JP7362667B2 - Toll様受容体リガンド - Google Patents
Toll様受容体リガンド Download PDFInfo
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- JP7362667B2 JP7362667B2 JP2020564809A JP2020564809A JP7362667B2 JP 7362667 B2 JP7362667 B2 JP 7362667B2 JP 2020564809 A JP2020564809 A JP 2020564809A JP 2020564809 A JP2020564809 A JP 2020564809A JP 7362667 B2 JP7362667 B2 JP 7362667B2
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- alkylene
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Description
本出願は、2018年2月12日に出願された米国仮特許出願第62/629,513号明細書に対する優先権を主張するものであり、この仮特許出願は、全体が参照により本明細書に援用される。
本発明は、アメリカ国立アレルギー・感染症研究所(National Institutes of Allergy and Infectious Diseases)によって与えられた助成金番号1R43AI136081-01A1の下で政府の支援を受けてなされた。米国政府は、本発明に一定の権利を有する。
R1は、
R2a、R2b及びR2cは、それぞれ独立して、C4~22アルキル、-X1-C3~21アルキル、-CH2-X1-C2~20アルキル又は-CH(R10)(R11)であり;
R10は、出現するごとに、独立して、C1~21アルキル、-X1-C2~20アルキル又は-CH2-X1-C1~19アルキルであり;
R11は、出現するごとに、独立して、C3~17アルキル、-X2-C2~16アルキル、-CH2-X2-C1~15アルキル、-X2-C(=Y4)C1~15アルキル、-CH2-C(=Y4)C1~15アルキル、-X2-C(=Y4)C1~15アルキレン-Z1-C1~15アルキル、-CH2-C(=Y4)C1~15アルキレン-Z1-C1~15アルキル、-C3~17アルキレン-Z1-C1~15アルキル、-X2-C2~16アルキレン-Z1-C1~15アルキル、-CH2-X2-C1~15アルキレン-Z1-C1~15アルキル、-X2-C(=Y4)C1~15アルキル-Z2又は-X2-C2~16アルキレン-Z2であり;
R3a、R3b及びR3cは、それぞれ独立して、CO2H、-OSO3H、-OP(O)(OH)2、-C1~6アルキレン-CO2H、-C1~6アルキレン-OSO3H、-C1~6アルキレン-OP(O)(OH)2、-OC1~6アルキレン-P(O)(OH)2、-C1~6アルキレン-P(O)(OH)2、-C1~6ハロアルキレン-P(O)(OH)2、H又はCO2H、-OSO3H、-OP(O)(OH)2、-C1~6アルキレン-CO2H、-C1~6アルキレン-OSO3H、-C1~6アルキレン-OP(O)(OH)2、-OC1~6アルキレン-P(O)(OH)2、-C1~6アルキレン-P(O)(OH)2若しくは-C1~6ハロアルキレン-P(O)(OH)2のエステルであり;
R3dは、CO2H、-SO3H、-P(O)(OH)2、-C1~6アルキレン-CO2H、-C1~6アルキレン-OSO3H、-C1~6アルキレン-OP(O)(OH)2、-OC1~6アルキレン-P(O)(OH)2、-C1~6アルキレン-P(O)(OH)2、-C1~6ハロアルキレン-P(O)(OH)2、H、C1~6アルキル、C1~6ハロアルキル、C3~8シクロアルキル又はCO2H、-OSO3H、-OP(O)(OH)2、-C1~6アルキレン-CO2H、-C1~6アルキレン-OSO3H、-C1~6アルキレン-OP(O)(OH)2、-OC1~6アルキレン-P(O)(OH)2、-C1~6アルキレン-P(O)(OH)2若しくは-C1~6ハロアルキレン-P(O)(OH)2のエステルであり;
R4aは、CO2H、CH2OSO3H、CH2CO2H、CH2P(O)(OH)2、CH2OH、H又はCO2H、CH2SO3H、CH2CO2H若しくはCH2P(O)(OH)2のエステルであり;
R4bは、出現するごとに、独立して、CO2H、CH2OSO3H、CH2CO2H、CH2P(O)(OH)2、CH2OH、H又はCO2H、CH2SO3H、CH2CO2H若しくはCH2P(O)(OH)2のエステルであり;
R5及びR6は、出現するごとに、独立して、H、C1~6アルキル、C1~6ハロアルキル、-O-C1~6アルキル又は-C1~6アルキレン-OHであり;
X1及びX2は、出現するごとに、独立して、O、S又はNHであり;
X3は、O、S、NH又はCH2であり;
Y1、Y2及びY3は、独立して、O、S、NH又はH2であり;
Y4は、出現するごとに、独立して、O、S又はNHであり;
Z1は、出現するごとに、独立して、フェニレン又は5員~6員ヘテロアリーレンであり、フェニレン及びヘテロアリーレンは、C1~4アルキル、C1~4ハロアルキル、-OC1~4アルキル、-OC1~4ハロアルキル、シアノ及びハロゲンから独立して選択される1~4つの置換基で任意選択的に置換され;
Z2は、出現するごとに、独立して、フェニル又は5員~6員ヘテロアリールであり、ここで、Z2は、C1~4アルキル、C1~4ハロアルキル、-OC1~4アルキル、-OC1~4ハロアルキル、シアノ及びハロゲンから独立して選択される1~5つの置換基で任意選択的に置換され;及び
k及びqは、それぞれ独立して、0~4の整数である)
の化合物又はその薬学的に許容される塩を提供する。
本明細書に記載されるように、本発明の化合物は、上に一般に示されるような又は本発明の特定のクラス、サブクラス及び種によって例示されるような1つ以上の置換基で任意選択的に置換され得る。本明細書に記載されるように、式I中の変数は、例えば、アルキル及びシクロアルキルなどの特定の基を包含する。当業者が認識するように、本発明によって想定される置換基の組合せは、安定した又は化学的に実現可能な化合物の形成をもたらす組合せである。本明細書において使用される際の「安定した」という用語は、それらの生成、検出並びに好ましくはそれらの回収、精製及び本明細書に開示される目的の1つ以上のための使用を可能にする条件に曝されたときに実質的に変化しない化合物を指す。ある実施形態において、安定した化合物又は化学的に実現可能な化合物は、少なくとも1週間にわたり、水分又は他の化学的反応性の高い条件の非存在下で40℃以下の温度に保持されたときに実質的に変化しないものである。
本発明の第1の態様は、式(I)(式中、R1、R2a、R2b、R3a、R4a、Y1及びY2は、本明細書において定義されるとおりである)の化合物又はその薬学的に許容される塩を提供する。
で表され得る。R3aは、-OP(O)(OH)2、-OSO3H又は-OCH2-P(O)(OH)2であり得、ここで、R2a、R2b、R2c及びR3bは、本明細書において定義されるとおりである。R3aは、-OP(O)(OH)2、-OSO3H又は-OCH2-P(O)(OH)2であり得、ここで、R3bは、H、CO2H又はCO2Hのエステルであり、R2a、R2b及びR2cは、本明細書において定義されるとおりである。例えば、R2a、R2b及びR2cは、-CH(R10)(R11)であり得、ここで、R10は、出現するごとに、独立して、C1~21アルキル、-X1-C2~20アルキル又は-CH2-X1-C1~19アルキルであり;R11は、出現するごとに、独立して、C3~17アルキル、-X2-C2~16アルキル、-CH2-X2-C1~15アルキル、-X1-C(=Y4)C1~15アルキル、-CH2-C(=Y4)C1~15アルキル、-X2-C(=Y4)C1~15アルキレン-Z1-C1~15アルキル、-CH2-C(=Y4)C1~15アルキレン-Z1-C1~15アルキル、-C3~17アルキレン-Z1-C1~15アルキル、-X2-C2~16アルキレン-Z1-C1~15アルキル、-CH2-X2-C1~15アルキレン-Z1-C1~15アルキル、-X2-C(=Y4)C1~15アルキレン-Z2又は-X2-C2~16アルキレン-Z2であり;X1、X2、Y4、Z1及びZ2は、本明細書において定義されるとおりである。R2a、R2b及びR2cは、-CH(R10)(R11)であり得、ここで、R10は、出現するごとに、独立して、C1~21アルキル、-X1-C2~20アルキル又は-CH2-X1-C1~19アルキルであり;R11は、出現するごとに、独立して、C3~17アルキル、-X2-C2~16アルキル、-CH2-X2-C1~15アルキル、-X1-C(=Y4)C1~15アルキル、-CH2-C(=Y4)C1~15アルキル、-X2-C(=Y4)C1~15アルキレン-Z1-C1~15アルキル、-CH2-C(=Y4)C1~15アルキレン-Z1-C1~15アルキル、-C3~17アルキレン-Z1-C1~15アルキル、-X2-C2~16アルキレン-Z1-C1~15アルキル、-CH2-X2-C1~15アルキレン-Z1-C1~15アルキル又は-X2-C(=Y4)C1~15アルキレン-Z2であり;X1、X2、Y4、Z1及びZ2は、本明細書において定義されるとおりである。
で表され得る。ある実施形態において、R10は、C1~21アルキルであり;R11は、出現するごとに、独立して、-O-C(=O)C1~15アルキル、-O-C2~16アルキル、-O-C(=O)C1~15アルキレン-Z2又は-X2-C2~16アルキレン-Z2であり;R3aは、-OP(O)(OH)2、-OSO3H又は-OCH2-P(O)(OH)2であり;R3bは、H、CO2H又はCO2Hのエステルであり;Z2は、出現するごとに、独立して、フェニル又は5員~6員ヘテロアリールであり、ここで、Z2は、C1~4アルキル、C1~4ハロアルキル、-OC1~4アルキル、-OC1~4ハロアルキル、シアノ及びハロゲンから独立して選択される1~5つの置換基で任意選択的に置換される。ある実施形態において、R10は、C1~21アルキルであり;R11は、出現するごとに、独立して、-O-C(=O)C1~15アルキル、-O-C2~16アルキル又は-O-C(=O)C1~15アルキレン-Z2であり;R3aは、-OP(O)(OH)2、-OSO3H又は-OCH2-P(O)(OH)2であり;R3bは、H、CO2H又はCO2Hのエステルであり;Z2は、出現するごとに、独立して、フェニル又は5員~6員ヘテロアリールであり、ここで、Z2は、C1~4アルキル、C1~4ハロアルキル、-OC1~4アルキル、-OC1~4ハロアルキル、シアノ及びハロゲンから独立して選択される1~5つの置換基で任意選択的に置換される。ある実施形態において、R10は、C1~21アルキルであり;R11は、出現するごとに、独立して、-O-C(=O)C1~15アルキル、-O-C2~16アルキル又は-O-C(=O)C1~15アルキレン-Z2であり;R3aは、-OP(O)(OH)2、-OSO3H又は-OCH2-P(O)(OH)2であり;R3bは、H、CO2H又はCO2Hのエステルであり;Z2は、出現するごとに、独立して、C1~4アルキル、C1~4ハロアルキル、-OC1~4アルキル、-OC1~4ハロアルキル、シアノ及びハロゲンから独立して選択される1~5つの置換基で任意選択的に置換されるフェニルである。
外来抗原が免疫系に抗原を付与する場合、それは、自然及び獲得免疫系の両方の調整の取れた相互作用によって特徴付けられる防御反応を引き起こすことによって応答する。これらの2つの独立した系は、速度(自然系によって寄与される)及び特異性(適応系によって寄与される)という2つの相互に排他的な要件を満たす。
本発明の別の態様において、薬学的に許容される組成物が提供され、ここで、これらの組成物は、本明細書に記載される化合物のいずれかを含み、任意選択的に薬学的に許容される担体、アジュバント又はビヒクルを含む。特定の実施形態において、これらの組成物は、任意選択的に、1つ以上のさらなる治療剤をさらに含む。一実施形態において、医薬組成物は、治療有効量の本発明の化合物又はその薬学的に許容される塩及び1つ以上の薬学的に許容される担体又はビヒクルを含む。
本発明の化合物は、以下のスキーム及び実施例に示されるように調製され得る。
Bn:ベンジル
Calcd:計算値
Cbz:ベンジルオキシカルボニル
DIAD:アゾジカルボン酸ジイソプロピル
DPPA:ジフェニルホルホリルアジド
EDC:1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミドメチオジド
Et:エチル
ESI-TOF:飛行時間型エレクトロスプレーイオン化
FA:脂肪酸
HRMS:高分解能質量分析法
Me:メチル
Ph:フェニル
ppm:百万分率
psig:ポンド/平方インチ
pyr:ピリジン
Tf:トリフラート
TFA:トリフルオロ酢酸
2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]エチル2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-ホスホノ-β-D-アロピラノシド(化合物1)の調製
塩化メチレン(350mL)及びH2O(350mL)中の1,3,4,6-テトラ-O-アセチル-2-アミノ-2-デオキシ-β-D-グルコピラノース塩酸塩(76.47g、0.23mol)の溶液を、ゆっくりと少しずつ加えられる炭酸水素ナトリウム(149.94g、1.79mol)で処理した。クロロギ酸ベンジル(79.17g、0.46mol)を、ガス発生を制御するために少しずつ加え、反応物を2.5時間にわたって激しく撹拌した。層を分離し、水性層を塩化メチレン(100mL)で抽出した。組み合わされた有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウム上で乾燥させ、ろ過し、約100mLになるまで濃縮した。メチル-t-ブチルエーテル(200mL)を加え、得られた混合物を撹拌し、0℃に冷却し、沈殿物をろ過によって収集し、低温のメチル-t-ブチルエーテルで洗浄し、真空オーブン中で乾燥させて、88.89g(81%)の1,3,4,6-テトラ-O-アセチル-2-(ベンジルオキシカルボニルアミノ)2-デオキシ-β-D-グルコピラノシドを得た。
-15℃に冷却された、無水塩化メチレン(80mL)中の上記の実施例1Aにおいて調製された化合物(10g、20.8mmol)及びベンジルN-(2-ヒドロキシエチル)カルバメート(4.48g、22.9mmol)の溶液をトリメチルシリルトリフラート(0.37mL、2.08mmol)により滴下処理した。反応混合物を5.5時間にわたって室温に温めた。反応物を飽和炭酸水素ナトリウム水溶液(40mL)でクエンチし、層を分離した。水性層を塩化メチレン(2×20mL)で抽出し、組み合わされた有機層を無水硫酸ナトリウム上で乾燥させ、ろ過し、減圧下で濃縮した。得られた粗生成物を塩化メチレン/ヘプタンから結晶化させて、10.4g(81%)の2-(ベンジルオキシカルボニルアミノ)エチル3,4,6-トリ-O-アセチル-2-ベンジルオキシカルボニルアミノ-2-デオキシ-β-D-グルコピラノシドを白色の固体として得た。
メタノール(160mL)中の上記の実施例1Bにおいて調製された化合物(10g、16.3mmol)の溶液を室温で2時間にわたって水酸化アンモニウム(20当量)で処理した。反応混合物を濃縮し、高真空下で一晩乾燥させて、8g(100%)の2-(ベンジルオキシカルボニルアミノ)エチル2-ベンジルオキシカルボニルアミノ-2-デオキシ-β-D-グルコピラノシドを白色の固体として得て、それをさらに精製せずに使用した。
アセトニトリル(180mL)中の上記の実施例1Cにおいて調製された化合物(8g、16.3mmol)の溶液をベンズアルデヒドジメチルアセタール(4.9mL、32.6mmol)及びカンファースルホン酸(1.9g、8.2mmol)で処理した。反応物を3時間撹拌し、飽和炭酸水素ナトリウム水溶液で中和し、ろ過し、減圧下で濃縮した。粗生成物を酢酸エチル/ヘプタンから結晶化させて、7.1g(75%)の2-(ベンジルオキシカルボニルアミノ)エチル4,6-O-ベンジリデン-2-デオキシ-2-ベンジルオキシカルボニルアミノ-2-デオキシ-β-D-グルコピラノシドを白色の固体として得た。
無水テトラヒドロフラン(40mL)中の上記の実施例1Dにおいて調製された化合物(1.5g、2.59mmol)の溶液をトリエチルアミン(0.54mL、3.89mmol)及びトリフェニルホスフィン(1.09g、4.14mmol)で処理した。反応混合物を0℃に冷却し、アゾジカルボン酸ジイソプロピル(0.82mL、4.14mmol)を加えた。0℃で45分後、ジフェニルホルホリルアジド(0.89mL、4.14mmol)を加えた。反応物を徐々に室温まで温め、撹拌を18時間にわたって続けた。反応混合物を減圧下で濃縮し、残渣をシリカゲル上でクロマトグラフィー(グラジエント溶離、20→70%の酢酸エチル/ヘプタン)にかけて、1.16g(74%)の2-(ベンジルオキシカルボニルアミノ)エチル3-アジド-4,6-O-ベンジリデン-2-ベンジルオキシカルボニルアミノ-2,3-ジデオキシ-β-D-アロピラノシドを白色の固体として得た。
無水テトラヒドロフラン(100mL)中の上記の実施例1Eにおいて調製された化合物(2.95g、4.89mmol)の溶液を0.1Nの水酸化ナトリウムの溶液(9.8mL、0.98mmol)及びテトラヒドロフラン(7.8mL、7.82mmol)中の1.0Mのトリメチルホスフィンの溶液で処理した。反応物を室温で18時間撹拌した。反応混合物を減圧下で濃縮した。残渣をシリカゲル上でクロマトグラフィー(グラジエント溶離、30→100%の酢酸エチル/ヘプタン、次に0→10%のメタノール/クロロホルム)にかけて、2.37g(84%)の2-(ベンジルオキシカルボニルアミノ)エチル3-アミノ-4,6-O-ベンジリデン-2-ベンジルオキシカルボニルアミノ-2,3-ジデオキシ-β-D-アロピラノシドを白色の固体として得た。
無水塩化メチレン(10mL)中の上記の実施例1Fにおいて調製された化合物(0.5g、0.87mmol)の溶液を2時間にわたって室温において(R)-3-デカノイルオキシテトラデカン酸(414mg、1.04mmol)及び1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミドメチオジド(310mg、1.04mmol)でアシル化した。反応混合物を飽和炭酸水素ナトリウム水溶液(5mL)でクエンチし、層を分離した。水性層をクロロホルム(2×5mL)で抽出し、組み合わされた有機層を水(5mL)で洗浄し、無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮した。シリカゲル上でのクロマトグラフィー(グラジエント溶離、10→60%の酢酸エチル/ヘプタン)により、748mg(90%)の2-(ベンジルオキシカルボニルアミノ)エチル4,6-O-ベンジリデン-2-ベンジルオキシカルボニルアミノ-3-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシドを無色油として得た。
無水テトラヒドロフラン(20mL)中の上記の実施例1Gにおいて調製された化合物(745mg、0.78mmol)の溶液を24時間にわたって室温及び50psigでParr水素化装置を用いて、10%のパラジウム炭素(220mg)とともに水素化した。反応混合物をCeliteに通してろ過し、ろ液を減圧下で濃縮した。得られた油を塩化メチレン(10mL)に溶解させ、2時間にわたって室温において(R)-3-デカノイルオキシテトラデカン酸(680mg、1.71mmol)及び1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミドメチオジド(510mg、1.71mmol)でアシル化した。反応混合物を飽和炭酸水素ナトリウム水溶液(10mL)でクエンチし、層を分離した。水性層を塩化メチレン(2×10mL)で抽出し、組み合わされた有機層を水(10mL)で洗浄し、無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮した。シリカゲル上でのクロマトグラフィー(グラジエント溶離、20→80%の酢酸エチル/ヘプタン)により、732mg(65%)の2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]エチル4,6-O-ベンジリデン-2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシドをガラス状固体として得た。
0℃に冷却された無水塩化メチレン(20mL)中の上記の実施例1Hにおいて調製された化合物(400mg、0.282mmol)の溶液をシアノ水素化ホウ素ナトリウム(42mg、0.655mmol)で処理した後、トリフルオロ酢酸(0.06mL、0.786mmol)を加えた。反応混合物を徐々に室温まで温め、3時間にわたって撹拌し続けた。反応物をメタノール(2mL)でクエンチし、減圧下で濃縮し、次に塩化メチレンでもどし、炭酸水素ナトリウムの飽和溶液で洗浄した。層を分離し、水性層を塩化メチレン(2×10mL)で抽出し、組み合わされた有機層を無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮した。シリカゲル上でのクロマトグラフィー(グラジエント溶離、10→95%の酢酸エチル/ヘプタン)により、380mg(93%)の2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]エチル6-O-ベンジル-2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシドを無色油として得た。
無水塩化メチレン(10mL)中の上記の実施例1Iにおいて調製された化合物(150mg、0.103mmol)の溶液をジベンジルジイソプロピルホスホロアミダイト(0.049mL、0.144mmol)及び4,5-ジシアノイミダゾール(17mg、0.144)でリン酸化し、室温で2時間撹拌した。反応混合物を0℃に冷却し、30分間にわたって過酸化水素(2mL)で処理した。反応混合物を飽和炭酸水素ナトリウム水溶液(5mL)の添加によってクエンチし、室温で15分間撹拌した。水性層を塩化メチレン(3×5mL)で抽出し、組み合わされた有機層を水(5mL)で洗浄し、無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮した。シリカゲル上でのクロマトグラフィー(グラジエント溶離、10→70%の酢酸エチル/ヘプタン)により、112mg(64%)の2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]エチル6-O-ベンジル-4-O-ジベンジルホスフィノ-2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシドを泡状固体として得た。
無水テトラヒドロフラン(3mL)中の上記の実施例1Jにおいて調製された化合物(110mg、0.064mmol)の溶液を、36時間にわたって室温及び50psigでParr水素化装置を用いて、10%のパラジウム炭素(30mg)の存在下で水素化した。反応混合物をCeliteに通してろ過し、ろ液を減圧下で濃縮した。クロロホルム-メタノール-水-トリエチルアミンを用いたシリカゲル上でのクロマトグラフィー(グラジエント溶離;90:10:0.5:0.5→70:30:2:0.5)。精製された生成物を含有する画分を組み合わせて、減圧下で濃縮し、次に低温の2:1のクロロホルム-メタノール(14mL)に再溶解させ、低温の0.1Nの塩酸塩水溶液(5.52mL)で洗浄した。下側の有機層を無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮して、64mg(70%)の2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]エチル2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-ホスホノ-β-D-アロピラノシドをガラス状固体として得た:1H NMR(CDCl3/CD3OD):δ(ppm)5.21(br s,3H)、4.60-4.50(m,3H)、4.08-4.01(m,2H)、3.85-3.80(m,2H)、3.71-3.68(m,1H)、3.52-3.31(m,4H)、2.64-2.18(m,12H)、1.59(br s,12H)、1.40-1.15(m,90H)、0.88(t,J=6.4Hz、18H);HRMS(ESI-TOF)m/z:C80H152N3O16P[M-H]-についての計算値1441.0832、実測値1441.0755。
2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]エチル2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-スルホキシ-β-D-アロピラノシド(化合物2)の調製
無水ジメチルホルムアミド(5mL)中の実施例1I-(9)において調製された化合物(105mg、0.072mmol)の溶液を三酸化硫黄トリエチルアミン錯体(78mg、0.43mmol)で処理した。反応物を5時間にわたって50℃に加熱した。さらなる量の三酸化硫黄トリエチルアミン錯体(100mg、0.55mmol)を加え、反応物を50℃で18時間撹拌した。反応混合物を減圧下で濃縮した。C18カラム上でのクロマトグラフィー(グラジエント溶離、5→20%の塩化メチレン+1%のトリエチルアミン/メタノール)により、90mg(82%)の2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]エチル6-O-ベンジル-2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-スルホキシ-β-D-アロピラノシドトリエチルアンモニウム塩を白色の塩として得た。
2:1の無水テトラヒドロフラン:メタノールの混合物(5mL)中の上記の実施例2Aにおいて調製された化合物(70mg、0.045mmol)の溶液を、18時間にわたって室温及び50psigでParr水素化装置を用いて、20%の水酸化パラジウム/炭素(30mg)及びトリエチルアミン(0.034mL、0.00024mmol)の存在下で水素化した。反応混合物をCeliteに通してろ過し、ろ液を減圧下で濃縮した。C18シリカカラム上でのクロマトグラフィー(グラジエント溶離、5→20%の塩化メチレン+1%のトリエチルアミン/メタノール)を行い、精製された材料を低温の2:1のクロロホルム-メタノール(8mL)に溶解させ、低温の0.1Nの塩酸塩水溶液(1.6mL)で洗浄した。下側の有機層を無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮した。残渣を(1~2当量)トリエチルアミンで塩にして、28mg(43%)の2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]エチル2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-スルホキシ-β-D-アロピラノシドトリエチルアンモニウム塩をガラス状固体として得た:1H NMR(CDCl3/CD3OD):δ(ppm)7.84(t,J=5.5Hz、1H)、7.55(d,J=8.0Hz、1H)、7.22(d,J=9.0Hz、1H)、5.27-5.23(m,3H)、4.65(br s,1H)、4.59-4.55(m,2H)、4.26-4.21(m,1H)、4.19-4.15(m,1H)、3.85-3.79(m,2H)、3.73-3.70(m,1H)、3.51-3.43(m,2H)、3.18(q,J=7.5Hz、7H、トリエチルアミン(約1.2当量)のCH2)、2.62-2.19(m,12)、1.64-1.52(m,12H)、1.37-1.26(m,100H、トリエチルアミンの10個のCH3を含む)、0.88(t,J=7.0Hz、18H);HRMS(ESI-TOF)m/z:C80H151N3O16S[M-H]-についての計算値1441.0737、実測値1441.0714。
N-[(R)-3-デカノイルオキシテトラデカノイル]-O-[2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-ホスホノ-β-D-アロピラノシル]-L-セリンメチルエステル(化合物3)の調製
1:1の塩化メチレン:水(160mL)中のL-セリンメチルエステル塩酸塩(11.4g、73.3mmol)の懸濁溶液を炭酸水素ナトリウム(74g、879mmol)で処理した後、クロロギ酸ベンジル(12.4mL、87.9mmol)を滴下して加えた。反応物を18時間にわたって激しく撹拌した。層を分離し、水性層を塩化メチレン(2×30mL)で抽出し、組み合わされた有機層を無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮した。シリカゲル上でのクロマトグラフィー(グラジエント溶離、10→50%の酢酸エチル/ヘプタン)により、16.8g(91%)のN-ベンジルオキシカルボニル-L-セリンメチルエステルを無色油として得た。
実施例1Bに記載されるのと類似の方法において、上記の実施例3Aにおいて調製された化合物(16.8g、66.3mmol)及び実施例1Aにおいて調製された化合物(38g、73.0mmol)の溶液を三フッ化ホウ素エーテラート(11.3mL、79.6mmol)の存在下で反応させて、45.5g(定量的)のN-ベンジルオキシカルボニル-O-(3,4,6-トリ-O-アセチル-2-ベンジルオキシカルボニルアミノ-2-デオキシ-β-D-グルコピラノシル)-L-セリン-メチルエステルを粘性油として得て、それをさらに精製せずに使用した。
実施例1Cに記載されるのと類似の方法において、実施例3Bにおいて調製された化合物(15g、22.2mmol)の溶液をメタノール(6mL、44.5mmol)中のマグネシウムメトキシドの6~10%の溶液の存在下で脱アシル化して、4.7g(39%)のN-ベンジルオキシカルボニル-O-[2-ベンジルオキシカルボニルアミノ)-2-デオキシ-β-D-グルコピラノシル]-L-セリン-メチルエステルを無色油として得た。
実施例1Dに記載されるのと類似の方法において、アセトニトリル(20mL)中の上記の実施例3Cにおいて調製された化合物(4.7g、8.57mmol)の溶液を、ベンズアルデヒドジメチルアセタール(2.6mL、17.14mmol)及びカンファースルホン酸(1.0g、4.28mmol)を用いて保護して、4.08g(75%)のN-ベンジルオキシカルボニル-O-[4,6-O-ベンジリデン-2-ベンジルオキシカルボニルアミノ-2-デオキシ-β-D-グルコピラノシル]-L-セリンメチルエステルを白色の固体として得た。
実施例1Eに記載されるのと類似の方法において、実施例3Dにおいて調製された化合物(2.0g、3.14mmol)の溶液にトリエチルアミン(0.66mL、4.71mmol)、トリフェニルホスフィン(1.32g、5.03mmol)及びアゾジカルボン酸ジイソプロピル(1.0mL、5.03mmol)により光延反応を行った後、ジフェニルホルホリルアジド(1.08mL、5.03mmol)を加えて、1.37g(66%)のN-ベンジルオキシカルボニル-O-[3-アジド-4,6-O-ベンジリデン-2-ベンジルオキシカルボニルアミノ-2,3-ジデオキシ-β-D-アロピラノシル]-L-セリン-メチルエステルを白色の泡状固体として得た。
無水テトラヒドロフラン(10mL)中の上記の実施例3Eにおいて調製された化合物(0.52g、0.79mmol)の溶液を、36時間にわたって室温及び50psigでParr水素化装置を用いて、10%のパラジウム炭素(100mg)及び(0.10mL)ピリジンとともに水素化した。反応混合物をCeliteのパッドに通過させ、減圧下で濃縮し、トルエン(2×10mL)で共沸的に(azeotropically)洗浄し、次に減圧下で濃縮し、48時間にわたって減圧下に保った。0℃に冷却された無水塩化メチレン(10mL)中の得られた泡状固体を(R)-3-デカノイルオキシテトラデカン酸(1.0g、2.50mmol)及び1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミドメチオジド(0.74g、2.50mmol)でアシル化した。室温で2時間撹拌した後、反応混合物を飽和炭酸水素ナトリウム水溶液(10mL)でクエンチし、層を分離した。水性層をクロロホルム(2×10mL)で抽出し、組み合わされた有機層を水(10mL)で洗浄し、無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮した。シリカゲル上でのクロマトグラフィー(グラジエント溶離、20→60%の酢酸エチル/ヘプタン)により、230mg(20%)のN-[(R)-3-デカノイルオキシテトラデカノイル]-O-[4,6-O-ベンジリデン-2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシル]-L-セリンメチルエステルをガラス状固体として得た。
実施例1Iと類似の方法において、上記の実施例3Fにおいて調製された化合物(210mg、0.15mmol)をシアノ水素化ホウ素ナトリウム(46mg、0.73mmol)及びトリフルオロ酢酸(0.066mL、0.87mmol)で処理して、200mg(91%)のN-[(R)-3-デカノイルオキシテトラデカノイル]-O-[6-O-ベンジル-2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシル]-L-セリンメチルエステルを無色油として得た。
実施例1Jと類似の方法において、上記の実施例3Gにおいて調製された化合物(200mg、0.13mmol)の溶液をジベンジルジイソプロピルホスホロアミダイト((、0.079mL、0.234mmol)、4,5-ジシアノイミダゾール(27mg、0.234mmol)及び過酸化水素(1mL)でリン酸化して、45mg(19%)のN-[(R)-3-デカノイルオキシテトラデカノイル]-O-[6-O-ベンジル-4-O-ジベンジルホスフィノ-2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシル]-L-セリンメチルエステルを泡状固体として得た。
実施例1Kと類似の方法において、上記の実施例3Hにおいて調製された化合物(45mg、0.025mmol)の溶液を、16時間にわたって室温及び50psigでParr水素化装置を用いて、10%のパラジウム炭素(30mg)の存在下で水素化した。反応混合物をCeliteに通してろ過し、ろ液を減圧下で濃縮した。C18カラム上でのクロマトグラフィー(グラジエント溶離、5→20%の塩化メチレン+1%のトリエチルアミン/メタノール)により、材料を得て、それを低温の2:1のクロロホルム-メタノール(8mL)に溶解させ、低温の0.1Nの塩酸塩水溶液(1.6mL)で洗浄した。下側の有機層を分離し、無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮して、28mg(82%)のN-[(R)-3-デカノイルオキシテトラデカノイル]-O-[2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-ホスホノ-β-D-アロピラノシル]-L-セリンメチルエステルをガラス状固体として得た:1H NMR(CDCl3/CD3OD):δ(ppm)7.93(d,J=8.0Hz、1H)、7.21(d,J=9.0Hz、1H)、5.26-5.19(m,3H)、4.67-4.64(m,1H)、4.59(d,J=2.5Hz、1H)、4.51-4.45(m,2H)、4.21-4.19(m,1H)、4.09-4.06(m,2H)、3.76(s,3H)、3.74-3.70(m,1H)、3.66-3.63(m,2H)、2.64-2.19(m,12H)、1.60(br s,12H)、1.26(br s,90H)、0.88(t,J=7.0Hz、18H);HRMS(ESI-TOF)m/z:C82H154N3O18P[M-H]-についての計算値1499.0887、実測値1499.0816。
N-[(R)-3-デシルオキシテトラデカノイル]-O-[2,3-ジ-[(R)-3-デシルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-ホスホノ-]-β-D-アロピラノシル]-L-セリン(化合物4)の調製
実施例3Fと類似の方法において、実施例3Eにおいて調製された化合物(1.37g、2.07mmol)の溶液を、36時間にわたって室温及び50psigでParr水素化装置を用いて、10%のパラジウム炭素(200mg)及び(0.20mL)ピリジンの存在下で水素化した。対応する残渣を(R)-3-デシルオキシテトラデカン酸(2.64g、7.24mmol)(米国特許第7,960,522号明細書)及び1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミドメチオジド(2.15g、7.24mmol)でアシル化して、940mg(31%)のN-[(R)-3-デシルオキシテトラデカノイル]-O-[4,6-O-ベンジリデン-2-デオキシ-2-[(R)-3-デシルオキシテトラデカノイルアミノ]-3-デオキシ-3-[(R)-3-デシルオキシテトラデカノイルアミノ]-β-D-アロピラノシル]-L-セリンメチルエステルをガラス状固体として得た。
実施例1Iと類似の方法において、上記の実施例4Aにおいて調製された化合物(940mg、0.64mmol)の溶液をシアノ水素化ホウ素ナトリウム(242mg、3.84mmol)及びトリフルオロ酢酸(0.24mL、3.2mmol)で処理して、600mg(64%)のN-[(R)-3-デシルオキシテトラデカノイル]-6-ベンジル-4-ヒドロキシ-2-デオキシ-2-デシルオキシテトラデカンアミド-3-デオキシ-3-[(R)-3-デシルオキシテトラデカノイルアミノ-β-D-アロピラノシド]-L-セリンメチルエステルを無色油として得た。
実施例1Jと類似の方法において、上記の実施例4Bにおいて調製された化合物(450mg、0.31mmol)の溶液をジベンジルジイソプロピルホスホロアミダイト(0.14mL、0.44mmol)、4,5-ジシアノイミダゾール(51mg、0.44mmol)及び過酸化水素(3mL)でリン酸化して、410mg(78%)のN-[(R)-3-デシルオキシテトラデカノイル]-O-[6-O-ベンジル-4-O-ジベンジルホスフィノ-2,3-ジ-[(R)-3-デシルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシル]-L-セリンメチルエステルを泡状固体として得た。
実施例1Kと類似の方法において、上記の実施例4Cにおいて調製された化合物(200mg、0.12mmol)の溶液を、16時間にわたって室温及び50psigでParr水素化装置を用いて、10%のパラジウム炭素(80mg)の存在下で水素化した。反応混合物をCeliteのパッドに通してろ過し、ろ液を減圧下で濃縮した。C18カラム上でのクロマトグラフィー(グラジエント溶離、5→20%の塩化メチレン+1%のトリエチルアミン/メタノール)により、70mg(40%)のN-[(R)-3-デシルオキシテトラデカノイル]-O-[2,3-ジ-[(R)-3-デシルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-ホスフィノ-β-D-アロピラノシル]-L-セリンメチルエステルをガラス状固体として得た。
上記の実施例4Dにおいて調製された化合物(70mg、0.048mmol)の溶液をTHF(1mL)に溶解させ、0℃に冷却し、1時間にわたって1Nの水酸化ナトリウム(0.012mL、0.192mmol)で水素化した。反応混合物を、氷冷した1Nの塩酸塩で中和して、pHを3にした。層を分離し、水性層を塩化ナトリウムで飽和させ、クロロホルム(3×5mL)で抽出した。有機層を組み合わせて、無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮した。シリカゲル上でのクロマトグラフィーを、クロロホルム-メタノール-水-トリエチルアミン(グラジエント溶離;90:10:0.5:0.5→70:30:2:0.5)を用いて行った。精製された生成物を含有する画分を組み合わせて、減圧下で濃縮し、次に低温の2:1のクロロホルム-メタノール(14mL)に再溶解させ、低温の0.1Nの塩酸塩水溶液(5.52mL)で洗浄した。下側の有機層を分離し、無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮して、30mg(41%)のN-[(R)-3-デシルオキシテトラデカノイル]-O-[2,3-ジ-[(R)-3-デシルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-ホスホノ-β-D-アロピラノシル]-L-セリンをガラス状固体として得た:1H NMR(CDCl3/CD3OD):δ(ppm)4.68-4.63(m,3H)、4.44-4.40(m,1H)、4.13(dd,J=11&6.5Hz、1H)、4.08(t,J=4.75Hz、1H)、3.79-3.66(m,6H)、3.50-3.38(m,7H)、2.52-2.28(m,6H)、1.53-1.50(m,12H)、1.33-1.25(m,96)0.87(t,J=7.0Hz、18H);HRMS(ESI-TOF)m/z:C81H158N3O15P[M-H]-についての計算値1443.1352、実測値1443.1295。
N-[(R)-3-デシルオキシテトラデカノイル]-O-[2,3-ジ-[(R)-3-デシルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-スルホキシ-β-D-アロピラノシル]-L-セリン(化合物5)の調製
無水ジメチルホルムアミド(5mL)に溶解された実施例4Bにおいて調製された化合物(150mg、0.102mmol)の溶液を三酸化硫黄トリエチルアミン錯体(111mg、0.613mmol)で処理した。反応物、5時間にわたって50℃に加熱した。さらなる量の三酸化硫黄トリエチルアミン錯体(111mg、0.613mmol)を再度加え、反応物を50℃で18時間撹拌した。反応混合物を減圧下で濃縮した。シリカゲル上でのクロマトグラフィーを、クロロホルム-メタノール-水-トリエチルアミン(グラジエント溶離;90:10:0.5:0.5→70:30:2:0.5)を用いて行って、96mg(62%)のN-[(R)-3-デシルオキシテトラデカノイル]-O-[6-O-ベンジル-2,3-ジ-[(R)-3-デシルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-スルホキシ-β-D-アロピラノシル]-L-セリンメチルエステルをガラス状固体として得た。
2:1の無水テトラヒドロフラン:メタノールの混合物(5mL)に溶解された上記の実施例5Aにおいて調製された化合物(96mg、0.062mmol)の溶液を、18時間にわたって室温及び50psigの圧力でParr水素化装置を用いて、20%の水酸化パラジウム/炭素(60mg)及びトリエチルアミン(0.044mL、0.0003mmol)の存在下で水素化した。反応混合物をCeliteのパッドに通してろ過し、ろ液を減圧下で濃縮した。シリカゲル上でのクロマトグラフィーを、クロロホルム-メタノール-水-トリエチルアミン(グラジエント溶離;90:10:0.5:0.5→70:30:2:0.5)を用いて行って、58mg(55%)のN-[(R)-3-デシルオキシテトラデカノイル]-O-[2,3-ジ-[(R)-3-デシルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-スルホキシ-β-D-アロピラノシル]-L-セリンメチルエステルをガラス状固体として得た。
上記の実施例5Bにおいて調製された化合物(58mg、0.040mmol)の溶液をTHF(2mL)に溶解させ、0℃に冷却し、1時間にわたって1Nの水酸化ナトリウム(0.08mL、0.08mmol)で水素化した。反応混合物を、氷冷した1Nの塩酸塩で中和して、pHを3にした。層を分離し、水性層を塩化ナトリウムで飽和させ、クロロホルム(3×5mL)で抽出した。組み合わされた有機層を無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮した。シリカゲル上でのクロマトグラフィーを、クロロホルム-メタノール-水-トリエチルアミン(グラジエント溶離;90:10:0.5:0.5→70:30:2:0.5)を用いて行った。精製された生成物を含有する画分を組み合わせて、減圧下で濃縮し、次に低温の2:1のクロロホルム-メタノール(14mL)に再溶解させ、低温の0.1Nの塩酸塩水溶液(5.52mL)で洗浄した。下側の有機層を無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮して、15mg(26%)のN-[(R)-3-デシルオキシテトラデカノイル]-O-[2,3-ジ-[(R)-3-デシルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-スルホキシ-β-D-アロピラノシル]-L-セリンをガラス状固体として得た:1H NMR(CDCl3/CD3OD):δ(ppm)7.74(d,J=7.0Hz、1H)、7.30(d,J=8.0Hz、1H)、7.02(d,J=8.0Hz、1H)、4.62-4.55(m,3H)、4.17-4.08(m,3H)、3.71-3.60(m,5H)、3.45-3.31(m,6H)、2.49-2.25(m,6H)、1.48-1.45(m,12H)、1.33-1.25(m,96H)0.87(t,J=7.0Hz、18H);HRMS(ESI-TOF)m/z:C81H157N3O15S[M-H]-についての計算値1443.1257、実測値1443.1187。
2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]エチル2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-メチルホスホノ-β-D-アロピラノシド(化合物6)の調製
亜リン酸ジベンジル(1.54g、5.87mmol)中のパラホルムアルデヒド(190mg、6.3mmol)の溶液を無水トリエチルアミン(100mg、mmol)で処理した。反応物を15分間にわたって50℃に加熱し、温度を、2時間にわたって85℃まで徐々に上昇させた。反応混合物をクロロホルム(20mL)で希釈し、次に減圧下で濃縮した。シリカゲル上でのクロマトグラフィー(グラジエント溶離、20→100%の酢酸エチル/ヘプタン)により、1.04g(58%)のジベンジルヒドロキシメチルホスホネートを無色油として得た。
無水塩化メチレン(5mL)中の、-50℃に冷却された、上記の実施例6Aにおいて調製された化合物(500mg、1.71mmol)及び2,6-ルチジン(5.0mL、42.8mmol)の溶液をトリフルオロメタンスルホン酸無水物(0.33mL、2.05mmol)の滴下添加により処理した。反応物を0℃まで徐々に温めた。反応混合物をEt2O(30mL)で希釈し、H2O(10mL)、1NのHCl(10mL)及び塩水(10mL)で連続して洗浄した。有機層を無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮して、724mg(定量的)の[ジ(ベンジルオキシ)ホスホリル]メチルトリフラートをピンク色の油として得た。
無水THF(2mL)中の実施例1Iにおいて調製された化合物(100mg、0.065mmol)の溶液を不活性雰囲気下で0℃に冷却し、テトラヒドロフラン(0.089mL、0.085mmol)中の1Mのリチウムビス(トリメチルシリル)アミドの溶液で処理した。反応物を0℃で10分間撹拌し、その後、それを、上記の実施例6Bにおいて調製された化合物(50mg、0.24mmol)のテトラヒドロフラン溶液(0.5mL)の滴下添加により処理した。反応混合物を0.1Nの塩酸塩(5滴)でクエンチし、クロロホルム(5mL)で希釈し、分離し、有機物を飽和炭酸水素ナトリウム水溶液(2mL)で洗浄した。水性層をクロロホルム(2×5mL)で抽出し、組み合わされた有機層を無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮した。シリカゲル上でのクロマトグラフィー(グラジエント溶離、20→100%の酢酸エチル/ヘプタン)により、43mg(36%)の2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]エチル6-O-ベンジル-4-O-ジベンジルメチルホスホノ-2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシドを無色油として得た。
無水テトラヒドロフラン(20mL)に溶解された上記の実施例6Cにおいて調製された化合物(43mg、0.025mmol)の溶液を、10%のパラジウム炭素とともにH-Cubeを用いて水素化した(30mm CatCart(登録商標)、1分間にわたって60℃でフルH2モード、これは、周囲圧力での水素化であり、ここで、導入されるH2量は、30mL/分であった)。反応混合物を減圧下で濃縮した。クロロホルム-メタノール-水-トリエチルアミンを用いたシリカゲル上でのクロマトグラフィー(グラジエント溶離;90:10:0.5:0.5→70:30:2:0.5)後、精製された生成物を含有する画分を組み合わせて、減圧下で濃縮し、低温の2:1のクロロホルム-メタノール(8.6mL)に再溶解させ、低温の0.1Nの塩酸塩水溶液(3.4mL)で洗浄した。下側の有機層を無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮して、27mg(75%)の2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]エチル2,3-ジ-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-メチルホスホノ-β-D-アロピラノシドをガラス状固体として得た:1H NMR(CDCl3/CD3OD):δ(ppm)5.19-5.16(m,3H);4.54-4.52(m,2H);3.98(s,2H);3.84-3.82(m,1H);3.78-3.75(m,2H);3.71(s,1H);3.68-3.63(m,2H);3.45-3.37(m,2H);3.31-3.29(m,1H);2.54-2.37(m,6H);2.28-2.22(m,6H);1.56(br s,12H);1.22(br s,90H);0.85(t,J=7.25Hz、18H);HRMS(ESI-TOF)m/z:C81H154N3O16P[M-H]+についての計算値1457.1145、実測値1457.1185。
N-[(R)-3-デシルオキシテトラデカノイル]-O-[2,3-ジ-[(R)-3-デシルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-メチルホスホノ-β-D-アロピラノシル]-L-セリントリエチルアンモニウム塩(化合物7)の調製
実施例6Cと類似の方法において、無水THF(2mL)中の上記の実施例4Bにおいて調製された化合物(150mg、0.102mmol)の溶液を不活性雰囲気下で0℃に冷却し、テトラヒドロフラン(0.135mL、0.133mmol)中の1Mのリチウムビス(トリメチルシリル)アミドの溶液で処理した。反応物を0℃で10分間撹拌し、その後、それを、上記の実施例6Bにおいて調製された化合物(90mg、0.173mmol)のテトラヒドロフラン溶液(0.5mL)の滴下添加により処理した。反応物を0℃で2時間撹拌した。反応混合物を0.1Nの塩酸塩(5滴)でクエンチし、クロロホルム(5mL)で希釈し、分離し、有機層を飽和炭酸水素ナトリウム水溶液(2mL)で洗浄した。水性層をクロロホルム(2×5mL)で抽出し、組み合わされた有機層を無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮した。シリカゲル上でのクロマトグラフィー(グラジエント溶離、20→100%の酢酸エチル/ヘプタン)により、48mg(27%)のN-[(R)-3-デシルオキシテトラデカノイル]-O-[6-O-ベンジル-2,3-ジ-[(R)-3-デシルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-ジベンジルメチルホスホノ-β-D-アロピラノシル]-L-セリンメチルエステルを無色油として得た。
無水テトラヒドロフラン(20mL)に溶解された上記の実施例7Aにおいて調製された化合物(160mg、0.092mmol)の溶液を、18時間にわたって室温及び50psigの圧力でParr水素化装置を用いて、10%のパラジウム炭素(48mg)の存在下で水素化した。反応混合物をCeliteのパッドに通してろ過し、ろ液を減圧下で濃縮した。C18カラムを用いた逆相クロマトグラフィー(グラジエント溶離、0→100%のクロロホルム/メタノール)により、91mg(67%)のN-[(R)-3-デシルオキシテトラデカノイル]-O-[2,3-ジ-[(R)-3-デシルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-メチルホスホノ-β-D-アロピラノシル]-L-セリンメチルエステルをガラス状固体として得た。
上記の実施例7Bにおいて調製された化合物(91mg、0.062mmol)の溶液をTHF(2mL)に溶解させ、0℃に冷却し、1時間にわたって1Nの水酸化リチウム(0.26mL、0.26mmol)で水素化した。反応混合物を、氷冷した1Nの塩酸塩で中和して、pHを5にした。層を分離し、水性層を塩化ナトリウムで飽和させ、クロロホルム(3×5mL)で抽出した。組み合わされた有機層を無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮した。シリカゲル上でのクロマトグラフィーを、(グラジエント溶離;0→30%の[90:10のMeOH/H2O]/クロロホルム)を用いて行った。精製された生成物を含有する画分を組み合わせて、減圧下で濃縮し、次に低温の2:1のクロロホルム-メタノール(14mL)に再溶解させ、低温の0.1Nの塩酸塩水溶液(5.52mL)で洗浄した。下側の有機層を分離し、無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮し、次にトリエチルアミンで塩にして、56mg(62%)のN-[(R)-3-デシルオキシテトラデカノイル]-O-[2,3-ジ-[(R)-3-デシルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-メチルホスホノ-β-D-アロピラノシル]-L-セリントリエチルアンモニウム塩をガラス状固体として得た:1H NMR(CDCl3/CD3OD):δ(ppm)4.61-4.54(m,2H);4.14-4.06(m,2H);3.84(br m,2H);3.69(br m,6H);3.47-3.39(m,8H);3.09(q,J=7.6Hz、2H、Et3N(約1.2当量)のCH2;2.47-2.33(m,6H);1.51-1.45(m,12H);1.26-1.14(m,101H);0.88(t,J=7.0Hz、18H);HRMS(ESI-TOF)m/z:C82H160N3O15P[M-H]-についての計算値1457.1507、実測値1457.1367。
2-[(R)-3-(8-フェニル)オクタノイルオキシテトラデカノイルアミノ]エチル2,3-ジ-[(R)-3-(8-フェニル)オクタノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-ホスホノ-β-D-アロピラノシドトリエチルアンモニウム塩(化合物8)の調製
実施例1Gと類似の方法において、無水塩化メチレン(10mL)中の上記の実施例1Fにおいて調製された化合物(250mg、0.43mmol)の溶液を(R)-3-(8-フェニル)オクタノイルオキシテトラデカン酸(231mg、0.52mmol)((R)-3-ヒドロキシルテトラデカノイルエステルを8-フェニルオクタン酸でアシル化することから調製された)及び1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミドメチオジド(153mg、0.52mmol)でアシル化して、378mg(88%)の2-(ベンジルオキシカルボニルアミノ)エチル4,6-O-ベンジリデン-2-ベンジルオキシカルボニルアミノ-3-[(R)-3-(8-フェニル)オクタノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシドを無色油として得た。
実施例1Hと類似の方法において、無水テトラヒドロフラン(10mL)中の上記の実施例8Aにおいて調製された化合物(189mg、0.19mmol)の溶液を、18時間にわたって室温及び50psigでParr水素化装置を用いて、10%のパラジウム炭素(50mg)とともに水素化した。反応混合物をCeliteに通してろ過し、ろ液を減圧下で濃縮した。塩化メチレン(10mL)に溶解された得られた油を2時間にわたって室温において(R)-3-(8-フェニル)オクタノイルオキシテトラデカン酸(180mg、0.402mmol)及び1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミドメチオジド(119mg、0.402mmol)でアシル化した。反応混合物を飽和炭酸水素ナトリウム水溶液(10mL)でクエンチし、層を分離した。水性層を塩化メチレン(2×10mL)で抽出し、組み合わされた有機層を水(10mL)で洗浄し、無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮した。シリカゲル上でのクロマトグラフィー(グラジエント溶離、20→80%の酢酸エチル/ヘプタン)により、290mg(99%)の2-[(R)-3-(8-フェニル)オクタノイルオキシテトラデカノイルアミノ]エチル4,6-O-ベンジリデン-2,3-ジ-[(R)-3-(8-フェニル)オクタノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシドをガラス状固体として得た。
実施例1Iと類似の方法において、上記の実施例8Bにおいて調製された化合物(290mg、0.182mmol)の溶液をシアノ水素化ホウ素ナトリウム(57mg、0.91mmol)及びトリフルオロ酢酸(0.083mL、1.09mmol)で処理して、231mg(80%)の2-[(R)-3-(8-フェニル)オクタノイルオキシテトラデカノイルアミノ]エチル6-O-ベンジル-2,3-ジ-[(R)-3-(8-フェニル)オクタノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシドを無色油として得た。
実施例1Jと類似の方法において、無水塩化メチレン(10mL)中の上記の実施例8Cにおいて調製された化合物(231mg、0.145mmol)の溶液をジベンジルジイソプロピルホスホロアミダイト(0.070mL、0.203mmol)及び4,5-ジシアノイミダゾール(24mg、0.203)及び過酸化水素(2mL)でリン酸化して、269mg(76%)の2-[(R)-3-(8-フェニルオクタノイルオキシテトラデカノイルアミノ]エチル6-O-ベンジル-4-O-ジベンジルホスフィノ-2,3-ジ-[(R)-3-(8-フェニル)オクタノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシドを泡状固体として得た。
実施例1Kと類似の方法において、無水テトラヒドロフラン(5mL)中の上記の実施例8Dにおいて調製された化合物(269mg、0.145mmol)の溶液を18時間にわたって大気水素ガス(H2バルーン)下において、10%のパラジウム炭素(50mg)の存在下で水素化した。反応混合物をCeliteに通してろ過し、ろ液を減圧下で濃縮した。クロロホルム-メタノール-水-トリエチルアミンを用いたシリカゲル上でのクロマトグラフィー(グラジエント溶離;90:10:0.5:0.5→70:30:2:0.5)。精製された生成物を含有する画分を組み合わせて、減圧下で濃縮し、次に低温の2:1のクロロホルム-メタノール(17mL)に再溶解させ、低温の0.1Nの塩酸塩水溶液(6.72mL)で洗浄した。下側の有機層を無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮し、トリエチルアミンで塩にして、75mg(33%)の2-[(R)-3-(8-フェニル)オクタノイルオキシテトラデカノイルアミノ]エチル2,3-ジ-[(R)-3-(8-フェニル)オクタノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-ホスホノ-β-D-アロピラノシドトリエチルアンモニウム塩をガラス状固体として得た:1H NMR(CDCl3/CD3OD):δ(ppm)7.69(br s,1H)、7.26-7.16(m,15H)、5.21(br s,3H)、4.54-4.39(m,3H)、4.09-4.05(m,2H)、3.78(br s,3H)、3.53-3.39(m,4H)、3.08(q,J=6.8Hz、5H、Et3N(約5/6当量)のCH2、2.58-2.46(m,12H)、2.27(br m,6H)、1.58(br s,12H)、1.31-1.24(m,81H)、0.87(t,J=6.8Hz、9H);HRMS(ESI-TOF)m/z:C92H152N3O16P[M-H]-についての計算値1586.0832、実測値1586.0799。
2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]エチル、2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-3-[(R)-3-(8-フェニル)オクタノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-ホスホノ-β-D-アロピラノシドトリエチルアンモニウム塩(化合物9)の調製
実施例1Hと類似の方法において、無水テトラヒドロフラン(10mL)中の上記の実施例8Aにおいて調製された化合物(189mg、0.19mmol)の糖液を、18時間にわたって室温及び50psigでParr水素化装置を用いて、10%のパラジウム炭素(50mg)とともに水素化した。反応混合物をCeliteに通してろ過し、ろ液を減圧下で濃縮した。塩化メチレン(10mL)に溶解された得られた油を2時間にわたって室温において(R)-3-デカノイルオキシテトラデカン酸(160mg、0.402mmol)及び1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミドメチオジド(119mg、0.402mmol)でアシル化した。反応混合物を飽和炭酸水素ナトリウム水溶液(10mL)でクエンチし、層を分離した。水性層を塩化メチレン(2×10mL)で抽出し、組み合わされた有機層を水(10mL)で洗浄し、無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮した。シリカゲル上でのクロマトグラフィー(グラジエント溶離、20→80%の酢酸エチル/ヘプタン)により、145mg(53%)の2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]エチル4,6-O-ベンジリデン-2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-3-[(R)-3-(8-フェニル)オクタノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシドをガラス状固体として得た。
実施例1Iと類似の方法において、上記の実施例9Aにおいて調製された化合物(145mg、0.097mmol)の溶液をシアノ水素化ホウ素ナトリウム(30mg、0.48mmol)及びトリフルオロ酢酸(0.044mL、0.58mmol)で処理して、103mg(71%)の2-[(R)-デカノイルオキシテトラデカノイルアミノ]エチル6-O-ベンジル-2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-3-[(R)-3-(8-フェニル)オクタノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシドを無色油として得た。
実施例1Jと類似の方法において、無水塩化メチレン(10mL)中の上記の実施例9Bにおいて調製された化合物(103mg、0.069mmol)の溶液をジベンジルジイソプロピルホスホロアミダイト(0.033mL、0.096mmol)及び4,5-ジシアノイミダゾール(11mg、0.096)でリン酸化し、過酸化水素(2mL)で処理して、105mg(87%)の2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]エチル6-O-ベンジル-4-O-ジベンジルホスフィノ-2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-3-[(R)-3-(8-フェニル)オクタノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-β-D-アロピラノシドをガラス状固体として得た。
実施例1Kと類似の方法において、無水テトラヒドロフラン(5mL)中の上記の実施例9Cにおいて調製された化合物(100mg、0.057mmol)の溶液を、18時間にわたって水素大気圧(H2バルーン)を用いて、10%のパラジウム炭素(30mg)の存在下で水素化した。反応混合物をCeliteに通してろ過し、ろ液を減圧下で濃縮した。クロロホルム-メタノール-水-トリエチルアミンを用いたシリカゲル上でのクロマトグラフィー(グラジエント溶離;90:10:0.5:0.5→70:30:2:0.5)。精製された生成物を含有する画分を組み合わせて、減圧下で濃縮し、次に低温の2:1のクロロホルム-メタノール(12mL)に再溶解させ、低温の0.1Nの塩酸塩水溶液(4.8mL)で洗浄した。下側の有機層を無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮し、トリエチルアミンで塩にして、36mg(43%)の2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]エチル2-[(R)-3-デカノイルオキシテトラデカノイルアミノ]-3-[(R)-3-(8-フェニル)オクタノイルオキシテトラデカノイルアミノ]-2,3-ジデオキシ-4-O-ホスホノ-β-D-アロピラノシドをガラス状固体として得た:1H NMR(CDCl3/CD3OD):δ(ppm)7.56(br s,1H)、7.10-7.18(m,5H)、5.14(br m,3H)、4.33-4.47(m,3H)、3.97-4.03(m,2H)、3.63-3.75(m,3H)、3.13-3.40(m,3H)、3.01(q,J=6.8Hz、6H、Et3N(約1当量)のCH2、2.38-2.52(m,8H)、2.21(br s,6H)、1.52(br s,12H)、1.18-1.25(m,87H)、0.88(t,J=6.4Hz、15H);HRMS(ESI-TOF)m/z:C84H152N3O16P[M]-についての計算値1490.0910、実測値1490.0813。
インビトロアッセイを、化合物1~9及び市販のTLR4アゴニストMPLを用いて行った。生物学的活性の測定のために、様々な細胞を広い用量範囲の各化合物で刺激した後、転写活性化(HEK hTLR4 NF-κB-SEAP細胞)又はサイトカイン産生(hMM6若しくはhPBMC)のいずれかの評価を行った。各化合物についての用量反応曲線は、100μM又は20μMのいずれかから開始し、その後、ビヒクル(2%のグリセロール又はグリシン、「IN」)中での5倍連続希釈が続き、最終濃度は、1.6×10-8μM(1.6fM)又は3.3×10-8μM(3.3fM)であった。用量範囲の化合物との18~24時間にわたるインキュベーション後、細胞上清を分析のために収集した。
化合物1、2、3、4、5及び6の水性製剤を2℃~8℃、25℃及び40℃の温度において、安定性評価のために、発熱物質除去された小さいバイアルに等分した。これは、ICH安定性温度指針を反映しているが、湿度は制御しなかった。バイアルを各時点/温度について取り、2週間から開始して12か月まで以下のスケジュールに従って逆相HPLCによって分析した(図9~14)。
R10は、C1~21アルキルであり;
R11は、出現するごとに、独立して、-O-C(=O)C1~15アルキル、-O-C2~16アルキル、-O-C(=O)C1~15アルキレン-Z2又は-X2-C2~16アルキレン-Z2であり;
R3aは、-OP(O)(OH)2、-OSO3H又は-OCH2-P(O)(OH)2であり;
R3bは、H、CO2H又はCO2Hのエステルであり;及び
Z2は、出現するごとに、独立して、フェニル又は5員~6員ヘテロアリールであり、ここで、Z2は、C1~4アルキル、C1~4ハロアルキル、-OC1~4アルキル、-OC1~4ハロアルキル、シアノ及びハロゲンから独立して選択される1~5つの置換基で任意選択的に置換される)
の化合物又はその薬学的に許容される塩。
R1は、
R2a、R2b及びR2cは、それぞれ独立して、C4~22アルキル、-X1-C3~21アルキル、-CH2-X1-C2~20アルキル又は-CH(R10)(R11)であり;
R10は、出現するごとに、独立して、C1~21アルキル、-X1-C2~20アルキル又は-CH2-X1-C1~19アルキルであり;
R11は、出現するごとに、独立して、C3~17アルキル、-X2-C2~16アルキル、-CH2-X2-C1~15アルキル、-X2-C(=Y4)C1~15アルキル、-CH2-C(=Y4)C1~15アルキル、-X2-C(=Y4)C1~15アルキレン-Z1-C1~15アルキル、-CH2-C(=Y4)C1~15アルキレン-Z1-C1~15アルキル、-C3~17アルキレン-Z1-C1~15アルキル、-X2-C2~16アルキレン-Z1-C1~15アルキル、-CH2-X2-C1~15アルキレン-Z1-C1~15アルキル、-X2-C(=Y4)C1~15アルキレン-Z2又は-X2-C2~16アルキレン-Z2であり;
R3a、R3b及びR3cは、それぞれ独立して、CO2H、-OSO3H、-OP(O)(OH)2、-C1~6アルキレン-CO2H、-C1~6アルキレン-OSO3H、-C1~6アルキレン-OP(O)(OH)2、-OC1~6アルキレン-P(O)(OH)2、-C1~6アルキレン-P(O)(OH)2、-C1~6ハロアルキレン-P(O)(OH)2、H又はCO2H、-OSO3H、-OP(O)(OH)2、-C1~6アルキレン-CO2H、-C1~6アルキレン-OSO3H、-C1~6アルキレン-OP(O)(OH)2、-OC1~6アルキレン-P(O)(OH)2、-C1~6アルキレン-P(O)(OH)2若しくは-C1~6ハロアルキレン-P(O)(OH)2のエステルであり;
R3dは、CO2H、-SO3H、-P(O)(OH)2、-C1~6アルキレン-CO2H、-C1~6アルキレン-OSO3H、-C1~6アルキレン-OP(O)(OH)2、-OC1~6アルキレン-P(O)(OH)2、-C1~6アルキレン-P(O)(OH)2、-C1~6ハロアルキレン-P(O)(OH)2、H、C1~6アルキル、C1~6ハロアルキル、C3~8シクロアルキル又はCO2H、-OSO3H、-OP(O)(OH)2、-C1~6アルキレン-CO2H、-C1~6アルキレン-OSO3H、-C1~6アルキレン-OP(O)(OH)2、-OC1~6アルキレン-P(O)(OH)2、-C1~6アルキレン-P(O)(OH)2若しくは-C1~6ハロアルキレン-P(O)(OH)2のエステルであり;
R4aは、CO2H、CH2OSO3H、CH2CO2H、CH2P(O)(OH)2、CH2OH、H又はCO2H、CH2SO3H、CH2CO2H若しくはCH2P(O)(OH)2のエステルであり;
R4bは、出現するごとに、独立して、CO2H、CH2OSO3H、CH2CO2H、CH2P(O)(OH)2、CH2OH、H又はCO2H、CH2SO3H、CH2CO2H若しくはCH2P(O)(OH)2のエステルであり;
R5及びR6は、出現するごとに、独立して、H、C1~6アルキル、C1~6ハロアルキル、-O-C1~6アルキル又は-C1~6アルキレン-OHであり;
X1及びX2は、出現するごとに、独立して、O、S又はNHであり;
X3は、O、S、NH又はCH2であり;
Y1、Y2及びY3は、独立して、O、S、NH又はH2であり;
Y4は、出現するごとに、独立して、O、S又はNHであり;
Z1は、出現するごとに、独立して、フェニレン又は5員~6員ヘテロアリーレンであり、フェニレン及びヘテロアリーレンは、C1~4アルキル、C1~4ハロアルキル、-OC1~4アルキル、-OC1~4ハロアルキル、シアノ及びハロゲンから独立して選択される1~4つの置換基で任意選択的に置換され;
Z2は、出現するごとに、独立して、フェニル又は5員~6員ヘテロアリールであり、ここで、Z2は、C1~4アルキル、C1~4ハロアルキル、-OC1~4アルキル、-OC1~4ハロアルキル、シアノ及びハロゲンから独立して選択される1~5つの置換基で任意選択的に置換され;及び
k及びqは、それぞれ独立して、0~4の整数である)
の化合物又はその薬学的に許容される塩。
R1は、
R2a、R2b及びR2cは、それぞれ独立して、C4~22アルキル、-X1-C3~21アルキル、-CH2-X1-C2~20アルキル又は-CH(R10)(R11)であり;
R10は、C1~21アルキル、-X1-C2~20アルキル又は-CH2-X1-C1~19アルキルであり;
R11は、C3~17アルキル、-X2-C2~16アルキル、-CH2-X2-C1~15アルキル、-X2-C(=Y4)C1~15アルキル、-CH2-C(=Y4)C1~15アルキル、-X2-C(=Y4)C1~15アルキレン-Z1-C1~15アルキル、-CH2-C(=Y4)C1~15アルキレン-Z1-C1~15アルキル、-C3~17アルキレン-Z1-C1~15アルキル、-X2-C2~16アルキレン-Z1-C1~15アルキル又は-CH2-X2-C1~15アルキレン-Z1-C1~15アルキルであり;
R3a、R3b及びR3cは、それぞれ独立して、CO2H、-OSO3H、-OP(O)(OH)2、-C1~6アルキレン-CO2H、-C1~6アルキレン-OSO3H、-C1~6アルキレン-OP(O)(OH)2、-OC1~6アルキレン-P(O)(OH)2、-C1~6アルキレン-P(O)(OH)2、-C1~6ハロアルキレン-P(O)(OH)2、H又はCO2H、-OSO3H、-OP(O)(OH)2、-C1~6アルキレン-CO2H、-C1~6アルキレン-OSO3H、-C1~6アルキレン-OP(O)(OH)2、-OC1~6アルキレン-P(O)(OH)2、-C1~6アルキレン-P(O)(OH)2若しくは-C1~6ハロアルキレン-P(O)(OH)2のエステルであり;
R3dは、CO2H、-SO3H、-P(O)(OH)2、-C1~6アルキレン-CO2H、-C1~6アルキレン-OSO3H、-C1~6アルキレン-OP(O)(OH)2、-OC1~6アルキレン-P(O)(OH)2、-C1~6アルキレン-P(O)(OH)2、-C1~6ハロアルキレン-P(O)(OH)2、H、C1~6アルキル、C1~6ハロアルキル、C3~8シクロアルキル又はCO2H、-OSO3H、-OP(O)(OH)2、-C1~6アルキレン-CO2H、-C1~6アルキレン-OSO3H、-C1~6アルキレン-OP(O)(OH)2、-OC1~6アルキレン-P(O)(OH)2、-C1~6アルキレン-P(O)(OH)2若しくは-C1~6ハロアルキレン-P(O)(OH)2のエステルであり;
R4a及びR4bは、それぞれ独立して、CO2H、CH2OSO3H、CH2CO2H、CH2P(O)(OH)2、CH2OH、H又はCO2H、CH2SO3H、CH2CO2H若しくはCH2P(O)(OH)2のエステルであり;
R5及びR6は、出現するごとに、独立して、H、C1~6アルキル、C1~6ハロアルキル、-O-C1~6アルキル又は-C1~6アルキレン-OHであり;
X1及びX2は、独立して、O、S又はNHであり;
X3は、O、S、NH又はCH2であり;
Y1、Y2及びY3は、独立して、O、S、NH又はH2であり;
Y4は、O、S又はNHであり;
Z1は、フェニレン又は5員~6員ヘテロアリーレンであり、フェニレン及びヘテロアリーレンは、C1~4アルキル、C1~4ハロアルキル、-OC1~4アルキル、-OC1~4ハロアルキル、シアノ及びハロゲンから独立して選択される1~4つの置換基で任意選択的に置換され;及び
k及びqは、それぞれ独立して、0~4の整数である)
の化合物又はその薬学的に許容される塩。
kは、1であり;
R3bは、水素又はCOOH若しくはそのエステルであり;及び
R3d、R5及びR6は、それぞれ水素である、項29に記載の化合物又はその薬学的に許容される塩。
項1~34のいずれかに記載の化合物若しくはその薬学的に許容される塩又は項35~44のいずれかに記載の医薬組成物と;
医薬組成物の使用説明書と
を含むキット。
Claims (28)
- 式(I)
R1は、
R2a、R2b及びR2cは、それぞれ独立して、-CH(R10)(R11)であり;
R10は、出現するごとに、独立して、C1~21アルキル、-X1-C2~20アルキル又は-CH2-X1-C1~19アルキルであり;
R11は、出現するごとに、独立して、C3~17アルキル、-X2-C2~16アルキル、-CH2-X2-C1~15アルキル、-X2-C(=Y4)C1~15アルキル、-CH2-C(=Y4)C1~15アルキル、-X2-C(=Y4)C1~15アルキレン-Z1-C1~15アルキル、-CH2-C(=Y4)C1~15アルキレン-Z1-C1~15アルキル、-C3~17アルキレン-Z1-C1~15アルキル、-X2-C2~16アルキレン-Z1-C1~15アルキル、-CH2-X2-C1~15アルキレン-Z1-C1~15アルキル、-X2-C(=Y4)C1~15アルキレン-Z2又は-X2-C2~16アルキレン-Z2であり;
R3aは、-OSO3H、-OP(O)(OH)2、又は-OCH2P(O)(OH)2であり;
R3bは、H又はCO2Hであり、又は前記CO2Hのエステルであり;
R3dは、Hであり;
R4aは、CO2H、CH2OSO3H、CH2CO2H、CH2P(O)(OH)2、CH2OH、H、又は前記CO2H、CH2SO3H、CH2CO2H若しくはCH2P(O)(OH)2のエステルであり;
R5及びR6は、Hであり;
X1及びX2は、出現するごとに、独立して、O、S又はNHであり;
X3は、Oであり;
Y1、Y2及びY3は、Oであり;
Y4は、Oであり;
Z1は、出現するごとに、独立して、フェニレン又は5員~6員ヘテロアリーレンであり、前記フェニレン及びヘテロアリーレンは、C1~4アルキル、C1~4ハロアルキル、-OC1~4アルキル、-OC1~4ハロアルキル、シアノ及びハロゲンから独立して選択される1~4つの置換基で任意選択的に置換されてよく;
Z2は、出現するごとに、独立して、フェニル又は5員~6員ヘテロアリールであり、ここで、Z2は、C1~4アルキル、C1~4ハロアルキル、-OC1~4アルキル、-OC1~4ハロアルキル、シアノ及びハロゲンから独立して選択される1~5つの置換基で任意選択的に置換されてよく;及び
kは、0~4の整数である)
の化合物又はその薬学的に許容される塩。 - R10は、C1~21アルキル、-X1-C2~20アルキル又は-CH2-X1-C1~19アルキルであり;
R11は、C3~17アルキル、-X2-C2~16アルキル、-CH2-X2-C1~15アルキル、-X2-C(=Y4)C1~15アルキル、-CH2-C(=Y4)C1~15アルキル、-X2-C(=Y4)C1~15アルキレン-Z1-C1~15アルキル、-CH2-C(=Y4)C1~15アルキレン-Z1-C1~15アルキル、-C3~17アルキレン-Z1-C1~15アルキル、-X2-C2~16アルキレン-Z1-C1~15アルキル又は-CH2-X2-C1~15アルキレン-Z1-C1~15アルキルであり;及び
Z1は、フェニレン又は5員~6員ヘテロアリーレンであり、前記フェニレン及びヘテロアリーレンは、C1~4アルキル、C1~4ハロアルキル、-OC1~4アルキル、-OC1~4ハロアルキル、シアノ及びハロゲンから独立して選択される1~4つの置換基で任意選択的に置換されてよい、
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。 - R10の少なくとも1つの出現は、C1~21アルキルである、請求項1または2に記載の化合物又はその薬学的に許容される塩。
- 式(II)
R10は、C1~21アルキルであり;及び
R11は、出現するごとに、独立して、-O-C(=O)C1~15アルキル、-O-C2~16アルキル、または-O-C(=O)C1~15アルキレン-Z2である)
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。 - R11の少なくとも1つの出現は、-X2-C(=Y4)C1~15アルキル、-X2-C(=Y4)C1~15アルキレン-Z2、-X2-C2~16アルキレン-Z2、-X2-C2~16アルキル、または-CH2-X2-C1~15アルキルある、請求項1乃至3のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- X2は、Oである、請求項1乃至3、及び5のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- X3は、Oである、請求項1乃至3、5及び6のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R4aは、CH2OHである、請求項1乃至3、及び5乃至7のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- kは、1である、請求項1乃至3、及び5乃至8のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R10は、出現するごとに、独立して、C8-14アルキルである、請求項1乃至9のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R10は、出現するごとに、独立して、C11アルキルである、請求項10に記載の化合物又はその薬学的に許容される塩。
- R10は、出現するごとに、独立して、直鎖C11アルキルである、請求項11に記載の化合物又はその薬学的に許容される塩。
- R11は、出現するごとに、独立して、-O-C(=O)C9アルキル、-O-C10アルキル、-O-C(=O)C7アルキレン-Z2、または-O-C8~9アルキレン-Z2である、請求項1乃至12のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- -CH(R10)(R11)は、
-
- 以下
- 以下
- 請求項1乃至17のいずれか一項に記載の化合物又はその薬学的に許容される塩と、薬学的に許容される担体とを含む医薬組成物。
- 抗原をさらに含む、請求項18に記載の医薬組成物。
- 筋肉内、皮内、皮下、局所、静脈内又は粘膜投与のための、請求項18または19に記載の医薬組成物。
- 鼻腔内投与のための、請求項20に記載の医薬組成物。
- 対象における免疫応答を引き起こすか若しくは増強するか又は調節するための、請求項18乃至21のいずれか一項に記載の医薬組成物。
- 前記免疫応答は、前記対象における癌、感染症、またはアレルギーを治療する、請求項22に記載の医薬組成物。
- 対象における癌または感染症を治療するか、予防するか、又はそれに対する感受性を低下させるための、請求項18乃至21のいずれか一項に記載の医薬組成物。
- 対象におけるアレルギー、自己免疫性疾患、細菌感染、ウイルス感染、プリオン感染、虚血再かん流、敗血症、または、眼疾患を治療するか、予防するか、又はそれに対する感受性を低下させるための、請求項18乃至21のいずれか一項に記載の医薬組成物。
- 前記眼疾患が、黄斑変性症、高眼圧症または眼感染症である、請求項25に記載の医薬組成物。
- 対象におけるてんかん発作を治療若しくは予防するか、又はその重症度を低下させるための、請求項18乃至21のいずれか一項に記載の医薬組成物。
- 請求項1乃至17のいずれか一項に記載の化合物又はその薬学的に許容される塩、または、請求項18乃至21のいずれか一項に記載の医薬組成物と
使用説明書と
を含むキット。
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US20230287027A1 (en) * | 2020-06-22 | 2023-09-14 | Sumitomo Pharma Co., Ltd. | Adjuvant with tlr4 agonist activity |
WO2022060905A1 (en) | 2020-09-15 | 2022-03-24 | The University Of Montana | Compositions and methods targeting filamentous bacteriophage |
CN116847830A (zh) | 2020-10-28 | 2023-10-03 | 赛诺菲巴斯德有限公司 | 含tlr4激动剂的脂质体、其制备和用途 |
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