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WO2007137513A1 - NOUVEAU TYPE DE COMPOSÉS 2'-α-HYDROXYALKYL TAXEL ET LEURS PROCÉDÉS DE PRÉPARATION - Google Patents

NOUVEAU TYPE DE COMPOSÉS 2'-α-HYDROXYALKYL TAXEL ET LEURS PROCÉDÉS DE PRÉPARATION Download PDF

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Publication number
WO2007137513A1
WO2007137513A1 PCT/CN2007/001733 CN2007001733W WO2007137513A1 WO 2007137513 A1 WO2007137513 A1 WO 2007137513A1 CN 2007001733 W CN2007001733 W CN 2007001733W WO 2007137513 A1 WO2007137513 A1 WO 2007137513A1
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WO
WIPO (PCT)
Prior art keywords
compound
ethoxy
cycloalkyl
alkyl
hydroxy substituted
Prior art date
Application number
PCT/CN2007/001733
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English (en)
Chinese (zh)
Inventor
Fajun Nan
Jia Li
Jing Zhou
Chuanming Xie
Yangming Zhang
Original Assignee
Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
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 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences filed Critical Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Publication of WO2007137513A1 publication Critical patent/WO2007137513A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms 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 a class of semi-synthetic paclitaxel compounds, and more particularly to a class of 2,- ⁇ -hydroxyalkyl taxanes Class of compounds.
  • Cancer is a large group of diseases characterized by abnormal cell proliferation and metastasis. It has become one of the most serious diseases that endanger human health. According to the World Health Organization, there are 6 million new cancer cases every year worldwide. In China, cancer has become the second leading cause of death after cardiovascular and cerebrovascular diseases.
  • Paclitaxel (trade name Taxol) is a diterpenoid compound having anticancer activity isolated from the yew tree. By binding to cellular tubulin, paclitaxel promotes the polymerization of tubulin to form stable microtubules and inhibits the depolymerization of microtubules, ultimately leading to the loss of function of microtubule bundles, thereby blocking cell mitosis and achieving anticancer effects. Recent studies have shown that in addition to inhibiting the mitosis of cancerous cells, paclitaxel also has a strong ability to promote cancerous cell apoptosis. Docetaxel (trade name Taxotere) is synthesized by semi-synthetic methods during structural modification and modification of paclitaxel.
  • the anticancer mechanism of docetaxel is the same as that of paclitaxel, but it has better bioavailability and less toxic side effects than paclitaxel. Anticancer activity is superior to paclitaxel, and due to its increased water solubility, it makes Dorsey Paclitaxel is easier to formulate.
  • the inventors of the present invention synthesized a novel 2,- ⁇ -hydroxyalkyl taxane compound by coupling 10-DAB with a suitable substituted ⁇ -lactam.
  • One object of the present invention is to structurally modify and design a novel 2,- ⁇ -hydroxyalkyl taxane compound for paclitaxel and the phenylisoserine side chain 2 of docetaxel. In-depth study of its structure and activity.
  • Another object of the present invention is to provide a process for preparing the 2,- ⁇ -hydroxyalkyl taxane compound.
  • a further object of the invention is to provide the use of the compound in a pharmaceutical composition for the treatment of cancer.
  • the compound of the present invention has a structure represented by the following formula 1: Formula 1
  • R 2 represents -H; C1-C6 alkyl; C3-C6 cycloalkyl; decyloxy, ethoxy or hydroxy substituted C1-C6 alkyl; decyloxy, ethoxy or hydroxy substituted C3-C6 Cycloalkyl; phenyl; or benzyl;
  • R 3 represents -H or -C(0)CH 3 ;
  • R4 represents -H, -OH or -F
  • R 3 is -C(0)CH 3 ;
  • R 2 is -H; C1-C6 alkyl; C3-C6 cycloalkyl; methoxy, ethoxy or hydroxy substituted C1-C6 alkyl; decyloxy, ethoxy or hydroxy substituted C3-C6 Cycloalkyl; phenyl; or benzyl;
  • the compound is a compound having the formula: Wherein, when -C(0)OC(CH 3 ) 3 , R 3 is -H;
  • R 2 is -H; C1-C6 alkyl; C3-C6 cycloalkyl; decyloxy, ethoxy or hydroxy substituted C1-C6 alkyl; decyloxy, ethoxy or hydroxy substituted C3-C6 Cycloalkyl; phenyl; or benzyl;
  • R4 is -H, -OH or -F, and the compound is a compound having the following structural formula:
  • the compounds of the invention are selected from the group comprising the following compounds:
  • the invention also provides a method for preparing a 2,-o;-hydroxyalkyl taxane compound, which comprises the following steps: after esterification of compound 2 with compound 3 to obtain a coupled product, the protective group is removed to obtain a final Compound 1.
  • the esterification reaction uses THF, toluene or pyridine as a solvent, and a condensing agent such as DCC, 72-BuLi, bistridecylsilylamide or bistrimethylsilylamide is used, and DMAP can be added as a catalyst according to the reaction requirement.
  • the reaction temperature is between -50 ° C and 90 ° C. Different protection group removal methods can be selected depending on the protecting group.
  • the reaction time is usually determined according to the specific conditions.
  • TLC is usually used to track the completion degree of the reaction. After the reaction is completed, it is generally extracted with a solvent such as ethyl acetate or dichloromethane, and then washed with 5% HCl, water and saturated saline. After drying, the solvent is removed under reduced pressure at a low temperature, and the concentrate is separated and purified by column chromatography, and the final product is proved by a method such as nuclear magnetic.
  • a solvent such as ethyl acetate or dichloromethane
  • R 2 represents -H; C1-C6 alkyl; C3-C6 cycloalkyl; methoxy, ethoxy or hydroxy substituted C1-C6 alkyl; methoxy, ethoxy or hydroxy substituted C3-C6 Cycloalkyl; phenyl; or benzyl;
  • R 3 represents -H or -C(0)C3 ⁇ 4
  • R4 represents -H, -OH or -F
  • R 5 represents a hydroxyl protecting group such as TMS, TES, TBDMS, EE;
  • R6 represents a hydroxy protecting group such as -C(0)C3 ⁇ 4, TMS, TES, Troc;
  • R 7 represents a hydroxy protecting group such as TMS, TES, Troc or the like.
  • compound 2 adopts two different synthesis methods according to its cis-trans isomerization difference:
  • Ri represents -C(0)C 6 3 ⁇ 4, -C(0)OC(CH 3 ) 3 ;
  • R 2 represents -H; C1-C6 alkyl; C3-C6 cycloalkyl; decyloxy, ethoxy or hydroxy substituted C1-C6 alkyl; methoxy, ethoxy or hydroxy substituted C3-C6 Cycloalkyl; phenyl; or benzyl;
  • C3 ⁇ 4C1 2 is used as a solvent, and compound 6 is reacted with PhC(0)Cl or (Boc) 20 under TEA and a small amount of catalyst DMAP to give compound 3,4- ⁇ « ⁇ -2.
  • the compound 4 can be synthesized according to the method of Patent ⁇ 0369691.
  • R represents -C(0)C 6 H 5 , -C(0)OC(CH 3 ) 3 ;
  • R 2 represents -H; C1-C6 alkyl; C3-C6 cycloalkyl; methoxy, ethoxy or hydroxy substituted C1-C6 alkyl; decyloxy, ethoxy or hydroxy substituted C3-C6 Cycloalkyl; phenyl; or benzyl;
  • R 5 represents a hydroxy protecting group such as TMS, TES, TBDMS or EE.
  • the reaction temperature of the above reaction is usually from 0 ° C to room temperature or from heating to 80 ° C to 120 ° C.
  • the reaction time depends on the specific reactants, and TLC is usually used to track the completion of the reaction.
  • the post-treatment methods generally employed after the completion of the reaction include cooling, concentration of the reaction solution to remove the solvent, extraction, separation by column chromatography, and the like. The final product was tested by NMR.
  • the compound can be used to prepare a medicament for treating cancer.
  • the present invention will be more specifically described by way of examples and comparative examples. However, the following examples are provided for illustrative purposes only, and thus the invention is not limited to or by the embodiments.
  • BEST MODE FOR CARRYING OUT THE INVENTION the conventional post-treatment method is: after the reaction is completed, an appropriate amount of water is added to the reaction liquid to separate the organic phase and the aqueous phase, and the aqueous phase is subjected to ethyl acetate, diethyl ether or dichloromethane. After the organic solvent is sufficiently extracted, the organic phases are combined. Use if necessary
  • Example 3 Preparation of Compound 2a
  • Compound 2a was prepared according to the following reaction formula. 472 mg of compound 6a (1.55 mmol), 0.5 ml of triethylamine (2.3 mmol), 405 mg (Boc) 2 0 (1.86 mmol), and a catalytic amount of DMAP were added to 10 ml of dichloromethane. The reaction solution was stirred at room temperature for 6 hours, and after completion of the reaction, 564 mg of Compound 2a was obtained by conventional workup.
  • MTT 4,5-dimethylthylthiazol-2- yl) -2,5- diphenyl tetrazolium bromide
  • MTT 4,5-dimethylthylthiazol-2- yl -2,5- diphenyl tetrazolium bromide
  • the MTT is reduced to the insoluble blue-purple Formazan, the dead fine packet disappears and the MTT is not reduced.
  • the optical density can be measured at a wavelength of 550/690 nm using a microplate reader.
  • MTT assay cell proliferation assay procedure Take the logarithmic growth phase, good cell growth state of the adherent fine MCF-7 and MCF-7/ADR by 0.05% trypsin digestion, counting, using the medium to prepare cell suspension Liquid, counted and inoculated into 96-well plates at 3000 cells per well of 3000 cells; The 96-well plate was transferred to a 37 ° C, 5 % (0 2 incubator overnight until the cells were attached; the next day, the dosing was started.
  • each compound made three duplicate wells (pipetting 6 ul of compound in the sterilized eppendorf tube, add 300 ul of medium was mixed and added to three wells), and each compound was subjected to six concentration gradients; three days later (72 hours), 40 ul of MTT solution (5 mg/ml) was directly added to each well (no need to aspirate the medium), After entering the incubator for three hours, take out the liquid in the well and add 100 ⁇ l of DMSO. Shake it gently to dissolve the crystals completely. Check the light absorption value of each well on the enzyme-linked detector (550/690) as the drug. Cell density.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Epoxy Compounds (AREA)

Abstract

L'invention concerne un type de composés 2'-α-hydroxyalkyl taxel de formule suivante (I), des compositions les contenant et leurs utilisations. Ces composés peuvent efficacement inhiber la croissance de cellules tumorales, notamment celles résistantes aux médicaments multiples (telles que les cellules MCF-7/ADR). Ces composés sont plus efficaces que le Paclitaxel (Taxol®) ou le Docetaxel (Taxotere®).
PCT/CN2007/001733 2006-05-29 2007-05-29 NOUVEAU TYPE DE COMPOSÉS 2'-α-HYDROXYALKYL TAXEL ET LEURS PROCÉDÉS DE PRÉPARATION WO2007137513A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNA2006100270237A CN101081841A (zh) 2006-05-29 2006-05-29 一类新颖的2’－α－羟烷基紫杉烷类化合物及其制备方法
CN200610027023.7 2006-05-29

Publications (1)

Publication Number Publication Date
WO2007137513A1 true WO2007137513A1 (fr) 2007-12-06

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PCT/CN2007/001733 WO2007137513A1 (fr) 2006-05-29 2007-05-29 NOUVEAU TYPE DE COMPOSÉS 2'-α-HYDROXYALKYL TAXEL ET LEURS PROCÉDÉS DE PRÉPARATION

Country Status (2)

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CN (1) CN101081841A (fr)
WO (1) WO2007137513A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101838251B (zh) * 2010-06-01 2011-08-31 翟雄 紫杉醇及多西紫杉醇的半合成方法
CN104689330A (zh) * 2013-12-06 2015-06-10 上海交通大学 抗肿瘤药物peg化及其在逆转肿瘤多药耐药上的应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002284772A (ja) * 2001-03-27 2002-10-03 Tokyo Inst Of Technol 新規化合物及びそれを用いた蛋白質のスクリーニング方法
WO2004013096A2 (fr) * 2002-08-04 2004-02-12 Natural Pharmaceuticals Inc. Procedes et compositions pour transformer des amides de taxane en paclitaxel ou en autres taxanes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002284772A (ja) * 2001-03-27 2002-10-03 Tokyo Inst Of Technol 新規化合物及びそれを用いた蛋白質のスクリーニング方法
WO2004013096A2 (fr) * 2002-08-04 2004-02-12 Natural Pharmaceuticals Inc. Procedes et compositions pour transformer des amides de taxane en paclitaxel ou en autres taxanes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GENISSON Y. ET AL.: "Effective enantioselective approach to a-aminoalkylacrylic acid derivatives via a synthetic equivalent of an asymmetric Baylis-Hillman reaction: application to the synthesis of two C-2 hydroxymethyl analogs of docetaxel", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1: ORGANIC AND BIO-ORGANIC CHEMISTRY, vol. 24, 1996, pages 2869 - 2872, XP008093194 *

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