WO2023138147A1 - Promédicament de triptolide, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Promédicament de triptolide, son procédé de préparation et son utilisation pharmaceutique Download PDF

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Publication number
WO2023138147A1
WO2023138147A1 PCT/CN2022/128608 CN2022128608W WO2023138147A1 WO 2023138147 A1 WO2023138147 A1 WO 2023138147A1 CN 2022128608 W CN2022128608 W CN 2022128608W WO 2023138147 A1 WO2023138147 A1 WO 2023138147A1
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acid
triptolide
cancer
compound
hours
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PCT/CN2022/128608
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English (en)
Chinese (zh)
Inventor
胡立宏
王均伟
康迪
朱学军
潘祥
宋祎
刘琰
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南京中医药大学
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Publication of WO2023138147A1 publication Critical patent/WO2023138147A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to a class of triptolide water-soluble prodrugs or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing these compounds, their preparation methods and medical applications.
  • Tripterygium wilfordii extract The main active components of Tripterygium wilfordii extract are diterpenoids, triterpenoids and alkaloids, among which triptolide, a diterpenoid, is one of the main active ingredients of Tripterygium wilfordii, and it is also the main active ingredient of preparations such as tripterygium glycosides and tripterygium.
  • triptolide can effectively prevent the rejection caused by transplanted organs after heart, kidney, liver or bone marrow transplantation, and significantly prolong the survival period of animals [Transplantation 2000; 70(3):447-55; Transplant Proc 1999; 31(7):2719-23].
  • triptolide regulates the overall transcription level of cells by covalently binding and inhibiting XPB activity in the TFHII transcription complex, so that triptolide has broad-spectrum anti-tumor activity [Angew Chem Int Ed Engl, 2015, 54(6): 1859-1863; Mol Cancer Ther, 2003, 2: 65-72].
  • the object of the present invention is to provide a triptolide prodrug or a pharmaceutically acceptable salt thereof whose water solubility is significantly improved and can be rapidly transformed in plasma as represented by general formula (I).
  • HA is selected from hydrochloric acid, sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid;
  • Liquid phase analysis method mobile phase 0.1% FA-H2O (A) and ACN (B); flow rate: 0.3mL/min; gradient elution degree: 0 ⁇ 2min, 15%B ⁇ 80%B; 2 ⁇ 3min, 80%B ⁇ 80%B; 3 ⁇ 4min, 80%B ⁇ 15%B; 4 ⁇ 5min, 15%B ⁇ 15%B; injection volume: 5 ⁇ L;
  • the compound TP-P1 could dose-dependently inhibit the growth of the tumor, and had no effect on the body weight of the mice; the tumor inhibition rate at a dose of 25 ⁇ g/kg/d reached 54.31%, and the dose of 100 ⁇ g/kg/d could completely regress the xenograft tumor, and the tumor inhibition rate reached 100% (Table 4).
  • the compound TP-P1 could dose-dependently inhibit the growth of the tumor after continuous intraperitoneal injection for 4 weeks, and had no effect on the body weight of the mice.
  • the tumor inhibition rate at a dose of 100 ⁇ g/kg/d reached 93.87%
  • the dose of 300 ⁇ g/kg/d and above could completely regress the transplanted tumor, and the tumor inhibition rate reached 100% (Table 5).
  • the tumor inhibition rate of the combination group was 78.12% higher than that of the corresponding dose of single drug geritinib group (48.27%), and higher than that of the double dose of single drug geritinib group (71.96%) (Table 6); therefore, the combination of compound TP-P1 and geritinib for the treatment of acute myeloid leukemia has a synergistic effect.
  • TP-P1 alleviates the effect of LPS-induced sepsis mice lung inflammation
  • TP-P1 can inhibit the release of inflammatory factors such as IL-1 ⁇ , IL-6, TNF- ⁇ , IFN- ⁇ , and in a dose-dependent manner, relieve LPS-induced lung inflammation in septic mice (Table 7).
  • mice 8 male SD rats were divided into 2 groups by random grouping. The randomly grouped SD rats were fasted overnight but allowed to drink water freely; 12 hours later, the first group was given the aqueous solution of compound TP-P1, and the dosage was 1.6 mg/kg; the second group was given the olive oil suspension of TP, and the dosage was 1.0 mg/kg; Blood was collected at min, 90min, 2h, 4h, and 6h, transferred to a 1.5mL centrifuge tube pretreated with sodium heparin, and centrifuged (8000rpm/min, 5min, 4°C) to obtain plasma, which was stored in a -80°C refrigerator.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Pulmonology (AREA)
  • Communicable Diseases (AREA)
  • Pain & Pain Management (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Dermatology (AREA)
  • Transplantation (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention relève du domaine de la chimie médicinale. L'invention concerne un promédicament de triptolide, son procédé de préparation et son utilisation pharmaceutique. Les étapes de préparation consistent à : 1, faire réagir du triptolide avec du chlorure d'acyle sous l'action de DMAP pour produire un intermédiaire II ; 2, faire réagir l'intermédiaire II avec un composé d'acide carboxylique sous l'action de l'iodure de sodium et du carbonate de potassium pour produire un composé III ; et 3, réaliser une formation de sel sur le composé III et un acide pour obtenir un composé cible I. La présente invention a une meilleure solubilité dans l'eau et des propriétés pharmacocinétiques, et a une vitesse de transformation plus rapide dans un environnement sanguin in vivo par comparaison avec le minnelide, un procédé de synthèse plus efficace, et un meilleur effet thérapeutique sur des tumeurs malignes, des maladies inflammatoires, des maladies auto-immunes, etc. En outre, le promédicament de triptolide a une bonne solubilité dans l'eau, et est par conséquent efficace en administration orale, et peut être préparé en une injection pour utilisation.
PCT/CN2022/128608 2022-01-21 2022-10-31 Promédicament de triptolide, son procédé de préparation et son utilisation pharmaceutique WO2023138147A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210072229.0A CN114478684B (zh) 2022-01-21 2022-01-21 一类雷公藤甲素前药、其制备方法及其医药用途
CN202210072229.0 2022-01-21

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Publication number Priority date Publication date Assignee Title
CN114478684B (zh) * 2022-01-21 2023-10-31 南京中医药大学 一类雷公藤甲素前药、其制备方法及其医药用途

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1246121A (zh) * 1996-03-01 2000-03-01 法玛吉尼西斯公司 免疫抑制化合物及方法
WO2008087202A1 (fr) * 2007-01-18 2008-07-24 Pierre Fabre Medicament Dérivés de triptolide utilisés pour le traitement de la leucémie myéloïde aiguë
CN101235041A (zh) * 2007-10-26 2008-08-06 北京美迪克斯生物技术有限公司 四种雷公藤甲素衍生物及其制剂的制备方法
CN104327152A (zh) * 2014-10-14 2015-02-04 厦门大学 雷公藤甲素衍生物及其应用
US20210023238A1 (en) * 2019-07-23 2021-01-28 City Of Hope Triptolide antibody conjugates
CN114478684A (zh) * 2022-01-21 2022-05-13 南京中医药大学 一类雷公藤甲素前药、其制备方法及其医药用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4680589B2 (ja) * 2002-05-31 2011-05-11 ファーマジェネシス， インコーポレイテッド アポトーシスおよび免疫抑制の調節のためのトリプトリド誘導体
CN101759763A (zh) * 2009-12-29 2010-06-30 中山大学 雷公藤内酯醇衍生物及其制备方法和应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1246121A (zh) * 1996-03-01 2000-03-01 法玛吉尼西斯公司 免疫抑制化合物及方法
WO2008087202A1 (fr) * 2007-01-18 2008-07-24 Pierre Fabre Medicament Dérivés de triptolide utilisés pour le traitement de la leucémie myéloïde aiguë
CN101235041A (zh) * 2007-10-26 2008-08-06 北京美迪克斯生物技术有限公司 四种雷公藤甲素衍生物及其制剂的制备方法
CN104327152A (zh) * 2014-10-14 2015-02-04 厦门大学 雷公藤甲素衍生物及其应用
US20210023238A1 (en) * 2019-07-23 2021-01-28 City Of Hope Triptolide antibody conjugates
CN114478684A (zh) * 2022-01-21 2022-05-13 南京中医药大学 一类雷公藤甲素前药、其制备方法及其医药用途

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