WO2009127116A1 - Esters d'acide 13-halo-3,15-dioxy gibbérellique et procédés de préparation correspondants - Google Patents

Esters d'acide 13-halo-3,15-dioxy gibbérellique et procédés de préparation correspondants Download PDF

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Publication number
WO2009127116A1
WO2009127116A1 PCT/CN2009/000242 CN2009000242W WO2009127116A1 WO 2009127116 A1 WO2009127116 A1 WO 2009127116A1 CN 2009000242 W CN2009000242 W CN 2009000242W WO 2009127116 A1 WO2009127116 A1 WO 2009127116A1
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WO
WIPO (PCT)
Prior art keywords
compound
substrate
carbon
phch
dioxoerythritol
Prior art date
Application number
PCT/CN2009/000242
Other languages
English (en)
Chinese (zh)
Inventor
张洪彬
陈静波
孙竹先
卿晨
刘建平
曾祥慧
张雁丽
Original Assignee
云南大学
昆明医学院
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
Application filed by 云南大学, 昆明医学院 filed Critical 云南大学
Publication of WO2009127116A1 publication Critical patent/WO2009127116A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to pharmaceutical compounds in the fields of medicine, hygiene and chemistry, in particular to a 13-halo-3, 15-dioxoerythronate and a process for the preparation thereof. Background technique
  • Cancer is a type of disease that poses a serious threat to human health.
  • the primary means currently used to treat cancer is chemotherapy.
  • Most of the chemotherapy drugs used in clinical applications have toxic side effects such as nausea, vomiting, leukopenia, and myelosuppression, which affect the patient's emotional and physical health, thus greatly limiting the clinical application of chemotherapy drugs. Therefore, the search for anti-cancer compounds with high activity, non-toxic or low toxicity has become an important topic in new drug research.
  • Gibberellin is a class of tetracyclic diterpenoids that are widely present in plants and microorganisms, have plant growth-promoting or plant growth-inhibiting biological activities, and are produced by commercial fermentation of gibberellins (eg, GA 3 , GA 4 , GA). 7 ) Structural modification and modification of raw materials, in order to find gibberellins and their derivatives with better plant growth promotion or plant growth inhibition activity and other new activities such as antibacterial and anticancer, have important academic value and practical value.
  • the object of the present invention is to provide a compound of the formula (I): 13-halo-3, 15-dioxo gibberellate and a process for the preparation thereof, which compounds have an anticancer effect.
  • R 1 is a methyl group, a fluorenyl group of 2 carbons to 5 carbons, or a benzyl group; and R 2 is fluorine, chlorine, bromine or iodine.
  • the present invention synthesizes a series of 13-halogenated 3, 15-dioxocitrate compounds, which have strong antitumor activity and low toxicity to normal cells.
  • the low polar solvent is benzene, toluene, methylene chloride, trichloromethane, n-hexyl, cyclohexane, petroleum ether, and the amount is 10 ⁇ 100 mL solvent/g substrate; dimethyl sulfoxide and The compound formed by oxalyl chloride or dimethyl sulfoxide and thionyl chloride at 70 ° C to 40 ° C is an oxidizing agent. After adding the substrate of oxidized and chlorinated, the reaction is carried out for 5-30 minutes, and then triethylamine is added. The reaction was carried out for 5-30 minutes.
  • 13-bromo-3, 15-dioxoglucopyr (7) and (8) are based on 13-chloro-3, 15-dioxoerythritol (3) or (4), respectively.
  • a polar aprotic solvent such as tetrahydrofuran, acetone, diethyl ether, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphoric triamide, etc.
  • brominating reagents with sodium bromide, potassium bromide, Lithium bromide, tetrabutylammonium bromide and other brominating reagents are prepared by reacting acetonitrile, brominating reagent with lithium bromide, and the reaction temperature is acetonitrile reflux temperature.
  • 13-iodo-3, 15-dioxoerythritol (9) and (10) are based on 13-chloro-3, 15-dioxoerythritol (3) or (4), respectively.
  • a polar aprotic solvent such as tetrahydrofuran, acetone, diethyl ether, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphoric triamide, etc.
  • the target is prepared by reacting triphenylphosphine, iodine and imidazole in dichloromethane.
  • the amount of formazan is 10 ⁇ 100 mL/mraol substrate, and the reaction temperature is _10 °C ⁇ 0 °C. (9) or (10) is prepared as follows,
  • 13-Hydroxy-3, 15-dioxoerythritol (11) and (12) may be prepared by the method of ZL200410021939, and may also be composed of 13-chloro-3, 15-dioxoerythrate (3). Or (4) in acetone, acetonitrile, tetrahydrofuran, dichloromethyl 00242
  • a polar aprotic solvent such as alkane is prepared by reacting with water and a base such as sodium hydrogencarbonate, sodium carbonate, silver carbonate, triethylamine or diisopropylethylamine.
  • the amount of water used is 1/4 of the volume of acetone, and the amount of acetone is 5 to 10 mL / mmol of substrate.
  • the preparation steps of (11) or (12) are as follows:
  • R, CH 3 ; 2- 5 carbon sulfhydryl groups (11)
  • R, CH 3 ; 2-5 carbon sulfhydryl groups
  • Combinations of a compound of structural formula (I) with at least one pharmaceutically acceptable excipient or carrier can be used to treat cancer.
  • the preparation process is as follows:
  • the mixture was dried over anhydrous sodium sulfate (MgSO4), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés médicinaux de formule générale (I) utilisés dans le domaine de la médecine, de la santé et de la chimie. Elle concerne des esters d'acide 13-halo-3,15-dioxy gibbérellique et des procédés de préparation correspondants. Des expériences relatives à l'activité antitumorale prouvent que ces composés présentent des effets antitumoraux plus importants et une faible cytotoxicité envers des cellules normales. R1=CH3, alkyle à 2-5 atomes de carbone, PhCH2 R2=F, Cl, Br, I.
PCT/CN2009/000242 2008-04-18 2009-03-06 Esters d'acide 13-halo-3,15-dioxy gibbérellique et procédés de préparation correspondants WO2009127116A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2008100582971A CN101260095B (zh) 2008-04-18 2008-04-18 13-卤代-3,15-二氧代赤霉酸酯及其制备方法
CN200810058297.1 2008-04-18

Publications (1)

Publication Number Publication Date
WO2009127116A1 true WO2009127116A1 (fr) 2009-10-22

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Application Number Title Priority Date Filing Date
PCT/CN2009/000242 WO2009127116A1 (fr) 2008-04-18 2009-03-06 Esters d'acide 13-halo-3,15-dioxy gibbérellique et procédés de préparation correspondants

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CN (1) CN101260095B (fr)
WO (1) WO2009127116A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101260095B (zh) * 2008-04-18 2012-05-23 云南大学 13-卤代-3,15-二氧代赤霉酸酯及其制备方法
CN108276370B (zh) * 2018-02-09 2022-02-15 云南大学 17-烷硫基赤霉酸酯类化合物及其制备方法与抗肿瘤用途
CN108276369B (zh) * 2018-02-09 2022-04-01 云南大学 多硫代赤霉酸酯类化合物及其制备方法与抗肿瘤用途
CN108354928A (zh) * 2018-02-09 2018-08-03 云南大学 多硫代赤霉酸酯类化合物在制备抗肿瘤药物中的应用
CN108354929A (zh) * 2018-02-09 2018-08-03 云南大学 17-烷硫基赤霉酸酯类化合物在制备抗肿瘤药物中的应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1560044A (zh) * 2004-02-27 2005-01-05 云南大学 3,15-二羰基赤霉酸类化合物及其酯和盐
CN101260095A (zh) * 2008-04-18 2008-09-10 云南大学 13-卤代-3,15-二氧代赤霉酸酯及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1560044A (zh) * 2004-02-27 2005-01-05 云南大学 3,15-二羰基赤霉酸类化合物及其酯和盐
CN101260095A (zh) * 2008-04-18 2008-09-10 云南大学 13-卤代-3,15-二氧代赤霉酸酯及其制备方法

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CN101260095B (zh) 2012-05-23
CN101260095A (zh) 2008-09-10

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