INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/US99/01682
`
`CLASSIFICATION OF SUBJECT MATTER
`A.
`lPC(6)
`:A6IK 31/505: C07C 409/14
`US CL :5 14/253‘. 544/293
`According to Intemntional Patent Classification (IPC) or to both national classification and IPC
`11
`FIELDS SEARCHED
`
`Minimum documentation searched (classification system followed by classification symbols)
`
`U.S.
`
`:
`
`514/253', 544/293
`
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`
`Electronic data base consulted during the international search (name of data base and, where practicable. search terms used)
`
`C.
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Citation of document. with indication. when appropriate, of the relevant passages
`
`Relevant to claim No.
`
`.
`
`US5,612,353A(EWINGetal.)18March1997,wholedocument.
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`
`Date of the aetunl completion of the inteluationnl search
`30 MARCH 1999
`Name and niailin eddies: of the lSA/US
`Commissioner of atenta and Ttadematlu
`Bo 1-cr
`wghhmm nu ma
`Facsimile No.
`(703) 305-3230
`Fonn PCT/ISAIIIO (second aheetxluly l992)t
`
`‘
`
`Date of mailing of the international search report
`
`Authorized dflieer
`
`RICHARD L. RAYMOND
`Telephone No.
`(703) 308-1235
`
`MYLAN - EXHIBIT 1006 - Part 12 of 14
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`3547
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`MYLAN - EXHIBIT 1006 - Part 12 of 14
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`Page 1 of 2
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`" Uxrrrzra S'I".*\Tl.ES PATEN'l" ANED 'I‘.rmt>L=M~uu< Omc.:s
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`
`10/181,051
`
`Alexander Straub
`
`Le A 34122
`
`PCT/EPOO/12492
`27941
`JEFFREY M. GREENMAN
`VICE PRESIDENT, PATENTS AND LICENSING
`12/11/2000
`12/24/1999
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`CONFIRMATION NO. 5850
`371 ACCEPTANCE LETTER
`IIiIflI1IIIIIIIIIIIIIIIIIIIII/IIIIIIIIIIIIIIIIIIIIIIIII
`
`
`Date Mailed: 09/19/2002
`
`The United States Application Number assigned to the application is shown above and the relevant dates are:
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`A Filing Receipt (PTO-103X) will be issued for the present a
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`o U.S. Basic National Fee
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`3548
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`emark Office must be mailed
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`WINSTON M ALVARADO
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`PART 3 - OFFICE COPY
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`3549
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`3549
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`PATENT APPLICATION SERIAL NO.
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`3550
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`3550
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`

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`U.S, DEPARTMENTOF COMMERCE PATENIAND TRADBVIARK OFFICE
`FORM PTO-1390
`ATTORNEY 's DOCKET NUMBER
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`U.S. APPLICATION NO. (Ifknown, see 3
`10/18105
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`TRANSMITTAL LETTER TO THE UNITED STATES
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`Le A 34 122
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` This is a FIRST submission of items concerning a filing under 35 U.S.C. 371.
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`2. D This is a SECOND or SUBSEQUENT submission of items concerning a filing under 35 U.S.C. 371.
`3.12] This is an express request to begin national examination procedures (35 U.S.C. 371(f)). The submission must include
`items (5), (6), (9) and (21) indicated below.
`4- ii The US has been elected by the expiration of 19 months from the priority date (Article 31).
`5. E] A copy of the International Application as filed (35 U.S.C. 371(c)(2))
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`USPTO but lntemational Search Report prepared by the EPO or JPO ,
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`PCTIEP00/12492
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`ammaafigaameawma
`528Rec’dl.’PTO 24 JUNZDDZ
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`but all claims did not satisfy provisions of PCT Article 33(1)-(4)
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`3552
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`( 10/131051
`528Fle.PCT/PTO 24 JUNZODZ
`
`Attorney's Docket No. Le A 34 122
`
`PA TENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of: Alexander Straub, et al.
`
`Serial No.2
`
`[to be assigend]
`National Phase Filing of PCT/EPOO/12492
`
`Filed: herewith
`
`For: Substituted Oxazolidinones and Their Use in the Field of Blood Coagulation
`
`BOX PCT
`
`Assistant Commissioner for Patents
`Washington, D.C. 20231
`
`CERTIFICATE OF MAILING UNDER 37 CFR 1.10
`
`I hereby certify that the attached correspondence comprising:
`
`Transmittal Letter to the United States Designated/Elected Office
`(DO/E0/US) Concerning a Filing under 35 U.S.C. 371 [IN DUPLICATE];
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`Original Combined Declaration and Power of'Attorney (35 U.S.C.
`371(c)(4));
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`English Translation of the International Application as filed (35 U.S.C.
`371(c)(2));
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`Copy of the International Application as filed (35 U.S.C. 371(c)(2));
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`Information Disclosure Statement under 37 C.F.R. 1.97 and 1.98
`consisting of Transmittal of Information Disclosure Statement under 37
`C.F.R. 1.97(b), Information Disclosure Citation (Modified Form PTO-
`1449) and copies of references cited therein;
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`Return Receipt Post Card.
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`is, on the date shown below, being deposited with the United States Postal
`Service, in an envelope as “Express Mail Post Office to Addressee” Mailing
`Label Number EUO54495463US, addressed to:
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`Box PCT
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`Assistant Commissioner for Patents
`Washington, D. C. 20231
`
`June 24, 2002
`Date
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` S’ n ture of Pe on Certifying
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`3553
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` &myM .10/181051
`-1-
`528Rec’dPCT/PTO 24 JUN2002
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`.31.. ilfil .31.. $3.1 SD! 55333 3!. m 21:31 11%:
`
`i1—!l~i".}l
`
`Substituted oxazolidinones and their use
`
`The present invention relates to the field of blood coagulation. In particular, the
`
`present invention relates to novel oxazolidinone derivatives, to processes for their
`
`5
`
`preparation and to their use as active compounds in medicarnents.
`
`Blood coagulation is a protective mechanism of the organism which helps to “seal”
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`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 bloodivessels is
`
`10
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`effected mainly by the coagulation system in which an enzymatic cascade of complex
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`reactions of plasma proteins is triggered. Numerous blood coagulation factors are
`
`involved in this process, each of which factors converts, on activation,
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`the
`
`respectively next inactive precursor into its active form. At the end of the cascade
`
`15
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`comes the conversion of soluble fibrinogen into insoluble fibrin, resulting in the
`formation of a blood clot. In blood coagulation, traditionally the intrinsic and 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
`
`fibrinogen to fibrin, a
`
`20
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`fibrouslgelatinous coagulant. In addition, thrombin is a potent effector of platelet
`
`aggregation which likewise contributes significantly to haemostasis.
`
`Maintenance of normal haernostasis - between bleeding and thrombosis - is subject to .
`a complex regulatory mechanism. Uncontrolled activation of the coagulant system or
`defective inhibition of the activation processes may cause formation of local thrombi
`
`25
`
`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,
`
`30
`
`pulmonary embolisms or deep venous thromboses; hereinbelow, these disorders are
`
`collectively also referred to as thromboembolic disorders. In addition, in the case of
`
`consumption coagulopathy, hypercoagulability may — systemically —
`
`result
`
`in
`
`disseminated intravascular coagulation.
`
`35
`
`These thromboembolic disorders are the most frequent cause of morbidity and
`
`mortality in most
`
`industrialized countries (Pschyrembel, Klinisches Worterbuch
`
`3554
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`
`Le A 34 122-1-‘oivni Countries
`
`Ell ;‘§L E1} :31. iii?! 15 ..‘:.lL
`
`0
`
`.1. El iliifu 3?-.3 *’~ll~ifI§l
`
`-2-
`
`[clinical dictionary], 257"’ edition, 1994, Walter de Gruyter Verlag, page 199 ff.,
`entry “Blutgerinnung” [blood coagulation]; Rompp Lexikon Chemie, Version 1.5,
`1998, Georg Thieme Verlag Stuttgart, entry “Blutgerinnung”; Luben Stryer,
`Biochemie [biochemistry], Spektrum der Wissenschaft Verlagsgesellschaft mbH
`Heidelberg, 1990, page 259 ff.).
`
`The anticoagulants, i.e. substances for inhibiting or preventing blood coagulation,
`which are known from the prior art have various, often grave disadvantages.
`Accordingly,
`in practice,
`an efficient
`treatment method or prophylaxis of
`thromboembolic disorders is very difficult and unsatisfactory.
`
`In the therapy and prophylaxis of thromboembolic disorders, use is firstly 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. 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 Worterbuch, 257"‘ edition, 1994, Walter de
`Gruyter Verlag, page 610, entry “Heparin”; Rompp Lexikon Chemie, Version 1.5,
`1998, Georg Thieme Verlag Stuttgart, entry “Hepa1in”).
`
`_
`
`as watfarin,
`such
`especially compounds
`and
`1,3-indanediones,
`phenprocoumon, dicumarol and other coumarin derivatives which inhibit ‘T 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, 257"‘ edition, 1994, Walter de Gruyter Verlag,
`
`10
`
`‘15
`
`20
`
`25
`
`30
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`35
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`3555
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`3555
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`Le A 34 122-For-hm Countries
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`:31. ID! .31. El
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`ID! ‘.55: ..“.ll.
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`1131 35:: E9 i’-«ll~il’3l $5.’
`
`page 292 ff., entry “coumarin derivatives”; Ullmann’s Encyclopedia of Industrial
`Chemistry, 5”‘ edition, VCH Verlagsgesellschaft, Weinheim, 1985 -1996, 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. W0-A-99/37304; W0-A—99/06371;
`
`J. Hauptmann,
`
`J. Stiiuzebecher, 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, I (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 efficient prophylaxis and/or
`
`treatment of thromboembolic disorders, avoiding - at
`
`least
`
`to some extent - the
`
`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 embolisms or deep venous thromboses.
`
`10
`
`15
`
`20
`
`It is another object of the present invention to provide novel anticoagulants which”
`
`30
`
`inhibit the blood coagulation factor Xa with increased selectivity, avoiding - at least
`
`to some extent -
`
`the problems of the therapeutic methods for thromboembolic
`
`disorders known from the prior art.
`
`3556
`
`3556
`
`

`
`Le A 34 122440? Countries
`
`Ill. 53! Ill, Ell .Ifl, ll§'.3l fi ;'lL .1; El £155: E‘? *3-ll“ ll'.3l
`
`.
`
`Accordingly, the present invention provides substituted oxazolidinones of the general
`formula (I)
`
`UL
`
`in which:
`
`R‘
`
`represents optionally benzo-fused thiophene (thienyl) which may optionally
`be mono- or polysubstituted;
`
`10
`
`R2
`
`represents any organic radical;
`
`R3, R4, R5, R6, R7 and R8 are identical or different and each represents hydrogen or
`represents (C 1 —C5)-alkyl
`
`15
`
`20
`
`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, R‘, R7 and R8
`are each
`simultaneously hydrogen.
`
`Preference is given here to compounds of the general formula (I),
`
`in which
`
`R‘
`
`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-C3)-alkyl which for its part
`may optionally be mono- or polysubstituted by halogen; (C3-C7)-cycloalkyl;
`
`3557
`
`3557
`
`

`
`Le A 34 122-Firm’, Countries
`
`Lil. I131 :31. El ill. lliil ‘E5 .13..
`
`0
`
`cu ilfll
`
`E53.‘ 3’-=i!~ $31 2335?!
`
`(C;~Cg)-alkoxy; irnidazolinyl; -C(=NH)NHz; carbamoyl; and mono- and di—'
`(C;-C4)—alkyl-aminocarbonyl,
`
`represents one of the groups below:
`A-.
`
`A—M-,
`
`D-M-A-,
`
`B-M-A-,
`
`B-,
`
`B-M-,
`
`.
`
`B-M-B—,
`
`D-M-B-,
`
`where:
`
`the radical “A” represents (C5—C;4)-aryl, preferably (C5-Cm)—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 consisting 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;
`the radical “M” represents —NH-, -CH2-, ~CH2CH2-, -0-, -NH-CH2-,
`-CH2-NH-, -OCH;-, -CH2O-, -CONH-, -NHCO-, -COO-, ~OOC-, -S—.
`-SO2— or represents a covalent bond;
`
`where
`
`the groups “A”, “B" and “D” defined above may each optionally be
`mono- or polysubstituted by a radical from the group consisting of
`halogen; trifluoromethyl; oxo; cyano; nitro; carbamoyl; pyridyl; (C1-
`C5)-alkanoyl; (C3-C7)-cycloalkanoyl; (C5-C.4)-arylcarbonyl; (Cs—Cio)-
`heteroarylcarbonyl; (C 1-C5)-alkanoyloxymethyloxy; (C 1 -C4)-hydroxy—
`alkylcarbonyl; -COOR27; -SO2R27; -C(NR27R28)=NR29; -CONRZBR”;
`-SO2NR28R29; -OR3°; -NR3°R3’, (C;-C6)-alkyl and (C3-C7)-cycloalkyl,
`
`3558
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`3558
`
`

`
`Le A 34 l22—FoW' Countries
`
`U
`
`,:iL IE3! :3!“
`
`:31. 11:31 323
`
`.5 EB!
`
`E3 ‘1-HZ?! E3?
`
`10
`
`15
`
`25
`
`30
`
`35
`
`where (C,-C6)-alkyl and (C3-C7)-cycloalkyl for their part may
`optionally be substituted by a radical from the group consisting
`of
`cyano;
`-OR27;
`-NRZSRZ9;
`-CO(N'H)v(NR27R28)
`and
`_C(NR27R2s)__:NR29
`
`where:
`
`v
`
`is either 0 or 1 and
`
`R27, R28 and R29 are identical or different and independently of one
`another each represents hydrogen,
`(C.—C4)-alkyl,
`(C3-C7)-
`cycloalkyl,
`(C1-C4)-alkanoyl,
`carbamoyl,
`trifluoromethyl,
`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
`
`R” and R3‘ are identical or different and independently of one another
`each represents hydrogen,
`(C;-C4)—all<yl,
`(C3-C7)-cycloalkyl,
`(C 1-C4)-alkylsulphonyl,
`(C1-C4)-hydroxyalkyl,
`(C1-C4)-
`aminoalkyl,
`di-(C.-C4)-alkylamino—(C1-C4)-alkyl,
`-CHgC(NR27R28)=NR29 or -COR33,
`
`where
`
`, ‘K;;._.,
`
`R33
`
`(C;—C4)~alkoxy-(C.-C4)-
`(C.-C5)—alkoxy,
`represents
`alkyl,
`(C , -C4)—alkoxycarbonyl—(C 1 -C4)-alkyl,
`(C 1 —C4)-
`
`aminoalkyl, (C 1—C4)—alkoxycarbonyl, (C.-C4)-alkanoyl—
`(C;~C4)-alkyl,
`(C3-C7)-cycloalkyl,
`(C;-C5)-alkenyl,
`(C1-C3)-alkyl, which may optionally be substituted by
`
`3559
`
`3559
`
`

`
`Le A 34 I22-Fi'gr_1 Countries
`
`.
`
`L31. 5.231 :33,
`
`1131 E3 :§L .—., $31 152323? ii-334133! El!
`
`(C5-Cm)-heteroaryl,
`(C5-C14)-aryl,
`phenyl or acetyl,
`trifluoromethyl, tetrahydrofuranyl or butyrolactone,
`
`R3, R4, R5, R‘, R7 and R3 are identical or different and each represents
`hydrogen or represents (C1-C6)-alkyl
`
`and their pharmaceutically acceptable salts, hydrates and prodrugs,
`
`except for compounds of the general fonnula(I) in which the radical R‘ is an
`unsubstituted 2-thiophene radical and the radical R2 is simultaneously a mono- or
`polysubstituted phenyl radical-and the radicals R3, R‘: R5, R‘, R7 and R3 are each
`simultaneously hydrogen.
`'
`
`Preference is also given here to compounds of the general formula (I),
`
`in which
`
`R‘
`
`in particular 2-thiophene, which may
`(thienyl),
`thiophene
`represents
`optionally be mono- or polysubstituted by halogen, preferably chlorine or
`bromine, by amino, aminomethyl or (C1-C3)-alkyl, preferably methyl, where
`the (C1-C3)-alkyl
`radical
`for
`its part may optionally be mono~ or
`polysubstituted by halogen, preferably fluorine,
`
`10
`
`15
`
`20
`
`25
`
`R‘
`
`represents one of the groups below:
`A-.
`
`A-M-,
`
`D-M-A-,
`
`B~M—A—.
`
`B-,
`
`B-M-,
`
`B-M-B-.
`
`D—M—B—.
`
`where:
`
`30
`
`35
`
`3560
`
`3560
`
`

`
`Le A 34 122-F0‘ Countries
`
`immmmmgmtmflflwwa
`
`the radical “A” represents (C5—C14)-aryl, preferably (C5-Cm)-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 consisting of S, N, NO (N-oxide) and O;
`
`the radical “D” represents a saturated or partially unsaturated 4- to 7-
`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;
`
`the radical “M” represents -NH-, -CH2-, -CH2CHz-, -O-, -NH—CHz-, -
`CH2-NH-, -OCH2-, -CH2O-, -CONH-, -NHCO-, -COO-, -OOC-, -S-
`or represents a covalent bond;
`o
`
`where
`
`the groups “A”, “B” and “D” defined above may in each case
`optionally be mono— or polysubstituted by a radical from the group
`consisting of halogen; trifluoromethyl; oxo; cyano; nitro; carbamoyl;
`pyridyl;
`(C.-C5)~alkanoyl;
`(C3—C-,)-cycloalkanoyl;
`(C6‘Cl4)'
`arylcarbonyl;
`(C5-C;o)—heteroarylcarbonyl;
`(C1-C5)-
`alkanoyloxymethyloxy;
`-cook”; —so2R27;
`-c(NR”R23)=NR’°;
`-CONRZSR”; -SO2NR28R2°; -OR3°; -NR3°R3', (C;-C5)-alkyl and (C3-
`C7)-cycloalkyl,
`
`where (C1-C5)-alkyl and (C3—C-;)—cycloalkyl for their part may
`optionally be substituted by a radical from the group consisting
`of
`cyano;
`-011“;
`-NR28R29;
`-CO(NH).,(NR27R28)
`and
`_C(NR27R2s =NR29,
`
`where:
`
`v
`
`is either 0 or 1 and
`
`R27, R23 and R29 are identical or different and independently of one
`another each represents hydrogen, (C.-C4)-alkyl or (C3-C7)-
`cycloalkyl,
`
`3561
`
`10
`
`15
`
`20
`
`30
`
`35
`
`3561
`
`

`
`Le A 34 122-iion,= Countries
`
`SE}! 31,
`
`11:3!
`
`O
`
`135
`
`1113} 115::
`
`§L%§"1l:‘d E’?
`
`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 hcterocycle having up to three, preferably up to
`two,
`identical or different heteroatoms
`from the group
`consisting of N, 0 and S, and
`’
`
`R30 and R3 ' are identical or different and independently of one another
`each represents hydrogen, (C;-C4)-alkyl, (C3-C7)-cycloalkyl,
`(C;-C4)-alkylsulphonyl,
`(C1-C4)-hydroxyalkyl,
`(C;-C4)-
`aminoalkyl,
`di-(C;-C4)-all(ylamino—(C;-C4)-alkyl,
`(C1-C4)-
`alkanoyl,
`(C5—C14)-arylcarbonyl,
`(C5-Cm)-heteroarylcarbonyl,
`(C1-C4)-alkylarninocarbonyl or -CH2C(NR27R28)=N'R29,
`
`R3, R4, R5, R6, R7 and R8 are identical or different and each represents
`hydrogen or represents (C;—C5)—alkyl
`
`and their pharmaceutically acceptable salts, hydrates and prodrugs,
`
`-
`
`is an
`except for compounds of the general formula (I) in which the radical R’
`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.
`
`Particular preference is given here to compounds of the general formula (I),
`
`in which
`
`10
`
`15
`
`20
`
`25
`
`30
`
`R1
`
`35
`
`in particular 2-thiophene, which may
`(thienyl),
`thiophene
`represents
`optionally be mono- or polysubstituted by halogen, preferably chlorine or
`bromine, or by (C1-C3)-alkyl, preferably methyl, where the (C;-Cg)-alkyl
`radical for its part may optionally be mono- or polysubstituted by halogen,
`preferably fluorine,
`
`represents one of the groups below:
`
`3562
`
`3562
`
`

`
`Le A 34 122-Foij Countries
`
`.10.
`
`11L 31:3! 331..
`
`.31.. IE‘.
`
`531..
`
`31:31 15-33: “E33
`
`E2’!
`
`A":
`
`A-M-,
`
`D-M—A—,
`
`B-M-A—,
`
`B-,
`
`B-M-,
`
`B-M-B-,
`
`D-M-B-,
`
`where:
`
`the radical “A” represents phenyl or naphthyl, in particular phenyl;
`the radical “B” represents a 5- or 6-membered aromatic heterocycle
`which contains up to 2 heteroatoms from the group consisting of S, N,
`NO (N-oxide) and O;
`
`the radical “D” represents a saturated or partially unsaturated 5- or 6-
`
`membered heterocycle which contains up to two heteroatoms and/or
`
`hetero chain members from the group consisting of S, SO, S02, N, NO
`
`(N-oxide) and O;
`
`the radical “M” represents —NH—, -0-, -NH-CH2-, -CH2-NH-, -OCH;-,
`
`—CH2O-, -CONH-, -NHCO- or represents a covalent bond;
`
`where
`
`the groups
`“B” and “D" defined above may in each case
`optionally be mono- or polysubstituted by a radical from the group
`consisting of halogen; trifluoromethyl; oxo; cyano; pyridyl; (C1-C3)-
`alkanoyl; (C6-Cm)-arylcarbonyl; (C5-C5)-heteroarylcarbonyl; (C1-C3)-
`alkanoyloxymethyloxy;
`-C(NR27R28)=NR29;
`-CONRZSRZ9;
`-SO2NR28R2°;
`-OH;
`-NR3°R3';
`cyclopentyl or cyclohexyl,
`
`(C1-C4)-alkyl;
`
`and cyclopropylhuit
`
`where
`
`(C1-C4)-alkyl
`
`and
`
`cyclopropyl,
`
`cyclopentyl
`
`or
`
`cyclohexyl for their part may optionally be substituted by a
`
`-OCH3;
`radical from the group consisting of cyano; -OH;
`_NR2sR29; _CO(NH)v(NR27R2s) and _C(NR27R2s)___NR29’
`
`where:
`
`3563
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`3563
`
`

`
`Le A 34 122-Fion Countries
`
`.'§1.i£;'.ll.?ll,§iT’:fi;iL¥;ll5;‘lL El
`
`.
`
`ilI§ll£::§E‘;iE3-¥l~.*lI’3!I=?7':.‘3
`
`-11..
`
`v
`
`is either 0 or 1, preferably 0, and
`
`R27, R28 and R29 are identical or different and independently of
`one another each represents hydrogen, (C;-C4)-alkyl or
`else cyclopropyl, cyclopentyl or cyclohexyl
`
`and/or
`
`R27 and R28 or R27 and R29 together with the nitrogen atom to which
`
`R30 and R3‘ are identical or different and independently of one another
`each
`represents
`hydrogen,
`(C1—C4)—alkyl,
`cyclopropyl,
`cyclopentyl,
`cyclohexyl,
`(C;-C4)-alkylsulphonyl,
`(C1-C4)-
`(C 1 -C4)-aminoalkyl,
`di-(C; -C4)—alkylamino-
`(C;-C4)—alkyl, (C;~C3)-alkanoyl or phenylcarbonyl,
`
`hydroxyalkyl,
`
`R3, R4, R5, R6, R7 and R8 are identical or different and each represents hydrogen or
`represents (C 1-C5)-alkyl
`
`and their pharmaceutically acceptable salts, hydrates and prodrugs,
`
`except for compounds of the general formula (I) in which the radical R’
`is an
`unsubstituted 2-thiophene radical and the radical R2 is simultaneously a mono- or
`polysubstituted phenyl radical and the radicals R3, R4, R5, R‘, R7 and R8 are each._,
`simultaneously hydrogen.
`I
`R
`A
`i
`
`Particular preference is given here to compounds of the general formula (I),
`
`in which
`
`10
`
`15
`
`20
`
`25
`
`30
`
`3564
`
`3564
`
`

`
`Le A 34 122-Foiron Countries
`
`Ill. IE3} ISL £2 .31. iii}!
`
`.
`
`5. £131
`
`5?: iii" 31:35
`
`-12-
`
`R‘
`
`represents 2-thiophene which may optionally be substituted in the 5-position
`by a radical from the group consisting of chlorine, bromine, methyl or
`trifluoromethyl,
`
`S
`
`R2
`
`represents one of the groups below:
`A-,
`
`10
`
`A—M-,
`
`D-M-A-,
`
`B-M-A-,
`
`B-,
`
`.B-M-.
`
`B-M-B-,
`
`D-M-B-,
`
`15
`
`where:
`
`the radical “A" represents phenyl or naphthyl, in particular phenyl;
`the radical “B” represents a 5- or 6-membered aromatic heterocyclc
`which contains up to 2 heteroatoms from the group consisting of S, N,
`NO (N—oxide) and o;
`‘
`the radical “D” represents a saturated or partially unsaturated 5- or 6-
`membered heterocycle which contains a nitrogen atom and optionally
`a further heteroatom and/or hetero chain member from the group
`consisting of S, SO, S02 and O; or contains up to two heteroatoms
`and/or hetero chain members from the group consisting of S, SO, SO;
`and O;
`
`-NH-CH3-, ~CH2-NH-,
`represents —NH-, -0-,
`the radical
`—OCH2-, -CH2O-, -CONH-, -NHCO— or represents a covalent bond;
`
`where
`
`the groups “A”, “B” and “D” defined above may in each case
`optionally be mono- or polysubstituted by a radical from the group
`consisting of halogen; trifluoromethyl; oxo; cyano; pyridyl; (C.-C3)-
`alkanoyl; (C6-Clo)-arylcarbonyl; (C5-C6)-heteroarylcarbonyl; (C1-C3)-
`alkanoyloxymethyloxy; -CONR28R29; -SOZNRZSR29; -OH;