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WO2006032164A1 - Dérivés de 2-indolinone substituée en position 1 et 3, préparation, composition et utilisation de ceux-ci - Google Patents

Dérivés de 2-indolinone substituée en position 1 et 3, préparation, composition et utilisation de ceux-ci Download PDF

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Publication number
WO2006032164A1
WO2006032164A1 PCT/CN2004/001081 CN2004001081W WO2006032164A1 WO 2006032164 A1 WO2006032164 A1 WO 2006032164A1 CN 2004001081 W CN2004001081 W CN 2004001081W WO 2006032164 A1 WO2006032164 A1 WO 2006032164A1
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formula
compound
ethyl
group
piperidine
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PCT/CN2004/001081
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English (en)
Chinese (zh)
Inventor
Song Li
Jizhou Liu
Lili Wang
Zhibing Zheng
Hongying Liu
Chengmai Ruan
Yunde Xie
Beifen Shen
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Beijing Molecule Science And Technology Co., Ltd.
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Priority to PCT/CN2004/001081 priority Critical patent/WO2006032164A1/fr
Publication of WO2006032164A1 publication Critical patent/WO2006032164A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel anthrone derivatives, geometric isomers thereof and pharmaceutically acceptable salts thereof, processes for their preparation, and pharmaceutical compositions containing the compounds.
  • the present invention also relates to the use of an anthrone derivative for the preparation of an antitumor drug having an antagonistic effect on vascular endothelial growth factor receptor (VEGFR), inducing tumor cell apoptosis, anti-tumor neovascularization, and blocking tumor malignant metastasis .
  • VEGFR vascular endothelial growth factor receptor
  • Tumor chemotherapy is one of the three basic methods of cancer treatment. After more than 50 years of development, the drugs used for cancer treatment have made great achievements, and a large number of clinical antibiotics with different mechanisms of action have been obtained.
  • Oncology drugs unfortunately, these anti-tumor drugs have different degrees of toxic and side effects, so many patients in clinical practice can not adhere to continuous treatment;
  • chemotherapy resistance and tumor metastasis are currently unresolved in anti-tumor drug research.
  • Judah Fo lkraan proposed a tumor growth-dependent angiogenesis hypothesis based on a large amount of clinical practice and experience: The tumor is limited to 2 ⁇ 3 millimeters in the early stage of formation due to the lack of new blood vessels. Rice, the number of cells does not exceed 1 million; only when the tumor-angiogenes is factor (TAF) mediated by the tumor enters the angiogenesis phase, the tumor can grow rapidly after obtaining sufficient oxygen and nutrient supply. (Footman J, N. Engl. J. Med., 1971, 285 (21): 1182- 1186); and thus proposed the concept of anti-angiogenesis (Folkman J, Ann. Surg., 1972, 175 ( 3 ) : 409-416 ).
  • Anti-angiogenic therapy It has good specificity, because the formation of blood vessels in normal adults is basically stopped. Only in the case of pregnancy, menstrual cycle, inflammation, tumors, etc., angiogenesis is initiated, and vascular inhibitors have no effect on resting blood vessels.
  • the gene expression of endothelial cells is relatively stable, rarely mutated, and the heterogeneity between cells is small, so it is not easy to produce drug resistance and can be used for a long time.
  • All vascular endothelial cells are exposed to the blood, and the drug can directly act, without the need for penetration, so the drug dosage is small and the effect is high.
  • Neovascularization refers to the development of a new vascular system from existing blood vessels.
  • Normal angiogenesis occurs only in certain short-term, specific physiological processes, such as reproduction, wound healing, etc.
  • Angiogenesis is a complex process involving intercellular A wide range of interactions between cytokines and extracellular matrices.
  • the steps of angiogenesis include endothelial cell degradation of existing blood vessels The basement membrane is transferred and invaded into other organs, which require the participation of MMPs (metalloproteinases) and the PA system (Mignatti P, Enzyme Protein 1996; 49: 117-37); the second step is the proliferation of endothelial cells, which is required for this step.
  • the last step is the interaction between endothelial cells, cells and extracellular matrix to form capillaries. This step requires the integration of cell viscous molecules, and the cell viscous molecules also participate in the last two steps (Bischoff J, J Clin Invest 1997; 100: S37-9).
  • TAF tumor angiogenesis factor
  • tumor angiogenesis inducer such as fibroblast growth factor (FGF), macrophage-derived epidermal growth factor, angiogenic nutrients, IL-1, IL-8, prostaglandins (PGE1, PGE2), butyrylglycerol. , nicotinamide and adenosine, hyaluronic acid metabolites and some metal copper complexes.
  • FGF fibroblast growth factor
  • macrophage-derived epidermal growth factor angiogenic nutrients
  • IL-1 IL-8
  • PGE1, PGE2 prostaglandins
  • butyrylglycerol. butyrylglycerol.
  • nicotinamide and adenosine hyaluronic acid metabolites and some metal copper complexes.
  • bFGF basic fibroblast growth factor
  • aFGF acidic fibroblast growth factor
  • the peptide sequence is a member of the growth factor family, which promotes the regeneration of epidermal endothelial cells, promotes intravascular cell division, stimulates endothelial cells to chemotactic movement of tumor tissues and forms tubular structures, and also enhances plasminogen activator in tissues.
  • PAs plasminogen activator in tissues.
  • endothelial cells to produce other proteases, which are relatively direct inducers of angiogenesis.
  • PPF vascular permeability factor
  • VEGF vascular endothelial growth factor
  • VEGF is highly specific It acts on vascular endothelial cells and has a strong mitogenic and chemotactic effect. It can promote the growth of endothelial cells in vitro and induce angiogenesis in vivo. Experiments show that tumor cells can synthesize and secrete VEGF. The expression level of VEGF in tumor tissues is higher than that in paraneoplastic tissues.
  • VEGF is a regulator of tumor angiogenesis (Warren RS) , Endocr. Rev. , 1997, 18 (1): 4-25) 0
  • VEGF vascular permeability increase of 50,000 times that of histamine, which is beneficial to blood vessels. Transfer and diffusion (Berkman RA, Science, 1983, 219 (4587): 983-985). Therefore, VEGF is an ideal target for anti-angiogenic drugs.
  • Bel- 2 participates in the formation of new blood vessels through two pathways: l) Bcl-2 can prevent the apoptosis of microvascular epithelial cells, which plays an important role in the presence and density of microvessels in tumors (Jacques E, Amer ican Journal of Pathology 1999; 154: 375-384).
  • Bcl-2 blocks apoptosis induced by many stimuli, such as chemotherapy, radiation, heat shock, certain viruses, free radicals, lipid peroxidation, p53, c-myc, and others.
  • Bel-2 is present in some long-lived and easily damaged normal tissue cells, such as nerve cells, non-secretory glandular duct cells, basal keratinocytes, colonic glandular cells, adult and embryonic skin, and embryonic kidney and cartilage.
  • Bcl-2 protein inhibitors can induce tumor cell apoptosis and enhance the sensitivity of tumor cells to other chemotherapeutic drugs, so they can be used as anti-tumor drugs; and the biological function of Beb 2 is not absolutely necessary in normal cells. Inhibition of Bcl-2 protein function will not have a significant impact on the body.
  • the anthrone derivative of the present invention can target Bel-2 protein, induce tumor cell apoptosis with high expression of Bel-2 protein and increase tumor sensitivity to chemotherapeutic drugs; and the compound of the present invention can block FGF receptor
  • the signal transduction function of the body and VEGF receptors blocks the ability of vascular endothelial cells to form new blood vessels, inhibits the formation of tumor blood vessels, and prevents the malignant metastasis of tumors. Summary of the invention
  • the present inventors have found that the indolone derivatives of the general formula I can induce apoptosis of tumor cells and inhibit the formation of tumor blood vessels, and thus the indolone derivatives of the formula I can be used for the treatment and/or prevention of Bel-2 protein.
  • Highly expressed malignancies include: colon cancer, rectal cancer, nasopharyngeal carcinoma, bone marrow cancer, breast cancer, non-Hodgkin's lymphoma, gastric cancer, prostate cancer, neuroblastoma, and lung cancer.
  • the invention relates to a steroid derivative of the formula I, a geometric isomer thereof, and a pharmaceutically acceptable salt:
  • n is equal to 2 or 3;
  • the aryl group may be unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, d ⁇ C 6 straight chain or branch Chain pit group, C 2 ⁇ C fi straight or branched alkenyl group, d ⁇ C 4 alkoxy group, d ⁇ C 4 alkoxy group, C 2 ⁇ C 4 alkenyloxy group, phenoxy group, benzyloxy group, Carboxyl or amino group;
  • R 2 is selected from hydrogen, ! 3 ⁇ 4, cyano, sulfoxide, sulfone, nitro, carboxy, d ⁇ C 3 alkoxy, d ⁇ C 3 alkanoyl, d ⁇ C 3 alkyl ester, d ⁇ C 3 alkanoyl;
  • R 3 and R 4 are independently selected from d Cs straight or branched alkyl, C 2 to C 7 straight or branched alkenyl; or R 3 and R 4 together with the nitrogen atom to which they are attached constitute 4 to 6
  • a heterocyclic ring selected from the group consisting of tetrahydropyrrole, piperidine, morpholine, piperazine or nitrogen methylpiperazine.
  • One aspect of the invention relates to an indolone derivative of the formula I, a geometric isomer thereof or a pharmaceutically acceptable salt or hydrate thereof.
  • the present inventors have unexpectedly found that when n is equal to 2 or 3, the fluorenone derivatives of the formula I and their geometric isomers have excellent pharmaceutical stability, and are particularly suitable for industrial large-scale preparation and long-term storage.
  • PCT Patent No. 0,190,104, 190,103 and 190,068 disclose Mannich Base prodrugs of 3-',5'-dimethyl-2'-pyrrolidinyl-2-indanone derivatives, However, such compounds are unstable, for example, 3-(3',5'-dimercapto-2'-pyrrole in a 10% ethanol solution at a temperature of 4 to 30 ° C for 30 minutes.
  • the methylidene)-2-indolone piperidine Mannich base is decomposed by about 5%, is not suitable for large-scale preparation and long-term storage, and does not meet the quality control requirements for drug stability.
  • the oxime derivative of the formula I of the present invention has excellent pharmaceutical stability, for example, in a 10% ethanol solution at a temperature of 4 to 30 ° C for 30 minutes, 1-[2, -( 1 '-morpholine ) ]ethyl " ⁇ -( ⁇ -bromo ⁇ thiophene-alkenyl)-2-indanone is not decomposed at all, the purity of the drug remains unchanged, and the quality control requirements for drug stability are met. It is especially suitable for large-scale industrial preparation and long-term storage.
  • the invention relates to compounds of formula I, geometric isomers thereof and pharmaceutically acceptable salts thereof:
  • n 2;
  • heteroaryl group selected from furan, thiophene, pyrrole or pyridine; the heteroaryl group may be unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of: halogen, d ⁇ C 6 straight or branched chain Base, d ⁇ C 4 alkoxyl;
  • R 2 is selected from the group consisting of hydrogen and halogen
  • R 3 and R 4 together with the nitrogen atom to which they are attached constitute a 4-6-membered heterocyclic ring selected from piperidine and morpholine.
  • the compound of the formula I of the present invention or a pharmaceutically acceptable salt thereof is particularly preferably the following compound, but these compounds are not intended to limit the present invention.
  • the most preferred compound of the invention is (Z)- 1-[2,-(piperidinyl)ethyl-3-(4'-bromo-2-thiophenenyl)-2-nonanone:
  • Another aspect of the invention relates to a process for the preparation of a compound of formula I, which comprises: reaction scheme 1
  • R 2 is as defined for the compound of formula I, reacting with an amino 3 ⁇ 4 hydrocarbon derivative of formula m
  • n, R 3 and R 4 are as defined for the compound of formula I
  • X is CI or Br
  • an anthrone derivative of the formula available from ACROS
  • an aminohalogenated hydrocarbon of the formula m are derived.
  • the product purchased from ACR0S
  • ACR0S is dissolved in an appropriate amount of acetone, and an appropriate amount of carbonic acid clock, tetrabutylammonium bromide and KI are added, and the mixture is heated to reflux temperature for about 8 hours, filtered, and concentrated in vacuo to obtain a crude product.
  • Intermediate compound IV is obtained (refer to Mokrosz, MJ, Pharmazie [PHARAT] 1997, 52 (6), 423-428),
  • n, R 2 , R 3 and R 4 are as defined for the compound of formula I, reacting a compound of formula IV with a heteroaryl formaldehyde V
  • the compound of the formula IV obtained in the step a is prepared from a heteroarylmethylaldehyde V (available from a commercial reagent source or according to the method provided in the literature De Groot JA, Org. prep, precedures Int. 1981, 13 (2): 97-101.
  • a suitable solvent or dispersant such as a suitable alcohol such as methanol or ethanol, at 10 ° C ⁇ 50 ° C
  • a base such as an inorganic base such as sodium carbonate, or an organic base such as diethylamine or piperidine, or an acid gas such as hydrogen chloride is introduced, and the reaction is carried out for 8 - 24 hours to obtain a compound of the formula I (refer to Adreani A, Eur. J med. Chem. , 1990, 25, 187- 190 ) ,
  • R 1 3 ⁇ 4 R 2 , R 3 and R 4 are as defined for the compound of formula I.
  • the compounds of the invention may be prepared by a variety of reaction routes, and the compounds of formula I may also be prepared by the following reaction scheme:
  • R 2 is as defined for the compound of formula I, reacting with a heteroaryl formaldehyde of formula V Wherein the definition is the same as the compound of formula I,
  • Anthraquinone derivatives of the formula (purchased from ACROS) and heteroarylmethylaldehyde V (purchased from commercial reagents or according to the literature De Groot JA, 0rg prep precedures Int 1981, 13 ( 2 ) : 97-101 Method for preparing) in a suitable solvent or dispersant such as a suitable alcohol such as methanol or ethanol, at a temperature of 10 ° C ⁇ 50 ° C, adding a base such as an inorganic base such as sodium carbonate, or an organic base such as two Ethylamine or piperidine, or an acid gas such as hydrogen chloride, catalyzed for 8 to 24 hours to obtain a compound of formula VI (cf. Adreani A, Eur. J. med. Chem., 1990, 25, 187-190),
  • n, R 3 and R 4 are the same as defined in the formula I, X is CI or Br, and the compound of the formula VI obtained in the step c and the halogenated hydrocarbon derivative are dissolved in acetone, and an appropriate amount of potassium carbonate and tetrabutyl are added.
  • the ammonium bromide and KI are heated and refluxed for about 8 hours, filtered, and concentrated in vacuo to give the crude compound (m. 423-428),
  • n, R:, R 2 , R 3 and R 4 are as defined for the compound of formula I.
  • the compound of the present invention can be purified by high vacuum distillation or chromatography.
  • the silica gel used here is silica gel for conventional chromatography, and the particle size is 10-40 micrometers.
  • the eluent is prepared from a single solvent or a plurality of solvents, preferably A mixed solvent of chloroform and methanol in different ratios.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one indolone compound of the formula I or a geometric isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • compositions of the present invention can be prepared by methods known in the art, such as by mixing a compound of formula I, a geometric isomer thereof, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier or excipient.
  • Another aspect of the invention relates to at least one steroid of the formula I, a geometric isomer thereof or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of a disease or condition associated with high expression of Bel- 2 Use, or for preparing antagonizing vascular endothelial growth factor receptor, inducing tumor cell apoptosis, inhibiting tumor neovascularization Or the use of an anti-tumor drug that blocks the malignant metastasis of tumor cells.
  • the present invention also provides a method for evaluating cytological function of a ketone ketone compound of the formula Ip , a test result of antitumor activity, and an activity test result for inducing apoptosis of a tumor cell.
  • the term "pharmaceutically acceptable salt” in the present invention may be a pharmaceutically acceptable inorganic or organic salt.
  • the compound having a basic group in the formula I of the present invention may form a pharmaceutically acceptable salt with a mineral acid, such as a sulfate, a hydrochloride, a hydrobromide or a phosphate; or a pharmaceutically acceptable salt with an organic acid, such as B.
  • the compound of the formula I having an acidic group may form a pharmaceutically acceptable salt with an alkali metal or alkaline earth metal, preferably but not limited to a sodium salt, a potassium salt, a magnesium salt or a calcium salt.
  • the compounds of the invention may be administered alone or in the form of a pharmaceutical composition.
  • the route of administration can be oral, parenteral or topical.
  • the pharmaceutical composition can be formulated into various suitable dosage forms depending on the route of administration.
  • composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, Intrathecal, intraventricular, intrasternal and intracranial injection or input, or by means of an explant reservoir.
  • oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the capsule preparation generally comprises lactose and dried corn starch.
  • Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension.
  • some sweeteners, fragrances or colorants may also be added to the above oral formulation forms.
  • the compounds of the present invention can be formulated into different topical preparations according to different affected faces or organs.
  • the form is specifically described as follows:
  • the compound of the present invention can be formulated into a preparation form of a micronized suspension or solution, and the carrier used is isotonic sterile saline having a certain pH, which may or may not be added. Preservatives such as benzyl chloride alkoxide are added.
  • the compound can also be formulated in the form of a cream such as a Vaseline cream.
  • the compounds of the invention When applied topically to the skin, the compounds of the invention may be in the form of a suitable ointment, lotion or cream preparation wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers which may be used in the ointment formulation include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; detergents or creams may be used, including but not limited to minerals. Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile aqueous or oily suspension or sterile injection solutions.
  • a sterile injectable preparation including sterile aqueous or oily suspension or sterile injection solutions.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • the dosage and method of use of the compounds of the invention depends on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and Subjective judgment of the doctor.
  • the preferred dosage is from 0.01 to 100 mg/kg body weight per day, wherein the optimal dose is from 20 mg/kg to 30 mg/kg body weight per day.
  • the hydrochloride salt was prepared by dissolving the free base in chloroform, adding anhydrous diethyl ether-hydrogen chloride solution to strong acidity, filtering, and washing with anhydrous diethyl ether.
  • the obtained crude product was crystallized from water-free ethanol to give a pure product.
  • Example 1 According to the method of Example 1, an equimolar amount of 1-[2,-piperidine)]ethyl-2-indanone (refer to Mokrosz, MJ, Pharmazie [PHARAT] 1997, 52 (6), 423-428) The reaction was carried out with 5-acetoxymethyl-2-furancarboxaldehyde (available from ACROS) to give the title compound as a red solid, yield 94%.
  • Example 1 According to the method of Example 1, an equimolar amount of 1-U,-(1'-morpholine)-ethyl 2-nonanone (refer to Mokrosz, MJ, Pharmazie [PHARAT] 1997, 52 (6), 423- Process prepared by the method of 428) and 4-bromo-2-thiophenecarboxaldehyde (purchased from ACROS) were reacted as starting materials except that the reaction temperature was 25 ° C and the reaction time was 35 hours to obtain the title compound, which was Yellow solid, yield
  • Example 11 Indole ketone inhibits proliferation of endothelial cells (ECV-304) And experiments on selective inhibition of bFGF and VEGF.
  • Endothelial cells (ECV-304) were purchased from the Cell Bank of the Committee of Culture Collection of the Chinese Academy of Sciences. The cells in the log phase of growth were inoculated into 96-well plates at 3-4 X 10 3 cells/ ⁇ per well for 1 hour. After 24 hours, the culture medium was aspirated, and a complete medium containing different concentrations of the drug was added to each well (growth). In the factor-selective inhibition assay, the complete medium was replaced with a culture medium supplemented with 10 ng/ml bFGF or VEGF in 1% fetal bovine serum.
  • Table 1 Indole ketone compounds inhibit ECV-304 cell proliferation
  • the concentration of cells (4X10 3 cells / well), IR (3 ⁇ 10- 5) : inhibition rate of the drug when 3 ⁇ 10- 5 Mol at this time the most sensitive to inhibition of drug, to facilitate comparison of different strength inhibitory compounds.
  • the tested compounds have different degrees of inhibition on the proliferation of ECV-304 under 1% NBS + 1640 culture conditions; they have different selective inhibition effects on VEGF and bFGF.
  • compounds 1 and 2 were more selective for bFGF-induced proliferation than VEGF
  • compounds 3, 4 and 8 were more selective for VEGF than bFGF
  • compound 5 was equally selective for both growth factors.
  • Example 12 Inhibition of ketone ketone compounds on proliferation of human umbilical vein endothelial cells HUVEC by brominated thymidine (Brdu) incorporation assay
  • HUVEC cell forest was purchased from Cascade Biologies, USA, and the culture medium was supplemented with LSGS supplement for HUVEC-specific medium medium200.
  • the assay was performed according to the Roche, Cell Proliferation ELISA, BrdU (colorimetr ic) Kit method. Briefly described as follows, HUVECs grown in log phase were inoculated into 96-well plates at 4 ⁇ 10 3 cells/ ⁇ ⁇ per well. After 24 hours, the culture medium was discarded, and ⁇ ⁇ medium containing different concentrations of drug was added to each well.
  • optical density 0D value of each well of a 96-well plate was measured at a wavelength of 450 nm (690 reference wavelength) using a BI0RAD 550 plate reader.
  • Each compound was set to 4-5 concentrations between lG _fi - 10 - 4 , each A 'test set 3-4 parallel holes, repeat 2-3 times.

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Abstract

L'invention concerne des dérivés de 2-indolinone substituée en position 1 et 3 de formule (I), le procédé de préparation de ceux-ci, une composition pharmaceutique comprenant ceux-ci et l'utilisation de ceux-ci dans la préparation de médicaments antinéoplasiques, dans laquelle n est 2 ou 3 ; R1 est un hétéroaryle sélectionné dans le groupe constitué des groupes furyle, thiényle, pyrrolyle, pyridyle et similaires ; R2 est sélectionné parmi un hydrogène, un halogène, un cyano et similaires ; R3 et R4 sont sélectionnés indépendamment dans le groupe constitué d'alkyles en C1∼C6, d'alcényles en C2∼C7 ; ou bien R3 et R4, ainsi que l'atome d'azote auquel ils sont attachés, se combinent pour former un hétérocycle à 4∼6 éléments, lequel est sélectionné dans le groupe constitué des groupes tétrahydropyrrolyle, pipéridyle, morpholinyle, pipérazine ou nitrométhylpipérazine.
PCT/CN2004/001081 2004-09-23 2004-09-23 Dérivés de 2-indolinone substituée en position 1 et 3, préparation, composition et utilisation de ceux-ci WO2006032164A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018514572A (ja) * 2015-04-30 2018-06-07 エムユーエスシー ファウンデーション フォー リサーチ ディベロップメント オキシンドール化合物およびその医薬組成物

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