JP7523449B2 - 活性剤の脂質ナノ粒子送達のための脂質 - Google Patents
活性剤の脂質ナノ粒子送達のための脂質 Download PDFInfo
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- JP7523449B2 JP7523449B2 JP2021540131A JP2021540131A JP7523449B2 JP 7523449 B2 JP7523449 B2 JP 7523449B2 JP 2021540131 A JP2021540131 A JP 2021540131A JP 2021540131 A JP2021540131 A JP 2021540131A JP 7523449 B2 JP7523449 B2 JP 7523449B2
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Classifications
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- 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
- C07C233/45—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 carboxyl groups
- C07C233/46—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 carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—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 carboxyl groups 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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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
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Description
[式中、R1、R2、R3、R4、R5、L1、L2、L3、G1、G2、およびG3は、本明細書で定義された通りである。]
で示される化合物、または、その薬学的に許容される塩、互変異性体、または立体異性体、が提供される。
(i)疾患または病気が哺乳動物に発生するのを防ぐこと(特に、その哺乳動物がその病気になりやすいが、まだそれを有していると診断されていない場合);
(ii)疾患または病気を抑制すること(すなわち、その発症を止めること);
(iii)疾患または病気を緩和すること(すなわち、疾患または病気の退行を引き起こすこと);または、
(iv)疾患または病気に起因する症状を緩和すること(すなわち、根本の疾患または病気を対処せずに痛みを緩和すること)。
本明細書において、「疾患」および「病気」との用語は、交換可能に使用され得るか、または、特定の病気または病態が既知の原因物質を有さない(したがって、病因はまだ解明されていない)かもしれないという点で異なる可能性があり、したがって、それは、まだ疾患として認識されないが、臨床医によって多少の特定の症状が確認された望ましくない病気または症候群としてのみ認識されるものである。
一態様において、本開示は、中性脂質、荷電脂質、ステロイド、および/またはポリマー結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を有する脂質ナノ粒子を形成することができる、新規な脂質化合物を提供する。理論によって拘束されるものではないが、これらの脂質ナノ粒子は、オリゴヌクレオチドを血清中での分解から保護し、インビトロおよびインビボにおいてオリゴヌクレオチドの効果的な細胞への送達を提供するものと考えられる。
[式中、
R1は、任意に置換されていてもよいC1-C24アルキル、または任意に置換されていてもよいC2-C24アルケニルであり;
R2およびR3は、それぞれ独立して、任意に置換されていてもよいC1-C36アルキルであり;
R4およびR5は、それぞれ独立して、任意に置換されていてもよいC1-C6アルキルであるか、または、R4およびR5は、それらが結合しているNと一緒になって、ヘテロシクリルまたはヘテロアリールを形成し;
L1、L2、およびL3は、それぞれ独立して、任意に置換されていてもよいC1-C18アルキレンであり;
G1は、直接結合、-(CH2)nO(C=O)-、-(CH2)n(C=O)O-、または、-(C=O)-であり;
G2およびG3は、それぞれ独立して、-(C=O)O-、または-O(C=O)-であり;および、
nは、0より大きい整数である。]
で示される化合物、またはその薬学的に許容される塩、互変異性体、または立体異性体である。
のうちの1つで示される。
[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岐の飽和または不飽和のアルキル鎖であり、ここで該アルキル鎖は、任意に、1つ以上のエステル結合が割り込まれていてもよく;および
wの平均値は、30~60の範囲である。]
で示されるペグ化脂質、またはその薬学的に許容される塩、互変異性体、または立体異性体、を含む。
[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岐の飽和または不飽和のアルキル鎖であり、ここで該アルキル鎖は、任意に、1つ以上のエステル結合が割り込まれていてもよく;および
wの平均値は、30~60の範囲である。]
で示されるペグ化脂質、またはその薬学的に許容される塩、互変異性体、または立体異性体である。
[式中、R1、R2、R3、R4、R5、L1、L2、L3、G1、G2、およびG3は、本明細書で定義された通りである。]
で示される化合物、またはその薬学的に許容される塩、互変異性体、または立体異性体、を製造するための例示的な方法を示している。当業者は、同様の方法によって、または当業者に知られている他の方法を組み合わせることによって、これらの化合物を製造することができることが理解される。また、当業者は、以下に記載されるのと同様の方法で、適切な出発成分を用い、必要に応じて合成のパラメータ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(I)の他の化合物を製造できることも理解される。一般に、出発成分は、Sigma Aldrich、Lancaster Synthesis,Inc.、Maybridge、Matrix Scientific、TCI、および、Fluorochem USAなどの供給元から入手するか、または当業者に知られている供給源に従って合成することができ(例えば、Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)参照)、あるいは本開示に記載されたように製造することができる。
脂質ナノ粒子組成物を用いたルシフェラーゼmRNAインビボ評価
脂質ナノ粒子は、PCT公開番号WO2015/199952およびWO2017/004143に記載された一般的な方法に従って、製造および試験され、これらの開示は全て、参照により本明細書に組み込まれる。簡単に説明すると、カチオン性脂質、DSPC、コレステロール、およびPEG脂質を、約50:10:38.5:1.5、または約47.5:10:40.8:1.7のモル比で、エタノールに可溶化した。脂質ナノ粒子(LNP)を、脂質合計とmRNAとの重量比が約10:1~30:1で製造した。mRNAを、10~50mMのクエン酸または酢酸緩衝液(pH4)で、0.2mg/mLに希釈する。シリンジポンプを用いて、総流量15mL/min以上で、エタノール性脂質溶液を、mRNA水溶液と、約1:5~1:3(vol/vol)の比率で混合する。次いで、エタノールを除去し、透析によって外部のバッファーをPBSに置き換えた。最後に、脂質ナノ粒子を、0.2μm細孔の滅菌フィルターでろ過した。脂質ナノ粒子の粒子サイズは、粒径約55~95nmであり、場合によっては、粒径約70~90nmであり、Malvern Zetasizer Nano ZS(Malvern、UK)を用いた準弾性光散乱によって決定した。
製剤化した脂質のPKAの測定
他の箇所で説明するように、製剤化されたカチオン性脂質のpKaは、核酸送達のLNPの有効性と相関している(Jayaraman et al, Angewandte Chemie, International Edition (2012), 51(34), 8529-8533; Semple et al, Nature Biotechnology 28, 172-176 (2010)、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で測定した。PBS中に、総脂質0.4mMの濃度で、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した。TNSを、蒸留水中に100mMのストック溶液として調製した。ビヒクルを、10mMのHEPES、10mMのMES、10mMの酢酸アンモニウム、130mMのNaClを含む、緩衝液2mLで、脂質24mMに希釈し、ここで、pHは2.5~11の範囲とした。TNS溶液のアリコートを加えて、最終濃度1μMとし、次いで、ボルテックス混合を行い、蛍光強度を、SLM Aminco Series 2 Luminescence Spectrophotometerにより、励起および発光の波長として321nmおよび445nmを用いて、室温で測定した。シグモイドベストフィット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させるpHとして測定した。
インビボのルシフェラーゼmRNA発現げっ歯類モデルを用いた、様々なカチオン性脂質を含む脂質ナノ粒子製剤の有効性の測定
表2に示すカチオン性脂質は、以前に核酸で試験されている。比較の目的で、これらの脂質を使用して、実施例1およびPCT/US10/22614(これはその全体が参照により本明細書に組み込まれる)に記載されているインライン混合法を用いて、FLuc mRNA(L-6107)を含む脂質ナノ粒子を製剤化した。脂質ナノ粒子は、次のモル比により製剤化された: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(「PEG-DMG」、すなわち、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、平均PEG分子量2000)。代わりの実施形態において、カチオン性脂質、DSPC、コレステロール、およびPEG脂質は、約47.5:10:40.8:1.7のモル比で製剤化した。相対活性は、実施例1に記載のように、尾静脈注射による投与4時間後の肝臓におけるルシフェラーゼ発現を測定することにより求めた。活性は、0.3mgおよび1.0mgのmRNA/kgの用量で比較し、実施例1に記載のように、投与4時間後に測定したngルシフェラーゼ/g肝臓として、表した。
ケトン4-1(1.10g、1.62mmol)および1-デシルアミン(2.43mmol、382mg、0.486mL)のDCE(10mL)の溶液を室温で15分間撹拌し、続いてトリアセトキシ水素化ホウ素ナトリウム(2.43mmol、515mg)および酢酸(2.43mmol、146mg;0.138mL)を加えた。混合物を室温で2日間撹拌した後、反応混合物を濃縮した。残渣をヘキサンの混合で希釈し、希NaOH、飽和NaHCO3および食塩水で洗浄した。有機相を分離し、硫酸ナトリウムで乾燥させ、濃縮した(無色の油、1.41g)。粗生成物をシリカゲルのカラムクロマトグラフィー(ヘキサン/EtOAc/Et3N、95:5:0~80:20:1)で精製した。目的の生成物を無色の油として得た(863mgの無色の油、1.05mmol、収率65%)。
1H NMR (400 MHz, CDCl3) δ: 3.98 (d, 5.8 Hz, 4H), 2.54 (t, 7.1 Hz, 2H), 2.43 (quintet, 5.5 Hz, 1H), 2.30 (t, 7.5 Hz, 4H), 1.68-1.57 (m, 6H), 1.50-1.41 (m, 2H), 1.41-1.08 (70H), 0.92-0.86 (m, 15H), 0.86-0.77 (br. 1H).
室温でCH2Cl2(1mL)に5-ブロモ吉草酸(1.12mmol、204mg)を撹拌した溶液に、塩化チオニル(3.36mmol、400mg、0.25mL)のCH2Cl2(5mL)の溶液を、1分間かけて加え、続いて、DMF(約16mg)を加えた。次いで、混合物を2時間加熱還流した。次に、反応混合物を真空で濃縮した。酸塩化物を次の工程にそのまま使用した。
上記の5-ブロモペンタノイルクロリドのベンゼン溶液(5mL)を、4-2(230mg、0.28mmol)およびトリエチルアミン(5.6mmol、565mg、0.780mL)、およびDMAP(5mg)のベンゼン(5mL)の溶液に、室温で2分間で滴下して加えた。添加後、反応物を室温で1時間撹拌した。メタノール(1mL)を加え、混合物を2時間撹拌した。反応混合物を減圧下で濃縮した。粗生成物をシリカゲルのカラムクロマトグラフィー(ヘキサン/EtOAc、98:2~85:15)で精製した。目的の生成物を無色の油として得た(250mg、0.25mmol、91%、無色の油)。
4-2(250mg、0.25mmol)にジメチルアミン(THF中2M、10mL)を加えた。溶液を64℃で一晩撹拌した。反応混合物を濃縮した。残渣をヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのパッドを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して、茶色がかった油(約233mg)を得た。粗生成物(233mg)をシリカゲルの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0~6%のメタノール)によって精製した。目的の生成物を、(194mg、無色の油、0.20mmol、82%)として得た。
1H NMR (400 MHz, CDCl3) δ: 4.60-4.20 (br, 推定0.3H, アミド結合について異性化が遅いため), 3.97, 3.96 (2セットのダブレット, 5.8 Hz, 4H), 3.60 (クインテット状, 7.0 Hz, 0.7H), 3.06-2.99 (m, 2H), 2.34-2.24 (m, 8H), 2.21 (シングレット, 6H), 1.72-1.56 (m, 8H), 1.56-1.37 (m, 8H), 1.37-1.10 (66H), 0.91-0.85 (m, 15H).
室温でCH2Cl2(10mL)に4-(ジメチルアミノ)酪酸塩酸塩(1.12mmol、188mg)およびDMF(10~20μL)を撹拌した溶液に、塩化オキサリル(5.6mmol、722mg、0.496mL)を加えた。得られた混合物を室温で一晩撹拌した。反応混合物(濃い赤色)を減圧下で濃縮した。得られた酸塩化物(ブロック状の赤色の固体)を、次の工程にそのまま使用した。
上記のアシルクロライドのCH2Cl2(10mL)溶液を、4-2(230mg、0.28mmol)、トリエチルアミン(5.6mmol、565mg、0.780μL)およびDMAP(5mg)のCH2Cl2溶液(5mL)に、室温で滴下して加えた。得られた混合物を室温で一晩撹拌し、減圧下で濃縮した。粗生成物をシリカゲルのカラムクロマトグラフィー(ヘキサン/EtOAc/Et3N、80:20:0.1~75:25:1)で精製し、さらにシリカゲルの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0~5%のメタノール)で精製した。目的の生成物を、(92mg、無色の油、0.10mmol、35%)として得た。
1H NMR (400 MHz, CDCl3) δ: 4.57-4.29 (br. 0.4H), 3.97, 3.96 (2セットのダブレット, 5.8 Hz, 5.8 Hz, 4H), 3.63 (クインテット状, 6.8 Hz, 0.6H), 3.06-3.00 (m, 2H), 2.35-2.26 (m, 8H), 2.213, 2.211 (2セットのシングレット, 6H), 1.82 (セクステット状, 7.6 Hz, 2H), 1.65-1.56 (m, 6H), 1.54-1.48 (m, 2H), 1.47-1.37 (m, 4H), 1.36-1.06 (66H), 0.91-0.86 (m, 15H).
4-ジメチルアミノ酪酸塩酸塩(2当量、3.04mmol、510mg)、および4-ジメチルアミノピリジン(3当量、DMAP、4.56mmol、557mg)のアセトニトリル(30mL)の溶液に、DCC(2.2当量、3.34mmol、690mg)を加え、混合物を室温で45分間撹拌した。4-2(1.25g、1.52mmol)のCH2Cl2(6mL)溶液を加え、得られた混合物を一晩撹拌した。次の日、さらにDCC(450mg)を加え、混合物をさらに1日撹拌した。その後、混合物を減圧下で濃縮した。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのショートカラムを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して、無色の油を得た。生成物を、シリカゲルのフラッシュドライカラムクロマトグラフィー(微量のEt3Nを含むクロロホルム中0~5%メタノール)によってさらに精製した。目的の生成物を無色の油として得た(1.14g、81%)。
4-3(179mg、0.18mmol)、ジエチルアミン(0.90mmol、66mg、0.093mL)、N,N-ジイソプロピルエチルアミン(0.36mmol、46mg、0.063mL)のアセトニトリル(6mL)混合物を密封し、83℃で24時間加熱した。反応混合物を濃縮した。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのパッドを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して、茶色がかった油(153mg)を得た。粗生成物(233mg)を、シリカゲルの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0~6%のMeOH)によって精製した。目的の生成物を、(136mg、無色の油、0.14mmol、77%)として得た。
4-3(200mg、0.20mmol)、ピロリジン(50当量、0.83mL、10mmol)のTHF(10mL)混合物を密封し、64℃で24時間加熱した。反応混合物を濃縮した。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのパッドを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して、茶色がかった油を得た。粗生成物(233mg)を、シリカゲルの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0~6%のMeOH)によって精製した。目的の生成物を、(158mg、無色の油、0.16mmol、80%)として得た。
8-1(1当量、1.15g、1.62mmol)および1-デシルアミン(1.5当量、2.43mmol、382mg、0.486mL)のDCE(10mL)溶液を室温で約15分間撹拌した。溶液に、トリアセトキシ水素化ホウ素ナトリウム(1.5当量、2.43mmol、515mg)およびAcOH(1.5当量、2.43mmol、146mg、0.14mL)を加えた。混合物を室温で3日間撹拌した。次に、反応混合物を濃縮した。残渣を、ヘキサン/EtOAc(99:1)で希釈し、希NaOH溶液、飽和NaHCO3、および食塩水で洗浄した。有機抽出物を硫酸ナトリウムで乾燥させ、シリカゲルのショートカラムに注いだ。カラムをヘキサン、EtOAcおよびEt3Nの混合物(95:5:0~80:20:1)で溶出した。純粋な生成物を含む画分を合わせて、濃縮した。目的の生成物を無色の油として得た(1.28g、1.51mmol、93%)。
1HNMR (400 MHz, CDCl3) δ: 3.97 (d, 5.8 Hz, 4H), 2.53 (t, 7.2 Hz, 2H), 2.43 (クインテット状, 5.5 Hz, 1H), 2.30 (t, 7.5 Hz, 4H), 1.68-1.57 (m, 6H), 1.49-1.40 (m, 2H), 1.40-1.08 (74H), 0.91-0.85 (m, 15H), 0.83-0.74 (br. 1H).
室温で4-(ジメチルアミノ)酪酸塩酸塩(2.1mmol、352mg)およびDMF(約13mg)を撹拌したCH2Cl2(15mL)溶液に、Ar下、塩化オキサリル(3当量、6.3mmol、800mg、0.55mL)を加えた。得られた混合物を室温で一晩撹拌した。反応混合物(薄オレンジ色の溶液)を真空で濃縮した。得られた酸塩化物(8-3、薄褐色の固体)を次の反応にそのまま使用した。
上記のアシルクロライドのCH2Cl2(10mL)溶液を、室温で、8-2(300mg、0.35mmol)、トリエチルアミン(10.5mmol、1.06g、1.5mL)およびDMAP(5mg)のCH2Cl2(5mL)溶液に加えた。添加後、反応混合物を室温で一晩撹拌した。混合物を濃縮した後、生成物をシリカゲルのカラムクロマトグラフィー(ヘキサン、EtOAcおよびEt3N、80:20:0.1~70:30:1)によって単離し、生成物をシリカゲルの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0~5%MeOH)によってさらに精製した。目的の生成物を、淡黄色の油(110mg、0.11mmol、32%)として得た。
1HNMR (400 MHz, CDCl3, 7.26 ppm) δ: 4.57-4.34 (br. 0.4H), 3.98-3.94 (m, 4H), 3.64 (クインテット状, 6.8 Hz, 0.6H), 3.06-3.00 (m, 2H), 2.35-2.25 (m, 8H), 2.213, 2.210 (2セットのシングレット, 6H), 1.82 (セクステット状, 7.4 Hz, 2H), 1.65-1.56 (m, 6H), 1.54-1.48 (m, 2H), 1.48-1.37 (m, 4H), 1.37-1.06 (70H), 0.91-0.86 (m, 15H).
9-1(1当量、0.82g、1.21mmol)および2-エチル-1-ヘキシルアミン(1.5当量、1.81mmol、234mg)のDCE(8mL)溶液を室温で約15分間撹拌した。溶液にトリアセトキシ水素化ホウ素ナトリウム(1.5当量、1.81mmol、384mg)およびAcOH(1.5当量、1.81mmol、109mg)を加えた。混合物を室温で2日間撹拌した。次に、反応混合物を濃縮した。残渣を、ヘキサンおよびEtOAc(約99:5)で希釈し、希NaOH、飽和NaHCO3および食塩水で洗浄した。抽出物をシリカゲルのショートカラムを通して濾過した。カラムをヘキサンとEtOAcの混合物(95:5)で洗浄し、次に、ヘキサン、EtOAcおよびEt3Nの混合物(80:20:0.5)で洗浄した。後者の洗浄で得た濾液を濃縮し乾燥させた。これにより、純粋な生成物を無色の油として得た(888mg、1.12mmol、93%)。
1HNMR (400 MHz, CDCl3) δ: 3.98 (d, 5.8 Hz, 4H), 2.45 (d, 5.1 Hz, 2H), 2.39 (クインテット状, 5.5 Hz, 1H), 2.30 (t, 7.5 Hz, 4H), 1.68-1.57 (m, 6H), 1.41-1.08 (65H), 0.92-0.85 (m, 18H), 0.84-0.78 (br. 1H).
室温で5-ブロモ吉草酸(2.24mmol、405mg)を撹拌したCH2Cl2(2mL)溶液に、塩化チオニル(3当量、6.72mmol、800mg、0.49mL)のCH2Cl2(5mL)溶液を1分間でゆっくりと加えた。DMF(小さな2滴、約16mg)を反応混合物に加えた。次に、混合物を2時間加熱還流した。反応混合物を真空で濃縮した。得られた酸塩化物9-3を次の工程にそのまま使用した。
上記の5-ブロモペンタノイルクロリドのベンゼン(8mL)溶液を、9-2(444mg、0.56mmol)、トリエチルアミン(1.56mL)およびDMAP(5mg)のベンゼン(5mL)溶液に、室温で、2分で加えた。添加後、混合物を室温で一晩撹拌した。真空で溶媒をエバポレーションした後、生成物をシリカゲルのカラムクロマトグラフィー(ヘキサン/EtOAc、99:1~90:10)によって単離した。目的の生成物は、次の工程のために十分に純粋であった(無色の油、527mg、0.55mmol、98%)。
9-4(260mg、0.27mmol)を含む圧力フラスコに、ジメチルアミン(THF中2M、10mL)を加えた。溶液を64℃(油浴温度)で一晩撹拌した。過剰のアミンと溶媒をエバポレーションした。残渣を、酢酸エチルとヘキサンの混合物(95:5)に取り、シリカゲルのパッドを通して濾過した。パッドをヘキサンとEtOAcの混合物(95:5)で洗浄し、次に、ヘキサン、EtOAcおよびEt3Nの混合物(80:20:1)で洗浄した。後者の洗浄からの濾液を濃縮して乾燥させた。これにより、粗生成物を褐色の油(233mg)として得た。粗生成物を、シリカゲルの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0~5%のMeOH)によってさらに精製した。目的の生成物を無色の油として得た(204mg、0.22mmol、82%)。
1HNMR (400 MHz, CDCl3, 7.27 ppm) δ: 3.97 (d, 5.8 Hz, 4H), 3.66-3.57 (m, ca 1H), 3.19-2.99 (2セットのピーク, 2H), 2.38-2.24 (m, 8H), 2.22 (シングレット, 6H), 1.72-1.37 (m, 15H), 1.37-1.10 (60H), 0.91-0.85 (m, 18H).
3-ブロモプロピオン酸(2.02mmol、311mg)のCH2Cl2(5mL)およびDMF(0.01mL)の溶液に、塩化オキサリル(5.05mmol、641mg、0.44mL)を室温で加えた。得られた混合物を室温で一晩撹拌した。次に、混合物を真空で濃縮した。残留した液体/固体(黄色)を10mLのCH2Cl2に溶解し、4-2(833mg、1.02mmol)、トリエチルアミン(5.05mmol、0.7mL)およびDMAP(5mg)のCH2Cl2(10mL)溶液に、室温で、4分で加えた。添加後、混合物を室温で2時間撹拌した。真空で溶媒をエバポレーションした後、生成物をシリカゲルのカラムクロマトグラフィー(ヘキサン/EtOAc、99:1~90:10)によって単離した。目的の生成物を無色の油として得た(794mg、0.83mmol、81%)。
10-1(283mg、0.30mmol)およびジメチルアミン(THF中2M、12mL)の混合物を、圧力フラスコ中で、68℃(油浴温度)で一晩撹拌した。反応混合物を濃縮した。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのパッドを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して、茶色がかった油(302mg)を得た。粗生成物(302mg)を、シリカゲルのフラッシュドライカラムクロマトグラフィー(微量のEt3Nを含むクロロホルム中0~5%のMeOH)によって精製した。目的の生成物を無色の油として得た(169mg、0.18mmol、61%)。
1HNMR (400 MHz, CDCl3, 7.26) δ: 4.50-4.31 (br, 推定0.3H, アミド結合について異性化が遅いため), 3.97 (ショルダーダブレット, 5.8 Hz, 4H), 3.60 (クインテット状, 7.0 Hz, 0.7H), 3.07-3.00 (m, 2H), 2.65 (q状, 7.6 Hz, 2H), 2.48 (q状, 7.6 Hz, 2H), 2.29 (ショルダートリプレット, 7.6 Hz, 4H), 2.26, 2.25 (2セットのシングレット, 6H), 1.66-1.56 (m, 6H), 1.56-1.48 (m,2H), 1.48-1.37 (m, 4H), 1.37-1.10 (66H), 0.91-0.85 (m, 15H).
4-ブロモ酪酸(0.97mmol、161mg)のCH2Cl2(3mL)およびDMF(0.01mL)の溶液に、塩化オキサリル(3当量、2.91mmol、370mg、0.25mL)を室温で加えた。混合物を室温で一晩撹拌した。次に、反応混合物を真空で濃縮した。残留した液体/固体(淡黄色)を5mLのCH2Cl2に溶解し、8-2(410mg、0.48mmol)、トリエチルアミン(0.4mL)、およびDMAP(2mg)のCH2Cl2(20mL)溶液を、室温で、2分で加えた。添加後、得られた混合物を室温で2.5時間撹拌した。TLC(ヘキサン/酢酸エチル=9:1)は、2つの主要なスポットを示した。次に、反応混合物を減圧下、室温で濃縮した。残渣を精製せずに次の反応に使用した。
11-1を含む上記の残渣を、ピロリジン(2.10mL、25mmol)およびTHF(15mL)の混合物に取った。混合物を圧力フラスコに移し、68℃で一晩加熱した。混合物を冷却し、減圧下で濃縮した。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのショートカラムを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して、黄色の油/固体を得た。粗生成物(300mg)をシリカゲルのカラムクロマトグラフィー(CH2Cl2中、0%~10%のMeOHおよび0%~0.5%のEt3N)によって精製した。目的の生成物を黄色の油(215mg)として得た。生成物(215mg)を、シリカゲルの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0~5%のMeOH)によってさらに精製した。目的の生成物を無色の油として得た(162mg、0.16mmol、34%)。
1HNMR (400 MHz, CDCl3, 7.26 ppm) δ: 4.57-4.34 (br. 0.4H), 3.98-3.94 (m, 4H), 3.64 (クインテット状, 6.8 Hz, 0.6H), 3.06-3.00 (m, 2H), 2.51-2.44 (m, 6H), 2.37-2.21(m, 6H), 1.86 (セクステット状, 7.6 Hz, 2H), 1.80-1.71 (m, 4H), 1.65-1.48 (m, 8H), 1.48-1.37 (m, 4H), 1.37-1.06 (70H), 0.91-0.86 (m, 15H).
4-ジメチルアミノ酪酸塩酸塩(0.50mmol、85mg)および4-ジメチルアミノピリジン(3当量、DMAP、0.75mmol、92mg)のアセトニトリル(5mL)溶液に、DCC(1.1mmol×2、226mg)を加え、混合物を室温で45分間撹拌した。9-2(160mg、0.20mmol)のCH2Cl2(1mL)溶液を反応混合物に加え、得られた混合物を週末にわたって撹拌した。さらにDCC(135mg)を加え、さらに1日撹拌した。TLC分析に基づき進行が観察されなかった。反応混合物を減圧下で濃縮した。残渣を、ヘキサンとEtOAcの混合物(約99:5)に取り、シリカゲルのショートカラムを通して濾過した。カラムをヘキサンとEtOAcの混合物(95:5)で洗浄し、次に、ヘキサン、EtOAcおよびEt3Nの混合物(80:20:1)で洗浄した。後者の洗浄からの濾液を濃縮して乾燥させた(133mg)。粗生成物(133mg)を、シリカゲルのフラッシュドライカラムクロマトグラフィー(微量のEt3Nを含むクロロホルム中0~5%のMeOH)によってさらに精製した。目的の生成物を、(48mg、無色の油、0.053mmol、27%)として得た。
1HNMR (400 MHz, CDCl3, 7.27 ppm) δ: 3.97 (d, 5.8 Hz, 4H), 3.70-3.60 (m, ca 1H), 3.19-2.99 (2セットのピーク, 2H), 2.39-2.25 (m, 8H), 2.22 (シングレット, 6H), 1.86-1.76 (m, 2H), 1.72-1.37 (m, ca 11H), 1.37-1.10 (60H), 0.91-0.85 (m, 18H).
4-3(284mg、0.29mmol)、THF(10mL)、ヨウ化ナトリウム(5mg)およびジブチルアミン(10mmol、1.29g、1.68mL)の混合物を、圧力フラスコ中で、78℃で一晩撹拌した。反応混合物を濃縮した。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのパッドを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して、褐色がかった油(生成物およびジブチルアミン)を得た。油をヘキサンで希釈し、希HCl水溶液(0.5M)で2回洗浄し、飽和NaHCO3および食塩水で洗浄し、硫酸ナトリウムで乾燥させた。抽出物を減圧下で濃縮した。粗生成物(309mg)を、シリカゲルのフラッシュドライカラムクロマトグラフィー(微量のEt3Nを含むクロロホルム中0~5%のMeOH)によって精製した。目的の生成物を無色の油として得た(216mg、0.21mmol、72%)。
1HNMR (400 MHz, CDCl3) δ: 4.50-4.35 (br, 推定0.3H, アミド結合について異性化が遅いため), 3.97, 3.96 (2セットのダブレット, 5.8 Hz, 4H), 3.61 (クインテット状, 7.0 Hz, 0.7H), 3.07-2.99 (m, 2H), 2.45-2.36 (m, 6H), 2.34-2.27 (m, 6H), 1.70-1.56 (m, 8H), 1.56-1.36 (m, 12H), 1.37-1.10 (70 H), 0.97-0.85 (m, 21H).
4-ジメチルアミノ酪酸塩酸塩(2当量、1.08mmol、181mg)、および4-ジメチルアミノピリジン(3当量、DMAP、1.62mmol、198mg)のアセトニトリル(10mL)溶液に、DCC(2.2当量、1.18mmol、245mg)を加え、混合物を室温で45分間撹拌した。次に、14-1(442mg、0.54mmol)のCH2Cl2(2mL)溶液を加えた。得られた混合物を一晩撹拌した。さらにDCC(140mg)を加え、混合物をさらに1日撹拌した。次に、混合物を減圧下で濃縮した。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのショートカラムを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して、黄色の油(381mg)を得た。粗生成物(381mg)を、シリカゲルのフラッシュドライカラムクロマトグラフィー(微量のEt3Nを含むクロロホルム中0~5%のMeOH)によって精製した。目的の生成物を無色の油として得た(345mg、0.38mmol、70%)。
1HNMR (400 MHz, CDCl3, 7.26 ppm) δ: 5.30-4.34 (br., 0.3H), 4.061, 4.056 (2セットのトリプレット, 6.7 Hz, 4H), 3.64 (クインテット状, 6.8 Hz, 0.7H), 3.07-3.01 (m, 2H), 2.35-2.26 (m, 6H), 2.214, 2.211 (2セットのシングレット, 6H), 1.82 (セクステット状, 7.6 Hz, 2H), 1.65-1.48 (m, 10H), 1.48-1.37 (m, 8H), 1.37-1.02 (60H), 0.90-0.85 (m, 15H).
10-1(283mg、0.30mmol)、ピロリジン(1.25mL、15mmol)およびTHF(10mL)の混合物を、圧力管内で、64℃で一晩加熱した。混合物を冷却し、減圧下で濃縮した。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのショートカラムを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して黄色の油を得た。粗生成物(314mg)を、シリカゲルのフラッシュドライカラムクロマトグラフィー(微量のEt3Nを含むクロロホルム中0~5%のMeOH)によってさらに精製した。目的の生成物を無色の油として得た(113mg、0.12mmol、40%)。
1HNMR (400 MHz, CDCl3, 7.26) δ: 4.55-4.30 (br, 推定0.3H, アミド結合について異性化が遅いため), 3.97 (ショルダーダブレット, 5.8 Hz, 4H), 3.61 (クインテット状, 7.0 Hz, 0.7H), 3.06-3.00 (t状, 2H), 2.81 (q状, 7.6 Hz, 2H), 2.58-2.51(m, 6H), 2.292, 2.285 (2セットのトリプレット, 7.5 Hz, 4H), 1.83-1.73 (m, 4H), 1.65-1.56 (m, 6H), 1.56-1.48 (m,2H), 1.48-1.37 (m, 4H), 1.37-1.10 (66H), 0.91-0.85 (m, 15H).
4-3(200mg、0.20mmol)、ヘキシルアミン(20mmol、2g)、N,N-ジイソプロピルエチルアミン(5当量、1.0mmol、0.17mL)、およびヨウ化ナトリウム(10mg)のアセトニトリル(6mL)の混合物を密封し、70℃で24時間加熱した。反応混合物を減圧下(約30mmHg)で75~85℃で濃縮した。TLCは、過剰のヘキシルアミンのほとんどが除去されたことを示した。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのショートカラムを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して褐色の油(192mg)を得て、これをさらに精製することなく次の工程に使用した。
16-1(192mg、0.19mmol)のTHF(5mL)溶液に、室温でホルムアルデヒドHCHO溶液(500mg、37重量%水溶液)を加えた。得られた混合物を30分間撹拌した後、トリアセトキシ水素化ホウ素ナトリウム(1.2mmol、243mg)を加えた。得られた混合物を室温で一晩撹拌した。反応混合物を濃縮した。残渣を、ヘキサンの混合で取り、希NaOH溶液、飽和重炭酸ナトリウム溶液および食塩水で洗浄した。硫酸ナトリウムで乾燥させた後、溶液を濃縮して乾燥させた(黄色の油)。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのショートカラムを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して、黄色の油(220mg)を得た。粗生成物(220mg)を、シリカゲルのフラッシュドライカラムクロマトグラフィー(微量のEt3Nを含むクロロホルム中0~5%のMeOH)によってさらに精製した。目的の生成物を無色の油として得た(113mg、0.13mmol、69%)。
1HNMR (400 MHz, CDCl3, 7.26 ppm) δ: 4.50-4.35 (br, 推定0.3H, アミド結合について異性化が遅いため), 3.97, 3.96 (2セットのダブレット, 5.8 Hz, 4H), 3.60 (クインテット状, 7.0 Hz, 0.7H), 3.06-2.98 (m, 2H), 2.36-2.26 (m, 10H), 2.191, 2.189 (2セットのシングレット, 3H), 1.70-1.56 (m, 8H), 1.56-1.36 (m, 10H), 1.37-1.10 (72 H), 0.91-0.85 (m, 18H).
3-ジメチルアミノプロピオン酸塩酸塩(2当量、0.62mmol、95mg)および4-ジメチルアミノピリジン(3当量、DMAP、0.93mmol、114mg)のアセトニトリル(10mL)溶液に、DCC(2.2当量、0.68mmol、141mg)を加え、混合物を室温で45分間撹拌した。8-2(262mg、0.31mmol)のCH2Cl2(2mL)溶液を加え、得られた混合物を週末にかけて撹拌した。TLC(クロロホルム/MeOH、9:1)は、溶媒前に主要なスポットを示し、これは、脱離生成物で、出発物質でなく、少しの目的の生成物であり得る。反応混合物を濃縮した。可能性のある脱離生成物(107mgの無色の油)をカラムクロマトグラフィー(ヘキサン-EtOAc、95:5)によって単離し、ジメチルアミンのTHF溶液(2M、9mL)で、室温で4日間処理した。混合物を濃縮した。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのショートカラムを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して黄色の油を得た。粗生成物を、シリカゲルのフラッシュドライカラムクロマトグラフィー(微量のEt3Nを含むクロロホルム中0~5%MeOH)によってさらに精製した。目的の生成物を無色の油として得た(62mg)。
1HNMR (400 MHz, CDCl3, 7.26) δ: 4.50-4.36 (br, 推定0.3H, アミド結合について異性化が遅いため), 3.97, 3.96 (2セットのダブレット, 5.8 Hz, 4H), 3.61 (クインテット状, 7.0 Hz, 0.7H), 3.07-3.00 (m, 2H), 2.65 (q状, 7.2 Hz, 2H), 2.53-2.41 (m, 2H), 2.31-2.26 (m, 4H), 2.26, 2.25 (2セットのシングレット, 6H), 1.66-1.56 (m, 6H), 1.56-1.48 (m,2H), 1.48-1.37 (m, 4H), 1.37-1.10 (70H), 0.91-0.85 (m, 15H)
3-ブロモプロピオニル酸(0.34mmol、52mg)のCH2Cl2(3mL)およびDMF(細い針から1滴)の溶液に、塩化オキサリル(0.86mmol、109mg、74μL)を室温で加えた。混合物を室温で一晩撹拌した。次に、混合物を減圧下、室温で60分間濃縮した。残留した液体/固体(黄色)を5mLのCH2Cl2に溶解し、18-1(160mg、0.17mmol)、トリエチルアミン(0.86mmol、0.12mL)およびDMAP(1mg)のCH2Cl2(5mL)溶液に、室温で、1分で加えた。添加後、混合物を室温で3時間撹拌し、次に濃縮した。生成物をシリカゲルのカラムクロマトグラフィー(ヘキサン、EtOAc、およびEt3N、95:5~85:15)によって単離した。目的の生成物を無色の油として得た(99mg、0.09mmol、53%)。
18-2(99mg、0.09mmol)を含む圧力フラスコに、ジメチルアミン(THF中2M、5mL)を加えた。溶液を68℃(油浴温度)で2日間撹拌した。混合物を冷却し、減圧下で濃縮した。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのショートカラムを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して、褐色の油(94mg)を得た。生成物(94mg)を、シリカゲルのフラッシュドライカラムクロマトグラフィー(微量のEt3Nを含むクロロホルム中0~5%のMeOH)によってさらに精製した。目的の生成物を無色の油として得た(71mg、0.069mmol、76%)。
1HNMR (400 MHz, CDCl3, 7.26) δ: 4.53-4.35 (br, 推定0.3H, アミド結合について異性化が遅いため), 4.02-3.93 (m, 6H), 3.62 (クインテット状, 7.0 Hz, 0.7H), 3.07-3.01 (m, 2H), 2.65 (q状, 7.6 Hz, 2H), 2.50-2.44 (m, 2H), 2.34-2.26 (m, 6H), 2.26, 2.25 (2セットのシングレット, 6H), 1.69-1.56-1.48 (m, 推定11H, 水のピークと重複), 1.49-1.37 (m, 4H), 1.37-1.10 (66H), 0.92-0.86 (m, 18H).
19-1(1当量、0.493g、0.70mmol)および1-デシルアミン(1.5当量、1.05mmol、165mg、0.21mL)のDCE(10mL)溶液を、室温で約15分間撹拌した。この溶液に、トリアセトキシ水素化ホウ素ナトリウム(1.5当量、1.05mmol、222mg)およびAcOH(1.5当量、1.05mmol、63mg、0.059mL)を加えた。混合物を室温で2日間撹拌した。次に、反応混合物を濃縮した。残渣をヘキサンで希釈し、希NaOH、飽和NaHCO3および食塩水で洗浄した。有機抽出物を硫酸ナトリウムで乾燥させた後、溶媒を減圧下で除去した。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのショートカラムを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して、目的の生成物を無色の油として得た(582mg、0.69mmol、98%)。生成物をさらに精製することなく次の工程に使用した。
4-ジメチルアミノ酪酸塩酸塩(1.71mmol、287mg)および4-ジメチルアミノピリジン(3当量、DMAP、2.07mmol、253mg)のアセトニトリル(15mL)溶液に、DCC(2.2当量、1.52mmol、313mg)を加え、混合物を室温で45分間撹拌した。19-2(582mg、0.69mmol)のCH2Cl2(3mL)溶液を加え、得られた混合物を一晩撹拌した。次の日、さらにDCC(200mg)を加え、週末(4日間)撹拌を続けた。次に、混合物を減圧下で濃縮した。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのショートカラムを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して黄色の油を得た。生成物を、シリカゲルのフラッシュドライカラムクロマトグラフィー(微量のEt3Nを含むクロロホルム中0~5%MeOH)によってさらに精製した。目的の生成物を無色の油として得た。
ケトン20-1(0.92g、1.16mmol)および1-デシルアミン(2.03mmol、319mg、0.40mL)のDCE(6mL)溶液を、室温で15分間撹拌し、続いて、トリアセトキシ水素化ホウ素ナトリウム(2.03mmol、429mg)およびAcOH(2.03mmol、121mg、0.115mL)を加えた。混合物を室温で2日間撹拌した後、反応混合物を濃縮した。残渣をヘキサンで希釈し、希NaOH、飽和NaHCO3および食塩水で洗浄した。有機相を分離し、硫酸ナトリウムで乾燥させた。抽出物をシリカゲルのショートカラムで濾過し、カラムをヘキサン/EtOAc/Et3Nの混合物(95:5:0~80:20:1)で洗浄した。目的の生成物を無色の油として得た(814mg、無色の油、0.87mmol、収率75%)。
4-ジメチルアミノ酪酸塩酸塩(2当量、0.76mmol、127mg)、および4-ジメチルアミノピリジン(3当量、1.14mmol、139mg)のCH3CN(5mL)溶液に、DCC(2.2当量、0.84mmol、172mg)を加え、混合物を室温で45分間撹拌した。20-2(350mg、0.38mmol)のDCM(1mL)溶液を加え、得られた混合物を一晩撹拌した。次の日、さらにDCC(50mg)を加え、さらに1日撹拌した。次に、混合物を減圧下で濃縮した。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのショートカラムを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して無色の油を得た。生成物を、シリカゲルのフラッシュドライカラムクロマトグラフィー(微量のEt3Nを含むクロロホルム中0~5%MeOH)によってさらに精製した。目的の生成物を無色の油として得た(260mg)。
4-ブロモ酪酸(1.00mmol、167mg)のDCM(3mL)およびDMF(小さな1滴)の溶液に、室温で塩化オキサリル(3当量、3.00mmol、381mg、0.26mL)を加えた。混合物を室温で一晩撹拌した。次に、反応混合物を真空で濃縮した。残留した液体/固体(淡黄色)を5mLのDCMに溶解し、20-2(464mg、0.50mmol)、トリエチルアミン(0.42mL)およびDMAP(2mg)のDCM(5mL)溶液を、室温で、2分で加えた。添加後、得られた混合物を室温で2.5時間撹拌した。TLC(ヘキサン/酢酸エチル=9:1)は、2つの主要なスポットを示した。次に、反応混合物を減圧下、室温で濃縮した。残渣を精製せずに次の反応に使用した。
上記の残渣を、ピロリジン(2.20mL、26mmol)およびTHF(15mL)の混合物に取った。混合物を圧力フラスコに移し、68℃で一晩加熱した。混合物を冷却し、減圧下で濃縮した。残渣を、ヘキサン、酢酸エチルおよびEt3Nの混合物(80:20:1)に取り、シリカゲルのショートカラムを通して濾過し、同様の溶媒混合物で洗浄した。濾液を濃縮して、黄色の油/固体(359mg)を得た。粗生成物(359mg)を、シリカゲルの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0~5%のMeOH)によってさらに精製した。目的の生成物を無色の油として得た(165mg)。
Claims (77)
- 下記の構造(I):
[式中、
R1は、任意に置換されていてもよいC1-C24アルキル、または任意に置換されていてもよいC2-C24アルケニルであり;
R2およびR3は、それぞれ独立して、任意に置換されていてもよいC1-C36アルキルであり;
R4およびR5は、それぞれ独立して、任意に置換されていてもよいC1-C6アルキルであるか、または、R4およびR5は、それらが結合しているNと一緒になって、ヘテロシクリルまたはヘテロアリールを形成し;
L1、L2、およびL3は、それぞれ独立して、任意に置換されていてもよいC1-C18アルキレンであり;
G1は、直接結合、-(CH2)nO(C=O)-、-(CH2)n(C=O)O-、または、-(C=O)-であり;
G2およびG3は、それぞれ独立して、-(C=O)O-、または-O(C=O)-であり;および、
nは、0より大きい整数である。]
で示される化合物、またはその薬学的に許容される塩、互変異性体、または立体異性体。 - R1が、任意に置換されていてもよいC6-C18アルキル、またはC14-C18アルケニルである、請求項1~3のいずれか1項に記載の化合物。
- R1が、C8アルキル、C9アルキル、C10アルキル、C12アルキル、C14アルキル、またはC16アルキルである、請求項1~4のいずれか1項に記載の化合物。
- R1が、C16アルケニルである、請求項1~4のいずれか1項に記載の化合物。
- R1が分岐していない、請求項1~6のいずれか1項に記載の化合物。
- R1が分岐している、請求項1~6のいずれか1項に記載の化合物。
- R1が非置換である、請求項1~8のいずれか1項に記載の化合物。
- G1が、直接結合、-(CH2)nO(C=O)-、または、-(CH2)n(C=O)O-である、請求項1~9のいずれか1項に記載の化合物。
- G1が直接結合である、請求項10に記載の化合物。
- G1が-(CH2)n(C=O)O-であり、nが1より大きい、請求項10に記載の化合物。
- nが、5、6、7、8、9、または10である、請求項12に記載の化合物。
- nが7である、請求項13に記載の化合物。
- nが8である、請求項13に記載の化合物。
- L1が、C1-C6アルキレンである、請求項1~15のいずれか1項に記載の化合物。
- L1が、C2アルキレン、C3アルキレン、またはC4アルキレンである、請求項16に記載の化合物。
- L1が分岐していない、請求項1~17のいずれか1項に記載の化合物。
- L1が非置換である、請求項1~18のいずれか1項に記載の化合物。
- R2がC8-C24アルキルである、請求項1~19のいずれか1項に記載の化合物。
- R3がC8-C24アルキルである、請求項1~20のいずれか1項に記載の化合物。
- R2およびR3が、両方ともC8-C24アルキルである、請求項1~21のいずれか1項に記載の化合物。
- R2およびR3が、それぞれ独立して、C11アルキル、C12アルキル、C13アルキル、C14アルキル、C15アルキル、C16アルキル、C18アルキル、またはC20アルキルである、請求項1~22のいずれか1項に記載の化合物。
- R2が分岐している、請求項1~23のいずれか1項に記載の化合物。
- R3が分岐している、請求項1~24のいずれか1項に記載の化合物。
- L2およびL3が、それぞれ独立して、C4-C10アルキレンである、請求項1~27のいずれか1項に記載の化合物。
- L2およびL3が、両方ともC5アルキレンである、請求項1~28のいずれか1項に記載の化合物。
- L2およびL3が、両方ともC6アルキレンである、請求項1~28のいずれか1項に記載の化合物。
- L2およびL3が、両方ともC8アルキレンである、請求項1~28のいずれか1項に記載の化合物。
- L2およびL3が、両方ともC9アルキレンである、請求項1~28のいずれか1項に記載の化合物。
- L2が分岐していない、請求項1~32のいずれか1項に記載の化合物。
- L3が分岐していない、請求項1~33のいずれか1項に記載の化合物。
- L2が非置換である、請求項1~34のいずれか1項に記載の化合物。
- L2が非置換である、請求項1~35のいずれか1項に記載の化合物。
- R4およびR5が、それぞれ独立して、C1-C6アルキルである、請求項1~36のいずれか1項に記載の化合物。
- R4およびR5が、両方ともメチルである、請求項37に記載の化合物。
- R4およびR5が、両方ともエチルである、請求項37に記載の化合物。
- R4がメチルであり、R5がn-ブチルである、請求項37に記載の化合物。
- R4およびR5が、それらが結合しているNと一緒になって、ヘテロシクリルを形成している、請求項1~36のいずれか1項に記載の化合物。
- 前記ヘテロシクリルが、5員のヘテロシクリルである、請求項41に記載の化合物。
- 請求項1~44のいずれか1項に記載の化合物、および治療剤を含む、組成物。
- 中性脂質、ステロイド、およびポリマー結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45に記載の組成物。
- DSPC、DPPC、DMPC、DOPC、POPC、DOPE、およびSMから選択される1つ以上の中性脂質を含む、請求項46に記載の組成物。
- 中性脂質が、DSPCである、請求項47に記載の組成物。
- 化合物と中性脂質とのモル比が、約2:1~約8:1の範囲である、請求項46~48のいずれか1項に記載の組成物。
- ステロイドがコレステロールである、請求項46~49のいずれか1項に記載の組成物。
- 化合物とコレステロールとのモル比が、5:1~1:1の範囲である、請求項50に記載の組成物。
- ポリマー結合脂質が、ペグ化脂質である、請求項46~51のいずれか1項に記載の組成物。
- 化合物とペグ化脂質とのモル比が、約100:1~約20:1の範囲である、請求項52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ジアルキルオキシプロピルカルバメートである、請求項52または53のいずれか1項に記載の組成物。
- 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55に記載の組成物。
- wの平均値が、約49である、請求項55または56のいずれか1項に記載の組成物。
- 治療剤が、核酸を含む、請求項45~57のいずれか1項に記載の組成物。
- 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58に記載の組成物。
- 該組成物が、脂質ナノ粒子を含む、請求項45~59のいずれか1項に記載の組成物。
- 該組成物が、治療剤を患者に送達するための組成物である、請求項45~60のいずれか1項に記載の組成物。
- 請求項1~44のいずれか1項に記載の化合物を含む、脂質ナノ粒子。
- 治療剤をさらに含む、請求項62に記載の脂質ナノ粒子。
- 治療剤が核酸を含む、請求項63に記載の脂質ナノ粒子。
- 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64に記載の脂質ナノ粒子。
- 中性脂質、ステロイドおよびポリマー結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62~65のいずれか1項に記載の脂質ナノ粒子。
- 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66に記載の脂質ナノ粒子。
- 中性脂質が、DSPCである、請求項67に記載の脂質ナノ粒子。
- 化合物と中性脂質とのモル比が、約2:1~約8:1の範囲である、請求項66~68のいずれか1項に記載の脂質ナノ粒子。
- ステロイドが、コレステロールである、請求項66~69のいずれか1項に記載の脂質ナノ粒子。
- 化合物とコレステロールとのモル比が、5:1~1:1の範囲である、請求項70に記載の脂質ナノ粒子。
- ポリマー結合脂質が、ペグ化脂質である、請求項66~71のいずれか1項に記載の脂質ナノ粒子。
- 化合物とペグ化脂質とのモル比が、約100:1~約20:1の範囲である、請求項72に記載の脂質ナノ粒子。
- ペグ化脂質が、PEG-DAG、PEG-PE、PEG-S-DAG、PEG-cer、またはPEGジアルキルオキシプロピルカルバメートである、請求項72または73に記載の脂質ナノ粒子。
- 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75に記載の脂質ナノ粒子。
- wの平均値が、約49である、請求項75または76のいずれか1項に記載の脂質ナノ粒子。
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