JP5858434B2 - Janusキナーゼ阻害薬としてのシクロブタンおよびメチルシクロブタン誘導体 - Google Patents
Janusキナーゼ阻害薬としてのシクロブタンおよびメチルシクロブタン誘導体 Download PDFInfo
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- JP5858434B2 JP5858434B2 JP2012554055A JP2012554055A JP5858434B2 JP 5858434 B2 JP5858434 B2 JP 5858434B2 JP 2012554055 A JP2012554055 A JP 2012554055A JP 2012554055 A JP2012554055 A JP 2012554055A JP 5858434 B2 JP5858434 B2 JP 5858434B2
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Description
本願は、「Janusキナーゼ阻害薬としてのシクロブタンおよびメチルシクロブタン誘導体」という発明の名称で2010年2月18日に出願された、米国仮出願番号第61/305,630号の優先権を主張する。その明細書を通して引用されている任意の特許、特許出願および参考資料の内容は、その全体が出典明示により本明細書の一部となる。
本発明は、シクロブタンおよびメチルシクロブタン誘導体、ならびにそれらの塩、組成物、および使用方法に関する。これらの化合物は、例えば、炎症性疾患および自己免疫疾患、ならびに癌および骨髄増殖性疾患を含む、JAK関連疾患の処置に有用なJanusキナーゼ(JAK)阻害薬である。
プロテインキナーゼ(PKs)は、とりわけ、細胞増殖、生存および分化、臓器形成および形態形成、新血管形成、組織修復および再生を含む、種々の重要な生体内作用を調節する酵素の一群である。プロテインキナーゼは、タンパク質(または基質)のリン酸化を触媒することによって、種々の生物学的状況における基質の細胞内活性を調節して、それらの生理作用を発揮する。正常な組織/臓器における機能に加えて、種々のプロテインキナーゼはまた、癌を含む、種々のヒト疾患においてより特異的な役割を果たす。プロテインキナーゼのサブセット(発癌性プロテインキナーゼとも称される)は、調節されない場合、腫瘍形成および成長を引き起こし、さらに腫瘍維持および進行に寄与しうる。これまで、発癌性プロテインキナーゼは、癌処置介入および薬剤開発のための最大かつ最も魅力的な標的タンパク質群の一つを表している。
本発明は、3−シクロブチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルである化合物またはその医薬上許容される塩を提供する。ある実施態様において、上記の化合物は、R型またはS型エナンチオマーである。
本発明は、とりわけ、JAK阻害化合物:3−シクロブチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル(式I)およびその医薬上許容される塩を提供する。
3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−((trans)−3−メチルシクロブチル)プロパンニトリル(式II−trans);および
3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−((cis)−3−メチルシクロブチル)プロパンニトリル(式II−cis)。
(3R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−((3−メチルシクロブチル)プロパンニトリル(式II−R);および
(3S)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−(3−メチルシクロブチル)プロパンニトリル(式II−S)。
(3R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−((trans)−3−メチルシクロブチル)プロパンニトリル(式II−R/trans)、
(3S)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−((trans)−3−メチルシクロブチル)プロパンニトリル(式II−S/trans)、
(3R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−((cis)−3−メチルシクロブチル)プロパンニトリル(式II−R/cis)、および
(3S)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−((cis)−3−メチルシクロブチル)プロパンニトリル(式II−S/cis)。
本発明の化合物および塩は、1種またはそれ以上のJanusキナーゼ(JAK)の活性を阻害しうる。本発明の化合物が結合および/または阻害するJAKには、任意のメンバーのJAKファミリーが含まれる。本発明の化合物は、JAK1およびJAK2の両方の活性を阻害する。
1種またはそれ以上のさらなる医薬物質、例えば、化学療法剤、抗炎症剤、ステロイド類、免疫抑制剤、ならびにBcr−Abl、Flt−3、RAFおよびFAKキナーゼ阻害薬、例えば、WO2006/056399に記載されるもの、または他の治療剤などは、JAK関連疾患、障害または病態の処置のために本発明の化合物または塩と組み合わせて用いられうる。1種またはそれ以上のさらなる医薬物質は、同時にまたは連続して患者に投与されうる。
医薬品として用いる場合、本発明の化合物および塩は、医薬組成物の形態で投与されうる。これらの組成物は、医薬分野における周知の手法で調製され、局所または全身処置が望ましいかどうかおよび処置される領域に応じて、種々の経路によって投与されうる。投与は、局所投与(経皮投与、表皮投与、眼投与ならびに鼻腔内投与、膣内投与および直腸輸送を含む粘膜への投与を含む)、肺投与(例えば、ネブライザーによる投与を含む、粉末またはエアロゾルの吸入または注入による投与;気管内投与または鼻腔内投与)、経口投与または非経口投与でありうる。非経口投与には、静脈内、動脈内、皮下、腹腔内または筋肉内注射または注入;または頭蓋内、例えば、髄腔内または脳室内投与が含まれる。非経口投与は、単回ボーラス投与の形態でありうるか、または例えば、持続注入ポンプによるものでありうる。局所投与のための医薬組成物および処方物には、経皮パッチ、軟膏、ローション、クリーム、ゲル、滴剤、坐剤、スプレー、液体および粉末が含まれうる。慣習的な医薬担体、水性、粉末状または油性基剤、増粘剤などは、必要であってもよくまたは望ましくてもよい。被覆されたコンドーム、グローブなども有用でありうる。
実施例1
(RまたはS)−3−シクロブチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル
ジメチルスルホキシド(34.6mL、0.488mol)の塩化メチレン(100mL)中溶液を、−78℃にて塩化メチレン(700mL、10mol)中塩化オキサリル(20.6mL、0.244mol)に加えた。10分後、塩化メチレン(100mL)中シクロブチルメタノール(Aldrich、17.5g、0.203mol)を加え、得られた混合物を−78℃にて30分間撹拌した。次いで、トリエチルアミン(140mL、1.0mol)の塩化メチレン(100mL)中溶液を加え、混合物を室温(rt)まで徐々に昇温させた温度にて5時間撹拌した。水でクエンチした後、混合物を分離した。有機層を水(x2)、ブラインで洗浄し、硫酸ナトリウムで乾燥させて、濾過した。濾液を蒸留し、86−92℃の画分を回収して、アルデヒドを得た(18.6g、54.4%)。
0℃にて、1.00Mカリウムtert−ブトキシドのテトラヒドロフラン(116mL、0.116mol)中溶液に、ジエチルシアノメチルホスホネート(Aldrich、19.7mL、0.122mol)のテトラヒドロフラン(200mL)中溶液を滴下した。反応物を室温に昇温させ、次いで、再度0℃に冷却した。反応混合物にシクロブタンカルボキシアルデヒド(工程1参照、18.6g、0.110mol)のテトラヒドロフラン(100mL)中溶液を加えた。反応物を、室温(rt)まで昇温させ、室温にて一晩撹拌した。水でクエンチした後、混合物をエーテルで抽出した。合した有機層を、水、ブラインで洗浄し、乾燥させて、蒸発乾固した。粗混合物を、ヘキサン中0〜40%EtOAcで溶出する、シリカゲルに付して精製して、所望の生成物を得た(5.30g、44.7%)。C7H10N(M+H)+について算出されたLCMS:m/z=108.1;実測値:108.1.
4−(1H−ピラゾール−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(米国公開番号US2007/0135461を参照のこと、15.6g、0.050mol)のアセトニトリル(124mL、2.37mol)中溶液に、3−シクロブチルアクリロニトリル(5.30g、0.050mol)、次いで、1,8−ジアザビシクロ[5.4.0]ウンデカ−7−エン(3.70mL、0.025mol)を加えた。得られた混合物を室温にて一晩撹拌し、次いで、蒸発乾固した。混合物を、ヘキサン中0〜60%EtOAcで溶出する、シリカゲルに付して精製し、ラセミ混合物として所望の生成物を得た(16g、76%)。C22H31N6OSi(M+H)+について算出されたLCMS:m/z=423.2;実測値:423.0。ラセミ混合物を、キラルHPLC(カラム:ChiralCel OJ−H,30x250mm,5μm;移動相:30%エタノール/70%ヘキサン;流速:24mL/分)で分離して、2種のエナンチオマーを得た。キラル分析HPLC上(カラム:ChiralCel OJ−H,4.6x250mm,5μm;移動相:30%エタノール/70%ヘキサン;流速:0.8mL/分):第1ピークの保持時間:6.6分;第2ピークの保持時間:8.1分。
スターラーバー、コンデンサー、および窒素入口を備えている500mL丸底フラスコ中に、アセトニトリル(55mL)、水(4.8mL)および(RまたはS)−3−シクロブチル−3−[4−(7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル(工程3におけるキラル分離からの第2ピーク、2.8g、6.6mmol)を加えた。リチウムテトラフルオロボレート(7.50g、0.078mol)を加えた。得られた混合物を、一晩還流温度に昇温させ、室温に冷却し、5分かけて少しずつ3.00Mの水中水酸化アンモニウム(9.78mL)を加え、pHを9〜10に調整した。30分後、得られた混合物を、RP−HPLC(XBridge C18 30x100mmカラム、注入量5mL(約50mg/注入)、0.15%NH4OHを含有するアセトニトリル/水の勾配で溶出、流速60mL/分)に付して精製し、遊離塩基として所望の生成物を得た(1.51g、77.96%)。C16H17N6(M+H)+について算出されたLCMS:m/z=293.2;実測値:293.1。1H NMR(300MHz,CD3OD)δ8.65(1H,s),8.59(1H,s),8.34(1H,s),7.50(1H,d,J=3.6Hz),6.94(1H,d,J=3.6Hz),4.69(1H,m),3.07〜2.97(3H,m),2.21(1H,m),1.97〜1.84(5H,m)ppm。ee98.8%。
他のエナンチオマーは、工程3におけるキラル分離から得られる第1ピークに相当する化合物で出発して同一手法にて調製されうる。
(3Rまたは3S)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−((trans)−3−メチルシクロブチル)プロパンニトリル リン酸塩
コンデンサーを取り付けた丸底フラスコに、3−メチレンシクロブタンカルボニトリル(BePharma、10.0g、0.107mol)を加えた。フラスコに、水酸化カリウム(24.1g、0.365mol)のエタノール(112mL)および水(88mL)中溶液を加え、混合物を100℃に加熱した。約2時間後、アンモニアの発生が終了し、溶媒を減圧下で蒸発乾固した。固体を水(75mL)に溶解し、氷浴中で冷却し、濃塩酸で約1のpHに酸性化した。得られた上層を、ジクロロメタンで2回抽出した。有機層を合し、無水硫酸マグネシウムで乾燥させた。有機溶媒を除去して、所望の粗生成物を得た(11.8g、97.67%)。
3−メチレンシクロブタンカルボン酸(工程1、5.88g、52.4mmol)の塩化メチレン(100mL)中混合物に、塩化オキサリル(Aldrich、5.33mL、62.9mmol)、次いで、触媒量のジメチルホルムアミド(DMF)を加えた。反応物を室温にて2時間撹拌し、次いで、蒸発乾固した。粗酸塩化物を、塩化メチレン(200mL)に溶解した。得られた溶液に、N,O−ジメチルヒドロキシアミン塩酸塩(Aldrich、6.14g、62.9mmol)、次いで、トリエチルアミン(TEA)(21.9mL、0.157mol)を0℃にて滴下した。反応物を室温にて一晩撹拌し、TEA HCl塩を濾去した。濾液を1N HClで、次いで、水性重炭酸ナトリウム、ブラインで洗浄し、硫酸マグネシウムで乾燥させて、蒸発乾固した。粗アミド(7.30g、89.7%)を、次の工程において直接用いた。C8H14NO2(M+H)+について算出されたLCMS:m/z=156.1;実測値:156.3。
リチウムテトラヒドロアルミネート(2.18g、57.5mmol)のエーテル(200mL)中懸濁液に、N−メトキシ−N−メチル−3−メチレンシクロブタンカルボキサミド(工程2、7.14g、46.0mmol)のテトラヒドロフラン(75mL)中溶液を−15℃にて滴下した。反応物を、0〜−15℃にて30分間撹拌し、次いで、水性硫酸水素カリウムでクエンチした。得られた混合物を、エーテルで抽出した。合した有機層を、ブラインで洗浄し、硫酸マグネシウムで乾燥させ、蒸発させた。粗生成物(6.70g、151.5%)を、次の工程において直接用いた。
0℃にて、1.00Mのカリウムtert−ブトキシドのテトラヒドロフラン(48.3mL、48.3mmol)中溶液に、ジエチルシアノメチルホスホネート(Aldrich、8.19mL、50.6mmol)のテトラヒドロフラン(80mL)中溶液を滴下した。反応物を、室温に昇温させ、次いで、0℃に冷却した。反応混合物に、3−メチレンシクロブタンカルバルデヒド(工程4、4.42g、46.0mmol)のテトラヒドロフラン(40mL)中溶液を加えた。反応物を、室温に昇温させ、次いで、室温にて一晩撹拌した。水でクエンチした後、混合物をエーテルで抽出した。合した有機層を、水、ブラインで洗浄し、乾燥させ、蒸発乾固した。粗混合物(5.90g、107.7%)を次の工程において直接用いた。
4−(1H−ピラゾール−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(米国公開番号US2007/0135461参照、7.25g、23.0mmol)のアセトニトリル(57.4mL)中溶液に、粗3−(3−メチレンシクロブチル)アクリロニトリル(工程4、2.74g、23.0mmol)、次いで、1,8−ジアザビシクロ[5.4.0]ウンデカ−7−エン(3.44mL、23.0mmol)を加えた。得られた混合物を、室温にて週末にわたって撹拌し、次いで、蒸発乾固した。残渣を、ヘキサン中0〜80%EtOAcで溶出する、シリカゲルに付して精製し、所望の生成物を得た(6.0g、60.1%)。C23H31N6OSi(M+H)+について算出されたLCMS:m/z=435.2;実測値:435.4。
3−(3−メチレンシクロブチル)−3−[4−(7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル(工程5、4.0g、9.2mol)の100mLのメタノール中混合物を、水素のバルーン圧下で1時間、0.6gの10%Pd/Cの存在下において水素化した。触媒を濾去した後、濾液を蒸発乾固し、ヘキサン中0〜100%EtOAcで溶出する、シリカゲルに付して精製し、trans−およびcis−異性体の混合物として所望の生成物を得た。C23H33N6OSi(M+H)+について算出されたLCMS:m/z=437.3;実測値:437.4。生成物をキラルHPLCカラムに付して2回精製した。最初のHPLC分離(カラム:ChiralCel OD−H、30x250mm、5μm;移動相:15%エタノール/85%ヘキサン;流速:28mL/分)により、2つの画分、AおよびBを得た。画分Aは、1種のエナンチオマーのcis/trans混合物であった。保持時間:10.51分。画分Bは、保持時間が13.05分と13.92分である2種の非分離ピークを示す、他のエナンチオマーのcis/trans混合物であった。第1画分(A)は、さらなるキラルHPLC分離(カラム:ChiralPak IA,20x250mm,5μm;移動相:10%エタノール/90%ヘキサン;流速:15mL/分)に付して、2つのピーク、A1およびA2を得た(1のピークはcisに相当し、もう一方はtransに相当する)。キラル分析HPLCによれば(カラム:ChiralPak IA、4.6x250mm、5μm;移動相:15%エタノール/85%ヘキサン;流速:1.0mL/分):第1ピーク(A1)保持時間:11.79分;第2ピーク(A2)保持時間:12.78分。第2画分(B)は、キラルHPLC分離(カラム:ChiralPak IA,20x250mm、5μm;移動相:15%エタノール/85%ヘキサン;流速:15mL/分)に付して、2つのピーク、B1およびB2を得た(各ピークは、800mg、19.9%)。その後、B1はNOEによりcis異性体であることが示され、B2は他のエナンチオマーのtrans異性体であることが示された。キラル分析HPLCによれば(カラム:ChiralPak IA,4.6x250mm,5μm;移動相:15%エタノール/85%ヘキサン;流速:1.0mL/分):第1ピーク(B1)保持時間:12.48分および第2ピーク(B2)保持時間:14.16分。
スターラーバー、コンデンサーおよび窒素入口を備えている500mL丸底フラスコ中に、アセトニトリル(9.69mL)、水(0.84mL)および3−((trans)−3−メチルシクロブチル)−3−[4−(7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル(0.60g、1.4mol)(前工程におけるキラル分離からのB2(すなわち、第2画分のピーク2))を得た。リチウムテトラフルオロボレート(1.31g、13.7mmol)を加えた。混合物を一晩還流温度に昇温させ、次いで、室温にて5分かけて少しずつ7.2Mの水中水酸化アンモニウム(0.71mL、5.1mmol)を加えて、pHを9−10に調整した。反応物を室温にて2時間撹拌した。固体を濾去し、濾液をRP−HPLC((XBridge C18 30x100mmカラム、注入量5mL(約50mg/注入)、0.15%NH4OHを含有するアセトニトリル/水の勾配で溶出、流速60mL/分)に付して精製し、遊離塩基として所望の生成物を得た。C17H19N6(M+H)+について算出されたLCMS:m/z=307.2;実測値:307.4。1H NMR(500MHz,DMSO−d6)δ12.08(1H,s),8.78(1H,s),8.68(1H,s),8.36(1H,s),7.59(1H,d,J=3.0Hz),6.99(1H,d,J=3.0Hz),4.78(1H,m),3.12(2H,m),2.88(1H,m),2.30(1H,m),2.06(1H,m),1.88(1H,m),1.74(1H,m),1.44(1H,m),1.08(3H,d,J=7.0Hz)ppm。ee93.3%。
他のエナンチオマーは、工程6の画分Aに相当する化合物で出発して同一方法によって調製されうる。
(3Rまたは3S)−3−((trans)−3−メチルシクロブチル)−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル(工程7、0.275g、0.898mmol)のイソプロピルアルコール(5.83mL)中溶液に、60℃にて1.0mLイソプロパノール中リン酸(96.8mg、0.987mmol)を加えた。1時間撹拌した後、混合物を室温に冷却した。沈殿物を濾去し、空気乾燥し、次いで、エチルエーテルでリンスして、さらに空気乾燥して、所望のホスフェート生成物を得た(330mg、90.9%)。
(3Rまたは3S)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−((cis)−3−メチルシクロブチル)−プロパンニトリル リン酸塩
スターラーバー、コンデンサーおよび窒素入口を備えている500mL丸底フラスコ中に、アセトニトリル(8.1mL)、水(0.70mL)および(3Rまたは3S)−3−((cis)−3−メチルシクロブチル)−3−[4−(7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル(0.50g、1.1mmol)(実施例2、工程6に記載のキラル分離からのB1(すなわち、第2画分のピーク1))を加えた。リチウムテトラフルオロボレート(1.10g、11.4mmol)を加えた。溶液を一晩還流温度に昇温させた。次いで、水酸化アンモニウムの水中溶液(7.2M、0.59mL、4.3mmol)を、室温にて5分かけて少しずつ該溶液に加えて、pHを9〜10に調整した。反応物を室温にて2時間撹拌した。固体を濾去し、濾液をRP−HPLC(XBridge C18 30x100mmカラム、注入量5mL(約50mg/注入)、0.15%NH4OHを含有するアセトニトリル/水の勾配で溶出、流速60mL/分)に付して精製し、所望の生成物を得た。C17H19N6(M+H)+について算出されたLCMS:m/z=307.2;実測値:307.4。1H NMR(500MHz,DMSO−d6)δ12.08(1H,s),8.75(1H,s),8.68(1H,s),8.36(1H,s),7.59(1H,d,J=3.0Hz),6.99(1H,d,J=3.0Hz),4.66(1H,m),3.11(2H,m),2.66(1H,m),2.20(2H,m),1.88(1H,m),1.42(2H,m),0.97(3H,d,J=6.0Hz)ppm。ee99.8%。
他のエナンチオマーは、実施例2、工程6からの画分Aに相当する化合物で出発して同一方法によって調製されうる。
(3Rまたは3S)−3−((cis)−3−メチルシクロブチル)−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル(工程1、0.23g、0.751mmol)のイソプロピルアルコール(4.87mL)中溶液に、60℃にて1.0mLイソプロパノール中リン酸(80.9mg、0.83mmol)を加えた。混合物を2時間撹拌し、次いで、室温に冷却した。沈殿物を濾去し、空気乾燥し、次いで、エチルエーテルでリンスして、さらに空気乾燥して、所望のホスフェート生成物を得た(300mg、98.8%)。1H NMR(400MHz,DMSO−d6)δ12.08(1H,s),8.75(1H,s),8.65(1H,s),8.34(1H,s),7.58(1H,d,J=2.4Hz),6.97(1H,d,J=2.4Hz),4.63(1H,m),3.09(2H,m),2.64(1H,m),2.18(2H,m),1.86(1H,m),1.40(2H,m),0.96(3H,d,J=6.4Hz)ppm。
本発明の化合物は、Parkら,Analytical Biochemistry 1999,269,94−104に記載された以下のインビトロアッセイにしたがって、JAK標的の抑制活性について試験された。N末端Hisタグを有するヒトJAK1(a.a.837−1142)、JAK2(a.a.828−1132)およびJAK3(a.a.781−1124)の触媒ドメインを、昆虫細胞中でバキュロウイルスを用いて発現して、精製した。JAK1、JAK2またはJAK3の触媒活性を、ビオチン化ペプチドのリン酸化を測定することによってアッセイした。リン酸化ペプチドを、均一系時間分解蛍光法(homogenous time resolved fluorescence)(HTRF)によって検出した。化合物のIC50は、100mM NaCl、5mM DTT、および0.1mg/mL(0.01%)BSAを有する50mM Tris(pH7.8)バッファー中に酵素、ATPおよび500nMペプチドを含有する反応物中の各キナーゼを測定した。反応物中のATP濃度は、JAK1については90μM、JAK2については30μMおよびJAK3については3μMであった。室温にて1時間反応を実施し、次いで、20μLのアッセイバッファー中45mM EDTA、300nM SA−APC、6nM Eu−Py20で停止した(Perkin Elmer,Boston,MA)。ユーロピウム標識抗体に対する結合が40分間生じ、HTRFシグナルをFusionプレートリーダー上で測定した(Perkin Elmer,Boston,MA)。実施例1、2および3の化合物は、JAK1については2nM未満およびJAK2については1nM未満のIC50値を有することが見出された。
1種またはそれ以上の本発明の化合物は、以下の細胞アッセイの少なくとも1つにしたがって、JAK標的の抑制活性について試験された。
本発明の化合物は、免疫不全マウスにおけるヒト腫瘍異種移植モデルにおいて評価されうる。例えば、INA−6形質細胞腫細胞株の腫瘍形成変異体は、SCIDマウスに皮下接種するために用いられうる(Burger,R.ら.Hematol J.2:42−53,2001)。次いで、担癌動物は、薬物処置群またはビヒクル処置群に無作為に分類され得、化合物の異なる用量は、経口、腹腔内、または埋め込み型ポンプを用いる持続注入を含む種々の通常の経路によって投与されうる。キャリバーを用いて徐々に腫瘍成長が起こる。さらに、腫瘍サンプルは、JAK活性および下流シグナル経路における化合物効果を評価するために上記(実施例B)の分析のための処置の開始後いつでも採取されうる。さらに、化合物(群)の選択性は、他の既知のキナーゼ(例えば、Bcr−Abl)によって誘導される異種移植腫瘍モデル、例えば、K562腫瘍モデルを用いて評価されうる。
本発明の化合物はまた、T細胞誘導性マウス遅延型過敏症試験モデルにおいて(JAK標的の阻害の)それらの効果について試験されうる。マウス皮膚接触遅延型過敏症(DTH)反応は、臨床接触性皮膚炎、および他の皮膚のTリンパ球媒介免疫疾患、例えば、乾癬の有効なモデルであると考えられている(Immunol Today.1998 Jan;19(1):37−44)。マウスDTHは、免疫浸潤、炎症サイトカインの付随増加、およびケラチン生成細胞過剰増殖を含む、多数の特性を乾癬と共有する。さらに、外来において乾癬を処置するのに効果的である多種類の物質はまた、マウスにおけるDTH反応の有効な阻害剤である(Agents Actions.1993 Jan;38(1−2):116−21)。
本発明の化合物は、単一または複数の炎症反応を再現するために設計された齧歯類モデルまたは非齧歯類モデルにおいて評価されうる。例えば、関節炎の齧歯類モデルは、予防的にまたは治療的に投与された化合物の治療可能性を評価するために用いられうる。これらのモデルには、限定されるものではないが、マウスまたはラットコラーゲン誘導性関節炎、ラットアジュバント誘導性関節炎、およびコラーゲン抗体誘導性関節炎が含まれる。限定されるものではないが、多発性硬化症、I型糖尿病、ブドウ膜網膜炎、甲状腺炎、重症筋無力症、免疫グロブリン腎症、心筋炎、気道感作(喘息)、紅斑性狼瘡、または大腸炎を含無事故免疫疾患はまた、本発明の化合物の治療可能性を評価するために用いられうる。これらのモデルは、研究団体において確立されており、当業者によく知られている(Current Protocols in Immunology,Vol 3.,Coligan,J.E.ら,Wiley Press.;Methods in Molecular Biology:Vol.225,Inflammation Protocols.,Winyard,P.G.and Willoughby,D.A.,Humana Press,2003.)。
化合物は、限定されるものではないが、ウサギコンカナバリンA(ConA)涙腺モデル、スコポラミンマウスモデル(皮下または経皮)、ボツリヌスマウス涙腺モデル、または眼の腺機能不全をもたらす多数の自発齧歯類自己免疫モデルのいずれか(例えば、NOD−SCID、MRL/lpr、またはNZB/NZW)を含む、1つまたはそれ以上の当業者に周知のドライアイの前臨床モデルにおいて評価されうる(Barabinoら,Experimental Eye Research 2004,79,613−621およびSchraderら,Developmental Opthalmology,Karger 2008,41,298−312、その各々はその全体が出典明示により本明細書の一部となる)。これらのモデルのエンドポイントには、眼の腺および眼(角膜など)の組織病理および場合によっては、涙液産生を測定する一般的なシルマー試験またはその改良バージョン(Barabinoら)が含まれる。活性は、測定可能な疾患が存在する前または後に開始しうる複数の投与経路(例えば、全身または局所)を介する投与によって評価されうる。
Claims (26)
- 3−シクロブチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルである化合物またはその医薬上許容される塩。
- (R)−3−シクロブチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルである請求項1記載の化合物、またはその医薬上許容される塩。
- (S)−3−シクロブチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルである請求項1記載の化合物、またはその医薬上許容される塩。
- 3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−(3−メチルシクロブチル)プロパンニトリルである化合物またはその医薬上許容される塩。
- 3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−((trans)−3−メチルシクロブチル)プロパンニトリルである請求項4記載の化合物、またはその医薬上許容される塩。
- (3R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−((trans)−3−メチルシクロブチル)プロパンニトリルである請求項5記載の化合物、またはその医薬上許容される塩。
- (3S)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−((trans)−3−メチルシクロブチル)プロパンニトリルである請求項5記載の化合物、またはその医薬上許容される塩。
- 3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−((cis)−3−メチルシクロブチル)プロパンニトリルである請求項4記載の化合物、またはその医薬上許容される塩。
- (3R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−((cis)−3−メチルシクロブチル)プロパンニトリルである請求項8記載の化合物、またはその医薬上許容される塩。
- (3S)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−((cis)−3−メチルシクロブチル)プロパンニトリルである請求項8記載の化合物、またはその医薬上許容される塩。
- 請求項1〜10のいずれか1項に記載の化合物のリン酸塩。
- 請求項1〜10のいずれか1項に記載の化合物またはその医薬上許容される塩と、少なくとも1種の医薬上許容される担体とを含む組成物。
- 請求項1〜10のいずれか1項に記載の化合物またはその医薬上許容される塩を含む、自己免疫疾患処置用医薬。
- 前記自己免疫疾患が、皮膚疾患、多発性硬化症、関節リウマチ、乾癬性関節炎、若年性関節炎、I型糖尿病、紅斑性狼瘡、炎症性腸疾患、クローン病、重症筋無力症、免疫グロブリン腎症、心筋炎、または自己免疫性甲状腺疾患である、請求項13記載の医薬。
- 前記自己免疫疾患が関節リウマチである、請求項13記載の医薬。
- 前記自己免疫疾患が皮膚疾患である、請求項13記載の医薬。
- 前記皮膚疾患が、アトピー性皮膚炎、乾癬、皮膚感作、皮膚炎、皮膚発疹、接触性皮膚炎またはアレルギー性接触感作である、請求項16記載の医薬。
- 請求項1〜10のいずれか1項に記載の化合物またはその医薬上許容される塩を含む、癌処置用医薬。
- 前記癌が固形腫瘍である、請求項18記載の医薬。
- 前記癌が、前立腺癌、腎臓癌、肝臓癌、乳癌、肺癌、甲状腺癌、カポジ肉腫、キャッスルマン病または膵臓癌である、請求項18記載の医薬。
- 前記癌が、リンパ腫、白血病または多発性骨髄腫である、請求項18記載の医薬。
- 請求項1〜10のいずれか1項に記載の化合物またはその医薬上許容される塩を含む、骨髄増殖性疾患処置用医薬。
- 前記骨髄増殖性疾患(MPD)が、真性赤血球増加症(PV)、本態性血小板血症(ET)、原発性骨髄線維症(PMF)、骨髄化生を伴う骨髄線維症(MMM)、慢性骨髄性白血病(CML)、慢性骨髄単球性白血病(CMML)、好酸球増加症候群(HES)、特発性骨髄線維症(IMF)、全身性肥満細胞疾患(SMCD)、または真性赤血球増加症/本態性血小板血症後の骨髄線維症(Post−PV/ET MF)である、請求項22記載の医薬。
- 請求項1〜10のいずれか1項に記載の化合物またはその医薬上許容される塩を含む、炎症性疾患処置用医薬。
- 請求項1〜10のいずれか1項に記載の化合物またはその医薬上許容される塩を含む、臓器移植拒絶反応処置用医薬。
- 請求項1〜10のいずれか1項に記載の化合物またはその医薬上許容される塩を含む、ドライアイ処置用医薬。
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AU2011217961B2 (en) | 2016-05-05 |
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EA201290807A1 (ru) | 2013-03-29 |
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CN102844317A (zh) | 2012-12-26 |
WO2011103423A1 (en) | 2011-08-25 |
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US20150087662A1 (en) | 2015-03-26 |
AU2011217961A1 (en) | 2012-09-06 |
CA2790070C (en) | 2018-03-06 |
KR20130009763A (ko) | 2013-01-23 |
CA2790070A1 (en) | 2011-08-25 |
BR112012020693A8 (pt) | 2017-07-11 |
BR112012020693B1 (pt) | 2020-05-12 |
MX2012009541A (es) | 2012-10-01 |
US20110207754A1 (en) | 2011-08-25 |
JP2013520436A (ja) | 2013-06-06 |
BR112012020693A2 (pt) | 2016-07-26 |
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