JP7453269B2 - 核酸のデリバリーのための新規脂質および脂質ナノ粒子製剤 - Google Patents
核酸のデリバリーのための新規脂質および脂質ナノ粒子製剤 Download PDFInfo
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- JP7453269B2 JP7453269B2 JP2022025427A JP2022025427A JP7453269B2 JP 7453269 B2 JP7453269 B2 JP 7453269B2 JP 2022025427 A JP2022025427 A JP 2022025427A JP 2022025427 A JP2022025427 A JP 2022025427A JP 7453269 B2 JP7453269 B2 JP 7453269B2
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- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0004—Oxidoreductases (1.)
- C12N9/0069—Oxidoreductases (1.) acting on single donors with incorporation of molecular oxygen, i.e. oxygenases (1.13)
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- C12Y—ENZYMES
- C12Y113/00—Oxidoreductases acting on single donors with incorporation of molecular oxygen (oxygenases) (1.13)
- C12Y113/12—Oxidoreductases acting on single donors with incorporation of molecular oxygen (oxygenases) (1.13) with incorporation of one atom of oxygen (internal monooxygenases or internal mixed function oxidases)(1.13.12)
- C12Y113/12007—Photinus-luciferin 4-monooxygenase (ATP-hydrolysing) (1.13.12.7), i.e. firefly-luciferase
Description
生物系における所望の応答に影響を及ぼす核酸のデリバリーには多くの課題がある。核酸ベースの治療薬は莫大な可能性を秘めているが、この可能性を実現するためには、細胞または生物体内の適切な部位に核酸をより効果的にデリバリーする必要性が依然として存在する。治療用核酸として、たとえば、メッセンジャーRNA(mRNA)、アンチセンスオリゴヌクレオチド、リボザイム、DNAザイム、プラスミド、免疫刺激核酸、アンタゴミル(antagomir)、アンチミル(antimir)、模倣物、スーパーミル(supermir)およびアプタマーが挙げられる。いくつかの核酸、たとえば、mRNAまたはプラスミドは、たとえば、タンパク質または酵素の欠乏に関連する疾患の治療に有用であるように、特定の細胞産物の発現を達成させるために使用されうる。翻訳可能なヌクレオチドデリバリーの治療的応用は、系に固有であるか否かにかかわらず、任意の選択されたタンパク質配列を産生するように構築物を合成することができるので、極めて広い。核酸の発現産物は、既存のタンパク質レベルを増大させることができ、タンパク質の欠損または非機能バージョンを置き換えることができ、または細胞または生物に新しいタンパク質および関連する機能性を導入することができる。
要約すると、本発明は、その立体異性体、薬学的に許容される塩または互変異性体を含む、脂質化合物を提供し、それらは、単独で、または中性脂質、荷電脂質、ステロイド(たとえば、すべてのステロールを含む)および/またはそれらの類縁体などの他の脂質成分、および/またはポリマー複合脂質と組み合わせて使用して、治療薬のデリバリーのための脂質ナノ粒子を形成することができる。いくつかの例では、脂質ナノ粒子は、アンチセンスおよび/またはメッセンジャーRNAなどの核酸をデリバリーするために使用される。感染性実体および/またはタンパク質の不足により引き起こされるような、さまざまな疾患または状態の治療のためのこのような脂質ナノ粒子の使用方法もまた提供される。
[式中、R1、R2、R3、L1、L2、G1、G2およびG3は、本明細書で定義される通りである]
を有する化合物、またはその薬学的に許容される塩、互変異性体もしくは立体異性体が、提供される。
図面において、同じ参照番号は、同様の要素を示す。図面中の要素のサイズおよび相対位置は、必ずしも縮尺通りに描かれておらず、これらの要素のいくつかは、図の判読性を改善するために任意に拡大され配置される。さらに、描かれた要素の特定の形状は、特定の要素の実際の形状に関する情報を伝達することを意図するものではなく、図面の認識を容易にするためにのみ選択されている。
以下の説明において、ある特定の詳細は、本発明のさまざまな実施態様の完全な理解を提供するために記載される。しかしながら、当業者であれば、本発明はこれらの詳細なしに実施されうることを理解するであろう。
対照と比較したmRNAなどの核酸を用いて得られた値の倍率の増加が約1.05、1.1、1.2、1.3、1.4、1.5、1.75、2、2.5、3、4、5、6、7、8、9、10、15、20、25、30、40、50、75、100、250、500、750、1000、5000、10000またはそれ以上である場合に、発現の増加が達成される。標的遺伝子または標的配列の発現の阻害は、対照に対してアンチセンスオリゴヌクレオチドなどの核酸を用いて得られる値が、約95%、90%、85%、80%、75%、70%、65%、60%、55%、50%、45%、40%、35%、30%、25%、20%、15%、10%、5%、または0%である場合に達成される。標的遺伝子または標的配列の発現を測定するための適切なアッセイとして、ドットブロット、ノーザンブロット、インサイチュハイブリダイゼーション、ELISA、免疫沈降、酵素機能、適切なレポータータンパク質の蛍光または発光、ならびに当業者に公知の表現型アッセイなどの当業者に公知の技術を用いたタンパク質またはmRNAレベルの検査が挙げられるが、これらに限定されない。
(i)特に、このような哺乳動物がその状態に罹りやすいがまだそれを有すると診断されていない場合に、その疾患または状態が哺乳動物において起こるのを防止すること;
(ii)疾患または状態を阻害すること、すなわちその発症を阻止すること;
(iii)疾患または状態を緩和すること、すなわち疾患または状態を退行させること;または
(iv)疾患または状態に起因する症状を緩和すること、すなわち、根底にある疾患または状態に対処することなく疼痛を緩和すること。本明細書中で使用される場合、用語「疾患」および「状態」は互換的に使用されうるか、または特定の疾病または状態が、既知の原因物質を有さず(病因がまだ解明されていない)、したがって、疾患として認識されておらず、臨床医によって多かれ少なかれ特異的な症状のセットが特定されている望ましくない状態または症候群としてのみ認識されるという点で異なる可能性がある。
1つの態様では、本発明は、中性脂質、荷電脂質、ステロイドおよび/またはポリマー複合脂質などの他の脂質成分と組み合わせてオリゴヌクレオチドと脂質ナノ粒子を形成することができる新規脂質化合物を提供する。理論に縛られることを望むものではないが、これらの脂質ナノ粒子は、オリゴヌクレオチドを血清中の分解から遮蔽し、インビトロおよびインビボで細胞にオリゴヌクレオチドの効果的なデリバリーを提供すると考えられる。
[式中、
L1またはL2の一方は、-O(C=O)-、-(C=O)O-、-C(=O)-、-O-、-S(O)x-、-S-S-、-C(=O)S-、SC(=O)-、-NRaC(=O)-、-C(=O)NRa-、NRaC(=O)NRa-、-OC(=O)NRa-または-NRaC(=O)O-であり、L1またはL2の他方は、-O(C=O)-、-(C=O)O-、-C(=O)-、-O-、-S(O)x-、-S-S-、-C(=O)S-、SC(=O)-、-NRaC(=O)-、-C(=O)NRa-、,NRaC(=O)NRa-、-OC(=O)NRa-または-NRaC(=O)O-または直接結合である;
G1およびG2はそれぞれ独立して、非置換C1-C12アルキレンまたはC1-C12アルケニレンである;
G3は、C1-C24アルキレン、C1-C24アルケニレン、C3-C8シクロアルキレン、C3-C8シクロアルケニレンである;
Raは、HまたはC1-C12アルキルである;
R1およびR2はそれぞれ独立して、C6-C24アルキルまたはC6-C24アルケニルである;
R3は、H、OR5、CN、-C(=O)OR4、-OC(=O)R4または-NR5C(=O)R4である;
R4は、C1-C12アルキルである;
R5は、HまたはC1-C6アルキルである;および
xは、0、1または2である]
を有する化合物、またはその医薬的に許容される塩、互変異性体、プロドラッグもしくは立体異性体である。
または
[式中、
Aは、3~8員のシクロアルキルまたはシクロアルキレン環である;
R6は、出現するごとに独立して、H、OHまたはC1-C24アルキルである;
nは、1~15の整数である]
の1つを有する。
R7aおよびR7bは、出現するごとに独立して、HまたはC1-C12アルキルである;および
aは、2~12の整数である;
ここで、R7a、R7bおよびaはそれぞれ、R1およびR2がそれぞれ独立して、6~20個の炭素原子を含むように選択される]
を有する。たとえば、いくつかの実施態様では、aは、5~9または8~12の整数である。
[式中、
R8およびR9はそれぞれ独立して、10~30個の炭素原子を含む直鎖または分枝鎖の、飽和または不飽和アルキル鎖であり、ここで、アルキル鎖は、1つ以上のエステル結合によって任意に中断される;および
wは、30~60の範囲の平均値を有する]
を有するPEG化脂質、またはその医薬的に許容される塩、互変異性体もしくは立体異性体を含む。
[式中、R1、R2、R3、L1、L2、G1、G2およびG3は、本明細書で定義される通りである]
の化合物、またはその薬学的に許容される塩、互変異性体もしくは立体異性体を製造する方法を説明する。当業者は、類似の方法によって、または当業者に公知の他の方法を組み合わせて、これらの化合物を製造することができると理解される。また、当業者が、以下に説明するものと同様の方法で、適切な出発成分を使用し、必要に応じて合成のパラメーターを変更することにより、以下に具体的に示されていない構造式(I)の他の化合物を製造することができるであろうことも理解される。一般に、出発成分は、Sigma Aldrich、Lancaster Synthesis、Inc.、Maybridge、Matrix Scientific、TCI、およびFluorochem USAなどの供給元から得ることができるか、または当業者に公知の情報源(たとえば、Advanced Organic Chemistry:Reactions、Mechanisms、and Structure、5th edition (Wiley、December 2000)を参照)に従って合成されるか、または本発明に記載のように調製されうる。
カチオン性脂質、DSPC、コレステロールおよびPEG-脂質を、50:10:38.5:1.5または47.5:10:40.8:1.7のモル比でエタノールに可溶化した。約10:1~30:1の総脂質対mRNA重量比で、脂質ナノ粒子(LNP)を調製した。簡潔に述べると、mRNAを10~50mMのクエン酸緩衝液、pH4中で、0.2mg/mLに希釈した。シリンジポンプを使用して、15ml/分を超える全流速で、約1:5~1:3(vol/vol)の比でエタノール性脂質溶液をmRNA水溶液と混合した。次いで、エタノールを除去し、透析により外部緩衝液をPBSで置換した。最後に、脂質ナノ粒子を0.2μm細孔無菌フィルターを通して濾過した。脂質ナノ粒子の粒子サイズは、Malvern Zetasizer Nano ZS(Malvern、UK)を用いる準弾性光散乱によって測定した場合、直径約55~95nm、場合によっては約70~90nmであった。
他のところで説明されているように、製剤されたカチオン性脂質のpKaは、核酸のデリバリーに対するLNPの有効性と相関する(Jayaraman et al、Angewandte Chemie、International Edition (2012)、51(34)、8529-8533;Semple et al、Nature Biotechnology 28、172-176 (2010)を参照)。pKaの好ましい範囲は~5から~7である。各カチオン性脂質のpKaは、2-(p-トルイジノ)-6-ナフタレンスルホン酸(TNS)の蛍光に基づくアッセイを用いて脂質ナノ粒子中で測定された。総脂質0.4mMの濃度のPBS中のカチオン性脂質/DSPC/コレステロール/PEG-脂質(50/10/38.5/1.5mol%)を含む脂質ナノ粒子を、実施例1に記載のインラインプロセスを用いて調製する。TNSは、蒸留水中の100μMストック溶液として調製された。小胞を、10mMのHEPES、10mMのMES、10mMの酢酸アンモニウム、130mMのNaClを含有する2mLの緩衝溶液(ここで、pHは2.5~11の範囲であった)中で24μMの脂質に希釈した。TNS溶液のアリコートを加えて1μMの最終濃度とし、ボルテックス混合後、321nmおよび445nmの励起および発光波長を用いて、SLM Aminco Series 2発光分光光度計で室温にて蛍光強度を測定した。S字状の最良適合分析を蛍光データに適用し、pKaを最大蛍光強度の半分を生じるpHとして測定した(図2参照)。
第2表に示されたカチオン性脂質は、以前に核酸で試験されている。比較目的のために、実施例1およびPCT/US10/22614(その全体が参照により本明細書に組み込まれる)に記載されているように、これらの脂質を用い、インライン混合法を用いてFLuc mRNA(L-6107)を含有する脂質ナノ粒子を製剤化した。50%カチオン性脂質/ 10%ジステアロイルホスファチジルコリン(DSPC)/38.5%コレステロール/1.5% PEG脂質のモル比を用いて、脂質ナノ粒子を製剤した(「PEG-DMG」、すなわち、平均PEG分子量2000の(1-(モノメトキシ-ポリエチレングリコール)-2,3-ジミリストイルグリセロール)。相対活性を、実施例1に記載したように、尾静脈注射による投与の4時間後に肝臓におけるルシフェラーゼ発現を測定することによって決定した。活性は、0.3および1.0mg mRNA/kgの用量で比較し、実施例1に記載したように、投与4時間後に測定したルシフェラーゼng/肝臓gとして表した。
塩化メチレン(475mL)中のヘキサン-1,6-ジオール(27.6g)の溶液を、2-ヘキシルデカン酸(19.8g)、DCC(18.2g)およびDMAP(11.3g)で処理した。溶液を3日間撹拌した。反応混合物を濾過し、ヘキサン(500mL)を濾液に加えた。混合物を撹拌し、沈殿を沈降させた。上清をデカントし、希塩酸で洗浄した。有機相を無水硫酸マグネシウムで乾燥させ、濾過し、溶媒を除去して30gの粗生成物を得た。
塩化メチレン(200ML)中のブタン-1,4-ジオール(12.5G)の溶液を、2-ヘキシルデカン酸(9.2G)、DCC(8.8G)およびDMAP(4.9G)で処理した。溶液を一晩攪拌した。反応混合物を濾過し、溶媒を除去した。残渣を塩化メチレンに溶解し、希塩酸で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、シリカゲル床で濾過し、溶媒を除去した。
塩化メチレン(50mL)中の6-(2'-ヘキシルデカノイルオキシ)ヘキサン-1-アール(3.0g)、酢酸(0.21g)およびエタノールアミン(0.14g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.4g)で一晩処理した。溶液を希水酸化ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣をメタノール/塩化メチレン(0-8/100-92%)勾配を用いてシリカゲルカラムに通し、化合物1を無色油状物(0.63g)として得た。
塩化メチレン(20mL)中の6-(2'-ヘキシルデカノイルオキシ)ヘキサン-1-アール(3.0g)、酢酸(0.33g)および3-アミノプロパン-1-オール(0.17g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.3g)で1時間処理した。溶液を希水酸化ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣をメタノール/塩化メチレン(0-8/100-92%)勾配を用いてシリカゲルカラムに通し、化合物2を無色油状物(1.1g)として得た。
塩化メチレン(20mL)中の6-(2'-ヘキシルデカノイルオキシ)ヘキサン-1-アール(2.4g)、酢酸(0.33g)および4-アミノブタン-1-オール(0.17g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.3g)で2時間処理した。溶液を重炭酸ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣をメタノール/塩化メチレン(0-8/100-92%)勾配を用いてシリカゲルカラムに通し、化合物3を無色油状物(0.4g)として得た。
塩化メチレン(20mL)中の4-(2'-ヘキシルデカノイルオキシ)ブタン-1-アール(2.4g)、酢酸(0.30g)および4-アミノブタン-1-オール(0.22g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.3g)で2時間処理した。溶液を希水酸化ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣をメタノール/塩化メチレン(0-8/100-92%)勾配を用いてシリカゲルカラムに通した。酢酸/メタノール/塩化メチレン(2-0/0-10/98-90%)勾配を使用して、部分精製画分を第2カラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物4を無色油状物(0.9g)として得た。
塩化メチレン(20mL)中の4-(2'-ヘキシルデカノイルオキシ)ブタン-1-アール(2.4g)、酢酸(0.31g)および3-アミノプロパン-1-オール(0.17g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.4g)で1時間処理した。溶液を重炭酸ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣をメタノール/塩化メチレン(0-8/100-92%)勾配を用いてシリカゲルカラムに通した。酢酸/メタノール/塩化メチレン(2-0/0-8/98-92%)勾配を使用して、部分精製画分を第2カラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物5を無色油状物(0.57g)として得た。
塩化メチレン(20mL)中の4-(2'-ヘキシルデカノイルオキシ)ブタン-1-アール(2.4g)、酢酸(0.30g)およびエタノールアミン(0.14g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.3g)で2時間処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣をメタノール/塩化メチレン(0-10/100-90%)勾配を用いてシリカゲルカラムに通した。酢酸/メタノール/塩化メチレン(2-0/0-9/98-92%)勾配を使用して、部分精製画分を第2カラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物6を無色油状物(0.2g)として得た。
塩化メチレン(20mL)中の6-(2'-ヘキシルデカノイルオキシ)ヘキサン-1-アール(2.4g)、酢酸(0.14g)および5-アミノペンタン-1-オール(0.24g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.3g)で2時間処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣をメタノール/塩化メチレン(0-8/100-92%)勾配を用いてシリカゲルカラムに通し、化合物7を無色油状物(0.5g)として得た。
塩化メチレン(20mL)中の6-(2'-ヘキシルデカノイルオキシ)ヘキサン-1-アール(2.4g)、酢酸(0.17g)および6-アミノヘキサン-1-オール(0.26g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.3g)で2時間処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣をメタノール/塩化メチレン(0-8/100-92%)勾配を用いてシリカゲルカラムに通し、化合物8を無色油状物(0.5g)として得た。
塩化メチレン(10mL)/テトラヒドロフラン(10mL)中の6-(2'-ヘキシルデカノイルオキシ)ヘキサン-1-アール(2.4g)およびトランス-2-アミノシクロヘキサノール塩酸塩(0.35g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.3g)で1.5時間処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣をメタノール/塩化メチレン(0-8/100-92%)勾配を用いてシリカゲルカラムに通し、化合物9を無色油状物(0.6g)として得た。
無水THF(15mL)中の2-アミノエタノール(106mg、1.75mmol)の溶液に、6-ブロモヘキサン酸2-オクチルドデシル(2当量、1.66g、3.5mmol)、炭酸カリウム(2当量、3.5mmol、477mg)および炭酸セシウム(0.3当量、0.525mmol、171mg)を加え、63℃(油浴)で16時間加熱した。痕跡量のテトラブチルアンモニウムヨウ化物を混合物に加え、混合物をさらに4日間加熱還流した。溶媒を減圧下で蒸発させ、残渣をヘキサンおよび酢酸エチル(約9:1)の混合物に取り、水およびブラインで洗浄した。有機層を分離し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で蒸発させて油状物(1.6g)を得た。残渣(1.6g)をシリカゲルカラムクロマトグラフィー(クロロホルム中のMeOH、0~4%)により精製した。これにより、化合物10を無色油状物(700mg、0.82mmol、47%)として得た。
無水THF(15mL)中の2-アミノエタノール(116mg、1.9mmol、115 μL)の溶液に、6-ブロモヘキサン酸2-ヘキシルデシル(1.9当量、1.52g、3.62mmol)、炭酸カリウム(1.9当量、3.62mmol、500mg)、炭酸セシウム(0.3当量、0.57mmol、186mg)およびヨウ化ナトリウム(10mg)を加え、アルゴン下で6日間加熱還流した。溶媒を減圧下で蒸発させ、残渣をヘキサンに取り、水およびブラインで洗浄した。有機層を分離し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で蒸発させて無色油状物を得た。粗生成物をシリカゲルフラッシュカラムクロマトグラフィー(クロロホルム中のMeOH、0~4%)で精製して、化合物11を無色油状物(936mg、1.27mmol、70%)として得た。
化合物12を、化合物11の手順と類似の方法で調製して、538mgの無色油状物、0.86mmol、57%を得た。
無水THF(30mL)中の2-アミノエタノール(171mg、2.81mmol、169μL)の溶液に、4-ブロモ酪酸2-オクチルドデシル(1.9 当量、2.386g、5.33mmol)、炭酸カリウム(1.9当量、5.33mmol、736mg)、炭酸セシウム(0.3当量、0.84mmol、275mg)およびヨウ化ナトリウム(10mg)を加え、アルゴン下で16時間加熱還流した。TLC(ヘキサン/酢酸エチル=9:1、CHCl3/MeOH=19:1)は、有意な量の2-オクチル-1-ドデカノールが生成されることを示した。混合物を冷却し、濾過した。濾液を濃縮し、残渣を2-オクチル-1-ドデカノール(2.1g)に溶解した。4Åモレキュラーシーブの数個のビーズおよびN,N-ジイソプロピルエチルアミン(1.9当量、5.33mmol、683mg、0.92mL)を添加した。混合物を密封し、62℃でさらに4日間加熱した。反応混合物を冷却した。ヘキサンを添加した。ヘキサン溶液をデカントし、濃縮乾固した。残渣をシリカゲルカラムクロマトグラフィー(クロロホルム中のMeOH、0~4%)により精製して、化合物13を無色油状物(282mg、0.35mmol、13%)として得た。
無水THF(15mL)中のヘプタデカン-9-イル6-ブロモヘキサノエート(2当量、1.13g、2.61mmol)の溶液に、炭酸カリウム(2当量、2.61mmol、361mg)、炭酸セシウム(0.3当量、0.39mmol、128mg)およびヨウ化ナトリウム(6mg)を加えた。混合物をアルゴン下で7日間加熱還流した。溶媒を減圧下で蒸発させ、残渣をヘキサン/酢酸エチル(約10%)に取り、水およびブラインで洗浄した。有機層を分離し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で蒸発させて無色油状物(1g)を得た。残渣(1g)をシリカゲルの重力カラムクロマトグラフィー(DCM中のMeOH、0~4%)により精製した。これにより、化合物14を無色油状物(757mg、0.99mmol、76%)として得た。
無水THF(15mL)(開封2ヶ月)中の5-ブロモペンタン酸2-ヘキシルデシル(2当量、1.22g、3mmol)の溶液に、炭酸カリウム(2当量、3ミリモル、415mg)、炭酸セシウム(0.3当量、0.45ミリモル、146mg)およびヨウ化ナトリウム(6mg)、4-アミノ-1-ブタノール(1当量1.5ミリモル、0.134mg、139μL)を加えた。混合物をアルゴン下で6日間加熱還流した。溶媒を減圧下で蒸発させ、残渣をヘキサンおよび酢酸エチルの混合物(約10%)に取り、水およびブラインで洗浄した。有機層を分離し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で蒸発させて無色油状物(1.12g)を得た。残渣(1g)をシリカゲルカラムクロマトグラフィー(クロロホルム中のMeOH、0~5%)により精製した。これにより、化合物15を無色油状物(487mg、0.66mmol、44%)として得た。1HNMR (400 MHz、CDCl3) δ:5.99 (s、1H)、3.98 (d、5.8 Hz、4H)、3.56 (t-様、4.8 Hz、2H)、2.48-2.41 (m、6H)、2.33 (t、7.4 Hz、4H)、1.70-1.57 (m、10H)、1.55-1.47 (m、4H)、1.35-1.21 (48H)、0.89 (t-様、6.8 Hz、12H)。
無水アセトニトリル(15mL)中の3-アミノ-1-プロパノール(0.37mmol、28mg)の溶液に、6-ブロモヘキサン酸2-ヘキシルデシル(1.9当量、294mg、0.7mmol)、N,N-ジイソプロピルエチルアミン(2当量、0.74mmol、96mg)およびヨウ化ナトリウム(5mg)を加え、混合物(2層)を圧力フラスコ内で59℃(油浴)にて3日間加熱した。混合物を濃縮し、残渣をヘキサンと酢酸エチルの混合物(約5:1、100mL)に取り、水、ブラインで洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮した。わずかに黄色の油状物(約300mg)が得られた。粗生成物(300mg)をシリカゲルフラッシュクロマトグラフィー(クロロホルム中のMeOH、0~4.4%)で精製した。これにより、化合物16を無色油状物(95mg、0.13mmol、36%)として得た。1HNMR (400 MHz、CDCl3) δ:5.61-5.44 (br. s、1H)、3.97 (d、5.8 Hz、4H)、3.80 (t-様、5.1 Hz、2H)、2.63 (t-様、5.6 Hz、2H)、2.43-2.39 (m、4H)、2.32 (t、7.5 Hz、4H)、1.70-1.59 (m、8H)、1.55-1.45 (m、4H)、1.36-1.21 (52H)、0.89 (t-様、6.8 Hz、12H)。
15mlの無水THF中の6-ブロモヘキサン酸2-ヘキシルデシル(2当量、1.32g、3.14mmol)の溶液に、4-アミノ-1-ブタノール(1当量、1.57mmol、140mg、145μL)、炭酸カリウム(2当量、3.14mmol、434mg)、炭酸セシウム(0.3当量、0.47mmol、153mg)およびヨウ化ナトリウム(6mg)を加えた。この混合物を、圧力丸底フラスコ中、75℃(油浴)にてアルゴン下で6日間加熱した。反応混合物を冷却し、濃縮した。残留物をヘキサンおよび酢酸エチルの混合物(約9:1)に溶解し、水、ブラインで洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮乾固した(1.28gの無色油状物)。粗生成物をシリカゲルフラッシュカラムクロマトグラフィー(クロロホルム中のMeOH、0~5%)により精製した。これにより、化合物17を無色油状物(581mg、0.76mmol、48%)として得た。1HNMR (400 MHz、CDCl3) δ:6.43-6.17 (br. s、1H)、3.97 (d、5.8 Hz、4H)、3.55 (t-様、4.7 Hz、2H)、2.46-2.40 (m、6H)、2.31 (t、7.5 Hz、4H)、1.70-1.59 (m、10H)、1.55-1.45 (m、4H)、1.36-1.21 (52H)、0.89 (t-様、6.7 Hz、12H)。
30mlの無水THF中の8-ブロモオクタン酸2-ヘキシルデシル(2当量、3.09g、6.9mmol)の溶液に、4-アミノ-1-ブタノール(1当量、3.45mmol、308mg)、炭酸カリウム(2当量、6.9mmol、954mg)、炭酸セシウム(0.3当量、1.04mmol、337mg)およびヨウ化ナトリウム(10mg)を加えた。アルゴン下、圧力丸底フラスコ中の混合物を、64-70℃(油浴)で6日間加熱した。混合物を冷却し、濃縮した。残渣をヘキサンおよび酢酸エチルの混合物(9:1)に取り、水、ブラインで洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮乾固した(無色油状物)。粗生成物をシリカゲルフラッシュドライカラムクロマトグラフィー(クロロホルム中のMeOH、0~4.2%)で精製した。これにより、化合物20を無色油状物(1.28 g、1.56mmol、45%)として得た。1HNMR (400 MHz、CDCl3) δ:6.64-6.45 (br. s、1H)、3.97 (d、5.8 Hz、4H)、3.62-3.51 (br. 2H)、3.07-2.34 (br. 6H)、2.30 (t、7.5 Hz、4H)、1.71-1.40 (m、14H)、1.39-1.19 (m、60H)、0.89 (t-様、6.8 Hz、12H)。
塩化メチレン(150mL)中のノナン-1,9-ジオール(10.1g)の溶液を2-エチルヘキサン酸(9.0g)、DCC(14.3g)およびDMAP(9.1g)で処理した。溶液を一晩撹拌した。反応混合物を濾過し、溶媒を除去した。残渣をヘキサンに懸濁させ、濾過した。濾液を希塩酸で洗浄した。有機相を無水硫酸マグネシウムで乾燥させ、シリカゲル床を通して濾過し、溶媒を除去した。粗生成物を、メタノール/塩化メチレン(0-8%)勾配を用いてシリカゲルカラムに通して、9-(2'-エチルヘキサノイルオキシ)ノナン-1-オールを油状物(7.2g)として得た。
塩化メチレン(150mL)中のノナン-1,9-ジオール(12.0g)の溶液を、2-ブチルオクタン酸(5.0g)、DCC(7.7g)およびDMAP(4.5g)で処理した。溶液を一晩撹拌した。反応混合物を濾過し、溶媒を除去した。残渣をヘキサンに懸濁させ、濾過した。濾液を希塩酸で洗浄した。有機相を無水硫酸マグネシウムで乾燥させ、シリカゲル床を通して濾過し、溶媒を除去した。粗生成物を、メタノール/塩化メチレン(0~4%)勾配を用いてシリカゲルカラムに通して、9-(2'-ブチルオクタノイルオキシ)ノナン-1-オールを油状物(6g)として得た。
塩化メチレン(150mL)中のヘキサン-1,6-ジオール(9.4g)の溶液を、2-ブチルオクタン酸(5.0g)、DCC(7.6g)およびDMAP(4.8g)で処理した。溶液を一晩撹拌した。反応混合物を濾過し、溶媒を除去した。残渣をヘキサンに懸濁させ、濾過した。濾液を希塩酸で洗浄した。有機相を無水硫酸マグネシウムで乾燥させ、シリカゲル床を通して濾過し、溶媒を除去した。粗生成物を、メタノール/塩化メチレン(0~4%)勾配を用いてシリカゲルカラムに通して、6-(2'-ブチルオクタノイルオキシ)ヘキサン-1-オールを油状物(4.5g)として得た。
塩化メチレン(150mL)/THF(20mL)中のヘキサン-1,6-ジオール(11.5g)の溶液を、2-オクチルドデカン酸(9.9g)、DCC(7.5g)およびDMAP(4.7g)で処理した。溶液を一晩撹拌した。反応混合物を濾過し、溶媒を除去した。残渣をヘキサンに懸濁させ、濾過した。濾液を希塩酸で洗浄した。有機相を無水硫酸マグネシウムで乾燥させ、シリカゲル床を通して濾過し、溶媒を除去した。粗生成物を、メタノール/塩化メチレン(0~4%)勾配を用いてシリカゲルカラムに通して、6-(2'-オクチルドデカノイルオキシ)ヘキサン-1-オールを油状物(7.4g)として得た。
塩化メチレン(150mL)中のヘキサン-1,6-ジオール(9.6g)の溶液を、2-デシルテトラデカン酸(6.1g)、DCC(4.9g)およびDMAP(3.1g)で処理した。溶液を一晩撹拌した。反応混合物を濾過し、溶媒を除去した。残渣をヘキサンに懸濁させ、濾過した。濾液を希塩酸で洗浄した。有機相を無水硫酸マグネシウムで乾燥させ、シリカゲル床を通して濾過し、溶媒を除去した。粗生成物を、メタノール/塩化メチレン(0~4%)勾配を用いてシリカゲルカラムに通して、6-(2'-デシルテトラデカノイルオキシ)ヘキサン-1-オールを油状物(4.6g)として得た。
塩化メチレン(300mL)/THF(100mL)中のドデカン-1,6-ジオール(25.0g)の溶液を、2-ヘキシルドデカン酸(10.6g)、DCC(10.2g)およびDMAP(7.5g)で処理した。溶液を一晩撹拌した。反応混合物を濾過し、溶媒を除去した。残渣をヘキサンに懸濁させ、濾過した。濾液を水で洗浄した。有機相を無水硫酸マグネシウムで乾燥させ、シリカゲル床を通して濾過し、溶媒を除去した。粗生成物を、ヘキサン、次いで、塩化メチレンを用いてシリカゲルカラムに通し、12-(2'-ヘキシルデカノイルオキシ)ドデカン-1-オールを油状物(7.9g)として生成した。
塩化メチレン(600mL)中のノナン-1,9-ジオール(46.8g)の溶液を、2-ヘキシルデカン酸(25.0g)、DCC(22.0g)およびDMAP(15.0g)で処理した。溶液を一晩撹拌した。反応混合物を濾過し、溶媒を除去した。残渣をヘキサンに懸濁させ、濾過した。濾液を希塩酸で洗浄した。有機相を無水硫酸マグネシウムで乾燥させ、シリカゲル床を通して濾過し、溶媒を除去した。粗生成物を、ヘキサン、次いで、メタノール/塩化メチレン(0~8%)勾配を用いてシリカゲルカラムに通して、9-(2'-ヘキシルデカノイルオキシ)ノナン-1-オールを油状物(22g)として得た。
塩化メチレン(20mL)中の9-(2'-ヘキシルデカノイルオキシ)ノナン-1-アール(2.2g)、酢酸(0.15g)および4-アミノブタン-1-オール(0.20g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.30g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-12/98-88%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物22を無色油状物(0.93g)として得た。
塩化メチレン(20mL)中の12-(2'-ヘキシルデカノイルオキシ)ドデカン-1-アール(2.0g)、酢酸(0.09g)および4-アミノブタン-1-オール(0.14g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(0.71g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-12/98-88%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物23を無色油状物(1.0g)として得た。
塩化メチレン(50mL)中の9-(2'-エチルヘキサノイルオキシ)ノナン-1-アール(3.0g)、酢酸(0.11g)および4-アミノブタン-1-オール(0.17g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(0.89g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-10/98-88%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物24を無色油状物(0.69g)として得た。
塩化メチレン(50mL)中の9-(2'-ブチルオクタノイルオキシ)ノナン-1-アール(2.6g)、酢酸(0.20g)および4-アミノブタン-1-オール(0.26g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.42g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-12/98-88%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物25を無色油状物(0.82g)として得た。
塩化メチレン(20mL)中の6-(2'-オクチルドデカノイルオキシ)ヘキサン-1-アール(2.7g)、酢酸(0.20g)および4-アミノブタン-1-オール(0.20g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.30g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-12/98-88%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物26を無色油状物(0.21g)として得た。
塩化メチレン(30mL)中の6-(2'-デシルテトラデカノイルオキシ)ヘキサン-1-アール(2.1g)、酢酸(0.11g)および4-アミノブタン-1-オール(0.13g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(0.70g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-12/98-88%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物27を無色油状物(0.90g)として得た。
塩化メチレン(20mL)中の6-(2'-ブチルオクタノイルオキシ)ヘキサン-1-アール(2.0g)、酢酸(0.13g)および4-アミノブタン-1-オール(0.13g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.0g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-8/98-92%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物28を無色油状物(0.77g)として得た。
塩化メチレン(20mL)中の6-(2'-ヘキシルデカノイルオキシ)ヘキサン-1-アール(2.4g)、酢酸(0.15g)および3-アミノプロパン-1,2-ジオール(0.21g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.76g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-12/98-88%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物30を無色油状物(0.60g)として得た。
塩化メチレン(20mL)中の6-(2'-ヘキシルデカノイルオキシ)ヘキサン-1-アール(2.4g)、酢酸(0.15g)および2-アミノブタン-1-オール(0.20g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.1g)で2時間処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-4/98-96%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物31を無色油状物(0.31g)として得た。
塩化メチレン(20mL)中の6-(2'-オクチルドデカノイルオキシ)ヘキサン-1-アール(2.7g)、酢酸(0.20g)および3-アミノプロパン-1-オール(0.17g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.3g)で2時間処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-12/98-88%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物37を無色油状物(0.22g)として得た。
塩化メチレン(10mL)中の12-(2'-ヘキシルデカノイルオキシ)ドデカン-1-アール(1.8g)、酢酸(0.08g)および3-アミノプロパン-1-オール(0.11g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(0.64g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-10/98-90%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物38を無色油状物(0.83g)として得た。
無水アセトニトリル(15mL)中の4-アミノ酪酸エチル塩酸塩(1.28mmol、214mg)、6-ブロモヘキサン酸2-ヘキシルデシル(1.9当量、2.43mmol、1.02g)、N,N-ジイソプロピルエチルアミン(3.5当量、4.48mmol、579mg)およびヨウ化ナトリウム(5mg)の混合物を、圧力フラスコ中で60℃にて2日間加熱した。混合物を冷却し、濃縮した。残渣をヘキサンおよび酢酸エチルの混合物(約5:1、100mL)に溶解し、水、ブラインで洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮した。褐色の油状物(約1.04g)が得られた。粗生成物を、シリカゲルフラッシュカラムクロマトグラフィー(DCM中のMeOH、0~3.5%)により精製した。これにより、化合物39を無色油状物(334mg、0.41mmol、43%)として得た。1HNMR (400 MHz、CDCl3) δ:4.13 (q、7.1 Hz、2H)、3.97 (d、5.8 Hz、4H)、2.43-2.34 (m、6H)、2.33-2.28 (m、6H)、1.73 (quintet、7.3 Hz、2H)、1.68-1.58 (m、6H)、1.47-1.37 (m、4H)、1.36-1.20 (54H)、0.89 (t-様、6.8 Hz、12H)。
塩化メチレン(20mL)中の6-(2'-ヘキシルデカノイルオキシ)ヘキサン-1-アール(2.4g)、酢酸(0.15g)および1-アミノブタン-2-オール(0.10g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.8g)で2時間処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-8/98-92%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物40を無色油状物(0.85g)として得た。
塩化メチレン(20mL)中の6-(2'-ヘキシルデカノイルオキシ)ヘキサン-1-アール(2.4g)、酢酸(0.19g)および1-アミノブタン-2-オール(0.21g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.8g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-8/98-92%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物41を無色油状物(0.77g)として得た。
塩化メチレン(20mL)中の6-(2'-ブチルオクタノイルオキシ)ヘキサン-1-アール(2.0g)、酢酸(0.13g)および4-アミノブタン-2-オール(0.20g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.03g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-8/98-92%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物42を無色油状物(0.54g)として得た。
塩化メチレン(50mL)中の9-(2'-エチルヘキサノイルオキシ)ノナン-1-アール(3.0g)、酢酸(0.11g)および3-アミノプロパン-1-オール(0.14g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(0.91g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-6/98-94%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物43を無色油状物(1.01g)として得た。
塩化メチレン(30mL)中の6-(2'-デシルテトラデカノイルオキシ)ヘキサン-1-アール(2.1g)、酢酸(0.11g)および3-アミノプロパン-1-オール(0.11g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(0.71g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-8/98-96%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物44を無色油状物(1.07g)として得た。
塩化メチレン(50mL)中の9-(2'-ブチルオクタノイルオキシ)ノナン-1-アール(2.6g)、酢酸(0.17g)および3-アミノプロパン-1-オール(0.21g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.34g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-8/98-96%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物45を無色油状物(1.1g)として得た。
15mlの2-プロパノール中の2-アミノエタノール(96.5mg、1.58mmol、95.4μL、MW 61.08、d 1.012)の溶液に、8-ブロモオクタン酸2-ヘキシルデシル(1.8当量、1.27g、2.84mmol)、炭酸カリウム(1.9当量、3mmol、414mg)、炭酸セシウム(0.3当量、0.47mmol、154mg)およびヨウ化ナトリウム(10mg)を加え、3日間加熱した(油浴60℃)。混合物を濃縮し、残渣をTHF(10mL)に取った。この混合物に、さらにアミノエタノール(80mg、1.3mmol)を添加した。加熱を70℃でさらに3日間続けた。合計6日後、反応混合物を冷却し、濾過し、濃縮した。残渣を、シリカゲルフラッシュドライカラムクロマトグラフィー(クロロホルム中のメタノール、1~4.2%)で精製した。これにより、化合物46を無色油状物(334mg、0.42mmol、30%)として得た。1HNMR (400 MHz、CDCl3) δ:4.09-4.06 (m、2H)、3.97 (d、5.8 Hz、4H)、3.39-3.36 (m、2H)、3.31-3.23 (m、4H)、2.31 (t、7.5 Hz、4H)、1.88-1.56 (m、12H)、1.43-1.19 (59H)、0.89 (t-様、6.8 Hz、12H)。
塩化メチレン(30mL)中の6-(2'-ヘキシルデカノイルオキシ)ヘキサン-1-アール(3.0g)、酢酸(0.20g)および3-アミノプロピオニトリル(0.21g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.3g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-6/98-94%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物47を無色油状物(0.29g)として得た。
塩化メチレン(30mL)中の6-(2'-ヘキシルデカノイルオキシ)ヘキサン-1-アール(3.0g)および4-アミノ酪酸エチル塩酸塩(0.46g)の溶液を、トリアセトキシ水素化ホウ素ナトリウム(1.4g)で一晩処理した。溶液を炭酸水素ナトリウム水溶液で洗浄した。有機相を無水硫酸マグネシウムで乾燥し、濾過し、溶媒を除去した。残渣を、酢酸/メタノール/塩化メチレン(2-0/0-8/98-92%)勾配を使用してシリカゲルカラムに通した。純粋な画分を重炭酸ナトリウム水溶液で洗浄し、化合物48を無色油状物(0.80g)として得た。
20mlの無水THF中の8-ブロモオクタン酸2-ブチルオクチル(2当量、1.877g、4.8mmol)の溶液に、4-アミノ-1-ブタノール(1当量2.4mmol、214mg、221μl)、炭酸カリウム(2当量、4.8mmol、664mg)、炭酸セシウム(0.3当量、0.72mmol、234mg)およびヨウ化ナトリウム(約5mg)を加えた。圧力丸底フラスコ中の混合物を6日間加熱(油浴、80℃)した。反応混合物を冷却し、濃縮した。残渣をヘキサンおよび酢酸エチルの混合物(約5:1)に溶解し、水、ブラインで洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮した。残渣をシリカゲルフラッシュカラムクロマトグラフィー(クロロホルム中のメタノール、1~4%)で精製した。これにより、化合物49を無色油状物(857mg、1.21mmol、50%)として得た。1HNMR (400 MHz、CDCl3) δ:6.55 (br. s、1H)、3.97 (d、5.8 Hz、4H)、3.55 (not well resolved triplet、2H)、2.45-2.40 (m. 6H)、2.30 (t、7.5 Hz、4H)、1.71-1.58 (m、10 H)、1.51-1.42 (m、4H)、1.39-1.19 (m、44H)、0.93-0.87 (m、12H)。
Claims (34)
- 以下の構造式(IF):
[式中、
G1およびG2はそれぞれ独立して、非置換C 4 -C12アルキレンまたはC 4 -C12アルケニレンであり;
G3は、C 3 -C 6 アルキレン、C 3 -C 6 アルケニレン、C3-C8シクロアルキレン、またはC3-C8シクロアルケニレンであり、これらはそれぞれ1つ以上のOHまたはC 1 -C 6 アルキルで任意に置換されていてもよく;
R1およびR2はそれぞれ独立して、分岐鎖のC6-C24アルキルであり;
R3は、H、OR5、CN、-C(=O)OR4、-OC(=O)R4または-NR5C(=O)R4であり;
R4は、C1-C12アルキルであり;および、
R5は、HまたはC1-C6アルキルである]
で示される化合物、またはその医薬的に許容される塩、もしくは立体異性体。 - 各R 6 が、Hである、請求項2に記載の化合物。
- nが、3または4である、請求項3に記載の化合物。
- yおよびzがそれぞれ独立して、4~10の整数である、請求項2~4のいずれか1つに記載の化合物。
- yおよびzがそれぞれ独立して、4~9の整数である、請求項2~4のいずれか1つに記載の化合物。
- aが、8~12の整数である、請求項7に記載の化合物。
- R7aの少なくとも1つの存在が、Hである、請求項7~8のいずれか1つに記載の化合物。
- R7aが、出現するごとに、Hである、請求項7~8のいずれか1つに記載の化合物。
- R7bの少なくとも1つの存在が、C1-C8アルキルである、請求項7~10のいずれか1つに記載の化合物。
- C1-C8アルキルが、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、tert-ブチル、n-ヘキシルまたはn-オクチルである、請求項11に記載の化合物。
- R3が、OHである、請求項1~13のいずれか1つに記載の化合物。
- R3が、CNである、請求項1~13のいずれか1つに記載の化合物。
- R3が、-C(=O)OR4、-OC(=O)R4または-NHC(=O)R4である、請求項1~13のいずれか1つに記載の化合物。
- R4が、メチルまたはエチルである、請求項16に記載の化合物。
- 請求項1~18のいずれか1つに記載の化合物および治療薬を含む組成物。
- 中性脂質、ステロイドおよびポリマー複合脂質から選択される1つ以上の賦形剤をさらに含む、請求項19に記載の組成物。
- 中性脂質が、DSPC、DPPC、DMPC、DOPC、POPC、DOPEおよびSMから選択される、請求項20に記載の組成物。
- 中性脂質が、DSPCである、請求項21に記載の組成物。
- 中性脂質に対する化合物のモル比が、2:1~8:1の範囲である、請求項20~22のいずれか1つに記載の組成物。
- ステロイドが、コレステロールである、請求項20~23のいずれか1つに記載の組成物。
- コレステロールに対する化合物のモル比が、5:1~1:1の範囲である、請求項24に記載の組成物。
- ポリマー複合脂質が、ペグ化脂質である、請求項20~25のいずれか1つに記載の組成物。
- 化合物のペグ化脂質に対するモル比が、100:1~20:1の範囲である、請求項26に記載の組成物。
- ペグ化脂質が、PEG-DAG、PEG-PE、PEG-S-DAG、PEG-cerまたはPEGジアルコキシプロピルカルバメートである、請求項26または27のいずれか1つに記載の組成物。
- R8およびR9がそれぞれ独立して、12~16個の炭素原子を含む直鎖の、飽和アルキル鎖である、請求項29に記載の組成物。
- 平均wが、49である、請求項29または30のいずれか1つに記載の組成物。
- 治療薬が、核酸を含む、請求項19~31のいずれか1つに記載の組成物。
- 核酸が、アンチセンスRNAおよびメッセンジャーRNAから選択される、請求項32に記載の組成物。
- それを必要とする患者において、治療薬をデリバリーするための、請求項19~33のいずれか1つに記載の組成物。
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