WO2006032164A1 - 1,3-substitued-2-indolinone derivatives, the preparation, the composition and the use thereof - Google Patents

1,3-substitued-2-indolinone derivatives, the preparation, the composition and the use thereof Download PDF

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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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French (fr)
Chinese (zh)
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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/en
Publication of WO2006032164A1 publication Critical patent/WO2006032164A1/en

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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.

Abstract

1,3-substitued-2-indolinone derivatives of formula (I), the process of preparing them, the pharmaceutical composition comprising them and the use of them in the preparation of antineoplastic medicaments. wherein n is 2 or 3 ; R1 is heteroaryl selected from the group consisting of furyl, thienyl, pyrrolyl, pyridyl and the like; R2 is selected from the group consisting of hydrogen, halo, cyano and the like; R3 and R4 are independently selected from the group consisting of C1∼C6 alkyl, C2∼C7 alkenyl; or R3 and R4, together with the nitrogen atom to which they are attached, combine to form a 4∼6 membered heterocycle, which is selected from the group consisting of tetrohydropyrrolyl, piperidyl, morpholinyl, piperazine or nitromethyl piperazine.

Description

1， 3—取代的一2—吲哚酮衍生物、 其制备方法、 药物组合物及其用途 吲哚酮类衍生物及其用于制备  1,3-substituted 1-oxanone derivative, preparation method thereof, pharmaceutical composition and use thereof, anthrone derivative and preparation thereof
抗肿瘤药物的用途 技术领域  Use of anti-tumor drugs
本发明涉及新的吲哚酮类衍生物、 其几何异构体及药学上 可接受的盐、 它们的制备方法、 含有所述化合物的药物組合物。 本发明还涉及吲哚酮类衍生物用于制备具有拮抗血管内皮细胞生 长因子受体 （VEGFR ) 、 诱导肿瘤细胞凋亡、 抗肿瘤新生血管形 成以及阻断肿瘤恶性转移作用的抗肿瘤药物的用途。 背景技术  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 . Background technique
恶性肿瘤是一类威胁人类健康及生命的严重疾病。 据世界卫 生组织 （WHO ) 的统计资料表明： 目前全世界每年约有 1000万人 发生肿瘤， 700 万人死亡， 恶性肿瘤已成为仅次于心血管疾病的 类第二杀手。 因此， 肿瘤防治受到社会各界的普遍关注。 肿瘤 化学治疗 （以下筒称化疗）是肿瘤治疗的三个基本手段之一， 经 过 50 多年的发展， 用于肿瘤治疗的药物已取得了巨大的成就， 获得了一大批具有不同作用机制的临床抗肿瘤药物， 遗憾的是这 些抗肿瘤药物都有不同程度的毒副作用， 因而在临床上使许多病 人不能坚持连续接受治疗； 另外， 化疗耐药和肿瘤转移是目前抗 肿瘤药物研究还未解决的另一个重要问题， 肿瘤抗药性和肿瘤转 移性的产生常常使肿瘤治疗达不到预期的效果。 因此， 需要寻找 新的毒副作用小、 没有耐药性并能够阻止肿瘤转移的抗肿瘤药 物。  Malignant tumors are a serious disease that threatens human health and life. According to statistics from the World Health Organization (WHO), there are about 10 million cancers and 7 million deaths every year in the world. Malignant tumors have become the second killer after cardiovascular disease. Therefore, cancer prevention and treatment has received widespread attention from all walks of life. Tumor chemotherapy (hereinafter referred to as 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; In addition, chemotherapy resistance and tumor metastasis are currently unresolved in anti-tumor drug research. An important issue, the emergence of tumor resistance and tumor metastasis often makes tumor treatment less than expected. Therefore, there is a need to find new anti-tumor drugs that have little toxic side effects, are not resistant, and are capable of preventing tumor metastasis.
早在 20世纪 70年代初期， Judah Fo lkraan 就在大量临床实 践和经验积累的基础上， 提出了肿瘤生长依赖血管生成假说： 肿 瘤在形成的早期阶段由于缺乏新生血管， 直径限制在 2 ~ 3 毫 米， 细胞个数不超过 100万个； 只有在肿瘤分泌的血管生成因子 ( tumor-angiogenes i s factor, TAF ) 的介导下进入血管生成 期， 获得充足的氧气和养料供应后， 肿瘤才能迅速生长 ( Folkman J, N. Engl. J. Med. ， 1971 , 285 ( 21 ) : 1182- 1186 ) ； 并由此提出 了抗血管生成的概念 （ Folkman J, Ann. Surg. , 1972 , 175 ( 3 ) ： 409-416 ) 。 As early as the early 1970s, 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 ).
经过 30 多年的发展， 尤其是近 10 年分子生物学的迅猛发 展， 关于血管生成的大量基础研究成果不仅完全证实了 Folkman 的假说， 还发现血管生成也是肿瘤转移必需的 （Gaspar ini G, Oncol. Rep. , 1994 , 1 ( 1 ) : 7-12 ) ， 并且与肿瘤的多药耐药有 关 ( Zhang XS， Acta. Pharmacol. Sin. , 2001 , 22 ( 8 ) : 731- 735 ) 。  After more than 30 years of development, especially the rapid development of molecular biology in the past 10 years, a large number of basic research on angiogenesis not only fully confirms the Folkman hypothesis, but also found that angiogenesis is also necessary for tumor metastasis (Gaspar ini G, Oncol. Rep., 1994, 1 (1): 7-12), and is associated with multidrug resistance in tumors (Zhang XS, Acta. Pharmacol. Sin., 2001, 22(8): 731-735).
由于肿瘤的发生和发展都依赖于新生血管的形成， 而且肿瘤 区血管的生长是正常组织的 50-200 倍， 以肿瘤区血管为靶来抑 制其生长具备以下优点： （1 ) 抗血管形成治疗具有良好的特异 性， 因为正常成年人血管形成基本停止， 只有在妊娠、 月经周 期、 炎症、 肿瘤等情况下， 血管形成才被启动， 血管抑制剂对静 止的血管是没有作用的。 （2 ) 内皮细胞的基因表达相对稳定， 很少突变， 细胞之间异质性很小， 故不易产生耐药性， 可长期使 用。 （ 3 ) 所有血管内皮细胞全部暴露在血液中， 药物能直接发 挥作用， 而不需要渗透等环节， 故药物剂量小疗效高。  Because the occurrence and development of tumors depend on the formation of new blood vessels, and the growth of blood vessels in the tumor area is 50-200 times that of normal tissues. The inhibition of growth by targeting tumor blood vessels has the following advantages: (1) 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. (2) 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. (3) 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.
1. 血管形成过程  Angiogenesis process
新生血管是指从已存在的血管上发育出新的血管系统。 正常 的血管生成只在某些短期、 特定的生理过程中存在， 如生殖， 伤 口愈合等（Hyder SM, Mol Endocrinol 1999; 13: 806-11) 0 血管 生成是一个复杂的过程， 包括细胞间各种细胞因子和细胞外基质 广泛的相互作用。 血管形成的步驟包括现存血管的内皮细胞降解 基底膜并转移入侵到其它器官， 其中需要 MMPs (金属蛋白酶） 和 PA 系统参与（Mignatti P, Enzyme Protein 1996; 49: 117- 37); 第二步是内皮细胞的增殖， 这一步需要的各种生长因子参 与； 最后一步是内皮细胞之间、 细胞与细胞外基质之间相互作用 形成毛细血管， 这一步需要细胞粘性分子整合， 另外细胞粘性分 子也参与了上两步过程（Bischoff J， J Clin Invest 1997; 100: S37-9)。 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. (Hyder SM, Mol Endocrinol 1999; 13: 806-11). 0 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. Growth factor participation; 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).
2. 血管形成因子与新生血管  2. Angiogenesis factors and neovascularization
促进肿瘤新血管形成的血管生成因子很多， 从 1971 年 Fo 1 kraan 等从人体和动物实体瘤与腹水瘤中分离出一种可以促进 血管形成的可溶性物质， 称为肿瘤血管形成因子 （ TAF ) (Folkman J, N. Engl. J.Med. , 1971, 285 ( 21 ) : 1182-1186 ) 开始， 近 20 年来的研究发现， 促进血管生成因子是一大类生长 因子和细胞因子类的多肽物质， 称为肿瘤血管形成诱导物， 如成 纤维细胞生长因子 （FGF) 、 巨噬细胞来源的表皮生长因子、 血 管形成营养素、 IL- 1、 IL- 8、 前列腺素 （PGE1, PGE2 ) 、 丁酰甘 油、 烟酰胺及腺苷、 透明质酸代谢产物及一些金属铜的复合物 等。 1982 年发现第一个血管形成因子是碱性成纤维细胞生长因 子 （bFGF) ， 随后确定了酸性成纤维细胞生长因子 （aFGF) ， 这 两种蛋白均与肝素具有高亲和力， 并缺乏传统的信号肽序列为特 征的生长因子家族成员， 能促进表皮内皮细胞再生， 促进血管内 细胞分裂， 刺激内皮细胞向肿瘤组织趋化运动并形成管状结构， 还提高组织中血纤维蛋白溶解酶原激活因子类 （PAs)及诱导内 皮细胞产生其它蛋白酶， 是血管生成较为直接的诱导物。 相继又 确定了另一种分泌蛋白称为血管通透性因子 （VPF) 或血管内皮 细胞生长因子 （VEGF) , 它是一种分子量为 40KD- 45KD的分泌性 糖蛋白， 其两种主要受体是 fit- 1和 flk-l， VEGF可高效特异性 地作用于血管内皮细胞， 对其有强烈的促分裂作用和趋化作用。 体外可促进内皮细胞生长， 体内可诱导血管发生， 实验证明肿瘤 细胞可以合成和分泌 VEGF, VEGF 在肿瘤组织中的表达水平比瘤 旁组织高， 而正常组织中仅腎、 卵巢等少数脏器有高水平表达 (Neufeld G， FASEB J, 1999, 13 (1)： 9-22)„ 在有些肿瘤中证实其 与恶性程度、 侵袭、 转移有关， 所以 VEGF 是诱导肿瘤血管发生 的调节因素（Warren RS， Endocr. Rev. , 1997, 18 (1)： 4-25) 0 There are many angiogenic factors that promote tumor neovascularization. From 1971, Fo 1 kraan and other human and animal solid tumors and ascites tumors isolated a soluble substance that promotes angiogenesis, called tumor angiogenesis factor (TAF). Folkman J, N. Engl. J.Med., 1971, 285 ( 21 ) : 1182-1186 ) At the beginning, research in the past 20 years found that promoting angiogenic factors is a large class of polypeptides of growth factors and cytokines. It is called 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. The first angiogenic factor was found in 1982 as basic fibroblast growth factor (bFGF), followed by the identification of acidic fibroblast growth factor (aFGF), both of which have high affinity for heparin and lack traditional signals. 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) and induction of endothelial cells to produce other proteases, which are relatively direct inducers of angiogenesis. It has also identified another secreted protein called vascular permeability factor (VPF) or vascular endothelial growth factor (VEGF), a secreted glycoprotein with a molecular weight of 40KD-45KD, and its two main receptors. Is fit-1 and flk-l, 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. In normal tissues, only a few organs such as kidney and ovary have High levels of expression (Neufeld G, FASEB J, 1999, 13 (1): 9-22) „ In some tumors it is associated with malignancy, invasion, metastasis, so VEGF is a regulator of tumor angiogenesis (Warren RS) , Endocr. Rev. , 1997, 18 (1): 4-25) 0
肿瘤细胞分泌的多种血管生成因子之间相互联系和调控， 其 中 VEGF 处于核心地位， 是目前已知活性最强、 专属性最高的血 管生成因子， 其它血管生成因子大都通过增强 VEGF 的表达产生 血管生成的作用 ( Zhang QX， J. Surg. Res. , 1997, 67 (2)： 147- 154 ) , 而且 VEGF有相当于组胺 5万倍的促血管通透性增加的活 性 ， 有 利 于 血 管 的 转 移 和 扩 散 (Berkman RA, Science, 1983, 219 (4587)： 983-985)。 因此 VEGF是抗血管生成药 物的理想作用靶点。  The various angiogenic factors secreted by tumor cells are related and regulated. Among them, VEGF is at the core, and it is the most active and specific angiogenic factor. The other angiogenic factors mostly produce blood vessels by enhancing the expression of VEGF. The role of the formation (Zhang QX, J. Surg. Res., 1997, 67 (2): 147-154), and VEGF has an activity of 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.
3. Bel- 2与肿瘤新生血管形成  3. Bel-2 and tumor neovascularization
肿瘤新生血管形成还与其它 （非血管生成因子）类型的基因 有关， Bel- 2 基因家族就是一例。 Bel- 2 参与新血管的形成是通 过以下两种途径来实现的： l ) Bcl-2 能够阻止微血管上皮细胞 的凋亡， 从而对微血管在肿瘤中的存在和密度起着重要作用 (Jacques E, Amer ican Journal of Pathology 1999; 154: 375- 384)。 2)引发其它血管生成因子的表达， 由其它血管生成因子刺 激新血管的生成， 这种关系主要体现在 Bel- 2诱导内皮细胞表达 VEGF 方面（Blancher C, FASED J, 2000, 14: 652-660) , 这说明 了 Bel- 2在新血管生成过程中的重要作用， 提示人们在抗血管生 成治疗中要同时抑制 Bcl-2的作用， 否则很难达到使肿瘤消退的 治疗效果。 另外， Bcl-2 基因及其基因家族的主要功能是调节细胞凋 亡， 在保持细胞的合适形态以及通过消除有害或无用的细胞来调 整细胞的数量方面起着重要作用（Adams J, Science 281, 1322- 1326)。 Bcl-2 能阻止由许多刺激诱发的细胞凋亡， 如化疗、 射 线、 热休克、 某些病毒、 自由基、 脂质过氧化、 p53、 c-myc 等。 Bel- 2 存在于一些长寿命和易损伤的正常组织细胞中， 如神 经细胞、 非分泌腺的导管细胞、 基底角朊细胞、 结肠腺管底部细 胞、 成人和胚胎的皮肤以及胚胎的肾脏与软骨組织（Adams J， Science 281, 1322-1326) 0 但在异常情况下 Bcl-2 基因的高效 表达， 不仅是肿瘤形成的原因之一（Folkman J， Cel l 79, 185- 188)， 也是肿瘤产生耐药性的原因之一（El l i s LM， Eur. J. Cancer 32a, 2451-2460) , 因为它能够阻止种类繁多且作用机制 不同的化疗药物所诱导的细胞调亡； 因此 Bel- 2基因及其受体也 是很好的抗肿瘤靶点。 Bcl-2 蛋白抑制剂能够诱导肿瘤细胞调 亡， 并增强肿瘤细胞对其它化疗药物的敏感性， 因此能够作为抗 肿瘤药物使用； 而且 Be卜 2的生物功能在正常细胞中并不是绝对 必需的， 抑制 Bcl-2蛋白功能将不会对机体产生很大影响。 Tumor neovascularization is also associated with other (non-angiogenic factor) types of genes, and the Bel-2 gene family is one example. 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). 2) Initiating the expression of other angiogenic factors, and stimulating the formation of new blood vessels by other angiogenic factors, which is mainly reflected in the expression of VEGF by endothelial cells induced by Bel-2 (Blancher C, FASED J, 2000, 14: 652-660). ), which illustrates the important role of Bel-2 in the process of neovascularization, suggesting that people should simultaneously inhibit the action of Bcl-2 in anti-angiogenic therapy, otherwise it is difficult to achieve the therapeutic effect of tumor regression. In addition, the main function of the Bcl-2 gene and its gene family is to regulate apoptosis, which plays an important role in maintaining the proper morphology of cells and by regulating the number of cells by eliminating harmful or useless cells (Adams J, Science 281, 1322- 1326). 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. Tissue (Adams J, Science 281, 1322-1326) 0 However, the high expression of Bcl-2 gene under abnormal conditions is not only one of the causes of tumor formation (Folkman J, Cel l 79, 185-188), but also tumor production. One of the causes of drug resistance (El lis LM, Eur. J. Cancer 32a, 2451-2460), because it can prevent cell apoptosis induced by a wide variety of chemotherapeutic drugs with different mechanisms of action; therefore, the Bel-2 gene and Its receptor is also a good anti-tumor target. 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.
本发明所涉及的吲哚酮类衍生物可以靶向 Bel- 2蛋白， 诱导 高表达 Bel- 2蛋白的肿瘤细胞调亡及提高肿瘤对化疗药物的敏感 性； 同时本发明化合物可以阻断 FGF受体和 VEGF受体的信号传 导功能， 阻断血管内皮细胞形成新生血管的能力， 抑制肿瘤新生 血管的形成， 阻止肿瘤的恶性转移。 发明内容  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
本发明的目的在于提供能够选择性地阻断或打开 Bcl-2 I BAX异二聚体， 通过调节 Bel- 2 I BAX异二聚与 BAX / BAX同二 聚之间的比率来诱导肿瘤细胞的凋亡及提高肿瘤对化疗药物治疗 的敏感性， 并通过抑制血管内皮细胞生长因子受体的信号转导， 阻断血管内皮细胞形成新生血管的能力来抑制肿瘤新生血管的形 成并阻止肿瘤的恶性转移。 It is an object of the present invention to provide a method for selectively blocking or opening a Bcl-2 I BAX heterodimer, which induces tumor cells by modulating the ratio between Bel-2I BAX heterodimerization and BAX/BAX homodimerization. Apoptosis and tumor enhancement for chemotherapy Sensitivity, and by inhibiting vascular endothelial growth factor receptor signaling, blocks the ability of vascular endothelial cells to form new blood vessels to inhibit tumor angiogenesis and prevent malignant metastasis of tumors.
本发明已经发现通式 I吲哚酮类衍生物可以诱导肿瘤细胞的 凋亡和抑制肿瘤新生血管的形成， 因此通式 I吲哚酮类衍生物可 以用于治疗和 /或预防 Bel- 2 蛋白高表达的恶性肿瘤， 包括： 结 肠癌、 直肠癌、 鼻咽癌、 骨髓癌、 乳腺癌、 非何杰金氏淋巴癌、 胃癌、 前列腺癌、 神经母细胞瘤和肺癌。  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.
根据本发明的一个实施方案， 本发明涉及通式 I吲哚酮类衍 生物、 其几何异构体、 及药学上可接受的盐：  According to one embodiment of the invention, the invention relates to a steroid derivative of the formula I, a geometric isomer thereof, and a pharmaceutically acceptable salt:
Figure imgf000008_0001
其中：
Figure imgf000008_0001
among them:
n等于 2或 3;  n is equal to 2 or 3;
为选自呋喃， 噻吩， 吡咯， 吡唑， 咪唑， 噻唑， 唑， 异 恶 唑， 吡啶， 哒，秦， 嘧啶， 吡療， 吲哚， 苯并呋喃或喹啉的杂 芳基， 所述杂芳基可以未被取代或被 1或 2个选自下面的取代基 取代： 卤素， 硝基， 羟基， 羟甲基， 三氟甲基， 三氟甲氧基， d~C6直链或支链坑基， C2~Cfi直链或支链烯基， d~C4烷氧基， d~C4烷氧酰基， C2~C4烯氧基， 苯氧基， 苄氧基， 羧基或氨 基； Is a heteroaryl group selected from the group consisting of furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, oxazole, isoxazole, pyridine, hydrazine, pyrimidine, pyridinium, pyrene, benzofuran or quinoline. 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;
R2选自氢， ！¾素， 氰基， 亚砜基， 砜基， 硝基， 羧基， d~ C3烷氧基, d~C3烷酰基, d~C3烷酯基, d~C3烷酰氨基； R3、 R4独立选自 d Cs直链或支链烷基， C2~C7直链或支链 烯基； 或 R3和 R4和与它们相连的氮原子一起构成 4~6元杂环， 其选自四氢吡咯， 哌啶， 吗啉， 哌嗪或氮甲基哌嗪。 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.
本发明的一方面涉及通式 I 吲哚酮类衍生物， 其几何异构 体或其可药用盐或水合物。 本发明出乎意料地发现， 当 n等于 2 或 3时， 通式 I吲哚酮类衍生物及其几何异构体具有优良的药学 稳定性， 特别适合工业化大量制备和长期储存。  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 专利 O0190104, 画 190103 和 画 190068披露了 3- '， 5' -二甲基 -2' -吡咯甲烯基） -2-吲哚酮衍生物的麦尼氏碱 (Mannich Base) 前药， 但该类化合物不稳定， 例如， 在 10%的 乙醇溶液中、 温度为 4~ 30°C、 时间为 30 分钟的条件下， 3- (3'， 5' -二曱基- 2' -吡咯甲烯基） -2-吲哚酮的哌啶麦尼氏碱大约 有 5%分解， 不适合大量制备和长期储存， 不符合药物稳定性的 质量控制要求。 而本发明通式 I吲哚酮类衍生物具有优异的药学 稳定性， 例如， 在 10%的乙醇溶液中、 温度为 4~30°C、 时间为 30 分钟的条件下， 1-[2， -（ 1'-吗啉） ]乙基 "^-(^-溴^^噻 吩甲烯基) -2-吲哚酮完全不分解， 药物的纯度保持不变， 符合药 物稳定性的质量控制要求， 特别适合大量工业化制备和长期储 存。  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.
根据本发明的一个优选实施方案， 本发明涉及通式 I 化合 物、 其几何异构体及药学上可接受的盐： According to a preferred embodiment of the invention, the invention relates to compounds of formula I, geometric isomers thereof and pharmaceutically acceptable salts thereof:
Figure imgf000010_0001
其中：
Figure imgf000010_0001
among them:
n等于 2;  n is equal to 2;
为选自呋喃， 噻吩， 吡咯或吡啶的杂芳基； 所述杂芳基 可以未被取代或被 1或 2个选自下面的取代基取代： 卤素， d~ C6直链或支链烷基， d~C4烷氧酰基； Is a 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;
R2选自氢， 卤素； R 2 is selected from the group consisting of hydrogen and halogen;
R3和 R4和与它们相连的氮原子一起构成 4~6元杂环， 其选 自哌啶， 吗啉。 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.
本发明式 I化合物或其药学上可接受的盐特别优选以下化合 物， 但这些化合物并不意味着对本发明的任何限制。  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.
Figure imgf000010_0002
Figure imgf000011_0001
Figure imgf000012_0001
本发明最优选的化合物为（Z)- 1-[2， - ( 哌啶） ]乙基 -3- (4' -溴 -2 -噻吩曱烯基） -2 -吲哚酮：
Figure imgf000010_0002
Figure imgf000011_0001
Figure imgf000012_0001
The most preferred compound of the invention is (Z)- 1-[2,-(piperidinyl)ethyl-3-(4'-bromo-2-thiophenenyl)-2-nonanone:
Figure imgf000013_0001
Figure imgf000013_0001
本发明的另一方面涉及制备通式 I化合物的方法， 其包括: 反应方案 1  Another aspect of the invention relates to a process for the preparation of a compound of formula I, which comprises: reaction scheme 1
Figure imgf000013_0002
Figure imgf000013_0002
Figure imgf000013_0003
Figure imgf000013_0003
a) 将式 Π的吲哚酮衍生物
Figure imgf000013_0004
a) an anthrone derivative of the formula
Figure imgf000013_0004
其中 R2的定义同通式 I 化合物， 与具式 m的氨基 ¾代烃衍生物 反应
Figure imgf000014_0001
Wherein R 2 is as defined for the compound of formula I, reacting with an amino 3⁄4 hydrocarbon derivative of formula m
Figure imgf000014_0001
其中 n、 R3和 R4的定义同通式 I化合物， X为 CI或 Br， 具体来说， 将式 Π的吲哚酮衍生物 （购自 ACR0S公司） 和式 m的氨基卤代烃衍生物 （购自 ACR0S公司 )溶于适量丙酮中， 并 加入适量的碳酸钟、 四丁基溴化铵和 KI, 升温至回流温度反应 8 小时左右， 过滤， 真空浓缩， 得到粗品， 用硅胶柱纯化得到中间 体化合物 IV (可参考 Mokrosz, M. J. , Pharmazie [PHARAT] 1997， 52 (6), 423-428 ) , Wherein n, R 3 and R 4 are as defined for the compound of formula I, X is CI or Br, in particular, an anthrone derivative of the formula (available from ACROS) and an aminohalogenated hydrocarbon of the formula m are derived. The product (purchased from 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),
Figure imgf000014_0002
Figure imgf000014_0002
n、 R2、 R3和 R4的定义同通式 I化合物, 将式 IV化合物与杂芳基甲醛 V反应 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
Figure imgf000014_0003
Figure imgf000014_0003
其中 的定义同通式 I化合物，  Wherein the definition is the same as the compound of formula I,
将步骤 a得到的式 IV化合物与杂芳基甲基醛 V (购自商品试 剂 来源 或按照 文献 De Groot JA, Org. prep, precedures Int.1981, 13 (2) ： 97-101 提供的方法制备）在一种合适的溶 剂或分散剂如一种合适的醇如甲醇或乙醇中， 于 10°C ~50°C的 温度下， 加入碱如无机碱如碳酸钠， 或有机碱如二乙胺或哌啶， 或通入酸性气体如氯化氢， 催化反应 8 - 24小时得到通式 I的化 合物 （ 参考 Adreani A, Eur. J med. Chem. , 1990， 25, 187- 190 ) ， 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. In a suitable solvent or dispersant such as a suitable alcohol such as methanol or ethanol, at 10 ° C ~ 50 ° C At a temperature, 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 ) ,
Figure imgf000015_0001
Figure imgf000015_0001
其中 n、 R1 ¾ R2、 R3和 R4的定义同通式 I化合物。 Wherein n, R 1 3⁄4 R 2 , R 3 and R 4 are as defined for the compound of formula I.
本发明化合物可选择多种反应路线制备， 通式 I 化合物还可 以通过下面的反应方案制备：  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:
反应方案 2
Figure imgf000015_0002
Reaction scheme 2
Figure imgf000015_0002
Figure imgf000015_0003
C) 将式 Π吲哚酮衍生物
Figure imgf000016_0001
Figure imgf000015_0003
C) the fluorenone derivative
Figure imgf000016_0001
其中 R2的定义同通式 I化合物， 与具式 V的杂芳基甲醛反应
Figure imgf000016_0002
其中 的定义同通式 I化合物， Wherein R 2 is as defined for the compound of formula I, reacting with a heteroaryl formaldehyde of formula V
Figure imgf000016_0002
Wherein the definition is the same as the compound of formula I,
将式 Π的吲哚酮衍生物 （购自 ACR0S公司 ) 与杂芳基甲基醛 V ( 购 自 商品试剂或按照文献 De Groot JA, 0rg prep precedures Int 1981 , 13 ( 2 ) : 97-101 提供的方法制备） 在 一种合适的溶剂或分散剂如一种合适的醇如甲醇或乙醇中， 于 10°C ~ 50°C的温度下， 加入碱如无机碱如碳酸钠， 或有机碱如二 乙胺或哌啶， 或通入酸性气体如氯化氢， 催化反应 8 ~ 24小时得 到式 VI 化合物 （参考 Adreani A, Eur. J. med. Chem. , 1990, 25, 187-190 ) ,
Figure imgf000016_0003
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),
Figure imgf000016_0003
其中 1^和 R2的定义同通式 I化合物， d) 将式 vi化合物与氨基卤代烃衍生物 m反应 Wherein 1^ and R 2 are as defined for the compound of formula I, d) reacting a compound of formula vi with an aminohalogenated hydrocarbon derivative m
Figure imgf000016_0004
其中 n、 R3和 R4的定义同通式 I化合物， X为 CI或 Br， 将步骤 c 得到的式 VI 化合物和卤代烃衍生物 ΠΙ溶解丙酮 中， 并加入适量的碳酸钾、 四丁基溴化铵和 KI， 升温回流反应 8 小时左右， 过滤， 真空浓缩， 得到粗品， 用硅胶柱纯化得到目的 化合物 I (参考 Mokrosz, Μ· J. , Pharmazie [PHARAT] 1997, 52 (6)， 423-428 ) ,
Figure imgf000016_0004
Wherein 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),
Figure imgf000017_0001
其中 n、 R:, R2、 R3和 R4的定义同通式 I的化合物。
Figure imgf000017_0001
Wherein n, R:, R 2 , R 3 and R 4 are as defined for the compound of formula I.
本发明化合物可以采用的纯化方式为高真空蒸馏或者层析， 这里所使用的硅胶为常规层析用硅胶， 颗粒度 10 ~ 40 微米， 洗 脱剂由单一或者多种溶剂配制而成， 优选由氯仿与甲醇按不同比 例配制而成的混合溶剂。  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.
本发明的另一方面涉及药物组合物， 其包括至少一种通式 I 吲哚酮类化合物或其几何异构体或其药学上可接受的盐以及药用 载体或赋形剂。  Another aspect of the invention relates to 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.
本发明中的药物組合物可按本领域已知方法制备， 如将式 I 化合物、 其几何异构体或其药学上可接受的盐与药用载体或赋形 剂混合。  The pharmaceutical 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.
本发明的另一方面涉及至少一种通式 I 吲哚酮类化合物、 其 几何异构体或其药学上可接受的盐用于制备治疗与 Bel- 2高表达 有关的疾病或症状的药物的用途， 或用于制备具有拮抗血管内皮 细胞生长因子受体、 诱导肿瘤细胞凋亡、 抑制肿瘤新生血管形成 或阻断肿瘤细胞恶性转移作用的抗肿瘤药物的用途。 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.
本发明还提供了对式 I p引哚酮类化合物进行细胞学功能评价 的方法、 抗肿瘤活性的测试结果以及诱导肿瘤细胞凋亡的活性测 试结果。 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.
本发明中的术语 "药用盐" 可以是药用无机或有机盐。 本发 明通式 I中具有碱性基团的化合物可以与无机酸形成药用盐， 例 如硫酸盐、 盐酸盐、 氢溴酸盐、 磷酸盐； 也可与有机酸形成药用 盐， 例如乙酸盐、 草酸盐、 柠檬酸盐、 葡萄糖酸盐、 琥珀酸盐、 酒石酸盐、 对甲苯磺酸盐、 甲磺酸盐、 苯甲酸盐、 乳酸盐、 马来 酸盐等。 本发明通式 I 中具有酸性基团 （如 中含有游离羧 基） 的化合物可以与碱金属或碱土金属形成药用盐， 优选但不限 于钠盐、 钾盐， 镁盐或钙盐。  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. Acid salts, oxalates, citrates, gluconates, succinates, tartrates, p-toluenesulfonates, methanesulfonates, benzoates, lactates, maleates, and the like. The compound of the formula I having an acidic group (e.g., containing a free carboxyl 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.
本发明化合物可以单独或以药物組合物的形式给药。 给药途 径可以是口服、 非肠道或局部给药。 药物组合物可根据给药途径 配成各种适宜的剂型。  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.
本发明化合物的药物组合物可以以下面的任意方式施用： 口 服， 喷零吸入， 直肠用药， 鼻腔用药， 颊部用药， 局部用药， 非 肠道用药， 如皮下，静脉，肌内，腹膜内，鞘内，心室内，胸骨内和颅 内注射或输入，或借助一种外植储器用药。 其中优选口服、 腹膜 内或静脉内给药方式。  The pharmaceutical 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. Among them, oral, intraperitoneal or intravenous administration is preferred.
当口服用药时，本发明化合物可制成任意口服可接受的制剂 形式，包括但不限于片剂、 胶嚢、 水溶液或水悬浮液。 其中，片剂 使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬 脂酸镁。 胶嚢制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。 水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合 使用。 任选地，以上口服制剂形式中还可加入一些甜味剂、 芳香 剂或着色剂。 当局部用药时，特别是治疗局部外敷容易达到的患面或器官， 如眼睛、 皮肤或下肠道神经性疾病时，可根据不同的患面或器官 将本发明化合物制成不同的局部用药制剂形式，具体说明如下： 当眼部局部施用时，本发明化合物可配制成一种微粉化悬浮 液或溶液的制剂形式，所使用载体为等渗的具有一定 pH的无菌盐 水，其中可加入也可不加防腐剂如氯化苄基烷醇盐。 对于眼用，也 可将化合物制成膏剂形式如凡士林膏。 When administered orally, 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. Among them, 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. Optionally, some sweeteners, fragrances or colorants may also be added to the above oral formulation forms. In the case of topical administration, especially in the treatment of facial surfaces or organs easily accessible by topical application, such as eye, skin or lower intestinal neurological diseases, 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: When the eye is topically applied, 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. For ophthalmic use, the compound can also be formulated in the form of a cream such as a Vaseline cream.
当皮肤局部施用时，本发明化合物可制成适当的软膏、 洗剂 或霜剂制剂形式，其中将活性成分悬浮或溶解于一种或多种载体 中。 软膏制剂可使用的载体包括但不限于：矿物油、 液体凡士 林、 白凡士林、 丙二醇、 聚氧化乙烯、 聚氧化丙烯、 乳化蜡和水; 洗剂或霜剂可使用的载体包括但不限于：矿物油、 脱水山梨糖醇 单硬脂酸酯、 吐温 60、 十六烷酯蜡、 十六碳烯芳醇、 2-辛基十 二烷醇、 苄醇和水。  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.
本发明化合物还可以无菌注射制剂形式用药，包括无菌注射 水或油悬浮液或无菌注射溶液。 其中，可使用的载体和溶剂包括 水、 林格氏溶液和等渗氯化钠溶液。 另外，灭菌的非挥发油也可 用作溶剂或悬浮介质，如单甘油酯或二甘油酯。  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. Among them, carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution. Alternatively, sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
另外需要指出，本发明化合物的使用剂量和使用方法取决于诸 多因素，包括患者的年龄、 体重、 性别、 自然健康状况、 营养状 况、 化合物的活性强度、 服用时间、 代谢速率、 病症的严重程度 以及诊治医师的主观判断。 优选的使用剂量介于 0. 01 ~ 100mg/kg 体重 /天， 其中最优剂量在 20mg/kg-30mg/kg 体重 / 天。 具体实施方案  It should also be noted that 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. Specific implementation
本发明可以通过下面的实施例得到说明， 但这些实施例不意 味着对本发明有任何限制。 The invention can be illustrated by the following examples, but these examples are not intended There is no limit to the invention.
实施例 1: (Z) - 1-[2， - ( 1 -哌啶） ]乙基- S- ' '-二 甲基—2, -吡咯甲烯基） -2-吲哚酮 Example 1: (Z) - 1-[2, -( 1 -Piperidine)]ethyl-S- ''-dimethyl- 2 ,-pyrroleyl)-2-indanone
取等摩尔的 1- [2， -（ 1'-哌啶） ]乙基- 2-吲哚酮（2.44g， 0. Olmol , 参考 Mokrosz, M. J. , Pharraazie [PHARAT] 1997, 52 (6), 423- 428文献提供的方法制备）和 3， 5-二甲基 -2-吡咯甲 酸 ( 1.23g， 0. Olmol , 按照 De Groot JA, Org. prep, precedures Int.1981, 13 (2) ： 97-101 文献制备） 置于圆底烧瓶中， 加入 20. Oml 甲醇， 0.20ml 哌啶， 于室温氮气保护下搅拌反应 24 小 时， 抽滤， 用甲醇洗涤， 得到粗品， 用无水乙醇结晶得到标题化 合物纯品， 其为黄色固体， 产率 70.9%.  An equimolar amount of 1-[2,-(1'-piperidine)]ethyl-2-indanone (2.44 g, 0. Olmol, reference Mokrosz, MJ, Pharraazie [PHARAT] 1997, 52 (6), 423-428 prepared by the method) and 3,5-dimethyl-2-pyrrolecarboxylic acid (1.23 g, 0. Olmol, according to De Groot JA, Org. prep, precedures Int. 1981, 13 (2): 97 -101 Preparation of the literature) In a round bottom flask, 20. Oml of methanol, 0.20 ml of piperidine was added, and the reaction was stirred at room temperature under nitrogen for 24 hours, suction filtered, and washed with methanol to give a crude product. Pure compound, which is a yellow solid with a yield of 70.9%.
'H-NMR: 6ppm(CDCl3)： 0· 71 (s， 1H)， 8.74 (s， 2H)， 7.71(d, 2H) 7.56 (s， 1H)， 7.36 - 7.41 (d, 1H)， 7.34 - 7.24 (t， 1H) ，'H-NMR: 6 ppm (CDCl 3 ): 0·71 (s, 1H), 8.74 (s, 2H), 7.71 (d, 2H) 7.56 (s, 1H), 7.36 - 7.41 (d, 1H), 7.34 - 7.24 (t, 1H),
6.89 - 6.86 (t, 1H), (d, 1H)。 MS (m/e) : 223 [M+1]。 6.89 - 6.86 (t, 1H), (d, 1H). MS (m/e): 223 [M+1].
盐酸盐的制备： 将游离碱溶于三氯甲烷中， 加入无水乙醚- 氯化氢溶液至强酸性， 过滤， 用无水乙醚洗涤，得到的粗品用无 水乙醇结晶， 得到纯品。  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.
实施例 2: (Z) -1-[2' - ( 1'-哌啶） ]乙基- 3-(2' -吡咯甲 烯基） -2-吲哚酮  Example 2: (Z)-1-[2'-(1'-piperidine)]ethyl-3-(2'-pyrrolidinyl)-2-indanone
按实施例 1 方法， 以等摩尔的 1- [2， -（1'-哌啶） ]乙基- 2-吲哚酮 （参考 Mokrosz, M. L， Pharmazie [PHARAT] 1997, 52 (6)， 423-428 文献提供的方法制备） 和 2-吡咯甲醛〔购自 ACR0S 公司〕 为原料进行反应， 得到标题化合物纯品， 其为黄色 固体， 收率 90.5%。  In the same manner as in Example 1, an equimolar amount of 1-[2,-(1'-piperidine)]ethyl-2-indanone (cf. Mokrosz, M. L, Pharmazie [PHARAT] 1997, 52 (6) , 423-428 prepared by the method) and 2-pyrrolidine (purchased from ACROS) were reacted to give the title compound as a yellow solid in a yield of 90.5%.
'H-NMR: δρρηι (DMSO -d6)： 13.38 (宽单峰, 1H) , 10.88 (宽 单峰， 1H ) ， 8.02 ~ 8.0 1 (d, 1H) , 7.69 (s, 1H) , 7.23 ~'H-NMR: δρρηι (DMSO -d 6 ): 13.38 (width single peak, 1H), 10.88 (width single peak, 1H), 8.02 ~ 8.0 1 (d, 1H), 7.69 (s, 1H) , 7.23 ~
7.20 (q, 1Η)， 6.82 ~ 6.80 (d, 1H)， 6.03 (s， 1H)， 2.50 (s, 3H)， 2.30(s，3H)。 MS (m/e)： 317 (95), 319 (100) , 238， 133， 112， 85, 69。 7.20 (q, 1Η), 6.82 ~ 6.80 (d, 1H), 6.03 (s, 1H), 2.50 (s, 3H), 2.30 (s, 3H). MS (m/e): 317 (95), 319 (100), 238, 133, 112, 85, 69.
实施例 3: ( Z) -1-[2' - ( Ι'-哌啶） ]乙基 -3- (4， -溴- 2， -噻吩甲烯基）-2-吲哚酮  Example 3: (Z)-1-[2'-( Ι'-piperidine)]ethyl-3-(4,-bromo-2,-thiophenemethyl)-2-indanone
按实施例 1 方法， 以等摩尔的 1-[2， -（1'-哌啶） ]乙基- 2-吲哚酮 （参考 Mokrosz, M. J.， Pharmazie [PHARAT] 1997， 52 (6)， 423-428 文献提供的方法制备） 和 4， -溴 -2， -噻吩甲 醛（购自 ACR0S公司） 为原料进行反应， 得到标题化合物。 黄色 固体， 收率 95%。  Equimolar 1-[2,-(1'-piperidine)]ethyl-2-indanone according to the method of Example 1 (refer to Mokrosz, MJ, Pharmazie [PHARAT] 1997, 52 (6), 423 -428 Preparation of the method provided by the method) and 4,-bromo-2,-thiophenecarboxaldehyde (purchased from ACROS) were reacted as starting materials to give the title compound. Yellow solid, yield 95%.
'H-NMR: 5ppm (DMS0-d6)： 12.01 (宽单峰， 1H)， 10.84 (宽单 峰， 1H, ) , 8.22 (s, 1H) , 7.87 (s, 1H) , 7.75 ~ 7.73 (d, 1H),7.65 - 7.64 (d, 1H)， 7.50 - 7.52 (d, 1H)， 7.27 ~ 7.23(t, 1H) , 7.20 ~'H-NMR: 5ppm (DMS0-d 6 ): 12.01 (width single peak, 1H), 10.84 (width single peak, 1H, ), 8.22 (s, 1H), 7.87 (s, 1H), 7.75 ~ 7.73 ( d, 1H), 7.65 - 7.64 (d, 1H), 7.50 - 7.52 (d, 1H), 7.27 ~ 7.23(t, 1H) , 7.20 ~
7.17(t,2H), 6.95 ~ 6.91 (t，lH)， 6.89 - 6.87 (d， 1H ) 。 7.17(t, 2H), 6.95 ~ 6.91 (t, lH), 6.89 - 6.87 (d, 1H).
Ms (m/e)： 261 [M+, 100], 232, 204.0, 117 Ms (m/e): 261 [M + , 100], 232, 204.0, 117
实施例 4: (Z) - 1-[2， - (1 -哌啶） 〗乙基- 3-(2'-吡啶甲 烯基） -2-吲哚酮  Example 4: (Z) - 1-[2, -(1 -piperidinyl)ethyl 3-(2'-pyridylmethyl)-2-indanone
按实施例 1方法， 以等摩尔的 1- [2， -（1'-哌啶） ]乙基- 2- 吲哚酮 （参考 Mokrosz, M. L , Pharmazie [PHARAT] 1997, 52 (6)， 423-428 文献提供的方法制备） 和 2-吡啶甲醛 （购自 ACR0S 公司） 为原料进行反应， 得标题化合物， 其为红色固体， 产率 83.7%。  In the same manner as in Example 1, an equimolar amount of 1-[2,-(1'-piperidine)]ethyl-2-indanone (cf. Mokrosz, M. L, Pharmazie [PHARAT] 1997, 52 (6) The title compound was obtained as a red solid in a yield of 83.7% from the title compound.
'H-NMR: 5ppm (DMS0 - d6): 10.31 (s ， 1H) , 9. ll(d, 1H),'H-NMR: 5ppm (DMS0 - d 6 ): 10.31 (s , 1H) , 9. ll(d, 1H),
8.92 (d, 1H), 8.00 ~ 7.97 (m, 1H), 7.69 (s, 1H), 7.52 ~ 7.50(m, 1H) ， 7.43 - 7.40 (m, 1H) , 7.32 - 7.30 (d, 1H) , 7.13 ~ 7.10 (t， 1H)， 4.28 - 4.23 (t, 2H)， 3.62 - 3.60 (d, 2H) , 3.33 -8.92 (d, 1H), 8.00 ~ 7.97 (m, 1H), 7.69 (s, 1H), 7.52 ~ 7.50 (m, 1H), 7.43 - 7.40 (m, 1H), 7.32 - 7.30 (d, 1H) , 7.13 ~ 7.10 (t, 1H), 4.28 - 4.23 (t, 2H), 3.62 - 3.60 (d, 2H), 3.33 -
3.30 (q, 2H), 3.00 - 2.94 (q, 2H), 1.83 - 1.70 (m, 5H) , 1.39 ~ 1.36(m，lH)。 Ms (m/e): 333.2 [M], 2307.1， 290.2, 192.1, 98.1 (100)，71.1。 3.30 (q, 2H), 3.00 - 2.94 (q, 2H), 1.83 - 1.70 (m, 5H), 1.39 ~ 1.36 (m, lH). Ms (m/e): 333.2 [M], 2307.1, 290.2, 192.1, 98.1 (100), 71.1.
实施例 5: ( Z) -1-[2' - ( 1' -哌啶） ]乙基- 3-(5'-乙酰氧 甲基 -2-呋喃甲烯基) -2-吲哚酮  Example 5: (Z)-1-[2'-(1'-piperidine)]ethyl-3-(5'-acetoxymethyl-2-furanylenyl)-2-indanone
按实施例 1方法， 以等摩尔的 1-[2， ― 哌啶） ]乙基- 2- 吲哚酮 （参考 Mokrosz, M. J.， Pharmazie [PHARAT] 1997, 52 (6)， 423-428文献提供的方法制备）和 5-乙酰氧甲基 -2-呋喃甲 醛（购自 ACR0S公司） 为原料进行反应， 得到标题化合物， 其为 红色固体， 产率 94%。  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%.
^-NMR: 5ppm (DMS0 - d6)： 7.74 (d, 1H), 7.56 (s, 1H) , 7.50 ~ 7.48(ra, 2H), 7.29 ~ 7.26 (m, 1H) ， 7.06 - 7.04 (m, 2H) , 4.34(s,2H) , 4.30 - 4.28 (t, 2H), 3.51 - 3.50(d, 2H) , 3.30 -^-NMR: 5ppm (DMS0 - d 6 ): 7.74 (d, 1H), 7.56 (s, 1H), 7.50 ~ 7.48 (ra, 2H), 7.29 ~ 7.26 (m, 1H) , 7.06 - 7.04 (m, 2H) , 4.34(s,2H) , 4.30 - 4.28 (t, 2H), 3.51 - 3.50(d, 2H) , 3.30 -
3.29 (q, 2H) , 3.00 - 2.93 (q, 3H)， 2.40 (s， 3H) , 1.80 - 1.68 (m，5H)， 1.350 ~ 1.32 (m, 1H) 。 Ms (m/e): 394 [M] , 283, 98.1 (100) 3.29 (q, 2H), 3.00 - 2.93 (q, 3H), 2.40 (s, 3H), 1.80 - 1.68 (m, 5H), 1.350 ~ 1.32 (m, 1H). Ms (m/e): 394 [M] , 283, 98.1 (100)
实施例 6: ( Z) -l-[2' - ( 1'-哌啶） ]乙基 - 3-（3， -曱基- V -呋喃甲烯基）-2-吲哚酮  Example 6: (Z) -l-[2'-(1'-piperidine)]ethyl-3-(3,-indolyl-V-furanylenyl)-2-indanone
按实施例 1 方法， 以等摩尔的 1- [2， -（1'-哌啶） ]乙基 -2- 吲哚酮 （参考 Mokrosz, Μ· J. , Pharmazie [PHARAT] 1997, 52 (6)， 423-428文献提供的方法制备）和 3-甲基 -2-呋喃甲醛（购 自 ACR0S 公司 ) 为原料进行反应， 所不同的是反应温度为 14 °C， 反应时间为 48 小时， 得到标题化合物的粗品。 用乙醇重结 晶得到纯品， 其为黄色固体， 收率 88.7%。  Equimolar 1-[2,-(1'-piperidine)]ethyl-2-indanone according to the method of Example 1 (refer to Mokrosz, ΜJ., Pharmazie [PHARAT] 1997, 52 (6 ), prepared by the method provided in 423-428) and 3-methyl-2-furaldehyde (purchased from ACR0S) as a raw material, except that the reaction temperature was 14 ° C and the reaction time was 48 hours. The crude product of the title compound. Recrystallization from ethanol gave a pure product as a yellow solid, yield 88.7%.
^-NMR: δρριη (DMS0-d6)： 7.82 (d, 1H)， 7.6 (s， 1H)， 7.50 - 7.48(m, 2H), 7.29 ~ 7.26 (m, 1H) ， 7.06 - 7.04 (m, 2H) ,^-NMR: δρριη (DMS0-d 6 ): 7.82 (d, 1H), 7.6 (s, 1H), 7.50 - 7.48 (m, 2H), 7.29 ~ 7.26 (m, 1H) , 7.06 - 7.04 (m, 2H),
4.34(s,2H), 3.51 ~ 3.50(d, 2H) , 3.30 ~ 3.29 (q, 2H) , 3.23 (s, 3H) , 3.00 - 2.93 (q, 2H) , 2.40 (s, 3H) , 1.80 ~ l, 68(m，5H)， 1.350 - 1.32 (m, 1H). Ms (m/s) : 336.2 (M) , 111.1， 98 (100)。 4.34(s,2H), 3.51 ~ 3.50(d, 2H) , 3.30 ~ 3.29 (q, 2H) , 3.23 (s, 3H) , 3.00 - 2.93 (q, 2H) , 2.40 (s, 3H) , 1.80 ~ l, 68(m,5H), 1.350 - 1.32 (m, 1H). Ms (m/s) : 336.2 (M) , 111.1, 98 (100).
实施例 7: (Z) -1-[2' - ( Ι'-哌啶） ]乙基- 3-(3'-甲基- Example 7: (Z)-1-[2'-( Ι'-piperidine)]ethyl-3-(3'-methyl-
2 ,一噻吩甲烯基）—2— P引哚酮 2 , monothiophene alkenyl) - 2 - P fluorenone
按实施例 1 方法， 以等摩尔的 1-[2， - 哌啶） ]乙基 -2- 吲哚酮 （参考 Mokrosz, Μ· J. , Pharmazie [PHARAT] 1997, 52 (6)， 423-428文献提供的方法制备） 和 3-甲基- 2-噻吩甲醛（购 自 ACR0S 公司） 为原料进行反应， 所不同的是反应温度为 16 °C， 反应时间为 46 小时， 得到标题化合物， 其为黄色固体， 收 率 93.4%。  In the same manner as in Example 1, equimolar 1-[2,-piperidinyl]]ethyl-2-indanone (cf. Mokrosz, ΜJ., Pharmazie [PHARAT] 1997, 52 (6), 423- Process prepared by the method of 428) and 3-methyl-2-thiophenecarboxaldehyde (purchased from ACR0S) were reacted as starting materials except that the reaction temperature was 16 ° C and the reaction time was 46 hours to obtain the title compound. It was a yellow solid with a yield of 93.4%.
^-NMR: 5ppm (DMS0-d6)： 7.74 (d, 1H) , 7.56 (s, 1H) , 7.50 ~ 7.48(ra, 2H), 7.29 ~ 7.26 (m, 1H) ， 7.06 ~ 7.04 (m, 2H) , 4.34(s,2H) , 4.30 - 4.28 (t,2H), 3.51 - 3.50(d, 2H) , 3.30 -^-NMR: 5ppm (DMS0-d 6 ): 7.74 (d, 1H), 7.56 (s, 1H), 7.50 ~ 7.48 (ra, 2H), 7.29 ~ 7.26 (m, 1H) , 7.06 ~ 7.04 (m, 2H) , 4.34(s,2H) , 4.30 - 4.28 (t,2H), 3.51 - 3.50(d, 2H) , 3.30 -
3.29(q,2H), 2.40(s，3H)， 1.80 ~ 1.68 (ra, 5H) , 1.350 ~3.29(q,2H), 2.40(s,3H), 1.80 ~ 1.68 (ra, 5H) , 1.350 ~
1.32 (m, 1H) 0 MS (m/e) : 352.1 [M] , 241.1, 98 ( 100 )， 77.0。 1.32 (m, 1H) 0 MS (m/e): 352.1 [M] , 241.1, 98 ( 100 ), 77.0.
实施例 8: (Z) -l-[2' - ( 1'-吗啉） ]乙基- 3- (4' -溴 -2'- 噻吩甲烯基） -2-吲哚酮  Example 8: (Z) -l-[2'-(1'-morpholine)]ethyl-3-(4'-bromo-2'-thiophenenyl)-2-indanone
按实施例 1 方法， 以等摩尔的 1-U， -（1'-吗啉） 〗乙基- 2- 吲哚酮 （参考 Mokrosz, M. J.， Pharmazie [PHARAT] 1997， 52 (6)， 423-428文献提供的方法制备）和 4-溴 -2-噻吩甲醛〔购自 ACR0S公司〕 为原料进行反应， 所不同的是反应温度为 25°C, 反 应时间为 35 小时， 得到标题化合物， 其为黄色固体， 产率  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
'H-NMR: 5ppm(DMS0-d6)： 8.09 (s, 1H) , 7.99 (d, 1H) , 7.98 ~ 7.97 (d, 1H), 7.71 - 7.70 (d, 1H) , 7.32 - 7.29 (m, 1H) , 7.09 - 7.06(m, 2H), 3.90 - 3.88. (t,2H), 3.52 ~ 3.50 (t， 4H)， 2.55 -'H-NMR: 5 ppm (DMS0-d 6 ): 8.09 (s, 1H), 7.99 (d, 1H), 7.98 ~ 7.97 (d, 1H), 7.71 - 7.70 (d, 1H), 7.32 - 7.29 (m , 1H) , 7.09 - 7.06(m, 2H), 3.90 - 3.88. (t,2H), 3.52 ~ 3.50 (t, 4H), 2.55 -
2.51(s，4H)， 2.50 ~ 2.49 (m，2H) 。 MS ( m/e ) : 420 (M+2), 418 [M], 256, 100 (100) 0 实施例 9: (Z) -1-[2' - ( 1'-吗啉） ]乙基 -3- (3'，5' -二 甲基 -2' -吡咯甲烯基） -2-吲哚酮 2.51 (s, 4H), 2.50 ~ 2.49 (m, 2H). MS ( m/e ) : 420 (M+2), 418 [M], 256, 100 (100) 0 Example 9: (Z)-1-[2'-(1'-morpholine)]ethyl-3-(3',5'-dimethyl-2'-pyrroleyl)-2-indole Anthrone
按实施例 1方法， 以等摩尔的 1- [2， -（1'-吗淋） ]乙基 -2- 吲哚酮 （参考 Mokrosz, M. J. , Pharmazie [PHARAT] 1997， 52 (6)， 423-428文献提供的方法制备）和 3， 5-二甲基 -2-吡咯甲醛 ( 按照 De Groot JA, Org. prep, precedures Int.1981 , 13 (2) ： 97-101 文献制备） 为原料进行反应， 得到标题化合物， 其为黄色固体， 产率 80.9%。  In the same manner as in Example 1, an equimolar amount of 1-[2,-(1'-norlin)]ethyl-2-indanone (cf. Mokrosz, MJ, Pharmazie [PHARAT] 1997, 52 (6), 423 -428 prepared by the method) and 3,5-dimethyl-2-pyrrolidine (prepared according to De Groot JA, Org. prep, precedures Int. 1981, 13 (2): 97-101) Reaction gave the title compound as a yellow solid.
!H-NMR: 5ppm (CDC13)： 13.18 (s, 1H) , 7.49 ~ 7.47(d, 1H) , 7.37 (s, 1H) , 7.25 (s, 1H) , 7.18 ~ 7.15 (t， 1H)， 7.06 - 7.03 (t， 1H) ， 6.95 - 6.94 (d, 1H)， 4.10 (t， 2H)， 4.03 - 4.01(t,4H), 2.64(t,3H) , 2.54(m, 4H), 2.38 (s, 3H) , 1.45(m，2H)。 MS(m/e): 351 [M], 238, 98.1 (100). ! H-NMR: 5ppm (CDC1 3): 13.18 (s, 1H), 7.49 ~ 7.47 (d, 1H), 7.37 (s, 1H), 7.25 (s, 1H), 7.18 ~ 7.15 (t, 1H), 7.06 - 7.03 (t, 1H) , 6.95 - 6.94 (d, 1H), 4.10 (t, 2H), 4.03 - 4.01(t,4H), 2.64(t,3H) , 2.54(m, 4H), 2.38 ( s, 3H), 1.45 (m, 2H). MS (m/e): 351 [M], 238, 98.1 (100).
实施例 10; (Z) - 1-[2， -（ -哌啶 ：！乙基^-^， -溴 - V -噻吩甲烯基 )-2-吲哚酮  Example 10; (Z)-1-[2, -(-piperidine:!ethyl^-^,-bromo-V-thiophenemethyl)-2-indanone
按实施例 1 方法， 以等摩尔的 1- [2， -（1'-哌啶） ]乙基- 2- 吲味酮 （参考 Mokrosz, M. J. , Pharmazie [PHARAT] 1997, 52 (6)， 423-428文献提供的方法制备） 和 3-溴- 2-噻吩甲醛〔购自 ACR0S 公司〕 为原料进行反应， 得到标题化合物， 其为黄色固 体， 产率 80.9%。  An equimolar amount of 1-[2,-(1'-piperidine)]ethyl-2-oxazinone was obtained as in Example 1 (cf. Mokrosz, MJ, Pharmazie [PHARAT] 1997, 52 (6), 423 - </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;
'H-NMR: δρριη (DMS0-d6)： 'H-NMR: δρριη (DMS0-d 6 ):
8.08 (s, 1H), 7.99 (d, 1H) , 7.98 一 7.97 (d, 1H), 7.71 - 7.70(d，lH)， 7.32-7.29 (m, 1H) , 7.09- 7.06 (m, 2H) 3.90- 3.88. (t， 2H) , 3.52 - 3.50 (t， 4H)， 2.55 - 2.51 (s， H)， 2.50 - 2.49(m, 2H) 。 MS ( ra/e ) ： 420 (M+2), 418 (M) , 256, 100 (100)。  8.08 (s, 1H), 7.99 (d, 1H), 7.98 a 7.97 (d, 1H), 7.71 - 7.70(d,lH), 7.32-7.29 (m, 1H) , 7.09- 7.06 (m, 2H) 3.90 - 3.88. (t, 2H) , 3.52 - 3.50 (t, 4H), 2.55 - 2.51 (s, H), 2.50 - 2.49 (m, 2H). MS (ra/e): 420 (M+2), 418 (M), 256, 100 (100).
实施例 11: 吲哚酮类化合物抑制内皮细胞（ECV-304 )增殖 及对 bFGF和 VEGF选择性抑制作用实验。 Example 11: Indole ketone inhibits proliferation of endothelial cells (ECV-304) And experiments on selective inhibition of bFGF and VEGF.
内皮细胞（ECV- 304)购自中国科学院典型培养物保藏委员会 细胞库。 取处于生长对数期的细胞接种于 96孔板中， 每孔 3-4 X 103个细胞 /ΙΟΟμ 1, 24h后， 吸取培养液， 每孔加入 ΙΟΟμΙ含 不同浓度药物的完全培养液（生长因子选择性抑制试验中， 完全 培养液由 1%胎儿牛血清培养液中分别补充 10ng/ml bFGF或 VEGF 的培养液替换） 。 继续培养 72h, 弃去培养液， 每孔加 0.5mg/ml 的四曱基偶氮唑蓝 （MTT) ΙΟΟμ 1, 37°C, 孵育 4h, 吸取四甲基 偶氮唑蓝液， 每孔加入 100 μ ΐ 的二甲基亚砜（DMS0) ， 轻轻震 摇 10 min, 用 BI0RAD 550型读板机于 490 nm波长下测定 96孔 板每一孔的光密度 0D 值， 每一化合物在 10—δ-10—4间设定 5-6 个浓度， 每一测试设 3-4个平行孔， 重复 3-4次。 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/μμμ 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. Continue to culture for 72h, discard the culture solution, add 0.5mg/ml tetradecylazozolium blue (MTT) to each well, incubate at 37 °C for 4h, and aspirate tetramethylazolyl blue solution. Add in each well. 100 μM dimethyl sulfoxide (DMS0) was shaken gently for 10 min. The optical density 0D value of each well of a 96-well plate was measured at a wavelength of 490 nm using a BI0RAD 550 plate reader. - δ -10- 4 set between 5-6 concentrations, each test set 3-4 parallel wells, repeated 3-4 times.
药物对细胞的生长抑制率 （％) = (溶剂对照组平均 0D 值 - 用药组平均 0D值） /对照组平均 0D值， 然后根据不同药物浓度 对细胞的生长抑制率 （％)计算药物的 IC5。值。 表 1.吲哚酮类化合物抑制 ECV-304细胞增殖 The inhibition rate of the drug on the cells (%) = (the average 0D value of the solvent control group - the average 0D value of the drug group) / the average 0D value of the control group, and then calculate the IC of the drug according to the growth inhibition rate (%) of the drug concentration 5 . value. Table 1. Indole ketone compounds inhibit ECV-304 cell proliferation
Figure imgf000025_0001
注： 细胞浓度（4X103个 /孔） ， I.R ( 3χ 10—5) : 药物在 3χ 10—5 Mol 时的抑制率， 此时药物抑制作用最为敏感， 便于比较不同化 合物的抑制作用强弱。
Figure imgf000025_0001
Note: the concentration of cells (4X10 3 cells / well), IR (3χ 10- 5) : inhibition rate of the drug when 3χ 10- 5 Mol at this time the most sensitive to inhibition of drug, to facilitate comparison of different strength inhibitory compounds.
由图表中可以看出， 所试化合物对 ECV- 304 在 1%NBS + 1640 培养条件下的增殖具有不同程度的抑制作用； 对 VEGF 和 bFGF具有不同的选择性抑制作用。 其中， 化合物 1和 2对 bFGF 诱导的增殖作用选择性强于 VEGF, 化合物 3、 4和 8对 VEGF的 选择性强于 bFGF， 化合物 5 对两种生长因子的选择性抑制作用 相当。  It can be seen from the graph that 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. Among them, compounds 1 and 2 were more selective for bFGF-induced proliferation than VEGF, and compounds 3, 4 and 8 were more selective for VEGF than bFGF, and compound 5 was equally selective for both growth factors.
实施例 12: 溴化胸腺嘧啶（Brdu)掺入法评价吲哚酮类化 合物对脐静脉内皮细胞 HUVEC增殖的抑制作用  Example 12: Inhibition of ketone ketone compounds on proliferation of human umbilical vein endothelial cells HUVEC by brominated thymidine (Brdu) incorporation assay
HUVEC细胞林购自美国 Cascade Biologies公司， 培养液为 HUVEC专用培养基 medium200补充 LSGS添加物。 按照 Roche公 司， Cell Proliferation ELISA, BrdU (colorimetr ic) Kit 方 法进行试验。 简述如下， 取对数期生长的 HUVEC, 接种于 96 孔 板中， 每孔 4χ 103个细胞 /ΙΟΟμ Ι, 24h 后， 弃去培养液， 每孔 加入 ΙΟΟμ Ι 含不同浓度药物的培养液， 继续培养 72h， 每孔加 入 ΙΟμ Ι ( 100 μΜ) BrdU 掺入液， 继续培养 18h， 弃去培养 液， 每孔加入 200 μ 1 的固定变性液， 处理 40min， 吸干固定变 性液， 室温 40min; 每孔加入 10μ 1 抗 BrdU-POD抗体工作液， 室温孵育 90min， 用 200- 300 μ 1 清洗工作液洗板 3次， 弃去清 洗工作液； 每孔加入 lOOul底物反应液， 室温显色 10min， 每孔 加入 25 μ ΐ lmol/L 硫酸终止反应。 采用 BI0RAD 550 型读板机 于 450nm波长（ 690参比波长） 下测定 96孔板每一孔的光密度 0D值， 每一化合物在 lG_fi- 10— 4间设定 4-5 个浓度， 每一'测试 设 3-4个平行孔， 重复 2-3次。 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 4χ 10 3 cells/μμ 每 per well. After 24 hours, the culture medium was discarded, and ΙΟΟμ 培养 medium containing different concentrations of drug was added to each well. Continue to culture for 72 h, add ΙΟμ Ι (100 μΜ) BrdU incorporation to each well, continue to culture for 18 h, discard the culture solution, add 200 μl of fixed denaturing solution to each well, treat for 40 min, blot dry and fix the denaturing solution, room temperature for 40 min. Add 10μ 1 anti-BrdU-POD antibody working solution per well, incubate for 90min at room temperature, wash plate with 200-300 μ 1 cleaning working solution 3 times, discard the cleaning working solution; add lOOul substrate reaction solution per well, develop color at room temperature At 10 min, the reaction was stopped by adding 25 μM ΐlmol/L sulfuric acid per well. The 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.
药物对细胞的生长抑制率 （％) = (溶剂对照组平均 0D值 - 用药组平均 0D值） /对照组平均 0D值， 然后才艮据不同药物浓度 对细胞的生长抑制率 （％)计算药物的 IC5。值。 Drug inhibition rate of cells (%) = (average 0D value of solvent control group - The mean 0D value of the drug group) / the average 0D value of the control group, and then the IC 5 of the drug was calculated according to the growth inhibition rate (%) of the cells at different drug concentrations. value.
表 2 溴化胸腺嘧啶（Brdu)掺入法评价吲哚酮类化合物 对脐静脉内皮细胞 HUVEC增殖的抑制作用的试验结果 实施例化合物 IC5。 ( X+SD ) (μιηοΙ/L) Table 2 Evaluation of the inhibitory effect of anthrone on the proliferation of human umbilical vein endothelial cells HUVEC by brominated thymine (Brdu) incorporation Example Compound IC 5 . (X+SD) (μιηοΙ/L)
1 11.2 ±1.9  1 11.2 ±1.9
3 4.8 ± 0.5  3 4.8 ± 0.5
4 19.4 ±1.87  4 19.4 ±1.87
由图表中数据可以看出， 三种化合物对 HUVEC 的 D 合成 具有不同程度的抑制作用， 其抑制作用的强弱顺序是 3>1〉4。  It can be seen from the data in the graph that the three compounds have different degrees of inhibition on the D synthesis of HUVEC, and the order of inhibition is 3>1>4.
实施例 13: (Z)-l- [2， - ( 1'-哌啶） ]乙基 -3-(4'-溴- 2'- 噻吩甲烯基） -2-吲哚酮化合物诱导肿瘤细胞 U937的凋亡研究  Example 13: (Z)-l-[2,-(1'-Piperidine)]ethyl-3-(4'-bromo-2'-thiophenemethyl)-2-indanone compound induces tumor Apoptosis of cell U937
胰酶消化不同处理贴壁的肿瘤细胞 U937， 离心， 用 PB轻轻 洗细胞， 收集细胞 105个以上， 以 75%水冷乙醇固定细胞， PI 染 色 DNA, 流式细胞仪上检测 DNA含量的分布。 （Z)- 1- [2， - ( V- 哌啶） ]乙基- 3- (4'-溴- 2'-噻吩甲烯基) - 2-吲哚酮化合物在浓度 为 50μΜ、 处理时间 72h时可明显诱导肿瘤细胞 U937凋亡， 流式 细胞仪上检测 DNA含量的分布表明药物引起的是明显的凋亡而不 是坏死。 Different trypsinized adherent treatment of U937 tumor cells, centrifugation, cells were washed gently with PB, 10 5 cells were collected, to the water-cooled 75% ethanol-fixed cells, the PI DNA staining, flow cytometry distribution of DNA content . (Z)- 1-[2, -(V-piperidinyl)]ethyl-3-(4'-bromo-2'-thiophenenyl)-2-nonanone compound at a concentration of 50 μM, treatment time At 72h, the apoptosis of U937 cells was significantly induced. The distribution of DNA content on the flow cytometer showed that the drug caused obvious apoptosis rather than necrosis.

Claims

权 利 要 求 Rights request
1. 通式 I化合物、 其几何异构体及其药学上可接受的盐， 1. A compound of formula I, a geometric isomer thereof, and a pharmaceutically acceptable salt thereof,
Figure imgf000028_0001
Figure imgf000028_0001
其中：  among them:
n等于 2或 3，  n is equal to 2 or 3,
为选自呋喃， 哈， 吡咯， 吡唑， 咪唑， 唑， 唑， 异 唑， 吡啶， p达，秦， 嘧啶， 吡噪， 吲味， 苯并呋喃或喹啉的杂 芳基； 所述杂芳基可以未被取代或被 1或 2个选自下面的取代基 取代： 卤素， 硝基， 羟基， 羟曱基， 三氟甲基， 三氟甲氧基， d~C6直链或支链烷基， C2~Cfi直链或支链烯基， 烷氧基， d~C4烷氧酰基， C2~C4烯氧基， 苯氧基， 苄氧基， 羧基或氨 基， Is a heteroaryl group selected from the group consisting of furan, ha, pyrrole, pyrazole, imidazole, oxazole, oxazole, isoxazole, pyridine, pda, qin, pyrimidine, pyridyl, astringent, benzofuran or quinoline; The aryl group may be unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxydecyl, trifluoromethyl, trifluoromethoxy, d~C 6 straight or branched Alkenyl, C 2 ~C fi straight or branched alkenyl, alkoxy, d~C 4 alkoxy, C 2 ~C 4 alkenoxy, phenoxy, benzyloxy, carboxy or amino,
R2选自氢， ！¾素， 氰基， 亚砜基， 砜基， 硝基， 羧基， c3烷氧基， d~C3烷酰基， d~C3烷酯基, (^~0；3烷酰氨基， R 2 is selected from hydrogen, ! 3⁄4, cyano, sulfoxide, sulfone, nitro, carboxy, c 3 alkoxy, d~C 3 alkanoyl, d~C 3 alkyl ester, (^~0; 3 alkanoylamino,
R3、 R4独立选自 d~C6直链或支链烷基， C2~C7直链或支链 烯基； 或 R3和 R4和与它们相连的氮原子一起构成 4~6元杂环， 其选自四氢吡咯， 哌啶， 吗啉， 哌嗪或氮甲基哌嗪。 R 3 and R 4 are independently selected from d to C 6 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 4~ A 6-membered heterocyclic ring selected from the group consisting of tetrahydropyrrole, piperidine, morpholine, piperazine or nitrogen methylpiperazine.
2. 权利要求 1所述的化合物， 2. The compound of claim 1
Figure imgf000029_0001
其中：
Figure imgf000029_0001
among them:
n等于 2;  n is equal to 2;
为选自呋喃， 噻吩， 吡咯和吡啶的杂芳基； 所述杂芳基 可以未被取代或被 1或 2个选自下面的取代基取代： 卤素， d~ C6直链或支链烷基， d~C4烷氧酰基； Is a heteroaryl group selected from the group consisting of furan, thiophene, pyrrole and 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;
R2选自氢， 卤素； R 2 is selected from the group consisting of hydrogen and halogen;
R3和 R4和与它们相连的氮原子一起构成 4~6元杂环， 其选 自哌啶或吗啉。 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 or morpholine.
3. 权利要求 1的化合物， 其包括：  3. The compound of claim 1 comprising:
(Z) -1- [2， - ( 1'-哌啶） ]乙基 -3- Ο',δ'-二甲基 - 2'-吡咯甲 烯基) -2-吲哚酮，  (Z)-1-[2,-(1'-piperidine)]ethyl-3- Ο',δ'-dimethyl-2'-pyrrolyl)-2-indanone,
(Ζ) - 1-[2， 一 哌啶） ]乙基 -3- (2' -吡咯甲烯基) -2-吲哚酮, (Ζ) -1-[2， - ( -哌啶) ]乙基 -3- (4' -溴- 2'-噻吩甲烯基) -2- 吲味酮，  (Ζ) - 1-[2,-piperidine)]ethyl-3-(2'-pyrroleyl)-2-indanone, (Ζ)-1-[2, -(-piperidine) Ethyl-3-(4'-bromo-2'-thiophenenyl)-2-oxenone
(Ζ) -1-[2' - (1 哌啶) ]乙基 -3- (2' -吡啶甲烯基） -2-吲哚酮， (Ζ) -1-[2' - ( 哌啶） ]乙基 -S- -乙酰氧甲基- 2， -呋喃 甲烯基）-2-吲哚酮，  (Ζ) -1-[2' - (1 piperidine)]ethyl-3-(2'-pyridylalkenyl)-2-indanone, (Ζ) -1-[2' - (piperidine )]ethyl-S--acetoxymethyl-2,-furanylenyl-2-indanone,
(Z) -1-[2， - (1 哌啶) ]乙基 -3- (3' -甲基 -2'-呋喃甲烯基) - 2-吲味酮，  (Z)-1-[2, - (1 piperidine)]ethyl-3-(3'-methyl-2'-furanylenyl)-2-nonanone
(Z) -1一[2， - ( -哌啶) ]乙基- 3-(3'-曱基- 2'-噻吩甲烯基） - 2 -吲咮酮， (Z) -1 -[2,-(-piperidinyl)]ethyl-3-(3'-indolyl-2'-thiophenenyl) - 2 - fluorenone,
(Z) -1-[2， - 吗啉） ]乙基- 3- (4'-溴 -2'-噻吩甲烯基） -2- 吲味酮，  (Z)-1-[2,-morpholine]]ethyl-3-(4'-bromo-2'-thiophenenyl)-2-oxenone
( Z) -1-[2' - ( -吗啉） ]乙基 -S- S'-二曱基 - 2' -吡咯甲 烯基） -2-吲哚酮，  (Z)-1-[2'-(-morpholine)]ethyl-S-S'-dimercapto-2'-pyrroleyl)-2-indanone,
(Z) -1-[2， - 哌啶） ]乙基- 3- (5 -溴- 2'-噻吩曱烯基） -2- 吲哚酮。  (Z)-1-[2,-Piperidine)]ethyl-3-(5-bromo-2'-thiophenenhenyl)-2-indanone.
4. 药物组合物， 其含有权利要求 1 - 3 任一项所述的化合 物、 其几何异构体或其药学上可接受的盐以及至少一种药学上可 接受的载体。  A pharmaceutical composition comprising the compound according to any one of claims 1 to 3, a geometric isomer thereof or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
5. 制备权利要求 1- 3 任一项所述化合物的方法， 该方法包 括将式 Π的吲哚酮衍生物
Figure imgf000030_0001
5. A process for the preparation of a compound according to any one of claims 1 to 3, which process comprises an anthrone derivative of the formula
Figure imgf000030_0001
其中 R2同权利要求 1式 （I )化合物的定义, Wherein R 2 is as defined in the compound of formula (I) of claim 1
与具式 m的氨基 ¾代烃衍生物反应，
Figure imgf000030_0002
Reacting with an amino 3⁄4 hydrocarbon derivative having the formula m,
Figure imgf000030_0002
其中 n、 R3和 R4同权利要求 1式（I )化合物的定义， X为 C1 或 Br， Wherein n, R 3 and R 4 are as defined for the compound of formula (I) according to claim 1, X is C1 or Br,
得到式 IV化合物，
Figure imgf000031_0001
Obtaining a compound of formula IV,
Figure imgf000031_0001
其中 n、 R2、 R3和 R4同权利要求 1式 （I )化合物的定义， 将式 IV化合物与杂芳基甲醛 V反应，
Figure imgf000031_0002
Wherein n, R 2 , R 3 and R 4 are as defined in the compound of formula (I) according to claim 1, reacting a compound of formula IV with a heteroaryl formaldehyde V,
Figure imgf000031_0002
其中 同权利要求 1式 （I )化合物的定义，  Wherein the definition of the compound of formula (I) of claim 1
得到通式 I化合物，  Obtaining a compound of formula I,
Figure imgf000031_0003
Figure imgf000031_0003
其中 n、 R2、 R3和 R4的定义同权利要求 1式 I化合物; 或者， Wherein n, R 2 , R 3 and R 4 are as defined in the formula 1 compound; or
使式 Π的吲哚酮衍生物
Figure imgf000031_0004
Anthrone derivative
Figure imgf000031_0004
其中 R2的定义同权利要求 1式 I化合物。 与具式 V的杂芳基甲醛反应, Wherein R 2 is as defined in the formula I. Reacting with a heteroaryl formaldehyde of formula V,
R1  R1
0:  0:
H V  H V
其中 的定义同权利要求 1式 I化合物  Wherein the definition is the same as the compound of formula 1
得到式 VI化合物，  To obtain a compound of formula VI,
Figure imgf000032_0001
Figure imgf000032_0001
其中 1^和112的定义同权利要求 1式 I化合物, Wherein 1^ and 11 2 are as defined in the formula I,
将式 VI化合物与氨基卤代烃衍生物 m反应 Reacting a compound of formula VI with an aminohalohydrocarbon derivative m
Figure imgf000032_0002
Figure imgf000032_0002
其中 n、 R3和 R4的定义同权利要求 1式 I化合物， X为 C1或Wherein n, R 3 and R 4 are as defined in the formula I, and X is C1 or
Br , Br,
得到通式 I的化合物，  To obtain a compound of formula I,
Figure imgf000032_0003
Figure imgf000032_0003
6. 权利要求 1― 3 任一项所述的化合物用于制备抗肿瘤药物 的用途。 6. Use of a compound according to any one of claims 1 to 3 for the preparation of an anti-tumor drug.
7. 权利要求 6的用途， 其中的抗肿瘤作用包括诱导肿瘤细胞 凋亡、 抗肿瘤新生血管形成、 防止肿瘤化疗耐药和阻止肿瘤恶性 转移。  7. The use of claim 6, wherein the anti-tumor effect comprises inducing tumor cell apoptosis, anti-tumor neovascularization, preventing tumor chemoresistance and preventing malignant metastasis of the tumor.
PCT/CN2004/001081 2004-09-23 2004-09-23 1,3-substitued-2-indolinone derivatives, the preparation, the composition and the use thereof WO2006032164A1 (en)

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