`
`111111111111110 111111010 111111FlOpli11,11IpA11111111010 111111111101M
`
`
`
`
`
`
`
`US 20030153610A1
`
`(19) United States
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2003/0153610 Al
`(12) Patent Application Publication (10) Pub. No.: US 2003/0153610 A1
`Aug. 14, 2003
`(43) Pub. Date:
`Aug. 14, 2003
`Straub et al.
`(43) Pub. Date:
`Straub et al.
`
`(54) SUBSTITUTED OXAZOLIDINONES AND
`(54) SUBSTITUTED OXAZOLIDINONES AND
`THEIR IN THE FIELD OF BLOOD
`THEIR IN THE FIELD OF BLOOD
`COAGULATION
`COAGULATION
`
`(76)
`(76) Inventors: Alexander Straub, Wuppertal (DE);
`Inventors: Alexander Straub, Wuppertal (DE);
`Thomas Lampe, Wuppertal (DE); Jens
`Thomas Lampe, Wuppertal (DE); Jens
`Pohlmann, Wuppertal (DE); Susanne
`Pohlmann, Wuppertal (DE); Susanne
`Rohrig, Essen (DE); Elisabeth
`Rohrig, Essen (DE); Elisabeth
`Perzborn, Wuppertal (DE); Karl-Heinz
`Perzborn, Wuppertal (DE); Karl-Heinz
`Schlemmer, Wuppertal (DE); Joseph
`Schlemmer, Wuppertal (DE); Joseph
`Pernerstorfer, Wuppertal (DE)
`Pernerstorfer, Wuppertal (DE)
`
`Publication Classi?cation
`Publication Classification
`
` CO7D 413/02; A61K 31/421
`(51) Int. C1.7
`C07D 413/02; A61K 31/421
`(51) Int. Cl? .
` 514/376; 548/229
`(52) U.S. Cl.
`(52) Us. 01. .......................................... .. 514/376; 548/229
`
`(57)
`(57)
`
`ABSTRACT
`ABSTRACT
`
`The invention relates to the ?eld of blood coagulation. Novel
`The invention relates to the field of blood coagulation. Novel
`oXaZolidinone derivatives of the general formula (I)
`oxazolidinone derivatives of the general formula (I)
`
`o
`
`(I)
`(I)
`
`R2
`
`R2 A N
`
`0
`O
`R5
`R5
`R6
`R6
`
`3
`R3
`R
`
`Correspondence Address:
`Correspondence Address:
`JEFFREY M. GREENMAN
`JEFFREY M. GREENMAN
`VICE PRESIDENT, PATENTS AND
`VICE PRESIDENT, PATENTS AND
`LICENSING
`LICENSING
`BAYER CORPORATION
`BAYER CORPORATION
`400 MORGAN LANE
`400 MORGAN LANE
`WEST HAVEN, CT 06516 (US)
`WEST HAVEN, CT 06516 (US)
`
`(21) Appl. No.:
`Appl. No.:
`(21)
`
`10/181,051
`10/181,051
`
`(22) PCT Filed:
`PCT Filed:
`(22)
`
`Dec. 11, 2000
`Dec. 11, 2000
`
`4
`R4
`R
`R8- N
`
`R7
`R7
`
`R1,
`
`R8—N\"/ R1,
`
`O
`0
`
`(86) PCT No.:
`PCT No.:
`(86)
`
`PCT/EP00/12492
`PCT/EP00/12492
`
`(30)
`(30)
`
`Foreign Application Priority Data
`Foreign Application Priority Data
`
`Dec. 24, 1999
`(DE)
` 199 62 924.2
`Dec. 24, 1999 (DE) ................................... .. 199 62 924.2
`
`processes for their preparation and their use as medicinally
`processes for their preparation and their use as rnedicinally
`active compounds for the prophylaxis and/or treatment of
`active compounds for the prophylaxis and/or treatment of
`disorders are described.
`disorders are described.
`
`MYLAN - EXHIBIT 1005
`
`

`

`US 2003/0153610 Al
`US 2003/0153610 A1
`
`Aug. 14, 2003
`Aug. 14, 2003
`
`1
`
`SUBSTITUTED OXAZOLIDINONES AND THEIR
`SUBSTITUTED OXAZOLIDINONES AND THEIR
`IN THE FIELD OF BLOOD COAGULATION
`IN THE FIELD OF BLOOD COAGULATION
`
`[0001] The present invention relates to the ?eld of blood
`[0001] The present invention relates to the field of blood
`coagulation. In particular, the present invention relates to
`coagulation. In particular, the present invention relates to
`novel oxazolidinone derivatives, to processes for their
`novel oxaZolidinone derivatives, to processes for their
`preparation and to their use as active compounds in medi-
`preparation and to their use as active compounds in medi
`caments.
`caments.
`
`[0002] Blood coagulation is a protective mechanism of the
`[0002] Blood coagulation is a protective mechanism of the
`organism Which helps to “seal” defects in the Wall of the
`organism which helps to "seal" defects in the wall of the
`blood vessels quickly and reliably. Thus, loss of blood can
`blood vessels quickly and reliably. Thus, loss of blood can
`be avoided or kept to a minimum. Haemostasis after injury
`be avoided or kept to a minimum. Haemostasis after injury
`of the blood vessels is effected mainly by the coagulation
`of the blood vessels is effected mainly by the coagulation
`system in Which an enZymatic cascade of complex reactions
`system in which an enzymatic cascade of complex reactions
`of plasma proteins is triggered. Numerous blood coagulation
`of plasma proteins is triggered. Numerous blood coagulation
`factors are involved in this process, each of which factors
`factors are involved in this process, each of Which factors
`converts, on activation, the respectively next inactive pre-
`converts, on activation, the respectively next inactive pre
`cursor into its active form. At the end of the cascade comes
`cursor into its active form. At the end of the cascade comes
`the conversion of soluble ?brinogen into insoluble ?brin,
`the conversion of soluble fibrinogen into insoluble fibrin,
`resulting in the formation of a blood clot. In blood coagu-
`resulting in the formation of a blood clot. In blood coagu
`lation, traditionally the intrinsic ?nd the extrinsic system,
`lation, traditionally the intrinsic find the extrinsic system,
`Which end in a joint reaction path, are distinguished. Here
`which end in a joint reaction path, are distinguished. Here
`factor Xa, Which is formed from the proenZyme factor X,
`factor Xa, which is formed from the proenzyme factor X,
`plays a key role, since it connects the tWo coagulation paths.
`plays a key role, since it connects the two coagulation paths.
`The activated serine protease Xa cleaves prothrombin to
`The activated serine protease Xa cleaves prothrombin to
`thrombin. The resulting thrombin, in turn, cleaves ?brinogen
`thrombin. The resulting thrombin, in turn, cleaves fibrinogen
`to ?brin, a ?brous/gelatinous coagulant. In addition, throm
`to fibrin, a fibrous/gelatinous coagulant. In addition, throm-
`bin is a potent effector of platelet aggregation Which likeWise
`bin is a potent effector of platelet aggregation which likewise
`contributes signi?cantly to haemostasis.
`contributes significantly to haemostasis.
`
`[0003] Maintenance of normal haemostasis—betWeen
`[0003] Maintenance of normal haemostasis—between
`bleeding and thrombosis—is subject to a complex regulatory
`bleeding and thrombosis—is subject to a complex regulatory
`mechanism. Uncontrolled activation of the coagulant system
`mechanism. Uncontrolled activation of the coagulant system
`or defective inhibition of the activation processes may cause
`or defective inhibition of the activation processes may cause
`formation of local thrombi or embolisms in vessels (arteries,
`formation of local thrombi or embolisms in vessels (arteries,
`veins, lymph vessels) or in heart cavities. This may lead to
`veins, lymph vessels) or in heart cavities. This may lead to
`serious disorders, such as myocardial infarct, angina pectoris
`serious disorders, such as myocardial infarct, angina pectoris
`(including unstable angina), reocclusions and restenoses
`(including unstable angina), reocclusions and restenoses
`after angioplasty or aortocoronary bypass, stroke, transitory
`after angioplasty or aortocoronary bypass, stroke, transitory
`ischaemic attacks, peripheral arterial occlusive disorders,
`ischaemic attacks, peripheral arterial occlusive disorders,
`pulmonary embolisms or deep venous thromboses; herein-
`pulmonary embolisms or deep venous thromboses; herein
`below, these disorders are collectively also referred to as
`beloW, these disorders are collectively also referred to as
`thromboembolic disorders. In addition, in the case of con-
`thromboembolic disorders. In addition, in the case of con
`sumption coagulopathy, hypercoagulability may—systemi
`sumption coagulopathy, hypercoagulability may—systemi-
`cally—result in disseminated intravascular coagulation.
`cally—result in disseminated intravascular coagulation.
`
`[0004] These thromboembolic disorders are the most fre-
`[0004] These thromboembolic disorders are the most fre
`quent cause of morbidity and mortality in most industrial
`quent cause of morbidity and mortality in most industrial-
`iZed countries (Pschyrembel, Klinisches Worterbuch [clini
`ized countries (Pschyrembel, Klinisches Worterbuch [clini-
`cal dictionary], 257th edition, 1994, Walter de Gruyter
`cal dictionary], 257th edition, 1994, Walter de Gruyter
`Verlag, page 199 ff., entry “Blutgerinnung”[blood coagula
`Verlag, page 199 ff., entry "Blutgerinnung"[blood coagula-
`tion]; Rompp Lexikon Chemie, Version 1.5, 1998, Georg
`tion]; Rompp Lexikon Chemie, Version 1.5, 1998, Georg
`Thieme Verlag Stuttgart, entry “Blutgerinnung”; Lubert
`Thieme Verlag Stuttgart, entry "Blutgerinnung"; Lubert
`Stryer, Biochemie [biochemistry], Spektrum der Wissen
`Stryer, Biochemie [biochemistry], Spektrum der Wissen-
`schaft Verlagsgesellschaft mbH Heidelberg, 1990, page 259
`schaft Verlagsgesellschaft mbH Heidelberg, 1990, page 259
`ff.).
`ff.).
`[0005] The anticoagulants, i.e. substances for inhibiting or
`[0005] The anticoagulants, i.e. substances for inhibiting or
`preventing blood coagulation, Which are knoWn from the
`preventing blood coagulation, which are known from the
`prior art have various, often grave disadvantages. Accord
`prior art have various, often grave disadvantages. Accord-
`ingly, in practice, an efficient treatment method or prophy-
`ingly, in practice, an efficient treatment method or prophy
`laxis of thromboembolic disorders is very difficult and
`laxis of thromboembolic disorders is very dif?cult and
`unsatisfactory.
`unsatisfactory.
`[0006] In the therapy and prophylaxis of thromboembolic
`In the therapy and prophylaxis of thromboembolic
`[0006]
`disorders, use is firstly made of heparin, which is adminis-
`disorders, use is ?rstly made of heparin, Which is adminis
`
`tered parenterally or subcutaneously. OWing to more favour
`tered parenterally or subcutaneously. Owing to more favour-
`able pharmacokinetic properties, preference is noWadays
`able pharmacokinetic properties, preference is nowadays
`more and more given to loW-molecular-Weight heparin;
`more and more given to low-molecular-weight heparin;
`hoWever, even With loW-molecular-Weight heparin, it is not
`however, even with low-molecular-weight heparin, it is not
`possible to avoid the knoWn disadvantages described beloW,
`possible to avoid the known disadvantages described below,
`Which are involved in heparin therapy. Thus, heparin is
`which are involved in heparin therapy. Thus, heparin is
`ineffective When administered orally and has a relatively
`ineffective when administered orally and has a relatively
`short half-life. Since heparin inhibits a plurality of factors of
`short half-life. Since heparin inhibits a plurality of factors of
`the blood coagulation cascade at the same time, the action is
`the blood coagulation cascade at the same time, the action is
`nonselective. Moreover, there is a high risk of bleeding; in
`nonselective. Moreover, there is a high risk of bleeding; in
`particular, brain haemorrhages and gastrointestinal bleeding
`particular, brain haemorrhages and gastrointestinal bleeding
`may occur, Which may result in thrombopenia, drug-induced
`may occur, which may result in thrombopenia, drug-induced
`alopecia or osteoporosis (Pschyrembel, Klinisches Worter
`alopecia or osteoporosis (Pschyrembel, Klinisches Worter-
`buch, 257th edition, 1994, Walter de Gruyter Verlag, page
`buch, 257th edition, 1994, Walter de Gruyter Verlag, page
`610, entry “Heparin”; Rompp Lexikon Chemie, Version 1.5,
`610, entry "Heparin"; Rompp Lexikon Chemie, Version 1.5,
`1998, Georg Thieme Verlag Stuttgart, entry “Heparin”).
`1998, Georg Thieme Verlag Stuttgart, entry "Heparin").
`
`[0007] A second class of anticoagulants are the vitamin K
`[0007] A second class of anticoagulants are the vitamin K
`antagonists. These include, for example, 1,3-indanediones,
`antagonists. These include, for example, 1,3-indanediones,
`and especially compounds such as Warfarin, phenprocou
`and especially compounds such as warfarin, phenprocou-
`mon, dicumarol and other coumarin derivatives which
`mon, dicumarol and other coumarin derivatives Which
`inhibit the synthesis of various products of certain vitamin
`inhibit the synthesis of various products of certain vitamin
`K-dependent coagulation factors in the liver in a non-
`K-dependent coagulation factors in the liver in a non
`selective manner. Owing to the mechanism of action, how-
`selective manner. OWing to the mechanism of action, hoW
`ever, the onset of the action is very slow (latency to the onset
`ever, the onset of the action is very sloW (latency to the onset
`of action 36 to 48 hours). It is possible to administer the
`of action 36 to 48 hours). It is possible to administer the
`compounds orally; hoWever, oWing to the high risk of
`compounds orally; however, owing to the high risk of
`bleeding and the narroW therapeutic index, a time-consum
`bleeding and the narrow therapeutic index, a time-consum-
`ing individual adjustment and monitoring of the patient are
`ing individual adjustment and monitoring of the patient are
`required. Moreover, other adverse effects, such as gas-
`required. Moreover, other adverse effects, such as gas
`trointestinal disturbances, hair loss and skin necroses, have
`trointestinal disturbances, hair loss and skin necroses, have
`been described (Pschyrembel, Klinisches Worterbuch, 257th
`been described (Pschyrembel, Klinisches Worterbuch, 257th
`edition, 1994, Walter de Gruyter Verlag, page 292 ff., entry
`edition, 1994, Walter de Gruyter Verlag, page 292 ff., entry
`“coumarin derivatives”; Ullmann’s Encyclopedia of Indus
`"coumarin derivatives"; Ullmann's Encyclopedia of Indus-
`trial Chemistry, 5th edition, VCH Verlagsgesellschaft, Wein
`trial Chemistry, 5th edition, VCH Verlagsgesellschaft, Wein-
`heim, 1985-1996, entry “vitamin K”).
`heim, 1985-1996, entry "vitamin K").
`[0008] Recently, a novel therapeutic approach for the
`[0008] Recently, a novel therapeutic approach for the
`treatment and prophylaxis of thromboembolic disorders has
`treatment and prophylaxis of thromboembolic disorders has
`been described. This novel therapeutic approach aims to
`been described. This novel therapeutic approach aims to
`inhibit factor Xa (cf. WO-A-99/37304; WO-A-99/06371; J.
`inhibit factor Xa (cf. WO-A-99/37304; WO-A-99/06371; J.
`Hauptmann, J. StiirZebecher, Thrombosis Research 1999,
`Hauptmann, J. Stiirzebecher, Thrombosis Research 1999,
`93, 203; F. Al-Obeidi, J. A. Ostrem, Factor Xa inhibitors by
`93, 203; F. Al-Obeidi, J. A. Ostrem, Factor Xa inhibitors by
`classical and combinatorial chemistry, DDT 1998, 3, 223; F.
`classical and combinatorial chemistry, DDT 1998, 3, 223; F.
`Al-Obeidi, J. A. Ostrem, Factor Xa inhibitors, Exp. Opin.
`Al-Obeidi, J. A. Ostrem, Factor Xa inhibitors, Exp. Opin.
`Ther. Patents 1999, 9, 931; B. Kaiser, Thrombin and factor
`Ther. Patents 1999, 9, 931; B. Kaiser, Thrombin and factor
`Xa inhibitors, Drugs of the Future 1998, 23, 423; A. Uzan,
`Xa inhibitors, Drugs of the Future 1998, 23, 423; A. UZan,
`Antithrombotic agents, Emerging Drugs 1998, 3, 189; B. -Y.
`Antithrombotic agents, Emerging Drugs 1998, 3, 189; B. -Y.
`Zhu, R. M. Scarborough, Curr. Opin. Card. Pulm. Ren. Inv.
`Zhu, R. M. Scarborough, Curr. Opin. Card. Pulm. Ren. Inv.
`Drugs 1999, 1 (1), 63). It has been shoWn that, in animal
`Drugs 1999, 1 (1), 63). It has been shown that, in animal
`models, various both peptidic and nonpeptidic compounds
`models, various both peptidic and nonpeptidic compounds
`are effective as factor Xa inhibitors.
`are effective as factor Xa inhibitors.
`
`[0009] Accordingly, it is an object of the present invention
`[0009] Accordingly, it is an object of the present invention
`to provide novel substances for controlling disorders, Which
`to provide novel substances for controlling disorders, which
`substances have a wide therapeutic spectrum.
`substances have a Wide therapeutic spectrum.
`
`In particular, they should be suitable for a more
`[0010]
`[0010] In particular, they should be suitable for a more
`ef?cient prophylaxis and/or treatment of thromboembolic
`efficient prophylaxis and/or treatment of thromboembolic
`disorders, avoiding—at least to some extent—the disadvan-
`disorders, avoiding—at least to some extent—the disadvan
`tages of the prior art described above, where the term
`tages of the prior art described above, Where the term
`"thromboembolic disorders" in the context of the present
`“thromboembolic disorders” in the context of the present
`invention is to be understood as meaning, in particular,
`invention is to be understood as meaning, in particular,
`serious disorders, such as myocardial infarct, angina pectoris
`serious disorders, such as myocardial infarct, angina pectoris
`(including unstable angina), reocclusions and restenoses
`(including unstable angina), reocclusions and restenoses
`after angioplasty or aortocoronary bypass, stroke, transitory
`after angioplasty or aortocoronary bypass, stroke, transitory
`
`

`

`US 2003/0153610 Al
`US 2003/0153610 A1
`
`Aug. 14, 2003
`Aug. 14, 2003
`
`2
`
`ischaemic attacks, peripheral arterial occlusive disorders,
`ischaemic attacks, peripheral arterial occlusive disorders,
`pulmonary embolisms or deep venous thromboses.
`pulmonary embolisms or deep venous thromboses.
`
`It is another object of the present invention to
`[0011]
`[0011] It is another object of the present invention to
`provide novel anticoagulants Which inhibit the blood coagu
`provide novel anticoagulants which inhibit the blood coagu-
`lation factor Xa With increased selectivity, avoiding—at
`lation factor Xa with increased selectivity, avoiding—at
`least to some extent—the problems of the therapeutic meth-
`least to some eXtent—the problems of the therapeutic meth
`ods for thromboembolic disorders known from the prior art.
`ods for thromboembolic disorders knoWn from the prior art.
`[0012] Accordingly, the present invention provides sub
`[0012] Accordingly, the present invention provides sub-
`stituted oXaZolidinones of the general formula (I)
`stituted oxazolidinones of the general formula (I)
`
`0
`
`(I)
`(0
`
`0
`
`in which:
`[0013]
`[0013] in Which:
`benZo-fused
`optionally
`represents
`[0014] R1
`benzo-fused
`optionally
`represents
`[0014] R1
`thiophene (thienyl) Which may optionally be mono
`thiophene (thienyl) which may optionally be mono-
`or polysubstituted;
`or polysubstituted;
`[0015] R2 represents any organic radical;
`[0015] R2 represents any organic radical;
`[0016] R3, R4, R5, R6, R7 and R8 are identical or
`[0016] R3, R4, R5, R6, R7 and R8 are identical or
`different and each represents hydrogen or represents
`different and each represents hydrogen or represents
`(C1-C6)-alkyl
`(C1-C6)-alkyl
`[0017] and their pharmaceutically acceptable salts,
`[0017] and their pharmaceutically acceptable salts,
`hydrates and prodrugs,
`hydrates and prodrugs,
`[0018] eXcept for compounds of the general formula
`[0018] except for compounds of the general formula
`(I) in which the radical R1 is an unsubstituted
`(I) in Which the radical R1 is an unsubstituted
`2-thiophene radical and the radical R2 is simulta
`2-thiophene radical and the radical R2 is simulta-
`neously a mono- or polysubstituted phenyl radical
`neously a mono- or polysubstituted phenyl radical
`and the radicals R3, R4, R5, R6, R7 and R8 are each
`and the radicals R3, R4, R5, R6, R7 and R8 are each
`simultaneously hydrogen.
`simultaneously hydrogen.
`[0019] Preference is given here to compounds of the
`[0019] Preference is given here to compounds of the
`general formula (I),
`general formula (I),
`[0020]
`in which
`[0020] in which
`benZo-fused
`optionally
`represents
`[0021] R1
`benzo-fused
`optionally
`represents
`[0021] R1
`thiophene (thienyl) Which may optionally be mono
`thiophene (thienyl) which may optionally be mono-
`or polysubstituted by a radical from the group con-
`or polysubstituted by a radical from the group con
`sisting of halogen; cyano; nitro; amino; aminom
`sisting of halogen; cyano; nitro; amino; aminom-
`ethyl; (C1-C8)-alkyl Which for its part may optionally
`ethyl; (C1-C8)-alkyl which for its part may optionally
`be mono- or polysubstituted by halogen; (C3-C7)-
`be mono- or polysubstituted by halogen; (C3-C7)
`cycloalkyl;
`(C1-C8)-alkoXy;
`imidaZolinyl;
`cycloalkyl;
`(C1-C8)-alkoxy;
`imidazolinyl;
`—C(=NH)NH2; carbamoyl; and mono- and di-(C1-
`—C(=NH)NH2; carbamoyl; and mono- and di-(C1
`C4)-alkyl-aminocarbonyl,
`C4)-alkyl-aminocarbonyl,
`[0022] R2 represents one of the groups below:
`[0022] R2 represents one of the groups beloW:
`[0023] A-,
`[0023] A-,
`[0024] A-M-,
`[0024] A-M-,
`[0025] D-M-A-,
`[0025] D-M-A-,
`[0026] B-M-A-,
`[0026] B-M-A-,
`
`B-,
`
`B-M-,
`
`B-M-B-,
`
`[0027]
`[0027]
`[0028]
`[0028]
`[0029]
`[0029]
`[0030]
`[0030]
`D-M-B-,
`[0031] Where:
`[0031] where:
`[0032] the radical “A” represents (CG-C14)
`[0032]
`the radical "A" represents (C6-C14)-
`aryl, preferably (C6-C1O)-aryl, in particular
`aryl, preferably (C6-C10)-aryl, in particular
`phenyl or naphthyl, very particularly prefer
`phenyl or naphthyl, very particularly prefer-
`ably phenyl;
`ably phenyl;
`the radical "B" represents a 5- or
`[0033]
`[0033] the radical “B” represents a 5- or
`6-membered aromatic heterocycle Which
`6-membered aromatic heterocycle which
`contains up to 3 heteroatoms and/or hetero
`contains up to 3 heteroatoms and/or hetero
`chain members, in particular up to 2 heteroa-
`chain members, in particular up to 2 heteroa
`toms and/or hetero chain members, from the
`toms and/or hetero chain members, from the
`group consisting of S, N, NO (N-oxide) and
`group consisting of S, N, NO (N-oXide) and
`0;
`O;
`the radical "D" represents a saturated
`[0034]
`[0034] the radical “D” represents a saturated
`or partially unsaturated, mono- or bicyclic,
`or partially unsaturated, mono- or bicyclic,
`optionally benzo-fused 4- to 9-membered
`optionally benZo-fused 4- to 9-membered
`heterocycle which contains up to three het-
`heterocycle Which contains up to three het
`eroatoms and/or hetero chain members from
`eroatoms and/or hetero chain members from
`the group consisting of S, SO, S02, N, NO
`the group consisting of S, SO, SO2, N, NO
`(N-oxide) and 0;
`(N-oXide) and O;
`[0035]
`the radical "M" represents —NH—,
`[0035] the radical “M” represents —NH—,
`—CH2—, —CH2CH2—, —0—, —NH—
`CH2—, —CH2—NH—, —OCH2—,
`—CH20—, —CONH—, —NHCO—,
`—COO—, —00C—, —5—, —SO2— or
`represents a covalent bond;
`represents a covalent bond;
`[0036] where
`[0036] Where
`[0037]
`the groups "A", "B" and "D" defined
`[0037] the groups “A”, “B” and “D” de?ned
`above may each optionally be mono- or
`above may each optionally be mono- or
`polysubstituted by a radical from the group
`polysubstituted by a radical from the group
`consisting of halogen; tri?uoromethyl; oXo;
`consisting of halogen; trifluoromethyl; oxo;
`cyano; nitro; carbamoyl; pyridyl; (C1-C6)
`cyano; nitro; carbamoyl; pyridyl; (C1-C6)-
`alkanoyl; (C3-C7)-cycloalkanoyl; (CG-C14)
`alkanoyl; (C3-C7)-cycloalkanoyl; (C6-C14)-
`arylcarbonyl; (C5—ClO)-heteroarylcarbonyl;
`arylcarbonyl;
`(C,-C10)-heteroarylcarbonyl;
`(C1-C6)-alkanoyloXymethyloXy; (C1-C4)-hy
`(C1-C6)-alkanoyloxymethyloxy; (C1-C4)-hy-
`droXy-alkylcarbonyl;
`—COOR27;
`droxy-alkylcarbonyl;
`—COOR27;
`C(NR27R28)=NR29;
`—SO2R27;
`C(NR27R28)=NR29;
`—502R27;
`_coNR28R29; —5 02NR28R29 ; —0R30,
`—CONR28R29; —SO2NR28R29; —OR30;
`—NR3OOR31, (C1-C6)-alkyl and (C3-C7)-cy
`—NR300R31, (C1-C6)-alkyl and (C3-C7)-cy-
`cloalkyl, Where (C1-C6)-alkyl and (C3-C7)
`cloalkyl, where (C1-C6)-alkyl and (C3-C7)-
`cycloalkyl for their part may optionally be
`cycloalkyl for their part may optionally be
`substituted by a radical from the group con-
`substituted by a radical from the group con
`sisting of cyano; —0R27; —NR28R29;
`sisting of cyano; —OR27; —NR28R29;
`—CO(NH),(NR27R28)
`and
`—CO(NH)V(NR27R28)
`and
`_C(NR27R28):NR29,
`[0038] where:
`[0038] Where:
`[0039] v is either 0 or 1 and
`[0039] v is either 0 or 1 and
`
`C(NR27R28)_NR29
`
`,
`
`[0040] R27, R28 and R29 are identical or dif-
`[0040] R27, R28 and R29 are identical or dif
`ferent and independently of one another each
`ferent and independently of one another each
`represents hydrogen, (C1-C4)-alkyl, (C3-C7)
`represents hydrogen, (C1-C4)-alkyl, (C3-C7)-
`cycloalkyl, (C1-C4)-alkanoyl, carbamoyl, tri
`cycloalkyl, (C1-C4)-alkanoyl, carbamoyl, tri-
`?uoromethyl, phenyl or pyridyl, and/or
`fluoromethyl, phenyl or pyridyl, and/or
`[0041] R27 and R28 or R27 and R29 toether
`[0041] R27 and R28 or R27 and R29 toether
`with the nitrogen atom to which they are
`With the nitrogen atom to Which they are
`
`

`

`US 2003/0153610 Al
`US 2003/0153610 A1
`
`Aug. 14, 2003
`Aug. 14, 2003
`
`3
`
`attached form a saturated or partially unsat-
`attached form a saturated or partially unsat
`urated 5- to 7-membered heterocycle having
`urated 5- to 7-membered heterocycle having
`up to three, preferably up to two, identical or
`up to three, preferably up to tWo, identical or
`different heteroatoms from the group consist-
`different heteroatoms from the group consist
`ing of N, O and S, and
`ing of N, 0 and S, and
`
`[0042] R3° and R31 are identical or different
`[0042] R30 and R31 are identical or different
`and independently of one another each rep-
`and independently of one another each rep
`resents hydrogen, (C1-C4)-alkyl, (C3-C7)-cy
`resents hydrogen, (C1-C4)-alkyl, (C3-C7)-cy-
`cloalkyl, (C1-C4)-alkylsulphonyl, (C1-C4)
`cloalkyl, (C1-C4)-alkylsulphonyl, (C1-C4)-
`hydroXyalkyl, (C1-C4)-aminoalkyl, di-(C1
`hydroxyalkyl, (C1-C4)-aminoalkyl, di-(C1-
`C4)-alkylamino-(C1-C4)-alkyl,
`C4)-alkylamino-(C1-C4)-alkyl,
`-CH2C(NR271228)=NR29 or -COR33,
`—CH2C(NR27R28)=NR29 or —COR33,
`[0043] Where
`[0043] where
`[0044] R33 represents (C1-C6)-a1k0Xy> (C1'
`[0044] R33 represents (C1-C6)-alkoxy, (C1-
`C4)-alkoXy-(C1-C4)-alkyl, (C1-C4)-alkoXy
`C4)-alkoxy-(C1-C4)-alkyl,
`(C1-C4)-alkoxy-
`carbonyl-(C1-C4)-alkyl, (C1-C4)-aminoalkyl,
`carbonyl-(C1-C4)-alkyl, (C1-C4)-aminoalkyl,
`(C1-C4)-alkoXycarbonyl, (C1-C4)-alkanoyl
`(C1-C4)-alkoxycarbonyl, (C1-C4)-alkanoyl-
`(C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)
`(C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)-
`alkenyl, (C1-C8)-alkyl, Which may optionally
`alkenyl, (C1-C8)-alkyl, which may optionally
`be substituted by phenyl or acetyl, (CG-C14)
`be substituted by phenyl or acetyl, (C6-C14)-
`aryl, (C5-C1O)-heteroaryl, tri?uoromethyl,
`aryl, (C5-C10)-heteroaryl,
`trifluoromethyl,
`tetrahydrofuranyl or butyrolactone,
`tetrahydrofuranyl or butyrolactone,
`
`[0045]
`R3, R4, R5, R6, R7 and R8 are identical or
`[0045] R3, R4, R5, R6, R7 and R8 are identical or
`different and each represents hydrogen or repre-
`different and each represents hydrogen or repre
`sents (C1-C6)-alkyl
`sents (C1-C6)-alkyl
`[0046] and their pharmaceutically acceptable salts,
`[0046] and their pharmaceutically acceptable salts,
`hydrates and prodrugs,
`hydrates and prodrugs,
`
`[0047]
`eXcept for compounds of the general formula
`[0047] except for compounds of the general formula
`(I) in which the radical R1 is an unsubstituted
`(I) in
`Which the radical R1 is an unsubstituted
`2-thiophene radical and the radical R2 is simulta
`2-thiophene radical and the radical R2 is simulta-
`neously a mono- or polysubstituted phenyl radical
`neously a mono- or polysubstituted phenyl radical
`and the radicals R3, R4, R5, R6, R7 and R8 are each
`and the radicals R3, R4, R5, R6, R7 and R8 are each
`simultaneously hydrogen.
`simultaneously hydrogen.
`
`[0048] Preference is also given here to compounds of the
`[0048] Preference is also given here to compounds of the
`general formu 1a (1),
`general formula (I),
`in which
`[0049]
`[0049] in which
`[0050] R1 represents thiophene (thienyl), in particular
`[0050] R1 represents thiophene (thienyl), in particular
`2-thiophene, which may optionally be mono- or
`2-thiophene, Which may optionally be mono- or
`polysu bstituted by halogen, preferably chlorine or
`polysubstituted by halogen, preferably chlorine or
`bromine, by amino, aminomethyl or (C1-C8)-alkyl,
`bromine, by amino, aminomethyl or (C1-C8)-alkyl,
`preferably methyl, Where the (C1-C8)-alkyl radical
`preferably methyl, where the (C1-C8)-alkyl radical
`for its part may optionally be mono- or polysubsti-
`for its part may optionally be mono- or polysubsti
`tuted by halogen, preferably ?uorine,
`tuted by halogen, preferably fluorine,
`[0051]
`[0051] R2 represents one of the groups below:
`R2 represents one of the groups beloW:
`[0052]
`[0052] A-,
`A‘,
`[0053]
`[0053] A-M-,
`A-M-,
`[0054]
`[0054] D-M-A-,
`D-M-A-,
`[0055]
`[0055] B-M-A-,
`B-M-A-,
`[0056]
`[0056] B-,
`[0057]
`[0057] B-M-,
`[0058]
`[0058] B-M-B-,
`[0059]
`[0059] D-M-B-,
`
`[0060] Where:
`[0060] where:
`[0061] the radical “A” represents (CG-C14)
`[0061]
`the radical "A" represents (C6-C14)-
`aryl, preferably (C6-C1O)-aryl, in particular
`aryl, preferably (C6-C10)-aryl, in particular
`phenyl or naphthyl, very particularly prefer
`phenyl or naphthyl, very particularly prefer-
`ably phenyl;
`ably phenyl;
`the radical "B" represents a 5- or
`[0062]
`[0062] the radical “B” represents a 5- or
`6-membered aromatic heterocycle Which
`6-membered aromatic heterocycle which
`contains up to 3 heteroatoms and/or hetero
`contains up to 3 heteroatoms and/or hetero
`chain members, in particular up to 2 heteroa-
`chain members, in particular up to 2 heteroa
`toms and/or hetero chain members, from the
`toms and/or hetero chain members, from the
`group consisting of S, N, NO (N-oxide) and
`group consisting of S, N, NO (N-oXide) and
`0;
`O;
`the radical "D" represents a saturated
`[0063]
`[0063] the radical “D” represents a saturated
`or partially unsaturated 4 to 7-membered
`or partially unsaturated 4 to 7-membered
`heterocycle which contains up to three het-
`heterocycle Which contains up to three het
`eroatoms and/or hetero chain members from
`eroatoms and/or hetero chain members from
`the group consisting of S, SO, SO2, N, NO
`the group consisting of S, SO, SO2, N, NO
`(N-oxide) and 0;
`(N-oXide) and O;
`[0064]
`the radical "M" represents -NH-,
`[0064] the radical “M” represents —NH—,
`- CH2-, -CH2CH2-, -0-,
`-NH-
`CH2-,
`-CH2-NH-,
`-OCH2-,
`- CH20-,
`-CONH-,
`-NHCO-,
`- 000-, -00C-, -5- or represents a
`—COO—, —OOC—, —S— or represents a
`covalent bond;
`covalent bond;
`[0065] Where
`[0065] where
`[0066]
`the groups "A", "B" and "D" defined
`[0066] the groups “A”, “B” and “D” de?ned
`above may in each case optionally be mono-
`above may in each case optionally be mono
`or polysubstituted by a radical from the
`or polysubstituted by a radical from the
`group consisting of halogen; tri?uoromethyl;
`group consisting of halogen; trifluoromethyl;
`oXo; cyano; nitro; carbamoyl; pyridyl; (C1
`oxo; cyano; nitro; carbamoyl; pyridyl; (C1-
`C6)-alkanoyl; (C3-C7)-cycloalkanoyl; (C6
`C6)-alkanoyl; (C3-C7)-cycloalkanoyl; (C6-
`C14)-arylcarbonyl; (C5-C1O)-heteroarylcar
`C14)-arylcarbonyl;
`(C5-C10)-heteroarylcar-
`bonyl;
`(C1-C6)-alkanoyloXymethyloXy;
`bonyl;
`(C1-C6)-alkanoyloxymethyloxy;
`—COOR27;
`—SO2R27;
`- COOR27;
`-50 2R27;
`—C(NR27R28)=NR29; —CONR R28R29;
`- C(NR27R28)=NR29; -CONR R28R29;
`- 502NR28R29; -0R 30, -NR30R31, (C1-
`—SO2NR28R29; —OR30; —NR3OR31, (C1
`C6)-alkyl and (C3-C7)-cycloalkyl,
`C6)-alkyl and (C3-C7)-cycloalkyl,
`[0067] Where (C1-C6)-alkyl and (C3-C7)-cy
`[0067] where (C1-C6)-alkyl and (C3-C7)-cy-
`cloalkyl for their part may optionally be
`cloalkyl for their part may optionally be
`substituted by a radical from the group con-
`substituted by a radical from the group con
`sisting of cyano; —OR27; —NR28R29;
`sisting of cyano; -0R 27; -NR28R29;
`—CO(NH)V(NR27R28) and —C(NR27R28
`- CO(NH),(NR27R28) and -C(NR27R28
`):NR29,
`)=NR29,
`[0068] where:
`[0068] Where:
`[0069] v is either 0 or 1 and
`[0069] v is either 0 or 1 and
`
`[0070] R27, R28 and R29 are identical or dif-
`[0070] R27, R28 and R29 are identical or dif
`ferent and independently of one another each
`ferent and independently of one another each
`represents hydrogen, (C1-C4)-alkyl or (C3
`represents hydrogen, (C1-C4)-alkyl or (C3-
`C7)-cycloalkyl, and/or
`C7)-cycloalkyl, and/or
`[0071] R27 and R28 or R27 and R29 together
`[0071] R27 and R28 or R27 and R29 together
`with the nitrogen atom to which they are
`With the nitrogen atom to Which they are
`attached form a saturated or partially unsat-
`attached form a saturated or partially unsat
`urated 5- to 7-membered heterocycle having
`urated 5- to 7-membered heterocycle having
`up to three, preferably up to two, identical or
`up to three, preferably up to tWo, identical or
`different heteroatoms from the group consist-
`different heteroatoms from the group consist
`ing of N, 0 and S, and
`ing of N, O and S, and
`[0072] R3° and R31 are identical or different
`[0072] R30 and R31 are identical or different
`and independently of one another each rep-
`and independently of one another each rep
`
`

`

`US 2003/0153610 Al
`US 2003/0153610 A1
`
`Aug. 14, 2003
`Aug. 14, 2003
`
`4
`
`resents hydrogen, (C 1 -C4)-alkyl, (C3-C7)-cy
`resents