JP5592395B2 - ピリダジノン誘導体 - Google Patents
ピリダジノン誘導体 Download PDFInfo
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- JP5592395B2 JP5592395B2 JP2011542689A JP2011542689A JP5592395B2 JP 5592395 B2 JP5592395 B2 JP 5592395B2 JP 2011542689 A JP2011542689 A JP 2011542689A JP 2011542689 A JP2011542689 A JP 2011542689A JP 5592395 B2 JP5592395 B2 JP 5592395B2
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- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 title description 9
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- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 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
- 238000001291 vacuum drying Methods 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
- 150000003751 zinc Chemical class 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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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/または調整が作用を奏する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.によってCancer Res. 2003, 63(21), 7345-55に記載されている。
他のピリダジン誘導体は、WO 2007/065518においてMETキナーゼ阻害剤として記載されている。
チアジアジノン類は、DE19604388、WO2003/037349、WO2007/057093およびWO2007/057092に記載されている。
免疫系の疾患、虚血性および炎症性疾患を処置するための他のピリダジン類は、EP 1 043 317 A1およびEP 1 061 077 A1から知られている。
EP 0 738 716 A2およびEP 0 711 759 B1には、殺真菌薬および殺虫剤としての他のジヒドロピリダジノン類およびピリダジノン類が記載されている。
他のピリダジノン類は、US 4,397,854において強心薬として記載されている。
特開昭57-95964号公報には、他のピリダジノン類が開示されている。
本発明は、式I
R1は、Ar、Het、A、OR2、O[C(R2)2]nAr、O[C(R2)2]nHet、N(R2)2、NR2[C(R2)2]nArまたはNR2[C(R2)2]nHetを示し、
R2は、HまたはA’を示し、
R3、R3’は、各々、互いに独立してH、Hal、A、OR2、CN、COOR2、CON(R2)2、NR2COA、NR2SO2A、SO2N(R2)2またはS(O)mA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、[C(R2)2]nOR2、[C(R2)2]nN(R2)2、SR2、NO2、CN、COOR2、CON(R2)2、NR2COA、NR2SO2A、SO2N(R2)2、S(O)mA、CO−Het、Het、O[C(R2)2]nN(R2)2、O[C(R2)2]nHet、NHCOOA、NHCON(R2)2、NHCOO[C(R2)2]nN(R2)2、NHCOO[C(R2)2]nHet、NHCONH[C(R2)2]nN(R2)2、NHCONH[C(R2)2]nHet、OCONH[C(R2)2]nN(R2)2、OCONH[C(R2)2]nHet、CONR2[C(R2)2]nN(R2)2、CONR2[C(R2)2]nHetおよび/またはCOAによって単置換、二置換もしくは三置換されており、
Het2は、2−メトキシカルボニルピロリジン−4−イル、2−カルボキシピロリジン−4−イル、1−シクロプロピルメチルピペリジン−4−イル、ピペリジン−4−イル、モルホリン−2−もしくは4−イル、1−イソプロピルピペリジン−4−イル、1−メチルピペリジン−4−イル、4−ピペラジニル、1−メチルピロリジン−2−イル、1−tert−ブトキシカルボニル−ピペリジン−4−イル、1−エチルピペリジン−2−イル、1−(2−メトキシエチル)ピペリジン−4−イル、1−[2−(N,N−ジメチルアミノ)エチル]ピペリジン−4−イル、1,2,2,6,6−ペンタメチルピペリジン−4−イル、1−アザビシクロ[2.2.2]オクタ−3−イル、テトラヒドロピラン−4−イル、1−ホルミルピペリジン−4−イルまたは1−メチル−1−オキシ−ピペリジン−4−イルを示し、
あるいは、
3〜7個のC原子を有する環状アルキルを示し、
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、ここで、1〜5個のH原子は、Fによって置き換えられていてもよく、
Cycは、3〜7個のC原子を有するシクロアルキレンを示し、
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、0、1、2、3または4を示し、
pは、1、2、3、4または5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。
用語「治療的に有効な量」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
で表される化合物を、
式III
Lは、Cl、Br、Iまたは遊離の、もしくは反応的に官能基修飾されたOH基を示す、
で表される化合物と反応させ、
あるいは、
i)アミノ基をアシル化またはアルキル化し、
ii)水酸基をエーテル化する
ことによって変換し、
あるいは
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、前記方法に関する。
1回よりも多く出現するすべてのラジカル、例えばR2について、それらの意味は、互いに独立している。
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。
A’は、極めて特に好ましくはメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、ヘキシルまたはトリフルオロメチルを示す。
Cycは、好ましくはシクロプロピレン、シクロブチレン、シクロペンチレンまたはシクロヘキシレンを示す。
R1は、極めて特に好ましくは3−シアノフェニルまたは1−メチルピラゾール−4−イルを示す。
R2は、好ましくはHまたは1、2、3もしくは4個のC原子を有するアルキル、特に好ましくはH、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチルまたはtert−ブチルを示す。
R2は、極めて特に好ましくはHまたはメチルを示す。
R3、R3’は、好ましくはHを示す。
Arは、極めて特に好ましくはCN、F、Cl、メトキシおよび/またはCONH2によって単置換または二置換されているフェニルを示す。
他の置換基とは無関係に、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。
pは、好ましくは1、2、3または4、極めて特に好ましくは1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、したが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、CN、F、Cl、メトキシおよび/またはCONH2によって単置換または二置換されているフェニルを示し;
Icにおいて、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、2−ヒドロキシエチルおよび/または2−メトキシエチルによって単置換もしくは二置換されていてもよい、単環式の芳香族複素環を示し;
ここで、1〜5個のH原子は、Fおよび/またはCl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;
Igにおいて、R2は、Hまたは1、2、3もしくは4個のC原子を有するアルキルを示し;
R2は、Hまたは1、2、3もしくは4個のC原子を有するアルキルを示し、
R3、R3’は、Hを示し、
Arは、CN、F、Cl、メトキシおよび/またはCONH2によって単置換または二置換されているフェニルを示し、
Het1は、ピロリジン、ピペリジン、ピペラジンまたはモルホリンを示し、その各々は、非置換であるか、またはA、OA、OH、COOHおよび/またはCOOAによって単置換もしくは二置換されており、
ここで1〜5個のH原子は、Fおよび/またはCl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、
Cycは、3〜7個のC原子を有するシクロアルキレンを示し、
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、0、1、2、3または4を示し、
p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。
用いる式IIで表されるピリダジノン類は、商業的に入手できない場合には、一般的にW. J. Coates, A. McKillop, Synthesis, 1993, 334-342の方法により調製する。
式IIIで表される化合物において、Lは、好ましくはCl、Br、Iまたは遊離の、もしくは反応的に修飾されたOH基、例えば1〜6個のC原子を有する活性化エステル、イミダゾリドまたはアルキルスルホニルオキシ(好ましくはメチルスルホニルオキシもしくはトリフルオロメチルスルホニルオキシ)または6〜10個のC原子を有するアリールスルホニルオキシ(好ましくはフェニルもしくはp−トリルスルホニルオキシ)を示す。
アルカリもしくはアルカリ土類金属水酸化物、炭酸塩もしくは重炭酸塩、またはアルカリもしくはアルカリ土類金属、好ましくはカリウム、ナトリウム、カルシウムもしくはセシウムの弱酸の他の塩を加えることがまた、好ましい場合がある。
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−10℃〜90℃、特に約0℃〜約70℃である。
特に好ましいのは、アセトニトリル、ジクロロメタンおよび/またはDMFである。
式Iで表される化合物をさらに、加溶媒分解、特に加水分解によって、または水素化分解によってそれらをそれらの官能的誘導体から遊離させることにより、得ることができる。
Pbf(ペンタメチルベンゾフラニル)基を用いて、Argを保護する。それを、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、そ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って、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そ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、この好適な塩の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って生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を、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、薬用キャンディー、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を、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を、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、固形腫瘍、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)の成長を促進する腫瘍細胞、病理学的血管新生(または血管形成)の増殖が含まれる。
血管形成が関係するこのような疾患は、眼の疾患、例えば網膜血管化、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からの骨の病態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/または調整が作用を奏する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た(例えば、Dhanabal et al., Cancer Res. 59:189-197; Xin et al., J. Biol. Chem. 274:9116-9121; Sheu et al., Anticancer Res. 18:4435-4441; Ausprunk et al., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. Cancer Inst. 52:413-427; Nicosia et al., In Vitro 18:538- 549を参照)。
製造者のデータ(Met、活性、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)によって行う。
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。それらを、7日間本発明者らの維持条件に順応させた。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。
維持条件: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)で飼育した。
化合物「A18」および「A22」は、顕著な抗腫瘍作用を有する。
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)+。
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。
カラム:Chromolith RP18e 100*3mm
流量:2ml/分
溶媒A:H2O+0.1%のトリフルオロ酢酸
溶媒B:アセトニトリル+0.1%のトリフルオロ酢酸
勾配 5分
0〜4分:99:1→1:99
4〜5分:1:99−1:99
カラム:Chromolith RP18e 100*3mm
流量:2ml/分
99:01〜0:100の水+0.1%(体積)のTFA:アセトニトリル+0.1%(体積)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
波長:220nm
カラム:Chromolith RP18e 100*3mm
流量:2ml/分
99:01〜0:100の水+0.01%(体積)のギ酸:アセトニトリル+0.01%(体積)のギ酸
0.0〜0.2分:99:01
0.2〜3.8分:99:01→0:100
3.8〜4.2分:0:100
波長:220nm
カラム:Chromolith RP18e 100*3mm
流量:2ml/分
99:01〜0:100の水+0.05%(体積)のギ酸:アセトニトリル+0.05%(体積)のギ酸
0.0〜0.2分:99:01
0.2〜3.8分:99:01→0:100
3.8〜4.2分:0:100
波長:220nm
保持時間Rt、単位分[min]。
ピリダジノンを一般的に、W. H. Coates, A. McKillop, Synthesis 1993, p. 334からのプロセスによって調製する。
750mg(0.65mmol)のテトラキス(トリフェニルホスフィン)パラジウムを、6.11g(21.5mmol)の5−ブロモ−2−ヨードピリミジン、3.91g(25.7mmol)の3−(ヒドロキシメチル)ベンゼンボロン酸および9.11g(42.9mmol)のリン酸三カリウム三水和物を120mlのジオキサンおよび14mlの水に溶解した、窒素の下に保持した溶液に加え、混合物を、90℃にて18時間撹拌する。反応混合物を室温に冷却し、tert−ブチルメチルエーテルおよび水を加え、混合物を、珪藻土を通して濾過する。濾液の有機相を分離し、硫酸ナトリウムで乾燥し、蒸発させる。残留物を、ジクロロメタン/メタノールを溶離剤としてシリカゲルカラム上でクロマトグラフィー分離する:
生成物:2.49g;m.p.114〜117°、ESI:265、267(M+H)、HPLC:Rt.=2.51分(方法B)。
80g(302mmol)の[3−(5−ブロモピリミジン−2−イル)フェニル]メタノールを、300mlのジクロロメタンに懸濁させ、33ml(453mmol)の塩化チオニルを、冷却しながらゆっくりと加える。反応混合物を、室温にて3時間撹拌する。溶媒を蒸留して除去し、トルエンと共に3回同時蒸発させ(co-evaporate)、ジエチルエーテルと共に撹拌する:
淡黄色結晶、m.p.146〜148°、HPLC:Rt.=3.15分(方法B)。
61.13gの3−シアノフェニルピリダジノン(0.31mol)および87.9gの5−ブロモ−2−(3−クロロメチルフェニル)ピリミジン(0.31mol)を、1000mlの1つ首フラスコ中で不活性ガス雰囲気下で610mlのDMFに溶解し、111.11gの炭酸セシウム(0.34mol)を、その後加える。反応混合物を、40℃にて72時間撹拌する。精製操作のために、混合物を、撹拌しながら600mlの水で希釈し、生成した沈殿物を、大量の水および少量のメタノールで洗浄し、1kgのシリカゲル上でクロマトグラフィー分離する。生成物画分を混ぜ合わせ、ロータリーエバポレーター中で蒸発乾固させ、生成物を、少量のメタノールでスラリーにし、吸引により濾別し、70℃にて真空において乾燥する;m.p.178〜9℃。
35.57gの3−{1−[3−(5−ブロモピリミジン−2−イル)ベンジル]−6−オキソ−1,6−ジヒドロピリダジン−3−イル}ベンゾニトリル(0.08mol)、26.43gのビス(ピナコラト)ジボレート(0.104mol)および23.75gの酢酸カリウム(0.240mol)を、500mlの3つ首フラスコ中で、165mlの無水DMFにN2雰囲気下で懸濁させ、撹拌しながら70℃に加熱し、1.686gの(PPh3)2PdCl2(2.4mmol)を、その後加え、反応バッチを、70℃にて6時間撹拌し、その間暗い茶色の溶液が生成する。精製操作のために、反応混合物を撹拌しながらRTにて600mlの水で希釈し、生成した沈殿物を吸引により濾別する。生成した沈殿物を、500mlのジクロロメタン中に吸収させ、200mlの水と共に2回振盪し、硫酸ナトリウムで乾燥し、蒸発乾固させる。残留物を200mlのアセトン中でスラリーにし、吸引により濾別し、少量のアセトンで洗浄する。m.p.203〜5℃。
220mlのTHFおよび220mlの水の混合物中の50.46gの3−(6−オキソ−1−{3−[5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ピリミジン−2−イル]ベンジル}−1,6−ジヒドロピリダジン−3−イル)ベンゾニトリル(102.7mmol)および33.81gの過ホウ酸ナトリウム四水和物(339mmol)を、1000mlの1つ首フラスコ中で混合し、室温にて2時間撹拌し、その間淡い色の沈殿物が沈澱する。反応混合物を800mlのジクロロメタンで希釈し、500mlの飽和水性塩化アンモニウム溶液と共に振盪し、硫酸ナトリウムで乾燥し、ロータリーエバポレーター中で蒸発乾固させる。残留物をメタノールでスラリーにし、吸引により濾別し、ジエチルエーテルで洗浄する。m.p.245〜8℃。
(2S,3S)−2−アミノ−3−メトキシ−N−[2−(2−{3−[3−(1−メチル−1H−ピラゾール−4−イル)−6−オキソ−6H−ピリダジン−1−イルメチル]フェニル}ピリミジン−5−イルオキシ)エチル]ブチルアミド(「A1」)の調製
721mg(2mmol)の2−[3−(5−ヒドロキシピリミジン−2−イル)ベンジル]−6−(1−メチル−1H−ピラゾール−4−イル)−2H−ピリダジン−3−オンを、10mlのDMFに溶解し、1g(3mmol)のポリマー結合トリフェニルホスフィン(3mmol/g)および347μl(2.2mmol)のtert−ブチルN−(2−ヒドロキシエチル)カルバメートを加える。反応混合物を室温にて15分間振盪し、705mg(3mmol)のジ−tert−ブチルアゾジカルボキシレートを、その後加える。反応混合物を室温にて3時間振盪し、さらに500mg(1.5mmol)のポリマー結合トリフェニルホスフィン(3mmol/g)および352mg(1.5mmol)のジ−tert−ブチルアゾジカルボキシレートを加え、混合物を室温にて18時間振盪する。反応混合物を、珪藻土を通して吸引により濾別し、少量のメタノールで洗浄する。濾液を蒸発乾固させ、シリカゲル上のカラムクロマトグラフィーによってクロマトグラフィー分離する;
HPLC:Rt.=2.83分(方法C)、ESI: 504(M+H)。
977mg(1.94mmol)のtert−ブチル[2−(2−{3−[3−(1−メチル−1H−ピラゾール−4−イル)−6−オキソ−6H−ピリダジン−1−イルメチル]フェニル}ピリミジン−5−イルオキシ)エチル]カルバメート(「B1」)を、10mlのジオキサンに溶解し、ジオキサン中の9.7mlの4N HClを加える。混合物を室温にて8時間撹拌し、生成した沈殿物を吸引により濾別し、ジオキサンで洗浄し、真空において乾燥する;HPLC:Rt.=2.89分(方法C)、ESI:404(M+H)。
100mg(0.23mmol)の2−{3−[5−(2−アミノエトキシ)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)−2H−ピリダジン−3−オン塩酸塩、58mg(0.25mmol)の(2S,3S)−2−tert−ブトキシカルボニルアミノ−3−メトキシ酪酸、66mg(0.34mmol)のEDCI、41mg(0.30mmol)のHOBtを、2mlのDMFに溶解し、76μl(0.68mmol)の4−メチルモルホリンを加える。反応混合物を室温にて18時間撹拌し、酢酸エチルを加え、混合物を水で洗浄する。有機相を乾燥し、除去して乾燥させる。粗生成物を2mlのジオキサンに溶解し、ジオキサン中の2mlの4N HClを加える。反応混合物を室温にて12時間撹拌し、蒸発させ、分取HPLCによって精製する;
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.63 (s, 2H), 8.28 (s, 1H), 8.24 - 8.15 (m, 3H), 7.88 (s, 1H), 7.80 (d, J = 9.6, 1H), 7.52 - 7.38 (m, 2H), 7.05 (d, J = 9.6, 1H), 5.33 (s, 2H), 4.23 (t, J = 5.6, 2H), 3.87 (s, 3H), 3.66 - 3.58 (m, 1H), 3.57 - 3.45 (m, 2H), 3.17 (s, 3H), 3.04 (d, J = 3.7, 1H), 1.06 (d, J = 6.3, 3H).
tert−ブチル[2−(2−{3−[3−(3−シアノフェニル)−6−オキソ−6H−ピリダジン−1−イルメチル]フェニル}ピリミジン−5−イルオキシ)エチル]カルバメート(「B2」)
N−[2−(2−{3−[3−(1−メチル−1H−ピラゾール−4−イル)−6−オキソ−6H−ピリダジン−1−イルメチル]フェニル}ピリミジン−5−イルオキシ)エチル]−(2S,4R)−4−ヒドロキシピロリジン−2−カルボキサミド(「A2」)
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.63 (s, 2H), 8.28 (s, 1H), 8.21 (m, 3H), 8.17 (s, 1H), 7.88 (s, 1H), 7.80 (d, J = 9.6, 1H), 7.45 (dt, J = 7.6, 15.0, 2H), 7.05 (d, J = 9.6, 1H), 5.33 (s, 2H), 4.80 - 4.45 (b, 1H), 4.22 (t, J = 5.7, 2H), 4.14 (s, 1H), 3.87 (s, 3H), 3.74 (t, J = 8.2, 1H), 3.49 (dd, J = 5.7, 11.5, 3H), 2.76 (dd, J = 7.6, 15.1, 2H), 1.99 - 1.88 (m, 1H), 1.72 - 1.58 (m, 1H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.64 (s, 2H), 8.28 (s, 1H), 8.22 (m, 3H), 7.89 (s, 1H), 7.81 (d, J = 9.6, 1H), 7.53 - 7.40 (m, 2H), 7.06 (d, J = 9.6, 1H), 5.33 (s, 2H), 4.23 (t, J = 5.6, 2H), 3.87 (s, 3H), 3.57 (dd, J = 5.5, 8.8, 1H), 3.50 (d, J = 5.9, 2H), 2.81 (ddd, J = 3.7, 10.2, 16.6, 2H), 1.94 (s, 1H), 1.66 - 1.51 (m, 3H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 9.65 (s, 1H), 8.85 (t, 1H), 8.63-8.74 (m, 3H), 8.38 (d, J = 8.6, 2H), 8.25 (m, 2H), 8.17 (d, J = 9.8, 1H), 7.93 (d, J = 7.7, 1H), 7.72 (t, J = 7.9, 1H), 7.56 - 7.43 (m, 2H), 7.29 - 6.99 (m, 2H), 5.45 (s, 2H), 4.43 (s, 1H), 4.27 (m, 3H), 3.58 (m, 2H), 3.31 (m, 2H), 3.04 - 3.13 (m, 1H), 2.33 - 2.17 (m, 1H), 2.00 - 1.80 (m, 1H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 9.28 (s, 1H), 8.79 (t, J = 5.5, 1H), 8.66 (s, 2H), 8.55 (b, 1H), 8.38 (d, J = 9.3, 2H), 8.28 - 8.21 (m, 2H), 8.17 (d, J = 9.8, 1H), 7.93 (d, J = 7.7, 1H), 7.72 (t, J = 7.9, 1H), 7.56 - 7.42 (m, 2H), 7.16 (d, J = 9.7, 1H), 5.45 (s, 2H), 4.33 - 4.24 (m, 2H), 4.16 (s, 2H), 3.65 - 3.51 (m, 2H), 3.32 - 3.11 (m, 1H), 2.26 (dt, J = 10.4, 22.4, 1H), 1.92 - 1.79 (m, 3H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.81 (t, J = 5.5, 1H), 8.65 (s, 2H), 8.38 (d, J = 10.3, 2H), 8.28 - 8.22 (m, 2H), 8.12 - 8.22 (m, 4H), 7.92 (d, J = 7.8, 1H), 7.72 (t, J = 7.9, 1H), 7.56 - 7.42 (m, 2H), 7.15 (d, J = 9.8, 1H), 5.44 (s, 2H), 4.27 (m, 2H), 3.67 (m, 2H), 3.62 - 3.47 (m, 2H), 3.27 (s, 3H), 1.14 (d, J = 6.2, 3H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.62 (s, 2H), 8.28 (s, 1H), 8.19 - 8.25 (m, 3H), 7.88 (s, 1H), 7.84 (d, J = 8.9, 1H), 7.80 (d, J = 9.6, 1H), 7.52 - 7.38 (m, 2H), 7.05 (d, J = 9.6, 1H), 5.33 (s, 2H), 4.21 (t, J = 5.5, 2H), 4.16 - 4.04 (m, 1H), 3.58 - 3.37 (m, 2H), 1.91 (dt, J = 6.6, 13.6, 1H), 1.85 (s, 3H), 0.82 (d, J = 6.8, 6H).
(S)−2−アセチルアミノ−N−[2−(2−{3−[3−(3−シアノフェニル)−6−オキソ−6H−ピリダジン−1−イルメチル]フェニル}ピリミジン−5−イルオキシ)エチル]−3−メチルブチルアミド(「A8」)
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.65 (s, 2H), 8.43 (s, 1H), 8.38 (s, 1H), 8.26 (d, J = 7.2, 2H), 8.17 (d, J = 9.8, 1H), 7.91 (d, J = 7.6, 1H), 7.72 (t, J = 7.7, 1H), 7.45-7.55 (m, 2H), 7.16 (d, J = 9.7, 1H), 5.47 (s, 2H), 4.24 (m, 2H), 4.15 (d, J = 7.0, 1H), 3.43-3.61 (m, 2H), 1.95 (m, 1H), 1.89 (s, 3H), 0.85 (d, J = 6.6, 6H).
HPLC:Rt.=2.53分(方法B)、ESI:509(M+H);生成物は、トリフルオロ酢酸塩の形態である。
HPLC:Rt.=2.31分(方法D)、ESI:494(M+H);生成物は、トリフルオロ酢酸塩の形態である。
(S)−2−アミノ−5−(2−{3−[3−(1−メチル−1H−ピラゾール−4−イル)−6−オキソ−6H−ピリダジン−1−イルメチル]フェニル}ピリミジン−5−イルオキシ)ペンタン酸(「A11」)
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.62 (d, J = 3.0, 2H), 8.28 (s, 1H), 8.21 (s, 2H), 7.88 (s, 1H), 7.80 (d, J = 9.6, 1H), 7.45 (m, 2H), 7.05 (d, J = 9.6, 1H), 5.33 (s, 2H), 4.19 (t, J = 6.1, 2H), 3.87 (b, 3H), 3.17 (m, 2H), 1.87 (m, 3H), 1.78 - 1.67 (m, 1H).
100mg(0.28mmol)の2−[3−(5−ヒドロキシピリミジン−2−イル)ベンジル]−6−(1−メチル−1H−ピラゾール−4−イル)−2H−ピリダジン−3−オンを、6mlのDMFに溶解し、277mg(0.83mmol)のポリマー結合トリフェニルホスフィン(3mmol/g)および78mg(0.32mmol)のtert−ブチル(4−ヒドロキシメチルシクロヘキシルメチル)カルバメート(WO2008/040934と同様にして調製)を加える。反応混合物を室温にて15分間振盪し、196mg(0.83mmol)のジ−tert−ブチルアゾジカルボキシレートを、その後加える。反応混合物を室温にて3時間振盪し、さらに277mg(0.83mmol)のポリマー結合トリフェニルホスフィン(3mmol/g)および196mg(0.83mmol)のジ−tert−ブチルアゾジカルボキシレートを加え、混合物を室温にて18時間振盪する。反応混合物を、珪藻土を通して吸引により濾別し、酢酸エチルで洗浄する。濾液を蒸発させ、分取HPLCによって精製する。ジオキサン中の4N HCl1mlを、中間体に加え、混合物を室温にて15時間撹拌し、蒸発させる。
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.64 (d, J = 9.9, 2H), 8.28 (s, 1H), 8.21 (m, 2H), 7.96 (b, 3H), 7.89 (s, 1H), 7.81 (d, J = 9.6, 1H), 7.45 (m, 2H), 7.05 (d, J = 9.6, 1H), 5.33 (s, 2H), 4.12 (d, J = 7.0, 1H), 4.02 (d, J = 6.4, 1H), 2.70 - 2.80 (m, 1H), 2.70 - 2.59 (m, 1H), 1.80-1.91 (m, 3H), 1.78 - 1.69 (m, 1H), 1.42 - 1.62 (m, 4H), 1.13 - 0.93 (m, 2H).
40mg(0.077mmol)の2−{3−[5−(4−アミノメチルシクロヘキシルメトキシ)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)−2H−ピリダジン−3−オン(「A13a」)を、2mlのギ酸に溶解し、24μl(0.31mmol)のホルムアルデヒド溶液(35%)を加える。反応混合物を、100℃にて48時間撹拌する。反応混合物を蒸発させ、分取HPLCによって精製する。
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.62 (d, J = 5.8, 2H), 8.28 (s, 1H), 8.21 (d, J = 4.7, 2H), 7.89 (s, 1H), 7.80 (d, J = 9.7, 1H), 7.52 - 7.37 (m, 2H), 7.05 (d, J = 9.6, 1H), 5.33 (s, 2H), 4.09 (d, J = 7.0, 1H), 4.00 (d, J = 6.3, 1H), 2.13 - 2.07 (m, 6H), 0.82 - 2.10 (m, 12H).
3−(1−{3−[5−(4−アミノメチルシクロヘキシルメトキシ)ピリミジン−2−イル]ベンジル}−6−オキソ−1,6−ジヒドロピリダジン−3−イル)ベンゾニトリル(「A13b」)
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.64 (s, 2H), 8.30 (s, 1H), 8.22 (d, J = 7.5, 2H), 8.05 (s, 3H), 7.89 (s, 1H), 7.82 (d, J = 9.6, 1H), 7.53 - 7.37 (m, 2H), 7.06 (d, J = 9.6, 1H), 5.33 (s, 2H), 4.15 (s, 2H), 2.94 (d, J = 5.6, 2H), 0.82 (d, J = 6.4, 2H), 0.72 (d, J = 5.2, 2H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.63 (s, 2H), 8.33 - 8.41 (m, 3H), 8.22 - 8.26 (m, 2H), 8.17 (d, J = 9.8, 1H), 7.93 (d, J = 7.8, 1H), 7.72 (t, J = 7.9, 1H), 7.54 - 7.41 (m, 2H), 7.16 (d, J = 9.7, 1H), 5.45 (s, 2H), 4.12 (s, 2H), 2.77 (s, 2H), 0.65 (q, J = 6.5, 2H), 0.61 (q, J = 6.5, 2H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.62 (d, J = 7.4, 2H), 8.42 - 8.30 (m, 3H), 8.21-8.27 (m, 2H), 8.16 (d, J = 9.8, 1H), 7.92 (d, J = 7.8, 1H), 7.71 (t, J = 7.9, 1H), 7.44 - 7.51 (m, 2H), 7.15 (d, J = 9.8, 1H), 5.44 (s, 2H), 4.16 (dd, J = 6.5, 10.4, 1H), 4.00 (dd, J = 7.4, 10.5, 1H), 2.67 (d, J = 7.1, 2H), 1.26 (s, 1H), 1.05 (s, 1H), 0.69 - 0.57 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.62 (s, 2H), 8.37 (d, J = 10.0, 2H), 8.20-8.31 (m, 3H), 8.16 (d, J = 9.8, 1H), 7.92 (d, J = 7.8, 1H), 7.72 (t, J = 7.9, 1H), 7.46 - 7.52 (m, 2H), 7.15 (d, J = 9.7, 1H), 5.45 (s, 2H), 4.04 - 4.12 (m, 2H), 2.37 (dd, J = 6.1, 12.5, 1H), 2.25 (d, J = 4.0, 6H), 2.18 (dd, J = 7.2, 12.5, 1H), 1.12 (s, 1H), 0.95 (s, 1H), 0.69 - 0.58 (m, 1H), 0.49 (dt, J = 4.9, 9.7, 1H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.63 (s, 2H), 8.28 (s, 1H), 8.20 - 8.25 (m, 2H), 7.95 (b, 3H), 7.89 (s, 1H), 7.81 (d, J = 9.6, 1H), 7.53 - 7.38 (m, 2H), 7.05 (d, J = 9.6, 1H), 5.33 (s, 2H), 4.21 (dd, J = 6.3, 10.5, 1H), 4.01 (dd, J = 7.5, 10.5, 1H), 2.83 - 2.71 (m, 2H), 1.36 (d, J = 4.2, 1H), 1.11 (s, 1H), 0.77 - 0.65 (m, 2H).
生成物は、ギ酸塩の形態である;
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.66 (s, 2H), 8.38 (d, J = 8.1, 2H), 8.28 (s, 1H), 8.27 - 8.19 (m, 2H), 8.17 (d, J = 9.8, 1H), 7.92 (d, J = 7.7, 1H), 7.72 (t, J = 7.9, 1H), 7.54 - 7.42 (m, 2H), 7.15 (d, J = 9.7, 1H), 5.44 (s, 2H), 4.84 - 4.72 (m, 1H), 3.43 (dd, J = 7.8, 12.2, 1H), 2.05 (dd, J = 6.2, 11.6, 1H), 1.98 - 1.72 (m, 3H), 1.68 - 1.51 (m, 2H).
生成物は、塩酸塩の形態である;
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.69 (s, 2H), 8.30 (s, 3H), 8.21 - 8.25 (m, 2H), 7.89 (s, 1H), 7.81 (d, J = 9.6, 1H), 7.54 - 7.40 (m, 2H), 7.05 (d, J = 9.6, 1H), 5.34 (s, 2H), 4.99 (d, J = 2.5, 1H), 3.70 (s, 1H), 2.17 - 2.02 (m, 2H), 1.86 (t, J = 9.9, 3H), 1.67 (d, J = 9.1, 1H).
生成物は、塩酸塩の形態である;
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.89 (b, 1H), 8.66 (s, 2H), 8.64 - 8.51 (m, 1H), 8.39 (d, J = 6.8, 2H), 8.22 - 8.28 (m, 2H), 8.18 (d, J = 9.8, 1H), 7.94 (d, J = 7.8, 1H), 7.73 (t, J = 7.9, 1H), 7.44 - 7.52 (m, 2H), 7.17 (d, J = 9.7, 1H), 5.46 (s, 2H), 4.11 (d, J = 6.3, 2H), 3.31 (d, J = 12.5, 2H), 2.91 (d, J = 12.0, 2H), 2.13 (s, 1H), 1.94 (d, J = 12.4, 2H), 1.52 (d, J = 10.5, 2H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.57 (s, 2H), 8.28 (s, 1H), 8.21 (t, J = 3.7, 2H), 7.89 (s, 1H), 7.81 (d, J = 9.6, 1H), 7.53 - 7.37 (m, 2H), 7.05 (d, J = 9.6, 1H), 5.33 (s, 2H), 5.00 - 4.87 (m, 1H), 4.66 (dd, J = 3.9, 9.7, 1H), 4.18 - 4.10 (m, 1H), 3.87 (s, 3H), 2.39 (dt, J = 6.9, 14.0, 1H), 2.08 - 1.97 (m, 1H), 1.89 (dt, J = 7.0, 13.1, 1H), 1.80 - 1.54 (m, 3H).
3−(1−{3−[5−(3−ヒドロキシシクロペンチルオキシ)ピリミジン−2−イル]ベンジル}−6−オキソ−1,6−ジヒドロピリダジン−3−イル)ベンゾニトリル(「A23」)
1H NMR (500 MHz, DMSO-d6) δ [ppm] 9.09 (b, 1H), 8.67 (s, 2H), 8.39 (d, J = 7.1, 2H), 8.22-8.26 (m, 2H), 8.18 (d, J = 9.8, 1H), 7.94 (d, J = 7.8, 1H), 7.73 (t, J = 7.9, 1H), 7.56 - 7.44 (m, 2H), 7.17 (d, J = 9.7, 1H), 5.46 (s, 2H), 4.13 (d, J = 6.0, 2H), 3.61 (d, J = 11.2, 2H), 3.05 - 2.91 (m, 4H), 2.16 - 1.75 (m, 3H), 1.59 (dd, J = 11.4, 24.4, 2H), 1.08 (s, 1H), 0.72 - 0.60 (m, 2H), 0.38 (q, J = 4.5, 2H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.94 (s, 2H), 8.45 (s, 1H), 8.38 (t, J = 1.5, 1H), 8.30 (dt, J = 1.6, 7.4, 1H), 8.28 - 8.22 (m, 1H), 8.18 (d, J = 9.8, 1H), 7.99 - 7.87 (m, 1H), 7.72 (t, J = 7.9, 1H), 7.50 - 7.60 (m, 2H), 7.17 (d, J = 9.8, 1H), 5.47 (s, 2H), 4.95 (hept, J = 6.2, 1H), 1.35 (d, J = 6.2, 6H).
3.0g(8.33mmol)の2−[3−(5−ヒドロキシピリミジン−2−イル)ベンジル]−6−(1−メチル−1H−ピラゾール−4−イル)−2H−ピリダジン−3−オンを、30mlのDMFに溶解し、800μl(8.33mmol)のブロモ酢酸メチルおよび3.01g(9.16mmol)の炭酸セシウムを加え、混合物を室温にて1時間撹拌する。次に、約50mlの氷水を、反応混合物に撹拌しながらゆっくりと加える。沈殿物を吸引により濾別し、水で洗浄し、真空乾燥キャビネット中で50℃にて乾燥する。
m.p.175〜176°、ESI:433(M+H)。
3.4g(7.86mmol)の(2−{3−[3−(1−メチル−1H−ピラゾール−4−イル)−6−オキソ−6H−ピリダジン−1−イルメチル]フェニル}ピリミジン−5−イルオキシ)酢酸を、40mlのメタノールに懸濁させ、4mlの水および576mg(23.59mmol)の水酸化リチウムを加える。懸濁液を、RTにて1時間撹拌する。混合物を氷水で希釈し、濃塩酸を用いてpH3に調整し、その後短時間撹拌し、吸引により濾別し、50℃にて真空において乾燥する。
m.p.256〜259℃、ESI:419(M+H)。
1mlの塩化チオニルを、113mg(0.27mmol)の(2−{3−[3−(1−メチル−1H−ピラゾール−4−イル)−6−オキソ−6H−ピリダジン−1−イルメチル]フェニル}ピリミジン−5−イルオキシ)酢酸に加え、混合物を1時間還流する。混合物を、その後室温に冷却し、蒸発させ、トルエンと共に3回同時蒸発させる。粗生成物を、さらに精製せずに反応させる。
128mg(0.27mmol)の(2−{3−[3−(1−メチル−1H−ピラゾール−4−イル)−6−オキソ−6H−ピリダジン−1−イルメチル]フェニル}ピリミジン−5−イルオキシ)アセチルクロリドを、10mlのテトラヒドロフランに溶解し、1.35mlのテトラヒドロフラン中の2Mエチルアミンを加え、混合物を、室温にて1時間、室温における密封容器中で撹拌する。水を反応混合物に加え、それを次に吸引により濾別する。沈殿物を、水、メタノールおよびエーテルで洗浄し、乾燥する。
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.63 (s, 2H), 8.30 (s, 1H), 8.18-8.26 (m, 3H), 7.90 (s, 1H), 7.82 (d, J = 9.6, 1H), 7.54 - 7.39 (m, 2H), 7.06 (d, J = 9.6, 1H), 5.34 (s, 2H), 4.71 (s, 2H), 3.24 - 3.11 (m, 2H), 1.06 (t, J = 7.2, 3H).
N−メチル−2−(2−{3−[3−(1−メチル−1H−ピラゾール−4−イル)−6−オキソ−6H−ピリダジン−1−イルメチル]フェニル}ピリミジン−5−イルオキシ)アセトアミド(「A27」):
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.63 (s, 2H), 8.31 (s, 1H), 8.26 - 8.20 (m, 2H), 7.90 (d, J = 0.7, 1H), 7.81 (d, J = 9.6, 1H), 7.65 (s, 1H), 7.53 - 7.38 (m, 3H), 7.06 (d, J = 9.6, 1H), 5.35 (s, 2H), 4.70 (s, 2H).
6−(3−クロロフェニル)−2−{3−[5−(ピペリジン−4−イルメトキシ)ピリミジン−2−イル]ベンジル}−2H−ピリダジン−3−オン(「C1」)
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.64 (s, 2H), 8.36 (s, 1H), 8.21 - 8.26 (m, 1H), 8.12 (d, J = 9.8, 1H), 7.95 (s, 1H), 7.91 - 7.83 (m, 1H), 7.57 - 7.50 (m, 2H), 7.45 - 7.50 (m, 2H), 7.13 (d, J = 9.7, 1H), 5.44 (s, 2H), 4.06 (d, J = 6.3, 2H), 3.18 (b, 2H), 2.77 (b, 2H), 1.78 - 2.10 (m, 3H), 1.32 - 1.48 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.61 (s, 2H), 8.47 - 8.35 (m, 2H), 8.31 - 8.26 (m, 1H), 8.23 (d, J = 7.5, 1H), 8.10 (d, J = 9.8, 1H), 7.58 (t, J = 9.0, 1H), 7.45 (dt, J = 7.6, 15.1, 2H), 7.11 (d, J = 9.8, 1H), 5.42 (s, 2H), 4.08 (d, J = 6.1, 2H), 3.48 (d, J = 12.4, 2H), 3.35 - 3.09 (m, 1H), 2.98 (t, J = 11.7, 2H), 2.78 (d, J = 15.4, 3H), 2.11 - 1.77 (m, 4H), 1.54 (dd, J = 11.5, 24.3, 2H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.65 (s, 2H), 8.38 (d, J = 8.7, 2H), 8.22-8.27 (m, 2H), 8.17 (d, J = 9.8, 1H), 7.93 (d, J = 7.7, 1H), 7.72 (t, J = 7.8, 1H), 7.55 - 7.42 (m, 2H), 7.16 (d, J = 9.7, 1H), 5.44 (s, 2H), 4.28 (t, J = 5.6, 2H), 2.76 - 2.65 (m, 6H), 2.39 (d, J = 22.8, 4H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.66 (s, 2H), 8.28 (s, 2H), 8.22 (d, J = 7.6, 1H), 7.91 (s, 1H), 7.83 (d, J = 9.6, 1H), 7.42 - 7.51 (m, 2H), 7.07 (d, J = 9.6, 1H), 5.76 (s, 2H), 5.34 (s, 2H), 4.31 (t, J = 5.6, 2H), 4.17 (q, J = 7.3, 2H), 3.63 - 3.54 (m, 2H), 3.30 (superimposed, 4H), 2.74 (t, J = 5.6, 2H), 1.39 (t, J = 7.3, 3H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.66 (s, 2H), 8.29 (s, 1H), 8.21 - 8.26 (m, 2H), 7.93 (s, 1H), 7.84 (d, J = 9.6, 1H), 7.57 - 7.38 (m, 2H), 7.07 (d, J = 9.6, 1H), 5.76 (s, 2H), 5.35 (s, 2H), 4.30 (dd, J = 5.6, 11.5, 4H), 3.70 (t, J = 5.3, 2H), 3.64 - 3.52 (m, 2H), 3.30 (superimposed, 7H), 2.74 (t, J = 5.6, 2H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.63 (s, 2H), 8.39 (s, 1H), 8.26 (s, 1H), 8.23 (d, J = 6.9, 1H), 8.19 (d, J = 9.8, 1H), 8.12 (d, J = 9.9, 1H), 7.95 (d, J = 8.3, 1H), 7.55 - 7.42 (m, 2H), 7.16 (d, J = 9.8, 1H), 5.45 (s, 2H), 4.04 (d, J = 6.0, 2H), 2.80 (d, J = 11.0, 2H), 2.17 (s, 3H), 1.90 (t, J = 10.7, 2H), 1.75 (d, J = 10.4, 3H), 1.43 - 1.17 (m, 2H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.84 (s, 1H), 8.71 (s, 2H), 8.29 (s, 1H), 8.24 (d, J = 9.5, 2H), 7.90 (s, 1H), 7.82 (d, J = 9.6, 1H), 7.56 - 7.42 (m, 2H), 7.07 (d, J = 9.6, 1H), 5.35 (s, 2H), 5.08 - 5.19 (m, 1H), 3.88 (s, 3H), 2.77 (d, J = 7.0, 2H), 2.44 (d, J = 10.4, 2H), 2.09 (s, 12H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.63 (s, 2H), 8.36 (s, 1H), 8.22 (d, J = 5.9, 1H), 8.12 (d, J = 9.7, 1H), 7.96 (s, 1H), 7.87 (d, J = 4.4, 1H), 7.59 - 7.41 (m, 4H), 7.12 (d, J = 9.7, 1H), 5.44 (s, 2H), 4.04 (d, J = 5.8, 2H), 2.78 (d, J = 11.2, 2H), 2.15 (s, 3H), 1.85 (t, J = 11.3, 2H), 1.74 (d, J = 10.7, 3H), 1.32 (t, J = 11.9, 2H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 10.11 - 9.66 (m, 1H), 8.71 (s, 2H), 8.28 (s, 1H), 8.23 (d, J = 8.7, 2H), 7.89 (s, 1H), 7.81 (d, J = 9.6, 1H), 7.48 (dd, J = 5.1, 12.7, 2H), 7.06 (d, J = 9.6, 1H), 5.34 (s, 2H), 5.14 (b, 1H), 3.95 (s, 2H), 3.73 (s, 3H), 3.20 - 4.10 (b, 8H), 1.32 (d, J = 6.1, 3H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 9.80 (b, 1H), 8.70 (s, 2H), 8.30 (s, 1H), 8.23 (d, J = 8.6, 2H), 7.89 (s, 1H), 7.81 (d, J = 9.6, 1H), 7.53 - 7.40 (m, 2H), 7.05 (d, J = 9.6, 1H), 5.34 (s, 2H), 4.40 - 4.60 (m, 2H), 3.20 - 4.10 (b, 8H), 1.43 (s, 3H).
段階1:
[4−(6−オキソ−1,6−ジヒドロピリダジン−3−イル)ピラゾール−1−イル]エチルアセテートの調製
3−クロロ−6−{1−[2−(テトラヒドロピラン−2−イルオキシ)エチル]−1H−ピラゾール−4−イル}ピリダジンを、上記のプロセスと同様にして、リン酸三カリウム三水和物およびビス(トリフェニルホスフィン)パラジウム(II)クロリドを用いて調製する。
10mlの酢酸を、3.28g(5.5mmol)の3−クロロ−6−{1−[2−(テトラヒドロピラン−2−イルオキシ)エチル]−1H−ピラゾール−4−イル}ピリダジンに加え、反応混合物を、80℃にて15時間撹拌する。反応混合物を蒸発させ、残留物を、ジクロロメタンおよび飽和炭酸水素ナトリウム溶液に溶解し、水相をジクロロメタンで多数回抽出し、混ぜ合わせた有機相を硫酸ナトリウムで乾燥し、溶媒を蒸留して除去する。粗生成物を、シリカゲル上のカラムクロマトグラフィーによって精製する;ESI:249(M+H)。
2−[4−(1−{3−[5−(2−モルホリン−4−イルエトキシ)ピリミジン−2−イル]ベンジル}−6−オキソ−1,6−ジヒドロピリダジン−3−イル)ピラゾール−1−イル]エチルアセテートの調製
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.65 (s, 2H), 8.29 (s, 1H), 8.25 - 8.18 (m, 2H), 7.92 (s, 1H), 7.84 (d, J = 9.6, 1H), 7.54 - 7.37 (m, 2H), 7.06 (d, J = 9.6, 1H), 5.34 (s, 2H), 4.92 (b, 1H), 4.30 (t, J = 5.6, 2H), 4.17 (t, J = 5.5, 2H), 3.74 (t, J = 5.3, 2H), 3.65 - 3.50 (m, 4H), 3.32 (s, 2H), 2.80 - 2.66 (m, 2H), 2.50 (superimposed, 2H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.90 (s, 1H), 8.67 (s, 2H), 8.39 (d, J = 6.5, 2H), 8.29 - 8.21 (m, 2H), 8.18 (d, J = 9.8, 1H), 7.94 (d, J = 7.8, 1H), 7.73 (t, J = 7.9, 1H), 7.56 - 7.44 (m, 2H), 7.17 (d, J = 9.8, 1H), 5.46 (s, 2H), 4.12 (d, J = 6.0, 2H), 3.40 (superimposed, 3H), 3.01 (q, J = 10.1, 2H), 2.14 (m, 1H), 2.03 (d, J = 13.3, 2H), 1.59 (dd, J = 12.5, 23.3, 2H), 1.27 (t, J = 6.8, 6H).
NMR STI105/241.
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.66 (s, 2H), 8.44 (s, 1H), 8.38 (t, J = 1.5, 1H), 8.31 - 8.22 (m, 2H), 8.17 (d, J = 9.8, 1H), 7.96 - 7.85 (m, 1H), 7.72 (t, J = 7.9, 1H), 7.50 (dt, J = 7.5, 15.0, 2H), 7.16 (d, J = 9.8, 1H), 5.48 (s, 2H), 4.13 (d, J = 6.0, 2H), 3.20 - 3.60 (m, 3H), 3.13 (q, J = 7.3, 2H), 2.97 (t, J = 11.5, 2H), 2.24 - 2.01 (m, 3H), 1.50 - 1.70 (m, 2H), 1.24 (dt, J = 9.9, 17.5, 3H).
3−[1−(3−{5−[1−(2−メトキシエチル)ピペリジン−4−イルメトキシ]ピリミジン−2−イル}ベンジル)−6−オキソ−1,6−ジヒドロピリダジン−3−イル]ベンゾニトリル(「C24」)
1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.51 - 9.29 (b, 1H), 8.64 (s, 2H), 8.35 - 8.39 (m, 2H), 8.29 - 8.19 (m, 2H), 8.17 (d, J = 9.8, 1H), 7.93 (d, J = 8.0, 1H), 7.72 (t, J = 7.9, 1H), 7.54 - 7.44 (m, 2H), 7.15 (d, J = 9.8, 1H), 5.44 (s, 2H), 4.30 (b, 2H), 4.02 - 4.11 (m, 2H), 3.35 - 3.41 (m, 2H), 2.84 (m, 8H), 2.10 - 1.96 (m, 1H), 1.75 - 1.85 (m, 2H), 1.23 (d, J = 9.0, 2H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.64 (s, 2H), 8.37 (d, J = 9.4, 2H), 8.21 - 8.26 (m, 2H), 8.16 (d, J = 9.8, 1H), 8.00 (s, 1H), 7.92 (d, J = 7.7, 1H), 7.72 (t, J = 7.9, 1H), 7.55 - 7.41 (m, 2H), 7.16 (d, J = 9.7, 1H), 5.44 (s, 2H), 4.21 (d, J = 12.9, 1H), 4.08 (d, J = 6.3, 2H), 3.72 (d, J = 13.1, 1H), 3.02 - 3.11 (m, 1H), 2.61 - 2.69 (m, 1H), 2.04 - 2.16 (m, 1H), 1.83 (t, J = 15.8, 2H), 1.31 - 1.03 (m, 2H).
HPLC:2.48分(方法A)、ESI:512(M+H)。
3−{1−[3−(5−ヒドロキシピリミジン−2−イル)ベンジル]−6−オキソ−1,6−ジヒドロピリダジン−3−イル}ベンズアミド(「D1」)
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.62 (s, 2H), 8.37 (dd, J = 3.5, 4.9, 2H), 8.23 (tdd, J = 2.3, 4.0, 6.5, 2H), 8.17 (d, J = 9.8, 1H), 7.98 - 7.87 (m, 1H), 7.72 (t, J = 7.9, 1H), 7.55 - 7.42 (m, 2H), 7.16 (d, J = 9.7, 1H), 5.44 (s, 2H), 4.84 (hept, J = 6.0, 1H), 1.33 (d, J = 6.0, 6H).
1H NMR (400 MHz DMSO-d6) δ [ppm] 8.65 (s, 2H), 8.35 - 8.40 (m, 2H), 8.28 - 8.20 (m, 2H), 8.17 (d, J = 9.8, 1H), 7.99 - 7.87 (m, 1H), 7.72 (t, J = 7.9, 1H), 7.55 - 7.42 (m, 2H), 7.16 (d, J = 9.8, 1H), 5.45 (s, 2H), 3.95 (s, 3H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.65 (s, 2H), 8.30 (s, 1H), 8.23 (d, J = 7.9, 2H), 7.93 (s, 1H), 7.84 (d, J = 9.6, 1H), 7.54 - 7.38 (m, 2H), 7.06 (d, J = 9.6, 1H), 5.35 (s, 2H), 4.39 - 4.24 (m, 4H), 3.71 (dd, J = 5.0, 9.8, 4H), 3.30 (superimposed, s, 3H), 3.23 (s, 3H).
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.67 (s, 2H), 8.42 (s, 1H), 8.34 (s, 1H), 8.24 (dd, J = 8.7, 10.7, 2H), 8.13 (d, J = 9.8, 1H), 7.86 (d, J = 7.7, 1H), 7.66 (dd, J = 6.8, 14.7, 1H), 7.47 (dt, J = 7.6, 15.1, 2H), 7.12 (d, J = 9.8, 1H), 5.44 (s, 2H), 4.45 (ddd, J = 5.3, 10.9, 17.1, 2H), 3.78 (ddd, J = 4.9, 12.0, 29.8, 2H), 3.65 - 3.54 (m, 1H), 2.68 (s, 3H).
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.92 (s, 1H), 8.70 (s, 2H), 8.45 - 8.33 (m, 2H), 8.31 - 8.23 (m, 2H), 8.19 (d, J = 9.8, 1H), 7.95 (d, J = 7.8, 1H), 7.73 (t, J = 7.9, 1H), 7.47 - 7.53 (m, 2H), 7.17 (d, J = 9.8, 1H), 5.46 (s, 2H), 4.07 (s, 2H), 3.25 (d, J = 4.0, 2H), 2.89 (d, J = 4.7, 6H), 1.17 (s, 6H).
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.67 (s, 2H), 8.30 (s, 1H), 8.23 (t, J = 3.7, 2H), 7.90 (s, 1H), 7.82 (d, J = 9.6, 1H), 7.54 - 7.38 (m, 2H), 7.07 (d, J = 9.6, 1H), 5.34 (s, 2H), 5.08 (d, J = 5.0, 1H), 4.74 (m, 1H), 4.30 - 4.04 (m, 2H), 3.84 (d, J = 5.0, 1H), 3.46 (dd, J = 6.1, 11.4, 2H).
3−(1−{3−[5−(2,3−ジヒドロキシプロポキシ)ピリミジン−2−イル]ベンジル}−6−オキソ−1,6−ジヒドロピリダジン−3−イル)ベンゾニトリル(「D10」)
3−(1−{3−[5−(2−アミノエトキシ)ピリミジン−2−イル]ベンジル}−6−オキソ−1,6−ジヒドロピリダジン−3−イル)ベンゾニトリル(「D11」)
表1 Metキナーゼ阻害(酵素アッセイおよび/または細胞アッセイ)
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 (25)
- 式I
R1は、Ar、Het、A、OR2、O[C(R2)2]nAr、O[C(R2)2]nHet、N(R2)2、NR2[C(R2)2]nArまたはNR2[C(R2)2]nHetを示し、
R2は、HまたはA’を示し、
R3、R3’は、各々、互いに独立してH、Hal、A、OR2、CN、COOR2、CON(R2)2、NR2COA、NR2SO2A、SO2N(R2)2またはS(O)mAを示し、
Yは、[C(R2)2]nNR2COZ、[C(R2)2]nNR2COHet1、[C(R2)2]nCyc[C(R2)2]nN(R2)2、[C(R2)2]nCyc[C(R2)2]nOR2、[C(R2)2]nCyc[C(R2)2]nHet1、
Zは、CR2(NR2)2CR2(OR2)A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、[C(R2)2]nOR2、[C(R2)2]nN(R2)2、SR2、NO2、CN、COOR2、CON(R2)2、NR2COA、NR2SO2A、SO2N(R2)2、S(O)mA、CO−Het、Het、O[C(R2)2]nN(R2)2、O[C(R2)2]nHet、NHCOOA、NHCON(R2)2、NHCOO[C(R2)2]nN(R2)2、NHCOO[C(R2)2]nHet、NHCONH[C(R2)2]nN(R2)2、NHCONH[C(R2)2]nHet、OCONH[C(R2)2]nN(R2)2、OCONH[C(R2)2]nHet、CONR2[C(R2)2]nN(R2)2、CONR2[C(R2)2]nHetおよび/またはCOAによって単置換、二置換もしくは三置換されており、
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Hal、A、[C(R2)2]nOR2、[C(R2)2]nN(R2)2、SR2、NO2、CN、COOR2、CON(R2)2、NR2COA、NR2SO2A、SO2N(R3)2、S(O)mA、CO−Het1、[C(R2)2]nHet1、O[C(R2)2]nN(R2)2、O[C(R2)2]nHet1、NHCOOA、NHCON(R2)2、NHCOO[C(R2)2]nN(R2)2、NHCOO[C(R2)2]nHet1、NHCONH[C(R2)2]nN(R2)2、NHCONH[C(R2)2]nHet1、OCONH[C(R2)2]nN(R2)2、OCONH[C(R2)2]nHet1、CO−Het1、CHO、COA、=S、=NH、=NAおよび/または=O(カルボニル酸素)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、二環式または三環式の飽和、不飽和または芳香族の複素環を示し、
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、それは、A、OA、OH、COOH、COOA、[C(R2)2]nCyc、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、
Het2は、2−メトキシカルボニルピロリジン−4−イル、2−カルボキシピロリジン−4−イル、1−シクロプロピルメチルピペリジン−4−イル、ピペリジン−4−イル、モルホリン−2−もしくは4−イル、1−イソプロピルピペリジン−4−イル、1−メチルピペリジン−4−イル、4−ピペラジニル、1−メチルピロリジン−2−イル、1−tert−ブトキシカルボニル−ピペリジン−4−イル、1−エチルピペリジン−2−イル、1−(2−メトキシエチル)ピペリジン−4−イル、1−[2−(N,N−ジメチルアミノ)エチル]ピペリジン−4−イル、1,2,2,6,6−ペンタメチルピペリジン−4−イル、1−アザビシクロ[2.2.2]オクタ−3−イル、テトラヒドロピラン−4−イル、1−ホルミルピペリジン−4−イルまたは1−メチル−1−オキシ−ピペリジン−4−イルを示し、
Aは、1〜10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、ここで、1〜7個のH原子は、F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、
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、ここで、1〜5個のH原子は、Fによって置き換えられていてもよく、
Cycは、3〜7個のC原子を有するシクロアルキレンを示し、
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、0、1、2、3または4を示し、
pは、1、2、3、4または5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、互変異性体もしくは立体異性体、またはすべての比率でのそれらの混合物。 - R3、R3’が、Hを示す、
請求項1に記載の化合物、またはそれらの薬学的に使用可能な塩、互変異性体もしくは立体異性体、またはすべての比率でのそれらの混合物。 - Arが、CN、F、Cl、メトキシおよび/またはCONH2によって単置換または二置換されているフェニルを示す、
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、互変異性体もしくは立体異性体、またはすべての比率でのそれらの混合物。 - Hetが、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、2−ヒドロキシエチルおよび/または2−メトキシエチルによって単置換もしくは二置換されていてもよい、単環式の芳香族複素環を示す、
請求項1〜3のいずれか一項に記載の化合物、またはそれらの薬学的に使用可能な塩、互変異性体もしくは立体異性体、またはすべての比率でのそれらの混合物。 - 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、
ここで、1〜5個のH原子が、Fおよび/またはCl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す、
請求項1〜4のいずれか一項に記載の化合物またはそれらの薬学的に使用可能な塩、互変異性体もしくは立体異性体、またはすべての比率でのそれらの混合物。 - Hetが、フリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソキサゾリル、チアゾリル、イソチアゾリル、ピリジル、ピリミジニル、トリアゾリル、テトラゾリル、オキサジアゾリル、チアジアゾリル、ピリダジニルまたはピラジニルを示し、その各々が、A、2−ヒドロキシエチルまたは2−メトキシエチルによって単置換されている、
請求項1〜5のいずれか一項に記載の化合物またはそれらの薬学的に使用可能な塩、互変異性体もしくは立体異性体、またはすべての比率でのそれらの混合物。 - Het1が、ピロリジン、ピペリジン、ピペラジンまたはモルホリンを示し、その各々が、非置換であるか、またはA、OA、OH、COOHおよび/またはCOOAによって単置換もしくは二置換されている、
請求項1〜6のいずれか一項に記載の化合物またはそれらの薬学的に使用可能な塩、互変異性体もしくは立体異性体、またはすべての比率でのそれらの混合物。 - R2が、Hまたは1、2、3もしくは4個のC原子を有するアルキルを示す、
請求項1〜7のいずれか一項に記載の化合物またはそれらの薬学的に使用可能な塩、互変異性体もしくは立体異性体、またはすべての比率でのそれらの混合物。 - R1が、ArまたはHetを示し、
R2が、Hまたは1、2、3もしくは4個のC原子を有するアルキルを示し、
R3、R3’が、Hを示し、
Yが、[C(R2)2]nNR2COZ、[C(R2)2]nNR2COHet1、[C(R2)2]nCyc[C(R2)2]nN(R2)2、[C(R2)2]nCyc[C(R2)2]nOR2、[C(R2)2]nCyc[C(R2)2]nHet1、
Zが、CR2(NR2)2CR2(OR2)Aを示し、
Arが、CN、F、Cl、メトキシおよび/またはCONH2によって単置換または二置換されているフェニルを示し、
Hetが、1〜4個のN、Oおよび/またはS原子を有する単環式の芳香族複素環を示し、それが、非置換であるか、またはA、2−ヒドロキシエチルおよび/または2−メトキシエチルによって単置換もしくは二置換されていてもよく、
Het1が、ピロリジン、ピペリジン、ピペラジンまたはモルホリンを示し、その各々が、非置換であるか、またはA、OA、OH、COOH、COOAおよび/または[C(R2)2]nCycによって単置換もしくは二置換されており、
Het2が、2−メトキシカルボニルピロリジン−4−イル、2−カルボキシ−ピロリジン−4−イル、1−シクロプロピルメチルピペリジン−4−イル、ピペリジン−4−イル、モルホリン−2−または4−イル、1−イソプロピルピペリジン−4−イル、1−メチルピペリジン−4−イル、4−ピペラジニル、1−メチルピロリジン−2−イル、1−tert−ブトキシカルボニルピペリジン−4−イル、1−エチルピペリジン−2−イル、1−(2−メトキシエチル)ピペリジン−4−イル、1−[2−(N,N−ジメチルアミノ)エチル]ピペリジン−4−イル、1,2,2,6,6−ペンタメチルピペリジン−4−イル、1−アザビシクロ[2.2.2]オクタ−3−イル、テトラヒドロピラン−4−イル、1−ホルミルピペリジン−4−イル、1−メチル−1−オキシピペリジン−4−イルを示し、
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、
ここで1〜5個のH原子が、Fおよび/またはCl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、
Cycが、3〜7個のC原子を有するシクロアルキレンを示し、
Halが、F、Cl、BrまたはIを示し、
mが、0、1または2を示し、
nが、0、1、2、3または4を示し、
pが、1、2、3または4を示す、
請求項1〜8のいずれか一項に記載の化合物またはそれらの薬学的に使用可能な塩、互変異性体もしくは立体異性体、またはすべての比率でのそれらの混合物。 - 以下の群
- 請求項1〜10のいずれか一項に記載の化合物、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の製造方法であって、
a)式II
で表される化合物を、
式III
Lは、Cl、Br、Iまたは遊離の、もしくは反応的に官能基修飾されたOH基を示す、
で表される化合物と反応させること、
あるいは、
b)ラジカルYを、別のラジカルYに、
i)アミノ基をアシル化またはアルキル化すること、
ii)水酸基をエーテル化すること
によって変換すること、
あるいは
c)それらを、加溶媒分解剤または水素化分解剤で処理することによってそれらの官能的誘導体の1種から遊離させること、
および/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1〜10のいずれか一項に記載の少なくとも1種の化合物、および/または、それらの薬学的に使用可能な塩、互変異性体もしくは立体異性体、またはすべての比率でのそれらの混合物、ならびに、任意に賦形剤および/または補助剤を含む、医薬。
- 哺乳類における愁訴、血管形成、癌、腫瘍形成、成長または増殖、動脈硬化、眼の疾患、年齢により誘発された黄斑変性症、脈絡膜血管新生または糖尿病性網膜症、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、代謝性疾患または免疫系の疾患、自己免疫性疾患、肝硬変、糖尿病または血管の疾患、または不安定性または浸透性の処置のための、請求項12に記載の医薬。
- 固形腫瘍、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、または炎症、乾癬、または関節リウマチの成長を促進する腫瘍細胞、病理学的血管新生または血管形成の増殖の処置のための、請求項12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13または14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15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15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16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13または14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19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20に記載の使用。
- (a)請求項1〜10のいずれか一項に記載の式Iで表される化合物および/または、それらの薬学的に使用可能な塩、互変異性体もしくは立体異性体、またはすべての比率でのそれらの混合物の有効量、
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)。 - 以下の群
- 請求項23に記載の少なくとも1種の化合物、および/または、それらの薬学的に使用可能な塩、互変異性体もしくは立体異性体、またはすべての比率でのそれらの混合物、ならびに、任意に賦形剤および/または補助剤を含む、医薬。
- 請求項23に記載の化合物、または、それらの薬学的に使用可能な塩、互変異性体もしくは立体異性体、またはすべての比率でのそれらの混合物の、
腫瘍、癌および癌疾患の処置のための医薬の製造のための使用。
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- 2009-11-24 CN CN200980152038.8A patent/CN102264727B/zh active Active
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ZA201105440B (en) | 2012-03-28 |
JP2012513418A (ja) | 2012-06-14 |
US8637518B2 (en) | 2014-01-28 |
WO2010072296A1 (de) | 2010-07-01 |
PT2367815E (pt) | 2015-02-20 |
AR074688A1 (es) | 2011-02-02 |
CN102264727A (zh) | 2011-11-30 |
BRPI0923497A2 (pt) | 2019-09-24 |
KR20110098854A (ko) | 2011-09-01 |
EP2367815A1 (de) | 2011-09-28 |
HRP20150375T1 (hr) | 2015-05-22 |
AU2009331991B2 (en) | 2015-10-22 |
AU2009331991A1 (en) | 2011-08-11 |
PL2367815T3 (pl) | 2015-04-30 |
EP2367815B1 (de) | 2015-01-14 |
CY1116191T1 (el) | 2017-02-08 |
HUE025138T2 (en) | 2016-03-29 |
EA201100966A1 (ru) | 2012-01-30 |
MX2011006652A (es) | 2011-07-12 |
SI2367815T1 (sl) | 2015-05-29 |
DK2367815T3 (en) | 2015-03-09 |
CA2747863A1 (en) | 2010-07-01 |
CA2747863C (en) | 2016-08-23 |
DE102008062826A1 (de) | 2010-07-01 |
CN102264727B (zh) | 2014-11-05 |
ES2532139T3 (es) | 2015-03-24 |
US20110257181A1 (en) | 2011-10-20 |
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