JP6847942B2 - 二環式複素環式誘導体 - Google Patents
二環式複素環式誘導体 Download PDFInfo
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- JP6847942B2 JP6847942B2 JP2018524530A JP2018524530A JP6847942B2 JP 6847942 B2 JP6847942 B2 JP 6847942B2 JP 2018524530 A JP2018524530 A JP 2018524530A JP 2018524530 A JP2018524530 A JP 2018524530A JP 6847942 B2 JP6847942 B2 JP 6847942B2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
Description
本発明は、ピルビン酸デヒドロゲナーゼキナーゼ(PDHK)を阻害する新規な二環式複素環式誘導体、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。
ピルビン酸デヒドロゲナーゼキナーゼ(またピルビン酸デヒドロゲナーゼ複合キナーゼ、PDCキナーゼ、またはPDHK)は、酵素ピルビン酸デヒドロゲナーゼをATPを用いてそれをリン酸化することによって不活性化するように作用するキナーゼ酵素である。
(ピルビン酸デヒドロゲナーゼキナーゼを、また時には「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と混同すべきではない。)
ヒトにおけるPDHKの4種の既知のアイソザイムがある:PDHK1〜PDHK4。
ウィキペディア、ピルビン酸デヒドロゲナーゼキナーゼ;
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IaまたはIb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。
疼痛および炎症の処置のための二環式ピラゾロ−複素環式誘導体は、WO 2010/088050に記載されている。
タンパク質キナーゼインヒビターとしての他の二環式複素環式化合物は、WO 2009/143477に記載されている。
炎症の処置のための他のピラゾロピリジンは、US 3423414に記載されている。
本発明は、式Iaまたは式Ib
Xは、CHまたはNを示し、
Yは、CHまたはNを示し、
R1は、H、A、(CH2)nAr、(CH2)nHetまたはCycを示し、
R2は、HまたはCH3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、ならびに/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を示し、
X=CHである場合、Y=Nであり、
または
Y=CHである場合、X=Nである、
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、ならびにすべての比率でのそれらの混合物に関する。
化合物の溶媒和物という用語は、それらの相互の引力に起因して形成する不活性溶媒分子の化合物上への付加物(adduction)を意味するものと解釈される。溶媒和物は、例えば、一水和物もしくは二水和物またはアルコキシドである。
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により単置換されている。
式IaまたはIb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、したがって様々な立体異性体の形態で存在し得る。式IaまたはIbは、すべてのこれらの形態を包含する。
Iabにおいて、Hetは、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、その各々は、非置換であるか、またはHal、Aおよび/もしくはOAにより単置換もしくは二置換されており;
Yは、CHまたはNを示し、
R1は、H、A、(CH2)nAr、(CH2)nHetまたはCycを示し、
R2は、HまたはCH3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により単置換、二置換、三置換、四置換もしくは五置換されており、
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、ならびに/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、
Halは、F、Cl、BrまたはIを示し、
nは、0,1または2を示し、
X=CHである場合、Y=Nであり、
または
Y=CHである場合、X=Nである、
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、すべての比率でのそれらの混合物を含む。
式IaまたはIbで表される化合物を、好ましくは、式IIaまたはIIb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って得ることができる。
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IaまたはIb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IaまたはIb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。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。
さらに、式IaまたはIb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IaまたはIb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個または2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IaまたはIb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、糖尿病および心臓虚血の処置のための使用のための、式IaまたはIb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、ならびにすべての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、サプラシタビン(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ェート)、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ェート、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−テトラメチルウロニウムテトラフルオロボレート、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−プロパンスルホネート
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。当該アッセイを、2つのステップにおいて行う;単離したPDCを、ATPを共基質としてPDHK2によってリン酸化する酵素的PDHK2反応、ならびにピルビン酸塩およびNADをアセチル−CoAおよびNADHに変換するPDC活性アッセイ。PDC活性は、NADHの増大に相関し、それにより増大する蛍光シグナル(Exc 340nm、Em 450nm)を介して直接的に検出可能である。PDHK2の阻害の結果、より低いリン酸化状態、ならびにそれによってPDCの活性のより低い低下およびNADH蛍光シグナルのより強い増大がもたらされる。
ITC測定を、VP−ITC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の注射において滴定することによって行った。すべての結合実験を、30℃で行った。一般に、試験化合物を、DMSOストック溶液から、1%DMSOの最大最終濃度を有する測定緩衝液中に希釈した。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、細胞免疫蛍光アッセイにおいて測定した。ヒトHEK293T細胞を、透明な底部を有する黒色384ウェルプレート中に播種し、一晩増殖させた。
HPLC方法:
勾配:3.3分;流量:0分、4%のBから2.4ml/分、2.8分、100%のB、3.3分、100%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装置
式Iaで表され、式中X=NかつY=CHである化合物を製造するための一般的反応スキーム
(2R)−1−[1−(4−クロロフェニル)−6,7−ジヒドロ−4H−ピラゾロ[4,3−c]ピリジン−5−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(「A1」)
3−[1−ジメチルアミノ−メタ−(E)−イリデン]−4−オキソ−ピペリジン−1−カルボン酸tert−ブチルエステル(200mg;0.786mmol)および4−クロロフェニルヒドラジン塩酸塩(155mg;0.865mmol)を、メタノール(4mL)および水(1mL)に懸濁させた。氷酢酸(0.23mL;3.932mmol)を、撹拌しながら加え、数分後にオレンジ色溶液が生成した。混合物を、室温で1h撹拌し、酢酸エチルで希釈し、水、飽和NaHCO3溶液およびブラインで洗浄し、Na2SO4で乾燥し、濾過し、蒸発乾固させた。油状残留物を、フラッシュクロマトグラフィー(Companion RF;40gのSi50シリカゲルカラム)により精製した。収量:145.5mgの褐色油;LC/MS、Rt:2.61分;(M+H) 334.1。
化合物1.1(145.5mg;0.436mmol)を、乾燥1,4−ジオキサン(3mL)に溶解し、塩化水素(ジオキサンに溶解した4M溶液;4mL)を、室温で加えた。数分後、薄茶色固体が沈殿した。反応混合物を、室温で2時間撹拌し、ジエチルエーテル(7mL)で希釈し、5分間撹拌した。沈殿物を吸引濾過し、ジエチルエーテルで洗浄し、室温で2h乾燥した。収量:155mgの黄色固体;LC/MS、Rt:1.16分;(M+H) 234.1。
化合物1.2(155mg;0.505mmol)、(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−プロピオン酸(159mg;1.006mmol)および[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ェート(383mg;1.007mmol)を、DMF(2.5mL)に溶解した。N−エチルジイソプロピルアミン(0.857mL;5.037mmol)を加え、黄色溶液を室温で一晩撹拌した。反応混合物を水(40mL)で希釈し、酢酸エチルで抽出した。
(2R)−1−[2−(4−クロロフェニル)−6、7−ジヒドロ−4H−ピラゾロ[4,3−c]ピリジン−5−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(「A2」)
ステップ1.1の異性体の環化生成物である「A2」を、ステップ1.3において、分取HPLC(Agilent 1260;カラム:Waters SunFire C18、5μm、30×150mm)により単離した。収量:7mg(4%)の無色粉末。LC/MS、Rt:2.26分:(M+H) 374.1;1H NMR (500 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.82-7.76 (m, 2H), 7.55-7.50 (m, 2H), 7.21 (s, 1H), 5.16-4.94 (m, 1H), 4.69-4.50 (m, 1H), 4.28-4.02 (m, 1H), 3.94-3.68 (m, 1H), 2.93-2.68 (m, 2H), 1.66-1.45 (m, 3H).
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−1−(1−フェニル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル)−プロパン−1−オン(「A3」)
(R)−3,3,3−トリフルオロ−1−[1−(4−フルオロ−フェニル)−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A4」)
(R)−1−[1−(2,4−ジフルオロ−フェニル)−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−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(「A5」)
(R)−1−[2−(2,4−ジフルオロ−フェニル)−2,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−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(「A6」)
ステップ5.1の異性体の環化生成物を、フラッシュクロマトグラフィー(Companion RF;24gのSi50シリカゲルカラム)により単離し、例1(ステップ1.2〜1.3)について記載したように例6に変換した。収量:51mg(79%)の無色固体;LC/MS、Rt:2.09分;(M+H) 376.1;1H NMR (400 MHz, DMSO-d6, 80 °C) δ 7.95 (d, J = 2.4 Hz, 1H), 7.81-7.74 (m, 1H), 7.46-7.39 (m, 1H), 7.23-7.16 (m, 1H), 6.95 (s, 1H), 4.88-4.73 (m, 2H), 4.15-3.95 (m, 2H), 2.82 (t, J = 5.9 Hz, 2H), 1.59 (s, 3H).
(R)−1−(1−tert−ブチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−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(「A7」)
(R)−1−(2−tert−ブチル−2,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−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(「A8」)
ステップ7.1の異性体の環化生成物を、分取HPLC(Agilent 1260;カラム:Waters SunFire C18、5μm、30×150mm)により単離し、例1(ステップ1.2〜1.3)について記載したように例8に変換した。収量:16mg(26%)の無色固体;LC/MS、Rt:1.85分;(M+H) 320.1。
(2R)−1−[1−(4−クロロフェニル)−7−メチル−6,7−ジヒドロ−4H−ピラゾロ[4,3−c]ピリジン−5−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(「A9」);ジアステレオマーの混合物
N−Boc−3−メチル−4−ピペリドン(1.00g、4.689mmol)を、tert−ブトキシビス(ジメチルアミノ)メタン(1.14g;6.564mmol)に溶解した。反応バイアルを隔壁で密封し、100℃で30分間撹拌した。反応混合物を室温に冷却し、水(20mL)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、Na2SO4で乾燥し、吸引により濾過し、蒸発乾固させた。黄色油(1.24g)を、さらに精製せずに次のステップにおいて使用した。
(R)−1−[(R)−1−(4−クロロ−フェニル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−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(「A10」)
(R)−1−[(S)−1−(4−クロロ−フェニル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−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(「A11」)
「A11」:68mgの黄色固体;LC/MS、Rt:2.23分;(M+H) 388.1;1H NMR (400 MHz, DMSO-d6, 80°C) δ 7.65-7.48 (m, 4H), 6.94 (s, 1H), 5.20-4.59 (m, 2H), 4.08-3.66 (m, 2H), 3.52-3.30 (m, 1H), 1.58 (s, 3H), 0.87 (d, J = 6.8 Hz, 3H).
(2R)−3,3,3−トリフルオロ−1−[1−(4−フルオロフェニル)−7−メチル−6,7−ジヒドロ−4H−ピラゾロ[4,3−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A12」);ジアステレオマーの混合物
(2R)−3,3,3−トリフルオロ−1−[2−(4−フルオロフェニル)−7−メチル−6,7−ジヒドロ−4H−ピラゾロ[4,3−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A13」);ジアステレオマーの混合物
ステップ12.1の異性体の環化生成物を、フラッシュクロマトグラフィー(Companion RF;24gのSi50シリカゲルカラム)により単離し、例9(ステップ9.3〜9.4)について記載したように例13に変換する。収量:29mg(75%)の無色粉末;LC/MS、Rt:2.20/2.22分;(M+H) 372.1;1H NMR (400 MHz, DMSO-d6) δ 8.29-8.24 (m, 1H), 7.83-7.75 (m, 2H), 7.37-7.28 (m, 2H), 7.27-7.14 (m, 1H), 5.34-4.97 (m, 1H), 4.95-4.50 (m, 1H), 4.25-3.91 (m, 1H), 3.39-3.20 (m, 1H), 3.19-2.89 (m, 1H), 1.68-1.45 (m, 3H), 1.25 (d, J = 5.8 Hz, 3H).
(R)−3,3,3−トリフルオロ−1−[(R)−1−(4−フルオロ−フェニル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A14」)
(R)−3,3,3−トリフルオロ−1−[(S)−1−(4−フルオロ−フェニル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A15」)
「A15」:65mgの無色固体;LC/MS、Rt:2.08分;(M+H) 372.1;1H NMR (400 MHz, DMSO-d6, 80°C) δ 7.64-7.53 (m, 2H), 7.51 (s, 1H), 7.39-7.23 (m, 2H), 6.91 (s, 1H), 5.16-4.56 (m, 2H), 4.19-3.58 (m, 2H), 3.44-3.27 (m, 1H), 1.57 (s, 3H), 0.83 (d, J = 6.8 Hz, 3H).
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−1−(7−メチル−1−フェニル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル)−プロパン−1−オン(「A16」);ジアステレオマーの混合物
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−1−(7−メチル−2−フェニル−2,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル)−プロパン−1−オン(「A17」);ジアステレオマーの混合物。
ステップ16.1の異性体の環化生成物を、フラッシュクロマトグラフィー(Companion RF;24gのSi50シリカゲルカラム)により単離し、「A9」(ステップ9.3〜9.4)について記載したように例17に変換する。収量:41mg(71%)の淡黄色固体;LC/MS、Rt:2.16/2.18分;(M+H) 354.2;1H NMR (400 MHz, DMSO-d6) δ 8.33-8.25 (m, 1H), 7.79-7.73 (m, 2H), 7.52-7.44 (m, 2H), 7.31-7.25 (m, 1H), 7.25-7.12 (m, 1H), 5.36-4.99 (m, 1H), 4.97-4.53 (m, 1H), 4.27-3.88 (m, 1H), 3.41-2.92 (m, 2H), 1.69-1.44 (m, 3H), 1.31-1.19 (m, 3H).
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−1−((R)−7−メチル−1−フェニル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル)−プロパン−1−オン(「A18」)
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−1−((S)−7−メチル−1−フェニル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル)−プロパン−1−オン(「A19」)
「A19」:63mgの無色固体;LC/MS、Rt:2.03分;(M+H) 354.1;1H NMR (400 MHz, DMSO-d6, 80°C) δ 7.57-7.46 (m, 5H), 7.45-7.34 (m, 1H), 6.91 (s, 1H), 5.23-4.51 (m, 2H), 4.10-3.59 (m, 2H), 3.50-3.31 (m, 1H), 1.57 (s, 3H), 0.83 (d, J = 6.8 Hz, 3H).
(R)−1−[(R)−1−(2,4−ジフルオロ−フェニル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−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(「A20」)
(R)−1−[(S)−1−(2,4−ジフルオロ−フェニル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−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(「A21」)
「A21」:35mgの無色固体;LC/MS、Rt:2.10分;(M+H) 390.1;1H NMR (400 MHz, DMSO-d6, 80°C) δ 7.67-7.54 (m, 2H), 7.53-7.40 (m, 1H), 7.27-7.18 (m, 1H), 6.96 (s, 1H), 5.08-4.49 (m, 2H), 4.21-3.44 (m, 2H), 3.19-2.96 (m, 1H), 1.58 (s, 3H), 0.81 (d, J = 6.8 Hz, 3H).
(R)−1−((R)−1−tert−ブチル−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−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(「A22」)
(R)−1−((S)−1−tert−ブチル−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−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(「A23」)
「A23」:42mgの無色固体;LC/MS、Rt:1.85分;(M+H) 334.2;1H NMR (400 MHz, DMSO-d6, 80°C) δ 7.21 (s, 1H), 6.84 (s, 1H), 5.36-5.02 (m, 1H), 4.60 (d, J = 12.8 Hz, 1H), 4.21 (d, J = 16.0 Hz, 1H), 3.40-3.32 (m, 1H), 3.07-2.98 (m, 1H), 1.59-1.53 (m, 12H), 1.19 (d, J = 6.7 Hz, 3H).
(R)−3,3,3−トリフルオロ−1−[(R)−1−(2−フルオロ−フェニル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A24」)
(R)−3,3,3−トリフルオロ−1−[(S)−1−(2−フルオロ−フェニル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A25」)
「A25」:45mgの無色固体;LC/MS、Rt:2.03分;(M+H) 372.1;1H NMR (400 MHz, DMSO-d6, 90°C) δ 7.61-7.32 (m, 5H), 6.90 (s, 1H), 4.95-4.66 (m, 2H), 4.13-3.60 (m, 2H), 3.15-3.04 (m, 1H), 1.59 (d, J = 1.2 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H).
2−[(R)−7−メチル−5−((R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−プロピオニル)−4,5,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−1−イル]−ベンゾニトリル(「A26」)
2−[(S)−7−メチル−5−((R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−プロピオニル)−4,5,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−1−イル]−ベンゾニトリル(「A27」)
「A27」:32mgの黄色固体;LC/MS、Rt:2.06分;(M+H) 379.1;1H NMR (400 MHz, DMSO-d6, 90°C) δ 8.64 (s, 1H), 8.24 (dd, J = 8.3, 1.2 Hz, 1H), 7.85 (dd, J = 8.7, 1.0 Hz, 1H), 7.63 (ddd, J = 8.4, 6.7, 1.2 Hz, 1H), 7.34-7.27 (m, 1H), 7.08 (s, 1H), 4.86-4.67 (m, 2H), 3.96-3.87 (m, 1H), 3.65-3.50 (m, 1H), 3.13-3.02 (m, 1H), 1.68 (d, J = 1.2 Hz, 3H), 1.50 (d, J = 6.9 Hz, 3H).
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−1−((R)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル)−プロパン−1−オン(「A28」)
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−1−((S)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル)−プロパン−1−オン(「A29」)
「A28」:30mgの無色固体;LC/MS、Rt:1.42分;(M+H) 278.1;
「A29」:34mgの無色固体;LC/MS、Rt:1.46分;(M+H) 278.1。
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−1−[(R)−1−(6−メトキシ−ピリジン−3−イル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−メチル−プロパン−1−オン(「A30」)
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−1−[(S)−1−(6−メトキシ−ピリジン−3−イル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−メチル−プロパン−1−オン(「A31」)
「A31」:82mgの無色固体;LC/MS、Rt:1.93分;(M+H) 385.1;1H NMR (400 MHz, DMSO-d6, 90°C) δ 8.32 (d, J = 2.5 Hz, 1H), 7.85 (dd, J = 8.8, 2.8 Hz, 1H), 7.54 (s, 1H), 6.95 (d, J = 8.7 Hz, 1H), 6.89 (s, 1H), 5.05-4.77 (m, 1H), 4.68 (d, J = 15.7 Hz, 1H), 4.02-3.77 (m, 5H), 3.39-3.27 (m, 1H), 1.59 (d, J = 1.1 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H).
(R)−3,3,3−トリフルオロ−1−[(R)−1−(3−フルオロ−ピリジン−2−イル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A32」)
(R)−3,3,3−トリフルオロ−1−[(S)−1−(3−フルオロ−ピリジン−2−イル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A33」)
「A33」:65mgの無色固体;LC/MS、Rt:1.83分;(M+H) 373.1;1H NMR (400 MHz, DMSO-d6, 90°C) δ 8.41 (dt, J = 4.6, 1.2 Hz, 1H), 7.98 (ddd, J = 10.1, 8.3, 1.4 Hz, 1H), 7.66-7.56 (m, 2H), 6.92 (s, 1H), 5.00-4.73 (m, 2H), 4.10-3.72 (m, 2H), 3.44-3.33 (m, 1H), 1.59 (d, J = 1.1 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H).
(R)−1−[(R)−1−(3,5−ジフルオロ−ピリジン−2−イル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−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(「A34」)
(R)−1−[(S)−1−(3,5−ジフルオロ−ピリジン−2−イル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−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(「A35」)
「A35」:33mgの無色固体;LC/MS、Rt:1.95分;(M+H) 391.1;1H NMR (400 MHz, DMSO-d6, 90 °C) δ 8.55-8.37 (m, 1H), 8.14 (ddd, J = 9.8, 8.3, 2.5 Hz, 1H), 7.61 (s, 1H), 6.90 (s, 1H), 5.03-4.56 (m, 2H), 4.08-3.61 (m, 2H), 3.41-3.20 (m, 1H), 1.57 (s, 3H), 0.86 (d, J = 6.8 Hz, 3H).
(R)−3,3,3−トリフルオロ−1−[(R)−1−(5−フルオロ−2−メトキシ−ピリミジン−4−イル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A36」)
(R)−3,3,3−トリフルオロ−1−[(S)−1−(5−フルオロ−2−メトキシ−ピリミジン−4−イル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A37」)
「A37」:48mgの無色固体;LC/MS、Rt:1.96分;(M+H) 404.1;1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 3.9 Hz, 1H), 8.50 (s, 1H), 7.33-7.06 (m, 1H), 5.41-5.02 (m, 1H), 5.02-4.51 (m, 1H), 4.24-3.89 (m, 4H), 3.39-2.93 (m, 2H), 1.72-1.38 (m, 3H), 1.24 (d, J = 6.7 Hz, 3H).
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−1−[(R)−1−(4−ヒドロキシ−シクロヘキシル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−メチル−プロパン−1−オン(「A38」)
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−1−[(S)−1−(4−ヒドロキシ−シクロヘキシル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−メチル−プロパン−1−オン(「A39」)
「A39」:7mgの無色固体;LC/MS、Rt:1.65分;(M+H) 376.2;1H NMR (400 MHz, DMSO-d6, 90 °C) δ 7.22 (s, 1H), 6.80 (s, 1H), 5.24-4.90 (m, 1H), 4.42-4.18 (m, 2H), 4.08 (d, J = 2.8 Hz, 1H), 3.99 (tt, J = 10.9, 3.7 Hz, 1H), 3.91-3.79 (m, 1H), 3.48-3.30 (m, 1H), 3.21-3.08 (m, 1H), 2.41-2.11 (m, 2H), 1.88-1.73 (m, 2H), 1.68-1.44 (m, 7H), 1.14 (d, J = 6.8 Hz, 3H).
(R)−3,3,3−トリフルオロ−1−[(R)−1−(5−フルオロ−ピリジン−2−イル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A40」)
(R)−3,3,3−トリフルオロ−1−[(S)−1−(5−フルオロ−ピリジン−2−イル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A41」)
「A41」:35mgの無色固体;LC/MS、Rt:2.16分;(M+H) 373.2;1H NMR (400 MHz, DMSO-d6, 90 °C) δ 8.44 (d, J = 2.8 Hz, 1H), 7.95-7.84 (m, 2H), 7.61 (s, 1H), 6.88 (s, 1H), 5.30-5.00 (m, 1H), 4.48 (d, J = 16.2 Hz, 1H), 4.28 (dd, J = 12.9, 3.8 Hz, 1H), 3.84-3.73 (m, 1H), 3.67-3.43 (m, 1H), 1.59 (s, 3H), 1.13 (d, J = 6.7 Hz, 3H).
1−[(R)−1−(4−フルオロ−フェニル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A42」)
「A42」:30mgの無色固体;LC/MS、Rt:1.82分;(M+H) 318.2;1H NMR (400 MHz, DMSO-d6, 90 °C) δ 7.60-7.54 (m, 2H), 7.52 (s, 1H), 7.36-7.28 (m, 2H), 5.18 (s, 1H), 4.85 (d, J = 15.8 Hz, 1H), 4.70 (d, J = 15.8 Hz, 1H), 3.95-3.78 (m, 2H), 3.40-3.28 (m, 1H), 1.40 (s, 3H), 1.39 (s, 3H), 0.86 (d, J = 6.8 Hz, 3H).
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−1−(3−フェニル−3,4,6,7−テトラヒドロ−イミダゾ[4,5−c]ピリジン−5−イル)−プロパン−1−オン(「A43」)
4,5,6,7−テトラヒドロ−1H−イミダゾ[4,5−c]ピリジン(500.0mg;4.060mmol)を、乾燥THF(10.0mL)およびDIPEA(1.59mL;9.338mmol)に懸濁させ、4−(ジメチルアミノ)ピリジン(99.2mg;0.812mmol)を加え、続いてジ−tert−ブチルジカーボネート(1.95g;8.932mmol)を加えた。反応混合物を、メタノール(2.0mL)で希釈し、室温で16h撹拌した。反応混合物を、酢酸エチルで希釈し、0.5N HCl、飽和NaHCO3溶液およびブラインで洗浄し、Na2SO4で乾燥し、吸引濾過し、蒸発乾固させた。残留物を、メタノール(5.0mL)に懸濁し、1N水酸化ナトリウム溶液(0.32mL;8.323mmol)で処理した。反応混合物を室温で20min撹拌し、真空下で濃縮して、水性残留物とした。この残留物を、水で希釈し、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、Na2SO4で乾燥し、吸引により濾過し、蒸発乾固させた。
収量:682.5mg(75%)の黄色油
1,4,6,7−テトラヒドロ−イミダゾ[4,5−c]ピリジン−5−カルボン酸tert−ブチルエステル(219.0mg;0.981mmol)、ベンゼンボロン酸(239.2mg;1.962mmol)および酢酸銅(II)(89.1mg;0.490mmol)を、アルゴン下で乾燥ジクロロメタン(4.0mL)に懸濁させた。乾燥ピリジン(158μL;1.962mmol)を加え、暗青色の反応混合物を室温で43h撹拌した。さらなるベンゼンボロン酸(239.2mg;1.962mmol)、酢酸銅(II)(89.1mg;0.490mmol)および乾燥ピリジン(158μL;1.962mmol)を、アルゴン下で加え、混合物を、室温で21h撹拌した。
(R)−3,3,3−トリフルオロ−1−[1−(4−フルオロ−フェニル)−1,4,6,7−テトラヒドロ−イミダゾ[4,5−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A44」)
(R)−1−[1−(4−クロロ−フェニル)−1,4,6,7−テトラヒドロ−イミダゾ[4,5−c]ピリジン−5−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(「A45」)
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−1−(1−フェニル−1,4,6,7−テトラヒドロ−[1,2,3]トリアゾロ[4,5−c]ピリジン−5−イル)−プロパン−1−オン(「A46」)
4−クロロ−3−ニトロ−ピリジン(1.50g;9.177mmol)、アニリン(1.02mL;11.013mmol)および無水酢酸ナトリウム(3.76g;45.887mmol)を、氷酢酸(7.50mL)に懸濁させ、130℃で14h撹拌した。混合物を室温に冷却し、水中に注ぎ、NaHCO3水溶液で中和し、ジクロロメタンで抽出した。合わせた有機層を、硫酸ナトリウムで乾燥し、濾過し、真空下で濃縮した。残留物を、フラッシュクロマトグラフィー(CombiFlashRF 200)により精製した。収量:1.90g(96%)の黄色固体;LC/MS、Rt:1.40分;(M+H) 216.1。
化合物46.1(2.30g;10.645mmol)を、室温でTHF(30.0mL)中で14h、Pd−C(5%)を用いて水素化した。溶液を濾過し、蒸発乾固させ、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。収量:1.91g(97%)の無色固体;LC/MS、Rt:1.13分;(M+H) 186.1。
化合物46.2(500.0mg;2.683mmol)を、塩酸(40.3mL;4.025mmol)に溶解し、0℃に冷却した。水(5.0mL)に溶解した亜硝酸ナトリウム(280.5mg;4.025mmol)をゆっくり加え、その間無色沈殿物が生成した。懸濁液を、0℃で30min撹拌し、次に室温まで14h放置して加温した。反応混合物を、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、濾過し、真空中で濃縮した。残留物を、フラッシュクロマトグラフィー(CombiFlashRF 200)により精製した。収量:496mg(94%)のベージュ色固体;LC/MS、Rt:1.71分;(M+H) 197.1。
化合物46.3(299.0mg;1.524mmol)を、メタノール(10.0mL)に溶解し、Pd−C(5%)上で室温および2.9〜3.2barで14h水素化した。反応物を濾過し、蒸発乾固させた。収量:305mg(100%)の無色油;LC/MS、Rt:0.89分;(M+H) 201.1。
アシル化を、「A9」(ステップ9.4)について記載したように行った。収量:378mg(72%)の無色固体;LC/MS、Rt:1.88分;(M+H) 341.1;1H NMR (400 MHz, DMSO-d6, 90 °C) δ 7.68-7.62 (m, 2H), 7.62-7.56 (m, 2H), 7.56-7.48 (m, 1H), 6.97 (s, 1H), 4.92 (s, 2H), 4.16-4.04 (m, 1H), 4.04-3.94 (m, 1H), 2.94 (t, J = 5.7 Hz, 2H), 1.61-1.57 (m, 3H).
(R)−3,3,3−トリフルオロ−1−[1−(4−フルオロ−フェニル)−1,4,6,7−テトラヒドロ−[1,2,3]トリアゾロ[4,5−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A47」)
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−1−(3−フェニル−5,6−ジヒドロ−8H−[1,2,4]トリアゾロ[4,3−a]ピラジン−7−イル)−プロパン−1−オン(「A48」)
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−1−(3−フェニル−5,6−ジヒドロ−8H−イミダゾ[1,2−a]ピラジン−7−イル)−プロパン−1−オン(「A49」)
(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−1−(3−フェニル−5,6−ジヒドロ−8H−イミダゾ[1,5−a]ピラジン−7−イル)−プロパン−1−オン(「A50」)
(ピラジン−2−イル)メタンアミン(500.0mg;4.353mmol)を、ジクロロメタン(20.0mL)に、アルゴン下で溶解し、0℃に冷却した。N−エチルジイソプロピルアミン(0.89mL;5.223mmol)を加え、続いて塩化ベンゾイル(0.56mL;4.788mmol)を加えた。反応混合物を、室温に放置して加温し、18h撹拌した。反応混合物を、飽和NaHCO3溶液で希釈した。有機相を分離し、水層をジクロロメタンで3回洗浄した。合わせた有機層を硫酸ナトリウムで乾燥し、濾過し、蒸発乾固させた。残留物を、フラッシュクロマトグラフィー(Companion RF;40gのSi50シリカゲルカラム)によって精製した。収量:895mg(96%)の黄色固体;LC/MS、Rt:1.36分;(M+H) 214.1。
N−ピラジン−2−イルメチル−ベンズアミド(300.0mg;1.353mmol)を、乾燥アセトニトリル(25.0mL)に溶解した。POCl3(1.24mL;13.534mmol)を、窒素雰囲気下で加え、反応混合物を、85℃で4h加熱した。反応混合物を室温に冷却し、蒸発乾固させた。残留物を、DCM、氷水およびNaHCO3溶液の混合物で希釈した。有機層を分離し、水層をジクロロメタンで抽出した。合わせた有機層を、硫酸ナトリウムで乾燥し、濾過し、蒸発乾固させた。収量:244mg(92%)の茶色油;LC/MS、Rt:1.40分;(M+H) 196.1。
化合物50.2(244.0mg;1.249mmol)を、メタノール(10.0mL)に溶解し、Pd−C(5%)上で室温および2.8barで14h水素化した。反応物を濾過し、蒸発乾固させた。収量:233mg(94%)の黄色油;LC/MS、Rt:0.32分;(M+H) 200.1。
化合物50.3(233.0mg;1.169mmol)を、(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−プロピオン酸(43.6mg;0.276mmol)と、例9(ステップ9.4)について記載したようにカップリングさせた。収量:171mg(43%)の無色固体;LC/MS、Rt:1.25分;(M+H) 340.1;1H NMR (400 MHz, DMSO-d6, 90 °C) δ 7.73-7.68 (m, 2H), 7.51-7.45 (m, 2H), 7.44-7.39 (m, 1H), 7.02 (s, 1H), 6.94-6.90 (m, 1H), 4.97 (s, 2H), 4.22 (t, J = 5.3 Hz, 2H), 4.18-4.05 (m, 2H), 1.66-1.58 (m, 3H).
(R)−3,3,3−トリフルオロ−1−[3−(4−フルオロ−フェニル)−5,6−ジヒドロ−8H−イミダゾ[1,5−a]ピラジン−7−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A51」)
(R)−3,3,3−トリフルオロ−1−[(R)−3−(4−フルオロ−フェニル)−5−メチル−5,6−ジヒドロ−8H−イミダゾ[1,5−a]ピラジン−7−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A52」)
(R)−3,3,3−トリフルオロ−1−[(S)−3−(4−フルオロ−フェニル)−5−メチル−5,6−ジヒドロ−8H−イミダゾ[1,5−a]ピラジン−7−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A53」)
2,6−ジメチルピラジン(500.0mg;4.623mmol)およびN−クロロスクシンイミド(617.4mg;4.531mmol)に、テトラクロロメタン(12.5mL)を、窒素の下で加え、混合物を、加熱還流した。ベンゾイルベンゼンカルボペルオキソエート(22.2mg;0.077mmol)を加え、無色懸濁液を85℃で3h加熱した。N−クロロスクシンイミド(61.7mg;0.453mmol)を加え、反応物をさらに2時間加熱し、次に室温で14h撹拌した。反応物を水で希釈し、ジクロロメタンで抽出した。合わせた有機層を、硫酸ナトリウムで乾燥し、濾過し、真空中で濃縮した。残留物を、フラッシュクロマトグラフィー(CombiFlashRF 200)により精製した。収量:328mg(51%)の無色油;LC/MS、Rt:1.35分;(M+H) 143.1/145.1。
化合物52.1(310.0mg;2.174mmol)、炭酸水素ナトリウム(219.0mg;2.609mmol)およびフタルイミドカリウム塩(403.0mg;2.174mmol)を、DMF(4.0mL)に溶解し、暗赤色/茶色溶液を、室温で14h撹拌した。混合物を濃縮し、水で希釈し、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、濾過し、真空中で濃縮した。残留物を、フラッシュクロマトグラフィー(CombiFlashRF)によって精製した。収量:226mg(41%)の無色固体;LC/MS、Rt:1.74分;(M+H) 254.1。
2−(6−メチル−ピラジン−2−イルメチル)−イソインドール−1,3−ジオン(1.57g;6.191mmol)をエタノール(60.0mL)に懸濁させた懸濁液に、水酸化ヒドラジニウム(2.41mL;49.531mmol)を、攪拌しながらゆっくり加え、混合物を、80℃に加熱した。5分後、無色溶液が生成し、それは、30分後に無色懸濁液に変化した。反応混合物をさらに6時間還流し、室温に冷却し、水(80mL)および0.1N NaOH(30mL)で希釈し、ジクロロメタン−メタノール(1/1)の混合物で抽出した。合わせた有機層を、硫酸ナトリウムで乾燥し、濾過し、真空中で濃縮した。収量:417mg(55%)の無色油;LC/MS、Rt:0.33分;(M+H) 124.2。
化合物52.3(416.0mg;3.378mmol)を、ジクロロメタン(15.0mL)に溶解し、氷浴中で冷却した。N−エチルジイソプロピルアミン(0.69mL;4.053mmol)および4−フルオロベンゾイルクロリド(0.43mL;3.547mmol)を加え、氷浴を取り外した。黄色溶液が生成し、4h撹拌した。混合物を、飽和水性NaHCO3溶液および水で希釈した。有機相を分離し、水層をジクロロメタンで洗浄した。合わせた有機層を、硫酸ナトリウムで乾燥し、濾過し、真空中で濃縮した。粗生成物を、フラッシュクロマトグラフィー(CombiFlashRF 200)により精製した。収量:728mg(88%)の黄色固体;LC/MS、Rt:1.56分;(M+H) 246.1。
化合物52.4(728.0mg;2.967mmol)を、乾燥アセトニトリル(40.1mL)に溶解した。POCl3(2.77mL;29.669mmol)を加えた。オレンジ色の混合物を、95℃で18h撹拌した。反応混合物を室温に冷却し、水(150mL)で慎重に希釈し、重炭酸ナトリウムで中和した。有機相を分離し、水層をジクロロメタンで洗浄した。合わせた有機層を、硫酸ナトリウムで乾燥し、濾過し、真空中で濃縮した。粗残留物を、フラッシュクロマトグラフィー(CombiFlashRF 200)により精製した。収量:617mg(91%)の黄色固体;LC/MS、Rt:1.47分;(M+H) 228.1。
化合物52.5(617.0mg;2.713mmol)を、メタノール(10.0mL)に溶解し、Pd−C(5%)上で室温および3.0barで4h水素化した。反応物を濾過し、蒸発乾固させた。収量:606mg(97%)のオフホワイト油;LC/MS、Rt:0.34分;(M+H) 232.2。
化合物52.6(606.0mg;2.619mmol)を、(R)−3,3,3−トリフルオロ−2−ヒドロキシ−2−メチル−プロピオン酸と、例9(ステップ9.4)に記載したようにカップリングさせた。収量:576mg(59%)の黄色油。
「A53」:57mgの無色固体;LC/MS、Rt:1.43分;(M+H) 372.1;1H NMR (400 MHz, DMSO-d6, 90 °C) δ 7.74 -7.67 (m, 2H), 7.31-7.22 (m, 2H), 6.98 (s, 1H), 6.86 (s, 1H), 5.43-5.16 (m, 1H), 4.80-4.72 (m, 1H), 4.64 (d, J = 16.4 Hz, 1H), 4.51-4.44 (m, 1H), 3.59 (d, J = 12.1 Hz, 1H), 1.58 (s, 3H), 1.08 (d, J = 6.5 Hz, 3H).
(R)−1−[(R)−3−(2,4−ジフルオロ−フェニル)−5−メチル−5,6−ジヒドロ−8H−イミダゾ[1,5−a]ピラジン−7−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(「A54」)
(R)−1−[(S)−3−(2,4−ジフルオロ−フェニル)−5−メチル−5,6−ジヒドロ−8H−イミダゾ[1,5−a]ピラジン−7−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(「A55」)
「A55」:342mgの無色固体;LC/MS、Rt:1.42分;(M+H) 390.2;1H NMR (400 MHz, DMSO-d6, 90 °C) δ 7.67-7.46 (m, 1H), 7.30 (td, J = 10.2, 2.5 Hz, 1H), 7.18 (td, J = 8.5, 2.4 Hz, 1H), 7.00 (s, 1H), 6.91 (s, 1H), 5.29 (br, 1H), 4.69 (d, J = 16.5 Hz, 1H), 4.46-4.31 (m, 2H), 3.66 (d, J = 10.1 Hz, 1H), 1.58 (s, 3H), 1.00 (d, J = 6.4 Hz, 3H).
(R)−1−[(S)−3−(3,5−ジフルオロ−ピリジン−2−イル)−5−メチル−5,6−ジヒドロ−8H−イミダゾ[1,5−a]ピラジン−7−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(「A56」)
(R)−1−[(R)−3−(3,5−ジフルオロ−ピリジン−2−イル)−5−メチル−5,6−ジヒドロ−8H−イミダゾ[1,5−a]ピラジン−7−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(「A57」)
「A57」:342mgの無色固体;LC/MS、Rt:1.45分;(M+H) 391.1;1H NMR (400 MHz, DMSO-d6, 90 °C) δ 8.54 (d, J = 2.3 Hz, 1H), 7.99-7.87 (m, 1H), 7.04 (s, 1H), 6.95 (s, 1H), 5.41 (s, br, 1H), 5.17-5.00 (m, 1H), 4.68 (d, J = 16.7 Hz, 1H), 4.56 (d, J = 13.9 Hz, 1H), 3.55 (d, J = 12.8 Hz, 1H), 1.61 (s, 3H), 1.17 (d, J = 6.4 Hz, 3H).
特に好ましい化合物は、14、20、34、38、40、54および57である。
例A:注射バイアル
100gの式IaまたはIb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IaまたはIb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。
940mlの2回蒸留水中の1gの式IaまたはIb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IaまたはIb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IaまたはIb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IaまたはIb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IaまたはIb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 (12)
- 式Iaまたは式Ib
Xは、CHまたはNを示し、
Yは、CHまたはNを示し、
R1は、H、A、(CH2)nAr、(CH2)nHetまたはCycを示し、
R2は、HまたはCH3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により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、これは、非置換であるかまたはOHにより単置換されており、
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、ならびに/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を示し、
ただし、
X=CHである場合、Y=Nであり、
または
Y=CHである場合、X=Nである、
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、ならびにすべての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により単置換、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、ならびにすべての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および/もしくはOAにより単置換もしくは二置換されている、
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、ならびにすべての比率でのそれらの混合物。 - XがCHまたはNを示し、
YがCHまたはNを示し、
R1がH、A、(CH2)nAr、(CH2)nHetまたはCycを示し、
R2がHまたはCH3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により単置換、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および/もしくはOAにより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により単置換されており、
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、ならびに/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、
HalがF、Cl、BrまたはIを示し、
nが0,1または2を示し、
ただし、
X=CHである場合、Y=Nであり、
または
Y=CHである場合、X=Nである、
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、ならびにすべての比率でのそれらの混合物。 - 請求項1〜4のいずれか一項に記載の式IaまたはIbで表される化合物、または、請求項5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の製造方法であって、式IIaまたはIIb
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IaまたはIb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1〜4のいずれか一項に記載の式IaまたはIbで表される化合物、または、請求項5に記載の化合物、および/または、それらの薬学的に許容し得る塩、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少なくとも1種と、任意に薬学的に許容し得る担体、賦形剤またはビヒクルとを含む、医薬。
- がん、糖尿病、心臓虚血、インスリン抵抗性症候群、メタボリックシンドローム、高血糖症、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/または防止のための使用のための、請求項7に記載の医薬。
- 頭部、頸部、目、口、喉、食道、気管支、喉頭、咽頭、胸、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/または防止のための使用のための、請求項8に記載の医薬。
- 請求項1〜4のいずれか一項に記載の式IaまたはIbで表される化合物、または、請求項5に記載の化合物、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、ならびにすべての比率でのそれらの混合物の少なくとも1種と、さらなる医薬活性成分の少なくとも1種とを含む、医薬。
- (a)請求項1〜4のいずれか一項に記載の式IaまたはIbで表される化合物、または、請求項5に記載の化合物、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
の別個のパックからなる、セット(キット)。 - 化合物1−[(R)−1−(4−フルオロ−フェニル)−7−メチル−1,4,6,7−テトラヒドロ−ピラゾロ[4,3−c]ピリジン−5−イル]−2−ヒドロキシ−2−メチル−プロパン−1−オン(「A42」)ならびに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、ならびにすべての比率でのそれらの混合物。
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