U.S. patent application number 12/551487 was filed with the patent office on 2010-03-11 for substituted 2-oxo-3-phenyl-5-carbonylaminomethyl-1, 3-oxazolines and their use as anticoagulant and antithrombotics.
This patent application is currently assigned to Bayer Schering Pharma Aktiengesellschaft. Invention is credited to Thomas Lampe, Josef Pernerstorfer, Elisabeth Perzborn, Jens Pohlmann, Susanne Rohrig, Karl-Heinz Schlemmer, Alexander Straub.
Application Number | 20100063043 12/551487 |
Document ID | / |
Family ID | 7673458 |
Filed Date | 2010-03-11 |
United States Patent
Application |
20100063043 |
Kind Code |
A1 |
Straub; Alexander ; et
al. |
March 11, 2010 |
SUBSTITUTED 2-OXO-3-PHENYL-5-CARBONYLAMINOMETHYL-1, 3-OXAZOLINES
AND THEIR USE AS ANTICOAGULANT AND ANTITHROMBOTICS
Abstract
The invention relates to the field of blood coagulation, more
particularly, to novel compounds of general formula (I),
##STR00001## to a method for producing said compounds and to their
use as active ingredients in medicaments for the prevention and/or
the treatment of diseases.
Inventors: |
Straub; Alexander;
(Wuppertal, DE) ; Lampe; Thomas; (Dusseldorf,
DE) ; Pernerstorfer; Josef; (Wuppertal, DE) ;
Perzborn; Elisabeth; (Wuppertal, DE) ; Pohlmann;
Jens; (Wuppertal, DE) ; Rohrig; Susanne;
(Essen, DE) ; Schlemmer; Karl-Heinz; (Wuppertal,
DE) |
Correspondence
Address: |
Barbara A. Shimei;Director, Patents & Licensing
Bayer HealthCare LLC - Pharmaceuticals, 555 White Plains Road, Third Floor
Tarrytown
NY
10591
US
|
Assignee: |
Bayer Schering Pharma
Aktiengesellschaft
Leverkusen
DE
|
Family ID: |
7673458 |
Appl. No.: |
12/551487 |
Filed: |
August 31, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11394543 |
Mar 31, 2006 |
7582666 |
|
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12551487 |
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10470861 |
Apr 9, 2004 |
7034017 |
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PCT/EP02/00857 |
Jan 28, 2002 |
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11394543 |
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Current U.S.
Class: |
514/230.8 ;
435/375; 514/376; 544/137; 548/231 |
Current CPC
Class: |
A61P 9/00 20180101; C07D
413/14 20130101; A61P 35/00 20180101; A61P 25/28 20180101; A61P
9/10 20180101; C07D 413/10 20130101; A61P 19/02 20180101; A61P 7/02
20180101 |
Class at
Publication: |
514/230.8 ;
544/137; 548/231; 514/376; 435/375 |
International
Class: |
A61K 31/421 20060101
A61K031/421; C07D 413/10 20060101 C07D413/10; C07D 413/14 20060101
C07D413/14; A61K 31/5377 20060101 A61K031/5377; A61P 9/00 20060101
A61P009/00; A61P 9/10 20060101 A61P009/10; A61P 25/28 20060101
A61P025/28; A61P 35/00 20060101 A61P035/00; C12N 5/00 20060101
C12N005/00 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 9, 2001 |
DE |
101 05 989.2 |
Claims
1. A compound of the formula (I) ##STR00023## in which R.sup.1
represents (C.sub.6-C.sub.14)-aryl, 5- to 10-membered heteroaryl
having up to three heteroatoms from the group consisting of N, O
and S or 5- to 10-membered heterocyclyl having up to three
heteroatoms from the group consisting of N, O and S, where the
rings may be mono- to trisubstituted, independently of one another,
by halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, oxo, carboxyl or cyano, R.sup.2
represents a radical --C(O)NR.sup.8R.sup.9,
--N(R.sup.10)C(O)R.sup.11 or ##STR00024## where R.sup.8 represents
hydrogen, (C.sub.1-C.sub.6)-alkyl which for its part may be
substituted by halogen, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano,
(C.sub.6-C.sub.14)-aryl which for its part may be substituted by
halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, carboxyl or cyano, or
(C.sub.3-C.sub.7)-cycloalkyl, and R.sup.9 represents
(C.sub.1-C.sub.6)-alkyl which for its part may be substituted by
halogen, amino, mono- or di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano,
(C.sub.6-C.sub.14)-aryl which for its part may be substituted by
halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, carboxyl or cyano, or
(C.sub.3-C.sub.7)-cycloalkyl, or R.sup.8 and R.sup.9 together with
the nitrogen atom to which they are attached form a 4- to
7-membered heterocycle which may contain up to two further
heteroatoms from the group consisting of N, O and S and which may
furthermore be mono- to trisubstituted, independently of one
another, by halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, R.sup.10 and
R.sup.11, independently of one another, represent
(C.sub.1-C.sub.6)-alkyl which for its part may be substituted by
halogen, amino, mono- or di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano,
(C.sub.6-C.sub.14)-aryl which for its part may be substituted by
halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, carboxyl or cyano, or
(C.sub.3-C.sub.7)-cycloalkyl, or R.sup.10 and R.sup.11 together
with the N--C(O) group to which they are attached form a 4- to
7-membered heterocycle which may contain up to two further
heteroatoms from the group consisting of N, O and S and which may
furthermore be mono- to trisubstituted, independently of one
another, by halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, x represents 0
or 1, R.sup.12 and R.sup.13 together with the nitrogen atom to
which they are attached form a 4- to 6-membered heterocycle which
may contain a further heteroatom from the group consisting of N, O
and S and which may be up to disubstituted, independently of one
another, by amino, hydroxyl, halogen, trifluoromethyl, cyano, oxo,
mono- or di-(C.sub.1-C.sub.4)-alkylamino, (C.sub.1-C.sub.4)-alkoxy,
carboxamido, (C.sub.1-C.sub.4)-alkylcarbonyl or
(C.sub.3-C.sub.5)-cycloalkylcarbonyl, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6, independently of one another, represent hydrogen, halogen,
(C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, mono- or
di-(C.sub.1-C.sub.6)-alkylaminocarbonyl, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkanoyl,
(C.sub.1-C.sub.6)-alkanoylamino, trifluoromethyl, carbamoyl, nitro
or cyano, and R.sup.7 represents hydrogen or
(C.sub.1-C.sub.6)-alkyl, and its salts, hydrates, hydrates of the
salts and solvates, but excluding compounds of the general formula
(I) in which the radical R.sup.1 is an optionally substituted
thiophene radical.
2. A compound of the formula (I) as claimed in claim 1, in which
R.sup.1 represents (C.sub.6-C.sub.14)-aryl, 5- to 10-membered
heteroaryl having one nitrogen or oxygen atom as heteroatom and
optionally up to two further heteroatoms from the group consisting
of N, O and S or 5- to 10-membered heterocyclyl having up to three
heteroatoms from the group consisting of N, O and S, where the
rings may be mono- to trisubstituted, independently of one another,
by halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, oxo, carboxyl or cyano, R.sup.2
represents a radical --C(O)NR.sup.8R.sup.9,
--N(R.sup.10)C(O)R.sup.11 or ##STR00025## where R.sup.8 represents
hydrogen, (C.sub.1-C.sub.6)-alkyl which for its part may be
substituted by halogen, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano,
(C.sub.6-C.sub.14)-aryl which for its part may be substituted by
halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, carboxyl or cyano, or
(C.sub.3-C.sub.7)-cycloalkyl, and R.sup.9 represents
(C.sub.1-C.sub.6)-alkyl which for its part may be substituted by
halogen, amino, mono- or di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano,
(C.sub.6-C.sub.14)-aryl which for its part may be substituted by
halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, carboxyl or cyano, or
(C.sub.3-C.sub.7)-cycloalkyl, or R.sup.8 and R.sup.9 together with
the nitrogen atom to which they are attached form a 4- to
7-membered heterocycle which may contain up to two further
heteroatoms from the group consisting of N, O and S and which may
furthermore be mono- to trisubstituted, independently of one
another, by halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, R.sup.10 and
R.sup.11, independently of one another, represent
(C.sub.1-C.sub.6)-alkyl which for its part may be substituted by
halogen, amino, mono- or di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano,
(C.sub.6-C.sub.14)-aryl which for its part may be substituted by
halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, carboxyl or cyano, or
(C.sub.3-C.sub.7)-cycloalkyl, or R.sup.10 and R.sup.11 together
with the N--C(O) group to which they are attached form a 4- to
7-membered heterocycle which may contain up to two further
heteroatoms from the group consisting of N, O and S and which may
furthermore be mono- to trisubstituted, independently of one
another, by halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, x represents 0
or 1, R.sup.12 and R.sup.13 together with the nitrogen atom to
which they are attached form a 4- to 6-membered heterocycle which
may contain a further heteroatom from the group consisting of N, O
and S and which may be up to disubstituted, independently of one
another, by amino, hydroxyl, halogen, trifluoromethyl, cyano, oxo,
mono- or di-(C.sub.1-C.sub.4)-alkylamino, (C.sub.1-C.sub.4)-alkoxy,
carboxamido, (C.sub.1-C.sub.4)-alkylcarbonyl or
(C.sub.3-C.sub.5)-cycloalkylcarbonyl, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6, independently of one another, represent hydrogen, halogen,
(C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, mono- or
di-(C.sub.1-C.sub.6)-alkylaminocarbonyl, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkanoyl,
(C.sub.1-C.sub.6)-alkanoylamino, trifluoromethyl, carbamoyl, nitro
or cyano, and R.sup.7 represents hydrogen or
(C.sub.1-C.sub.6)-alkyl, and its salts, hydrates, hydrates of the
salts and solvates.
3. A compound of the formula (I) as claimed in claim 1, in which
R.sup.1 represents phenyl, naphthyl, 5- to 8-membered heteroaryl
having one nitrogen or oxygen atom as heteroatom and optionally up
to two further heteroatoms from the group consisting of N, O and S
or 5- to 8-membered heterocyclyl having up to three heteroatoms
from the group consisting of N, O and S, where the rings may be
mono- to trisubstituted, independently of one another, by halogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkoxy, cyano,
trifluoromethyl, trifluoromethoxy or trifluoromethylthio, R.sup.2
represents a radical --C(O)NR.sup.8R.sup.9,
--N(R.sup.10)C(O)R.sup.11 or, ##STR00026## where R.sup.8 represents
hydrogen, (C.sub.1-C.sub.4)-alkyl which for its part may be
substituted by halogen, amino, mono- or
di-(C.sub.1-C.sub.4)-alkylamino, hydroxyl, oxo,
(C.sub.1-C.sub.4)-alkoxy, trifluoromethyl or cyano or
(C.sub.3-C.sub.7)-cycloalkyl, and R.sup.9 represents
(C.sub.1-C.sub.4)-alkyl which for its part may be substituted by
halogen, amino, mono- or di-(C.sub.1-C.sub.4)-alkylamino, hydroxyl,
oxo, (C.sub.1-C.sub.4)-alkoxy, trifluoromethyl or cyano, or
(C.sub.3-C.sub.7)-cycloalkyl, or R.sup.8 and R.sup.9 together with
the nitrogen atom to which they are attached form a 4- to
7-membered heterocycle which may contain up to two further
heteroatoms from the group consisting of N, O and S and which may
furthermore be mono- to trisubstituted, independently of one
another, by halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, R.sup.10 and
R.sup.11, independently of one another, represent
(C.sub.1-C.sub.6)-alkyl which for its part may be substituted by
halogen, amino, mono- or di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, or
(C.sub.3-C.sub.7)-cycloalkyl, or R.sup.10 and R.sup.11 together
with the N--C(O) group to which they are attached form a 4- to
7-membered heterocycle which may contain up to two further
heteroatoms from the group consisting of N, O and S and which may
furthermore be mono- to trisubstituted, independently of one
another, by halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, x represents 0
or 1, R.sup.12 and R.sup.13 together with the nitrogen atom to
which they are attached form a 4- to 6-membered heterocycle which
may contain a further heteroatom from the group consisting of N, O
and S and which may be monosubstituted by amino, hydroxyl, halogen,
trifluoromethyl, cyano, oxo, mono- or
di-(C.sub.1-C.sub.4)-alkylamino, (C.sub.1-C.sub.4)-alkoxy,
carboxamido, (C.sub.1-C.sub.4)-alkylcarbonyl or
(C.sub.3-C.sub.5)-cycloalkylcarbonyl, R.sup.3 and R.sup.6,
independently of one another, represent hydrogen, halogen,
(C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkanoylamino, cyano,
trifluoromethyl or nitro, R.sup.4 and R.sup.5 represent hydrogen,
and R.sup.7 represents hydrogen or (C.sub.1-C.sub.4)-alkyl, and its
salts, hydrates, hydrates of the salts and solvates.
4. A compound of the formula (I) as claimed in claim 1, in which
R.sup.1 represents phenyl, furyl, dihydrothienyl, thiazolyl,
pyrrolyl or pyridyl, where the rings may be mono- to
trisubstituted, independently of one another, by fluorine,
chlorine, bromine, (C.sub.1-C.sub.4)-alkyl, trifluoromethyl,
trifluoromethoxy or trifluoromethylthio, R.sup.2 represents a
radical --C(O)NR.sup.8R.sup.9, --N(R.sup.10)C(O)R.sup.11 or
##STR00027## where R.sup.8 and R.sup.9, independently of one
another, represent (C.sub.1-C.sub.4)-alkyl which for its part may
be substituted by halogen, amino, mono- or
di-(C.sub.1-C.sub.4)-alkylamino, hydroxyl, oxo,
(C.sub.1-C.sub.4)-alkoxy, trifluoromethyl or cyano, or
(C.sub.3-C.sub.7)-cycloalkyl, or R.sup.8 and R.sup.9 together with
the nitrogen atom to which they are attached represent morpholinyl,
pyrrolidinyl, thiomorpholinyl or piperidinyl, where the rings may
be mono- or disubstituted by (C.sub.1-C.sub.4)-alkyl and/or oxo,
R.sup.10 and R.sup.11, independently of one another, represent
(C.sub.1-C.sub.6)-alkyl which for its part may be substituted by
halogen, amino, mono- or di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, or
(C.sub.3-C.sub.7)-cycloalkyl, or R.sup.10 and R.sup.11 together
with the N--C(O) group to which they are attached represent
morpholinonyl, pyrrolidinonyl, thiomorpholinonyl or piperidinonyl,
where the rings may be mono- or disubstituted by
(C.sub.1-C.sub.4)-alkyl, x represents 0 or 1, R.sup.12 and R.sup.13
together with the nitrogen atom to which they are attached form a
5- or 6-membered saturated heterocycle which may contain a further
oxygen atom in the ring and which may be monosubstituted by amino
or hydroxyl, R.sup.3 represents hydrogen, fluorine, chlorine,
bromine, (C.sub.1-C.sub.4)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.3)-alkylamino, cyano or nitro, R.sup.4, R.sup.5
and R.sup.6 represent hydrogen, and R.sup.7 represents hydrogen,
and its salts, hydrates, hydrates of the salts and solvates.
5. A process for preparing compounds of the formula (I) as claimed
in claim 1, characterized in that compounds of the formula (II)
##STR00028## in which R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6
and R.sup.7 are as defined above are reacted with carboxylic acids
of the formula (III) ##STR00029## in which R.sup.1 is as defined
above, or else with the corresponding carbonyl halides or else with
the corresponding symmetric or mixed carboxylic anhydrides of the
carboxylic acids of the formula (III) defined above.
6. A compound of the formula (I) as claimed in claim 1 for the
prevention and/or treatment of disorders.
7. A medicament comprising at least one compound of the formula (I)
as claimed in claim 1 and at least one further auxiliary.
8. The use of compounds of the formula (I) for preparing a
medicament for the prevention and/or treatment of thromboembolic
disorders, in particular myocardial infarction, angina pectoris
(including unstable angina), reocclusions and restenoses after
angioplasty or aortocoronary bypass, cerebro vascular accident,
transitory ischemic attacks, peripheral occlusive diseases,
pulmonary embolisms or deep vein thromboses.
9. The use of compounds of the formula (I) as claimed in claim 1
for preparing a medicament for the prevention and/or treatment of
disseminated intravasal coagulation (DIC).
10. The use of compounds of the formula (I) as claimed in claim 1
for preparing a medicament for the prevention and/or treatment of
disorders such as atherosclerosis; arthritis; Alzheimer's disease
or cancer.
11. A process for preventing the coagulation of blood in vitro, in
particular in banked blood or biological samples containing factor
Xa, characterized in that compounds of the general formula (I) as
claimed in claim 1 are added.
Description
[0001] The present invention relates to the field of blood
coagulation. In particular, the present invention relates to novel
oxazolidinone derivatives, to processes for their preparation and
to their use as active compounds in medicaments.
[0002] 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. Hemostasis after injury of the blood vessels is effected
mainly by the coagulation system in which an enzymatic cascade of
complex reactions of plasma proteins is triggered. Numerous blood
coagulation factors are involved in this process, each of which
factors converts, on activation, the respectively next inactive
precursor into its active form. At the end of the cascade comes the
conversion of soluble fibrinogen into insoluble fibrin, resulting
in the formation of a blood clot. In blood coagulation,
traditionally the intrinsic and the extrinsic system, which end in
a joint reaction path, are distinguished. Here factor Xa, which is
formed from the proenzyme factor X, plays a key role, since it
connects the two coagulation paths. The activated serine protease
Xa cleaves prothrombin to thrombin. The resulting thrombin, in
turn, cleaves fibrinogen to fibrin, a fibrous/gelatinous coagulant.
In addition, thrombin is a potent effector of platelet aggregation
which likewise contributes significantly to hemostasis.
[0003] Maintenance of normal hemostasis--between bleeding and
thrombosis--is subject to a complex regulatory mechanism.
Uncontrolled activation of the coagulant system or defective
inhibition of the activation processes may cause formation of local
thrombi or embolisms in vessels (arteries, veins, lymph vessels) or
in heart cavities. This may lead to serious disorders, such as
myocardial infarct, angina pectoris (including unstable angina),
reocclusions and restenoses after angioplasty or aortocoronary
bypass, stroke, transitory ischemic attacks, peripheral arterial
occlusive disorders, pulmonary embolisms or deep vein thromboses;
hereinbelow, these disorders are collectively also referred to as
thromboembolic disorders. In addition, in the case of consumption
coagulopathy, hypercoaguability may--systemically--result in
disseminated intravascular coagulation.
[0004] These thromboembolic disorders are the most frequent cause
of morbidity and mortality in most industrialized countries
(Pschyrembel, Klinisches Worterbuch [Clinical Dictionary],
257.sup.th edition, 1994, Walter de Gruyter Verlag, page 199 ff.,
entry "Blutgerinnung" [Blood Coagulation]; Rompp Lexikon Chemie,
Version 1.5, 1998, Georg Thieme Verlag Stuttgart, entry
"Blutgerinnung"; Lubert Stryer, Biochemie [Biochemistry], Spektrum
der Wissenschaft Verlagsgesellschaft mbH Heidelberg, 1990, page 259
ff.).
[0005] The anticoagulants, i.e. substances for inhibiting or
preventing blood coagulation, which are known from the prior art
have various, often grave disadvantages. Accordingly, in practice,
an efficient treatment method or prophylaxis of thromboembolic
disorders is very difficult and unsatisfactory.
[0006] In the therapy and prophylaxis of thromboembolic disorders,
use is firstly made of heparin, which is administered parenterally
or subcutaneously. Owing to more favorable pharmacokinetic
properties, preference is nowadays more and more given to
low-molecular-weight heparin; however, even with
low-molecular-weight heparin, it is not possible to avoid the known
disadvantages described below, which are involved in heparin
therapy. Thus, heparin is ineffective when administered orally and
has a relatively short half-life. Since heparin inhibits a
plurality of factors of the blood coagulation cascade at the same
time, the action is nonselective. Moreover, there is a high risk of
bleeding; in particular, brain hemorrhages and gastrointestinal
bleeding may occur, which may result in thrombopenia, drug-induced
alopecia or osteoporosis (Pschyrembel, Klinisches Worterbuch,
257.sup.th edition, 1994, Walter de Gruyter Verlag, page 610, entry
"Heparin"; Rompp Lexikon Chemie, Version 1.5, 1998, Georg Thieme
Verlag Stuttgart, entry "Heparin").
[0007] A second class of anticoagulants are the vitamin K
antagonists. These include, for example, 1,3-indanediones, and
especially compounds such as warfarin, phenprocoumon, dicumarol and
other coumarin derivatives which inhibit the synthesis of various
products of certain vitamin K-dependent coagulation factors in the
liver in a nonselective manner. Owing to the mechanism of action,
however, the onset of the action is very slow (latency to the onset
of action 36 to 48 hours). It is possible to administer the
compounds orally; however, owing to the high risk of bleeding and
the narrow therapeutic index, a time-consuming individual
adjustment and monitoring of the patient are required. Moreover,
other adverse effects, such as gastrointestinal disturbances, hair
loss and skin necroses, have been described (Pschyrembel,
Klinisches Worterbuch, 257.sup.th edition, 1994, Walter de Gruyter
Verlag, page 292 ff., entry "coumarin derivatives"; Ullmann's
Encyclopedia of Industrial Chemistry, 5.sup.th edition, VCH
Verlagsgesellschaft, Weinheim, 1985-1996, entry "vitamin K").
[0008] Recently, a novel therapeutic approach for the treatment and
prophylaxis of thromboembolic disorders has been described. This
novel therapeutic approach aims to inhibit factor Xa (cf.
WO-A-99/37304; WO-A-99/06371; J. Hauptmann, J. Sturzebecher,
Thrombosis Research 1999, 93, 203; F. Al-Obeidi, J. A. Ostrem,
Factor Xa inhibitors by classical and combinatorial chemistry, DDT
1998, 3, 223; F. Al-Obeidi, J. A. Ostrem, Factor Xa inhibitors,
Exp. Opin. Ther. Patents 1999, 9, 931; B. Kaiser, Thrombin and
factor Xa inhibitors, Drugs of the Future 1998, 23, 423; A. Uzan,
Antithrombotic agents, Emerging Drugs 1998, 3, 189; B.-Y. Zhu, R.
M. Scarborough, Curr. Opin. Card. Pulm. Ren. Inv. Drugs 1999, 1
(1), 63). It has been shown that, in animal models, various both
peptidic and nonpeptidic compounds are effective as factor Xa
inhibitors.
[0009] Accordingly, it is an object of the present invention to
provide novel substances for controlling disorders, which
substances have a wide therapeutic spectrum.
[0010] In particular, they should be suitable for a more efficient
prophylaxis and/or treatment of thromboembolic disorders,
avoiding--at least to some extent--the disadvantages of the prior
art described above, where the term "thromboembolic disorders" in
the context of the present invention is to be understood as
meaning, in particular, serious disorders, such as myocardial
infarct, angina pectoris (including unstable angina), reocclusions
and restenoses after angioplasty or aortocoronary bypass, stroke,
transitory ischemic attacks, peripheral arterial occlusive
disorders, pulmonary embolisms or deep venous thromboses.
[0011] It is another object of the present invention to provide
novel anticoagulants which inhibit the blood coagulation factor Xa
with increased selectivity, avoiding--at least to some extent--the
problems of the therapeutic methods for thromboembolic disorders
known from the prior art.
[0012] The present invention provides compounds of the formula
(I),
##STR00002##
in which [0013] R.sup.1 represents (C.sub.6-C.sub.14)-aryl, 5- to
10-membered heteroaryl having up to three heteroatoms from the
group consisting of N, O and S or 5- to 10-membered heterocyclyl
having up to three heteroatoms from the group consisting of N, O
and S, where the rings may be mono- to trisubstituted,
independently of one another, by halogen, (C.sub.1-C.sub.6)-alkyl,
amino, mono- or di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, oxo, carboxyl or cyano, [0014] R.sup.2
represents a radical --C(O)NR.sup.8R.sup.9,
--N(R.sup.10)C(O)R.sup.11 or
[0014] ##STR00003## [0015] where [0016] R.sup.8 represents
hydrogen, [0017] (C.sub.1-C.sub.6)-alkyl which for its part may be
substituted by halogen, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, [0018]
(C.sub.6-C.sub.14)-aryl which for its part may be substituted by
halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, carboxyl or cyano, [0019] or
(C.sub.3-C.sub.7)-cycloalkyl, [0020] and [0021] R.sup.9 represents
(C.sub.1-C.sub.6)-alkyl which for its part may be substituted by
halogen, amino, mono- or di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, [0022]
(C.sub.6-C.sub.14)-aryl which for its part may be substituted by
halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, carboxyl or cyano, [0023] or
(C.sub.3-C.sub.7)-cycloalkyl, [0024] or [0025] R.sup.8 and R.sup.9
together with the nitrogen atom to which they are attached form a
4- to 7-membered heterocycle which may contain up to two further
heteroatoms from the group consisting of N, O and S and which may
furthermore be mono- to trisubstituted, independently of one
another, by halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, [0026] R.sup.10
and R.sup.11, independently of one another, represent
(C.sub.1-C.sub.6)-alkyl which for its part may be substituted by
halogen, amino, mono- or di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano,
(C.sub.6-C.sub.14)-aryl which for its part may be substituted by
halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, carboxyl or cyano, [0027] or
(C.sub.3-C.sub.7)-cycloalkyl, [0028] or [0029] R.sup.10 and
R.sup.11 together with the N--C(O) group to which they are attached
form a 4- to 7-membered heterocycle which may contain up to two
further heteroatoms from the group consisting of N, O and S and
which may furthermore be mono- to trisubstituted, independently of
one another, by halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, [0030] x
represents 0 or 1, [0031] R.sup.12 and R.sup.13 together with the
nitrogen atom to which they are attached form a 4- to 6-membered
heterocycle which may contain a further heteroatom from the group
consisting of N, O and S and which may be up to disubstituted,
independently of one another, by amino, hydroxyl, halogen,
trifluoromethyl, cyano, oxo, mono- or
di-(C.sub.1-C.sub.4)-alkylamino, (C.sub.1-C.sub.4)-alkoxy,
carboxamido, (C.sub.1-C.sub.4)-alkylcarbonyl or
(C.sub.3-C.sub.5)-cycloalkylcarbonyl, [0032] R.sup.3, R.sup.4,
R.sup.5 and R.sup.6, independently of one another, represent
hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, mono- or
di-(C.sub.1-C.sub.6)-alkylaminocarbonyl, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkanoyl,
(C.sub.1-C.sub.6)-alkanoylamino, trifluoromethyl, carbamoyl, nitro
or cyano, and [0033] R.sup.7 represents hydrogen or
(C.sub.1-C.sub.6)-alkyl, and their salts, hydrates, hydrates of the
salts and solvates, but excluding compounds of the general formula
(I) in which the radical R.sup.1 is an optionally substituted
thiophene radical.
[0034] 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-[acylaminomethyl] group (preferably 5-[acetylaminomethyl])
appears to be essential for the antibacterial activity.
[0035] Substituted aryl- and heteroarylphenyloxazolidinones in
which a mono- or polysubstituted phenyl radical may be attached to
the N atom of the oxazolidinone ring and which may have an
unsubstituted N-methyl-2-thiophenecarboxamide radical in the
5-position of the oxazolidinone ring, and their use as
antibacterial substances, are known from U.S. Pat. No. 5,929,248,
U.S. Pat. No. 5,801,246, U.S. Pat. No. 5,756,732, U.S. Pat. No.
5,654,435, U.S. Pat. No. 5,654,428 and U.S. Pat. No. 5,565,571.
[0036] 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).
[0037] Depending on the substitution pattern, the compounds of the
general formula (I) according to the invention may exist in
stereoisomeric forms which are either like image and mirror image
(enantiomers) or not like image and mirror image (diastereomers).
The invention relates both to the enantiomers or diastereomers and
to their respective mixtures. The racemic forms, like the
diastereomers, can be separated in a known manner into the
stereoisomerically uniform components.
[0038] 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.
[0039] Salts of the compounds according to the invention are
physiologically acceptable salts of the compounds according to the
invention with inorganic or organic acids. Preference is given to
salts with inorganic acids, such as, for example, hydrochloric
acid, hydrobromic acid, phosphoric acid or sulfuric acid, or to
salts with organic carboxylic or sulfonic acids, such as, for
example, acetic acid, trifluoroacetic acid, propionic acid, maleic
acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic
acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid,
benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic
acid.
[0040] Salts may also be physiologically acceptable salts with
customary bases, such as, for example, alkali metal salts (for
example sodium or potassium salts), alkaline earth metal salts (for
example calcium or magnesium salts) or ammonium salts, derived from
ammonia or organic amines, such as, for example, diethylamine,
triethylamine, ethyldiisopropylamine, procaine, dibenzylamine,
N-methylmorpholine, dihydroabietyl-amine or methylpiperidine.
[0041] Moreover, the invention also embraces prodrugs of the
compounds according to the invention. According to the invention,
prodrugs are those forms of the compounds of the formula (I) which
for their part may be biologically active or inactive, but which
can be converted into the corresponding biologically active form
(for example metabolically or solvolytically) under physiological
conditions.
[0042] According to the invention, "hydrates" or "solvates" are
forms of the compounds of the general formula (I) which form a
molecule compound or a complex in the solid or liquid state by
hydration with water or coordination with solvent molecules.
Examples of hydrates are sesquihydrates, monohydrates, dihydrates
or trihydrates. Equally suitable are the hydrates or solvates of
salts of the compounds according to the invention.
[0043] Halogen represents fluorine, chlorine, bromine and iodine.
Preference is given to chlorine, bromine or fluorine.
[0044] (C.sub.1-C.sub.6)-Alkyl represents a straight-chain or
branched alkyl radical having 1 to 6 carbon atoms. Examples which
may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, tert-butyl, n-pentyl and n-hexyl. The corresponding alkyl
groups with fewer carbon atoms, such as, for example,
(C.sub.1-C.sub.4)-alkyl, are derived analogously from this
definition. In general, preference is given to
(C.sub.1-C.sub.4)-alkyl.
[0045] The meaning of the corresponding component of other more
complex substituents, such as, for example, in the case of mono- or
dialkylamino or mono- or dialkylaminocarbonyl, is likewise derived
from this definition.
[0046] (C.sub.3-C.sub.7)-Cycloalkyl represents a cyclic alkyl
radical having 3 to 7 carbon atoms. Examples which may be mentioned
are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl. Preference is given to cyclopropyl, cyclopentyl and
cyclohexyl.
[0047] (C.sub.1-C.sub.6)-Alkoxy represents a straight-chain or
branched alkoxy radical having 1 to 6 carbon atoms. Examples which
may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, isobutoxy, tert-butoxy, n-pentoxy and n-hexoxy. The
corresponding alkoxy groups having fewer carbon atoms, such as, for
example, (C.sub.1-C.sub.4)-alkoxy, are derived analogously from
this definition. In general, preference is given to
(C.sub.1-C.sub.4)-alkoxy.
[0048] (C.sub.1-C.sub.6)-Alkanoyl represents a straight-chain or
branched alkyl radical having 1 to 6 carbon atoms which carries a
doubly attached oxygen atom in the 1-position and is attached via
the 1-position. Examples which may be mentioned are: formyl,
acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl, n-hexanoyl. The
corresponding alkanoyl groups with fewer carbon atoms, such as, for
example, (C.sub.1-C.sub.5)-alkanoyl, (C.sub.1-C.sub.4)-alkanoyl and
(C.sub.1-C.sub.3)-alkanoyl, are derived analogously from this
definition. In general, preference is given to
(C.sub.1-C.sub.3)-alkanoyl.
[0049] The meaning of the corresponding component of other more
complex substituents, such as, for example, alkanoylamino, is
likewise derived from this definition.
[0050] (C.sub.6-C.sub.14)-Aryl represents an aromatic radical
having 6 to 14 carbon atoms. Examples which may be mentioned are:
phenyl, naphthyl, phenanthrenyl and anthracenyl. The corresponding
aryl groups with fewer carbon atoms, such as, for example,
(C.sub.6-C.sub.10)-aryl are derived analogously from this
definition. In general, preference is given to
(C.sub.6-C.sub.10)-aryl.
[0051] 5- to 10-membered heteroaryl having up to 3 heteroatoms from
the group consisting of N, O and S represents a mono- or bicyclic,
optionally benzofused heteroaromatic which is attached via a carbon
ring atom or, via a nitrogen ring atom of the heteroaromatic.
Examples which may be mentioned are: pyridyl, pyridyl N-oxide,
pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl,
pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl,
indolinyl, indolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl,
quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl. The
corresponding heteroaromatics having a smaller ring size, such as,
for example, 5- to 8-membered heteroaryl, 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.
[0052] 5- to 10-membered heterocyclyl having up to 3 heteroatoms
from the group consisting of S, N and O represents a saturated or
partially unsaturated mono- or bicyclic, optionally benzofused
heterocycle which is attached via a carbon ring atom or a nitrogen
ring atom. Examples which may be mentioned are: tetrahydrofuryl,
pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl,
1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl
N-oxide, thiomorpholinyl, azepinyl and 1,4-diazepinyl. Preference
is given to piperidinyl, morpholinyl, thiomorpholinyl and
pyrrolidinyl.
[0053] The corresponding heterocycles having a smaller ring size,
such as, for example, 4- to 8-membered heterocycles, are derived
analogously from this definition.
[0054] Preference is given to compounds of the formula (I),
in which [0055] R.sup.1 represents (C.sub.6-C.sub.14)-aryl, 5- to
10-membered heteroaryl having one nitrogen or oxygen atom as
heteroatom and optionally up to two further heteroatoms from the
group consisting of N, O and S or 5- to 10-membered heterocyclyl
having up to three heteroatoms from the group consisting of N, O
and S, where the rings may be mono- to trisubstituted,
independently of one another, by halogen, (C.sub.1-C.sub.6)-alkyl,
amino, mono- or di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, oxo, carboxyl or cyano, [0056] R.sup.2
represents a radical --C(O)NR.sup.8R.sup.9,
--N(R.sup.10)C(O)R.sup.11 or
[0056] ##STR00004## [0057] where [0058] R.sup.8 represents
hydrogen, [0059] (C.sub.1-C.sub.6)-alkyl which for its part may be
substituted by halogen, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, [0060]
(C.sub.6-C.sub.14)-aryl which for its part may be substituted by
halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, carboxyl or cyano, [0061] or
(C.sub.3-C.sub.7)-cycloalkyl, [0062] and [0063] R.sup.9 represents
(C.sub.1-C.sub.6)-alkyl which for its part may be substituted by
halogen, amino, mono- or di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, [0064]
(C.sub.6-C.sub.14)-aryl which for its part may be substituted by
halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, carboxyl or cyano, [0065] or
(C.sub.3-C.sub.7)-cycloalkyl, [0066] or [0067] R.sup.8 and R.sup.9
together with the nitrogen atom to which they are attached form a
4- to 7-membered heterocycle which may contain up to two further
heteroatoms from the group consisting of N, O and S and which may
furthermore be mono- to trisubstituted, independently of one
another, by halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, [0068] R.sup.10
and R.sup.11, independently of one another, represent
(C.sub.1-C.sub.6)-alkyl which for its part may be substituted by
halogen, amino, mono- or di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano,
(C.sub.6-C.sub.14)-aryl which for its part may be substituted by
halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkanoyl, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro, carboxyl or cyano, [0069] or
(C.sub.3-C.sub.7)-cycloalkyl, [0070] or [0071] R.sup.10 and
R.sup.11 together with the N--C(O) group to which they are attached
form a 4- to 7-membered heterocycle which may contain up to two
further heteroatoms from the group consisting of N, O and S and
which may furthermore be mono- to trisubstituted, independently of
one another, by halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, [0072] x
represents 0 or 1, [0073] R.sup.12 and R.sup.13 together with the
nitrogen atom to which they are attached form a 4- to 6-membered
heterocycle which may contain a further heteroatom from the group
consisting of N, O and S and which may be up to disubstituted,
independently of one another, by amino, hydroxyl, halogen,
trifluoromethyl, cyano, oxo, mono- or
di-(C.sub.1-C.sub.4)-alkylamino, (C.sub.1-C.sub.4)-alkoxy,
carboxamido, (C.sub.1-C.sub.4)-alkylcarbonyl or
(C.sub.3-C.sub.5)-cycloalkylcarbonyl, [0074] R.sup.3, R.sup.4,
R.sup.5 and R.sup.6, independently of one another, represent
hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, mono- or
di-(C.sub.1-C.sub.6)-alkylaminocarbonyl, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkanoyl,
(C.sub.1-C.sub.6)-alkanoylamino, trifluoromethyl, carbamoyl, nitro
or cyano, and [0075] R.sup.7 represents hydrogen or
(C.sub.1-C.sub.6)-alkyl, and their salts, hydrates, hydrates of the
salts and solvates.
[0076] Particular preference is given to compounds of the formula
(I),
in which [0077] R.sup.1 represents phenyl, naphthyl, 5- to
8-membered heteroaryl having one nitrogen or oxygen atom as
heteroatom and optionally up to two further heteroatoms from the
group consisting of N, O and S or 5- to 8-membered heterocyclyl
having up to three heteroatoms from the group consisting of N, O
and S, where the rings may be mono- to trisubstituted,
independently of one another, by halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy, cyano, trifluoromethyl, trifluoromethoxy
or trifluoromethylthio, [0078] R.sup.2 represents a radical
--C(O)NR.sup.8R.sup.9, --N(R.sup.10)C(O)R.sup.11 or
[0078] ##STR00005## [0079] where [0080] R.sup.8 represents
hydrogen, (C.sub.1-C.sub.4)-alkyl which for its part may be
substituted by halogen, amino, mono- or
di-(C.sub.1-C.sub.4)-alkylamino, hydroxyl, oxo,
(C.sub.1-C.sub.4)-alkoxy, trifluoromethyl or cyano or
(C.sub.3-C.sub.7)-cycloalkyl, [0081] and [0082] R.sup.9 represents
(C.sub.1-C.sub.4)-alkyl which for its part may be substituted by
halogen, amino, mono- or di-(C.sub.1-C.sub.4)-alkylamino, hydroxyl,
oxo, (C.sub.1-C.sub.4)-alkoxy, trifluoromethyl or cyano, or
(C.sub.3-C.sub.7)-cycloalkyl, [0083] or [0084] R.sup.8 and R.sup.9
together with the nitrogen atom to which they are attached form a
4- to 7-membered heterocycle which may contain up to two further
heteroatoms from the group consisting of N, O and S and which may
furthermore be mono- to trisubstituted, independently of one
another, by halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, [0085] R.sup.10
and R.sup.11, independently of one another, represent
(C.sub.1-C.sub.6)-alkyl which for its part may be substituted by
halogen, amino, mono- or di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, or
(C.sub.3-C.sub.7)-cycloalkyl, [0086] or [0087] R.sup.10 and
R.sup.11 together with the N--C(O) group to which they are attached
form a 4- to 7-membered heterocycle which may contain up to two
further heteroatoms from the group consisting of N, O and S and
which may furthermore be mono- to trisubstituted, independently of
one another, by halogen, (C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, [0088] x
represents 0 or 1, [0089] R.sup.12 and R.sup.13 together with the
nitrogen atom to which they are attached form a 4- to 6-membered
heterocycle which may contain a further heteroatom from the group
consisting of N, O and S and which may be monosubstituted by amino,
hydroxyl, halogen, trifluoromethyl, cyano, oxo, mono- or
di-(C.sub.1-C.sub.4)-alkylamino, (C.sub.1-C.sub.4)-alkoxy,
carboxamido, (C.sub.1-C.sub.4)-alkylcarbonyl or
(C.sub.3-C.sub.5)-cycloalkylcarbonyl, [0090] R.sup.3 and R.sup.6,
independently of one another, represent hydrogen, halogen,
(C.sub.1-C.sub.6)-alkyl, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkanoylamino, cyano,
trifluoromethyl or nitro, [0091] R.sup.4 and R.sup.5 represent
hydrogen, and [0092] R.sup.7 represents hydrogen or
(C.sub.1-C.sub.4)-alkyl, and their salts, hydrates, hydrates of the
salts and solvates.
[0093] Very particular preference is given to compounds of the
formula (I),
in which [0094] R.sup.1 represents phenyl, furyl, dihydrothienyl,
thiazolyl, pyrrolyl or pyridyl, where the rings may be mono- to
trisubstituted, independently of one another, by fluorine,
chlorine, bromine, (C.sub.1-C.sub.4)-alkyl, trifluoromethyl,
trifluoromethoxy or trifluoromethylthio, [0095] R.sup.2 represents
a radical --C(O)NR.sup.8R.sup.9, --N(R.sup.10)C(O)R.sup.11 or
[0095] ##STR00006## [0096] where [0097] R.sup.8 and R.sup.9,
independently of one another, represent (C.sub.1-C.sub.4)-alkyl
which for its part may be substituted by halogen, amino, mono- or
di-(C.sub.1-C.sub.4)-alkylamino, hydroxyl, oxo,
(C.sub.1-C.sub.4)-alkoxy, trifluoromethyl or cyano, or
(C.sub.3-C.sub.7)-cycloalkyl, [0098] or [0099] R.sup.8 and R.sup.9
together with the nitrogen atom to which they are attached
represent morpholinyl, pyrrolidinyl, thiomorpholinyl or
piperidinyl, where the rings may be mono- or disubstituted by
(C.sub.1-C.sub.4)-alkyl and/or oxo, [0100] R.sup.10 and R.sup.11,
independently of one another, represent (C.sub.1-C.sub.6)-alkyl
which for its part may be substituted by halogen, amino, mono- or
di-(C.sub.1-C.sub.6)-alkylamino, hydroxyl, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethyl or cyano, or
(C.sub.3-C.sub.7)-cycloalkyl, [0101] or [0102] R.sup.10 and
R.sup.11 together with the N--C(O) group to which they are attached
represent morpholinonyl, pyrrolidinonyl, thiomorpholinonyl or
piperidinonyl, where the rings may be mono- or disubstituted by
(C.sub.1-C.sub.4)-alkyl, [0103] x represents 0 or 1, [0104]
R.sup.12 and R.sup.13 together with the nitrogen atom to which they
are attached form a 5- or 6-membered saturated heterocycle which
may contain a further oxygen atom in the ring and which may be
monosubstituted by amino or hydroxyl, [0105] R.sup.3 represents
hydrogen, fluorine, chlorine, bromine, (C.sub.1-C.sub.4)-alkyl,
amino, mono- or di-(C.sub.1-C.sub.3)-alkylamino, cyano or nitro,
[0106] R.sup.4, R.sup.5 and R.sup.6 represent hydrogen, and [0107]
R.sup.7 represents hydrogen, and their salts, hydrates, hydrates of
the salts and solvates.
[0108] The present invention also provides a process for preparing
the compounds of the general formula (I) according to the invention
where
compounds of the formula (II)
##STR00007##
in which R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7
are as defined above are reacted with carboxylic acids of the
formula (III)
##STR00008##
in which R.sup.1 is as defined above, 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 formula (III) defined
above in inert solvents, if appropriate in the presence of
auxiliaries and/or bases, to give compounds of the formula (I).
[0109] Solvents suitable for the process described above are
organic solvents which are inert under the reaction conditions.
These include halogenated hydrocarbons, such as dichloromethane,
trichloromethane, carbon tetrachloride or 1,2-dichloroethane,
ethers, such as diethyl ether, dioxane or tetrahydrofuran, or other
solvents, such as ethyl acetate, dimethylformamide, acetonitrile,
pyridine, N-methylpyrrolidone (NMP) or dimethylacetamide.
[0110] It is also possible to use solvent mixtures of the solvents
mentioned above.
[0111] Suitable for use as auxiliaries for the formation of the
amide are customary condensing agents and/or activating agents,
such as carbodiimides, for example
N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide.HCl (EDC),
N,N'-dicyclohexylcarbodiimide (DCC), if appropriate in the presence
of 1-hydroxy-1H-benzotriazole.H.sub.2O(HOBt),
benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate
(PyBOP.RTM.), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TBTU),
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU),
2-(2-oxo-1-(2H)-pyridyl-1,1,3,3-tetramethyluronium
tetrafluoroborate (TPTU) or
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), or carbonyl compounds, such as
carbonyldiimidazole.
[0112] Suitable for use as bases are trialkylamines, for example
triethylamine, N-methylmorpholine (NMM), N-methylpiperidine,
diisopropylethylamine (Hunig base) or 4-N,N-dimethylaminopyridine
(DMAP) or pyridine.
[0113] The reactions are generally carried out in a temperature
range of from 0.degree. C. to the reflux temperature, preferably in
the range of from 0.degree. C. to room temperature.
[0114] The reactions can be carried out under atmospheric, elevated
or reduced pressure (for example in the range of from 0.5 to 5
bar). In general, the reactions are carried out under atmospheric
pressure.
[0115] The compounds of the general formulae (II) and (1H) are
known per se to the person skilled in the art or can be prepared by
customary methods. For oxazolidinones, in particular the
5-(aminomethyl)-2-oxooxazolidines required, cf. WO-A-98/01446;
WO-A-93/23384; WO-A-97/03072; J. A. Tucker et al., J. Med. Chem.
1998, 41, 3727; S. J. Brickner et al., J. Med. Chem. 1996, 39, 673;
W. A. Gregory et al., J. Med. Chem. 1989, 32, 1673.
[0116] The compounds of the general formula (I) according to the
invention have an unforeseeable useful pharmacological activity
spectrum and are therefore particularly suitable for the
prophylaxis and/or treatment of disorders.
[0117] The compounds of the general formula (I) according to the
invention act in particular as anticoagulants and can therefore
preferably be employed in medicaments for the prophylaxis and/or
therapy of thromboembolic disorders. For the purpose of the present
invention, "thromboembolic disorders" include, in particular,
serious disorders such as myocardial infarct, angina pectoris
(including unstable angina), reocclusions and restenoses after
angioplasty or aortocoronary bypass, stroke, transitory ischemic
attacks, peripheral arterial occlusion disorders, pulmonary
embolisms or deep vein thromboses.
[0118] Furthermore, the compounds of the general formula (I)
according to the invention are also suitable for treating
disseminated intravascular coagulation (DIC).
[0119] Finally, the compounds of the general formula (I) according
to the invention are also suitable for the prophylaxis and/or
treatment of atherosclerosis and arthritis, and additionally also
for the prophylaxis and/or treatment of Alzheimer's disease and
cancer.
[0120] Furthermore, the present invention also includes a method
for preventing blood coagulation in vitro, in particular in banked
blood or biological samples which contain factor Xa, which method
is characterized in that compounds of the general formula (I) are
added.
[0121] The compounds of the general formula (I) according to the
invention act in particular as selective inhibitors of the blood
coagulation factor Xa and do not inhibit, or only inhibit at
considerably higher concentrations, other serine proteases as well,
such as thrombin, plasmin or trypsin.
[0122] In the context of the present invention, inhibitors of the
blood coagulation factor Xa in which the IC.sub.50 values for the
factor Xa inhibition are lower by a factor of 100, preferably by a
factor of 500, in particular by a factor of 1000, than the
IC.sub.50 values for the inhibition of other serine proteases, in
particular thrombin, plasmin and trypsin, are referred to as being
"selective", where with a view to the test methods for selectivity,
reference is made to the test methods of Examples A-1) a.1) and
a.2) described below.
[0123] All customary administration forms are suitable for
administration of the compounds according to the invention.
Administration is preferably carried out orally, lingually,
sublingually, buccally, rectally or parenterally (i.e. bypassing
the intestinal tract, that is intravenously, intraarterially,
intracardially, intracutaneously, subcutaneously, transdermally,
intraperitoneally or intramuscularly). Particularly suitable are
oral and intravenous administration. Very particular preference is
given to oral administration, this being a further advantage with
respect to the prior-art therapy of thromboembolic disorders.
[0124] The novel active compounds of the general formula (I) can be
converted in a known manner into the customary formulations, such
as tablets, sugar-coated tablets, pills, granules, aerosols,
syrups, emulsions, suspensions and solutions, using inert non-toxic
pharmaceutically suitable excipients or solvents. Here, the
therapeutically active compound should in each case be present in a
concentration of from about 0.1 to 95% by weight, preferably from
0.5 to 90% by weight, in particular from 1 to 85% by weight, of the
total mixture, i.e. in amounts which are sufficient in order to
achieve the dosage range indicated.
[0125] In spite of this, if appropriate, it may be necessary to
depart from the amounts mentioned, namely depending on the body
weight or on the type of administration route, on the individual
response to the medicament, on the manner of its formulation and
the time or interval at which administration takes place. Thus, in
some cases it may be adequate to manage with less than the
abovementioned minimum amount, while in other cases the upper limit
mentioned must be exceeded. In the case of the administration of
relatively large amounts, it may be advisable to divide these into
several individual administrations over the course of the day.
[0126] 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.
[0127] In general it has proved advantageous in the case of
intravenous administration to administer amounts from approximately
0.001 to 10 mg/kg, preferably approximately 0.01 to 10 mg/kg, in
particular approximately 0.1 to 8 mg/kg, of body weight to achieve
effective results.
[0128] In general, it has proved advantageous in the case of oral
administration to administer amounts from approximately 0.01 to 50
mg/kg, preferably approximately 0.1 to 10 mg/kg, in particular
approximately 0.5 to 8 mg/kg, of body weight to achieve effective
results.
[0129] In spite of this, if appropriate, it may be necessary in the
case of intravenous or oral administration to depart from the
amounts mentioned, namely depending on the body weight or on the
type of administration route, on the individual response to the
medicament, on the manner of its formulation and the time or
interval at which administration takes place. Thus, in some cases
it may be adequate to manage with less than the abovementioned
minimum amount, while in other cases the upper limit mentioned must
be exceeded. In the case of the administration of relatively large
amounts, it may be advisable to divide these over the course of the
day, namely into several individual doses or as a continuous
infusion.
[0130] Compared to the conventional preparations for treating
thromboembolic disorders, the compounds of the general formula (I)
according to the invention are distinguished in particular by the
fact that a greater therapeutic range is achieved by the selective
inhibition of factor Xa. For the patient, this means a lower risk
of bleeding, and for the treating physician, this means that the
patient is easier to adjust. Moreover--owing to the mechanism--the
onset of action is more rapid. Above all, however, the compounds
according to the invention permit an oral administration form,
which is a further advantage of the therapy with the compounds
according to the invention.
[0131] The present invention is illustrated by the examples
below.
A EVALUATION OF THE PHYSIOLOGICAL ACTIVITY
1. General Test Methods
[0132] The particularly advantageous biological properties of the
compounds according to the invention can be determined by the
following methods.
a) Test Description (In Vitro)
a.1) Determination of the Factor Xa Inhibition
[0133] The enzymatic activity of human factor Xa (FXa) was measured
using the conversion of a chromogenic substrate specific for FXa.
Factor Xa cleaves p-nitroaniline from the chromogenic substrate.
The determinations were carried out in microtiter plates as
follows.
[0134] The test substances, in various concentrations, were
dissolved in DMSO and incubated at 25.degree. C. with human FXa
(0.5 nmol/l dissolved in 50 mmol/l of tris buffer
[C,C,C-tris(hydroxymethyl)aminomethane], 150 mmol/l of NaCl, 0.1%
BSA (bovine serum albumin), pH=8.3) for 10 minutes. Pure DMSO was
used as control. The chromogenic substrate (150 .mu.mol/l of
Pefachrome.RTM. FXa from Pentapharm) was then added. After an
incubation time of 20 minutes at 25.degree. C., the extinction at
405 nm was determined. The extinctions of the test mixtures
containing test substance were compared with the control mixtures
without test substance, and the IC.sub.50 values were calculated
from these data.
TABLE-US-00001 Example IC.sub.50 1 20 nM 6 26 nM
a.2) Determination of the Selectivity
[0135] 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/l, 20 mmol/l CaCl.sub.2, pH=8.0) and incubated with test
substance or solvent for 10 minutes. The enzymatic reaction was
then started by adding the corresponding specific chromogenic
substrates (Chromozym Thrombin.RTM. from Boehringer Mannheim,
Chromozym Trypsin.RTM. from Boehringer Mannheim, Chromozym
Plasmin.RTM. from Boehringer Mannheim) and the extinction at 405 nm
was determined after 20 minutes. All determinations were carried
out at 37.degree. C. The extinctions of the test mixtures
containing test substance were compared with the control samples
without test substance, and the IC.sub.50 values were calculated
from these data.
a.3) Determination of the Anticoagulant Action
[0136] The anticoagulant action of the test substances was
determined in vitro in human plasma. To this end, human blood was
drawn off in a mixing ratio of sodium citrate/blood of 1/9 using a
0.11 molar sodium citrate solution as receiver. Immediately after
the blood had been drawn off, it was mixed thoroughly and
centrifuged at about 2000 g for 10 minutes. The supernatant was
pipetted off. The prothrombin time (PT, synonyms: thromboplastin
time, quick test) was determined in the presence of varying
concentrations of test substance or the corresponding solvent using
a commercial test kit (Neoplastin.RTM. from Boehringer Mannheim).
The test compounds were incubated with the plasma at 37.degree. C.
for 10 minutes. Coagulation was then started by addition of
thromboplastin, and the time when coagulation occurred was
determined. The concentration of test substance which effected a
doubling of the prothrombin time was determined.
b) Determination of the Antithrombotic Activity (In Vivo)
b.1) Arteriovenous Shunt Model (Rat)
[0137] Fasting male rats (strain: HSD CPB:WU) having a weight of
200-250 g were anesthetized using a Rompun/Ketavet solution (12
mg/kg/50 mg/kg). Thrombus formation was initiated in an
arteriovenous shunt in accordance with the method described by
Christopher N. Berry et al., Br. J. Pharmacol. (1994), 113,
1209-1214. To this end, the left jugular vein and the right carotid
artery were exposed. The two vessels were connected by an
extracorporeal shunt using a polyethylene tube (PE 60) of a length
of 10 cm. In the middle, this polyethylene tube was attached to a
further polyethylene tube (PE 160) of a length of 3 cm which
contained a roughened nylon thread which had been arranged to form
a loop, to form a thrombogenic surface. The extracorporeal
circulation was maintained for 15 minutes. The shunt was then
removed and the nylon thread with the thrombus was weighed
immediately. The weight of the nylon thread on its own had been
determined before the experiment was started. Before the
extracorporeal circulation was set up, the test substances were
administered to the animals while awake either intravenously via
the tail vein or orally using a pharyngeal tube.
b.2) Arterial Thrombosis Model (Rat)
[0138] Male fasting rats (strain: HSD CPB: WU) were anesthetized as
described above. On average, the rats had a weight of about 200 g.
The left carotid artery was exposed (about 2 cm). The formation of
an arterial thrombus was induced by mechanical injury to the blood
vessel in accordance with the method described by K. Meng et al.,
Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. To
this end, the exposed carotid artery was clamped from the blood
flow, cooled to -12.degree. C. in a metal trough for 2 minutes and,
to standardize the size of the thrombi, simultaneously compressed
using a weight of 200 g. The blood flow was then additionally
reduced by a clip which was placed around the carotid artery
distally from the injured section of the vessel. The proximal clamp
was removed, and the wound was closed and re-opened after 4 hours
to remove the injured section of the vessel. The section of the
vessel was opened longitudinally and the thrombus was removed from
the injured section of the vessel. The moist weight of the thrombi
was determined immediately. The test substances were administered
to the animals while awake at the beginning of the experiment,
either intravenously via the tail vein or orally using a pharyngeal
tube.
b.3) Venous Thrombosis Model (Rat)
[0139] Male fasting rats (strain: HSD CPB: WU) were anesthetized as
described above. On average, the rats had a weight of about 200 g.
The left jugular vein was exposed (about 2 cm). The formation of a
venous thrombus was induced by mechanical injury to the blood
vessel in accordance with the method described by K. Meng et al.,
Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. To
this end, the jugular vein was clamped from the blood flow, cooled
to -12.degree. C. in a metal trough for 2 minutes and, to
standardize the size of the thrombi, simultaneously compressed
using a weight of 200 g. The blood flow was re-opened and the wound
was closed. After 4 hours, the wound was re-opened to remove the
thrombi from the injured sections of the vessel. The moist weight
of the thrombi was determined immediately. The test substances were
administered to the animals while awake at the beginning of the
experiment, either intravenously via the tail vein or orally using
a pharyngeal tube.
B PREPARATION EXAMPLES
HPLC Parameters
[0140] [1] Column: Kromasil C18 60*2, L-R temperature: 30.degree.
C., flow rate=0.75 mlmin.sup.-1, mobile phase: A=0.01 M
H.sub.3PO.sub.4, B=CH.sub.3CN, gradient: ->0.5 min 90% A
->4.5 min 10% A ->6.5 min 10% A. [2] Column: Kromasil C18
60*2, L-R temperature: 30.degree. C., flow rate=0.75 mlmin.sup.-1,
mobile phase: A=0.005 M HClO.sub.4, B=CH.sub.3CN, gradient:
->0.5 min 98% A ->4.5 min 10% A ->6.5 min 10% A. [3]
Column: Symmetry C18 2.1.times.150 mm, column oven: 50.degree. C.,
flow rate=0.6 mlmin.sup.-1, mobile phase: A=0.6 g 30% strength
HCl/1 water, B=CH.sub.3CN, gradient: 0.0 min 90% A ->4.0 min 10%
A ->9 min 10% A.
[4] MHZ-2P, Instrument Micromass Platform LCZ
[0141] Column Symmetry C18, 50 mm.times.2.1 mm, 3.5 .mu.m,
temperature: 40.degree. C., flow rate=0.5 mlmin.sup.+1, mobile
phase A=CH.sub.3CN+0.1% formic acid, mobile phase B=water+0.1%
formic acid, gradient: 0.0 min 10% A ->4 min 90% A ->6 min
90% A.
Starting Materials
Example I
4-(4-Morpholin-3-onyl)aniline
##STR00009##
[0142] I-a 4-(4-Morpholin-3-onyl)nitrobenzene
[0143] The preparation of morpholin-3-one is described in U.S. Pat.
No. 5,349,045.
[0144] Over a period of 2 hours, sodium hydride (88 g, 2.2 mol, 60%
in paraffin) is added a little at a time to a solution of
morpholin-3-one (202 g, 2 mol) in N-methylpyrrolidone (2 l). After
the evolution of hydrogen has ceased, 4-fluoronitrobenzene (282 g,
2 mol) is added dropwise with cooling over a period of one hour,
and the reaction mixture is stirred overnight. At 12 mbar and
76.degree. C., 1.7 l of the volume of the liquid is then distilled
off, the residue is poured into water (2 l) and this mixture is
extracted twice with ethyl acetate (in each case 1 l). The combined
organic phases are washed with water, dried over sodium sulfate,
filtered and concentrated under reduced pressure. Purification is
carried out by chromatography (on silica gel, hexane/ethyl acetate
1:1) and subsequent crystallization from ethyl acetate. Yield: 78 g
(colorless to brownish solid), 17.6% of theory.
[0145] .sup.1H NMR (300 MHz, CDCl.sub.3): 3.86 (m, 2H,
CH.sub.2CH.sub.2), 4.08 (m, 2H, CH.sub.2CH.sub.2), 4.49 (s, 2H,
CH.sub.2CO), 7.61 (d, 2H, .sup.3J=8.95 Hz, CHCH), 8.28 (d, 2H,
.sup.3J=8.95 Hz, CHCH);
[0146] MS (r.I. %)=222 (74, M.sup.+.), 193 (100), 164 (28), 150
(21), 136 (61), 117 (22), 106 (24), 90 (37), 76 (38), 63 (32), 50
(25).
I-b 4-(4-Morpholin-3-onyl)aniline
[0147] In an autoclave, 4-(4-morpholin-3-onyl)nitrobenzene (63 g,
0.275 mol) is dissolved in tetrahydrofuran (200 ml), Pd/C (3.1 g,
5%) is added and the mixture is hydrogenated at 70.degree. C. and a
hydrogen pressure of 50 bar for 8 hours. The catalyst is filtered
off and the solvent is then distilled off under reduced pressure
and the product is purified by crystallization from ethyl acetate.
Yield: 20 g (colorless to bluish solid), 37.6% of theory.
Alternatively, purification can also be carried out by
chromatography (on silica gel, hexane/ethyl acetate mixture).
[0148] .sup.1H NMR (300 MHz, CDCl.sub.3): 3.67 (m, 2H,
CH.sub.2CH.sub.2), 3.99 (m, 2H, CH.sub.2CH.sub.2), 4.27 (s, 2H,
CH.sub.2CO), 6.68 (d, 2H, .sup.3J=8.71 Hz, CHCH), 7.03 (d, 2H,
.sup.3J=8.71 Hz, CHCH);
[0149] MS (r.I. %)=192 (100, M.sup.+.), 163 (48), 133 (26), 119
(76), 106 (49), 92 (38), 67 (27), 65 (45), 52 (22), 28 (22).
Example II
4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-3-morpholinon-
e
##STR00010##
[0150] II-a
2-((2R)-2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoi-
ndole-1,3(2H)-dione
[0151] A suspension of
2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (A. Gutcait et
al. Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mmol) and
4-(4-aminophenyl)-3-morpholinone (5.37 g, 27.9 mmol) in
ethanol/water (9:1, 140 ml) is heated under reflux for 14 hours
(the precipitate dissolves; after some time, another precipitate is
formed). The precipitate (desired product) is filtered off, washed
three times with diethyl ether and dried. The combined mother
liquors are concentrated under reduced pressure and, after addition
of a second portion of
2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3-(2H)-dione (2.84 g, 14.0
mmol), suspended in ethanol/water (9:1, 70 ml) and heated under
reflux for 13 hours (the precipitate dissolves; after some time,
another precipitate is formed). The precipitate (desired product)
is filtered off, washed three times with diethyl ether and dried.
Total yield: 10.14 g, 92% of theory.
[0152] MS (ESI): m/z (%)=418 ([M+Na].sup.+, 84), 396 ([M+H].sup.+,
93);
[0153] HPLC (method 2): rt=3.34 min.
II-b
2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}-
methyl)-1H-isoindole-1,3(2H)-dione
[0154] Under argon, N,N'-carbonyldiimidazole (2.94 g, 18.1 mmol)
and dimethylaminopyridine (catalytic amount) are added at room
temperature to a suspension of the aminoalcohol (3.58 g, 9.05 mmol)
in tetrahydrofuran (90 mol). The reaction suspension is stirred at
60.degree. C. for 12 hours (the precipitate dissolves; after some
time, another precipitate is formed), a second portion of
N,N'-carbonyldiimidazole (2.94 g, 18.1 mmol) is added and the
mixture is stirred at 60.degree. C. for another 12 hours. 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.
[0155] MS (ESI): m/z (%)=422 ([M+H].sup.+, 100);
[0156] HPLC (method 3): rt=3.37 min.
II-c
4-{4[(5S)-5-Aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}-3-morphol-
inone
[0157] At room temperature, methylamine (40% 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
heated under reflux for one hour and concentrated under reduced
pressure. The crude product is used for the next reaction without
further purification.
[0158] MS (EST): m/z (%)=292 ([M+H].sup.+, 100);
[0159] HPLC (method 2): rt=2.66 min.
Example III
(5S)-5-(Aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-o-
ne
##STR00011##
[0160] III-a Benzyl 4-(2-oxo-1-pyrrolidinyl)phenylcarbamate
[0161] At -20.degree. C., benzyl chloroformate (4.27 g, 25.03 mmol)
is slowly added dropwise to 1-(4-aminophenyl)pyrrolidin-2-one (4 g,
22.7 mmol) and N,N-dimethylaniline (3.6 ml, 28.4 mmol) in
tetrahydrofuran (107 ml). The reaction mixture is stirred at
-20.degree. C. for 30 min and then warmed to room temperature.
After addition of ethyl acetate (0.5 l), the organic phase is
washed with saturated NaCl solution (0.5 l). The combined organic
phase are dried (magnesium sulfate), filtered and concentrated
under reduced pressure. The residue is titrated with diethyl ether
and filtered off with suction. Yield: 5.2 g, 74% of theory,
light-beige crystals, melting point: 174.degree. C.
III-b
(5R)-5-(Hydroxymethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazol-
idin-2-one
[0162] Under argon, n-butyllithium (7.27 ml, 2.5 M solution in
hexane) is, at -10.degree. C., added dropwise to isoamyl alcohol
(1.47 g, 16.66 mmol) in tetrahydrofuran (200 ml) and further
n-butyllithium is added until the added indicator
N-benzylidenebenzylamine changes its color. The reaction mixture is
stirred at -10.degree. C. for 10 minutes and cooled to -78.degree.
C., and a solution of benzyl
4-(2-oxo-1-pyrrolidinyl)phenylcarbamate (4.7 g, 15.14 mmol) is
added slowly. n-Butyllithium (2.5 M solution in hexane) is then
added again, until the color of the indicator changes to pink. The
reaction mixture is stirred at -78.degree. C. for 10 minutes,
R-glycidyl butyrate (2.62 g, 18.17 g) is added and the mixture is
stirred at -78.degree. C. for 30 minutes. The reaction mixture is
warmed to room temperature overnight, and water (200 ml) is added.
The tetrahydrofuran fraction is removed under reduced pressure. The
aqueous residue is extracted with ethyl acetate and the combined
organic phases are dried with (magnesium sulfate), filtered and
concentrated under reduced pressure. The residue is titrated with
diethyl ether (500 ml) and the precipitated crystals are filtered
off with suction. Yield: 3.76 g, 90% of theory.
[0163] Melting point: 148.degree. C.,
[0164] R.sub.f(SiO.sub.2, toluene/ethyl acetate 1:1)=0.04,
(starting material=0.3).
III-c
(5S)-5-(Aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolid-
in-2-one
[0165] At 0.degree. C., methanesulfonyl chloride (1.79 g, 15.64
mmol) is added to a solution of
(5R)-5-(hydroxymethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin--
2-one (3.6 g, 13.0 mmol) and triethylamine (2.9 g, 28.7 mmol) in
dichloromethane (160 ml). The reaction mixture is stirred at
0.degree. C. for 1.5 hours and at room temperature for 3 hours and
then washed with water, and the aqueous phase is reextracted with
dichloromethane. The combined organic phases are dried (magnesium
sulfate), filtered and concentrated under reduced pressure. The
residue (1.67 g) is then dissolved in acetonitrile (70 ml),
phthalimide potassium (2.62 g, 14.16 mmol) is added and the mixture
is stirred in a closed vessel in a microwave oven at 180.degree. C.
for 45 min. Insoluble residue is removed from the mixture by
filtration, the filtrate is evaporated under reduced pressure, the
residue (1.9 g) is dissolved in methanol and hydrazine hydrate
(0.47 g, 9.37 mmol) is added. The reaction mixture is heated under
reflux for 2 hours and cooled, saturated sodium bicarbonate
solution is added and the mixture is extracted six times with
methylene chloride (2 l in total). The combined organic phases are
dried (magnesium sulfate), filtered and concentrated under reduced
pressure.
[0166] The resulting product is used without further
purification.
SYNTHESIS EXAMPLES
Example 1
4-Chloro-N-({(5S)-2-oxo-4-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-
-yl}methyl)benzamide
##STR00012##
[0168] Under argon, 4-chlorobenzoyl chloride (72.1 mg, 0.41 mmol)
is added dropwise at room temperature to a solution of the amine II
(80.0 mg, 0.27 mmol) in pyridine (2 ml). The reaction mixture is
stirred at room temperature for 2 hours and then diluted with
pyridine (4 ml), aminomethylpolystyrene resin (2.5 eq.) is added
and the mixture is shaken at room temperature for 1.5 hours. The
resin is filtered and washed repeatedly with
dichloromethane/methanol (5:1). The combined filtrates are
concentrated under reduced pressure. The desired product is
purified by flash chromatography (dichloromethane/methanol
mixtures). Yield: 105.1 mg, 89% of theory.
[0169] .sup.1H NMR (DMSO-d.sup.6, 200 MHz): 8.90 (t, 1H), 7.86 (d,
2H), 7.60-7.50 (m, 4H), 7.40 (d, 2H), 4.92-4.82 (m, 1H), 4.24-4.15
(m, 1H), 4.19 (s, 2H), 4.00-3.93 (m, 2H), 3.93-3.85 (dd, 1H),
3.75-3.68 (m, 2H), 3.68-3.60 (m, 2H);
[0170] MS (DCI, NH.sub.3): m/z (%)=447 ([M+NH.sub.4].sup.+,
100);
[0171] HPLC (method 2): rt=3.76 min.
[0172] The following compounds were prepared analogously:
TABLE-US-00002 Ex- HPLC ample method: num- retention ber Structure
Mass time 2 ##STR00013## MS (ESI): m/z (%) = 414 ([M + H].sup.+,
100) Method 4: 3.44 min 3 ##STR00014## MS (ESI): m/z (%) = 458/460
([M + H].sup.+, 100) Method 4: 3.53 min 4 ##STR00015## MS (ESI):
m/z (%) = 414 ([M + H].sup.+, 100) Method 2: 3.57 min 5
##STR00016## MS (ESI): m/z (%) = 386 ([M + H].sup.+, 100) Method 2:
3.24 min
Example 6
5-Bromo-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5--
yl}methyl)-2-furamide
##STR00017##
[0174] Under argon, N-(3-dimethylaminopropyl)ethylcarbodiimide
hydrochloride (79.0 mg, 0.41 mmol) and dropwise,
N,N-diisopropylethylamine (120 .mu.l, 0.69 mmol) are added at room
temperature to a solution of the amine II (100.0 mg, 0.34 mmol),
5-bromo-2-furancarboxylic acid (78.7 mg, 0.41 mmol) and
1-hydroxy-1H-benzotriazole (55.7 mg, 0.41 mmol) in
dimethylformamide (3.4 ml). The reaction mixture was stirred at
room temperature for 16 hours and concentrated under reduced
pressure. The desired product is purified by flash chromatography
(dichloromethane/methanol mixtures). Yield: 79.6 mg, 50% of
theory.
[0175] .sup.1H NMR (DMSO-d.sup.6, 200 MHz): 8.79 (t, 1H), 7.56 (d,
2H), 7.41 (m, 4H), 7.19 (d, 1H), 6.77 (d, 1H) 4.88-4.77 (m, 1H),
4.19 (s, 2H), 4.18 (dd, 1H), 4.00-3.93 (m, 2H), 3.90-3.82 (dd, 1H),
3.75-3.67 (m, 2H), 3.62-3.53 (m, 2H);
[0176] MS (ESI): m/z (%)=464 ([M+H].sup.+, 100);
[0177] HPLC (method 1): rt=3.31 min.
[0178] The following compounds were prepared analogously:
TABLE-US-00003 Ex- HPLC ample method: num- retention ber Structure
Mass time 7 ##STR00018## MS (ESI): m/z (%) = 448 ([M + H].sup.+,
100) Method 4: 3.18 min 8 ##STR00019## MS (ESI): m/z (%) = 431 ([M
+ H].sup.+, 100) Method 2: 3.46 min 9 ##STR00020## MS (ESI): m/z
(%) = 385 ([M + H].sup.+, 100) Method2: 2.57 min 10 ##STR00021## MS
(ESI): m/z (%) = 404 ([M + H].sup.+, 100) Method 2: 3.40 min 11
##STR00022## MS (DCI, NH.sub.3): m/z (%) = 447 ([M +
NH.sub.4].sup.+, 100) Method 2: 3.79 min
* * * * *