JP6898334B2 - 2−オキシインドール化合物 - Google Patents
2−オキシインドール化合物 Download PDFInfo
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- JP6898334B2 JP6898334B2 JP2018537816A JP2018537816A JP6898334B2 JP 6898334 B2 JP6898334 B2 JP 6898334B2 JP 2018537816 A JP2018537816 A JP 2018537816A JP 2018537816 A JP2018537816 A JP 2018537816A JP 6898334 B2 JP6898334 B2 JP 6898334B2
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Landscapes
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- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Description
本出願は、2016年1月20日に出願されたアメリカ合衆国仮出願第62/280,969号の35 U.S.C. 119条(e)のもとでの恩恵を主張する出願であり、この出願の全体があらゆる目的で参照により本明細書に組み込まれている。
適用なし。
適用なし。
Arは、5〜10員の芳香族環又はヘテロ芳香族環であり、場合によっては1〜3個のR3で置換されており;
L1は、結合、C1-6アルキレン及びC1-6ヘテロアルキレンからなる群から選択され;
L2は、結合、C1-6アルキレン及びC1-6ヘテロアルキレンからなる群から選択され;
Yは、CO2H又はカルボン酸生物学的等価体であり;
それぞれのR1とそれぞれのR2aは、独立に、ハロゲン、シアノ、C1-6アルキル、C1-6アルコキシ、C1-6ハロアルキル、C1-6ハロアルコキシ、C3-6シクロアルキル及びC2-6アルケニルからなる群から選択され、ここで、アルキル部分、シクロアルキル部分及びアルケニル部分は、場合によっては、フルオロ、OH、CN、C1-3アルキル、C1-3ハロアルキル及びC1-3アルコキシから選択される1〜3個のメンバーで置換されており;
R2bは、H、ハロゲン、シアノ、C1-6アルキル、C1-6アルコキシ、C3-6シクロアルキル及びC2-6アルケニルからなる群から選択され、ここで、アルキル部分、シクロアルキル部分及びアルケニル部分は、場合によっては、フルオロ、CN、C1-3アルキル、C1-3ハロアルキル及びC1-3アルコキシから選択される1〜3個のメンバーで置換されており;
あるいは、場合によっては1つのR2aとR2bは、フェニル環の隣り合った頂点上にあるときには互いに結合して、O、N及びSから独立に選択される1個又は2個の原子を環の頂点に有する5員又は6員のヘテロシクリルアルキル環を形成することができ、そのヘテロシクリルアルキル環は、場合によっては、フルオロ及びC1-3アルキルから選択される1〜3個のメンバーで置換されており;
それぞれのR3は、独立に、ハロゲン、シアノ、C1-6アルキル、C1-6アルコキシ、C1-6ハロアルキル、C1-6ハロアルコキシ、C3-6シクロアルキル及びC2-6アルケニルからなる群から選択され;
下添字mは、0〜4の整数であり;
下添字nは、0〜3の整数である。
該当せず。
概要
本開示は、ケモカイン受容体の機能、特にCCR(9)の機能を調節するのに役立つ化合物とその塩、組成物、方法に関する。ケモカイン受容体の活性の調節は、本明細書にさまざまな形で出現しており、特定のケモカイン受容体(CCR(9)受容体が好ましい)に付随する活性の拮抗、及び/又は作動、及び/又は部分的拮抗、及び/又は逆作動、及び/又は部分的作動を包含することを想定している。したがって本開示の化合物は、哺乳動物のCCR(9)(例えばヒトCCR(9)タンパク質)の少なくとも1つの機能又は特徴を調節する化合物である。ある化合物がCCR(9)の機能を調節する能力は、結合アッセイ(例えばリガンドの結合、又はアゴニストの結合)、及び/又は走化性アッセイ(移動アッセイ)、及び/又はシグナル伝達アッセイ(例えば哺乳動物のGタンパク質の活性化、細胞質内遊離カルシウムの濃度の急速かつ一過性の増加の誘導)、及び/又は細胞応答アッセイ(例えば白血球による走化性の刺激、エキソサイトーシス、炎症メディエータ放出)で明らかにすることができる。
特に断わらない限り、「アルキル」という用語は、単独で、又は別の置換基の一部として、指定された数の炭素原子(すなわちC1-8は1〜8個の炭素を意味する)を有する直鎖又は分岐鎖の炭化水素基を意味する。アルキル基の例に含まれるのは、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、s-ブチル、n-ペンチル、n-ヘキシル、n-ヘプチル、n-オクチルなどである。「アルケニル」という用語は、1つ以上の二重結合を有する不飽和アルキル基を意味する。同様に、「アルキニル」という用語は、1つ以上の三重結合を有する不飽和アルキル基を意味する。そのような不飽和アルキル基の例に含まれるのは、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-プロピニル、3-プロピニル、3-ブチニルと、より高次のホモログと異性体である。「シクロアルキル」という用語は、指定された数の炭素原子(例えばC3-6シクロアルキル)を有し、完全に飽和しているか、環の頂点間に二重結合を2つ以上持たない炭化水素環を意味する。「シクロアルキル」は、二環又は多環の炭化水素環も意味し、例えばビシクロ[2.2.1]ヘプタン、ビシクロ[2.2.2]オクタンなどが挙げられる。「ヘテロシクロアルカン」又は「ヘテロシクロアルキル」は、N、O、Sから選択した1〜5個のヘテロ原子(ただし窒素原子とイオウ原子は場合によっては酸化されており、窒素原子は場合によっては四級化されている)を含有するシクロアルキル基を意味する。ヘテロシクロアルカンは、単環系、二環系、多環系のどれでもよい。ヘテロシクロアルカン基の非限定的な例に含まれるのは、ピロリジン、イミダゾリジン、ピラゾリジン、ブチロラクタム、バレロラクタム、イミダゾリジノン、ヒダントイン、ジオキソラン、フタルイミド、ピペリジン、1,4-ジオキサン、モルホリン、チオモルホリン、チオモルホリン-S-オキシド、チオモルホリン-S,S-オキシド、ピペラジン、ピラン、ピリドン、3-ピロリン、チオピラン、ピロン、テトラヒドロフラン、テトラヒドロチオフェン、キヌクリジンなどである。ヘテロシクロアルカン基は、環の炭素又はヘテロ原子を通じて分子の残部に結合させることができる。
本開示により、CCR(9)の活性を調節する化合物が提供される。ケモカイン受容体は、細胞外リガンド(例えばケモカイン)と相互作用してそのリガンドに対する細胞応答(例えば走化性、細胞内カルシウムイオン濃度の増加など)に関与する統合膜タンパク質である。したがってケモカイン受容体の機能を調節する(例えばケモカイン受容体-リガンド相互作用に干渉する)と、ケモカイン受容体が関与する反応が調節され、ケモカイン受容体が関与する病気又は疾患が治療又は予防される。ケモカイン受容体の機能の調節には、機能の誘導と抑制の両方が含まれる。実現される調節のタイプは、化合物の性質、すなわちアンタゴニストであるか、完全なアゴニスト、部分的なアゴニスト、逆アゴニストのいずれであるかに依存することになろう。
Arは、5〜10員の芳香族環又はヘテロ芳香族環であり、場合によっては1〜3個のR3で置換されており;
L1は、結合、C1-6アルキレン及びC1-6ヘテロアルキレンからなる群から選択され;
L2は、結合、C1-6アルキレン及びC1-6ヘテロアルキレンからなる群から選択され;
Yは、CO2H又はカルボン酸生物学的等価体であり;
それぞれのR1とそれぞれのR2a は、独立に、ハロゲン、シアノ、C1-6アルキル、C1-6アルコキシ、C1-6ハロアルキル、C1-6ハロアルコキシ、C3-6シクロアルキル及びC2-6アルケニルからなる群から選択され、ここで、アルキル部分、シクロアルキル部分及びアルケニル部分は、場合によっては、フルオロ、OH、CN、C1-3アルキル、C1-3ハロアルキル及びC1-3アルコキシから選択される1〜3個のメンバーで置換されており;
R2bは、H、ハロゲン、シアノ、C1-6アルキル、C1-6アルコキシ、C3-6シクロアルキル及びC2-6アルケニルからなる群から選択され、ここで、アルキル部分、シクロアルキル部分及びアルケニル部分は、場合によっては、フルオロ、CN、C1-3アルキル、C1-3ハロアルキル及びC1-3アルコキシから選択される1〜3個のメンバーで置換されており;
あるいは場合によっては1つのR2aとR2bは、フェニル環の隣り合った頂点上にあるときには互いに結合して、O、N及びSから独立に選択される1個又は2個の原子を環の頂点に有する5員又は6員のヘテロシクリルアルキル環を形成することができ、そのヘテロシクリルアルキル環は、場合によっては、フルオロ及びC1-3アルキルから選択される1〜3個のメンバーで置換されており;
それぞれのR3は、独立に、ハロゲン、シアノ、C1-6アルキル、C1-6アルコキシ、C1-6ハロアルキル、C1-6ハロアルコキシ、C3-6シクロアルキル及びC2-6アルケニルからなる群から選択され;
下添字mは、0〜4の整数であり;
下添字nは、0〜3の整数である。
Arは、5〜10員の芳香族環又はヘテロ芳香族環であり、場合によっては1〜3個のR3で置換されており;
L1は、結合、C1-6アルキレン及び、C1-6ヘテロアルキレンからなる群から選択され;
L2は、結合、C1-6アルキレン及びC1-6ヘテロアルキレンからなる群から選択され;
それぞれのR1とそれぞれのR2aは、独立に、ハロゲン、シアノ、C1-6アルキル、C1-6アルコキシ、C1-6ハロアルキル、C1-6ハロアルコキシ、C3-6シクロアルキル及びC2-6アルケニルからなる群から選択され、ここで、アルキル部分、シクロアルキル部分及びアルケニル部分は、場合によっては、フルオロ、CN、C1-3アルキル、C1-3ハロアルキル及びC1-3アルコキシから選択される1〜3個のメンバーで置換されており;
R2bは、H、ハロゲン、シアノ、C1-6アルキル、C1-6アルコキシ、C3-6シクロアルキル及びC2-6アルケニルからなる群から選択され、ここで、アルキル部分、シクロアルキル部分及びアルケニル部分は、場合によっては、フルオロ、CN、C1-3アルキル、C1-3ハロアルキル及びC1-3アルコキシから選択される1〜3個のメンバーで置換されており;
あるいは、場合によっては1つのR2aとR2bは、フェニル環の隣り合った頂点上にあるときには互いに結合して、O、N及びSから独立に選択される1個又は2個の原子を環の頂点に有する5員又は6員のヘテロシクリルアルキル環を形成することができ、そのヘテロシクリルアルキル環は、場合によっては、フルオロ及びC1-3アルキルから選択される1〜3個のメンバーで置換されており;
それぞれのR3は、独立に、ハロゲン、シアノ、C1-6アルキル、C1-6アルコキシ、C1-6ハロアルキル、C1-6ハロアルコキシ、C3-6シクロアルキル及びC2-6アルケニルからなる群から選択され;
下添字mは、0〜4の整数であり;
下添字nは、0〜3の整数である。
本明細書に提示した化合物は、下記の一般的なスキームによって調製することができる。適切に置換されたフェニル酢酸エステルから出発し、塩基の存在下で、置換されたハロニトロベンゼンと反応させた後、ヨウ化メチルと反応させることで、カルボン酸に対する四級中心αを有する2-オキシインドール環構造のための枠組みを設定する。異性体を分割した後、ニトロ基を還元し、環化すると、置換された2-オキシインドールが生成する。インドールの窒素原子の位置で反応させることにより、置換されたAr基を結合させるか、置換されたAr基が付着したリンカー(L1)を結合させると、示してある標的化合物になる。当業者は、下記のスキームの一般的なガイダンスに従って改変することで、式(I)の多彩な化合物を得られることがわかるであろう。
別の1つの側面では、本開示により、ケモカイン活性、特にCCR(9)活性を調節する組成物が提供される。一般に、ヒトと動物でケモカイン受容体の活性を調節する組成物は、医薬として許容可能な賦形剤又は希釈剤と、式I、I'、Ia、Ib、Ia1、Ia2、Ia3、Ia1'、Ia2'、Ia3'、Ib1、Ib2、Ib3、Ib1'、Ib2'及びIb3'のいずれかを有する化合物を含むことになる。
治療する疾患と対象の状態に応じ、本開示の化合物と組成物は、経口、非経口(例えば筋肉内、腹腔内、静脈内、ICV、嚢内への注射又は輸液、皮下注射、インプラント)、吸入、鼻腔、膣、直腸、舌下、局所といった経路で投与することができ、単独で、又は組み合わせて、各投与経路に適していて医薬として許容可能な通常の非毒性の基剤、アジュバント、ビヒクルを含有する適切な単位剤形に製剤化することができる。本開示では、本開示の化合物と組成物をデポ剤にして投与することも考慮する。
さらに別の側面では、本開示により、CCR(9)が関与する病気又は疾患を治療又は予防する方法として、そのような病気又は疾患を有する対象に、式I、I'、Ia、Ib、Ia1、Ia2、Ia3、Ia1'、Ia2'、Ia3'、Ib1、Ib2、Ib3、Ib1'、Ib2'又はIb3'のいずれかの化合物の治療に有効な量を投与することによって治療又は予防する方法が提供される。この方法で用いる化合物に含まれるのは、式I、I'、Ia、Ib、Ia1、Ia2、Ia3、Ia1'、Ia2'、Ia3'、Ib1、Ib2、Ib3、Ib1'、Ib2'及びIb3'の化合物と、実施態様に提示した化合物と、下記の実施例に具体的に提示した化合物と、本明細書に具体的な構造を提示した化合物である。「対象」は、本明細書では、動物(例えば哺乳動物)を含むと定義され、その非限定的な例に含まれるのは、霊長類(例えばヒト)、ウシ、ヒツジ、ヤギ、ウマ、イヌ、ネコ、ウサギ、ラット、マウスなどである。好ましい実施態様では、対象はヒトである。
「キット」と「医薬キット」という用語は、1つ以上の適切な容器の中に、1つ以上の組成物と、それを使用するための指示を含む市販のキット又はパッケージを意味する。一実施態様では、式I、I'、Ia、Ib、Ia1、Ia2、Ia3、Ia1'、Ia2'、Ia3'、Ib1、Ib2、Ib3、Ib1'、Ib2'又はIb3'のいずれかの化合物、又はその医薬として許容可能な塩と、それを投与するための指示を含むキットが提供される。一実施態様では、式I、I'、Ia、Ib、Ia1、Ia2、Ia3、Ia1'、Ia2'、Ia3'、Ib1、Ib2、Ib3、Ib1'、Ib2'又はIb3'のいずれかの化合物、又はその医薬として許容可能な塩と、それと組み合わされる1つ以上(例えば1種類、2種類、3種類、又は1種類か2種類、又は1〜3種類)の追加治療剤と、それらを投与するための指示を含むキットが提供される。
本開示の化合物は、単独で、又は1つ以上の他の薬と組み合わせて供給することができる。別々に投与するか、同じ医薬組成物の中で投与するため、本開示の化合物又は組成物と組み合わせることのできる治療剤の例の非限定的な例に含まれるのは、CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CCR11、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5、CXCR6、CXCR7、CX3CR1、ChemR23、C5aR、C5a、C5のモジュレータ、又はこれらの任意の組み合わせである。いくつかの実施態様では、モジュレータはアンタゴニストである。
HPLC、高圧液体クロマトグラフィ;DMF、ジメチルホルムアミド;TFA、トリフルオロ酢酸;THF、テトラヒドロフラン;EtOAc、酢酸エチル;BOC2O、ジカルボン酸ジt-ブチル又は無水BOC;DIPEA、ジイソプロピルエチルアミン;HBTU、ヘキサフルオロリン酸O-(ベンゾトリアゾル-1-イル)-N,N,N’,N’-テトラメチルウロニウム;dppf、1,1'-ビス(ジフェニルホスフィノ)フェロセン;Pd2(dba)3、トリス(ジベンジリデンアセトン)ジパラジウム(0);DMP、フタル酸ジメチル;Me、メチル;Et、エチル;DCM、ジクロロメタン。
+、20000 nM≧A2≧500 nM;++、500 nM>A2≧100 nM;+++、100 nM>A2。
ケモカインモジュレータの有効性測定
インビトロアッセイの実施例 - 試薬
MOLT-4細胞をAmerican Type Culture Collection(マナサス、ヴァージニア州)から取得し、37℃の湿潤にした5%CO2インキュベータの中で、10%ウシ胎仔血清(FCS)を補足したRPMI組織培地の中で培養した。組み換えヒトケモカインタンパク質TECKをR&D Systems社(ミネアポリス、ミネソタ州)から取得した。ChemoTX(商標)走化性マイクロチェンバーをNeuro Probe社(ゲザースバーグ、メリーランド州)から購入した。CyQUANT(商標)細胞増殖キットをMolecular Probes社(ユージン、オレゴン州)から購入した。カルシウムインジケータ染料Fluo-4 AMをMolecular Devices社(マウンテン・ヴュー、カリフォルニア州)から購入した。
本明細書に示した化合物を評価するのに多彩なアッセイ(シグナル伝達アッセイ、走化性(移動)アッセイ、リガンド結合アッセイや、細胞応答の他のアッセイが含まれる)を利用することができる。ある化合物(例えば潜在的なCCR(9)アンタゴニスト)がCCR(9)リガンド(例えばTECK)によって誘導されるシグナル伝達を阻止する能力を測定するのにケモカイン受容体シグナル伝達アッセイを利用できる。そのようなシグナル伝達を阻止することは、さまざまな疾患(例えば炎症性腸疾患、アレルギー性疾患、乾癬、アトピー性皮膚炎、喘息、線維性疾患、移植片拒絶、免疫が関与する食品アレルギー、自己免疫疾患、セリアック病、関節リウマチ、胸腺腫、胸腺癌、白血病、固形腫瘍、急性リンパ性白血病、メラノーマ、原発性硬化性胆管炎、肝炎、炎症性肝疾患、術後イレウス)の治療において有用である可能性がある。
血清走化性アッセイを利用して、潜在的な受容体アンタゴニストが、ケモカイン受容体(例えばCCR(9))が関与する移動を阻止する効率を求めることができる。このアッセイは、孔のサイズが5μmのポリカーボネート膜を備えるChemoTX(登録商標)マイクロチェンバーシステムを用いて実施した。MOLT-4細胞を室温にて400×gで遠心分離することによって回収した後、50 mMのHEPES(最終的なpHは7.2)を含有するヒト血清中に5000万個/mlの割合で懸濁させた。次に、試験する化合物、又は同体積の溶媒(DMSO)を、DMSOの最終濃度0.125%(v/v)で細胞/血清混合物に添加した後、この混合物を一緒に37℃で1時間インキュベートした。それとは別に組み換えヒトTECKを走化性緩衝液(HBSS+0.1%BSA)で希釈し(一般に0.1 nM〜500 nMの範囲)、その後、希釈した29μlのケモカインをChemoTX(登録商標)プレートの下部ウエルの中に入れた。5μm(孔のサイズ)のポリカーボネート膜をプレートの上に置き、20μlの細胞/化合物混合物を膜の各ウエルの上に移した。プレートを37℃で90分間インキュベートした後、ポリカーボネート膜を除去し、5μlのDNAインターカレーティング試薬CyQUANT(Invitrogen社、カールスバッド、カルフォルニア州)を下部ウエルに添加した。移動した細胞の数に対応する蛍光の量を、Spectrafluor Plusプレート読み取り機(TECAN社、サンノゼ、カルフォルニア州)を用いて測定した。
Log(A2)= log[薬(M)] - log[(A’/A)-1]
(この式において、薬が所与の濃度([薬(M)])であるとき、Aは、アンタゴニストの不在下でのアゴニストの力価を表わし、A'は、アンタゴニストの存在下でのアゴニストの力価である)を用いて行ない、活性なケモカインのレベルが同じときの試験化合物の効率とDMSOのみである対照の効率を比較した。
小腸と大腸へのT細胞の浸潤は、ヒト炎症性腸疾患(セリアック病、クローン病、潰瘍性大腸炎が含まれる)の発症と結び付いている。関係するT細胞の集団が腸に移動するのを阻止することが、ヒトIBDを治療するための効果的なアプローチであると考えられている。CCR(9)は末梢血の中の腸管ホーミングT細胞の表面に発現し、小腸炎(例えばクローン病やセリアック病)の患者で上昇している。CCR(9)リガンドTECKは小腸で発現する。そのためこのリガンド-受容体ペアが、腸へのT細胞の移動に関与することによってUBDの進展においてある役割を演じていると考えられている。いくつかの動物モデルが存在しているため、そうした動物モデルを用いると、興味ある化合物(例えば潜在的なCCR(9)アンタゴニスト)がそのようなT細胞の移動及び/又は病気又は疾患に影響を与える能力を評価することができる。その評価から、ヒトにおけるアンタゴニストの有効性を予測することが可能になろう。
Panwalaとその共同研究者が報告しているマウスモデル(Panwala他、J Immunol.、第161巻(10):5733〜5744ページ(1998年))は、マウス多剤耐性遺伝子(MDR)を遺伝的に欠失している。MDRノックアウトマウス(MDR-/-)は、特別な無病原設備条件に維持すると、重症の自発的腸炎を発症しやすい。MDR-/-マウスに見られる腸炎は、ヒト炎症性腸疾患(IBD)の腸炎と似た病状を有し、大腸の粘膜固有層へのTh1型T細胞浸潤によって定義される。
より最近になり、ヒトのクローン病におけるTNFの役割が、Targan他、N. Engl. J Med.、第337巻(15):1029〜1035ページ(1997年)による抗TNFα抗体を用いた治療の成功によって明らかになった。TNF遺伝子の遺伝子改変が原因でTNFαの産生が異常なマウス(ARE-/-)は、クローン病様炎症性腸疾患を発症する(Kontoyiannis他、Immunity、第10巻(3):387〜398ページ(1999年)を参照されたい)。
CCD(9)依存性T細胞移動モデルにおける試験モジュレータの評価
OT-I Tg CD45.1マウスの脾臓とリンパ節から単細胞浮遊液を調製した。合計15×106個の細胞(約3×106個のCD8 T細胞)を、性別を一致させたコンジェニックCD45.2 C57BL/6nマウス(8〜10週齢)に注入した。24時間後、25 mgのオボアルブミンタンパク質(Sigma-Aldrich社、セントルイス、ミズーリ州)+10μgのコレラ毒素(Calbiochem社、サン・ディエゴ、カルフォルニア州)を口から強制的に摂取させることによってマウスを免疫化した。CCD(9)アンタゴニスト化合物1.063(表1)の後にオボアルブミンを経口で投与することを、それら薬剤に関するマウスの薬物動態によって決まる時間フレームで実施し、全体を通じてその投与法にした。免疫化の5日後、マウスを安楽死させて小腸を回収した。パイエル板を除去し、PBSで洗浄した後、腸を湿らせた正方形のOptimaファブリック(Allegiance Healthcare社)の上に広げた。粘膜を外科用メスでかき集め、次いで10%ウシ新生児血清とDTT(1 mM)を含有する50 mlの培地の中で室温にて15分間撹拌して解離させた。遠心分離の後、ペレットを、10%ウシ新生児血清を含有するPBSの中に再懸濁させ、3分間ボルテックスし、ガラスウールカラム(20mlの注射器に1.6 gを充填;Fisher Scientific社)を迅速に通過させた。Ficoll-Paque 勾配上でIELをさらに精製し、フローサイトメトリー分析のためmAbsで染色した。移されたOT-1 Tg CD45.1 T細胞を検出し、フローサイトメトリーによって定量した。このモデルでは、本開示の化合物を用いた処理により、抗原に反応して小腸に移動するOT-1 Tg CD45.1 T細胞の頻度が有意に低下した。
骨髄/肝臓/胸腺マウス、すなわち「BLT」マウスにおいて、SCID-hu系におけるように、非肥満糖尿病(NOD)/SCIDマウス(内在性のT細胞とB細胞を欠く)に胎仔の胸腺オルガノイドと肝臓オルガノイドを手術によって埋め込む。次にマウスに致死量未満の放射線を照射し、胎仔肝臓から取得した自家移植CD34+幹細胞を移植する。その幹細胞はマウス骨髄に定着して移植されるヒト骨髄をうまく受け入れる結果として、末梢血の中で多彩なヒト細胞になる。そのようなヒト細胞に含まれるのは、成熟したTリンパ球、Bリンパ球、単球、マクロファージ、樹状細胞であり、そのすべてが、臓器や組織(肝臓、肺、胃腸管が含まれる)に広く浸潤する。移植の後、T細胞/HIV相互作用の主要源であるヒト細胞が胃腸管に移動するのを抑制するため、移植を受けたマウスに本開示の化合物を投与する。化合物の有効性は、標準的な技術によって血液ウイルス負荷の低下として測定される。
II型コラーゲンによって誘導される関節炎に関する17日間にわたる研究を実施し、関節炎によって誘導される臨床的くるぶし腫脹にモジュレータが及ぼす効果を評価する。ラットのコラーゲンによって誘導される関節炎は多関節炎の実験モデルであり、多数の抗関節炎剤の前臨床試験で広く使用されてきた(Trentham他、J. Exp. Med.、第146巻(3):857〜868ページ(1977年)、Bendele他、Toxicologic Pathol、第27巻:134〜142ページ(1999年)、Bendele他、Arthritis. Rheum、第42巻:498〜506ページ(1999年)を参照されたい)。このモデルの目印は、確実で容易に測定できる多関節炎の信頼できる発症及び進行と、パンヌス形成を伴う顕著な軟骨破壊と、軽度から中度の骨再吸収及び骨膜骨の増殖である。
この実施例では、喘息治療のためのアンタゴニストの有効性を評価する手続きを記述する。喘息の動物モデルは、標準的な免疫化によってマウスを実験的抗原(例えばOVA)に対して感受性にした後、同じ抗原をエーロゾル化してそのマウスの肺に導入することによって誘導できる。マウス群(1つの群に10匹のマウスが含まれる)の3つのシリーズを、0日目に100μgのOVAを含むリン酸塩緩衝化食塩水(PBS)をアジュバント(例えば水酸化アルミニウム)とともに1回だけ腹腔内注射することによって能動的に感作する。感作後11日目にマウスをPlexiglasチェンバーの中に入れた後、超音波噴霧器(De Vibliss社)を使用して、エーロゾル化したOVA(1%)によるチャレンジを30分間実施する。1つのシリーズのマウスにはそれに加えて最初の感作時にPBSとトゥイーン0.5%を腹腔内注射し、その後は、エーロゾル化したOVAによるチャレンジまで異なる投与スケジュールにする。第2のシリーズは、最初の感作時に、異なる用量のCCR4アンタゴニストを、腹腔内、静脈内、皮下、筋肉内、経口いずれかの投与経路、又は他の任意の投与経路で投与し、その後は、エーロゾル化したOVAによるチャレンジまで異なる投与スケジュールにするマウスの群からなる。第3のシリーズのマウスは陽性対照として機能し、最初の感作時に、マウスIL-10の腹腔内注射、又は抗IL-4抗体の腹腔内注射、又は抗IL-5抗体の腹腔内注射で処理し、その後は、エーロゾル化したOVAによるチャレンジまで異なる投与スケジュールにする群からなる。その後、マウスを、エーロゾル化したOVAによるチャレンジ後の異なる時点で、肺機能、気管支肺胞洗浄液(BAL)中の細胞浸潤物、肺の組織学的検査、血清OVA特異的IgE力価の測定に関して分析する。
Claims (45)
- 式(I)を有する化合物、又はその医薬として許容可能な塩:
Arは、5〜10員の芳香族環又はヘテロ芳香族環であり、場合によっては1〜3個のR3で置換されており;
L1は、結合、C1-6アルキレン、及びアルキレン基の1又は2個の炭素原子が、N、O又はSで置換されたC1-6ヘテロアルキレンからなる群から選択され;
L2は、結合、C1-6アルキレン、及びアルキレン基の1又は2個の炭素原子が、N、O
又はSで置換されたC1-6ヘテロアルキレンからなる群から選択され;
Yは、CO2H、又はテトラゾリル及びテトラゾロニルから成る群から選択され、当該テトラゾリル及びテトラゾロニルは、場合により、C 1-6 アルキル、C 1-6 ハロアルキル、C 1-6 ヒドロキシアルキル、C 1-6 アルコキシ又はC 1 -C 4 アルキル-O-C 1 -C 4 アルキルで置換され;
それぞれのR1とそれぞれのR2aは、独立に、ハロゲン、シアノ、C1-6アルキル、C1-6アルコキシ、C1-6ハロアルキル、C1-6ハロアルコキシ、C3-6シクロアルキル及びC2-6アルケニルからなる群から選択され、ここで、アルキル部分、シクロアルキル部分及びアルケニル部分は、場合によっては、フルオロ、OH、CN、C1-3アルキル、C1-3ハロアルキル、C1-3アルコキシから選択される1〜3個のメンバーで置換されており;
R2bは、H、ハロゲン、シアノ、C1-6アルキル、C1-6アルコキシ、C3-6シクロアルキル及びC2-6アルケニルからなる群から選択され、ここで、アルキル部分、シクロアルキル部分及びアルケニル部分は、場合によっては、フルオロ、CN、C1-3アルキル、C1-3ハロアルキル及びC1-3アルコキシから選択される1〜3個のメンバーで置換されており;
あるいは、場合によっては1つのR2aとR2bは、フェニル環の隣り合った頂点上にあるときには互いに結合して、O、N及びSから独立に選択される1個又は2個の原子を環の頂点に有する5員又は6員のヘテロシクリルアルキル環を形成することができ、そのヘテロシクリルアルキル環は、場合によっては、フルオロ及びC1-3アルキルから選択される1〜3個のメンバーで置換されており;
それぞれのR3は、独立に、ハロゲン、シアノ、C1-6アルキル、C1-6アルコキシ、C1-6ハロアルキル、C1-6ハロアルコキシ、C3-6シクロアルキル、C2-6アルケニルからなる群から選択され;
下添字mは、0〜4の整数であり;
下添字nは、0〜3の整数である)。 - 式(I')を有する、請求項1に記載の化合物、又はその医薬として許容可能な塩:
Arは、5〜10員の芳香族環又はヘテロ芳香族環であり、場合によっては1〜3個のR3で置換されており;
L1は、結合、C1-6アルキレン、及びアルキレン基の1又は2個の炭素原子が、N、O又はSで置換されたC1-6ヘテロアルキレンからなる群から選択され;
L2は、結合、C1-6アルキレン、及びアルキレン基の1又は2個の炭素原子が、N、O又はSで置換されたC1-6ヘテロアルキレンからなる群から選択され;
それぞれのR1とそれぞれのR2aは、独立に、ハロゲン、シアノ、C1-6アルキル、C1-6アルコキシ、C1-6ハロアルキル、C1-6ハロアルコキシ、C3-6シクロアルキル及びC2-6アルケニルからなる群から選択され、ここで、アルキル部分、シクロアルキル部分及びアルケニル部分は、場合によっては、フルオロ、CN、C1-3アルキル、C1-3ハロアルキル及びC1-3アルコキシから選択される1〜3個のメンバーで置換されており;
R2bは、H、ハロゲン、シアノ、C1-6アルキル、C1-6アルコキシ、C3-6シクロアルキル及びC2-6アルケニルからなる群から選択され、ここで、アルキル部分、シクロアルキル部分及びアルケニル部分は、場合によっては、フルオロ、CN、C1-3アルキル、C1-3ハロアルキル及びC1-3アルコキシから選択される1〜3個のメンバーで置換されており;
あるいは、場合によっては1つのR2aとR2bは、フェニル環の隣り合った頂点上にあるときには互いに結合して、O、N及びSから独立に選択される1個又は2個の原子を環の頂点に有する5員又は6員のヘテロシクリルアルキル環を形成することができ、そのヘテロシクリルアルキル環は、場合によっては、フルオロ及びC1-3アルキルから選択される1〜3個のメンバーで置換されており;
それぞれのR3は、独立に、ハロゲン、シアノ、C1-6アルキル、C1-6アルコキシ、C1-6ハロアルキル、C1-6ハロアルコキシ、C3-6シクロアルキル及びC2-6アルケニルからなる群から選択され;
下添字mは、0〜4の整数であり;
下添字nは、0〜3の整数である)。 - Arが、ベンゼン、ピリジン及びキノリンから選択され、そのそれぞれが、場合によっては1個又は2個のR3で置換されている、請求項1〜4のいずれか1項に記載の化合物。
- L1が、結合、-CH2-及び-CH(CH3)-からなる群から選択される、請求項1〜5のいずれか1項に記載の化合物。
- L2が、結合、-O-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH2-及び-CH2CH2CH2-からなる群から選択される、請求項1〜6のいずれか1項に記載の化合物。
- nが1又は2である、請求項1〜7のいずれか1項に記載の化合物。
- mが1、2又は3のいずれかである、請求項1〜8のいずれか1項に記載の化合物。
- Arが、ベンゼン、ピリジン及びキノリンから選択され、そのそれぞれが、場合によっては1個又は2個のR3で置換されている、請求項10に記載の化合物。
- L1が、結合、-CH2-及び-CH(CH3)-からなる群から選択される、請求項10又は11に記載の化合物。
- L2が、結合、-O-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH2-及び-CH2CH2CH2-からなる群から選択される、請求項10〜12のいずれか1項に記載の化合物。
- Arが、ベンゼン、ピリジン及びキノリンからなる群から選択され、そのそれぞれが、場合によっては1個又は2個のR3で置換されている、請求項14に記載の化合物。
- Arが、1,3-フェニレン及び1,4-フェニレンからなる群から選択され、そのそれぞれが、場合によっては1個又は2個のR3で置換されている、請求項14又は15に記載の化合物。
- L1が、結合、-CH2-及び-CH(CH3)-からなる群から選択される、請求項14〜16のいずれか1項に記載の化合物。
- L2が、結合、-O-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH2-及び-CH2CH2CH2-からなる群から選択される、請求項14〜17のいずれか1項に記載の化合物。
- R1が、ハロゲン、シアノ、C1-3アルキル、C1-3アルコキシ、C1-3ハロアルキル、C1-3ハロアルコキシ、C3-5シクロアルキル及びC2-3アルケニルからなる群から選択される、請求項14〜18のいずれか1項に記載の化合物。
- R1が、クロロ、メチル、シアノ、エチル、シクロプロピル、トリフルオロメチル及びトリフルオロメトキシからなる群から選択される、請求項14〜18のいずれか1項に記載の化合物。
- R2bが水素である、請求項22に記載の化合物。
- Arが、ベンゼン、ピリジン及びキノリンからなる群から選択され、そのそれぞれが、場合によっては1個又は2個のR3で置換されている、請求項22又は23に記載の化合物。
- L1が、結合、-CH2-及び-CH(CH3)-からなる群から選択される、請求項22〜24のいずれか1項に記載の化合物。
- L2が、結合、-O-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH2-及び-CH2CH2CH2-からなる群から選択される、請求項22〜25のいずれか1項に記載の化合物。
- Arが、ベンゼン、ピリジン及びキノリンからなる群から選択され、そのそれぞれが、場合によっては1個又は2個のR3で置換されている、請求項27に記載の化合物。
- Arが、1,3-フェニレン及び1,4フェニレンからなる群から選択され、そのそれぞれが、場合によっては1個又は2個のR3で置換されている、請求項27又は28に記載の化合物。
- R3が、CH3、CH2CH3、CH2CH2CH3、及びCH(CH3) 2 からなる群から選択される、請求項27〜29のいずれか1項に記載の化合物。
- L1が、結合、-CH2-及び-CH(CH3)-からなる群から選択される、請求項27〜30のいずれか1項に記載の化合物。
- L2が、結合、-O-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH2-及び-CH2CH2CH2-からなる群から選択される、請求項27〜31のいずれか1項に記載の化合物。
- R1が、ハロゲン、シアノ、C1-3アルキル、C1-3アルコキシ、C1-3ハロアルキル、C1-3ハロアルコキシ、C3-5シクロアルキル及びC2-3アルケニルからなる群から選択される、請求項27〜32のいずれか1項に記載の化合物。
- R1が、クロロ、メチル、シアノ、エチル、シクロプロピル、トリフルオロメチル及びトリフルオロメトキシからなる群から選択される、請求項27〜32のいずれか1項に記載の化合物。
- 医薬として許容可能な賦形剤と、請求項1〜36のいずれか1項に記載の少なくとも1つの化合物、又はその医薬として許容可能な塩とを含む医薬組成物。
- ケモカイン受容体-9(CCR(9))が関与する疾患又は病気の治療を必要とする対象における、当該疾患又は病気を治療するための、請求項37に記載の医薬組成物であって、請求項1〜36のいずれか1項に記載の有効量の化合物、又はその医薬として許容可能な塩、場合によっては医薬として許容可能な賦形剤又は基剤を含む、医薬組成物。
- 前記疾患又は病気が、炎症性腸疾患、アレルギー性疾患、乾癬、アトピー性皮膚炎、喘息、線維性疾患、移植片拒絶、免疫が関与する食品アレルギー、自己免疫疾患、セリアック病、関節リウマチ、胸腺腫、胸腺癌、白血病、シェーグレン症候群、GvHD(移植片対宿主病)、固形腫瘍、急性リンパ性白血病、メラノーマ、原発性硬化性胆管炎、肝炎、炎症性肝疾患又は術後イレウスからなる群から選択される、請求項38に記載の医薬組成物。
- 前記疾患又は病気が、さまざまな炎症性腸疾患からなる群から選択される、請求項38に記載の医薬組成物。
- 前記疾患又は病気が、クローン病及び潰瘍性大腸炎からなる群から選択される、請求項38に記載の医薬組成物。
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US4265874A (en) | 1980-04-25 | 1981-05-05 | Alza Corporation | Method of delivering drug with aid of effervescent activity generated in environment of use |
FR2686878B1 (fr) * | 1992-01-30 | 1995-06-30 | Sanofi Elf | Derives du n-sulfonyl oxo-2 indole, leur preparation, les compositions pharmaceutiques en contenant. |
US5514555A (en) | 1993-03-12 | 1996-05-07 | Center For Blood Research, Inc. | Assays and therapeutic methods based on lymphocyte chemoattractants |
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