JP2021501171A - 抗炎症性腸疾患の作用を有する医薬、その調製方法および使用 - Google Patents
抗炎症性腸疾患の作用を有する医薬、その調製方法および使用 Download PDFInfo
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- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
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- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
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Abstract
Description
R3は水素、アセチル基、スルホン酸基、またはリン酸基から選ばれるいずれか1種であり、
式Iにおいて、R1、R2およびR3が同時に水素ではなく、R1、R2およびR3が同時にアセチル基ではなく、R1およびR2が同時にベンジル基ではないことと、式IIにおいて、R1およびR2が同時に水素またはベンジル基ではないこととを満たす。)
以下の反応式のように、式IIIで表される化合物ミリカノールが、塩基性試薬の存在下で求核試薬と置換反応を経て式Iで表される化合物を得ることを含む調製方法を提供する。
R3は水素、アセチル基、スルホン酸基、またはリン酸基から選ばれるいずれか1種であり、
R1、R2およびR3が同時に水素ではなく、R1、R2およびR3が同時にアセチル基ではなく、R1およびR2が同時にベンジル基ではないことを満たす。)
以下の反応式のように、式IVで表される化合物が、酸化剤の存在下で酸化反応により式IIで表される化合物を得ることを含む調製方法を更に提供する。
R1およびR2が同時に水素またはベンジル基ではないことを満たす。)
本実施例は以下の方法により、5,17−ジアセトキシミリカノールを調製した。
本実施例は以下の方法により、5−n−プロポキシミリカノールを調製した。
本実施例は以下の方法により、5−ベンジルオキシミリカノールを調製した。
本実施例は以下の方法により、5,17−ジアリルオキシミリカノールを調製した。
本実施例は以下の方法により、5−アリルオキシミリカノールを調製した。
本実施例は以下の方法により、5,17−アリルオキシミリセチンを調製した。
本実施例は以下の方法により、5−アセトキシミリカノールを調製した。
本実施例は以下の方法により、11−スルホニルオキシミリカノールを調製した。
本実施例は以下の方法により、5,17−ジアセトキシミリセチンを調製した。
本実施例において、実施例1〜8で調製した化合物A〜Hに対してインビトロ抗炎症活性テストを行った。
本実施例において、ミリカノール誘導体化合物Hの、デキストラン硫酸ナトリウム(DSS)により誘導されたIBDマウスインビボモデルに対するインビボにおける薬力学的活性をテストした。
本実施例において、化合物Hの、2,4,6−トリニトロベンゼンスルホン酸(TNBS)により誘導されたIBDラットインビボモデルに対するインビボにおける薬力学的活性をテストした。
本実施例において、化合物A、B、Gおよび化合物Hの急性毒性をテストし、具体的なステップは以下のとおりである。
Claims (15)
- 抗炎症性腸疾患の作用を有する医薬であって、式Iまたは式IIで表される構造を有する、医薬。
R3は水素、アセチル基、スルホン酸基、またはリン酸基から選ばれるいずれか1種であり、
式Iにおいて、R1、R2およびR3が同時に水素ではなく、R1、R2およびR3が同時にアセチル基ではなく、R1およびR2が同時にベンジル基ではないことと、式IIにおいて、R1およびR2が同時に水素またはベンジル基ではないこととを満たす。) - 以下のような化合物A〜J構造のうちのいずれか1種を有する、請求項1に記載の抗炎症性腸疾患の作用を有する医薬。
- 式Iで表される構造を有する、抗炎症性腸疾患の作用を有する医薬の調製方法であって、
以下の反応式のように、式IIIで表される化合物ミリカノールが、塩基性試薬の存在下で求核試薬と置換反応を経て式Iで表される化合物を得ることを含む、調製方法。
R3は水素、アセチル基、スルホン酸基、またはリン酸基から選ばれるいずれか1種であり、
R1、R2およびR3が同時に水素ではなく、R1、R2およびR3が同時にアセチル基ではなく、R1およびR2が同時にベンジル基ではないことを満たす。) - 前記式IIIで表される化合物ミリカノールと求核試薬とのモル比は1:(1〜6)であり、
好ましくは、前記置換反応の溶媒は、ジクロロメタン、テトラヒドロフラン、アセトニトリル、ピリジン、またはトリエチルアミンのうちのいずれか1種または少なくとも2種の組み合わせを含み、
好ましくは、前記置換反応の温度は0〜80℃であり、
好ましくは、前記置換反応の時間は1〜30hであり、
好ましくは、前記塩基性試薬は、ピリジン、トリエチルアミン、N,N−ジイソプロピルエチルアミン、N−メチルモルホリン、炭酸カリウム、炭酸ナトリウム、炭酸セシウム、水酸化カリウム、水酸化ナトリウム、またはカリウム−t−ブトキシドのうちのいずれか1種または少なくとも2種の組み合わせを含み、ピリジンまたはトリエチルアミンであることが好ましい、請求項3に記載の調製方法。 - 式IIで表される構造を有する、抗炎症性腸疾患の作用を有する医薬の調製方法であって、
以下の反応式のように、式IVで表される化合物が、酸化剤の存在下で酸化反応により式IIで表される化合物を得ることを含む、調製方法。
R1およびR2が同時に水素またはベンジル基ではないことを満たす。) - 前記式IVで表される化合物と酸化剤とのモル比は1:(0.5〜5)であり、
好ましくは、前記酸化剤は、クロロクロム酸ピリジニウム塩、三酸化クロム、オゾン、 過酸化水素水、または三酸化硫黄のいずれか1種または少なくとも2種の組み合わせを含み、
好ましくは、前記酸化反応の溶媒は、ジクロロメタン、テトラヒドロフラン、トルエン、N,N−ジメチルホルムアミド、n−ヘプタン、またはジメチルスルホキシドのうちのいずれか1種または少なくとも2種の組み合わせを含み、
好ましくは、前記酸化反応の温度は0〜50℃であり、
好ましくは、前記酸化反応の時間は1〜10hである、請求項5に記載の調製方法。 - 請求項1または2に記載の抗炎症性腸疾患の作用を有する医薬の医薬的に許容される塩。
- 前記医薬的に許容される塩は、式Iで表される化合物の金属塩または式IIで表される化合物の金属塩であり、
好ましくは、前記金属塩は、リチウム塩、ナトリウム塩、カリウム塩、マグネシウム塩、またはカルシウム塩のうちのいずれか1種を含み、ナトリウム塩またはカリウム塩であることが好ましい、請求項7に記載の医薬的に許容される塩。 - 請求項1または2に記載の抗炎症性腸疾患の作用を有する医薬の溶媒和物。
- 前記溶媒和物は、式Iで表される化合物の水和物、式Iで表される化合物のアルコール和物、式IIで表される化合物の水和物、または式IIで表される化合物のアルコール和物である、請求項9に記載の溶媒和物。
- 請求項1または2に記載の抗炎症性腸疾患の作用を有する医薬の互変異性体もしくは立体化学異性体。
- 請求項1または2に記載の抗炎症性腸疾患の作用を有する医薬のプロドラッグ。
- 請求項1または2に記載の抗炎症性腸疾患の作用を有する医薬を含む、医薬組成物。
- 前記医薬組成物は補助材料を更に含み、
好ましくは、前記補助材料は、賦形剤、希釈剤、担体、調味剤、粘着剤、または充填剤のうちのいずれか1種または少なくとも2種の組み合わせを含み、
好ましくは、前記抗炎症性腸疾患の医薬組成物の剤形は、経口投与製剤、外用製剤、または非経口投与製剤のうちのいずれか1種を含む、請求項13に記載の医薬組成物。 - 請求項1または2に記載の抗炎症性腸疾患の作用を有する医薬、請求項7または8に記載の抗炎症性腸疾患の作用を有する医薬の医薬的に許容される塩、請求項9または10に記載の抗炎症性腸疾患の作用を有する医薬の溶媒和物、請求項11に記載の抗炎症性腸疾患の作用を有する医薬の互変異性体もしくは立体化学異性体、請求項12に記載の抗炎症性腸疾患の作用を有するプロドラッグ、あるいは請求項13または14に記載の医薬組成物の、炎症性腸疾患を治療する医薬の調製における使用。
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CN115505021B (zh) * | 2021-06-23 | 2023-08-15 | 沈阳药科大学 | 具有炎症性肠病治疗作用的乌苏酸衍生物及其制备方法和用途 |
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J CHEM SOC PEKIN TRANS I, vol. 2, JPN6021050804, 1980, pages 623 - 628, ISSN: 0004852355 * |
J NAT PROD, vol. 75, JPN6021011145, 2012, pages 1798 - 1802, ISSN: 0004852354 * |
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EP3756660A1 (en) | 2020-12-30 |
CN111315370B (zh) | 2023-09-29 |
EP3756660A4 (en) | 2021-10-13 |
US20210015780A1 (en) | 2021-01-21 |
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