US007585860B2
`
`(12) United States Patent
`Straub et a].
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 7,585,860 B2
`*Sep. 8, 2009
`
`(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) Assignee: Bayer Schering Pharma
`Aktiengesellschaft, Berlin (DE)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis
`claimer.
`
`(21) Appl.No.: 12/027,553
`
`(22) Filed:
`
`Feb. 7, 2008
`
`(65)
`
`Prior Publication Data
`
`US 2008/0200674 A1
`
`Aug. 21, 2008
`
`Related US. Application Data
`
`(60) Division of application No. 11/460,529, ?led on Jul.
`27, 2006, Which is a continuation of application No.
`10/181,051, ?led as application No. PCT/EP00/ 12492
`on Dec. 11, 2000, noW Pat. No. 7,157,456.
`
`(30)
`
`Foreign Application Priority Data
`
`Dec. 24, 1999
`
`(DE) .............................. .. 199 62 924
`
`(51) Int. Cl.
`(2006.01)
`A61K 31/53 77
`(2006.01)
`C07D 409/14
`(52) US. Cl. .................................. .. 514/236.8; 544/139
`(58) Field of Classi?cation Search ............ .. 514/236.8;
`544/139
`See application ?le for complete search history.
`
`8/1997 Barbachyn et a1.
`5,654,435 A
`5,688,792 A 11/1997 Barbachyn et a1.
`5,756,732 A
`5/1998 Barbachyn et a1.
`5,792,765 A
`8/1998 Riedl et a1.
`5,801,246 A
`9/1998 Barbachyn et a1.
`5,827,857 A 10/1998 Riedl et a1.
`5,910,504 A
`6/1999 Hutchinson et al.
`5,922,708 A
`7/1999 Riedl et a1.
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`10/2004 Kanikanti et a1.
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`7,034,017 B2
`4/2006 Straub et a1.
`7,045,631 B2
`5/2006 Rosentreter et al.
`7,078,417 B2
`7/2006 Rosentreter et al.
`7,109,218 B2
`9/2006 Rosentreter et al.
`7,129,255 B2 10/2006 Rosentreter et al.
`7,157,456 B2
`1/2007 Straub et a1.
`7,351,823 B2
`4/2008 Berwe et a1.
`2001/0029351 A1
`10/2001 Falotico et al.
`2003/0153610 A1
`8/ 2003 Straub et al.
`2003/0161882 A1
`8/2003 Waterman
`(Continued)
`FOREIGN PATENT DOCUMENTS
`744002
`7/1999
`(Continued)
`OTHER PUBLICATIONS
`Riedl, B., Endermann, “Recent Developments with OXaZolidinone
`Antibiotics,” R., Exp. Opin. Ther. Patents 1999, 9 (5), 625-633.
`(Continued)
`Primary ExamineriRebecca L Anderson
`(74) Attorney, Agent, or F irm4Connolly Bove Lodge & HutZ
`LLP
`
`AU
`
`ABSTRACT
`(57)
`The invention relates to the ?eld of blood coagulation. Novel
`oxaZolidinone derivatives of the general formula (I)
`
`(56)
`
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`MYLAN - EXHIBIT 1001
`
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`

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`US 7,585,860 B2
`Page 5
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`
`

`
`US 7,585,860 B2
`
`1
`SUBSTITUTED OXAZOLIDINONES AND
`THEIR USE IN THE FIELD OF BLOOD
`COAGULATION
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a divisional application of US. appli
`cation Ser. No. 11/460,529 ?led Jul. 27, 2006, Which is hereby
`incorporated herein by reference in its entirety, Which is a
`continuation of US. application Ser. No. 10/181,051 ?led,
`Jun. 24, 2002, Which issued on Jan. 2, 2007 as US. Pat. No.
`7,157,456, Which is hereby incorporated herein by reference
`in its entirety, Which is the national stage entry under 3 5 US .C
`§ 371 of international application No. PCT/EP00/12492, ?led
`Dec. 11, 2000, Which claims priority to German application
`No. 199 62 924.2, ?led Dec. 24, 1999.
`
`FIELD OF THE INVENTION
`
`The present invention relates to the ?eld of blood coagula
`tion. In particular, the present invention relates to novel
`oxaZolidinone derivatives, to processes for their preparation
`and to their use as active compounds in medicaments.
`
`BACKGROUND OF THE INVENTION
`
`Blood coagulation is a protective mechanism of the organ
`ism 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. Haemo stasis after injury of the
`blood vessels is effected mainly by the coagulation system in
`Which an enzymatic cascade of complex reactions of plasma
`proteins is triggered. Numerous blood coagulation factors are
`involved in this process, each of Which factors converts, on
`activation, the respectively next inactive precursor into its
`active form. At the end of the cascade comes the conversion of
`soluble ?brinogen into insoluble ?brin, resulting in the for
`mation of a blood clot. In blood coagulation, traditionally the
`intrinsic and the extrinsic system, Which end in a joint reac
`tion path, are distinguished. Here factor Xa, Which is formed
`from the proenZyme factor X, plays a key role, since it con
`nects 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, thrombin is a potent effector of platelet
`aggregation Which likeWise contributes signi?cantly to hae
`mostasis.
`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; hereinbe
`loW, these disorders are collectively also referred to as throm
`boembolic disorders. In addition, in the case of consumption
`coagulopathy, hypercoagulability mayisystemicallyire
`sult in disseminated intravascular coagulation.
`These thromboembolic disorders are the most frequent
`cause of morbidity and mortality in mo st industrialiZed coun
`tries (Pschyrembel, Klinisches Worterbuch [clinical dictio
`nary], 257th edition, 1994, Walter de GruyterVerlag, page 199
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`ff., entry “Blutgerinnung” [blood coagulation]; Rompp Lex
`ikon Chemie, Version 1.5, 1998, Georg Thieme Verlag Stut
`tgart, entry “Blutgerinnung”; Lubert Stryer, Biochemie [bio
`chemistry], Spektrum der Wissenschaft Verlagsgesellschaft
`mbH Heidelberg, 1990, page 259 ff.).
`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 dif?cult and unsatisfactory.
`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
`avoid the knoWn disadvantages described beloW, Which are
`involved in heparin therapy. Thus, heparin is ineffective When
`administered orally and has a relatively short half-life. Since
`heparin inhibits a plurality of factors of the blood coagulation
`cascade at the same time, the action is nonselective. More
`over, there is a high risk of bleeding; in particular, brain
`hemorrhages and gastrointestinal bleeding may occur, Which
`may result in thrombopenia, drug-induced alopecia or
`osteoporosis (Pschyrembel, Klinisches Worterbuch, 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 antago
`nists. These include, for example, 1,3-indanediones, and
`especially compounds such as Warfarin, phenprocoumon,
`dicumarol and other coumarin derivatives Which inhibit the
`synthesis of various products of certain vitamin K-dependent
`coagulation factors in the liver in a non-selective manner.
`OWing to the mechanism of action, hoWever, the onset of the
`action is very sloW (latency to the onset of action 36 to 48
`hours). It is possible to administer the compounds orally;
`hoWever, oWing to the high risk of bleeding and the narroW
`therapeutic index, a time-consuming individual adjustment
`and monitoring of the patient are required. Moreover, other
`adverse effects, such as gastrointestinal disturbances, hair
`loss and skin necroses, have been described (Pschyrembel,
`Klinisches Worterbuch, 257th edition, 1994, Walter de
`Gruyter Verlag, page 292 ff., entry “coumarin derivatives”;
`Ullmann’s Encyclopedia of Industrial Chemistry, 5”’ edition,
`VCH Verlagsgesellschaft, Weinheim, 1985-1996, entry “vita
`min 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 199