JP7443296B2 - 核酸の送達のための脂質および脂質ナノ粒子製剤 - Google Patents
核酸の送達のための脂質および脂質ナノ粒子製剤 Download PDFInfo
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 238000001447 template-directed synthesis Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000005985 thienyl[1,3]dithianyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- DYWSVUBJGFTOQC-UHFFFAOYSA-N xi-2-Ethylheptanoic acid Chemical compound CCCCCC(CC)C(O)=O DYWSVUBJGFTOQC-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Description
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。
R. T.およびKraus, W. L.、2001年、In Vitro Transcription. Current Protocols in Cell Biology.2:11.6:11.6.1~11.6.17;Beckert, B.およびMasquida, B.、(2010年)Synthesis of RNA by In Vitro Transcription in RNA in Methods in Molecular Biology、703巻(Neilson, H.編)、New York、N.Y. Humana Press、2010年;Brunelle, J.L.およびGreen, R.、2013年、第5章In vitro transcription from plasmid or PCR-amplified DNA, Methods in Enzymology、530巻、101~114頁を参照されたい)。
(i)哺乳動物において、特に、このような哺乳動物がその状態に罹りやすくなっているが、それを有するとまだ診断されていない場合、その疾患もしくは状態が生じるのを防止すること、
(ii)疾患もしくは状態を阻害する、すなわち、その発症を抑止すること、
(iii)疾患もしくは状態を緩和する、すなわち、その疾患もしくは状態の退行を引き起こすこと、または
(iv)疾患もしくは状態に起因する症状を緩和する、すなわち、根底にある疾患もしくは状態に対処することなく疼痛を緩和すること
を含む。本明細書で使用される場合、「疾患」および「状態」という用語は、交換可能に使用してもよいし、または特定の疾病もしくは状態が公知の原因物質を有さないこともあり(そのため、原因がまだ解決されておらず)、したがって疾患としてまだ認識されていないが、望ましくない状態もしくは症候群としてのみ認識され、程度の差はあるが特定の一連の症状が臨床医により確認されているという点で異なる場合もある。
化合物
一実施形態では、脂質化合物は、式(I):
L1およびL2は、それぞれ独立して、-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-、-NRaC(=O)O-または直接結合であり、
G1は、C1~C2アルキレン、-(C=O)-、-O(C=O)-、-SC(=O)-、-NRaC(=O)-または直接結合であり、
G2は、-C(=O)-、-(C=O)O-、-C(=O)S-、-C(=O)NRa-または直接結合であり、
G3はC1~C6アルキレンであり、
Raは、HまたはC1~C12アルキルであり、
R1aおよびR1bは、出現ごとに、独立して、(a)HもしくはC1~C12アルキルであるか、または(b)R1aは、HもしくはC1~C12アルキルであり、R1bとそれが結合している炭素原子は、隣接するR1bとそれが結合している炭素原子と一緒になって、炭素-炭素二重結合を形成し、
R2aおよびR2bは、出現ごとに、独立して、(a)HもしくはC1~C12アルキルであるか、または(b)R2aは、HもしくはC1~C12アルキルであり、R2bとそれが結合している炭素原子は、隣接するR2bとそれが結合している炭素原子と一緒になって、炭素-炭素二重結合を形成し、
R3aおよびR3bは、出現ごとに、独立して、(a)HもしくはC1~C12アルキルであるか、または(b)R3aは、HもしくはC1~C12アルキルであり、R3bとそれが結合している炭素原子は、隣接するR3bとそれが結合している炭素原子と一緒になって、炭素-炭素二重結合を形成し、
R4aおよびR4bは、出現ごとに、独立して、(a)HもしくはC1~C12アルキルであるか、または(b)R4aは、HもしくはC1~C12アルキルであり、R4bとそれが結合している炭素原子は、隣接するR4bとそれが結合している炭素原子と一緒になって、炭素-炭素二重結合を形成し、
R5およびR6は、それぞれ独立して、Hまたはメチルであり、R7はC4~C20アルキルであり、
R8およびR9は、それぞれ独立して、C1~C12アルキルであるか、またはR8およびR9は、それらが結合している窒素原子と一緒になって、5、6または7員の複素環を形成し、
a、b、cおよびdは、それぞれ独立して、1~24の整数であり、
xは0、1または2である)
の構造またはその薬学的に許容される塩、互変異性体、プロドラッグもしくは立体異性体を有する。
一部の実施形態では、L1およびL2は、それぞれ独立して、-O(C=O)-、-(C=O)O-または直接結合である。他の実施形態では、G1およびG2は、それぞれ独立して、-(C=O)-または直接結合である。一部の異なる実施形態では、L1およびL2は、それぞれ独立して、-O(C=O)-、-(C=O)O-または直接結合であり、G1およびG2は、それぞれ独立して、-(C=O)-または直接結合である。
R10およびR11は、それぞれ独立して、10~30個の炭素原子を含有する直鎖状または分枝状の、飽和または不飽和のアルキル鎖であり、アルキル鎖は、1つまたは複数のエステル結合により、任意選択で分断されており、
zは、30~60の範囲の平均値を有する)
を有するペグ化脂質またはその薬学的に許容される塩、互変異性体もしくは立体異性体を含む。
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作製する方法を例示している。当業者は、同様の方法で、または当業者に公知の他の方法を組み合わせることによりこれらの化合物を作製することができることが理解されている。当業者であれば、適当な開始構成成分を使用し、必要に応じて合成パラメーターを改変することによって、以下に具体的に図示されていない他の式(I)の化合物を、以下に記載されているものと同様の方式で作製することができることもまた理解されている。一般的に、開始構成成分は、Sigma Aldrich、Lancaster Synthesis,Inc.、Maybridge、Matrix Scientific、TCIおよびFluorochem USAなどの供給元から得てもよいし、または当業者に公知の情報元に従い合成してもよいし(例えば、Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure、5版(Wiley、2000年12月)を参照されたい)、または本発明に記載の通り調製してもよい。
化合物1の合成
方法Aに従い、化合物5から化合物1を調製して、240mgの無色の油状物質を生成した(0.32mmol、61%)。1HNMR (400 MHz, CDCl3) δ: 5.43-5.30 (m, 8H), 2.78 (t, 6.5 Hz, 4H), 2.39-2.25 (m, 7H), 2.22 (s, 6H), 2.06 (q, 6.8 Hz, 8H), 1.53 (五重線, 7.3 Hz, 2H), 1.41-1.11 (54H), 0.92-0.87 (m, 9H).
(実施例2)
化合物2の合成
化合物7(0.84g、0.96mmol)をTHF(15mL)に溶解し、LAH(2当量1.92mmol、73mg、MW37.95)を室温で少しずつ加えた。反応混合物を60℃で一晩加熱した後、硫酸ナトリウム水和物を加えた。混合物を2時間撹拌し、シリカゲルの層を介して濾過した。濾液を濃縮して、わずかに黄色の油状物質を得た(0.86g)。粗生成物をシリカゲル上での重力カラムクロマトグラフィー(クロロホルム中0~4%MeOH)により精製した。これにより、所望の生成物を無色の油状物質として得た(420mg、0.49mmol、51%)。1HNMR (400 MHz, CDCl3) δ: 5.43-5.30 (m, 12H), 2.78 (t, 6.4 Hz, 6H), 2.40-2.25 (m, 7H), 2.22 (s, 6H), 2.06 (q, 6.8 Hz, 12H), 1.53 (五重線, 7.3 Hz, 2H), 1.41-1.10 (58H), 0.90 (t, 6.8 Hz, 9H).
(実施例3)
化合物3の合成
(実施例4)
化合物5の合成
ステップ1
ステップ2
(実施例5)
化合物6の合成
(実施例6)
化合物7の合成
化合物7を方法Aに従い以下の通り調製した:
(実施例7)
化合物8の合成
(実施例8)
化合物9の合成
ステップ1
3-ジメチルアミン-1-プロピルアミン(1当量1.3mmol、133mg、163μL;MW102.18、d0.812)およびケトン9a(1当量、0.885g、1.3mmol)をDCE(8mL)中で混合し、次いで、トリアセトキシ水素化ホウ素ナトリウム(1.4当量、1.82mmol、386mg;MW211.94)およびAcOH(1当量、1.3mmol、78mg、74μL、MW60.05、d1.06)で処理した。混合物をAr雰囲気下、室温で2日間撹拌した。反応混合物をヘキサン-EtOAc(9:1)で希釈し、0.1N NaOH(20mL)を加えることによってクエンチした。有機相を分離し、飽和NaHCO3、ブラインで洗浄し、硫酸ナトリウムで乾燥させ、デカントし、濃縮して、所望の生成物9bをわずかに黄色の濁った油状物質として得た(1.07g、1.398mmol)。
ステップ2
(実施例9)
化合物10の合成
(実施例10)
化合物11の合成
(実施例11)
化合物12の合成
(実施例12)
化合物13の合成
(実施例13)
化合物14の合成
(実施例14)
化合物15の合成
(実施例15)
化合物16の合成
(実施例16)
化合物24の合成
(実施例17)
化合物35の合成
(実施例18)
化合物17の合成
ステップ1
ステップ2
ステップ3
ステップ4
(実施例19)
化合物36の合成
(実施例20)
化合物37の合成
(実施例21)
化合物38の合成
化合物38を方法Aに従い以下の通り調製した:
ステップ2
(実施例22)
化合物39の合成
(実施例23)
化合物40の合成
(実施例24)
化合物41の合成
(実施例25)
化合物42の合成
(実施例26)
化合物43の合成
(実施例27)
化合物44の合成
(実施例28)
脂質ナノ粒子組成物を使用したルシフェラーゼmRNAのin vivo評価
(実施例29)
in vivoで、ルシフェラーゼmRNA発現げっ歯類モデルを使用する、様々なカチオン性脂質を含有する脂質ナノ粒子製剤の効力の判定
製剤化した脂質のpKaの判定
Claims (45)
- 式(IA):
L1およびL2は、それぞれ直接結合であり、
G3は、飽和C1~C6アルキレンであり、
R1aおよびR1bは、出現ごとに、独立して、(a)Hもしくは飽和C1~C12アルキルであるか、または(b)R1aはHもしくは飽和C1~C12アルキルであり、R1bとそれが結合している炭素原子は、隣接するR1bとそれが結合している炭素原子と一緒になって、炭素-炭素二重結合を形成し、ここで、R1aおよびR1bの少なくとも1つの出現に対して、R1aがHまたは飽和C1~C12アルキルであり、R1bとそれが結合している炭素原子が、隣接するR1bとそれが結合している炭素原子と一緒になって、炭素-炭素二重結合を形成し、
R2aおよびR2bは、出現ごとに、独立して、(a)Hもしくは飽和C1~C12アルキルであるか、または(b)R2aはHもしくは飽和C1~C12アルキルであり、R2bとそれが結合している炭素原子は、隣接するR2bとそれが結合している炭素原子と一緒になって、炭素-炭素二重結合を形成し、
R3aおよびR3bは、出現ごとに、独立して、(a)Hもしくは飽和C1~C12アルキルであるか、または(b)R3aはHもしくは飽和C1~C12アルキルであり、R3bとそれが結合している炭素原子は、隣接するR3bとそれが結合している炭素原子と一緒になって、炭素-炭素二重結合を形成し、
R4aおよびR4bは、出現ごとに、独立して、(a)Hもしくは飽和C1~C12アルキルであるか、または(b)R4aはHもしくは飽和C1~C12アルキルであり、R4bとそれが結合している炭素原子は、隣接するR4bとそれが結合している炭素原子と一緒になって、炭素-炭素二重結合を形成し、ここで、R4aおよびR4bの少なくとも1つの出現に対して、R4aがHまたは飽和C1~C12アルキルであり、R4bとそれが結合している炭素原子が、隣接するR4bとそれが結合している炭素原子と一緒になって、炭素-炭素二重結合を形成し、
R5およびR6は、それぞれ独立して、Hまたはメチルであり、
R7は、飽和または不飽和のC4~C20アルキルであり、
R8およびR9は、それぞれ独立して、飽和C1~C12アルキルであるか、またはR8およびR9は、それらが結合している窒素原子と一緒になって、5、6または7員の複素環を形成し、
a、b、cおよびdは、それぞれ独立して、1~24の整数である)
の構造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。 - R2aおよびR2bの少なくとも1つの出現に対して、R2aがHまたは飽和C1~C12アルキルであり、R2bとそれが結合している炭素原子が、隣接するR2bとそれが結合している炭素原子と一緒になって、炭素-炭素二重結合を形成する、請求項1に記載の化合物。
- R3aおよびR3bの少なくとも1つの出現に対して、R3aがHまたは飽和C1~C12アルキルであり、R3bとそれが結合している炭素原子が、隣接するR3bとそれが結合している炭素原子と一緒になって、炭素-炭素二重結合を形成する、請求項1から2のいずれか一項に記載の化合物。
- e、f、gおよびhが、それぞれ独立して、4~10の整数である、請求項4に記載の化合物。
- a、b、cおよびdが、それぞれ独立して、2~12の整数である、請求項1から5のいずれか一項に記載の化合物。
- a、b、cおよびdが、それぞれ独立して、5~9の整数である、請求項6に記載の化合物。
- R1a、R2a、R3aおよびR4aが出現ごとにHである、請求項1から7のいずれか一項に記載の化合物。
- R1a、R2a、R3aおよびR4aの少なくとも1つが飽和C1~C8アルキルである、請求項1から7のいずれか一項に記載の化合物。
- 飽和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9に記載の化合物。
- R1b、R2b、R3bおよびR4bの少なくとも1つがHである、請求項1から10のいずれか一項に記載の化合物。
- R5またはR6の1つがメチルである、請求項1から11のいずれか一項に記載の化合物。
- R5およびR6のそれぞれがメチルである、請求項1から12のいずれか一項に記載の化合物。
- R7が、飽和または不飽和のC6~C16アルキルである、請求項1から13のいずれか一項に記載の化合物。
- R7が、飽和または不飽和のC6~C9アルキルである、請求項1から14のいずれか一項に記載の化合物。
- R7が、-(C=O)ORbまたは-O(C=O)Rbで置換されている、請求項16に記載の化合物。
- R8またはR9の少なくとも1つがメチルである、請求項1から19のいずれか一項に記載の化合物。
- R8およびR9のそれぞれがメチルである、請求項20に記載の化合物。
- R8およびR9が、これらが結合している窒素原子と一緒になって、5、6または7員の複素環を形成する、請求項1から19のいずれか一項に記載の化合物。
- 前記複素環がピロリジニルである、請求項22に記載の化合物。
- 前記複素環がピペラジニルである、請求項22に記載の化合物。
- G3が飽和C2~C4アルキレンである、請求項1から24のいずれか一項に記載の化合物。
- G3が飽和C3アルキレンである、請求項1から25のいずれか一項に記載の化合物。
- 請求項1から27のいずれか一項に記載の化合物と、治療剤とを含む組成物。
- 中性脂質、ステロイドおよびポリマーコンジュゲート脂質から選択される1種または複数の賦形剤をさらに含む、請求項28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種または複数の中性脂質を含む、請求項29に記載の組成物。
- 前記中性脂質がDSPCである、請求項30に記載の組成物。
- 前記化合物と前記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29から31のいずれか一項に記載の組成物。
- 前記ステロイドがコレステロールである、請求項29から32のいずれか一項に記載の組成物。
- 前記化合物とコレステロールとのモル比が、約2:1~1:1の範囲である、請求項33に記載の組成物。
- 前記ポリマーコンジュゲート脂質がペグ化脂質である、請求項29から34のいずれか一項に記載の組成物。
- 前記化合物と前記ペグ化脂質とのモル比が、約100:1~約25:1の範囲である、請求項35に記載の組成物。
- 前記ペグ化脂質が、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35または36のいずれか一項に記載の組成物。
- R10およびR11が、それぞれ独立して、12~16個の炭素原子を含有する直鎖状の、飽和したアルキル鎖である、請求項38に記載の組成物。
- 前記zの平均が約45である、請求項38または39のいずれか一項に記載の組成物。
- 前記治療剤が核酸を含む、請求項28から40のいずれか一項に記載の組成物。
- 前記核酸が、アンチセンスおよびメッセンジャーRNAから選択される、請求項41に記載の組成物。
- 治療剤の投与を必要とする患者に治療剤を投与するための方法において使用するための、請求項28から42のいずれか一項に記載の組成物であって、前記方法は、前記組成物を調製または提供するステップと、前記組成物を前記患者に投与するステップとを含む、組成物。
- 請求項1から27のいずれか一項に記載の化合物を含む脂質ナノ粒子。
- 前記組成物が脂質ナノ粒子を含む、請求項28から42のいずれか一項に記載の組成物。
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