JP5161873B2 - (2r)−2−[(4−スルホニル)アミノフェニル]プロパンアミド類と、それらを含有する医薬組成物 - Google Patents
(2r)−2−[(4−スルホニル)アミノフェニル]プロパンアミド類と、それらを含有する医薬組成物 Download PDFInfo
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- JP5161873B2 JP5161873B2 JP2009510463A JP2009510463A JP5161873B2 JP 5161873 B2 JP5161873 B2 JP 5161873B2 JP 2009510463 A JP2009510463 A JP 2009510463A JP 2009510463 A JP2009510463 A JP 2009510463A JP 5161873 B2 JP5161873 B2 JP 5161873B2
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- phenyl
- amino
- propanamide
- sulfonyl
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Description
本発明は、フェニル基の4−位置に4−スルホニルアミノ置換基を有する、新規な(2R)−2−フェニルプロパンアミド類と、それらを含有し、多形核細胞及び単核細胞の走化性の阻害剤として用いられ、種々なELR+CXCケモカイン仲介障害の治療に有用である医薬組成物に関する。特に、本発明の化合物は、例えばBOS、COPD、血管新生及び黒色腫のような、特定のCXCR2依存性の病状(CXCR2 dependent pathologies)の治療及び制御に有用である。
ケモカインは、7TM−GPCRsファミリーに属する受容体との相互作用を介して、それらの作用を発揮する化学走化性サイトカインの大きなファミリーを構成する。ケモカイン系は、恒常性及び炎症性の基底白血球運動の調節及び制御のために極めて重要である。ケモカイン受容体活性化の機能的結果は、白血球の移動運動(leukocyte locomotion)、デグラニュレーション(degranulation)、遺伝子転写、細胞分裂効果及びアポトーシス効果apoptotic effect)を包含する。造血細胞以外の多くの細胞種類が、ケモカイン受容体を発現し;これらの細胞は、内皮細胞、平滑筋細胞、間質細胞、神経細胞及び上皮細胞を包含する。これらの細胞の活性化は、腫瘍発生及び転移の他に、例えば、器官形成中の血管形成及び形態形成運動のような、組織調節及びホメオスタシスの他の態様に、へケモカイン受容体活性化の関与を広げる。
肺疾患(肺損傷、急性呼吸窮迫症候群、喘息、慢性肺炎症及び嚢胞性線維症)における、特に、COPD(慢性閉塞性肺疾患)の病因におけるCXCR2経路を介してのCXCL8の可能な病原的役割は既に述べられている[Barnes PJ., Cytokine Growth Factor Rev., 14, 511, 2003]。抗CXCL8抗体は、COPD喀痰に対する走化性反応に阻害効果を有する[Hill A.T. et al, Am. J. Respir. Crit. Care med., 160, 893, 1999]。多くの炎症細胞とメディエーターを含む末梢気道上の炎症を特徴とする疾患である。これは、気道及び組織中のマクロファージ数の増加を含めた炎症細胞流入増加(increased inflammatory cell influx)を付随する。肺胞マクロファージは単球から成長し(develop)、COPDに関連した病理学的変化を惹起する能力を有する。循環からの単球の補充(recruitment)の結果として、COPDにおけるマクロファージ数の増加が報告されている。COPD患者からの末梢血単核細胞の走化性アッセイは、GRO−α(MCP−1、CXCL8若しくはNAP(ENA)−78ではなく)に対する制御と比較した場合に、走化性反応の増強を示す[Traves S. L. et al., J. Leuk. Biol, 76, 441, 2004]。この反応は、細胞受容体CXCR1とCXCR2の発現の差によって仲介されるのではなく、COPD患者においては、CXCR2の単球発現が異なる形式で調節される:CXCR1は高濃度のCXCL8に反応して、好中球の活性化及びスーパーオキシド・アニオンと好中球エラスターゼの放出の原因となるが、他方では、CXCR2は低濃度のCXCケモカインに反応して、走化性反応に関与する。例えばSB225002のような、CXCR2の強力なSMW分子阻害剤が現在、CXCL8及びGRO−αに対する好中球の走化性反応の遮断薬として開発されている。この拮抗薬は、GRO−αの濃度が高いCOPD喀痰に対する走化性反応に有意な阻害効果を及ぼす[Traves S.L., et al., Thorax, 57, 590, 2002]。それ故、CXCR2拮抗薬は、COPD患者における単球走化性とマクロファージ蓄積を低下させる可能性もある。この結果は、COPDの治療と肺損傷の抑制における選択的CXCR2対CXCR1 SMW拮抗薬の可能性を強調する。
本発明においては、フェニル基の4位置に4−スルホニルアミノ置換基を有する、新規な種類の(2R)−2−フェニルプロパンアミドと、それらを含有する医薬組成物を開示する、該医薬組成物は、多形核細胞及び単核細胞の走化性の阻害剤として用いられ、種々なELR+CXCケモカイン仲介障害(COPDとしての急性炎症性疾患のような)の治療に又は悪性黒色腫のような腫瘍形成をもたらしうるELR+CXCケモカイン仲介血管新生の治療に有用である可能性を秘めている。これらの化合物は、R’環置換基の化学的特性のための良好な水溶性を特徴とし、R残基の性質から独立している。このような置換基の例は、アルキルスルホニルアミノ基、アリールスルホニルアミノ基及びヘテロアリールスルホニルアミノ基である。上記アミドの一部は、GRO−α誘導走化性に対して良好な特異性を発揮する、既述した2−アリールプロピオン酸から誘導される。意外にも、アミドへの該酸の化学的修飾は、CXCR1受容体に対しては活性を有さず、CXCR2に対しては強化された活性を有する、新規な化合物を得ることを可能にしている。上記新規なアミドのCXCR2に対する選択性は、CXCL8に応答したCXCR1/L1.2及びCXCR2/L1.2トランスフェクタント遊走の阻害の実験によって評価されている。表1に報告するデータは、該化合物がIC50 約10−8Mを有する、CXCL1誘導hPMN走化性の強力な阻害剤であることを示している。これに対して、同化合物は10−7M濃度ではCXCL8誘導hPMN走化性を顕著には阻害しない。これらの結果は、CXCL8によって誘導される走化性促進にCXCR1が果たす主要な役割と一致する。これと一致して、選択性アッセイにおいて、該化合物は10−6MまでCXCL8に反応したCXCR1/L1.2トランスフェクタント遊走に対する有意な阻害活性を示さない。
序論で上述したことに基づくと、腫瘍領域(特に、黒色腫)及び肺領域(COPD、BOS)におけるCXCR2依存性病理の治療における、この新規な種類の化合物の可能な役割が明らかである。
本出願人らは、現在、多形核細胞及び単核細胞の走化性の阻害剤としての(2R)−2−フェニルプロパンアミドの新規な種類を見出している。特に、本発明の該化合物は、改良された薬物動態的及び薬理学的活性プロフィルを有する、CXCL1誘導好中球走化性の強力な阻害剤である。
Rは、H、OH、C1−C5アルキル、C3−C6シクロアルキル、C2−C5アルケニル、C1−C5アルコキシ及びフェニル;ヘテロアリール基(置換及び非置換のピロール、チオフェン、フラン、インドール、イミダゾール、チアゾール、オキサゾール、ピリジン及びピリミジンから選択される);及び式:−CH2−CH2−O−(CH2−CH2O)nR”[式中、R”はH若しくはC1−C5アルキルであり、nは0〜2の整数である]で示される残基から選択されるか、又はRは、それが結合するNH基と共に、例えば(2S)−2−アミノプロパンアミド、(2S)−2−アミノ−3−フェニルプロパンアミド、(2S)−2−アミノ−3−ヒドロキシプロパンアミド、(2S)−2−アミノ−3−カルボキシプロパンアミド、(2S)−2,6−ジアミノエキサンアミドのような天然アミノ酸の第1級アミドのラジカル基である。天然アミノ酸の第1級アミドのラジカル基の一部としての上記NH基は、該天然アミノ酸のアミノ基を表す。
R’は、直鎖若しくは分枝鎖のC1−C5アルキル、C3−C6シクロアルキル、C2−C5アルケニル及びトリフルオロメチル;置換若しくは非置換のフェニル;置換若しくは非置換のベンジル;及びヘテロアリール基(置換及び非置換のピリジン、ピリミジン、ピロール、チオフェン、フラン、インドール、チアゾール及びオキサゾールから選択される)から選択される。
1:(2R)−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}プロパンアミド;
2:(2R)−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}プロパンアミド・ナトリウム塩;
3:(2R)−2−(4−{[(2−クロロフェニル)スルホニル]アミノ}フェニル)プロパンアミド;
4:(2R)−2−(4−{[(2,6−ジクロロフェニル)スルホニル]アミノ}フェニル)プロパンアミド;
5:(2R)−2−{4−[(メチルスルホニル)アミノ]フェニル}プロパンアミド;
6:(2R)−2−{4−[(フェニルスルホニル)アミノ]フェニル}プロパンアミド;
7:(2R)−2−(4−{[(4−メチルフェニル)スルホニル]アミノ}フェニル)プロパンアミド;
8:(2R)−2−(4−{[(4−メトキシルフェニル)スルホニル]アミノ}フェニル)プロパンアミド;
9:(2R)−2−{4−[(ベンジルスルホニル)アミノ]フェニル}プロパンアミド;
10:(2R)−2−(4−{[(4−クロロフェニル)スルホニル]アミノ}フェニル)プロパンアミド;
11:(2R)−2−(4−{[(4−(トリフルオロメチル)フェニル)スルホニル]アミノ}フェニル)プロパンアミド;
12:(2R)−2−{4−[(チエン−2−イルスルホニル)アミノ]フェニル}プロパンアミド;
13:(2R)−2−{4−[(シクロペンチルスルホニル)アミノ]フェニル}プロパンアミド;
14:(2R)−2−(4−{[(トリフルオロメチル)スルホニル]アミノ}フェニル)プロパンアミド;
15:(2R)−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}−N−メチルプロパンアミド;
16:(2R)−N−[(1S)−2−アミノ−1−メチル−2−オキソエチル]−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}プロパンアミド;
17:(2R)−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}−N−[4−(トリフルオロメチル)−1,3−チアゾル−2−イル]プロパンアミド;
18:(2R)−2−(4−{[(2−クロロフェニル)スルホニル]アミノ}フェニル)−N−[4−(トリフルオロメチル)−1,3−チアゾル−2−イル]プロパンアミド;
19:(2R)−2−(4−{[(2−クロロフェニル)スルホニル]アミノ}フェニル)−N−[2−(2−ヒドロキシエトキシ)エチル]プロパンアミド;
20:(2R)−2−(4−{[(2−クロロフェニル)スルホニル]アミノ}フェニル)−N−シクロプロピルプロパンアミド。
本発明の化合物は、CXCL1によって誘導されるヒトPMNs走化性の強力な阻害剤である。
これらの塩基の例は、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、(D,L)−リシン、L−リシン、トロメタミンである。
本発明の化合物は、実際には、慣用的に用いられるアジュバンド、キャリヤー、希釈剤又は賦形剤と共に、医薬組成物の形態及びその単位投与形にすることができ、このような形態で、全て経口的使用のための固体(例えば、錠剤若しくは充填カプセル)又は液体(例えば、溶液、懸濁液、エマルジョン、エリキシル剤若しくはこれらを充填したカプセル)として用いることができる、或いは非経口的(皮下を含む)使用のための無菌注射用溶液の形態で用いることができる。このような医薬組成物とその単位投与形は、付加的な活性化合物若しくは有効成分(active principles)の有無に拘わらず、慣用的な割合で成分を含むことができ、このような単位投与形は、用いるべき予定の1日投与量範囲に相応した、任意の適当な有効量の有効成分を含有することができる。
(2R)−2−(4−ニトロフェニル)プロパン酸(6g,30.6mmol)を乾燥CH2Cl2(80ml)中に溶解して、1,1−カルボニルジイミダゾール(5.58g,34.41mmol)を加えて、得られた溶液を室温において2時間撹拌した。次に、IR分析によってチェックして、中間体が完全に消失するまで(8時間)、ガス状アンモニアを該溶液中にバブルさせた。該有機溶液に、NH4Clの飽和溶液(20ml)を加えて、2相をディベートさせ(debated)、分離させた。有機相を再び水(2x25ml)で洗浄し、Na2SO4上で乾燥させ、濾過し、真空下で蒸発させて、(2R)−2−(4−ニトロフェニル)プロパンアミドを白色固体(5.1g,26.15mmol)として得た。
(2R)−2−(4−アミノフェニル)プロパンアミド(0.5g,3.05mmol)をピリジン(2ml)中に溶解し、2−プロパンスルホニルクロリド(0.53ml,3.66mmol)を加えた。得られた溶液を4時間還流させ、室温において一晩放置した。出発アミドが完全に消失した後に、該溶液をEt2O(10ml)で希釈して、有機層を1N HCl(2x5ml)及びH2O(2x5ml)で洗浄し、Na2SO4上で乾燥させ、濾過し、真空下で蒸発させて、(2R)−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}プロパンアミドを淡黄色固体(667mg,2.47mmol)として得た。収率81%.mp125〜127℃:
(2R)−2−(4−{[(2−クロロフェニル)スルホニル]アミノ}フェニル)プロパンアミド(2);ワックス状固体;
WO 03/042625に記載されたとおりに製造した(2R)−2−{[4−(イソプロピルスルホニルアミノ)フェニル]}プロパン酸(0.65g,2.4mmol)をCH2Cl2(8ml)中に溶解して;N−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド塩酸塩(WSC)(0.46g,2.4mmol)と1−ヒドロキシベンゾトリアゾール水和物(HOBT)(0.324g,2.4mmol)を加えて、得られた混合物を室温において30分間撹拌状態に放置した。次に、CH2Cl2(2ml)中の塩酸メチルアミン(0.155g,2.43mmol)とトリエチルアミン(0.33ml,2.4mmol)との混合物を滴加し、得られた混合物を室温において一晩撹拌状態に放置した。該混合物をCH2Cl2(10ml)で希釈し、有機層を1N HCl(2x10ml)とH2O(2x10ml)で洗浄し、Na2SO4上で乾燥させ、濾過し、真空下で蒸発させて、(2R)−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}−N−メチルプロパンアミドをワックス状固体(0.63g,2.23mmol)として得た。収率93%.
で示されるプロパン酸から出発して、下記アミド類を製造した:
(2R)−N−[(1S)−2−アミノ−1−メチル−2−オキソエチル]−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}プロパンアミド(15);白色粉末;mp.132〜135℃;
(2R)−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}プロパンアミド(1)(500mg,1.85mmol)をCH3OH(15ml)中に溶解した。NORMEX IN NaOH(1.85ml,1.85mmol)を滴加し、得られた溶液を室温において2時間撹拌状態に放置した。溶媒を蒸発させた後に、水(3ml)を加えて、透明な溶液を凍結させ、次に、凍結乾燥させて、(2R)−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}プロパンアミド・ナトリウム塩(541mg,1.85mmol)を淡黄色粉末として得た。定量的収率。
表1において、本発明の典型的な化合物の生物学的活性を報告する。
表1
Claims (9)
- 式(I):
Rは、H、C1−C5アルキル、C3−C6シクロアルキル;非置換のチアゾール、若しくはトリフルオロメチルで置換されたチアゾール;及び式:−CH2−CH2−O−(CH2−CH2O)nR”[式中、R”はHであり、nは0〜2の整数である]で示される残基から選択されるか、又はRは、それが結合するNH基と共に、(2S)−2−アミノプロパンアミドである;
R’は、直鎖若しくは分枝鎖のC1−C5アルキル、C3−C6シクロアルキル、及びトリフルオロメチル;非置換のフェニル若しくは、ハロゲン、C 1 −C 4 アルキル、C 1 −C 4 アルコキシ及びトリフルオロメチルから選択される置換基で置換されたフェニル;非置換のベンジル;及び非置換のチオフェンから選択される。 - (2R)−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}プロパンアミド;
(2R)−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}プロパンアミド・ナトリウム塩;
(2R)−2−(4−{[(2−クロロフェニル)スルホニル]アミノ}フェニル)プロパンアミド;
(2R)−2−(4−{[(2,6−ジクロロフェニル)スルホニル]アミノ}フェニル)プロパンアミド;
(2R)−2−{4−[(メチルスルホニル)アミノ]フェニル}プロパンアミド;
(2R)−2−{4−[(フェニルスルホニル)アミノ]フェニル}プロパンアミド;
(2R)−2−(4−{[(4−メチルフェニル)スルホニル]アミノ}フェニル)プロパンアミド;
(2R)−2−(4−{[(4−メトキシルフェニル)スルホニル]アミノ}フェニル)プロパンアミド;
(2R)−2−{4−[(ベンジルスルホニル)アミノ]フェニル}プロパンアミド;
(2R)−2−(4−{[(4−クロロフェニル)スルホニル]アミノ}フェニル)プロパンアミド;
(2R)−2−(4−{[(4−(トリフルオロメチル)フェニル)スルホニル]アミノ}フェニル)プロパンアミド;
(2R)−2−{4−[(チエン−2−イルスルホニル)アミノ]フェニル}プロパンアミド;
(2R)−2−{4−[(シクロペンチルスルホニル)アミノ]フェニル}プロパンアミド;
(2R)−2−(4−{[(トリフルオロメチル)スルホニル]アミノ}フェニル)プロパンアミド;
(2R)−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}−N−メチルプロパンアミド;
(2R)−N−[(1S)−2−アミノ−1−メチル−2−オキソエチル]−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}プロパンアミド;
(2R)−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}−N−[4−(トリフルオロメチル)−1,3−チアゾル−2−イル]プロパンアミド;
(2R)−2−(4−{[(2−クロロフェニル)スルホニル]アミノ}フェニル)−N−[4−(トリフルオロメチル)−1,3−チアゾル−2−イル]プロパンアミド;
(2R)−2−(4−{[(2−クロロフェニル)スルホニル]アミノ}フェニル)−N−[2−(2−ヒドロキシエトキシ)エチル]プロパンアミド;
(2R)−2−(4−{[(2−クロロフェニル)スルホニル]アミノ}フェニル)−N−シクロプロピルプロパンアミド
から選択される請求項1に記載の化合物。 - (2R)−2−{4−[(イソプロピルスルホニル)アミノ]フェニル}プロパンアミド又はそのナトリウム塩である、請求項1又は2に記載の化合物。
- 請求項1〜3のいずれかに記載の化合物を含む薬剤。
- 請求項1〜3のいずれかに記載の化合物を含む、CXCL1誘導ヒトPMNs走化性を必要とする疾患の治療のための薬剤。
- 請求項1〜3のいずれかに記載の化合物を含む、黒色腫、血管新生、慢性閉塞性肺疾患(COPD)又は閉塞性細気管支炎症候群(BOS)の治療のための薬剤。
- 請求項1〜3のいずれかに記載の化合物をその適当なキャリヤーとの混合物として含む薬剤。
- (2R)−2−(4−アミノフェニル)プロパンアミドと、式:R’SO2Cl[式中、R’は請求項1で定義した意味と同じ意味を有する]で示される塩化スルホニルとの反応を含む、請求項1記載の式(I)で示される化合物の製造方法。
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PCT/EP2007/054806 WO2007135080A2 (en) | 2006-05-18 | 2007-05-17 | (2r)-2-[(4-sulfonyl)aminophenyl]propanamides and pharmaceutical compositions containing them |
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KR101298651B1 (ko) * | 2011-03-16 | 2013-08-21 | 연세대학교 산학협력단 | 효능이 강화된 혈관신생 억제용 약제학적 조성물 |
CN103159674A (zh) * | 2013-04-03 | 2013-06-19 | 苏州安诺生物医药技术有限公司 | 2-苯烷酰胺类化合物及其制备方法、药物组合物和用途 |
EP3011012B1 (en) | 2013-06-18 | 2018-09-12 | New York University | Cellular factors involved in the cytotoxicity of staphylococcus aureus leukocidins: novel therapeutic targets |
AU2015295507A1 (en) * | 2014-07-31 | 2017-02-02 | Glaxosmithkline Intellectual Property Development Limited | Use of CXCR2 antagonists for the prevention and/or treatment of chemotherapy induced peripheral neuropathy (cipn) |
EP3884932A1 (en) | 2020-03-26 | 2021-09-29 | Dompe' Farmaceutici S.P.A. | Cxcl8 inhibitors for use in the treatment of covid-19 |
EP4008325A1 (en) | 2020-12-02 | 2022-06-08 | Dompe' Farmaceutici S.P.A. | Cxcl8 inhibitors for use in the treatment of covid-19 |
CN115397404A (zh) | 2020-03-26 | 2022-11-25 | 东佩制药股份公司 | 用于治疗covid-19的cxcl8抑制剂 |
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