JP6155193B2 - ヒト免疫不全ウイルスに対する抗体動員及び進入阻害活性を有する二官能性分子 - Google Patents
ヒト免疫不全ウイルスに対する抗体動員及び進入阻害活性を有する二官能性分子 Download PDFInfo
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- JP6155193B2 JP6155193B2 JP2013540011A JP2013540011A JP6155193B2 JP 6155193 B2 JP6155193 B2 JP 6155193B2 JP 2013540011 A JP2013540011 A JP 2013540011A JP 2013540011 A JP2013540011 A JP 2013540011A JP 6155193 B2 JP6155193 B2 JP 6155193B2
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
本出願は、2010年11月18日出願の発明の名称「Development of Small Molecule Antibody Recruiting Therapeutics for the Treatment of HIV,ARM−HI13 Species and Synthetic Route(HIVの治療のための低分子抗体動員療法、ARM−HI13種及び合成経路の開発)」である米国特許仮出願第61/414,977号、及び2011年8月11日出願の発明の名称「Bifunctional Molecules with Antibody−Recruiting and Entry Inhibitory Activity Against the Human Immunodeficiency Virus(ヒト免疫不全ウイルスに対する抗体動員及び進入阻害活性を有する二官能性分子)」である米国特許仮出願第61/522,518号に基づく優先権を主張し、これらの出願の全内容は、本明細書において参照によって援用される。
近年では、抗体に基づいた治療法は、ヒトの疾患を治療するのに重要な手段となっている(非特許文献1)。現在の抗体に基づいた治療法は、病理学的分子のエフェクター作用をブロックすること、又は免疫媒介性の破壊のために細胞表面上で特異的なエピトープを標的とすることのいずれかで機能する。しかし、これらのアプローチは、重い副作用、経口での生物学的利用能を欠くこと、及び費用が高いことを含めて、何らかの制限を受ける(非特許文献2)。従って、ヒトの血流に既に存在する抗体の強力な細胞傷害能をやはり活用しながら、これらの多くの不利な点を回避する代替法が求められている。
RYは存在しないか、又は必要に応じて置換されているアリール若しくはヘテロアリール基、又はO、(CH2)j、NR1、−S−、−NHC(O)−、−NHC(O)NH−、S(O)、S(O)2、−S(O)2O、−OS(O)2、若しくはOS(O)2Oであり(このアリール若しくはヘテロアリール基はまた、これら及び/又は他の基で置換されていてもよく、並びに/又はこれらの基のそれぞれはまた、アリール又はヘテロアリール基をインドール部分に連結してもよい)、
X2は、H、−(CH2)nOH、−(CH2)nCOOH、C1−C6アルキル、−(CH2)nO−(C1−C6アルキル)、−(CH2)nC(O)−(C1−C6アルキル)、−(CH2)nNHC(O)−R1、−(CH2)nC(O)−NR1R2、−(CH2O)nH、−(CH2O)nCOOH、−(OCH2)nO−(C1−C6アルキル)、−(CH2O)nC(O)−(C1−C6アルキル)、−(OCH2)nNHC(O)−R1、−(CH2O)nC(O)−NR1R2、NO2、CN又はハロゲン(F、Cl、Br、I、好ましくはF若しくはCl)であり、
X3は、H、−(CH2)nOH、−(CH2)nCOOH、C1−C6アルキル、−(CH2)nO−(C1−C6アルキル)、−(CH2)nC(O)−(C1−C6アルキル)、−(CH2)nNHC(O)−R1、−(CH2)nC(O)−NR1R2、−(CH2O)nH、−(CH2O)nCOOH、−(OCH2)nO−(C1−C6アルキル)、−(CH2O)nC(O)−(C1−C6アルキル)、−(OCH2)nNHC(O)−R1、−(CH2O)nC(O)−NR1R2、NO2、CN、ハロゲン(F、Cl、Br、I、好ましくはF若しくはCl)、又は単環式アリール若しくはヘテロアリール基であり、それ自体が必要に応じて置換されており、
R1は、H又はC1−C3アルキル基であり、
R1及びR2は、それぞれ独立してH又はC1−C6アルキル基であり、
iは、0又は1、好ましくは1であり、
jは、1、2又は3であり、
kは、0、1、2又は3、好ましくは0、1又は2であり、
nは、0、1、2、3、4、5、6、好ましくは0〜3であり、
Y3は、H又はC1−C3アルキル基であり、好ましくは平面外に又は平面内に配置され、好ましくはキラル炭素上の平面外に配置され、
RNは、H又はC1−C3アルキル基であり、必要に応じて1つ若しくは2つのヒドロキシル基又は最大3個までのハロゲン基(好ましくはF)で置換されている。
W’は、H、−(CH2)nOH、−(CH2)nCOOH、C1−C6アルキル、−(CH2)nO−(C1−C6アルキル)又はハロゲン(好ましくはF若しくはCl)であり、
Xは、化学結合又は基−(CH2)nNH−、−(CH2)nNHC(O)−、−(CH2)nO−、−(CH2)m−、−(CH2)nS−、−(CH2)nS(O)−、−(CH2)nSO2−又は(CH2)nNH−C(O)−NH−であり、これが、
Yは、O、S又はN−Rであり、ここでRは、H又はC1−C3アルキル基であり、
X2は、H、−(CH2)nOH、−(CH2)nCOOH、C1−C6アルキル、−(CH2)nO−(C1−C6アルキル)、−(CH2)nC(O)−(C1−C6アルキル)、−(CH2)nNHC(O)−R1、−(CH2)nC(O)−NR1R2、−(CH2O)nH、−(CH2O)nCOOH、C1−C6アルキル、−(OCH2)nO−(C1−C6アルキル)、−(CH2O)nC(O)−(C1−C6アルキル)、−(OCH2)nNHC(O)−R1、又は−(CH2O)nC(O)−NR1R2であり、
R1及びR2は、それぞれ独立してH又はC1−C6アルキル基であり、
Y3は、H又はC1−C3アルキル基であり(好ましくは平面の外側に又は平面内に、好ましくはキラル炭素上の平面の外側に配置されており)、かつ
RNは、H又はC1−C3アルキル基であり、これが1つ若しくは2つのヒドロキシル基又は最大3個までのハロゲン基(好ましくはF)で必要に応じて置換されており、
iは、0又は1、好ましくは1であり、
mは、1、2、3、4又は5、好ましくは1、2又は3、さらに好ましくは1であり、
それぞれのnは、独立して0、1、2、3、4、5又は6、好ましくは0、1、2又は3である。
W’は、H、−(CH2)nOH、−(CH2)nCOOH、C1−C6アルキル、−(CH2)nO−(C1−C6アルキル)又はハロゲン(好ましくはF若しくはCl)であり、
Yは、O、S又はN−Rであり、ここでRは、H又はC1−C3アルキル基である。
Xは、基−NH−、−NHC(O)−、−O−、−(CH2)m−、−S−、−S(O)−、SO2−又はNH−C(O)−NH−であり、
Yは、O、S又はN−Rであり、ここでRは、H又はC1−C3アルキル基である。
細菌性血管腫症
カンジダ症、中咽頭(鵞口瘡)
カンジダ症、外陰膣;持続性、頻発、又は治療に対する反応に乏しい
子宮頸部形成異常(中度又は重度)/子宮頸上皮内癌
全身症状、例えば1ヶ月以上継続する発熱(38.5C)又は下痢
毛髪状白斑、口腔
帯状ヘルペス(帯状疱疹)、少なくとも2つの個別の症状の発現又は1より多い皮節を伴う
ヘルペス・ゾスター(帯状疱疹)(少なくとも2回の別個のエピソード又は2つ以上の皮節に関与する)
特発性血小板減少性紫斑病
リステリア症
骨盤内炎症性疾患、特に、卵管卵巣膿瘍によって合併された場合
末梢神経障害
T細胞が200未満に低下したことがあるか、又は患者が、以下の指標疾患のうちの少なくとも1つを有している。
脳トキソプラズマ症
気管支、気管又は肺のカンジダ症
カンジダ症、食道
子宮頸癌、侵潤性**
コクシジオイデス症、播種性又は肺外
クリプトコッカス症、肺外
クリプトスポリジウム症、慢性腸管(1ヶ月を超える期間)
サイトメガロウイルス症(肝臓、脾臓、又はリンパ節以外)
サイトメガロウイルス網膜炎(失明を伴う)
脳症、HIV関連
単純ヘルペス:慢性潰瘍(1ヶ月を超える期間);又は気管支炎、肺炎、又は食道炎
ヒストプラズマ症、播種性又は肺外
イソスポーラ症、慢性腸管(1ヶ月を超える期間)
カポジ肉腫
リンパ腫、バーキット(又は同義語)
リンパ腫、免疫芽球性(又は同義語)
リンパ腫、主に脳
マイコバクテリウム アビウム複合体又はマイコバクテリウム カンサシ、播種性又は肺外
結核菌、部位を問わない(肺**又は肺外)
マイコバクテリウム、他の種又は未特定の種、播種性又は肺外
ニューモシスチス カリニ肺炎
肺炎、反復性
進行性多巣性白質脳症
サルモネラ敗血症、反復性
HIVによる消耗症候群
Xは、O、CH2、NR1、S(O)、S(O)2、−S(O)2O、−OS(O)2、又はOS(O)2Oであり、
R1は、H、C1−C3アルキル基、又はC(O)(C1−C3)基である。
R1’は、H又はC1−C3アルキルであり、
Zは、化学結合、単糖、二糖、オリゴ糖、糖タンパク質又は糖脂質であり、好ましくは糖類であり、さらに好ましくはアルドース及びケトースを含む単糖類及び本明細書に記載の二糖類などの二糖類から選択される糖類である。単糖アルドース類としては、アルドトリオース(特に、D−グリセルアルデヒド)、アルドテトロース類(特に、D−エリトロース及びD−トレオース)、アルドペントース(特に、D−リボース、D−アラビノース、D−キシロース、D−リキソース)、アルドヘキソース(特に、D−アロース、D−アルトロース、D−グルコース、D−マンノース、D−グロース、D−イドース、D−ガラクトース及びD−タロース)などの単糖類が挙げられ、単糖ケトース類としては、ケトトリオース(特に、ジヒドロキシアセトン)、ケトテトロース(特に、D−エリトルロース)、ケトペントース(特に、D−リブロース及びD−キシルロース)、ケトヘキソース類(特に、D−プシコン、D−フルクトース、D−ソルボース、D−タガトース)、特にガラクトースアミン、シアル酸、N−アセチルグルコサミンを含むアミノ糖類、及び特にスルホキノボースを含むスルホ糖類(sulfosugars)などの単糖類が挙げられる。本発明での使用が分かっている例示の二糖類としては、スクロース(必要に応じてN−アセチル化されたグルコースを有してもよい)、ラクトース(必要に応じてN−アセチル化されたガラクトース及び/又はグルコースを有してもよい)、マルトース(必要に応じてN−アセチル化された1つ又は両方のグルコース残基を有してもよい)、トレハロース(必要に応じてN−アセチル化された1つ又は両方のグルコース残基を有してもよい)、セロビオース(必要に応じてN−アセチル化された1つ又は両方のグルコース残基を有してもよい)、コージビオース(必要に応じてN−アセチル化された1つ又は両方のグルコース残基を有してもよい)、ニゲロース(必要に応じてN−アセチル化された1つ又は両方のグルコース残基を有してもよい)、イソマルトース(必要に応じてN−アセチル化された1つ又は両方のグルコース残基を有してもよい)、β,β−トレハロース(必要に応じてN−アセチル化された1つ又は両方のグルコース残基を有してもよい)、ソホロース(必要に応じてN−アセチル化された1つ又は両方のグルコース残基を有してもよい)、ラミナリビオース(必要に応じてN−アセチル化された1つ又は両方のグルコース残基を有してもよい)、ゲンチオビオース(必要に応じてN−アセチル化された1つ又は両方のグルコース残基を有してもよい)、ツラノース(必要に応じてN−アセチル化されたグルコース残基を有してもよい)(必要に応じてN−アセチル化されたグルコース残基を有してもよい)、マルツロース(必要に応じてN−アセチル化されたグルコース残基を有してもよい)、パラチノース(必要に応じてN−アセチル化されたグルコース残基を有してもよい)、ゲンチオビルオース(必要に応じてN−アセチル化されたグルコース残基を有してもよい)、マンノビオース、メリビオース(必要に応じてN−アセチル化されたグルコース残基及び/又はガラクトース残基を有してもよい)、メリビウロース(必要に応じてN−アセチル化されたガラクトース残基を有してもよい)、ルチノース(必要に応じてN−アセチル化されたグルコース残基を有してもよい)、ルチヌロース及びキシロビオースが特に挙げられる。本発明でのZとして使用のためのオリゴ糖類は、上記のようないずれかの糖の3つ以上(最大約100個)の個々の糖(サッカライド)単位(すなわち、上記のいずれか1つ以上のサッカライド単位を、任意の順序で、特に上記のようなグルコース及び/又はガラクトース単位を含んで)を含むことができ、又は例えば大きさにおいて3〜約10−15の糖単位であるフルクト−オリゴ糖類、ガラクトオリゴ糖類及びマンナン−オリゴ糖類を含むことができる。本発明における使用のための糖タンパク質としては、例えばN−グリコシル化及びO−グリコシル化の糖タンパク質などであり、特にムチン類、コラーゲン類、トランスフェリング、セルロプラスミン、主要組織適合性複合体タンパク質(MHC)、酵素類、レクチン類及びセレクチン類、カルネキシン、カルレティキュリン、並びにインテグリン糖タンパク質IIb/IIaが挙げられる。本発明における使用のための糖脂質としては、例えばグリセロ糖脂質(ガラクト脂質、スルホ脂質)、グリコスフィンゴ脂質などであり、グリコスフィンゴ脂質としては、特にセレブロシド、ガラクトセレブロシド、グルコセレブロシド(グルコビカラナテオエートを含む)、ガングリオシド、グロボシド、スルファチド、グリコホスフィンゴリピド及びグリコカリックスなどである。
RYは存在しないか、又は必要に応じて置換されているアリール若しくはヘテロアリール基、又はO、(CH2)j、NR1、−S−、−NHC(O)−、−NHC(O)NH−、S(O)、S(O)2、−S(O)2O、−OS(O)2、又はOS(O)2Oであり、
X2は、H、−(CH2)nOH、−(CH2)nCOOH、C1−C6アルキル、−(CH2)nO−(C1−C6アルキル)、−(CH2)nC(O)−(C1−C6アルキル)、−(CH2)nNHC(O)−R1、−(CH2)nC(O)−NR1R2、−(CH2O)nH、−(CH2O)nCOOH、C1−C6アルキル、−(CH2O)nO−(C1−C6アルキル)、−(CH2O)nC(O)−(C1−C6アルキル)、−(CH2O)nNHC(O)−R1、−(CH2O)nC(O)−NR1R2、NO2、CN又はハロゲン(F、Cl、Br、I、好ましくはF若しくはCl)であり、
X3は、H、−(CH2)nOH、−(CH2)nCOOH、C1−C6アルキル、−(CH2)nO−(C1−C6アルキル)、−(CH2)nC(O)−(C1−C6アルキル)、−(CH2)nNHC(O)−R1、−(CH2)nC(O)−NR1R2、−(CH2O)nOH、−(CH2O)nCOOH、C1−C6アルキル、−(CH2O)nO−(C1−C6アルキル)、−(CH2O)nC(O)−(C1−C6アルキル)、−(CH2O)nNHC(O)−R1、−(CH2O)nC(O)−NR1R2、NO2、CN、ハロゲン(F、Cl、Br、I、好ましくはF若しくはCl)、又は単環式のアリール若しくはヘテロアリール基であり、それ自体が必要に応じて置換されており、
R1は、H又はC1−C3アルキル基であり、
R1及びR2は、それぞれ独立してH又はC1−C6アルキル基であり、
iは、0又は1、好ましくは1であり、
jは、1、2又は3であり、
kは、0、1、2又は3、好ましくは0、1又は2であり、
nは、0、1、2、3、4、5、6、好ましくは0〜3であり、
Y3は、H又はC1−C3アルキル基であり(好ましくは平面外に又は平面内に配置され、好ましくはキラル炭素上の平面外に配置され)、
RNは、H又はC1−C3アルキル基であり、必要に応じて1つ若しくは2つのヒドロキシル基又は最大3個までのハロゲン基(好ましくはF)で置換されている。
W’は、H、−(CH2)nOH、−(CH2)nCOOH、C1−C6アルキル、−(CH2)nO−(C1−C6アルキル)又はハロゲン(好ましくはF若しくはCl)であり、
Xは、基−(CH2)nNH−、−(CH2)nNHC(O)−、−(CH2)nO−、−(CH2)m−、−(CH2)nS−、−(CH2)nS(O)−、−(CH2)nSO2−又は(CH2)nNH−C(O)−NH−であり、これが、
Yは、O、S又はN−Rであり、ここでRは、H又はC1−C3アルキル基であり、
X2は、H、−(CH2)nOH、−(CH2)nCOOH、C1−C6アルキル、−(CH2)nO−(C1−C6アルキル)、−(CH2)nC(O)−(C1−C6アルキル)、−(CH2)nNHC(O)−R1、−(CH2)nC(O)−NR1R2、−(CH2O)nOH、−(CH2O)nCOOH、C1−C6アルキル、−(CH2O)nO−(C1−C6アルキル)、−(CH2O)nC(O)−(C1−C6アルキル)、−(CH2O)nNHC(O)−R1、又は−(CH2O)nC(O)−NR1R2、NO2であり、
R1及びR2は、それぞれ独立してH又はC1−C6アルキル基であり、
Y3は、H又はC1−C3アルキル基であり(好ましくは平面の外側に又は平面内に、好ましくはキラル炭素上の平面の外側に配置されており)、
RNは、H又はC1−C3アルキル基であり、これが1つ若しくは2つのヒドロキシル基又は最大3個までのハロゲン基(好ましくはF)で必要に応じて置換されており、
iは、0又は1、好ましくは1であり、
mは、1、2、3、4又は5、好ましくは1、2又は3、さらに好ましくは1であり、
それぞれのnは、独立して0、1、2又は3である。
式中、Raは、H、C1−C3アルキル若しくはアルカノールであるか、又はR3(プロリン)と環を形成し、そしてR3は、アミノ酸由来の側鎖であり、このアミノ酸は、好ましくはアラニン(メチル)、アルギニン(プロピレングアニジン)、アスパラギン(メチレンカルボキシアミド)、アスパラギン酸(エタン酸)、システイン(チオール、還元又は酸化されたジ−チオール)、グルタミン(エチルカルボキシアミド)、グルタミン酸(プロパン酸)、グリシン(H)、ヒスチジン(メチレンイミダゾール)、イソロイシン(1−メチルプロパン)、ロイシン(2−メチルプロパン)、リジン(ブチレンアミン)、メチオニン(エチルメチルチオエーテル)、フェニルアラニン(ベンジル)、プロリン(R3は、Ra及び隣接する窒素基と環状のリングを形成して、ピロリジン基を形成する)、ヒドロキシプロリン、セリン(メタノール)、トレオニン(エタノール、1−ヒドロキシエタン)、トリプトファン(メチレンインドール)、チロシン(メチレンフェノール)又はバリン(イロプロピル)からなる群から選択され、
m(この文脈において)は、1〜100、1〜75、1〜60、1〜55、1〜50、1〜45、1〜40、2〜35、3〜30、1〜15、1〜10、1〜8、1〜6、1、2、3、4又は5の整数であり、
n(この文脈において)は、約1〜100、約1〜75、約1〜60、約1〜50、約1〜45、約1〜35、約1〜25、約1〜20、約1〜15、2〜10、約4〜12、約5〜10、約4〜6、約1〜8、約1〜6、約1〜5、約1〜4、約1〜3などの整数である。
それぞれのRは、H、又はC1−C3アルキル若しくはアルカノール基であり、
それぞれのR2は、独立してH又はC1−C3アルキル基であり、
それぞれのYは、独立して化学結合、O、S又はN−Rであり、
それぞれのiは、独立して1〜100、1〜75、1〜60、1〜55、1〜50、1〜45、1〜40、2〜35、3〜30、1〜15、1〜10、1〜8、1〜6、1、2、3、4又は5であり、
Dは、
jは、1〜100、1〜75、1〜60、1〜55、1〜50、1〜45、1〜40、2〜35、3〜30、1〜15、1〜10、1〜8、1〜6、1、2、3、4又は5であり、
m’は、1〜100、1〜75、1〜60、1〜55、1〜50、1〜45、1〜40、2〜35、3〜30、1〜15、1〜10、1〜8、1〜6、1、2、3、4又は5であり、
nは、1〜100、1〜75、1〜60、1〜55、1〜50、1〜45、1〜40、2〜35、3〜30、1〜15、1〜10、1〜8、1〜6、1、2、3、4又は5であり、
X1は、O、S又はN−Rであり、
Rは、上記のとおりである。
X3は、O、S、NR4であり、
R4はH、C1−C3アルキル若しくはアルカノール基、又はC(O)(C1−C3)基である。上で示されるトリアゾール基が、好ましいコネクター基である。
材料及び一般的な情報:購入した出発材料は、他に注記しない限り、受け取ったまま用いた。全ての湿度感受性の反応は、火炎乾燥したガラス製品中で、不活性な窒素の乾燥雰囲気中で行った。試薬等級の溶媒を、抽出及びフラッシュクロマトグラフィーに用いた。反応の進行は、分析薄層クロマトグラフィー(TLC,Merckシリカゲル60F−254プレート)によってチェックした。このプレートを、UV照射を用いて、又はアニスアルデヒド(95%のEtOH中における2.5%のp−アニスアルデヒド、1%のAcOH、3.5%のH2SO4(濃縮))又はニンヒドリン(0.3%ニンヒドリン(w/v)、97:3のEtOH−AcOH)染色によるチャーリング(charring)によって監視した。フラッシュカラムクロマトグラフィーを、シリカゲル(230〜400メッシュ)を用いて行った。全てのクロマトグラフィー分離について報告された溶媒の組成は、容積/容積(v/v)基準である。ELISA及びCDC実験を3組で行い、別段注記しない限り少なくとも3回繰り返した。
ジクロロメタン(1mL)中の16(10mg、0.01mmol)に、アレーンカルボン酸(0.018mmol、1.8当量)、EDC−HCl(3.5mg、0.018mmol、1.8当量)、HOBT(3.0mg、0.019mmol、1.9当量)及びジイロプロピルエチルアミン(10μL)を添加した。得られた溶液を、LC/MSが反応終了を示すまで、窒素雰囲気下において室温で撹拌させた(5〜14時間)。得られた溶液をジクロロメタン(5mL)で希釈し、次いで炭酸水素ナトリウム(5mL)の飽和溶液及び塩化アンモニウム(5mL)を用いて洗浄した。有機層を無水硫酸マグネシウムで乾燥し、濾過して揮発性物質を真空中で除去した。粗物質をHPLCによって精製した。
本発明は、ARM−HIと一般に呼ばれる二官能性の低分子を提供することによって、HIV感染に関する新たな治療についての方策の必要性を満たし、ARM−HIは、HIVの細胞感染及び伝播の予防において、直交する経路を通じて(gp120−CD4相互作用を阻害すること及びgp120発現細胞に対して抗DNP抗体を動員することの両方によって)機能する。本発明によるARM−HIは、以前に公開されたARM−H化合物よりもかなり大きい活性を示すことが示される。
Claims (28)
- 次の化学構造による化合物であって、
Y’は、H又はNO2であり、
X’は、O、CH2、NR1、S(O)、S(O)2、−S(O)2O、−OS(O)2、又はOS(O)2Oであり、
R1は、H、C1−C3アルキル基、又はC(O)(C1−C3)基であり、
(1)次の化学式による化合物
それぞれのRが、H、又はC1−C3アルキル若しくはアルカノール基であり、
それぞれのR2が、独立してH又はC1−C3アルキル基であり、
それぞれのY"が、独立して単結合、O、S又はN−Rであり、
それぞれのi’が、独立して1〜50であり、
Dは、
jは、1〜100であり、
m’は、1〜100であり、
n”は、1〜100であり、
X1は、O、S又はN−Rであり、
Rは、上記のとおりであり、
(2)1〜8のグリコール単位を有するポリエチレングリコール
(3)次の化学式による基
(4)次の化学式による基
R3は、アラニン(メチル)、アルギニン(プロピレングアニジン)、アスパラギン(メチレンカルボキシアミド)、アスパラギン酸(エタン酸)、システイン(チオール、還元又は酸化されたジ−チオール)、グルタミン(エチルカルボキシアミド)、グルタミン酸(プロパン酸)、グリシン(H)、ヒスチジン(メチレンイミダゾール)、イソロイシン(1−メチルプロパン)、ロイシン(2−メチルプロパン)、リジン(ブチレンアミン)、メチオニン(エチルメチルチオエーテル)、フェニルアラニン(ベンジル)、プロリン(R3は、Ra及び隣接する窒素基と環状のリングを形成して、ピロリジン基を形成する)、ヒドロキシプロリン、セリン(メタノール)、トレオニン(エタノール、1−ヒドロキシエタン)、トリプトファン(メチレンインドール)、チロシン(メチレンフェノール)又はバリン(イロプロピル)からなる群より選択されるアミノ酸由来の側鎖であり、
mは、1〜15の整数であり、
R Y は、ARYL2−Xであり、
ARYL2は、必要に応じて置換されているヘテロアリールであるか、又は必要に応じて置換されているアリール基であり、前記必要に応じて置換されているヘテロアリール及び必要に応じて置換されているアリールは、イミダゾール、フリル、ピロール、フラニル、チエン、チアゾール、ピリジン、ピリミジン、ピラジン、トリアゾール、オキサゾール、インドール、キノリン、ピリドン、ピリダジン、ピラゾール、トリアジン、テトラゾール、インドール、イソインドール、インドリジン、プリン、インダゾール、イソキノリン、キノリジン、フタラジン、ナフチリジン、キノキサリン、キナゾリン、シンノリン、プテリジン、イミダゾピリジン、イミダゾトリアジン、ピラジノピリダジン、アクリジン、フェナントリジン、カルバゾール、カルバゾリン、ペリミジン、フェナントロリン、フェナセン、オキサジアゾール、ベンズイミダゾール、ピロロピリジン、ピロロピリミジン、ピリドピリミジン;チオフェン、ベンゾチオフェン;フラン、ピラン、シクロペンタピラン、ベンゾフラン、イソベンゾフラン;チアジアゾール、イソチアゾール、ベンゾキサゾール、ベンゾチアゾール、ベンゾチアジアゾール、フェノチアジン、イソキサゾール、フラザン、フェノキサジン、ピラゾロオキサゾール、イミダゾチアゾール、チエノフラン、フロピロール、ピリドキサジン、フロピリジン、フロピリミジン、チエノピリミジン、フェニル、ナフチル、2−ピリジル、3−ピリジル、4−ピリジル、チアゾリル、2−チアゾール、4−チアゾール、5−チアゾール、イソチアゾリル、オキサゾリル、2−オキサゾール、4−オキサゾール、5−オキサゾール、イソオキサゾリル、フラニル、2−フラン、3−フラン、チオフェニル、2−チオフェン、3−チオフェン、単環式及び二環式のアリール、ベンジル、アントラセニル、フェナントレニルからなる群において選択され、
Xは、単結合又は基−(CH 2 ) n' NH−、−(CH 2 ) n' NHC(O)−、−(CH 2 ) n' O−、−(CH 2 ) m" −、−(CH 2 ) n' S−、−(CH 2 ) n' S(O)−、−(CH 2 ) n' SO 2 −若しくは(CH 2 ) n' NH−C(O)−NH−であり、これが
を、前記リンカーに連結しており、
m"は、1、2、3、4又は5であり、
それぞれのn’は、独立して0、1、2又は3であり、
X2は、−(CH2)nO−(C1−C6アルキル)、−(OCH2)nO−(C1−C6アルキル)、H、−(CH2)nOH、−(CH2)nCOOH、必要に応じて置換されているC1−C6アルキル、−(CH2)nC(O)−(C1−C6アルキル)、−(CH2)nNHC(O)−R1、−(CH2)NR1R2、−(CH2)nC(O)−NR1R2、−(CH2O)nH、−(CH2O)nCOOH、−(CH2O)nC(O)−(C1−C6アルキル)、−(OCH2)nNHC(O)−R1、−(CH2O)nC(O)−NR1R2、NO2、CN、又はハロゲンであり、
X3は、H、−(CH2)nOH、−(CH2)nCOOH、必要に応じて置換されているC1−C6アルキル、−(CH2)nO−(C1−C6アルキル)、−(CH2)nC(O)−(C1−C6アルキル)、−(CH2)NR1R2、−(CH2)nNHC(O)−R1、−(CH2)nC(O)−NR1R2、−(CH2O)nH、−(CH2O)nCOOH、−(OCH2)nO−(C1−C6アルキル)、−(CH2O)nC(O)−(C1−C6アルキル)、−(OCH2)nNHC(O)−R1、−(CH2O)nC(O)−NR1R2、NO2、CN、ハロゲン、又は単環式のアリール若しくはヘテロアリール基であり、それ自体が必要に応じて置換されており、
R1及びR2は、それぞれ独立してH又はC1−C6アルキル基であり、
iは、0又は1であり、
kは、0、1、2又は3であり、
nは、0、1、2、3、4、5、6であり、
Y3は、H又はC1−C3アルキル基であり、
RNは、H又はC1−C3アルキル基であり、1つ若しくは2つのヒドロキシル基又は最大3個までのハロゲン基で必要に応じて置換され、
ここで、用語「置換され」は、ある炭素又は窒素位置において、ヒドロキシル、カルボキシル、シアノ(C≡N)、ニトロ(NO2)、ハロゲン、C1−C10アルキル基、フェニル、置換フェニル、ベンジル、ベンゾイルC1−C6、アルコキシ基、フェニル、置換フェニル、C1−C6アルキルエステル又はアリールエステル、アルキレンエステル(結合は、エステル官能基よりはアルキレン基上である)、アリール、5員又は6員の環状アルキレンアミン、C1−C6アルキルアミン、C1−C6ジアルキルアミン(アルキル基が1つ以上のヒドロキシル基で置換されていてもよい)、1つ若しくは2つのC1−C6アルキル基で置換されたアミド、1つ若しくは2つのC1−C6アルキル基で置換されているカルボキサミド、C1−C6アルキルアルカノール又はアリールアルカノール、アルカン酸、C1−C6アルキル又はアリールで置換されることを意味する、
化合物、又はその薬学的に許容される塩、鏡像異性体、溶媒和物若しくは多形体。 -
W’は、H、−(CH2)nOH、−(CH2)nCOOH、C1−C6アルキル、−(CH2)nO−(C1−C6アルキル)又はハロゲンであり、
Xは、基−(CH2)n'NH−、−(CH2)n'NHC(O)−、−(CH2)n'O−、−(CH2)m"−、−(CH2)n'S−、−(CH2)n'S(O)−、−(CH2)n'SO2−又は(CH2)n'NH−C(O)−NH−であり、これが
Yは、O、S又はN−R'であり、ここでR'は、H又はC1−C3アルキル基であり、
X2は、−(CH2O)nO−(C1−C6アルキル)、H、−(CH2)nOH、−(CH2)nCOOH、C1−C6アルキル、−(CH2)nO−(C1−C6アルキル)、−(CH2)nC(O)−(C1−C6アルキル)、−(CH2)nNHC(O)−R1、−(CH2)nC(O)−NR1R2、−(CH2O)nOH、−(CH2O)nCOOH、C1−C6アルキル、−(CH2O)nC(O)−(C1−C6アルキル)、−(CH2O)nNHC(O)−R1、−(CH2O)nC(O)−NR1R2、又はNO2であり、
R1及びR2は、それぞれ独立してH又はC1−C6アルキル基である、
請求項1に記載の化合物、又はその薬学的に許容される塩、鏡像異性体、溶媒和物若しくは多形体。 - ARYL2が、必要に応じて置換されているヘテロアリール基である、請求項1に記載の化合物。
- ARYL2が、必要に応じて置換されているフラニル、テトラゾリル、フェニル、ナフチル、ピリジル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、又はチオフェニル基である、請求項4に記載の化合物。
- 前記ARYL基が、必要に応じて置換されているフェニル基である、請求項1、4又は5に記載の化合物。
- RNがHであり、X2がH又はOCH3であり、X3がH、OCH3、CH3又はNO2であり、Y3がH又はCH3(ラセミ体又は鏡像異性体)であり、k及びiがそれぞれ1である、請求項1、4又は5に記載の化合物、又はその薬学的に許容される塩、鏡像異性体、溶媒和物若しくは多形体。
- Y3がCH3基である、請求項1〜5のいずれかに記載の化合物。
- ARYL2が、必要に応じて置換されているフラニル基である、請求項1、3〜7のいずれかに記載の化合物。
- 前記リンカーが、1〜8のグリコール単位を有するポリエチレングリコールのリンカーである、請求項1に記載の化合物。
- 前記リンカーが、1〜6のグリコール単位を有するポリエチレングリコールのリンカーである、請求項1に記載の化合物。
- 前記ARYL基が、フェニル、o−、m−若しくはp−トルイル、o−、m−若しくはp−エチルフェニル、o−、m−若しくはp−イロプロピルフェニル、ナフチル、o−、m−若しくはp−フェノール、3,5−ジヒドロキシルフェニル、o−、m−若しくはp−ヒドロキシメチルフェニル、又は2−、3−若しくは4−ピリジル基からなる群より選択される、請求項2に記載の化合物。
- 前記ARYL基が、フェニル、o−、m−若しくはp−トルイル、o−、m−若しくはp−エチルフェニル、o−、m−若しくはp−イロプロピルフェニル、ナフチル、o−、m−若しくはp−フェノール、3,5−ジヒドロキシルフェニル、o−、m−若しくはp−ヒドロキシメチルフェニル、又は2−、3−若しくは4−ピリジル基からなる群より選択される、請求項1、4〜9のいずれかに記載の化合物。
- X2は、H又はOCH3であり、
Xは、基−(CH2)nNHC(O)−、−(CH2)nNH−、−(CH2)nO−、−(CH2)m−、−(CH2)nS−、−(CH2)nS(O)−、−(CH2)nSO2−又は(CH2)nNH−C(O)−NH−であり、
W2は、Hであり、
RNは、Hであり、
Y3は、H又はCH3基であり、
ABTは、
iは、1であり、
m”は、1、2、3、4又は5であり、
それぞれのnは、独立して1、2、3、4、5又は6である、
請求項2に記載の化合物、又はその薬学的に許容される塩、鏡像異性体、溶媒和物若しくは多形体。 - 請求項1〜18のいずれかに記載の二官能性化合物の有効量を、薬学的に許容される担体、添加物又は賦形剤と組み合わせて、更に必要に応じて追加の抗HIV剤と組み合わせて含む、医薬組成物。
- 前記追加の抗HIV剤が、ヌクレオシド系逆転写酵素阻害薬(NRTI)、非ヌクレオシド系逆転写酵素阻害薬、プロテアーゼ阻害薬及び融合阻害薬からなる群より選択される、請求項19に記載の組成物。
- 前記追加の抗HIV剤が、アンプレナビル、アバカビル、アセマンナン、アシクロビル、AD−439、AD−519、アデホビルジピボキシル、αインターフェロン、アンサマイシン、AR177、β−フルオロ−ddA、BMS−232623(CGP−73547)、BMS−234475(CGP−61755)、CI−1012、シドフォビル、硫酸カードラン、サイトメガロウイルス免疫グロビン、ガンシクロビル、ジデオキシイノシン、DMP−450、エファビレンツ(DMP−266)、EL10、ファムシクロビル、FTC、GS840、HBY097、ヒペリシン、組み換えヒトインターフェロンβ、インターフェロンα−n3、インジナビル、ISIS−2922、KNI−272、ラミブジン(3TC)、ロブカビル、ネルフィナビル、ネビラピン、ノバプレン、ペプチドTオクタペプチド配列、ホスホノギ酸トリナトリウム、PNU−140690、プロブコール、RBC−CD4、リトナビル、サキナビル、バラシクロビル、ビラゾールリバビリン、VX−478、ザルシタビン、ジドブジン(AZT)、テノホビルジソプロキシルフマレート塩、コンビビル、アバカビルコハク酸塩、T−20、AS−101、ブロピリミン、CL246、EL10、FP−21399、γインターフェロン、顆粒球マクロファージコロニー刺激因子(GM−CSF)、HIVコア粒子免疫刺激剤、インターロイキン−2(IL−2)、静脈内免疫グロブリン、IMREG−1、IMREG−2、イムチオールジエチルジチオカルバミン酸、α−2インターフェロン、メチオニン−エンケファリン、MTP−PE(ムラミル−トリペプチド)、顆粒球コロニー刺激因子(GCSF)、レムネ、rCD4(組み換え可溶性ヒトCD4−IgG)、rCD4−IgGハイブリッド、組み換え可溶性ヒトCD4、インターフェロンα2a、SK&F1−6528、可溶性T4、チモペンチン、腫瘍壊死因子(TNF)、AK602、アロブジン、アムドキソビル、AMD070、アタナザビル(レイアタッツ)、AVX754(アプリシタビン)、ベビリマット、BI−201、BMS−378806、BMS−488043、BMS−707035、C31G、カルボポール974P、カラノリドA、カラギーナン、硫酸セルロース、シアノビリン−N、ダルナビル、デラビルジン、ジダノシン(ヴァイデックス)、エファビレンツ、エルブシタビン、エムトリシタビン、ホスアンプレナビル(レキシバ)、フォジブジンチドキシル、GS9137、GSK−873、140(アプラビロク)、GSK−364735、GW640385(ブレカナビル)、HG0004、HGTV43、INCB9471、KP−1461、ロピナビル、ミフェプリストン(VGX410)、MK−0518、PPL−100、PRO140、PRO542、PRO2000、ラシビル、SCH−D(ビクリビロック)、SP01A、SPL7013、TAK−652、チプラナビル(アプティバス)、TNX−355、TMC125(エトラビリン)、UC−781、UK−427,857(マラビロク)、バルプロ酸、VRX496、ザルシタビン、バルガンシクロビル、クリンダマイシンとプリマキン、フルコナゾール・パスチル、ニスタイン・パスチル、エフロルニチン、ペンタミジン、イセチオネート、トリメトプリム、トリメトプリム/サルファ、ピリトレキシム、イセチオン酸ペンタミジン、スピラマイシン、イントラコナゾール−R51211、トリメトレキサート、ダウノルビシン、組み換えヒトエリスロポエチン、組み換えヒト成長ホルモン、酢酸メゲストロール、テストステロン、アルデスロイキン(プロロイキン)、アンホテリシンB、アジスロマイシン(ジスロマック)、カルシウムヒドロキシアパタイト、ドキソルビシン、ドロナビノール、エンテカビル、エポエチンα、エトポシド、フルコナゾール、イソニアジド、イトラコナゾール(スポラノックス)、メゲストロール、パクリタキセル(タキソール)、ペグインターフェロンα−2、ポリ−L−乳酸(スカルプトラ)、リファブチン(マイコブチン)、リファンピン、ソマトロピン及びスルファメトキサゾール/トリメトプリムからなる群より選択される、請求項19に記載の組成物。
- 前記追加の抗HIV剤が、3TC(ラミブジン)、AZT(ジドブジン)、(−)−FTC、ddI(ジダノシン)、ddC(ザルシタビン)、アバカビル(ABC)、テノホビル(PMPA)、D−D4FC(レバーセット)、D4T(スタブジン)、ラシビル、L−FddC、L−FD4C、NVP(ネビラピン)、DLV(デラビルジン)、EFV(エファビレンツ)、SQVM(メシル酸サキナビル)、RTV(リトナビル)、IDV(インジナビル)、SQV(サキナビル)、NFV(ネルフィナビル)、APV(アンプレナビル)、LPV(ロピナビル)、T20、それらの融合物及び混合物からなる群より選択される、請求項19に記載の組成物。
- 経口投与剤形である請求項19〜22のいずれかに記載の組成物。
- 非経口投与剤形である請求項19〜22のいずれかに記載の組成物。
- 医薬として使用される請求項1〜18のいずれかに記載の化合物。
- 患者におけるHIV感染の治療において使用される請求項19〜24のいずれかに記載の組成物。
- HIVに感染した患者におけるAIDS又はARCの確率を減少させるために使用される請求項19〜24のいずれかに記載の組成物。
- HIVに感染した患者におけるHIV感染CD細胞を減少又は根絶するために使用される請求項19〜24のいずれかに記載の組成物。
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JP2017052776A (ja) * | 2010-11-18 | 2017-03-16 | イェール ユニバーシティーYale University | ヒト免疫不全ウイルスに対する抗体動員及び進入阻害活性を有する二官能性分子 |
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