WO2013159698A1 - Composé cyclique condensé de quinazoline-acide hydroximique et son utilisation comme médicament antitumoral - Google Patents

Composé cyclique condensé de quinazoline-acide hydroximique et son utilisation comme médicament antitumoral Download PDF

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WO2013159698A1
WO2013159698A1 PCT/CN2013/074611 CN2013074611W WO2013159698A1 WO 2013159698 A1 WO2013159698 A1 WO 2013159698A1 CN 2013074611 W CN2013074611 W CN 2013074611W WO 2013159698 A1 WO2013159698 A1 WO 2013159698A1
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quinazolin
oxy
methoxy
quinazolino
group
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PCT/CN2013/074611
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Chinese (zh)
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李建其
张子学
解鹏
***
叶宇翔
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深圳信立泰药业股份有限公司
上海医药工业研究所
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Publication of WO2013159698A1 publication Critical patent/WO2013159698A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the present invention relates to a fused ring quinazoline hydroxamic acid compound, and the use of such a compound as an antitumor drug.
  • Tumors are major diseases that threaten human health, and the treatment of tumors has been closely watched by the whole world.
  • Conventional chemotherapeutic drugs non-specifically block cell division and cause cell death, while killing tumor cells, and destroying normal human cells.
  • cytotoxic drugs have a limited range of treatments that can cause treatment-related adverse effects, while drugs that target specific pathways can prevent tumor growth and reduce toxicity to normal cells.
  • the development of anti-tumor drugs has shifted from empirical random screening to rational drug development based on mechanisms of action that target specific cellular dysfunction. Many anti-tumor targets have been discovered, among which tyrosine kinase and histone deacetylase are important targets for the development of new anticancer drugs.
  • Tyrosine kinase is a key protein in the cell signal transduction pathway. During tumorigenesis, a variant or overexpressed protein tyrosine kinase can transform normal cells into tumor cells, while promoting tumor cell growth and mitosis. .
  • the tyrosine kinase family can be broadly classified into three categories: receptor tyrosine kinases, such as epidermal growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor, etc.; cytoplasmic tyrosine kinases, such as Src family, Tec family and Jak family; nuclear tyrosine kinases, such as Abl, Wee, etc.
  • EGFR Epidermal growth factor receptor
  • malignant tumors such as glioma, breast cancer, lung cancer, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer
  • Overexpression is found in esophageal cancer, prostate cancer, liver cancer, colon cancer, gastric cancer, etc.
  • Activation of EGFR accelerates tumor cell proliferation, promotes tumor angiogenesis, accelerates tumor metastasis, and blocks tumor apoptosis.
  • Histone deacetylases are one of the key enzymes that maintain the equilibrium of histone acetylation in the nucleosomes of the basic constituent units of chromosomes, which catalyze the deacetylation of histones, and genes. Transcriptional repression is closely related, involving many processes that promote gene silencing, and is associated with the development and progression of a variety of diseases such as cancer, acute myeloid leukemia, viruses and infections. Clinical studies have shown that by inhibiting the activity of HDACs, the level of histone acetylation is increased, resulting in the activation of specific genes, which in turn leads to terminal differentiation of cells or apoptosis of cancer cells. Histone deacetylase has become a hot target in the development of new anticancer drugs.
  • Histone deacetylase inhibitors can be classified into four classes according to their structure: benzamides, hydroxamic acids, fatty acids, and cyclic peptides.
  • SAHA also known as Vorinostat
  • SAHA is a hydroxamic acid and is the first listed histone deacetylase inhibitor for the treatment of cutaneous T-cell lymphoma.
  • SAHA has a strong inhibitory effect on tumors, but due to the poor selectivity of SAHA for HDACs subtypes, serious adverse reactions such as pulmonary embolism, dehydration and anemia may occur in clinical treatment.
  • tyrosine kinase inhibitors and histone deacetylase inhibitors are used in clinical tumor therapy. They can be used not only in the treatment of tumors, but also in combination with other anticancer drugs (mostly cytotoxic drugs).
  • tumors are a complex disease. The growth and survival of tumors depends not only on one receptor or one signaling pathway. Drugs acting on a single target usually have some shortcomings, such as their efficacy only for specific patient populations. It is preferable, and long-term use is prone to drug resistance and the like; in addition, the combination of two single-target drugs may cause drug interaction and the like.
  • Patent WO2008033747 discloses a series of new derivatized structures of compounds which have been shown to have dual inhibitory activity against tyrosine kinases and histone deacetylases in vitro.
  • the compound CUDC-101 under the general structure has entered the phase I clinical trial stage in order to develop a drug having dual targeted inhibitory activity of tyrosine kinase and histone deacetylase.
  • the structure of CUDC-101 is as follows:
  • this compound has dual inhibitory activity against tyrosine kinase and histone deacetylase, it has poor selectivity and strong inhibitory activity against normal cells.
  • Patent WO2011144059 filed in the preliminary work of the present invention, discloses a class of fused ring quinazoline compounds which are intended to acquire a series of compounds by synthetic means for finding epidermal growth factor receptors and aurora. Compounds with dual inhibitory activity of kinases are expected to develop ideal anti-tumor drugs.
  • the selective inhibitory activity of the chemotherapeutic drug on tumor cells and normal cells is improved to reduce the adverse reactions caused by chemotherapy.
  • a drug candidate for obtaining better antitumor activity the present invention designs and obtains a series of fused ring quinazoline hydroxamic acid compounds.
  • the fused ring quinazoline hydroxamic acid compound of the present invention is a compound having the structural formula of the following formula V, and/or
  • Ri is an alkyl group of a substituted or unsubstituted Ci-Cs
  • R 2 , R 3 are independently one of hydrogen, a decyloxy group of d_C 5 , a C 2 -C 4 unsaturated aliphatic chain, a nitro group, a hydroxyl group, a cyano group, a halogen, a substituted or unsubstituted amino group;
  • X is 0, NR 4 , S or NHCO, wherein R 4 is hydrogen or a d-C 5 alkyl group;
  • n l, 2, 3 or 4.
  • substitution means that at least one hydrogen atom on each group is replaced by a substituent selected from halogen, hydroxy, nitro, cyano, alkyl, alkoxy, phenyl, heterocycle. , amino groups, etc.
  • the fluorenyl group refers to a branched, unbranched and cyclic saturated hydrocarbon chain containing a specified number of carbon atoms, preferably a Ci-Cs alkyl group, including methyl, ethyl, propyl, isopropyl a group, a cyclopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a cyclobutyl group, a n-pentyl group, an isopentyl group, a neopentyl group, etc.; a substituted fluorenyl group means at least a fluorenyl group A hydrogen atom is replaced by a phenyl group or a substituted phenyl group, a heterocyclic ring or a substituted heterocyclic ring, an alkoxy group of Ci—C 5 , or the like, for example, a benzy
  • the decyloxy group means a decyl ether radical, preferably an alkoxy group of Q-C 5 , which comprises a methoxy group, an ethoxy group, a n-propoxy group, and a different Propyloxy, n-butoxy, isobutoxy, pentyloxy, methoxyethoxy, ethoxymethoxy, and the like.
  • the heterocyclic ring means that the ring of the aliphatic ring contains more than one hetero atom, the hetero atom is selected from nitrogen, oxygen or sulfur, etc., preferably a saturated or unsaturated five-membered heterocyclic ring or six-membered one containing more than one hetero atom.
  • a heterocyclic ring comprising furan, tetrahydropyrrole, dihydropyrazole, piperidine, piperazine, morpholine, oxazole or pyridine, etc.; said substituted heterocyclic ring means that the hydrogen on the heterocyclic ring is partially or wholly independently of each other Substituted by a hydroxyl group, a nitro group, a cyano group, an alkyl group, an alkoxy group, an amino group or the like, preferably an alkyl group, a decyloxy group, and a decyl group is preferably a d-C 5 fluorenyl group, for example, N-methyl-piperidine or N-pentyl group.
  • the methoxy group is preferably d-decyloxy, such as 3-methoxy-tetrahydropyrrole, 2-pentyloxy-peri
  • the amino group means -NH 2
  • the substituted amino group means that the hydrogen on the -NH 2 is partially or completely replaced by a thiol group, a phenyl group or the like, for example, a methylamino group, an ethylamino group, a propylamino group or a butylamino group. , pentoamino, phenylamino and the like.
  • the substituted phenyl group means that a part or all of the hydrogen atoms on the benzene ring are independently replaced by a halogen, a hydroxyl group, a nitro group, a cyano group, a decyl group, a decyloxy group, an amino group or the like, preferably a halogen, Nitro or alkyl, the alkyl group is preferably ⁇ (3 ⁇ 4 alkyl).
  • the halogen refers to fluorine, chlorine, bromine or iodine.
  • the NHCO is an amide group.
  • the compound of the formula V may be salted with an inorganic or organic acid to give a salt form of the compound of the formula V.
  • an inorganic or organic acid to give a salt form of the compound of the formula V.
  • the fused ring quinazoline hydroxamic acid compounds of the present invention are not limited to the following compounds:
  • V-33 6-((9,11-Divinyl-3-pentyloxypropoxy-8H-quinazolin[4,3-b]quinazolin-2-yl)oxy)-N -hydroxycaproamide
  • V-34 7-((9-ethynyl-11-(1-butenyl)-3-((1-pentyl-piperidinyl-4-yl)methoxy)-8H-quinazoline [4,3-b]quinazolin-2-yl)oxy)-N-hydroxyheptanamide
  • V-36 7-((9-Nitro-11-(1-butenyl)-3-(3-(3-(pentyloxy)piperazinyl-1-yl)propoxy)-8H- Quinazolino[4,3-b]quinazolin-2-yl)amino)-N-hydroxyheptanamide
  • V-37 7-((10-Methyl-11-cyano-3-(3-(3-methoxy-tetrahydropyrrolyl-1-yl)propoxy)-8 /-quinazoline [4,3-b]quinazolin-2-yl)indenyl)-N-hydroxyheptanamide,
  • V-38 7-((11-Hydroxy-12-pentyloxy-3-(3-(2-bromo-4-methyl-phenyl)propoxy)-8ff-quinazoline[4,3 -b]quinazolin-2-yl)indolyl)-N-hydroxyheptanamide
  • V-40 7-((9-Hydroxy-11-pentylamino-3-pentyloxy-8H-quinazolin[4,3-b]quinazolin-2-yl)pentylamino)-N-hydroxyl
  • the compounds of the formula V of the present invention can be prepared by the following synthetic methods:
  • R 2 independently one of hydrogen, ⁇ (alkoxy, C 2 C 4 unsaturated fatty chain, nitro, hydroxy, cyano, halogen, substituted or unsubstituted amino;
  • X is 0, NR 4, S, or NHC0, wherein is hydrogen or a C r C 5 alkyl
  • n l, 2, 3 or 4;
  • Y C1 or Br.
  • halogenated reagents are thionyl chloride (S0C1 2 ), phosphorus oxychloride (POCl 3 ), phosphorus tribromide, oxalyl chloride, tetrabromocycloketone, N-bromosuccinimide, tribromide
  • S0C1 2 thionyl chloride
  • POCl 3 phosphorus oxychloride
  • phosphorus tribromide phosphorus tribromide
  • oxalyl chloride tetrabromocycloketone
  • N-bromosuccinimide tribromide
  • the solvent is one of N,N-dimethylformamide (DMF) or CH 2 C1 2 .
  • the organic solvent is one of isopropanol, ethanol, acetonitrile, N,N-dimethylformamide, as follows: isopropanol (i-PrOH), reflux; or ethanol, reflux; or acetonitrile, reflux Or hydrazine, hydrazine-dimethylformamide (DMF), reflux; or isopropanol (i-PrOH), concentrated hydrochloric acid (con HCl), room temperature;
  • the ring closure reagent is one of P0C1 3 or methylsulfonyl chloride, refluxed;
  • the alkaline reagent is LiOH, K0H or NaOH or a hydrate thereof, and the organic solvent is one of methanol, ethanol or a mixed solution thereof with water;
  • the organic solvent is one of hydrazine, hydrazine-dimethylformamide (DMF) or acetonitrile or acetone, and the basic substance is K 2 C0 3 ;
  • the organic solvent is one of methanol or ethanol.
  • the above intermediate 1, intermediate 3, and intermediate 7 can be produced by the methods described in the commercially available and the examples.
  • the "room temperature" as used in the present invention means 25 ° C ⁇ 2 ° C; the concentrated hydrochloric acid is a hydrochloric acid having a mass fraction of 36% - 38%.
  • the above preparation method may further comprise reacting a compound of the formula V with a mineral acid or an organic acid/organic solvent (acid/solvent, organic solvent including ethanol, etc.), and cooling the salt of the compound of the formula V.
  • a mineral acid or an organic acid/organic solvent ascid/solvent, organic solvent including ethanol, etc.
  • a further object of the present invention is to screen anti-tumor drugs with good drug resistance and less side effects.
  • the compound of the formula V disclosed in the invention has good inhibitory effects on both tyrosine kinase and histone deacetylase dual targets, and has good inhibitory activity against various tumor cells, revealing its Preparation of antitumor drugs, and, due to tumors The diversity of pathogenesis suggests that it has better resistance in the expected treatment.
  • the compound of the formula V of the present invention can be administered to a mammal (including a human) in need of tumor treatment by oral, injection or the like in the form of a composition.
  • composition comprises a therapeutically effective amount of a compound of the formula V and/or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the carrier refers to a conventional carrier in the pharmaceutical field, such as: a diluent, an excipient such as water, microcrystalline cellulose, etc.; a binder such as a cellulose derivative, gelatin, polyvinylpyrrolidone, etc.; A filler such as starch or the like; a cracking agent such as calcium carbonate or sodium hydrogencarbonate; in addition, other adjuvants such as a flavoring agent and a sweetener may be added to the composition.
  • a diluent an excipient such as water, microcrystalline cellulose, etc.
  • a binder such as a cellulose derivative, gelatin, polyvinylpyrrolidone, etc.
  • a filler such as starch or the like
  • a cracking agent such as calcium carbonate or sodium hydrogencarbonate
  • other adjuvants such as a flavoring agent and a sweetener may be added to the composition.
  • composition of the present invention can be prepared into a conventional solid preparation such as a tablet, a capsule or the like for oral administration; it can also be prepared into an injection preparation or the like for injection.
  • compositions of the present invention can be prepared by conventional methods in the pharmaceutical art, wherein the active ingredient of the compound of the formula V is present in an amount of from 0.1% to 99.5% by weight based on the total weight of the composition.
  • the compounds of the formula V according to the present invention can be administered clinically to mammals (including humans) by oral or injection means, particularly preferably orally.
  • the dosage is 0.0001 mg/kg to 200 mg/kg body weight per day.
  • the optimal dose will depend on the individual, usually at the beginning of the dose, and then gradually increase the amount.
  • the compound of the present invention has a good dual-target inhibitory activity of tyrosine kinase and histone deacetylase, and has a good inhibitory activity against various tumor cells in human body.
  • the compounds of the present invention have a weak inhibitory effect on normal cells while exhibiting a good selective inhibitory activity, and have a good resistance. Prospects for clinical application of tumors.
  • the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate added to about lOOmL, washed with saturated aqueous sodium bicarbonate and saturated brine, liquid separation, the organic layer with saturated brine (50mL), dried the organic layer was dried over anhydrous M g S0 4 After drying and concentration by filtration, 4-chloro-6-acetoxy-7-methoxyquinazoline (white solid) 22.9 g, yield: 91.2%, MS (m/ z ): 253 +1] +.
  • Example 11 7-((l l-Amino-3-methoxy-8H-quinazolin[4,3-b]quinazolin-2-yl)oxy)-N-hydroxyheptanamide (V-11)
  • Preparation of 7-((11-nitro-3-methoxy-8H-quinazolino[4,3-b]quinazolin-2-yl)oxy)- N-hydroxyheptanamide (1 mmol) was dissolved in 25 ml of ethanol, added with O.lg 10% Pd-C, and hydrogenated at 30 ° C for about 2 h. Filtration, the filtrate was concentrated under reduced pressure to give a white solid.
  • oxy)-N-hydroxyheptanamide (V-11) (white solid) 0.20 g, yield 45%.
  • step (O.Olmol) was dissolved in POCl 3 (50mL), the method according to the through three 2.61 g of off-white solid, 69% yield,
  • the hydrazine product (10.Ommol) was dissolved in hydrazine, hydrazine-dimethylformamide (10 mL), and potassium carbonate (25.0 mmol) and ethyl 7-bromoheptanoate (ll.Ommol) were added. Five reactions gave 4.71 g of an off-white solid, yield 80%, MS (m/ Z ): 522.2 [ ⁇ +1] + .
  • the hydrazine product (2.0 mmol) was taken up in 10 mL of N,N-dimethylformamide, and potassium carbonate (4.0 mmol) was added, and iodomethane (1.5 mmol) was added. The temperature was raised to 60 ° C for 1.5 h.
  • 6-Acetoxy-7-ethoxyquinazolidone (0.1 mol) was dissolved in POCl 3 (75 mL), and 4-chloro-6-acetoxy-7-ethoxyquin was obtained according to General Method A.
  • Oxazoline (white solid) 18.62 g, yield 70%, MS (m/ z ): 267.1 [M+l]+.
  • 6-Acetoxy-7-methoxyethoxyquinazolidone (0.1 mol) was dissolved in POCl 3 (75 mL), and 4-chloro-6-acetoxy-7-methyl was obtained according to General Method A.
  • Oxyethoxy quinazoline (white solid) 26.6 g, yield 90%, MS ( / z ): 297.1 [ ⁇ +1] + .
  • step (O.Olmol) was dissolved in POCl 3 (50mL), the method according to the through three 3.24 g of off-white solid, yield 83%, MS (m / z ): 400 ⁇ 1 [ ⁇ + 1 ]+.
  • 6-Acetoxy-7-pentyloxyquinazolidone (1) (O.lmol) dissolved in P0C1 3 (75 mL), according to General Method A to give 4-chloro-6-acetoxy-7-pentane quinazoline group (white solid) 28.1g, yield 91%, MS (m / z ): 309.1 [ ⁇ + 1] +.
  • step (O.Olmol) was dissolved in POCl 3 (50mL), the method according to the through three 3.19 g of off-white solid, yield 75%, MS (m / z ): 426 ⁇ 1 [ ⁇ + 1 ] + .
  • the hydrazine product (10.Ommol) was dissolved in hydrazine, hydrazine-dimethylformamide (10 mL), and potassium carbonate (25.0 mmol) and ethyl 7-bromoheptanoate (S.Ommol) were added. Five reactions gave 3.94 g of an off-white solid, yield 87%, MS (m / z ): 453.2 [M+l] + 0 [0159]
  • the top product (5.0 mmol) was dissolved in methanol (30 mL), ice water bath A freshly prepared solution of hydroxylamine in methanol (15.0 mmol) was added.
  • the hydrazine product (10.Ommol) was dissolved in hydrazine, hydrazine-dimethylformamide (10 mL), and potassium carbonate (25.0 mmol) and ethyl 7-bromoheptanoate (8.0 mmol) were added. Reaction gave 1.81 g of an off-white solid, yield 40 ⁇ 3 ⁇ 4, MS (m/ z ): 453.2 [M+1] [0165]
  • the above product (5.0 mmol) was dissolved in methanol (30 mL) A solution of hydroxylamine in methanol (15.0 mmol).
  • 6-Acetylhydrazino-7-methoxyquinazolidone (0.1 mol) was dissolved in POCl 3 (75 mL), and 4-chloro-6-acetylindol-7-methoxyquinazoline was obtained according to General Method A. (white solid) 25.2 g, yield 94%, MS (m/z): 269.1 [M+l]+.
  • step (O.Olmol) was dissolved in POCl 3 (50mL), the method according to the through three off-white solid 2.7g, Yield 73%, MS (m / z ): 372 ⁇ 1 [ ⁇ + 1 ] + .
  • step (O.Olmol) was dissolved in POCl 3 (50mL), the method according to the through three 2.52 g of off-white solid, yield 70%, MS (mlz): 360.1 [M + l
  • the oxime product O.Ommol was taken up in DMF (200 mL), and then potassium carbonate (7.5 mmol) and 4-(3-chloropropyl)morpholine (3.3 mmol) were sequentially added. Stir at 60 ° C for 3 h. It was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was recrystallized from ethanol to give a white solid type 1.60g, yield Sl%, MS (m / z ): 660.3 [ ⁇ + 1] +.
  • the preparation of the compounds V-31 to V-40 can be carried out by referring to the specific preparation methods of the above V-1 to V-30, by the methods of the general method 1 to the general method 6.
  • Benzo-6-bromoacetic acid benzyl ester (12.65 g, 92%). Add 2-nitro-6-bromoacetic acid benzyl ester (2.73g, O.Olmol) to 100mL of water, add 20mL of 10% potassium hydroxide aqueous solution, drip, heat up to reflux for 2h, complete reaction, cooling The mixture was extracted with EtOAc (3 mL EtOAc).
  • Some compounds of the present invention were randomly selected, and these compounds were assayed for in vitro inhibitory activity of epidermal growth factor receptor tyrosine kinase by reference to EGFR inhibitor screening reagents (Cat# PV 3872, InVitrogen) and kits (HTRF® KinEASE).
  • the TM-TK 62 ⁇ 0 ⁇ , Cisbio Bioassays) manual (Rev 03, 2009 version) was carried out.
  • the final concentration of compounds to act 4 fold dilution from 2000nM to 0.02nM, a total of 11 points, the measurement values of the compounds IC 5Q to EGFR.
  • the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib was selected as a positive control drug and SAHA was used as a negative control drug. The results are as follows:
  • HDACs histone deacetylase
  • the assay method is described in the HDAC Inhibitor Drug Screening Kit (Cat: K340-100). , BioVsion) manual (Rev. 05/11 version).
  • the IC 5Q values of the compounds against HDACs were determined by plotting the final concentration of the compound from 2000 nM to 0.02 nM in a 4-fold gradient dilution of 11 points.
  • the histone deacetylase (HDACs) inhibitor SAHA was selected as a positive control drug and gefitinib was used as a negative control drug.
  • Table 3 In vitro inhibitory activity of the compound of the present invention and a control drug against histone deacetylase
  • V -4 4.2 V-22 39.7 V -5 37.6 V -23 32.7
  • the randomly selected compounds of the present invention tested have strong dual inhibitory activity against both EGFR and HDACs, indicating that the fused ring quinazoline hydroxamic acid compounds of the present invention have higher Strong EGFR and HDACs dual target inhibitory activity, should be very resistant as a tumor drug.
  • the compounds of the present invention were assayed for Jurkat E6-1 (human T cell lymphoma), Hut78 (T lymphocytic leukemia cells), Colo320 (human rectal cancer cell line), Caki-1 (human renal cell carcinoma cell line), MDA-MB.
  • the activity of -435s human breast cancer cells
  • A549 human lung cancer cells
  • PANC-1 human pancreatic cancer cells
  • IC 5Q values were measured by CCK-8 method (Cat# CK04-13, Dojindo).
  • An anti-proliferation test of tumor cell lines was performed using erlotinib hydrochloride as a positive control drug.
  • V- 12 0.05 0.12 1.78 0.76 0.07 0.57 1.78
  • Colo320 human rectal cancer cell line
  • Caki-1 human renal cell carcinoma cell line
  • MDA-MB-435S human breast cancer cell
  • A549 human lung cancer cell
  • PANC-1 human Pancreatic cancer cells have better activity in tumor cell proliferation, indicating that the fused ring quinazoline hydroxamic acid compounds of the present invention have good inhibitory activity against various tumor cells.
  • the activity of the compound of the present invention against MCF10A was measured, and the IC 5 o value was measured by the CCK-8 method (Cat# CK04-13, Dojindo).
  • the dual target active compound CUDC-101 which is a tyrosine kinase and histone deacetylase, and the histone deacetylase drug SAHA were selected as control drugs for the in vitro inhibitory activity test of normal cell lines.
  • the specific results are as follows (unit: ⁇ ⁇ ):
  • the compounds V-1 to V-30 of the present invention tested were less active against normal cells than the control drugs CUDC-101 and SAHA, and had lower toxic side effects, indicating the present invention.
  • the fused ring quinazoline hydroxamic acid compound has better selectivity for inhibiting proliferation of tumor cells and normal cells, and predicts that it has lower toxic side effects when used as an antitumor drug, and is easy to be used as a tumor drug.
  • Acute toxicity test The method reported by Zhang Juntian's "Modern Pharmacological Experimental Method” (Beijing Medical University, China Union Medical University, published in 1998, published in 1998), preliminary screening, using Bliss method statistics ("Practical Pharmaceutical Preparation Technology” , People's Health Publishing House, published in 1999), the LD 50 of single V4, V-7, V-9, V-17 and V-23 mice was 2.63g/kg, 2.12g kg, respectively. 0.95 g kg 1.88 g/kg and 2.14 g/kg.
  • the active ingredient V-1 to V-40 is mixed with sucrose and corn starch, moistened with water, stirred uniformly, dried, pulverized and sieved, added with calcium stearate, uniformly mixed, and compressed.
  • Each tablet weighs 290 mg and has an active ingredient content of 100 mg.
  • Preparation method Dissolving any compound of active ingredient V-1 to V-40 in water for injection, mixing uniformly, filtering, and obtaining the obtained solution Dispense under sterile conditions in ampoules, 95 mg per bottle, with an active ingredient content of 15 mg/bottle.

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Abstract

La présente invention concerne un composé cyclique condensé de quinazoline-acide hydroximique. Le composé fait partie d'une classe d'inhibiteurs doubles de protéine tyrosine kinases et d'histone désacétylases, et le composé cyclique condensé de quinazoline-acide hydroximique peut être utilisé dans la préparation de médicaments destinés au traitement de maladies néoplasiques chez des mammifères. Les inhibiteurs doubles de protéine tyrosine kinases et d'histone désacétylases sont des composés de formule structurelle générale (I) ou leurs sels.
PCT/CN2013/074611 2012-04-26 2013-04-24 Composé cyclique condensé de quinazoline-acide hydroximique et son utilisation comme médicament antitumoral WO2013159698A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114031507A (zh) * 2021-11-11 2022-02-11 辽宁科信生物科技有限公司 邻氨基苯甲醇类化合物的合成方法
CN114929704A (zh) * 2019-12-27 2022-08-19 微境生物医药科技(上海)有限公司 含螺环的喹唑啉化合物

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