JP7196378B2 - 高分子-シクロデキストリン-脂質共役体 - Google Patents
高分子-シクロデキストリン-脂質共役体 Download PDFInfo
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- JP7196378B2 JP7196378B2 JP2017557414A JP2017557414A JP7196378B2 JP 7196378 B2 JP7196378 B2 JP 7196378B2 JP 2017557414 A JP2017557414 A JP 2017557414A JP 2017557414 A JP2017557414 A JP 2017557414A JP 7196378 B2 JP7196378 B2 JP 7196378B2
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- Prior art keywords
- acid
- cyclodextrin
- lipid
- group
- mpeg
- Prior art date
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- 229920000858 Cyclodextrin Polymers 0.000 claims description 122
- -1 stanols Chemical class 0.000 claims description 96
- 229920001223 polyethylene glycol Polymers 0.000 claims description 91
- 150000001875 compounds Chemical class 0.000 claims description 74
- 239000002202 Polyethylene glycol Substances 0.000 claims description 71
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 54
- 229920001427 mPEG Polymers 0.000 claims description 50
- 150000002632 lipids Chemical class 0.000 claims description 45
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 42
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 40
- 239000000126 substance Substances 0.000 claims description 39
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 36
- 229930182558 Sterol Natural products 0.000 claims description 33
- 150000003432 sterols Chemical class 0.000 claims description 33
- 235000003702 sterols Nutrition 0.000 claims description 33
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 239000000194 fatty acid Substances 0.000 claims description 22
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 21
- 229930195729 fatty acid Natural products 0.000 claims description 21
- 150000004665 fatty acids Chemical class 0.000 claims description 21
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 18
- 235000012000 cholesterol Nutrition 0.000 claims description 18
- 150000004985 diamines Chemical class 0.000 claims description 18
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 16
- 229920000642 polymer Polymers 0.000 claims description 16
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 15
- 239000004472 Lysine Substances 0.000 claims description 14
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 14
- 235000005282 vitamin D3 Nutrition 0.000 claims description 14
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 claims description 13
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 claims description 12
- 150000001414 amino alcohols Chemical class 0.000 claims description 12
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 12
- 229920000768 polyamine Polymers 0.000 claims description 12
- 229960004853 betadex Drugs 0.000 claims description 11
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 11
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- 239000001116 FEMA 4028 Substances 0.000 claims description 10
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims description 10
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 claims description 10
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 9
- 239000011647 vitamin D3 Substances 0.000 claims description 9
- 229940021056 vitamin d3 Drugs 0.000 claims description 9
- YWWVWXASSLXJHU-AATRIKPKSA-N (9E)-tetradecenoic acid Chemical compound CCCC\C=C\CCCCCCCC(O)=O YWWVWXASSLXJHU-AATRIKPKSA-N 0.000 claims description 8
- ZAXCZCOUDLENMH-UHFFFAOYSA-N 3,3,3-tetramine Chemical compound NCCCNCCCNCCCN ZAXCZCOUDLENMH-UHFFFAOYSA-N 0.000 claims description 8
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 claims description 8
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 claims description 8
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 claims description 8
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 8
- OTBHHUPVCYLGQO-UHFFFAOYSA-N bis(3-aminopropyl)amine Chemical compound NCCCNCCCN OTBHHUPVCYLGQO-UHFFFAOYSA-N 0.000 claims description 8
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 8
- SECPZKHBENQXJG-FPLPWBNLSA-N palmitoleic acid Chemical compound CCCCCC\C=C/CCCCCCCC(O)=O SECPZKHBENQXJG-FPLPWBNLSA-N 0.000 claims description 8
- NLQLSVXGSXCXFE-UHFFFAOYSA-N sitosterol Natural products CC=C(/CCC(C)C1CC2C3=CCC4C(C)C(O)CCC4(C)C3CCC2(C)C1)C(C)C NLQLSVXGSXCXFE-UHFFFAOYSA-N 0.000 claims description 8
- 229930003799 tocopherol Natural products 0.000 claims description 8
- 239000011732 tocopherol Substances 0.000 claims description 8
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- 235000019148 tocotrienols Nutrition 0.000 claims description 8
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 claims description 8
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 claims description 7
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 7
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 7
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- 235000021466 carotenoid Nutrition 0.000 claims description 7
- 150000001747 carotenoids Chemical class 0.000 claims description 7
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- GJJVAFUKOBZPCB-ZGRPYONQSA-N (r)-3,4-dihydro-2-methyl-2-(4,8,12-trimethyl-3,7,11-tridecatrienyl)-2h-1-benzopyran-6-ol Chemical class OC1=CC=C2OC(CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-ZGRPYONQSA-N 0.000 claims description 6
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- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 5
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Description
APIはエトミデート、プロポフォール、アルファキサロン、ドセタキセル、ボリコナゾール、ポサコナゾール、ゲムシタビン、プラチン、タクロリムス、シタラビン、イホスファミド、ストレプトゾシン、プリカマイシン、パクリタキセル、オメプラゾール、アルプロスタジル、マイトマイシン、ジプラシドン、ニメスリド、スルホメチアゾール、ロラゼパム、グリセオフルビン、プラジカンテル、クロルチアリドン、エキソドラク、ピロキシカム、イトラコナゾール、イブプロフェン、プラジカンテル、プラジカンテル、オメプラゾール、ジゴキシン、アルベンダゾール、レベモパミルHCl、スルホメチアゾール、ケトプロフェン、グリセオフルビン、イトラコナゾール、カルバマゼピン、ゾルピデム、フェニトイン、ルチン、カンプトテシン、フルアステロン、スピララノラクトン、ラパマイシンを用いることができる。精製水中の10%w/w溶液を調製するために、水酸化ナトリウムが用いられる。目標pHは4.0から7.5の範囲である。必要であれば、pHを調節するために希NaOH又は希HClを用いることができる。
1つを含むカプラーである。
a.3つの担体と中心骨格との間の結合のために、少なくとも3つの利用可能な部位を有し、薬物残基を欠いた中心骨格を選択する工程;
b.第1の担体として高分子を選択する工程;
c.前記高分子担体上の末端基を選択する工程;
d.第2の担体として脂質を選択する工程;
e.第3の担体としてシクロデキストリンを選択する工程;
f.第4の担体として高分子又は脂質を選択する工程;
g.代替的に、ステロール又は親油性ビタミン以外の疎水性化合物を第4の担体として選択する工程;
h.担体と中心骨格との間でN-アルキル化又はO-アルキル化を含むアルキル化、エステル化、エーテル化、又はアミド化のカップリング反応のための連結基(1又は複数)を選択する工程。
a.ヒドロキシ基又はアミノ基を保護する工程;
b.前記第1の担体を前記中心骨格に結合する工程;
c.前記第2の担体を前記中心骨格に結合する工程;
d.ヒドロキシ基又はアミノ基の保護基を除去する工程;及び
e.第3の担体を中心保護基に結合させる工程。
Claims (9)
- 以下の式(A)で表される構造を含む、化合物:
「Backbone」は、少なくとも3つの担体基と共有的に結合し、且つグリセロール、ジアミン、トリアミン、テトラアミン、ポリアミン、アミノアルコール、アミノジオール、アミノトリオール、トリオール、テトラオール、及びカルボキシル基含有ジオールからなる群から選択され;
「Lipid」は、前記「Backbone」と共有的に結合し、脂肪酸、ステロール、スタノール、コレカルシフェロール、エルゴカルシフェロール、レチノイド、カロテノイド、トコフェロール、及びトコトリエノールからなる群から選択される親油性担体基であり;
「CD」は、前記「Backbone」と共有的に結合し、α-シクロデキストリン、β-シクロデキストリン、又はγ-シクロデキストリンからなる群から選択されるシクロデキストリン担体基であり;
「mPEG」は、前記「Backbone」と共有的に結合し、メトキシ基で終結されたポリエチレングリコールの重合体である重合性担体基である。 - 前記「Lipid」、「CD」、及び「mPEG」はそれぞれ、前記「Backbone」上で、消耗可能なアミノ基、ヒドロキシル基、アクリロイル基、又はカルボキシル基を介して、前記「Backbone」と共有的に結合される、請求項1に記載の化合物。
- 前記「Backbone」は、エタンジアミン、プロパンジアミン、ブタンジアミン、ペンタンジアミン、ヘキサンジアミン、ジエチレントリアミン、ジエチレントリアミン、ビス(3-アミノプロピル)アミン、ビス(3-アミノプロピル)-1,3-プロパンジアミン、N,N’-ビス(3-アミノプロピル)-1,3-プロパンジアミン、トリエチレンテトラアミン、1,2-ビス(3-アミノプロピルアミノ)エタン、スペルミン、トリス(2-アミノエチル)アミン、スペルミジン、ビス(ヘキサメチレン)トリアミン、トリス(ヒドロキシメチル)アミノメタン、トリメチルビス(ヘキサメチレン)トリアミン、3-アミノ-1,2-プロパンジオール、DL-グリセリン酸、ジアミノプロパン酸、1,3-ジアミノ-2-プロパノール、2-(3-アミノプロピルアミノ)エタノール、3-((3-アミノプロピル)アミノ)プロパノール、リシン、又はセリンである、請求項1に記載の化合物。
- 前記「mPEG」は、5~115サブユニットを有する単一のPEG鎖又は2以上の副鎖を有する分枝PEGを含み、前記2以上の副鎖はそれぞれ5~115サブユニットを有する、請求項1記載の化合物。
- 前記「Lipid」が、コレステロール、スティグマステロール、エルゴステロール、フィトステロール、シトステロール、カンペステロール、ブラシカステロール、アベナステロール アドステロール、レチノール、レチナール、レチノイン酸、トレチノイン、カロテノイド、β-カロテン、及びエルゴカルシフェロールからなる群から選択される、請求項1に記載の化合物。
- 前記脂質が、5~22個の炭素を有する脂肪酸である、請求項1に記載の化合物。
- 前記「Lipid」は、ミリスチン酸、パルミチン酸、オレイン酸、ステアリン酸、ミリストレイン酸、パルミトレイン酸、サピエン酸、エライジン酸、バクセン酸、リノール酸、トコフェロール、トコトリエノール、レチノイド、カロテノイド、コレカルシフェロール、ステロイド、又はステロールであり、
前記mPEGは、mPEGn(nは5~115の範囲のエチレングリコールサブユニットの数である。)である、請求項1に記載の化合物。 - 更に、担体基「D」が前記「Backbone」と共有的に結合し、前記「D」は前記「Lipid」又は前記「mPEG」のいずれかと同じである、請求項1に記載の化合物。
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US15/184,014 US9605305B2 (en) | 2015-07-07 | 2016-06-16 | Method for reducing primer-dimer amplification |
US15/184,014 | 2016-06-16 | ||
PCT/US2016/038134 WO2016209732A1 (en) | 2015-06-23 | 2016-06-17 | Polymer-cyclodextrin-lipid conjugates |
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US11512314B2 (en) | 2019-07-12 | 2022-11-29 | Duke University | Amphiphilic polynucleotides |
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CN110551226B (zh) * | 2019-07-30 | 2021-06-08 | 大连理工大学 | 一种亲/疏水性可控转换的叔胺型含氮聚糖衍生物及其制备方法和应用 |
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EP3313857A4 (en) | 2019-02-06 |
JP2018521152A (ja) | 2018-08-02 |
US20160375150A1 (en) | 2016-12-29 |
EP3313857A1 (en) | 2018-05-02 |
EP3313857B1 (en) | 2021-01-06 |
US10064954B2 (en) | 2018-09-04 |
CA2988587A1 (en) | 2016-12-29 |
CA2988587C (en) | 2021-07-27 |
CN108026131B (zh) | 2021-12-10 |
CN108026131A (zh) | 2018-05-11 |
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