JP2012502080A - 有機化合物 - Google Patents
有機化合物 Download PDFInfo
- Publication number
- JP2012502080A JP2012502080A JP2011526479A JP2011526479A JP2012502080A JP 2012502080 A JP2012502080 A JP 2012502080A JP 2011526479 A JP2011526479 A JP 2011526479A JP 2011526479 A JP2011526479 A JP 2011526479A JP 2012502080 A JP2012502080 A JP 2012502080A
- Authority
- JP
- Japan
- Prior art keywords
- amide
- methyl
- thiazol
- dicarboxylic acid
- pyrrolidine
- 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
Links
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- OAWXZFGKDDFTGS-BYPYZUCNSA-N (2s)-pyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(O)=O OAWXZFGKDDFTGS-BYPYZUCNSA-N 0.000 claims description 155
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Abstract
Description
Aはヘテロアリールであり;
R1は(1)場合により置換されていてよいアルキル;(2)場合により置換されていてよいシクロアルキル;(3)場合により置換されていてよいアリール;(4)場合により置換されていてよいアミン;(5)場合により置換されていてよいスルホニル;(6)ハロであり;
R2は水素、重水素またはR1について定義した置換基であり;
R3は水素、ハロまたは場合により置換されていてよいアルキルである。〕
の化合物、またはその塩を提供する;(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(tert−ブチル)−ピリミジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド)を除く。
ハロゲン(またはハロ)はフッ素、臭素、塩素またはヨウ素、特にフッ素、塩素を意味する。ハロゲン置換された基および部分、例えばハロゲンで置換されたアルキル(ハロアルキル)は、モノ−、ポリ−またはペル−ハロゲン化され得る。
(1) 非置換または置換、好ましくは置換C1−C7−アルキルであって、該置換基は以下の部分から独立して選択される1個以上、好ましくは1〜9個である:重水素、ハロ、シアノ、C3−C12−シクロアルキル、C1−C7−アルキルアミノ、ジ(C1−C7−アルキル)アミノ、C1−C7−アルキルアミノカルボニル、ジ(C1−C7−アルキル)アミノカルボニル、C1−C7−アルコキシ、フェニル(これは非置換であるか、または1個以上、好ましくは1個のC1−C7−アルキル、C1−C7−アルコキシ、ジ(C1−C7−アルキル)アミノ−C1−C7−アルコキシで置換されている)、フェノキシ、(これは非置換であるか、または1個以上、好ましくは1個のC1−C7−アルキル、C1−C7−アルコキシ、ジ(C1−C7−アルキル)アミノ−C1−C7−アルコキシで置換されている);
(2) 非置換または置換C3−C12−シクロアルキルであって、該置換基は以下の部分から独立して選択される1個以上、好ましくは1〜4個である:重水素、ハロ、シアノ、C1−C7−アルキル、C1−C7−アルキルアミノ、ジ(C1−C7−アルキル)アミノ、アミノカルボニル、C1−C7−アルキルアミノカルボニル、ジ(C1−C7−アルキル)アミノカルボニル、C1−C7−アルコキシ、フェニル(これは非置換であるか、または1個以上、好ましくは1個のC1−C7−アルキル、C1−C7−アルコキシ、ジ(C1−C7−アルキル)アミノ−C1−C7−アルコキシで置換されている)、フェノキシ、(これは非置換であるか、または1個以上、好ましくは1個のC1−C7−アルキル、C1−C7−アルコキシ、ジ(C1−C7−アルキル)アミノ−C1−C7−アルコキシで置換されている);
(3) 非置換または置換フェニルであって、該置換基は以下の部分から独立して選択される1個以上、好ましくは1〜2個である:重水素、ハロ、シアノ、C1−C7−アルキル、C1−C7−アルキルアミノ、ジ(C1−C7−アルキル)アミノ、C1−C7−アルキルアミノカルボニル、ジ(C1−C7−アルキル)アミノカルボニル、C1−C7−アルコキシ;
(4) 非置換、モノ−またはジ−置換アミン;ここで、該置換基は独立して以下の部分から選択される:重水素、C1−C7−アルキル(これは非置換であるか、または重水素、フルオロ、クロロ、ヒドロキシからなる群から選択される1個以上の置換基で置換されている)、C1−C7−アルキルカルボニル、フェニル(これは非置換であるか、または1個以上、好ましくは1個のC1−C7−アルキル、C1−C7−アルコキシ、ジ(C1−C7−アルキル)アミノ−C1−C7−アルコキシで置換されている)、フェニルスルホニル(これは非置換であるか、または1個以上、好ましくは1個のC1−C7−アルキル、C1−C7−アルコキシ、ジ(C1−C7−アルキル)アミノ−C1−C7−アルコキシで置換されている)、
(5) 置換スルホニル;ここで、該置換基は以下の部分から選択される:C1−C7−アルキル(これは非置換であるか、または重水素、フルオロ、クロロ、ヒドロキシからなる群から選択される1個以上の置換基で置換されている)、C1−C7−アルキルアミノ(ここで、本アルキル部分は非置換であるか、または重水素、フルオロ、クロロ、ヒドロキシルからなる群から選択される1個以上の置換基で置換されている) ジ−C1−C7−アルキルアミノ(ここで、本アルキル部分は非置換であるか、または重水素、フルオロ、クロロ、ヒドロキシルからなる群から選択される1個以上の置換基で置換されている);
(6) フルオロ、クロロ。
(1) 非置換または置換、好ましくは置換C1−C7−アルキルであって、該置換基は重水素、フルオロから独立して選択される1個以上、好ましくは1〜9個であるか、またはC3−C5−シクロアルキルである1個または2個である;
(2) 場合により置換されていてよいC3−C5−シクロアルキルであって、該置換基は以下の部分から独立して選択される1個以上、好ましくは1〜4個である:重水素、C1−C4−アルキル(好ましくはメチル)、フルオロ、シアノ、アミノカルボニル;
(3) 場合により置換されていてよいフェニルであって、該置換基は以下の部分から独立して選択される1個以上、好ましくは1〜2個である:重水素、ハロ、シアノ、C1−C7−アルキル、C1−C7−アルキルアミノ、ジ(C1−C7−アルキル)アミノ、C1−C7−アルキルアミノカルボニル、ジ(C1−C7−アルキル)アミノカルボニル、C1−C7−アルコキシ;
(4) 場合によりモノ−またはジ−置換アミン;ここで、該置換基は独立して以下の部分から選択される:重水素、C1−C7−アルキル(これは非置換であるか、または重水素、フルオロ、クロロ、ヒドロキシからなる群から選択される1個以上の置換基で置換されている)、フェニルスルホニル(これは非置換であるか、または1個以上、好ましくは1個のC1−C7−アルキル、C1−C7−アルコキシ、ジ(C1−C7−アルキル)アミノ−C1−C7−アルコキシで置換されている)、
(5) 置換スルホニル;ここで、該置換基は以下の部分から選択される:C1−C7−アルキル(これは非置換であるか、または重水素、フルオロからなる群から選択される1個以上の置換基で置換されている)、ピロリジノ、(これは非置換であるか、または重水素、ヒドロキシ、オキソからなる群から選択される1個以上;特に1個のオキソで置換されている)、
(6) フルオロ、クロロ。
(1) シクロプロピルメチルまたは場合により置換されていてよい、分枝C3−C7−アルキルであって、該置換基は以下の部分から独立して選択される1個以上、好ましくは1〜9個である:重水素、フルオロ;
(2) 場合により置換されていてよいシクロプロピルまたはシクロブチルであって、該置換基は以下の部分から独立して選択される1個以上、好ましくは1〜4個である:メチル、重水素、フルオロ、シアノ、アミノカルボニル;
(3) 場合により置換されていてよいフェニルであって、該置換基は以下の部分から独立して選択される1個以上、好ましくは1〜2個である:重水素、ハロ、シアノ、C1−C7−アルキル、C1−C7−アルキルアミノ、ジ(C1−C7−アルキル)アミノ、C1−C7−アルキルアミノカルボニル、ジ(C1−C7−アルキル)アミノカルボニル、C1−C7−アルコキシ;
(4) 場合によりモノ−またはジ−置換アミン;ここで、該置換基は独立して以下の部分から選択される:重水素、C1−C7−アルキル(これは非置換であるか、または重水素、フルオロ、クロロ、ヒドロキシからなる群から選択される1個以上の置換基で置換されている)、フェニルスルホニル(これは非置換であるか、または1個以上、好ましくは1個のC1−C7−アルキル、C1−C7−アルコキシ、ジ(C1−C7−アルキル)アミノ−C1−C7−アルコキシで置換されている)、
(5) 置換スルホニル;ここで、該置換基は以下の部分から選択される:C1−C7−アルキル(これは非置換であるか、または重水素、フルオロからなる群から選択される1個以上の置換基で置換されている)、ピロリジノ、(これは非置換であるか、または重水素、ヒドロキシ、オキソからなる群から選択される1個以上;特に1個のオキソで置換されている)、
(6) フルオロ、クロロ。
R2は、さらに好ましくは水素または重水素である。
R2は、特に好ましくは水素である。
R2は、他の態様においてメチルである。
本発明は、さらに、式(I)の化合物の薬学的に許容されるプロドラッグに関する。
本発明は、さらに、式(I)の化合物の薬学的に許容される代謝物に関する。
式(II)
のイソシアネート中間体を介して反応できる反応性基、例えばイミダゾリルカルボニルである。〕
の化合物と反応させ(“方法B”)、
得られた式(I)の化合物を遊離形または塩の形態で回収し、場合により方法Aまたは方法Bに従い得られる式(I)の化合物を異なる式(I)の化合物に変換し、および/または得られる式(I)の化合物の塩をその異なる塩に変換し、および/または得られる遊離の式(I)の化合物をその塩に変換し、および/または得られる式(I)の化合物の異性体を、得られる1個以上の異なる式Iの異性体から単離することを含む。
本方法は、当分野で既知の方法に従い、または以下の実施例に記載する通りに実施し得る。例えば式IIの化合物を、式IIIの化合物と溶媒、例えばジメチルホルムアミド中、塩基、例えば有機アミン、例えばトリエチルアミンの存在下で反応させ得る。
反応に参加すべきでないかまたは反応を妨害するために、出発物質でまたは何らかの他の前駆体で1個以上の他の官能基、例えばカルボキシ、ヒドロキシ、アミノ、スルフヒドリルなどがここに記載する必要があるならば、これらは、ペプチド化合物、およびまたセファロスポリンおよびペニシリン類、ならびに核酸誘導体および糖類の合成に使用されるような基である。保護基は、除去されたら最終化合物にはもはや存在しない基であり、一方置換基として残る基は、出発物質または中間体段階で付加され、最終化合物を得るために除去される基であるここで使用する意味では保護基ではない。式(I)の化合物の異なる式(I)の化合物への変換の場合に、有用であるか、必要であるならば、保護基を導入し、除去してよい。
式(I)の化合物を、異なる式Iの化合物に変換し得る。
R3がフルオロである式(I)の化合物において;かかる化合物を対応する塩素誘導体からフルオロ化合物に変換することにより得られ得る。かかる反応は既知であり、置換反応と言う。この変換は式(IIIAまたはB)の出発物質の段階で、または対応する式Iの化合物の変換により行い得る。
式IIおよびIIIの出発物質、ならびに本明細書に、例えば以下に記載する他の出発物質は、当分野で既知の方法に従いまたは準じて製造できる、当分野で既知であるおよび/または市販されている。出発物質が特に記載されていないならば、該化合物は既知であるか、または当分野で、例えばWO05/021519またはWO04/096797で既知の方法に準じて、または以下に記載するとおりに製造できる。新規出発物質、ならびにその製造方法は、同様に本発明の一態様である。好ましい態様において、好ましい化合物が得られるように、出発物質を使用し、反応を選択する。
(工程1) 式(IV)
の化合物と、式(V)
の化合物を、場合により希釈剤の存在下、そして場合により反応助剤の存在下ヘック条件下で反応させ;
得られた式(IIIA)の化合物を遊離形または塩の形態で回収し、
場合により得られる式(IIIA)の化合物を異なる式(IIIA)の化合物に変換し、および/または得られる式(IIIA)の化合物の塩をその異なる塩に変換し、および/または得られる遊離の式(IIIA)の化合物をその塩に変換し、および/または得られる式(IIIA)の化合物の異性体を、得られる1個以上の異なる式Iの異性体から単離することを含む。
の化合物、またはその塩に関する。
の化合物と、活性化剤、例えば1,1'−カルボニルジイミミダゾールを、場合により希釈剤の存在下、そして場合により反応助剤の存在下反応させ;そして
得られた式(IIIB)の化合物を遊離形または塩の形態で回収し、
場合により得られる式(IIIB)の化合物を異なる式(IIIB)の化合物に変換し、および/または得られる式(IIIB)の化合物の塩をその異なる塩に変換し、および/または得られる遊離の式(IIIB)の化合物をその塩に変換し、および/または得られる式(IIIB)の化合物の異性体を、得られる1個以上の異なる式Iの異性体から単離することを含む。
の化合物と、式(VII)
の化合物を、場合により希釈剤の存在下、そして場合により反応助剤の存在下反応させ;そして
得られた式(IIIC)の化合物を遊離形または塩の形態で回収し、
場合により得られる式(IIIC)の化合物を異なる式(IIIC)の化合物に変換し、および/または得られる式(IIIC)の化合物の塩をその異なる塩に変換し、および/または得られる遊離の式(IIIC)の化合物をその塩に変換し、および/または得られる式(IIIC)の化合物の異性体を、得られる1個以上の異なる式Iの異性体から単離することを含む。
の化合物、またはその塩に関する。
の化合物と活性化剤、例えば1,1'−カルボニルジイミミダゾールを、場合により希釈剤の存在下、そして場合により反応助剤の存在下、反応させ;そして
得られた式(IIID)の化合物を遊離形または塩の形態で回収し、
場合により得られる式(IIID)の化合物を異なる式(IIID)の化合物に変換し、および/または得られる式(IIID)の化合物の塩をその異なる塩に変換し、および/または得られる遊離の式(IIID)の化合物をその塩に変換し、および/または得られる式(IIID)の化合物の異性体を、得られる1個以上の異なる式Iの異性体から単離することを含む。
の化合物と、ジメチルホルムアミドのアセタール、例えばDMF−ジメチルアセタールを反応させて式(VI)の化合物を得て;
得られた式(IIID)の化合物を遊離形または塩の形態で回収し、
場合により得られる式(IIX)の化合物を異なる式(IIX)の化合物に変換し、および/または得られる式(IIX)の化合物の塩をその異なる塩に変換し、および/または得られる遊離の式(IIX)の化合物をその塩に変換し、および/または得られる式(IIX)の化合物の異性体を、得られる1個以上の異なる式Iの異性体から単離することを含む。
Aはヘテロアリールであり;
R1は(1)場合により置換されていてよいアルキル;(2)場合により置換されていてよいシクロアルキル;(3)場合により置換されていてよいアリール;(4)場合により置換されていてよいアミン;(5)場合により置換されていてよいスルホニル;(6)ハロであり;
R2は水素、重水素またはR1について定義した置換基であり;
R3は水素、ハロ、場合により置換されていてよいアルキルである。〕
の化合物は、下位式(IA)、(IB)、および薬学的に許容されるその塩類も含み、医薬として有用である。本発明は、それ故、一態様において、PI3K阻害が指示される、ヒトまたは獣医使用のための組成物に関する。この態様はまた化合物(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(tert−ブチル)−ピリミジン−4−イル]−4−メチル−チアゾール−2−イル}−アミドを含み、あるいは、該化合物を除外する。
・ 処置を必要とする対象における、例えば上記のような、PI3K(例えばPI3キナーゼアルファ)酵素の活性化が仲介する状態、障害または疾患の処置方法であって、該対象に有効量の式(I)の化合物または薬学的に許容されるその塩を投与することを含む、方法。
・ 例えば、ここに示す方法のいずれかのための、医薬としての遊離形または薬学的に許容される塩形態の式(I)の化合物。
・ ここに示す方法のいずれかのための、特に1個以上のホスファチジルイノシトール3−キナーゼ仲介疾患において使用するための、医薬として使用するための、遊離形または薬学的に許容される塩形態の式(I)の化合物。
・ ここに記載する方法のいずれかにおける、特に1個以上のホスファチジルイノシトール3−キナーゼ仲介疾患の処置のための遊離形または薬学的に許容される塩形態の式(I)の化合物の使用。
・ ここに示す方法のいずれかにおける、特に1個以上のホスファチジルイノシトール3−キナーゼ仲介疾患の処置用医薬の製造のための、遊離形または薬学的に許容される塩形態の式(I)の化合物の使用。
を提供する。
・ 遊離形または薬学的に許容される塩形態の式(I)の化合物を薬学的に許容される希釈剤および/または担体と共に含む、例えば、ここに記載する方法のいずれか一つに使用するための組合せ医薬組成物。
・ 活性成分として遊離形または薬学的に許容される塩形態の式(I)の化合物;1個以上の薬学的に許容される担体物質および/または希釈剤および場合により1個以上のさらなる医薬物質を含む、組合せ医薬組成物。かかる組合せ医薬組成物は一投与量単位形態でも複数パーツのキットとしてでもよい。
・ 同時または連続投与のための治療有効量の遊離形または薬学的に許容される塩形態の式(I)の化合物および第二の活性物質を含む、組合せ医薬組成物。
・ 治療有効非毒性量の式(I)の化合物または薬学的に許容されるその塩と、少なくとも1個の、例えば上に示した第二の活性物質の、例えば同時のまたは連続的な併用投与を含む、上に定義した方法。
・ a)遊離形または薬学的に許容される塩形態のここに開示する式(I)の化合物である第一剤、およびb)少なくとも1個の、例えば上に示す併用剤を含む医薬組合せ剤、例えばキット;ここで、かかるキットはその投与のための指示書を含み得る。
シクロプロピルマグネシウムブロマイド(THF中0.5M、100mL、50mmol、2.2当量)を、4−クロロピリジンヒドロクロライド(3.4g、22mmol)のTHF(68mL)の冷(−78℃)懸濁液に一度に添加する。10分間、−78℃で撹拌後、フェニルクロロホルメート(2.76mL、22mmol)を滴下する。反応混合物を−78℃で15分間撹拌し、rtに温め、20%NH4Cl水溶液の添加によりクエンチし、Et2O(2×100mL)で抽出する。有機相をNaHCO3飽和溶液(50mL)で洗浄し、乾燥させ(Na2SO4)、濾過し、濃縮する。トルエン(100mL)に溶解した残留物に、o−クロラニル(6g、24.2mmol、1.1当量)の氷AcOH(50mL)溶液を添加する。反応混合物を14時間、rtで撹拌し、0℃に冷却し、10%NaOH水溶液の添加により塩基性化し、セライトのパッドを通して濾過する。濾液からの有機層をH2O(20mL)で洗浄し、10%HCl水溶液(3×25mL)で抽出する。合わせた酸性層を20%NaOH水溶液の添加により塩基性化し、DCM(3×25mL)で抽出する。有機相をH2O(50mL)で洗浄し、乾燥させ(Na2SO4)、濾過し、濃縮する。残留物をシリカゲルカラムクロマトグラフィー(DCM/MeOH、1:0→99:1)で精製して、0.951gの表題化合物を無色油状物として得る:ESI-MS: 154.1 [M+H]+; tR = 1.41分(系1); TLC: Rf = 0.85 (DCM/MeOH, 9:1)。
表題化合物:ESI-MS: 386.1 [M+H]+; TLC: Rf = 0.11 (DCM/MeOH, 95:5)。
表題化合物: ESI-MS: 386.1 [M+H]+; TLC: Rf = 0.40 (DCM/MeOH, 9:1). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 0.71 - 0.87 (m, 2 H) 1.11 - 1.26 (m, 2 H) 1.47 (s, 3 H) 1.74 - 1.96 (m, 3 H) 2.00-2.15 (m, 1 H) 2.39 (s, 3 H) 3.35 - 3.52 (m, 1 H) 3.52 - 3.73 (m, 1 H) 4.10-4.40 (m, 1 H) 6.93 (br. s., 1 H) 7.15 (dd, 1 H) 7.27 (s, 1 H) 7.35 (s, 1 H) 8.40 (d, 1 H) 10.99 (br. s., 1 H)
表題化合物:ESI-MS: 400.1 [M+H]+; TLC: Rf = 0.06 (DCM/MeOH/NH3 aq, 94:5:1)。
表題化合物:ESI-MS: 374.1 [M+H]+; tR = 2.16分(系1); TLC: Rf = 0.10 (DCM/MeOH/NH3 aq, 94:5:1)。
表題化合物:ESI-MS: 374.1 [M+H]+; tR = 1.99分(系1); TLC: Rf = 0.10 (DCM/MeOH/NH3 aq, 94:5:1)。
表題化合物:ESI-MS: 372.1 [M+H]+; TLC: Rf = 0.13 (DCM/MeOH/NH3 aq, 91.5:7.5:1)。
表題化合物:ESI-MS: 372.1 [M+H]+; TLC: Rf = 0.43 (DCM/MeOH, 9:1)。
表題化合物:ESI-MS: 426.0 [M+H]+; tR = 2.35分(系1); TLC: Rf = 0.25 (DCM/MeOH, 9:1)。
表題化合物:ESI-MS: 428.0 [M+H]+; tR = 2.75分(系1); TLC: Rf = 0.21 (DCM/MeOH, 9:1)。
表題化合物:ESI-MS: 440.0 [M+H]+; tR = 2.68分(系1); TLC: Rf = 0.08 (DCM/MeOH/NH3 aq, 91.5:7.5:1)。
表題化合物:ESI-MS: 440.0 [M+H]+; tR = 2.65分(系1); TLC: Rf = 0.36 (DCM/MeOH, 9:1). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 1.41 (s, 4 H) 1.70-1.90 (m, 3 H) 2.00 - 2.10 (m, 1 H) 2.40 (s, 3 H) 3.36 - 3.52 (m, 1 H) 3.52-3.65( m, 1 H) 4.10-4.40 (m, 1 H) 6.95 (br. s., 1 H) 7.37 (d, 2 H) 7.47 (s, 1 H) 8.52 (d, 1 H) 10.94 (br. s., 1 H)
表題化合物:ESI-MS: 442.0 [M+H]+; tR = 3.02分(系1); TLC: Rf = 0.35 (DCM/MeOH, 9:1). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 1.60 (s, 6 H) 1.70-1.95 (m, 3 H) 1.99 - 2.16 (m, 1 H) 2.40 (s, 3 H) 3.38 - 3.51 (m, 1 H) 3.51 - 3.69 (m, 1 H) 4.10-4.40 (m, 1 H) 6.95 (br. s., 1 H) 7.39 (d, 2 H) 7.53 (s, 1 H) 8.58 (d, 1 H) 10.93 (br. s., 1 H)
表題化合物:ESI-MS: 454.1 [M+H]+; tR = 2.90分(系1); TLC: Rf = 0.22 (DCM/MeOH/NH3 aq, 91.5:7.5:1)。
表題化合物:ESI-MS: 386.1 [M+H]+; tR = 2.32分(系1); TLC: Rf = 0.05 (DCM/MeOH/NH3 aq, 94:5:1)。
表題化合物:ESI-MS: 397.0 [M+H]+; tR = 2.90分(系1); TLC: Rf = 0.08 (DCM/MeOH/NH3 aq, 94:5:1). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 1.69 - 1.93 (m, 7 H) 2.00-2.20 (m, 1 H) 2.42 (s, 3 H) 3.38-3.50 (m, 1 H) 3.50-3.65 (m, 1 H) 4.10-4.40 (m, 1 H) 6.94 (br. s., 1 H) 7.34 (dd, 1 H) 7.37 (br. s., 1 H) 7.47 (s, 1 H) 8.47 (d, 1 H)
表題化合物: ESI-MS: 411.1 [M+H]+; TLC: Rf = 0.36 (DCM/MeOH, 9:1)。
表題化合物:ESI-MS: 429.1 [M+H]+; tR = 2.90分(系1); TLC: Rf = 0.11 (DCM/MeOH, 9:1)。
表題化合物:ESI-MS: 431.1 [M+H]+; TLC: Rf = 0.12 (DCM/MeOH, 9:1)。
表題化合物:ESI-MS: 403.2 [M+H]+; tR = 2.38分(系1); TLC: Rf = 0.10 (DCM/MeOH/NH3 aq, 91.5:7.5:1)。
表題化合物:ESI-MS: 389.2[M+H]+; tR=2.28分(系1); TLC: Rf = 0.34 (DCM/MeOH/NH3 aq, 91.5:7.5:1)。
表題化合物:ESI-MS: 413.2 [M+H]+; tR = 2.29分(系1); TLC: Rf = 0.45 (DCM/MeOH, 9:1)。
表題化合物:ESI-MS: 427.2 [M+H]+; tR = 2.37分(系1); TLC: Rf = 0.38 (DCM/MeOH, 9:1)。
表題化合物:ESI-MS: 399.1 [M+H]+; tR = 1.73分(系1); TLC: Rf = 0.25 (DCM/MeOH, 9:1)。
表題化合物:ESI-MS: 480.0 [M+H]+; tR = 3.05分(系1); TLC: Rf = 0.13 (DCM/MeOH/NH3 aq, 94:5:1)。
表題化合物:ESI-MS: 466.1 [M+H]+; tR = 2.91分(系1); TLC: Rf = 0.23 (DCM/MeOH/NH3 aq, 94:5:1)。
表題化合物:ESI-MS: 478.1 [M+H]+; tR = 2.65分(系1); TLC: Rf = 0.09 (DCM/MeOH/NH3 aq, 94:5:1)。
表題化合物:ESI-MS: 464.1 [M+H]+; tR = 2.90分(系1); TLC: Rf = 0.06 (DCM/MeOH/NH3 aq, 94:5:1)。
表題化合物:ESI-MS: 551.1 [M+H]+; tR = 2.38分(系1); TLC: Rf = 0.05 (DCM/MeOH/NH3 aq, 94:5:1)。
表題化合物:ESI-MS: 306.0/308.0 [M+H]+; tR = 3.94分(系1); TLC: Rf = 0.55 (Hex/EtOAc, 7: 3)。
表題化合物:ESI-MS: 403.2 [M+H]+; TLC: Rf = 0.22 (DCM/MeOH/NH3 aq, 91.5:7.5:1)。
表題化合物:ESI-MS: 389.2 [M+H]+; tR = 2.30分(系1); TLC: Rf = 0.11 (DCM/MeOH/NH3 aq, 91.5:7.5:1)。
表題化合物:ESI-MS: 389.2 [M+H]+; tR = 2.12分(系1); TLC: Rf = 0.35 (DCM/MeOH, 9:1)。
表題化合物:API-ES-MS: 445.1 [M+H]+; tR = 3.00分(系1); TLC: Rf = 0.51 (DCM/MeOH, 9:1)。
表題化合物:ESI-MS: 446.1 [M+H]+; TLC: Rf = 0.40 (DCM/MeOH/NH3 aq, 89:10: 1)。
表題化合物:ESI-MS: 305.2 [M+H]+; TLC: Rf = 0.24 (Hex/EtOAc, 1: 4)。
表題化合物:ESI-MS: 322.1 [M+H]+; tR = 3.58分(系1); TLC: Rf = 0.45 (DCM/MeOH, 9:1)。
表題化合物:ESI-MS: 460.0 [M+H]+; TLC: Rf = 0.44 (DCM/MeOH/NH3 aq, 91.5:7.5:1]
表題化合物:ESI-MS: 362.1 [M+H]+; tR = 4.18分(系1); TLC: Rf = 0.29 (Hex/EtOAc, 1:1)。
表題化合物:ESI-MS: 424.1 [M+H]+; tR = 2.40分(系1); TLC: Rf = 0.35 (DCM/MeOH, 9:1)。
表題化合物:ESI-MS: 406.1 [M+H]+; tR = 2.20分(系1); TLC: Rf = 0.47 (DCM/MeOH, 9:1)。
3.64g(27.5mmol)の3−ヒドロキシ−2,2−ジメチル−プロピオン酸メチルエステルおよび4.82mL(41.3mmol)の2,6−ルチジンの50mL乾燥DCM溶液に、トリフルオロ−メタンスルホン酸無水物(5.12mL、30.3mmol)を−70℃で窒素下にゆっくり添加する。黄色溶液を5分間、−70℃で撹拌し、冷却浴を除き、混合物を3時間、RTで撹拌する。色が黄色からオレンジ色乃至褐色に変わる。DCM(50mL)を添加し、溶液を2回2N HClで洗浄し、硫酸ナトリウムで乾燥させ、蒸発乾固する。褐色残留物を真空下に乾燥させ、表題化合物をさらに精製せずに使用する。TLC: Rf = 0.72 (EtOAc/ヘキサン 1:2)。
直線勾配20−100%溶媒Aを5分間+1.5分間100%溶媒A;215nmで検出、流速1mL/分、30℃。カラム:Nucleosil 100-3 C18 (70×4.0mm)。溶媒A=CH3CN+0.1%TFA;溶媒B=H2O+0.1%TFA。
装置:Micromass Platform II、溶離剤:15%メタノールの水溶液、0.2%の25%水酸化アンモニウム溶液含有
装置:Hewlett Packard Agilent 1100シリーズ、カラム:XBridgeTM C18 2.5ミクロン(microm) 3.0×30mm、温度:50℃、溶離剤:2チャネルシステム:チャネルA 5%アセトニトリルの水溶液、チャネルB 1.0%ギ酸含有アセトニトリル
装置:Gilson分取HPLC系、カラム:SunfireTM Prep C18 OBDTM 5ミクロン(microm)30×100mm、温度:25℃、溶離剤:勾配20分間にわたり0.05%水性トリフルオロ酢酸中5から100%アセトニトリル、流速:30ml/分、検出:UV 254nm。
PI3K KinaseGloアッセイ:50nLの化合物希釈液を黒色384ウェル低容積Non Binding Styrene(NBS)プレート(Costar Cat. No. NBS#3676)に分配した。メタノール中10mg/ml溶液として提供されたL−a−ホスファチジルイノシトール(PI)をガラスチューブに移し、窒素ビーム下に乾燥させた。それを3%オクチルグルコシド(OG)にボルテックス処理により溶解し、4℃で貯蔵した。KinaseGlo発光キナーゼアッセイ(Promega, Madison/WI, USA)は、キナーゼ反応後に溶液に残ったATP量を定量することによるキナーゼ活性を測定する均質HTS方法である。
PI3Kα、PI3KβおよびPI3Kδ構築物は、p85α iSH2ドメインおよび各p110アイソフォームの融合体である。p85αフラグメントおよびp110アイソフォーム遺伝子を、以下に記載する通り、胎盤、精巣および脳由来の市販RNAからのRT−PCRにより産生した第一鎖cDNAからPCRにより産生した。PI3Kγ構築物はRoger Williams lab, MRC Laboratory of Molecular Biology, Cambridge, UK(November, 2003)から得て、記載されている(Pacold, Michael E.; Suire, Sabine; Perisic, Olga; Lara-Gonzalez, Samuel; Davis, Colin T.; Walker, Edward H.; Hawkins, Phillip T.; Stephens, Len; Eccleston, John F.; Williams, Roger L. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma. Cell (2000), 103(6), 931-943)。
BV 1075のタンパク質配列:
1 MREYDRLYEE YTRTSQEIQM KRTAIEAFNE TIKIFEEQCQ TQERYSKEYI EKFKREGNEK
61 EIQRIMHNYD KLKSRISEII DSRRRLEEDL KKQAAEYREI DKRMNSIKPG GGGGGGGGGG
121 GLVECLLPNG MIVTLECLRE ATLITIKHEL FKEARKYPLH QLLQDESSYI FVSVTQEAER
181 EEFFDETRRL CDLRLFQPFL KVIEPVGNRE EKILNREIGF AIGMPVCEFD MVKDPEVQDF
241 RRNILNVCKE AVDLRDLNSP HSRAMYVYPP NVESSPELPK HIYNKLDKGQ IIVVIWVIVS
301 PNNDKQKYTL KINHDCVPEQ VIAEAIRKKT RSMLLSSEQL KLCVLEYQGK YILKVCGCDE
361 YFLEKYPLSQ YKYIRSCIML GRMPNLMLMA KESLYSQLPM DCFTMPSYSR RISTATPYMN
421 GETSTKSLWV INSALRIKIL CATYVNVNIR DIDKIYVRTG IYHGGEPLCD NVNTQRVPCS
481 NPRWNEWLNY DIYIPDLPRA ARLCLSICSV KGRKGAKEEH CPLAWGNINL FDYTDTLVSG
541 KMALNLWPVP HGLEDLLNPI GVTGSNPNKE TPCLELEFDW FSSVVKFPDM SVIEEHANWS
601 VSREAGFSYS HAGLSNRLAR DNELRENDKE QLKAISTRDP LSEITEQEKD FLWSHRHYCV
661 TIPEILPKLL LSVKWNSRDE VAQMYCLVKD WPPIKPEQAM ELLDCNYPDP MVRGFAVRCL
721 EKYLTDDKLS QYLIQLVQVL KYEQYLDNLL VRFLLKKALT NQRIGHFFFW HLKSEMHNKT
781 VSQRFGLLLE SYCRACGMYL KHLNRQVEAM EKLINLTDIL KQEKKDETQK VQMKFLVEQM
841 RRPDFMDALQ GFLSPLNPAH QLGNLRLEEC RIMSSAKRPL WLNWENPDIM SELLFQNNEI
901 IFKNGDDLRQ DMLTLQIIRI MENIWQNQGL DLRMLPYGCL SIGDCVGLIE VVRNSHTIMQ
961 IQCKGGLKGA LQFNSHTLHQ WLKDKNKGEI YDAAIDLFTR SCAGYCVATF ILGIGDRHNS
1021 NIMVKDDGQL FHIDFGHFLD HKKKKFGYKR ERVPFVLTQD FLIVISKGAQ ECTKTREFER
1081 FQEMCYKAYL AIRQHANLFI NLFSMMLGSG MPELQSFDDI AYIRKTLALD KTEQEALEYF
1141 MKQMNDAHHG GWTTKMDWIF HTIKQHALNE LGGAHHHHHH(配列番号4)
BV949のタンパク質配列:
1 MREYDRLYEE YTRTSQEIQM KRTAIEAFNE TIKIFEEQCQ TQERYSKEYI EKFKREGKEK
61 EIQRIMHNYD KLKSRISEII DSRRRLEEDL KKQAAEYREI DKRMNSIKPG GGGGGCFSFI
121 MPPAMADILD IWAVDSQIAS DGSIPVDFLL PTGIYIQLEV PREATISYIK QMLWKQVHNY
181 PMFNLLMDID SYMFACVNQT AVYEELEDET RRLCDVRPFL PVLKLVTRSC DPGEKLDSKI
241 GVLIGKGLHE FDSLKDPEVN EFRRKMRKFS EEKILSLVGL SWMDWLKQTY PPEHEPSIPE
301 NLEDKLYGGK LIVAVHFENC QDVFSFQVSP NMNPIKVNEL AIQKRLTIHG KEDEVSPYDY
361 VLQVSGRVEY VFGDHPLIQF QYIRNCVMNR ALPHFILVEC CKIKKMYEQE MIAIEAAINR
421 NSSNLPLPLP PKKTRIISHV WENNNPFQIV LVKGNKLNTE ETVKVHVRAG LFHGTELLCK
481 TIVSSEVSGK NDHIWNEPLE FDINICDLPR MARLCFAVYA VLDKVKTKKS TKTINPSKYQ
541 TIRKAGKVHY PVAWVNTMVF DFKGQLRTGD IILHSWSSFP DELEEMLNPM GTVQTNPYTE
601 NATALHVKFP ENKKQPYYYP PFDKIIEKAA EIASSDSANV SSRGGKKFLP VLKEILDRDP
661 LSQLCENEMD LIWTLRQDCR EIFPQSLPKL LLSIKWNKLE DVAQLQALLQ IWPKLPPREA
721 LELLDFNYPD QYVREYAVGC LRQMSDEELS QYLLQLVQVL KYEPFLDCAL SRFLLERALG
781 NRRIGQFLFW HLRSEVHIPA VSVQFGVILE AYCRGSVGHM KVLSKQVEAL NKLKTLNSLI
841 KLNAVKLNRA KGKEAMHTCL KQSAYREALS DLQSPLNPCV ILSELYVEKC KYMDSKMKPL
901 WLVYNNKVFG EDSVGVIFKN GDDLRQDMLT LQMLRLMDLL WKEAGLDLRM LPYGCLATGD
961 RSGLIEVVST SETIADIQLN SSNVAAAAAF NKDALLNWLK EYNSGDDLDR AIEEFTLSCA
1021 GYCVASYVLG IGDRHSDNIM VKKTGQLFHI DFGHILGNFK SKFGIKRERV PFILTYDFIH
1081 VIQQGKTGNT EKFGRFRQCC EDAYLILRRH GNLFITLFAL MLTAGLPELT SVKDIQYLKD
1141 SLALGKSEEE ALKQFKQKFD EALRESWTTK VNWMAHTVRK DYRSGAHHHH HHGA(配列番号12)
1 MSEESQAFQR QLTALIGYDV TDVSNVHDDE LEFTRRGLVT PRMAEVASRD PKLYAMHPWV
61 TSKPLPEYLW KKIANNCIFI VIHRSTTSQT IKVSPDDTPG AILQSFFTKM AKKKSLMDIP
121 ESQSEQDFVL RVCGRDEYLV GETPIKNFQW VRHCLKNGEE IHVVLDTPPD PALDEVRKEE
181 WPLVDDCTGV TGYHEQLTIH GKDHESVFTV SLWDCDRKFR VKIRGIDIPV LPRNTDLTVF
241 VEANIQHGQQ VLCQRRTSPK PFTEEVLWNV WLEFSIKIKD LPKGALLNLQ IYCGKAPALS
301 SKASAESPSS ESKGKVRLLY YVNLLLIDHR FLLRRGEYVL HMWQISGKGE DQGSFNADKL
361 TSATNPDKEN SMSISILLDN YCHPIALPKH QPTPDPEGDR VRAEMPNQLR KQLEAIIATD
421 PLNPLTAEDK ELLWHFRYES LKHPKAYPKL FSSVKWGQQE IVAKTYQLLA RREVWDQSAL
481 DVGLTMQLLD CNFSDENVRA IAVQKLESLE DDDVLHYLLQ LVQAVKFEPY HDSALARFLL
541 KRGLRNKRIG HFLFWFLRSE IAQSRHYQQR FAVILEAYLR GCGTAMLHDF TQQVQVIEML
601 QKVTLDIKSL SAEKYDVSSQ VISQLKQKLE NLQNSQLPES FRVPYDPGLK AGALAIEKCK
661 VMASKKKPLW LEFKCADPTA LSNETIGIIF KHGDDLRQDM LILQILRIME SIWETESLDL
721 CLLPYGCIST GDKIGMIEIV KDATTIAKIQ QSTVGNTGAF KDEVLNHWLK EKSPTEEKFQ
781 AAVERFVYSC AGYCVATFVL GIGDRHNDNI MITETGNLFH IDFGHILGNY KSFLGINKER
841 VPFVLTPDFL FVMGTSGKKT SPHFQKFQDI CVKAYLALRH HTNLLIILFS MMLMTGMPQL
901 TSKEDIEYIR DALTVGKNEE DAKKYFLDQI EVCRDKGWTV QFNWFLHLVL GIKQGEKHSA
961 HHHHHH(配列番号13)
1 MREYDRLYEE YTRTSQEIQM KRTAIEAFNE TIKIFEEQCQ TQERYSKEYI EKFKREGNEK
61 EIQRIMHNYD KLKSRISEII DSRRRLEEDL KKQAAEYREI DKRMNSIKPG GGGGGPPGVD
121 CPMEFWTKEE NQSVVVDFLL PTGVYLNFPV SRNANLSTIK QLLWHRAQYE PLFHMLSGPE
181 AYVFTCINQT AEQQELEDEQ RRLCDVQPFL PVLRLVAREG DRVKKLINSQ ISLLIGKGLH
241 EFDSLCDPEV NDFRAKMCQF CEEAAARRQQ LGWEAWLQYS FPLQLEPSAQ TWGPGTLRLP
301 NRALLVNVKF EGSEESFTFQ VSTKDVPLAL MACALRKKAT VFRQPLVEQP EDYTLQVNGR
361 HEYLYGSYPL CQFQYICSCL HSGLTPHLTM VHSSSILAMR DEQSNPAPQV QKPRAKPPPI
421 PAKKPSSVSL WSLEQPFRIE LIQGSKVNAD ERMKLVVQAG LFHGNEMLCK TVSSSEVSVC
481 SEPVWKQRLE FDINICDLPR MARLCFALYA VIEKAKKARS TKKKSKKADC PIAWANLMLF
541 DYKDQLKTGE RCLYMWPSVP DEKGELLNPT GTVRSNPNTD SAAALLICLP EVAPHPVYYP
601 ALEKILELGR HSECVHVTEE EQLQLREILE RRGSGELYEH EKDLVWKLRH EVQEHFPEAL
661 ARLLLVTKWN KHEDVAQMLY LLCSWPELPV LSALELLDFS FPDCHVGSFA IKSLRKLTDD
721 ELFQYLLQLV QVLKYESYLD CELTKFLLDR ALANRKIGHF LFWHLRSEMH VPSVALRFGL
781 ILEAYCRGST HHMKVLMKQG EALSKLKALN DFVKLSSQKT PKPQTKELMH LCMRQEAYLE
841 ALSHLQSPLD PSTLLAEVCV EQCTFMDSKM KPLWIMYSNE EAGSGGSVGI IFKNGDDLRQ
901 DMLTLQMIQL MDVLWKQEGL DLRMTPYGCL PTGDRTGLIE VVLRSDTIAN IQLNKSNMAA
961 TAAFNKDALL NWLKSKNPGE ALDRAIEEFT LSCAGYCVAT YVLGIGDRHS DNIMIRESGQ
1021 LFHIDFGHFL GNFKTKFGIN RERVPFILTY DFVHVIQQGK TNNSEKFERF RGYCERAYTI
1081 LRRHGLLFLH LFALMRAAGL PELSCSKDIQ YLKDSLALGK TEEEALKHFR VKFNEALRES
1141 WKTKVNWLAH NVSKDNRQEL GGAHHHHHH(配列番号20)
PI3Kα、PI3KβおよびPI3Kγを、2クロマトグラフィー工程で精製した:Niセファロース樹脂(GE Healthcare)上の固定化金属親和性クロマトグラフィー(IMAC)およびSuperdex 200 26/60カラム(GE Healthcare)を使用するゲル濾過。全緩衝液を4℃に冷却し、溶解を氷上で冷却しながら行った。カラム分別は室温で行った。PI3Kβの精製に使用した全緩衝液は、以下に記載するものに加えて0.05%Triton X100を含んだ。
PI3Kδを3クロマトグラフィー工程で精製した:Niセファロース樹脂(GE Healthcare)上での固定化金属親和性クロマトグラフィー、Superdex 200 26/60カラム(GE Healthcare)を使用するゲル濾過、および最後にQ−HPカラム(GE Healthcare)でのイオン交換工程。全緩衝液を4℃に冷却し、溶解を氷上で冷却しながら行った。カラム分別は室温で行った。
DMSOはCYP活性に対する阻害効果を有することが知られている。それ故、インキュベーション媒体中のDMSO濃度は、代謝過程への影響を最小化するために0.01%(v/v)に限定した。
Eq.(1):t1/2=0.693/−kmic
Eq.(2):Clint=0.693/−kmic・V/M
発光はATP濃度測定のために充分に確立されている読み出しであり、それ故に、基質に関係なく多くのキナーゼ類の活性の追跡に使用できる。KinaseGlo発光キナーゼアッセイ(Promega, Madison/WI, USA)は、キナーゼ反応後に溶液に残ったATP量を定量することによるキナーゼ活性を測定する均質HTS方法である。
BV 1147のタンパク質配列:
1 MREYDRLYEE YTRTSQEIQM KRTAIEAFNE TIKIFEEQCQ TQERYSKEYI EKFKREGNEK
61 EIQRIMHNYD KLKSRISEII DSRRRLEEDL KKQAAEYREI DKRMNSIKPG GISGGGGGIM
121 VLVECLLPNG MIVTLECLRE ATLITIKHEL FKEARKYPLH QLLQDESSYI FVSVTQEAER
181 EEFFDETRRL CDLRLFQPFL KVIEPVGNRE EKILNREIGF AIGMPVCEFD MVKDPEVQDF
241 RRNILNVCKE AVDLRDLNSP HSRAMYVYPP NVESSPELPK HIYNKLDKGQ IIVVIWVIVS
301 PNNDKQKYTL KINHDCVPEQ VIAEAIRKKT RSMLLSSEQL KLCVLEYQGK YILKVCGCDE
361 YFLEKYPLSQ YKYIRSCIML GRMPNLMLMA KESLYSQLPM DCFTMPSYSR RISTATPYMN
421 GETSTKSLWV INSALRIKIL CATYVNVNIR DIDKIYVRTG IYHGGEPLCD NVNTQRVPCS
481 NPRWNEWLNY DIYIPDLPRA ARLCLSICSV KGRKGAKEEH CPLAWGNINL FDYTDTLVSG
541 KMALNLWPVP HGLEDLLNPI GVTGSNPNKE TPCLELEFDW FSSVVKFPDM SVIEEHANWS
601 VSREAGFSYS HAGLSNRLAR DNELRENDKE QLKAISTRDP LSEITKQEKD FLWSHRHYCV
661 TIPEILPKLL LSVKWNSRDE VAQMYCLVKD WPPIKPEQAM ELLDCNYPDP MVRGFAVRCL
721 EKYLTDDKLS QYLIQLVQVL KYEQYLDNLL VRFLLKKALT NQRIGHFFFW HLKSEMHNKT
781 VSQRFGLLLE SYCRACGMYL KHLNRQVEAM EKLINLTDIL KQEKKDETQK VQMKFLVEQM
841 RRPDFMDALQ GFLSPLNPAH QLGNLRLEEC RIMSSAKRPL WLNWENPDIM SELLFQNNEI
901 IFKNGDDLRQ DMLTLQIIRI MENIWQNQGL DLRMLPYGCL SIGDCVGLIE VVRNSHTIMQ
961 IQCKGGLKGA LQFNSHTLHQ WLKDKNKGEI YDAAIDLFTR SCAGYCVATF ILGIGDRHNS
1021 NIMVKDDGQL FHIDFGHFLD HKKKKFGYKR ERVPFVLTQD FLIVISKGAQ ECTKTREFER
1081 FQEMCYKAYL AIRQHANLFI NLFSMMLGSG MPELQSFDDI AYIRKTLALD KTEQEALEYF
1141 MKQMNDAHHG GWTTKMDWIF HTIKQHALNE LGGAHHHHHH(配列番号23)。
BV 1097のタンパク質配列:
1 MREYDRLYEE YTRTSQEIQM KRTAIEAFNE TIKIFEEQCQ TQERYSKEYI EKFKREGNEK
61 EIQRIMHNYD KLKSRISEII DSRRRLEEDL KKQAAEYREI DKRMNSIKPG GISGGGGGIM
121 VLVECLLPNG MIVTLECLRE ATLITIKHEL FKEARKYPLH QLLQDESSYI FVSVTQEAER
181 EEFFDETRRL CDLRLFQPFL KVIEPVGNRE EKILNREIGF AIGMPVCEFD MVKDPEVQDF
241 RRNILNVCKE AVDLRDLNSP HSRAMYVYPP NVESSPELPK HIYNKLDKGQ IIVVIWVIVS
301 PNNDKQKYTL KINHDCVPEQ VIAEAIRKKT RSMLLSSEQL KLCVLEYQGK YILKVCGCDE
361 YFLEKYPLSQ YKYIRSCIML GRMPNLMLMA KESLYSQLPM DCFTMPSYSR RISTATPYMN
421 GETSTKSLWV INSALRIKIL CATYVNVNIR DIDKIYVRTG IYHGGEPLCD NVNTQRVPCS
481 NPRWNEWLNY DIYIPDLPRA ARLCLSICSV KGRKGAKEEH CPLAWGNINL FDYTDTLVSG
541 KMALNLWPVP HGLEDLLNPI GVTGSNPNKE TPCLELEFDW FSSVVKFPDM SVIEEHANWS
601 VSREAGFSYS HAGLSNRLAR DNELRENDKE QLKAISTRDP LSEITEQEKD FLWSHRHYCV
661 TIPEILPKLL LSVKWNSRDE VAQMYCLVKD WPPIKPEQAM ELLDCNYPDP MVRGFAVRCL
721 EKYLTDDKLS QYLIQLVQVL KYEQYLDNLL VRFLLKKALT NQRIGHFFFW HLKSEMHNKT
781 VSQRFGLLLE SYCRACGMYL KHLNRQVEAM EKLINLTDIL KQEKKDETQK VQMKFLVEQM
841 RRPDFMDALQ GFLSPLNPAH QLGNLRLEEC RIMSSAKRPL WLNWENPDIM SELLFQNNEI
901 IFKNGDDLRQ DMLTLQIIRI MENIWQNQGL DLRMLPYGCL SIGDCVGLIE VVRNSHTIMQ
961 IQCKGGLKGA LQFNSHTLHQ WLKDKNKGEI YDAAIDLFTR SCAGYCVATF ILGIGDRHNS
1021 NIMVKDDGQL FHIDFGHFLD HKKKKFGYKR ERVPFVLTQD FLIVISKGAQ ECTKTREFER
1081 FQEMCYKAYL AIRQHANLFI NLFSMMLGSG MPELQSFDDI AYIRKTLALD KTEQEALEYF
1141 MKQMNDARHG GWTTKMDWIF HTIKQHALNE LGGAHHHHHH(配列番号26)。
Claims (17)
- 式(I)
Aは:
R1は以下の置換基の1個であり:(1)非置換または置換、好ましくは置換C1−C7−アルキルであって、該置換基は重水素、フルオロから独立して選択される1個以上、好ましくは1〜9個であるか、または部分C3−C5−シクロアルキルの1個または2個である;(2)場合により置換されていてよいC3−C5−シクロアルキルであって、該置換基は以下の部分から独立して選択される1個以上、好ましくは1〜4個である:重水素、C1−C4−アルキル(好ましくはメチル)、フルオロ、シアノ、アミノカルボニル;(3)場合により置換されていてよいフェニルであって、該置換基は以下の部分から独立して選択される1個以上、好ましくは1〜2個である:重水素、ハロ、シアノ、C1−C7−アルキル、C1−C7−アルキルアミノ、ジ(C1−C7−アルキル)アミノ、C1−C7−アルキルアミノカルボニル、ジ(C1−C7−アルキル)アミノカルボニル、C1−C7−アルコキシ;(4)場合によりモノ−またはジ−置換アミン;ここで、該置換基は独立して以下の部分から選択される:重水素、C1−C7−アルキル(これは非置換であるか、または重水素、フルオロ、クロロ、ヒドロキシからなる群から選択される1個以上の置換基で置換されている)、フェニルスルホニル(これは非置換であるか、または1個以上、好ましくは1個のC1−C7−アルキル、C1−C7−アルコキシ、ジ(C1−C7−アルキル)アミノ−C1−C7−アルコキシで置換されている);(5)置換スルホニル;ここで、該置換基は以下の部分から選択される:C1−C7−アルキル(これは非置換であるか、または重水素、フルオロからなる群から選択される1個以上の置換基で置換されている)、ピロリジノ、(これは非置換であるか、または重水素、ヒドロキシ、オキソからなる群から選択される1個以上;特に1個のオキソで置換されている);(6)フルオロ、クロロ;
R2は水素であり;
R3は(1)水素、(2)フルオロ、クロロ、(3)場合により置換されていてよいメチルであって、ここで、該置換基は以下の部分から独立して選択される1個以上、好ましくは1〜3個である:重水素、フルオロ、クロロ、ジメチルアミノ。〕
の化合物またはその塩;(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(tert−ブチル)−ピリミジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド)を除く。 - Aが:
R1が:(1)シクロプロピルメチルまたは場合により置換されていてよい、分枝C3−C7−アルキルであって、該置換基は以下の部分から独立して選択される1個以上、好ましくは1〜9個である:重水素、フルオロ;(2)場合により置換されていてよいシクロプロピルまたはシクロブチルであって、該置換基は以下の部分から独立して選択される1個以上、好ましくは1〜4個である:メチル、重水素、フルオロ、シアノ、アミノカルボニル;(3)場合により置換されていてよいフェニルであって、該置換基は以下の部分から独立して選択される1個以上、好ましくは1〜2個である:重水素、ハロ、シアノ、C1−C7−アルキル、C1−C7−アルキルアミノ、ジ(C1−C7−アルキル)アミノ、C1−C7−アルキルアミノカルボニル、ジ(C1−C7−アルキル)アミノカルボニル、C1−C7−アルコキシ;(4)場合によりモノ−またはジ−置換アミン;ここで、該置換基は独立して以下の部分から選択される:重水素、C1−C7−アルキル(これは非置換であるか、または重水素、フルオロ、クロロ、ヒドロキシからなる群から選択される1個以上の置換基で置換されている)、フェニルスルホニル(これは非置換であるか、または1個以上、好ましくは1個のC1−C7−アルキル、C1−C7−アルコキシ、ジ(C1−C7−アルキル)アミノ−C1−C7−アルコキシで置換されている);(5)置換スルホニル;ここで、該置換基は以下の部分から選択される:C1−C7−アルキル(これは非置換であるか、または重水素、フルオロからなる群から選択される1個以上の置換基で置換されている)、ピロリジノ、(これは非置換であるか、または重水素、ヒドロキシ、オキソからなる群から選択される1個以上;特に1個のオキソで置換されている);(6)フルオロ、クロロであり;
R2が水素であり;
R3が水素、メチル、CD3、CH2Cl、CH2F、CH2N(CH3)3である;
請求項1に記載の化合物;(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(tert−ブチル)−ピリミジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド)を除く。 - 次のものから選択される、遊離形または薬学的に許容される塩形態の化合物:
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−tert−ブチル−ピリジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−シクロプロピル−ピリジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(2−フルオロ−フェニル)−ピリジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−シクロブチル−ピリジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(1−メチル−シクロプロピル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(1−メチル−シクロブチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−tert−ブチル−ピリジン−4−イル)−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−イソプロピル−ピリジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−シクロブチル−ピリジン−4−イル)−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(1−メチル−シクロプロピル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(1−トリフルオロメチル−シクロプロピル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(2,2,2−トリフルオロ−1,1−ジメチル−エチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(1−トリフルオロメチル−シクロブチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(1−トリフルオロメチル−シクロプロピル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(2,2,2−トリフルオロ−1,1−ジメチル−エチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(1−トリフルオロメチル−シクロブチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(1−メチル−シクロブチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(1−シアノ−シクロプロピル)−ピリジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(1−シアノ−シクロブチル)−ピリジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(1−カルバモイル−シクロブチル)−ピリジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(2−ジメチルアミノ−1,1−ジメチル−エチル)−ピリジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−ジエチルアミノ−ピリジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−ジエチルアミノ−ピリジン−4−イル)−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(3−tert−ブチル−3H−ベンゾイミダゾール−5−イル)−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(3−tert−ブチル−2−メチル−3H−ベンゾイミダゾール−5−イル)−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(3−エチル−3H−ベンゾイミダゾール−5−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−[(5−{2−[1−(4−メトキシ−フェニル)−1−メチル−エチル]−ピリジン−4−イル}−4−メチル−チアゾール−2−イル)−アミド];
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−[(5−{2−[1−(4−メトキシ−フェニル)−1−メチル−エチル]−ピリジン−4−イル}−チアゾール−2−イル)−アミド];
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−[(5−{2−[1−(4−メトキシ−フェニル)−シクロプロピル]−ピリジン−4−イル}−4−メチル−チアゾール−2−イル)−アミド];
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−[(5−{2−[1−(4−メトキシ−フェニル)−シクロプロピル]−ピリジン−4−イル}−チアゾール−2−イル)−アミド];
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−{1−[4−(3−ジメチルアミノ−プロポキシ)−フェニル]−1−メチル−エチル}−ピリジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(1−d3−メチル−シクロブチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(1−d3−メチル−シクロブチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−d3−メチル−5−[2−(1−メチル−シクロプロピル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−d3−メチル−5−[2−(2,2,2−トリフルオロ−1,1−ジメチル−エチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−ジメチルアミノメチル−5−[2−(1−d3−メチル−シクロブチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−クロロ−5−[2−(2,2,2−トリフルオロ−1,1−ジメチル−エチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−フルオロメチル−5−[2−(2,2,2−トリフルオロ−1,1−ジメチル−エチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(5−ベンゼンスルホニルアミノ−6−クロロ−ピリジン−3−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(5−ベンゼンスルホニルアミノ−6−クロロ−ピリジン−3−イル)−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(6−アミノ−5−トリフルオロメチル−ピリジン−3−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(1−メチル−シクロプロピル)−ピリミジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−イソプロピル−ピリミジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−ベンジル−ピリミジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−エチル−ピリミジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−メトキシメチル−ピリミジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(2,6−ジクロロ−ベンジル)−ピリミジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−イソブチル−ピリミジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(4−メトキシ−フェノキシメチル)−ピリミジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(3−メトキシ−フェノキシメチル)−ピリミジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(2−フルオロ−フェニル)−ピリミジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−トリフルオロメチル−ピリミジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(1,1,2−トリメチル−プロピル)−ピリミジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−[(5−{2−[1−(4−メトキシ−フェニル)−1−メチル−エチル]−ピリミジン−4−イル}−4−メチル−チアゾール−2−イル)−アミド];
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(1,1−ジメチル−プロピル)−ピリミジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(1−メチル−1−p−トリル−エチル)−ピリミジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(1−フェニル−シクロペンチル)−ピリミジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−シクロプロピル−ピリミジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−シクロブチル−ピリミジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−d9−tert−ブチル−ピリミジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(2−メチル−シクロプロピル)−ピリミジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−ジエチルアミノ−ピリミジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(2,2,2−トリフルオロ−1,1−ジメチル−エチル)−ピリミジン−4−イル]−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(エチル−メチル−アミノ)−ピリミジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(6−シクロプロピル−ピラジン−2−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[4−メチル−5−(5−トリフルオロメチル−ピリジン−3−イル)−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(6−d10−ジエチルアミノ−ピラジン−2−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(6−ジエチルアミノ−ピラジン−2−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−シクロプロピルメチル−ピリミジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(2−フルオロ−1,1−ジメチル−エチル)−ピリミジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−{[5−(2−tert−ブチル−6−メチル−ピリミジン−4−イル)−4−メチル−チアゾール−2−イル]−アミド};
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(2−フルオロ−1,1−ジメチル−エチル)−ピリジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド);
(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(2−フルオロ−1−フルオロメチル−1−メチル−エチル)−ピリジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド。 - 医薬として使用するための、遊離形または薬学的に許容される塩形態の、請求項1〜6のいずれか1項に記載の化合物。
- 1種以上のホスファチジルイノシトール3−キナーゼ(PI3K)仲介疾患の処置に使用するための、遊離形または薬学的に許容される塩形態の、請求項1〜6のいずれか1項に記載の化合物。
- 1種以上のホスファチジルイノシトール3−キナーゼ(PI3K)仲介疾患の処置用医薬の製造のための、遊離形または薬学的に許容される塩形態の、請求項1〜6のいずれか1項に記載の化合物の使用。
- ホスファチジルイノシトール3−キナーゼ(PI3K)仲介疾患の処置方法であって、それを必要とする対象に治療有効量の遊離形または薬学的に許容される塩形態の、請求項1〜6のいずれか1項に記載の化合物を投与することを含む、方法。
- 治療有効量の遊離形または薬学的に許容される塩形態の、請求項1〜6のいずれか1項に記載の化合物および1個以上の薬学的許容物を含む、医薬組成物。
- 治療有効量の遊離形または薬学的に許容される塩形態の、請求項1〜6のいずれか1項に記載の化合物および治療有効量の1個以上の組合せ相手;および1個以上の薬学的に許容される賦形剤を含む、同時または連続投与に適した組合せ医薬組成物。
- aタンパク質チロシンキナーゼ仲介疾患、特にホスファチジルイノシトール3−キナーゼ(PI3K)仲介疾患の処置に使用するための、請求項11に記載の医薬組成物または請求項12に記載の組合せ医薬組成物。
- 該ホスファチジルイノシトール3−キナーゼ(PI3K)仲介疾患がPI3Kアルファ仲介疾患である、請求項8記載の使用のための化合物、請求項9に記載の化合物の使用、または請求項10に記載の処置方法。
- 該ホスファチジルイノシトール3−キナーゼ(PI3K)仲介疾患がPI3Kアルファの過発現または増幅、PIK3CAの体細胞突然変異またはPTENの生殖系列変異または体細胞突然変異またはp85−p110複合体の上方制御に作用するp85αの変異および転座に依存性である、請求項8記載の使用のための化合物、請求項9に記載の化合物の使用、または請求項10に記載の処置方法。
- 増殖性疾患;良性または悪性腫瘍;肉腫から選択される癌;肺;気管支;前立腺;乳房(散発性乳癌およびカウデン病罹患者を含む);膵臓;消化器癌;結腸;直腸;結腸癌腫;結腸直腸腺腫;甲状腺;肝臓;肝内胆管;肝細胞;副腎;胃;胃;神経膠腫;神経膠芽腫;子宮内膜;黒色腫;腎臓;腎盂;膀胱;子宮体;子宮頸;膣;卵巣;多発性骨髄腫;食道;白血病;急性骨髄性白血病;慢性骨髄性白血病;リンパ球性白血病;骨髄球性白血病;脳;脳の癌腫;口腔および咽頭;喉頭;小腸;非ホジキンリンパ腫;黒色腫;絨毛結腸腺腫;腫瘍;上皮特性の腫瘍;リンパ腫;乳癌腫;基底細胞癌腫;扁平細胞癌腫;光線性角化症;固形腫瘍を含む腫瘍疾患;頭頚部腫瘍;真性多血症;本態性血小板血症;骨髄化生を伴う骨髄線維症;およびワルデンストレーム病の処置に使用するための、請求項1〜6のいずれか1項に記載の化合物または薬学的に許容されるその塩。
- 請求項1〜6のいずれか1項に記載のの式(I)の化合物の製造方法であって、
式II
化合物を、活性化剤の存在下で反応させるか(“方法A”)、または
式(IIIB)
の化合物と反応させ(“方法B”);
いずれの場合も場合により希釈剤の存在下であってよく、そして場合により反応助剤の存在下であってよく;
aそして
得られた式(I)の化合物を遊離形または塩の形態で回収し、場合により方法Aまたは方法Bに従い得られる式(I)の化合物を異なる式(I)の化合物に変換し、および/または得られる式(I)の化合物の塩をその異なる塩に変換し、および/または得られる遊離の式(I)の化合物をその塩に変換し、および/または得られる式(I)の化合物の異性体を、得られる1個以上の異なる式Iの異性体から単離することを含む、方法。
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JP2015514080A (ja) * | 2012-03-29 | 2015-05-18 | ノバルティス アーゲー | 診断用薬 |
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JP2021505579A (ja) * | 2017-12-08 | 2021-02-18 | バーテックス ファーマシューティカルズ インコーポレイテッドVertex Pharmaceuticals Incorporated | 嚢胞性線維症膜コンダクタンス制御因子のモジュレーターを作成するためのプロセス |
JP7245834B2 (ja) | 2017-12-08 | 2023-03-24 | バーテックス ファーマシューティカルズ インコーポレイテッド | 嚢胞性線維症膜コンダクタンス制御因子のモジュレーターを作成するためのプロセス |
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