WO2017211245A1 - Composé de pyrrolopyrimidine substitué et son application - Google Patents

Composé de pyrrolopyrimidine substitué et son application Download PDF

Info

Publication number
WO2017211245A1
WO2017211245A1 PCT/CN2017/087129 CN2017087129W WO2017211245A1 WO 2017211245 A1 WO2017211245 A1 WO 2017211245A1 CN 2017087129 W CN2017087129 W CN 2017087129W WO 2017211245 A1 WO2017211245 A1 WO 2017211245A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
mmol
cancer
pyrrolopyrimidine compound
hydrogen
Prior art date
Application number
PCT/CN2017/087129
Other languages
English (en)
Chinese (zh)
Inventor
王义汉
邢青峰
Original Assignee
深圳市塔吉瑞生物医药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 深圳市塔吉瑞生物医药有限公司 filed Critical 深圳市塔吉瑞生物医药有限公司
Priority to CN201780004353.0A priority Critical patent/CN108290899B/zh
Publication of WO2017211245A1 publication Critical patent/WO2017211245A1/fr

Links

Classifications

    • 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
    • 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
    • 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

  • the invention belongs to the field of medicine.
  • the present invention relates to a substituted pyrrolopyrimidine compound and use thereof, and more particularly to a pyrrolopyrimidine compound and a pharmaceutical composition thereof for use as a CDK inhibitor for the treatment and prevention of diseases associated with CDK inhibitors .
  • Cyclin-dependent kinase is a serine-threonine protein kinase that plays a key role in regulating the transition between different phases of the cell-cycle, such as from the quiescent phase of G1 (mitosis and A new round of cell division begins with a pause in DNA replication to the progression of S (active DNA synthesis), or progression from G2 to M phase, in which active mitosis and cell division occur.
  • CDK complexes regulate the cyclin subunits (eg, cyclin A, B1, B2, D1, D2, D3, and E) and catalytic kinase subunits (eg, CDK1, CDK2, CDK4, CDK5, and CDK6) Formed together.
  • cyclin subunits eg, cyclin A, B1, B2, D1, D2, D3, and E
  • catalytic kinase subunits eg, CDK1, CDK2, CDK4, CDK5, and CDK6
  • CDKs show absolute dependence on cyclin subunits in order to phosphorylate their target substrates, and different kinase/cyclin pairs act to regulate progression through specific phases of the cell-cycle.
  • These protein kinases are a class of proteins (enzymes) that regulate a variety of cellular functions. This is accompanied by phosphorylation of specific amino acids on the protein substrate, resulting in a conformational change in the substrate protein.
  • a conformational change modulates the activity of a substrate or its ability to interact with other binding ligands.
  • the enzymatic activity of a protein kinase refers to the rate at which a kinase adds a phosphate group to a substrate. It can be measured, for example, by measuring the amount of substrate converted to product as a function of time. Phosphorylation of the substrate occurs at the active site of the protein kinase.
  • CDK Crohn's disease .
  • Tumor development is closely related to genetic changes and dysregulation of CDK and its regulatory factors, suggesting that CDK inhibitors may be useful anticancer therapeutics.
  • Early results indicate that transformed cells and normal cells differ in their demand for, for example, cyclin A/CDK2, and it is possible to develop novel antibiotics that lack the general host toxicity observed with conventional cytotoxic drugs and cytostatic drugs. Tumor agent.
  • inhibition of cell cycle-associated CDK is clearly associated with, for example, oncology applications, inhibition of RNA polymerase-regulated CDK can also be highly correlated with cancer indications.
  • CDK has been shown to be involved in cell cycle progression and cellular transcription, and loss of growth control is associated with abnormal cell proliferation of the disease (see, eg, Malumbres and Barbacid, Nat. Rev. Cancer 2001, 1: 222). Increased or transient abnormal activation of cyclin-dependent kinases has been shown to result in the development of human tumors (Sherr C. J., Science 1996, 274: 1672-1677).
  • diseases are associated with abnormal cellular responses triggered by the above protein kinase-mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, metamorphosis Response to asthma, Alzheimer's disease and hormone-related diseases. Therefore, a great deal of efforts have been made in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
  • CDK cyclin-dependent kinase
  • Palbociclib is the first CDK4/6 inhibitor approved by the US FDA for breast cancer treatment. Because all living cells are undergoing cell division, and Palbociclib has the ability to block the cell division process (also known as the "cell cycle"), it has the potential for broad applicability. Palbociclib in combination with other anti-cancer therapies such as endocrine therapy, chemotherapy, and targeted therapies may be effective against a variety of cancers. Clinical trials, whether breast cancer or other cancers, have shown that it is safe to administer Palbociclib once a day. The main side effect is reversible neutropenia, when the count is reduced, side effects should be suspended, and lower doses should be restarted. Medication. Other side effects include fatigue (33%), nausea (30%), diarrhea (18%), constipation (12%), and rash (12%). In addition, Novartis's CDK inhibitor Ribociclib (LEE011) is still in Phase III clinical trials.
  • the present invention discloses a pyrrolopyrimidine compound and a composition comprising the same as an effective cyclin-dependent kinase (CDK) inhibitor and/or with better pharmacodynamics/ Pharmacokinetic properties.
  • CDK cyclin-dependent kinase
  • CDK potent cyclin dependent kinase
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 And R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 and R 27 are each independently selected from the group consisting of “hydrogen (H), ⁇ (D)”;
  • the pyrrolopyrimidine compound contains at least one ruthenium atom.
  • the cerium isotope content of the cerium in the deuterated position is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%.
  • the ground is greater than 95%, more preferably greater than 99%.
  • the osmium isotope content of each of the R 5 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 and R 27 is at least 5%.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 and R 8 are each independently hydrazine or hydrogen.
  • R 9 , R 10 and R 11 are each independently hydrazine or hydrogen.
  • R 12 and R 13 are each independently hydrazine or hydrogen.
  • R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21 are each independently hydrazine or hydrogen.
  • R 22 , R 23 , R 24 , R 25 , R 26 and R 27 are each independently hydrazine or hydrogen.
  • the compound is selected from the group consisting of the compounds or pharmaceutically acceptable salts thereof, but is not limited to the following compounds:
  • the compound does not include a non-deuterated compound and only compounds in which R 22 , R 23 , R 24 , R 25 , R 26 and R 27 are all deuterated.
  • a method of preparing a pharmaceutical composition comprising the steps of: pharmaceutically acceptable carrier and a compound of the first aspect of the invention, or a crystalline form thereof, pharmaceutically acceptable
  • the accepted salt, hydrate or solvate is mixed to form a pharmaceutical composition.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the first aspect of the invention, or a crystalline form thereof, a pharmaceutically acceptable salt, hydrated Or a solvate.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, any glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents A dispersing agent, a disintegrating agent, a suspending agent, a stabilizer, an isotonic agent, a solvent or an emulsifier.
  • the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, coagulation Glues, microspheres and aerosols.
  • Typical routes of administration of the pharmaceutical compositions of the invention include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal , intramuscular, subcutaneous, intravenous administration. Oral administration or injection administration is preferred.
  • the pharmaceutical composition of the present invention can be produced by a method known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a pulverization method, an emulsification method, a freeze-drying method, and the like.
  • the compounds of the invention are useful as inhibitors of cyclin dependent kinases.
  • the compounds of the invention are inhibitors of cyclin-dependent kinases, particularly preferred cyclin-dependent kinases are selected from the group consisting of CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK9, more particularly preferably selected from the group consisting of CDK1, CDK2 CDK3, CDK4, CDK5 and CDK9.
  • CDK plays a role in cell cycle regulation, apoptosis, transcription, differentiation and CNS function.
  • CDK inhibitors are useful in the treatment of diseases with cell proliferation, apoptosis or differentiation disorders such as cancer.
  • RB+ve tumors may be particularly sensitive to CDK inhibitors. These include tumor harboring mutations in ras, Raf, growth factor receptors or overexpression of growth factor receptors. Hypermethylated promoter regions with CDK inhibitors and cyclin-dependent kinase overexpressing cyclin partners additional tumors may also show sensitivity. RB-ve tumors can also be sensitive to CDK inhibitors.
  • cancers examples include, but are not limited to, cancers such as bladder cancer, breast cancer, colon cancer (eg, colorectal cancer such as colon adenocarcinoma and colon adenoma), kidney cancer, epidermal cancer, liver cancer, lung cancer such as adenocarcinoma , small cell lung cancer and non-small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer such as exocrine pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, nasal cancer, head and neck cancer, prostate cancer or skin cancer such as squamous cell carcinoma Lymphoid hematopoietic tumors, such as leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (eg, diffuse large B-cell lymphoma), T-cell lymphoma, multiple myeloma, Hodge Gold lymphoma, non-Hodgkin'
  • cyclin dependent kinase inhibitors of the invention can be used in combination with other anticancer agents.
  • cyclin dependent kinase inhibitors have been used in combination therapy with other anticancer drugs.
  • the use or method of the invention for treating a disease or condition comprising abnormal cell growth in one embodiment is cancer.
  • cancer includes human breast cancer (eg, primary breast tumor, node-negative breast cancer, breast invasive ductal adenocarcinoma, non-endometrioid breast cancer); and mantle cell lymphoma.
  • human breast cancer eg, primary breast tumor, node-negative breast cancer, breast invasive ductal adenocarcinoma, non-endometrioid breast cancer
  • mantle cell lymphoma e.g, primary breast tumor, node-negative breast cancer, breast invasive ductal adenocarcinoma, non-endometrioid breast cancer
  • other cancers are colorectal cancer and endometrial cancer.
  • lymphoid hematopoietic tumors such as leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, and B-cell lymphoma (eg, diffuse large B-cell lymphoma).
  • Another subtype of cancer that may be useful in the treatment of a compound of the invention includes sarcoma, leukemia, glioma, familial melanoma, and melanoma.
  • halogen means F, Cl, Br, and I unless otherwise specified. More preferably, the halogen atom is selected from the group consisting of F, Cl and Br.
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated is used interchangeably with “one or more deuterated”.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • 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, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid; Amino acids such as amino acid, phenylalanine, aspartic acid, and glutamic acid.
  • salts of the compounds of the invention with bases such as alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), ammonium salts (for example lower alkanolammonium).
  • bases such as alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), ammonium salts (for example lower alkanolammonium).
  • Salts and other pharmaceutically acceptable amine salts such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butyl
  • a base amine salt an ethylenediamine salt, a hydroxyethylamine salt, a dihydroxyethylamine salt, a trihydroxyethylamine salt, and an amine salt formed of morpholine, piperazine, and lysine, respectively.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable carrier.
  • the carrier is "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, in a quantity which is not deleterious to the recipient thereof.
  • compositions comprising the compounds are CDK inhibitors and can be used to treat, prevent or ameliorate various CDK related disorders.
  • Pharmaceutical compositions comprising these compounds are useful for treating, preventing, or slowing the progression of the disease or disorder in different therapeutic areas, such as cancer.
  • the beneficial effects of the present invention are that the substituted pyrrolopyrimidine compound disclosed in the present invention and the composition comprising the same have excellent inhibition to CDK and have better pharmacokinetic parameter characteristics. .
  • the dosage can be varied and a long acting formulation can be formed to improve suitability.
  • Replacing a hydrogen atom in a compound with hydrazine can increase the drug concentration of the compound in an animal to improve the efficacy of the drug due to its strontium isotope effect.
  • Substitution of a hydrogen atom in a compound with hydrazine may increase the safety of the compound due to inhibition of certain metabolites.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • Step 4 4-(6-((7-Cyclopentyl-6-dimethylamide-7-H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-pyridin-3-yl) Synthesis of piperazine-2,2,3,3,5,5,6,6-d8-1-carboxylic acid tert-butyl ester (Compound 13).
  • Step 8 4-(6-((7-(Cyclopentyl-3,4-d2)-6-dimethylformamide-7-H-pyrrolo[2,3-d]pyrimidin-2-yl)amino) Synthesis of -pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (Compound 29).
  • Step 5 Synthesis of 2-chloro-N-cyclopentyl-5-(3,3-diethoxypropyl-1-yn-1-yl)pyrimidine-6-d-4-amine (Compound 36) .
  • CDK2/cyclin A CDK4/cyclin D1, CDK6/cyclin D1.
  • the vision-labeled anti-myelin basic protein antibody and the sputum-labeled rabbit-derived antibody were detected by Envision multi-label analyzer.
  • the compound to be tested was diluted threefold, including 10 concentration gradients.
  • the initial concentration of CDK2/cyclin A test compound was 10 uM, and the initial concentration of CDK4/cyclin D1 and CDK6/cyclin D1 test compounds was 1 uM.
  • the standard Lance Ultra method was performed by a 10 microliter enzyme reaction system containing 0.5 nanomolar CDK2/cyclin A protein, 100 nanomolar ULight-MBP polypeptide, and 25 micromolar ATP. They were dissolved in the enzyme buffer.
  • the buffer components were: hydroxyethylpiperazine ethanesulfuric acid solution 50 mM in PH7.5, ethylenediaminetetraacetic acid 1 mM, magnesium chloride 10 mM, 0.01% Brij-35. , dithiothreitol 2 mmol.
  • the OptiPlate 384 well plate was sealed with a top heat seal film TopSeal-A and incubated for 60 minutes at room temperature.
  • the standard Lance Ultra method was performed by a 10 microliter enzyme reaction system containing 1 nanomolar CDK4/cyclin D1 protein, 50 nanomolar ULight-4E-BP1 polypeptide, and 350 micromolar ATP. They were dissolved in the enzyme buffer.
  • the buffer components were: hydroxyethylpiperazine ethanesulfuric acid solution 50 mM in PH7.5, ethylenediaminetetraacetic acid 1 mM, magnesium chloride 10 mM, 0.01% Brij-35. , dithiothreitol 2 mmol.
  • the OptiPlate 384 well plate was sealed with a top heat seal film TopSeal-A and incubated at room temperature for 90 minutes.
  • the standard Lance Ultra method was performed by a 10 microliter enzyme reaction system containing 0.8 nanograms of CDK6/cyclin D1 protein, 50 nanomolar ULight-4E-BP1 polypeptide, and 250 micromolar ATP. They were dissolved in an enzyme buffer, which consisted of 50 mM hydroxyethylpiperazine ethanesulfuric acid solution at pH 7.5, 1 mM ethylenediaminetetraacetic acid, 10 mmol of magnesium chloride, and 0.01% Brij-35. Dithiothreitol 2 mmol. After the reaction was started, the OptiPlate 384 well plate was sealed with a top heat seal film TopSeal-A and incubated at room temperature for 180 minutes.
  • an enzyme buffer which consisted of 50 mM hydroxyethylpiperazine ethanesulfuric acid solution at pH 7.5, 1 mM ethylenediaminetetraacetic acid, 10 mmol of magnesium chloride, and 0.01% Bri
  • the enzyme reaction termination buffer was prepared, and EDTA was dissolved in a 1-fold diluted assay buffer, and the reaction was terminated at room temperature for 5 minutes.
  • Five microliters of the assay mixture (configured with tritiated anti-myelin basic antibody and tritiated rabbit-derived antibody, respectively) was added to the CDK2/cyclin A, CDK4/cyclin D1, and CDK6/cyclin D1 reactions, respectively.
  • the reaction signal was detected using an Envision instrument according to the principle of time-resolved fluorescence resonance energy transfer.
  • the original data is converted to the inhibition rate using the equation (Max-Ratio)/(Max-Min)*100%, and the value of IC50 can be obtained by curve fitting with four parameters.
  • the compound of the present invention exhibited excellent inhibitory activity against CDK4/cyclin D1 and CDK6/cyclin D1, and showed low inhibitory activity against CDK2/cyclin A.
  • the compounds of Examples 4 and 5 have superior inhibitory activity against CDK4/cyclin D1 and CDK6/cyclin D1 than the non-deuterated compound Ribociclib.
  • Cell culture RPMI-1640 medium, fetal bovine serum, antibiotic (Penicillin-Streptomycin)
  • Detection reagent live cell detection kit CellTiter-Glo
  • the amount of ATP directly reflects the number of cells and the state of the cells, and the number of viable cells in the culture is detected by quantitatively measuring ATP.
  • the live cell assay kit uses luciferase as a test substance.
  • the kit uses a stable glow-type signal generated by UltraGlow luciferase. During the luminescence process, luciferase requires the participation of ATP, and the respiration of metabolically active cells. And other life activity processes can produce ATP.
  • the assay plate was analyzed using PE company's Envision.
  • MCF-7 and MDA-MB-436 cells were separately seeded in 384-well plates, MCF-7 assay contained 200 cells per well, and MDA-MB-436 assay contained 600 cells per well. The cell plates were placed in a carbon dioxide incubator for overnight culture.
  • Compounds were transferred to cell plates at a starting concentration of 10 uM.
  • the cell plates were incubated in a carbon dioxide incubator for 6 days.
  • the Promega CellTiter-Glo reagent was added to the cell plate and incubated for 10 minutes at room temperature to stabilize the luminescence signal. Readings were performed using a PerkinElmer Envision multi-label analyzer.
  • the compound of the present invention exhibited excellent inhibitory activity against MCF-7 and MDA-MB-436 cells.
  • the compounds of Examples 4 and 5 have superior inhibitory activity against MCF-7 and MDA-MB-436 cells than the non-deuterated compound Ribociclib. Therefore, the compounds of the present invention are promising as a drug for treating ER-positive, HER2-negative breast cancer.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the metabolic stability of human and rat liver microsomes was evaluated by simultaneously testing the compounds of the present invention and their compounds without deuteration.
  • the half-life and liver intrinsic clearance as indicators of metabolic stability are shown in Table 3.
  • the undeuterated compound Ribociclib was used as a control sample in Table 3.
  • the compounds of the present invention can significantly improve metabolic stability by comparison with the undeuterated compound Ribociclib.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at a later time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
  • the experimental results show that the compound of the present invention has better pharmacokinetics in animals relative to the control compound, and thus has better pharmacodynamics and therapeutic effects.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention porte sur un composé de pyrrolopyrimidine substitué et sur une composition contenant ledit composé, ainsi que sur une application de ce dernier. L'invention porte spécifiquement sur le composé de pyrrolopyrimidine représenté par la formule (I), ou sur une composition pharmaceutique de sa forme cristalline, d'un sel de qualité pharmaceutique, d'un promédicament, d'un stéréoisomère, d'un hydrate ou d'un solvate. Le composé peut être utilisé en tant qu'inhibiteur de kinase dépendante des cyclines (CDK), et peut donc être utilisé en tant que médicament pour traiter des maladies liées aux CDK (telles que le cancer du sein).
PCT/CN2017/087129 2016-06-06 2017-06-05 Composé de pyrrolopyrimidine substitué et son application WO2017211245A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201780004353.0A CN108290899B (zh) 2016-06-06 2017-06-05 一种取代的吡咯并嘧啶化合物及其应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610392792.0 2016-06-06
CN201610392792 2016-06-06

Publications (1)

Publication Number Publication Date
WO2017211245A1 true WO2017211245A1 (fr) 2017-12-14

Family

ID=60577638

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/087129 WO2017211245A1 (fr) 2016-06-06 2017-06-05 Composé de pyrrolopyrimidine substitué et son application

Country Status (2)

Country Link
CN (1) CN108290899B (fr)
WO (1) WO2017211245A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111100128A (zh) * 2018-10-26 2020-05-05 广安凯特制药有限公司 一种瑞博西尼中间产品的合成方法及其中间体化合物
CN111995569A (zh) * 2019-05-27 2020-11-27 成都博腾药业有限公司 一种细胞周期蛋白依赖性激酶抑制剂中间体的制备方法
CN113636973A (zh) * 2021-09-07 2021-11-12 山东铂源药业有限公司 一种4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯的工业化制备方法
CN114957248A (zh) * 2022-05-09 2022-08-30 南开大学 一种吡咯并嘧啶化合物及其制备方法、药物组合物和应用
CN117069663A (zh) * 2023-08-31 2023-11-17 四川维亚本苑生物科技有限公司 一种瑞博西尼中间体v的合成方法及瑞博西尼的合成方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114573591B (zh) * 2022-04-16 2023-04-25 成都施贝康生物医药科技有限公司 一种取代的吡咯并嘧啶化合物及其应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102186856A (zh) * 2008-08-22 2011-09-14 诺瓦提斯公司 作为cdk抑制剂的吡咯并嘧啶化合物
CN103003280A (zh) * 2010-02-19 2013-03-27 诺瓦提斯公司 作为cdk4/6抑制剂的氘化吡咯并嘧啶化合物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015181737A1 (fr) * 2014-05-28 2015-12-03 Piramal Enterprises Limited Association pharmaceutique pour le traitement du cancer

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102186856A (zh) * 2008-08-22 2011-09-14 诺瓦提斯公司 作为cdk抑制剂的吡咯并嘧啶化合物
CN103003280A (zh) * 2010-02-19 2013-03-27 诺瓦提斯公司 作为cdk4/6抑制剂的氘化吡咯并嘧啶化合物

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111100128A (zh) * 2018-10-26 2020-05-05 广安凯特制药有限公司 一种瑞博西尼中间产品的合成方法及其中间体化合物
CN111100128B (zh) * 2018-10-26 2022-09-06 广安凯特制药有限公司 一种瑞博西尼中间产品的合成方法及其中间体化合物
CN111995569A (zh) * 2019-05-27 2020-11-27 成都博腾药业有限公司 一种细胞周期蛋白依赖性激酶抑制剂中间体的制备方法
CN111995569B (zh) * 2019-05-27 2023-12-05 成都博腾药业有限公司 一种细胞周期蛋白依赖性激酶抑制剂中间体的制备方法
CN113636973A (zh) * 2021-09-07 2021-11-12 山东铂源药业有限公司 一种4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯的工业化制备方法
CN114957248A (zh) * 2022-05-09 2022-08-30 南开大学 一种吡咯并嘧啶化合物及其制备方法、药物组合物和应用
CN114957248B (zh) * 2022-05-09 2023-12-29 南开大学 一种吡咯并嘧啶化合物及其制备方法、药物组合物和应用
CN117069663A (zh) * 2023-08-31 2023-11-17 四川维亚本苑生物科技有限公司 一种瑞博西尼中间体v的合成方法及瑞博西尼的合成方法
CN117069663B (zh) * 2023-08-31 2023-12-26 四川维亚本苑生物科技有限公司 一种瑞博西尼中间体v的合成方法及瑞博西尼的合成方法

Also Published As

Publication number Publication date
CN108290899B (zh) 2020-09-18
CN108290899A (zh) 2018-07-17

Similar Documents

Publication Publication Date Title
US10738067B2 (en) Inhibitors of cyclin-dependent kinase 7 (CDK7)
EP3630761B1 (fr) Inhibiteurs de kras g12c et leurs procédés d'utilisation
TWI776835B (zh) 胺基-三唑并吡啶化合物及其在治療癌症中之用途
CN108290899B (zh) 一种取代的吡咯并嘧啶化合物及其应用
AU2017312561B2 (en) Certain chemical entities, compositions, and methods
EP2606051B1 (fr) Composés de pyrrolopyrimidine et leurs utilisations
KR102339228B1 (ko) 특정 화학 물질, 조성물, 및 방법
EP3159340B1 (fr) Inhibiteur de la tyrosine kinase de bruton
WO2018045957A1 (fr) Inhibiteur de cdk4/6, son procédé de préparation et son application
Heinrich et al. Fragment-based discovery of new highly substituted 1 H-pyrrolo [2, 3-b]-and 3 H-imidazolo [4, 5-b]-pyridines as focal adhesion kinase inhibitors
WO2018090939A1 (fr) Composé 8,9-dihydroimidazole [1,2-a] pyrimido [5,4-e] pyrimidine -5 (6h)-cétone
MXPA04010288A (es) Imidazo[1,2-a]pirazin-8-ilaminas, y metodos para su fabricacion y usos.
TWI760005B (zh) 具有大環結構的含氟並雜環衍生物及其用途
AU2011311814A1 (en) Substituted pyridazine carboxamide compounds
KR20210151859A (ko) 카세인 키나아제 1ε 억제제 및 약학 조성물 및 그 응용
EP3865488A1 (fr) Composé macrocyclique servant d'inhibiteur de cdk, son procédé de préparation et son utilisation en médecine
JP2022539259A (ja) キナーゼ阻害剤としてのヘテロ環式化合物
Argyros et al. Design and synthesis of novel 7-aminosubstituted pyrido [2, 3-b] pyrazines exhibiting anti-breast cancer activity
EP3412657B1 (fr) Nouvel inhibiteur irréversible de la tyrosine kinase de bruton
KR20230154436A (ko) 아미노피리미딘 화합물 및 그의 사용 방법
Wu et al. Structure-based discovery of potent inhibitors of Axl: design, synthesis, and biological evaluation
McConnell Identification and Development of Novel TRKA, FLT3, and Dual Aurora B/CSF-1R Kinase Inhibitors
WO2022082056A1 (fr) Schémas posologiques pour inhibiteurs de la kinase 7 dépendante des cyclines (cdk7)
CN117327101A (zh) 取代的杂环化合物
CN115746002A (zh) 一种氘代氮杂吲哚氨基-吡唑甲酰胺类化合物及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17809684

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17809684

Country of ref document: EP

Kind code of ref document: A1