(12) United States Patent
`Straub et a1.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 7,157,456 B2
`Jan. 2, 2007
`
`US007157456B2
`
`(54) SUBSTITUTED OXAZOLIDINONES AND
`THEIR USE IN THE FIELD OF BLOOD
`COAGULATION
`
`(75) Inventors: Alexander Straub, Wuppertal (DE);
`Thomas Lampe, Wuppertal (DE); Jens
`Pohlmann, Wuppertal (DE); Susanne
`Rohrig, Essen (DE); Elisabeth
`Perzborn, Wuppertal (DE); Karl-Heinz
`Schlemmer, Wuppertal (DE); Joseph
`Pernerstorfer, Wuppertal (DE)
`
`73
`
`Assi nee: Ba er HealthCare AG, Leverkusen
`g
`y
`(DE)
`
`*
`
`Notice:
`
`Sub'ect to an disclaimer, the term of this
`J
`y
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 59 days.
`
`(21) App1.No.:
`
`10/1s1,051
`
`(22) PCT Filed:
`
`Dec. 11, 2000
`
`(86) PCT N0.:
`
`PCT/EP00/12492
`
`§ 371 (0X1)’
`(2), (4) Date:
`
`Jun. 24, 2002
`
`(87) PCT Pub. No.: WO01/47919
`
`PCT Pub. Date: Jul. 5, 2001
`
`(65)
`
`Prior Publication Data
`
`US 2003/0153610 A1
`
`Aug. 14, 2003
`
`(30)
`
`Foreign Application Priority Data
`
`Dec. 24, 1999 (DE) .............................. .. 199 62 924
`
`(51) Int. Cl.
`(2006.01)
`A61K 31/53 77
`(2006.01)
`0070 409/14
`(52) US. Cl. .................................. .. 514/236.8;544/139
`(58) Field of Classi?cation Search .............. .. 544/139;
`514/236.8
`See application ?le for complete search history.
`
`(56)
`
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`FOREIGN PATENT DOCUMENTS
`
`AU
`CA
`CA
`CA
`DE
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`WO
`WO
`WO
`WO
`WO
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`
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`
`(Continued)
`OTHER PUBLICATIONS
`
`*This reference is not being furnished since it Was cited in the
`International Search Report for PCT/EP 00/ 12492.*
`
`(Continued)
`Primary ExamineriKamal A. Saeed
`Assistant ExamineriRebecca Anderson
`(74) Attorney, Agent, or FirmiConnolly Bove Lodge &
`HutZ LLP
`
`(57)
`
`ABSTRACT
`
`The invention relates to the ?eld of blood coagulation. Novel
`oxaZolidinone derivatives of the general formula (I)
`
`o
`
`R2 JR
`\N
`0
`R5
`R6
`
`R7
`
`0
`
`processes for their preparation and their use as medicinally
`active compounds for the prophylaxis and/or treatment of
`disorders are described.
`
`30 Claims, No Drawings
`
`MYLAN - EXHIBIT 1001
`
`

`
`US 7,157,456 B2
`Page 2
`
`FOREIGN PATENT DOCUMENTS
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`
`WO-99/03846
`9906371
`WO-99/24428
`WO-99/29688
`WO-99-31092
`9937304
`WO-99/37630
`WO-99/37641
`WO-99/40094
`WO-99/59616
`WO-01/42242
`WO-01/44212
`WO-01/46185
`WO-02/064575
`WO-03/000256
`WO-03/035133
`
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`Receptor Cascade Between EPR-l and PAR-2,” Arteriosclerosis,
`Thrombosis, and Vascular Biology: pp 1-6; (Nov. 2000).
`
`* cited by examiner
`
`

`
`US 7,157,456 B2
`
`1
`SUBSTITUTED OXAZOLIDINONES AND
`THEIR USE IN THE FIELD OF BLOOD
`COAGULATION
`
`This application is a 371 of PCT/EP00/12492 ?led 11
`Dec. 2000.
`The present invention relates to the ?eld of blood coagu
`lation. In particular, the present invention relates to novel
`oxaZolidinone derivatives, to processes for their preparation
`and to their use as active compounds in medicaments.
`Blood coagulation is a protective mechanism of the
`organism Which helps to “seal” defects in the Wall of the
`blood vessels quickly and reliably. Thus, loss of blood can
`be avoided or kept to a minimum. Haemostasis after injury
`of the blood vessels is effected mainly by the coagulation
`system in Which an enZymatic cascade of complex reactions
`of plasma proteins is triggered. Numerous blood coagulation
`factors are involved in this process, each of Which factors
`converts, on activation, the respectively next inactive pre
`cursor into its active form. At the end of the cascade comes
`the conversion of soluble ?brinogen into insoluble ?brin,
`resulting in the formation of a blood clot. In blood coagu
`lation, traditionally the intrinsic ?nd the extrinsic system,
`Which end in a joint reaction path, are distinguished. Here
`factor Xa, Which is formed from the proenZyme factor X,
`plays a key role, since it connects the tWo coagulation paths.
`The activated serine protease Xa cleaves prothrombin to
`thrombin. The resulting thrombin, in turn, cleaves ?brinogen
`to ?brin, a ?brous/gelatinous coagulant. In addition, throm
`bin is a potent effector of platelet aggregation Which likeWise
`contributes signi?cantly to haemostasis.
`Maintenance of normal haemostasisibetween bleeding
`and thrombosisiis subject to a complex regulatory mecha
`nism. Uncontrolled activation of the coagulant system or
`defective inhibition of the activation processes may cause
`formation of local thrombi or embolisms in vessels (arteries,
`veins, lymph vessels) or in heart cavities. This may lead to
`serious disorders, such as myocardial infarct, angina pectoris
`(including unstable angina), reocclusions and restenoses
`after angioplasty or aortocoronary bypass, stroke, transitory
`ischaemic attacks, peripheral arterial occlusive disorders,
`pulmonary embolisms or deep venous thromboses; herein
`beloW, these disorders are collectively also referred to as
`thromboembolic disorders. In addition, in the case of con
`sumption coagulopathy, hypercoagulability mayisystemi
`callyiresult in disseminated intravascular coagulation.
`These thromboembolic disorders are the most frequent
`cause of morbidity and mortality in most industrialiZed
`countries (Pschyrembel, Klinisches Wor‘terbuch [clinical
`dictionary], 257th edition, 1994, Walter de Gruyter Verlag,
`page 199 if, entry “Blutgerinnung” [blood coagulation];
`Rompp Lexikon Chemie, Version 1.5, 1998, Georg Thieme
`Verlag Stuttgart, entry “Blutgerinnung”; Lubert Stryer, Bio
`chemie [biochemistry], Spektrum der Wissenschaft Verlags
`gesellschaft mbH Heidelberg, 1990, page 259 if).
`The anticoagulants, i.e. substances for inhibiting or pre
`venting blood coagulation, Which are knoWn from the prior
`art have various, often grave disadvantages. Accordingly, in
`practice, an ef?cient treatment method or prophylaxis of
`thromboembolic disorders is very difficult and unsatisfac
`tory.
`In the therapy and prophylaxis of thromboembolic disor
`ders, use is ?rstly made of heparin, Which is administered
`parenterally or subcutaneously. OWing to more favourable
`pharmacokinetic properties, preference is noWadays more
`and more given to loW-molecular-Weight heparin; hoWever,
`even With loW-molecular-Weight heparin, it is not possible to
`
`20
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`avoid the knoWn disadvantages described beloW, Which are
`involved in heparin therapy. Thus, heparin is ineffective
`When administered orally and has a relatively short half-life.
`Since heparin inhibits a plurality of factors of the blood
`coagulation cascade at the same time, the action is nonse
`lective. Moreover, there is a high risk of bleeding; in
`particular, brain haemorrhages and gastrointestinal bleeding
`may occur, Which may result in thrombopenia, drug-induced
`alopecia or osteoporosis (Pschyrembel, Klinisches Wor‘ter
`buch, 257th edition, 1994, Walter de Gruyter Verlag, page
`610, entry “Heparin”; Rompp Lexikon Chemie, Version 1.5,
`1998, Georg Thieme Verlag Stuttgart, entry “Heparin”).
`A second class of anticoagulants are the vitamin K
`antagonists. These include, for example, 1,3-indanediones,
`and especially compounds such as Warfarin, phenprocou
`mon, dicumarol and other coumarin derivatives Which
`inhibit the synthesis of various products of certain vitamin
`K-dependent coagulation factors in the liver in a non
`selective manner. OWing to the mechanism of action, hoW
`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
`compounds orally; hoWever, oWing to the high risk of
`bleeding and the narroW therapeutic index, a time-consum
`ing individual adjustment and monitoring of the patient are
`required. Moreover, other adverse effects, such as gas
`trointestinal disturbances, hair loss and skin necroses, have
`been described (Pschyrembel, Klinisches Wor‘terbuch, 257th
`edition, 1994, Walter de Gruyter Verlag, page 292 if, entry
`“coumarin derivatives”; Ullmann’s Encyclopedia of Indus
`trial Chemistry, 5”’ edition, VCH Verlagsgesellschaft, Wein
`heim, 198541996, entry “vitamin K”).
`Recently, a novel therapeutic approach for the treatment
`and prophylaxis of thromboembolic disorders has been
`described. This novel therapeutic approach aims to inhibit
`factor Xa (cf. WO-A-99/37304; WO-A-99/06371; J. Haupt
`mann, J. StiirZebecher, Thrombosis Research 1999, 93, 203;
`F. Al-Obeidi, J. A. Ostrem, Factor Xa inhibitors by classical
`and combinatorial chemistry, DDT 1998, 3, 223; F. Al
`Obeidi, J. A. Ostrem, Factor Xa inhibitors, Exp. Opin. Ther.
`Patents 1999, 9, 931; B. Kaiser, Thrombin and factor Xa
`inhibitors, Drugs of the Future 1998, 23, 423; A. UZan,
`Antithrombotic agents, Emerging Drugs 1998, 3, 189; B.-Y.
`Zhu, R. M. Scarborough, Curr. Opin. Card. Pulm. Ren. Inv.
`Drugs 1999, 1 (1), 63). It has been shoWn that, in animal
`models, various both peptidic and nonpeptidic compounds
`are effective as factor Xa inhibitors.
`Accordingly, it is an object of the present invention to
`provide novel substances for controlling disorders, Which
`substances have a Wide therapeutic spectrum.
`In particular, they should be suitable for a more ef?cient
`prophylaxis and/or treatment of thromboembolic disorders,
`avoidingiat least to some extentithe disadvantages of the
`prior art described above, Where the term “thromboembolic
`disorders” in the context of the present invention is to be
`understood as meaning, in particular, serious disorders, such
`as myocardial infarct, angina pectoris (including unstable
`angina), reocclusions and restenoses after angioplasty or
`aortocoronary bypass, stroke, transitory ischaemic attacks,
`peripheral arterial occlusive disorders, pulmonary embo
`lisms or deep venous thromboses.
`It is another object of the present invention to provide
`novel anticoagulants Which inhibit the blood coagulation
`factor Xa With increased selectivity, avoidingiat least to
`some extentithe problems of the therapeutic methods for
`thromboembolic disorders knoWn from the prior art.
`
`

`
`US 7,157,456 B2
`
`3
`Accordingly, the present invention provides substituted
`oXaZolidinones of the general formula (I)
`
`o
`
`(I)
`
`5
`
`R2 A \N
`
`0
`R5
`R6
`
`3
`R
`
`4
`R
`
`R8—N\"/R1,
`
`R7
`
`o
`
`in which:
`R1 represents optionally benZo-fused thiophene (thienyl)
`Which may optionally be mono- or polysubstituted;
`R2 represents any organic radical;
`R3, R4, R5, R6, R7 and R8 are identical or different and each
`represents hydrogen or represents (CliC6)-alkyl
`and their pharmaceutically acceptable salts, hydrates and
`prodrugs,
`except for compounds of the general formula (I) in Which the
`radical R1 is an unsubstituted 2-thiophene radical and the
`radical R2 is simultaneously a mono- or polysubstituted
`phenyl radical and the radicals R3, R4, R5, R6, R7 and R8 are
`each simultaneously hydrogen.
`Preference is given here to compounds of the general
`formula (I),
`in which
`R1 represents optionally benZo-fused thiophene (thienyl)
`Which may optionally be mono- or polysubstituted by a
`radical from the group consisting of halogen; cyano; nitro;
`amino; aminomethyl; (C1*C8)-alkyl Which for its part
`may optionally be mono- or polysubstituted by halogen;
`(C3iC7)-cycloalkyl;
`(CliCs)-alkoxy;
`imidaZolinyl;
`4C(=NH)NH2; carbamoyl; and mono- and di-(C1*C4)
`alkyl-aminocarbonyl,
`R2 represents one of the groups beloW:
`A-s
`A-M-,
`D-M-A-,
`B-M-A-,
`13-:
`B-M-,
`B-M-B-,
`D-M-B-,
`Where:
`the radical “A” represents (C6£l4)-aryl, preferably
`(C6*C1O)-aryl, in particular phenyl or naphthyl, very
`particularly preferably phenyl;
`the radical “B” represents a 5- or 6-membered aromatic
`heterocycle Which contains up to 3 heteroatoms and/or
`hetero chain members, in particular up to 2 heteroatoms
`and/or hetero chain members, from the group consist
`ing of S, N, NO (N-oxide) and O;
`the radical “D” represents a saturated or partially
`unsaturated, mono- or bicyclic, optionally benZo-fused
`4- to 9-membered heterocycle Which contains up to
`three heteroatoms and/or hetero chain members from
`the group consisting of S, SO, S02, N, NO (N-oxide)
`and O;
`
`20
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`4
`the radical “M” represents iNHi, iCH2i,
`%H2CH2i, iOi, iNH%H2i, %H2i
`NHi, iOCHzi, iCHzOi, %ONHi,
`iNHCOi, %OOi, iOOCi, iSi, iSOZi
`or represents a covalent bond;
`Where
`the groups “A”, “B” and “D” de?ned above may each
`optionally be mono- or polysubstituted by a radical
`from the group consisting of halogen; tri?uoromethyl;
`oxo; cyano; nitro; carbamoyl; pyridyl; (Cl£6)-al
`kanoyl; (C3iC7)-cycloalkanoyl; (C6£l4)-arylcarbo
`nyl; (CsiClO)-heteroarylcarbonyl; (CliC6)-alkanoy
`loxymethyloxy;
`(C l£4)-hydroxy-alkylcarbonyl;
`%OOR27;
`iSO2R27;
`C(NR27R28)=NR29;
`A 1ONR28R29;
`iSO2NR28R29;
`iOR3O;
`iNR3OOR3l, (CliC6)-alkyl and (C3iC7)-cycloalkyl,
`Where (CliC6)-alkyl and (C3iC7)-cycloalkyl for their
`part may optionally be substituted by a radical from
`the group consisting of cyano; 40R”; iNR28R29;
`iCO(NH)v(NR27R28) and iC(NR27R28)=NR29,
`Where:
`v is either 0 or 1 and
`R27, R28 and R29 are identical or different and indepen
`dently of one another each represents hydrogen,
`(CliC4)-alkyl,
`(C3iC7)-cycloalkyl,
`(Cl£4)-al
`kanoyl, carbamoyl, tri?uoromethyl, phenyl or
`pyridyl, and/or
`R27 and R28 or R27 and R29 together With the nitrogen
`atom to Which they are attached form a saturated or
`partially unsaturated 5- to 7-membered heterocycle
`having up to three, preferably up to tWo, identical or
`different heteroatoms from the group consisting of
`N, O and S, and
`R30 and R31 are identical or different and independently
`of one another each represents hydrogen, (CliC4)
`alkyl, (C3£7)-cycloalkyl, (CliC4)-alkylsulphonyl,
`(CliC4)-hydroxyalkyl, (CliC4)-aminoalkyl, di
`(CliC4)-alkylamino-(CliC4)-alkyl,
`iCHZC
`(NR27R28)=NR29 or 4COR33,
`Where
`R33 represents (CliC6)-alkoxy, (Cl£4)-alkoxy
`(Cl£4)-alkyl, (C1£4)-alkoxycarbonyl-(C1*C4)
`alkyl, (CliC4)-aminoalkyl, (Cl£4)-alkoxycarbo
`nyl, (CliC4)-alkanoyl-(CliC4)-alkyl, (C3*C7)
`cycloalkyl,
`(Cl£6)-alkenyl,
`(Cl*C8)-alkyl,
`Which may optionally be substituted by phenyl or
`acetyl, (C6£l4)-aryl, (C5*ClO)-heteroaryl, trif
`luoromethyl, tetrahydrofuranyl or butyrolactone,
`R3, R4, R5, R6, R7 and R8 are identical or different and
`each represents hydrogen or represents (CliC6)-alkyl
`and their pharmaceutically acceptable salts, hydrates and
`prodrugs,
`except for compounds of the general formula (I) in Which the
`radical R1 is an unsubstituted 2-thiophene radical and the
`radical R2 is simultaneously a mono- or polysubstituted
`phenyl radical and the radicals R3 , R4, R5 , R6, R7 and R8 are
`each simultaneously hydrogen.
`Preference is also given here to compounds of the general
`formula (I),
`
`in which
`R1 represents thiophene (thienyl), in particular 2-thiophene,
`Which may optionally be mono- or polysubstituted by
`halogen, preferably chlorine or bromine, by amino, ami
`nomethyl or (C l*C8)-alkyl, preferably methyl, Where the
`
`

`
`US 7,157,456 B2
`
`5
`(C 1*C8)-alkyl radical for its part may optionally be mono
`or polysubstituted by halogen, preferably ?uorine,
`R2 represents one of the groups beloW:
`A-s
`A-M-,
`D-M-A-,
`B-M-A-,
`13-:
`B-M-,
`B-M-B-,
`D-M-B-,
`Where:
`the radical “A” represents (C6£l4)-aryl, preferably
`(C6*C1O)-aryl, in particular phenyl or naphthyl, very
`particularly preferably phenyl;
`the radical “B” represents a 5- or 6-membered
`aromatic heterocycle Which contains up to 3
`heteroatoms and/or hetero chain members, in
`particular up to 2 heteroatoms and/or hetero
`chain members, from the group consis