiophenecarboxamide
MS (ESI): m/z (%) - 336 (M+H, 100);
5 HPLC (method 1): rt (%) = 4.12 min (100).
Example 25
5-ChIoro-N-{3-[4-(cyanomethyI)anilino]-2-hydroxypropyl}-2-
thiophenecarboxamide
10 MS (ESI): m/z (%) = 350 (M+H, 100);
HPLC (method 4): rt (%) = 3.60 min (95.4).
Example 26
15 5.Chloro-N-{3-[3-(cyanomethyl)anilino]-2-hydroxypropyl}-2-
thiophenecarboxamide
MS (ESI); m/z (%) = 350 (M+H, 100); HPLC (method 4): rt (%) - 3.76 min (94.2).
20 Example 58
tert-Butyl 4-[(3-{[(S-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]-benzylcarbamate
25 starting from fert-butyl 4-aminobenzylcarbamate {Bioorg. Med. Chem. Lett.", 1997;
1921-1926):
MS (ES-pos): m/z (%) = 440 (M+H, 100), (ES-neg): m/z (%) - 438 (M-H, 100); HPLC (method 1): rt (%) = 4.08 (100).
30 Example 59
terf-Butyl 4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]-phenyl-carbamate
35 starting from N-tert-butyloxycarbonyl-l,4-phenylenediamine:
MS (ESI): m/z (%) = 426 (M+H, 45), 370 (100);




HPLC (method 1): it (%) = 4.06 (100).
Example 60
5 fert-Butyl 2-hydroxy-3-{[4-(2-oxo-l-pyrrolidinyI)phenyI]amino}propyI-carb-
amate
starting from l-(4-aminophenyl)-2-pyrroiidinone (Justus Liebigs Ann. Chem.\ 1955;
596; 204):
10 MS (DCI, NH3): m/z (%) = 350 (M+H, 100);
HPLC (method 1): rt (%) = 3.57 (97).
Example 61
15 5-Chloro-N-(3-{[3-fluoro-4-(3-oxo-4-morphoIinyI)phenyI]amino}-2-hydroxypro-
pyI)-2-thiophenecarboxamide
S00 mg (3.8 mmol) of 4-(4-amino-2-fluorophenyl)-3-morpholinone and 700 mg
(3.22 mmol) of 5-chloro-N-(2-oxiranyImethyl)-2-thiophenecarboxamide in 15 ml of
20 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.
Rf (ethyl acetate): 0.25. 25
Example 62
(N-(3-Anilino-2-hydroxypropyI)-5-chloro-2-thiophenecarboxamide
starting from aniline:
30 MS (DCI, NH3): m/z (%) = 311 ([M+H]+, 100), CI pattern;
HPLC (method 3): rt {%) = 3.79 (100).
Example 63
35 5-Chloro-N-(2-hydroxy-3-{[4-(3-oxo-4-morpholinyi)phenyl]amino}propyl)-2-
thiophenecarboxamide





79
starting from 4-(4-aminophenyl)-3-morphoIinone: MS (ESI): m/z (%) = 410 ([M+Hf, 50), CI pattern; HPLC (method 3): rt (%) - 3.5S (100).
5 Example 64
N-[3-({4-[AcetyI(cycIopropyl)amino]phenyI}aniino)-2-hydroxypropyl]-5-chIoro-2-thiophenecarboxamide
starting from N-(4-aminophenyI)-N-cyclopropylacetamide:
10 MS (ESI): m/z (%) - 408 ([M+H]+, 100), CI pattern;
HPLC (method 3): it (%) = 3.77 (100).
Example 65
15 N-[3-({4-[Acetyl(methyl)amino]phenyl}amino)-2-hydroxypropyl]-5-chloro-2-
thiophenecarboxamide
starting from N-(4-aminophenyI)-N-methyIacetamide: MS (ESI): m/z (%) - 382 (M+H, 100); HPLC (method 4): it = 3.31 min. 20
Example 66
5-Chloro-N-(2-hydroxy-3-{[4-(lH-l,2,3-triazol-l-yl)phenyl]amino}propyl)-2-thiophenecarboxamide
25 starting from 4-(lH-l,2,3-triazol-l-yI)aniIine (Bouchet et al.; J.Chem.Soc.Perkin
Trans.2; 1974; 449): MS (ESI): m/z (%) = 378 (M+H, 100); HPLC (method 4): rt = 3.55 min.
30 Example 67
tert-butyl l-{4-[(3-{[(5-chIoro-2-thienyl)carbonyl]amino}-2-hydroxypropyi)-amino]phenyI}-L-proIinate
MS (ESI): m/z (%) = 480 (M+H, 100);
35 HPLC (method 4): rt = 3.40 min.




Example 68
l-{4-[(3-{[(5-ChIoro-2-thienyl)carbonyl}amino}-2-hydroxypropyI)amino]phe-nyl}-4-piperidinecarboxamide
5 MS (ESI): m/z (%) = 437 (M+H, 100);
HPLC (method 4): rt = 2.39 min.
Example 69
10 l-{4-[(3-{[(5-Chloro-2-tbienyI)carbonyI]amino}-2-hydroxypropyI)-aniino]phe-
nyl}-3-piperidinecarboxamide
MS (ESI): m/z (%) = 437 (M+H, 100); HPLC (method 4): rt = 2.43 min,
15 Example 70
5-ChIoro-N-(2-hydroxy-3-{[4-(4-oxo-l-piperidinyl)phenyI]amino}propyI)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 408 (M+H, 100);
20 HPLC (method 4): rt = 2.43 min.
Example 71
l-{4-[(3-{[(5-ChIoro-2-thienyl)carbonyI]amino}-2-hydroxypropyl)amino]phe*
25 nyl}-L-prolinamide
MS (ESI): m/z (%) = 423 (M+H, 100); HPLC (method 4): rt = 2.51 min.
Example 72
30
5-Chloro-N-[2-hydroxy-3-({4-[3-(hydroxymethyI)-l-piperidinyI]phenyI}-
amino)propyl]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 424 (M+H, 100); HPLC (method 4): rt - 2.43 min.





Example 73
5-Chloro--N-[2-hydroxy-3-({4-[2-(hydroxymethyI)-l-piperidinyI]phenyl}-amino)propyl]-2-thiophenccarboxamide
5 MS (ESI): m/z (%) = 424 (M+H, 100);
HPLC (method 4): it = 2.49 min.
Example 74
10 Ethyl l-{4-[(3-{[(5-cfaIoro-2-thienyl)carbonyI]aniino}-2-hydroxypropyl)-
amino]phenyI}-2-piperidinecarboxyIate
MS (ESI): m/z (%) = 466 (M+H, 100); HPLC (method 4): it = 3.02 min.
15 Example 75
5-Chloro-N-[2-hydroxy-3-({4-[2-(hydroxymethyI)-l-pyrrolidinyl]phenyl}amino)-propyl]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 410 (M+H, 100);
20 HPLC (method 4): rt = 2.48 min.
Example 16
5-Chloro-N-(2-hydroxy-3-{[4-(2-methylhexahydro-5H-pyrrolo[3,4-d]isoxa2ol-5-
25 yI)phenyI]amino}propyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 437 (M+H, 100). HPLC (method 5): rt = 1.74 min.
-1 Example 77 30
5-ChIoro-N-(2-hydroxy-3-{[4-(l-pyrrolidinyI)-3-(trinuoromethyI)phenyI]-arnino}propyI)-2-thiophenecarboxamide MS (ESI): m/z (%) s 448 (M+H, 100); HPLC (method 4): rt = 3.30 min.





Example 78
5-ChIoro-N-(2-hydroxy-3-{[4-(2-oxo-l-pyrrolidinyl)-3-(trifluoromethyl)phenyI]-amino}propyl)-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 462 (M+H, 100);
HPLC (method 4): rt = 3.50 mm.
Example 79
10 5-Chloro-N-(3-{[3-chloro-4-(3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxy-
propyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 444 (M+H, 100); HPLC (method 4): rt = 3.26 min.
15 Example 80
S-ChIoro-N-(2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)-3.(trifluoromethyl)pfaenyl]-amino}propyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 478 (M+H, 100);
20 HPLC (method 4): rt - 3.37 min.
Example 81
5-Chtoro-N-(2-hydroxy-3-{(3-methyI-4-(3-oxo-4-morphoIinyI)phenyI]amino}-
25 propyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 424 (M+H, 100); HPLC (method 4): rt - 2.86 min.
Example 82
30
5-Chloro-N-(3-{[3-cyano-4-(3-oxo-4-morphoIinyl)phenyl]amino}-2-hydroxypro-
pyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 435 (M+H, 100); HPLC (method 4): it = 3.10 min.
35



Example 83
5-Chloro-N-(3-{[3-chIoro-4-(l-pyrrolidinyI)phenyl]amino}-2-hydroxypropyI)-2-thiophenecarboxamide
5 MS (ESI); m/z (%) = 414 (M+H, 100);
HPLC (method 4): rt = 2.49 min.
Example 84
10 5-Chloro-N-(3-{[3-chloro-4-(2-oxo-l-pyrrolidinyl)phenyl]amino}-2-hydroxypro-
pyI)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 428 (M+H, 100); HPLC (method 4): rt = 3.39 min.
15 Example 85
5-Chloro-N-(3-{[3^-dimethyl-4-(3-oxo-4-morpbolinyl)phenyI]aniino}-2-hydro-
xypropyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) =: 438 (M+H, 100);
20 HPLC (method 4): rt = 2.84 min.
Example 86
N-(3-{[3-(Aininocarbonyl)-4-(4-morpholinyl)phenyI]anino}-2-hydroxypropyI)-
25 5-chloro-2-thiophenecarboxamide
MS (ESI): m/z (%) = 439 (M+H, 100); HPLC (method 4): rt = 2.32 min.
Example S7
30
5-Chloro-N-(2-hydroxy-3-{[3-methoxy-4-(4-morphoIinyl)phenyl]amino}propyl)-
2-thiophenecarboxamide
MS (ESI): m/z (%) = 426 (M+H, 100); HPLC (method 4): rt = 2.32 mm.




Example 88
N-(3-{[3-Acetyl-4-(4-morphoiinyI)phenyl]amino}-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 438 (M+H, 100);
HPLC (method 4): rt = 2.46 min.
Example 89
10 N-(3-{ [3-Amino-4-(3-oxo-4-morpholiny l)phenyl]amino}-2-hydroxy propyl)-5-
chloro-2-thiophenecarboxamide
MS (ESI): m/z (%) = 425 (M+H, 100); HPLC (method 4): rt = 2,45 min.
15 Example 90
5-Chloro-N-(3-{[3-chloro-4-(2-methyl-3-oxo-4-morphoUnyl)phenyl]amino}-2-hydroxypropyI)-2-thiophenecarboxamide
MS (ESI): m/z (%) - 458 (M+H, 100);
20 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-
25 hydroxypropyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 458 (M+H, 100); HPLC (method 4): rt = 3.48 min.
Example 91a 30
5-Chloro-N-[2-hydroxy-3-({4-[(3-oxo-4-morphoIinyI)methyI]phenyl}amino)-propyI]-2-thiophenecarboxamide
starting from 4-(4-amino-benzyI)-3-morphoIinone (Surrey et al.; J. Amer. Chem.
35 Soc; 77; 1955; 633):
MS (ESI): m/z (%) = 424 (M+H, 100);


HPLC (method 4): it = 2.66 min.
General method for preparing 3-substituted 5-chloro-N-[(2-oxo-l,3-oxazolidin-
5-yl)methyI)-2-thiophenecarboxamide derivatives starting from substituted
5 iV-(3-amino-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide derivatives

At room temperature, carbodiimidazole (1.2 to 1.8 eq.) or a similar phosgene
10 equivalent are added to a solution of the substituted Af-(3-amino-2-hydroxypropyI)-5-
chloro-2-thtophenecarboxamide derivative (1.0 eq.) in absolute THF (about
0.1 mol/1). At room temperature or, if appropriate, at elevated temperature (up to
70°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
15 (dichloromethane/methanol mixtures or cyclohexane/ethyl acetate mixtures).
The following compounds were prepared in an analogous manner.
Example 27 20
N-[(3-Benzyl-2-oxo-l,3-oxa2oIidin-5-yI)methyI]-5-choro-2-thiophenecarboxamide
MS (DCI, NH4): m/z (%) = 372 (M+Na, 100), 351 (M+H, 45); HPLC (method 1): rt (%) = 4.33 min (100). 25
Example 28
5-Chioro-N-{[3-(3-cyanophenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide
30 MS (DCI, NH4): m/z (%) = 362 (M+H, 42), 145 (100);
HPLC (method 2): it (%) = 4.13 min (100).



^S6^—-Example 29

tbiophenecarboxamide
5 MS (ESI): m/z (%) = 376 (M+H, 100);
HPLC (method 4): it = 4.12 min
Example 30
10 5-ChIoro-N-({3-[3-(cyanomethyl)phenyl]-2-oxo-l,3-oxazoIidin-5-yl}inethyl)-2-
thiophenecarboxamide
MS (ESI): m/z (%) = 376 (M+H, 100); HPLC (method 4): rt = 4.17 min
15 Example 92
tert-Butyl 4-[5-({[(5-chIorO-2-thienyI)carbonyI]amino}methyl)-2-oxo-l,3-oxa-zolidin-3-yl]benzylcarbamate
starting from Example 58:
20 MS (ESI): m/z (%) = 488 (M+Na, 23), 349 (100);
HPLC (method 1): rt (%) = 4.51 (98.5).
Example 93
25 terf-Butyl 4-[5-({[(5-chloro-2-thienyl)carbonyI]amino}methyI)-2-oxo-l,3-oxazoIi-
din-3~yl]phenylcarbamate
starting from Example 59:
MS (ESI): m/z (%) = 493 (M+Na, 70), 452 (M+H, 10), 395 (100);
HPLC (method 1): rt (%) = 4.41 (100).
30
Example 94
terf-Butyl 2-oxo-3-[4-(2-oxo.l-pyrrolidinyI)phenyI]-l,3-oxazoHdin-5-yl}methyl-carbamate
35 starting from Example 60:
MS (DCI, NH3): m/z (%) = 393 (M+NH4,100);
h^





























HPLC (method 3); rt (%) = 3.97 (100).
Example 95
5 5-Chloro-N-({3-[3-fluoro-4-(3-oxo-4-morphoIinyl)phenyl]-2-oxo-l,3-oxazolidin-
5-yl}methyI)-2-thiophenecarboxamide




10 260 mg (0.608 mmol) of 5-chloro-N-(3-{[3-fluoro-4-(3-oxo-4-morpholinyl)phenyl]-
amino}-2hydroxypropyl)-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°C for 30 minutes.
15 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.
NMR (300 MHz, d6-DMSO): 5= 3.6-3.7 (m,4H), 3.85 (dd,lH), 3.95 (m,2H), 4.2
(m,lH), 4.21 (s,2H), 4.85 (m,lH), 4.18 (s,2H), 7.19 (d,lH,thiophene), 7.35 (dd,1H),
20 7.45 (t,lH), 7.55 (dd,lH), 7.67 (d,lH,thiophene), $.95 (t,lH,CONH).
Example 96
5-Chloro-N-[(2-oxo-3.phenyI-l,3-oxazoIidin-5-y!)methyI]-2-
25 thiophenecarboxamide
starting from Example 62:
MS (ESI): m/z (%) = 359 ([M+Na]+, 71), 337 ([M+H)+, 100), Cl pattern;
HPLC (method 3): rt (%) = 4.39 (100).
IC50: 2 pM 30




Example 97
5-Chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholmyl)phenyl]-l,3-oxa2olidin-5-yl}-methyI)-2-thiophenecarboxamide
5 starting from Example 63:
MS (ESI): m/z (%) = 458 ([M+Na)+, 66), 436 ([M+H]+, 100), CI pattern;
HPLC (method 3): rt (%) = 3.89 (100),
IC50:1.4nM
10 Example 98
iV-[(3-{4+[Acetyl(cyclopropyl)amino]phenyl}-2-oxo-l,3-oxazolidm-5-yl)methyl]-5-chloro-2-thiophenecarboxamide)+de
starting from Example 64:
15 MS (ESI): m/z (%) = 456 ([M+Na]+ ,55), 434 ([M+H]+, 100), CI pattern;
HPLC (method 3): rt (%) = 4.05 (100). IC50: 50 nM
Example 99
20
N-[(3-{4-[Acetyl(methyl)amino]phenyl}-2-oxo-l3.oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamide
MS (ESI): m/z (%) = 408 (M+H, 30), 449 (M+H+MeCN, 100); HPLC (method 4): rt - 3.66 min. 25
Example 100
S-ChIoro-N-({2-oxo-3-[4-(1H-l,2,3.triazol-l-yl)phenyl]-l,3-oxazoIidin-5-yl}-methyl)-2-thiophenecarboxamide
30 MS (ESI): m/z (%) = 404 (M+H, 45), 445 (M+H+MeCN, 100);
HPLC (method 4): rt = 3.77 min.
Example 101
35 Tert-butyl l-{4-[S-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-l-3-
oxazoIidin-3-yl]phenyI}-L-prolinate








MS (ESI): m/z (%) = 450 (M+H-56,25), 506 (M+H, 100); HPLC (method 4): rt = 5.13 min.
Example 102
5
l-{4-[5-({[(5-Chloro-2-thienyl)carbonyl]amino}methyl)-2"Oxo-1,3-oxazolidin"3-yl]phenyI}-4-piperidinecarboxamide
MS (ESI): m/z (%) = 463 (M+H, 100); HPLC (method 4): rt = 2.51 rain. 10
Example 103
l-{4-[5-({[(5-Chloro-2-thienyl)carbonyI]amino}methyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}-3-piperidinecarboxamide
15 MS (ESI): m/z (%) = 463 (M+H, 100);
HPLC (method 4): rt = 2.67 min.
Example 104
20 5-Chloro-N-({2-oxo-3-[4-(4-oxo-l-piperidinyI)phenyI]-l,3-oxazolidin-5-
yI}methyI)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 434 (M+H, 40), 452 (M+H+H20, 100), 475 (M+H+MeCN, 60);
HPLC (method 4): rt - 3.44 min. 25
Example 105
l-{4-[5-({[(5-Chloro-2-thienyl)carbonyI]amino}methyl)-2-oxo-l-3-oxazolidin-3-yl]phenyl}-L-prolinamide
30 MS (ESI): m/z (%) = 449 (M+H, 100);
HPLC (method 4): rt = 3.54 min.


Example 106
5-ChIoro-N-[(3-{4-[3-(hydroxymethyI)-l-piperidinyl]phenyI}-2-oxo-l;3-oxazoIi-din-5-yI)methyI]-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 450 (M+H, 100);
HPLC (method 5): rt = 2,53 min.
Example 107
10 5-Chloro-N-[(3-{4-[2-(hydroxymethyl)-l-piperidinyI]phenyl}-2-oxo-l?3-oxazoli-
din-5-yI)methyl]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 450 (M+H, 100); HPLC (method 5): rt = 2.32 mm.
15 Example 108
Ethyl l-{4-[5-({[(5-chloro-2-thienyl)carbonyI]amino}methyl)-2-oxo-13-oxazoli-din-3-yl]phenyl}-2-piperidinecarboxylate
MS (ESI): m/z (%) = 492 (M+H, 100);
20 HPLC (method 5): rt = 4.35 min.
Example 109
5-Chloro-N.[(3-{4-[2-(hydroxymethyl)-l-pyrrolidmyl]phenyl}-2-oxo-l>3-oxazoli
25 dm-5-yl)methyI]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 436 (M+H, 100); HPLC (method 4): rt = 2.98 min.
Example 110
30
5.Chloro-N-({2- oxo-3-[4-(l-pyrrolidinyl).3-(trifluoromethyl)phenyl]-l,3-oxazoli-
din-5-yl}methyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) - 474 (M+H, 100); HPLC (method 4): rt = 4.63 min.




Example lit
5-Chloro-N-({3-[4-(2-methylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-yl)phenyl3-2-oxo-l,3-oxazoIidin-5-yl}methyl)-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 463 (M+H, 100);
HPLC (method 4): rt = 2.56 min.
Example 112
10 5-Chloro-N-({2-oxo-3.[4-(2-oxo-l-pyrrolidinyl)-3-(trifiuoromethyl)phenyl]-1,3-
oxazoIidm-5-yI}methyI)-2-thiophcnecarboxamide
MS (ESI): m/z (%) = 488 (M+H, 100); HPLC (method 4): rt = 3.64 min.
15 Example 113
5-Chloro-N-({3-[3-chIoro-4-(3-oxo-4-morphoIinyl)phenyI]-2-oxo-1,3-oxazolidin-5-yl}methyI)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 470 (M+H, 100);
20 HPLC (method 4): rt = 3.41 min.
Example 114
5-Chloro-N-({2-oxo-3-[4-(3-oxo-4-morphoIinyl)-3-(trifluoromethyI)phenyI]-l,3-
25 oxazolidin-5-yI}methyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 504 (M+H, 100); HPLC (method 4): rt = 3.55 min.
Example 115
30
5-ChIoro-N-({3-[3-methyI-4-(3-oxo-4-morphoIinyl)phenyl]-2-oxo-lr3-oxazolidin-5-yI}methyl)"2-thiophenecarboxamide
MS (ESI): m/z (%) = 450 (M+H, 100); HPLC (method 4): rt = 3.23 min.



Example 116
5-ChIoro-N-({3-[3-cyano-4-(3-oxo-4"morpholinyl)phenyl]-2-oxo-lT3-oxazoU 5 MS (ESI): m/z (%) = 461 (M+H, 100);
HPLC (method 4): rt = 3.27 min.
Example 117
10 5-Chloro-N-({3-[3-chIoro-4-(l-pyrroHdinyI)pheayI]-2-oxo"l^-oxazolidin-5-
yl}methyl)-2-thiophenecarboxamide
MS (ESI): m/2 (%) = 440 (M+H, 100); HPLC (method 4): rt = 3.72 min.
15 Example 118
S-Chloro-N-({3-[3-chloro-4-(2-oxo*l-pyrroHdinyl)phetiyl]-2-oxo-l,3-oxazolidin-5-yI}methyI)-2"thiophenecarboxamide
MS (ESI): m/z 20 HPLC (method 4): n = 3.49 min.
Example 119

25 zolidin-5-yI}methyl)-2"thiophenecarboxamide
MS (ESI): m/z (%) = 464 (M+H, 100); HPLC (method 4): rt = 3.39 min.
Example 120 30
N-({3-[3-(Aminocarbonyl)-4-(4-morpholinyI)phenyI]-2-oxo-l,3-oxazoiidin-5-yl}methyI)-5-chIoro-2-thiophenecarboxamide
MS (ESI); m/z (%) = 465 (M+H, 100); HPLC (method 4): rt - 3.07 min.




Example 121
5-ChIoro-N-({3-[3-methoxy-4-(4-morphoIinyI)phenyl]-2-oxo-lr3-oxazolidin-5-yI}methyI)-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 452 (M+H, 100);
HPLC (method 4): rt = 2.86 min.
Example 122
10 N-({3-[3-Acety]-4-(4-morphoIinyl)phenyI]-2-oxo-l,3-oxa2oIidin-5-yI}methyl)-5-
chloro-2-thiophenecarboxamide
MS (ESI): m/z (%) = 464 (M+H, 100); HPLC (method 4): it = 3.52 min.
15 Example 123
N-({3-[3-Amino-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yI}-methyI)-5-chloro-2-thiophenecarboxamide
MS (ESI): m/z (%) - 451 (M+H, 100);
20 HPLC (method 6): rt = 3.16 min.
Example 124
5-Chloro-N-({3-[3-chIoro-4-(2-methyl-3-oxo-4-morphoIinyl)phenyl]"2-oxo-l,3-
25 oxazolidin-5-yI}methyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 484 (M+H, 100); HPLC (method 4): rt = 3.59 min.
Example 125
30
5-ChIoro-N-({3-[3-chloro-4-(2-methyl-5-oxo-4-morphoIinyI)phenyl]-2-oxo-ly3-oxazolidin-5-yl}niethyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 484 (M+H, 100); HPLC (method 4): rt = 3.63 min.



Example 125a
S-Chloro-N-[(2-oxo-3-{4-[(3-oxo-4-morpholinyl)methyl]phenyl}-l,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 450 (M+H, 100);
HPLC (method 4): rt - 3.25 min.
Via epoxide opening with an amine and subsequent cyclization to give the
corresponding oxazolidinone, it was also possible to prepare the following
10 compounds:









/
/


/
/




Examples 14 to 16 below are working examples for the optional oxidation step. Example 14
5 5-Chloro-N-({(SS)-3-[3-fluoro-4-(l-oxo-lDambda]4,4-thiazinan-4-yl)pheny»]-2-

oxo-l^-oxazolidin-5-yI}methyl)-2-tMophenecarboxaniide
F O
n r~0=S N
o
10 At 0°C, 5-chloro-N-({(5S)-3-[3-fluoro-4*Cl,4-thiazinan^-yl)phenyl]-2-oxo-l,3-
oxazolidin-5~yl}methyI)-2-thiophenecarboxarnide (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°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
15 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. M.p.: 257°C;
20 Rf (silica gel, toluene/ethyl acetate 1:1)- 0.54 (starting material = 0.46);
IC5o value =1.1pM: MS (DCl) 489 (M+NH4), CI pattern.




Example 15
Preparation of5-chloro-N-({{5S)-3"[4-(l,l-dioxO"l[lambda]*,4-thiazinan-4-yl)-3-
fluorophenyll^-oxo-l^-oxazolidin-S-ylJmethyD-Z-thiophenecarboxamide
5
F O
O
5 -Choro-N -({(5S)-3-[3-fluoro-4-( l ,4-thiazrnan-4-yl)pheyl] -2-oxo-1,3-oxazolidin-5-yl}rnethyl)-2-thiophenecarboxamide from Example 3 (0.1 g, 0.22 mmol) in 3.32 ml
10 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
15 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. M.p.: 238°C; Rf (toluene/ethyl acetate 1:1) = 0.14 (starting material = 0.46);
20 1C50 value = 210 nM;
MS (DO): 505 (M+NH4), CI pattern.
Example 16
25 5-ChIoro-N-{[(5S)-3-(3-fluoro~4-morpholinophenyl)-2-oxo-l,3-oxazoIidin-5-
yl]methyl}-2-thiophenecarboxamide N-oxide
is obtained by treating 5-chloro-N-{[(5S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-
l,3-oxazoIidin-5-y]]methyl}-2-thiophenecarboxarnide from Example 1 with the
magnesium salt of monoperoxyphthalic acid.
30 MS (ESI): 456 (M+H, 21 %, CI pattern), 439 (100%).




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
5 cyanomethylphenyl-substituted 5-chIoro-N-[(2-oxo-l,3-oxazoIidin-5-yl)methyl]-
2-thiophenecarboxamide derivatives
The cyanomethylphenyl-substituted 5-chloro-N-[(2-oxo-l,3-oxazolidin-5-yl)methyl]-
2-thiophenecarboxamide derivative in question (1.0 eq.) is, together with
10 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 MgSO4, filtered and concentrated under reduced pressure.
15 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.
The residue is dissolved in methanol (0.01-0.1 mol/l) and, to prepare the
20 unsubstituted amidines, admixed with ammonium acetate (3 eq.) and ammonium
chloride (2 eq.). To prepare the substituted amidine derivatives, primary or secondary
amines (l.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%
25 trifluoroacetic acid).
The following compounds were prepared in an analogous manner:
Example 31:
30
N-({3-[4-(2-Amino-2-iminoethyl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methy1)-5-cbloro-2-thiophenecarboxamide
MS (ESI): m/z (%) = 393 (M+H, 100); HPLC (method 4): rt = 2.63 min 35


Le A M W-F^WFV Countries

Example 32;
5-Chloro-N-({3-[3-(425-dihydro-lH-imidazol-2-yImethyl)phenyI]-2-oxo-1,3-oxazoIidin-5-yI}methyl)-2-thiophenecarboxamide
5 MS (ESI): m/z (%) - 419 (M+H, 100);
HPLC (method 4): rt =2.61 min
Example 33:
10 5-Chloro-N-t(3-{3-[2-imino-2-(4-raorpholinyl)ethyl]phenyI}-2-oxo-l,3-oxazoIi-
din-5-yI)methyI]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 463 (M+H, 100); HPLC (method 4): rt - 2.70 min
Example 34:
S-Chloro-N-[(3-{3-[2-imino-2-(l-pyrroIidinyl)ethyl]phenyI}-2-oxo-l,3-oxazoIi-din-5-yl)methyl]-2-thiophenecarboxamide
20 MS (ESI): m/z (%) = 447 (M+H, 100);
HPLC (method 4): rt = 2.82 min
Example 35:
25 N-({3-[3-(2-Amino-2-iminoethyl)phenyl]-2-oxo-l;3-oxazolidin-5-yI}inethyl)-5-
chloro-2-thiophenecarboxamide
MS (ESI): m/z (%) = 393 (M+H, 100); HPLC (method 4): rt = 2.60 min
30 Example 140
5-Chloro-N-({3-[4-(4,5-dihydro-lH-imidazoI-2-ylmethyl)phenyl]-2-oxo-l,3-oxa-zolidin-5-yI}methyI)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 419 (M+H, 100);
35 HPLC (method 4): rt = 2.65 min


Example 141
5-Chloro-N-[(3-{4-[2-imino-2-(4-morphoIinyI)ethyl]phenyl}-2-oxo-13-oxazoli. din-5-yI)methyI]-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 463 (M+H, 100);
HPLC (method 4): it = 2,65 min
Example 142
10 5-Chloro-N-[(3-{4-[2-imino-2-(l-piperidinyl)ethyl]phenyl}-2-oxo-l,3-oxazolidin-
5-yl)methyl]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 461 (M+H, 100); HPLC (method 4): rt = 2,83 min
15 Example 143
5-Chloro.N-[(3-{4-[2-imino-2-(l-pyrrolidinyl)ethyl]phenyI}-2-oxo-l,3-oxazoli-din-5-yl)methyl]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 447 (M+H, 100);
20 HPLC (method 4): rt = 2.76 min
Example 144
5-Chloro-N-[(3-{4-[2-(cyclopentylamino)-2-iminoethyl]phenyl}-2-oxo-1,3-oxazo-
25 Iidin-5-yl)methyl]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 461 (M+H, 100); HPLC (method 4): rt = 2.89 min
Example 145
30
5-ChIoro-N.{[3-(4-{2-imino-2.[(2,2,2-trifuoroethyI)amino]ethyl}phenyI)-2-oxo-
l,3-oxazoIidin-5-yl]methyl}-2-thiophenecarboxamide
MS (ESI): m/z (%) = 475 (M+H, 100); HPLC (method 4): rt = 2,79 min


T^ A M 177-Frtn-iyn Cntmtnn
Example 146
N-({3-[4-(2-Anilino-2-iminoethyI)phenyl]-2-oxo-l^-oxazoljdin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 469 (M+H, 100);
HPLC (method 4): rt = 2.83 min
Example 147
10 5-Chloro-N- [(3-{4- [2-itnino-2-(2-py ridiny lamino)ethy l]pheny l}-2-oxo-1,3-oxa-
zolidin-5-yl)mcthyl]-2-thiophenecarbox:amide
MS (ESI): m/z (%) = 470 (M+H, 100); HPLC (method 4): rt = 2.84 min
15 Examples 148 to 151 below refer to the removal of BOC amino protective groups:
General method for removing Boc protective groups (tert-butyloxycarbonyl):

20
Aqueous trifluoroacetic arid (TFA, about 90%) is added dropwise to an ice-cooled solution of a ferr-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
25 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 IN 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
30 or ether/dichloromethane mixtures.
The following compounds were prepared in an analogous manner from the corresponding Boc-protected precursors:


Example 148
Ar-({3-[4-(Aminotnethyl)phenyI]-2-oxo-l^-oxazoIidin-5-yI}methyI)-5-chIoro-2-thiophene-carboxamide
5 starting from Example 92:
MS (ESI): m/z (%) = 349 (M-NH2, 25), 305 (100); HPLC (method I); rt (%) = 3.68 (98). IC50: 22 fiU
10 Example 149
^-{[S-t^AminophenylJ-I-oxo-l^-oxazolidin-S-ylJmethylJ-S-chloro-l-thiophenecarboxamide
starting from Example 93:
15 MS (ESI): m/z (%) ~ 352 (M+H, 25);
HPLC (method 1): rt (%) = 3.50 (100). IC50: 2 fiM
An alternative enantiomerically pure synthesis of this compound is shown in the
20 scheme below (cf. also Delalande S.A., DE 2836305,1979; Chem.Abstr. 90,
186926):

1.) phthalimide, DEAD/PPh




Example 150
5-Chloro-iVK{3-[4^glycyiamino)phenyl]-2-oxo-i^-oxa2oIidm-5-yl}inethyl)-2-thiophenecarboxamide
5 starting from Example 152:
MS (ES-pos): m/z (%) = 408 (100); HPLC (method 3): rt (%) = 3.56 (97). IC50: 2 fiM
10 Example 151
5-(Aminomethyl)-3-[4-(2-oxo-l-pyrrolidinyl)ph^nyl]-13-oxazolidin-2-one
starting from Example 60;
MS (ESI): m/z (%) = 276 (M+H, 100);
15 HPLC (method 3): rt (%) = 2.99 (100).
IC5o:2/iM
The Examples 152 to 166 below refer to the amino group derivatizatjon of aniline- or benzylamine-substituted oxazolidinones using various reagents: 20
Example 152
5-Chloro-Ar-({3-[4-(N-te/t-butyIoxycarbonyl-glyi:yIamino)pheny]]-2-oxo-l,3-oxazolidm-5-yI}methyI)~2-thiophenecarboxamide
25
At 0°C, 754 mg (2.1 mmol) of JV-{[3-(4-aminophenyI)-2-oxo-l,3-oxazolidin-5-
yl]methyI}-5-chloro-2-thiophenecarboxamide (from Example 149) are added to a
30 solution of 751 mg (4.3 mmol) of Boc-glycine, 870 mg (6.4 mmol) of HOBT

(1-hydroxy-lH-benzotriazole x H20), 1790 mg (4.7 mmol) of HBTU [0-(benzotriazol-l-yl)-N,N,N",N"-tetramethyIuronium hexafluorophosphate] and 1.41 ml (12.9 mmol) of N-methylmorpholine in 15 ml of DMF/CH2C12 (1:1). The


mixture is stirred at room temperature overnight and then diluted with water. The precipitated solid is filtered off and dried. Yield: $94 mg (79.7% of theory); MS (DCI, NH3): m/z (%) = 526 (M+NH4, 100); HPLC (method 3): rt (%) = 4.17 (97).
Example 153
N-[(3"{4-[(AcetyIamino)methyI]phenyI}-2-oxo-1,3-oxazolidin-S-yl)methyl]-5-chIoro-2-thiophenecarboxamide

10
1U

At O0C, a mixture of 30 mg (0.082 mmol) of N -({3-[4-(aminomethyl)phenyl]-2-oxo-
l,3-oxazolidin-5-yl}methyl)-5-chloro-2-rhiophene-carboxamide (from Example 148)
in 1.5 ml of absolute THF and 1.0 ml of absolute dichloromethane, and 0.02 ml of
15 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. Yield: 30 mg (87% of theory),
MS (ESI): m/z (%) = 408 (M+H, 18), 305 (85);
HPLC (method 1): rt (%) = 3.78 (97).
20 IC50: 0.6 pM
Example 154
25 methyl}-5-chIoro-2-thiophenecarboxamide


-
K




At room temperature, 0.19 ml (0.82 mmol) of trimethylsilylisocyanate are added
dropwise to a mixture of 30 mg (0.082 mmol) of iV-({3-[4-(aminomethyl)phenyl]-2-
oxo-l,3-oxazolidin-5-yl }methyI)-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),
MS (ESI): m/z (%) = 409 (M+H, 5), 305 (72);
HPLC (method 1): rt (%) = 3.67 (83).
10
IC50:1-3/AM
General method for acylating Ar-{[3-(4-aminophenyl)-2-oxo-l,3-oxazolidin-S-yl]methyl}-5-chloro-2-thiophenecarboxamJde with carbony) chlorides:

^ _ .. ..
-CI
tr
Under argon, an approximately 0.1 molar solution of N-{[3-(4-aminophenyl)-2-oxo-
15 l,3-oxazolidin-5-y]]methyI}-5-chloro-2-thiophenecarboxamide (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
20 filtrate is concentrated. If appropriate, the products are purified by preparative RP-
HPLC.
The following compounds were prepared in an analogous manner:
25 Example 155
N-({3-[4-(AcetyIamino)phenyl]-2-oxo-1,3-oxazolidin-5--yl}methyl)-5-chloro-2-thiophene-carboxamide
LC-MS: m/z (%) = 394 (M+H, 100);




LC-MS (method 6): rt (%) = 3.25 (100). IC50: 1.2 pM
Example 156
5
5-ChIoro-N-[(2-oxo-3-{4-[(2-thienylcarbonyl)amino]phenyI}-l,3-oxazolidin-5-yl)methyl] -2-thiophenecarboxamide
LC-MS: m/z (%) = 462 (M+H, 100);
LC-MS (method 6): rt (%) = 3.87 (100).
10 IC50: 1.3 pM
Example 157
5-Chloro-N-[(3-{4-[(methoxyacetyl)amino]phenyl}-2-oxo-l,3-oxazolidin-5-yI)-
15 methyI]-2-thiophenecarboxamide
LC-MS: m/z (%) = 424 (M+H, 100); LC-MS (method 6): rt (%) = 3.39 (100). IC5o:0.73pM
20 Example 158
N-{4.[5-({[(5-Chloro-2-thienyl)carbonyl]amino}methyI)-2-oxo-l,3oxazolidin-3-yl]phenyl}-3,5-dimethyl-4-isoxazolecarboxamide
LC-MS: m/z (%) - 475 (M+H, 100).
25 IC50: 0.46pM
Example 159
5-Chloro-Af-{[3-(4-{[(3-chIoropropyl)suIphonyl]amino}phenyl)-2-oxo-1,3-
30 oxazolidin-5-yl]methyl}-2-thiophenecarboxamide
O







An ice-cooled solution of 26.4 mg (0.15 mmol) of 3-chloro-l-propanesulphonyI
chloride and 0.03 ml (0.2 mmol) of triethylamine in 3.5 ml of absolute dichloro-
methane is admixed with 35 mg (0.1 mmol) of A^[3-(4-arninophenyI)-2-oxo-l,3-
oxazoHdin-5-yl]-niethyl}-5-chloro-2-thiophene-carboxamide (from Example 149).
5 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-trisamme (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%
10 of theory),
LC-MS; m/z (%) - 492 (M+H, 100); LC-MS (method 5): it (%) = 3.82 (91).
15 Example 160
5-Chloro-A^-({3-[4-(l,l-dioxido-2-isothia2oIidinyl)phenyI]-2-oxo-l,3-OxazoIidin-5-yl}methyI)-2-thiophenecarboxamide
20
A mixture of 13.5 mg (0.027 mmol) of 5-chloro-N-{(3-(4-{[(3-chloropropyl)sul-phonyl]amino}phenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl}-2-thiophene-carboxamide (from Example 159) and 7.6 mg (0.055 mmol) of potassium carbonate in 0.2 ml of
25 DMF is heated at 100°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), MS (ESI): m/z (%) = 456 (M+H, 15), 412 (100);
30 LC-MS (method 4): it (%) = 3.81 (90).
IC50: 0.14 pM




Example 161
5-Chloro-N-t((5S)-3-{4-[(5-chloropentanoyi)amino]phenyl}-2-oxo-l,3-oxazoli-din-5-yl)methyl]-2-thiophenecarboxamide


CI 0

5

0.5 g (1.29 mmol) of N-{[(5S)-3-(4-aminophenyl)-2-oxo-l,3-oxazoIidin-5-
yI]methyl}-5-chloro-2-thiophenecarboxamide (from Example 149) is dissolved in
10 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=l:l -> ethyl acetate gradient. This gives 315 mg (52% of theory) of a solid. M.p.:211°C.
15
Example 162
5-Chloro-N-({(SS)-2-oxo-3-[4-(2-oxo-l-piperidinyI)phenyl]-l,3-oxazolidin-5.yl}. methyl)-2-thiophenecarboxamide
20

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°C for 30 min, until the evolution of gas
25 has ceased, A solution of 290 mg (0.617 mmol) of 5-chloro-N-[((5S)-3-{4-[(5-
chloropentanoyl)amino]phenyl}-2-oxo-l,3-oxa2olidin-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
109


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. M,p.: 205°C;
NMR (300 MHz, d6-DMSO): 5= 1.85 (m,4H), 2.35 (m,2H), 3.58 (m,4H), 3.85 (m,lH), 4.2 (t,lH), 4.82 (m,lH), 7.18 (d,lH,thiophene), 7.26 (d,2H), 7.5 (d,2H), 2.68 (d,lH,thiophene), 9.0 (t,lH,CONH). IC50: 2.8 nM
10 Example 163
5-ChIoro-N-[((5S)-3-{4-[(3-bromopropionyl)amino]phenyI}-2-oxo-l,3-oxazoli-din-5-yl)methyi}-2-thiophenecarboxamide

15
is obtained in an analogous manner from Example 149.
Example 164
20 5-ChIoro-N-({(5S).2-oxo-3-[4-(2-oxo-l-.azetidinyl)phenyI]-1,3-oxazolidin-5-yl}-
methyI)-2-thiophenecarboxamide

25 is obtained in an analogous manner by cyclization of the open-chain bromopropionyl
compound from Example 163 using NaH/DMSO. MS (ESI): m/z (%) = 406 ([M+H]+, 100), CI pattern. 1C50: 380 nM



Example 165
tert-Butyl 4-{4-[5-({[(5-chIoro-2-thienyI)carbonyllainino}methyl)-2-oxo-l,3-oxa-zolidin-3-yI]phenyl}-3,5-dioxo-l-piperazinecarboxylate



A solution of 199 mg (0.85 mmol) of Boc-iminodi acetic acid, 300 mg (2.2 mmol) of HOBT, 0.66 ml (6 mmol) of N-methylmorphoIine and 647 mg (1.7 mmol) of HBTU
10 is admixed with 300 mg (0.S5 mmol) of N-[3-(4-aminophenyI)-2-oxo-l,3-
oxazolidin-5-yl]-methyl }-5-chloro-2-thiophene-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
15 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); MS (ESI): m/z (%) = 571 (M+Na, 82), 493 (100); HPLC (method 3): rt (%) - 4.39 (90).
20 IC50: 2 pM
Example 166
N-[((5S)-3-{4-[(3R)-3-Amino-2-oxo-l-pyrToIidinyI]pheny!}-2-oxo-l,3-oxazolidin-
25 5-yI)methyI]-5-chloro-2-thiophepecarboxamide trifluoroacetate

O BOCNH^COOH
.g^^Cl s^ EDC, DIEA
CH-
r/9 L HOBT








N2-(tert-Butoxycarbonyl)-Nl-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}
5 methyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}-D-methionineamide
429 mg (1.72 mmol) of N-BOC-D-methionine, 605 mg (1.72 mmol) of N^[(5S)-3-(4-aminophen yl)-2-oxo-1,3 -oxazol idin-5-yl]methyl) -5-ch loro-2-thiophenecarbox-amide, and 527 mg (3.44 mmol) of HOBT hydrate are dissolved in 35 ml of DMF
10 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
15 using a toluene -> T10EA7 gradient. This gives 170 mg (17% of theory) of the target
compound of melting point 183°C. Rf (Si02, toluene/ethyl acetate=l:l):0.2.
}H-NMR (300 MHz. d6-DMSO): (s,lH,BOC), 1.88-1.95 (m,2H), 2.08
(s,3H,SMe), 2.4-2.5 (m,2H, partially obscurbed by DMSO), 3.6 (m,2H), 3.8 (m,lH),
20 4.15 (m,2H), 4.8 (m7lH), 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,lH, CH2NHCO), 9.93 (bs,lH,NH).



tert-Butyl (3R)-l.{4-[(5S)-5-({[(5-chIoro-2-thieiiyI)carbonyI]aniino}methyi)-2-oxo-1,3-oxazoIidin-3-yl]pheny l}-2-oxo-3-pyrroIidinylcarbamate
170 mg (0.292 mmol) of N2-(tert-butoxycarbonyl)-Nl-{4-[(S$)-5-({[(5-chloro-2-
5 thienyl)carbony]] amino }methyl)-2-oxo~l ,3-oxazolidin-3-yl]phenyl }-D-methionine-
amide are dissolved in 2 ml of DMSO and admixed with 178.5 mg (0.875 mmol) of trimethylsulphonium iodide and 60.4 mg (0.437 mmol) of potassium carbonate, and the mixture is stirred at 80°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
10 remain.
}H-NMR (300 MHz, d6*DMSO): 6 =1.4 (s,lH,BOC), 1.88-2.05 (m,lH), 23-2.4 (m,lH), 3.7-3.8 (m,3H), 3.8-3.9 (m,lH), 4.1-4.25 (m,lH), 4.25-4.45 (m,lH), 4.75-4.95 (m,lH), 7.15 (1H, thiophene), 7.25 (d,lH), 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,lH).
15
N-[((5S)-3-{4-t(3R)-3-Aminio-2-oxo-l-pyrroIidinyI]phenyl}-2-oxo-l,3-oxazoUdm-5-y l)methyl] -S-chloro-2-thiophenecarboxamide trifluoroacetate
97 mg (0.181 mmol) of tert-butyl (3R)-l-{4-[(5S)-5-({[(5-chloro-2-
20 thienyl)carbonyl]amino}methyl)-2-oxo-l,3-oxazolidin-3-yI]phenyl}-2-oxo-3-pyrroli-
dinylcarbamate 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
25 fraction gives 29 mg (37% of theory) of the target compound of melting point 241 °C
(decomp.).
Rf (Si02,EtOH/TEA=17:l) 0.19.
]H-NMR (300 MHz, d6-DMSO): =1.92-2.2 (m,lH), 2.4-2.55 (m,lH, partially.
obscured by DMSO peak), 3.55-3.65 (m,2H), 3.75-3.95 (m,3H), 4.1-4.3 (m,2H),
30 4.75-4.9 (m,lH), 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, NIB), 8.9
(t,lH,NHCO).



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 5-chIoro-N-[(2-oxo-3-phenyI-1,3-oxazolidin-5-yl)methyl]-2-
thiophenecarboxamide

10 Under argon and at 5°C, 5-chloro-N-[(2-oxo-"3-phenyl-l,3-oxa2olidin-5-yl)methyl]-2-
thiophenecarboxamide (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.
15 Under argon and at room temperature, the precipitate is then dissolved in
tetrahydrofuran (0.1 mol/1) 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). .
20
The following compounds were prepared in an analogous manner:
Example 167
25 5-Chloro-N-({2-oxo.3-[4- methyl)-2-thiophenecarboxamide
MS (ESI): m/2 (%) = 492 ([M+Na]+, 100), 470 ([M+H]+, 68), CI pattern;
114



10

HPLC (method 3): rt (%) = 4.34 (100). IC50: 0.5 pM
Example 168
5-ChIoro-N-[(3-{4-[(4-methyl-1-piperazinyI)sulphonyI]phenyl}-2-oxo-l,3-oxa-zolidin-5-yI)methyI]-2-thiaphenecarboxamide
MS (ESI): m/z (%) = 499 ([M+H]+, 100), CI pattern; HPLC (method 2); rt (%) = 3.3 (100).
Example 169

5-Chloro-N-({2-oxo-3-[4-(l-piperidinylsuIphonyl)phenyl]-l,3-oxazolidin-5-yI}-methyl)-2-thiophcnecarboxamide
15 MS (ESI): m/z (%) = 484 ([M+H]+, 100), Cl pattern;
HPLC (method 2): it {%) = 4.4 (100).
Example 170
20 5-Chloro-N-[(3-{4-[(4-hydroxy-l-piperidinyl)sulphonyl]phenyI}-2-oxo-l,3-oxa-
zoUdin-5-yl)methyl]»2-thiophenecarboxamide
MS (ESI): m/z (%) = 500 ([M+H]+, 100), Cl pattern; HPLC (method 3): rt (%) = 3.9 (100).
25 Example 171
5-Chloro-N-({2-oxo-3-[4-(l-pyrrolidinyl)phenyl]-l,3-oxa2oIidin-5-yl)methyl)-2-thiophenecarboxamide

H N
H,CT;CH,
30









780 mg (1.54 mmol) of tert-butyl l-{4-[5-({[(5-chIoro-2-thienyl)carbonyl]amino}-
methyl)-2-oxo-l,3-oxazohdin-3-yl]phenyl}prolinate are dissolved in 6 ml of
dichloromethane and 9 ml of trifluoroacetic acid, and the mixture is stirred at 40°C
5 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 stin-ed
with ether and 2N hydrochloric acid. The organic phase of this extraction is dried
over MgS04, filtered and concentrated. The crude product is chromatographed over
silica gel (CH2Cl2/EtOH/conc. aqu. NH3 sol. = 100/1/0.1 to 20/1/0.1).
10 This gives 280 mg (40% of theory) of the product.
MS (ESI): m/z (%) = 406 (M+H, 100); HPLC (method 4): rt = 3.81 min.
HPLC parameter and LC-MS parameter for the HPLC and LC-MS data given in the
15 examples above (the unit of the retention time (rt) is minutes):
[1] Column; Kromasil C18, L-R temperature: 30°C, flow rate = 0.75 ml min-1, eluent: A = 0-01 M HC104, B = CH3CN, gradient: -> 0.5 min 98%A -> 4.5 min 10%A ->6.5 min 10%A 20
[2] Column: Kromasil C18 60*2, L-R temperature: 30oC, flow rate = 0.75 ml min"-1, eluent: A = 0.01 M H3P04, B = CH3CN, gradient: -> 0.5 min 90%A -> 4,5 min 10%A ->6.5 min 10%A
25 [3] Column: Kromasil C18 60*2, L-R temperature: 30°C, flow rate = 0.75 ml min-1,
eluent: A = 0.005 M HC104, B = CH3CN, gradient: -> 0.5 min 98%A -> 4.5 min 10%A ->6.5 min 10%A
[4] Column: Symmetry C18 2.1x150 mm, column oven: 50°C, flow rate =
30 0.6 ml min"1, eluent: A = 0.6 g 30% strength HC1/ 1 of water, B = CH3CN, gradient:
0.0 min 90%A -> 4.0 min 10%A ->9 min 10%A
/■ /
/



/ 116
/ f



[5] MHZ-2Q, Instrument Micromass Quattro LCZ
Column Symmetry C18, 50 mm x 2.1 mm, 3.5 pm, temperature: 40°C, flow rate =
0.5 ml min-1, eluent A = CH3CN + 0.1% formic acid, eluent B = water + 0.1% formic
5 acid, gradient: 0.0 min 10% A -> 4 min 90% A -> 6 min 90% A
[6] MH2-2P, Instrument Micromass Platform LCZ
Column Symmetry C18, 50 mm x 2.1 mm, 3.5 pm, temperature: 40°C, flow rate =
0.5 ml min-1, eluent A - CH3CN + 0.1% formic acid, eluent B = water + 0.1% formic
10 acid, gradient: 0.0 min 10% A -> 4 min 90% A -> 6 min 90% A
[7] MHZ-7Q, Instrument Micromass Quattro LCZ
Column Symmetry C18, 50 mm x 2.1 mm, 3.5 pm, temperature: 40°C, flow rate =
0.5 ml min"1, eluent A = CH3CN + 0,1% formic acid, eluent B = water + 0.1% formic
15 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
20 Reactions with different resin-bonded products were carried out in a set of separated
reaction vessels.
5-(Bromomethyl)-3-(4-fluoro-3-nitrophenyl)-l,3-oxazolidin-2-one A (prepared from epibromohydrin and 4-fluoro-3-nitrophenyl isocyanate using LiBr/Bu3PO in xylene
25 analogously to US 4128654, 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°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°C for 48 h. The resin was filtered, washed repeatedly with methanol
30 (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-carboxyIic acid (5 eq,) and l-chloro-l-dimethylamino-2-methylpropene (5 eq.) in DCM (20 ml) at room temperature for 15 minutes] and
35 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
117


suspended in DMF/water (v/v 9:2, 80 ml), admixed with SnCl2*2H20 (5 eq.) and
reacted at room temperture 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°C, with an acid chloride (5 eq. of acid
5 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 l-dimethylamino-l-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
10 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
15 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.





2
TentaGelSAM"
"TentaGelSAM
oHr° -PA -








"1>V_A o .s

5 Compounds which were prepared by solid-phase-supported synthesis:
Example 172
N-({3-[3-Amino-4-(l-pyrrolidinyl)phenyl]-2-oxo-l,3-oxazolidin-5-yI}metbyl)-5-
10 chloro-2-thiophenecatboxamide

Analogously to the general procedure for preparing the derivatives B, 5 g
15 (1.25 mmol) of TentaGel SAM resin were reacted with pyrrolidine as amine
derivative 1. The aniline obtained after reduction with SnCL2*2H20 was, without any further acylarion step, removed from the solid phase and concentrated. The crude product was partitioned between ethyl acetate and NaHC03 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 (dichloro-methane/ethyl acetate, 3:1- 1:2).
]H-NMR (300 MHz, CX>C13): 1.95 - 2.08, br, 4 H; 3.15-3.30, br, 4 H; 3.65-3.81, m,
2 H; 3.89, ddd, 1H; 4.05, dd, 1 H; 4.81, dddd, 1 H; 6.46, dd, 1 H; 6.72, dd, 1 H; 6.90,
5 dd, 1 H; 6.99, dd, 1 H; 7.03, dd, 1 H; 7.29, d, 1 H,
Example 173
N-[(3-{3-(B-Alanylamino)-4-t(3-hydroxypropyl)amino]phenyl}-2-oxo-l,3-oxa-
10 zoIidin-5-y))methyl]-5-chloro-2-thiophenecar boxamide



Analogously to the general procedure for preparing the derivatives B, 5 g
15 (1.25 mmol) of TentaGel SAM resin were reacted with azetidine as amine derivative
1 and Fmoc-B-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.
20 "H-NMR (400 MHz, CD3OD): 2.31, tt, 2 H; 3.36, t, 2 H; 3.54, t, 2 H; 3.62, t, 2 H;
3.72, dd, 1 H; 3.79, dd, 1 H; 4.01, dd, 1 H; 4.29, dd, 2 H; 4.43, t, 2 H; 4.85-4,.95, m, 1 H; 7.01, d, 1 H; 4.48 - 7.55, m, 2 H; 7.61, d, 1 H; 7.84, d, 1 H.

25

Example 174
N-({3-[4-(3-Amino-l-pyrrolidinyl)-3-nitrophenyl]-2-oxo-l,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophenecarboxamide









NO. Q S-/


10

Analogously to the general procedure for preparing the derivatives B, 130 mg (32.5 p.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.
"H-NMR (400 MHz, CD3OH): 2.07-2.17, m, 1 H; 2.39-2.49, m, 1 H; 3.21-3.40, m, 2 H; 3.45, dd, 1 H; 3.50-3.60, m, 1 H; 3.67, dd, 1 H; 3.76, dd, 1 H; 3.88-4.00, m, 2 H; 4.14 - 4.21, t, 1 H; 4.85 - 4.95, m, 1 H; 7.01, d, 1 H; 7,11, d, 1 H; 7.52, d, 1 H; 7.66, dd, 1 H; 7.93, d, 1 H.



15

Example 175
N-({3-[3-Amino-4-(l-piperidinyI)phenyI]-2-oxo-l,3-oxazolidin-5-yI}methyI>5-chloro-2-thiophenecarboxamide






20
25

Analogously to the general procedure for preparing the derivatives B, 130 mg (32.5 pmol) 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. "H-NMR (400 MHz, CD3OH): 1.65-1.75, m, 2 H; 1.84-1.95, m, 4 H; 3.20-3.28, m, 4 H; 3.68, dd, 1 H; 3.73, dd, 1H; 3.90, dd, 1 H; 4.17, dd, 1 H; 4.80-4.90, m, 1 H; 7.00, d, 1 H; 7.05, dd, 1 H; 7.30-7.38, m, 2H; 7.50, d, 1 H.







Example 176
N-({3-[3-(Acetylamino)-4-(l-pyrrolidinyI)phenyI]-2-oxo-l^-oxazoIidin-5-y|}-methyl)-5-chlorO"2-thiophenecarboxamide
5
Analogously to the general procedure for preparing the derivatives B, 130 mg (32.5 pmol) of TentaGel SAM resin were reacted pyrrolidine as amine derivative 1
10 and acetyl chloride as acid derivative 1. The crude product was partitioned between
ethyl acetate NaHCO3 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). "H-NMR (400 MHz, CD3OH): 1.93 - 2.03, br, 4 H; 2.16, s, 3 H; 3.20-3.30, br, 4 H;
15 3.70, d, 2 H; 3.86, dd, 1H; 4.10, dd, 1 H; 4.14, dd, 1 H; 4.80^.90, m, I H; 7.00, d, 1
H; 7.07, d, 1 H; 7.31, dd, 1 H; 7.51, d, 1 H; 7.60, d, 1 H.

The following compounds were prepared analogously to the general procedure.
























































WE CLAIM:
1. Oxazolidinones of the general formula (I)

in which:
R1 represents 2-thiophene which is substituted in the 5-position by a radical from the group consisting of chlorine, bromine, methyl and trifluoromethyl,
R2 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 0;
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,
R3, R4, R5, R6, R7 and R8 each represent hydrogen
137

and their pharmaceuticaliy acceptable salts, hydrates, hydrates of salts of the kind such as herein described.
2. Oxazolidinones as claimed in Claim 1 having the following formula



and its pharmaceuticaliy acceptable salts, hydrates, hydrates of salts cf the kind such as herein described.
3. Process for preparing substituted oxazolidinones as claimed in
Claim 1, where
either according to a process alternative
[A] compounds of the general formula (II)



R T \ p6

in which
the radicals R2, R3, R4, R5, R6 and R 7 are each as defined in Claim 1 are reacted with carboxylic acids of the general formula (III)
138





in which
the radical R1 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 of the kind such as herein described, if appropriate in the presence of an activating or coupling agent and/or a base of the kind such as herein described, to give compounds of the general formula (I)


(I),

in which
the radicals R1, R2, R3, R4, R5, R6, R7 and R8 are each as defined in Claim 1,
or else according to a process alternative [B] compounds of the general formula (IV)



r,5 J.S

in which
the radicals R1, R3, R«, R5j R6? R7 and RS as defined in Claim 1,
are converted, using a suitable selective oxidizing agent of the kind such as herein described in an inert solvent of the kind such as herein described, into the corresponding epoxide of the general formula (V)


in which
the radicals R1, R3, R4 R5, R6,R7 and R8 are each as defined in Claim 1,
and, by reaction in an inert solvent of the kind such as herein described, if appropriate in the presence of a catalyst of the kind such as herein described, with an amine of the general formula (VI)
R2-NH2 (VI),
in which
the radical R2 is as defined in Claim 1,
the compounds of the general formula (VII)


in which
the radicals R1, R2, R3, R4, R5, R6, R7 and R8are each as defined in Claim
1,
140

are initially prepared and,
subsequently, in an inert solvent of the kind such as herein described in the presence of phosgene or phosgene equivalents, such as, for example, carbonyldiimidazole (CDI), cyclized to give the compounds of the general formula [\)


(I),

in which
the radicals R1, R2, R3, R4, R5, R6, R7 and R8are each as defined in Claim 1.
4. Medicaments, comprising at least one compound as defined in Claim 1 or 2 in a concentration of from 0.1 to 95% by weight of the total mixture and one or more pharmacologically acceptable auxiliaries or excipients of the kind such as herein described.

Dated this 11th day of June, 2002.
(RANJNA MEHTA-DUTT)
OF REMFRY & SAGAR
ATTORNEY FOR THE APPLICANTS
141














































FORM 2
THE PATENTS ACT 1970 [39 OF 1970]
86
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"OXAZOLIDINONES AND THEIR USE"
BAYER HEALTHCARE AG, a body corporate organized under the laws of Germany of 51368 Leverkusen, Germany,
The following specification particularly describes the invention and the manner in which it is to be performed:


The present invention relates to the field of blood coagulation. In particular, the
present invention relates to novel oxazolidinone derivatives, to processes for their
5 preparation and to their use as active compounds in medicaments.
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
10 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
15 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
20 fibrous/gelatinous coagulant. In addition, thrombin is a potent effector of platelet
aggregation which likewise contributes significantly to haemostasis.
Maintenance of normal haemostasis - between bleeding and thrombosis - is subject to . a complex regulatory mechanism. Uncontrolled activation of the coagulant system or
25 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,
30 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.
35 These thromboembolic disorders are the most frequent" cause of morbidity and
mortality in most industrialized countries (Pschyrembel, Klinisches Worterbuch



[clinical dictionary], 257th edition, 1994, Walter de Gruyter Verlag, page 199 ff.,
entry "Blutgerinnung" [blood coagulation]; R6rPPP Lexikon Chemie, Version 1.5,
1998, Georg Thieme Verlag Stuttgart, entry "Blutgerinnung"; Lubert Stryer,
Biochemie [biochemistry], Spektrum der Wisenschaft Verlagsgesellschaft mbH
5 Heidelberg, 1990, page 259 ff.).
The anticoagulants, i.e. substances for inhibiting or preventing blood coagulation,
which are known from the prior an have various, often grave disadvantages.
Accordingly, in practice, an efficient treatment method or prophylaxis of
10 thromboembolic disorders is very difficult and unsatisfactory.
In the therapy and prophylaxis of thromboembolic disorders, use is firstly made of heparin, which is administered parenterally of subcutaneously. Owing to more favourable pharmacokinetic properties, preference is nowadays more and more given
15 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,
20 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, 257th edition, 1994, Walter de Gruyter Verlag, page 610, entry "Heparin"; Rornpp Lexikon Chemie, Version 1.5, 1998, Georg Thieme Verlag Stuttgart, entry "Heparin").
25
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 coumafin derivatives which inhibit the synthesis of various products of certain vitamin K-dependent coagulation factors in
30 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
35 gastrointestinal disturbances, hair loss and skin necroses, have been described
(Pschyrembel, Klinisches Worterbuch, 257th edition, 1994, Walter de Gruyter Verlag,
3-3



ax
0 R1 . represents 2-thiophenc which is substituted in the 5-position by a radical from the group consisting of chlorine, bromine, methyl and trifluoromethyl,
R2 represents D-A-:
where:
the radical "A" represents phonylene;
the radical "D" represents a saturated 5~ or 6-membered heterocyclic,
which is attached to "A" via a nitrogen atom.
which has a carbonyl group directly adjacent In 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 0;
where
the group "A" defined above may optionally be mono- or disubstituted in the metaposition
with respect to the point of attachment to the oxazolidinone, by a radical fromthe group
consisting of fluorine, chlorine, nitro. amino, trilhioroinethyl, methyl andeyano,
R3; R4, R5, R6 R.7and R8each represent hydrogen
and their pharmaeeuticaily acceptable salts, hydrates. liydrates of sails.
except for compounds of the general formula (1) in which the radical R is an unsubstituted 2-thiopbene radical and the radical R" is simultaneously a mono- or polysubstituted phenyl radical and the radicals R~", R4, R5, R6, R7 and R are each simultaneously hydrogen.
Preference is given here to compounds of the. general formula (I),
in which
R represents optionally benzo-fused thiophenc (thienyl) which may optionally be mono- or polysubstituted by a radical from the group consisting of halogen; cyano; nitro; amino; aminomethyl; (C7-C8)-alkyl which for its part may optionally be mono- or polysubstituted bv halogen; (C3-C7)-eyeloalkyl:




(C1-C-8)-alkoxy; imidazolinyl; -C(=NH)NH2; carbamoyl; and mono- and di-(C1-C-4)-alkyl-aminocarbonyI,
R2 represents one of the groups below:
5 A-,
A-M-,
D-M-A-,
B-M-A-,
B-,
10 B-M",
B-M"B-, D-M-B-,
where:
15 the radical "A" represents ( 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
20 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,SO2,N,NO (N-oxide)and G,
25 the radical "M" represents -NH-, -CH2-, -CH2CH2-, -O-, -NH-CH2-,
-CH2-NH-, -OCHr, -CH2CK -CONH-, -NHCO-, -COO-, -OOC-, -S-, -S02- or represents a covalent bond;
where
30 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; (Cr C6)-alkanoyl; (C3-C7)-cycloalkanoyl; (C6-C14)-arylcarbonyl; (C5-C10)-heteroarylcarbonyl; (C1-C6)-alkanoyloxymethyloxy; (C1-C4)hydroxy-
35 alkylcarbonyl; -COOR27; -S02R27; -C(NR27R28)=NR29; -CONR28R29;
-SO2NR28R29; -OR30; -NR30R31, (CrC6)-alkyl and (C3-C7)-cycloalkyl,








where (C1-C6)-aIkyI and (C3-C7)-cycloalkyl for their part may optionally be substituted by a radical from the group consisting of cyano; -OR27; -NR28R29; -CO(NH)v(NR27R28) and
-C(NR27R28)=NR29,
where:
v is either 0 or 1 and
10
R27, R28 and R29 are identical or different and independently of one
another each represents hydrogen, (C1-C4)-alkyI1 (C3-C7)-
cycloalkyl, (C1-C4)-alkanoyl, carbamoyl, trifluoromethyl,
phenyl or pyridyl,
15 and/or
R27 and R28 or R27 and R29 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
20 two, identical or different heteroatoms from the group
consisting of N, O and S, and
R30 and R31 are identical or different and independently of one another
each represents hydrogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl,
25 (CrC4)alkylsuIphonyI, (C1-C4)-hydroxyaikyl, (CrC4)-
aminoalkyl, di-(C 1 -C4)-alkylamino-(C 1 -C4)-alkyl,
-CH2C(NR27R2S)=NR29 or -COR33,

where
30
.33
R33 represents (CrC6)-alkoxy, (C1-C4)-aIkoxy-(CI-C4)-
alkyl, (C1-C4)-aIkoxycarbonyl-(CI-C4)-alkyI, (CrC4>
aminoalkyl, (C1-C4)~alkoxycarbonyl, (C1-C4)-alkanoyl-
(Ci-C4)-alkyl, (C3-C7)-cycloalkylT (C1-C6)-alkenyl,
35 (Ct-Cg^alkyl, which may optionally be substituted by
7-






phenyl or acetyl, (C6-CI4)-aryl, (C5-C10)-heteroaryI, trifluoromethyl, tetrahydrofuranyl or butyrolactone,
R3, R4, R5, R6, R7 and R8 are identical or different and each represents hydrogen or represents (C1-C6)-alkyl
and their pharmaceutically acceptable salts, hydrates and prodrugs,

1
except for compounds of the general formula (I) in which the radical R is an
10 unsubstituted 2-thiophene radical and the radical R2 is simultaneously a mono- or
polysubstituted phenyl radical and the radicals R3, R4; R5, Rs, R7 and R8 are each
simultaneously hydrogen.

15
Preference is also given here to compounds of the general formula (I),
in which
R1 represents thiophene (thienyl), in particular 2-thiophene, which may
optionally be mono- or polysubstituted by halogen, preferably chlorine or
20 bromine, by amino, aminomethyl or (C1-C8)-alkyl, preferably methyl, where
the (C1-C8)-alkyl radical for its part may optionally be mono- or
polysubstituted by halogen, preferably fluorine,
R2 represents one of the groups below:
25 A-,
A-M-,
D-M-A-,
B-M-A-,
B-,
30 B-M-,
B-M-B-,
D-M-B-,

35

where:

5


the radical "A" represents (C6-C14)-aryl preferably (C6-C1o)-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
5 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, S02, N, NO
10 (N-oxide) and O;
the radical "M" represents -NH-, -CH2-, -CH2CH2-, -0~, -NH-CH2-, -CH2-NH-, -OCH2-, -CH20-, -CONH-, -NHCO-, -COO-, -OOC-, -S-or represents a covalent bond;
15 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; (C1-C6)-alkanoyl; (C3-C7)-cycloalkanoyl; (C6-C14)-
20 arylcarbonyl; (C5-C1o)-heteroarylcarbonyl; (C1-C6)-
alkanoyloxymethyloxy; -COOR27; -S02R27; -C(NR27R28)=NR29;
-CONR28R29; -S02NR28R29; -OR30; -NR30R31, (C1C6)-alkyl and (C3-
C7)-cycloaIkyl,
25 where (C1-C6)-alkyl and (C3-C7)-cycloalkyl for their part may
optionally be substituted by a radical from the group consisting of cyano; -OR27; -NR28R29; -CO(NH)v(NR27R28) and
-C(NR27R28)=NR29,
30 where:
v is either 0 or 1 and
R27, R28 and R29 are identical or different and independently of one
35 another each represents hydrogen, (C1-C4)-alkyl or (C3-C7)-
cycloalkyl,
9



and/or
R27 and R28 or R27 and R29 together with the nitrogen atom to which
they are attached form a saturated or partially unsaturated 5- to
5 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
R30 and R31 are identical or different and independently of one another 10each represents hydrogen,
alkylsulphonyl, aminoalkyl, (Ci-C4)~
alkanoyl,
15
R3, R4, R5, R6, R7 and Rs are identical or different and each represents hydrogen or represents (Ci-C6)-alkyl
and their phannaceutically acceptable salts, hydrates and prodrugs,
20
except for compounds of the general formula (I) in which the radical R1 is an unsubstituted 2-thiophene radical and the radical R is simultaneously a mono- or polysubstituted phenyl radical and the radicals R3, R4, R5, R6, R7 and Rs are each simultaneously hydrogen.
25
Particular preference is given here to compounds of the general formula (I),
in which - ,;J
30 R1 represents thiophene (thienyl), in particular 2-thiophene, which may
optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, or by (Ci-Cg)-alkyl, preferably methyl, where the (Ci-Cg)-alkyl radical for its part may optionally be mono- or polysubstituted by halogen, preferably fluorine,

35

R2 represents one of the groups below;

10


A-,
A-M-,
D-M-A-,
B-M-A-,
5 B-,
B-M-,
B-M-B-,
D-M-B-,
10 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;
15 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, SO2, N, NO
(N-oxide) and O;
the radical "M" represents -NH-, -O-, -NH-CH2-, -CH2-NH-, -OCHz-,
20 -CH2O-, -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
25 consisting of halogen; trifluoromethyl; oxo; cyano; pyridyl; (C1-C3)-
alkanoyl; (C6-Cio)-arylcarbonyI; (C5-C6)-heteroarylcarbonyl; (C1-C3)-
alkanoyloxymethyloxy; -C(NR27R28)=NR29; -CONR28R29;
-S02NR28R29; -OH; -NR30R31; (C1-C4)-alkyl; and cyclopropyl, cyclopentyl or cyclohexyl, 30
where (C1-C4)-alkyl and cyclopropyl, cyclopentyl or cyclohexyl for their part may optionally be substituted by a radical from the group consisting of cyano; -OH; -OCH3; -NR28R29; -CO(NH)v(NR27R28) and -C(NR27R28)=NR29, 35
where:
1)





v is either 0 or 1, preferably 0, and
R27, R28 and R29 are identical or different and independently of
5 one another each represents hydrogen, (C1-G4)-alkyl or
else cyclopropyl, cyclopentyl or cyclohexyl and/or
R27 and R28 or R27 and R29 together with the nitrogen atom to which
10 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
15 R30 and R31 are identical or different and independently of one another
each represents hydrogen, (Ci-GO-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C1-C4)-alkylsulphonyl, (C1-C4)-hydroxyalkyl, (C1-C4)-aminoalkyl, di-(C1-C4)-alkylamino-(C1-C4)-alkyl, (C1C3)-alkanoyl or phenylcarbonyl,

20
25
30

R3, R4, R5, R6, R7 and Rs are identical or different and each represents hydrogen or represents (C1-C6)-alkyl
and their pharmaceutically acceptable salts, hydrates and prodrugs,
except for compounds of the general formula (I) in which the radical R is an unsubstituted 2-thiophene radical and the radical R2 is simultaneously a mono- or polysubstituted phenyl radical and the radicals R3, R4, R5, R6, R7 and R8 are each simultaneously hydrogen.
Particular preference is given here to compounds of the general formula (I),
in which







R1 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,
5 R2 represents one of the groups below:
A-,
A-M-,
D-M-A-,
B-M-A-,
10 B-,
B-M-,
B-M-P-,
D-M-B-,
15 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;
20 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, SO2 and O; or contains up to two heteroatoms and/or hetero chain members from the group consisting of S, SO, SOx
25 and O;
the radical "M" represents -NH-, -O-, -NH-CH2-, -CH2-NH-, -OCH2-, -CH2O-, -CONH-, -NHCO- or represents a covalent bond;
where
30 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; (C1-C3)-alkanoyl; (C6-C10)-aryIcarbonyl; (C5-C6)-hetefoarylcarbonyl; (C1-C3)-alkanoyloxymethyloxy; -CONR28R29; -S02NR28R29; -OH; -NR30R31;
35 (C1-C4)-alkyl; and cyclopropyl, cyclopentyl or cyclohexyl,




may, in particular, represent a group of the following formula:
Y-X-(CH2),-X-(CO)n-(CH2)1-(CR9R10)m-(CH3)02-
where
m is an integer from 0 to 6, preferably from 1 to 3,
n is either 0 or 1,
p is an integer from 0 to 3, preferably either 0 or 1,
o{ is an integer 0 or J,
o2 is an integer 0 or 1,
R9 and R10 are identical or different and each represents hydrogen; (C1-C4)-alkyl, preferably methyl; (C1-C4)-alkoxy, preferably methoxy; (C3-C7)-cycloalkyl; hydroxyl or fluorine,
X and X" are identical or different and each represents O; N-R11 or a covalent bond,
where R11 represents H; (C1-C4)-aIkyI, preferably methyl, or (C3-C7)-cycloalkyl,
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 $O2,
where:
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; (C1-C4)-alkyl; -C(=NR12)NR13R!3"; and-NRI4R!5,
where:
R12 represents hydrogen, (C1-C4)-alkyl or (C3-C7)-cycloalkyl;
R13 and R13 are identical or different and independently of one another each represents hydrogen, (C1-C4)-alkyl or (C3-C7)-cycloalkyl
and/or
R13 and R13 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;
R14 and R15 are identical or different and independently of one another each represents hydrogen, (C1-C4)-alkyI, (C3-C7)-cyc]oalky) or (C1-C5)-alkanoyl;
and/or
this radical Y may furthermore optionally be substituted by a radical from the group consisting of oxo; cyano; thiono; halogen; -OR16; =NR16; -NR16R17; -C(=NR18)NRI9R19" and (C1C4)-alkyl,
in which (C1-C4)-alkyi for its part may optionally be substituted by a radical from the group consisting of hydroxyl; cyano; -NR16R17 and -C(=NR18)NR19R19",


18






where:
R16 and R17 are identical or different and independently of one another each represents hydrogen, (C1-C4)-alkyl, (C3-C7)-cycIoalkyI or (C1-C3)-alkanoyl;
R18 represents hydrogen, (C1-C4)-alkyl or (C3-C7)-cycloalkyl;
10
R19 and R19 are identical or different and independently of one
another each represents hydrogen, (C1-C4)-aIkyI or (C3-
C7)-cycloalkyl
and/or
15 R19 and R19 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, 0 and S.
20 Particular preference is given to compounds of the general fonnula (I) in which the
radical
R2 represents a group of the following fonnula:
25 Y-X"-(CH2)p-X-(CO)n-(CH2)Ol-(CR9Rl0)m-(CH2)o2-
where
m is an integer from 0 to 3, 30
n is an integer 0 or 1,
p is an integer 0 or 1,
35 01 is an integer 0 or 1,





19 —
02 is an integer 0 or 1,
R9 and R10 are identical or different and each represents hydrogen; methyl;
5
X and X" are identical or different and each represents O; N-R11 or a covalent
bond,
where R1" represents H or methyl,
10
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 SO2, in particular cyclohexyl, piperazinyl, morpholinyl,
15 thiomorpholinyl, diazepinyl, pyrrolidinyl and piperidinyl,
where:
this radical Y may optionally be substituted by a 5- or 6-membered
20 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
where this radical for its pan may be substituted by a radical from the
25 group consisting of cyano; hydroxyl; fluorine; chlorine; (C1-C4)-alkyl;
-C(=NR12)NR13R13"; and -NR14R15,
where:
30 R12 represents hydrogen, methyl, ethyl, cyclopropyl, cyclopentyl or
cyclohexyl;
R13 and R13 are identical or different and independently of one
another each represents hydrogen, methyl, ethyl, cyclopropyl,
35 cyclopentyl or cyclohexyl
and/or








R13 and R13" 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
5 and S, in particular piperidinyl, piperazinyl, morpholinyl and
thiomorpholinyl;
R14and R15 are identical or different and independently of one another
each represents hydrogen, methyl, ethyl, cyclopropyl,
. 10 cyclopentyl or cyclohexyi or else acetyl;
and/or
this radical Y may furthermore optionally be substituted by a
15 radical from the group consisting of oxo; cyano; thiono;
fluorine; chlorine; -OH; -OCH3; =NR16; -NH2; -N(CH3)2; -C(=NR18)NR19R19" and methyl,
in which methyl for its part may optionally be substituted by a
20 radical from the group consisting of hydroxyl; cyano; -NR16R17
and-C(=NRI8)NR19R19",
where:
25 R16 and R17 are identical or different and independently of one
another each represents hydrogen, methyl, (C3-C7)-cycloalkyl or acetyl;

30


R18 reprsents hydrogen, methyl or (C3-C7)-cycloalkyl;
R19 and R19" are identical or different and independently of one another each represents hydrogen, methyl or {C3-C7)-cycloalkyl and/or



35

21




-2*-=—=
R19 and R19" 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
5 piperidinyl, piperazinyl, morpholinyl and thio-
morpholinyl.
Likewise, in the compounds of the general formula (I), the radical
10 R2 may represent a group of the formula below:
Z-(CO)r(CR20R2I)s-
where; 15
s is an integer from 1 to 6,
t is either 0 or 1,
20 R20 and R21 are identical or different and each represents hydrogen, (C1-C4)-
alkyl, (C1-C4)-alkoxy, (C3-C7)-cycIoaIkyl, hydroxyl or fluorine,
Z represents a radical which is selected from the group consisting of cyano; -C(NR22R23)=NR24; -CO(NH)uNR22R23; and-NR25R26,
25
where:
u is either 0 or 1, preferably 0, and
30 R22, R23 and R24 are identical or different and independently of one
another each represents hydrogen, (C1-C4)-alkyI or (C3-C7)-cycloalkyl, preferably hydrogen or methyl, and/or
35 R22 and R23 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 SO2;
R25 and R26 are identical or different and independently of one another
5 each represents hydrogen, (C1-C4)-aIkyl or (C3-C7)-cycloalkyl,
preferably hydrogen, methyl or ethyl, where (C1-C4)-alkyl and (C3-C7)-cycloalkyl for their part may optionally be substituted by hydroxy! or (C1-C6)-alkoxy.
10 Furthermore, in the compounds of the general formula (I), the radical
R2 may represent one of the following groups:
A-,
A-M-,
15 D-M-A-,
B-M-A-,
B-,
B-M-,
B-M-B-,
20 D-M-B-,
where:
the radical "A" represents (C6-C14)-aryl, preferably (C6-C10)-aryl, in particular
25 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;
30 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, S02, N, NO (N-oxide)
and O;
the radical "M" represents -NH-, -CH2-, -CH2CB2-, -0-, -NH-CH2->
35 -CH2-NH-, -OCH2-, -CH20-, -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; (C1-C6)-alkanoyI; (C3-C7)-cycloalkanoyI; (C6-C14)-arylcarbonyl; (C5-C1o)-heteroarylcarbonyl; (C1-C6)-alkanoyloxymethyloxy; -COOR27; -S02R27; -C(NR27R28)=NR29; -CONR28R29; -S02NR28R29; -OR30; -NR30R31 (CrC6)-aIkyl and (C3-C7)-cycloalkyl,
10
where (C1-C6)-alkyl and (C3-C7)-cycloalkyl for their part may optionally be substituted by a radical from the group consisting of cyano; -OR ; -NR R ; -CO(NH)v(NR27R2s) and -C(NR27R28)=NR29,
15 where:
v is either 0 or 1 and
R27, R28 and R29 are identical ov different and independently of one another
20 each represents hydrogen, (C1-C4)-alkyl or (C3-C7)-cycloalkyl
and/or
R27 and R28 or R27 and R29 together with the nitrogen atom to which they are
attached form a saturated or partially unsaturated 5- to 7-membered
25 heterocycle having up to three, preferably up to two, identical or
different heteroatoms from the group consisting of N, O and S, and
R30 and R31 are identical or different and independently of one another each
represents hydrogen, (C1-C4)-aIkyl, (C3-C7)-cycloalkyl, (C1C4)-alkyl-
30 sulphonyl, (C1-C4)-hydroxyaIkyl, (C1C4)-aminoalkyl, di-(C1-C4)-
alkylamino-(C1-C4)-alkyl, (C1C4)-aIkanoyl, (C6-C14)-aryIcarbonyI,
(C5-C10)-heteroarylcarbonyl, (C1-C4)-alkylaminocarbonyl or
-CH2C(NR27R28)=NR29.
35 Preference is also given to compounds of the general formula (I) in which the radical



Infi-A ^4-P3-T6it;i!Hi Countries


-24-
R2 represents one of the groups below: A-, A-M-, D-M-A-, B-M-A-, B-, B-M-, B-M-B-, D-M-B-,

10
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)
15 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, S02l N, NO (N-oxide) and O;
20 the radical "M" represents -NH-, -O-, -NH-CH2-, -CH2-NH-, -OCH2-,
-CH20-, -CONH-, -NHCO- or represents a covalent bond;
where
the groups "A", "B" and "D" defined above may in each case optionally be
25 mono- or polysubstituted by a radical from the group consisting of halogen;
trifluoromethyl; oxo; cyano; pyridyl; (C1-C3)-alkanoyl; (C6-C10)-arylcarbonyl;
(C5-C6)-heteroarylcarbonyl; (C1-C3)-alkanoyloxymethyloxy;
-C(NR27R28)=NR29; -CONR28R29; -S02NR28R29; -OH; -NR30R31; (C1-C4)-alkyl; and cyclopropyl, cyclopentyl or cyclohexyl,
30
where (C1-C4)-alkyI and cyclopropyl, cyclopentyl or cyclohexyl for their part may optionally be substituted by a radical from the group consisting of cyano; OH; -OCH3; -NR28R29; -CO(NH)v(NR27R28) and -C(NR27R28)=NR29,
35 where:







v is either 0 or 1, preferably 0, and
R27, R28 and R29 are identical or different and independently of one another
each represents hydrogen, (C1-C4)-alkyl or else cyclopropyl,
5 cyclopentyl or cyclohexyl
and/or
R27 and R28 or R27 and R29 together with the nitrogen atom to which they are
attached may form a saturated or partially unsaturated 5- to 7-
10 membered heterocycle having up to two identical or different
heteroatoms from the group consisting of N, O and S, and
R30 and R31 are identical or different and independently of one another each
represents, hydrogen, (C1-C4)-alkyl, cyclopropyl, cyclopentyl,
15 cyclohexyl, (C1-C4)-alkyIsulphonyI, (C1-C4)-hydroxyalkyl, (C1-C4)-
aminoalkyl, di-(C1-C4)-alkylaminO-(C1-C4)-alkyl, (C1-C3)-alkanoyI or phenylcarbonyl.

20

Likewise, in the compounds of the general formula (I), the radical R2 may represent a group of the following formula:






25
30

R32 represents hydrogen or (C1-C4)-alkyl, preferably hydrogen or methyl, and
W represents S, NH or O, preferably S.
Moreover, in the compounds of the general formula (I), the radical
R2 may be a group of the formula below

26



where (C1-C4)-alkyl and cyclopropyl, cyclopentyl or cyclohexyl for their part may optionally be substituted by a radical from the group consisting of cyano; -OH; -OCH3; -NR28R29;-CO(NH)v(NR27R28) and -C(NR27R28)=NR29, 5
where:
v is either 0 or 1, preferably 0, and
10 R27, R28 and R29 are identical or different and independently of one
another each represents hydrogen, (C1-C4)-alkyl or else cyclopropyl, cyclopentyl or cyclohexyl and/or
15 R27 and R28 or R27 and R29 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
20
R30 and R31 are identical or different and independently of one another each represents hydrogen, (C1-C4)-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C1-C4)-alkylsulphonyl, (C1-C4)-hydroxyalkyl, (C1-C4)-aminoalkyl, di-(C1-C4)-aIkylarnino-
25 (C1-C4)-alkyl, (C1-C3)-alkanoyl or phenylcarbonyl,
R3, R4, R5, R6, R7 and R8 are identical or different and each represents hydrogen or represents (C1-C4)-alkyl
30 and their pharmaceutically acceptable salts, hydrates and prodrugs,
except for compounds of the general formula (I) in which the radical R1 is an
unsubstituted 2-thiophene radical and the radical R2 is simultaneously a mono- or
polysubstituted phenyl radical and the radicals R3, R4, R5, R6, R7 and R8 are each
35 simultaneously hydrogen.





--14-
Very particular preference is given here to compounds of the general formula (I),
in which
5 R1 represents 2-thiophene which is substituted in the 5-position by a radical from
the group consisting of chlorine, bromine, methyl and trifluoromethyl,
R2 represents D-A-:
10 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
15 atom and
in which one carbon ring member may be replaced by a heteroatom
from the group consisting of S, N and O;
where
20 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,
25 R3, R4, R5, R6, R7 and R8 each represent hydrogen
and their pharmaceutically acceptable salts, hydrates and prodrugs.
Very particular preference is also given here to the compound having the following
30 formula
/










NW

and to its pharmaceutically acceptable salts, hydrates and prodrugs.
In the compounds of the general formula (I) above, the radical 5
R1 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; (C1-C8)-alkyl, which for its part may
optionally be mono- or polysubstituted by halogen; (C3-C7)-cycIoalkyl;
10 (C1-C8)-alkoxy; imidazolinyl; -C(=NH)NH2; carbamoyl; and mono- and di-
(C1-C4)-alkylaminocarbonyI.
In the compounds of the general formula (I), the radical
15 R1 may preferably represent thiophene (thienyl), in particular 2-thiophene, which
may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, or by (C1-C8)-alkyl, preferably methyl, where the (C1-C8)-alkyl radical, preferably the methyl radical, may for its part optionally be mono- or polysubstituted by halogen, preferably fluorine.
20
In the compounds of the general formula (I), the radicals

R3, R4, R5, R6, R7 and R8 may be identical or different and may represent, in
particualr, hydrogen or (C1-C6)-alkyl, preferably hydrogen or (C1-C4)-alkyl,
25 very particularly preferably hydrogen.
The radical R2, i.e. the organic radical, can in particular be selected from the substituent groups listed below:
30 In the compounds of the general formula (I), the radical

6



5 Finally, in the compounds of the general formula (I), the radical
R2 may be a group of the formula below


10
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-
15 aminomethyl] group (preferably 5-[acetylarninoinethyl]) appears to be essential for
the antibacterial activity.
Substituted aryl- and heteroarylphenyloxazolidinones in which a mono- or
polysubstituted phenyl radical may be attached to the N atom of the oxazolidinone
20 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. Patents US-A-5 929 248, US-A-5 801 246, US-A-5 756 732, US-A-5 654 435, US-A-5 654 428 and US-A-5 565 571.
25 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).
Depending on the substitution pattern, the compounds of the general formula (I)
30 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





27
(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.
5 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.
Physiologically acceptable, i.e. pharmaceutically compatible, salts can be salts of the
10 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
15 acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid,
benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
Other pharmaceutically compatible salts which may be mentioned are salts with
customary bases, such as, for example, alkali metal salts (for example sodium or
20 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, dibenzylarnine, N-methylmorpholine, dihydroabietylamine or methylpiperidine.
25 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
30 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.
According to the invention, "prodrugs" are forms of the compounds of the general
35 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).
Halogen represents fluorine, chlorine, bromine and iodine. Preference is given to
5 chlorine or fluorine.
(C1-C8)-Alkvl represents a straight-chain or branched alkyl radical having 1 to S 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
10 fewer carbon atoms, such as, for example, (C1-C6)-aIkyI and (C1-C4)-alkyl, are derived
analogously from this definition. In genera], preference is given to (C1-C4)-alkyl
The meaning of the corresponding component of other more complex substituents,
such as, for example, alkvlsulphonyl. hvdroxvalkvl. hvdroxyalkvlcarbonvl, alkoxy-
15 alkyl, alkoxvcarbonvl-alkvl alkanoylalkyl, aminoalkvl or alkylaminoalkyl is likewise
derived from this definition.
(C3-C7)-CvcloaIkvl represents a cyclic alkyl radical having 3 to 7 carbon atoms.
Examples which may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl,
20 cyclohexyl or cycloheptyl. The corresponding cycloalkyl groups having fewer carbon
atoms, such as, for example, (C3-C5)-cycloalkyl, are derived analogously from this definition. Preference is given to cyclopropyl, cyclopentyl and cyclohexyl.
The meaning of the corresponding component of other more complex substituents,
25 such as, for example, cvcloalkanoyl, is likewise derived from this definition.
In the context of the invention, (C2-C6)-alkenvl 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
30 mentioned are; vinyl, allyl, isopropenyl and n-but-2-en-l-yI.
(C1-C8)-Alkoxv 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
35 n-octoxy. The corresponding alkoxy groups having fewer carbon atoms, such as, for







example, (C1-C6)-alkoxy and (C1-C4)-Alkoxy, are derived analogously from this definition. In general, preference is given to (C1-C4)-alkoxy.
The meaning of the corresponding component of other more complex substituents,
5 such as, for example alkoxy-alkyl. alkoxvcaibonvl-alkvl and alkoxycarbonyl. is
likewise derived from this definition.
Mono- or di-(C1-C4)-alkylaminocarbonvl represents an amino group which is attached via a carbonyl group and which has a straight-chain or branched or two identical or
10 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.
15
(C1-C6)-Alkanovl 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
20 groups with fewer carbon atoms, such as, for example, (C1-C5)-alkanoyl,
(C1-C4)-alkanoyl and (C1-C3)-alkanoylr are derived analogously from this definition. In general, preference is given to (C1-C3)-alkanoyl.
The meaning of the corresponding component of other more complex substituents,
25 such as, for example, cvcloalkanoyl and alkanovlalkvl. is likewise derived from this
definition.
(C3-C7)-Cycloalkanovl represents a cycloalkyl radical having 3 to 7 carbon atoms .as, defined above which is attached via a carbonyl group.
30
(C1-C6)-AlkanovloxymethvIoxv represents a straight-chain or branched alkanoyloxymethyioxy radical having 1 to 6 carbon atoms. Examples which may be mentioned are: acetoxymethyloxy, propionoxymethyloxy, n-butyroxymethyloxy, i-butyroxymethyloxy, pivaloyloxymethyloxy, n-hexanoyloxymethyloxy. The
35 corresponding alkanoyloxymethyioxy groups having fewer carbon atoms, such as, for

30


example, (CrC3)-aIkanoyIoxymethyloxy, are derived analogously from this definition, In general, preference is given to (C1-C3)-alkanoyloxymethyloxy.
(C6-C14)-Aryl represents an aromatic radical having 6 to 14 carbon atoms. Examples
5 which may be mentioned are: phenyl, naphthyl, phenanthrenyl and anthracenyl. The
corresponding aryl groups with fewer carbon atoms, such as, for example, (C6-C1o)-aryl are derived analogously from this definition. In general, preference is given to (C6-C10)-aryl
10 The meaning of the corresponding component of other more complex substituents,
such as, for example, arylcarbonyl. is likewise derived from this definition.
(C5-C10)-Heteroarvl 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
15 (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, thiazotyl, oxazolyl or isoxazolyl, indolizinyl, indolyl, benzofbjthienyl, benzo[b]fuiyl,
20 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.
25
The meaning of the corresponding component of other more complex substituents, such as, for example, (C5-C10)-heteroarvlcarbonyl is likewise derived from this definition.
30 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. SO2, N. NO (N-oxide) and Q 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
35 which is attached via a carbon ring atom or a mtrogen 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, 1,4-diazepinyl and cyclohexyi. Preference is given to piperidinyl, morpholinyl and pyrrolidinyl.
5 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
10 alternative
[A] compounds of the general formula (II)

O
R R8
15
in which
the radicals R2, R3, R4, R5, R6 and R7 are each as defined above,
20 are reacted with carboxylic acids of the general formula (HI)

HO^.R1 (HI),


25

in which
the radical R1 is as defined above,

32-




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 (HI) 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)


(D,

10 in which
the radicals R\ R2, R3, R4, R5, R6, R7 and R8 are each as defined
above,

15 or else according to a process alternative
[B] compounds of the general formula (IV)


R3 R6 R7 Q

20
in which
the radicals R1, R3, R4, R5, R6, R7 and R8 are each as defined above,
25 are converted, using a suitable selective oxidizing agent in an inert solvent,
into the corresponding epoxide of the general formula (V)
33








R3 R6 B7 ft


in which
the radicals R1, R3, R4, R5, R6, R7 and R8 are each as defined above,
and, by reaction in an inert solvent, if appropriate in the presence of a catalyst, with an amine of the general formula (VI)

10
R2-NH2 (VI),
in which
15 the radical R2 is as defined above,


the compounds of the general formula (VII) R4 R3 R6 R7 ft
20
in which

25

the radicals R1, R2, R3, R4, R5, R6, R7 and R8 are each as defined above,
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
30 give the compounds of the general formula (I)




~?A~-



in which
5 the radicals R1, R2, R3, R4, R5, R6, R7 and R8 are each as defined
above,
where - both for process alternative [A] and for process alternative [B] - in
the case where R2 contains a 3- to 7-membered saturated or partially
10 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
15 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
20 follow
and/or
where - both for process alternative [A] and for process alternative [B] - in the
25 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
30





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

10

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 iicid and subsequent reaction with amines to give the corresponding sulphonamides may follow.

15 The processes according to the invention can be illustrated in an exemplary manner
by the equations below:












The oxidation step described above, which is optional, can be illustrated in an
5 exemplary manner by the equation below:

Suitable solvents for the processes described above are organic solvents which are
10 inert under the reaction conditions. These include halogenated hydrocarbons, such as
dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane,
trichloroethane, tetrachloroethane, 1,2-dichIoroethyIene 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,
15 n-butanol or tert-butanol, hydrocarbons, such as benzene, xylene, toluene, hexane or
cyclohexane, dimethylformamide, dimethyl sulphoxide, acetonitrile, pyridine, hexa-methylphosphoric triamide or water.
It is also possible to use solvent mixtures of the solvents mentioned above.
20





37
Suitable activating or coupling agents for the processes described above are the reagents which are customarily used for this purpose, for example N"-(3-dimemyIaminopropyI)-N-ethylcarbodiimide . HO, N,N"-dicyclohexylcarbo-diimide, 1-hydroxy-lH-benzotriazole • H20 and the like. 5
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
10 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-dimethylamino-pyridine or pyridine.
15 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).
The reactions are generally carried out in a temperature range of from -78°C to reflux temperature, preferably in the range from 0°C to reflux temperature. 20
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,
25 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.
30 With respect to the preparation of the epoxides, the preparation conditions which are
customary for this purpose are employed.
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:
35 M. R. Barbachyn et al., J. Med. Chem. 1996,39, 680 and WO-A-97/10223.





Furthermore, reference is made to Examples 14 to 16 given in the experimental part.
The optional amidation is carried out under customary conditions. For more details, reference is made to Examples 31 to 35 and 140 to 147. 5
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 etal., J.Med,
10 Chem. 1998, 41, 3727; S.J.Brickner etal., J.Med Chem. 1996, 39, 673;
W. A. Gregory et al., J. Med. Chem. 1989,32,1673.
The compounds of the general formula (I) according to the invention have an
unforeseeabte useful pharmacological activity spectrum and are therefore parrkttlarYy
15 suitable for the prophylaxis and/or treatment of disorders.
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
20 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
25 occlusion disorders, pulmonary embolisms or deep venous thromboses.
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
30 coagulation (DIC).
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
35 atherosclerosis and arthritis, and additionally also for the prophylaxis and/or
treatment of Alzheimer"s disease and cancer.
39


4frA-34^l2i-froreign Lountrfes


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
5 inhibit, or only inhibit at considerably higher concentrations, other serine proteases as
well, such as thrombin, plasmin or trypsin.
In the context of the present invention, inhibitors of the blood coagulation factor Xa in which the IC50 values for the factor Xa inhibition are lower by a factor of 100,
10 preferably by a factor of 500, in particular by a factor of 1000, than the IC50 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-l) a.l) and a.2) described below.
15
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,
20
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,
25
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
30 the indications mentioned above.
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
35 to the invention - including the compounds excluded by disclaimer from the chemical
product protection.




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
5 formula (I) - including the compounds excluded by disclaimer from the chemical
product protection - are added.
All customary administration forms are suitable for administration of the compounds according to the invention. Administration is preferably carried out orally, lingually,
10 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
15 disorders.
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-
20 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.
25
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
30 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.
35 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.
In general it has proved advantageous in the case of intravenous administration to
5 administer amounts from approximately 0,001 to 10 mg/kg, preferably approximately
0.01 to 10 mg/kg, in particular approximately 0.1 to 8mg/kg, of body weight to
achieve effective results.
In general, it has proved advantageous in the case of oral administration to administer
10 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.
In spite of this, if appropriate, it may be necessary in the case of intravenous or oral
15 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 mininum amount, while in other cases the upper limit
20 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.
Compared to the conventional preparations for treating thromboembolic disorders,
25 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.
30 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.
35 The present invention is illustrated by the examples below; however, these examples
are not meant to restrict the invention in any way.





-"42- "
Examples
A Evaluation of the physiological activity
5 1. General test methods
The particularly advantageous biological properties of the compounds according to the invention can be determined by the following methods.
10 a) Test description (in vitro)
a.l) Determination of the factor Xa inhibition
The enzymatic activity of human factor Xa (FXa) was measured using the conversion
15 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.
The test substances, in various concentrations, were dissolved in DMSO and
20 incubated at 25°C with human FXa (0.5 nmol/l dissolved in 50 mmol/1 of tris buffer
[C,C,C-tris(hydroxymethyl)-aminomethane], 150 mmol/1 of NaCI, 0.1% BSA
(bovine serum albumin), pH = 8.3) for 10 minutes. Pure DMSO was used as control.
The chromogenic substrate (150 /imol/1 of Pefachrome® FXa from Pentapharm) was
then added. After an incubation time of 20 minutes at 25°C, the extinction at 405 nm
25 was determined. The extinctions of the test mixtures containing test substance were
compared with the control mixtures without test substance, and the IC5o values were
calculated from these data.
- ^
a.2) Determination of the selectivity
30
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/l), these enzymes were dissolved in tris buffer (100 mmol/1,
35 20 mmol/1 CaCl2, pH = 8.0) and incubated with test substance or solvent for 10
minutes. The enzymatic reaction was then started by adding the corresponding





removed and the nylon thread with the thrombus was weighed immediately. The weight of the nylon thread on its own had been detennined 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.




specific chromogenic substrates (Chromozym Thrombin® from Boehringer
Mannheim, Chromozym Trypsin® from Boehringer Mannheim, Chromozym
Plasmin® from Boehringer Mannheim) and the extinction at 405 nm was determined
after 20 minutes. All determinations were carried out at 37°C. The extinctions of the
5 test mixtures containing test substance were compared with the control samples
without test substance, and the IC50 values were calculated from these data.
a3) Determination of the anticoagulant action
10 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
15 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® from Boehringer Mannheim). The test compounds were incubated with the plasma at 37°C for 10 minutes. Coagulation was then started by addition of thromboplastin, and the time when coagulation occurred
20 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)
25 b.l) Arteriovenous shunt model (rat)
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
30 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
35 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



LfrA-3+i23=Fb15i"gn countries
45-
The results are shown in Table 1:
Table 1: Antithrombotic activity in the arteriovenous shunt model (rat) after oral or intravenous administration


Example ED56 [mg/kfi] p.o. ED50 [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)
Male fasting rats (strain: HSD CPB: WU) were anaesthetized as described above. On
10 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°C in a metal
15 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 ofthe
20 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.
25





b.3) Venous thrombosis model (rat)
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
5 (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°C in a metal trough for 2 minutes and, to standardize the size of the thrombi, simultaneously compressed
10 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
15 tube.





B Preparation Examples Starting materials
5 The preparation of 3-morphoIinone is described in US 5 349 045.
The preparation of N-(2,3-epoxypropyI)phthalimide is described in J.-W. Chcm et al. Tetrahedron Lett. 1998,39,8483.
10 The substituted anilines can be obtained by reacting, for example, 4-fluoronitro-
benzene, 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)2/DPPF/NaOt-Bu (Tetrahedron Lett 1999,40,2035) or copper (Kenger, Synthesis 1985.856; Aebischer et a]., Heterocycles 1998,48,2225).
15 Likewise, it is possible to initially convert halogenated aromatics without nitro group
into the corresponding amides, followed by nitration in the 4-position (US3279880).
I. 4-(4-Morpholin-3-onyl)nitrobenzene

NO,

rV°
20 O
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
25 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°C, 1,71 of the liquid volume are then distilled off, the residue is poured into 2 1 of water and this mixture is extracted twice with in each case 11 of ethyl acetate. After washing of the combined organic phases with water, the mixture is dried over sodium sulphate and
30 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









10
15

from ethyl acetate. This gives 78 g of product as a colourless to brownish solid, in a
yield of 17.6% of theory.
"H-NMR (300 MHz, CDC13): 3,86 (m, 2 H, CH2CH2), 4.08 (m, 2 H, CH2C#2), 4.49
(s, 2H, CH2CO), 7.61 (d, 2H, 3/=8.95 Hz, CHCH), 8.28 (d, 2H, 37=8.95Hz,
CHCtf)
MS (r.L%) = 222 (74, M+), 193 (100), 164 (28), 150 (21), 136 (61), 117 (22), 106
(24), 90 (37), 76 (38), 63 (32), 50 (25)
The following compounds were synthesized analogously: 3-fluoro-4-(4-morpholin-3-onyl)nitrobenzene 4-(N-piperidonyl)nitrobenzene 3-fluoro-4-(N-piperidonyl)nitrobenzene 4-(N-pyrrolidonyl)nitrobenzene 3-fluoro-4-(N-pyrrolidonyl)nitrobenzene
II. 4-(4-Morpholin-3-onyI)aniline


In an autoclave, 63 g (0.275 mol) of 4-(4-morpholin-3-onyl)nitrobenzene are
20 dissolved in 200 ml of tetrahydrofuran, admixed with 3.1 g of Pd/C (5%ig) and
hydrogenated at 70°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. 25
Purification can also be carried out by silica gel chromatography using hexane/ethyl acetate.
]H-NMR (300 MHz, CDC13): 3.67 (m, 2 H, CH2CH2), 3.99 (m, 2 H, CH2CH2), 4.27
(s, 2H, CH2CO), 6.68 (d, 2H, 3/=8.71 Hz, CHCH), 7.03 (d, 2 H, 3/=8.71 Hz,
30 CHCH)









10

MS (r.L%) = 192 (100, M+), 163 (48), 133 (26), 119 (76), 106 (49), 92 (38), 67 (27), 65 (45), 52 (22), 28 (22)
The following compounds were synthesized analogously: 3-fluoro-4-(4-morpholin-3-onyl)aniIine 4-(N-piperidonyI)aniline 3-fluoro-4-(N-piperidonyl)aniline 4-(N-pyrrolidonyl)aniline 3-fluoro-4-(N-pyrrolidonyl)aniline
General method for preparing 4-substituted anilines by reacting l-fluoro-4-nitrobenzenes and l-chloro-4-nitrobenzenes with primary or secondary amines, followed by reduction







15 X = F.CI
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°C overnight. After cooling to RT, the reaction mixture is
20 diluted with ether and washed with water. The organic phase is dried over MgSO4,
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-
25 and dichloromethane/ethanol mixtures).
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
30 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).





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°C, six
equivalents of iron powder and water (0.3 to 0.5 times the volume of the acetic acid)
5 are added a little at a time over a period of 10-15 rnin. After a further 30 min at 90°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
10 preparative reversed-phase HPLC (acetonitrile/water mixtures).
The following starting materials were prepared in an analogous manner:
III-l. tert-butv1-1-(4-aminophesyl)-L-proIinate
15 MS (ESI): m/z (%) = 304 (M+H+MeCN, 100), 263 (M+H, 20);
HPLC (method 4): rt = 2.79 min.
III-2. l-(4-aminoDhenvl)"3-piperidinecarboxamide
MS (ESI): m/z (%) = 220 (M+H, 100);
20 HPLC (method 4): rt = 0.59 min.
1H-3. l-(4-aminophenvl)-4-piperidincarboxamide
MS (ESI): m/z (%) = 220 (M+H, 100); HPLC (method 4)-. rt = 0.57 min. 25
III-4. l-(4-aminophenvl)-4-piperidinone MS (ESI): m/z (%) = 191 (M+H, 100); HPLC (method 4): n = 0.64 min.
30 III-5. l-(4-aminophenvl)-L-prolinamide
MS (ESI): m/z (%) = 206 (M+H, 100); HPLC (method 4); rt = 0.72 min.
III-6. [1-(4-anninophenvl)-3-piperidinvl]methanol
35 MS (ESI): m/z (%) s 207 (M+H, 100);
HPLC (method 4): rt - 0.60 min.




III-7. [1-(4-aminophenvl)-2-Diperidinvl1methanol
MS (ESI): m/z (%) = 207 (M+H, 100); HPLC (method 4): rt = 0.59 min. 5
III-8. ethvl l-(4-aminophenvl)-2-piperiduiecarboxylate
MS (ESI): m/z (%) = 249 (M+H, 35), 175 (100); HPLC (method 4): rt = 2.43 min.
10 III-9, [1-(4-aminophenvI)-2-pvrroIidinynmethanol
MS (ESI): m/z (%) = 193 (M+H, 45); HPLC (method 4): rt = 0.79 min.
111-10. 4-(2-methvlhexahvdro-5H-Pvrrolor3.4:d]isoxazol-5-vl)phenviamine
15 starting from 2-methylhexahydro-2H-pyrrolo[3,4-d]isoxazoIe (Ziegler, Carl B., et al.;
J. Heterocycl Chem.; 25; 2; 1988; 719-723) MS (ESI): m/z (%) = 220 (M+H, 50), 171 (100); HPLC (method 4): rt = 0.54 min.
20 III-11. 4-(l-pvrrolidinvI)-3-(trifluoromethvl)aniline
MS (ESI): m/z (%) = 231 (M-fH, 100); HPLC (method 7): rt = 3.40 min.
III-12. 3-chloro-4-(l-pvrrolidinyl)aniIine
25 MS (ESI): m/z (%) = 197 (M+H, 100);
HPLC (method 4); rt = 0.78 min.
111,-13. 5-amino-2-(4-morpholinvl)benzamide
MS (ESI): m/z (%) = 222 (M+H, 100);
30 HPLC (method 4): rt = 0.77 min.
111-14. 3-methoxv-4-(4-morDholinvI)aniline
MS (ESI): m/z (%) = 209 (M+H, 100); HPLC (method 4): rt = 0.67 min. 35
111-15. l-f5-aminO-2-(4-morpholinvl)phenvIlethanone







MS (ESI): m/z (%) = 221 (M+H, 100); HPLC (method 4): rt = 0.77 min,

General method for preparing 4-substituted anilines by reacting l-fluoro-4-
5 nitrobenzenes with amides, followed by reduction
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 l-fluoro-4-
10 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).
15
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
20 (dichloromethane/ethanol mixtures) or preparative reversed-phase HPLC
(acetonitrile/water mixtures).
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°C; six
25 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°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
30 can be purified by silica gel chromatography (dichloromethane/ethanol mixtures) or
preparative reversed-phase HPLC (acetonitrile/water mixtures).





The following starting materials were prepared in an analogous manner:
IV-1, l-[4-amino-2-(trifluoromethyl)phenyl]-2-PvrroIidinone
MS (ESI): m/z (%) = 245 (M+H, 100);
5 HPLC (method 4): rt = 2.98 min
IV-2. 4-[4-amino-2-(trifluoromethyl)phenvl]-3-morpholinone
MS (ESI): m/z (%) = 261 (M+H, 100); HPLC (method 4): it = 2.54 min. 10
IV-3. 4-(4-amino-2-chlorophenyl)"3-morpholinone
MS (ESI): m/z (%) = 227 (M+H, 100); HPLC (method 4): rt = 1.96 min.
15 IV-4. 4-(4-amino-2-methylphenvl)-3-morpholinone
MS (ESI): m/z (%) = 207 (M+H, 100); HPLC (method 4): rt = 0.71 min.
IV-5. 5-amino-2-(3-oxo-4-morpholinvl)benzoilitrile
20 MS (ESI): m/z (%) = 218 (M+H, 100);
HPLC (method 4): rt = 1.85 min.
IV-6. l-(4-ajnino-2-chlorophenvl)-2-pvrrolidinone
MS (ESI): m/z (%) = 211 (M+H, 100);
25 HPLC (method 4): rt = 2,27 min.
IV-7. 4-(4-aniino-2.6-dimethvlphenvl)-3-morpholinone
starting from 2-fluoro-l,3-dimethyl-5-nitrobenzene (Bartoli et al., J. Org. Cherry
1975,40, 872):
30 MS (ESI): m/z (%) = 221 (M+H, 100);
HPLC (method 4): rt = 0.77 min.
IV-8. 4-(2,4-diaminophenvI)-3-_morpholinone
starting from l-fluoro-2,4-drnitrobenzene:
35 MS (ESI): m/z (%) = 208 (M+H, 100);
HPLC (method 4): rt = 0.60 min.





IV-9. 4-(4-amino-2-chlorophenyl)-2-methvl-3-morpholinone
starting from 2-methyl-3-morpholinone (Pfeil, E.; Harder, U.; Angew. Chem. 1967,
79,188):
5 MS (ESI): m/z (%) = 241 (M+H, 100);
HPLC (method 4); rt = 2.27 min.
IV-10. 4-(4-amino-2-chloropheny)-6-methvl-3-morphollone
starting from 6-methyl-3-morpholinone (EP 350 002):
10 MS (ESI): m/z (%) = 241 (M+H, 100);
HPLC (method 4): rt - 2.43 min.





Synthesis Examples
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-morpholinophenyI)-2-oxo-l,3-oxazolidin-5-yI]methyl}-2-thiophenecarboxamide

10
(5S)-5-(Aminomethyl)-3-(3-fluoro-4-morpholinophenyl)-lt3-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
15 1-hydroxy-lH-benzotriazole hydrate (HOBT) (0.3 g7 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 (EDO) 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
20 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°C. Rf (Si02, toluene/ethyl acetate 1:1) = 0.29 (starting material = 0.0);
25 MS (DCI) 440.2 (M+H), CI pattern;
"H-NMR (D6VDMSO, 300 MHz) 2.95 (m, 4H), 3.6 (t, 2H), 3.72 (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).




LftA-34 122^FefektQ-Countries





Example 2
5-Chloro-N-{[(5S)-3-(4-morphoIinophenyl)-2-oxo-13-oxazoIidin-5-yl]methyl}-2-thiophenecarboxamide



is obtained analogously from benzyl 4-morpholinophenylcarbamate via the (5S)-5-
(aminomethyI)-3-(3-fluorc-4-morpholinophenyl)-l,3-oxazolidin-2-one intermediate
(see Example 1).
M.p.: 198°C;
10 IC50 value = 43 nM;
Rf (Si02, toluene/ethyl acetate 1:1) = 0.24.
Example 3
15 5-Chloro-N-({(5S)-3-[3-fluoro-4-(l,4-thiazinan-4-yI)phenyl]-2-oxo-l,3-oxazoIi-
din-5-yl}methyl)-2-thiophcnecarboxamide




is obtained analogously from (5S)-5-(aminomethyl)-3-[3-fluoro-4-(l,4-thiazinan-4-
20 yl)phenyl]-l,3-oxazolidin-2-one (preparation see M. R. Barbachyn et ah, J, Med.
Chem. 1996,39, 680). M.p.: 193°C; Yield: 82%; Rf (Si02, toluene/ethyl acetate 1:1) = 0.47 (starting material =0.0).
25





Example 4
5-Bromo-N-({(5S)-3-[3-fluoro-4-(l,4-thiazinan-4-yl)phenyI]-2-oxo-l,3-oxazolidin-5-yI}methyl)-2-thiophenecarboxamide



is obtained analogously from 5-bromothiophene-2-carboxylic acid. M.p.: 200°C.
10 Example 5

15

N-({(5S)-3-[3-Fluoro-4-(l,4-thia2inan-4-yl)phenyl]-2-oxo-13-oxazolidin-5-yl}methyI)-5-methyI-2-thiophenecarboxamide

Fv Q
S\J*-\J~\ 1 CH.






Example 6
5-ChIoro-N-{[(5S)-3-(6-methylthieno[2r3-b]pyrldin-2-yl)-2-oxo-l73-oxazoIidin-5. yl]methyl}-2-thiopheriecarboxarnide

is obtained analogously from (5S)-5-(aminomethyl)-3-(6--niethylthieno[213-b]pyridin-2-yl)-l,3-oxazolidin-2-one (preparation see EP-A-785 200). M.p.: 247°C.
Example 7
5-Chloro-N-{[(5S)-3-(3-methyl-2-oxo-2,3-dihydro-l,3-benzothiazol-6-yI)-2-oxo-l,3-oxazolidin-5-yI]methyl}-2-thiophenecarboxomide

is obtained analogously from 6-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazoIidin-3-yl]-3-methyl-l,3-benzothiazoI-2(3H)-one (preparation see EP-A-738 726). M.p.:217°C.




Example 8
5-Chloro-N.[((5S)-3-{3-fluoro-4-[4-(4-pyridinyl)piperazino]phenyl}-2-oxo-l,3-oxazoIidin-5-yI)methyI]-2-thiophenecarboxamide
5

o
is obtained analogously from (5S)-5-(aminomethyl)-3-{3-fluoro-4-[4-(4-
pyridinyl)piperazino]phenyl}-l,3-oxazolidin-2-one (preparation analogously to J. A.
Tucker et al., J. Med. Chem. 1998, 41, 3727).
10 MS (EST) 516 (M+H),C1 pattern.
Example 9
5-Chloro-N-({(5S)-3-[3-fluoro-4-(4-methylpiperazino)phenyI3-2-oxo-l,3-oxazoli-
15 dm-5-yl}methyI)-2-thiophenecarboxamide

O is obtained analogously from (5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-methylpiperazino)phenyl]-l73-oxazolidin-2-one.

20






Example 10
5-Chloro-N-({(5S)-3-[3-fluoro-4-(4-tert-butoxycarbonyIpiperazin-l-yI)phenyI]-2-oxo-l^-oxazoIidin-5-yI}methyl)-2-thiophenecarboxamide
5




a o"
is obtained analogously from (5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-tert-butoxy-
carbonylpiperazin-l-yl)phenyl]-l,3-oxazoIidin-2-one (preparation see
WO-A-93/23384, which has already been cited).
10 M.p.: 184°C;
Rf(Si02, toluene/ethyl acetate 1:1) = 0.42.
Example 11
15 5-Chloro-N-({(5S)-3-[3-fluoro-4-(piperazin-l-yl)phenyl]-2-oxo-l,3-oxazoIidin-5-
yl}methyl)-2-thiophenecarboxamide


C! O"

is obtained by reacting Example 12 with trifluoroacetic acid in methylene chloride.
20 IC5o value = 140 nM;








4H-NMR [d6-DMSO]: 3.01-3.25 (m, SH), 3.5-3.65 (m, 2H), 3.7-3.9 (m, IH), 4.05-4.2 (m, IH), 4.75-4.9 (m, IH), 7.05-7.25 (m, 3H), 7.5 (dd, IH), 7.7 (d, IH), 8.4 (broad s, IH), 9.0 (t, IH).
Example 12
5-Chloro-N-[((5S)-3-(2?4-bipyiridinyl-5-yI)-2-oxo-1,3-oxazolidin-5-yI)methyl]-2-thiophenecarboxamide

10
15


is obtained analogously from (5S)-5-aminomethyl-3-(2,4-bipyridinyl-5-yI)-2-oxo-l,3-oxazolidin-2-one (preparation see EP-A-789 026). Rf (Si02, ethyl acetate/ethanol 1:2) = 0.6; MS (ESI) 515 (M+H), C\ pattern.
Example 13
5-Chloro-N-{[(5S)-2-oxo-3-(4-piperidinophenyl)-l,3-oxazolidin-5-yl3methyI}-2-thiophenecarboxamide

20





■-^62-
is obtained from 5-(hydroxymethyl)-3-(4-piperidinophenyl)-13-o\azolidin-2-one
(preparation see DE 2708236) after mesylation, reaction with potassium phthalimide,
hydrazinolysis and reaction with 5-chIorothiophene-2-carboxylic acid.
Rf (Si02, ethyl acetate/toluene 1:1) = 0,31;
5 m.p. 205°C.
Example 17
S-Chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-l-pyrroIidinyl)phenyl]-l^-oxazolidin-5-
10 yl}methyI)-2-thiophenecarboxamide


Analogously to the known synthesis scheme (see S.J Brickner et al., J. Med. Chem. 1996, 39, 673), l-(4-aminophenyl)pytrolidin-2-one (preparation see Reppe et al.,
15 Justus Liebigs Ann. Chem.; 596; 1955; 209) gives, after reaction with
benzyloxycarbonyl chloride, followed by reaction with i?-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- l-pyrrolidinyl)phenyl]-1,3-oxazolidhv5-yl }methyl)-2-thio-
20 phenecarboxamide. The 5-chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-l-pyrrolidinyI)-
phenyl]-l,3-oxazoIidin-5-yl}methyl)-2-thiophenecarboxamide obtained in this
manner has an IC50 value of 4 nM (test method for the IC50 value according to
Example A-l.a.1 described above) "determination of the inhibition of factor Xa").
M.p.:229°C; v
25 Rf value (SiO2, toluene/ethyl acetate 1:1) = 0.05 (starting material: = 0.0);
MS (ESI): 442.0 (21%, M+Na, CI pattern), 420.0 (72%, M+H, CI pattern), 302.3 (12%), 215(52%), 145 (100%);
"H-NMR (d6-DMSO, 300 MHz): 2.05 (m,2H), 2.45 (m,2H), 3.6 (t,2H), 3.77-3.85 (m,3H), 4.15(t,lH), 4.75-4.85 (m,lH), 7.2 (d,lH), 7.5 (d,2H), 7,65 (d,2H), 7.69
30 (d,iH),8.96(t,lH).














The following compounds were prepared in an analogous manner
Example 18
5
yI}methyI)-2-thiophenecarboxamide
Analogously to Example 17, 4-pyrroIidin-l-yl-aniIine (Reppe et al., Justus Liebigs
Ann. Chem.; 596; 1955; 151) gives the compound 5-chloro-N-({(5S)-2-oxo-3-[4-(l-
10 pyrrolidinyl)phenyl]-l,3-oxazolidin-5-yI}methyI)-2-thiophenecarboxamide.
IC5o=40 nM; m.p.: 216°C; Rf value (Si02, toluene/ethyl acetate 1:1) = 0.31 [starting material: = 0.0].
15 Example 19
5-Chloro-N-({(5S)-2-oxo-3-[4-(diethyIamino)phenyl]-l,3-oxazoIidin-5-yl}methyl)-2-thiophenecarboxamide
20 Analogously, N,N-diethyipheny]-l,4-diamine (US-A-2 811 555; 1955) gives the
compound 5-chloro-N-({(5S)-2-oxo-3-[4-(diethylamino)phenyl]-l,3-oxazolidin-5-
yl }methyl)-2-thiophenecarboxamide.
IC50=270 nM;
m.p.: 181°C;
25 Rf value (Si02, toluene/ethyl acetate 1:1) = 0.25 [starting material: = 0.0].
Example 36
5-Chloro-N-({(5S)-3-2-methyI-4-(4-morpholinyI)phenyl]-2-oxo-l,3-oxazoIidin-5-
30 yI}methyI)-2-thiophenecarboxamide
starting from 2-methyI-4-(4-morpholinyl)aniIine (J.EXuValle et al. J.Am.Chem.Soc. 1948, 70, 2223):
MS (ESI): m/z {%) = 436 ([M+H]+, 100), CI pattern;
HPLC (method 1): it (%) = 3.77 (98).
35 IC50: 1-26 fiM




Le^i M 172-Foreign CosHtries

Example 37
5-Chloro-N-{[(55)-3-(3-chIoro-4-morphoIinophenyI)-2-oxo-l,3-oxazolidin-5-yI]methyI}-2-thiophenecarboxamide
5 starting from 3-chloro-4-(4-morpholinyl)aniline (H.R.Snyder et al J.Pharm.Scl
1977,66,1204):
MS (ESI): m/z (%) = 456 ([M+H]+, 100), Cl2 pattern; HPLC (method 2): rt (%) = 4.31 (100). IC50: 33 nM 10
Example 38
5-Chloro-N-({(55)-3-[4-(4-morphoIinylsuIphonyl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)-2-thiophenecerboxamide
15 starting from 4-(4-morphoIinylsulphony])aniline (Adams et al J.Am.Chem.Soc.
1939,61,2342):
MS (ESI): m/z (%) = 486 ([M+H]+, 100), CI pattern;
HPLC (method 3): rt (%) - 4.07 (100).
IC50: 2 fiM 20
Example 39
S-Chloro-N-({(5S)-3-[4-(l-a2etidinylsulphonyl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
25 starting from 4-(l-azetidinylsulphonyl)aniIine:
MS (DCI, NH3): m/z (%) = 473 ([M+NH4]+, 100), CI pattern;
HPLC (method 3): rt (%) = 4.10 (100).
IC50:0.84pM
30 Example 40
5-Chloro-N-[((S5)-3-{4-[(dimethylainino)suIphonyl]phenyl}-2-oxo-l,3-oxazoIidin-5-yl)methyl]-2-thiophenecarboxamide
starting from 4-amino-N,N-dimethyIben2enesulphonamide (I.K.Khanna el al
35 JMed.Chem. 1997,40, 1619):
MS (ESI): m/z (%) = 444 ([M-4-H]+ 100), CI pattern;





HPLC (method 3): rt (%) = 4.22 (100). IC50:90nM
General method for the acylation of 5-(aminomethyl)-3-[4-(2-oxo-l-pyrro-
5 IidinyI)phenyl]-l,3-oxazolidin-2-one with carbonyl chlorides.



Under argon and at room temperature, an about 0.1 molar solution of 5-
10 (aminomethyl)-3-[4-(2-oxo-l-pyrroIidinyl)phenyl]-l,3-oxazoIidin-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
15 for 2h, 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.

20

The following compounds were prepared in an analogous manner: Example 41

N-({2-oxo-3-[4-(2-oxo-l-pyrrolidinyi)phenyl]-l,3-oxazoIidin-5-yl}methyl)-2-thiophene-carboxamide
25 LC-MS (method 6): m/z (%) = 386 (M+H, 100);
LC-MS;rt(%) = 3.04 (100). IC50: 1.3 fiM







General method for preparing acyl derivatives starting from 5-(aminomethyl)-3-[4-(2-oxo-l-pyrroIidinyl)phenyI]-l,3-oxazoIidin*2-one and carboxylic adds

5 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-carbodnmide, Argonaut Technologies), The mixture is shaken gently at room temperature for about 15 min, 5-(aminomethyl)-3-[4-(2-oxo-l-pyrrolidinyl)phenyl]-l,3-oxazo!idin-2-one (from Example 45) (1.0 eq.) is then added and the mixture is
10 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.

15

The following compounds were prepared in an analogous manner Example 42

5-MethyI-N-({2-oxo-3-[4-(2-oxo-l-pyrrolidinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
20 LC-MS: m/z (%) = 400 (M+H, 100);
LC-MS (method 6): it (%) = 3.23 (100). IC50:0.16/iM

25

Example 43
5-Bromo-N-({2-oxo-3-[4-(2-oxo-l-pyrroIidinyI)phenyl]-lT3-oxazoIidin-5-yl}methyl)-2-thiophenecarboxamide
LC-MS : m/z (%) = 466 (M+H, 100); LC-MS (method 5): n (%) = 3.48 (78).








Example 44
5 5-Chloro-^V-({(55)-2-oxo-3-[4-(3-oxo-4-morphoIinyI)phenyI]-l^-oxa2olidin-5-
yI}methyI)-2-thiophenecarboxainide
10
a) 2-((2R)-2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyI)-1h-iso-
15 indole-l,3(2H)-dione:
A suspension of 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,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-oxiranylmethyI]-lH-isoindole-
5 l,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.
MS (ESI): m/z (%) = 418 ([M+Na]+, 84), 396 ([M+H]+, 93);
10 HPLC (method 3): rt (%) = 3.34 (100).
b) 2-({(55)-2-Oxo-3-[4-(3-oxo-4-morpholinyI)phenyl]-l,3-oxazolidin-5-yI}me-
thyl)-lH-isoindole-1,3(2H)-dione:
15 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°C for 12 h (the precipitate dissolves, after some time again formation of a precipitate), admixed with a second portion of N,N"-
20 carbonyldiimidazole (2.94 g, 18.1 mmol) and stirred at 60°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,
25 MS (ESI): m/z (%) = 422 (EM+H]+ 100);
HPLC (method 4): rt (%) = 3.37 (100).
c) S-Chloro-N-({(55)-2-oxo-3-[4-(3-oxo-4-morphoIinyI)phenyl]-lr3-oxazolidin-5-
yl}methyI)-2-thiophenecarboxamide:
30
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. 35
7/



Under argon and at 0°C, 5-chlorothiophene-2-carbonyI 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
5 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 gt 86% of theory. M.p: 232-233°C;
10 lH NMR (DMSO-d6, 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, / = 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); MS (ESI): m/z (%) = 436 ([M+H]+ 100, CI pattern);
15 HPLC (method 2): rt (%) = 3.60 (100);
[a]21D = -38° (c 0.2985, DMSO); ee: 99%. IC50: 0.7 nM
The following compounds were prepared in an analogous manner: 20
Example 45
5-MethyI-N-({(55)-2-oxo-3-[4-(3-oxo-4-morphoIinyl)phenyI}-l,3-oxazolidin-5-yI}methyl)-2-thiophenecarboxamide
25 MS (ESI): m/z (%) = 831 ([2M+H]+, 100), 416 ([M+H]+, 66);
HPLC (method 3): rt (%) = 3.65 (100). IC50:4.2nM
Example 46
30
5-Bromo-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl }methyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 480 ([M+H]+ 100, Br pattern);
HPLC (method 3): rt (%) = 3.87 (100).
35 IC50: 0.3 nM




Example 47
5-ChIoro-N-{[(5S)-3-(3-isopropyl-2-oxo-2,3-dihydro-l,3-benzoxazoI-6-yl)-2-oxo-l,3-oxazolidin-5-yI]methyI}-2-thiophenecarboxatnide

200 mg (0.61 mmol) of 6-[(5S)-5-(aminomethyl)-2-oxo-lT3-oxazolidin-3-yl]-3-isO" pfopyI-l»3-benzoxa2oI-2(3H)-one hydrochloride (EP 738726) are suspended in 5 ml of tetrahydrofuran and admixed with 0,26 ml (1.83 mmol) of tnethylamine and
10 132 mg (0.73 mmol) of 5-chlorothiophene-2-carboriyl 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. MS (ESI): m/z (%) = 436 (M+H, 100);
15 HPLC (method 4): rt = 3.78 min.
The following compounds were prepared in an analogous manner:







Example No. Structure M.p. [°Cj IC5o {uM}
48 0 S-^C|Chira" 0 210 0.12
49 O CJwal 234 0.074
50 • Ctwai 195 1.15
51 ° 0 212 1.19
52 O Cm 160 0.19
53 O Cnirai MS (ESI): m/z (%) = 431
(IM+H)+, 100), CI pattern 0.74

/
,/
/
/
/

/
74







Example No. Structure M-P- [°C] 1C50 [uM]
54 O CJiiraJ
4
N O
from 5-amino-2-pyrrolidino-benzonitrile (Grell, W., Hurnaus, R.; Griss, G., Sauter, R.; Rupprecht, E. et al; J.MedChem.1998, 41; 5219) 221 0.13
55 0
from 3-(4-amino-phenyl)-oxazoIidin-2-one (Artico, M. et al.; Farmaco Ed.Sci. 1969,24; 179) 256 0.04
56 Q CWnU 218 0.004
51 O Chital
0 i 226 0.58
255 228-230
/
/
/ /"


-75-


5

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-aIIyI-5-chIoro-2-thiophenecarboxamide
o

10 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
15 purified by flash chromatography over silica gel (dichloromethane).
Yield: 7.20 g (99% of theory);
MS (DCI, NH4): m/z (%) = 219 (M+NH4, 100), 202 (M+H, 32); HPLC (method 1): rt (%) = 3.96 min (98.9).
20 Example 21
Preparation of 5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide

25
An ice-cooled solution of 2,0 g (9.92 mmol) of N-aIlyI-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
30 10% sodium hydrogen sulphate solution (three times). The organic phase is washed
with saturated sodium bicarbonate solution (twice) and with saturated sodium




Le A34 I22^ercrgTreountrics

chloride solution, dried over magnesium sulphate and concentrated. The product is purified by silica gel chromatography (cyclohexane/ethyl acetate 1:1). Yield: 837 mg (39% of theory);
MS (DCI, NHi): m/z (%) =253 (M+NH4,100), 218 (M+H, 80);
5 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-iV-{2-oxiranylmethyl)-2-thiophenecarboxamide
10
At room temperature or at temperatures up to 80°C, 5-chloro-N-(2-oxiranyImethyI)-2-thiophenecarboxamide (1.0 eq.) is added a little at a time to a solution of the
15 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
20 mixtures).
The following compounds were prepared in an analogous manner
Example 22 25
iV-[3-(Benzylamino)-2-hydroxypropyl3-5-chloro-2-thiophenecarboxamide
MS (ESI): m/z (%) = 325 (M+H, 100); HPLC (method 1): rt (%) = 3.87 min (97.9).
30 Example 23
5-Chloro-N-[3-(3-cyanoanilino)-2-hydroxypropyl]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 336 (M+H, 100); HPLC (method 2); rt (%) = 4.04 min (100).





Example 24
5-Chloro-iV-[3-(4-cyanoaniIino)-2-hydroxypropyI]-2-thiophenecarboxamide
MS (ESI): m/z (%) - 336 (M+H, 100);
5 HPLC (method 1): rt (%) = 4.12 min (100).
Example 25
5-ChIoro-N-{3-[4-(cyanomethyI)anilino]-2-hydroxypropyl}-2-
thiophenecarboxamide
10 MS (ESI): m/z (%) = 350 (M+H, 100);
HPLC (method 4): rt (%) = 3.60 min (95.4).
Example 26
15 5.Chloro-N-{3-[3-(cyanomethyl)anilino]-2-hydroxypropyl}-2-
thiophenecarboxamide
MS (ESI); m/z (%) = 350 (M+H, 100); HPLC (method 4): rt (%) - 3.76 min (94.2).
20 Example 58
tert-Butyl 4-[(3-{[(S-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]-benzylcarbamate
25 starting from fert-butyl 4-aminobenzylcarbamate {Bioorg. Med. Chem. Lett.", 1997;
1921-1926):
MS (ES-pos): m/z (%) = 440 (M+H, 100), (ES-neg): m/z (%) - 438 (M-H, 100); HPLC (method 1): rt (%) = 4.08 (100).
30 Example 59
terf-Butyl 4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]-phenyl-carbamate
35 starting from N-tert-butyloxycarbonyl-l,4-phenylenediamine:
MS (ESI): m/z (%) = 426 (M+H, 45), 370 (100);




HPLC (method 1): it (%) = 4.06 (100).
Example 60
5 fert-Butyl 2-hydroxy-3-{[4-(2-oxo-l-pyrrolidinyI)phenyI]amino}propyI-carb-
amate
starting from l-(4-aminophenyl)-2-pyrroiidinone (Justus Liebigs Ann. Chem.\ 1955;
596; 204):
10 MS (DCI, NH3): m/z (%) = 350 (M+H, 100);
HPLC (method 1): rt (%) = 3.57 (97).
Example 61
15 5-Chloro-N-(3-{[3-fluoro-4-(3-oxo-4-morphoIinyI)phenyI]amino}-2-hydroxypro-
pyI)-2-thiophenecarboxamide
S00 mg (3.8 mmol) of 4-(4-amino-2-fluorophenyl)-3-morpholinone and 700 mg
(3.22 mmol) of 5-chloro-N-(2-oxiranyImethyl)-2-thiophenecarboxamide in 15 ml of
20 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.
Rf (ethyl acetate): 0.25. 25
Example 62
(N-(3-Anilino-2-hydroxypropyI)-5-chloro-2-thiophenecarboxamide
starting from aniline:
30 MS (DCI, NH3): m/z (%) = 311 ([M+H]+, 100), CI pattern;
HPLC (method 3): rt {%) = 3.79 (100).
Example 63
35 5-Chloro-N-(2-hydroxy-3-{[4-(3-oxo-4-morpholinyi)phenyl]amino}propyl)-2-
thiophenecarboxamide





79
starting from 4-(4-aminophenyl)-3-morphoIinone: MS (ESI): m/z (%) = 410 ([M+Hf, 50), CI pattern; HPLC (method 3): rt (%) - 3.5S (100).
5 Example 64
N-[3-({4-[AcetyI(cycIopropyl)amino]phenyI}aniino)-2-hydroxypropyl]-5-chIoro-2-thiophenecarboxamide
starting from N-(4-aminophenyI)-N-cyclopropylacetamide:
10 MS (ESI): m/z (%) - 408 ([M+H]+, 100), CI pattern;
HPLC (method 3): it (%) = 3.77 (100).
Example 65
15 N-[3-({4-[Acetyl(methyl)amino]phenyl}amino)-2-hydroxypropyl]-5-chloro-2-
thiophenecarboxamide
starting from N-(4-aminophenyI)-N-methyIacetamide: MS (ESI): m/z (%) - 382 (M+H, 100); HPLC (method 4): it = 3.31 min. 20
Example 66
5-Chloro-N-(2-hydroxy-3-{[4-(lH-l,2,3-triazol-l-yl)phenyl]amino}propyl)-2-thiophenecarboxamide
25 starting from 4-(lH-l,2,3-triazol-l-yI)aniIine (Bouchet et al.; J.Chem.Soc.Perkin
Trans.2; 1974; 449): MS (ESI): m/z (%) = 378 (M+H, 100); HPLC (method 4): rt = 3.55 min.
30 Example 67
tert-butyl l-{4-[(3-{[(5-chIoro-2-thienyl)carbonyl]amino}-2-hydroxypropyi)-amino]phenyI}-L-proIinate
MS (ESI): m/z (%) = 480 (M+H, 100);
35 HPLC (method 4): rt = 3.40 min.




Example 68
l-{4-[(3-{[(5-ChIoro-2-thienyl)carbonyl}amino}-2-hydroxypropyI)amino]phe-nyl}-4-piperidinecarboxamide
5 MS (ESI): m/z (%) = 437 (M+H, 100);
HPLC (method 4): rt = 2.39 min.
Example 69
10 l-{4-[(3-{[(5-Chloro-2-tbienyI)carbonyI]amino}-2-hydroxypropyI)-aniino]phe-
nyl}-3-piperidinecarboxamide
MS (ESI): m/z (%) = 437 (M+H, 100); HPLC (method 4): rt = 2.43 min,
15 Example 70
5-ChIoro-N-(2-hydroxy-3-{[4-(4-oxo-l-piperidinyl)phenyI]amino}propyI)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 408 (M+H, 100);
20 HPLC (method 4): rt = 2.43 min.
Example 71
l-{4-[(3-{[(5-ChIoro-2-thienyl)carbonyI]amino}-2-hydroxypropyl)amino]phe*
25 nyl}-L-prolinamide
MS (ESI): m/z (%) = 423 (M+H, 100); HPLC (method 4): rt = 2.51 min.
Example 72
30
5-Chloro-N-[2-hydroxy-3-({4-[3-(hydroxymethyI)-l-piperidinyI]phenyI}-
amino)propyl]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 424 (M+H, 100); HPLC (method 4): rt - 2.43 min.





Example 73
5-Chloro--N-[2-hydroxy-3-({4-[2-(hydroxymethyI)-l-piperidinyI]phenyl}-amino)propyl]-2-thiophenccarboxamide
5 MS (ESI): m/z (%) = 424 (M+H, 100);
HPLC (method 4): it = 2.49 min.
Example 74
10 Ethyl l-{4-[(3-{[(5-cfaIoro-2-thienyl)carbonyI]aniino}-2-hydroxypropyl)-
amino]phenyI}-2-piperidinecarboxyIate
MS (ESI): m/z (%) = 466 (M+H, 100); HPLC (method 4): it = 3.02 min.
15 Example 75
5-Chloro-N-[2-hydroxy-3-({4-[2-(hydroxymethyI)-l-pyrrolidinyl]phenyl}amino)-propyl]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 410 (M+H, 100);
20 HPLC (method 4): rt = 2.48 min.
Example 16
5-Chloro-N-(2-hydroxy-3-{[4-(2-methylhexahydro-5H-pyrrolo[3,4-d]isoxa2ol-5-
25 yI)phenyI]amino}propyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 437 (M+H, 100). HPLC (method 5): rt = 1.74 min.
-1 Example 77 30
5-ChIoro-N-(2-hydroxy-3-{[4-(l-pyrrolidinyI)-3-(trinuoromethyI)phenyI]-arnino}propyI)-2-thiophenecarboxamide MS (ESI): m/z (%) s 448 (M+H, 100); HPLC (method 4): rt = 3.30 min.





Example 78
5-ChIoro-N-(2-hydroxy-3-{[4-(2-oxo-l-pyrrolidinyl)-3-(trifluoromethyl)phenyI]-amino}propyl)-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 462 (M+H, 100);
HPLC (method 4): rt = 3.50 mm.
Example 79
10 5-Chloro-N-(3-{[3-chloro-4-(3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxy-
propyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 444 (M+H, 100); HPLC (method 4): rt = 3.26 min.
15 Example 80
S-ChIoro-N-(2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)-3.(trifluoromethyl)pfaenyl]-amino}propyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 478 (M+H, 100);
20 HPLC (method 4): rt - 3.37 min.
Example 81
5-Chtoro-N-(2-hydroxy-3-{(3-methyI-4-(3-oxo-4-morphoIinyI)phenyI]amino}-
25 propyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 424 (M+H, 100); HPLC (method 4): rt - 2.86 min.
Example 82
30
5-Chloro-N-(3-{[3-cyano-4-(3-oxo-4-morphoIinyl)phenyl]amino}-2-hydroxypro-
pyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 435 (M+H, 100); HPLC (method 4): it = 3.10 min.
35



Example 83
5-Chloro-N-(3-{[3-chIoro-4-(l-pyrrolidinyI)phenyl]amino}-2-hydroxypropyI)-2-thiophenecarboxamide
5 MS (ESI); m/z (%) = 414 (M+H, 100);
HPLC (method 4): rt = 2.49 min.
Example 84
10 5-Chloro-N-(3-{[3-chloro-4-(2-oxo-l-pyrrolidinyl)phenyl]amino}-2-hydroxypro-
pyI)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 428 (M+H, 100); HPLC (method 4): rt = 3.39 min.
15 Example 85
5-Chloro-N-(3-{[3^-dimethyl-4-(3-oxo-4-morpbolinyl)phenyI]aniino}-2-hydro-
xypropyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) =: 438 (M+H, 100);
20 HPLC (method 4): rt = 2.84 min.
Example 86
N-(3-{[3-(Aininocarbonyl)-4-(4-morpholinyl)phenyI]anino}-2-hydroxypropyI)-
25 5-chloro-2-thiophenecarboxamide
MS (ESI): m/z (%) = 439 (M+H, 100); HPLC (method 4): rt = 2.32 min.
Example S7
30
5-Chloro-N-(2-hydroxy-3-{[3-methoxy-4-(4-morphoIinyl)phenyl]amino}propyl)-
2-thiophenecarboxamide
MS (ESI): m/z (%) = 426 (M+H, 100); HPLC (method 4): rt = 2.32 mm.




Example 88
N-(3-{[3-Acetyl-4-(4-morphoiinyI)phenyl]amino}-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 438 (M+H, 100);
HPLC (method 4): rt = 2.46 min.
Example 89
10 N-(3-{ [3-Amino-4-(3-oxo-4-morpholiny l)phenyl]amino}-2-hydroxy propyl)-5-
chloro-2-thiophenecarboxamide
MS (ESI): m/z (%) = 425 (M+H, 100); HPLC (method 4): rt = 2,45 min.
15 Example 90
5-Chloro-N-(3-{[3-chloro-4-(2-methyl-3-oxo-4-morphoUnyl)phenyl]amino}-2-hydroxypropyI)-2-thiophenecarboxamide
MS (ESI): m/z (%) - 458 (M+H, 100);
20 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-
25 hydroxypropyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 458 (M+H, 100); HPLC (method 4): rt = 3.48 min.
Example 91a 30
5-Chloro-N-[2-hydroxy-3-({4-[(3-oxo-4-morphoIinyI)methyI]phenyl}amino)-propyI]-2-thiophenecarboxamide
starting from 4-(4-amino-benzyI)-3-morphoIinone (Surrey et al.; J. Amer. Chem.
35 Soc; 77; 1955; 633):
MS (ESI): m/z (%) = 424 (M+H, 100);


HPLC (method 4): it = 2.66 min.
General method for preparing 3-substituted 5-chloro-N-[(2-oxo-l,3-oxazolidin-
5-yl)methyI)-2-thiophenecarboxamide derivatives starting from substituted
5 iV-(3-amino-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide derivatives

At room temperature, carbodiimidazole (1.2 to 1.8 eq.) or a similar phosgene
10 equivalent are added to a solution of the substituted Af-(3-amino-2-hydroxypropyI)-5-
chloro-2-thtophenecarboxamide derivative (1.0 eq.) in absolute THF (about
0.1 mol/1). At room temperature or, if appropriate, at elevated temperature (up to
70°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
15 (dichloromethane/methanol mixtures or cyclohexane/ethyl acetate mixtures).
The following compounds were prepared in an analogous manner.
Example 27 20
N-[(3-Benzyl-2-oxo-l,3-oxa2oIidin-5-yI)methyI]-5-choro-2-thiophenecarboxamide
MS (DCI, NH4): m/z (%) = 372 (M+Na, 100), 351 (M+H, 45); HPLC (method 1): rt (%) = 4.33 min (100). 25
Example 28
5-Chioro-N-{[3-(3-cyanophenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide
30 MS (DCI, NH4): m/z (%) = 362 (M+H, 42), 145 (100);
HPLC (method 2): it (%) = 4.13 min (100).



^S6^—-Example 29

tbiophenecarboxamide
5 MS (ESI): m/z (%) = 376 (M+H, 100);
HPLC (method 4): it = 4.12 min
Example 30
10 5-ChIoro-N-({3-[3-(cyanomethyl)phenyl]-2-oxo-l,3-oxazoIidin-5-yl}inethyl)-2-
thiophenecarboxamide
MS (ESI): m/z (%) = 376 (M+H, 100); HPLC (method 4): rt = 4.17 min
15 Example 92
tert-Butyl 4-[5-({[(5-chIorO-2-thienyI)carbonyI]amino}methyl)-2-oxo-l,3-oxa-zolidin-3-yl]benzylcarbamate
starting from Example 58:
20 MS (ESI): m/z (%) = 488 (M+Na, 23), 349 (100);
HPLC (method 1): rt (%) = 4.51 (98.5).
Example 93
25 terf-Butyl 4-[5-({[(5-chloro-2-thienyl)carbonyI]amino}methyI)-2-oxo-l,3-oxazoIi-
din-3~yl]phenylcarbamate
starting from Example 59:
MS (ESI): m/z (%) = 493 (M+Na, 70), 452 (M+H, 10), 395 (100);
HPLC (method 1): rt (%) = 4.41 (100).
30
Example 94
terf-Butyl 2-oxo-3-[4-(2-oxo.l-pyrrolidinyI)phenyI]-l,3-oxazoHdin-5-yl}methyl-carbamate
35 starting from Example 60:
MS (DCI, NH3): m/z (%) = 393 (M+NH4,100);
h^





























HPLC (method 3); rt (%) = 3.97 (100).
Example 95
5 5-Chloro-N-({3-[3-fluoro-4-(3-oxo-4-morphoIinyl)phenyl]-2-oxo-l,3-oxazolidin-
5-yl}methyI)-2-thiophenecarboxamide




10 260 mg (0.608 mmol) of 5-chloro-N-(3-{[3-fluoro-4-(3-oxo-4-morpholinyl)phenyl]-
amino}-2hydroxypropyl)-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°C for 30 minutes.
15 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.
NMR (300 MHz, d6-DMSO): 5= 3.6-3.7 (m,4H), 3.85 (dd,lH), 3.95 (m,2H), 4.2
(m,lH), 4.21 (s,2H), 4.85 (m,lH), 4.18 (s,2H), 7.19 (d,lH,thiophene), 7.35 (dd,1H),
20 7.45 (t,lH), 7.55 (dd,lH), 7.67 (d,lH,thiophene), $.95 (t,lH,CONH).
Example 96
5-Chloro-N-[(2-oxo-3.phenyI-l,3-oxazoIidin-5-y!)methyI]-2-
25 thiophenecarboxamide
starting from Example 62:
MS (ESI): m/z (%) = 359 ([M+Na]+, 71), 337 ([M+H)+, 100), Cl pattern;
HPLC (method 3): rt (%) = 4.39 (100).
IC50: 2 pM 30




Example 97
5-Chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholmyl)phenyl]-l,3-oxa2olidin-5-yl}-methyI)-2-thiophenecarboxamide
5 starting from Example 63:
MS (ESI): m/z (%) = 458 ([M+Na)+, 66), 436 ([M+H]+, 100), CI pattern;
HPLC (method 3): rt (%) = 3.89 (100),
IC50:1.4nM
10 Example 98
iV-[(3-{4+[Acetyl(cyclopropyl)amino]phenyl}-2-oxo-l,3-oxazolidm-5-yl)methyl]-5-chloro-2-thiophenecarboxamide)+de
starting from Example 64:
15 MS (ESI): m/z (%) = 456 ([M+Na]+ ,55), 434 ([M+H]+, 100), CI pattern;
HPLC (method 3): rt (%) = 4.05 (100). IC50: 50 nM
Example 99
20
N-[(3-{4-[Acetyl(methyl)amino]phenyl}-2-oxo-l3.oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamide
MS (ESI): m/z (%) = 408 (M+H, 30), 449 (M+H+MeCN, 100); HPLC (method 4): rt - 3.66 min. 25
Example 100
S-ChIoro-N-({2-oxo-3-[4-(1H-l,2,3.triazol-l-yl)phenyl]-l,3-oxazoIidin-5-yl}-methyl)-2-thiophenecarboxamide
30 MS (ESI): m/z (%) = 404 (M+H, 45), 445 (M+H+MeCN, 100);
HPLC (method 4): rt = 3.77 min.
Example 101
35 Tert-butyl l-{4-[S-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-l-3-
oxazoIidin-3-yl]phenyI}-L-prolinate








MS (ESI): m/z (%) = 450 (M+H-56,25), 506 (M+H, 100); HPLC (method 4): rt = 5.13 min.
Example 102
5
l-{4-[5-({[(5-Chloro-2-thienyl)carbonyl]amino}methyl)-2"Oxo-1,3-oxazolidin"3-yl]phenyI}-4-piperidinecarboxamide
MS (ESI): m/z (%) = 463 (M+H, 100); HPLC (method 4): rt = 2.51 rain. 10
Example 103
l-{4-[5-({[(5-Chloro-2-thienyl)carbonyI]amino}methyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}-3-piperidinecarboxamide
15 MS (ESI): m/z (%) = 463 (M+H, 100);
HPLC (method 4): rt = 2.67 min.
Example 104
20 5-Chloro-N-({2-oxo-3-[4-(4-oxo-l-piperidinyI)phenyI]-l,3-oxazolidin-5-
yI}methyI)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 434 (M+H, 40), 452 (M+H+H20, 100), 475 (M+H+MeCN, 60);
HPLC (method 4): rt - 3.44 min. 25
Example 105
l-{4-[5-({[(5-Chloro-2-thienyl)carbonyI]amino}methyl)-2-oxo-l-3-oxazolidin-3-yl]phenyl}-L-prolinamide
30 MS (ESI): m/z (%) = 449 (M+H, 100);
HPLC (method 4): rt = 3.54 min.


Example 106
5-ChIoro-N-[(3-{4-[3-(hydroxymethyI)-l-piperidinyl]phenyI}-2-oxo-l;3-oxazoIi-din-5-yI)methyI]-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 450 (M+H, 100);
HPLC (method 5): rt = 2,53 min.
Example 107
10 5-Chloro-N-[(3-{4-[2-(hydroxymethyl)-l-piperidinyI]phenyl}-2-oxo-l?3-oxazoli-
din-5-yI)methyl]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 450 (M+H, 100); HPLC (method 5): rt = 2.32 mm.
15 Example 108
Ethyl l-{4-[5-({[(5-chloro-2-thienyl)carbonyI]amino}methyl)-2-oxo-13-oxazoli-din-3-yl]phenyl}-2-piperidinecarboxylate
MS (ESI): m/z (%) = 492 (M+H, 100);
20 HPLC (method 5): rt = 4.35 min.
Example 109
5-Chloro-N.[(3-{4-[2-(hydroxymethyl)-l-pyrrolidmyl]phenyl}-2-oxo-l>3-oxazoli
25 dm-5-yl)methyI]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 436 (M+H, 100); HPLC (method 4): rt = 2.98 min.
Example 110
30
5.Chloro-N-({2- oxo-3-[4-(l-pyrrolidinyl).3-(trifluoromethyl)phenyl]-l,3-oxazoli-
din-5-yl}methyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) - 474 (M+H, 100); HPLC (method 4): rt = 4.63 min.




Example lit
5-Chloro-N-({3-[4-(2-methylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-yl)phenyl3-2-oxo-l,3-oxazoIidin-5-yl}methyl)-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 463 (M+H, 100);
HPLC (method 4): rt = 2.56 min.
Example 112
10 5-Chloro-N-({2-oxo-3.[4-(2-oxo-l-pyrrolidinyl)-3-(trifiuoromethyl)phenyl]-1,3-
oxazoIidm-5-yI}methyI)-2-thiophcnecarboxamide
MS (ESI): m/z (%) = 488 (M+H, 100); HPLC (method 4): rt = 3.64 min.
15 Example 113
5-Chloro-N-({3-[3-chIoro-4-(3-oxo-4-morphoIinyl)phenyI]-2-oxo-1,3-oxazolidin-5-yl}methyI)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 470 (M+H, 100);
20 HPLC (method 4): rt = 3.41 min.
Example 114
5-Chloro-N-({2-oxo-3-[4-(3-oxo-4-morphoIinyl)-3-(trifluoromethyI)phenyI]-l,3-
25 oxazolidin-5-yI}methyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 504 (M+H, 100); HPLC (method 4): rt = 3.55 min.
Example 115
30
5-ChIoro-N-({3-[3-methyI-4-(3-oxo-4-morphoIinyl)phenyl]-2-oxo-lr3-oxazolidin-5-yI}methyl)"2-thiophenecarboxamide
MS (ESI): m/z (%) = 450 (M+H, 100); HPLC (method 4): rt = 3.23 min.



Example 116
5-ChIoro-N-({3-[3-cyano-4-(3-oxo-4"morpholinyl)phenyl]-2-oxo-lT3-oxazoU 5 MS (ESI): m/z (%) = 461 (M+H, 100);
HPLC (method 4): rt = 3.27 min.
Example 117
10 5-Chloro-N-({3-[3-chIoro-4-(l-pyrroHdinyI)pheayI]-2-oxo"l^-oxazolidin-5-
yl}methyl)-2-thiophenecarboxamide
MS (ESI): m/2 (%) = 440 (M+H, 100); HPLC (method 4): rt = 3.72 min.
15 Example 118
S-Chloro-N-({3-[3-chloro-4-(2-oxo*l-pyrroHdinyl)phetiyl]-2-oxo-l,3-oxazolidin-5-yI}methyI)-2"thiophenecarboxamide
MS (ESI): m/z 20 HPLC (method 4): n = 3.49 min.
Example 119

25 zolidin-5-yI}methyl)-2"thiophenecarboxamide
MS (ESI): m/z (%) = 464 (M+H, 100); HPLC (method 4): rt = 3.39 min.
Example 120 30
N-({3-[3-(Aminocarbonyl)-4-(4-morpholinyI)phenyI]-2-oxo-l,3-oxazoiidin-5-yl}methyI)-5-chIoro-2-thiophenecarboxamide
MS (ESI); m/z (%) = 465 (M+H, 100); HPLC (method 4): rt - 3.07 min.




Example 121
5-ChIoro-N-({3-[3-methoxy-4-(4-morphoIinyI)phenyl]-2-oxo-lr3-oxazolidin-5-yI}methyI)-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 452 (M+H, 100);
HPLC (method 4): rt = 2.86 min.
Example 122
10 N-({3-[3-Acety]-4-(4-morphoIinyl)phenyI]-2-oxo-l,3-oxa2oIidin-5-yI}methyl)-5-
chloro-2-thiophenecarboxamide
MS (ESI): m/z (%) = 464 (M+H, 100); HPLC (method 4): it = 3.52 min.
15 Example 123
N-({3-[3-Amino-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yI}-methyI)-5-chloro-2-thiophenecarboxamide
MS (ESI): m/z (%) - 451 (M+H, 100);
20 HPLC (method 6): rt = 3.16 min.
Example 124
5-Chloro-N-({3-[3-chIoro-4-(2-methyl-3-oxo-4-morphoIinyl)phenyl]"2-oxo-l,3-
25 oxazolidin-5-yI}methyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 484 (M+H, 100); HPLC (method 4): rt = 3.59 min.
Example 125
30
5-ChIoro-N-({3-[3-chloro-4-(2-methyl-5-oxo-4-morphoIinyI)phenyl]-2-oxo-ly3-oxazolidin-5-yl}niethyl)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 484 (M+H, 100); HPLC (method 4): rt = 3.63 min.



Example 125a
S-Chloro-N-[(2-oxo-3-{4-[(3-oxo-4-morpholinyl)methyl]phenyl}-l,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 450 (M+H, 100);
HPLC (method 4): rt - 3.25 min.
Via epoxide opening with an amine and subsequent cyclization to give the
corresponding oxazolidinone, it was also possible to prepare the following
10 compounds:









/
/


/
/




Examples 14 to 16 below are working examples for the optional oxidation step. Example 14
5 5-Chloro-N-({(SS)-3-[3-fluoro-4-(l-oxo-lDambda]4,4-thiazinan-4-yl)pheny»]-2-

oxo-l^-oxazolidin-5-yI}methyl)-2-tMophenecarboxaniide
F O
n r~0=S N
o
10 At 0°C, 5-chloro-N-({(5S)-3-[3-fluoro-4*Cl,4-thiazinan^-yl)phenyl]-2-oxo-l,3-
oxazolidin-5~yl}methyI)-2-thiophenecarboxarnide (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°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
15 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. M.p.: 257°C;
20 Rf (silica gel, toluene/ethyl acetate 1:1)- 0.54 (starting material = 0.46);
IC5o value =1.1pM: MS (DCl) 489 (M+NH4), CI pattern.




Example 15
Preparation of5-chloro-N-({{5S)-3"[4-(l,l-dioxO"l[lambda]*,4-thiazinan-4-yl)-3-
fluorophenyll^-oxo-l^-oxazolidin-S-ylJmethyD-Z-thiophenecarboxamide
5
F O
O
5 -Choro-N -({(5S)-3-[3-fluoro-4-( l ,4-thiazrnan-4-yl)pheyl] -2-oxo-1,3-oxazolidin-5-yl}rnethyl)-2-thiophenecarboxamide from Example 3 (0.1 g, 0.22 mmol) in 3.32 ml
10 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
15 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. M.p.: 238°C; Rf (toluene/ethyl acetate 1:1) = 0.14 (starting material = 0.46);
20 1C50 value = 210 nM;
MS (DO): 505 (M+NH4), CI pattern.
Example 16
25 5-ChIoro-N-{[(5S)-3-(3-fluoro~4-morpholinophenyl)-2-oxo-l,3-oxazoIidin-5-
yl]methyl}-2-thiophenecarboxamide N-oxide
is obtained by treating 5-chloro-N-{[(5S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-
l,3-oxazoIidin-5-y]]methyl}-2-thiophenecarboxarnide from Example 1 with the
magnesium salt of monoperoxyphthalic acid.
30 MS (ESI): 456 (M+H, 21 %, CI pattern), 439 (100%).




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
5 cyanomethylphenyl-substituted 5-chIoro-N-[(2-oxo-l,3-oxazoIidin-5-yl)methyl]-
2-thiophenecarboxamide derivatives
The cyanomethylphenyl-substituted 5-chloro-N-[(2-oxo-l,3-oxazolidin-5-yl)methyl]-
2-thiophenecarboxamide derivative in question (1.0 eq.) is, together with
10 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 MgSO4, filtered and concentrated under reduced pressure.
15 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.
The residue is dissolved in methanol (0.01-0.1 mol/l) and, to prepare the
20 unsubstituted amidines, admixed with ammonium acetate (3 eq.) and ammonium
chloride (2 eq.). To prepare the substituted amidine derivatives, primary or secondary
amines (l.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%
25 trifluoroacetic acid).
The following compounds were prepared in an analogous manner:
Example 31:
30
N-({3-[4-(2-Amino-2-iminoethyl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methy1)-5-cbloro-2-thiophenecarboxamide
MS (ESI): m/z (%) = 393 (M+H, 100); HPLC (method 4): rt = 2.63 min 35


Le A M W-F^WFV Countries

Example 32;
5-Chloro-N-({3-[3-(425-dihydro-lH-imidazol-2-yImethyl)phenyI]-2-oxo-1,3-oxazoIidin-5-yI}methyl)-2-thiophenecarboxamide
5 MS (ESI): m/z (%) - 419 (M+H, 100);
HPLC (method 4): rt =2.61 min
Example 33:
10 5-Chloro-N-t(3-{3-[2-imino-2-(4-raorpholinyl)ethyl]phenyI}-2-oxo-l,3-oxazoIi-
din-5-yI)methyI]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 463 (M+H, 100); HPLC (method 4): rt - 2.70 min
Example 34:
S-Chloro-N-[(3-{3-[2-imino-2-(l-pyrroIidinyl)ethyl]phenyI}-2-oxo-l,3-oxazoIi-din-5-yl)methyl]-2-thiophenecarboxamide
20 MS (ESI): m/z (%) = 447 (M+H, 100);
HPLC (method 4): rt = 2.82 min
Example 35:
25 N-({3-[3-(2-Amino-2-iminoethyl)phenyl]-2-oxo-l;3-oxazolidin-5-yI}inethyl)-5-
chloro-2-thiophenecarboxamide
MS (ESI): m/z (%) = 393 (M+H, 100); HPLC (method 4): rt = 2.60 min
30 Example 140
5-Chloro-N-({3-[4-(4,5-dihydro-lH-imidazoI-2-ylmethyl)phenyl]-2-oxo-l,3-oxa-zolidin-5-yI}methyI)-2-thiophenecarboxamide
MS (ESI): m/z (%) = 419 (M+H, 100);
35 HPLC (method 4): rt = 2.65 min


Example 141
5-Chloro-N-[(3-{4-[2-imino-2-(4-morphoIinyI)ethyl]phenyl}-2-oxo-13-oxazoli. din-5-yI)methyI]-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 463 (M+H, 100);
HPLC (method 4): it = 2,65 min
Example 142
10 5-Chloro-N-[(3-{4-[2-imino-2-(l-piperidinyl)ethyl]phenyl}-2-oxo-l,3-oxazolidin-
5-yl)methyl]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 461 (M+H, 100); HPLC (method 4): rt = 2,83 min
15 Example 143
5-Chloro.N-[(3-{4-[2-imino-2-(l-pyrrolidinyl)ethyl]phenyI}-2-oxo-l,3-oxazoli-din-5-yl)methyl]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 447 (M+H, 100);
20 HPLC (method 4): rt = 2.76 min
Example 144
5-Chloro-N-[(3-{4-[2-(cyclopentylamino)-2-iminoethyl]phenyl}-2-oxo-1,3-oxazo-
25 Iidin-5-yl)methyl]-2-thiophenecarboxamide
MS (ESI): m/z (%) = 461 (M+H, 100); HPLC (method 4): rt = 2.89 min
Example 145
30
5-ChIoro-N.{[3-(4-{2-imino-2.[(2,2,2-trifuoroethyI)amino]ethyl}phenyI)-2-oxo-
l,3-oxazoIidin-5-yl]methyl}-2-thiophenecarboxamide
MS (ESI): m/z (%) = 475 (M+H, 100); HPLC (method 4): rt = 2,79 min


T^ A M 177-Frtn-iyn Cntmtnn
Example 146
N-({3-[4-(2-Anilino-2-iminoethyI)phenyl]-2-oxo-l^-oxazoljdin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide
5 MS (ESI): m/z (%) = 469 (M+H, 100);
HPLC (method 4): rt = 2.83 min
Example 147
10 5-Chloro-N- [(3-{4- [2-itnino-2-(2-py ridiny lamino)ethy l]pheny l}-2-oxo-1,3-oxa-
zolidin-5-yl)mcthyl]-2-thiophenecarbox:amide
MS (ESI): m/z (%) = 470 (M+H, 100); HPLC (method 4): rt = 2.84 min
15 Examples 148 to 151 below refer to the removal of BOC amino protective groups:
General method for removing Boc protective groups (tert-butyloxycarbonyl):

20
Aqueous trifluoroacetic arid (TFA, about 90%) is added dropwise to an ice-cooled solution of a ferr-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
25 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 IN 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
30 or ether/dichloromethane mixtures.
The following compounds were prepared in an analogous manner from the corresponding Boc-protected precursors:


Example 148
Ar-({3-[4-(Aminotnethyl)phenyI]-2-oxo-l^-oxazoIidin-5-yI}methyI)-5-chIoro-2-thiophene-carboxamide
5 starting from Example 92:
MS (ESI): m/z (%) = 349 (M-NH2, 25), 305 (100); HPLC (method I); rt (%) = 3.68 (98). IC50: 22 fiU
10 Example 149
^-{[S-t^AminophenylJ-I-oxo-l^-oxazolidin-S-ylJmethylJ-S-chloro-l-thiophenecarboxamide
starting from Example 93:
15 MS (ESI): m/z (%) ~ 352 (M+H, 25);
HPLC (method 1): rt (%) = 3.50 (100). IC50: 2 fiM
An alternative enantiomerically pure synthesis of this compound is shown in the
20 scheme below (cf. also Delalande S.A., DE 2836305,1979; Chem.Abstr. 90,
186926):

1.) phthalimide, DEAD/PPh




Example 150
5-Chloro-iVK{3-[4^glycyiamino)phenyl]-2-oxo-i^-oxa2oIidm-5-yl}inethyl)-2-thiophenecarboxamide
5 starting from Example 152:
MS (ES-pos): m/z (%) = 408 (100); HPLC (method 3): rt (%) = 3.56 (97). IC50: 2 fiM
10 Example 151
5-(Aminomethyl)-3-[4-(2-oxo-l-pyrrolidinyl)ph^nyl]-13-oxazolidin-2-one
starting from Example 60;
MS (ESI): m/z (%) = 276 (M+H, 100);
15 HPLC (method 3): rt (%) = 2.99 (100).
IC5o:2/iM
The Examples 152 to 166 below refer to the amino group derivatizatjon of aniline- or benzylamine-substituted oxazolidinones using various reagents: 20
Example 152
5-Chloro-Ar-({3-[4-(N-te/t-butyIoxycarbonyl-glyi:yIamino)pheny]]-2-oxo-l,3-oxazolidm-5-yI}methyI)~2-thiophenecarboxamide
25
At 0°C, 754 mg (2.1 mmol) of JV-{[3-(4-aminophenyI)-2-oxo-l,3-oxazolidin-5-
yl]methyI}-5-chloro-2-thiophenecarboxamide (from Example 149) are added to a
30 solution of 751 mg (4.3 mmol) of Boc-glycine, 870 mg (6.4 mmol) of HOBT

(1-hydroxy-lH-benzotriazole x H20), 1790 mg (4.7 mmol) of HBTU [0-(benzotriazol-l-yl)-N,N,N",N"-tetramethyIuronium hexafluorophosphate] and 1.41 ml (12.9 mmol) of N-methylmorpholine in 15 ml of DMF/CH2C12 (1:1). The


mixture is stirred at room temperature overnight and then diluted with water. The precipitated solid is filtered off and dried. Yield: $94 mg (79.7% of theory); MS (DCI, NH3): m/z (%) = 526 (M+NH4, 100); HPLC (method 3): rt (%) = 4.17 (97).
Example 153
N-[(3"{4-[(AcetyIamino)methyI]phenyI}-2-oxo-1,3-oxazolidin-S-yl)methyl]-5-chIoro-2-thiophenecarboxamide

10
1U

At O0C, a mixture of 30 mg (0.082 mmol) of N -({3-[4-(aminomethyl)phenyl]-2-oxo-
l,3-oxazolidin-5-yl}methyl)-5-chloro-2-rhiophene-carboxamide (from Example 148)
in 1.5 ml of absolute THF and 1.0 ml of absolute dichloromethane, and 0.02 ml of
15 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. Yield: 30 mg (87% of theory),
MS (ESI): m/z (%) = 408 (M+H, 18), 305 (85);
HPLC (method 1): rt (%) = 3.78 (97).
20 IC50: 0.6 pM
Example 154
25 methyl}-5-chIoro-2-thiophenecarboxamide


-
K




At room temperature, 0.19 ml (0.82 mmol) of trimethylsilylisocyanate are added
dropwise to a mixture of 30 mg (0.082 mmol) of iV-({3-[4-(aminomethyl)phenyl]-2-
oxo-l,3-oxazolidin-5-yl }methyI)-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),
MS (ESI): m/z (%) = 409 (M+H, 5), 305 (72);
HPLC (method 1): rt (%) = 3.67 (83).
10
IC50:1-3/AM
General method for acylating Ar-{[3-(4-aminophenyl)-2-oxo-l,3-oxazolidin-S-yl]methyl}-5-chloro-2-thiophenecarboxamJde with carbony) chlorides:

^ _ .. ..
-CI
tr
Under argon, an approximately 0.1 molar solution of N-{[3-(4-aminophenyl)-2-oxo-
15 l,3-oxazolidin-5-y]]methyI}-5-chloro-2-thiophenecarboxamide (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
20 filtrate is concentrated. If appropriate, the products are purified by preparative RP-
HPLC.
The following compounds were prepared in an analogous manner:
25 Example 155
N-({3-[4-(AcetyIamino)phenyl]-2-oxo-1,3-oxazolidin-5--yl}methyl)-5-chloro-2-thiophene-carboxamide
LC-MS: m/z (%) = 394 (M+H, 100);




LC-MS (method 6): rt (%) = 3.25 (100). IC50: 1.2 pM
Example 156
5
5-ChIoro-N-[(2-oxo-3-{4-[(2-thienylcarbonyl)amino]phenyI}-l,3-oxazolidin-5-yl)methyl] -2-thiophenecarboxamide
LC-MS: m/z (%) = 462 (M+H, 100);
LC-MS (method 6): rt (%) = 3.87 (100).
10 IC50: 1.3 pM
Example 157
5-Chloro-N-[(3-{4-[(methoxyacetyl)amino]phenyl}-2-oxo-l,3-oxazolidin-5-yI)-
15 methyI]-2-thiophenecarboxamide
LC-MS: m/z (%) = 424 (M+H, 100); LC-MS (method 6): rt (%) = 3.39 (100). IC5o:0.73pM
20 Example 158
N-{4.[5-({[(5-Chloro-2-thienyl)carbonyl]amino}methyI)-2-oxo-l,3oxazolidin-3-yl]phenyl}-3,5-dimethyl-4-isoxazolecarboxamide
LC-MS: m/z (%) - 475 (M+H, 100).
25 IC50: 0.46pM
Example 159
5-Chloro-Af-{[3-(4-{[(3-chIoropropyl)suIphonyl]amino}phenyl)-2-oxo-1,3-
30 oxazolidin-5-yl]methyl}-2-thiophenecarboxamide
O







An ice-cooled solution of 26.4 mg (0.15 mmol) of 3-chloro-l-propanesulphonyI
chloride and 0.03 ml (0.2 mmol) of triethylamine in 3.5 ml of absolute dichloro-
methane is admixed with 35 mg (0.1 mmol) of A^[3-(4-arninophenyI)-2-oxo-l,3-
oxazoHdin-5-yl]-niethyl}-5-chloro-2-thiophene-carboxamide (from Example 149).
5 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-trisamme (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%
10 of theory),
LC-MS; m/z (%) - 492 (M+H, 100); LC-MS (method 5): it (%) = 3.82 (91).
15 Example 160
5-Chloro-A^-({3-[4-(l,l-dioxido-2-isothia2oIidinyl)phenyI]-2-oxo-l,3-OxazoIidin-5-yl}methyI)-2-thiophenecarboxamide
20
A mixture of 13.5 mg (0.027 mmol) of 5-chloro-N-{(3-(4-{[(3-chloropropyl)sul-phonyl]amino}phenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl}-2-thiophene-carboxamide (from Example 159) and 7.6 mg (0.055 mmol) of potassium carbonate in 0.2 ml of
25 DMF is heated at 100°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), MS (ESI): m/z (%) = 456 (M+H, 15), 412 (100);
30 LC-MS (method 4): it (%) = 3.81 (90).
IC50: 0.14 pM




Example 161
5-Chloro-N-t((5S)-3-{4-[(5-chloropentanoyi)amino]phenyl}-2-oxo-l,3-oxazoli-din-5-yl)methyl]-2-thiophenecarboxamide


CI 0

5

0.5 g (1.29 mmol) of N-{[(5S)-3-(4-aminophenyl)-2-oxo-l,3-oxazoIidin-5-
yI]methyl}-5-chloro-2-thiophenecarboxamide (from Example 149) is dissolved in
10 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=l:l -> ethyl acetate gradient. This gives 315 mg (52% of theory) of a solid. M.p.:211°C.
15
Example 162
5-Chloro-N-({(SS)-2-oxo-3-[4-(2-oxo-l-piperidinyI)phenyl]-l,3-oxazolidin-5.yl}. methyl)-2-thiophenecarboxamide
20

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°C for 30 min, until the evolution of gas
25 has ceased, A solution of 290 mg (0.617 mmol) of 5-chloro-N-[((5S)-3-{4-[(5-
chloropentanoyl)amino]phenyl}-2-oxo-l,3-oxa2olidin-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
109


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. M,p.: 205°C;
NMR (300 MHz, d6-DMSO): 5= 1.85 (m,4H), 2.35 (m,2H), 3.58 (m,4H), 3.85 (m,lH), 4.2 (t,lH), 4.82 (m,lH), 7.18 (d,lH,thiophene), 7.26 (d,2H), 7.5 (d,2H), 2.68 (d,lH,thiophene), 9.0 (t,lH,CONH). IC50: 2.8 nM
10 Example 163
5-ChIoro-N-[((5S)-3-{4-[(3-bromopropionyl)amino]phenyI}-2-oxo-l,3-oxazoli-din-5-yl)methyi}-2-thiophenecarboxamide

15
is obtained in an analogous manner from Example 149.
Example 164
20 5-ChIoro-N-({(5S).2-oxo-3-[4-(2-oxo-l-.azetidinyl)phenyI]-1,3-oxazolidin-5-yl}-
methyI)-2-thiophenecarboxamide

25 is obtained in an analogous manner by cyclization of the open-chain bromopropionyl
compound from Example 163 using NaH/DMSO. MS (ESI): m/z (%) = 406 ([M+H]+, 100), CI pattern. 1C50: 380 nM



Example 165
tert-Butyl 4-{4-[5-({[(5-chIoro-2-thienyI)carbonyllainino}methyl)-2-oxo-l,3-oxa-zolidin-3-yI]phenyl}-3,5-dioxo-l-piperazinecarboxylate



A solution of 199 mg (0.85 mmol) of Boc-iminodi acetic acid, 300 mg (2.2 mmol) of HOBT, 0.66 ml (6 mmol) of N-methylmorphoIine and 647 mg (1.7 mmol) of HBTU
10 is admixed with 300 mg (0.S5 mmol) of N-[3-(4-aminophenyI)-2-oxo-l,3-
oxazolidin-5-yl]-methyl }-5-chloro-2-thiophene-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
15 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); MS (ESI): m/z (%) = 571 (M+Na, 82), 493 (100); HPLC (method 3): rt (%) - 4.39 (90).
20 IC50: 2 pM
Example 166
N-[((5S)-3-{4-[(3R)-3-Amino-2-oxo-l-pyrToIidinyI]pheny!}-2-oxo-l,3-oxazolidin-
25 5-yI)methyI]-5-chloro-2-thiophepecarboxamide trifluoroacetate

O BOCNH^COOH
.g^^Cl s^ EDC, DIEA
CH-
r/9 L HOBT








N2-(tert-Butoxycarbonyl)-Nl-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}
5 methyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}-D-methionineamide
429 mg (1.72 mmol) of N-BOC-D-methionine, 605 mg (1.72 mmol) of N^[(5S)-3-(4-aminophen yl)-2-oxo-1,3 -oxazol idin-5-yl]methyl) -5-ch loro-2-thiophenecarbox-amide, and 527 mg (3.44 mmol) of HOBT hydrate are dissolved in 35 ml of DMF
10 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
15 using a toluene -> T10EA7 gradient. This gives 170 mg (17% of theory) of the target
compound of melting point 183°C. Rf (Si02, toluene/ethyl acetate=l:l):0.2.
}H-NMR (300 MHz. d6-DMSO): (s,lH,BOC), 1.88-1.95 (m,2H), 2.08
(s,3H,SMe), 2.4-2.5 (m,2H, partially obscurbed by DMSO), 3.6 (m,2H), 3.8 (m,lH),
20 4.15 (m,2H), 4.8 (m7lH), 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,lH, CH2NHCO), 9.93 (bs,lH,NH).



tert-Butyl (3R)-l.{4-[(5S)-5-({[(5-chIoro-2-thieiiyI)carbonyI]aniino}methyi)-2-oxo-1,3-oxazoIidin-3-yl]pheny l}-2-oxo-3-pyrroIidinylcarbamate
170 mg (0.292 mmol) of N2-(tert-butoxycarbonyl)-Nl-{4-[(S$)-5-({[(5-chloro-2-
5 thienyl)carbony]] amino }methyl)-2-oxo~l ,3-oxazolidin-3-yl]phenyl }-D-methionine-
amide are dissolved in 2 ml of DMSO and admixed with 178.5 mg (0.875 mmol) of trimethylsulphonium iodide and 60.4 mg (0.437 mmol) of potassium carbonate, and the mixture is stirred at 80°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
10 remain.
}H-NMR (300 MHz, d6*DMSO): 6 =1.4 (s,lH,BOC), 1.88-2.05 (m,lH), 23-2.4 (m,lH), 3.7-3.8 (m,3H), 3.8-3.9 (m,lH), 4.1-4.25 (m,lH), 4.25-4.45 (m,lH), 4.75-4.95 (m,lH), 7.15 (1H, thiophene), 7.25 (d,lH), 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,lH).
15
N-[((5S)-3-{4-t(3R)-3-Aminio-2-oxo-l-pyrroIidinyI]phenyl}-2-oxo-l,3-oxazoUdm-5-y l)methyl] -S-chloro-2-thiophenecarboxamide trifluoroacetate
97 mg (0.181 mmol) of tert-butyl (3R)-l-{4-[(5S)-5-({[(5-chloro-2-
20 thienyl)carbonyl]amino}methyl)-2-oxo-l,3-oxazolidin-3-yI]phenyl}-2-oxo-3-pyrroli-
dinylcarbamate 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
25 fraction gives 29 mg (37% of theory) of the target compound of melting point 241 °C
(decomp.).
Rf (Si02,EtOH/TEA=17:l) 0.19.
]H-NMR (300 MHz, d6-DMSO): =1.92-2.2 (m,lH), 2.4-2.55 (m,lH, partially.
obscured by DMSO peak), 3.55-3.65 (m,2H), 3.75-3.95 (m,3H), 4.1-4.3 (m,2H),
30 4.75-4.9 (m,lH), 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, NIB), 8.9
(t,lH,NHCO).



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 5-chIoro-N-[(2-oxo-3-phenyI-1,3-oxazolidin-5-yl)methyl]-2-
thiophenecarboxamide

10 Under argon and at 5°C, 5-chloro-N-[(2-oxo-"3-phenyl-l,3-oxa2olidin-5-yl)methyl]-2-
thiophenecarboxamide (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.
15 Under argon and at room temperature, the precipitate is then dissolved in
tetrahydrofuran (0.1 mol/1) 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). .
20
The following compounds were prepared in an analogous manner:
Example 167
25 5-Chloro-N-({2-oxo.3-[4- methyl)-2-thiophenecarboxamide
MS (ESI): m/2 (%) = 492 ([M+Na]+, 100), 470 ([M+H]+, 68), CI pattern;
114



10

HPLC (method 3): rt (%) = 4.34 (100). IC50: 0.5 pM
Example 168
5-ChIoro-N-[(3-{4-[(4-methyl-1-piperazinyI)sulphonyI]phenyl}-2-oxo-l,3-oxa-zolidin-5-yI)methyI]-2-thiaphenecarboxamide
MS (ESI): m/z (%) = 499 ([M+H]+, 100), CI pattern; HPLC (method 2); rt (%) = 3.3 (100).
Example 169

5-Chloro-N-({2-oxo-3-[4-(l-piperidinylsuIphonyl)phenyl]-l,3-oxazolidin-5-yI}-methyl)-2-thiophcnecarboxamide
15 MS (ESI): m/z (%) = 484 ([M+H]+, 100), Cl pattern;
HPLC (method 2): it {%) = 4.4 (100).
Example 170
20 5-Chloro-N-[(3-{4-[(4-hydroxy-l-piperidinyl)sulphonyl]phenyI}-2-oxo-l,3-oxa-
zoUdin-5-yl)methyl]»2-thiophenecarboxamide
MS (ESI): m/z (%) = 500 ([M+H]+, 100), Cl pattern; HPLC (method 3): rt (%) = 3.9 (100).
25 Example 171
5-Chloro-N-({2-oxo-3-[4-(l-pyrrolidinyl)phenyl]-l,3-oxa2oIidin-5-yl)methyl)-2-thiophenecarboxamide

H N
H,CT;CH,
30









780 mg (1.54 mmol) of tert-butyl l-{4-[5-({[(5-chIoro-2-thienyl)carbonyl]amino}-
methyl)-2-oxo-l,3-oxazohdin-3-yl]phenyl}prolinate are dissolved in 6 ml of
dichloromethane and 9 ml of trifluoroacetic acid, and the mixture is stirred at 40°C
5 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 stin-ed
with ether and 2N hydrochloric acid. The organic phase of this extraction is dried
over MgS04, filtered and concentrated. The crude product is chromatographed over
silica gel (CH2Cl2/EtOH/conc. aqu. NH3 sol. = 100/1/0.1 to 20/1/0.1).
10 This gives 280 mg (40% of theory) of the product.
MS (ESI): m/z (%) = 406 (M+H, 100); HPLC (method 4): rt = 3.81 min.
HPLC parameter and LC-MS parameter for the HPLC and LC-MS data given in the
15 examples above (the unit of the retention time (rt) is minutes):
[1] Column; Kromasil C18, L-R temperature: 30°C, flow rate = 0.75 ml min-1, eluent: A = 0-01 M HC104, B = CH3CN, gradient: -> 0.5 min 98%A -> 4.5 min 10%A ->6.5 min 10%A 20
[2] Column: Kromasil C18 60*2, L-R temperature: 30oC, flow rate = 0.75 ml min"-1, eluent: A = 0.01 M H3P04, B = CH3CN, gradient: -> 0.5 min 90%A -> 4,5 min 10%A ->6.5 min 10%A
25 [3] Column: Kromasil C18 60*2, L-R temperature: 30°C, flow rate = 0.75 ml min-1,
eluent: A = 0.005 M HC104, B = CH3CN, gradient: -> 0.5 min 98%A -> 4.5 min 10%A ->6.5 min 10%A
[4] Column: Symmetry C18 2.1x150 mm, column oven: 50°C, flow rate =
30 0.6 ml min"1, eluent: A = 0.6 g 30% strength HC1/ 1 of water, B = CH3CN, gradient:
0.0 min 90%A -> 4.0 min 10%A ->9 min 10%A
/■ /
/



/ 116
/ f



[5] MHZ-2Q, Instrument Micromass Quattro LCZ
Column Symmetry C18, 50 mm x 2.1 mm, 3.5 pm, temperature: 40°C, flow rate =
0.5 ml min-1, eluent A = CH3CN + 0.1% formic acid, eluent B = water + 0.1% formic
5 acid, gradient: 0.0 min 10% A -> 4 min 90% A -> 6 min 90% A
[6] MH2-2P, Instrument Micromass Platform LCZ
Column Symmetry C18, 50 mm x 2.1 mm, 3.5 pm, temperature: 40°C, flow rate =
0.5 ml min-1, eluent A - CH3CN + 0.1% formic acid, eluent B = water + 0.1% formic
10 acid, gradient: 0.0 min 10% A -> 4 min 90% A -> 6 min 90% A
[7] MHZ-7Q, Instrument Micromass Quattro LCZ
Column Symmetry C18, 50 mm x 2.1 mm, 3.5 pm, temperature: 40°C, flow rate =
0.5 ml min"1, eluent A = CH3CN + 0,1% formic acid, eluent B = water + 0.1% formic
15 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
20 Reactions with different resin-bonded products were carried out in a set of separated
reaction vessels.
5-(Bromomethyl)-3-(4-fluoro-3-nitrophenyl)-l,3-oxazolidin-2-one A (prepared from epibromohydrin and 4-fluoro-3-nitrophenyl isocyanate using LiBr/Bu3PO in xylene
25 analogously to US 4128654, 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°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°C for 48 h. The resin was filtered, washed repeatedly with methanol
30 (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-carboxyIic acid (5 eq,) and l-chloro-l-dimethylamino-2-methylpropene (5 eq.) in DCM (20 ml) at room temperature for 15 minutes] and
35 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
117


suspended in DMF/water (v/v 9:2, 80 ml), admixed with SnCl2*2H20 (5 eq.) and
reacted at room temperture 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°C, with an acid chloride (5 eq. of acid
5 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 l-dimethylamino-l-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
10 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
15 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.





2
TentaGelSAM"
"TentaGelSAM
oHr° -PA -








"1>V_A o .s

5 Compounds which were prepared by solid-phase-supported synthesis:
Example 172
N-({3-[3-Amino-4-(l-pyrrolidinyl)phenyl]-2-oxo-l,3-oxazolidin-5-yI}metbyl)-5-
10 chloro-2-thiophenecatboxamide

Analogously to the general procedure for preparing the derivatives B, 5 g
15 (1.25 mmol) of TentaGel SAM resin were reacted with pyrrolidine as amine
derivative 1. The aniline obtained after reduction with SnCL2*2H20 was, without any further acylarion step, removed from the solid phase and concentrated. The crude product was partitioned between ethyl acetate and NaHC03 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 (dichloro-methane/ethyl acetate, 3:1- 1:2).
]H-NMR (300 MHz, CX>C13): 1.95 - 2.08, br, 4 H; 3.15-3.30, br, 4 H; 3.65-3.81, m,
2 H; 3.89, ddd, 1H; 4.05, dd, 1 H; 4.81, dddd, 1 H; 6.46, dd, 1 H; 6.72, dd, 1 H; 6.90,
5 dd, 1 H; 6.99, dd, 1 H; 7.03, dd, 1 H; 7.29, d, 1 H,
Example 173
N-[(3-{3-(B-Alanylamino)-4-t(3-hydroxypropyl)amino]phenyl}-2-oxo-l,3-oxa-
10 zoIidin-5-y))methyl]-5-chloro-2-thiophenecar boxamide



Analogously to the general procedure for preparing the derivatives B, 5 g
15 (1.25 mmol) of TentaGel SAM resin were reacted with azetidine as amine derivative
1 and Fmoc-B-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.
20 "H-NMR (400 MHz, CD3OD): 2.31, tt, 2 H; 3.36, t, 2 H; 3.54, t, 2 H; 3.62, t, 2 H;
3.72, dd, 1 H; 3.79, dd, 1 H; 4.01, dd, 1 H; 4.29, dd, 2 H; 4.43, t, 2 H; 4.85-4,.95, m, 1 H; 7.01, d, 1 H; 4.48 - 7.55, m, 2 H; 7.61, d, 1 H; 7.84, d, 1 H.

25

Example 174
N-({3-[4-(3-Amino-l-pyrrolidinyl)-3-nitrophenyl]-2-oxo-l,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophenecarboxamide









NO. Q S-/


10

Analogously to the general procedure for preparing the derivatives B, 130 mg (32.5 p.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.
"H-NMR (400 MHz, CD3OH): 2.07-2.17, m, 1 H; 2.39-2.49, m, 1 H; 3.21-3.40, m, 2 H; 3.45, dd, 1 H; 3.50-3.60, m, 1 H; 3.67, dd, 1 H; 3.76, dd, 1 H; 3.88-4.00, m, 2 H; 4.14 - 4.21, t, 1 H; 4.85 - 4.95, m, 1 H; 7.01, d, 1 H; 7,11, d, 1 H; 7.52, d, 1 H; 7.66, dd, 1 H; 7.93, d, 1 H.



15

Example 175
N-({3-[3-Amino-4-(l-piperidinyI)phenyI]-2-oxo-l,3-oxazolidin-5-yI}methyI>5-chloro-2-thiophenecarboxamide






20
25

Analogously to the general procedure for preparing the derivatives B, 130 mg (32.5 pmol) 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. "H-NMR (400 MHz, CD3OH): 1.65-1.75, m, 2 H; 1.84-1.95, m, 4 H; 3.20-3.28, m, 4 H; 3.68, dd, 1 H; 3.73, dd, 1H; 3.90, dd, 1 H; 4.17, dd, 1 H; 4.80-4.90, m, 1 H; 7.00, d, 1 H; 7.05, dd, 1 H; 7.30-7.38, m, 2H; 7.50, d, 1 H.







Example 176
N-({3-[3-(Acetylamino)-4-(l-pyrrolidinyI)phenyI]-2-oxo-l^-oxazoIidin-5-y|}-methyl)-5-chlorO"2-thiophenecarboxamide
5
Analogously to the general procedure for preparing the derivatives B, 130 mg (32.5 pmol) of TentaGel SAM resin were reacted pyrrolidine as amine derivative 1
10 and acetyl chloride as acid derivative 1. The crude product was partitioned between
ethyl acetate NaHCO3 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). "H-NMR (400 MHz, CD3OH): 1.93 - 2.03, br, 4 H; 2.16, s, 3 H; 3.20-3.30, br, 4 H;
15 3.70, d, 2 H; 3.86, dd, 1H; 4.10, dd, 1 H; 4.14, dd, 1 H; 4.80^.90, m, I H; 7.00, d, 1
H; 7.07, d, 1 H; 7.31, dd, 1 H; 7.51, d, 1 H; 7.60, d, 1 H.

The following compounds were prepared analogously to the general procedure.
























































WE CLAIM:
1. Oxazolidinones of the general formula (I)

in which:
R1 represents 2-thiophene which is substituted in the 5-position by a radical from the group consisting of chlorine, bromine, methyl and trifluoromethyl,
R2 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 0;
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,
R3, R4, R5, R6, R7 and R8 each represent hydrogen
137

and their pharmaceuticaliy acceptable salts, hydrates, hydrates of salts of the kind such as herein described.
2. Oxazolidinones as claimed in Claim 1 having the following formula



and its pharmaceuticaliy acceptable salts, hydrates, hydrates of salts cf the kind such as herein described.
3. Process for preparing substituted oxazolidinones as claimed in
Claim 1, where
either according to a process alternative
[A] compounds of the general formula (II)



R T \ p6

in which
the radicals R2, R3, R4, R5, R6 and R 7 are each as defined in Claim 1 are reacted with carboxylic acids of the general formula (III)
138





in which
the radical R1 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 of the kind such as herein described, if appropriate in the presence of an activating or coupling agent and/or a base of the kind such as herein described, to give compounds of the general formula (I)


(I),

in which
the radicals R1, R2, R3, R4, R5, R6, R7 and R8 are each as defined in Claim 1,
or else according to a process alternative [B] compounds of the general formula (IV)



r,5 J.S

in which
the radicals R1, R3, R«, R5j R6? R7 and RS as defined in Claim 1,
are converted, using a suitable selective oxidizing agent of the kind such as herein described in an inert solvent of the kind such as herein described, into the corresponding epoxide of the general formula (V)


in which
the radicals R1, R3, R4 R5, R6,R7 and R8 are each as defined in Claim 1,
and, by reaction in an inert solvent of the kind such as herein described, if appropriate in the presence of a catalyst of the kind such as herein described, with an amine of the general formula (VI)
R2-NH2 (VI),
in which
the radical R2 is as defined in Claim 1,
the compounds of the general formula (VII)


in which
the radicals R1, R2, R3, R4, R5, R6, R7 and R8are each as defined in Claim
1,
140

are initially prepared and,
subsequently, in an inert solvent of the kind such as herein described in the presence of phosgene or phosgene equivalents, such as, for example, carbonyldiimidazole (CDI), cyclized to give the compounds of the general formula [\)


(I),

in which
the radicals R1, R2, R3, R4, R5, R6, R7 and R8are each as defined in Claim 1.
4. Medicaments, comprising at least one compound as defined in Claim 1 or 2 in a concentration of from 0.1 to 95% by weight of the total mixture and one or more pharmacologically acceptable auxiliaries or excipients of the kind such as herein described.

Dated this 11th day of June, 2002.
(RANJNA MEHTA-DUTT)
OF REMFRY & SAGAR
ATTORNEY FOR THE APPLICANTS
141

Documents:

986-MUMNP-2008-CORRESPONDENCE(8-10-2012).pdf

in-pct-2002-00763-mum-abstract(13-8-2007).pdf

in-pct-2002-00763-mum-abstract.doc

in-pct-2002-00763-mum-assignment(13-8-2007).pdf

in-pct-2002-00763-mum-cancelled page-23-7-2004.pdf

in-pct-2002-00763-mum-claims(granted)14-8-2007.doc

in-pct-2002-00763-mum-claims(granted)14-8-2007.pdf

IN-PCT-2002-00763-MUM-CORRESPONDENCE(19-7-2011).pdf

IN-PCT-2002-00763-MUM-CORRESPONDENCE(21-8-2012).pdf

IN-PCT-2002-00763-MUM-CORRESPONDENCE(30-9-2011).pdf

IN-PCT-2002-00763-MUM-CORRESPONDENCE-(19-7-2011).pdf

in-pct-2002-00763-mum-correspondence-16-7-2007.pdf

in-pct-2002-00763-mum-correspondence-ipo(14-8-2007).pdf

in-pct-2002-00763-mum-form 1(3-8-2007).pdf

in-pct-2002-00763-mum-form 13(13-8-2007).pdf

in-pct-2002-00763-mum-form 13(9-12-2005).pdf

in-pct-2002-00763-mum-form 18(13-12-2005).pdf

in-pct-2002-00763-mum-form 2(granted)14-8-2007.doc

in-pct-2002-00763-mum-form 2(granted)14-8-2007.pdf

IN-PCT-2002-00763-MUM-FORM 26(19-7-2011)-.pdf

IN-PCT-2002-00763-MUM-FORM 26(19-7-2011).pdf

in-pct-2002-00763-mum-form 3(11-6-2002).pdf

in-pct-2002-00763-mum-form 3(13-8-2007).pdf

in-pct-2002-00763-mum-form 5(11-6-2002).pdf

in-pct-2002-00763-mum-form 6(23-7-2004).pdf

in-pct-2002-00763-mum-form-pct-ipea-409(11-6-2002).pdf

IN-PCT-2002-00763-MUM-OTHER DOCUMENT(19-7-2011).pdf

in-pct-2002-00763-mum-petition under rule 137(13-8-2007).pdf

in-pct-2002-00763-mum-petition under rule 138(13-8-2007).pdf

in-pct-2002-00763-mum-power of attorney(13-8-2007).pdf

in-pct-2002-00763-mum-power of attorney(23-7-2004).pdf

IN-PCT-2002-00763-MUM-POWER OF ATTORNEY(30-9-2011).pdf


Patent Number 211300
Indian Patent Application Number IN/PCT/2002/00763/MUM
PG Journal Number 45/2007
Publication Date 09-Nov-2007
Grant Date 24-Oct-2007
Date of Filing 11-Jun-2002
Name of Patentee BAYER HEALTHCARE AG
Applicant Address D-51368 LEVERKUSEN, GERMANY
Inventors:
# Inventor's Name Inventor's Address
1 JENS POHLMANN KRONENSTR. 14, D-42285 WUPPERTAL
2 ALEXANDER STRAUB MOOSPFAD 30, D-42113 WUPPERTAL
3 THOMAS LAMPE BRILLER STR. 46, D-42105 WUPPERTAL
4 SUSANNE ROHRIG BUSCHSTR. 20, D-42327 WUPPERTAL
5 KARL-HEINZ SCHLEMMER WILDSTEIG 22a, D-42113 WUPPERTAL
6 JOSEPH PERNERSTORFER ALSENSTR. 19, D-42109 WUPPERTAL
PCT International Classification Number C07D413/14
PCT International Application Number PCT/EP00/12492
PCT International Filing date 2000-12-11
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 19962924.2 1999-12-24 Germany