WO2009036656A1 - Dérivés de coumarine, leurs procédés de préparation et leurs utilisations - Google Patents

Dérivés de coumarine, leurs procédés de préparation et leurs utilisations Download PDF

Info

Publication number
WO2009036656A1
WO2009036656A1 PCT/CN2008/070118 CN2008070118W WO2009036656A1 WO 2009036656 A1 WO2009036656 A1 WO 2009036656A1 CN 2008070118 W CN2008070118 W CN 2008070118W WO 2009036656 A1 WO2009036656 A1 WO 2009036656A1
Authority
WO
WIPO (PCT)
Prior art keywords
methoxy
compound
vinylcoumarin
preparation
benzene
Prior art date
Application number
PCT/CN2008/070118
Other languages
English (en)
Chinese (zh)
Inventor
Guoqiang Su
Original Assignee
Nanjing Zhongrui Medicine Co., Ltd
Jiangsu Kefeiping Medicine Co., Ltd
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 Nanjing Zhongrui Medicine Co., Ltd, Jiangsu Kefeiping Medicine Co., Ltd filed Critical Nanjing Zhongrui Medicine Co., Ltd
Publication of WO2009036656A1 publication Critical patent/WO2009036656A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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 coumarin derivative, a process for its preparation and the use as an angiogenesis inhibitor for the treatment of tumors and vascular retinopathy.
  • Tumor growth, metastasis, recurrence, and prognosis are closely related to angiogenesis.
  • Targeting tumor angiogenesis can greatly improve the therapeutic effect of solid tumors.
  • the angiogenesis inhibitory effect is almost the same vascular endothelial cells in different tumor tissues.
  • This tumor vascular endothelial cells have no significant difference compared with normal endothelial cells except for the rapid proliferation rate.
  • Normal endothelial cells have a long life span and a stable genotype.
  • endothelial cells are one of the longest-lived cells in the body. The endothelial cells present on the wall of adult blood vessels were only about 0.01% in the split state at the same time.
  • angiogenesis inhibitors The proliferation rate of tumor vascular endothelial cells was about 50 times higher than that of normal tissues. Therefore, the use of angiogenesis inhibitors has a relatively specific effect on tumor blood vessels, but does not significantly affect blood vessels in normal tissues.
  • endostatin and angiostatin are currently known as strong endogenous angiogenesis inhibitors, the production of such high-purity safe preparations requires high technical thresholds and the effects of these active proteins on short half-lives in vivo. This limits the clinical application of these active proteins. Therefore, the search for angiogenesis inhibitors in small molecule compounds has become the focus of research.
  • Combretastatin A-4 is a stilbene compound with antitumor activity isolated from the trunk of Combretum caffrum in South Africa (US Patent 4996237, Feb, 22, 1988). Due to the poor solubility of this compound, phosphorylation of the prodrug combertastatin A-4 sodium phosphate (CA4P) (US Patent 5,561,122, Dec, 22, 1994), its anti-tumor activity is greatly improved, CA4P rapidly dephosphorylates in vivo to form CA4 The plasma half-life is 30 min. CA4 acts directly on endothelial cells to induce proliferation of proliferating endothelial cells, thereby inhibiting angiogenesis.
  • CA4P phosphorylation of the prodrug combertastatin A-4 sodium phosphate
  • CA4P has not only made progress in the study of solid tumors, but also made breakthroughs in the treatment of abnormal angiogenesis in various ophthalmic diseases. Especially in the treatment of patients with advanced diabetes, visual blur and blindness caused by vascular retinopathy may become A new drug for the treatment of vascular proliferative retinopathy.
  • Combrastastatin A-4 Osthol is a coumarin compound extracted from the Chinese medicine Cnidium. In recent years, studies have shown that osthole can inhibit the growth of lung adenocarcinoma and lung squamous cell carcinoma to varying degrees. The aqueous extract of Cnidium can significantly inhibit the growth of S180 sarcoma in Kunming mice.
  • osthole has a significant inhibitory effect on EVC-304, but it is weaker than CA4. Structural modification on the structure of osthole, maintaining the basic structure of coumarin, and introducing a stilbene functional group to obtain a series of derivatives. 5 ⁇ 10 ⁇ The coumarin derivative EVC-304 inhibition is CA. Summary of the invention
  • Another object of the present invention is to provide a process for preparing a coumarin derivative.
  • a further object of the present invention is to provide the use of the above compound or a pharmaceutically acceptable salt thereof as an angiogenesis inhibitor for the preparation of a therapeutic antitumor drug.
  • a further object of the present invention is to provide the use of the above compound or a pharmaceutically acceptable salt thereof as an angiogenesis inhibitor for the preparation of a medicament for treating vascular retinopathy.
  • the object of the present invention can be achieved by the following measures:
  • the coumarin derivative of the present invention is represented by the following formula (I), which is obtained by modifying the structure of osthole.
  • the invention can also be obtained by the following method:
  • R1, R2, R3, R4 or R5 represents hydrogen, amino or substituted amino, fluorenyl or substituted fluorenyl or OM, respectively, wherein M is hydrogen, fluorenyl or substituted fluorenyl or phosphoric acid and salts thereof.
  • M is hydrogen, fluorenyl or substituted fluorenyl or phosphoric acid and salts thereof.
  • the starting materials for the preparation of the compounds 15 to 24 can be obtained by the following methods.
  • MTT dimethylthiazole diphenyltetrazolium bromide test EVC-304 cells in logarithmic growth phase, digested with 0.25% trypsin for 3 ⁇ 5min, terminate digestion with medium, adjust cell concentration 5 X 10 4 /mL , inoculate 150 ⁇ /well in 96-well plates, and add 150 ⁇ L of reagent.
  • the maximum concentration of the reagent was 200 ⁇ g/mL, which was decreased by 50% variable gradient, which was 200.00 ⁇ g/mL, 100.00 ⁇ g/mL 50.00 ⁇ g/mL 25.00 ⁇ g/mL 12.50 ⁇ g/mL 6.25 ⁇ g/ 8 concentrations of mL, 3.13 ⁇ g/mL and 1.06 ⁇ g/mL.
  • DMS0 dimethyl sulfoxide 150 ⁇ was added to each well, and placed in a carbon dioxide incubator for 10 min, and a 96-well microplate reader was used to measure the absorbance at a wavelength of 490 nm.
  • Figure 1 Comparison of growth inhibition rates of 24 coumarin derivatives and CA4 versus EVC-304 cells.
  • Compound 2 was prepared by the procedure of Example 1, substituting toluene for benzene. Mass Spectrum: ⁇ / ⁇ [ ⁇ +1] + , 293.
  • Example 3 Preparation of 7-methoxy-8-[2-(3,4-dimethylphenyl)]vinylcoumarin (Compound 4) According to the method of Example 1, a compound was prepared by replacing o-xylene with benzene. 4. Mass Spectrum: ⁇ / ⁇ [ ⁇ +1] + , 307.
  • Example 4 Preparation of 7-Methoxy-8-[2-[(benzo[1,2, a]cyclopentanyl)-4-yl]vinylcoumarin (Compound 5)
  • Example 8 Preparation of 7-methoxy-8-[2-(3,4-dimethoxyphenyl)]vinylcoumarin (Compound 9) Following the procedure of Example 1, substituting o-dimethoxybenzene Compound 9 was prepared from benzene. Mass Spectrum: ⁇ / ⁇ [ ⁇ +1] + , 339.
  • Example 9 Preparation of 7-methoxy-8-[2-(3,4-dihydroxyphenyl)]vinylcoumarin (Compound 10) According to the method of Example 1, a compound was prepared by replacing benzene with catechol. 10. Mass Spectrum: ⁇ / ⁇ [ ⁇ +1] + , 311.
  • Example 10 Preparation of 7-methoxy-8-[2-(2,3,4-trimethoxyphenyl)]vinylcoumarin (Compound 11)
  • Example 11 Preparation of 7-methoxy-8-[2-(2,3,4-trihydroxyphenyl)]vinylcoumarin (Compound 12) According to the method of Example 1, 1, 2, 3 - Compound 12 was prepared by replacing benzene with benzenetriol. Mass spectrometry: ⁇ / ⁇ [ ⁇ +1] + ,
  • the compound 7-methoxy-8-[2-(4-acetamidophenyl)]vinylcoumarin was prepared by replacing benzene with acetanilide.
  • Example 20 Preparation of 7-Methoxy-8-[2-(2-methoxy-5-(indolyl)aminophenyl)]vinylcoumarin (Compound 21)
  • 4-methoxy-(N-ethyl)acetanilide was used instead of benzene to prepare compound 7-methoxy-8-[2-(2-methoxy-5-(N-ethyl) ) Acetylaminophenyl)]vinylcoumarin.
  • 7-methoxy-8-[2-(2-methoxy-5-(N-ethyl)aminophenyl)]vinylcoumarin (Compound 21) was hydrolyzed according to the method of Example 14. Mass Spectrum: M/Z [M+1] + , 322.
  • Example 21 Preparation of 7-Methoxy-8-[2-(2-hydroxy-5-aminophenyl)]vinylcoumarin (Compound 22)

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés de coumarine représentés par la formule générale (I), leurs procédés de préparation et leurs utilisations en tant qu'inhibiteurs d'angiogenèse pour le traitement de tumeurs et de maladies angio-rétiniennes. Ce type de composés est obtenu par des modifications fondées sur la structure de l'osthol. Des expériences d'inhibition de la croissance cellulaire endothéliale vasculaire montrent que les composés de formule (I) présentent de toute évidence une activité d'inhibition de la multiplication des cellules EVC-304. En comparaison de la combrétastatine A-4 (CA4), l'activité inhibitrice des composés de formule (I)est plus forte et représente 1,5 à 4,0 fois l'activité de CA4.
PCT/CN2008/070118 2007-09-18 2008-01-16 Dérivés de coumarine, leurs procédés de préparation et leurs utilisations WO2009036656A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200710131803.0 2007-09-18
CN2007101318030A CN101121706B (zh) 2007-09-18 2007-09-18 一种香豆素衍生物及其制备方法和用途

Publications (1)

Publication Number Publication Date
WO2009036656A1 true WO2009036656A1 (fr) 2009-03-26

Family

ID=39084227

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2008/070118 WO2009036656A1 (fr) 2007-09-18 2008-01-16 Dérivés de coumarine, leurs procédés de préparation et leurs utilisations

Country Status (2)

Country Link
CN (1) CN101121706B (fr)
WO (1) WO2009036656A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103408530A (zh) * 2013-08-26 2013-11-27 中国人民解放军第三军医大学 具有生物活性的香豆素骨架多环化合物及制备方法和用途
WO2018236138A1 (fr) * 2017-06-20 2018-12-27 한국식품연구원 Composition pour la prévention, le soulagement, la réduction ou le traitement d'une maladie rétinienne

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109985036A (zh) * 2018-06-13 2019-07-09 上海交通大学医学院附属第九人民医院 蛇床子素的新用途及其应用
CN112062743B (zh) * 2020-08-19 2023-01-10 浙江工业大学 一种白藜芦醇衍生物及其应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001017984A1 (fr) * 1999-09-03 2001-03-15 Indena S.P.A. Coumarine à base de chalcone

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4136900C1 (fr) * 1991-11-09 1993-07-29 Schaper & Bruemmer Gmbh & Co Kg, 3320 Salzgitter, De

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001017984A1 (fr) * 1999-09-03 2001-03-15 Indena S.P.A. Coumarine à base de chalcone

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHAVEZ. D. ET AL.: "Novel stilbenes isolated from the root bark of Ekebergia besiguelensis.", TETRAHEDRON LETTERS, vol. 42, no. 22, 2001, pages 3685 - 3688, XP004249059, DOI: doi:10.1016/S0040-4039(01)00560-3 *
MOORTHY, JARUGU NARASIMHA ET AL.: "Cis->trans and trans->cis isomerizations of styrylcoumarins in the solid state. Importance of location of free volume in crystal lattices.", PHOTOCHEMICAL & PHOTOBIOLOGICAL SCIENCES, vol. 5, 2006, pages 903 - 913 *
SEO. E. K. ET AL.: "5-(4-hydroxyphenethenyl)-4,7-dimethoxycoumarin, a new constituent of Monotes engleri.", PLANTA MEDICA, vol. 66, no. 2, 2000, pages 182 - 184 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103408530A (zh) * 2013-08-26 2013-11-27 中国人民解放军第三军医大学 具有生物活性的香豆素骨架多环化合物及制备方法和用途
CN103408530B (zh) * 2013-08-26 2015-05-27 中国人民解放军第三军医大学 具有生物活性的香豆素骨架多环化合物及制备方法和用途
WO2018236138A1 (fr) * 2017-06-20 2018-12-27 한국식품연구원 Composition pour la prévention, le soulagement, la réduction ou le traitement d'une maladie rétinienne

Also Published As

Publication number Publication date
CN101121706B (zh) 2010-11-24
CN101121706A (zh) 2008-02-13

Similar Documents

Publication Publication Date Title
CN103961340B (zh) 一类lsd1抑制剂及其应用
EP2970123B1 (fr) Sel de omecamtiv mecarbil et son procédé de préparation
KR20190103285A (ko) 암의 치료를 위한 조합 요법
CN103086935B (zh) 二苯硒醚、二苯硒亚砜、二苯硒砜类化合物及其用途
CN106928236B (zh) 一种瑞博西尼的合成工艺
CA2950612C (fr) Composes de sulfonamide et leur utilisation comme inhibiteurs de stat5
WO2009036656A1 (fr) Dérivés de coumarine, leurs procédés de préparation et leurs utilisations
JP2016145212A (ja) Ｃｄｄｏエチルエステルの多形体及びその用途
WO2014008838A1 (fr) Dérivé d'acide bis-indolylacétique fixé à un groupe méthyle aryle-substitué et son procédé de préparation et son utilisation
CN108137589A (zh) 作为布罗莫区结构域抑制剂的咔啉衍生物
CN113831338B (zh) 一种组蛋白去乙酰化酶抑制剂及其制备方法和应用
KR102502749B1 (ko) 간 전달 엔테카비어 프로드러그 뉴클레오티드 시클로 포스페이트 화합물 및 응용
JP2014534208A5 (fr)
JP2004509939A (ja) Ｏ−置換６−メチル−トラマドール誘導体
CN111440138A (zh) 具有hdac抑制和抗肿瘤活性的新型漆酚基异羟肟酸衍生物的合成方法
WO2012171488A1 (fr) Dérivé de coumarine, composition pharmaceutique et utilisation associées
CN109134432B (zh) 氘代抗抑郁药物
CN112679400B (zh) Psammaplin A类衍生物及其制备方法和应用
WO2022037648A1 (fr) Composé d'acide boronique pyrazole, composition pharmaceutique le contenant et utilisations associées
CN106220582B (zh) N,4-二芳基噻唑-2-胺类化合物及其作为肿瘤细胞增殖抑制剂的用途
CN110240570A (zh) 一种帕瑞昔布钠杂质的制备方法
KR101510995B1 (ko) 마이크로ｒｎａ－３１ 관련 질환 치료 또는 예방용 약학조성물
CN104860898B (zh) 3‑芳基噁二唑类化合物及其用途
WO2009026837A1 (fr) Dérivés de phényl-3h-1,2-dithiole-3-thione, -one, -cétoxime 4,5-disubstituée et leur utilisation
CN109535060B (zh) 一种刺猬通路抑制剂及其制备方法和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08700776

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 16/07/2010)

122 Ep: pct application non-entry in european phase

Ref document number: 08700776

Country of ref document: EP

Kind code of ref document: A1