HK1092140B - Substituted oxazolidinones and their use in the field of blood coagulation - Google Patents
Substituted oxazolidinones and their use in the field of blood coagulation Download PDFInfo
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Description
The present application is a divisional application of an invention patent application having an international filing date of 12/11/2000 (international application number PCT/EP00/12492), an incoming national phase application number of 00818966.8, and an invention name of "substituted oxazolidinone and its use in the field of blood coagulation".
Technical Field
The present invention relates to the field of blood coagulation. In particular the invention relates to novel oxazolidinone derivatives, a process for their preparation and their use as biologically active substances in medicaments.
Background
Blood coagulation is a protective mechanism for organisms whereby defects in the vessel wall can be "sealed" quickly and reliably, thus avoiding or minimizing blood loss. Hemostasis following vascular injury occurs essentially through a coagulation system in which a complex reaction of the enzymatic cascade of plasma proteins is initiated. This process involves a number of blood coagulation factors, each of which, upon activation, converts the corresponding next inactive precursor into its active form. At the end of this cascade is the conversion of soluble fibrinogen to insoluble fibrin, resulting in the formation of blood clots. In blood coagulation, there is traditionally a division between endogenous and exogenous systems, both of which are finally merged into a reactive pathway. Since it is associated with two coagulation pathways, factor Xa, formed here from the zymogen factor X, plays a key role. The activated serine protease Xa cleaves prothrombin to thrombin, the resulting thrombin in turn converting fibrinogen to fibrin, a fibrous-gelatinous clotting material. In addition, thrombin is a highly efficient effector of platelet aggregation, which also plays an important role in hemostasis.
Maintaining normal hemostasis between the blood flow and the thrombus is controlled by a complex regulatory mechanism. Uncontrolled activation or defective inhibition of the coagulation system can lead to local thrombosis or embolism in vessels (arteries, veins, lymph vessels) or heart chambers. This can lead to serious diseases such as myocardial infarction, angina (including unstable angina), reocclusion and restenosis following angioplasty or aortic coronary bypass, stroke, transient ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis; these diseases are also summarized below as thromboembolic diseases. In addition, excessive coagulation in a wasting blood coagulation disorder may result in systemically dispersed intravascular coagulation.
These thromboembolic diseases are the most common cause of high morbidity and mortality in most industrialized countries (Pschyrembel, Klinisches)257 th edition, 1994, Walter de Gruyter Press, pages 199, the keyword "blood coagulation";Lexikon Chemie，Version 1.5，1998, Georg Thieme VerlagStuttgart, keyword "blood coagulation"; lubert Stryer, Biochemie, Spektrum der Wissenschaft Verlagsgesellschaft mbH Heidelberg, 1990, pp 259).
The anticoagulants known in the art, i.e. substances that inhibit or prevent blood coagulation, have various and often serious drawbacks. Therefore, effective treatment or prevention of thromboembolic diseases is difficult and unsatisfactory in practice.
Heparin is first administered parenterally or subcutaneously in the treatment and prevention of thromboembolic diseases. Due to their more beneficial pharmacokinetic properties, low molecular weight heparins are increasingly preferred at present; however, even with low molecular weight heparins, it is not possible to avoid the following known disadvantages in heparin therapy. Thus, heparin is not orally effective and has only a relatively low half-life. Since heparin inhibits multiple factors of the blood clotting cascade simultaneously, its action is non-selective. Furthermore, there is a high risk of bleeding, in particular cerebral and gastrointestinal bleeding, which can lead to thrombocytopenia, drug-induced alopecia or osteoporosis (Pschyrembel, Klinisches)257 th edition, 1994, Walter de Gruyter Verlag, page 610, keyword "heparin";lexikon Chemie, Version 1.5, 1998, Georg Thieme Verlag Stuttgart, keyword "heparin".
A second class of anticoagulants are vitamin K-antagonists, including, for example, 1, 3-indandiones, especially compounds such as warfarin, coumarins, dicumarol and other coumarin derivatives, which non-selectively inhibit the synthesis of various products of certain vitamin K-dependent coagulation factors in the liver. However, due to this mechanism of action, its onset is very slow (latency to onset 36-48 hours). Although these compounds can be administered orally, they are superior in that they are administered orallyBlood risk and narrow therapeutic index, requiring time-consuming individual conditioning and patient monitoring. In addition, other side effects have been reported, such as gastrointestinal disturbances, hair loss and skin necrosis (Pschyrembel, Klinisches)257 th edition, 1994, Walter de Gruyter Verlag, page 292, keyword "coumarin derivative"; ullmann's Encyclopedia of Industrial Chemistry, 5 th edition, VCH Press, Weinheim, 1985-.
Recently, a new therapeutic and prophylactic method for thromboembolic diseases has been reported. The aim of this new therapeutic approach is to inhibit factor XA (see WO-A-99/37304; W0-A-99/06371; J.Hauptmann, J.St. Zebelcher, Thrombosis Research1999, 93, 203; F.Al-Obeidi, J.A.Ostrem, factor XA inhibitors obtained by conventional 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 Drugs, Emerging Drugs 1998, 3, 189; B.Zhu, R.M.Scirborough, Curr.Opd.1. filtration, Inv.1, drug 1, 1 (drug 1, 1). Various peptidic and non-peptidic compounds have been shown to act as factor Xa inhibitors in animal models.
Disclosure of Invention
It is therefore an object of the present invention to provide a novel substance for controlling diseases over a broad spectrum.
In particular, these substances are to be suitable for the effective prophylaxis and/or treatment of thromboembolic diseases and to avoid the disadvantages of the prior art mentioned above at least to a certain extent, where "thromboembolic diseases" are to be understood in the context of the present invention in particular as serious diseases, such as myocardial infarction, angina pectoris (including unstable angina), reocclusion and restenosis after angioplasty or aortic coronary bypass, stroke, transient ischemic attacks, peripheral arterial occlusive diseases, pulmonary embolism or deep vein thrombosis.
It is another object of the present invention to provide novel anticoagulants with improved selectivity for inhibition of blood coagulation factor Xa and which avoid, at least to some extent, the problems of the methods of treating thromboembolic diseases known from the prior art.
Accordingly, the present invention provides substituted oxazolidinones of the general formula (I) and pharmaceutically acceptable salts, hydrates and prodrugs thereof
Wherein:
R1is an optionally benzo-fused thienyl group, which may be optionally substituted by one or more;
R2is any one organic group;
R3、R4、R5、R6、R7and R8Are identical or different and are each hydrogen or (C)1-C6) Alkyl, except for compounds of the general formula (I) in which the radical R1Being unsubstituted 2-thienyl and the radical R at the same time2Is one or more substituted phenyl radicals and the radicals R3、R4、R5、R6、R7And R8Each is hydrogen.
Preference is given to compounds of the general formula (I) and their pharmaceutically acceptable salts, hydrates and prodrugs,
wherein
R1Is an optionally benzo-fused thienyl group, which is optionally mono-or polysubstituted by a group selected from the group consisting of: halogen; a cyano group; a nitro group; an amino group; an aminomethyl group; (C)1-C8) Alkyl, which may itself be optionally substituted by halogenOne or more substitutions; (C)3-C7) -a cycloalkyl group; (C)1-C8) -an alkoxy group; an imidazolinyl group; -C (═ NH) NH2(ii) a A carbamoyl group; and mono-and di- (C)1-C4) -an alkyl-aminocarbonyl group,
R2is one of the following groups:
A-，
A-M-，
D-M-A-，
B-M-A-，
B-，
B-M-，
B-M-B-，
D-M-B-，
wherein:
the radical "A" is (C)6-C14) Aryl, preferably (C)6-C10) Aryl, in particular phenyl or naphthyl, particularly preferably phenyl;
the radical "B" is a 5-or 6-membered heteroaromatic ring which contains up to 3 heteroatoms and/or heterochain units, in particular up to 2 heteroatoms and/or heterochain units, selected from S, N, NO (N-oxide) and O;
the radical "D" is a saturated or partially unsaturated mono-or bicyclic, optionally benzo-fused 4-to 9-membered heterocycle which contains up to 3 substituents selected from S, SO2Heteroatoms and/or heterochain units of N, NO (N-oxide) and O;
the radical "M" being-NH-, -CH2-、-CH2-CH2-、-O-、-NH-CH2-、-CH2-NH-、-OCH2-、-CH2O-、-CONH-、-NHCO-、-COO-、-OOC-、-S-、-SO2-or is a covalent bond;
wherein
A radical as defined above "A "," B "and" D "may each be optionally substituted with one or more of the following groups: halogen, trifluoromethyl, oxo, cyano, nitro, carbamoyl, pyridyl, (C)1-C6) Alkanoyl radical, (C)3-C7) -cycloalkanoyl, (C)6-C14) -arylcarbonyl group, (C)5-C10) -heteroarylcarbonyl group, (C)1-C6) -alkanoyloxymethoxy, (C)1-C4) -hydroxyalkylcarbonyl, -COOR27、-SO2R27、-C(NR27R28)＝NR29、-CONR28R29、-SO2NR28R29、-OR30、-NR30R31、(C1-C6) -alkyl and (C)3-C7) -cycloalkyl, wherein (C)1-C6) -alkyl and (C)3-C7) Cycloalkyl may itself be optionally selected from cyano, -OR27、-NR28R29、-CO(NH)v(NR27R28) and-C (NR)27R28)＝NR29Is substituted with a group (b) of (a),
wherein:
v is 0 or 1, and
R27、R28and R29Are the same or different and are each independently hydrogen, (C)1-C4) Alkyl radicals, (C)3-C7) -cycloalkyl, (C)1-C4) Alkanoyl, carbamoyl, trifluoromethyl, phenyl or pyridyl,
and/or
R27And R28Or R27And R29May form, together with the nitrogen atom to which they are attached, a saturated or partially unsaturated 5-to 7-membered heterocyclic ring having up to 3, preferably up to 2 identical or different heteroatoms from the group consisting of N, O and S, and
R30and R31Are the same or different and are each independently hydrogen, (C)1-C4) Alkyl radicals, (C)3-C7) -cycloalkyl, (C)1-C4) -alkylsulfonyl, (C)1-C4) -hydroxyalkyl, (C)1-C4) Aminoalkyl, di- (C)1-C4) -alkylamino- (C)1-C4) -alkyl, -CH2C(NR27R28)＝NR29or-COR33，
Wherein the content of the first and second substances,
R33is (C)1-C6) -alkoxy, (C)1-C4) -alkoxy- (C)1-C4) Alkyl radicals, (C)1-C4) -alkoxycarbonyl- (C)1-C4) Alkyl radicals, (C)1-C4) Aminoalkyl radical, (C)1-C4) Alkoxycarbonyl, (C)1-C4) -alkanoyl- (C)1-C4) Alkyl radicals, (C)3-C7) -cycloalkyl, (C)2-C6) -alkenyl, (C)1-C8) Alkyl, which may be optionally substituted by phenyl or acetyl, (C)6-C14) -aryl, (C)5-C10) -heteroaryl, trifluoromethyl, tetrahydrofuranyl or butyrolactone,
R3、R4、R5、R6、R7and R8Are identical or different and are hydrogen or are (C)1-C6) -an alkyl group.
But in addition to the compounds of the general formula (I) in which the radical R1Being unsubstituted 2-thienyl and the radical R at the same time2Is one or more substituted phenyl radicals and the radicals R3、R4、R5、R6、R7And R8Each is hydrogen.
Preference is likewise given here to compounds of the general formula (I) and their pharmaceutically acceptable salts, hydrates and prodrugs,
wherein
R1Is thienyl, especially 2-thienyl, any of whichSelected from mono-or poly-substituted with a group selected from: halogen, preferably chlorine or bromine, amino, aminomethyl or (C)1-C8) Alkyl, preferably methyl, wherein (C)1-C8) The alkyl radical itself being optionally mono-or polysubstituted by halogen, preferably by fluorine, R2Is one of the following groups:
A-，
A-M-，
D-M-A-，
B-M-A-，
B-，
B-M-，
B-M-B-，
D-M-B-，
wherein:
the radical "A" is (C)6-C14) Aryl, preferably (C)6-C10) Aryl, in particular phenyl or naphthyl, particularly preferably phenyl;
the radical "B" is a 5-or 6-membered heteroaromatic ring which contains up to 3 heteroatoms and/or heterochain units, in particular up to 2 heteroatoms and/or heterochain units, selected from S, N, NO (N-oxide) and O;
the radical "D" is a saturated or partially unsaturated 4-to 7-membered heterocycle which contains up to 3 substituents selected from S, SO2Heteroatoms and/or heterochain units of N, NO (N-oxide) and O;
the radical "M" being-NH-, -CH2-、-CH2-CH2-、-O-、-NH-CH2-、-CH2-NH-、-OCH2-、-CH2O-, -CONH-, -NHCO-, -COO-, -OOC-, -S-or a covalent bond;
wherein
The previously defined radicals "A", "B" and "D" may in each case optionally be substituted by one or more of the following groups: halogenPlain, trifluoromethyl, oxo, cyano, nitro, carbamoyl, pyridyl, (C)1-C6) Alkanoyl radical, (C)3-C7) -cycloalkanoyl, (C)6-C14) -arylcarbonyl group, (C)5-C10) -heteroarylcarbonyl group, (C)1-C6) -alkanoyloxymethoxy, -COOR27、-SO2R27、-C(NR27R28)＝NR29、-CONR28R29、-SO2NR28R29、-OR30、-NR30R31、(C1-C6) -alkyl and (C)3-C7) -a cycloalkyl group,
wherein (C)1-C6) -alkyl and (C)3-C7) Cycloalkyl may itself be optionally selected from cyano, -OR27、-NR28R29、-CO(NH)v(NR27R28) and-C (NR)27R28)＝NR29Is substituted with a group (b) of (a),
wherein:
v is 0 or 1, and
R27、R28and R29Are the same or different and are each independently hydrogen, (C)1-C4) -alkyl or (C)3-C7) -a cycloalkyl group,
and/or
R27And R28Or R27And R29May form, together with the nitrogen atom to which they are attached, a saturated or partially unsaturated 5-to 7-membered heterocyclic ring having up to 3, preferably up to 2 identical or different heteroatoms from the group consisting of N, O and S, and
R30and R31Are the same or different and are each independently hydrogen, (C)1-C4) Alkyl radicals, (C)3-C7) -cycloalkyl, (C)1-C4) -alkylsulfonyl, (C)1-C4) -hydroxyalkyl, (C)1-C4) Aminoalkyl, di- (C)1-C4) -alkylamino- (C)1-C4) Alkyl radicals, (C)1-C4) Alkanoyl radical, (C)6-C14) -arylcarbonyl group, (C)5-C10) -heteroarylcarbonyl group, (C)1-C4) -alkylaminocarbonyl or-CH2C(NR27R28)＝NR29，
R3、R4、R5、R6、R7And R8Are identical or different and are hydrogen or are (C)1-C6) Alkyl, except for compounds of the general formula (I) in which the radical R1Being unsubstituted 2-thienyl and the radical R at the same time2Is one or more substituted phenyl radicals and the radicals R3、R4、R5、R6、R7And R8Each is hydrogen.
Particular preference is given here to compounds of the general formula (I) and their pharmaceutically acceptable salts, hydrates and prodrugs,
wherein
R1Is thienyl, in particular 2-thienyl, which is optionally mono-or polysubstituted with a group selected from the group consisting of: halogen, preferably chlorine or bromine, or (C)1-C8) Alkyl, preferably methyl, wherein (C)1-C8) The alkyl radical itself may optionally be mono-or polysubstituted by halogen, preferably by fluorine,
R5is one of the following groups:
A-，
A-M-，
D-M-A-，
B-M-A，
B-，
B-M-，
B-M-B-，
D-M-B-，
wherein:
the radical "A" is phenyl or naphthyl, in particular phenyl;
the group "B" is a 5-or 6-membered aromatic heterocycle containing up to 2 heteroatoms selected from S, N, NO (N-oxide) and O;
the radical "D" is a saturated or partially unsaturated 5-or 6-membered heterocycle which contains up to 2 substituents selected from S, SO2Heteroatoms and/or heterochain units of N, NO (N-oxide) and O;
the radical "M" is-NH-, -O-, -NH-CH2-、-CH2-NH-、-OCH2-、-CH2O-, -CONH-, -NHCO-or is a covalent bond;
wherein
The previously defined radicals "A", "B" and "D" may in each case optionally be substituted by one or more of the following groups: halogen, trifluoromethyl, oxo, cyano, pyridyl, (C)1-C3) Alkanoyl radical, (C)6-C10) -arylcarbonyl group, (C)5-C6) -heteroarylcarbonyl group, (C)1-C3) -alkanoyloxymethoxy, -C (NR)27R28)＝NR29、-CONR28R29、-SO2NR28R29、-OH、-NR30R31、(C1-C4) Alkyl and cyclopropyl, cyclopentyl or cyclohexyl,
wherein (C)1-C4) The alkyl and cyclopropyl, cyclopentyl or cyclohexyl radicals may themselves optionally be chosen from cyano, -OH, -OCH3、-NR28R29、-CO(NH)v(NR27R28) and-C (NR)27R28)＝NR29Is substituted with a group (b) of (a),
wherein:
v is 0 or 1, preferably 0, and
R27、R28and R29Are the same or different and are each independently hydrogen, (C)1-C4) -alkyl or cyclopropyl, cyclopentyl or cyclohexyl,
and/or
R27And R28Or R27And R29May form, together with the nitrogen atom to which it is attached, a saturated or partially unsaturated 5-to 7-membered heterocyclic ring having up to 2 identical or different heteroatoms selected from N, O and S, and
R30and R31Are the same or different and are each independently hydrogen, (C)1-C4) Alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C)1-C4) -alkylsulfonyl, (C)1-C4) -hydroxyalkyl, (C)1-C4) Aminoalkyl, di- (C)1-C4) -alkylamino- (C)1-C4) Alkyl radicals, (C)1-C3) -an alkanoyl group or a phenylcarbonyl group,
R3、R4、R5、R6、R7and R8Are identical or different and are hydrogen or are (C)1-C6) Alkyl, except for compounds of the general formula (I) in which the radical R1Being unsubstituted 2-thienyl and the radical R at the same time2Is one or more substituted phenyl radicals and the radicals R3、R4、R5、R6、R7And R8Each is hydrogen.
Compounds of the general formula (I) and their pharmaceutically acceptable salts, hydrates and prodrugs are particularly preferred here,
wherein
R1Is 2-thienyl, which may optionally be substituted in its 5-position by a group selected from chlorine, bromine, methyl or trifluoromethyl,
R2is one of the following groups:
A-，
A-M-，
D-M-A-，
B-M-A-，
B-，
B--M--
B-M-B-，
D-M-B-，
wherein:
the radical "A" is phenyl or naphthyl, in particular phenyl;
the group "B" is a 5-or 6-membered aromatic heterocycle containing up to 2 heteroatoms selected from S, N, NO (N-oxide) and O;
the radical "D" is a saturated or partially unsaturated 5-or 6-membered heterocyclic ring which contains one nitrogen atom and optionally one further ring selected from S, SO2And hetero atoms and/or hetero chain units of O; or containing up to two elements selected from S, SO2And hetero atoms and/or hetero chain units of O;
the radical "M" is-NH-, -O-, -NH-CH2-、-CH2-NH-、-OCH2-、-CH2O-, -CONH-, -NHCO-or is a covalent bond;
wherein
The previously defined radicals "a", "B" and "D" may in each case optionally be mono-or polysubstituted by groups selected from: halogen, trifluoromethyl, oxo, cyano, pyridyl, (C)1-C3) Alkanoyl radical, (C)6-C10) -arylcarbonyl group, (C)5-C6) -heteroarylcarbonyl group, (C)1-C3) -alkanoyloxymethoxy, -CONR28R29、-SO2NR28R29、-OH、-NR30R31、(C1-C4) Alkyl and cyclopropyl, cyclopentyl or cyclohexyl,
wherein (C)1-C4) The alkyl and cyclopropyl, cyclopentyl or cyclohexyl radicals may themselves optionally be chosen from cyano, -OH, -OCH3、-NR28R29、-CO(NH)v(NR27R28) and-C (NR)27R28)＝NR29Is substituted with a group (b) of (a),
wherein:
v is 0 or 1, preferably 0, and
R27、R28and R29Are the same or different and are each independently hydrogen, (C)1-C4) -alkyl or cyclopropyl, cyclopentyl or cyclohexyl,
and/or
R27And R28Or R27And R29May form, together with the nitrogen atom to which it is attached, a saturated or partially unsaturated 5-to 7-membered heterocyclic ring having up to 2 identical or different heteroatoms selected from N, O and S, and
R30and R31Are the same or different and are each independently hydrogen, (C)1-C4) Alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C)1-C4) -alkylsulfonyl, (C)1-C4) -hydroxyalkyl, (C)1-C4) Aminoalkyl, di- (C)1-C4) -alkylamino- (C)1-C4) Alkyl radicals, (C)1-C3) -an alkanoyl group or a phenylcarbonyl group,
R3、R4、R5、R6、R7and R8Are identical or different and are hydrogen or are (C)1-C4) Alkyl, except for compounds of the general formula (I) in which the radical R1Being unsubstituted 2-thienyl and the radical R at the same time2Is one or more substituted phenyl radicals and the radicals R3、R4、R5、R6、R7And R8Each is hydrogen.
Particular preference is given here to compounds of the general formula (I) and their pharmaceutically acceptable salts, hydrates and prodrugs,
wherein
R1Is 2-thienyl, substituted in its 5-position by a radical selected from the group consisting of chlorine, bromine, methyl and trifluoromethyl,
R2is D-A-:
wherein:
the group "A" is phenylene;
the group "D" is a saturated 5-or 6-membered heterocyclic ring,
which is attached to "A" via a nitrogen atom,
which has a carbonyl group ortho to the nitrogen atom to which it is attached and
wherein one ring carbon unit may be replaced by a heteroatom selected from S, N and O;
wherein
The previously defined group "a" may be optionally mono-or disubstituted in the meta position of the linkage to the oxazolidinone by a group selected from: fluorine, chlorine, nitro, amino, trifluoromethyl, methyl and cyano,
R3、R4、R5、R6、R7and R8Each is hydrogen.
Also particularly preferred herein are compounds of the formula and pharmaceutically acceptable salts, hydrates and prodrugs thereof.
In particular in these compounds of the general formula (I) above, the radical R1May be an optionally benzo-fused thienyl group which may be optionally mono-or polysubstituted with a group selected from: halogen;a cyano group; a nitro group; (C)1-C8) -alkyl, which may itself be optionally mono-or polysubstituted with halogen; (C)3-C7) -a cycloalkyl group; (C)1-C8) -an alkoxy group; an imidazolinyl group; -C (═ NH) NH2(ii) a A carbamoyl group; and mono-and di- (C)1-C4) -alkylaminocarbonyl.
In these compounds of the general formula (I), the radical R1Preference may be given to thienyl, in particular 2-thienyl, which may optionally be mono-or polysubstituted by a group selected from: halogen, preferably chlorine or bromine; or (C)1-C8) Alkyl, preferably methyl, wherein (C)1-C8) Alkyl, preferably methyl, may itself be optionally mono-or polysubstituted by halogen, preferably by fluorine.
In these compounds of the general formula (I), the radical R3、R4、R5、R6、R7And R8May be the same or different and is in particular hydrogen or (C)1-C6) -alkyl, preferably hydrogen or (C)1-C4) Alkyl, particularly preferably hydrogen.
Radical R2I.e. organic radicals, may in particular be selected from the following substituents:
in these compounds of the general formula (I), the radicals
R2In particular, there may be mentioned the radicals of the formula:
wherein:
m is an integer from 0 to 6, preferably from 1 to 3,
n is a number of 0 or 1,
p is an integer from 0 to 3, preferably 0 or 1,
o1is an integer of 0 or 1, and,
o2is an integer of 0 or 1, and,
R9and R10The same or different and is hydrogen; (C)1-C4) -alkyl, preferably methyl; (C)1-C4) -alkoxy, preferably methoxy; (C)3-C7) -a cycloalkyl group; a hydroxyl group or a fluorine group,
x and X' are the same or different and are 0; N-R11Or a covalent bond,
wherein R is11Is hydrogen; (C)1-C4) -alkyl, preferably methyl; or (C)3-C7) -cycloalkyl, Y is a 3-to 7-membered saturated or partially unsaturated cycloalkyl group optionally containing 1-3 substituents selected from N, O, S, SO and SO2The same or different heteroatoms and/or heterochain units,
wherein:
this group Y may optionally be substituted by a 5-or 6-membered aromatic hydrocarbon group or by a 3-to 7-membered saturated or partially unsaturated cyclic hydrocarbon group, said groups optionally containing up to 3 identical or different heteroatoms selected from N, O and S, and the group itself may optionally be selected from cyano; a hydroxyl group; halogen; (C)1-C4) -an alkyl group; -C (═ NR)12)NR13R13'; and-NR14R15Is substituted with one of the groups (a) or (b),
wherein:
R12is hydrogen, (C)1-C4) -alkyl or (C)3-C7) -a cycloalkyl group;
R13and R13' the same or different and each independently hydrogen, (C)1-C4) -alkyl or (C)3-C7) -cycloalkyl, and/or
R13And R13' together with the N atom to which they are attached form 5-to 7-membered ring optionally additionally containing up to two heteroatoms from N, O and/or SA heterocyclic ring;
R14and R15Are the same or different and are each independently hydrogen, (C)1-C4) Alkyl radicals, (C)3-C7) -cycloalkyl or (C)1-C5) -an alkanoyl group;
and/or
This group Y may furthermore be optionally substituted by one group selected from: oxo; a cyano group; carbonyl sulfide; halogen; -OR16；＝NR16；-NR16R17；-C(＝NR18)NR19R19' and (C)1-C4) -an alkyl group,
wherein (C)1-C4) The alkyl radical itself may optionally be chosen from hydroxy, cyano, -NR16R17and-C (═ NR)18)NR19R19The group of' is substituted with a substituent,
wherein:
R16and R17Are the same or different and are each independently hydrogen, (C)1-C4) Alkyl radicals, (C)3-C7) -cycloalkyl or (C)1-C3) -an alkanoyl group;
R18is hydrogen, (C)1-C4) -alkyl or (C)3-C7) -a cycloalkyl group;
R19and R19' the same or different and each independently hydrogen, (C)1-C4) -alkyl or (C)3-C7) -cycloalkyl radical
Such as/or
R19And R19' together with the N atom to which they are attached form a 5-to 7-membered heterocyclic ring which may optionally additionally contain up to two heteroatoms selected from N, O and/or S.
Particular preference is given to compounds of the formula (I) in which the radicals
R2Is a group of the formula:
wherein:
m is an integer of 0 to 3,
n is an integer of 0 or 1,
p is an integer of 0 or 1,
o1is an integer of 0 or 1, and,
o2is an integer of 0 or 1, and,
R9and R10The same or different and is hydrogen; a methyl group; a methoxy group; a hydroxyl group or a fluorine group,
x and X' are the same or different and are O, N-R11Or a covalent bond,
wherein R is11Is hydrogen or a methyl group,
y is a 5-to 7-membered saturated cyclic hydrocarbon group optionally containing 1 or 2 members selected from N, O, S, SO and SO2Identical or different heteroatoms and/or heterochain units of (A), in particular cyclohexyl, piperazinyl, morpholinyl, thiomorpholinyl, diazaA group selected from the group consisting of pyrrolidinyl and piperidinyl,
wherein:
this group Y may optionally be substituted by a 5-or 6-membered aromatic hydrocarbon group or by a 5-to 7-membered saturated or partially unsaturated cyclic hydrocarbon group, said groups optionally containing up to 2 identical or different heteroatoms selected from N, O and S, and the group itself may optionally be selected from cyano; a hydroxyl group; fluorine; chlorine; (C)1-C4) -an alkyl group; -C (═ NR)12)NR13R13'; and-NR14R15Is substituted with one of the groups (a) or (b),
wherein:
R12is hydrogen, methyl, ethyl, cyclopropyl, cyclopentyl or cyclohexyl;
R13and R13' are identical or different and are each independently hydrogen, methyl, ethyl, cyclopropyl, cyclopentyl or cyclohexyl,
and/or
R13And R13' together with the N atom to which they are attached form a 5-to 7-membered heterocyclic ring which may optionally additionally contain up to two heteroatoms selected from N, O and/or S; especially piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl;
R14and R15Identical or different and are each independently hydrogen, methyl, ethyl, cyclopropyl, cyclopentyl or cyclohexyl or acetyl;
and/or
This group Y may furthermore be optionally substituted by one group selected from: oxo; a cyano group; carbonyl sulfide; fluorine; chlorine; -OH; -OCH3；＝NR16；-NH2；-N(CH3)2；-C(＝NR18)NR19R19' and a methyl group in the presence of a hydrogen atom,
wherein methyl may itself optionally be substituted with one selected from hydroxy; a cyano group; -NR16R17and-C (═ NR)18)NR19R19' instead of the above-mentioned substituent,
wherein:
R16and R17Are identical or different and are each independently hydrogen, methyl, (C)3-C7) -cycloalkyl or acetyl;
R18is hydrogen, methyl or (C)3-C7) -a cycloalkyl group;
R19and R19' the same or different and each independently hydrogen, methyl or (C)3-C7) -cycloalkyl radical
And/or
R19And R19' together with the N atom to which they are attached form a 5-to 7-membered heterocyclic ring which may optionally additionally contain up to two heteroatoms selected from N, O and/or S, in particular piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
Also in the compounds of the formula (I), the radicals
R2Is a group of the formula:
Z-(CO)t-(CR20R21)s-
wherein:
s represents an integer of 1 to 6,
t represents a number of 0 or 1,
R20and R21Are identical or different and are hydrogen, (C)1-C4) Alkyl radicals, (C)1-C4) -alkoxy, (C)3-C7) -cycloalkyl, hydroxy or fluoro,
z is a group selected from cyano; -C (NR)22R22)＝NR24；-CO(NH)uNR22R23(ii) a and-NR25R26Wherein:
u is O or 1, preferably 0, and
R22、R23and R24Are the same or different and are each independently hydrogen, (C)1-C4) -alkyl or (C)3-C7) Cycloalkyl, preferably hydrogen or methyl, and/or
R22And R23Together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocyclic ring which may optionally contain up to 2 additional moieties selected from N, O, S, SO and/or SO2Hetero atom and/or hetero chain unit of；
R25And R26Are the same or different and are each independently hydrogen, (C)1-C4) -alkyl or (C)3-C7) Cycloalkyl, preferably hydrogen, methyl or ethyl, wherein (C)1-C4) -alkyl and (C)3-C7) Cycloalkyl may itself optionally be substituted by hydroxy or (C)1-C6) -alkoxy substitution.
In addition, in the compounds of the formula (I), the radicals
R2Is a group of the formula:
A-，
A-M-，
D-M-A-，
B-M-A-，
B-，
B-M-，
B-M-B-，
D-M-B-，
wherein:
the radical "A" is (C)6-C14) Aryl, preferably (C)6-C10) Aryl, in particular phenyl or naphthyl, particularly preferably phenyl;
the radical "B" is a 5-or 6-membered heteroaromatic ring which contains up to 3 heteroatoms and/or heterochain units, in particular up to 2 heteroatoms and/or heterochain units, selected from S, N, NO (N-oxide) and O;
the radical "D" is a saturated or partially unsaturated 4-to 7-membered heterocycle which contains up to 3 substituents selected from S, SO2Heteroatoms and/or heterochain units of N, NO (N-oxide) and O;
the radical "M" being-NH-, -CH2-、-CH2CH2-、-O-、-NH-CH2-、-CH2-NH-、-OCH2-、-CH2O-, -CONH-, -NHCO-, -COO-, -OOC-, -S-or a covalent bond;
wherein
The previously defined radicals "a", "B" and "D" may in each case optionally be substituted by one or more of the following groups: halogen, trifluoromethyl, oxo, cyano, nitro, carbamoyl, pyridyl, (C)1-C6) Alkanoyl radical, (C)3-C7) -cycloalkanoyl, (C)6-C14) -arylcarbonyl group, (C)5-C10) -heteroarylcarbonyl group, (C)1-C6) -alkanoyloxymethoxy, -COOR27、-SO2R27、-C(NR27R28)＝NR29、-CONR28R29、-SO2NR28R29、-OR30、-NR30R31、(C1-C6) -alkyl and (C)3-C7) -a cycloalkyl group,
wherein (C)1-C6) -alkyl and (C)3-C7) Cycloalkyl may itself be optionally selected from cyano, -OR27、-NR28R29、-CO(NH)v(NR27R28) and-C (NR)27R28)＝NR29Is substituted with a group (b) of (a),
wherein:
v is 0 or 1, and
R27、R28and R29Are the same or different and are each independently hydrogen, (C)1-C4) Alkyl radicals, (C)3-C7) -cycloalkyl, and/or
R27And R28Or R27And R29May form, together with the nitrogen atom to which they are attached, a saturated or partially unsaturated 5-to 7-membered heterocyclic ring having up to 3, preferably up to 2 identical or different heteroatoms from the group consisting of N, O and S, and
R30and R31Are the same or different and are each independently hydrogen, (C)1-C4) Alkyl radicals, (C)3-C7) -cycloalkyl, (C)1-C4) -alkylsulfonyl, (C)1-C4) -hydroxyalkyl, (C)1-C4) Aminoalkyl, di- (C)1-C4) -alkylamino- (C)1-C4) Alkyl radicals, (C)1-C4) Alkanoyl radical, (C)6-C14) -arylcarbonyl group, (C)5-C10) -heteroarylcarbonyl group, (C)1-C4) -alkylaminocarbonyl or-CH2C(NR27R28)＝NR29。
Preference is likewise given to compounds of the formula (I) in which the radicals
R2Is a group of the formula:
A-，
A-M-，
D-M-A-，
B-M-A-，
B-，
B-M-，
B-M-B-，
D-M-B-，
wherein:
the radical "A" is phenyl or naphthyl, in particular phenyl;
the group "B" is a 5-or 6-membered aromatic heterocycle containing up to 2 heteroatoms selected from S, N, NO (N-oxide) and O;
the radical "D" is a saturated or partially unsaturated 5-or 6-membered heterocycle which contains up to 2 substituents selected from S, SO2Heteroatoms and/or heterochain units of N, NO (N-oxide) and O;
the radical "M" is-NH-, -O-, -NH-CH2-、-CH2-NH-、-OCH2-、-CH2O-, -CONH-, -NHCO-or is a covalent bond;
wherein the previously defined groups "a", "B" and "D" may in each case optionally be substituted by one or more of the following groups: halogen, trifluoromethyl, oxo, cyano, pyridyl, (C)1-C3) Alkanoyl radical, (C)6-C10) -arylcarbonyl group, (C)5-C6) -heteroarylcarbonyl group, (C)1-C3) -alkanoyloxymethoxy, -C (NR)27R28)＝NR29、-CONR28R29、-SO2NR28R29、-OH、-NR30R31、(C1-C4) Alkyl and cyclopropyl, cyclopentyl or cyclohexyl, wherein (C)1-C4) The alkyl and cyclopropyl, cyclopentyl or cyclohexyl radicals may themselves optionally be chosen from cyano, -OH, -OCH3、-NR28R29、-CO(NH)v(NR27R28) and-C (NR)27R28)＝NR29Is substituted with a group (b) of (a),
wherein:
v is 0 or 1, preferably 0, and
R27、R28and R29Are the same or different and are each independently hydrogen, (C)1-C4) Alkyl or cyclopropyl, cyclopentyl or cyclohexyl, and/or
R27And R28Or R27And R29May form, together with the nitrogen atom to which it is attached, a saturated or partially unsaturated 5-to 7-membered heterocyclic ring having up to 2 identical or different heteroatoms selected from N, O and S, and
R30and R31Are the same or different and are each independently hydrogen, (C)1-C4) Alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C)1-C4) -alkylsulfonyl, (C)1-C4) -hydroxyalkyl, (C)1-C4) An aminoalkyl radical,Di- (C)1-C4) -alkylamino- (C)1-C4) Alkyl radicals, (C)1-C3) -alkanoyl or phenylcarbonyl.
Also in the compounds of the formula (I), the radical R2May be a group of the formula:
wherein
R32Is hydrogen or (C)1-C4) -alkyl, preferably hydrogen or methyl, and
w is S, NH or O, preferably S.
Furthermore, in the compounds of the formula (I), the radical R2May be a group of the formula:
finally, in the compounds of the formula (I), the radical R2May be a group of the formula:
oxazolidinones have been described to date essentially only as antibiotics and MAO inhibitors and fibrinogen antagonists (for review: Riedl, b., Endermann, r., exp. opin. thers. patents 1999, 9(5), 625), where small 5- [ acyl-aminomethyl ] -groups (preferably 5- [ acetyl-aminomethyl ]) appear to play a major role for their antibacterial activity.
Substituted aryl-and heteroarylphenyl oxazolidinones, wherein one or more substituted phenyl groups may be attached to the N-atom of the oxazolidinone ring and wherein the 5-position of the oxazolidinone ring may have an unsubstituted N-methyl-2-thienylcarboxamide group, and their use as antibacterial active substances are known from the following U.S. patents: US-A-5929248, US-A-5801246, US-A-5756732, US-A-5654435, US-A-5654428 and US-A-5565571.
Furthermore, benzamide-containing oxazolidinones are known as synthetic intermediates in the synthesis of factor XA inhibitors and/or fibrinogen antagonists (WO-A-99/31092, EP-A-623615).
Depending on the type of substituents, the compounds of general formula (I) according to the invention can exist in stereoisomeric forms, either as images and mirror images (enantiomers) or as images and non-mirror images (diastereomers). The invention relates both to these enantiomers or diastereomers and to the respective mixtures thereof. Racemic forms, such as diastereomers, can likewise be separated into the individual stereoisomeric components in a known manner.
Furthermore, certain compounds of formula (I) exist in tautomeric forms. This is known to the person skilled in the art and such compounds are likewise included within the scope of the present invention.
Physiologically acceptable, i.e. pharmaceutically acceptable, salts may be salts of the compounds of the invention with inorganic or organic acids. Preference is given to salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or with organic carboxylic or sulfonic acids, such as 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.
Other pharmaceutically acceptable salts which may be mentioned are salts with customary bases, such as alkali metal salts (e.g.sodium or potassium salts), alkaline earth metal salts (e.g.calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines, such as diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, diaropholamine or methylpiperidine.
“Hydrate of calcium and magnesium"means the compound of the above general formula (I) of the present invention in such a form that a solid or liquid molecular compound (solvate) is formed by hydration with water. In these hydrates, water molecules are connected via secondary valency bonds by intermolecular forces, especially hydrogen bonds. Solid hydrates contain water in stoichiometric proportions as the so-called water of crystallization, wherein a water molecule does not have to be equivalent to its binding state. For example, the hydrate is a sesquihydrate, monohydrate, dihydrate or trihydrate. Hydrates of salts of the compounds of the invention are also suitable.
“Prodrugs"refers to the compounds of formula (I) above in such forms of the invention, which may be biologically active or inactive per se, but which may be converted into the corresponding biologically active form (e.g. metabolised, solvated or otherwise).
Halogen elementRefers to fluorine, chlorine, bromine and iodine, preferably chlorine or fluorine.
(C 1 -C 8 ) -alkyl radicalStraight-chain or branched alkyl having 1 to 8 carbon atoms, for example, mention may be made of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. Corresponding alkyl groups having fewer carbon atoms, e.g. (C), can be derived analogously by this definition1-C6) -alkyl and (C)1-C4) -an alkyl group. In general (C)1-C4) Alkyl groups are preferred.
The meaning of the corresponding part of other, more complex substituents can also be derived from this definition, for exampleAlkyl radicalSulfonyl, hydroxyAlkyl radicalA hydroxyl groupAlkyl radicalCarbonyl, alkoxyAlkyl radicalAlkoxycarbonyl groupAlkane (I) and its preparation method Base ofAlkanoyl radicalAlkyl radicalAmino groupAlkyl radicalOr an alkylaminoalkyl group.
(C 3 -C 7 ) -cycloalkyl radicalRefers to cycloalkyl groups having 3 to 7 carbon atoms, and examples which may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Corresponding cycloalkyl radicals having fewer carbon atoms can be derived analogously by this definition, for example (C)3-C5) -a cycloalkyl group. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.
The meaning of the corresponding part of other, more complex substituents can also be derived from this definition, for exampleCycloalkanesAn acyl group.
(C 2 -C 6 ) -alkenyl radicalIn the present invention, a straight-chain or branched alkenyl group having 2 to 6 carbon atoms is referred to. Straight-chain or branched alkenyl groups having 2 to 4 carbon atoms are preferred. Examples which may be mentioned are: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.
(C 1 -C 8 ) -alkoxy radicalMeaning straight-chain or branched alkoxy groups having from 1 to 8 carbon atoms, examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy, n-heptoxy and n-octoxy. Corresponding alkoxy groups having fewer carbon atoms, e.g. (C), can be derived analogously by this definition1-C6) -alkoxy and (C)1-C4) -alkoxy groups. In general, (C) is preferred1-C4) -alkoxy groups.
The meaning of the corresponding part of other more complex substituents can also be derived from this definition. For exampleAlkoxy radicalAlkyl, aryl, heteroaryl, and heteroaryl,Alkoxy radicalCarbonylalkyl andalkoxy radicalA carbonyl group.
Mono-or di- (C) 1 -C 4 ) -alkylaminocarbonyl radicalRefers to an amino group which is linked via a carbonyl group and has one linear or branched or two identical or different linear or branched alkyl groups each having 1 to 4 carbon atoms. Examples which may be mentioned are: methylamino, ethylamino, N-propylamino, isopropylamino, tert-butylamino, N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-N-propylamino, N-isopropyl-N-N-propylamino and N-tert-butyl-N-methylamino.
(C 1 -C 6 ) -alkanoyl radicalRefers to a straight or branched chain alkyl group having 1 to 6 carbon atoms with a double bonded oxygen atom at the 1-position and attached through the 1-position. Examples which may be mentioned are: formyl, acetyl, propionyl, n-butyryl, isobutyryl, pivaloyl and n-hexanoyl. Corresponding alkanoyl groups having fewer carbon atoms, e.g. (C), can be derived analogously by this definition1-C5) Alkanoyl radical, (C)1-C4) Alkanoyl and (C)1-C3) -alkanoyl. In general, (C) is preferred1-C3) -alkanoyl.
The meaning of the corresponding part of other more complex substituents can also be derived from this definition. Such as cycloalkanoyl and alkanoylalkyl.
(C 3 -C 7 ) -cycloalkanoylRefers to the aforementioned cycloalkyl group having 3 to 7 carbon atoms attached via a carbonyl group.
(C 1 -C 6 ) -alkanoyloxymethyloxy radicalRefers to straight or branched chain alkanoyloxymethyloxy groups having 1 to 6 carbon atoms. Examples which may be mentionedComprises the following steps: acetoxymethyloxy, propionyloxymethyloxy, n-butyryloxymethyloxy, isobutyryloxymethyloxy, pivaloyloxymethyloxy, n-hexanoyloxymethyloxy. Corresponding alkanoyloxymethyloxy radicals having fewer carbon atoms can be derived analogously from this definition, for example (C)1-C3) -alkanoyloxymethyloxy. In general, (C) is preferred1-C3) -alkanoyloxymethyloxy.
(C 6 -C 14 ) -aryl radicalRefers to aryl groups having 6 to 14 carbon atoms, and examples which may be mentioned are: phenyl, naphthyl, phenanthryl and anthracyl. Corresponding aryl groups having fewer carbon atoms can be similarly derived by this definition, e.g. (C)6-C10) -an aryl group. In general, (C) is preferred6-C10) -an aryl group.
The meaning of the corresponding part of other more complex substituents can also be derived from this definition. For exampleAryl radicalsA carbonyl group.
(C 5 -C 10 ) -heteroaryl or 5-to 10-membered having up to 3 members selected from S, O, N and/or NO (N-oxide) heteroaromatic rings with hetero atoms and/or hetero chain unitsRefers to mono-or bicyclic heteroaryl groups, which are linked via a ring carbon atom of the heteroaryl group, optionally also via a ring nitrogen atom of the heteroaryl group, examples which may be mentioned being: pyridyl, pyridyl-N-oxide, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl, benzo [ b ] b]Thienyl, benzo [ b ]]Furyl, indazolyl, quinolyl, isoquinolyl, 1, 5-diazanaphthyl, quinazolinyl. Heterocycles with smaller rings, such as 5-or 6-membered aromatic heterocycles, can be derived analogously by this definition. In general, preference is given to 5-or 6-membered aromatic heterocycles, e.g.Pyridyl, pyridyl-N-oxide, pyrimidinyl, pyridazinyl, furyl and thienyl.
The meaning of the corresponding part of other more complex substituents can also be derived from this definition. For example(C 5 -C 10 ) -heteroaryl radicalA carbonyl group.
Having up to 3 groups selected from S, SO 2 N, NO (N-oxide) and/or O heteroatoms And/or 3-to 9-membered saturated or partially unsaturated, mono-or bicyclic, optionally benzene, of a heterochain unit Fused heterocyclic ringRefers to a heterocyclic ring, which may contain one or more double bonds, and may be monocyclic or bicyclic, wherein a benzene ring may be fused to two adjacent ring carbon atoms and is attached via a ring carbon atom or a ring nitrogen atom. Examples which may be mentioned are: tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1, 2-dihydropyridinyl, 1, 4-dihydropyridinyl, piperazinyl, morpholinyl-N-oxide, thiomorpholinyl, azaRadical (Azepinyl), 1, 4-diazaA cyclohexyl group and a cyclohexyl group. Piperidinyl, morpholinyl and pyrrolidinyl are preferred.
Corresponding rings with smaller rings, for example 5-to 7-membered rings, can be derived analogously by this definition.
The invention also provides processes for preparing the compounds of the general formula (I) according to the invention, in which or according to an alternative process
[A] A compound of the general formula (II)
Wherein
Radical R2、R3、R4、R5、R6、R7And R8Having the above-mentioned meaning, with carboxylic acids of the general formula (III)
Wherein
Radical R1Has the meaning of the above-mentioned formula,
or with the corresponding acid halides, preferably acid chlorides, of the carboxylic acids of the general formula (III) as defined above or with the corresponding symmetrical or mixed anhydrides in an inert solvent, optionally in the presence of an activator or coupling agent and/or a base, to give compounds of the general formula (I)
Wherein
Radical R1、R2、R3、R4、R5、R6、R7And R8Having the above-mentioned meanings, or according to an alternative method
[B] A compound of the general formula (IV)
Wherein
Radical R1、R3、R4、R5、R6、R7And R8Have the above meanings，
With a suitable selective oxidizing agent in an inert solvent to convert the corresponding epoxide of the formula (V)
Wherein
Radical R1、R3、R4、R5、R6、R7And R8Having the above-mentioned meaning, and by reaction with an amine of the formula (VI) in an inert solvent, optionally in the presence of a catalyst
R2-NH2 (VI)，
Wherein
Radical R2Has the meaning of the above-mentioned formula,
first, a compound of the formula (VII)
Wherein
Radical R1、R2、R3、R4、R5、R6、R7And R8Having the above-mentioned meaning and subsequent ring synthesis of compounds of the general formula (I) in an inert solvent in the presence of phosgene or a phosgene equivalent, for example Carbonyldiimidazole (CDI)
Wherein
Radical R1、R2、R3、R4、R5、R6、R7And R8Having the above-mentioned meaning, wherein the process [ A ] is optional]And optionally method [ B ]]For R2In the case of 3-to 7-membered saturated or partially unsaturated cyclic hydrocarbon radicals containing one or more heteroatoms, which may be identical or different, selected from N and S, can be subsequently oxidized with a selective oxidizing agent to the corresponding sulfone, sulfoxide or N-oxide
And/or
Wherein alternative Process [ A ] and alternative Process [ B ] in the case where the compound prepared in this manner has a cyano group in the molecule, amidination (Amidinerung) of the cyano group can be followed by a conventional method
And/or
Wherein alternative Process [ A ] and alternative Process [ B ] for the case where the compound molecule prepared in this manner has a BOC-amino protecting group, the BOC-amino protecting group can be subsequently deprotected by a conventional method
And/or
Wherein alternative Process [ A ] and alternative Process [ B ] in the case of compounds prepared in this way having phenylamino or benzylamino groups in the molecule, the amino groups can subsequently be converted into the corresponding derivatives with different reagents, such as carboxylic acids, carboxylic anhydrides, acid chlorides, isocyanates, sulfonyl chlorides or alkyl halides
And/or
Wherein alternative Process [ A ] and alternative Process [ B ] in the case of compounds prepared in this way having a benzene ring in the molecule, the reaction with chlorosulfonic acid and subsequent reaction with an amine can be followed to give the corresponding sulfonamide.
The process of the present invention can be illustrated by the following reaction scheme:
the foregoing optional oxidation step can be illustrated by the following reaction scheme:
suitable solvents for the aforementioned process are organic solvents which are inert under the reaction conditions. Suitable are halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethylene or trichloroethylene; ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; hydrocarbons, such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine or hexamethylphosphoric triamide or water.
Mixtures of the aforementioned solvents can likewise be used.
Suitable activators or coupling agents for the abovementioned process are the agents customary for this purpose, for example the hydrochloride of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide, N' -dicyclohexylcarbodiimide, the monohydrate of 1-hydroxy-1H-benzotriazole, etc.
Suitable bases are the customary inorganic or organic bases, preference being given to alkali metal hydroxides, for example sodium hydroxide or potassium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate, or sodium methoxide or potassium methoxide or sodium ethoxide or potassium ethoxide or tert-butyl potassium, or amides, such as sodium amide, lithium bis- (trimethylsilyl) amide or lithium diisopropylamide, or amines, such as triethylamine, diisopropylethylamine, diisopropylamine, 4-N, N-dimethylaminopyridine or pyridine.
Here, the base is used in an amount of 1 to 5 moles, preferably 1 to 2 moles, based on 1 mole of the compound of the formula (II).
The reaction is generally carried out at a temperature of-78 ℃ to reflux temperature, preferably in the range of 0 ℃ to reflux temperature.
The reaction may be carried out at atmospheric pressure, under increased pressure or under reduced pressure (for example at 0.5 to 5 bar), typically at atmospheric pressure.
Suitable selective oxidizing agents for preparing epoxides and optionally oxidizing to sulfones, sulfoxides or N-oxides are, for example, m-chloroperbenzoic acid (MCPBA), sodium metaperiodate, N-methylmorpholine-N-oxide (NMO), monoperoxyphthalic acid or osmium tetroxide.
For the preparation of epoxides, the preparation conditions customary for this apply.
For more detailed reaction conditions for the optionally carried out oxidation to give sulfones, sulfoxides or N-oxides, reference may be made to the following documents: M.R. Barbachyn et al, J.Med.chem.1996, 39, 680 and WO-A-97/10223.
See also examples 14-16 of the experimental part.
The amidation optionally carried out is carried out under conventional conditions. See examples 31-35 and 140-147 in particular.
The compounds of the formulae (II), (III), (IV) and (VI) are known per se to the person skilled in the art or can be prepared in a conventional manner. For oxazolidinones, in particular the desired 5- (aminomethyl) -2-oxooxazolidines, see 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; gregory et al, j.med.chem.1989, 32, 1673.
The compounds of the general formula (I) according to the invention exhibit an unexpectedly advantageous spectrum of pharmacological activity and are therefore particularly suitable for the prophylaxis and/or treatment of diseases.
The compounds of the general formula (I) according to the invention-also including the compounds excluded by chemical product protection-act in particular as anticoagulants and can therefore preferably be used as medicaments for the prophylaxis and/or treatment of thromboembolic diseases. By "thromboembolic disorder" is meant within the scope of the present invention, in particular, serious disorders such as myocardial infarction, angina pectoris (including unstable angina), reocclusion and restenosis following angioplasty or aortic coronary bypass, stroke, transient ischemic attacks, peripheral arterial occlusive disorders, pulmonary embolism or deep vein thrombosis.
Furthermore, the compounds of the general formula (I) according to the invention-also including chemical product protection exclusion-are also suitable for the treatment of Disseminated Intravascular Coagulation (DIC).
Finally, the compounds of the general formula (I) according to the invention-also including the compounds excluded from the protection of chemical products-are also suitable for the prophylaxis and/or treatment of atherosclerosis and arthritis and, in addition, for the prophylaxis and/or treatment of Alzheimer's disease and cancer.
The compounds of the general formula (I) according to the invention-also including compounds excluded from chemical product protection-act in particular as selective inhibitors of blood coagulation factor Xa and also inhibit other serine proteases such as thrombin, plasmin or trypsin, either not or only at significantly higher concentrations.
Such inhibitors of the blood coagulation factor Xa are referred to within the scope of the invention as being "selective", in that the IC for the inhibition of factor Xa50IC of value against inhibition by other serine proteases, in particular thrombin, plasmin and trypsin50The values are 100 times smaller, preferably 500 times smaller, in particular 1000 times smaller, where, for the test method of selectivity, reference is made to the test methods of examples A-1) a.1) and a.2) described below.
Furthermore, the compounds of the general formula (I) according to the invention-also including compounds excluded from the protection of chemical products-can also be used for preventing coagulation in vitro, for example for preserving coagulation of blood or biological samples containing factor Xa.
The present invention therefore provides oxazolidinone compounds of the formula (I) which exert an unexpected, strong and selective inhibitory effect, in particular on factor Xa, and among these compounds are also suitable compounds for the protection exclusion of chemical products.
The invention furthermore provides medicaments and pharmaceutical compositions which comprise at least one compound of the general formula (I) according to the invention together with one or more pharmaceutically acceptable auxiliaries or carriers and which can be used for the aforementioned indications.
Furthermore, the invention relates to methods for the prophylaxis and/or treatment of diseases in humans or animals, in particular for the prophylaxis and/or treatment of the aforementioned diseases, using the compounds of the general formula (I) according to the invention, also including the compounds excluded by protection of chemical products.
Furthermore, the invention also comprises a method for preventing coagulation of blood in vitro, in particular for preserving blood or biological samples containing factor Xa, which method is characterized in that a compound of the general formula (I) is added, including compounds which are excluded by chemical product protection.
All customary administration forms are suitable for the administration of the compounds according to the invention, preferably oral, lingual, sublingual, buccal, rectal or parenteral (i.e. bypassing the gastrointestinal tract, that is to say intravenous, intraarterial, intracardiac, intradermal, subcutaneous, transdermal, intraperitoneal or intramuscular). Oral and intravenous administration are particularly suitable, oral administration being particularly preferred, which is a further advantage over the treatment of thromboembolic diseases known from the prior art.
The novel active compounds of the general formula (I) can be converted in a known manner into the customary formulations, for example tablets, sugar-coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceutically acceptable carriers or solvents. In this connection, the therapeutically effective active compounds are each present in the total mixture in an amount of about 0.1 to 95% by weight, preferably 0.5 to 90% by weight, in particular 1 to 85% by weight, i.e. in an amount sufficient to achieve the stated dosage range.
Nevertheless, administration can be carried out in amounts deviating from those mentioned above, if desired, i.e. depending on the body weight or the mode of administration, the individual's response to the drug, the type of formulation and the time or interval of administration. Thus, it may be sufficient in some cases to lower than the above-mentioned minimum amount, while in other cases the above-mentioned maximum amount must be exceeded. In the case of higher doses administered, it may be advisable to divide them into several administrations over the course of the day.
The formulations are prepared, for example, by adding the active substances to solvent and/or carrier substances, optionally using emulsifiers and/or dispersants, if possible, for example in the case of water as diluent, optionally using organic solvents as dissolving assistants.
It has been advantageously demonstrated that in general an intravenous dose of about 0.001-10mg/kg, preferably about 0.01-10mg/kg, in particular about 0.1-8mg/kg of body weight, gives effective results.
It has been found that in general, effective results are obtained at a dose of about 0.01 to 50mg/kg, preferably about 0.1 to 10mg/kg, in particular about 0.5 to 8mg/kg of body weight, administered orally.
Nevertheless, in the case of intravenous or oral administration, administration may be carried out in amounts deviating from the above amounts, if necessary, depending on the body weight or the mode of administration, the individual's response to the drug, the type of formulation and the time or interval of administration. Thus, it may be sufficient in some cases to lower than the above-mentioned minimum amount, while in other cases the above-mentioned maximum amount must be exceeded. In the case of higher administered doses, it may be advisable to divide them into several times over the course of the day, i.e. multiple administrations or continuous instillations.
The compounds of general formula (I) of the invention-also including the compounds excluded by chemical product protection-are distinguished by their selective inhibition of factor Xa over a wider therapeutic range than conventional agents for the treatment of thromboembolic disorders. For the patient this means a lower risk of bleeding, and for the treating physician this means easier adjustment of the patient. Moreover, due to its mechanism, the action occurs more rapidly. But primarily the compounds of the invention allow for oral administration, which is another advantage of treatment with the compounds of the invention.
Detailed Description
The invention is illustrated by the following examples, which are not intended to be limiting in any way.
Examples
AEvaluation of physiological Activity
1.General test method
Particularly advantageous biological properties of the compounds of the invention can be determined by the following methods.
a) Description of the tests (in vitro)
a.1) determination of factor Xa-inhibition
The enzymatic activity of human factor xa (FXa) is determined by conversion of a chromogenic substrate specific for FXa. For this factor Xa cleaves p-nitroaniline from the chromogenic substrate. The assay was performed on microtiter plates as follows.
The test substances were dissolved in DMSO at various concentrations and reacted with human FXa (0.5mmol/l in 50mmol/l Tris-buffer [ C, C, C-Tris (hydroxymethyl) -aminomethane)]150mmol/l NaCl, 0.1% BSA (bovine serum albumin), pH 8.3) were incubated at 25 ℃ for 10 minutes. Pure DMSO was used as a control. Then a chromogenic substrate (150. mu. mol/l Pentapharm Co.) is addedFXa). After incubation at 25 ℃ for 20 minutes at 405nm excitation assays. The challenge of the test mixture containing the test substance is compared with a control mixture without the test substance and the IC is calculated from these data50The value is obtained.
a.2) determination of Selectivity
To demonstrate the selective FXa inhibition, the test substances were determined for other human serine methionineInhibition of white enzymes such as thrombin, trypsin and plasmin. To determine the enzymatic activities of thrombin (75mU/ml), trypsin (500mU/ml) and plasmin (3.2mmol/l), these enzymes were dissolved in Tris buffer (100mmol/l, 20mmol/l CaCl)2pH 8.0) and incubated with the test substance or solvent for 10 minutes. Followed by addition of the corresponding specific chromogenic substrate (Chromozym from Boehringer Mannheim)Chromozym from Boehringer MannheimChromozym from Boehringer Mannheim) The enzyme reaction was started and the assay was excited after 20 minutes at 405 nm. All measurements were performed at 37 ℃. The excitation of the test mixture with the test substance is compared with a control sample without the test substance and the IC is calculated from these data50The value is obtained.
a.3) measurement of anticoagulation
Anticoagulation of the test substances was determined in vitro with human plasma. For this purpose, human blood was collected using a 0.11M sodium citrate solution as acceptor in a sodium citrate/blood mixture ratio 1/9. Immediately after blood collection, mix well and centrifuge at about 2000g for 10 minutes. The supernatant is aspirated off, and the test substances are used in different concentrations or in the presence of corresponding solvents with commercially available kits (Boehringer Mannheim, Inc.)) Determination of prothrombin time (PT, synonym: thromboplastin time, rapid test). Test compounds were incubated with plasma for 10 minutes at 37 ℃ and then thromboplastin was added to initiate coagulation and the time at which coagulation occurred was determined. The concentration of the test substance that doubles the thromboplastin time is thus determined.
b) Determination of antithrombotic Activity (in vivo)
b.1) arteriovenous shunt model (rat)
Fasting male rats (species: HSD CPB: WU) weighing 200-250g were anesthetized with Rompun/Ketavet solution (12mg/kg/50 mg/kg). Thrombosis was induced as described by Christopher N.Berry et al, Br.J.Pharmacol (1994), 113, 1209-. To this end, the left and right jugular veins were opened and the integrated external shunt was connected to the two vessels via a 10cm long polyethylene tube (PE 60). The other 3cm long polyethylene tube (PE 160) containing a roughened nylon wire that has been looped to create a thrombogenic surface was attached to the middle of the polyethylene tube. The extracorporeal circulation was maintained for 15 minutes. The shunt was then removed and the thrombus-containing nylon wire weighed as soon as possible. The weight of the nylon thread itself was determined before the test began. Test substances were administered orally to conscious animals via the tail vein or via the pharyngeal tube prior to establishment of an external shunt.
The results are shown in table 1:
table 1: antithrombotic activity after oral or intravenous administration in arteriovenous shunt model (rat)
Property of (2)
| Examples | ED[mg/kg]Is administered orally | ED[mg/kg]Intravenous injection |
| 1 | 10 | |
| 17 | 6 | |
| 44 | 3 | |
| 95 | 3 | |
| 114 | 3 | |
| 115 | 3 | |
| 123 | 3 | |
| 162 | 3 |
b.2) thrombosis model of the artery (rat)
Male fasted rats (species: HSD CPB: WU) were anesthetized as described above and the average weight of the rats was about 200 g. The left carotid artery (about 2cm) was opened and arterial thrombosis was induced by mechanical injury to the vessel as described by K.Meng et al, Nauyn-Schmiedeberg's Arch.Pharmacol. (1977), 301, 115-. To this end, the open artery was clamped to block the blood flow and cooled to-12 ℃ for 2 minutes using a metal bath to normalize the thrombus size while being pressed with a weight of 200 g. Blood flow is then further reduced by placing a clamp around the artery distal to the damaged portion of the vessel. The proximal clip was removed, the wound closed and reopened after 4 hours to remove the damaged vessel portion. The vessel portion is opened longitudinally and the thrombus of the damaged vessel portion is removed. The wet weight of the thrombus was determined as soon as possible. Test substances were administered to conscious animals via the tail vein or via the mouth of the tube at the start of the experiment.
b.3) thrombosis model of veins (rat)
Male fasted rats (species: HSD CPB: WU) were anesthetized as described above. Rats weighed an average of about 200 g. The left jugular vein (about 2cm) was opened and venous thrombosis was induced by mechanical injury to the vessel as described by K.Meng et al, Nauyn-Schmiedeberg's Arch.Pharmacol. (1977), 301, 115-. In this regard, the open vein was clamped to block blood flow, cooled to-12 ℃ for 2 minutes using a metal bath and normalized for thrombus size while being pressed with a weight of 200 g. Reopen the blood flow and close the wound. The wound was reopened after 4 hours to remove the damaged vascular section. The wet weight of the thrombus was determined as soon as possible. Test substances were administered orally to conscious animals via the tail vein or via the pharyngeal conduit at the start of the experiment.
BPreparation examples
Raw materials
The preparation of 3-morpholinone is described in U.S. Pat. No. 3, 5349045.
The preparation of N- (2, 3-epoxypropyl) phthalimide is described in J. -W.Chern et al Tetrahedron Lett.1998, 39, 8483.
Substituted anilines can be prepared, for example, by 4-fluoronitrobenzene, 2, 4-difluoronitroBenzene or 4-chloronitrobenzene with a suitable amine or amide in the presence of a base. The reaction can also be carried out over a Pd catalyst, such as Pd (OAc)2In the presence of/DPPF/NaOt-Bu (Tetrahedron Lett.1999, 40, 2035) or copper (ringer, Synthesis 1985, 856; Aebishcher et al, Heterocycles 1998, 48, 2225). Likewise, nitro-free halogenated aromatic hydrocarbons are first converted into the corresponding amides and then nitrated at their 4-position (U.S. Pat. No. 3,3279880).
4- (4-Morpholin-3-onyl) nitrobenzene
2mol (202g) of morpholin-3-one (E.Pfeil, U.Harder, Angew. chem.79, 1967, 188) are dissolved in 2 l of N-methylpyrrolidone (NMP). 88g (2.2mol) of sodium hydride (60% dispersed in paraffin) were added in portions over a period of 2 hours. After the evolution of hydrogen had ended, 282g (2mol) of 4-fluoronitrobenzene were added dropwise at room temperature over 1 hour with cooling and the reaction mixture was stirred overnight, after which 1.7 l of liquid were distilled off at 12mbar and 76 ℃ and the residue was treated with 2 l of water and extracted twice with 1 l each time with ethyl acetate. The combined organic phases were washed with water, then dried over sodium sulfate and the solvent was distilled off under reduced pressure, purified by chromatography on silica gel, eluting with hexane/ethyl acetate (1: 1) and then crystallized from ethyl acetate to give 78g of a colorless to pale brown solid in a yield of 17.6% of theory.
1H-NMR(300MHz，CDCl3)：3,86(m，2H，CH2CH2)，4,08(m，2H，CH2CH2)，4,49(s，2H，CH2CO)，7,61(d，2H，3J＝8,95Hz，CHCH)，8,28(d，2H，3J＝8,95Hz，CHCH)
MS(r.I.％)＝222(74，M+)，193(100)，164(28)，150(21)，136(61)，117(22)，106(24)，90(37)，76(38)，63(32)，50(25)
Similarly, the following compounds were synthesized
3-fluoro-4- (4-morpholin-3-onyl) nitrobenzene
4- (N-piperidonyl) nitrobenzene
3-fluoro-4- (N-piperidonyl) nitrobenzene
4- (N-pyrrolidinonyl) nitrobenzene
3-fluoro-4- (N-pyrrolidinonyl) nitrobenzene
II.4- (4-morpholin-3-onyl) aniline
In an autoclave, 63g (0.275mol) of 4- (4-morpholin-3-onyl) nitrobenzene were dissolved in 200ml of tetrahydrofuran, mixed with 3.1g of Pd/C (5%) and hydrogenated at 70 ℃ and 50bar of hydrogen pressure for 8 h. After filtering off the catalyst, the solvent was distilled off under reduced pressure and the product was purified by crystallization from ethyl acetate to give 20g of a colorless to bluish solid in a yield of 37.6% of theory.
Purification can also be carried out by chromatography on silica gel, eluting with hexane/ethyl acetate.
1H-NMR(300MHz，CDCl3)：3,67(m，2H，CH2CH2)，3,99(m，2H，CH2CH2)，4,27(s，2H，CH2CO)，6,68(d，2H，3J＝8,71Hz，CHCH)，7,03(d，2H，3J＝8,71Hz，CHCH)
MS(r.I.％)＝192(100，M+)，163(48)，133(26)，119(76)，106(49)，92(38)，67(27)，65(45)，52(22)，28(22)
Similarly, the following compounds were synthesized
3-fluoro-4- (4-morpholin-3-onyl) aniline
4- (N-piperidonyl) aniline
3-fluoro-4- (N-piperidinonyl) aniline
4- (N-pyrrolidinonyl) aniline
3-fluoro-4- (N-pyrrolidinonyl) aniline
General procedure for the preparation of 4-substituted anilines by reacting 1-fluoro-4-nitrobenzene and 1-chloro-4-nitrobenzene with primary or secondary amines
Equal amounts of fluoronitrobenzene or chloronitrobenzene and the amine were dissolved in dimethyl sulfoxide or acetonitrile (0.1M-1M solution) and the mixture was stirred at 100 ℃ overnight. After cooling to room temperature, the reaction mixture was diluted with ether and washed with water. The organic phase is dried over magnesium sulfate, filtered and concentrated, and if a precipitate appears in the reaction mixture, it is filtered off and washed with diethyl ether or acetonitrile. If the mother liquor is found to contain product, it is treated with diethyl ether and water as described above and the crude product can be purified by chromatography on silica gel (eluting with dichloromethane/cyclohexane and dichloromethane/ethanol mixtures).
For the next reaction, the nitro compound is dissolved in methanol, ethanol or ethanol/dichloromethane mixtures (0.01M-0.5M solution), mixed with 10% palladium on charcoal and stirred overnight under normal pressure hydrogen, then filtered and concentrated, and the crude product can be purified by chromatography on silica gel (elution with dichloromethane/ethanol mixtures) or by preparative reverse phase HPLC (elution with acetonitrile/water mixtures).
Alternatively, iron powder may be used as the reducing agent. For this, the nitro compound is dissolved in acetic acid (0.1M-0.5M solution) and 6 equivalents of iron powder and water (0.3-0.5 times the volume of acetic acid) are added in portions over 10-15 minutes at 90 ℃. Stirring is continued for 30 minutes at 90 ℃ and filtration is carried out, the filtrate is concentrated and the residue is worked up by extraction with ethyl acetate and 2N aqueous sodium hydroxide solution. The organic phase is dried over magnesium sulfate, filtered and concentrated, and the crude product can be purified by chromatography on silica gel (eluting with a dichloromethane/ethanol mixture) or by preparative reverse phase HPLC (eluting with an acetonitrile/water mixture).
The following starting materials were prepared in a similar manner:
III-1. Tert-butyl-1- (4-aminophenyl) -L-proline ester
MS(ESI)：m/z(％)＝304(M+H+MeCN，100)，263(M+H，20)；
HPLC (method 4): rt 2.79 min.
III-2.1- (4-aminophenyl) -3-piperidinecarboxamide
MS(ESI)：m/z(％)＝220(M+H，100)；
HPLC (method 4): rt is 0.59 min.
III-3.1- (4-aminophenyl) -4-piperidinecarboxamide
MS(ESI)：m/z(％)＝220(M+H，100)；
HPLC (method 4): rt is 0.57 min.
III-4.1- (4-aminophenyl) -4-piperidone
MS(ESI)：m/z(％)＝191(M+H，100)；
HPLC (method 4): rt is 0.64 min.
III-5.1- (4-aminophenyl) -L-prolinamide
MS(ESI)：m/z(％)＝206(M+H，100)；
HPLC (method 4): rt is 0.72 min.
III-6[ 1- (4-aminophenyl) -3-piperidinyl group]Methanol
MS(ESI)：m/z(％)＝207(M+H，100)；
HPLC (method 4): rt is 0.60 min.
III-7[ 1- (4-aminophenyl) -2-piperidinyl]Methanol
MS(ESI)：m/z(％)＝207(M+H，100)；
HPLC (method 4): rt is 0.59 min.
III-8.1- (4-aminophenyl) -2-piperidinecarboxylic acid ethyl ester
MS(ESI)：m/z(％)＝249(M+H，35)，175(100)；
HPLC (method 4): rt 2.43 min.
III-9[ 1- (4-aminophenyl) -2-pyrrolidinyl]Methanol
MS(ESI)：m/z(％)＝193(M+H，45)；
HPLC (method 4): rt is 0.79 min.
III-10.4- (2-methylhexahydro-5H-pyrrolo [3, 4-d)]Isoxazol-5-yl) phenylamines
Synthesis from 2-methylhexahydro-2H-pyrrolo [3, 4-d ] isoxazole (Ziegler, Carl B. et al; J.Hrterocyl. chem.; 25; 2; 1988; 719 723)
MS(ESI)：m/z(％)＝220(M+H；50)，171(100)；
HPLC (method 4): rt is 0.54 min.
III-11.4- (1-pyrrolidinyl) -3- (trifluoromethyl) aniline
MS(ESI)：m/z(％)＝231(M+H，100)；
HPLC (method 7): rt 3.40 min.
III-12.3-chloro-4- (1-pyrrolidinyl) -phenylamine
MS(ESI)：m/z(％)＝197(M+H，100)；
HPLC (method 4): rt is 0.78 min.
III-13.5-amino-2- (4-morpholinyl) benzamides
MS(ESI)：m/z(％)＝222(M+H，100)；
HPLC (method 4): rt is 0.77 min.
III-14.3-methoxy-4- (4-morpholinyl) aniline
MS(ESI)：m/z(％)＝209(M+H，100)；
HPLC (method 4): rt is 0.67 min.
III-15.1- [ 5-amino-2- (4-morpholinyl) phenyl]Ethanones
MS(ESI)：m/z(％)＝221(M+H，100)；
HPLC (method 4): rt is 0.77 min.
General procedure for the preparation of 4-substituted anilines by reacting 1-fluoro-4-nitrobenzenes with amides
The amide was dissolved in DMF and mixed with 1.5 equivalents of potassium tert-butoxide (kalium-tert. -butyalt). The mixture was stirred at room temperature for 1 hour, then 1.2 equivalents of 1-fluoro-4-nitrobenzene were added in portions, the mixture was stirred at room temperature overnight, diluted with ether or ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, the organic phase was dried over magnesium sulfate, filtered and concentrated, and the crude product was purified by chromatography on silica gel (dichloromethane/ethanol mixture elution).
The nitro compound is then dissolved in ethanol (0.01M-0.5M solution), mixed with palladium on carbon (10%) and stirred under normal pressure hydrogen overnight, then the mixture is filtered and concentrated and the crude product can be purified by chromatography on silica gel (dichloromethane/ethanol mixture elution) or by preparative reverse phase HPLC (acetonitrile/water mixture elution).
Alternatively, iron powder may be used as the reducing agent. For this, the nitro compound is dissolved in acetic acid (0.1M-0.5M solution) and 6 equivalents of iron powder and water (0.3-0.5 times the volume of acetic acid) are added in portions over 10-15 minutes at 90 ℃. After stirring at 90 ℃ for a further 30 minutes, the filtrate is filtered and concentrated, and the residue is worked up by extraction with ethyl acetate and 2N aqueous sodium hydroxide solution. The organic phase is dried over magnesium sulfate, filtered and concentrated, and the crude product can be purified by chromatography on silica gel (eluting with a dichloromethane/ethanol mixture) or by preparative reverse phase HPLC (eluting with an acetonitrile/water mixture).
The following starting materials were prepared in a similar manner:
IV-1.1- [ 4-amino-2- (trifluoromethyl) phenyl]-2-pyrrolidone
MS(ESI)：m/z(％)＝245(M+H，100)；
HPLC (method 4): rt 2.98 min.
IV-2.4- [ 4-amino-2- (trifluoromethyl) phenyl]-3-morpholinone
MS(ESI)：m/z(％)＝261(M+H，100)；
HPLC (method 4): rt 2.54 min.
IV-3.4- (4-amino-2-aminophenyl) -3-morpholinone
MS(ESI)：m/z(％)＝227(M+H，100)；
HPLC (method 4): rt 1.96 min.
IV-4.4- (4-amino-2-methylphenyl) -3-morpholinone
MS(ESI)：m/z(％)＝207(M+H，100)；
HPLC (method 4): rt is 0.71 min.
IV-5.5-amino-2- (3-oxo-4-morpholinyl) benzonitrile
MS(ESI)：m/z(％)＝218(M+H，100)；
HPLC (method 4): rt 1.85 min.
IV-6.1- (4-amino-2-chlorophenyl) -2-pyrrolidone
MS(ESI)：m/z(％)＝211(M+H，100)；
HPLC (method 4): rt 2.27 min.
IV-7.4- (4-amino-2, 6-dimethylphenyl) -3-morpholinone
Prepared from 2-fluoro-1, 3-dimethyl-5-nitrobenzene (Bartoil et al, j.org.chem.1975, 40, 872):
MS(ESI)：m/z(％)＝221(M+H，100)；
HPLC (method 4): rt is 0.77 min.
IV-8.4- (2, 4-diaminophenyl) -3-morpholinone
Preparation from 1-fluoro-2, 4-dinitrobenzene:
MS(ESI)：m/z(％)＝208(M+H，100)；
HPLC (method 4): rt is 0.60 min.
IV-9.4- (4-amino-2-chlorophenyl) -2-methyl-3-morpholinone
Prepared from 2-methyl-3-morpholinone (Pfeil, e.; Harder, u.; angelw. chem.1967, 79, 188):
MS(ESI)：m/z(％)＝241(M+H，100)；
HPLC (method 4): rt 2.27 min.
IV-10.4- (4-amino-2-chlorophenyl) -6-methyl-3-morpholinone
Prepared from 6-methyl-3-morpholinone (EP 350002):
MS(ESI)：m/z(％)＝241(M+H，100)；
HPLC (method 4): rt 2.43 min.
Synthetic examples
The following examples 1 to 13, 17 to 19 and 36 to 57 are based on process variant [ A ].
Example 1
Preparation of 5-chloro-N- { [ (5S) -3- (3-fluoro-4-morpholinophenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -2-thiophenecarboxamide
(5S) -5- (aminomethyl) -3- (3-fluoro-4-morpholinophenyl) -1, 3-oxazolidin-2-one (see S.J.Brickner et al, J.Med.chem.1996, 39, 673) (0.45g, 1.52mmol), 5-chlorothiophene-2-carboxylic acid (0.25g, 1.52mmol) and 1-hydroxy-1H-benzotriazole Hydrate (HOBT) (0.3g, 1.3 equiv.) were dissolved in 9.9ml DMF, 0.31g (1.98mmol, 1.3 equiv.) of N' - (3-dimethylaminopropyl) -N-Ethylcarbodiimide (EDCI) were added and 0.39g (0.53ml, 3.05mmol, 2 equiv.) of Diisopropylethylamine (DIEA) was added dropwise at room temperature. The mixture is stirred at room temperature overnight, 2g of silica gel are added and the mixture is evaporated to dryness under reduced pressure, the residue is applied to silica gel and purified by chromatography with a toluene-ethyl acetate gradient to give 0.412g (61.5% of theory) of the expected compound with a melting point of 197 ℃.
Rf(SiO2Toluene/ethyl acetate 1: 1) ═ 0.29 (feed ═ 0.0);
ms (dci)440.2(M + H), C1-type;
1H-NMR(d6-DMSO，300MHz)2.95(m，4H)，3.6(t，2H)，3.72(m，4H)，3.8(dd，1H)，4.12(t，1H)，4.75-4.85(m，1H)，7.05(t，1H)，7.15-7.2(m，3H)，7.45(dd，1H)，7.68(d，1H)，8.95(t，1H)。
example 2
5-chloro-N- { [ (5S) -3- (4-morpholinophenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -2-thiophenecarboxamide
The title compound was obtained in an analogous manner from benzyl 4-morpholinophenyl carbamate via the intermediate (5S) -5- (aminomethyl) -3- (3-fluoro-4-morpholinophenyl) -1, 3-oxazolidin-2-one (see example 1).
Melting point: 198 ℃;
IC50the value 43 nM;
Rf(SiO2toluene/ethyl acetate 1: 1) ═ 0.24.
Example 3
5-chloro-N- ({ (5S) -3- [ 3-fluoro-4- (1, 4-thiazinan-4-yl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
The title compound was obtained in an analogous manner from (5S) -5- (aminomethyl) -3- [ 3-fluoro-4- (1, 4-thiazinan-4-yl) phenyl ] -1, 3-oxazolidin-2-one (for preparation see m.r. barbachyn et al, j.med.chem.1996, 39, 680).
Melting point: 193 ℃;
yield: 82%;
Rf(SiO2toluene/ethyl acetate 1: 1) ═ 0.47 (feed ═ 0.0).
Example 4
5-bromo-N- ({ (5S) -3- [ 3-fluoro-4- (1, 4-thiazinan-4-yl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
The title compound was synthesized in a similar manner from 5-bromothiophene-2-carboxylic acid.
Melting point: at 200 ℃.
Example 5
N- ({ (5S) -3- [ 3-fluoro-4- (1, 4-thiazinan-4-yl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -5-methyl-2-thiophenecarboxamide
The title compound was synthesized in a similar manner from 5-methylthiophene-2-carboxylic acid.
Melting point: 167 deg.C.
Example 6
5-chloro-N- { [ (5S) -3- (6-methylthieno [2, 3-b ] pyridin-2-yl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -2-thiophenecarboxamide
The title compound was synthesized in an analogous manner from (5S) -5- (aminomethyl) -3- (6-methylthieno [2, 3-b ] pyridin-2-yl) -1, 3-oxazolidin-2-one (for preparation see EP-A-785200).
Melting point: 247 deg.C.
Example 7
5-chloro-N- { [ (5S) -3- (3-methyl-2-oxo-2, 3-dihydro-1, 3-benzothiazol-6-yl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -2-thiophenecarboxamide
The title compound was synthesized in an analogous manner from 6- [ (5S) -5- (aminomethyl) -2-oxo-1, 3-oxazolidin-3-yl ] -3-methyl-1, 3-benzothiazol-2 (3H) -one (preparation cf. EP-A-738726).
Melting point: 217 deg.C.
Example 8
5-chloro-N- [ ((5S) -3- { 3-fluoro-4- [4- (4-pyridinyl) piperazinyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
The title compound was synthesized in an analogous manner from (5S) -5- (aminomethyl) -3- { 3-fluoro-4- [4- (4-pyridyl) piperazinyl ] phenyl } -1, 3-oxazolidin-2-one (prepared in an analogous manner to j.a. tucker et al, j.med.chem.1998, 41, 3727).
MS (ESI)516(M + H), Cl-type.
Example 9
5-chloro-N- ({ (5S) -3- [ 3-fluoro-4- (4-methylpiperazinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
The title compound was synthesized in an analogous manner from (5S) -5- (aminomethyl) -3- [ 3-fluoro-4- (4-methylpiperazinyl) phenyl ] -1, 3-oxazolidin-2-one.
Example 10
5-chloro-N- ({ (5S) -3- [ 3-fluoro-4- (4-tert-butoxycarbonylpiperazin-1-yl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
The title compound was synthesized in an analogous manner from (5S) -5- (aminomethyl) -3- [ 3-fluoro-4- (4-tert-butoxycarbonylpiperazin-1-yl) phenyl ] -1, 3-oxazolidin-2-one (for preparation see the already mentioned WO-A-93/23384).
Melting point: 184 ℃;
Rf(SiO2toluene/ethyl acetate 1: 1) ═ 0.42.
Example 11
5-chloro-N- ({ (5S) -3- [ 3-fluoro-4- (piperazin-1-yl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
The title compound was obtained by reaction of example 12 with trifluoroacetic acid in dichloromethane.
IC50Value 140 nM;
1H-NMR[d6-DMSO]: 3.01-3.25(m, 8H), 3.5-3.65(m, 2H), 3.7-3.9(m, 1H), 4.05-4.2(m, 1H), 4.75-4.9(m, 1H), 7.05-7.25(m, 3H), 7.5(dd, 1H), 7.7(d, 1H), 8.4 (broad s, 1H), 9.0(t, 1H).
Example 12
5-chloro-N- [ ((5S) -3- (2, 4' -bipyridyl-5-yl) -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
The title compound was synthesized in an analogous manner from (5S) -5-aminomethyl-3- (2, 4' -bipyridinyl-5-yl) -2-oxo-1, 3-oxazolidin-2-one (for preparation see EP-A-789026).
Rf(SiO2Ethyl acetate/ethanol 1: 2) ═ 0.6;
MS (ESI)515(M + H), Cl-type.
Example 13
5-chloro-N- { [ (5S) -2-oxo-3- (4-piperidinophenyl) -1, 3-oxazolidin-5-yl ] methyl } -2-thiophenecarboxamide
The title compound is obtained from 5- (hydroxymethyl) -3- (4-piperidinophenyl) -1, 3-oxazolidin-2-one (cf. DE 2708236 for preparation) by reaction with potassium phthalimide after mesylation, hydrazinolysis and reaction with 5-chlorothiophene-2-carboxylic acid.
Rf(SiO2Ethyl acetate/toluene 1: 1) ═ 0.31;
melting point: 205 deg.c.
Example 17
5-chloro-N- ({ (5S) -2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
5-chloro-N- ({ (5S) -2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) phenyl ] pyrrolidin-2-one (see Reppe et al, Justus Liebigs an. chem.; 596; 1955; 209) was prepared by a similar synthetic route to that known (see S.J. Brickner et al, J.Med.chem.1996, 39, 673) by reaction with benzyloxycarbonyl chloride, followed by reaction with R-glycidyl butyrate, mesylation, reaction with potassium phthalimide, hydrazinolysis in methanol and finally reaction with 5-chlorothiophene-2-carboxylic acid]-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide. 5-chloro-N- ({ (5S) -2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) phenyl) obtained in this manner]IC of (E) -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide50＝4nM(IC50Method for determining values the "determination of factor Xa inhibitory effect" of the preceding examples A-1.a.1) was followed.
Melting point: 229 ℃;
Rfvalue (SiO)2Toluene/ethyl acetate 1: 1) ═ 0.05 (raw material: 0.0) (ii) a Ms (esi): 442.0 (21%, M + Na, Cl-type), 420.0 (72%, M + H, Cl-type), 302.3 (12%), 215 (52%), 145 (100%);
1H-NMR(d6-DMSO，300MHz)：2.05(m，2H)，2.45(m，2H)，3.6(t，2H)，3.77-3.85(m，3H)，4.15(t，1H)，4.75-4.85(m，1H)，7.2(d，1H)，7.5(d，2H)，7.65(d，2H)，7.69(d，1H)，8.96(t，1H)。
the individual steps of the synthesis of example 17 above with the respective precursors are as follows:
4g (22.7mmol) of 1- (4-aminophenyl) pyrrolidin-2-one and 3.6ml (28.4mmol) of N, N-dimethylaniline are slowly mixed in 107ml of tetrahydrofuran at-20 ℃ with 4.27g (25.03mmol) of benzyl chloroformate, and the mixture is stirred at-20 ℃ for 30 minutes and allowed to warm to room temperature. 0.51 ethyl acetate was added and the organic phase was washed with 0.51 saturated NaCl solution and MgSO4The separated organic phase is dried and the solvent is evaporated under reduced pressure, the residue is triturated with ether and filtered with suction to give 5.2g (73.8% of theory) of benzyl 4- (2-oxo-1-pyrrolidinyl) phenylcarbamate as bright beige crystals with a melting point of 174 ℃.
7.27ml of a 2.5M solution of N-butyllithium (BuLi) in hexane was added dropwise to 1.47g (16.66mmol) of isoamyl alcohol in 200ml of tetrahydrofuran at-10 ℃ under an argon atmosphere, wherein it was necessary to additionally add 8ml of a BuLi solution until the indicator of N-benzylidenebenzylamine became colored. The mixture was stirred at-10 ℃ for 10 minutes, cooled to-78 ℃ and 4.7g (15.14mmol) of benzyl 4- (2-oxo-1-pyrrolidinyl) phenylcarbamate solution were slowly added, followed by 4ml of n-BuLi solution until the indicator became pink, the mixture was stirred at-78 ℃ for 10 minutes and 2.62g (18.17mmol) of R-glycidyl butyrate were added and stirring was continued at-78 ℃ for 30 minutes.
The reaction mixture is allowed to warm to room temperature overnight, 200ml of water are added and THF is distilled off under reduced pressure, the aqueous residue is extracted with ethyl acetate and the organic phase is MgSO4Drying and evaporation under reduced pressure, triturating the residue with 500ml of diethyl ether and suction-filtering the precipitated crystals under reduced pressure to give 3.76g (theoretical amount of 9)0%) (5R) -5- (hydroxymethyl) -3- [4- (2-oxo-1-pyrrolidinyl) phenyl]-1, 3-oxazolidin-2-one, melting point 148 ℃ and RfValue (SiO)2Toluene/ethyl acetate 1: 1) 0.04 (feedstock 0.3).
3.6g (13.03mmol) of (5R) -5- (hydroxymethyl) -3- [4- (2-oxo-1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-2-one and 2.9g (28.67mmol) of triethylamine are added to 160ml of dichloromethane with stirring at 0 deg.C, 1.79g (15.64mmol) of methanesulfonyl chloride is added with stirring and the mixture is stirred at 0 deg.C for 1.5 h at room temperature for 3 h.
The reaction mixture was washed with water, the aqueous phase was extracted with more dichloromethane, and the combined organic extracts were MgSO4Dried and concentrated, then the residue (1.67g) was dissolved in 70ml acetonitrile, mixed with 2.62g (14.16mmol) of potassium phthalimide and stirred in a closed vessel in a microwave oven at 180 ℃ for 45 minutes.
The insoluble residue is filtered off from the mixture, the filtrate is concentrated under reduced pressure, the residue (1.9g) is dissolved in methanol and mixed with 0.47g (9.37mmol) of hydrazine hydrate, the mixture is boiled for 2 hours, cooled, mixed with saturated sodium bicarbonate solution and extracted 6 times with 2 l dichloromethane in total, MgSO4Drying the combined crude product containing (5S) -5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) phenyl]-an organic extract of 1, 3-oxazolidin-2-one and concentrated under reduced pressure.
Preparation of the final product 5-chloro-N- ({ (5S) -2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide 0.32g (1.16mmol) of the above-prepared (5S) -5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-2-one, 5-chlorothiophene-2-carboxylic acid (0.19 g; 1.16mmol) and 1-hydroxy-1H-benzotriazole Hydrate (HOBT) (0.23g, 1.51mmol) were dissolved in 7.6ml of DMF and 0.29g (1.51mmol) of N' - (3-dimethylaminopropyl) -N-ethylcarbo-e Diimine (EDCI) was reacted and 0.3g (0.4 ml; 2.32mmol, 2 eq.) Diisopropylethylamine (DIEA) was added dropwise at room temperature and the mixture was stirred at room temperature overnight.
The mixture was evaporated to dryness under reduced pressure, the residue was dissolved in 3ml DMSO and purified by RP-MPLC chromatography, eluting with acetonitrile/water/0.5% TFA-gradient. From the appropriate fractions acetonitrile was distilled off and the precipitated compound was filtered off with suction to yield 0.19g (39% of theory) of the title compound.
The following compounds were prepared in a similar manner:
example 18
5-chloro-N- ({ (5S) -2-oxo-3- [4- (1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
The compound 5-chloro-N- ({ (5S) -2-oxo-3- [4- (1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide is obtained in analogy to example 17 from 4-pyrrolidin-1-yl-aniline (Reppe et al, Justus Liebigs Ann. chem.; 596; 1955; 151).
IC50＝40nM；
Melting point: 216 ℃;
Rfvalue (SiO)2Toluene/ethyl acetate 1: 1) 0.31[ raw material: 0.0 ═]。
Example 19
5-chloro-N- ({ (5S) -2-oxo-3- [4- (diethylamino) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
Analogously, the compound 5-chloro-N- ({ (5S) -2-oxo-3- [4- (diethylamino) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide was obtained from N, N-diethylphenyl-1, 4-diamine (U.S. Pat. No. 5, 2811555; l 955).
IC50＝270nM；
Melting point: 181 ℃;
Rfvalue (SiO)2Toluene/ethyl acetate 1: 1) 0.25[ raw material: 0.0 ═]。
Example 36
5-chloro-N- ({ (5S) -3- [ 2-methyl-4- (4-morpholinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
The title compound was obtained from 2-methyl-4- (4-morpholinyl) phenyl ] -aniline (j.e. luvalley et al, j.am. chem. soc.1948, 70, 2223).
MS(ESI)：m/z(％)＝436([M+H]+100), Cl-type;
HPLC (method 1): rt (%) 3.77 (98).
IC50：1.26μM
Example 37
5-chloro-N- { [ (5S) -3- (3-chloro-4-morpholinophenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -2-thiophenecarboxamide
The title compound was obtained from 3-chloro-4- (4-morpholinyl) aniline (h.r.snyder et al, j.pharm.sci.1977, 66, 1204).
MS(ESI)：m/z(％)＝456([M+H]+，100)，Cl2-a type;
HPLC (method 2): rt (%) -4.31 (100).
IC50：33nM
Example 38
5-chloro-N- ({ (5S) -3- [4- (4-morpholinylsulfonyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
The title compound was obtained from 4- (4-morpholinosulfonyl) aniline (Adams et al, J.Am.chem.Soc.1939, 61, 2342).
MS(ESI)：m/z(％)＝486([M+H]+100), Cl-type;
HPLC (method 3): rt (%) -4.07 (100).
IC50：2μM
Example 39
5-chloro-N- ({ (5S) -3- [4- (1-azetidinylsulfonyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
From 4- (1-azetidinylsulfonyl) aniline:
MS(DCI，NH3)：m/z(％)＝473([M+NH4]+100), Cl-type;
HPLC (method 3): rt (%) -4.10 (100).
IC50：0.84μM
Example 40
5-chloro-N- [ ((5S) -3- {4- [ (dimethylamino) sulfonyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
From 4-amino-N, N-dimethylbenzenesulfonamide (I.K. Khanna et al, J.Med. chem.1997, 40, 1619):
MS(ESI)：m/z(％)＝444([M+H]+100), Cl-type;
HPLC (method 3): rt (%) -4.22 (100).
IC50：90nM
General procedure for acylation of 5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-2-one with an acid chloride
To the corresponding acid chloride (2.5 equivalents) was added dropwise a solution of about 0.1 mole of 5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-2-one (from example 45) (1.0 equivalent) and anhydrous pyridine (about 6 equivalents) in anhydrous dichloromethane at room temperature under argon atmosphere. The mixture was stirred at room temperature for about 4 hours, then about 5.5 equivalents of PS-trisamine (Argonaut technologies) were added, the mixture was stirred gently for 2 hours, then diluted with dichloromethane/DMF (3: 1), filtered (resin washed with dichloromethane/DMF) and the filtrate was concentrated, and the resulting product was optionally purified by preparative RP-HPLC.
The following compounds were prepared in a similar manner:
EXAMPLE 41
N- ({ 2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
LC-MS (method 6): m/z (%) ═ 386(M + H, 100);
LC-MS：rt(％)＝3.04(100)。
IC50：1.3μM
general procedure for the preparation of acyl derivatives from 5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-2-one and a carboxylic acid
To 2.9 equivalents of resin bound carbodiimide (PS-carbodiimide, Argonaut technologies) was added a mixture of the appropriate carboxylic acid (about 2 equivalents) and anhydrous dichloromethane/DMF (about 9: 1), after gentle shaking for 15 minutes at room temperature, 5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-2-one (from example 45) (1.0 equivalent) was added and shaken overnight, after which the resin was filtered off (washed with dichloromethane) and the filtrate was concentrated and the resulting product was optionally purified by preparative RP-HPLC.
The following compounds were prepared in a similar manner:
example 42
5-methyl-N- ({ 2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
LC-MS：m/z(％)＝400(M+H，100)；
LC-MS (method 6): rt (%) -. 3.23 (100).
IC50：0.16μM
Example 43
5-bromo-N- ({ 2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
LC-MS：m/z(％)＝466(M+H，100)；
LC-MS (method 5): rt (%) 3.48 (78).
IC50：0.014μM
Example 44
5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
a)2- ((2R) -2-hydroxy-3- { [4- (3-oxo-4-morpholinyl) phenyl ] amino } propyl) -1H-isoindole-1, 3(2H) -dione:
a suspension of 2- [ (2S) -2-oxiranylmethyl ] -1H-isoindole-1, 3(2H) -dione (A. Gutcait et al, Tetrahedron Asym.1996, 7, 1641) (5.68g, 27.9mmol) and 4- (4-aminophenyl) -3-morpholinone (5.37g, 27.9mmol) in ethanol-water (9: 1, 140ml) was refluxed for 14 hours (precipitate dissolved and after some time precipitate formed). The precipitate (desired product) is filtered off, washed 3 times with diethyl ether and dried, the combined mother liquors are concentrated under reduced pressure and a second suspension of 2- [ (2S) -2-oxiranylmethyl ] -1H-isoindole-1, 3(2H) -dione (2.84g, 14.0mmol) in ethanol-water (9: 1, 70ml) is added and refluxed for 13 hours (precipitate dissolves and forms a precipitate again after some time). The precipitate (desired product) is filtered off, washed 3 times with diethyl ether and dried, total yield: 0.14g, 92% of theory.
MS(ESI)：m/z(％)＝418([M+Na]+，84)，396([M+H]+93); HPLC (method 3): rt (%) 3.34 (100).
b)2- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -1H-isoindole-1, 3(2H) -dione:
to a suspension of the amino alcohol (3.58g, 9.05mmol) in tetrahydrofuran (90ml) was added N, N '-carbonyldiimidazole (2.94g, 18.1mmol) and dimethylaminopyridine (catalytic amount) at room temperature under argon, the suspension was stirred at 60 ℃ for 12 hours (precipitation dissolved and formation of a precipitate again after a while), mixed with a second portion of N, N' -carbonyldiimidazole (2.94g, 18.1mmol) and stirred further at 60 ℃ for 12 hours, the precipitate (desired product) was filtered off, washed with tetrahydrofuran and dried, the filtrate was concentrated under reduced pressure and purified by flash chromatography (eluting with a dichloromethane-methanol mixture) to give further product. Total yield: 3.32g, 87% of theory.
MS(ESI)：m/z(％)＝422([M+H]+，100)；
HPLC (method 4): rt (%) -3.37 (100).
c) 5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
To a suspension of this oxazolidinone (4.45g, 10.6mmol) in ethanol (102ml) was added dropwise methylamine (40% in water, 10.2ml, 0.142mol) at room temperature, the reaction mixture was refluxed for 1 hour and concentrated under reduced pressure, and the crude product was used for the next reaction without further purification.
To a pyridine (90ml) solution of the amine was added 5-chloro-thiophene-2-carbonyl chloride (2.29g, 12.7mmol) dropwise at 0 ℃ under argon, the ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour and mixed with water, after addition of dichloromethane and phase separation, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure and purified by flash chromatography (eluting with a dichloromethane-methanol mixture) to give the desired product in total yield: 3.92g, 86% of theory.
Melting point: 232 ℃ and 233C;
1H NMR(DMSO-d6，200MHz)：9.05-8.90(t，J＝5.8Hz，1H)，7.70(d，J＝4.1Hz，1H)，7.56(d，J＝9.0Hz，2H)，7.41(d，J＝9.0Hz，2H)，，7.20(d，J＝4.1Hz，1H)，4.93-4.75(m，1H)，4.27-4.12(m，3H)，4.02-3.91(m，2H)，3.91-3.79(dd，J＝6.1Hz，9.2Hz，1H)，3.76-3.66(m，2H)，3.66-3.54(m，2H)；
MS(ESI)：m/z(％)＝436([M+H]+100, Cl-type);
HPLC (method 2): rt (%) -3.60 (100);
[α]21 D＝-38°(c 0.2985，DMSO)；ee：99％.
IC50：0.7nM
the following compounds were prepared in a similar manner:
example 45
5-methyl-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝831([2M+H]+，100)，416([M+H]+，66)；
HPLC (method 3): rt (%) 3.65 (100).
IC50：4.2nM
Example 46
5-bromo-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝480([M+H]+100, Br-type);
HPLC (method 3): rt (%) -, 3.87 (100).
IC50：0.3nM
Example 47
5-chloro-N- { [ (5S) -3- (3-isopropyl-2-oxo-2, 3-dihydro-1, 3-benzooxazol-6-yl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -2-thiophenecarboxamide
200mg (0.61mmol) of 6- [ (5S) -5- (aminomethyl) -2-oxo-1, 3-oxazolidin-3-yl ] -3-isopropyl-1, 3-benzoxazol-2 (3H) -one hydrochloride (EP 738726) are suspended in 5ml of tetrahydrofuran and mixed with 026ml (1.83mmol) of triethylamine and 132mg (0.73mmol) of 5-chlorothiophene-2-carbonyl chloride, the reaction mixture is stirred overnight at room temperature and subsequently concentrated, and purified by column chromatography (silica gel, dichloromethane/ethanol ═ 50/1-20/1) to give 115mg (43% of theory) of the expected product.
MS(ESI)：m/z(％)＝436(M+H，100)；
HPLC (method 4): rt (%) -3.78 min.
The following compounds were prepared in a similar manner:
the following examples 20-30 and 58-139 are based on process variant [ B ], where examples 20 and 21 describe the preparation of precursors.
Example 20
Preparation of N-allyl-5-chloro-2-thiophenecarboxamide
To an ice-cooled solution of 2.63ml (35mmol) of allylamine in 14.2ml of anhydrous pyridine and 14.2ml of THF was added dropwise 5-chloro-thiophene-2-carbonyl chloride (7.61g, 42 mmol). The ice bath was removed and the mixture was stirred at room temperature for 3h, then concentrated under reduced pressure, the residue was mixed with water and the solid was filtered off and the crude product was purified by flash chromatography on silica gel (dichloromethane). Yield: 7.20g (99% of theory);
MS(DCI，NH4)：m/z(％)＝219(M+NH4，100)，202(M+H，32)；
HPLC (method 1): rt (%) -3.96 min (98.9).
Example 21
Preparation of 5-chloro-N- (2-oxiranylmethyl) -2-thiophenecarboxamide
An ice-cooled solution of 2.0g (9.92mmol) of N-allyl-5-chloro-2-thiophenecarboxamide in10 ml of dichloromethane was mixed with m-chloroperbenzoic acid (3.83g, ca. 60% strength), the mixture was stirred overnight and warmed to room temperature, then washed with 10% sodium hydrogensulfate solution (three times), the organic phase was washed with saturated sodium bicarbonate solution (two times) and with saturated sodium chloride solution, dried over magnesium sulfate and concentrated, and the product was purified by chromatography on silica gel (cyclohexane/ethyl acetate 1: 1).
Yield: 837mg (39% of theory);
MS(DCI，NH4)：m/z(％)＝253(M+NH4，100)，218(M+H，80)；
HPLC (method 1): rt (%) -3.69 min (about 80).
General procedure for the preparation of substituted N- (3-amino-2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide derivatives from 5-chloro-N- (2-oxiranylmethyl) -2-thiophenecarboxamide
To a solution of a primary amine or aniline derivative (1.5-2.5 equivalents) in1, 4-dioxane, 1, 4-dioxane-water mixture or ethanol, ethanol-water mixture (about 0.3-1.0mol/l) at room temperature or at up to 80 ℃, 5-chloro-N- (2-oxiranylmethyl) -2-thiophenecarboxamide (1.0 equivalent) is added portionwise, the mixture is stirred for 2-6 hours, then concentrated and the product can be isolated from the reaction mixture by silica gel chromatography (cyclohexane-ethyl acetate mixture, dichloromethane-methanol mixture or dichloromethane-methanol-triethylamine mixture).
The following compounds were prepared in a similar manner:
example 22
N- [3- (benzylamino) -2-hydroxypropyl ] -5-chloro-2-thiophenecarboxamide
MS(ESI)：m/z(％)＝325(M+H，100)；
HPLC (method 1): rt (%) -3.87 min (97.9).
Example 23
5-chloro-N- [3- (3-cyanophenylamino) -2-hydroxypropyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝336(M+H，100)；
HPLC (method 2): rt (%) -4.04 min (100).
Example 24
5-chloro-N- [3- (4-cyanophenylamino) -2-hydroxypropyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝336(M+H，100)；
HPLC (method 1): rt (%) -4.12 min (100).
Example 25
5-chloro-N- {3- [4- (cyanomethyl) phenylamino ] -2-hydroxypropyl } -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝350(M+H，100)；
HPLC (method 4): rt (%) -3.60 min (95.4).
Example 26
5-chloro-N- {3- [3- (cyanomethyl) phenylamino ] -2-hydroxypropyl } -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝350(M+H，100)；
HPLC (method 4): rt (%) -3.76 min (94.2).
Example 58
4- [ (3- { [ (5-chloro-2-thienyl) carbonyl ] amino } -2-hydroxypropyl) amino ] -benzylcarbamic acid tert-butyl ester
Prepared from tert-butyl 4-aminobenzyl carbamate (bioorg. Med. chem. Lett, 1997; 1921-1926):
MS(ES-pos)：m/z(％)＝440(M+H，100)，(ES-neg)：m/z(％)＝438(M-H，100)；
HPLC (method 1): rt (%) -, 4.08 (100).
Example 59
4- [ (3- { [ (5-chloro-2-thienyl) carbonyl ] amino } -2-hydroxypropyl) amino ] -phenylcarbamic acid tert-butyl ester
Prepared from tert-butyloxycarbonyl-1, 4-phenylenediamine:
MS(ESI)：m/z(％)＝426(M+H，45)，370(100)；
HPLC (method 1): rt (%) -4.06 (100).
Example 60
Tert-butyl 2-hydroxy-3- { [ (4- (2-oxo-1-pyrrolidinyl) phenyl ] amino } propylcarbamate
Prepared from 1- (4-aminophenyl) -2-pyrrolidone (Justus liebig ann. chem.; 1955; 596, 204):
MS(DCI，NH3)：m/z(％)＝350(M+H，100)；
HPLC (method 1): rt (%) 3.57 (97).
Example 61
5-chloro-N- (3- { [ 3-fluoro-4- (3-oxo-4-morpholinyl) phenyl ] amino } -2-hydroxypropyl) -2-thiophenecarboxamide
800mg (3.8mmol) of 4- (4-amino-2-fluorophenyl) -3-morpholinone and 700mg (3.22mmol) of 5-chloro-N- (2-oxiranylmethyl) -2-thiophenecarboxamide are heated under reflux in 15ml of ethanol and 1ml of water for 6 hours, the mixture is concentrated under reduced pressure, the precipitated crystals are filtered off with suction after treatment with ethyl acetate, and the mother liquor is purified by chromatography to give 276mg (17% of theory) of the expected compound.
Rf(ethyl acetate): 0.25.
example 62
(N- (3-phenylamino-2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide
Preparation from aniline:
MS(DCI，NH3)：m/z(％)＝311([M+H]+100), Cl-type;
HPLC (method 3): rt (%) 3.79 (100).
Example 63
5-chloro-N- (2-hydroxy-3- { [4- (3-oxo-4-morpholinyl) phenyl ] amino } propyl) -2-thiophenecarboxamide
Prepared from 4- (4-aminophenyl) -3-morpholinone:
MS(ESI)：m/z(％)＝410([M+H]+50), Cl-type;
HPLC (method 3): rt (%) -3.58 (100).
Example 64
N- [3- ({4- [ acetyl (cyclopropyl) amino ] phenyl } amino) -2-hydroxypropyl ] -5-chloro-2-thiophenecarboxamide
Prepared from N- (4-aminophenyl) -N-cyclopropylacetamide:
MS(ESI)：m/z(％)＝408([M+H]+100), Cl-type;
HPLC (method 3): rt (%) 3.77 (100).
Example 65
N- [3- ({4- [ acetyl (methyl) amino ] phenyl } amino) -2-hydroxypropyl ] -5-chloro-2-thiophenecarboxamide
Prepared from N- (4-aminophenyl) -N-methylacetamide:
MS(ESI)：m/z(％)＝382(M+H，100)；
HPLC (method 4): rt 3.31 min.
Example 66
5-chloro-N- (2-hydroxy-3- { [4- (1H-1, 2, 3-triazol-1-yl) phenyl ] amino } propyl) -2-thiophenecarboxamide
Prepared from 4- (1H-1, 2, 3-triazol-1-yl) aniline (Bouchet al; J. chem Soc. PerkinTrans.2; 1974; 449):
MS(ESI)：m/z(％)＝378(M+H，100)；
HPLC (method 4): rt 3.55 min.
Example 67
1- {4- [ (3- { [ 5-chloro-2-thienyl) carbonyl ] amino } -2-hydroxypropyl) -amino ] phenyl } -L-proline tert-butyl ester
MS(ESI)：m/z(％)＝480(M+H，100)；
HPLC (method 4): rt 3.40 min.
Example 68
1- {4- [ (3- { [ (5-chloro-2-thienyl) carbonyl ] amino } -2-hydroxypropyl) -amino ] phenyl } -4-piperidinecarboxamide
MS(ESI)：m/z(％)＝437(M+H，100)；
HPLC (method 4): rt 2.39 min.
Example 69
1- {4- [ (3- { [ (5-chloro-2-thienyl) carbonyl ] amino } -2-hydroxypropyl) -amino ] phenyl } -3-piperidinecarboxamide
MS(ESI)：m/z(％)＝437(M+H，100)；
HPLC (method 4): rt 2.43 min.
Example 70
5-chloro-N- (2-hydroxy-3- { [4- (4-oxo-1-piperidinyl) phenyl ] amino } propyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝408(M+H，100)；
HPLC (method 4): rt 2.43 min.
Example 71
1- {4- [ (3- { [ (5-chloro-2-thienyl) carbonyl ] amino } -2-hydroxypropyl) amino ] phenyl } -L-prolinamide
MS(ESI)：m/z(％)＝423(M+H，100)；
HPLC (method 4): rt 2.51 min.
Example 72
5-chloro-N- [ 2-hydroxy-3- ({4- [3- (hydroxymethyl) -1-piperidinyl ] phenyl } amino) propyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝424(M+H，100)；
HPLC (method 4): rt 2.43 min.
Example 73
5-chloro-N- [ 2-hydroxy-3- ({4- [2- (hydroxymethyl) -1-piperidinyl ] phenyl } amino) propyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝424(M+H，100)；
HPLC (method 4): rt 2.49 min.
Example 74
1- {4- [ (3- { [ (5-chloro-2-thienyl) carbonyl ] amino } -2-hydroxypropyl) amino ] phenyl } -2-piperidinecarboxylic acid ethyl ester
MS(ESI)：m/z(％)＝466(M+H，100)；
HPLC (method 4): rt 3.02 min.
Example 75
5-chloro-N- [ 2-hydroxy-3- ({4- [2- (hydroxymethyl) -1-pyrrolidinyl ] phenyl } amino) propyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝410(M+H，100)；
HPLC (method 4): rt 2.48 min.
Example 76
5-chloro-N- (2-hydroxy-3- { [4- (2-methylhexahydro-5H-pyrrolo [3, 4-d ] isoxazol-5-yl) phenyl ] amino } propyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝437(M+H，100)；
HPLC (method 5): rt is 1.74 min.
Example 77
5-chloro-N- (2-hydroxy-3- { [4- (1-pyrrolidinyl) -3- (trifluoromethyl) phenyl ] amino } propyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝448(M+H，100)；
HPLC (method 4): rt 3.30 min.
Example 78
5-chloro-N- (2-hydroxy-3- { [4- (2-oxo-1-pyrrolidinyl) -3- (trifluoromethyl) phenyl ] amino } propyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝462(M+H，100)；
HPLC (method 4): rt 3.50 min.
Example 79
5-chloro-N- (3- { [ 3-chloro-4- (3-oxo-4-morpholinyl) phenyl ] amino } -2-hydroxypropyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝444(M+H，100)；
HPLC (method 4): rt 3.36 min.
Example 80
5-chloro-N- (2-hydroxy-3- { [4- (3-oxo-4-morpholinyl) -3- (trifluoromethyl) phenyl ] amino } propyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝478(M+H，100)；
HPLC (method 4): rt 3.37 min.
Example 81
5-chloro-N- (2-hydroxy-3- { [ 3-methyl-4- (3-oxo-4-morpholinyl) phenyl ] amino } propyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝424(M+H，100)；
HPLC (method 4): rt 2.86 min.
Example 82
5-chloro-N- (3- { [ 3-cyano-4- (3-oxo-4-morpholinyl) phenyl ] amino } -2-hydroxypropyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝435(M+H，100)；
HPLC (method 4): rt 3.10 min.
Example 83
5-chloro-N- (3- { [ 3-chloro-4- (1-pyrrolidinyl) phenyl ] amino } -2-hydroxypropyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝414(M+H，100)；
HPLC (method 4): rt 2.49 min.
Example 84
5-chloro-N- (3- { [ 3-chloro-4- (2-oxo-1-pyrrolidinyl) phenyl ] amino } -2-hydroxypropyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝428(M+H，100)；
HPLC (method 4): rt 3.39 min.
Example 85
5-chloro-N- (3- { [3, 5-dimethyl-4- (3-oxo-4-morpholinyl) phenyl ] amino } -2-hydroxypropyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝438(M+H，100)；
HPLC (method 4): rt 2.84 min.
Example 86
N- (3- { [3- (aminocarbonyl) -4- (4-morpholinyl) phenyl ] amino } -2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide
MS(ESI)：m/z(％)＝439(M+H，100)；
HPLC (method 4): rt 2.32 min.
Example 87
5-chloro-N- (2-hydroxy-3- { [ 3-methoxy-4- (4-morpholinyl) phenyl ] amino } propyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝426(M+H，100)；
HPLC (method 4): rt 2.32 min.
Example 88
N- (3- { [ 3-acetyl-4- (4-morpholinyl) phenyl ] amino } -2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide
MS(ESI)：m/z(％)＝438(M+H，100)；
HPLC (method 4): rt 2.46 min.
Example 89
N- (3- { [ 3-amino-4- (3-oxo-4-morpholinyl) phenyl ] amino } -2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide
MS(ESI)：m/z(％)＝425(M+H，100)；
HPLC (method 4): rt 2.45 min.
Example 90
5-chloro-N- (3- { [ 3-chloro-4- (2-methyl-3-oxo-4-morpholinyl) phenyl ] amino } -2-hydroxypropyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝458(M+H，100)；
HPLC (method 4): rt 3.44 min.
Example 91
5-chloro-N- (3- { [ 3-chloro-4- (2-methyl-5-oxo-4-morpholinyl) phenyl ] amino } -2-hydroxypropyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝458(M+H，100)；
HPLC (method 4): rt 3.48 min.
Example 91a
5-chloro-N- [ 2-hydroxy-3- ({4- [ (3-oxo-4-morpholinyl) methyl ] phenyl } amino) propyl ] -2-thiophenecarboxamide
Prepared from 4- (4-amino-benzyl) -3-morpholinone (Surrey et al, J.Amer.chem.Soc.; 77; 1955; 633):
MS(ESI)：m/z(％)＝424(M+H，100)；
HPLC (method 4): rt 2.66 min.
General procedure for the preparation of 3-substituted 5-chloro-N- [ (2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide derivatives from substituted N- (3-amino-2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide derivatives
To a solution of the substituted N- (3-amino-2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide derivative (1.0 equivalent) in anhydrous THF (ca. 0.1mol/l) at room temperature was added carbonyldiimidazole (1.2-1.8 equivalents) or an equivalent of phosgene equivalent. The mixture is stirred at room temperature or optionally at elevated temperature (up to 70 ℃) for 2-18h and then concentrated under reduced pressure, and the product can be purified by chromatography on silica gel (dichloromethane-methanol mixture or cyclohexane-ethyl acetate mixture).
The following compounds were prepared in a similar manner:
example 27
N- [ (3-benzyl-2-oxo-1, 3-oxazolidin-5-yl) methyl ] -5-chloro-2-thiophenecarboxamide
MS(DCI，NH4)：m/z(％)＝372(M+Na，100)，351(M+H，45)；
HPLC (method 1): rt (%) -4.33 min (100).
Example 28
5-chloro-N- { [3- (3-cyanophenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -2-thiophenecarboxamide
MS(DCI，NH4)：m/z(％)＝362(M+H，42)，145(100)；
HPLC (method 2): rt (%) -4.13 min (100).
Example 29
5-chloro-N- ({3- [4- (cyanomethyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝376(M+H，100)；
HPLC (method 4): rt is 4.12 min.
Example 30
5-chloro-N- ({3- [3- (cyanomethyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝376(M+H，100)；
HPLC (method 4): rt is 4.17 min.
Example 92
4- [5- ({ [ (5-chloro-2-thienyl) carbonyl ] amino } methyl) -2-oxo-1, 3-oxazolidin-3-yl ] benzylcarbamic acid tert-butyl ester
Prepared from example 58:
MS(ESI)：m/z(％)＝488(M+Na，23)，349(100)；
HPLC (method 1): rt (%) -4.51 (98.5).
Example 93
4- [5- ({ [ (5-chloro-2-thienyl) carbonyl ] amino } methyl) -2-oxo-1, 3-oxazolidin-3-yl ] phenylcarbamic acid tert-butyl ester
Prepared from example 59:
MS(ESI)：m/z(％)＝493(M+Na，70)，452(M+H，10)，395(100)；
HPLC (method 1): rt (%) -, 4.41 (100).
Example 94
2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl carbamic acid tert-butyl ester
Prepared from example 60:
MS(DCI，NH3)：m/z(％)＝393(M+NH4，100)；
HPLC (method 3): rt (%) 3.97 (100).
Example 95
5-chloro-N- ({3- [ 3-fluoro-4- (3-oxo-4-morpholinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
260mg (0.608mmol) of 5-chloro-N- (3- { [ 3-fluoro-4- (3-oxo-4-morpholinyl) phenyl ] amino } -2-hydroxypropyl) -2-thiophenecarboxamide (from example 61), 197mg (1.22mmol) of carbonyldiimidazole and 7mg of dimethylaminopyridine are heated at reflux in 20ml of dioxane for 5 hours. 20ml of acetonitrile are then added and stirred in a microwave oven in a sealed container at 180 ℃ for 30 minutes, the solution is concentrated using a rotary evaporator and purified by RP-HPLC column chromatography to give 53mg (19% of theory) of the expected compound.
NMR(300MHz，d6-DMSO): δ — 3.6-3.7(m, 4H), 3.85(dd, 1H), 3.95(m, 2H), 4.2(m, 1H), 4.21(s, 2H), 4.85(m, 1H), 4.18(s, 2H), 7.19(d, 1H, thiophene), 7.35(dd, 1H), 7.45(t, 1H), 7.55(dd, 1H), 7.67(d, 1H, thiophene), 8.95(t, 1H, CONH).
Example 96
5-chloro-N- [ (2-oxo-3-phenyl-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
Prepared from example 62:
MS(ESI)：m/z(％)＝359([M+Na]+，71)，337([M+H]+100), Cl-type;
HPLC (method 3): rt (%) -4.39 (100).
IC50：2μM
Example 97
5-chloro-N- ({ 2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
Prepared from example 63:
MS(ESI)：m/z(％)＝458([M+Na]+，66)，436([M+H]+100), Cl-type;
HPLC (method 3): rt (%) 3.89 (100).
IC50：1.4nM
Example 98
N- [ (3- {4- [ acetyl (cyclopropyl) amino ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -5-chloro-2-thiophenecarboxamide
Prepared from example 64:
MS(ESI)：m/z(％)＝456([M+Na]+，55)，434([M+H]+100), Cl-type;
HPLC (method 3): rt (%) -4.05 (100).
IC50：50nM
Example 99
N- [ (3- {4- [ acetyl (methyl) amino ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -5-chloro-2-thiophenecarboxamide
MS(ESI)：m/z(％)＝408(M+H，30)，449(M+H+MeCN，100)；
HPLC (method 4): rt 3.66 min.
Example 100
5-chloro-N- ({ 2-oxo-3- [4- (1H-1, 2, 3-triazol-1-yl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝404(M+H，45)，445(M+H+MeCN，100)；
HPLC (method 4): rt 3.77 min.
Example 101
1- {4- [5- ({ [ (5-chloro-2-thienyl) carbonyl ] amino } methyl) -2-oxo-1, 3-oxazolidin-3-yl ] phenyl } -L-proline tert-butyl ester
MS(ESI)：m/z(％)＝450(M+H-56，25)，506(M+H，100)；
HPLC (method 4): rt is 5.13 min.
Example 102
1- {4- [5- ({ [ (5-chloro-2-thienyl) carbonyl ] amino } methyl) -2-oxo-1, 3-oxazolidin-3-yl ] phenyl } -4-piperidinecarboxamide
MS(ESI)：m/z(％)＝463(M+H，100)；
HPLC (method 4): rt 2.51 min.
Example 103
1- {4- [5- ({ [ (5-chloro-2-thienyl) carbonyl ] amino } methyl) -2-oxo-1, 3-oxazolidin-3-yl ] phenyl } -3-piperidinecarboxamide
MS(ESI)：m/z(％)＝463(M+H，100)；
HPLC (method 4): rt 2.67 min.
Example 104
5-chloro-N- ({ 2-oxo-3- [4- (4-oxo-1-piperidinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝434(M+H，40)，452(M+H+H2O，100)，475(M+H+MeCN，60)；
HPLC (method 4): rt 3.44 min.
Example 105
1- {4- [5- ({ [ (5-chloro-2-thienyl) carbonyl ] amino } methyl) -2-oxo-1, 3-oxazolidin-3-yl ] phenyl } -L-prolinamide
MS(ESI)：m/z(％)＝449(M+H，100)；
HPLC (method 4): rt 3.54 min.
Example 106
5-chloro-N- [ (3- {4- [3- (hydroxymethyl) -1-piperidinyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝450(M+H，100)；
HPLC (method 5): rt 2.53 min.
Example 107
5-chloro-N- [ (3- {4- [2- (hydroxymethyl) -1-piperidinyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝450(M+H，100)；
HPLC (method 5): rt 2.32 min.
Example 108
1- {4- [5- ({ [ (5-chloro-2-thienyl) carbonyl ] amino } methyl) -2-oxo-1, 3-oxazolidin-3-yl ] phenyl } -2-piperidinecarboxylic acid ethyl ester
MS(ESI)：m/z(％)＝492(M+H，100)；
HPLC (method 5): rt 4.35 min.
Example 109
5-chloro-N- [ (3- {4- [2- (hydroxymethyl) -1-pyrrolidinyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝436(M+H，100)；
HPLC (method 4): rt 2.98 min.
Example 110
5-chloro-N- ({ 2-oxo-3- [4- (1-pyrrolidinyl) -3- (trifluoromethyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝474(M+H，100)；
HPLC (method 4): rt is 4.63 min.
Example 111
5-chloro-N- ({3- [4- (2-methylhexahydro-5H-pyrrolo [3, 4-d ] isoxazol-5-yl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝463(M+H，100)；
HPLC (method 4): rt 2.56 min.
Example 112
5-chloro-N- ({ 2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) -3- (trifluoromethyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝488(M+H，100)；
HPLC (method 4): rt 3.64 min.
Example 113
5-chloro-N- ({3- [ 3-chloro-4- (3-oxo-4-morpholinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝470(M+H，100)；
HPLC (method 4): rt 3.41 min.
Example 114
5-chloro-N- ({ 2-oxo-3- [4- (3-oxo-4-morpholinyl) -3- (trifluoromethyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝504(M+H，100)；
HPLC (method 4): rt 3.55 min.
Example 115
5-chloro-N- ({3- [ 3-methyl-4- (3-oxo-4-morpholinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝450(M+H，100)；
HPLC (method 4): rt 3.23 min.
Example 116
5-chloro-N- ({3- [ 3-cyano-4- (3-oxo-4-morpholinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝461(M+H，100)；
HPLC (method 4): rt 3.27 min.
Example 117
5-chloro-N- ({3- [ 3-chloro-4- (1-pyrrolidinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝440(M+H，100)；
HPLC (method 4): rt 3.72 min.
Example 118
5-chloro-N- ({3- [ 3-chloro-4- (2-oxo-1-pyrrolidinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝454(M+H，100)；
HPLC (method 4): rt 3.49 min.
Example 119
5-chloro-N- ({3- [3, 5-dimethyl-4- (3-oxo-4-morpholinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝464(M+H，100)；
HPLC (method 4): rt 3.39 min.
Example 120
N- ({3- [3- (aminocarbonyl) -4- (4-morpholinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -5-chloro-2-thiophenecarboxamide
MS(ESI)：m/z(％)＝465(M+H，100)；
HPLC (method 4): rt 3.07 min.
Example 121
5-chloro-N- ({3- [ 3-methoxy-4- (4-morpholinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝452(M+H，100)；
HPLC (method 4): rt 2.86 min.
Example 122
N- ({3- [ 3-acetyl-4- (4-morpholinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -5-chloro-2-thiophenecarboxamide
MS(ESI)：m/z(％)＝464(M+H，100)；
HPLC (method 4): rt 3.52 min.
Example 123
N- ({3- [ 3-amino-4- (3-oxo-4-morpholinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -5-chloro-2-thiophenecarboxamide
MS(ESI)：m/z(％)＝451(M+H，100)；
HPLC (method 6): rt 3.16 min.
Example 124
5-chloro-N- ({3- [ 3-chloro-4- (2-methyl-3-oxo-4-morpholinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝484(M+H，100)；
HPLC (method 4): rt 3.59 min.
Example 125
5-chloro-N- ({3- [ 3-chloro-4- (2-methyl-5-oxo-4-morpholinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝484(M+H，100)；
HPLC (method 4): rt 3.63 min.
Example 125a
5-chloro-N- [ (2-oxo-3- {4- [ (3-oxo-4-morpholinyl) methyl ] phenyl } -1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
MS(BSI)：m/z(％)＝450(M+H，100)；
HPLC (method 4): rt 3.25 min.
Alternatively, the following compounds can be prepared by ring opening and subsequent ring closure of the epoxide with an amine to give the corresponding oxazolidinone:
the following examples 14-16 are examples that optionally undergo an oxidation step:
example 14
5-chloro-N- ({ (5S) -3- [ 3-fluoro-4- (1-oxo-1 [ lambda. ] -]44-thiazinan-4-yl) phenyl]-2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
5-chloro-N- ({ (5S) -3- [ 3-fluoro-4- (1, 4-thiazinan-4-yl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide from example 3 (0.1g, 0.22mmol) was added to a solution of sodium periodate (0.05g, 0.23mmol) in water (0.54ml) at 0 ℃ and the mixture was stirred at 0 ℃ for 3h, then 1ml DMF was added and the mixture was stirred at room temperature for 8 h. After addition of a further 50mg of sodium periodate, stirring is carried out overnight at room temperature, then mixing with 50ml of water and suction-filtering off the insoluble product, washing with water and drying to give 60mg (58% of theory) of crystals.
Melting point: 257 ℃;
Rf(silica gel, toluene/ethyl acetate 1: 1) ═ 0.54 (feed ═ 0.46);
IC50the value is 1.1 μ M;
MS(DCI)489(M+NH4) And Cl-type.
Example 15
5-chloro-N- ({ (5S) -3- [4- (1, 1-dioxo-1 [ lambda ]]64-thiazinan-4-yl) -3-fluorophenyl]-2-oxo-1, 3-oxazolesAlk-5-yl } methyl) -2-thiophenecarboxamide
5-chloro-N- ({ (5S) -3- [ 3-fluoro-4- (1, 4-thiazinan-4-yl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide from example 3 (0.1g, 0.22mmol) in a mixture of 3.32ml of 1 part of water and 3 parts of acetone is mixed with a solution of 80mg (0.66mmol) of N-methylmorpholine N-oxide (NMO) and 0.1ml of 2-methyl-2-propanol of 2.5% osmium tetroxide, the mixture is stirred at room temperature overnight and 40mg of NMO are added, stirring is continued overnight, 50ml of water is then poured in and extraction is carried out three times with ethyl acetate, the organic phase is dried and concentrated to give 23mg of the expected compound and the aqueous phase is freed from insoluble solids by suction filtration to give 19mg (total 39% of theoretical amount) ) A target compound.
Melting point: 238 ℃;
Rf(toluene/ethyl acetate 1: 1) ═ 0.14 (feed ═ 0.46);
IC50value 210 nM;
MS(DCI)：505(M+NH4) And Cl-type.
Example 16
5-chloro-N- { [ (5S) -3- (3-fluoro-4-morpholinophenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -2-thiophenecarboxamide N-oxide
The title compound was obtained by treating 5-chloro-N- { [ (5S) -3- (3-fluoro-4-morpholinophenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -2-thiophenecarboxamide from example 1 with magnesium monoperoxyphthalate.
Ms (esi): 456(M + H, 21%, Cl-type), 439 (100%).
Examples 31-35 and 140-147 described below relate to an optional amidination step.
General procedure for the preparation of amidine and amidine derivatives starting from cyanomethylphenyl-substituted 5-chloro-N- [ (2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide derivatives.
Stirring cyanomethylphenyl substituted 5-chloro-N- [ (2-oxo-1, 3-oxazolidin-5-yl) methyl in a hydrogen sulfide saturated pyridine solution (about 0.05-0.1mol/l) at room temperature]-2-Thiophenecarboxamide derivative (1.0 eq) with triethylamine (8.0 eq) for 1-2 days, the reaction mixture was diluted with ethyl acetate (EtOAc) and washed with 2N hydrochloric acid and the organic phase with MgSO 24Dried, filtered and concentrated under reduced pressure, the crude product is dissolved in acetone (0.01-0.1mol/l) and mixed with methyl iodide (40 eq), the reaction mixture is stirred at Room Temperature (RT) for 2-5h and then concentrated under reduced pressure.
The residue was dissolved in methanol (0.01-0.1mol/l) and mixed with ammonium acetate (3 eq) and ammonium chloride (2 eq) to prepare the unsubstituted amidine, to which methanol solution a primary or secondary amine (1.5 eq) and acetic acid (2 eq) were added to prepare the substituted amidine derivative, after 5-30h the solvent was removed under reduced pressure and the residue was purified by RP8 silica gel column chromatography (eluting with water/acetonitrile 9/1-1/1+ 0.1% trifluoroacetic acid).
The following compounds were prepared in a similar manner:
example 31
N- ({3- [4- (2-amino-2-iminoethyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -5-chloro-2-thiophenecarboxamide
MS(ESI)：m/z(％)＝393(M+H，100)；
HPLC (method 4): rt 2.63 min.
Example 32
5-chloro-N- ({3- [3- (4, 5-dihydro-1H-imidazol-2-ylmethyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝419(M+H，100)；
HPLC (method 4): rt 2.61 min.
Example 33
5-chloro-N- [ (3- {3- [ 2-imino-2- (4-morpholinyl) ethyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝463(M+H，100)；
HPLC (method 4): rt 2.70 min.
Example 34
5-chloro-N- [ (3- {3- [ 2-imino-2- (1-pyrrolidinyl) ethyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝447(M+H，100)；
HPLC (method 4): rt 2.82 min.
Example 35
N- ({3- [3- (2-amino-2-iminoethyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -5-chloro-2-thiophenecarboxamide
M5(ESI)：m/z(％)＝393(M+H，100)；
HPLC (method 4): rt 2.60 min.
Example 140
5-chloro-N- ({3- [4- (4, 5-dihydro-1H-imidazol-2-ylmethyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝419(M+H，100)；
HPLC (method 4): rt 2.65 min.
Example 141
5-chloro-N- [ (3- {4- [ 2-imino-2- (4-morpholinyl) ethyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝463(M+H，100)；
HPLC (method 4): rt 2.65 min.
Example 142
5-chloro-N- [ (3- {4- [ 2-imino-2- (1-piperidinyl) ethyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝461(M+H，100)；
HPLC (method 4): rt 2.83 min.
Example 143
5-chloro-N- [ (3- {4- [ 2-imino-2- (4-pyrrolidinyl) ethyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝447(M+H，100)；
HPLC (method 4): rt 2.76 min.
Example 144
5-chloro-N- [ (3- {4- [2- (cyclopentylamino) -2-iminoethyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝461(M+H，100)；
HPLC (method 4): rt 2.89 min.
Example 145
5-chloro-N- { [3- (4- { 2-imino-2- [ (2, 2, 2-trifluoroethyl) amino ] ethyl } phenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝475(M+H，100)；
HPLC (method 4): rt 2.79 min.
Example 146
N- ({3- [4- (2-phenylamino-2-iminoethyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -5-chloro-2-thiophenecarboxamide
MS(ESI)：m/z(％)＝469(M+H，100)；
HPLC (method 4): rt 2.83 min.
Example 147
5-chloro-N- [ (3- {4- [ 2-imino-2- (2-pyridinylamino) ethyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝470(M+H，100)；
HPLC (method 4): rt 2.84 min.
Example 148-151 below relates to deprotection of the BOC-amino protecting group:
general procedure for deprotection of the BOC-protecting group (tert-butoxycarbonyl):
to an ice-cooled solution of tert-butoxycarbonyl- (BOC) protected compound in chloroform or dichloromethane (about 0.1-0.3mol/l) was added dropwise an aqueous trifluoroacetic acid (TFA, about 90%) solution, after about 15min the ice bath was removed and the mixture was stirred at room temperature for about 2-3 hours, then the solution was concentrated and dried under high vacuum, the residue was treated with dichloromethane or dichloromethane/methanol and washed with saturated sodium bicarbonate or 1N sodium hydroxide solution, the organic phase was washed with saturated sodium chloride solution, dried with a small amount of magnesium sulfate and concentrated, optionally purified by crystallization with diethyl ether or diethyl ether/dichloromethane mixture.
The following compounds were prepared in an analogous manner from the corresponding BOC-protected precursors:
example 148
N- ({3- [4- (aminomethyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -5-chloro-2-thiophenecarboxamide
Prepared starting from the compound of example 92:
MS(ESI)：m/z(％)＝349(M-NH2，25)，305(100)；
HPLC (method 1): rt is 3.68 (98).
IC50：2.2μM
Example 149
N- { [3- (4-aminophenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -5-chloro-2-thiophenecarboxamide
Prepared starting from the compound of example 93:
MS(ESI)：m/z(％)＝352(M+H，25)；
HPLC (method 1): rt (%) -3.50 (100).
IC50：2μM
Alternative enantiomerically pure syntheses of this compound are represented by the following reaction schemes (see also Delalande s.a., DE 2836305, 1979; chem.abstr.90, 186926):
example 150
5-chloro-N- ({3- [4- (glycylamino) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
Prepared starting from the compound of example 152:
MS(ES-pos)：m/z(％)＝408(100)；
HPLC (method 3): rt (%) -, 3.56 (97).
IC50：2μM
Example 151
5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-2-one prepared starting from the compound of example 60:
MS(ESI)：m/z(％)＝276(M+H，100)；
HPLC (method 3): rt (%) 2.99 (100).
IC50：2μM
The following example 152-166 involves amino derivatization of oxazolidinones substituted with aniline or benzylamine with various reagents:
example 152
5-chloro-N- ({3- [4- (N-tert-butoxycarbonylglycylamino) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
751mg (4.3mmol) of Boc-glycine and 870mg (6.4mmol) of HOBT (1-hydroxy-1H-benzotriazole xH were added at 0 ℃ C2O), 1790mg (4.7mmol) of HBTU [ O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate]And 1.41ml (12.9mmol) of N-methylmorpholine in 15ml of DMF/CH2Cl2(1: 1) to the solution was added 754mg (2.1mmol) of N- { [3- (4-aminophenyl) -2-oxo-1, 3-oxazolidin-5-yl]Methyl } -5-chloro-2-thiophenecarboxamide (from example 149) and the mixture was stirred at room temperatureThe compound was diluted overnight with water and the precipitated solid was filtered off and dried, yield: 894mg (79.7% of theory);
MS(DCI，NH3)：m/z(％)＝526(M+NH4，100)；
HPLC (method 3): rt (%) -, 4.17 (97).
Example 153
N- [ (3- {4- [ (acetylamino) methyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -5-chloro-2-thiophenecarboxamide
A mixture of 30mg (0.082mmol) of N- ({3- [4- (aminomethyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -5-chloro-2-thiophenecarboxamide from example 148 (1.5 ml) anhydrous THF and 1.0ml anhydrous dichloromethane and 0.02ml anhydrous pyridine was mixed with acetic anhydride (0.015ml, 0.164mmol) at 0 ℃ and the mixture was stirred at room temperature overnight. The product is obtained after addition of diethyl ether and crystallization. Yield: 30mg (87% of theory),
MS(ESI)：m/z(％)＝408(M+H，18)，305(85)；
HPLC (method 1): rt (%) 3.78 (97).
IC50：0.6μM
Example 154
N- { [3- (4- { [ (aminocarbonyl) amino ] methyl } phenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -5-chloro-2-thiophenecarboxamide
To a mixture of 30mg (0.082mmol) of N- ({3- [4- (aminomethyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -5-chloro-2-thiophenecarboxamide from example 148) in 1.0ml of dichloromethane was added dropwise 0.19ml (0.082mmol) of trimethylsilyl isocyanate at room temperature, the mixture was stirred overnight, diethyl ether was added and the product was obtained by filtration. Yield: 21.1mg (52% of theory),
MS(ESI)：m/z(％)＝409(M+H，5)，305(72)；
HPLC (method 1): rt (%) 3.67 (83).
IC50：1.3μM
General procedure for acylation of N- { [3- (4-aminophenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -5-chloro-2-thiophenecarboxamide with acid chloride
To the corresponding acid chloride (2.5 equivalents) was added dropwise an approximately 0.1 molar solution of N- { [3- (4-aminophenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -5-chloro-2-thiophenecarboxamide (from example 149) (1.0 equivalent) in anhydrous dichloromethane/pyridine (19: 1) under argon atmosphere the mixture was stirred overnight, then mixed with approximately 5 equivalents of PS-trisamine (Argonaut technologies) and 2ml of anhydrous dichloromethane, and after gentle stirring for 1h the filtrate was filtered and concentrated, optionally purifying the product by preparative RP-HPLC.
The following compounds were prepared by a similar method:
example 155
N- ({3- [4- (acetylamino) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -5-chloro-2-thiophenecarboxamide
LC-MS：m/z(％)＝394(M+H，100)；
LC-MS (method 6): rt (%) 3.25 (100).
IC50：1.2μM
Example 156
5-chloro-N- [ (2-oxo-3- {4- [ (2-thienylcarbonyl) amino ] phenyl } -1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
LC-MS：m/z(％)＝462(M+H，100)；
LC-MS (method 6): rt (%) -, 3.87 (100).
IC50：1.3μM
Example 157
5-chloro-N- [ (3- {4- [ (methoxyacetyl) amino ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
LC-MS：m/z(％)＝424(M+H，100)；
LC-MS (method 6): rt (%) -3.39 (100).
IC50：0.73μM
Example 158
N- {4- [5- ({ [ (5-chloro-2-thienyl) carbonyl ] amino } methyl) -2-oxo-1, 3-oxazolidin-3-yl ] phenyl } -3, 5-dimethyl-4-isoxazolecarboxamide
LC-MS：m/z(％)＝475(M+H，100)。
IC50：0.46μM
Example 159
5-chloro-N- { [3- (4- { [ (3-chloropropyl) sulfonyl ] amino } phenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -2-thiophenecarboxamide
An ice-cooled solution of 26.4mg (0.15mmol) of 3-chloro-1-propanesulfonyl chloride and 0.03ml (0.2mmol) of triethylamine in 3.5ml of dry dichloromethane is mixed with 35mg (0.1mmol) of N- { [3- (4-aminophenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -5-chloro-2-thiophenecarboxamide from example 149), after 30min the ice bath is removed and the mixture is stirred overnight at room temperature, 150mg (about 5.5 equivalents) of PS-Trisamine (Argonaut technologies) and 0.5ml of dichloromethane are then added, the suspension is stirred gently for 2h, the resin is filtered (washing with dichloromethane/methanol) and the filtrate is concentrated and the product is purified by preparative RP-HPLC. Yield: 19.6mg (40% of theory),
LC-MS：m/z(％)＝492(M+H，100)；
LC-MS (method 5): rt (%) 3.82 (91).
IC50：1.7μM
Example 160
5-chloro-N- ({3- [4- (1, 1-dioxo-2-isothiazolidinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
A mixture of 13.5mg (0.027mmol) of 5-chloro-N- { [3- (4- { [ (3-chloropropyl) sulfonyl ] amino } phenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -2-thiophenecarboxamide (from example 159) and 7.6mg (0.055mmol) of potassium carbonate was heated in 0.2ml of DMF to 100 ℃ for 2 hours, after cooling diluted with dichloromethane and washed with water, the organic phase was dried and concentrated, and the residue was purified by preparative thin-layer chromatography (silica gel, dichloromethane/methanol, 95: 5). Yield 1.8mg (14.4% of theory),
MS(ESI)：m/z(％)＝456(M+H，15)，412(100)；
LC-MS (method 4): rt (%) 3.81 (90).
IC50：0.14μM
Example 161
5-chloro-N- [ ((5S) -3- {4- [ (5-chloropentanoyl) amino ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
0.5g (1.29mmol) of N- { [ (5S) -3- (4-aminophenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -5-chloro-2-thiophenecarboxamide (from example 149) is dissolved in 27ml of tetrahydrofuran and combined with 0.2g (1.29mmol) of 5-chloropentanoyl chloride and 0.395ml (2.83mmol) of triethylamine. The mixture is concentrated under reduced pressure and purified by chromatography on silica gel, eluting with a gradient of toluene/ethyl acetate 1: 1- > ethyl acetate to give 315mg (52% of theory) of solid,
melting point: 211 ℃ C
Example 162
5-chloro-N- ({ (5S) -2-oxo-3- [4- (2-oxo-1-piperidinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
5ml of DMSO were mixed under inert conditions with 30mg of NaH (60% in paraffin oil) and heated at 75 ℃ for 30min until no more gas was formed, then a solution of 290mg (0.617mmol) of 5-chloro-N- [ ((5S) -3- {4- [ (5-chloropentanoyl) amino ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide (from example 161) in 5ml of dichloromethane was added dropwise and stirred at room temperature overnight. The reaction is terminated and the mixture is taken up in 100ml of water, extracted with ethyl acetate, the organic phase is concentrated and purified by RP-8 column chromatography and eluted with acetonitrile/water to yield 20mg (7.5% of theory) of the expected compound.
Melting point: 205 deg.C;
NMR(300MHz，d6-DMSO): δ is 1.85(m, 4H), 2.35(m, 2H), 3.58(m, 4H), 3.85(m, 1H), 4.2(t, 1H), 4.82(m, 1H), 7.18(d, 1H, thiophene), 7.26(d, 2H), 7.5(d, 2H), 2.68(d, 1H, thiophene), 9.0(t, 1H, CONH).
IC50：2.8nM
Example 163
5-chloro-N- [ ((5S) -3- {4- [ (3-bromopropionyl) amino ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
Prepared in a similar manner as example 149.
Example 164
5-chloro-N- ({ (5S) -2-oxo-3- [4- (2-oxo-1-azetidinyl) phenyl ] -1, 3-oxazolidin-5-yl } -methyl) -2-thiophenecarboxamide
The compound of example 163 is obtained in a similar manner by ring closure of the open-chain bromopropionyl compound with NaH/DMS.
MS(ESI)：m/z(％)＝406([M+H]+100), Cl-type;
IC50：380nM
example 165
4- {4- [5- ({ [ (5-chloro-2-thienyl) carbonyl ] amino } methyl) -2-oxo-1, 3-oxazolidin-3-yl ] phenyl } -3, 5-dioxo-1-piperazinecarboxylic acid tert-butyl ester
A solution of 199mg (0.85mmol) Boc-iminodiacetic acid, 300mg (2.2mmol) H0BT, 0.66ml (6mmol) N-methylmorpholine and 647mg (1.7mmol) HBTU was mixed with 300mg (0.85mmol) N- { [3- (4-aminophenyl) -2-oxo-1, 3-oxazolidin-5-yl ] -methyl } -5-chloro-2-thiophenecarboxamide in 6ml of a mixture of DMF and dichloromethane (1: 1), the mixture was stirred overnight, then washed with water, saturated ammonium chloride solution, saturated sodium bicarbonate solution, water and saturated sodium chloride solution after dilution with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated, and the crude product is chromatographed on silica gel (eluting with dichloromethane/methanol 98: 2). Yield: 134mg (29% of theory);
MS(ESI)：m/z(％)＝571(M+Na，82)，493(100)；
HPLC (method 3): rt (%) -, 4.39 (90).
IC50：2μM
Example 166
N- [ ((5S) -3- {4- [ (3R) -3-amino-2-oxo-1-pyrrolidinyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -5-chloro-2-thiophenecarboxamide trifluoroacetate
N2- (tert-Butoxycarbonyl) -N1- {4- [ (5S) -5- ({ [ (5-chloro-2-thienyl) carbonyl ] amino } methyl) -2-oxo-1, 3-oxazolidin-3-yl ] phenyl } -D-methionine amide
429mg (1.72mmol) of N-BOC-D-methionine, 605mg (1.72mmol) of N- { [ (5S) -3- (4-aminophenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } -5-chloro-2-thiophenecarboxamide and 527mg (3.44mmol) of HOBT-hydrate are dissolved in 35ml of DMF and mixed with 660mg (3.441mmol) of EDCI hydrochloride and 689mg (5.334mmol) of N-ethyldiisopropylamine are added dropwise. The mixture is stirred at room temperature for 2 days, the resulting suspension is filtered with suction, the residue is washed with DMF, the combined filtrates are mixed with a little silica gel, concentrated under reduced pressure and purified by chromatography on silica gel, eluting with a gradient of toluene- > T10EE7, to give 170mg (17% of theory) of the title compound, m.p.: 183 ℃ is prepared.
Rf(SiO2Toluene/ethyl acetate 1: 1): 0.2
1H-NMR(300MHz，d6-DMSO): δ ═ 1.4(s, 1H, BOC), 1.88-1.95(m, 2H), 2.08(s, 3H, SMe), 2.4-2.5(m, 2H, partially covered with DMSO), 3.6(m, 2H), 3.8(m, 1H), 4.15(m, 2H), 4.8(m, 1H), 7.2(1H, thiophene), 7.42(d, part of the AB system, 2H), 7.6(d, part of the AB system, 2H), 7.7(d, 1H, thiophene), 8.95(t, 1H, CH, c), 1.88-1.95(m, 2H), 2.8 (m, 1H, SMe), 2.4-2H, part of the AB system, 2H, c2NHCO)，9.93(bs，1H，NH).
(3R) -1- {4- [ (5S) -5- ({ [ (5-chloro-2-thienyl) carbonyl ] amino } methyl) -2-oxo-1, 3-oxazolidin-3-yl ] phenyl } -2-oxo-3-pyrrolidinecarboxylic acid tert-butyl ester
170mg (0.292mmol) of N2- (tert-butoxycarbonyl) -N1- {4- [ (5S) -5- ({ [ (5-chloro-2-thienyl) carbonyl ] amino } methyl) -2-oxo-1, 3-oxazolidin-3-yl ] phenyl } -D-methionine amide are dissolved in 2ml DMSO and combined with 178.5mg (0.875mmol) of trimethylsulfonium iodide and 60.4mg (0.437mmol) of potassium carbonate and the mixture is stirred at 80 ℃ for 3.5 h, after which the mixture is concentrated under high vacuum and the residue is washed with ethanol to give 99mg of the expected compound.
1H-NMR(300MHz，d6-DMSO): δ ═ 1.4(s, 1H, BOC), 1.88 to 2.05(m, 1H), 2.3 to 2.4(m, 1H), 3.7 to 3.8(m, 3H), 3.8 to 3.9(m, 1H), 4.1 to 4.25(m, 1H), 4.25 to 4.45(m, 1H), 4.75 to 4.95(m, 1H), 7.15(1H, thiophene), 7.25(d, 1H), 7.52(d, part of the AB system, 2H), 7.65(d, 1H, thiophene), 9.0 (broad s, 1H).
N- [ ((5S) -3- {4- [ (3R) -3-amino-2-oxo-1-pyrrolidinyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -5-chloro-2-thiophenecarboxamide trifluoroacetate
97mg (0.181mmol) of tert-butyl (3R) -1- {4- [ (5S) -5- ({ [ (5-chloro-2-thienyl) carbonyl ] amino } methyl) -2-oxo-1, 3-oxazolidin-3-yl ] phenyl } -2-oxo-3-pyrrolidinocarbamate are suspended in 4ml of dichloromethane, 1.5ml of trifluoroacetic acid are added and the mixture is stirred at room temperature for 1 hour, then the mixture is concentrated under reduced pressure and purified by RP-HPLC (acetonitrile/water/0.1% TFA-gradient elution) to give 29mg (37% of theory) of the expected compound after concentration of the relevant fraction, the melting point being 241 ℃ C (decomposition).
Rf(SiO2，EtOH/TEA＝17∶1)0.19.
1H-NMR(300Mhz，d6-DMSO): δ ═ 1.92-2.2(m, 1H), 2.4-2.55(m, 1H, partially covered with DMSO), 3.55-3.65(m, 2H), 3.75-3.95(m, 3H), 4.1-4.3(m, 2H), 4.75-4.9(m, 1H), 7.2(1H, thiophene), 7.58(d, part of the AB system, 2H), 7.7(d, part of the AB system, 2H), 7.68(d, 1H, thiophene), 8.4 (broad s, 3H, NH3), 8.9(t, 1H, NHCO).
The following example 167-170 involves the introduction of a sulfonamido group in a benzene-substituted oxazolidinone: general procedure for the preparation of substituted sulfonamides from 5-chloro-N- [ (2-oxo-3-phenyl-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
To chlorosulfonic acid (12 eq) was added 5-chloro-N- [ (2-oxo-3-phenyl-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide (from example 96) under argon atmosphere at 5 ℃, the mixture was stirred at room temperature for 2 hours, then poured into ice water, the resulting precipitate was filtered, washed with water and dried.
The precipitate was then dissolved in tetrahydrofuran (0.1mol/l) under argon at room temperature and mixed with the corresponding amine (3 eq), triethylamine (1.1 eq) and dimethylaminopyridine (0.1 eq), the mixture was stirred for 1-2 h, then concentrated under reduced pressure and purified by flash chromatography (eluting with a dichloromethane/methanol mixture) of the expected product.
The following compounds were prepared in a similar manner:
example 167
5-chloro-N- ({ 2-oxo-3- [4- (1-pyrrolidinylsulfonyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝492([M+Na]+，100)，470([M+H]+68), Cl-type;
HPLC (method 3): rt (%) -4.34 (100).
IC50：0.5μM
Example 168
5-chloro-N- [ (3- {4- [ (4-methyl-1-piperazinyl) sulfonyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝499([M+H]+100), Cl-type;
HPLC (method 2): rt (%) 3.3 (100).
Example 169
5-chloro-N- ({ 2-oxo-3- [4- (1-piperidinylsulfonyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝484([M+H]+100), Cl-type;
HPLC (method 2): rt (%) -, 4.4 (100).
Example 170
5-chloro-N- [ (3- {4- [ (4-hydroxy-1-piperidinyl) sulfonyl ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -2-thiophenecarboxamide
MS(ESI)：m/z(％)＝500([M+H]+100), Cl-type;
HPLC (method 3): rt (%) 3.9 (100).
Example 171
5-chloro-N- ({ 2-oxo-3- [4- (1-pyrrolidinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophenecarboxamide
780mg (1.54mmol) of 1- {4- [5- ({ [ (5-chloro-2-thienyl) carbonyl]Amino } methyl) -2-oxo-1, 3-oxazolidin-3-yl]Phenyl } proline tert-butyl ester was dissolved in 6ml dichloromethane and 9ml trifluoroacetic acid and the mixture was stirred at 40 ℃ for 2 days, then the reaction mixture was concentrated and stirred with diethyl ether and 2N aqueous sodium hydroxide, the aqueous phase was concentrated and stirred with diethyl ether and 2N hydrochloric acid. The organic phase extract was dried over magnesium sulfate, filtered and concentrated and the crude product was purified by silica gel chromatography (using CH)2Cl2elution/EtOH/concentrated ammonia 100/1/0.1-20/1/0.1) gave 280mg of product (40% of theory).
MS(ESI)：m/z(％)＝406(M+H，100)；
HPLC (method 4): rt 3.81 min.
Units of (retention time (rt) in the HPLC and LC-MS data given in the above examples
Is min) HPLC parameters and LC-MS parameters
[1]Column: kromasil C18, L-R temperature: flow rate 0.75mlmin at 30 DEG C-1Eluent: a ═ 0.01M HClO4，B＝CH3CN, gradient: - > 0.5min 98% A- > 4.5min 10% A- > 6.5min 10% A
[2]Column: kromasil C1860 x2, L-R temperature: flow rate 0.75mlmin at 30 DEG C-1Eluent: a is 0.01M H3PO4，B＝CH3CN, gradient: - > 0.5min 90% A- > 4.5min 10% A- > 6.5min 10% A
[3]Column: kromasil C1860 x2, L-R temperature: flow rate 0.75mlmin at 30 DEG C-1Eluent: a ═ 0.005M HClO4，B＝CH3CN, gradient: - > 0.5min 98% A- > 4.5min 10% A- > 6.5min 10% A
[4]Column: symmetry c182.1x150mm, column oven: flow rate 0.6mlmin at 50 DEG C-1Eluent: a is 0.6g HCl 30% concentration per liter and B is CH3CN, gradient: 0.0min 90% A- > 4min 10% A- > 9min 10% A
[5]MHZ-2Q, Instrument Micromass Quattro LCZ column Symmetry C18, 50mmx2.1mm, 3.5 μm, temperature: flow rate 0.5mlmin at 40 DEG C-1，
Eluent: a ═ CH3CN + 0.1% formic acid, eluent B ═ water + 0.1% formic acid, gradient: 0.0min 10% A- > 4min 90% A- > 6min 90% A
[6]MHZ-2P, Instrument Micromass Platform LCZ column Symmetry C18, 50mmx2.1mm, 3.5 μm, temperature: flow rate 0.5mlmin at 40 DEG C-1，
Eluent: a ═ CH3CN + 0.1% formic acid, eluent B ═ water + 0.1% formic acid, gradient: 0.0min 10％A-＞4min 90％A-＞6min 90％A
[7]MHZ-7Q, Instrument Micromass Quattro LCZ column Symmetry C18, 50mmx2.1mm, 3.5 μm, temperature: flow rate 0.5mlmin at 40 DEG C-1Eluent: a ═ CH3CN + 0.1% formic acid, eluent B ═ water + 0.1% formic acid, gradient: 0.0min 5% A- > 1min 5% A- > 5min 90% A- > 6min 90% A
General Process for the preparation of oxazolidinones of the general formula B by solid phase supported synthesis
The products fixed with the different resins are reacted in a set of separate reactors.
The 5- (bromomethyl) -3- (4-fluoro-3-nitrophenyl) -1, 3-oxazolidin-2-one A (prepared from epibromohydrin and 4-fluoro-3-nitrophenylisocyanate, LiBr/Bu in xylene3PO was prepared analogously to US 4128654, example 2) (1.20g, 3.75mmol) and ethyldiisopropylamine (DIEA, 1.91ml, 4.13mmol) were dissolved in DMSO (70ml), mixed with a secondary amine (1.1 eq, amine component 1) and reacted at 55 ℃ for 5 h. To this solution, TentaGel SAM resin (5.00g, 0.25mmol/g) was added and reacted at 75 ℃ for 48 hours. The resin was filtered and washed repeatedly with methanol (MeOH), Dimethylformamide (DMF), MeOH, Dichloromethane (DCM) and diethyl ether and dried. The resin (5.00g) was suspended in dichloromethane (80ml) and reacted with DIEA (10 equiv.) and 5-chlorothiophene-2-carbonyl chloride [ prepared by reacting 5-chlorothiophene-2-carboxylic acid (5 equiv.) with 1-chloro-1-dimethylamino-2-methylpropene (5 equiv.) in DCM (20ml) at room temperature for 15min]Mixing and reacting at room temperature for 5 hours, filtering the resulting resin and washing repeatedly with MeOH, DCM and diethyl ether and drying, then suspending the resin in DMF/water (v/v 9: 2, 80ml) and SnCl2*2H2O (5 equivalents) was mixed and reacted at room temperature for 18 hours. The resin was washed repeatedly with MeOH, DMF, water, MeOH, DCM, and diethyl ether and dried. The resin was suspended in DCM, mixed with DIEA (10 equivalents) and mixed with acid chloride (5 equivalents of acid derivative 1) at 0 ℃ and reacted overnight at room temperature. Before the reaction is carried out by reaction with 1-dimethylamino-1-chloro-2-methylpropene (1 equivalent based on the carboxylic acid) at DCM for 15 minutes at room temperature to convert the carboxylic acid to the corresponding acid chloride. The resin was washed back with DMF, water, DMF, MeOH, DCM and diethyl ether and dried. If the acid derivative 1 used is an Fmoc-protected amino acid, the Fmoc protecting group is removed in the last step by reaction with piperidine/DMF (v/v, 1/4) for 15 minutes at room temperature, and the resin is washed with DMF, MeOH, DCM and diethyl ether and dried, after which the product is cleaved from the solid phase with trifluoroacetic acid (TFA)/DCM (v/v, 1/1), the resin is filtered and the reaction is concentrated. The crude product was filtered through silica gel (DCM/MeOH, 9: 1) and concentrated to give a panel of product B.
Compound obtained by solid phase supported synthesis:
example 172
N- ({3- [ 3-amino-4- (1-pyrrolidinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -5-chloro-2-thiophenecarboxamide
In analogy to the general procedure for the preparation of derivative B, 5g (1.25mmol) of TentaGelSAM resin were reacted with pyrrolidine as amine derivative 1, SnCl2*2H2The aniline obtained by O reduction is cleaved from the solid phase without further acylation and concentrated, and the crude product is taken up in ethyl acetate and NaHCO3The solution was partitioned between and the organic phase was salted out with NaCl, decanted and concentrated to dryness. The crude product was purified by flash chromatography on silica gel under reduced pressure (using dichloromethane)Alkane/ethyl acetate, 3: 1-1: 2 elution).
1H-NMR(300MHz，CDCl3)：1.95-2.08，br，4H；3.15-3.30，br，4H；3.65-3.81，m，2H；3.89，ddd，1H；4.05，dd，1H；4.81，dddd，1H；6.46，dd，1H；6.72，dd，1H；6.90，dd，1H；6.99，dd，1H；7.03，dd，1H；7.29，d，1H.
Example 173
N- [ (3- {3- [ beta-alanylamino) -4- [ (3-hydroxypropyl) amino ] phenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] -5-chloro-2-thiophenecarboxamide
In analogy to the general procedure for the preparation of derivative B, 5g (1.25mmol) of TentaGelSAM resin were reacted with azetidine as amine derivative 1 and Fmoc-beta-alanine as acid derivative 1. The crude product obtained after cleavage was stirred in methanol at room temperature for 48 hours and concentrated to dryness and the crude product was purified by reverse phase HPLC eluting with a water/TFA/acetonitrile gradient.
1H-NMR(400MHz，CD3OD)：2.31，tt，2H；336，t，2H；3.54，t，2H；3.62，t，2H；3.72，dd，1H；3.79，dd，1H；4.01，dd，1H；4.29，dd，2H；4.43，t，2H，4.85-4.95，m，1H；7.01，d，1H；4.48-7.55，m，2H；7.61，d，1H；7.84，d，1H.
Example 174
N- ({3- [4- [ 3-amino-1-pyrrolidinyl) -3-nitrophenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl ] -5-chloro-2-thiophenecarboxamide
In analogy to the general procedure for the preparation of derivative B, 130mg (32.5. mu. mol) of TentaGel SAM resin were reacted with tert-butyl 3-pyrrolidinocarbamate as amine derivative 1. The nitrobenzene derivative obtained after acylation with 5-chlorothiophene carboxylic acid is cleaved from the solid phase and concentrated, and the crude product is purified by reverse phase HPLC eluting with a water/TFA/acetonitrile gradient.
1H-NMR(400MHz，CD3OH)：2.07-2.17，m，1H；2.39-2.49，m，1H；3.21-3.40，m，2H；3.45，dd，1H；3.50-3.60，m，1H；3.67，dd，1H；3.76，dd，1H；3.88-4.00，m，2H；4.14-4.21，t，1H；4.85-4.95，m，1H；7.01，d，1H；7.11，d，1H；7.52，d，1H；7.66，dd，1H；7.93，d，1H.
Example 175
N- ({3- [ 3-amino-4- (1-piperidinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -5-chloro-2-thiophenecarboxamide
In analogy to the general procedure for the preparation of derivative B, 130mg (32.5. mu. mol) of TentaGel SAM resin were reacted with piperidine as amine derivative 1, the aniline obtained after reduction was cleaved from the solid phase without further acylation step and concentrated, and the crude product was purified by reverse phase HPLC eluting with a water/TFA/acetonitrile gradient.
1H-NMR(400MHz，CD3OH)：1.65-1.75，m，2H；1.84-1.95，m，4H；3.20-3.28，m，4H；3.68，dd，1H；3.73，dd，1H；3.90，dd，1H；4.17，dd，1H；4.80-4.90，m，1H；7.00，d，1H；7.05，dd，1H；7.30-7.38，m，2H；7.50，d，1H.
Example 176
N- ({3- [3- (acetylamino) -4- (1-pyrrolidinyl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) -5-chloro-2-thiophenecarboxamide
In analogy to the general procedure for the preparation of derivative B, 130mg (32.5. mu. mol) of TentaGel SAM resin were reacted with pyrrolidine as amine derivative 1 and acetyl chloride as acid derivative 1, and the crude product was reacted in ethyl acetate and NaHCO3The solution was partitioned between, the organic phase was salted out with NaCl, decanted and concentrated to dryness and the crude product was purified by flash chromatography on silica gel under reduced pressure (eluting with dichloromethane/ethyl acetate, 1: 1-0: 1).
1H-NMR(400Mhz，CD3OH)：1.93-2.03，br，4H；2.16，s，3H；320-3.30，br，4H；3.70，d，2H；3.86，dd，1H；4.10，dd，1H；4.14，dd，1H；4.804.90，m，1H；7.000，d，1H；7.07，d，1H；7.31，dd，1H；7.51，d，1H；7.60，d，1H.
The following compounds were prepared analogously to this general procedure:
all solid phase supported synthesized products were characterized by LC-MS. The following standard separation systems were used for this: HP 1100 with UV-detector (208nm-400nm), oven temperature 40 ℃, Waters-Symmetry C18 column (50mmx2.1mm, 3.5 μm), mobile phase A: 99.9% acetonitrile/0.1% formic acid, mobile phase B: 99.9% water/0.1% formic acid; gradient:
| time of day | A：％ | B：％ | Flow rate of flow |
| 0,00 | 10,0 | 90,0 | 0,50 |
| 4,00 | 90,0 | 10,0 | 0,50 |
| 6,00 | 90,0 | 10,0 | 0,50 |
| 6,10 | 10,0 | 90,0 | 1,00 |
| 7,50 | 10,0 | 90,0 | 0,50 |
Verification of compounds using a Micromass Quattro LCZ MS, ionization: ESI positive/negative.
Containing radicals in the structures given aboveor-O in each case representsOr OH.
Claims (6)
1. Use of a compound of general formula (I) or a pharmaceutically acceptable salt, hydrate or hydrate of the salt thereof for the manufacture of a medicament for the prevention and/or treatment of atherosclerosis, arthritis, alzheimer's disease or tumors:
wherein:
R1is 2-thienyl, which is selected in its 5-position from chlorine, bromine,Methyl and trifluoromethyl groups, and the like,
R2is D-A-:
wherein: the group "A" is phenylene;
the group "D" is a saturated 5-or 6-membered heterocyclic ring,
which is linked to "A" via a nitrogen atom,
which has a carbonyl group in the ortho position to the attached nitrogen atom and
wherein one ring carbon unit is optionally replaced by a heteroatom selected from S, N and O;
wherein the previously defined group "a" is optionally mono-or disubstituted meta to the point of attachment to the oxazolidinone by a group selected from: fluorine, chlorine, nitro, amino, trifluoromethyl, methyl and cyano,
R3、R4、R5、R6、R7and R8Is hydrogen.
2. The use of claim 1, wherein the compound of formula (I) has the formula
3. Use of a compound of general formula (I) or a pharmaceutically acceptable salt, hydrate or hydrate of a salt thereof for preventing ex vivo blood clotting:
wherein:
R1is 2-thienyl, which is substituted in its 5-position by a radical selected from the group consisting of chlorine, bromine, methyl and trifluoromethyl,
R2is D-A-:
wherein: the group "A" is phenylene;
the group "D" is a saturated 5-or 6-membered heterocyclic ring,
which is linked to "A" via a nitrogen atom,
which has a carbonyl group in the ortho position to the attached nitrogen atom and
wherein one ring carbon unit is optionally replaced by a heteroatom selected from S, N and O;
wherein the previously defined group "a" is optionally mono-or disubstituted meta to the point of attachment to the oxazolidinone by a group selected from: fluorine, chlorine, nitro, amino, trifluoromethyl, methyl and cyano,
R3、R4、R5、R6、R7and R8Is hydrogen.
4. The use of claim 3, wherein the compound of formula (I) has the formula
5. Use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or hydrate of a salt thereof, for preventing coagulation of a biological sample containing factor Xa ex vivo:
wherein:
R1is 2-thienyl, which is substituted in its 5-position by a radical selected from the group consisting of chlorine, bromine, methyl and trifluoromethyl,
R2is D-A-:
wherein: the group "A" is phenylene;
the group "D" is a saturated 5-or 6-membered heterocyclic ring,
which is linked to "A" via a nitrogen atom,
which has a carbonyl group in the ortho position to the attached nitrogen atom and
wherein one ring carbon unit is optionally replaced by a heteroatom selected from S, N and O;
wherein the previously defined group "a" is optionally mono-or disubstituted meta to the point of attachment to the oxazolidinone by a group selected from: fluorine, chlorine, nitro, amino, trifluoromethyl, methyl and cyano,
R3、R4、R5、R6、R7and R8Is hydrogen.
6. The use of claim 5, wherein the compound of formula (I) has the formula
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|---|---|---|---|
| DE19962924A DE19962924A1 (en) | 1999-12-24 | 1999-12-24 | Substituted oxazolidinones and their use |
| DE19962924.2 | 1999-12-24 | ||
| HK04100440.2A HK1057556B (en) | 1999-12-24 | 2000-12-11 | Substituted oxazolidinones and their use in the field of blood coagulation |
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