WO2015188681A1 - Nouveau composé hétérocyclique et procédé de préparation correspondant et utilisation de ce composé comme inhibiteur de kinase - Google Patents

Nouveau composé hétérocyclique et procédé de préparation correspondant et utilisation de ce composé comme inhibiteur de kinase Download PDF

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WO2015188681A1
WO2015188681A1 PCT/CN2015/079384 CN2015079384W WO2015188681A1 WO 2015188681 A1 WO2015188681 A1 WO 2015188681A1 CN 2015079384 W CN2015079384 W CN 2015079384W WO 2015188681 A1 WO2015188681 A1 WO 2015188681A1
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compound
kinase
alkane
preparation
pharmaceutically acceptable
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PCT/CN2015/079384
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English (en)
Chinese (zh)
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江磊
耿美玉
丁健
刘磊
黄敏
查传涛
艾菁
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上海海和药物研究开发有限公司
中国科学院上海药物研究所
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Publication of WO2015188681A1 publication Critical patent/WO2015188681A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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

Definitions

  • Tyrosine kinase plays a very important role in the occurrence and development of tumors, and an important one is the non-receptor tyrosine kinase JAK.
  • the JAK family has four members, JAK1, JAK2, JAK3, and TYK2. At present, the correlation between JAK family members and tumors is most detailed and clear. Abnormal activation of JAK2 signaling pathway is most closely related to tumorigenesis and development. Early studies focused on the role of JAK2 gene fusion, amplification and mutation in a variety of abnormal activation forms in hematological tumors.
  • JAK2V617F the 617th proline mutation in phenyl kinase on the pseudokinase domain JH2
  • This mutation causes JAK2 to lose its self-inhibiting function, causing downstream Excessive activation of the signal eventually leads to malignant transformation of the cell.
  • Clinical data indicate that the incidence of this mutation in polycythemia vera, thrombocytopenia, and primary myelofibrosis is 81% to 99%, 41% to 72%, and 39% to 57%, respectively (SzpurkaH et al., Refractory anemia).
  • JAK2/STAT myeloproliferative condition characterized by JAK2V617F mutation
  • RARS-T ringedsideroblasts associated with marked thrombocytosis
  • JAK2V617F mutation another myeloproliferative condition characterized by JAK2V617F mutation [J].
  • RARS-T ringedsideroblasts associated with marked thrombocytosis
  • JAK2/STAT pathway may also play an important role in solid tumors, such as the pro-inflammatory cytokine IL-6, and also as an independent risk factor in liver cancer, mediated by STAT activation.
  • the signaling pathway plays a very important role.
  • IL-6 can only function by forming IL-6/IL-6R/gp130 complex with its receptor, and one of the most important downstream of gp130 is JAK2/STAT.
  • JAK small molecule inhibitors At present, there are more than 10 kinds of targeted JAK small molecule inhibitors at different stages of clinical research, most of which are selective inhibitors of JAK1 and JAK2.
  • the indications are mainly blood system related tumors and a small number of solid tumors.
  • the study found that the drug treatment can improve systemic symptoms such as splenomegaly associated with myeloproliferative neoplasms, but does not significantly reduce or eliminate tumor clones in most patients.
  • the drug has the characteristics of rapid absorption and high efficiency in metabolism, resulting in low bioavailability in patients.
  • R is a C1-C6 linear or branched alkane, a halogenated C1-C6 linear alkane or a branched alkane or a halogen;
  • A is H or CH 3 ;
  • X and Y are each independently selected from: N, CH or C-CH 3 ;
  • Z is N, CH or CX, wherein X is a halogen.
  • R is a C1-C4 linear alkane or a C1-C6 branched alkane, a halogenated C1-C4 linear alkane or a halogenated C1-C6 branched alkane, or a halogen.
  • the stereoisomer of the compound is as shown in Formula 1a,
  • R is a C1-C4 linear alkane or a C1-C6 branched alkane, a halogenated C1-C4 linear alkane or a halogenated C1-C6 branched alkane, a halogen;
  • A is H or CH 3 ;
  • X and Y are each independently selected from: N, CH or C-CH 3 ;
  • Z is N, CH or CX, wherein X is a halogen.
  • R, A, X, Y, and Z are as defined above.
  • the chiral separation step is also included:
  • R, A, X, Y, and Z are as defined above.
  • a pharmaceutical composition comprising (a) an active ingredient: a compound according to the first aspect of the invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; (b) a pharmaceutically acceptable carrier.
  • a compound according to the first aspect of the invention or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the invention
  • a pharmaceutical composition according to the third aspect of the invention for the preparation of kinase inhibitors or for the preparation of anti-tumor drugs.
  • the kinase is a tyrosine kinase.
  • the kinase is JAK2.
  • C1-C6 linear or branched alkane means a straight or branched alkane having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl. , isobutyl, tert-butyl, pentyl and the like.
  • halogenated means fluoro, chloro, bromo, iodo.
  • halogen means fluoro, chloro, bromo, iodo.
  • compound of the invention refers to a compound of formula 1.
  • the term also encompasses various stereoisomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of Formula 1.
  • the term "pharmaceutically acceptable salt” refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
  • the preparation method of the structural compound of the formula 1 of the present invention is more specifically described below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.
  • a particularly preferred preparation process is as follows:
  • R, A, X, Y, and Z are as defined above.
  • the method can also include the following chiral separation steps:
  • the compound of the present invention has an excellent inhibitory activity against a tyrosine kinase such as JAK2, the compound of the present invention and a stereoisomer thereof, or a pharmaceutically acceptable inorganic or organic salt, etc., and a compound containing the present invention are main active ingredients.
  • the pharmaceutical composition can be used to treat, prevent, and alleviate diseases mediated by tyrosine kinases.
  • the compounds of the invention are useful in the treatment of diseases such as cancer and the like.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 100 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) a humectant such as glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, For example, paraffin wax; (f) absorption accelerator, for example, quaternary amine compound; (g) wetting agent such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 10 to 100 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the compound of the present invention greatly enhances the metabolic stability of the drug, and the exposure amount (AUC) in the animal is increased by 3-5 times, and the half life is also significantly prolonged. We have reached our research expectations to improve its stability.
  • the enzyme activity reaction experiment is based on the principle of fluorescence resonance energy transfer (FRET) with one donor fluorescence at each end.
  • FRET fluorescence resonance energy transfer
  • the enzymatic reaction substrate of the group and a receptor fluorophore can be phosphorylated by the combination of ATP and kinase, and the substrate is protected from substrate enzyme A, thereby realizing fluorescence resonance energy transfer and adding an inhibitor. After that, the phenomenon is reduced.
  • the reagents used in this experiment are as follows:
  • Enzyme reaction substrate initial concentration of 1 mM, the tyrosine residue on the polypeptide can be phosphorylated by the combination of kinase and ATP; purchased from Invitrogen;
  • 100% phosphorylated substrate initial concentration of 1 mM, the tyrosine residue on the polypeptide has been completely phosphorylated; purchased from Invitrogen;
  • Reaction buffer containing 250 mM HEPES (pH 7.5), 50 mM MgCl 2 , 5 mM EGTA, 0.05% Brij-35; purchased from Invitrogen;
  • Substrate enzyme A the enzyme reaction substrate which is not phosphorylated can be digested; purchased from Invitrogen;
  • Stop solution purchased from Invitrogen.
  • the specific steps of the experiment are summarized as follows: the enzyme reaction substrate, 100% phosphorylated substrate, reaction buffer, ATP, substrate enzyme A, and stop solution were separately equilibrated to room temperature.
  • the JAK kinase domain recombinant proteins JAK1, JAK2JH1JH2, JAK2JH1JH2V617F, JAK3 purchased from Invitrogen
  • the JAK kinase domain recombinant proteins JAK1, JAK2JH1JH2, JAK2JH1JH2V617F, JAK3 purchased from Invitrogen
  • a black 384-well microplate (PerkinElmer) was used, and 2.5 ⁇ L of the enzyme reaction substrate diluted with the reaction buffer was added to each well to a final concentration of 2 ⁇ M.
  • the test compound (compound prepared in the examples of the present invention) was diluted to a suitable concentration with 4% DMSO (the initial concentration was generally set to 3 ⁇ M, diluted to a concentration gradient of 1/3 to 9 concentration gradients), and 2.5 ⁇ L was added per well. Add ATP solution diluted in the reaction buffer to each well.
  • the final concentration corresponds to JAK1, JAK2JH1JH2, JAK2JH1JH2V617F, and JAK3, respectively, 75 ⁇ M, 50 ⁇ M, 50 ⁇ M, 10 ⁇ M, and then add 2.5 ⁇ L of the JAK kinase domain recombinant protein diluted in the reaction buffer to start the reaction.
  • a 0% phosphorylation control group, a 100% phosphorylation control group, and a 0% inhibition control group were required.
  • Each reaction group is defined as follows:
  • 0% phosphorylation control group contains enzyme reaction substrate, ATP, but does not add kinase, or contains enzyme reaction substrate, kinase, but does not add ATP, that is, the control well ensures that the enzyme reaction substrate is not phosphorylated, can be Substrate enzyme A is completely digested;
  • 100% phosphorylation control group 100% phosphorylated substrate was added, that is, without the addition of kinase and ATP, the control group ensured that the substrate was completely phosphorylated and could not be digested by substrate enzyme A;
  • 0% inhibition control group containing enzyme reaction substrate, kinase, ATP, inhibitor solvent, but no inhibitor, the control group is used to indicate that the degree of phosphorylation of the substrate is linear in the kinase reaction system, it is recommended Between 20 and 50%;
  • the shaker plate was mixed for 1 minute, and the reaction was allowed to stand at 27 ° C for 1 hour in the dark. After the reaction is completed, all reactions are completed 5 ⁇ l of substrate enzyme A diluted with the reaction buffer was added to the well, and the dilution ratio was 1:1067. After the addition was completed, the vibrating plate was mixed for 1 minute, and the reaction was allowed to stand at 27 ° C for 1 hour in the dark. Finally, 5 ⁇ l of the stop solution was added to all wells to terminate the reaction. After the shaker was mixed, the fluorescence signal was detected by Synergy 2 Microplate Reader (BioTec) (excitation light wavelength was 400 nm, emission wavelength was 445 nm, 520 nm).
  • the inhibition rate of each well was calculated from the fully active pores and the background signal wells.
  • the data analysis method is as follows:
  • Emission ratio signal intensity of the donor fluorophore (at a wavelength of 445 nm) / signal intensity of the acceptor fluorophore (at a wavelength of 520 nm)
  • Percent phosphorylation 100 ⁇ ⁇ 1 - (emission ratio * signal intensity of the acceptor fluorophore of the 100% phosphorylated control group - signal intensity of the donor fluorophore of the 100% phosphorylated control group) / [0% phosphoric acid Signal intensity of the donor fluorophore in the control group - signal intensity + emission ratio of the donor fluorophore in the 100% phosphorylated control group ⁇ (signal intensity of the acceptor fluorophore in the 100% phosphorylated control group - 0 The signal intensity of the acceptor fluorophore in the % phosphorylation control group)] ⁇
  • Inhibition rate 100 ⁇ (1 - % phosphorylation in test compound group / 0% inhibition of phosphorylation in control group))
  • Test method The inhibitory effect of the compound on BaF3 (mouse pre-B cells) and HEL (human erythroleukemia cells) was examined by a CCK-8 cell counting kit (purchased from Dojindo).
  • the specific steps are as follows: BaF3 and HEL cells in logarithmic growth phase are inoculated into 96-well culture plates at a suitable density (10,000/well) at 90 ⁇ L per well. After 12 hours of culture, different concentrations are added (the initial concentration is generally set). 10 ⁇ L of the test compound (the compound prepared in the Example of the present invention) diluted to a concentration gradient of 50 ⁇ in a ratio of 1/3 was subjected to a reaction for 72 hours, and a solvent control group (negative control) was set. After 72 hours of treatment with the compound, the effect of the compound on cell proliferation was detected by CCK-8 cell counting kit.
  • the inhibition rate of the drug on tumor cell growth was calculated according to the following formula:
  • Inhibition rate (%) (OD control well-OD administration well) / OD control well ⁇ 100%.
  • IC 50 Compound Molecular level activity
  • BaF3, IC 50 Cell level activity 14 ⁇ 100nM ⁇ 500nM 15 ⁇ 100nM ⁇ 500nM 16 ⁇ 100nM 500-10000nM 20 100-500nM N/A twenty four ⁇ 100nM 500-10000nM 25 100-500nM 500-10000nM 26 500-10000nM N/A
  • N/A means not determined.
  • Test method 14 SD rats, males, weighing 200-220 g, were randomly divided into 4 groups, 4/3 each, and the positive compounds Ruxolitinib and Compound 15 were administered by gavage and intravenous administration respectively. Rats were fasted for 12 h before the test, free to drink water, and formulated with 5% DMSO / 5% Tween 80 / 90% 0.5% CMC-Na. The dose of intragastric administration was 50 mg/kg, the dose of intravenous administration was 10 mg/kg, and the rats were fed uniformly 2 hours after administration.
  • the intragastric administration group collected blood at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after administration, and the intravenous administration group was 5 min after administration, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and Blood was collected for 24 hours, 0.3 ml of venous blood was taken from the posterior venous plexus of the rat, and placed in a heparinized test tube, centrifuged at 11,000 rpm for 5 min, and the plasma was separated and frozen in a refrigerator at -20 °C. The concentration of the drug in the plasma sample was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • the plasma sample was separated by protein precipitation and separated by C18 column.
  • TSQ Quantum Ultra triple quadrupole mass spectrometer purchased from Thermo
  • the ion source is a heated electrospray ionization (HESI) source, positive ion detection.
  • HESI heated electrospray ionization
  • the pharmacokinetic parameters after administration were calculated using a non-compartmental model of Phoenix 1.3 software (purchased from Pharsight, USA).
  • the experimental results of the intragastric administration group are shown in Table 2 below, and the experimental results of the intravenous administration group are shown in Table 3.

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Abstract

L'invention concerne un composé ayant la structure représentée par la formule 1 et un procédé de préparation correspondant. Ce composé constitue un inhibiteur de kinase efficace et possède une biodisponibilité sensiblement élevée.
PCT/CN2015/079384 2014-06-09 2015-05-20 Nouveau composé hétérocyclique et procédé de préparation correspondant et utilisation de ce composé comme inhibiteur de kinase WO2015188681A1 (fr)

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CN201410250746.8A CN105218548A (zh) 2014-06-09 2014-06-09 一种新型杂环化合物及其制备方法和作为激酶抑制剂的用途
CN201410250746.8 2014-06-09

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EP3235819A4 (fr) * 2014-12-16 2017-11-01 Centaurus BioPharma Co., Ltd. Composé de pyrrolopyrimidine
JP2019521980A (ja) * 2016-06-16 2019-08-08 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッドChia Tai Tianqing Pharmaceutical Group Co., Ltd. Ｊａｋ阻害剤としてのピロロピリミジン化合物の結晶
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WO2019057103A1 (fr) * 2017-09-21 2019-03-28 上海华汇拓医药科技有限公司 Inhibiteur de jak, procédé de préparation de celui-ci et application dans le domaine de la médecine
CN115028638A (zh) * 2022-06-09 2022-09-09 安徽大学 一种鲁索替尼中间体的制备方法

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EP3235819A4 (fr) * 2014-12-16 2017-11-01 Centaurus BioPharma Co., Ltd. Composé de pyrrolopyrimidine
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JP2019521980A (ja) * 2016-06-16 2019-08-08 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッドChia Tai Tianqing Pharmaceutical Group Co., Ltd. Ｊａｋ阻害剤としてのピロロピリミジン化合物の結晶
WO2020215094A1 (fr) 2019-04-18 2020-10-22 The Johns Hopkins University Dérivés de 2-amino-pyrazolyl-[1,2,4]triazolo[1,5 a] pyridine substitués et leur utilisation

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