JP6527520B2 - ピルビン酸脱水素酵素キナーゼの阻害剤としてのn1−(3,3,3−トリフルオロ−2−ヒドロキソ−2−メチルプロピオニル)−ピペリジン誘導体 - Google Patents
ピルビン酸脱水素酵素キナーゼの阻害剤としてのn1−(3,3,3−トリフルオロ−2−ヒドロキソ−2−メチルプロピオニル)−ピペリジン誘導体 Download PDFInfo
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- JP6527520B2 JP6527520B2 JP2016540613A JP2016540613A JP6527520B2 JP 6527520 B2 JP6527520 B2 JP 6527520B2 JP 2016540613 A JP2016540613 A JP 2016540613A JP 2016540613 A JP2016540613 A JP 2016540613A JP 6527520 B2 JP6527520 B2 JP 6527520B2
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- methyl
- mmol
- trifluoro
- hydroxy
- pyrazol
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- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 1
- 229960004824 triptorelin Drugs 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
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229950010938 valspodar Drugs 0.000 description 1
- 108010082372 valspodar Proteins 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 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
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine 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
- 229960000237 vorinostat Drugs 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 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
- 229950008250 zalutumumab Drugs 0.000 description 1
- 229950009002 zanolimumab Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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Description
本発明は、ピルビン酸脱水素酵素キナーゼ(PDHK)を阻害する新規なピペリジン誘導体、それらを含む医薬組成物、それらの製造方法およびがんの処置のための療法におけるそれらの使用に関する。
ピルビン酸脱水素酵素キナーゼ(またピルビン酸脱水素酵素複合体キナーゼ、PDCキナーゼまたはPDHK)は、ATPを使用してそれをリン酸化することによって酵素ピルビン酸脱水素酵素を不活性化する役割を果たすキナーゼ酵素である。
(ピルビン酸脱水素酵素キナーゼを、また時々「PDK1」として知られているホスホイノシチド依存性キナーゼ1と混同するべきではない。)
ヒトにおけるPDHKの4種の知られているアイソザイムがある:PDHK1〜PDHK4。
ウィキペディア、ピルビン酸脱水素酵素キナーゼ;
T.E. Roche et al., Cell. Mol. Life Sci. 64 (2007) 830-849;
A. Kumar et al., Chemico-Biological Interactions 199 (2012) 29-37;
I.Papandreou et al., Int. J. Cancer: 128, 1001-1008 (2011);
G. Sutendra et al., frontiers in oncology, 2013, vol. 3, 1-11.
本発明は、特に、PDHK、好ましくはPDHK2を阻害する式Iで表される化合物、これらの化合物を含む組成物、ならびに、PDHKに誘導される疾患および愁訴の処置のためのその使用のための方法に関する。
フルオレン誘導体は、疾患、例えば糖尿病およびがんの処置のためのPDHK阻害剤としてEP 2 345 629 A1に記載されている。
TGR5アゴニストとしての使用のための他のピラゾール誘導体は、WO 2012/082947に開示されている。
LRRK2モジュレーターとしての使用のためのピラゾリルアミノピリミジン誘導体の製造は、WO 2012/062783に記載されている。
新規なプロリルカルボキシペプチダーゼ阻害剤としての置換ピラゾールおよびトリアゾールの製造は、WO 2011/143057に記載されている。
糖尿病および代謝障害の処置のための置換ピペリジニルチアゾール誘導体および類似体は、WO 2008/083238に開示されている。
p38キナーゼ阻害剤としてのヘテロアリールピラゾールは、US 6,979,686 B1に記載されている。
Rは、ピラゾール−ジイル、イミダゾール−ジイル、イソキサゾール−ジイルまたはトリアゾール−ジイルを示し、その各々は、非置換であるか、またはR2によって単置換されており、
R1は、(CH2)nAr、(CH2)nHet、AまたはCycを示し、
R2は、A’、メトキシ、ヒドロキシメチル、COOA’、CN、COOH、CONH2またはOHを示し、
R3は、H、A’、COOA’またはCN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つもしくは2つの隣接していないCHおよび/もしくはCH2基は、N−、O−および/もしくはS−原子によって置き換えられていてもよく、かつ/またはここで1〜7個のH原子は、R4によって置き換えられていてもよく、
R4は、F、ClまたはOHを示し、
R5は、HまたはA’を示し、
Halは、F、Cl、BrまたはIを示し、
mは、1、2、3または4を示し、
nは、0、1または2を示し、
pは、0、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許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物に関する。
さらに、本発明は、式Iで表される化合物の薬学的に許容し得る誘導体に関する。
薬学的に許容し得る誘導体という用語は、例えば、本発明の化合物の塩、またいわゆるプロドラッグ化合物をも意味するものと解釈される。
加えて、「治療的有効量」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、防止または解消、あるいはまた疾患、愁訴もしくは障害の進行の低減
を有する量を示す。
表現「治療的有効量」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も包含する。
これらは、特に好ましくは立体異性の化合物の混合物である。
で表される化合物を
式III
で表される化合物と反応させ、
ならびに/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。
Cyc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し、好ましくは非置換であるか、またはOHによって単置換されている。
R3は、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、ペンチル、ヘキシルまたはトリフルオロメチル、特に好ましくはH、メチルまたはトリフルオロメチルを示す。
R5は、好ましくはHまたはメチルを示す。
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以上のキラル中心を有していてもよく、したがって様々な立体異性体の形態で存在し得る。式Iは、すべてのこれらの形態を包含する。
Ibにおいて、R3は、HまたはA’を示し;
Icにおいて、Arは、フェニルを示し、それは、非置換であるか、またはHal、A、CNおよび/もしくはOAによって単置換、二置換、三置換、四置換もしくは五置換されており;
R1は、(CH2)nAr、(CH2)nHet、AまたはCycを示し、
R2は、A’、メトキシまたはヒドロキシメチルを示し、
R3は、HまたはA’を示し、
Arは、フェニルを示し、それは、非置換であるか、またはHal、A、CNおよび/もしくはOAによって単置換、二置換、三置換、四置換もしくは五置換されており、
Cycは、3、4、5、6または7個のC原子を有する環状アルキルを示し、それは、非置換であるか、またはOHによって単置換されており、
R4は、F、ClまたはOHを示し、
Halは、F、Cl、BrまたはIを示し、
nは、0、1または2を示す、
ならびにそれらの薬学的に許容し得る塩、互変異性体および立体異性体であり、あらゆる比率でのそれらの混合物を含む。
式Iで表される化合物を、好ましくは、式IIで表される化合物を式IIIで表される化合物と反応させることにより得ることができる。
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の、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別の塩の添加はまた、好ましい場合がある。
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。
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、当該分野で公知の手順によって、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の形態は、大部分、慣用的な方法によって製造される。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。かかる塩基は、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。
さらに、式Iで表される化合物が同位体で標識されたその形態を含むことを、意図する。式Iで表される化合物の同位体で標識された形態は、化合物の1個以上の原子が通常天然に存在する原子の原子質量または質量数と異なる原子質量または質量数を有する原子(単数)または原子(複数)によって置き換えられているという事実とは別に、この化合物と同一である。
局所投与に適合した医薬化合物を、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に適合した医薬製剤は、薬用キャンディー、トローチおよび洗口剤を包含する。
直腸内投与に適合した医薬製剤を、坐剤または浣腸剤の形態で投与することができる。
膣内投与に適合した医薬製剤を、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製剤として投与することができる。
(a)式Iで表される化合物ならびに/またはそれらの薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる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
の別個のパックからなるセット(キット)に関する。
ならびに、溶解した形態または凍結乾燥形態での有効量のさらなる医薬活性成分を含む個別のアンプルを含んでもよい。
本発明は特に、がん、糖尿病および心臓の虚血の処置のための使用のための、式Iで表される化合物ならびにそれらの薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物に関する。
特に好ましくは、本発明は、疾患ががんである方法に関し、投与が、同時、連続的または少なくとも1種の他の活性薬剤の投与との交互である。
例えばアルトレタミン、ベンダムスチン、ブスルファン、カルムスチン、クロラムブシル、クロルメチン、シクロホスファミド、ダカルバジン、イホスファミド、インプロスルファン、トシラート、ロムスチン、メルファラン、ミトブロニトール、ミトラクトール、ニムスチン、ラニムスチン、テモゾロミド、チオテパ、トレオスルファン、メクロレタミン、カルボコン;アパジコン、ホテムスチン、グルホスファミド(glufosfamide)、パリホスファミド(palifosfamide)、ピポブロマン、トロホスファミド、ウラムスチン(uramustine)、TH−3024、VAL−0834;
例えばカルボプラチン、シスプラチン、エプタプラチン(eptaplatin)、ミリプラチン水和物、オキサリプラチン、ロバプラチン(lobaplatin)、ネダプラチン、ピコプラチン、サトラプラチン;ロバプラチン、ネダプラチン、ピコプラチン、サトラプラチン;
例えばアムルビシン、ビサントレン(bisantrene)、デシタビン、ミトキサントロン、プロカルバジン、トラベクテジン、クロファラビン;アムサクリン、ブロスタリシン(brostallicin)、ピクサントロン、ラロムスチン(laromustine)1、3;
例えばエトポシド、イリノテカン、ラゾキサン、ソブゾキサン、テニポシド、トポテカン;アモナフィド(amonafide)、ベロテカン(belotecan)、エリプチニウムアセタート(elliptinium acetate)、ボレロキシン;
例えばカバジタキセル、ドセタキセル、エリブリン、イクサベピロン、パクリタキセル、ビンブラスチン、ビンクリスチン、ビノレルビン、ビンデシン、ビンフルニン;フォスブレタブリン、テセタキセル(tesetaxel);
例えばアスパラギナーゼ3、アザシチジン、レボホリナートカルシウム、カペシタビン、クラドリビン、シタラビン、エノシタビン、フロクスウリジン、フルダラビン、フルオロウラシル、ゲムシタビン、メルカプトプリン、メトトレキサート、ネララビン、ペメトレキセド、プララトレキサート、アザチオプリン、チオグアニン、カルモフール;ドキシフルリジン、エラシタラビン(elacytarabine)、ラルチトレキセド、サパシタビン(sapacitabine)、テガフール2、3、トリメトレキサート;
例えばブレオマイシン、ダクチノマイシン、ドキソルビシン、エピルビシン、イダルビシン、レバミソール、ミルテホシン、マイトマイシンC、ロミデプシン、ストレプトゾシン、バルルビシン、ジノスタチン、ゾルビシン、ダウノルビシン、プリカマイシン;アクラルビシン、ペプロマイシン、ピラルビシン;
例えばアバレリックス、アビラテロン、ビカルタミド、ブセレリン、カルステロン、クロロトリアニセン、デガレリクス、デキサメタゾン、エストラジオール、フルオコルトロン、フルオキシメステロン、フルタミド、フルベストラント、ゴセレリン、ヒストレリン、リュープロレリン、メゲストロール、ミトタン、ナファレリン、ナンドロロン、ニルタミド、オクトレオチド、プレドニゾロン、ラロキシフェン、タモキシフェン、サイロトロピンアルファ、トレミフェン、トリロスタン、トリプトレリン、ジエチルスチルベストロール;アコルビフェン(acolbifene)、ダナゾール、デスロレリン(deslorelin)、エピチオスタノール、オルテロネル(orteronel)、エンザルタミド1,3;
例えばアミノグルテチミド、アナストロゾール、エキセメスタン、ファドロゾール、レトロゾール、テストラクトン;ホルメスタン;
例えばクリゾチニブ、ダサチニブ、エルロチニブ、イマチニブ、ラパチニブ、ニロチニブ、パゾパニブ、レゴラフェニブ、ルキソリチニブ、ソラフェニブ、スニチニブ、バンデタニブ、ベムラフェニブ、ボスチニブ、ゲフィチニブ、アキシチニブ;アファチニブ、アリサーチブ(alisertib)、ダブラフェニブ、ダコミチニブ(dacomitinib)、ジナシクリブ(dinaciclib)、ドビチニブ(dovitinib)、エンザスタウリン、ニンテダニブ、レンバチニブ、リニファニブ、リンシチニブ(linsitinib)、マシチニブ(masitinib)、ミドスタウリン(midostaurin)、モテサニブ、ネラチニブ、オランチニブ(orantinib)、ペリフォシン、ポナチニブ、ラドチニブ(radotinib)、リゴセルチブ(rigosertib)、ティピファニブ、チバンチニブ、チボザニブ、トラメチニブ、ピマセルチブ(pimasertib)、ブリバニブアラニナート、セジラニブ、アパチニブ(apatinib)4、カボザンチニブS−マラート1,3、イブルチニブ1,3、イコチニブ(icotinib)4、ブパルリシブ(buparlisib)2、シパチニブ(cipatinib)4、コビメチニブ1,3、イデラリシブ1,3、フェドラチニブ(fedratinib)1、XL−6474;
例えばメトキサレン3;ポルフィマーナトリウム、タラポルフィン、テモポルフィン;
例えばアレムツズマブ、ベシレソマブ、ブレンツキシマブベドチン、セツキシマブ、デノスマブ、イピリムマブ、オファツムマブ、パニツムマブ、リツキシマブ、トシツモマブ、トラスツズマブ、ベバシズマブ、ペルツズマブ2,3;カツマキソマブ、エロツズマブ、エプラツズマブ、ファーレツズマブ、モガムリズマブ、ネシツムマブ、ニモツズマブ(nimotuzumab)、オビヌツズマブ、オカラツズマブ(ocaratuzumab)、オレゴボマブ、ラムシルマブ、リロツムマブ、シルツキシマブ、トシリズマブ、ザルツムマブ、ザノリムマブ、マツズマブ、ダロツズマブ(dalotuzumab)1,2,3、オナルツズマブ(onartuzumab)1,3、ラコツモマブ(racotumomab)1、タバルマブ(tabalumab)1,3、EMD−5257974、ニボルマブ1,3;
例えばアルデスロイキン、インターフェロンアルファ2、インターフェロンアルファ2a3、インターフェロンアルファ2b2、3;セルモロイキン、タソネルミン、テセロイキン、オプレルベキン1,3、組換えインターフェロンベータ−1a4;
例えばデニロイキンジフチトクス、イブリツモマブチウキセタン、イオベングアン(iobenguane)I123、プレドニムスチン、トラスツズマブエムタンシン、エストラムスチン、ゲムツズマブ、オゾガマイシン、アフリベルセプト;シトレデキンベスドトックス(cintredekin besudotox)、エドトレオチド(edotreotide)、イノツズマブオゾガマイシン、ナプツモマブ・エスタフェナトクス、オポルツズマブモナトックス(oportuzumab monatox)、テクネチウム(99mTc)アルシツモマブ1,3、ビンタフォリド1,3;
例えばシプロイセル3;ビテスペン3、エメペピムト(emepepimut)−S3、oncoVAX4、リンドペピムト(rindopepimut)3、troVax4、MGN−16014、MGN−17034;
アリトレチノイン、ベキサロテン、ボルテゾミブ、エベロリムス、イバンドロン酸、イミキモド、レナリドミド、レンチナン、メチロシン、ミファムルチド、パミドロン酸、ペグアスパルガーゼ、ペントスタチン、シプロイセル3、シゾフィラン、タミバロテン、テムシロリムス、サリドマイド、トレチノイン、ビスモデギブ、ゾレドロン酸、ボリノスタット;セレコキシブ、シレンジチド(cilengitide)、エンチノスタット(entinostat)、エタニダゾール、ガネテスピブ(ganetespib)、イドロノキシル(idronoxil)、イニパリブ(iniparib)、イキサゾミブ(ixazomib)、ロニダミン、ニモラゾール、パノビノスタット、ペレチノイン、プリチデプシン(plitidepsin)、ポマリドミド、プロコダゾール(procodazol)、リダフォロリムス、タスキニモド(tasquinimod)、テロトリスタット(telotristat)、チマルファシン(thymalfasin)、チラパザミン、トレドスタット(tosedostat)、トラベデルセン、ウベニメクス、バルスポダル(valspodar)、ゲンジシン(gendicine)4、ピシバニール4、レオリシン(reolysin)4、レタスピマイシン塩酸塩1、3、トレバナニブ(trebananib)2,3、ビルリジン(virulizin)4、カーフィルゾミブ1,3、エンドスタチン4、イムコテル(immucothel)4、ベリノスタット(belinostat)3、MGN−17034;
1Prop. INN(提唱された国際一般的名称(Proposed International Nonproprietary Name))
2Rec. INN(推奨された国際一般的名称(Recommended International Nonproprietary names))
3USAN(米国一般名(United States Adopted Name))
4INNなし。
aq(水溶性)、h(時間)、g(グラム)、L(リットル)、mg(ミリグラム)、MHz(メガヘルツ)、min.(分)、mm(ミリメートル)、mmol(ミリモル)、mM(ミリモル)、m.p.(融点)、eq(当量)、mL(ミリリットル)、L(マイクロリットル)、ACN(アセトニトリル)、AcOH(酢酸)、CDCl3(重水素化クロロホルム)、CD3OD(重水素化メタノール)、CH3CN(アセトニトリル)、c−hex(シクロヘキサン)、DCC(ジシクロヘキシルカルボジイミド)、DCM(ジクロロメタン)、DIC(ジイソプロピルカルボジイミド)、DIEA(ジイソプロピルエチル−アミン)、DMF(ジメチルホルムアミド)、DMSO(ジメチルスルホキシド)、DMSO−d6(重水素化ジメチルスルホキシド)、EDC(1−(3−ジメチル−アミノ−プロピル)−3−エチルカルボジイミド、ESI(エレクトロスプレーイオン化)、EtOAc(酢酸エチル)、Et2O(ジエチルエーテル)、EtOH(エタノール)、HATU(ジメチルアミノ−([1,2,3]トリアゾロ[4,5−b]ピリジン−3−イルオキシ)−メチレン]−ジメチル−アンモニウムヘキサフルオロホスファート)、HPLC(高速液体クロマトグラフィー)、i−PrOH(2−プロパノール)、K2CO3(炭酸カリウム)、LC(液体クロマトグラフィー)、MeOH(メタノール)、MgSO4(硫酸マグネシウム)、MS(質量分析)、MTBE(メチルtert−ブチルエーテル)、NaHCO3(重炭酸ナトリウム)、NaBH4(水素化ホウ素ナトリウム)、NMM(N−メチルモルホリン)、NMR(核磁気共鳴)、PyBOP(ベンゾトリアゾール−1−イル−オキシ−トリス−ピロリジノ−ホスホニウムヘキサフルオロホスファート)、RT(室温)、Rt(保持時間)、SPE(固相抽出)、TBTU(2−(1−H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロミウムテトラフルオロボラート、TEA(トリエチルアミン)、TFA(トリフルオロ酢酸)、THF(テトラヒドロフラン)、TLC(薄層クロマトグラフィー)、UV(紫外線)。
略語:
GST=グルタチオン−S−転移酵素
FRET=蛍光共鳴エネルギー移動
HTRF(登録商標)=(均質時間分解蛍光)
HEPES=4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルホン酸緩衝液
DTT=ジチオトレイトール
BSA=ウシ血清アルブミン
CHAPS=3−[(3−クロルアミドプロピル)ジメチルアンモニオ]−1−プロパンスルホナート
PDHK2についての生化学的活性アッセイは、PDHK2によるリン酸化によるPDCの不活性化に基づく。アッセイを、2ステップにおいて行う:単離したPDCがPDHK2によって補助基質としてのATPでリン酸化される酵素的PDHK2反応、ならびにピルビン酸塩およびNADがアセチル補酵素AおよびNADHに変換されるPDC活性アッセイ。PDC活性は、NADHの増大に対して相関し、そのために増大する蛍光シグナル(Exc 340nm、Em 450nm)によって直接検出可能である。PDHK2の阻害は、より低いリン酸化状態ならびにそのためにPDCの活性のより少ない減少およびNADH蛍光シグナルのより強い増大をもたらす。
ITC測定を、VP−ITCのマイクロ熱量計(Microcal, LLC / GE Healthcare Bio-Sciences AB, Uppsala, Sweden)で行った。一般に、滴定を、タンパク質(50μM)を試験化合物(5μM)に対して12μl注入において滴定することにより行った。すべての結合実験を、30℃で行った。一般に、試験化合物は、1%DMSOの最大の最終濃度を有する測定緩衝液中への希釈形態DMSO原液であった。測定緩衝液は、20mMのHEPES、135mMのKCl、1mMのTCEP、2mMのMgCl2、15mMのNaH2PO4、pH7.5であった。ヒトPDHK2(12−407)を、大腸菌中でHisタグタンパク質として産生し、アフィニティークロマトグラフィーによって精製した。
化合物活性を、細胞免疫蛍光検査法において決定した。ヒトHEK293T細胞を、透明な底を有する黒色384ウェルプレート中に播種し、一晩成長させた。
HPLC方法P:
勾配:3.3min;流量:2.4ml/min、0minから4%のB、2.8min100%のB、3.3min100%のB
A:水+HCOOH(0.05%Vol.);B:アセトニトリル+HCOOH(0.04%Vol.)
カラム:Chromolith SpeedROD RP 18e 50-4.6
波長:220nm
Agilent Apparatus
HPLC方法S:
勾配:流量:2ml/min、0minから5%のB、8.1min100%のB、8.5min5%のB、10min5%のB
A:水+TFA(0.1%Vol.);B:アセトニトリル+TFA(0.1%Vol.)
カラム:XBridge C8、3.5μm、4.6×50mm
波長:220nm
ピラゾリル−ピペリジン誘導体:
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−1−[4−(2−p−トリル−2H−ピラゾール−3−イル)−ピペリジン−1−イル]−プロパン−1−オン(「A1」)の合成
1.1 4−((E)−3−ジメチルアミノ−アクリロイル)−ピペリジン−1−カルボン酸tert−ブチルエステル
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−1−{4−[2−(4−メトキシ−フェニル)−2H−ピラゾール−3−イル]−ピペリジン−1−イル}−2−メチル−プロパン−1−オン(「A2」)
19.1 4−[2−(5−ブロモ−ピリミジン−2−イル)−2H−ピラゾール−3−イル]−ピペリジン−1−カルボン酸tert−ブチルエステル
「A32」(ステップ32.3)について記載した通りの製造。
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−1−{4−[2−(4−イソプロピル−フェニル)−2H−ピラゾール−3−イル]−ピペリジン−1−イル}−2−メチル−プロパン−1−オン(「A22」)
収率:70mg(56%)の無色固体;(純度100%、Rt:2.06min、[M+H]+ 416);1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.57 (d, J = 1.9 Hz, 1H), 7.43 (t, J = 8.9 Hz, 1H), 7.09 (dd, J = 12.1, 2.7 Hz, 1H), 7.02 (s, 1H), 6.95 - 6.90 (m, 1H), 6.36 - 6.24 (m, 1H), 4.88 - 4.21 (m, 2H), 3.85 (s, 3H), 3.12 - 2.77 (m, 1H), 2.71 - 2.60 (m, 1H), 2.59 - 2.44 (m, 1H), 1.82 - 1.65 (m, 2H), 1.63 - 1.33 (m, 5H).
29.1 4−(2H−ピラゾール−3−イル)−ピペリジン−1−カルボン酸tert−ブチルエステル
例「A32」(ステップ32.3)について記載したとおりの製造。
分取HPLC(Agilent(登録商標)、カラム:SunFireTM Prep C18 OBDTM 5μM;30×150mm)による精製。純粋な画分を凍結乾燥した;収率:13mg(41%)、無色固体;(純度100%、Rt:1.93min、[M+H]+ 403−405);1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.53 - 8.45 (m, 2H), 8.06 (dd, J = 8.8, 2.6 Hz, 1H), 7.91 - 7.85 (m, 1H), 7.07 (s, 1H), 6.50 (d, J = 2.6 Hz, 1H), 4.86 - 4.32 (m, 2H), 3.28 - 3.09 (m, 1H), 3.06 - 2.95 (m, 1H), 2.91 - 2.73 (m, 1H), 2.04 - 1.92 (m, 2H), 1.75 - 1.56 (m, 2H), 1.54 (s, 3H).
逆相フラッシュクロマトグラフィー(CombiFlashRF 200)による精製;収率:89mg(27%)の無色固体;(純度100%、Rt:2.05min、[M+H]+ 416);
1H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J = 1.9 Hz, 1H), 7.43 (t, J = 8.9 Hz, 1H), 7.09 (dd, J = 12.1, 2.7 Hz, 1H), 7.02 (s, 1H), 6.95 - 6.90 (m, 1H), 6.36 - 6.24 (m, 1H), 4.88 - 4.21 (m, 2H), 3.85 (s, 3H), 3.12 - 2.77 (m, 1H), 2.71 - 2.60 (m, 1H), 2.59 - 2.44 (m, 1H), 1.82 - 1.65 (m, 2H), 1.63 - 1.33 (m, 5H).
(R)−1−{4−[2−(2,4−ジフルオロ−フェニル)−2H−ピラゾール−3−イル]−3−メチル−ピペリジン−1−イル}−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A31」)、ジアステレオマー混合物の合成
32/33.1 4−[2−(2,4−ジフルオロ−フェニル)−2H−ピラゾール−3−イル]−3−メチル−ピペリジン−1−カルボン酸tert−ブチルエステル
32/33.2 (3R,4R)−4−[2−(2,4−ジフルオロ−フェニル)−2H−ピラゾール−3−イル]−3−メチル−ピペリジン−1−カルボン酸tert−ブチルエステルおよび(3S,4S)−4−[2−(2,4−ジフルオロ−フェニル)−2H−ピラゾール−3−イル]−3−メチル−ピペリジン−1−カルボン酸tert−ブチルエステル
ジアステレオマーを、キラルクロマトグラフィー(カラム:Chiralpak AD-H、溶媒:CO2+5%MeOH)によって分離した。
収率(32.2):79.8mg(26%)の無色油;HPLC(Chiralpak AD-H;CO2/MeOH−95/5):Rt 2.08min;
収率(33.2):75mg(25%)の無色油;HPLC(Chiralpak AD-H;CO2/MeOH−95/5):Rt 2.37min。
34.1 4−(5−メチル−2H−ピラゾール−3−イル)−ピリジン
逆相フラッシュクロマトグラフィー(CombiFlashRF 200)による精製。
収率:62mg(46%)の無色固体;(純度100%、Rt:2.38min、(M+H) 416.1−418.2);1H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.56 (m, 4H), 7.08 (s, 1H), 6.23 (s, 1H), 4.94 - 4.28 (m, 2H), 3.31 - 3.02 (m, 1H), 3.02 - 2.71 (m, 2H), 2.37 (s, 3H), 2.06 - 1.92 (m, 2H), 1.79 - 1.46 (m, 5H).
35.1 4−(5−トリフルオロメチル−2H−ピラゾール−3−イル)−ピペリジン塩酸塩
例「A34」(ステップ34.5)について記載したとおりの製造。
逆相フラッシュクロマトグラフィー(CombiFlashRF 200)による精製;収率:56mg(37%)の無色固体;(純度100%、Rt:2.54min、(M+H) 470.1−472.1);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.69 - 7.63 (m, 2H), 7.63 - 7.58 (m, 2H), 7.05 - 6.96 (m, 1H), 6.95 - 6.81 (m, 1H), 4.89 - 4.25 (m, 2H), 3.03 - 2.89 (m, 2H), 2.59 (s, 1H), 1.90 - 1.73 (m, 2H), 1.71 - 1.41 (m, 5H).
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.30 (d, J = 1.7 Hz, 1H), 7.07 (s, 1H), 5.98 (s, 1H), 4.81-4.79 (m, 1H), 4.46-4.44 (m, 1H), 4.16-4.10 (m, 1H), 3.12-3.10 (m, 1H), 3.06-3.03 (m, 1H), 2.76-2.74 (m, 1H), 1.84-1.64 (m, 10H), 1.52 (s, 3H), 1.48-1.39 (m, 3H), 1.22-1.16 (m, 1H).
逆相フラッシュクロマトグラフィー(CombiFlashRF 200)による精製。得られた位置異性体の分取HPLC(Agilent(登録商標)、カラム:Chromolith(登録商標)SpeedROD RP18e 50-4.6)による分離;例「A40」、収率:33mg(19%)の無色固体;(純度100%、Rt:2.23min、(M+H) 400.1);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.56 - 7.49 (m, 2H), 7.37 - 7.28 (m, 2H), 7.01 (s, 1H), 6.14 (s, 1H), 4.81 - 4.28 (m, 2H), 3.23 - 3.06 (m, 1H), 2.93 - 2.70 (m, 2H), 2.28 (s, 3H), 1.99 - 1.86 (m, 2H), 1.69 - 1.43 (m, 5H);
例「A41」、収率:12mg(7%)の無色固体;(純度100%、Rt:2.09min、(M+H) 400.1);1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.52 - 7.44 (m, 2H), 7.39 - 7.30 (m, 2H), 7.03 (s, 1H), 6.11 (s, 1H), 4.84 - 4.23 (m, 2H), 3.04 - 2.80 (m, 2H), 2.65 - 2.46 (m, 1H), 2.17 (s, 3H), 1.86 - 1.68 (m, 2H), 1.63 - 1.32 (m, 5H).
逆相フラッシュクロマトグラフィー(CombiFlashRF 200)による精製;収率:71mg(50%)の無色固体;(純度100%、Rt:2.43min、(M+H) 454.1);1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.66 - 7.58 (m, 2H), 7.47 - 7.39 (m, 2H), 7.07 - 6.95 (m, 1H), 6.93 - 6.77 (m, 1H), 2.70 - 2.52 (m, 1H), 4.88 - 4.25 (m, 2H), 3.07 - 2.84 (m, 2H), 1.90 - 1.72 (m, 2H), 1.69 - 1.40 (m, 5H).
逆相フラッシュクロマトグラフィー(CombiFlashRF 200)による精製;収率:104mg(55%)の無色固体;(純度100%、Rt:2.39min、(M+H) 436.2);1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.66 - 7.50 (m, 5H), 7.06 - 6.96 (m, 1H), 6.94 - 6.79 (m, 1H), 4.87 - 4.24 (m, 2H), 3.06 - 2.52 (m, 3H), 1.89 - 1.73 (m, 2H), 1.70 - 1.40 (m, 5H).
44.1 3−メチル−4−(2H−ピラゾール−3−イル)−ピリジン
(R)−3,3,3−トリフルオロ−1−{(3R,4R)−4−[1−(4−フルオロ−フェニル)−1H−ピラゾール−3−イル]−3−メチル−ピペリジン−1−イル}−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A45」)
収率(「A45」):100mg(25%)の無色オイル;(純度100%、Rt:2.36min、(M+H) 400.2);HPLC(Chiralpak AD-H;CO2/MeOH/ジエチルアミン−95/5/0.5):Rt 3.83min;1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.44 (d, J = 2.5 Hz, 1H), 7.94 - 7.84 (m, 2H), 7.44 - 7.34 (m, 2H), 7.25 - 6.95 (m, 1H), 6.46 (d, J = 2.5 Hz, 1H), 4.87 - 3.77 (m, 2H), 3.47 - 3.40 (m, 1H), 3.28 - 3.04 (m, 2H), 2.34 - 2.15 (m, 1H), 2.15 - 1.94 (m, 1H), 1.94 - 1.83 (m, 1H), 1.63 (s, 3H), 0.88 - 0.63 (m, 3H).
収率(「A46」):122mg(30%)の無色オイル;(純度98.5%、Rt:2.35min、(M+H) 400.2); HPLC(Chiralpak AD-H;CO2/MeOH−95/5):Rt 5.61min;
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.37 (d, J = 2.5 Hz, 1H), 7.88 - 7.78 (m, 2H), 7.36 - 7.26 (m, 2H), 7.02 (s, 1H), 6.38 (d, J = 2.5 Hz, 1H), 4.81 - 3.55 (m, 2H), 3.44 - 3.21 (m, 1H), 3.21 - 3.04 (m, 2H), 2.27 - 2.10 (m, 1H), 2.02 - 1.85 (m, 1H), 1.85 - 1.71 (m, 1H), 1.55 (s, 3H), 0.84 - 0.56 (m, 3H).
逆相フラッシュクロマトグラフィー(CombiFlashRF 200)による精製;収率:8mg(12%)の無色固体;(純度100%、Rt:2.20min、(M+H) 382.2);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.53 - 7.46 (m, 4H), 7.42 - 7.35 (m, 2H), 7.03 (s, 1H), 6.14 (s, 1H), 4.81 - 4.29 (m, 2H), 3.19 - 3.04 (m, 1H), 2.95 - 2.67 (m, 2H), 2.30 (s, 3H), 2.00 - 1.87 (m, 2H), 1.64 - 1.42 (m, 5H).
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.54 (d, J = 2.2 Hz, 2H), 7.42 (dd, J = 8.8, 2.6 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.00 (s, 1H), 6.33 - 6.26 (m, 1H), 4.83 - 4.28 (m, 2H), 3.94 (s, 3H), 3.06 - 2.82 (m, 2H), 2.69 - 2.51 (m, 1H), 1.87 - 1.70 (m, 2H), 1.62 - 1.35 (m, 5H).
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.54 (d, J = 1.8 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.24 - 7.16 (m, 2H), 7.00 (s, 1H), 6.33 - 6.26 (m, 1H), 4.85 (q, J = 8.8 Hz, 2H), 4.80 - 4.27 (m, 2H), 3.03 - 2.84 (m, 2H), 2.68 - 2.51 (m, 1H), 1.86 - 1.70 (m, 2H), 1.62 - 1.38 (m, 5H).
50.1 4−[2−(4−クロロ−フェニル)−5−メチル−2H−ピラゾール−3−イル]−ピペリジン
収率:38mg(14%)の黄色オイル、4−[1−(4−クロロ−フェニル)−5−メチル−1H−ピラゾール−3−イル]−ピペリジン−1−カルボン酸tert−ブチルエステル;
収率:24mg(12%)の黄色オイル(12%)、4−[2−(4−クロロ−フェニル)−5−メチル−2H−ピラゾール−3−イル]−ピペリジン;
収率:140mg(69%)の黄色オイル/固体(放置することで結晶した)
逆相フラッシュクロマトグラフィー(CombiFlashRF 200)による精製。
収率:136mg(67%)の無色固体;(純度99.5%、Rt:2.22min、(M+H) 416.2〜418.1);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.60 - 7.54 (m, 2H), 7.50 - 7.45 (m, 2H), 7.01 (s, 1H), 6.13 (s, 1H), 4.85 - 4.29 (m, 2H), 3.04 - 2.88 (m, 2H), 2.66 - 2.51 (m, 1H), 2.18 (s, 3H), 1.87 - 1.73 (m, 2H), 1.61 - 1.36 (m, 5H).
収率:55mg(11%)、無色固体;(純度99.1%、Rt:3.73min);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.32 (d, J = 1.5 Hz, 1H), 7.07 (s, 1H), 5.99 (s, 1H), 4.76-4.71 (m, 1H), 4.46-4.44 (m, 1H), 3.06-3.00 (m, 2H), 2.73-2.71 (m, 1H), 2.00-1.98 (m, 2H), 1.90-1.84 (m, 7H), 1.61-1.58 (m, 2H), 1.52 - 1.35 (m, 5H).
収率:98mg(11%)、茶色固体;(純度99.5%、Rt:2.45min);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.27 (d, J = 1.8 Hz, 1H), 7.08 (s, 1H), 6.03 (s, 1H), 4.79-4.78 (m, 1H), 4.46-4.44 (m, 1H), 3.77 (s, 3H), 3.24-3.18 (m, 1H), 3.00-2.98 (m, 1H), 2.69-2.67 (m, 1H), 1.89-1.87 (m, 2H), 1.63-1.30 (m, 5H).
収率:15mg(8%)、無色固体;(純度98%、Rt:3.54min);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.22 (d, J = 2.0 Hz, 1H), 7.68-7.66 (m, 2H), 6.91 (d, J = 8.7 Hz, 1H), 6.25 (s, 1H), 5.13-5.11 (m, 1H), 4.49-4.47 (m, 2H), 4.03 (s, 3H), 2.90-2.81 (m, 3H), 1.91-1.80 (m, 2H), 1.72-1.62 (m, 5H).
54.1 N−(1−ベンジル−ピペリジン−4−イル)−2−フルオロ−ベンズアミド
55.1 1−ベンジル−4−[3−(2−フルオロ−フェニル)−[1,2,4]トリアゾール−4−イル]−ピペリジン
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.91 (s, 1H), 7.71 - 7.64 (m, 1H), 7.59 (td, J = 7.5, 1.8 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.06 (s, 1H), 4.89 - 4.36 (m, 2H), 4.13 - 4.00 (m, 1H), 3.13 - 2.57 (m, 2H), 2.01 - 1.77 (m, 4H), 1.54 (s, 3H).
56.1 4−(4−クロロ−ベンゾイルアミノ)−ピペリジン−1−カルボン酸エチルエステル
57.1 4−[3−(4−メトキシ−フェニル)−3H−[1,2,3]トリアゾール−4−イル]−ピペリジン−1−カルボン酸tert−ブチルエステル
クロマトグラフィーによって精製した;収率:95mg(33%)の無色固体;(純度:100%、Rt:2.01min、(M+H) 399.1);1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.51 (s, 1H), 7.77 (d, J = 9.1 Hz, 2H), 7.12 (d, J = 9.1 Hz, 2H), 7.04 (s, 1H), 5.05 - 4.12 (m, 2H), 3.83 (s, 3H), 3.26 - 3.16 (m, 1H), 3.15 - 3.00 (m, 1H), 2.99 - 2.73 (m, 1H), 2.17 - 1.86 (m, 2H), 1.81 - 1.39 (m, 5H).
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.51 (s, 1H), 7.91 - 7.84 (m, 2H), 7.65 - 7.57 (m, 2H), 6.72 (s, 1H), 4.58 - 4.46 (m, 2H), 3.18 - 3.04 (m, 3H), 2.10 - 2.00 (m, 2H), 1.74 - 1.62 (m, 2H), 1.59 - 1.54 (m, 3H).
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.40 (s, 1H), 7.74 - 7.67 (m, 2H), 7.39 - 7.31 (m, 2H), 6.70 (s, 1H), 4.57 - 4.47 (m, 2H), 3.17 - 3.03 (m, 3H), 2.37 (s, 3H), 2.10 - 1.99 (m, 2H), 1.74 - 1.61 (m, 2H), 1.59 - 1.54 (m, 3H).
60.1 1−アジド−2−フルオロ−4−メチル−ベンゼン
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.22 (d, J = 1.9 Hz, 1H), 7.65 (t, J = 8.1 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.25 - 7.20 (m, 1H), 6.74 (s, 1H), 4.62 - 4.49 (m, 2H), 3.19 - 3.05 (m, 3H), 2.43 (s, 3H), 2.11 - 2.01 (m, 2H), 1.76 - 1.63 (m, 2H), 1.59 - 1.57 (m, 3H).
61.1 4−(2−フェニル−イミダゾール−1−イル)−ピペリジン−1−カルボン酸tert−ブチルエステル
4−(2−フェニル−イミダゾール−1−イル)−ピペリジン−1−カルボン酸tert−ブチルエステル(143.0mg;0.437mmol)を、ジクロロメタン(1.0mL)に溶解した。トリフルオロ酢酸(0.842ml;10.935mmol)を加え、反応混合物を室温で15min撹拌した。反応混合物を蒸発乾固させ、残留物(249mg)をさらに精製せずに次のステップにおいて使用した。
フラッシュクロマトグラフィー(Companion RF、24gSi50シリカゲルカラム;DCM/MeOH(2.5%))による精製;収率:55mg(68%)の無色固体;(純度:100%;Rt:1.46min、(M+H) 402.1〜404.1);1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.60 - 7.54 (m, 2H), 7.54 - 7.48 (m, 2H), 7.37 - 7.33 (m, 1H), 7.03 - 6.99 (m, 1H), 6.76 (s, 1H), 4.72 - 4.58 (m, 2H), 4.42 - 4.30 (m, 1H), 2.93 - 2.80 (m, 2H), 2.01 - 1.91 (m, 2H), 1.91 - 1.77 (m, 2H), 1.59 - 1.52 (m, 3H).
63.1 N−[(E)−2−フェニル−1−(トルエン−4−スルホニル)−ビニル]−ホルムアミド
フラッシュクロマトグラフィー(Companion RF、12gSi50シリカゲルカラム)による精製;収率:104mg(74%)の無色固体;(純度:100%;Rt:1.56min;(M+H) 402.1〜404.1);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.94 (s, 1H), 7.58 - 7.51 (m, 2H), 7.49 - 7.41 (m, 2H), 7.08 (s, 1H), 6.98 (s, 1H), 4.90 - 4.36 (m, 2H), 4.29 - 4.16 (m, 1H), 3.15 - 2.89 (m, 1H), 2.78 - 2.54 (m, 1H), 2.06 - 1.74 (m, 4H), 1.54 (s, 3H).
65.1 1−[2−(1−tert−ブトキシカルボニル−ピペリジン−4−イル)−2−オキソ−エチル]−3,5,7−トリアザ−1−アゾニア−トリシクロ[3.3.1.13,7]デカンブロミド
4−[2−(3−フェニル−チオウレイド)−アセチル]−ピペリジン−1−カルボン酸tert−ブチルエステル(180.0mg;0.477mmol)を、氷酢酸(2.0mL)に溶解し、2h還流させた。反応混合物を0〜5℃に冷却し、過酸化水素(30%;0.488ml;4.773mmol)を滴加した。冷却浴を除去し、反応混合物を5℃ないし室温で5min撹拌した。反応混合物をトルエンで希釈し、蒸発乾固させた。残留物をジクロロメタン(2.0mL)に溶解し、トリフルオロ酢酸(0.368mL;4.773mmol)を加えた。溶液を室温で20min撹拌し、蒸発乾固させた。残留物を、さらに精製せずに次のステップにおいて使用した。
66.1 4−ピラゾール−1−イル−ピリジン塩酸塩
収率:107.5mg(28%);(純度:98.4%、2.52min、(M+H−t−ブチル) 272.2)。
4−(5−フェニル−ピラゾール−1−イル)−ピペリジン−1−カルボン酸tert−ブチルエステル(107.5mg;0.328mmol)を、ジクロロメタン(1.0mL)に溶解した。トリフルオロ酢酸(0.631ml;8.189mmol)を加え、反応混合物を室温で15min撹拌した。反応混合物を蒸発乾固させた;収量:149mg(100%);(HPLC:99.2%、Rt:1.32min;(M+H) 228.2)。
67.1 4−(1H−イミダゾール−2−イル)−ピペリジン−1−カルボン酸tert−ブチルエステル
収率:128mg(53%);(純度:100%、Rt:1.47min、(M+H) 382.2);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.38 - 7.32 (m, 2H), 7.32 - 7.27 (m, 2H), 7.17 (d, J = 1.4 Hz, 1H), 7.03 (s, 1H), 6.95 (d, J = 1.3 Hz, 1H), 4.79 - 4.18 (m, 2H), 3.12 - 2.82 (m, 2H), 2.72 - 2.53 (m, 1H), 2.39 (s, 3H), 1.84 - 1.55 (m, 4H), 1.51 (s, 3H).
収率:23mg(22%);(純度:100%、Rt:1.52min、(M+H) 402.1〜404.1);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.65 - 7.59 (m, 2H), 7.51 - 7.44 (m, 2H), 7.23 (d, J = 1.4 Hz, 1H), 7.03 (s, 1H), 6.96 (d, J = 1.3 Hz, 1H), 4.77 - 4.22 (m, 2H), 3.16 - 2.81 (m, 2H), 2.78 - 2.53 (m, 1H), 1.86 - 1.54 (m, 4H), 1.51 (s, 3H).
収率:90mg(42%);(純度:100%、Rt:1.44min、(M+H) 398.3);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.42 - 7.34 (m, 2H), 7.28 (s, 1H), 7.16 - 7.06 (m, 3H), 7.03 (s, 1H), 4.81 - 4.21 (m, 2H), 3.83 (s, 3H), 3.09 - 2.84 (m, 2H), 2.75 - 2.54 (m, 1H), 1.85 - 1.56 (m, 4H), 1.51 (s, 3H).
71.1 4−[1,3,4]オキサジアゾール−2−イル−ピペリジン−1−カルボン酸tert−ブチルエステル
収率:1.04g(71%);Rt:1.78min、(M+H−t−ブチル) 198.1。
収率:74mg(42%);(純度:100%、Rt:1.75min、(M+H) 387.2);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.61 (s, 1H), 7.65 - 7.55 (m, 2H), 7.49 - 7.39 (m, 2H), 7.06 (s, 1H), 4.79 - 4.16 (m, 2H), 3.15 - 2.89 (m, 2H), 2.84 - 2.57 (m, 1H), 1.88 - 1.57 (m, 4H), 1.51 (s, 3H).
収率:55mg(50%);(純度:100%、Rt:1.70min、(M+H) 369.1);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.63 (s, 1H), 7.65 - 7.49 (m, 5H), 7.07 (s, 1H), 4.82 - 4.16 (m, 2H), 3.17 - 2.92 (m, 2H), 2.82 - 2.56 (m, 1H), 1.89 - 1.57 (m, 4H), 1.50 (s, 3H).
収率:165mg(67%);(純度:100%、Rt:1.89min、(M+H) 403.1〜405.1);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.19 (s, 1H), 7.77 - 7.63 (m, 4H), 7.47 - 6.73 (m, 1H), 4.80 - 4.17 (m, 2H), 3.18 - 2.98 (m, 2H), 2.81 - 2.59 (m, 1H), 1.90 - 1.60 (m, 4H), 1.51 (s, 3H).
(R)−1−[4−(2−シクロプロピル−2H−ピラゾール−3−イル)−1−ピペリジル]−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A74」)
4−((E)−3−ジメチルアミノ−アクリロイル)−ピペリジン−1−カルボン酸tert−ブチルエステル(2.00g;7.02mmol)およびヒドラジン一水和物(0.69mL;14.04mmol)をエタノール(20.00mL)に溶解した撹拌した溶液を、80℃で3h加熱した。反応混合物を濃縮し、残留物をジクロロメタン(50mL)で希釈し、水(30mL)で洗浄した。水層を、ジクロロメタン(2×15mL)で逆抽出した。合わせた有機層を、ブライン(10mL)で洗浄し、Na2SO4で乾燥し、真空中で濃縮して、4−(2H−ピラゾール−3−イル)−ピペリジン−1−カルボン酸tert−ブチルエステル(1.60g;6.22mmol;89%)を得た。粗生成物を、さらに精製せずに次のステップのために使用した。
348.3(M+H)
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.96-8.94 (m, 1H), 8.25 (d, J = 1.1 Hz, 2H), 7.74 (d, J = 1.72 Hz, 1H), 7.05 (s, 1H), 6.48 (brs, 1H), 4.72-4.70 (m, 1H), 4.40-4.38 (m, 1H), 3.14-3.12 (m, 1H), 2.97-2.95 (m, 1H), 2.71-2.50 (m, 1H), 1.85-1.82 (m, 2H), 1.50-1.40 (m, 5H).
1H NMR (400 MHz, MeOH-d4) δ [ppm] 8.37 (s, 1H), 7.84-7.81 (m, 1H), 7.62 (d, J = 8.0 Hz, 2H), 6.36 (s, 1H), 5.11-5.09 (m, 1H), 4.58-4.56 (m, 1H), 3.73-3.71 (m, 1H), 3.09-3.07 (m, 1H), 2.71-2.68 (m, 1H), 2.42 (s, 3H), 2.06-2.03 (m, 2H), 1.70-1.50 (m, 5H).
収率:30mg(8%)のオフホワイト固体;(純度94.0%、Rt:3.96min、(M+H) 411.0);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.21 (dd, J = 10.0, 1.6 Hz, 1H), 7.91 (dd, J = 8.0, 1.20 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.05 (s, 1H), 6.41 (brs, 1H), 4.70-4.67 (m, 1H), 4.39-4.37 (m, 1H), 2.97-2.95 (m, 2H), 2.74-2.72 (m, 1H), 1.75-1.72 (m, 2H), 1.50-1.37 (m, 5H).
1H NMR (500 MHz, DMSO-d6) δ [ppm] 7.87-7.76 (m, 2H), 7.63 (d, J = 1.8 Hz, 1H), 7.54 (dd, J = 8.6, 2.5 Hz, 1H), 7.03 (s, 1H), 6.38 (s, 1H), 4.92-4.21 (m, 2H), 3.19-2.55 (m, 3H), 1.98-1.35 (m, 7H).
4−アセチル−3−メチル−ピペリジン−1−カルボン酸tert−ブチルエステル(250.0mg;1.015mmol)およびtert−ブトキシビス(ジメチルアミノ)メタン(187.7mg;1.066mmol)を、バイアル中に配置し、100℃で45min撹拌した。透明な黄色の溶液が、生成した。混合物を室温に冷却し、エタノール(2.5mL)で希釈した。(4−フルオロ−フェニル)−ヒドラジン塩酸塩(168.4mg;1.015mmol)を加え、混合物を80℃で3h加熱した。混合物を蒸発乾固させ、残留物を逆相フラッシュクロマトグラフィー(CombiFlashRF 200)によって精製した。純粋な画分を合わせ、アセトニトリルを真空中で除去し、飽和NaHCO3水溶液で希釈し、酢酸エチルで抽出した。合わせた有機層を、ブラインで洗浄し、硫酸ナトリウムで乾燥し、ろ過し、真空中で濃縮した;収率:215mg(59%)のオレンジ色−赤色オイル(シス/トランス:95/5)。
SFC;カラム:ChiralPak AD-H;溶離剤:CO2/メタノール:95/5;220nm
収率:108.1:83mg(40%)、黄色オイル;
107.1:71mg(34%)、黄色オイル。
128.1 4−(3−フェニル−イソキサゾール−4−イル)−ピペリジン−1−カルボン酸tert−ブチルエステル
マイクロウェーブ容器中で、1−Boc−4−エチニルピペリジン(100.0mg;0.468mmol)および(Z)−N−ヒドロキシベンズイミドイルクロリド(88.4mg;0.515mmol)を、乾燥1,2−ジクロロエタン(4.50mL)に溶解し、トリエチルアミン(81.1μl;0.585mmol)を加え、混合物を窒素で脱気した。クロロ(1,5−シクロオクタジエン)(ペンタメチルシクロペンタジエニル)ルテニウム(9.17mg;0,023mmol)を、無色懸濁液に加えた。反応を、窒素で再び脱気し、室温で14h撹拌した。反応混合物を蒸発させ、残留物をフラッシュクロマトグラフィー(CombiFlashRF 200)によって精製した;収率:122mg(78%)の黄色オイル。
ジオキサン中のHCl(4.0M;4.58mL;18.315mmol)を、乾燥1,4−ジオキサン(4.54mL;53.112mmol)中の4−(3−フェニル−イソキサゾール−4−イル)−ピペリジン−1−カルボン酸tert−ブチルエステル(122.0mg;0.366mmol)に加え、室温で14h撹拌した。反応混合物を真空中で濃縮し、残留物をさらに精製せずに使用した。
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回蒸留水に溶解させた溶液を、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し、滅菌条件下で凍結乾燥させ、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。各々の坐剤は、20mgの活性成分を含む。
940mlの2回蒸留水中の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、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回蒸留水に溶解させた溶液を、滅菌濾過し、アンプル中に移送し、滅菌条件下で凍結乾燥させ、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 (13)
- 式I
Rは、ピラゾール−ジイル、イミダゾール−ジイル、イソキサゾール−ジイルまたはトリアゾール−ジイルを示し、その各々は、非置換であるか、またはR2によって単置換されており、
R1は、(CH2)nAr、(CH2)nHet、AまたはCycを示し、
R2は、A’、メトキシ、ヒドロキシメチル、COOA’、CN、COOH、CONH2またはOHを示し、
R3は、H、A’、COOA’またはCNを示し、
Arは、フェニルを示し、それは、非置換であるか、またはHal、A、CN、OA、[C(R5)2]pOH、[C(R5)2]pN(R5)2、NO2、[C(R5)2]pCOOR5、NR5COA、NR5SO2A、[C(R5)2]pSO2N(R5)2、S(O)nA、O[C(R5)2]mN(R5)2、NR5COOA、NR5CON(R5)2および/もしくはCOAによって単置換、二置換、三置換、四置換もしくは五置換されており、
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、CN、OA、[C(R5)2]pOH、[C(R5)2]pN(R5)2、NO2、[C(R5)2]pCOOR5、NR5COA、NR5SO2A、[C(R5)2]pSO2N(R5)2、S(O)nA、O[C(R5)2]mN(R5)2、NR5COOA、NR5CON(R5)2および/もしくはCOAによって単置換もしくは二置換されている、単環式または二環式の飽和、不飽和または芳香族複素環を示し、
Cycは、3、4、5、6または7個のC原子を有する環状アルキルを示し、それは、非置換であるか、またはOHによって単置換されており、
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つもしくは2つの隣接していないCHおよび/もしくはCH2基は、N、Oおよび/もしくはS原子によって置き換えられていてもよく、かつ/またはここで1〜7個のH原子は、R4によって置き換えられていてもよく、
R4は、F、ClまたはOHを示し、
R5は、HまたはA’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、
Halは、F、Cl、BrまたはIを示し、
mは、1、2、3または4を示し、
nは、0、1または2を示し、
pは、0、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許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物。 - R2が、A’、メトキシまたはヒドロキシメチルを示す、
請求項1に記載の化合物、ならびにそれらの薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物。 - R3が、HまたはA’を示す、
請求項1または2に記載の化合物、ならびにそれらの薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物。 - Arが、フェニルを示し、それが非置換であるか、またはHal、A、CNおよび/もしくはOAによって単置換、二置換、三置換、四置換もしくは五置換されている、
請求項1〜3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許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物。 - Hetが、ピリミジル、ピリジル、ピリダジニル、ピラジニル、ピペリジニル、ピロリジニル、ピラゾリル、チアゾリル、イミダゾリル、フラニル、チオフェニル、ピロリル、オキサゾリル、イソキサゾリル、トリアゾリル、オキサジアゾリルまたはチアジアゾリルを示し、その各々が非置換であるか、またはHal、A、CNおよび/もしくはOAによって単置換もしくは二置換されている、
請求項1〜4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許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物。 - Rが、ピラゾール−ジイル、イミダゾール−ジイル、イソキサゾール−ジイルまたはトリアゾール−ジイルを示し、その各々が非置換であるか、またはR2によって単置換されており、
R1が、(CH2)nAr、(CH2)nHet、AまたはCycを示し、
R2が、A’、メトキシまたはヒドロキシメチルを示し、
R3が、HまたはA’を示し、
Arが、フェニルを示し、それが非置換であるか、またはHal、A、CNおよび/もしくはOAによって単置換、二置換、三置換、四置換もしくは五置換されており、
Hetが、ピリミジル、ピリジル、ピリダジニル、ピラジニル、ピペリジニル、ピロリジニル、ピラゾリル、チアゾリル、イミダゾリル、フラニル、チオフェニル、ピロリル、オキサゾリル、イソキサゾリル、トリアゾリル、オキサジアゾリルまたはチアジアゾリルを示し、その各々が非置換であるか、または、Hal、A、CNおよび/もしくはOAによって単置換もしくは二置換されており、
Cycが、3、4、5、6または7個のC原子を有する環状アルキルを示し、それが非置換であるか、またはOHによって単置換されており、
Aが、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つもしくは2つの隣接していないCHおよび/もしくはCH2基がN、Oおよび/もしくはS原子によって置き換えられていてもよく、かつ/またはここで1〜7個のH原子がR4によって置き換えられていてもよく、
R4が、F、ClまたはOH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によって置き換えられていてもよく、
Halが、F、Cl、BrまたはIを示し、
nが、0、1または2を示す、
請求項1に記載の化合物、ならびにそれらの薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物。 - 以下の群
- 請求項1〜7のいずれか一項に記載の式Iで表される化合物ならびにそれらの薬学的に許容し得る塩、互変異性体および立体異性体の製造方法であって、式II
で表される化合物を
式III
で表される化合物と反応させ、
ならびに/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。 - 請求項1〜7のいずれか一項に記載の式Iで表される少なくとも1種の化合物、および/または、その薬学的に許容し得る塩、互変異性体または立体異性体、あるいは、あらゆる比率でのそれらの混合物、および任意に、薬学的に許容し得る担体、賦形剤またはビヒクルを含む、医薬。
- がん、糖尿病、心臓の虚血、インスリン抵抗性症候群、メタボリックシンドローム、高血糖、脂質異常症、アテローム性動脈硬化症、心不全、心筋症、心筋虚血、高乳酸血症、ミトコンドリア病、ミトコンドリア脳筋症の処置および/または予防のための使用のための、請求項1〜7のいずれか一項に記載の式Iで表される化合物、ならびにそれらの薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物。
- 頭部、頸部、目、口、喉、食道、気管支、喉頭、咽頭、胸部、骨、肺、結腸、直腸、胃、前立腺、膀胱、子宮、子宮頸部、乳房、卵巣、精巣または他の生殖器、皮膚、甲状腺、血液、リンパ節、腎臓、肝臓、膵臓、脳、中枢神経系のがん、固形腫瘍および血液由来の腫瘍の群から選択される疾患の処置および/または予防のための使用のための、請求項10に記載の化合物。
- 請求項1〜7のいずれか一項に記載の式Iで表される少なくとも1種の化合物、および/または、その薬学的に許容し得る塩、互変異性体または立体異性体、あるいは、あらゆる比率でのそれらの混合物、および、少なくとも1つのさらなる医薬活性成分を含む、医薬。
- (a)請求項1〜7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、その薬学的に許容し得る塩、互変異性体および立体異性体、あるいは、あらゆる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
の別個のパックからなる、セット(キット)。
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US (1) | US9751861B2 (ja) |
EP (1) | EP3083591B1 (ja) |
JP (1) | JP6527520B2 (ja) |
KR (1) | KR102374178B1 (ja) |
CN (1) | CN105814037B (ja) |
AU (1) | AU2014365904B2 (ja) |
CA (1) | CA2933927C (ja) |
ES (1) | ES2665148T3 (ja) |
IL (1) | IL246298B (ja) |
MX (1) | MX2016007810A (ja) |
NZ (1) | NZ721726A (ja) |
SG (1) | SG11201604940VA (ja) |
TW (1) | TW201605824A (ja) |
WO (1) | WO2015090496A1 (ja) |
ZA (1) | ZA201604932B (ja) |
Families Citing this family (6)
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EP3328857B1 (en) | 2015-07-31 | 2019-08-14 | Merck Patent GmbH | Bicyclic heterocyclic derivatives |
WO2017083219A1 (en) * | 2015-11-12 | 2017-05-18 | Merck Sharp & Dohme Corp. | Bispiperidinyl derivatives as liver x receptor beta agonists, compositions, and their use |
CA3019240A1 (en) * | 2016-03-29 | 2017-10-05 | Merck Patent Gmbh | N1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)-piperidine derivatives as inhibitors of pyruvate dehydrogenase kinase |
CN107356461A (zh) * | 2017-05-17 | 2017-11-17 | 华中科技大学 | Bckdk作为生物标志物在制备肿瘤诊断试剂盒中的应用 |
TWI803570B (zh) | 2018-02-01 | 2023-06-01 | 日商日本香煙產業股份有限公司 | 含氮雜環醯胺化合物以及其醫藥用途 |
TWI815137B (zh) * | 2018-06-15 | 2023-09-11 | 漢達生技醫藥股份有限公司 | 尼洛替尼十二烷基硫酸鹽之結晶 |
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US6979686B1 (en) | 2001-12-07 | 2005-12-27 | Pharmacia Corporation | Substituted pyrazoles as p38 kinase inhibitors |
US7638541B2 (en) | 2006-12-28 | 2009-12-29 | Metabolex Inc. | 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine |
CN102245610B (zh) * | 2008-10-08 | 2014-04-30 | 百时美施贵宝公司 | 吡咯并三嗪激酶抑制剂 |
AR074797A1 (es) | 2008-10-10 | 2011-02-16 | Japan Tobacco Inc | Compuesto de fluoreno , composiciones farmaceuticas , inhibidores de pdhk y pdhk2 , metodos de tratamiento , usos de los mismos y kit comercial |
JP2012509333A (ja) * | 2008-11-19 | 2012-04-19 | シェーリング コーポレイション | ジアシルグリセロールアシルトランスフェラーゼの阻害剤 |
JP2013519681A (ja) * | 2010-02-11 | 2013-05-30 | オーエスアイ・ファーマシューティカルズ,エルエルシー | 7−アミノフロピリジン誘導体 |
US9365539B2 (en) | 2010-05-11 | 2016-06-14 | Merck Sharp & Dohme Corp. | Prolylcarboxypeptidase inhibitors |
US8999966B2 (en) | 2010-10-29 | 2015-04-07 | Merck Sharp & Dohme Corp. | Compounds that are ERK inhibitors |
AU2011328139A1 (en) | 2010-11-10 | 2013-04-04 | F. Hoffmann-La Roche Ag | Pyrazole aminopyrimidine derivatives as LRRK2 modulators |
WO2012082947A1 (en) | 2010-12-16 | 2012-06-21 | Irm Llc | Compounds and compositions as tgr5 agonists |
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JP2016540807A (ja) | 2016-12-28 |
AU2014365904A1 (en) | 2016-07-28 |
NZ721726A (en) | 2021-07-30 |
EP3083591A1 (en) | 2016-10-26 |
AU2014365904B2 (en) | 2019-03-28 |
SG11201604940VA (en) | 2016-07-28 |
US9751861B2 (en) | 2017-09-05 |
US20160311798A1 (en) | 2016-10-27 |
KR20160098475A (ko) | 2016-08-18 |
MX2016007810A (es) | 2016-09-07 |
TW201605824A (zh) | 2016-02-16 |
CN105814037B (zh) | 2018-11-30 |
ZA201604932B (en) | 2019-04-24 |
IL246298B (en) | 2018-10-31 |
KR102374178B1 (ko) | 2022-03-14 |
CN105814037A (zh) | 2016-07-27 |
EP3083591B1 (en) | 2018-01-03 |
ES2665148T3 (es) | 2018-04-24 |
CA2933927C (en) | 2021-11-16 |
IL246298A0 (en) | 2016-08-02 |
WO2015090496A1 (en) | 2015-06-25 |
CA2933927A1 (en) | 2015-06-25 |
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