WO2014134750A1 - Dérivés de purine 2,6,9-trisubstitués et leurs procédé de préparation et utilisation - Google Patents

Dérivés de purine 2,6,9-trisubstitués et leurs procédé de préparation et utilisation Download PDF

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WO2014134750A1
WO2014134750A1 PCT/CN2013/000242 CN2013000242W WO2014134750A1 WO 2014134750 A1 WO2014134750 A1 WO 2014134750A1 CN 2013000242 W CN2013000242 W CN 2013000242W WO 2014134750 A1 WO2014134750 A1 WO 2014134750A1
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compound
hydroxymethyl
amino
formula
propyl
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PCT/CN2013/000242
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Chinese (zh)
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王升启
杨静
李爱星
伯晓晨
韩明明
张京玉
李康
齐向云
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中国人民解放军军事医学科学院放射与辐射医学研究所
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Priority to PCT/CN2013/000242 priority Critical patent/WO2014134750A1/fr
Priority to CN201380068392.9A priority patent/CN104936959B/zh
Publication of WO2014134750A1 publication Critical patent/WO2014134750A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to 6-(benzylamino)-2-[[1-(hydroxymethyl)propyl]amino]-9-isopropylindole derivatives and processes for their preparation and use.
  • the cell cycle is a fundamental feature of cell life activities.
  • a complete cell cycle is regulated by a variety of proteases, which can lead to excessive cell proliferation and tumors.
  • Cyclin-dependent kinases (CDKs) are the core of cell cycle regulation.
  • the binding of CDKs to the corresponding cyclins is a necessary condition for the initiation and progression of various molecular events in the cell cycle.
  • Drugs targeting cyclin-dependent kinases (CDKs) block the cell cycle and control cell proliferation for anti-tumor purposes.
  • CDKs cyclin-dependent kinases
  • CDKs rely on binding to cyclins to perform key functions in cell cycle progression; have potential therapeutic effects in proliferative disorders, especially for cancer cells. effect.
  • 2,6,9-trisubstituted guanidine is a selective ATP antagonist of CDKs, one of the small molecule compounds that can specifically inhibit CDK, is a treatment for cancer, neurodegenerative diseases, glomerulonephritis and viral Potential drugs for diseases such as infection.
  • Enterovirus 71 belongs to the Picomaradae Enterovirus and belongs to human enterovirus A. EV71 can cause a wide range of outbreaks, which can be accompanied by severe central nervous system complications or fatal pulmonary edema, and the infection is more serious.
  • EV71 is the latest virus found in the current enterovirus population, which is highly infectious and has a high morbidity, especially in the nervous system.
  • Other polioviruses are highly infectious and has a high morbidity, especially in the nervous system.
  • Enterovirus type 71 (English name: Human enterovirus 71). Referred to as EV71.
  • Coxsackieviruses were first isolated.
  • HFMD hand-foot and mouth disease
  • Human Enterovirus 71 was first isolated from sputum specimens of infants with central nervous system disorders in California in 1969. Humans are the only source of enterovirus infection, and the population is generally susceptible to enterovirus EV71, and immunity can be obtained after infection. Because of the lack of cross-protection of antibodies in different disease prototypes, the population can be repeatedly infected.
  • enterovirus infection has vaccines other than poliovirus, and there are no special treatment drugs for other enterovirus infections. Therefore, clinical treatment of uncomplicated patients can only adopt supportive therapy, but only patients with complications can only be symptomatic. Treatment, take some treatment to reduce intracranial pressure, cooling, and adjuvant antiviral. So far, the anti-EV71 virus treatment has only broad-spectrum antiviral drugs such as ribavirin, but the antiviral effect is general. Therefore, effective methods for preventing and controlling the EV71 virus have become a top priority. Based on the above analysis, the study of new anti-EV71 virus-infected drugs with high specificity and low toxicity has important practical significance for the treatment and prevention of EV71 virus infection and its related diseases.
  • (R)-6-(benzylamino)-2-[[1-(hydroxymethyl)propyl]amino]-9-isopropylindole is a cyclin-dependent Selective inhibitors of CDC2/cyclin B, CDK2/cyclinA, CDK2/cyclin E, and CDK5/p35 in the cyclin-depend kinases (CDKs) family.
  • the object of the present invention is to provide a 2,6,9-trisubstituted indole-6-(benzylamino)-2-[[1-(hydroxymethyl)propyl]amino]-9-isopropylindole derivative and A pharmaceutically acceptable salt thereof.
  • R 2 is a hydrogen atom and is selected from any one of the group consisting of: (RM1-hydroxymethyl)propyl, (SMi-hydroxymethyl)propyl, (RM1-hydroxymethyl)ethyl, (SM1-hydroxymethyl)ethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-aminoethyl, 6-hydroxyhexyl, 1-hydroxymethyl-2-hydroxyethyl, 2-hydroxy- 1-methyl-1-(hydroxymethyl)ethyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)ethylphenethyl and [(hydroxymethyl)ethyl-2-methyl ] propyl; or 3 ⁇ 4 and both are hydroxyethyl or isopropylhydroxy.
  • R 3 is selected from any one of the following groups: a benzylamino group, a substituted benzylamino group, a decylamino group, and a 2-thienylmethylamino group; any position on the benzene ring in the substituted benzylamino group is any of the following One group is substituted: fluorine atom, chlorine atom, methoxy group, methyl group, ethyl group, isopropyl group and trifluoromethyl group.
  • the compound represented by the above formula I may be specifically selected from any one of the following:
  • Compound 65 6-[(3-Methylanilino)]-2-(2-hydroxyethylamino)-9-ethylindole; Compound 66 6-[(4-isopropylanilino)]-2- (2-hydroxyethylamino)-9-ethylhydrazine; Compound 67 6-[(N-methylanilino)]-2-(2-hydroxyethylamino)-9-ethylanthracene; Compound 68 6 - [(3,4-Dimethoxybenzyl)amino]-2-(2-hydroxyethylamino)-9-ethylhydrazine.
  • the pharmaceutically acceptable salt of the compound of the above formula I is a salt of a compound of the formula I with a suitable acid or base.
  • the acid is: a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid; an organic carboxylic acid such as unsubstituted or substituted
  • alkanecarboxylic acids such as: saturated or unsaturated dicarboxylic acids, specifically oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, Phthalic acid or tetraphthalic acid, hydroxycarboxylic acid, specifically ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; amino acid, such as aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acid For example, (C1-C4) mercaptosulfonic acid or arylsulfonic acid, which is unsubstituted or substituted (e.g., halogenated), specifically methanesulfonic acid or p-toluenesulfonic acid.
  • alkanecarboxylic acids such as: saturated or unsaturated dicarboxylic acids, specifically oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, Phthalic acid
  • the compound of the formula I provided by the present invention is prepared by substituting 2,6-dichloropurine as a raw material for the 2, 6, and 9 positions.
  • the chemical reaction flow chart of the preparation method is shown in FIG.
  • the specific preparation method includes the following steps:
  • R 3 in Formula II has the same definition as Formula I, and Formula I has the same formula I.
  • R 3 H may specifically be: benzylamine, a substituted benzylamine, furfuryl amine, or 2-thienyl methylamino.
  • the substituted benzylamine includes 3-fluorobenzylamine, 4-fluorobenzylamine, 2-fluorobenzylamine, 2-methoxybenzylamine, 3-methoxybenzylamine, 2-chlorobenzylamine, 4-methyl Oxybenzylamine, 3,4-difluorobenzylamine, 3,4-dimethoxybenzylamine, and the like.
  • X represents halogen (such as chlorine, bromine, iodine), and X may specifically be: methyl iodide, ethyl bromide, bromopropane, bromocyclopropane, bromocyclopropane, Bromobutyl hydrazine, benzyl chloride or 4-bromobutyronitrile.
  • halogen such as chlorine, bromine, iodine
  • Ri and R 2 in the NH R2 is the same as the formula I, NHR, and R 2 may specifically be: (R)-aminobutanol, (S)-aminobutanol, (R)-aminopropanol, diethanolamine, 2-hydroxypropylamine, ethylenediamine, diisopropanolamine, aminohexanol, L-prolinol, 2-amino-2-methyl-1,3-propanediol, 3-amino-1,2-propanediol, D-Benzenol or 2-amino-1, 3-propanediol.
  • the reaction described in the above step 1) is carried out in a butanol (BuOH) solvent.
  • the reaction temperature of the reaction was 80 110. C, specifically 90 ° C.
  • the reaction described in the above step 2) is carried out in a dimethyl sulfoxide (DMSO) solvent.
  • DMSO dimethyl sulfoxide
  • the reaction also requires the addition of a base as an acid binding agent, and the base may specifically be potassium carbonate, sodium carbonate or the like.
  • the reaction described in the above step 3) is carried out in an inert atmosphere.
  • the reaction temperature of the reaction is 140 170 'C, specifically 160 ⁇ ; and the reaction time is 5 h - 8 h.
  • Another object of the invention is to provide the use of a compound of formula I.
  • the use of the compound of formula I or a pharmaceutically acceptable salt thereof provided by the present invention includes the following aspects: First, it can be used for the preparation of a preventive and/or therapeutic EV7K enterovirus 71 virus (Human enterovirus 71) infection.
  • the drug can be used to prepare eukaryotic tumor cell proliferation inhibitors; third, it can be used to prepare drugs for preventing and/or treating tumors; and fourth, it can be used for preparing cyclin-dependent kinase (CDKs) inhibitors.
  • CDKs cyclin-dependent kinase
  • the eukaryotic organism is a mammal; the tumor cell is a cancer cell; the cancer cell is a liver cancer cell, a swollen cancer cell, a breast cancer cell, a cervical cancer cell or a laryngeal cancer cell; and the liver cancer cell is a human liver cancer cell HepG -2 or human liver cancer cell PLC/PRF/5, the lung cancer cell is specifically human lung cancer cell A549, and the breast cancer cell is specifically human breast cancer cell MCF-7 or human breast duct cancer cell BT-474, the cervical cancer cell Specifically, it is human cervical cancer cell Hela, and the laryngeal cancer cell is specifically human laryngeal carcinoma epithelial cell Hep-2.
  • the tumor is cancer, and the cancer is specifically at least one of the following: liver cancer, lung cancer, breast cancer, cervical cancer, and laryngeal cancer.
  • the present invention demonstrates, by in vitro cell assay, a compound of formula I (ie, a small molecule selective inhibitor of CDKs 6-(amino)-2-[[1-(hydroxymethyl)propyl]amino]-9-isopropyl Anthraquinone derivatives can effectively inhibit the growth of a variety of tumor cells and can be developed into anti-tumor drugs.
  • a compound of formula I ie, a small molecule selective inhibitor of CDKs 6-(amino)-2-[[1-(hydroxymethyl)propyl]amino]-9-isopropyl
  • Anthraquinone derivatives can effectively inhibit the growth of a variety of tumor cells and can be developed into anti-tumor drugs.
  • Preferred compounds having antitumor effects among the compounds of the formula I may be the above compounds 4, 5, 6, 25, 26, 27, 46, 48, 49, 52, 53 and 54.
  • Compound 52 Compound 53 Compound 4 Compound 26 Compound 27
  • the present invention demonstrates, by animal experiments, a compound of formula I (i.e., CDKs small molecule selective inhibitor 6-(benzylamino)-2-[[1-(hydroxymethyl)propyl) The amino]amino]-9-isopropyl hydrazine derivative has a remarkable anti-EV71 virus action in vivo and can be developed into a drug for treating and preventing EV71 (Human enterovirus 71) infection.
  • the amino]amino]-9-isopropyl hydrazine derivative has a remarkable anti-EV71 virus action in vivo and can be developed into a drug for treating and preventing EV71 (Human enterovirus 71) infection.
  • Preferred compounds of formula I are compounds having anti-EV71 viral activity:
  • the medicament for preventing and/or treating EV71 virus infection and the medicament for preventing and/or treating tumors prepared by using the compound of the formula I as an active ingredient are also within the scope of the present invention.
  • the drug can be introduced into the body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, jetting, nasal drops, eye drops, infiltration, absorption, physical or chemical mediated methods; or mixed or wrapped by other substances. Import the body.
  • One or more pharmaceutically acceptable carriers may also be added to the above drugs as needed.
  • the carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrating agents, absorption enhancers, surfactants, adsorption carriers, lubricants and the like in the pharmaceutical field.
  • the medicament prepared by using the compound of the formula I or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared into various forms such as an injection, a suspension, a powder, a tablet, a granule, and the like.
  • the above various dosage forms of the drug can be prepared according to a conventional method in the pharmaceutical field.
  • the medicament provided by the invention includes pharmacokinetics, pharmacokinetics, mode of administration, route of administration, age of recipient, body weight, liver and kidney function state, nature, degree of treatment and treatment time limit of the specific drug according to different situations. Etc., administered at a suitable dose.
  • Figure 1 is a flow chart showing the chemical reaction of the compound of the formula I of the present invention.
  • Figure 2 is a graph showing the inhibitory activity of the compound of Formula I on cyclin-dependent kinase.
  • Figure 3 is a graph showing the effect of compounds 4, 5, 25, 26 on the survival rate of mice infected with EV71 virus.
  • Figure 4 is a graph showing the effect of compounds 48, 49, 52, 53 on the survival rate of EV71 virus-infected mice.
  • Figure 5 is a graph showing the effect of Compound 27 on the survival rate of EV71 virus-infected mice.
  • Figure 6 is a graph showing the effect of compounds 4, 5, 25, 26 on the body weight of mice infected with EV71 virus.
  • Figure 7 is a graph showing the effect of compounds 48, 49, 52, 53 on the body weight of mice infected with EV71 virus.
  • Figure 8 is a graph showing the effect of Compound 27 on the body weight of mice infected with EV71 virus.
  • 2,6-Dichloroindole (10 g, 52.91 mmol) and n-butanol (150 ml) were added to a 250 ml one-necked flask, and the mixture was heated to 90 ° C to dissolve it, and triethylamine (14 ml, 100.44 mmol) was added. 6.7 ml, 61.36 mmol), after reacting for 10 min, a white solid precipitated, and after the reaction was continued for 3 hours, the heating was stopped. After cooling to 5-10 ° C, filter.
  • the structure confirmation data is as follows: CCH 3 ), 3.52 (m,
  • 2,6-Dichloroindole (10 g, 52.91 mmol) and n-butanol (150 ml) were added to a 250 ml one-necked flask, and heated to 90 ° C to dissolve.
  • Triethylamine 14 ml, 100.44 mmol
  • the benzylamine (7 ml, 61.36 mmol) was reacted for 10 min, and then a white solid was precipitated. After the reaction was continued for 3 hours, the heating was stopped. After cooling to 5-10 ° C, filter.
  • the structure confirmation data is as follows:
  • the HepG2 cell culture medium was a DMEM (GIBCO) medium containing 10% fetal bovine serum. A maintenance solution containing 2% fetal calf serum was used before the addition of the derivative. 6-(Benzyl)- 2 ⁇ [[i-(hydroxymethyl)propyl]nitro] -9 ⁇ isopropyl hydrazine derivative was dissolved in DMSO to 20 mM, and diluted to lmM with PBS. Store at -20 °C for later use.
  • DMEM fetal bovine serum
  • Hepatoma cells HepG2 were cultured in a medium containing 10% fetal bovine serum (GIBCO) at 37 ° C in a 5% CO 2 incubator. The cells were observed to have good growth state. After culturing to logarithmic growth phase, the cells were seeded at 8000-10000 cells/well into 96-well cell culture plates, and 75-80% of the cells were overfilled the next day.
  • the compound of formula I i.e., 6-(nitroxymethylmethyl)propyl]amino] ⁇ 9-isopropylindole derivative
  • DMEM fetal bovine serum
  • the compounds of formula I were separately added to a 96-well plate at a concentration gradient of 10 and 20 ⁇ M, three replicate wells were set for each sequence, and a tumor cell control group was established, and cultured at 37 ° C for 2 days. The effect of the compound of formula I on cell morphology was observed under the microscope.
  • the degree of cytopathic effect (expressed as OD450) was measured on a microplate reader (BIO-RAD product, model: 680) using the Cell Counting Kit-8 (DoJinDo product) method, and the tumor inhibition rate of the drug was calculated by the following formula: (OD Tumor cell-OD assay) / OD tumor cell X 100. The test was repeated twice and the average was calculated.
  • Example 7 examines the normal cytotoxic effects of the primary screening compounds 4, 5, 6, 25, 26, 27, 46, 48, 49, 52, 53, 54 on BHK-21 and its CC 5 o
  • the BHK-21 cell culture medium is a DMEM (GIBCO) culture medium containing 7% fetal calf serum. A maintenance solution containing 0.7% fetal bovine serum was used before the addition of the derivative. 6 benzylidene) ⁇ 2 ⁇ [[1-(hydroxymethyl)propyl]nitro]-9-isopropylindole derivative was dissolved in DMSO to 20 mM, and diluted to lmM with DMEM (GIBCO) medium. Store at -20 °C after use.
  • DMEM DMEM
  • BHK-21 cells were plated in a 96-well cell culture plate, which was 75 to 80% over the next day. Replace 75-80% of BHK-21 cells with maintenance solution containing 0.7% fetal bovine serum.
  • the 6 benzylidene) ⁇ 2 ⁇ [[1-(hydroxymethyl)propyl]amino] 9 isopropyl hydrazine derivatives were respectively set up with five concentration gradients of 20, 40, 80, 160, 320 ⁇ , each concentration was established.
  • Three duplicate wells were established, and BHK-21 cells without drug were established as a negative control group. The cells were cultured at 37 °C for 2 days, and 6-(benzylamino)-2-[[1-(hydroxymethyl)propyl] was observed under the microscope.
  • Example 8 Investigating the growth inhibitory effects of compounds 4, 5, 6, 25, 26, 27, 46, 48, 49, 52, 53, 54 on various tumor cells and their half-inhibitory concentration IC 5 o
  • the A549 cell culture medium is a F12K (GIBCO) culture medium containing 10% fetal bovine serum.
  • HepG2, MCF-7, Hela, PLC/PRF/5 cell culture medium is DMEM (GIBCO) medium containing 10% fetal bovine serum.
  • the BT-474 cell culture medium was a RPMI 1640 (GIBCO) culture medium containing 10% fetal bovine serum.
  • the HCT-116 cell culture medium was a MCCOY' 5A (GIBCO) medium containing 10% fetal calf serum.
  • Hep-2 The cell culture medium was a MEM (GIBCO) culture medium containing 10% fetal bovine serum.
  • a maintenance solution of the corresponding 2% fetal calf serum was used before the addition of the derivative.
  • Tumor cells were cultured in a medium containing 10% fetal calf serum (GIBCO) at 37 ° C in a 5% CO 2 incubator. The cells were observed to have good growth state. After culturing to logarithmic growth phase, the cells were seeded at 8000-10000 cells/well into 96-well cell culture plates, and 75-80% of the cells were overfilled the next day. Dilute 6 amino groups of -24[1 hydroxymethyl)propyl]amino]-isopropyl hydrazine derivative to 200 ⁇ M in DMEM.
  • GEBCO fetal calf serum
  • the 6-(benzylidyl)-2-[[i(hydroxymethyl)propyl])yl]-9-isopropylindole derivatives were set to 2.5, 5, 10, 20, 40 ⁇ five concentration gradients.
  • the cells were placed in a 96-well plate, and three replicate wells were set in each sequence, and a tumor cell control group was established, and cultured at 37 ° C for 2 days.
  • Roscovitine i.e. (RHK benzyl-based 2-[[1-(hydroxymethyl)propyl)]] isopropyl] oxime
  • IC 5Q and its therapeutic index TI in the above 7 tumor cells are shown in Table 10. .
  • the TI value is greater than roscovitine:
  • TI values greater than roscovitine:27 in 4 cells Hela, HepG2, MCF-7, PLC/PRF/5)
  • TK ⁇ H7 Anti-phospho Cdc7 T376 Monoclonal Antibody TK-H7
  • the reaction well was sealed with sealing paper, and after incubation for 30 min at 25 ,, the liquid in the well was removed, the plate was washed 5 times, and the kit of ⁇ .1 was added.
  • HRP-conjugated anti-mouse IgG HRP-conjugated Anti-mouse IgG
  • seal the reaction well with sealing tape > 25 V freshly incubated for 30 min, remove the liquid in the well, wash the plate 5 times, add ⁇ color
  • the inhibition rate of the drug to the kinase was calculated by the following formula: (OD solvent control - OD test) / OD solvent control xl 00.
  • the animal model was SPF grade 7-day-old ICR suckling rat, and the EV71 strain was the international standard strain BrCr strain.
  • the positive control drug was IFNa-2a.
  • mice 12 litters of SPF-class 7-day-old ICR suckling mice were ordered and weighed and grouped before the start of the experiment. The mice were each set up with 6-(benzylidene)-2-[[1-(hydroxymethyl)propyl]nitro]isopropyl hydrazine derivatives 4, 5, 25, 26, 27, 48, 49, 52 53 groups, the dose was 4mg/kg/d, and the normal saline control group, EV71 virus infection control group and IFNa-2 a positive drug control group were established.
  • mice that had been grouped, first disinfected with iodophor at one side of the mouse, then disinfected with 75% alcohol, and then injected with the corresponding dose of saline, virus or drug according to body weight.
  • the normal saline control group was injected with five days of normal saline; the virus group was injected with the virus on the first day, and the same dose was administered to the normal saline for the next four days; IFNa- 2a positive drug control group and 6-(benzylidene)-2-
  • a certain amount of EV71 virus was injected according to the body weight, and the drug was injected 1 hour later, and the drug was continuously administered for four days. After 2 weeks of continuous observation, the body weight was weighed daily and the survival rate was calculated.
  • RESULTS The EV71 virus-infected control group began to die at 6 days after virus infection, and the survival rate decreased to 20% on the 14th day after infection. 6 Benzylamino 2-[[1-(hydroxymethyl)propyl]amino]isopropyl
  • the ruthenium-based derivative 4 administration group showed no significant effect, while the derivatives 5, 25, 26, 48, 49, 52, 53, 27 groups showed significant protective effects, and the survival rate on the 14th day after infection. 80%, 100%, 80%, 83,3%, 911%, 81.8%, 100% and 100%, respectively, are above 50% ( Figures 3, 4, 5).
  • the present invention obtains a series of modifications of the groups 2, 6, and 9 in 6-(benzylamino)-2-[[1-(hydroxymethyl)propyl]amino]-9-isopropyl hydrazine. Derivatives. And it has been proved by in vitro and in vivo experiments that it can effectively inhibit the activity of CDK1 and inhibit the growth of various tumor cells, and has a significant anti-EV71 virus effect, which can prevent and/or treat EV71 (intestinal virus type 71) virus ( Human enterovirus 71) Infects and anti-tumor provides new and effective drugs.

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Abstract

L'invention concerne des dérivés de purine 2,6,9-trisubstitués de la formule I et leurs procédé de préparation et utilisation, R1, R2, R3 et R4 étant tels que définis dans la description. Des expériences cellulaires in vitro ont montré que les composés de l'invention peuvent inhiber efficacement la croissance de diverses cellules tumorales, et peuvent être développés en médicaments anticancéreux; des expériences sur les animaux ont prouvé que les composés ont un effet anti-virus EV71 in vivo, et peuvent être développés en médicaments pour le traitement et la prévention d'infections par le virus EV71.
PCT/CN2013/000242 2013-03-08 2013-03-08 Dérivés de purine 2,6,9-trisubstitués et leurs procédé de préparation et utilisation WO2014134750A1 (fr)

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CN201380068392.9A CN104936959B (zh) 2013-03-08 2013-03-08 2,6,9-三取代嘌呤衍生物及其制备方法与应用

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US9879014B2 (en) 2013-07-12 2018-01-30 Kyoto University Method for screening substance capable of inhibiting abnormal splicing causative of onset or progress of disease
CN110256436A (zh) * 2019-06-27 2019-09-20 南京雷正医药科技有限公司 作为Trk激酶抑制剂的嘌呤类化合物
WO2020007698A1 (fr) * 2018-07-06 2020-01-09 Leo Pharma A/S Nouveaux dérivés d'amino-imidazopyrimidine utilisés en tant qu'inhibiteurs de janus kinase et leur utilisation pharmaceutique
WO2021148793A1 (fr) * 2020-01-22 2021-07-29 Cyclacel Limited Procédé de préparation de dérivés de purine présentant une activité inhibitrice de cdk
RU2772463C1 (ru) * 2018-07-06 2022-05-20 Лео Фарма А/С Новые производные аминоимидазопиримидина в качестве ингибиторов janus-киназ и их фармацевтическое применение

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