JP5662311B2 - Metキナーゼ阻害剤としての3−(3−ピリミジン−2−イルベンジル)−1,2,4−トリアゾロ[4,3−b]ピリダジン誘導体 - Google Patents
Metキナーゼ阻害剤としての3−(3−ピリミジン−2−イルベンジル)−1,2,4−トリアゾロ[4,3−b]ピリダジン誘導体 Download PDFInfo
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- JP5662311B2 JP5662311B2 JP2011513897A JP2011513897A JP5662311B2 JP 5662311 B2 JP5662311 B2 JP 5662311B2 JP 2011513897 A JP2011513897 A JP 2011513897A JP 2011513897 A JP2011513897 A JP 2011513897A JP 5662311 B2 JP5662311 B2 JP 5662311B2
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- CTEDVGRUGMPBHE-UHFFFAOYSA-N tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CO)CC1 CTEDVGRUGMPBHE-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
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- Urology & Nephrology (AREA)
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- Heart & Thoracic Surgery (AREA)
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Description
本発明は、有用な特性を有する新規な化合物、特に医薬を調製するために用いることができるものを見出す目的を有していた。
特に、本発明は、Metキナーゼによるシグナル伝達の阻害、調節および/または調整が役割を果たす化合物および化合物の使用に関する。
癌療法のための他のMetキナーゼ阻害剤は、J.G. Christensen et al.により、Cancer Res. 2003, 63(21), 7345-55に記載されている。
他のトリアゾロピリダジン誘導体は、WO 2007/064797、WO 2007/075567、WO 2007/138472、WO 2008/008539、WO 2008/051805にMetキナーゼ阻害剤として記載されている。
本発明は、式I
R1は、Ar、HetまたはAを示し、
R2は、H、A、Hal、OR5、N(R5)2、N=CR5N(R5)2、SR5、NO2、CN、COOR5、CON(R5)2、NR5COA、NR5SO2A、SO2N(R5)2、S(O)mA、Het、−[C(R5)2]nN(R5)2、−[C(R5)2]nHet、O[C(R5)2]nN(R5)2、O[C(R5)2]nHet、S[C(R5)2]nN(R5)2、S[C(R5)2]nHet、−NR5[C(R5)2]nN(R5)2、−NR5[C(R5)2]nHet、NHCON(R5)2、NHCONH[C(R5)2]nN(R5)2、NHCONH[C(R5)2]nHet、NHCO[C(R5)2]nN(R5)2、NHCO[C(R5)2]nHet、CON(R5)2、CONR5[C(R5)2]nN(R5)2、CONR5[C(R5)2]nHet、COHetまたはCOAを示し、
R3、R3’は、各々、互いに独立してH、FまたはAを示し、
また一緒になって2〜5個のC原子を有するアルキレンを示し、
R4は、H、AまたはHalを示し、
R5は、HまたはAを示し、
かつ/またはここで、1つまたは2つのCH2基が、O、NH、S、SO、SO2および/またはCH=CH基によって置き換えられていてもよく、
あるいは
3〜7個のC原子を有する環状アルキルを示し、
Arは、フェニル、ナフチルまたはビフェニルを示し、その各々は、非置換であるかまたはHal、A、OR5、N(R5)2、SR5、NO2、CN、COOR5、CON(R5)2、NR5COA、NR5SO2A、SO2N(R5)2および/またはS(O)mAによって単置換、二置換もしくは三置換されており、
Het1は、1〜2個のNおよび/またはO原子を有する単環式の飽和複素環を示し、ここで該環はA、OA、OH、Halおよび/または=O(カルボニル酸素)によって単置換または二置換されていてもよく、
Halは、F、Cl、BrまたはIを示し、
mは、0、1または2を示し、
nは、1、2、3または4を示す、
で表される化合物、ならびに、それらの薬学的に使用可能な塩、互変異性体および立体異性体、すべての比率でのそれらの混合物に関する。
薬学的に使用可能な誘導体は、例えば、本発明の化合物の塩、およびまたいわゆるプロドラッグ(prodrug)化合物を意味するものと解釈される。
これらはまた、例えばInt. J. Pharm. 115, 61-67 (1995)に記載されているように、本発明の化合物の生分解性ポリマー誘導体を含む。
さらに、「治療的に有効な量」の表現は、この量を施与されていない対応する対象と比較して、以下の結果:
疾患、症候群、状態、愁訴、障害もしくは副作用の改善された処置、治癒、防止もしくは解消、またはまた疾患、愁訴もしくは障害の進行の低減
を有する量を示す。
「治療的に有効な量」の用語はまた、正常な生理学的機能を増大させるのに有効である量を包含する。
これらは、特に好ましくは、立体異性体化合物の混合物である。
a)式II
Lは、ホウ素酸またはホウ素酸エステルラジカルを示す、
で表される化合物を、
式III
で表される化合物と反応させ、
あるいは、
式Iで表される塩基または酸を、その塩の1種に変換する
ことを特徴とする、前記方法に関する。
環状アルキル(シクロアルキル)は、好ましくはシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルまたはシクロヘプチルを示す。
ここで、これらの基はまた、Hal、[C(R5)2]nOR5および/またはAによって単置換、二置換もしくは三置換されていてもよく、
または
Halおよび/またはCNによって単置換、二置換もしくは三置換されているフェニル
または
Aを示す。
R4は、好ましくはHを示す。
さらなる置換基とは関係なく、Hetは、したがって、また、例えば、2,3−ジヒドロ−2−、−3−、−4−もしくは−5−フリル、2,5−ジヒドロ−2−、−3−、−4−もしくは−5−フリル、テトラヒドロ−2−もしくは−3−フリル、1,3−ジオキソラン−4−イル、テトラヒドロ−2−もしくは−3−チエニル、2,3−ジヒドロ−1−、−2−、−3−、−4−もしくは−5−ピロリル、2,5−ジヒドロ−1−、−2−、−3−、−4−もしくは−5−ピロリル、1−、2−もしくは3−ピロリジニル、テトラヒドロ−1−、−2−もしくは−4−イミダゾリル、2,3−ジヒドロ−1−、−2−、−3−、−4−もしくは−5−ピラゾリル、テトラヒドロ−1−、−3−もしくは−4−ピラゾリル、1,4−ジヒドロ−1−、−2−、−3−もしくは−4−ピリジル、1,2,3,4−テトラヒドロ−1−、−2−、−3−、−4−、−5−もしくは−6−ピリジル、1−、2−、3−もしくは4−ピペリジニル、2−、3−もしくは4−モルホリニル、テトラヒドロ−2−、−3−もしくは−4−ピラニル、1,4−ジオキサニル、1,3−ジオキサン−2−、−4−もしくは−5−イル、ヘキサヒドロ−1−、−3−もしくは−4−ピリダジニル、ヘキサヒドロ−1−、−2−、−4−もしくは−5−ピリミジニル、1−、2−もしくは3−ピペラジニル、1,2,3,4−テトラヒドロ−1−、−2−、−3−、−4−、−5−、−6−、−7−もしくは−8−キノリル、1,2,3,4−テトラヒドロ−1−、−2−、−3−、−4−、−5−、−6−、−7−もしくは−8−イソキノリル、2−、3−、5−、6−、7−もしくは8−3,4−ジヒドロ−2H−ベンゾ−1,4−オキサジニル、さらに好ましくは、2,3−メチレンジオキシフェニル、3,4−メチレンジオキシフェニル、2,3−エチレンジオキシフェニル、3,4−エチレンジオキシフェニル、3,4−(ジフルオロメチレンジオキシ)フェニル、2,3−ジヒドロベンゾフラン−5−もしくは−6−イル、2,3−(2−オキソメチレンジオキシ)フェニルまたはまた3,4−ジヒドロ−2H−1,5−ベンゾジオキセピン−6−もしくは−7−イル、さらに好ましくは、2,3−ジヒドロベンゾフラニル、2,3−ジヒドロ−2−オキソフラニル、3,4−ジヒドロ−2−オキソ−1H−キナゾリニル、2,3−ジヒドロベンゾキサゾリル、2−オキソ−2,3−ジヒドロベンゾキサゾリル、2,3−ジヒドロベンズイミダゾリル、1,3−ジヒドロインドール、2−オキソ−1,3−ジヒドロインドールまたは2−オキソ−2,3−ジヒドロベンズイミダゾリルを示すことができる。
Halは、好ましくは、F、ClまたはBr、しかしまたI、特に好ましくはFまたはClを示す。
式Iで表される化合物は、1つまたは2つ以上のキラル中心を有していてもよく、従って種々の立体異性体形態で存在し得る。式Iは、すべてのこれらの形態を包含する。
Ibにおいて、Arは、Halおよび/またはCNによって単置換、二置換または三置換されているフェニルを示し;
Icにおいて、Aは、1〜6個のC原子を有する非分枝状または分枝状アルキルを示し;
Idにおいて、R4は、Hを示し;
ここで、これらの基はまた、Hal、[C(R5)2]nOR5および/またはAによって単置換、二置換もしくは三置換されていてもよく、
または
Halおよび/またはCNによって単置換、二置換もしくは三置換されているフェニル
または
Aを示し;
R2は、H、OH、OA、O[C(R5)2]nOR5、Hal、Het、−[C(R5)2]nHetまたはO[C(R5)2]nHetを示し、
R3、R3’は、各々、互いに独立してH、FまたはAを示し、
一緒にまた、2〜5個のC原子を有するアルキレンを示し、
R4は、Hを示し、
R5は、HまたはAを示し、
Arは、Halおよび/またはCNによって単置換、二置換または三置換されているフェニルを示し、
Hetは、1〜4個のN、Oおよび/またはS原子を有し、非置換であるかまたはA、[C(R5)2]nOR5および/または[C(R3)2]nHet1によって単置換、二置換もしくは三置換されていてもよい、単環式の飽和、不飽和または芳香族複素環を示し、
Halは、F、Cl、BrまたはIを示し、
nは、1、2、3または4を示す;
ならびに、それらの薬学的に使用可能な塩、互変異性体および立体異性体であり、すべての比率でのそれらの混合物を含む。
該反応は、鈴木反応用として当業者に知られている条件下で行われる。
式IIで表される化合物において、Lは、好ましくは
用いる条件に依存して、反応時間は数分〜14日であり、反応温度は約−30℃〜140℃、通常0℃〜100℃、特に約60℃〜約90℃である。
特に好ましいのは、エタノール、トルエン、ジメトキシエタンである。
Pbf(ペンタメチルベンゾフラニル)基は、Argを保護するために用いられる。これを、例えばジクロロメタン中のTFAを用いて切断して除去する。
本発明の前述の化合物を、これらの最終的な非塩形態で用いることができる。一方、本発明はまた、これらの化合物を、当該分野において知られている手順により、種々の有機および無機酸類および塩基類から誘導し得るこれらの薬学的に許容し得る塩の形態で用いることを包含する。式Iで表される化合物の薬学的に許容し得る塩形態は、大部分、慣用的な方法により調製される。式Iで表される化合物がカルボキシル基を含む場合には、その好適な塩の1種を、当該化合物を好適な塩基と反応させて対応する塩基付加塩を得ることにより、形成することができる。このような塩基は、例えば、水酸化カリウム、水酸化ナトリウムおよび水酸化リチウムを含むアルカリ金属水酸化物;アルカリ土類金属水酸化物、例えば水酸化バリウムおよび水酸化カルシウム;アルカリ金属アルコキシド類、例えばカリウムエトキシドおよびナトリウムプロポキシド;ならびに種々の有機塩基、例えばピペリジン、ジエタノールアミンおよびN−メチルグルタミンである。
特に好ましいのは、塩酸塩、二塩酸塩、臭化水素酸塩、マレイン酸塩、メシル酸塩、リン酸塩、硫酸塩およびコハク酸塩である。
局所的投与用に適合された医薬化合物は、軟膏、クリーム、懸濁液、ローション、散剤、溶液、ペースト、ゲル、スプレー、エアゾールまたは油として処方することができる。
口における局所的適用のために適合された医薬処方物は、薬用キャンデー、トローチおよび洗口剤を包含する。
直腸内投与のために適合された医薬処方物は、坐剤または浣腸剤の形態で投与することができる。
膣内投与のために適合された医薬処方物は、膣坐薬、タンポン、クリーム、ゲル、ペースト、発泡体またはスプレー処方物として投与することができる。
(a)式Iで表される化合物および/または、その薬学的に使用可能な塩および立体異性体(すべての比率でのこの混合物を含む)の有効量、
ならびに
(b)さらなる医薬活性成分の有効量
の個別のパックからなる、セット(キット)に関する。
本発明の化合物は、哺乳動物のための、特にヒトのための、チロシンキナーゼにより誘発された疾患の処置における医薬活性成分として適する。これらの疾患には、腫瘍細胞の増殖、固形腫瘍の成長を促進する病理学的血管新生(または血管形成)、眼性血管新生(糖尿病性網膜症、年齢により誘発された黄斑変性症など)および炎症(乾癬、関節リウマチなど)が含まれる。
血管形成が関与するこのような疾患は、眼の疾患、例えば網膜血管形成、糖尿病性網膜症、年齢により誘発された黄斑変性症などである。
眼の疾患、例えば糖尿病性網膜症および年齢により誘発された黄斑変性症を処置または防止するための方法は、同様に本発明の一部である。炎症性疾患、例えば関節リウマチ、乾癬、接触性皮膚炎および遅延型過敏症応答の処置または防止、ならびに骨肉腫、骨関節炎およびくる病の群からの骨の病変の処置または防止のための使用もまた、同様に本発明の範囲内にある。
したがって、本発明は、式Iで表される化合物ならびにこれらの薬学的に使用可能な塩および立体異性体、すべての比率でのこれらの混合物の、キナーゼシグナル伝達の阻害、調節および/または調整が役割を果たす疾患を処置するための医薬を調製するための使用に関する。
好ましいのは、式Iで表される化合物ならびにこれらの薬学的に使用可能な塩および立体異性体、すべての比率でのこれらの混合物の、請求項1に記載の化合物によりチロシンキナーゼを阻害することによって影響される疾患を処置するための医薬を調製するための使用である。
特に好ましいのは、疾患が固形腫瘍である疾患を処置するための使用である。
固形腫瘍はさらに、好ましくは肺腺癌、小細胞肺癌、膵臓癌、神経膠芽腫、結腸癌および乳癌の群から選択される。
例に記載する式Iで表される化合物を、以下に記載するアッセイにより試験し、キナーゼ阻害活性を有することを見出した。他のアッセイは、文献から知られており、当業者が容易に行うことができるだろう(例えば、Dhanabalら、Cancer Res. 59:189-197; Xinら、J. Biol. Chem. 274:9116-9121; Sheuら、Anticancer Res. 18:4435-4441; Ausprunkら、Dev. Biol. 38:237-248; Gimbroneら、J. Natl. Cancer Inst. 52:413-427; Nicosiaら、In Vitro 18:538- 549を参照)。
製造者のデータ(Met, active, Upstate、カタログNo.14-526)に従って、Metキナーゼを、バキュロウイルス発現ベクター中の「N末端6Hisタグ化」組換えヒトタンパク質として、昆虫細胞(Sf21; S. frugiperda)におけるタンパク質産生およびその後のアフィニティークロマトグラフィー精製のために発現させる。
用いる試験プレートは、Perkin Elmer製の96ウェルのFlashplate(登録商標)マイクロタイタープレート(カタログNo. SMP200)である。以下に記載するキナーゼ反応の成分を、アッセイプレート中にピペットする。Metキナーゼおよび基質ポリAla−Glu−Lys−Tyr(pAGLT、6:2:5:1)を、試験物質の存在下および不存在下で、100μlの合計容積において、放射性標識33P−ATPと共に、3時間室温にてインキュベートする。反応を、150μlの60mMのEDTA溶液を用いて終了させる。室温でさらに30分間インキュベートした後に、上清を、吸引しながら濾別し、ウェルを、各々の回において200μlの0.9%NaCl溶液で3回洗浄する。結合した放射性の測定を、シンチレーション測定器(Topcount NXT, Perkin-Elmer)により行う。
30μlのアッセイ緩衝液
10μlの10%のDMSOを含むアッセイ緩衝液中の試験するべき物質
10μlのATP(最終濃度1μM、0.35μCiの冷33P−ATP)
50μlのアッセイ緩衝液中のMetキナーゼ/基質混合物;(10ngの酵素/ウェル、50ngのpAGLT/ウェル)
−アッセイ緩衝液:
50mMのHEPES
3mMの塩化マグネシウム
3μMのオルトバナジウム酸ナトリウム
3mMの塩化マンガン(II)
1mMのジチオトレイトール(DTT)
pH=7.5(水酸化ナトリウムを用いて調整)
60mMのTitriplex III(EDTA)
−33P−ATP:Perkin-Elmer;
−Metキナーゼ:Upstate, カタログNo. 14-526, Stock1μg/10μl;比活性954U/mg;
−ポリ−Ala−Glu−Lys−Tyr、6:2:5:1:SigmaカタログNo. P1152
実験手順:雌のBalb/Cマウス(ブリーダー:Charles River Wiga)は、到着時に5週齢であった。これらを、7日間本発明者らの飼育条件に順応させた。その後、各々のマウスに、100μlのPBS(Ca++およびMg++を含まない)中の400万個のTPR−Met/NIH3T3細胞を、骨盤領域に皮下注射した。5日後、各々の群の9匹のマウスが、110μl(範囲:55〜165)の平均腫瘍容積を有するように動物を3つの群に無作為に分けた。100μlのビヒクル(0.25%のメチルセルロース/100mMの酢酸緩衝液、pH5.5)を、毎日対照群に投与し、ビヒクル(容積は同様に100μl/動物であった)に溶解した200mg/kgの「A56」または「A91」を、各々の場合において胃管により、毎日処置群に投与した。9日後、対照は、1530μlの平均容積を有しており、実験を終了した。
飼育条件:ケージあたり4匹または5匹の動物、市販のマウスフード(Sniff)を給餌した。
質量分析法(MS):
EI(電子衝撃イオン化)M+
FAB(高速原子衝撃)(M+H)+
ESI(エレクトロスプレーイオン化)(M+H)+
APCI−MS(大気圧化学的イオン化−質量分析法)(M+H)+。
m.p.=融点[℃]
方法A:勾配:4.5分/流:3ml/分、99:01〜0:100
水+0.1%(容積)のTFA:アセトニトリル+0.1%(容積)のTFA
0.0〜0.5分:99:01
0.5〜3.5分:99:01→0:100
3.5〜4.5分:0:100
カラム:Chromolith SpeedROD RP18e 50-4.6
波長:220nm
水+0.1%(容積)のTFA:アセトニトリル+0.1%(容積)のTFA
0.0〜0.2分:99:01
0.2〜3.8分:99:01→0:100
3.8〜4.2分:0:100
カラム:Chromolith Performance RP18e;長さ100mm、内径3mm波長:220nm
滞留時間Rt.、単位[分]。
3−[3−(5−ブロモピリミジン−2−イル)ベンジル]−6−(1−メチル−1H−ピラゾール−4−イル)−1,2,4−トリアゾロ[4,3−b]ピリダジン(「A1」)の調製を、以下のスキームと同様にして行う。
6−(1−メチル−1H−ピラゾール−4−イル)−3−(3−{5−[1−(2−ピロリジン−1−イル−エチル)−1H−ピラゾール−4−イル]ピリミジン−2−イル}ベンジル)−1,2,4−トリアゾロ[4,3−b]ピリダジン(「A2」)の調製を、以下のスキームと同様にして行う。
3−{[3−(5−ブロモピリミジン−2−イル)フェニル]ジフルオロメチル}−6−(1−メチル−1H−ピラゾール−4−イル)−1,2,4−トリアゾロ[4,3−b]ピリダジン(「A3」)の調製を、以下のスキームと同様にして行う。
「A1」の調製と同様に、メチル1−(3−ブロモフェニル)シクロプロパンカルボキシレートから出発して、化合物「A4」が得られる。
3−{3−[3−(5−ブロモピリミジン−2−イル)ベンジル]−1,2,4−トリアゾロ[4,3−b]ピリダジン−6−イル}ベンゾニトリル(「A5」)の調製を、以下のスキームと同様にして行う。
「A1」の調製と同様にして、化合物「A6」が、1−クロロ−4−メチルピリダジン(EP1422218に従う調製)から出発して得られる。
以下の化合物が、「A2」の調製と同様にして得られる。
6−(1−メチル−1H−ピラゾール−4−イル)−3−[3−(5−モルホリン−4−イル−ピリミジン−2−イル)ベンジル]−1,2,4−トリアゾロ[4,3−b]ピリダジン(「A10」)の調製を、以下のスキームと同様にして行う。
化合物3−{3−[5−(4−メチルピペラジン−1−イル)ピリミジン−2−イル]ベンジル}−6−(1−メチル−1H−ピラゾール−4−イル)−1,2,4−トリアゾロ[4,3−b]ピリダジン(「A11」)の調製を、以下のスキームと同様にして行う。
3−(ジフルオロ−{3−[5−(2−モルホリン−4−イルエトキシ)ピリミジン−2−イル]フェニル}メチル)−6−(1−メチル−1H−ピラゾール−4−イル)−1,2,4−トリアゾロ[4,3−b]ピリダジン(「A12」)および3−[ジフルオロ−(3−ピリミジン−2−イルフェニル)メチル]−6−(1−メチル−1H−ピラゾール−4−イル)−1,2,4−トリアゾロ[4,3−b]ピリダジン(「A26」)の調製を、以下のスキームと同様にして行う。
無色結晶の3−[ジフルオロ−(3−ピリミジン−2−イルフェニル)メチル]−6−(1−メチル−1H−ピラゾール−4−イル)−1,2,4−トリアゾロ[4,3−b]ピリダジン;ESI 406;1H-NMR (d6-DMSO): δ [ppm] = 3.90 (s, 3H), 7.52 (t, J = 4.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.82 (d, J = 9.7 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 8.13 (s, 1H), 8.46 (d, J = 9.7 Hz, 1H), 8.47 (s, 1H), 8.59 (d, J = 7.7 Hz, 1H), 8.85 (bs, 1H), 8.96 (d, J = 4.7 Hz, 2H)。
以下の化合物が、同様にして得られる。
化合物3−{1−[3−(5−ブロモピリミジン−2−イル)フェニル]エチル}−6−(1−メチル−1H−ピラゾール−4−イル)−1,2,4−トリアゾロ[4,3−b]ピリダジン(「A18」)
以下の化合物が、「A7」の調製と同様にして得られる。
3−{[3−(5−ブロモピリミジン−2−イル)フェニル]ジフルオロメチル}−6−メチル−1,2,4−トリアゾロ[4,3−b]ピリダジン(「A27」)の調製を、以下のスキームと同様にして行う。
3−[3−(5−ブロモピリミジン−2−イル)ベンジル]−6−(1−メチル−1H−ピラゾール−4−イル)−1,2,4−トリアゾロ[4,3−b]ピリダジン(「A1」)および
3−{[3−(5−ブロモピリミジン−2−イル)フェニル]ジフルオロメチル}−6−(1−メチル−1H−ピラゾール−4−イル)−1,2,4−トリアゾロ[4,3−b]ピリダジン(「A3」)。
3−(ジフルオロ−{3−[5−(2−モルホリン−4−イルエトキシ)ピリミジン−2−イル]フェニル}メチル)−6−メチル−1,2,4−トリアゾロ[4,3−b]ピリダジン(「A28」)の調製を、以下のスキームと同様にして行う。
3−(ジフルオロ−{3−[5−(2−メトキシエトキシ)ピリミジン−2−イル]フェニル}メチル)−6−(1−メチル−1H−ピラゾール−4−イル)−1,2,4−トリアゾロ[4,3−b]ピリダジン(「A31」)
3−(ジフルオロ−{3−[5−(1−メチルピペリジン−4−イルメトキシ)ピリミジン−2−イル]フェニル}メチル)−6−メチル−1,2,4−トリアゾロ[4,3−b]ピリダジン(「A41」)の調製を、以下のスキームと同様にして行う。
2−(4−{3−[3−(5−ブロモピリミジン−2−イル)ベンジル]−1,2,4−トリアゾロ[4,3−b]ピリダジン−6−イル}ピラゾール−1−イル)エタノール(「A43」)および2−(4−{3−[3−(5−メチルピリミジン−2−イル)ベンジル]−1,2,4−トリアゾロ[4,3−b]ピリダジン−6−イル}ピラゾール−1−イル)エタノール(「A44」)の調製を、以下のスキームと同様にして行う。
Metキナーゼ阻害
表1
例A:注射バイアル
100gの式Iで表される活性成分および5gのリン酸水素二ナトリウムを3lの2回蒸留水に溶解した溶液を、2N塩酸を用いてpH6.5に調整し、滅菌濾過し、注射バイアル中に移送し、滅菌条件下で凍結乾燥し、滅菌条件下で密封する。各々の注射バイアルは、5mgの活性成分を含む。
20gの式Iで表される活性成分の100gの大豆レシチンおよび1400gのココアバターとの混合物を、溶融し、型中に注入し、放冷する。各々の座剤は、20mgの活性成分を含む。
1gの式Iで表される活性成分、9.38gのNaH2PO4・2H2O、28.48gのNa2HPO4・12H2Oおよび0.1gの塩化ベンザルコニウムから、940mlの2回蒸留水中に溶液を調製する。pHを6.8に調整し、溶液を1lにし、放射線により滅菌する。この溶液を、点眼剤の形態で用いることができる。
500mgの式Iで表される活性成分を、99.5gのワセリンと、無菌条件下で混合する。
1kgの式Iで表される活性成分、4kgのラクトース、1.2kgのジャガイモデンプン、0.2kgのタルクおよび0.1kgのステアリン酸マグネシウムの混合物を、慣用の方法で圧縮して、錠剤を得、各々の錠剤が10mgの活性成分を含むようにする。
例Eと同様にして、錠剤を圧縮し、次に、慣用の方法で、スクロース、ジャガイモデンプン、タルク、トラガカントおよび染料の被膜で被覆する。
2kgの式Iで表される活性成分を、硬質ゼラチンカプセル中に、慣用の方法で導入して、各々のカプセルが20mgの活性成分を含むようにする。
1kgの式Iで表される活性成分を60lの2回蒸留水に溶解した溶液を、滅菌濾過し、アンプル中に移送し、滅菌条件下で凍結乾燥し、滅菌条件下で密封する。各々のアンプルは、10mgの活性成分を含む。
Claims (11)
- 式I
R1が、チアゾリル、チオフェニル、フラニル、ピロリル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、ピラゾリル、イミダゾリル、チアジアゾリル、ピリダジニル、ピラジニル、ピリジニルまたはピリミジニルを示し、
ここで、これらの基はまた、Hal、[C(R5)2]nOR5および/またはAによって単置換、二置換もしくは三置換されていてもよい、
あるいは
Halおよび/またはCNによって単置換、二置換もしくは三置換されているフェニル
あるいはAを示し、
R2が、O[C(R5)2]nOR5、Het、−[C(R5)2]nHetまたはO[C(R5)2]nHetを示し、
R3、R3’が、各々、互いに独立してH、FまたはAを示し、
また一緒になって、2〜5個のC原子を有するアルキレンを示し、
R4が、Hを示し、
R5が、HまたはAを示し、
Aが、1〜6個のC原子を有する非分枝状または分枝状アルキルを示し、
Arが、Halおよび/またはCNによって単置換、二置換または三置換されているフェニルを示し、
Hetが、ピペリジニル、ピロリジニル、モルホリニル、ピペラジニル、オキサゾリジニル、ピラゾリル、ピリジニル、ピリミジニル、フリル、チエニル、オキサゾリル、オキサジアゾリル、イミダゾリル、ピロリル、イソオキサゾリルまたはイミダゾリジニルを示し、ここでこれらの基はまた、A、[C(R5)2]nOR5および/または[C(R5)2]nHet1によって単置換または二置換されていてもよい、
Het1が、ピペリジニル、ピロリジニル、モルホリニル、ピペラジニル、オキサゾリジニルまたはイミダゾリジニルを示し、ここでこれらの基はまた、=Oおよび/またはAによって単置換または二置換されていてもよく、
Halが、F、Cl、BrまたはIを示し、
nが、1、2、3または4を示す、
で表される化合物、またはそれらの薬学的に使用可能な塩。 - 以下の群
- 請求項1または2に記載の化合物、またはそれらの薬学的に使用可能な塩の調製のための方法であって、式II
Lは、ボロン酸またはボロン酸エステルラジカルを示す、
で表される化合物を、
式III
で表される化合物と反応させ、
および、必要な場合には、
ハロゲン原子をアミノ、アルコキシまたはアリール基によって置き換えることによって、ラジカルR2を別のラジカルR2に変換し、
かつ/または
式Iで表される塩基または酸を、その塩の1種に変換する
ことを特徴とする、前記方法。 - 請求項1または2に記載の少なくとも1種の化合物、および/または、これらの薬学的に使用可能な塩、ならびに、任意に賦形剤および/または補助剤を含む、医薬。
- 哺乳動物における血管形成、癌、腫瘍形成、成長および増殖、動脈硬化、眼の疾患、年齢により誘発された黄斑変性症、脈絡膜血管新生、糖尿病性網膜症、炎症性疾患、関節炎、血栓症、線維症、糸球体腎炎、神経変性、乾癬、再狭窄、創傷治癒、移植片拒絶、代謝性疾患および免疫系の疾患、自己免疫性疾患、肝硬変、糖尿病および血管の疾患、不安定性および浸透性からなる群から選択される疾患の処置のための、請求項4に記載の医薬。
- 処置するべき疾患が固形腫瘍である、請求項5に記載の医薬。
- 固形腫瘍が、扁平上皮、膀胱、胃、腎臓、頭頸部、食道、子宮頸部、甲状腺、腸、肝臓、脳、前立腺、尿生殖路、リンパ系、喉頭および/または肺の腫瘍の群に由来する、請求項6に記載の医薬。
- 固形腫瘍が、単球性白血病、肺腺癌、小細胞肺癌、膵臓癌、神経膠芽腫および乳癌の群に由来する、請求項6に記載の医薬。
- 固形腫瘍が、肺腺癌、小細胞肺癌、膵臓癌、神経膠芽腫、結腸癌および乳癌の群に由来する、請求項6に記載の医薬。
- 処置するべき疾患が、血液および免疫系の腫瘍である、請求項5に記載の医薬。
- 腫瘍が、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ性白血病および/または慢性リンパ性白血病の群に由来する、請求項10に記載の医薬。
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Also Published As
Publication number | Publication date |
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IL210063A0 (en) | 2011-02-28 |
ZA201100437B (en) | 2011-09-28 |
KR101661777B1 (ko) | 2016-09-30 |
MX2010013649A (es) | 2010-12-21 |
PT2285811E (pt) | 2013-03-05 |
CN102066378B (zh) | 2014-04-16 |
BRPI0915417B1 (pt) | 2020-02-11 |
EP2285811A1 (de) | 2011-02-23 |
CN102066378A (zh) | 2011-05-18 |
AU2009259764A1 (en) | 2009-12-23 |
KR20110031329A (ko) | 2011-03-25 |
PL2285811T3 (pl) | 2013-04-30 |
DE102008028905A1 (de) | 2009-12-24 |
DK2285811T3 (da) | 2013-03-11 |
BRPI0915417A2 (pt) | 2015-11-03 |
EA019534B1 (ru) | 2014-04-30 |
US8497266B2 (en) | 2013-07-30 |
IL210063A (en) | 2015-06-30 |
JP2011524385A (ja) | 2011-09-01 |
CA2728194C (en) | 2016-11-29 |
CA2728194A1 (en) | 2009-12-23 |
WO2009152920A1 (de) | 2009-12-23 |
AR072860A1 (es) | 2010-09-29 |
ES2400117T3 (es) | 2013-04-05 |
EP2285811B1 (de) | 2012-12-05 |
BRPI0915417B8 (pt) | 2021-05-25 |
EA201100031A1 (ru) | 2011-08-30 |
US20110092498A1 (en) | 2011-04-21 |
AU2009259764B2 (en) | 2013-09-26 |
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