WO2010129918A1 - Triptolide prodrugs - Google Patents

Triptolide prodrugs Download PDF

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Publication number
WO2010129918A1
WO2010129918A1 PCT/US2010/034117 US2010034117W WO2010129918A1 WO 2010129918 A1 WO2010129918 A1 WO 2010129918A1 US 2010034117 W US2010034117 W US 2010034117W WO 2010129918 A1 WO2010129918 A1 WO 2010129918A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
compound
formula
triptolide
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2010/034117
Other languages
English (en)
French (fr)
Other versions
WO2010129918A8 (en
Inventor
Ingrid Gunda Georg
Satish Prakash Patil
Ashok K. Saluja
Rohit Chugh
Selwyn M. Vickers
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Minnesota Twin Cities
University of Minnesota System
Original Assignee
University of Minnesota Twin Cities
University of Minnesota System
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to PL10719188T priority Critical patent/PL2427467T3/pl
Priority to EA201190293A priority patent/EA021135B1/ru
Priority to AU2010245669A priority patent/AU2010245669B2/en
Priority to US13/319,316 priority patent/US8507552B2/en
Priority to KR1020117029123A priority patent/KR101821823B1/ko
Priority to MX2011011776A priority patent/MX2011011776A/es
Priority to SG2011081122A priority patent/SG175885A1/en
Priority to CA2760953A priority patent/CA2760953C/en
Priority to CN201080031839.1A priority patent/CN102596977B/zh
Priority to DK10719188.4T priority patent/DK2427467T3/en
Priority to ES10719188.4T priority patent/ES2552163T3/es
Application filed by University of Minnesota Twin Cities, University of Minnesota System filed Critical University of Minnesota Twin Cities
Priority to HK12108820.5A priority patent/HK1168107B/en
Priority to BRPI1014802A priority patent/BRPI1014802B8/pt
Priority to JP2012510027A priority patent/JP6000122B2/ja
Priority to EP10719188.4A priority patent/EP2427467B1/en
Publication of WO2010129918A1 publication Critical patent/WO2010129918A1/en
Publication of WO2010129918A8 publication Critical patent/WO2010129918A8/en
Anticipated expiration legal-status Critical
Priority to US13/938,971 priority patent/US9150600B2/en
Priority to US14/836,570 priority patent/US9623035B2/en
Priority to US15/465,377 priority patent/US10183033B2/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings

Definitions

  • Figure 1 illustrates a chemical reaction diagram for preparing the compound 1.
  • Example 6 In Vitro enzymatic conversion compound 1.
  • Compound 1 is converted into the active tritpolide form by action of the enzyme alkaline phosphatase.
  • An in vitro experiment to study the bioconversion of the tritpolide prodrug compound of the invention was performed.
  • In vitro bioconversion was simulated using alkaline phosphatase (from bovine intestinal mucosa, Type VII-S available from Sigma-Aldrich (St. Louis, Missouri) in glycine buffer (pH 9.8).
  • mice (5X10 5 ) were suspended in matrigel and injected subcutaneously into the left flank of 4-6 week old female nude mice. Seven days post-cell implantation, mice were injected intraperitoneally with 0.3mg/kg of compound 1 BID for 25 days. Treatment was stopped at this point, and mice sacrificed. Tumor samples, if any, were harvested from these mice, and tumor weight and volume measured. If tumor burden exceeded University of Minnesota animal care guidelines, mice were sacrificed and their tumors harvested at an earlier time point. Control mice were injected with saline BID. Figure 17 shows the decreased tumor burden, as measured by tumor volume or tumor weight, of compound 1 treated mice versus control mice.
  • mice Neuroblastoma N2 cells (IXlO 6 ) were suspended in matrigel and injected into the left retroperitoneal space of 4-6 week old A/J immunocompetent mice. Three days post-cell implantation, mice were injected with 0.4mg/kg of triptolide intraperitoneally for 21 days. Treatment was stopped at this point, and mice sacrificed. Tumor samples, if any, were harvested from these mice, and tumor weight and volume measured. If tumor burden exceeded University of Minnesota animal care guidelines, mice were sacrificed and their tumors harvested at an earlier time point. Control mice were injected with DMSO for 21 days. Figure 18 shows the
  • Example 14 The following illustrate representative pharmaceutical dosage forms, containing a compound of formula I ('Compound X'), for therapeutic or prophylactic use in humans.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Oncology (AREA)
  • Neurosurgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
PCT/US2010/034117 2009-05-07 2010-05-07 Triptolide prodrugs Ceased WO2010129918A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
ES10719188.4T ES2552163T3 (es) 2009-05-07 2010-05-07 Profármacos de triptolida
AU2010245669A AU2010245669B2 (en) 2009-05-07 2010-05-07 Triptolide prodrugs
US13/319,316 US8507552B2 (en) 2009-05-07 2010-05-07 Triptolide prodrugs
KR1020117029123A KR101821823B1 (ko) 2009-05-07 2010-05-07 트립톨라이드 전구약물
MX2011011776A MX2011011776A (es) 2009-05-07 2010-05-07 Nuevos profarmacos de triptolite.
SG2011081122A SG175885A1 (en) 2009-05-07 2010-05-07 Triptolide prodrugs
HK12108820.5A HK1168107B (en) 2009-05-07 2010-05-07 Triptolide prodrugs
EA201190293A EA021135B1 (ru) 2009-05-07 2010-05-07 Пролекарства триптолида
DK10719188.4T DK2427467T3 (en) 2009-05-07 2010-05-07 Triptolid prodrugs
PL10719188T PL2427467T3 (pl) 2009-05-07 2010-05-07 Proleki tryptolidu
CN201080031839.1A CN102596977B (zh) 2009-05-07 2010-05-07 雷公藤内酯前药
CA2760953A CA2760953C (en) 2009-05-07 2010-05-07 Triptolide prodrugs
BRPI1014802A BRPI1014802B8 (pt) 2009-05-07 2010-05-07 profármacos de triptolida.
JP2012510027A JP6000122B2 (ja) 2009-05-07 2010-05-07 トリプトリド製品
EP10719188.4A EP2427467B1 (en) 2009-05-07 2010-05-07 Triptolide prodrugs
US13/938,971 US9150600B2 (en) 2009-05-07 2013-07-10 Triptolide prodrugs
US14/836,570 US9623035B2 (en) 2009-05-07 2015-08-26 Triptolide prodrugs
US15/465,377 US10183033B2 (en) 2009-05-07 2017-03-21 Triptolide prodrugs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17624909P 2009-05-07 2009-05-07
US61/176,249 2009-05-07

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US13/319,316 A-371-Of-International US8507552B2 (en) 2009-05-07 2010-05-07 Triptolide prodrugs
US13/938,971 Division US9150600B2 (en) 2009-05-07 2013-07-10 Triptolide prodrugs

Publications (2)

Publication Number Publication Date
WO2010129918A1 true WO2010129918A1 (en) 2010-11-11
WO2010129918A8 WO2010129918A8 (en) 2011-01-20

Family

ID=42244313

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/034117 Ceased WO2010129918A1 (en) 2009-05-07 2010-05-07 Triptolide prodrugs

Country Status (17)

Country Link
US (1) US8507552B2 (enExample)
EP (1) EP2427467B1 (enExample)
JP (3) JP6000122B2 (enExample)
KR (1) KR101821823B1 (enExample)
CN (1) CN102596977B (enExample)
AU (1) AU2010245669B2 (enExample)
BR (1) BRPI1014802B8 (enExample)
CA (2) CA2964631A1 (enExample)
DK (1) DK2427467T3 (enExample)
EA (1) EA021135B1 (enExample)
ES (1) ES2552163T3 (enExample)
MX (1) MX2011011776A (enExample)
MY (1) MY160392A (enExample)
PL (1) PL2427467T3 (enExample)
PT (1) PT2427467E (enExample)
SG (1) SG175885A1 (enExample)
WO (1) WO2010129918A1 (enExample)

Cited By (4)

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Publication number Priority date Publication date Assignee Title
WO2014031979A1 (en) 2012-08-23 2014-02-27 Dyer, Cheryl, A. Reducing the reproductive capacity of mammals
WO2014167581A3 (en) * 2013-04-01 2014-12-24 Laurus Labs Private Limited An improved process for the preparation of triptolide prodrugs
WO2020056174A1 (en) 2018-09-13 2020-03-19 Minneamrita Therapeutics, LLC Triptolide and prodrugs thereof for use in methods to treat fibrosis, nash, and nafld
WO2022040487A1 (en) 2020-08-21 2022-02-24 Reyoung Corporation Triptolide conjugates and uses thereof

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US9150600B2 (en) 2009-05-07 2015-10-06 Regents Of The University Of Minnesota Triptolide prodrugs
WO2014047783A1 (zh) * 2012-09-25 2014-04-03 鼎泓国际投资（香港）有限公司 含有雷公藤甲素及雷公藤甲素类衍生物和Bcl-2抑制剂的药物组合物及其应用
ES2881878T3 (es) * 2015-09-11 2021-11-30 Ys Ac Co Ltd Composición para el tratamiento del cáncer que combina el anticuerpo anti-CD26 y otro antineoplásico
CN109942665B (zh) * 2018-04-02 2021-04-06 欣凯医药化工中间体（上海）有限公司 雷公藤内酯醇衍生物及其制备方法和应用
CN110551171B (zh) * 2018-05-31 2021-07-27 欣凯医药化工中间体（上海）有限公司 一种雷公藤内酯醇衍生物的制备方法
WO2021221179A1 (ja) * 2020-04-28 2021-11-04 国立大学法人高知大学 ヒト膵癌オルガノイドを用いたマウスモデルの樹立
CN115227829B (zh) * 2022-02-22 2023-10-13 成都中医药大学 酸敏感性适配体雷公藤甲素偶联物及应用
KR20250154513A (ko) 2023-03-09 2025-10-28 미네암리타 테라퓨틱스, 엘엘씨 췌장암 치료용 약물 조합
WO2024187139A1 (en) 2023-03-09 2024-09-12 Minneamrita Therapeutics Llc Drug combination for treatment of gastric cancer
ES3035530T3 (en) 2023-03-09 2025-09-04 Minneamrita Therapeutics Llc Drug combination for the treatment of stomach cancer

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