JP2013538214A - トリアゾロピラジン誘導体 - Google Patents
トリアゾロピラジン誘導体 Download PDFInfo
- Publication number
- JP2013538214A JP2013538214A JP2013526335A JP2013526335A JP2013538214A JP 2013538214 A JP2013538214 A JP 2013538214A JP 2013526335 A JP2013526335 A JP 2013526335A JP 2013526335 A JP2013526335 A JP 2013526335A JP 2013538214 A JP2013538214 A JP 2013538214A
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- triazolo
- het
- pyrazin
- amine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
Description
本発明は、価値ある特性、特に、医薬の調製に使用することができる特性を有する新規化合物の発見を目的とした。
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30.Ponzoni, M., et al. Syk expression patterns differ among B-cell lymphomas. Leuk Res (2010).
32.Uckun, F.M., Ek, R.O., Jan, S.T., Chen, C.L. & Qazi, S. Targeting SYK kinase-dependent anti-apoptotic resistance pathway in B-lineage acute lymphoblastic leukaemia (ALL) cells with a potent SYK inhibitory pentapeptide mimic. Br J Haematol 149, 508-517 (2010).
33.Wilcox, R.A., et al. Inhibition of Syk protein tyrosine kinase induces apoptosis and blocks proliferation in T-cell non-Hodgkin's lymphoma cell lines. Leukemia 24, 229-232 (2009).
34.Feldman, A.L., et al. Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas. Leukemia 22, 1139-1143 (2008).
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固形腫瘍のがん処置の多くの戦略は、腫瘤のできる限りの外科的除去、ならびに、それに続く放射線治療およびより特異的にがん細胞経路を標的とする細胞毒性剤またはインヒビターによる化学療法による、残存するすべての腫瘍細胞の根絶に焦点を合わせている。しかしながら、かかるアプローチの成功は制限されており、かつ、しばしば持続しない。
1MTが、T細胞を仲介する抗腫瘍免疫の活性化を通して間接的に作用するという予想を立証した。IDOを標的にすることが1MTの作用に必須であるという重要な証拠は、遺伝的にIDOを欠損したマウスにおいて、1MTが抗腫瘍活性を欠いているという実証により提供された[Hou et al., 2007]。
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本発明は、特に、Sykによるシグナル伝達を阻害、調節および/または調整する式Iの化合物、これら化合物を含む組成物、ならびに、Sykにより誘発された病気および愁訴を処置するためにそれらを使用する方法に関する。
宿主または患者は、任意の哺乳類種、例えば、霊長類種、特にヒト;マウス、ラットおよびハムスターを含む齧歯類;ウサギ;ウマ、ウシ、イヌ、ネコなどに属してもよい。動物モデルは、実験的調査の対象とされ、ヒトの病気を処置するモデルを提供する。
他の複素環式Sykインヒビターは、WO2008/118823、WO2009/136995、WO 2010/027500に記載されている。
他の複素環式化合物は、WO2010/010188、WO2010/010184、WO2010/010189、WO2009/155551、WO2009/155565、WO2009/047514に記載されている。
本発明は、式Iの化合物、
R1は、Ar1またはHet1を表し、
R2は、Ar2、Het2、NH(CH2)nAr2、O(CH2)nAr2、NR3(CH2)nHet2、A、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、NHCycまたはNH(CH2)pNA2を表し、
Ar1は、非置換の、または、Hal、A、Alk、(CH2)nOH、(CH2)nOA、(CH2)nCOOH、(CH2)nCOOA、SO2A、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、[C(R3)2]nCN、NO2、(CH2)nCONH2、(CH2)nCONHA、(CH2)nCONA2、SO2NH2、SO2NHA、SO2NA2、NHCONH2、NHCOA、NHCOAlk、NHCOCH=CH(CH2)pNA2、CHO、COA、SO3H、O(CH2)pNH2、O(CH2)pNHA、O(CH2)pNA2、COHet3、S(CH2)nHet3、(CH2)nHet3および/もしくはO(CH2)nHet3で、一、二または三置換された、フェニル、ナフチルあるいはビフェニルを表し、
Het1は、1〜4個のN、Oおよび/もしくはS原子を有する、単環式のまたは二環式の、不飽和のあるいは芳香族の複素環を表し、該環は、非置換であっても、A、OH、OA、Hal、(CH2)nAr3および/もしくは=Oで一、二、三または四置換されてもよく、
Het3は、1〜4個のN、Oおよび/もしくはS原子を有する、単環式のまたは二環式の、飽和の、不飽和のあるいは芳香族の複素環を表し、該環は、非置換であっても、A、Hal、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、(CH2)nOH、(CH2)nOA、COOA、Ar3および/もしくは=Oで、一、二、三または四置換されてもよく、
R3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表し、
あるいは、
3〜7個のC原子を有する環状アルキルを表し、
Cycは、非置換であっても、NH2で一置換されてもよい、3〜7個のC原子を有する環状アルキルを表し、
Alkは、2、3、4、5もしくは6個のC原子を有するアルケニルまたはアルキニルを表し、
Ar3は、非置換の、または、Halおよび/もしくはAで一、二または三置換されたフェニルを表し、
Halは、F、Cl、BrまたはIを表し、
nは、0、1、2、3または4を表し、
pは、1、2、3または4を表す、
ならびに、その薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体および立体異性体、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の化合物の薬学的に許容し得る誘導体に関する。
化合物の溶媒和物という用語は、それらの相互引力のせいで形成される化合物上への不活性溶媒分子の付加を意味する。溶媒は、例えば、一もしくは二水和物またはアルコキシドである。
病気、症候群、疾患、愁訴、障害もしくは副作用の、改善した処置、治癒、防止または除去、あるいは、病気、愁訴または障害に先立つ軽減も。
「治療的有効量」という表現はまた、正常な生理学的機能を増大させるのに有効な量も包含する。
これらは、特に好ましくは立体異性体の化合物の混合物である。
R2−L III
(式中、R2は、請求項1に示した意味を有し、Lは、ボロン酸基またはボロン酸エステル基を表す)
b)式IIの化合物
R2−L III
(式中、R2は、請求項1に示した意味を有し、Lは、NH2またはOHを表す)
式Iの塩基または酸を、その塩の1つに変換すること。
上記および下記において、明示的に別段の定めをした場合を除き、R1およびR2のラジカルは、式Iに示した意味を有する。
さらに、Aは、例えば、CH2OCH3、CH2CH2OH、OCH2CH2NH2、CH2NHCH2またはNHCH2CH3を表す。
環式アルキル(シクロアルキル)およびcyc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表す。
Alkは、2、3、4、5もしくは6個のC原子を有する非分岐または分岐のアルケニルあるいはアルキニルを表し、好ましくはイソプロペニル、プロパ−2−インイル、ビニルまたはアリルを表す。
Ar3は、好ましくはフェニルを表す。
よって、さらなる置換に関係なく、Het2は、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−キノリニル、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−ジヒドロベンズオキサゾリル、2−オキソ−2,3−ジヒドロベンズオキサゾリル、2,3−ジヒドロベンズイミドアゾリル、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ドアゾリルも表すことができる。
複素環のラジカルもまた、一部または全部が水素化されてもよい。
本発明を通して、1回以上現れるすべてのラジカルは、同じであっても異なっていてもよい、すなわち、互いに独立している。
式Iの化合物は、1個または2個以上のキラル中心を有してもよく、よって、様々な立体異性体の形態に現れ得る。式Iはこれらすべての形態を包含する。
あるいは、
3〜7個のC原子を有する環状アルキルを表し;
R2は、Ar2、Het2、NH(CH2)nAr2、O(CH2)nAr2、NR3(CH2)nHet2、A、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、NHCycまたはNH(CH2)pNA2を表し、
Ar1は、非置換の、または、Hal、A、(CH2)nOH、(CH2)nOA、(CH2)nHet3および/もしくはS(CH2)nHet3で一、二または三置換されたフェニルを表し、
Ar2は、非置換の、または、Hal、A、(CH2)nOH、(CH2)nOA、(CH2)nCOOH、(CH2)nCOOA、OAr3、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、[C(R3)2]nCN、NO2、CONH(CH2)pNH2、CONH(CH2)pNHA、CONH(CH2)pNA2、(CH2)nCONH2、(CH2)nCONHA、(CH2)nCONA2、NHCOAr3、NHSO2A、OSO2A、(CH2)nHet3および/もしくはS(CH2)nHet3で一、二または三置換された、フェニル、ナフチルあるいはビフェニルを表し、
Het2は、非置換の、または、Hal、A、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、CN、CHO、(CH2)nOH、(CH2)nOA、(CH2)nAr3、(CH2)nHet3、SO2A、SO2Aおよび/もしくは=Oで一、二または三置換された、ピペリジニル、ピペラジニル、ピロリジニル、モルホリニル、テトラヒドロピラニル、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、イソオキサゾリル、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、ピラジニル、キノリル、イソキノリル、ジヒドロイソキノリル、テトラヒドロイソキノリル、キノキサリニル、ベンズイミダゾリル、ベンゾチオフェニル、ベンゾトリアゾリル、インドリル、インドリニル、ナフチリジニル、ジヒドロナフチリジニル、テトラヒドロナフチリジニル、ベンゾ−1,3−ジオキソリル、2,3−ジヒドロ−ベンゾ[1,4]ジオキシニル、フロピリジニル、インダゾリル、ベンゾ[1,4]オキサジニル、ピリド[3,2−b][1,4]オキサジニルあるいはベンゾチアジアゾリルを表し、
R3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表し、
Aは、1〜7個のH原子がFで交換されても、ならびに/あるいは、1もしくは2個の非近接のCH2基がOおよび/またはNHで交換されてもよい、1〜10個のC原子を有する非分岐のまたは分岐のアルキルを表すか、
あるいは、
3〜7個のC原子を有する環状アルキルを表し、
Cycは、非置換であっても、NH2で一置換されてもよい、3〜7個のC原子を有する環状アルキルを表し、
Ar3は、非置換の、または、Halおよび/もしくはAで一、二または三置換されたフェニルを表し、
nは、0、1、2、3または4を表し、
pは、1、2、3または4を表す;
ならびに、その薬学的に使用可能な塩、溶媒和物、互変異性体および立体異性体、あらゆる比率でのそれらの混合物。
使用する式IIのピリダジノンは、市販されていない場合、一般にW. J. Coates, A. McKillop, Synthesis, 1993, 334-342の方法で調製する。
式Iの化合物は、好ましくは、式IIの化合物を式IIIの化合物と反応させることによって、得ることができる。
式IIIの化合物において、Lは、好ましくは、
使用する条件次第で、反応時間は、数分間と14日間との間であり、反応温度は、約−30°と140°との間、通常0°と100°との間、特に約60°と約90°との間である。
R1は、Ar1またはHet1を表し、
Ar1は、非置換の、または、Hal、A、(CH2)nOH、(CH2)nOA、(CH2)nHet3および/もしくはS(CH2)nHet3で、一、二または三置換されたフェニルを表し、
Het1は、非置換の、または、A、OH、OA、Hal、(CH2)nAr3および/もしくは=Oで一、二または三置換された、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、イソオキサゾリル、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、ピラジニル、キノリル、イソキノリル、ベンズイミダゾリル、ベンゾトリアゾリル、インドリル、ベンゾ−1,3−ジオキソリル、2,3−ジヒドロ−ベンゾ[1,4]ジオキシニル、インダゾリル、ベンゾ[1,4]オキサジニル、1,3−もしくは2,3−ジヒドロ−インドリルあるいはベンゾチアジアゾリルを表し、
R3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表し、
Aは、1〜7個のH原子がFで交換されても、ならびに/あるいは、1もしくは2個の非近接のCH2基がOおよび/またはNHで交換されてもよい、1〜10個のC原子を有する非分岐のまたは分岐のアルキルを表すか、
あるいは、
3〜7個のC原子を有する環状アルキルを表し、
Ar3は、非置換の、または、Halおよび/もしくはAで一、二または三置換されたフェニルを表し、
nは、0、1、2、3または4を表し、
pは、1、2、3または4を表す。
ならびに、その薬学的に許容し得る塩、溶媒和物、互変異性体および立体異性体、あらゆる比率でのそれらの混合物。
式IIの化合物は、式Iの化合物の調製における有用な中間体である。
さらに、式IIの化合物は、Syk阻害活性を示すが故に、医薬として使用することができる。
本発明に従う該化合物を、最終の非塩形態で使用することができる。その一方で、本発明はまた、当該技術分野において知られている手順により様々な有機および無機の酸および塩基から誘導することができる、それらの薬学的に許容し得る塩の形態でのこれらの化合物の使用も包含する。式Iの化合物の薬学的に許容し得る塩形態のほとんどの部分を、従来の方法により調製する。式Iの化合物が、カルボキシル基を含む場合には、その好適な塩の1つを、化合物を好適な塩基と反応させて、対応する塩基付加塩を得ることにより形成させることができる。
特に、塩酸塩、二塩酸塩、臭化水素酸塩、マレアート、メシラート、ホスファート、スルファートおよびスクシナートが好ましい。
局所投与に適合された薬学的化合物を、軟膏、クリーム、懸濁液、ローション、粉末、溶液、ペースト、ジェル、スプレー、エアロゾルまたはオイルとして処方することができる。
口腔中の局所適用に適合された医薬製剤には、薬用キャンディー、トローチおよびマウスウォッシュが包含される。
直腸投与に適合された医薬製剤を、坐薬または浣腸の形態で投与することができる。
膣内投与に適合された医薬製剤を、ペッサリー、タンポン、クリーム、ジェル、ペースト、泡またはスプレー製剤として投与することができる。
以下の医薬は、好ましくは、これに限らないが、式Iの化合物と組み合わせる:
2.グルココルチコイド(低経口用量)
3.従来の疾患修飾性抗リウマチ薬(DMARD)
−メトトレキサート
−レフルノミド
−ヒドロキシクロロキン
−アザチオプリン
−シクロスポリン
−ミノサイクリン
−金
−TNFインヒビター
−エタネルセプト(Enbrel)
−インフリキシマブ(Remicade)
−アダリムマブ(Humira)
−B細胞への治療
−リツキシマブ(Rituxan)
−T細胞/B細胞の同時活性化シグナルインヒビター
−アバタセプト(Orencia)
−IL−1受容体アンタゴニスト
−アナキンラ(Kineret)
さらに、本発明は、式Iの化合物および/またはその薬学的に許容し得る塩、溶媒和物および立体異性体、あらゆる比率でのそれらの混合物の少なくとも1種、ならびに、さらなる医薬活性成分の少なくとも1種を含む医薬に関する。
(a)式Iの化合物および/またはその薬学的に許容し得る塩、溶媒和物および立体異性体、あらゆる比率でのそれらの混合物の有効量、
ならびに、
(b)さらなる医薬活性生物の有効量
の別箇のパックからなるセット(キット)にも関する。
ならびに溶解されたか、または凍結乾燥された形態での他の医薬活性成分の有効量を含有する。
傷害もしくは病気に関連する症状の全部または一部の緩和、あるいは、それら症状のさらなる進行もしくは悪化の緩徐または停止、あるいは、本明細書に開示された病気を発症するリスクがあるか、または該病気を有する患者において、病気もしくは障害の防止または予防の可能な量を意味し、前記病気としては、炎症性の疾患、免疫学的な疾患、がん、代謝性の疾患あるいはキナーゼもしくはキナーゼ経路(一態様において、Syk、FLT−3、JAK1および/またはJAK2および/またはJAK3および/またはBTK経路)の阻害により処置可能または防止可能な疾患などである。一態様において、式Iの化合物の有効量は、例えばインビトロまたはインビボなどでの細胞におけるキナーゼを阻害する量である。いくつかの態様において、式Iの化合物の有効量は、非処置の細胞におけるキナーゼ活性と比較して、細胞におけるキナーゼを10%、20%、30%、40%、50%、60%、70%、80%、90%または99%阻害する。例えば薬学的な組成物における式Iの化合物の有効量は、所望の効果を発揮するだろうレベルであってもよく;例えば、経口および腸管外の両方の投与のための単位用量において、約0.005mg/kg対象の体重〜約10mg/kg対象の体重である。
本発明の化合物は、哺乳動物に対して、特にヒトに対して、チロシンキナーゼにより誘発される病気の処置における薬学活性成として好適である。
本発明には、リウマチ性関節炎、全身性紅斑性狼瘡、ぜんそく、アレルギー性鼻炎、ITP、多発性硬化症、白血病、乳がんおよび悪性黒色腫の処置または防止のための医薬の調製のための、式Iの化合物および/またはそれらの生理学的に許容し得る塩および溶媒和物の使用が包含される。
炎症性の病気の例としては、リウマチ性関節炎、乾癬、接触皮膚炎、遅延型過敏反応などが挙げられる。
本発明はまた、網膜血管化の処置または防止のための医薬の調製における、式Iの化合物および/またはその生理学的に許容し得る塩および溶媒和物の使用も包含する。
本発明は、Sykの阻害に使用するための、式Iの化合物およびその薬学的に許容し得る塩、溶媒和物、互変異性体および立体異性体、あらゆる比率でのそれらの混合物に、特に関する。
他の態様において、線維症および障害を処置または防止する方法を本明細書に提供する。特定の態様において、特発性肺線維症、骨髄線維症、肝線維症、脂肪線維症および脂肪性肝炎を処置または防止する方法を本明細書に提供する。
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(ミリモーラー)、m.p.(融点)、eq(定量的)、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)、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(エレクトロスプレイイオン化)、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)、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)、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−テトラメチルウロニ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)、UV(紫外)。
SYKフラッシュプレートアッセイ
キナーゼアッセイを、(例えばトップカウント(Topcount)測定では)384ウェルのフラッシュプレートアッセイ、または(リードシーカー(LEADseeker)測定では)384ウェルイメージ(Image)−フラッシュプレートアッセイのいずれかとして実施する。
ここに記載のアッセイを、Caliper Life Sciences LC3000系で実施する。この技術は、酵素反応の最後に、リン酸化されたか、または非リン酸化の蛍光標識基質ペプチドの相対量の測定を介して酵素活性のデータを提供する。ペプチドのこれらの異なる状態を、試料間の潜在的な差異を適用することによって解消する。生成物(基質の対語として)上の荷電したリン酸基の存在によって、2種のペプチド間のペプチド移動度が異なる。これは、基質および生成物のペプチド上の蛍光標識の励起によって可視化され、分析ソフトウェア内のピークとして表される。
1.BCR架橋により誘発されるBLNKリン酸化
5%FCSを含むIMDM培地中で終夜インキュベートしたRamos細胞を、血清なしのIMDM培地中に再懸濁した(3.3×106細胞/ml)。90μlの細胞懸濁(300,000細胞)を、96ウェルプレート中、10μlのSYKインヒビター(3%DMSO中)とともに、37℃で20分間インキュベートした。予めインヒビターとインキュベートした後、細胞を、10μg/mlのヤギ抗ヒト抗IgMで、37℃で10分間活性化した。刺激後、細胞を、80μlの4%パラホルムアルデヒドの添加により固定し、続いて、RTで10分間インキュベートし、PBS中0.1%Triton X−100中で固定した。BLNKリン酸化を、BD pharmingenの抗BLNK−pY84抗体で細胞をRTで45分間染色した後、フローサイトメトリーで検出した。
末梢血単核細胞において、抗IgMにより誘発されるCD69の上方調節を定量化するために、90μlのPBMC細胞懸濁(1×106細胞を含む)を、予め、10μlのSYKインヒビターとともに、37℃/5%CO2で1hインキュベートした。予めインヒビターとともにインキュベーションした後、細胞を、10μg/mlのヤギ抗ヒト抗IgMにより、37℃/5%CO2で、18時間刺激した。刺激後、細胞を、4%FCSを含むPBS中ヤギIgG(1:200希釈)、CD19−PerCpCy5.5(5μl)およびCD69−APC(3μl)抗体を含むカクテルで染色した。CD19+細胞におけるCD69発現を、フローサイトメトリーにより定量化した。
CIA
コラーゲンにより誘発される関節炎(CIA)を誘導するために、オスDBA/1マウスに、500μlのプリスタンを、〜21日に、i.p.に注入する。0日に、マウスを、フロイント完全アジュバント(CFA)中100μgのニワトリII型コラーゲン(CII)により、0日に耳介とその裏側の一部位とに分けて経皮的に免疫する。21日に、マウスに、PBS中可溶化CIIを、i.p.追加免疫(100μg)を行う。Sykインヒビターの投薬は予防的である:0日に開始し、10日までおよび20日にブーストを開始する前まで継続し、30日まで継続する。化合物を、3、10および30mg/kgの用量で、1日に2回経口的に投与する。
グルコース−6−ホスファートイソメラーゼにより誘発される関節炎(GIA)を誘導するために、メスDBA/1マウスに、フロイント完全アジュバント(CFA)中100μgのG6PIにより、0日に耳介とその裏側の一部位とに分けて経皮的に免疫する。Sykインヒビターの投薬は、0日に予防的に開始し、14日まで継続する。化合物を、3、10および30mg/kgの用量で、1日に2回経口的に投与する。
質量分析(MS):EI(電子衝突イオン化)M+
FAB(高速原子衝撃)(M+H)+
ESI(エレクトロスプレイイオン化)(M+H)+
質量分析(MS):EI(電子衝突イオン化)M+
FAB(高速原子衝撃)(M+H)+
ESI(エレクトロスプレイイオン化)(M+H)+
APCI−MS(大気圧化学イオン化−質量分析)(M+H)+。
m.p.=融点
方法A:
1min 99%A、
2.5minに、99%Aから100%Bまで、
1.5min後に100%B、および1min後に99%A。
カラム:Chromolith SpeedRod RP-18e;50〜4.6mm;
検出220nM(溶媒A:H20(0.1%TFA)、
溶媒B:ACN(0.1%TFA);
0.1min以内に、98%Aまで、
1.9minの間に、98%A(溶媒A H20(0.1%TFA)、溶媒B:ACN(0.1%TFA));
カラム:Xbridge C8 5μM、4.6×50mm;流速:2mL/min。
例において提供されたLCMSデータは、保持時間、純度および/またはm/zでの質量とともに与えられる。結果が以下のようにして得られた:質量スペクトル:LC/MS Waters ZMD(ESI)またはHP 1100シリーズのHewlett Packard System(イオン源:エレクトロスプレイ(正モード);走査:100〜1000m/z;フラグメンテーション電圧:60V;ガス温度:300℃、DAD:220nm;流速:2.4ml/min。
方法B:A−0.1%HCOOH、B−MeOH:流れ−1.0ml/min.;カラム:Atlantis C8(50×4.6mm 5Um、+veモード);
方法D:A−H2O中0.1%TFA、B−ACN中0.1%TFA:流れ−2.0ml/min;カラム:XBridge C8(50×4.6mm 3.5Um、+veモード);
方法E:2.8min以内に、96%Cから100%Dまで、0.5min後に100%D、および0.1min後に96%Cまで;カラム Chromolith SpeedRod RP-18e;50〜4.6mm;検出220nm;溶媒C:H2O(0.05%HCOOH)、溶媒D:ACN(0.05%HCOOH)。
マイクロ波化学は、単一モードのマイクロ波反応器である、Personal ChemistryのEmrysTM Optimiserで実施する。
このアッセイは、セリンキナーゼGCN2(general control non-derepressible-2)の活性を定量化するものである。
このキナーゼは、細胞のストレス代謝に関与する。それは、飢餓(アミノ酸欠失)により活性化される。その天然の基質は、翻訳因子であるeIF2a(真核生物開始因子2アルファサブユニット)であり、該因子は、細胞においてアミノ酸がボトルネックになった場合にGCN2により活性化(リン酸化)される。これによって、順に、タンパク質合成が中断される。GCN2が阻害された結果、この機構が停止する:細胞は、「飢餓」ストレスによりタンパク質産生を停止することができない。
酵素反応は、EDTAの添加により停止する。リン酸化されたeIF2アルファの量を、TR−FRET(Lanthascreen)により決定する:複合体は、抗体と、340nmでFRETを励起することができるGFP標識リン酸−eIF2aとからなるように形成される。
GCN2活性は、520nmの発光波長(リン酸ペプチドに感受性のある波長=GFPの発光)での蛍光ユニットの、495nm(参照波長=テルビウムキレートの発光)での該ユニットに対する比率に直接的に比例する。
Hepes、pH7.0 50mM
MgCl2 10mM
MnCl2 5mM
BSA 0.1%
DMSO 1%
ATP 10μM
DTT 2mM
GFP−eIF2a 80nM(基質)
GCN2 30nM(酵素)
4μL 酵素溶液(アッセイ緩衝液中)
1.5μL 化合物(cmpd希釈緩衝液/6.3%DMSO中)
インキュベート RTで20min
4μL 基質/ATPミックス(アッセイ緩衝液中)
インキュベート RTで90min
10μL 停止/検出ミックス(抗体希釈緩衝液中)
インキュベート RTで60min
読み出し Lanthascreen 340/495/520
反応物質の調製
2−(2−クロロ−4−イソチオシアナト−フェニルスルファニル)−1−メチル−4,5−ジヒドロ−1H−イミダゾール(“A1”)
[3−クロロ−4−(1−メチル−1H−イミダゾール−2−イルスルファニル)−フェニル]−(8−クロロ−[1,2,4]トリアゾロ[1,5−a]ピラジン−2−イル)−アミン(“B6”)
方法1
[8−(3−アミノメチル−フェニル)−[1,2,4]トリアゾロ[1,5−a]ピラジン−2−イル]−(3,5−ジメトキシ−フェニル)−アミン(“C114”)
ジメトキシエタン(3ml)と水(1ml)との混合物中(8−クロロ−[1,2,4]トリアゾロ[1,5−a]ピラジン−2−イル]−(3,5−ジメトキシ−フェニル)−アミン(0.2g、0.65mmol、1eq)の溶液に、3−アミノメチルフェニルボロン酸(0.28g、1.31mmol、2eq)、炭酸ナトリウム(0.14g、1.31mmol、2eq))およびジクロロビス(トリフェニル−ホスフィン)パラジウム(II)(0.023g、0.03mmol、5%)を、マイクロ波バイアルに入れ、120℃で2時間加熱した。反応混合物を濃縮し、残渣をジクロロメタン(10ml×1)に取り込ませ、ブライン溶液(10ml×1)で洗浄し、有機層を無水MgSO4で乾燥し、濃縮した。得られた粗生成物を(230〜400)メッシュを使用するシリカゲルカラムで精製し、黄色固体として表題の生成物を得た。
(4−モルホリン−4−イル−フェニル)−[8−(2−フェノキシ−フェニル)−[1,2,4]トリアゾロ[1,5−a]ピラジン−2−イル]−アミン(“C289”)
乾燥圧力管に入れられたエタノール:トルエン(1:4)の混合物(10ml)中(8−クロロ−[1,2,4]トリアゾロ[1,5−a]ピラジン−2−イル−(4−モルホリン−4−イル−フェニル)−アミン(0.15g、0.45mmol、1eq)の溶液に、酢酸パラジウム(0.01g、0.045mmol、0.1eq)、無水炭酸カリウム(0.125g、0.90mmol、2eq)、2−ジシクロヘキシルホスフィノ−2’,6’−ジメトキシビフェニル、S−Phos(0.027g、0.06mmol、0.13eq)および2−フェノキシフェニルボロン酸(0.19g、0.90mmol、2eq)を加え、反応混合物を窒素で脱気した。反応混合物を120℃で1時間加熱した。反応混合物を濃縮し、残渣を、ジクロロメタン(50ml)中25%メタノールに取り込ませ、セライトを通してろ過して無機物を除去し、ろ過物を濃縮し、(230〜400)メッシュを使用するシリカカラムで精製し、淡黄色固体として生成物を得た。
N−{2−メチル−3−[2−(4−モルホリン−4−イル−フェニルアミノ)−[1,2,4]トリアゾロ[1,5−a]ピラジン−8−イル]−フェニル}−3−トリフルオロメチル−ベンズアミド(“C299”)
乾燥ジクロロメタン(25ml)中[8−(3−アミノ−2−メチル−フェニル)−[1,2,4]トリアゾロ[1,5−a]ピラジン−2−イル]−(3,5−ジメトキシ−フェニル)−アミン(0.125g、0.31mmol、1eq)の溶液に、トリエチルアミン(0.062g、0.62mmol、2eq)を加え、5分間撹拌し、反応混合物を冷却し、3−(トリフルオロメチル)ベンゾイルクロリド(0.072g、0.34mmol、1.1eq)を加え、2時間撹拌した。反応混合物を水で急冷し、分離した有機層を、10%aq.NaHCO3(20ml×1)、水(20ml×1)、ブライン溶液(20ml×1)で洗浄し、無水MgSO4で乾燥して、濃縮した。得られた粗生成物を、酢酸エチル(10ml)で粉末化し、淡黄色固体として生成物を得た。
(3,5−ジメチル−フェニル)−(8−フェニル−[1,2,4]トリアゾロ[1,5−a]ピラジン−2−イル)−アミン(“C7”)
N8−(2−アミノ−エチル)−N2−(3,5−ジメトキシ−フェニル)−[1,2,4]トリアゾロ[1,5−a]ピラジン−2,8−ジアミン(“C29”)
6−[2−(3,5−ジメチル−フェニルアミノ)−[1,2,4]トリアゾロ[1,5−a]ピラジン−8−イルアミノ]−2,2−ジメチル−4H−ピリド[3,2−b][1,4]オキサジン−3−オン(“C60”)
ベンゾ[1,2,5]チアジアゾール−5−イル−(8−クロロ−[1,2,4]トリアゾロ[1,5−a]ピラジン−2−イル)−アミン(“B10”)
(8−フェニル−[1,2,4]トリアゾロ[1,5−a]ピラジン−2−イル)−(3,4,5−トリメトキシ−フェニル)−アミン(“C89”)
HPLC純度(方法A):95%、RT3.23min、LCMS:(方法A)377.0(M+H)、RT.3.14min、95%;
HPLC純度(方法A):96%、RT2.13min、(Max)、93.80%(254nm);
LCMS:(方法A)402.0(M+H)、RT.2.02min;
HPLC純度(方法A):98%RT2.34min;LCMS:(方法A)348.0(M+H)、RT.2.26min;
HPLC純度(方法A):96%RT5.10min;LCMS:(方法A)415.3(M+H)、RT.4.87min;
HPLC純度(方法A):99%、RT3.69min、LCMS:(方法A)440.0(M+H)、RT.3.67min;
HPLC純度(方法A):98%、RT4.06min;LCMS:(方法A)386.0(M+H)、RT.4.06min;
HPLC純度(方法A):98%、RT3.74min;LCMS:(方法A)399.2(M+H)、RT.3.71min;
HPLC純度(方法A):100%、RT2.54min、LCMS:(方法A)424.3(M+H)、RT.2.43min;
HPLC純度(方法A):100%、RT2.78min、LCMS:(方法A)370.0(M+H)、RT.2.68min;
HPLC純度(方法A):95%、RT2.61min;LCMS:(方法A)394.0(M+H)、RT.2.55min、93.71%(Max)、95.02%(254nm);
HPLC純度(方法A):98%、RT3.44min、LCMS:(方法A)399.2(M+H)、RT.3.45min;
HPLC純度(方法A):99%、RT2.34min;LCMS:(方法A)424.0(M+H)、RT.2.34min;
HPLC純度(方法A):98%、RT2.63min、LCMS:(方法A)370.0(M+H)、RT.2.61min;
HPLC純度(方法A):98%、RT2.47min、LCMS:(方法A)394.0(M+H)、RT.2.33 min;
HPLC純度(方法A):99%、RT4.13min;LCMS:(方法A)364.0(M+H)、RT.4.03min;
HPLC純度(方法A):94%、RT2.68min、LCMS:(方法A)389.0(M+H)、RT.2.66min;
HPLC純度(方法A):98%、RT2.95min、LCMS:(方法A)335.0(M+H)、RT.2.91min;
HPLC純度(方法A):95%、RT4.14min、LCMS:(方法A)441.0(M+H)、RT.4.11min;
HPLC純度(方法A):97%、RT2.83min、LCMS:(方法A)466.3(M+H)、RT.2.68min;
HPLC純度(方法A):98%、RT3.06min;LCMS:(方法A)412.0(M+H)、RT.3.03min;
HPLC純度(方法A):98%、RT3.68min;LCMS:(方法A)391.3(M+H)、RT.3.53min;
HPLC純度(方法A):98%、RT2.45min;LCMS:(方法A)416.0(M+H)、RT.2.43min;
HPLC純度(方法A):98%、RT2.57min;LCMS:(方法A)362.0(M+H)、RT.2.45min;
HPLC純度(方法A):96%、RT3.60min、LCMS:(方法A)391.3(M+H)、RT.3.47min;
HPLC純度(方法A):97%、RT2.33min、LCMS:(方法A)416.0(M+H)、RT.2.32min;
HPLC純度(方法A):98%、RT2.52min、LCMS:(方法A)362.0(M+H)、RT.2.39min;
HPLC純度(方法A):97%、RT5.06min;LCMS:(方法A)424.2(M+H)、RT.5.10min;
HPLC純度(方法A):99%、RT3.98min;LCMS:(方法A)395.0(M+H)、RT.3.89min;
HPLC純度(方法A):95%、RT5.09min;LCMS:(方法A)440.3(M+H)、RT.5.01min;
HPLC純度(方法A):98%、RT3.68min;LCMS:(方法A)465.3(M+H)、RT.3.62min;
HPLC純度(方法A):98%、RT4.14min、LCMS:(方法A)411.0(M+H)、RT.4.15min;
HPLC純度(方法A):99%、RT3.07min、LCMS:(方法A)377.3(M+H)、RT.3.97min;
HPLC純度(方法A):98%、RT1.93min;LCMS:(方法A)402.0(M+H)、RT.1.81min;
HPLC純度(方法A):99%、RT2.16min;LCMS:(方法A)348.0(M+H)、RT.2.06min;
HPLC純度(方法A):95%、RT3.52min;LCMS:(方法A)372.0(M+H)、RT.1.90min;
HPLC純度(方法A):100%、RT5.44min;LCMS:(方法A)537.3(M+H)、RT.5.35min;
HPLC純度(方法A):97%、RT5.12min;LCMS:(方法A)549.0(M+H)、RT.4.95min;
HPLC純度(方法A):98%、RT4.28min、LCMS:(方法A)562.3(M+H)、RT.4.20min;
HPLC純度(方法A):97%、RT3.91min、LCMS:(方法A)574.0(M+H)、RT.3.81min;
HPLC純度(方法A):97%、RT3.64min、LCMS:(方法A)352.0(M+H)、RT.3.5min;
HPLC純度(方法A):95%、RT3.34min、LCMS:(方法A)338.0(M+H)、RT.3.23min;
HPLC純度(方法A):95%、RT4.03min;LCMS:(方法A)388.3(M+H)、RT.3.91min;
HPLC純度(方法A):98%、RT4.12min;LCMS:(方法A)316.0(M+H)、RT.3.98min;
混合物をRtまで冷却し、水で希釈する。pH14に達するまでNaOHを加えた後、得られた懸濁液を0℃まで冷却し、すべての固形物をろ過して除き、黄色固体として8−Iodo−[1,2,4]トリアゾロ[1,5−a]ピラジン−2−イルアミン(7.850g;30.074mmol)を得る。
粗生成物を、シリカにロードし、カラムクロマトグラフィにより精製する。
ねじ蓋式バイアルまたはマイクロ波バイアル中の1Eq.のトリアゾロピラジン、1.1eq.のハロゲンカップリングのパートナーおよび0.03eq.のクロロ[2−ジシクロヘキシルホスフィノ)−3,6−ジメトキシ−2’,4’,6’−トリ−イソプロピル−1’,1−ビフェニル[2−(2−アミノエチル)フェニル)Pd(II)(Brettphose-Precat)を、tert.−ブタノール(5mL/mmol)中に溶解する。混合物を、真空により脱気し窒素を充填(3回)した後、LHMDS(2eq. THF中1.1M)を加え、反応混合物を110℃まで加熱し、HPLCにより監視する。完了したら、混合物を水で急冷し、酢酸エチルで希釈し、セライトに通してろ過する。溶媒を真空除去し、残渣をクロマトグラフィまたは分取HPLCにより精製する。
撹拌子を有するマイクロ波バイアルに、1eq.のトリアゾロピラジン、1.1eq.の対応するアミンおよび炭酸カリウム(2eq)を加える。N,N−ジメチルホルムアミド(3mL/mmol)を加え、懸濁液をマイクロ波中180℃に加熱する。反応をHPLCにより監視する。完了したら、混合物を酢酸エチルで希釈し、セライトを通してろ過し、濃縮する。残渣を、カラムクロマトグラフィまたは分取HPLCにより精製する。
8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンおよび1−メチル−1H−ピラゾール−4−ボロン酸ピナコールエステルを、基本手順1に従い変換する。溶媒系としてDCMおよびメタノールを用いるシリカのフラッシュカラムクロマトグラフィにより、所望の純粋なカップリング生成物(desired coupling compound pure)がで得られる。
8−(1−メチル−1H−ピラゾール−4−イル)−[1,2,4]トリアゾロ[1,5−a]ピラジン−2−イルアミンおよび5−ブロモ−2−メチル−1H−1,3−ベンゾジアゾールを、基本手順2に従いカップリングする。分取HPLCでの精製により“D1”がベージュ色固体として得られる。
HPLC純度(方法E):100%、Rt:2.19min、観測[MH+]=346.2;
8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンおよび1−メチルインダゾール−5−ボロン酸を、基本手順1に記載の鈴木条件下で反応させる。カラムクロマトグラフィ(溶媒としてジクロロメタンおよびエタノール)を介する精製により、所望の中間体が得られる。
アミノ化反応を、ハロゲン化アリールとして4−(4−クロロ−フェニル)−モルホリンを用いる基本手順2を使用して実施する。精製を、分取HPLCを介して実施し、“D2”が得られる;
HPLC純度(方法E):95%、Rt.:1.95min、観測[MH+]427.2;
この場合、X−Phosの代わりに6mol−%のクロロ[2−ジシクロヘキシホスフィノル)−3,6−ジメトキシ−2’,4’,6’−トリ−イソプロピル−1’,1−ビフェニル[2−(2−アミノエチル)フェニル)Pd(II)(Brettphose-Precat)を用いる基本手順1を使用して、8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンと2−(ジメチルアミノ)ピリジン−5−ボロン酸塩酸塩とを反応させた後、フラッシュカラムクロマトグラフィ(シリカ、溶媒としてシクロヘキサン、酢酸エチル)での精製により、所望の生成物が得られる。
ブッフバルト−ハートウィッグのアミノ化を、“D2”に類似して行い、“D3”を得る;
HPLC純度(方法E):100%、Rt.:1.43min、観測[MH+]=417.2;
8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンおよび6−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−キノキサリンを、基本手順1を使用してカップリングする。粗材料を、SiO2のカラムクロマトグラフィ(溶媒としてDCMおよびメタノール)により精製する。
反応を、“D2”に記載の条件下で行い、“D4”を得る;
HPLC純度(方法E):98%、Rt:1.89min、観測[MH+]=425.2;
8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンおよび1−ベンジル−4−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−1H−ピラゾールを、基本手順1に従い反応させる。化合物を、クロマトグラフィ(SiO2、溶媒としてジクロロメタン/メタノール)により精製する。
反応を、“D2”に類似して行い、“D5”を得る;
HPLC純度(方法E):98%、Rt.:2.03min、観測[MH+]=453.2;
8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンおよび1−メトキシ−3−[4−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−ピラゾール−1−イル]−プロパン−2−オールを、基本手順1に従い反応させる。粗材料を、遊離液としてジクロロメタンおよびエタノールを使用するフラッシュクロマトグラフィにより精製する。
反応を、“D2”に類似して実施し、“D6”を得る;
HPLC純度(方法E):100%、Rt:1.56min、観測[MH+]451.2;
ステップ2を、“D2”に類似して行い、“D7”を得る;
HPLC純度(方法E):100%、Rt.:1.56min、観測[MH+]=377.2;
8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミン(500mg、2.95mmol)、(2−ヒドロキシフェニル)ボロン酸(428mg、3.00mmol)、リン酸三カリウム(1.29g、5.90mmol)、水酸化カリウム(148mg、2.65mmol)およびトランス−ジクロロビス(トリシクロヘキシルホスフィン)パラジウム(II)(153mg、0.21mmol)を、9mLの1,2−ジメトキシエタンおよび3mLのN,N−ジメチルホルムアミドに懸濁する。混合物を、短時間で脱気した後、マイクロ波中で加熱する(150℃、2h)。完了したら、混合物を、セライトのパッドに通してろ過し、濃縮して、カラムクロマトグラフィ(溶媒としてDCM/EtOH)により精製する。
反応を、ハロゲン化アリールとして1−クロロ−3,5−ジメトキシ−ベンゼンを使用する基本手順2に従い行い、化合物“D8”を得る;
HPLC純度(方法E):98%、Rt.:2.61min、観測[MH+]=364.2;
8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンおよび1−(2,2−ジメトキシ−エチル)−4−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−1H−ピラゾールを、基本手順1に記載の条件下で反応させる。
反応を、“D2”に類似して実施し、“D9”を得る;
HPLC純度(方法E):100%、Rt.:1.73min、観測[MH+]=451.2;
8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンおよびインドール−4−ボロン酸を、基本手順1に記載のやり方でカップリングする。
反応を“D2”に類似して実施し、“D10”を得る;
HPLC純度(方法E):100%、Rt.:1.82min、観測[MH+]=412.2;
標準手順1に記載の条件下での、8−ヨード−[1,2,4]トリアゾロピラジン−2−イルアミンおよび6−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−キノキサリンの、鈴木宮浦カップリング。
ハロゲン化アリールとして1−(4−ブロモ−フェニル)−4−メチル−ピペラジンを用いる反応を、基本手順2に従い行い、“D11”を得る;
HPLC純度(方法E):100%、Rt.:1.46min、観測[MH+]=438.2;
中間体を、“D9”に類似して調製する。
5−ブロモ−1,3−ジヒドロ−インドール−2−オンを、基本手順2に記載のブッフバルト−ハートウィッグの条件下で反応させ、“D12”を得る;
HPLC純度(方法E):100%、Rt.:1.62min、観測[MH+]=421.2;
手順1に記載の条件下で、3−キノリンボロン酸および8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンを反応させた後、溶媒としてシクロヘキサン/酢酸エチルを用いるカラムクロマトグラフィにより、所望の中間体が得られる。
反応を、ハロゲン化アリールとして4−(4−ブロモフェニル)モルホリン−3−オンを使用する基本手順2に記載の標準条件下で行い、“D13”を得る;
HPLC純度(方法E):100%、Rt.:1.85min、観測[MH+]=438.2;
1−メチル−4−[4−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−フェニル]−ピペラジンおよび8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンを、基本手順1を使用して反応させ、所望の中間体を得る。
反応を、“D2”に類似して実施し、“D14”を得た;
HPLC純度(方法E):98%、Rt.:1.43min、観測[MH+]=471.2;
1-メチルインダゾール-5-ボロン酸および8-クロロ-[1,2,4]トリアゾロピラジン-2−イルアミンを、基本手順1を使用して反応させ、所望の中間体を得る。
ハロゲン化アリールとして1−(4−ブロモ−フェニル)−4−メチル−ピペラジンを用いる反応を、基本手順2に従い行い、“D15”を得る;
HPLC純度(方法E):100%、Rt.:1.50min、観測[MH+]=440.2;
中間体を、“D13”に類似して調製する。
4−(5−ブロモ−ピリジン−2−イル)−モルホリンを、基本手順2に従うアミノ化のカップリングのパートナーとして使用して、“D16”を得る;
HPLC純度(方法E):100%;Rt.:1.40min、観測[MH+]=425.2;
中間体を、“D1”に類似して調製する。
HPLC純度(方法E):92%、Rt.:1.49min、観測[MH+]347.2;
ステップ2を“D15”に類似して行い、“D18”を得る;
HPLC純度(方法E):100%、Rt.:1.38min、観測[MH+]=390.2;
反応を、基本手順3およびカップリングのパートナーとしてrac−2−フェニル−ピロリジンを使用して、実施する。
HPLC純度(方法E):100%、Rt.:2.52min、観測[MH+]=417.2;
2−(2−ピペラジン−1−イルエチル)イソインドリン−1,3−ジオンを、基本手順2に記載の方法を使用して、8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンと反応させる。
ステップ3:
エタノール中の2−[2−[4−[2−(3,5−ジメトキシアニリノ)−[1,2,4]トリアゾロ[1,5−a]ピラジン−8−イル]ピペラジン−1−イル]エチル]イソインドリン−1,3−ジオンの懸濁液に、ヒドラジン(20eq)を加え、透明無色の溶液を2h還流し、HPLCで監視する。溶媒を減圧下で除去し、残渣を分取HPLCで精製し、表題の化合物“D20”が得られる;
HPLC純度(方法E):100%、Rt.:1.32min、観測[MH+]=399.2;
反応を、基本手順3およびカップリングのパートナーとしてrac−2−ピロリジン−2−イルピリジンを使用して実施する。
HPLC純度(方法E):100%、Rt.:1.75min、観測[MH+]=418.2;
反応を、基本手順3およびカップリングのパートナーとしてベンジルアミンを使用して実施する。
HPLC純度(方法E):95%、Rt.:2.33min、観測[MH+]377.2;
ステップ2を“D15”に類似して行い、“D23”を得る;
HPLC純度(方法E):100%、Rt.:1.47min、観測[MH+]=437.2;
4−ヒドロキシピぺリジンを、4eq.のトリエチルアミンを使用して、8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンと反応させる。
HPLC純度(方法E):84%、Rt.:1.83min、観測[MH+]=371.2;
ステップ2を“D2”に類似して行い、“D25”を得る;
HPLC純度(方法E):100%、Rt.:2.02min、観測[MH+]442.2;
N−メチル−N−テトラヒドロ−2H−ピラン−4−イルアミンを、基本手順3に従い、8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンとカップリングする。
HPLC純度(方法E):98%、Rt.:2.06min、観測[MH+]=385.2;
N,N−ジメチル−2−ピペラジン−1−イル−エタンアミンを、基本手順3に従い、8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンと反応させる。
HPLC純度(方法E):100%、Rt:1.45min、観測[MH+]=427.2;
カップリングのパートナーとして8−ヨード−[1,2,4]トリアゾロピラジン−2−イルアミンおよび2−[4−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−ピラゾール−1−イル]−エタノールを使用して、基本手順1に従う。
HPLC純度(方法E):100%、Rt.:1.44min、観測[MH+]=407.2;
ピリジン−3−ボロン酸および8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンを、基本手順1を使用して反応させる。
HPLC純度(方法E):100%、Rt:1.51min、観測[MH+]=374.2;
ピリジン−3−ボロン酸および8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンを、基本手順1を使用して反応させる。
ステップ1からの中間体を、基本手順2を使用して、4−(5−ブロモピリジン−2−イル)モルホリンと反応させ、“D30”を得る;
HPLC純度(方法E):100%、Rt:1.27min、観測[MH+]=375.2;
ステップ2を“D12”に類似して行い、“D31”を得る;
HPLC純度(方法E):90%、Rt:1.66min、観測[MH+]=344.2;
(2−モルホリノフェニル)ボロン酸を、手順1に従いボロン酸として使用する。
HPLC純度(方法E):95%、Rt:2.00min、観測[MH+]=433.2;
ステップ2を“D12”に類似して行い、“D33”を得る;
HPLC純度(方法E):88%、Rt:1.55min、観測[MH+]=428.28;
4−{2−[4−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−ピラゾール−1−イル]−エチル}−モルホリンをボロン酸として使用し、基本手順1に従い、8−クロロ−[1,2,4]トリアゾロ[1,5−a]ピラジン−2−イルアミンと反応させる。
HPLC純度(方法E):100%、Rt:1.29min、観測[MH+]=476.2;
5−キノリルボロン酸を、基本手順1を使用して、8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンとカップリングさせる。
HPLC純度(方法E):100%、Rt:1.83min、観測[MH+]=399.2;
鈴木カップリングを、反応物質として8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンおよび(2−イソプロピルフェニル)ボロン酸を用いる基本手順1を使用して実施する。
HPLC純度(方法E):95%、Rt:2.55min、観測[MH+]=390.2;
ステップ2を“D12”に類似して行い、“D37”を得る;
HPLC純度(方法E):100%、Rt:1.53min、観測[MH+]=421.2;
基本手順3に従い、rac2−(4−エトキシ−フェニル)−ピロリジンを、求核剤として使用した。
HPLC純度(方法E):100%、Rt:2.15min、観測[MH+]=486.2;
ステップ2を“D8”に類似して行い、“D39”を得る;
HPLC純度(方法E):100%、Rt:2.56min、観測[MH+]=461.2;
Rac−2−ピロリジン−2−イル−ピリジンを、基本手順3に記載されているように、8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンと反応させる。
HPLC純度(方法E):93%、Rt:1.43min、観測[MH+]=443.2;
8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンおよび2−ビフェニルボロン酸を、基本手順1に記載されいるように、反応させる。
5−クロロ−1,3−ジメチル−ピラゾールおよびステップ1からの中間体を、基本手順2を使用してカップリングし、“D41”を得る;
HPLC純度(方法E):90%、Rt:1.96min、観測[MH+]=382.2;
HPLC純度(方法E):90%、Rt:2.12min、観測[MH+]=442.0;
反応物質として(3−メトキシカルボニルフェニル)ボロン酸および8−ヨード−[1,2,4]トリアゾロピラジン−2−イルアミンを使用する基本手順1に従う。
HPLC純度(方法E):100%、Rt:1.80min、観測[MH+]=417.2;
中間体を、基本手順3および求核剤として4−(アミノメチル)テトラヒドロピランを使用して合成する。
HPLC純度(方法E):100%、Rt:1.92min、観測[MH+]=385.2;
鈴木宮浦カップリングを、手順1に従い、ボロン酸として7−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−ピリド[2,3−b]ピラジンを使用して実施する。
HPLC純度(方法E):100%、Rt:1.33min、観測[MH+]=439.2;
反応は、求核剤として4−アミノテトラヒドロピランを用いる基本手順3に従う。
HPLC純度(方法E):100%、Rt:1.90min、観測[MH+]=371.2;
ピぺリジンを、基本手順3を使用して、8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンと反応させる。
HPLC純度(方法E):100%、Rt:2.43min、観測[MH+]=355.2;
HPLC純度(方法E):100%、Rt:1.91min、観測[MH+]=315.25;
Rac−2−(4−フルオロフェニル)ピぺリジンを、基本手順3に従い、求核剤として使用する。
HPLC純度(方法E):100%、Rt:2.85min、観測[MH+]=449.2;
ピペラジンを、基本手順3を使用して、8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンとカップリングする。
HPLC純度(方法E):95%、Rt:1.45min、観測[MH+]=356.2;
HPLC純度(方法E):100%、Rt:1.89min、観測[MH+]=384.2;
5,6,7,8−テトラヒドロ−1,6−ナフチリジンを、基本手順3を使用して、8−クロロ−[1,2,4]トリアゾロピラジン−2−イルアミンと反応させる。
HPLC純度(方法E):100%、Rt:1.66min、観測[MH+]=404.2;
1,2,3,4−テトラヒドロイソキノリンを、基本手順3に従い反応させる。
ステップ2を“D8”に類似して行い、“D53”を得る;
HPLC純度(方法E):100%、Rt:2.66min、観測[MH+]=403.2;
N−メチル−N−テトラヒドロ−2H−ピラン−4−イルアミンを、基本手順3に従い、求核剤として使用する。
4−ブロモ−1,2−ジメトキシベンゼンを、基本手順2を使用するブッフバルト−ハートウィッグのアミノ化において使用する。
HPLC純度(方法E):100%、Rt:1.82min、観測[MH+]=385.2;
例A:注射バイアル
2回蒸留した3lの水中の式Iで表される100gの活性成分および5gのリン酸水素二ナトリウムの溶液を、2Nの塩酸を使用して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し、滅菌条件下で封をする。各々の注射バイアルは、5mgの活性成分を含む。
式Iで表される20gの活性成分と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、型中に注ぎ入れ、放冷する。各々の座剤は、20mgの活性成分を含む。
式Iで表される1gの活性成分、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、2回蒸留した940mlの水中に、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。この溶液は、点眼剤の形態で用いることができる。
式Iで表される500mgの活性成分を、無菌条件下で、99.5gのワセリンと混合する。
式Iで表される1kgの活性成分、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、従来のやり方で圧縮して、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に類似して錠剤を圧縮し、続いて、従来のやり方で、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。
式Iで表される2kgの活性成分を、従来のやり方で、硬質ゼラチンカプセル中に導入し、各々のカプセルが20mgの活性成分を含むようにする。
2回蒸留した60lの水中、式Iで表される1kgの活性成分の溶液を滅菌濾過し、アンプル中に移し、滅菌条件下で凍結乾燥し、滅菌条件下で封をする。各々のアンプルは、10mgの活性成分を含む。
Claims (17)
- 式Iの化合物、
R1は、Ar1またはHet1を表し、
R2は、Ar2、Het2、NH(CH2)nAr2、O(CH2)nAr2、NR3(CH2)nHet2、A、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、NHCycまたはNH(CH2)pNA2を表し、
Ar1は、非置換の、または、Hal、A、Alk、(CH2)nOH、(CH2)nOA、(CH2)nCOOH、(CH2)nCOOA、SO2A、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、[C(R3)2]nCN、NO2、(CH2)nCONH2、(CH2)nCONHA、(CH2)nCONA2、SO2NH2、SO2NHA、SO2NA2、NHCONH2、NHCOA、NHCOAlk、NHCOCH=CH(CH2)pNA2、CHO、COA、SO3H、O(CH2)pNH2、O(CH2)pNHA、O(CH2)pNA2、COHet3、S(CH2)nHet3、(CH2)nHet3および/もしくはO(CH2)nHet3で、一、二または三置換された、フェニル、ナフチルあるいはビフェニルを表し、
Ar2は、非置換の、または、Hal、A、(CH2)nOH、(CH2)nOA、OAr3、ベンジルオキシ、(CH2)nCOOH、(CH2)nCOOA、SO2A、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、[C(R3)2]nCN、NO2、CONH(CH2)pNH2、CONH(CH2)pNHA、CONH(CH2)pNA2、CONH(CH2)pOA、CONH(CH2)pOH、(CH2)nCONH2、(CH2)nCONHA、(CH2)nCONA2、SO2NH2、SO2NHA、SO2NA2、OSO2A、NHCONH2、NHCOA、CHO、COA、SO3H、O(CH2)pNH2、O(CH2)pNHA、O(CH2)pNA2、CONHAr3、NHCOAr3、CONHHet3、NHCOHet3、NHSO2A、COHet3、(CH2)nHet3、S(CH2)nHet3および/もしくはO(CH2)nHet3で、一、二または三置換された、フェニル、ナフチルあるいはビフェニルを表し、
Het1は、1〜4個のN、Oおよび/もしくはS原子を有する、単環式のまたは二環式の、不飽和のあるいは芳香族の複素環を表し、該環は、非置換であるか、または、A、OH、OA、Hal、(CH2)nAr3および/もしくは=Oで、一、二、三または四置換されてもよく、
Het2は、1〜4個のN、Oおよび/もしくはS原子を有する、単環式のまたは二環式の、飽和の、不飽和のあるいは芳香族の複素環を表し、該環は、非置換であるか、または、Hal、A、(CH2)nCOOH、(CH2)nCOOA、CHO、COA、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、CN、(CH2)nOH、(CH2)nOA、(CH2)nAr3、(CH2)nHet3、NHSO2A、NASO2A、SO2A、SO2Aおよび/もしくは=Oで、一、二、三または四置換されてもよく、
Het3は、1〜4個のN、Oおよび/もしくはS原子を有する、単環式のまたは二環式の、飽和の、不飽和のあるいは芳香族の複素環を表し、該環は、非置換であるか、または、A、Hal、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、(CH2)nOH、(CH2)nOA、COOA、Ar3および/もしくは=Oで、一、二、三または四置換されてもよく、
R3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表し、
Aは、1〜10個のC原子を有する、非分岐のまたは分岐のアルキルを表し、該アルキルにおいて、1〜7個のH原子がFで交換されてもよく、ならびに/あるいは、1もしくは2個の非近接CH2基がO、NH、S、SO、SO2および/またはCH=CH基で交換されてもよく、
あるいは、
3〜7個のC原子を有する環状アルキルを表し、
Cycは、非置換であるか、または、NH2で一置換されてもよい、3〜7個のC原子を有する環状アルキルを表し、
Alkは、2、3、4、5もしくは6個のC原子を有するアルケニルまたはアルキニルを表し、
Ar3は、非置換の、または、Halおよび/もしくはAで一、二または三置換されたフェニルを表し、
Halは、F、Cl、BrまたはIを表し、
nは、0、1、2、3または4を表し、
pは、1、2、3または4を表す、
または、その薬学的に許容し得る溶媒和物、塩、互変異性体もしくは立体異性体、またはあらゆる比率でのそれらの混合物。 - 請求項1に記載の化合物、式中、
Het1が、非置換の、または、A、OH、OA、Hal、(CH2)nAr3および/もしくは=Oで、一、二または三置換された、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、イソオキサゾリル、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、ピラジニル、キノリル、イソキノリル、ベンズイミダゾリル、ベンゾトリアゾリル、インドリル、ベンゾ−1,3−ジオキソリル、2,3−ジヒドロ−ベンゾ[1,4]ジオキシニル、インダゾリル、ベンゾ[1,4]オキサジニル、1,3−もしくは2,3−ジヒドロ−インドリルあるいはベンゾチアジアゾリルを表す、
または、その薬学的に許容し得る溶媒和物、塩、互変異性体もしくは立体異性体、またはあらゆる比率でのそれらの混合物。 - 請求項1または2に記載の化合物、式中、
Het2が、非置換の、または、Hal、A、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、CN、(CH2)nOH、(CH2)nOA、CHO、(CH2)nAr3、(CH2)nHet3、SO2A、SO2Aおよび/もしくは=Oで、一、二または三置換された、ピペリジニル、ピペラジニル、ピロリジニル、モルホリニル、テトラヒドロピラニル、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、イソオキサゾリル、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、ピラジニル、キノリル、イソキノリル、ジヒドロイソキノリル、テトラヒドロイソキノリル、キノキサリニル、ベンズイミダゾリル、ベンゾチオフェニル、ベンゾトリアゾリル、インドリル、インドリニル、ナフチリジニル、ジヒドロナフチリジニル、テトラヒドロナフチリジニル、ベンゾ−1,3−ジオキソリル、2,3−ジヒドロ−ベンゾ[1,4]ジオキシニル、フロピリジニル、インダゾリル、ベンゾ[1,4]オキサジニル、ピリド[3,2−b][1,4]オキサジニルあるいはベンゾチアジアゾリルを表す、
または、その薬学的に許容し得る溶媒和物、塩、互変異性体もしくは立体異性体、またはあらゆる比率でのそれらの混合物。 - 請求項1〜3のいずれか一項に記載の化合物、式中、
Het3が、非置換の、または、Aおよび/もしくは=Oで一または二置換された、ピペリジニル、ピペラジニル、ピロリジニル、モルホリニル、2,3−ジヒドロ−ピラゾリル、1,2−ジヒドロ−ピリジル、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、イソオキサゾリル、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、テトラヒドロ−ベンゾチオフェニル、ピリダジニルあるいはピラジニルを表す、
または、その薬学的に許容し得る溶媒和物、塩、互変異性体もしくは立体異性体、またはあらゆる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化合物、式中、
Aが、1〜10個のC原子を有する、非分岐のまたは分岐のアルキルを表し、該アルキルにおいて、1〜7個のH原子がFで交換されてもよく、ならびに/あるいは、1もしくは2個の非近接CH2基がOおよび/またはNHで交換されてもよく、
あるいは、
3〜7個のC原子を有する環状アルキルを表す、
または、その薬学的に許容し得る溶媒和物、塩、互変異性体もしくは立体異性体、またはあらゆる比率でのそれらの混合物。 - 請求項1〜5のいずれか一項に記載の化合物、式中、
Ar1が、非置換の、または、Hal、A、(CH2)nOH、(CH2)nOA、(CH2)nHet3および/もしくはS(CH2)nHet3で一、二または三置換されたフェニルを表す、
または、その薬学的に許容し得る溶媒和物、塩、互変異性体もしくは立体異性体、またはあらゆる比率でのそれらの混合物。 - 請求項1〜6のいずれか一項に記載の化合物、式中、
Ar2が、非置換の、または、Hal、A、(CH2)nOH、(CH2)nOA、(CH2)nCOOH、(CH2)nCOOA、OAr3、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、[C(R3)2]nCN、NO2、CONH(CH2)pNH2、CONH(CH2)pNHA、CONH(CH2)pNA2、(CH2)nCONH2、(CH2)nCONHA、(CH2)nCONA2、NHCOAr3、NHSO2A、OSO2A、(CH2)nHet3および/もしくはS(CH2)nHet3で一、二または三置換された、フェニル、ナフチルあるいはビフェニルを表す、
または、その薬学的に許容し得る溶媒和物、塩、互変異性体もしくは立体異性体、またはあらゆる比率でのそれらの混合物。 - 請求項1〜7のいずれか一項に記載の化合物、式中、
R1が、Ar1またはHet1を表し、
R2が、Ar2、Het2、NH(CH2)nAr2、O(CH2)nAr2、NR3(CH2)nHet2、A、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、NHCycまたはNH(CH2)pNA2を表し、
Ar1が、非置換の、または、Hal、A、(CH2)nOH、(CH2)nOA、(CH2)nHet3および/もしくはS(CH2)nHet3で一、二または三置換されたフェニルを表し、
Ar2が、非置換の、または、Hal、A、(CH2)nOH、(CH2)nOA、(CH2)nCOOH、(CH2)nCOOA、OAr3、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、[C(R3)2]nCN、NO2、CONH(CH2)pNH2、CONH(CH2)pNHA、CONH(CH2)pNA2、(CH2)nCONH2、(CH2)nCONHA、(CH2)nCONA2、NHCOAr3、NHSO2A、OSO2A、(CH2)nHet3および/もしくはS(CH2)nHet3で一、二または三置換された、フェニル、ナフチルあるいはビフェニルを表し、
Het1が、非置換の、または、A、OH、OA、Hal、(CH2)nAr3および/もしくは=Oで一、二または三置換された、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、イソオキサゾリル、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、ピラジニル、キノリル、イソキノリル、ベンズイミダゾリル、ベンゾトリアゾリル、インドリル、ベンゾ−1,3−ジオキソリル、2,3−ジヒドロ−ベンゾ[1,4]ジオキシニル、インダゾリル、ベンゾ[1,4]オキサジニル、1,3−もしくは2,3−ジヒドロ−インドリルあるいはベンゾチアジアゾリルを表し、
Het2が、非置換の、または、Hal、A、(CH2)nNH2、(CH2)nNHA、(CH2)nNA2、CN、CHO、(CH2)nOH、(CH2)nOA、(CH2)nAr3、(CH2)nHet3、SO2A、SO2Aおよび/もしくは=Oで一、二または三置換された、ピペリジニル、ピペラジニル、ピロリジニル、モルホリニル、テトラヒドロピラニル、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、イソオキサゾリル、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、ピラジニル、キノリル、イソキノリル、ジヒドロイソキノリル、テトラヒドロイソキノリル、キノキサリニル、ベンズイミダゾリル、ベンゾチオフェニル、ベンゾトリアゾリル、インドリル、インドリニル、ナフチリジニル、ジヒドロナフチリジニル、テトラヒドロナフチリジニル、ベンゾ−1,3−ジオキソリル、2,3−ジヒドロ−ベンゾ[1,4]ジオキシニル、フロピリジニル、インダゾリル、ベンゾ[1,4]オキサジニル、ピリド[3,2−b][1,4]オキサジニルあるいはベンゾチアジアゾリルを表し、
Het3が、非置換の、または、Aおよび/もしくは=Oで一または二置換された、ピペリジニル、ピペラジニル、ピロリジニル、モルホリニル、2,3−ジヒドロ−ピラゾリル、1,2−ジヒドロ−ピリジル、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、イソオキサゾリル、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、テトラヒドロ−ベンゾチオフェニル、ピリダジニルあるいはピラジニルを表し、
R3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表し、
Aが、1〜10個のC原子を有する、非分岐のまたは分岐のアルキルを表し、該アルキルにおいて、1〜7個のH原子がFで交換されてもよく、ならびに/あるいは、1もしくは2個の非近接CH2基がOおよび/またはNHで交換されてもよく、
あるいは、
3〜7個のC原子を有する環状アルキルを表し、
Cycが、3〜7個のC原子を有する環状アルキルを表し、該アルキルは、非置換であるか、または、NH2で一置換されてもよく、
Ar3が、非置換の、または、Halおよび/もしくはAで一、二または三置換されたフェニルを表し、
nが、0、1、2、3または4を表し、
pが、1、2、3または4を表す、
または、その薬学的に許容し得る溶媒和物、塩、互変異性体もしくは立体異性体、またはあらゆる比率でのそれらの混合物。 - 以下の群から選択される、請求項1に記載の化合物、
- 請求項1〜9のいずれか一項に記載の式Iの化合物、ならびに、その薬学的に許容し得る塩、溶媒和物、互変異性体もしくは立体異性体の調製方法であって、
a)式IIの化合物
R2−L III
(式中、R2は、請求項1に示した意味を有し、Lは、ボロン酸基またはボロン酸エステル基を表す)
あるいは、
b)式IIの化合物
R2−L III
(式中、R2は、請求項1に示した意味を有し、Lは、NH2またはOHを表す)
および/または
式Iの塩基もしくは酸を、その塩の1つに変換すること
を特徴とする、前記調製方法。 - 式Iの化合物、ならびに/または、その薬学的に許容し得る塩、溶媒和物、互変異性体もしくは立体異性体、あらゆる比率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、賦形剤またはベシクルとを含む医薬。
- Sykの阻害に使用するための、式Iの化合物、またはその薬学的に許容し得る塩、溶媒和物、互変異性体もしくは立体異性体、またはあらゆる比率のそれらの混合物。
- 炎症性疾患、免疫疾患、自己免疫疾患、アレルギー疾患、リウマチ性疾患、血栓性疾患、がん、感染症、神経変性病、神経炎症性の病気、心血管病、および代謝性疾患の処置ならびに/または防止、請求項1の化合物の有効量を、それらを必要とする対象に投与することを含む方法に使用するための、式Iの化合物、またはその薬学的に許容し得る塩、溶媒和物、互変異性体もしくは立体異性体、またはあらゆる比率のそれらの混合物。
- リウマチ性関節炎、全身性紅斑性狼瘡、ぜんそく、アレルギー性鼻炎、ITP、多発性硬化症、白血病、乳がん、悪性黒色腫の群から選択される病気の処置および/または防止に使用するための、請求項13に記載の化合物。
- 式Iの化合物、ならびに/または、その薬学的に許容し得る塩、溶媒和物、互変異性体もしくは立体異性体、あらゆる比率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)式I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、溶媒和物、互変異性体もしくは立体異性体、あらゆる比率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
の別箇のパックからなるセット(キット)。 - 式IIの化合物、
R1は、Ar1またはHet1を表し、
Ar1は、非置換の、または、Hal、A、(CH2)nOH、(CH2)nOA、(CH2)nHet3および/もしくはS(CH2)nHet3で一、二または三置換されたフェニルを表し、
Het1は、非置換の、または、A、OH、OA、Hal、(CH2)nAr3および/もしくは=Oで一、二または三置換された、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、イソオキサゾリル、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、ピラジニル、キノリル、イソキノリル、ベンズイミダゾリル、ベンゾトリアゾリル、インドリル、ベンゾ−1,3−ジオキソリル、2,3−ジヒドロ−ベンゾ[1,4]ジオキシニル、インダゾリル、ベンゾ[1,4]オキサジニル、1,3−もしくは2,3−ジヒドロ−インドリルあるいはベンゾチアジアゾリルを表し、
Het3は、非置換の、または、Aおよび/もしくは=Oで一または二置換された、ピペリジニル、ピペラジニル、ピロリジニル、モルホリニル、2,3−ジヒドロ−ピラゾリル、1,2−ジヒドロ−ピリジル、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、イソオキサゾリル、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、テトラヒドロ−ベンゾチオフェニル、ピリダジニルあるいはピラジニルを表し、
R3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表し、
Aは、1〜10個のC原子を有する非分岐のまたは分岐のアルキルを表すか、該アルキルにおいて、1〜7個のH原子がFで交換されても、ならびに/あるいは、1もしくは2個の非近接のCH2基がOおよび/またはNHで交換されてもよく、
あるいは、
3〜7個のC原子を有する環状アルキルを表し、
Cycは、3〜7個のC原子を有する環状アルキルを表し、該アルキルは、非置換であっても、NH2で一置換されてもよく、
Ar3は、非置換の、または、Halおよび/もしくはAで一、二または三置換されたフェニルを表し、
nは、0、1、2、3または4を表し、
pは、1、2、3または4を表す、
または、その薬学的に許容し得る溶媒和物、塩、互変異性体もしくは立体異性体、またはあらゆる比率でのそれらの混合物。
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EP10008927 | 2010-08-27 | ||
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PCT/EP2011/003830 WO2012025186A1 (en) | 2010-08-27 | 2011-07-29 | Triazolopyrazine derivatives |
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ES2614128T3 (es) | 2017-05-29 |
AR082726A1 (es) | 2012-12-26 |
CA2809331A1 (en) | 2012-03-01 |
US9023851B2 (en) | 2015-05-05 |
CN103068828A (zh) | 2013-04-24 |
EP2609098A1 (en) | 2013-07-03 |
MX2013002198A (es) | 2013-03-18 |
KR20130110163A (ko) | 2013-10-08 |
US20130225568A1 (en) | 2013-08-29 |
WO2012025186A1 (en) | 2012-03-01 |
EA201300282A1 (ru) | 2013-08-30 |
AU2011295440A1 (en) | 2013-04-11 |
IL224869A (en) | 2016-06-30 |
EP2609098B1 (en) | 2016-07-13 |
CA2809331C (en) | 2018-09-25 |
CN103068828B (zh) | 2015-09-09 |
SG188296A1 (en) | 2013-04-30 |
JP5951610B2 (ja) | 2016-07-13 |
AU2011295440B2 (en) | 2015-06-11 |
BR112013004517A2 (pt) | 2016-06-07 |
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