Substituted 2-oxo-3-phenyl-5-carbonylaminomethyl-1,3-oxazolines and their use as anticoagulant and antithrombotics
View Patent ↗The invention relates to the field of blood coagulation, more particularly, to novel compounds of general formula (I), to a method for producing the compounds and to their use as active ingredients in medicaments for the prevention and/or the treatment of diseases.
1. A compound of the formula (I)
in which
R 1 represents (C 6 -C 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 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, oxo, carboxyl or cyano,
R 2 represents a radical —C(O)NR 8 R 9 , —N(R 10 )C(O )R 11 or
where
R 8 represents hydrogen, (C 1- C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, (C 6 -C 14 )-aryl which for its part may be substituted by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, or (C 3 -C 7 )-cycloalkyl,
and
R 9 represents (C 1 -C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, (C 6 -C 14 )-aryl which for its part may be substituted by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, or (C 3 -C 7 )-cycloalkyl,
or
R 8 and R 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 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano,
R 10 and R 11 , independently of one another, represent (C 1 -C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, (C 6 -C 14 )-aryl which for its part may be substituted by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, or (C 3 -C 7 )-cycloalkyl,
or
R 10 and R 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 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano,
x represents 0 or 1,
R 12 and R 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 1 -C 4 )-alkylamino, (C 1 -C 4 )-alkoxy, carboxamido, (C 1 -C 4 )-alkylcarbonyl or (C 3 -C 5 ) cycloalkylcarbonyl,
R 3 , R 4 , R 5 and R 6 , independently of one another, represent hydrogen, halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, mono- or di-(C 1 -C 6 )-alkylaminocarbonyl, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkanoyl, (C 1 -C 6 )-alkanoylamino, trifluoromethyl, carbamoyl, nitro or cyano,
and
R 7 represents hydrogen or (C 1 -C 6 )-alkyl,
but excluding compounds of the general formula (I) in which the radical R 1 is an optionally substituted thiophene radical.
2. A compound of the formula (I) as claimed in claim 1 ,
in which
R 1 represents (C 6 -C 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 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 -alkoxy,) (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, oxo, carboxyl or cyano,
R 2 represents a radical—C(O)NR 8 R 9 , —N(R 10 )C(O)R 11 or
where
R 8 represents hydrogen,
(C 1 -C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, (C 6 -C 14 )-aryl which for its part may be substituted by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, or (C 3 -C 7 )-cycloalkyl,
and
R 9 represents (C 1 -C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, (C 6 -C 14 )-aryl which for its part may be substituted by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, or (C 3 -C 7 )-cycloalkyl,
or
R 8 and R 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 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano,
R 10 and R 11 , independently of one another, represent (C 1 -C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C6)-alkoxy, trifluoromethyl or cyano, (C 6 -C 14 )-aryl which for its part may be substituted by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, or (C 3 -C 7 )-cycloalkyl,
or
R 10 R 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 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano,
x represents 0 or 1,
R 12 and R 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 1 -C4)-alkylamino, (C 1 -C 4 )-alkoxy, carboxamido, (C 1 -C 4 )-alkylcarbonyl or (C 3 -C 5 )-cycloalkylcarbonyl,
R 3 , R 4 , R 5 and R 6 , independently of one another, represent hydrogen, halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, mono- or di-(C 1 -C 6 -alkylaminocarbonyl,) hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkanoyl, (C 1 -C 6 )-alkanoylamino, trifluoromethyl, carbamoyl, nitro or cyano,
and
R 7 represents hydrogen or (C 1 -C 6 )-alkyl.
3. A compound of the formula (I) as claimed in claim 1 ,
in which
R 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 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, cyano, trifluoromethyl, trifluoromethoxy or trifluoromethylthio,
R 2 represents a radical —C(O )NR 8 R 9 , —N(R 10 )C(O)R 11 or,
where
R 8 represents hydrogen, (C 1 -C 4 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 4 )-alkylamino, hydroxyl, oxo, (C 1 -C 4 )-alkoxy, trifluoromethyl or cyano or (C 3 -C 7 )-cycloalkyl,
and
R 9 represents (C 1 -C 4 )-alikyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 4 )-alkylamino, hydroxyl, oxo, (C 1 -C 4 )-alkoxy, trifluoromethyl or cyano, or (C 3 -C 7 )-cycloalkyl,
or
R 8 and R 2 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 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano,
R 10 and R 11 , independently of one another, represent (C 1 -C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, or
(C 3 -C 7 )-cycloalkyl, or
R 10 and R 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 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano,
x represents 0 or 1,
R 12 and R 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 1 -C 4 )-alkylamino, (C 1 -C 4 )-alkoxy, carboxamido, (C 1 -C 4 )-alkylcarbonyl or (C 3 -C 5 )-cycloalkylcarbonyl,
R 3 and R 6 , independently of one another, represent hydrogen, halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkanoylamino, cyano, trifluoromethyl or nitro,
R 4 and R 5 represent hydrogen,
and
R 7 represents hydrogen or (C 1 -C 4 )-alkyl.
4. A compound of the formula (I) as claimed in claim 1 ,
in which
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 1 -C 4 )-alkyl, trifluoromethyl, trifluoromethoxy or trifluoromethylthio,
R 2 represents a radical —C(O)NR 8 R 9 , —N(R10)C(O)R 11 or
where
R 8 and R 9 , independently of one another, represent (C 1 -C 4 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 4 )-alkylamino, hydroxyl, oxo, (C 1 -C 4 )-alkoxy, trifluoromethyl or cyano, or (C 3 -C 7 )-cycloalkyl,
or
R 8 and R 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 1 -C4)-alkyl and/or oxo,
R 10 and R 11 , independently of one another, represent (C 1 -C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, or (C 3 -C 7 )-cycloalkyl,
or
R 10 and R 11 together with the N—C(O) group to which they are attached represent morpholinonyl, pyrrolidinonyl, thiomorpho linonyl or piperidinonyl, where the rings may be mono- or disubstituted by (C 1 -C 4 )-alkyl,
x represents 0 or 1,
R 12 and R 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 3 represents hydrogen, fluorine, chlorine, bromine, (C 1 -C 4 )-alkyl, amino, mono- or di-(C 1 -C 3 )-alkylamino, cyano or nitro,
R 4 , R 5 and R 6 represent hydrogen,
and R 7 represents hydrogen.
5. A process for preparing compounds of the formula (I) as claimed in claim 1 , characterized in that compounds of the formula (II)
in which R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in claim 1 are reacted with carboxylic acids of the formula (III)
in which R 1 is as defined in claim 1 , 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 in claim 1 .
6. A medicament for the treatment of thromboembolic disorders comprising at least one compound of the formula (I) as claimed in claim 1 .
7. The medicament of claim 6 wherein the thromboembolic disorder is a myocardial infarction, angina pectoris, 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.
8. A medicament for the treatment of disseminated intravasal coagulation (DIC) comprising at least one compound of the formula (I) as claimed in claim 1 .
9. A process for inhibiting the coagulation of blood in vitro, banked blood or biological samples containing factor Xa, characterized in that compounds of the general formula (I) as claimed in claim 1 are added.