JP2008504303A - イミダゾロ関連化合物、組成物、及びその使用方法 - Google Patents
イミダゾロ関連化合物、組成物、及びその使用方法 Download PDFInfo
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- JP2008504303A JP2008504303A JP2007518381A JP2007518381A JP2008504303A JP 2008504303 A JP2008504303 A JP 2008504303A JP 2007518381 A JP2007518381 A JP 2007518381A JP 2007518381 A JP2007518381 A JP 2007518381A JP 2008504303 A JP2008504303 A JP 2008504303A
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- compound
- alkyl
- aryl
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- heteroalkyl
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Abstract
Description
本発明は、CXCR3受容体の新規モジュレーター、新規化合物を含む組成物、並びにリウマチ様関節炎、多発性硬化症、炎症性腸疾患、乾癬、アテローム性動脈硬化症など、喘息、アレルギー性疾患、及び自己免疫疾患を含めて、炎症性及び免疫調節性の障害及び疾患の治療のためのその使用方法に関する。
ケモカインは、マクロファージ、T細胞、好酸球、好塩基球、及び好中球を炎症部位に誘引するため広範囲の細胞から放出される化学走性サイトカインである(Schall, Cytokine, 3:165-183 (1991)、Schallら、Curr. Opin. Immunol., 6:865-873 (1994)、及びMurphy, Rev. Immun., 12:593-633 (1994)に概説されている)。応答細胞のケモカインにより、化学走性の刺激に加えて、細胞形状の変化、細胞内遊離カルシウムイオン([Ca2+])i濃度の一時的上昇、顆粒の開口分泌、インテグリンのアップレギュレーション、生物活性脂質(例えば、ロイコトリエン)の形成、及び呼吸バーストを含めて、白血球活性化を伴う他の変化が選択的に誘導される恐れがある。したがって、ケモカインは、感染又は炎症の部位への炎症性メディエータの放出、化学走化、及び血管外遊走を引き起こす、炎症反応の早期トリガーである。
本発明は、喘息、乾癬、炎症性腸疾患、アレルギー性疾患、及びリウマチ様関節炎や多発性硬化症などの自己免疫疾患を含めて、いくつかの炎症性及び免疫調節性の障害及び疾患の治療又は予防に有用である化合物を提供する。本明細書に提供される化合物は、一般式(I)を有する:
別の態様では、本発明は、式(I)の化合物、及び薬剤として許容できる賦形剤又は担体を含む薬剤組成物を提供する。
本発明は、CXCR3の調節のための方法であって、細胞を式(I)の化合物と接触させることを含む方法も提供する。
本発明は、CXCR3の調節のための方法であって、CXCR3タンパク質を式(I)の化合物と接触させることを含む方法をさらに提供する。
さらに、本発明は、式(I)の化合物の製造方法を提供する。
5.1(定義)
別段の記述のない限り、用語「アルキル」は単独で又は別の置換基の一部分として、完全飽和、モノ若しくはポリ不飽和とすることができ、指定された炭素原子数を有する(すなわち、C1〜C10は1〜10個の炭素を意味する)2価及び多価の基を含むことができる、直鎖若しくは分枝鎖、又は環状炭化水素基、或いはその組合せを意味する。飽和炭化水素基の例としては、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、t−ブチル、イソブチル、sec−ブチル、シクロヘキシル、(シクロヘキシル)メチル、シクロプロピルメチル;例えばn−ペンチル、n−ヘキシル、n−ヘプチル、n−オクチルなどの同族体及び異性体などの基が挙げられる。不飽和アルキル基は、1つ又は複数の二重結合又は三重結合を有するものである。不飽和アルキル基の例としては、ビニル、2−プロペニル、クロチル、2−イソペンテニル、2−(ブタジエニル)、2,4−ペンタジエニル、3−(1,4−ペンタジエニル)、エチニル、1−及び3−プロピニル、3−ブチニル、並びに高級の同族体及び異性体が挙げられる。
本明細書では、略語「Me」は、メチル(すなわち、−CH3)であるように意図され、略語「Et」は、エチルであるように意図され、略語「Ph」は、フェニルであるように意図されている。
本明細書では、用語「治療する」、「治療している」、又は「治療」は、疾患及び/又はその付帯症状を軽減又は抑止する方法を指す。本明細書では、用語「予防する」、「予防している」、又は「予防」は、対象が疾患を獲得するのを防止する方法を指す。
本発明は、ケモカイン受容体活性、具体的にはCXCR3の調節に有用である化合物、組成物、及び方法を対象とする。本発明の化合物は、例えば炎症性及び免疫調節性の障害の治療に有用であり、製剤化された薬剤として対象、例えばヒトに直接投与することができる。本発明の化合物は、CXCR3機能を調節する化合物、例えばCXCR3アンタゴニスト、及びCXCR3機能を生理的条件下で調節する1つ又は複数の化合物に変換される化合物を特定しかつ/又は設計するのにも有用である。
本発明は、炎症性又は免疫性の状態状態又は障害の治療又は予防に特定の有用性を有する、CXCR3のアンタゴニストとして有用な化合物を提供する。
Qは、−C(O)−、−CH2CO−、−CH2SO−、及び−CH2SO2−からなる群から選択されたメンバーである。
特定の実施態様では、Qは−C(O)−又は−CH2−である。
下付き文字nは、0、1、又は2である。
R1は、ヘテロアリール又はアリールである。
いくつかの実施態様では、R1は、置換フェニル又は置換ピリジルである。
特定の実施態様では、R1は、−F、−Cl、−I、−OCH3、−OCH2CH3、−OCH2CF3、−CN、−CH2OH、若しくは−CF3で置換されているフェニル又はピリジルである。
R1が置換フェニルであるいくつかの好ましい実施態様では、R1上の置換基は、メタ位又はパラ位である。
特定の実施態様では、R4は、メタ位及びパラ位の二置換ベンジルである。例えば、メタ位及びパラ位の置換基は、−F、−Cl、−I、−OCH3、−OCH2CH3、−OCH2CF3、−CN、−CH2OH、又は−CF3とすることができる。
いくつかの実施態様では、Qは、−CH2CO−、−CH2SO−、及び−CH2SO2−であり、R4はヘテロアリール又はアリールである。
R6及びR7は独立に、水素、(C1〜C8)アルキル、又は(C2〜C8)ヘテロアルキルである。
R8は、水素、(C1〜C8)アルキル、(C2〜C8)ヘテロアルキル、ヘテロアリール、又はアリールである。
R10はアリールである。
ZはCH又はNである。
Xは、結合、(C1〜C6)アルキレン、又は(C1〜C6)ヘテロアルキレンである。
Yは(C1〜C6)アルキレンである。
下付き文字mは、0、1、又は2である。
いくつかの実施態様では、A4はC(Rb)である。
Raは、水素、−OR’、=O、=NR’、=N−OR’、−NR’R’’、−SR’、−ハロゲン、−SiR’R’’R’’’、−OC(O)R’、−C(O)R’、−CO2R’、−CONR’R’’、−OC(O)NR’R’’、−NR’’C(O)R’、−NR’−C(O)NR’’R’’’、−NR’’C(O)2R’、−NH−C(NH2)=NH、−NR’C(NH2)=NH、−NH−C(NH2)=NR’、−S(O)R’、−S(O)2R’、−S(O)2NR’R’’、−CN、及びNO2からなる群から選択される。
下付き文字pは、整数の0、1、2、又は3である。
特定の実施態様では、本発明は、式I又は式IIの化合物(式中、R4は、フェニル又はヘテロアリールであり、−L−R3は一緒になって、置換又は非置換アルキルであり、Qは、−C(O)−でない)を提供する。
特定の実施態様では、RCはそれぞれ独立に、水素、ハロゲン、(C1〜C8)アルキル、(C1〜C8)ヘテロアルキル、アリール、ヘテロアリール、アリール(C1〜C8)アルキル、及びヘテロアリール(C1〜C8)アルキルからなる群から選択される。
R11は、水素、(C1〜C8)アルキル、又は(C2〜C8)ヘテロアルキルである。
特定の実施態様では、R11は、−H、−CH3、−CH2CH3、又は−CH2CF3である。
いくつかの実施態様では、結晶形の本発明の化合物は、少なくとも80%、少なくとも90%、少なくとも92%、少なくとも95%、少なくとも97%、又は少なくとも98%の純度を有する。
本発明の化合物は、様々な合成又は半合成技法で調製することができる。図1及び下記の第6節の実施例は、本明細書に提供される化合物への様々な合成経路を提供する。適切な出発材料の合成は、当業者に公知の又は自明の技法で調製することができ、或いは出発材料は市販の物とすることができる。例えば、それぞれ内容が参照によりその全体が本明細書に組み込まれる、米国特許出願公開第2002/0160159 A1号及び第2003/0055054 A1号、並びに国際公開第02/083143号の方法に従って、このような材料を調製することができる。
本明細書に記載する例示的な方法及び実施例は、本発明を例示するものであって、その範囲を限定するものとして解釈されるべきでない。
別の態様では、本発明は、ヒト及び動物においてケモカイン受容体活性を調節するための薬剤組成物を提供する。組成物は、本発明の化合物を薬剤として許容できる担体又は希釈剤と共に含む。
本発明の薬剤組成物及び方法は、本明細書で指摘したように、上記の病理学的状態の治療又は予防において通常適用される他の治療上有効な化合物をさらに含むことができる。
さらに別の態様では、本発明は、CXCR3によって媒介された疾患又は状態を有する対象に、治療上有効量の本発明の化合物又は組成物を投与することによってこのような状態又は疾患を治療する方法を提供する。本明細書では、「対象」は、霊長類(例えば、ヒト)、ウシ、ヒツジ、ヤギ、ウマ、ブタ、イヌ、ネコ、ウサギ、ラット、マウスなどを含めて、哺乳類などの動物を含むように定義されるが、これらに限定されない。
元素分析 (C32H32F5N3O4S) 計算値 %C 59.16 %H 4.96 %N 6.47. 実測値 %C 59.37 %H 5.09 %N 6.33.
化合物B2。PdCl2PPh3(19mg、0.02mmol)を、アルゴン雰囲気中、ヨウ化物B1(380mg、0.5mmol)及びビニルトリブチルスズ(206mg、0.6mmol)を含む、脱気した乾燥DMF溶液(2mL)に添加した。次いで、混合物を封止管中で、180℃で6分間マイクロ波にかけた。加熱した後、過剰のDMFを減圧で除去し、残留した残渣を、シリカにより50%ヘキサン/酢酸エチル溶液で溶離して精製した。同様な分画を貯留し、濃縮して、白色固体B2を得た。分析HPLC法 A @ 254 nm: rt=6.626分; ESI (MH+) m/z 603.
CXCR3−結合アッセイ:下記の実施例は、国際公開第02/083143号の実施例12に記載されているように、本発明の化合物を評価するために使用することができるCXCR3結合アッセイを例示する。
ヒト末梢血単核球(PBMC)を、OKT3(ハイブリドーマ細胞系OKT3(ATCC CRL−8001)からのAB溶液によって精製)及びIL−2(ペプロテック、米国ニュージャージー州ロッキーヒル(Peprotech,Inc.,Rocky Hill,NJ,USA))で活性化し、14日に、活性化PBMCを1ng/mLのCMFDAで、組織培養インキュベータ中で、37℃で>1.5時間インキュベートすることによって、細胞にクロロメチル−フルオレセイン−ジアセテート(CMFDA)(モレキュラープローブズ(Molecular Probes,Inc.))をローディングする。細胞はローディングしながら、試験化合物を、意図した最終アッセイ濃度の100倍の濃度にDMSOで希釈する。次に、ヒトプラズマ(EDTA、薬物を含まない、バイオロジカルスペシャルティ(Biological Specialty Corp))中100ng/mLのヒトITAC(ペプロテック(Peprotech))を調製する。試験化合物をヒトITAC調製物に添加する。細胞を予熱した(37℃)0.5%BSA含有RPMI(インビトロゲン(Invitrogen))培地で1回洗浄し、500万個の細胞/ヒトプラズマ1mlに再び懸濁する。試験化合物をPBMCに添加する。1ウェル当たり30uLのITAC/化合物混合物を下部のチャンバで添加し、不透過性膜をITAC/化合物ウェルの上に置き、50uLのPBMC/化合物混合物をウェルに添加することによって、96ウェル化学走性遊走プレート(ニューロプローブ(NeuroProbe,Inc.))を組み立てる。プレートに蓋をし、加湿した組織培養インキュベータで2.5時間インキュベートすることができる。試験プレートの参照として使用するCMFDAをローディングした細胞の検量線を作製することができる。遊走プレートを分解し、吸光については475nm、発光については517nmに設定した蛍光プレートリーダーで読み取る。蛍光示度は、検量線を使用し、遊走細胞の百分率を算出して、細胞数に変換することができる。
Claims (21)
- 式(I)を有する化合物:
(式中、Qは、−C(O)−、−CH2CO−、−CH2SO−、及び−CH2SO2−からなる群から選択されたメンバーであり;
Lは、結合、又は(C1〜C5)アルキレンであり;
R0は、水素、ハロゲン、(C1〜C8)アルキル、(C1〜C8)ヘテロアルキル、フルオロ(C1〜C4)アルキル、アリール、ヘテロアリール、アリール(C1〜C8)アルキル、又はヘテロアリール(C1〜C8)アルキルであり、或いは場合によっては、隣接する炭素原子上のR0基を組み合わせて、5員又は6員の縮合環を形成することができ;
下付き文字nは、0、1、又は2であり;
R1は、ヘテロアリール又はアリールであり;
R2は、水素、ハロゲン、(C1〜C10)アルキル、(C2〜C10)ヘテロアルキル、ヘテロ(C1〜C10)シクロアルキル、(C1〜C10)アルキルアリール、又は(C2〜C10)ヘテロアルキルアリールであり、或いは場合によっては、R2をLと組み合わせて、N、O、及びSからなる群から選択された1〜3個のヘテロ原子を含む5員、6員、7員、又は8員環を形成することができ;
R3は、不存在であるか、又は−H、−CHR6R7、−S(O)mR5、−S(O)mN(R8)R9、−S(O)mN(R8)CH2R6、−N(R8)SO2R5、−N(R8)CH2R10、
R5は、(C1〜C8)アルキル、(C2〜C8)ヘテロアルキル、アリール、及びヘテロアリールからなる群から選択され;
R6及びR7は独立に、水素、(C1〜C8)アルキル、又は(C2〜C8)ヘテロアルキルであり、
R8は、水素、(C1〜C8)アルキル、(C2〜C8)ヘテロアルキル、ヘテロアリール、又はアリールであり、
R9は(C1〜C8)アルキルであり;
R10はアリールであり、
ZはCH又はNであり、
Xは、結合、(C1〜C6)アルキレン、又は(C1〜C6)ヘテロアルキレンであり、
Yは(C1〜C6)アルキレンであり;
下付き文字mは、0、1、又は2であり;かつ
場合によっては、R3をR2と組み合わせて、N、O、及びSからなる群から選択された1〜3個のヘテロ原子を含む、4員、5員、6員、7員、又は8員の環を形成することができ;
R4は、(C1〜C20)アルキル、(C2〜C20)ヘテロアルキル、ヘテロアリール、アリール、ヘテロアリール(C1〜C6)アルキル、ヘテロアリール(C2〜C6)ヘテロアルキル、アリール(C1〜C6)アルキル、及びアリール(C2〜C6)ヘテロアルキルからなる群から選択されたメンバーである)。 - 式(II)を有する請求項1記載の化合物:
(式中、A4はC(Rb)又はNであり;
Raは、水素、−OR’、=O、=NR’、=N−OR’、−NR’R’’、−SR’、−ハロゲン、−SiR’R’’R’’’、−OC(O)R’、−C(O)R’、−CO2R’、−CONR’R’’、−OC(O)NR’R’’、−NR’’C(O)R’、−NR’−C(O)NR’’R’’’、−NR’’C(O)2R’、−NH−C(NH2)=NH、−NR’C(NH2)=NH、−NH−C(NH2)=NR’、−S(O)R’、−S(O)2R’、−S(O)2NR’R’’、−CN、及びNO2からなる群から選択され;
Rbは、水素、−OR’、=O、=NR’、=N−OR’、−NR’R’’、−SR’、−ハロゲン、−SiR’R’’R’’’、−OC(O)R’、−C(O)R’、−CO2R’、−CONR’R’’、−OC(O)NR’R’’、−NR’’C(O)R’、−NR’−C(O)NR’’R’’’、NR’’C(O)2R’、−NH−C(NH2)=NH、−NR’C(NH2)=NH、−NH−C(NH2)=NR’、−S(O)R’、−S(O)2R’、−S(O)2NR’R’’、−CN、及びNO2からなる群から選択され;
R’、R’’、及びR’’’はそれぞれ独立に、H、非置換(C1〜C8)アルキル、ヘテロアルキル、非置換アリール、又は置換アリールであり;
下付き文字pは、整数の0、1、2、又は3である)。 - A4が−C(Rb)−である、請求項1記載の化合物。
- R1がパラ−シアノフェニルである、請求項1記載の化合物。
- R2が、水素、ハロゲン、(C1〜C10)アルキル、(C2〜C10)ヘテロアルキル、ヘテロ(C1〜C10)シクロアルキル、(C1〜C10)アルキルアリール、及び(C2〜C10)ヘテロアルキルアリールからなる群から選択されたメンバーである、請求項5記載の化合物。
- Qが−C(O)−又は−CH2−である、請求項3又は5記載の化合物。
- R0がそれぞれ、水素である、請求項10記載の化合物。
- R11が、−H、−CH3、−CH2CH3、又は−CH2CF3である、請求項10記載の化合物。
- 請求項1記載の化合物、及び薬剤として許容できる担体、希釈剤、又は賦形剤を含む薬剤組成物。
- 対象において炎症性又は免疫性の状態又は疾患を治療する方法であって、このような治療を必要とする対象に、治療上有効量の請求項1記載の化合物を投与することを含む方法。
- 前記炎症性又は免疫性の状態又は疾患が、神経変性疾患、多発性硬化症、全身性紅斑性狼瘡、リウマチ様関節炎、アテローム性動脈硬化症、脳炎、髄膜炎、肝炎、腎炎、敗血症、サルコイドーシス、乾癬、湿疹、じんま疹、I型糖尿病、喘息、結膜炎、耳炎、アレルギー性鼻炎、慢性閉塞性肺疾患、副鼻腔炎、皮膚炎、炎症性腸疾患、潰瘍性大腸炎、クローン病、ベーチェット症候群、痛風、癌、ウイルス感染症、細菌感染症、臓器移植状態、皮膚移植状態、及び移植片対宿主病からなる群から選択される、請求項15記載の方法。
- 前記化合物を第2の治療剤と組み合わせて投与する、請求項16記載の方法であって、前記第2の治療剤が、神経変性疾患、多発性硬化症、全身性紅斑性狼瘡、リウマチ様関節炎、アテローム性動脈硬化症、脳炎、髄膜炎、肝炎、腎炎、敗血症、サルコイドーシス、乾癬、湿疹、じんま疹、I型糖尿病、喘息、結膜炎、耳炎、アレルギー性鼻炎、慢性閉塞性肺疾患、副鼻腔炎、皮膚炎、炎症性腸疾患、潰瘍性大腸炎、クローン病、ベーチェット症候群、痛風、癌、ウイルス感染症、細菌感染症、臓器移植状態、皮膚移植状態、又は移植片対宿主病を治療するのに有用である、前記方法。
- 前記炎症性又は免疫性の状態又は疾患が、多発性硬化症、リウマチ様関節炎、乾癬、喘息、炎症性腸疾患、臓器移植状態、及び皮膚移植状態からなる群から選択される、請求項15記載の方法。
- 前記化合物がCXCR3を調節する、請求項15記載の方法。
- 細胞におけるCXCR3機能の調節方法であって、前記細胞を請求項1記載の化合物と接触させることを含む方法。
- CXCR3機能の調節方法であって、CXCR3タンパク質を請求項1記載の化合物と接触させることを含む方法。
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