JP6486002B2 - Cxcr2モジュレーターとしてのアミノピリジンカルボキサミドおよびアミノピリミジンカルボキサミド - Google Patents
Cxcr2モジュレーターとしてのアミノピリジンカルボキサミドおよびアミノピリミジンカルボキサミド Download PDFInfo
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- JP6486002B2 JP6486002B2 JP2013526073A JP2013526073A JP6486002B2 JP 6486002 B2 JP6486002 B2 JP 6486002B2 JP 2013526073 A JP2013526073 A JP 2013526073A JP 2013526073 A JP2013526073 A JP 2013526073A JP 6486002 B2 JP6486002 B2 JP 6486002B2
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Description
ケモカインは、走化性タンパク質であり、これらは、マクロファージ、T細胞、好酸球、好塩基球、好中球および内皮細胞を炎症部位および腫瘍増殖部位に誘引する能力を有する。ケモカインは一般的に、低分子量(7−9kD)タンパク質であり、4種のサブファミリー:CC(またはβ−ケモカイン)、CXC、C(またはγ−ケモカイン)およびCX3C(またはδ−ケモカイン)に分けられる。ケモカインは、それらの一次アミノ酸構造によって分類される。CXCサブファミリーは、アミノ酸(X)により分断されているN末端に近い2つの保存されたCys残基(C)により特徴付けられる。CXC−ケモカインとしては、例えばインターロイキン−8(IL−8)、好中球活性化タンパク質−1(NAP−1)、好中球活性化タンパク質−2(NAP−2)、GROα、GROβ、GROγ、ENA−78、GCP−2、IP−10、MIGおよびPF4が挙げられる。ケモカインのCXCサブファミリーは、CXCモチーフの最初のCys残基の直前の、特定のアミノ酸配列、グルタミン酸−ロイシン−アルギニン(または、簡略してELR)の存在または不存在により特徴付けられる。ELRモチーフ(ELRCXC)を有する該ケモカインは、炎症部位への好中球の誘引および活性化に重要である。例えば、GROαおよびIL−8はELRCXCケモカインである。
本発明は、少なくとも1種の式(1)の化合物またはその薬学的に許容される塩もしくは溶媒和物および薬学的に許容される担体を含む医薬組成物を提供する。ある態様において、本発明は、CXCケモカイン−モジュレーターである新規化合物クラス、1種またはそれ以上のかかる化合物を含む医薬組成物、およびCXCケモカイン仲介と関係のある1種またはそれ以上の疾患の、本明細書に記載の化合物および組成物を用いる処置、予防、阻害または改善法を提供する。
[式中、R1およびR2は、水素、2−もしくは3−もしくは4−ハロ−フェニル、ヘテロアルキル、アルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロシクリル、およびヘテロシクリルアルキルからなる群より独立して選択され;
R3およびR4は、水素、ヘテロアルキル、アルキル、アミノアルキル、アリール、アリールアルキル、カルボキシアルキル、ヘテロアリール、ヘテロアリールアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロシクリル、およびヘテロシクリルアルキルからなる群より独立して選択されるか、またはR3およびR4は、カルボキシレート、アミン、ホスホネート、およびホスフェートからなる群より独立して選択されるイオン化基であり;
R3およびR4はまた、−B(R5R6)、−BF3 −M+、−R7−B(R5R6)、−R7−BF3 −M+、R7,−C(O)−R7、−O−R7、−S(O)y−R7(ここで、y=0、1または2である)、−P(O)−(R5R6)および−N(R8R9)からなる群より選択され;
R7は、アルキル、アリール、アリールアルキル、シクロアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリルおよびヘテロシクリルアルキルからなる群より選択され;
M+は、第IまたはII族の金属元素であり;
ここで、R5およびR6は、水素、ヒドロキシル、アリールオキシおよびアルコキシからなる群より独立して選択されるか、またはR5およびR6は共に、環状エステルまたは酸無水物を形成し(混合型または対称型);
R8およびR9は、水素、アルキル、ハロアルキル、アリール、シクロアルキル、アリールアルキル、ヘテロアルキル、ヘテロシクリルおよびヘテロシクリルアルキルからなる群より独立して選択されるか;R8およびR9は、両方とも酸素であってニトロ基を形成するか;または、R8およびR9は、それらが結合する窒素と一体となって、ヘテロシクリルを形成し;
X1は、炭素または窒素である]
で示される化合物;およびそれらの医薬組成物を提供する。
[式中、R1およびR2は、水素、2−もしくは3−もしくは4−ハロ−フェニル、ヘテロアルキル、アルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロシクリル、およびヘテロシクリルアルキルからなる群より独立して選択され;
R3およびR4は、水素、ヘテロアルキル、アルキル、アミノアルキル、アリール、アリールアルキル、カルボキシアルキル、ヘテロアリール、ヘテロアリールアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロシクリル、およびヘテロシクリルアルキルからなる群より独立して選択されるか、またはR3およびR4は、カルボキシレート、アミン、ホスホネート、およびホスフェートからなる群より独立して選択されるイオン化基であり;R3はR4と同じでもよく;
R3およびR4はまた、−B(R5R6)、−BF3 −M+、−R7−B(R5R6)、−R7−BF3 −M+、R7,−C(O)−R7、−O−R7、−S(O)y−R7(ここで、y=0、1または2である)、−P(O)−(R5R6)および−N(R8R9)からなる群より選択され;
R7は、アルキル、アリール、アリールアルキル、シクロアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリルおよびヘテロシクリルアルキルからなる群より選択され;
M+は、第IまたはII族の金属元素であり;
ここで、R5およびR6は、水素、ヒドロキシル、アリールオキシおよびアルコキシからなる群より独立して選択されるか、またはR5およびR6は共に、環状エステルまたは酸無水物を形成し(混合型または対称型);
R8およびR9は、水素、アルキル、ハロアルキル、アリール、シクロアルキル、アリールアルキル、ヘテロアルキル、ヘテロシクリルおよびヘテロシクリルアルキルからなる群より独立して選択されるか;R8およびR9は、両方とも酸素であってニトロ基を形成するか;または、R8およびR9は、それらが結合する窒素と一体となって、ヘテロシクリルを形成し;
X1は、炭素または窒素である]
で示される化合物を含む医薬組成物を提供する。
R3およびR4は、水素、ヘテロアルキル、アルキル、アミノアルキル、アリール、アリールアルキル、カルボキシアルキル、ヘテロアリール、ヘテロアリールアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロシクリル、およびヘテロシクリルアルキルからなる群より独立して選択されるか、またはR3は、カルボキシレート、アミン、ホスホネート、およびホスフェートからなる群より選択されるイオン化基であり;
R3およびR4はまた、−B(R5R6)、−BF3 −M+、−R7−B(R5R6)、−R7−BF3 −M+、R7,−C(O)−R7、−O−R7、−S(O)y−R7(ここで、y=0、1または2である)、−P(O)−(R5R6)および−N(R8R9)からなる群より選択され;
R7は、アルキル、アリール、アリールアルキル、シクロアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリルおよびヘテロシクリルアルキルからなる群より選択され;
M+は、第IまたはII族の金属元素であり;
ここで、R5およびR6は、水素、ヒドロキシル、アリールオキシおよびアルコキシからなる群より独立して選択されるか、またはR5およびR6は共に、環状エステルまたは酸無水物を形成し(混合型または対称型);
R8およびR9は、水素、アルキル、ハロアルキル、アリール、シクロアルキル、アリールアルキル、ヘテロアルキル、ヘテロシクリルおよびヘテロシクリルアルキルからなる群より独立して選択されるか;R8およびR9は、両方とも酸素であってニトロ基を形成するか;または、R8およびR9は、それらが結合する窒素と一体となって、ヘテロシクリルを形成し;
X1は、炭素または窒素である]
で示される化合物を投与することを含む方法を提供する。
定義
任意の置換基または変数が、任意の部分において、2回以上現れるとき、各出現でのその定義は、全ての他の出現でのその定義と無関係である。また、置換基および/または変数の組合せは、かかる組合せが安定な化合物を生じる場合にのみ、許容される。
チルが挙げられる。
好中球活性のモジュレーターは、多くの適応症に極めて治療的に有益であり得る。不適切に増強された好中球応答により特徴付けられる疾患状態において、好中球活性の阻害剤が好ましい。例えば好中球減少症のような疾患に罹患する患者において、好中球アゴニストまたはアクティベーターは、治療的有益性を有する。
以下の説明において、記載の式の置換基および/または可変基の組合せが、かかる貢献が好適な化合物に至るときのみ許容されることが理解される。
上記に記載の通り、6−ブロモニコチン酸(化合物1)を、種々の1級および2級アミンを用いてアミド化して、化合物2として示される一または二置換されたピリジンカルボキサミドを得ることができる。ペプチドカップリング剤を用いる好適な反応条件は、当分野で公知であり、EEDQ、DCCI、混合された無水炭酸ならびにPyBOPおよびPyBrOPのようなホスホニウムカップリング剤の使用が包含される。次いで、化合物2のハロゲン置換基を1級または2級アミンの窒素で置換して、化合物3を得る。このアルキル化反応は、塩基で触媒され、典型的に、好適な溶媒、例えばDMF中、好適な塩基、例えばトリエチルアミンを用いて行われる。あるいは、相間移動触媒条件(例えば、カリウム tert−ブトキシド、トルエン中の18−クラウン−6−エーテル)を用いて、このアルキル化を行うことができる。
化合物4および5の製造において、N−メチル−2−ブロモ−ベンジルアミンおよび2−ブロモ−ベンジルアミンをそれぞれ用いた(スキーム2)。ボロン酸部分を、パラジウム触媒による挿入反応により添加し、ボロン酸ピナコールエステルとした。ピナコールエステルを、KHF2で処理して除去し、ボロン酸部分を、好適な反応剤、例えばオキソン(登録商標)(Webb, K. S. and Levy, D, Tetrahedron Letters 36:5117−5118, 1995)またはペルオキシドを用いる酸化によりヒドロキシル基と置換し得る。
上記に記載の通り、2−クロロピリミジン−5−カルボン酸(化合物11)を、種々の1級および2級アミンを用いてアミド化して、化合物12として示される一または二置換されたピリミジンカルボキサミドを得ることができる。ペプチドカップリング剤を用いる好適な反応条件は当分野で公知であり、例えば、EEDQ、DCCI、混合された無水炭酸ならびにPyBOPおよびPyBrOPのようなホスホニウムカップリング剤の使用が包含される。次いで、化合物12のハロゲン置換基を1級または2級アミンの窒素で置換して、化合物13を得る。このアルキル化反応は、塩基で触媒され、典型的に、好適な溶媒、例えばDMF中、好適な塩基、例えばトリエチルアミンを用いて行われる。あるいは、相間移動触媒条件(例えば、カリウム tert−ブトキシド、トルエン中の18−クラウン−6−エーテル)を用いて、このアルキル化を行うことができる。
化合物14および15の製造において、N−メチル−4−ブロモ−ベンジルアミンを、化合物2および12(それぞれ、式中、R1はHであり、R2は4−フルオロフェニルである)と反応させた(スキーム4)。ボロン酸部分を、パラジウム触媒による挿入反応により添加し、ボロン酸ピナコールエステルとした。ピナコールエステルを、KHF2で処理して除去し、ボロン酸部分を、好適な反応剤、例えばオキソン(登録商標)(Webb, K. S. and Levy, D, Tetrahedron Letters 36:5117−5118, 1995)またはペルオキシドを用いる酸化によりヒドロキシル基と置換し得る。
一態様は、少なくとも1種の式(1)または式(2)の化合物、またはその薬学的に許容される塩もしくは溶媒和物を、薬学的に許容される担体と組み合わせて含む医薬組成物に関する。
(a)同種移植片拒絶反応が、急性同種移植片拒絶反応および慢性同種移植片拒絶反応からなる群より選択され;
(b)早期移植拒絶が、急性同種移植片拒絶反応であり;
(c)自己免疫性難聴が、メニエール病であり;
(d)心筋炎が、ウイルス性心筋炎であり;
(e)ニューロパシーが、IgAニューロパシー、膜性ニューロパシーおよび特発性ニューロパシーからなる群より選択され;
(f)自己免疫疾患、貧血であり;そして
(g)脈管炎症候群が、巨細胞性動脈炎、ベーチェット病およびウェゲナー肉芽腫症からなる群より選択される、方法である。
本明細書に記載の化合物から医薬組成物を製造するために、不活性な薬学的に許容される担体は、固体または液体のいずれかであり得る。固形製剤としては、散剤、錠剤、分散性顆粒剤、カプセル剤、カシェ剤および坐剤が挙げられる。散剤および錠剤は、約5%〜約95%の活性成分から構成され得る。好適な固体担体は、当技術分野で公知であり、例えば、炭酸マグネシウム、ステアリン酸マグネシウム、タルク、糖またはラクトースである。錠剤、散剤、カシェ剤およびカプセル剤は、経口投与に好適な固体投与量形態として使用され得る。薬学的に許容される担体および種々の組成物の製造方法の例は、A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, Md. に見いだされ得て、それらの内容は引用により本明細書中に包含される。
000mg、または約0.01mgないし約750mg、または約0.01mgないし約500mg、または約0.01mgないし約250mgで変えられ得るかまたは調整され得る。
6−ブロモニコチン酸(8.1g、40mmol)を、N2雰囲気下、無水DMF(50mL)中に溶解した。4−フルオロアニリン(3.9mL、41mmol)およびEEDQ(9.9g、40mmol)を添加し、室温で18時間撹拌した。生成物を脱イオン水(1.2L)中に希釈させることにより沈殿させ、該沈殿を濾取し、さらなる水で洗浄した。生成物を真空下で乾燥させて、8.1g(69%)の化合物2を白色固体として得た。ESI−MS m/z 294.9/296.9 [M+H]+。分析:C12H8BrFN2Oについての計算値:C、48.84;H、2.73;N、9.49。実測値:C、48.75;H、2.57;N、9.40。 1H NMR (500 MHz, DMSO−d6) δ 10.54 (s, 1H), 8.92 (d, J=2.3 Hz, 1H), 8.25−8.23 (m, 1H), 7.86−7.85 (m, 1H), 7.79 (d, J=3.8 Hz, 2H), 7.24−7.23 (m, 2H).
化合物2(1.486g、5.04mmol)、2−ブロモ−N−メチルベンジルアミン(0.74mL、5.00mmol)およびトリエチルアミン(1.40mL、10.0mmol)を、N2雰囲気下、無水ジメチルホルムアミド(10mL)に溶解し、耐圧瓶に入れた。反応を、130℃まで2日加熱した。反応物を室温まで冷却し、脱イオン水(250mL)で希釈した。懸濁液を、1N NaOHを用いてpH>9まで塩基性化し、酢酸エチルで2回抽出した。合わせた酢酸エチル抽出物をNa2SO4で乾燥させ、シリカゲルパッド(酢酸エチル)を通して濾過し、真空下で乾燥させた。粗生成物を酢酸エチルおよび最少量のメタノールに溶解し、シリカゲル(25g)に付着させた。シリカに付着した化合物をフラッシュシリカゲルクロマトグラフィー(250gシリカ、3:1 ヘキサン:酢酸エチル)により精製して、1.74g(84%)の化合物4を白色固体として得た。ESI−MS m/z 414.1/416.1 [M+H]+。分析:C20H17BrFN3Oについての計算値:C、57.98;H、4.14;N、10.14。実測値:C、58.08;H、4.20;N、10.02。1H NMR (500 MHz, DMSO−d6) δ 10.06 (s, 1H), 8.69 (d, J=2.3 Hz, 1H), 8.09 (dd, J=9.0 Hz, 2.3 Hz, 1H), 7.77−7.74 (m, 2H), 7.68 (d, J=8.0 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.18 (t, J=9.0 Hz, 2H), 6.99 (d, J=7.5 Hz, 1H), 6.78 (d, J=9.4 Hz, 1H), 4.89 (s, 2H), 3.20 (s, 3H).
塩酸2−ブロモベンジルアミン(1.520g、6.83mmol)を水に溶解し、1N NaOH(15mL)を用いてpH12まで塩基性とした。懸濁液を酢酸エチルで2回抽出し、合わせた酢酸エチル抽出物をNa2SO4で乾燥させ、濾過し、真空下で乾燥させた。化合物2(1.915g、6.49mmol)を耐圧瓶に入れ、2−ブロモベンジルアミン(1.244g、6.69mmol)を、N2雰囲気下、撹拌しながら添加し、N−メチルピロリジン(13mL)に溶解させた。トリエチルアミン(1.92mL、13.8mmol)をN2下で添加し、該耐圧瓶を130℃で3日間加熱した。反応物を室温まで冷却し、脱イオン水(300mL)の撹拌溶液に少しずつ添加し、細かい沈殿を形成させた。懸濁液を一晩冷蔵庫に入れ、濾過した。粗固体を減圧デシケーター中で乾燥させた。粗生成物をテトラヒドロフラン中に溶解し、上記の合成物(0.5mmolスケール)からの物質と合わせ、シリカゲル(25g)に付着させた。合わせた化合物をフラッシュシリカゲルクロマトグラフィー(250g シリカ、3:2 ヘキサン:酢酸エチル、次いで、2:1 酢酸エチル:ヘキサン)により精製して、1.86g(66%)の化合物5を白色固体として得た。ESI−MS m/z 400.0/402.0 [M+H]+。1H NMR (500 MHz, DMSO−d6) δ 9.99 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 7.96 (dd, J=8.8 Hz, 2.5 Hz, 1H), 7.79−7.74 (m, 3H), 7.65 (d, J=8.0 Hz, 1H), 7.36 (d, J=4.2 Hz, 2H), 7.24−7.20 (m, 1H), 7.17 (t, J=9.0 Hz, 2H), 6.68 (d, J=8.6 Hz, 1H), 4.61 (d, J=5.8 Hz, 2H).
化合物4(1.74g、4.2mmol)を無水ジメチルホルムアミドに溶解し、真空下で脱気した。耐圧瓶に、PdCl2(dppf)(255mg、0.312mmol)、ビス(ピナコラト)ジボロン(3.21g、12.6mmol)および酢酸カリウム(1.22g、12.4mmol)を、撹拌子と共に入れた。DMF溶液をオーブン乾燥させたピペットで該耐圧瓶に加え、乾燥DMF(5mL)で濯いだ。該耐圧瓶を窒素ガス下で密封し、80℃で41時間加熱し、次いで室温まで冷却した。反応物をセライトを通して濾過し、DMFで濯ぎ、真空下で乾燥させ、水と酢酸エチルの間に分配させて、水層を酢酸エチルで洗浄した。合わせた酢酸エチル層をNa2SO4で乾燥させ、シリカゲルパッド(酢酸エチル)を通して濾過した。濾液を真空下で乾燥させて、4.3gの化合物6を含む粗赤色混合物を得て、それをさらに精製することなく用いた。ESI−MS (of major product) m/z 462.2 [M+H]+.
化合物5(201mg、0.50mmol)を無水ジメチルホルムアミド中に溶解し、真空下で脱気した。耐圧瓶にPdCl2(dppf)(13mg、0.016mmol)、ビス(ピナコラト)ジボロン(384mg、1.5mmol)および酢酸カリウム(150mg、1.5mmol)を入れ、該溶液をN2雰囲気下で添加した。該耐圧瓶を撹拌しながら80℃で26時間加熱し、次いで室温まで冷却した。反応物を水と酢酸エチルの間に分配させて、水層を酢酸エチルで洗浄した。合わせた酢酸エチル層をNa2SO4で乾燥させ、シリカゲルパッド(酢酸エチル)を通して濾過した。濾液を真空下で乾燥させ、3:2 ヘキサン:酢酸エチル中に溶解し、フラッシュシリカゲルクロマトグラフィー(30g、3:2 ヘキサン:酢酸エチル)により精製して、123mg(67%)の化合物7を白色泡状物として得た。ESI−MS m/z 366.1 [(M-ピナコール)+H]+。1H NMR (500 MHz, DMSO−d6) δ 9.97 (s, 1H), 8.63 (d, J=1.9 Hz, 1H), 7.93 (dd, J=8.9 Hz, 2.2 Hz, 1H), 7.76−7.74 (m, 2H), 7.71 (d, J=7.6 Hz, 1H), 7.54 (t, J=5.7 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.26 (t, J=7.3 Hz, 1H), 7.17 (t, J=8.8 Hz, 2H), 6.61 (d, J=8.8 Hz, 1H), 4.78 (d, J=5.8 Hz, 2H), 1.31 (s, 12H)。全細胞アッセイにおけるIC50(薬理実施例1)=1.5±0.3μM。
粗化合物6(4.2mmol)を、撹拌しながらメタノール(36mL)中に懸濁し、4.5M KHF2(4.0mL、21mmol)をピペットで少しずつ添加した。フラスコの壁面を濯ぐためにさらにメタノールを添加し、反応物を室温で撹拌した。2.5時間後、さらに4.5M KHF2(8.0mL、42mmol)を添加して、反応を完了させた。さらに2時間撹拌後、反応物をメタノールで希釈し、真空下で乾燥させて、濃いタール状の物質を得て、それを水で希釈した。ソニケーションを行い褐色沈殿を得て、それを真空濾過により単離して、減圧デシケーター中で乾燥させて、灰色固体(1.8g)を得た。該固体をアセトニトリル(40mL)に溶解し、トリメチルシリルクロライド(4.8mL、38mmol)および水(0.68mL、38mmol)と共に室温で撹拌した。約2時間撹拌後、反応を飽和重炭酸ナトリウム(19mL)でクエンチした。数分の撹拌後、反応物を水(400mL)で希釈し、黄褐色固体(773mg)を真空濾過により単離し、減圧デシケーター中で乾燥させた。固体を酢酸エチルとメタノールの混合物中に溶解し、シリカゲル(8g)に付着させ、フラッシュシリカゲルクロマトグラフィー(80g、3:2 酢酸エチル:ヘキサンないし酢酸エチルの勾配の複数工程)により精製して赤色泡状物を得て、それを酢酸エチルに溶解し、それから294mg(化合物4から18%)の化合物8を細かい白色固体として沈殿させた。ESI−MS m/z 380.1 [M+H]+。1H NMR (500 MHz, DMSO−d6) δ 10.03 (s, 1H), 8.70 (d, J=2.1 Hz, 1H), 8.37 (s, 2H), 8.05 (dd, J=9.1 Hz, 2.1 Hz, 1H), 7.77−7.74 (m, 2H), 7.56 (d, J=7.3 Hz, 1H), 7.30−7.26 (m, 1H), 7.22 (d, J=7.3 Hz, 1H), 7.18 (t, J=8.8 Hz, 2H), 7.03 (d, J=7.9 Hz, 1H), 6.73 (d, J=9.3 Hz, 1H), 5.00 (s, 2H), 3.19 (s, 3H)。全細胞アッセイにおけるIC50(薬理実施例1)=3.7±0.6μM.
6−ブロモニコチンアミド(590mg、2.0mmol)、2−(N−メチルアミノメチル)フェニルボロン酸ピナコールエステル(495mg、2.0mmol)、カリウムtert−ブトキシド(450mg、4.0mmol)、および18−クラウン−6 エーテル(28mg、0.1mmol)を、N2雰囲気下、無水トルエン中に懸濁し、22時間還流した。反応混合物を酢酸エチルで希釈し、飽和重炭酸塩水溶液で2回抽出した。合わせた飽和重炭酸塩抽出物を酢酸エチルで2回抽出し、合わせた有機層を塩水で洗浄し、Na2SO4で乾燥させ、濾過し、蒸発させて、0.9gの粗ボロン酸ピナコールエステル中間体を得た。次いで、該中間体ボロン酸エステルをテトラヒドロフラン中の過酸化物およびメタノールで処理し、シリカゲルに付着させた。所望の化合物9と残留ボロン酸ピナコールエステルをフラッシュシリカゲルクロマトグラフィー(90g、2:1 ヘキサン:酢酸エチル)により単離した。化合物混合物をテトラヒドロフラン中の過酸化物に溶解し、シリカゲルに付着させ、フラッシュシリカゲルクロマトグラフィー(55g、ジクロロメタン:0、2、5および10%酢酸エチルの勾配の複数工程)により精製して、71mg(10%)の化合物9をオフホワイト色固体として得た。ESI−MS m/z 352.1 [M+H]+。分析:C20H18FN3O2 1/2 H2Oについての計算値:C、66.66;H、5.31;N、11.66。実測値:C、66.83;H、5.16;N、11.43。1H NMR (500 MHz, DMSO−d6) δ 10.04 (s, 1H), 9.92 (s, 1H), 8.73 (d, J=2.1 Hz, 1H), 8.06 (dd, J=9.2 Hz, 2.2 Hz, 1H), 7.80−7.75 (m, 2H), 7.18 (t, J=8.8 Hz, 2H), 7.09 (t, J=7.8 Hz, 1H), 6.98 (d, J=7.4 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 6.75−6.72 (m, 2H), 4.76 (s, 2H), 3.17 (s, 3H)。全細胞アッセイにおけるIC50(薬理実施例1)=0.59±0.09μM.
化合物7(522mg、1.17mmol)を撹拌しながらメタノール(10mL)中に懸濁し、4.5M KHF2(1.1mL、5.89mmol)をピペットで滴下した。1時間撹拌後、反応物をメタノールで希釈し、真空下で乾燥させて油状物固体を得て、それを水で希釈した。ソニケーションして沈殿を得て、それを真空濾過により単離し、減圧デシケーター中で乾燥させた。固体をアセトニトリル(10mL)に溶解し、トリメチルシリルクロライド(0.44mL、3.5mmol)および水(63μL、3.5mmol)と共に室温で撹拌した。1時間撹拌後、反応を飽和重炭酸ナトリウム(2mL)を用いてクエンチした。数分の撹拌後、反応物を容量80mLまで水で希釈し、形成した沈殿を真空濾過により単離して、化合物10を白色固体(323mg、76%)として得た。ESI−MS m/z 366.2 [M+H]+。1H NMR (500 MHz, DMSO−d6) δ 10.05 (s, 1H), 8.26 (dd, J=9.0 Hz, 2.0 Hz, 1H), 7.63−7.60 (m, 2H), 7.54 (d, J=1.9 Hz, 1H), 7.45−7.36 (m, 3H), 7.29 (t, J=7.1 Hz, 1H), 7.14 (t, J=8.8 Hz, 2H), 7.00 (d, J=9.2 Hz, 1H), 4.83−4.75 (m, 2H)。全細胞アッセイにおけるIC50(薬理実施例1)=1.7±0.2μM.
2−クロロピリミジン−5−カルボン酸(1.99g、12.5mmol)を、N2雰囲気下、無水DMF(10mL)中に溶解した。4−フルオロアニリン(1.2mL、12.5mmol)およびEEDQ(3.11g、12.6mmol)を添加し、室温で40時間撹拌した。生成物を脱イオン水と酢酸エチルの間に分配させた。水層を酢酸エチルで洗浄し、合わせた酢酸エチル層を硫酸ナトリウムで乾燥させ、濾過し、真空下で乾燥させた。粗生成物を酢酸エチルおよび最少量のメタノールに溶解し、シリカゲル(28g)に付着させた。シリカに付着した化合物をフラッシュシリカゲルクロマトグラフィー(340g、3:1 ヘキサン/酢酸エチル)により精製して、1.2g(37%)の化合物12を白色固体として得た。ESI−MS m/z 252.1 [M+H]+。1H NMR (500 MHz, DMSO−d6) δ 10.67 (s, 1H), 9.23 (s, 2H), 7.78−7.75 (m, 2H), 7.25 (t, J=8.8 Hz, 2H).
化合物2(1.486g、5.04mmol)、4−ブロモ−N−メチルベンジルアミン(1.00mL、5.00mmol)およびトリエチルアミン(1.40mL、10.0mmol)を、N2雰囲気下、無水ジメチルホルムアミド(10mL)に溶解し、耐圧瓶に入れた。反応物を130℃で3日間加熱した。反応物を室温まで冷却し、脱イオン水(250mL)で希釈し、わずかに褐色の塊を含む綿状の白色沈殿を得た。短時間で冷却後、該塊をソニケーションおよび圧砕し、沈殿を真空濾過により集め、脱イオン水で洗浄し、真空下で乾燥させた。粗生成物を酢酸エチルに溶解し、シリカゲル(20g)に付着させた。シリカに付着した化合物をフラッシュシリカゲルクロマトグラフィー(200g シリカ、3:2 ヘキサン:酢酸エチル)により精製して、1.67g(81%)の化合物14を白色固体として得た。ESI−MS m/z 414.1/416.1 [M+H]+。分析:C20H17BrFN3Oについての計算値:C、57.98;H、4.14;N、10.14。実測値:C、57.82;H、4.20;N、10.01。 1H NMR (500 MHz, DMSO−d6) δ 10.04 (s, 1H), 8.72 (s, 1H), 8.07 (d, J=9.3 Hz, 1H), 7.77−7.75 (m, 2H), 7.53 (d, J=7.0 Hz, 2H), 7.20−7.16 (m, 4H), 6.76 (d, J=9.7 Hz, 1H), 4.86 (s, 2H), 3.11 (s, 3H).
化合物12(254mg、1.01mmol)、4−ブロモ−N−メチルベンジルアミン(200μL、1.00mmol)およびトリエチルアミン(280μL、2.01mmol)を、N2雰囲気下、無水ジメチルホルムアミド(2mL)に溶解し、耐圧瓶に入れた。反応物を室温で3時間撹拌し、次いで脱イオン水(60mL)に滴下して希釈し、綿状の白色沈殿を得た。短時間で冷却後、沈殿を真空濾過により集め、脱イオン水で洗浄し、真空下で乾燥させて、410mg(99%)の化合物15を白色固体として得た。ESI−MS m/z 415.1/417.1 [M+H]+。1H NMR (500 MHz, DMSO−d6) δ 10.16 (s, 1H), 8.90 (s, 1H), 7.75−7.73 (m, 2H), 7.54 (d, J=8.6 Hz, 2H), 7.23−7.17 (m, 4H), 4.92 (s, 2H), 3.18 (s, 3H).
化合物14(1.65g、4.0mmol)を、無水ジメチルホルムアミド(10mL)に溶解し、真空下で脱気した。耐圧瓶にPdCl2(dppf)(244mg、0.299mmol)、ビス(ピナコラト)ジボロン(3.05g、12.0mmol)および酢酸カリウム(1.17g、11.9mmol)を、撹拌子と共に入れた。DMF溶液をオーブン乾燥させたピペットで該耐圧瓶に添加し、乾燥DMF(2x5mL)で
濯いだ。該耐圧瓶を窒素ガス下で密封し、80℃で8.5時間加熱し、次いで室温まで冷却した。反応物をセライトを通して濾過し、DMFで濯ぎ、真空下で乾燥させて、水と酢酸エチルの間に分配させて、水層を酢酸エチルで洗浄した。合わせた酢酸エチル層をNa2SO4で乾燥させ、シリカゲルパッド(酢酸エチル)を通して濾過した。濾液を真空下で乾燥させ、酢酸エチルに溶解し、シリカゲル(20g)に付着させた。シリカに付着した化合物をフラッシュシリカゲルクロマトグラフィー(200g、2:1 ヘキサン:酢酸エチル)により精製して、1.67g(91%)の化合物16を白色のフレーク状固体として得た。ESI−MS m/z 462.3 [M+H]+。1H NMR (500 MHz, DMSO−d6) δ 10.03 (s, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.06 (dd, J=9.2 Hz, 2.5 Hz, 1H), 7.77−7.74 (m, 2H), 7.65 (d, J=7.2 Hz, 2H), 7.24 (d, J=7.2 Hz, 2H), 7.17 (t, J=8.9 Hz, 2H), 6.75 (d, J=8.8 Hz, 1H), 4.91 (s, 2H), 3.11 (s, 3H), 1.28 (s, 12H).
化合物15(395mg、0.951mmol)を、無水ジメチルホルムアミド(4mL)に溶解し、真空下で脱気した。耐圧瓶にPdCl2(dppf)(60mg、0.074mmol)、ビス(ピナコラト)ジボロン(726mg、2.86mmol)および酢酸カリウム(280mg、2.85mmol)を、撹拌子と共に入れた。DMF溶液をオーブン乾燥させたピペットを用いて該耐圧瓶に加え、乾燥DMF(2x2mL)で濯いだ。該耐圧瓶を窒素ガス下で密封し、80℃で6.5時間加熱し、次いで室温まで冷却した。反応物をセライトを通して濾過し、DMFで濯ぎ、真空下で乾燥させ、水と酢酸エチルの間に分配させ、水層を酢酸エチルで洗浄した。合わせた酢酸エチル層をNa2SO4で乾燥させ、シリカゲルパッド(酢酸エチル)を通して濾過した。濾液を真空下で乾燥させ、酢酸エチルに溶解し、シリカゲル(7.5g)に付着させた。シリカに付着した化合物をフラッシュシリカゲルクロマトグラフィー(78g、5:2 ヘキサン:酢酸エチル)により精製して、379mg(86%)の化合物17を白色固体として得た。ESI−MS m/z 463.2 [M+H]+。 1H NMR (500 MHz, DMSO−d6) δ 10.15 (s, 1H), 8.90 (s, 2H), 7.75−7.72 (m, 2H), 7.66 (d, J=7.6 Hz, 2H), 7.26 (d, J=7.6 Hz, 2H), 7.19 (t, J=8.9 Hz, 2H), 4.98 (s, 2H), 3.17 (s, 3H), 1.28 (s, 12H).
化合物16(1.64g、3.55mmol)を撹拌しながらメタノール(50mL)中に懸濁し、4.5M KHF2(4.0mL、18.0mmol)をピペットで少しずつ滴下した。1.5時間撹拌後、反応物をメタノールで希釈し、真空下で乾燥させて、白色固体を得て、それを水で希釈した。ソニケーションにより沈殿を得て、それを真空濾過により単離し、減圧デシケーター中で乾燥させた。固体(1.43g、3.25mmol)をアセトニトリル(36mL)中に溶解し、トリメチルシリルクロライド(1.24mL、9.77mmol)および水(176μL、9.78mmol)と共に室温で撹拌した。1.5時間撹拌後、反応を飽和重炭酸ナトリウム(6mL)を用いてクエンチした。数分の撹拌後、反応物を水で希釈して化合物を溶解し、真空下で乾燥させた。残った固体をソニケーションしながら水に懸濁し、形成した沈殿を真空濾過により単離し、減圧デシケーター中で乾燥させて、化合物18を白色固体(1.33g、99%)として得た。ESI−MS m/z 380.2 [M+H]+。1H NMR (500 MHz, DMSO−d6) δ 10.10 (s, 1H), 8.72 (s, 1H), 8.11 (d, J=8.6 Hz, 1H), 7.76−7.75 (m, 4H), 7.20−7.16 (m, 4H), 6.84 (d, J=8.5 Hz, 1H), 4.90 (s, 2H), 3.15 (s, 3H)。全細胞アッセイにおけるIC50(薬理実施例1)=0.247±0.035μM.
化合物17(365mg、0.789mmol)を、撹拌しながらメタノール(7mL)中に懸濁し、4.5M KHF2(0.88mL、3.96mmol)をピペットで少しずつ添加した。1.5時間撹拌後、反応物をメタノールで希釈し、真空下で乾燥させて白色固体を得て、それを水で希釈した。ソニケーションして沈殿を得て、それを真空濾過により単離し、減圧デシケーター中で乾燥させた。固体(322mg、0.728mmol)をアセトニトリル(6mL)に溶解し、トリメチルシリルクロライド(276μL、2.18mmol)および水(40μL、2.22mmol)と共に室温で撹拌した。1.5時間撹拌後、反応を飽和重炭酸ナトリウム(1.3mL)でクエンチした。数分の撹拌後、反応物を真空下で濃縮し、ソニケーションしながら水(40mL)に懸濁して、綿状の白色固体を得て、それを真空濾過により単離し、減圧デシケーター中で乾燥させて、化合物19を白色固体(280mg、93%)として得た。ESI−MS m/z 381.2 [M+H]+。 1H NMR (500 MHz, DMSO−d6) δ 10.16 (s, 1H), 8.91 (s, 2H), 7.76−7.73 (m, 4H), 7.21−7.17 (m, 4H), 4.96 (s, 2H), 3.18 (s, 3H)。全細胞アッセイにおけるIC50(薬理実施例1)=0.244±0.015μM.
インビトロでのアッセイは、化合物9での処理によるCXCR2仲介細胞内カルシウム放出の阻害を示した(IC50=586±91nM)。簡単には、ヒト好中球細胞を、10mM HEPESおよびFLIPR カルシウム 3 ダイを含むHBSS−(Ca2+およびMg2+不含有)に懸濁した(全量1.7mL中、3.1x107細胞)。細胞をアリコートに分け(チューブ1本当たり200μLの細胞懸濁液、全8本のチューブ)、2μLの化合物9(適当に希釈して)を6本のチューブにそれぞれ添加した。化合物9の試験濃度は、156nM、312nM、625nM、1250nM、2500nMおよび5000nMであった。対照として、2μLのDMSO(1%終濃度)を別の2本のチューブに添加した。細胞を、37℃で30分間インキュベートした。ダイを添加後、チューブを6,000rpmで1分間遠心し、上清を除去し、細胞ペレットを、10mM HEPESを含む200μLのHBSS+(Ca2+およびMg2+含有)に再懸濁した。試験化合物またはDMSO(対照)を、上記の細胞処理中に用いたのと同じ濃度で再び添加した。細胞懸濁液を、96ウェル読み出しプレート(Corning)に90μL容量(105細胞/ウェル)で分けた。化合物プレートは、アゴニスト(HBSS−中、GROα)またはHBSS−(対照)を含んだ。FlexStation IIによる蛍光の基準レベルの15秒の読み出し後、10μLのGROαまたはHBSS−を、化合物プレートから読み出しプレートへ自動的に移した(GROαの終濃度は25nMであった)。蛍光変化を、240ないし500秒間、5秒毎に室温で測定した(λex=485nm、λem=525nm)。
Claims (13)
- 式(1):
R3は、メチルであり;
R4は、−R7−B(R5R6)、−R7−OH、−R7−ORまたは−R7−OC(O)Rであり;
R7は、フェニルであり;
R5およびR6は、いずれもヒドロキシルであり、それらが結合するホウ素原子と一体となって、環状ボロン酸エステルを形成してもよく;
RはC1−C6低級アルキルである]
で示される化合物。 - R4が4−ジヒドロキシボリルフェニルである、請求項1に記載の化合物。
- 式(1):
R3は、メチルであり;
R4は、−R7−B(R5R6)、−R7−OH、−R7−ORまたは−R7−OC(O)Rであり;
R7は、フェニルであり;
R5およびR6は、いずれもヒドロキシルであり、それらが結合するホウ素原子と一体となって、環状ボロン酸エステルを形成してもよく;
RはC1−C6低級アルキルである]
で示される化合物を含む医薬組成物。 - R4が4−ジヒドロキシボリルフェニルである、請求項3に記載の医薬組成物。
- 式(2):
R3は、メチルであり;
R4は、−R7−B(R5R6)、−R7−OH、−R7−ORまたは−R7−OC(O)Rであり;
R7は、フェニルであり;
R5およびR6は、いずれもヒドロキシルであり、それらが結合するホウ素原子と一体となって、環状ボロン酸エステルを形成してもよく;
RはC1−C6低級アルキルである]
で示される化合物。 - R4が4−ジヒドロキシボリルフェニルである、請求項5に記載の化合物。
- 式(2):
R3は、メチルであり;
R4は、−R7−B(R5R6)、−R7−OH、−R7−ORまたは−R7−OC(O)Rであり;
R7は、フェニルであり;
R5およびR6は、いずれもヒドロキシルであり、それらが結合するホウ素原子と一体となって、環状ボロン酸エステルを形成してもよく;
RはC1−C6低級アルキルである]
で示される化合物を含む医薬組成物。 - R4が4−ジヒドロキシボリルフェニルである、請求項7に記載の医薬組成物。
- 下記式で示される化合物SX-626、SX-628、SX-632およびSX-633から成る群より選択される化合物:
- 下記式で示される化合物SX-626、SX-628、SX-632およびSX-633から成る群より選択される化合物を含む医薬組成物:
- 患者の疾患または障害を処置するための、請求項3、4、7、8および10のいずれかに記載の医薬組成物。
- 疾患または障害が、喘息、気管支肺異形成症、COPD、成人呼吸器疾患、急性呼吸窮迫症候群、嚢胞性線維症、気流閉塞、気道過敏症、気管支拡張症、細気管支炎、閉塞性細気管支炎、慢性気管支炎、肺性心、肺線維症、末梢気道病変、呼吸困難、肺気腫、高炭酸ガス血症、低酸素血症、高酸素状態により誘発される炎症、低酸素症、肺性高血圧、換気−血流ミスマッチ、喘鳴、および風邪から成る群より選択される、請求項11に記載の医薬組成物。
- 疾患または障害が、疼痛、急性炎症、慢性炎症、関節リウマチ、乾癬、アトピー性皮膚炎、関節炎、炎症性腸疾患、クローン病、潰瘍性大腸炎、敗血症ショック、内毒素ショック、グラム陰性敗血症、毒素ショック症候群、脳卒中、虚血再灌流傷害、腎臓の再灌流傷害、糸球体腎炎、血栓症、アルツハイマー病、移植片対宿主反応、同種移植片拒絶反応、マラリア、急性呼吸窮迫症候群、遅延型過敏反応、アテローム性動脈硬化症、脳の虚血、心臓の虚血、骨関節症、多発性硬化症、再狭窄、血管形成、腫瘍増殖と関連する血管形成、骨粗鬆症、歯肉炎、呼吸器ウイルス感染症、疱疹ウイルス感染症、肝炎ウイルス感染症、HIV感染症、カポジ肉腫関連ウイルス感染症、髄膜炎、嚢胞性線維症、早期分娩、咳、掻痒症、多臓器不全、外傷、挫傷、捻挫、打撲傷、乾癬性関節炎、疱疹、脳炎、CNS血管炎、外傷性脳傷害、全身腫瘍、CNS腫瘍、増殖が血管形成に依存する腫瘍、白血球減少症および好中球減少症、化学療法誘発性白血球減少症および好中球減少症、好中球減少症または白血球減少症と関係のある日和見感染症、くも膜下出血、術後外傷、間質性肺炎、過敏症、結晶誘発性関節炎、急性膵炎、慢性膵炎、急性アルコール性肝炎、壊死性腸炎、慢性副鼻腔炎、血管新生眼疾患、眼の炎症、未熟児網膜症、糖尿病性網膜症、黄斑変性症、角膜血管新生、多発性筋炎、血管炎、ざ瘡、胃潰瘍、十二指腸潰瘍、セリアック病、食道炎、舌炎、右心室肥大、持続的携行式腹膜透析(CAPD)に関連した腹膜炎、顆粒球のエールリッヒ症、サルコイドーシス、痛風、アルコール性肝疾患、狼瘡、火傷治療、歯周病、癌、移植再灌流傷害、および早期移植拒絶からなる群より選択される、請求項11に記載の医薬組成物。
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- 2011-08-22 JP JP2013526073A patent/JP6486002B2/ja active Active
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- 2011-08-22 WO PCT/US2011/048668 patent/WO2012027289A1/en active Application Filing
- 2011-08-22 US US13/215,014 patent/US8779149B2/en not_active Ceased
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US20140256678A1 (en) | 2014-09-11 |
USRE47740E1 (en) | 2019-11-26 |
AU2011293612B2 (en) | 2015-11-26 |
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EP2608672A4 (en) | 2016-05-25 |
EP2608672B1 (en) | 2020-12-16 |
EP2608672A1 (en) | 2013-07-03 |
JP2013536234A (ja) | 2013-09-19 |
US8993541B2 (en) | 2015-03-31 |
WO2012027289A1 (en) | 2012-03-01 |
AU2011293612A1 (en) | 2013-04-11 |
JP2016164177A (ja) | 2016-09-08 |
CA2811990C (en) | 2023-03-21 |
CA2811990A1 (en) | 2012-03-01 |
US20120046243A1 (en) | 2012-02-23 |
JP2019069946A (ja) | 2019-05-09 |
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