WO2017092413A1 - Composés diaminopyrimidine et composition comprenant ceux-ci - Google Patents

Composés diaminopyrimidine et composition comprenant ceux-ci Download PDF

Info

Publication number
WO2017092413A1
WO2017092413A1 PCT/CN2016/096320 CN2016096320W WO2017092413A1 WO 2017092413 A1 WO2017092413 A1 WO 2017092413A1 CN 2016096320 W CN2016096320 W CN 2016096320W WO 2017092413 A1 WO2017092413 A1 WO 2017092413A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
preparation
pharmaceutical composition
deuterated
Prior art date
Application number
PCT/CN2016/096320
Other languages
English (en)
Chinese (zh)
Inventor
王义汉
李焕银
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
Publication of WO2017092413A1 publication Critical patent/WO2017092413A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a diaminopyrimidine compound and a composition comprising the same.
  • Non-small cell lung cancer accounts for more than 80% of all lung cancers. Only one-third of patients with NSCLC have a chance of surgery. About 70% of patients have a local advanced stage at the time of presentation. Or there is a distant metastasis and the chance of surgery is lost. In this case, drug treatment is particularly important.
  • the anaplastic lymphoma kinase (ALK) gene fusion has recently become an important biomarker for patients with specific NSCLC subgroups, and thus with the corresponding inhibitors.
  • the International Association for the Study of Lung Cancer recommends ALK fusion testing to guide patient screening, and patients with advanced adenocarcinoma who are eligible for ALK inhibitors regardless of gender, race, smoking history, or other clinical risk factors.
  • Fluorescence in situ hybridization FISH with dual-tag separation probes is used to select patients who are eligible for ALK-TKI therapy.
  • FISH Fluorescence in situ hybridization
  • This diagnostic method has been approved by the US FDA and has been used in the study of crizotinib for the treatment of ALK rearranged tumors.
  • Crizotinib is a competitive inhibitor of oral adenosine triphosphate (ATP) that inhibits ALK and MET tyrosine kinases and also inhibits the activity of ROS1 and RON kinases.
  • ATP oral adenosine triphosphate
  • crizotinib has the following side effects: visual impairment, gastrointestinal side effects, and elevated levels of grade 3-4 liver transaminases in 16% of cases.
  • ALK-positive patients inevitably acquire acquired resistance after the initial phase of crizotinib treatment.
  • the present invention discloses a diaminopyrimidine compound and a composition comprising the same which has better ALK kinase inhibitory activity and/or has better pharmacodynamic/pharmacokinetic properties.
  • R 1a , R 1b , R 1c , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6 , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 11 , R 12 , R 13 , R 14a , R 14b , R 14c , R 15 , R 16 , R 17a , R 17b , R 17c , R 18a , R 18b And R 18c , R 19 , R 20 , R 21 and R 22 are each independently hydrogen, deuterium, halogen or trifluoromethyl;
  • R 16 is hydrogen, deuterium, halogen, cyano, unsubstituted C 1 -C 6 alkyl or C 1 -C 6 alkoxy, one or more deuterated or fully deuterated C 1 -C 6 An alkyl or C 1 -C 6 alkoxy group, or one or more halogen-substituted or perhalogen-substituted C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • Additional conditions are R 1a , R 1b , R 1c , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6 , R 7a , R 7b , R 8a , R 8b And R 9a , R 9b , R 10a , R 10b , R 11 , R 12 , R 13 , R 14a , R 14b , R 14c , R 15 , R 16 , R 17a , R 17b , R 17c , R 18a , R At least one of 18b , R 18c , R 19 , R 20 , R 21 and R 22 is deuterated or deuterated.
  • the shape and volume of hydrazine in the drug molecule are substantially the same as hydrogen. If the hydrogen in the drug molecule is selectively replaced with hydrazine, the deuterated drug generally retains its original biological activity and selectivity. At the same time, the inventors have confirmed through experiments that the binding of carbon-germanium bonds is more stable than the combination of carbon-hydrogen bonds, which can directly affect the absorption, distribution, metabolism and excretion of some drugs, thereby improving the efficacy, safety and tolerability of the drugs.
  • the strontium isotope content of strontium at each metamorphic 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%. More preferably greater than 95%, more preferably greater than 99%.
  • ⁇ isotope content in each of the deuterated positions of R 18a , R 18b , R 18c , R 19 , R 20 , R 21 and R 22 is at least 5%, preferably more than 10%, more preferably more than 15%, more preferably More than 20%, more preferably more than 25%, more preferably more than 30%, more preferably more than 35%, more preferably more than 40%,
  • the compound of the formula (I) contains at least one deuterium atom, and the number of deuterium atoms may be any one of 1 to 38.
  • the compound of the formula (I) contains at least one deuterium atom, and the number of deuterium atoms may be any one of 1 to 38.
  • R 1a , R 1b and R 1c are each independently hydrazine or hydrogen.
  • R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a and R 5b are each independently hydrazine or hydrogen.
  • R 6 is deuterium or hydrogen.
  • R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a and R 10b are each independently hydrazine or hydrogen.
  • R 11 , R 12 and R 13 are each independently hydrazine or hydrogen.
  • R 14a, R 14b and R 14c are each independently hydrogen or deuterium.
  • R 17a , R 17b and R 17c are each independently hydrazine or hydrogen.
  • R 18a , R 18b and R 18c are each independently hydrazine or hydrogen.
  • R 19 , R 20 , R 21 and R 22 are each independently hydrazine or hydrogen.
  • R 16 is independently selected from the group consisting of halogen, trifluoromethyl, cyano, one or more deuterated alkyl groups and alkoxy groups.
  • the compound is selected from the group consisting of the compounds or pharmaceutically acceptable salts thereof:
  • the compound does not include a non-deuterated compound.
  • the non-deuterated compound is 5-chloro-N4-(2-(dimethylphosphinyl)phenyl)-N2-(2-methoxy-4-(4- (4-Methylpiperazin-1-yl)-piperidin-1-yl)phenyl)pyrimidine-2,4-diamine.
  • 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.
  • the pharmaceutical composition is an injection, a sachet, a tablet, a pill, a powder or a granule.
  • the pharmaceutical composition further comprises an additional therapeutic agent, which is cancer, cardiovascular disease, inflammation, infection, immune disease, cell proliferative disease, viral disease. , a metabolic disease, or a drug for organ transplantation.
  • an additional therapeutic agent which is cancer, cardiovascular disease, inflammation, infection, immune disease, cell proliferative disease, viral disease. , a metabolic disease, or a drug for organ transplantation.
  • the compound of the first aspect of the invention or a crystal form thereof, or a drug thereof
  • a physiologically acceptable salt, prodrug, stereoisomer, isotopic variation, hydrate or solvate for the preparation of a pharmaceutical composition for inhibiting protease.
  • the pharmaceutical composition is for treating and preventing diseases such as cancer, cell proliferative diseases, inflammation, infection, immune diseases, organ transplantation, viral diseases, cardiovascular diseases or metabolic diseases. .
  • the cancer includes, but is not limited to, lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, Blood cancer, osteosarcoma, melanoma, kidney cancer, stomach cancer, liver cancer, bladder cancer, thyroid cancer or colorectal cancer.
  • the immune disease or inflammation includes, but is not limited to, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gout, asthma, bronchitis, rhinitis, chronic obstructive pulmonary disease, Cystic fibrosis.
  • the cell proliferative disorder refers to lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, blood cancer. , osteosarcoma, melanoma, kidney cancer, stomach cancer, liver cancer, bladder cancer, thyroid cancer or colorectal cancer.
  • the cancer is non-small cell lung cancer.
  • a method of inhibiting a protein kinase such as ALK kinase
  • a disease such as cancer, cell proliferative disease, inflammation, infection, immune disease, organ transplantation, viral disease
  • a method of treating a cardiovascular disease or a metabolic disease comprising the step of administering a compound described in the first aspect of the invention, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvent thereof, to a subject in need of treatment
  • the composition, or the pharmaceutical composition described in the third aspect of the invention comprising the step of administering a compound described in the first aspect of the invention, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvent thereof, to a subject in need of treatment
  • the composition, or the pharmaceutical composition described in the third aspect of the invention comprising the step of administering a compound described in the first aspect of the invention, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvent thereof.
  • 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. In addition, heavier isotopic substitutions such as guanidine, or 2 H, are preferred in certain therapies due to their good metabolic stability, such as increased half-life or reduced dosage in vivo, and therefore may be preferred in certain circumstances. Isotopically labeled compounds can be prepared in a conventional manner by replacing the readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • 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.
  • C 1 -C 6 alkyl means a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, unless otherwise specified. Butyl, isobutyl, tert-butyl, or the like.
  • 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%).
  • pharmaceutically acceptable salts include inorganic salts 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 beneficial effects of the present invention are: the compound of the present invention has excellent inhibitory effect on a protein kinase (for example, ALK kinase); the technology of sputum is used to change the metabolism of the compound in the organism, so that The compounds have better pharmacokinetic parameter properties.
  • the dosage can be changed and a long-acting preparation can be formed to improve the applicability; replacing the hydrogen atom in the compound with hydrazine can increase the drug concentration of the compound in the animal due to its strontium isotope effect, thereby improving the therapeutic effect;
  • the substitution of a hydrogen atom in a compound by hydrazine may increase the safety of the compound due to inhibition of certain metabolites.
  • the preparation of the unsubstituted diaminopyrimidine compound and its physiologically compatible salt used in the present invention is known.
  • the preparation of the diaminopyrimidine compound corresponding to the deuterated can be carried out by the same route using the corresponding deuterated starting compound as a starting material.
  • the compound of the formula (I) of the present invention can be produced according to the preparation method described in WO2012061299, except that the non-deuterated raw material is replaced with a deuterated raw material in the reaction.
  • 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.
  • Compound 32 was prepared in the same manner as in the preparation of Compound 29 except that Compound 31 was used instead of Compound 26, and formaldehyde was substituted for deuterated formaldehyde, and sodium nitrile borohydride was used instead of sodium deuterated borohydride.
  • the target product was finally obtained as a white solid, 40 mg in total, yield 53.0%.
  • the compounds of the invention were evaluated in a number of tests to determine their biological activity.
  • Test compounds were dissolved in DMSO to make a 20 mM stock solution. Compounds were diluted to 0.1 mM in DMSO (100 times the final concentration of the dilution) before use and diluted in 3 folds at 11 concentrations. Dilute to 4 times the final concentration of the dilution solution with the buffer.
  • the compound of the present invention exhibited excellent inhibitory activity against the ALK L1196M mutant (IC 50 less than 20 nM) as compared with the existing ALK inhibitor crizotinib, indicating that the compound of the present invention is highly potent against ALK. Inhibition ability.
  • the inhibitory effects of the compounds of Examples 1 to 10 on tumor cells were examined by the tetrazolium salt (MTS) method, and crizotinib was used as a control.
  • the experimental results are shown in Table 2.
  • the compounds of the present invention all exhibited excellent anticancer activity against the growth of the ALK mutant L1196M cancer cells.
  • 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 comparing the compounds of the present invention and their compounds without deuteration.
  • the half-life and liver intrinsic clearance (Clint) as indicators of metabolic stability are shown in Table 3.
  • the undeuterated compound AP26113 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 AP26113, and are thus more suitable for the preparation of metastatic ALK-positive non-small cells for the treatment of crizotinib tolerance.
  • Drugs for lung cancer were used as a control sample in Table 3.
  • Rats Six male Sprague-Dawley rats, 7-8 weeks old, weighing 210 g, divided into 2 groups, 3 in each group, intravenously or orally administered a single dose of compound (3 mg/kg intravenously, 10 mg/kg orally). Its pharmacokinetic differences. 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, the rats were anesthetized with ether and sacrificed. Immediately after the blood sample is collected, gently invert the tube at least 5 times to ensure adequate mixing and place on ice. Blood 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 to indicate the name and time point 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Hematology (AREA)
  • Transplantation (AREA)
  • Obesity (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés diaminopyrimidine tels que présentés dans la formule (I), et une composition pharmaceutique comprenant lesdits composés ou une forme cristalline, un sel pharmaceutiquement acceptable, un hydrate ou un solvate, un stéréo-isomère, un promédicament ou une variante isotopique de ceux-ci. Les composés diaminopyrimidine et la composition comprenant lesdits composés présentent un excellent effet inhibiteur contre les protéines kinases. Ils présentent également de meilleures caractéristiques de paramètres pharmacocinétiques, ce qui permet d'augmenter la concentration en médicament des composés dans le corps d'un animal et d'améliorer l'efficacité et la sécurité des médicaments.
PCT/CN2016/096320 2015-12-02 2016-08-23 Composés diaminopyrimidine et composition comprenant ceux-ci WO2017092413A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201510875506.1 2015-12-02
CN201510875506 2015-12-02
CN201610587472.0 2016-07-22
CN201610587472.0A CN106188138B (zh) 2015-12-02 2016-07-22 一种二氨基嘧啶化合物及包含该化合物的组合物

Publications (1)

Publication Number Publication Date
WO2017092413A1 true WO2017092413A1 (fr) 2017-06-08

Family

ID=57491836

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/096320 WO2017092413A1 (fr) 2015-12-02 2016-08-23 Composés diaminopyrimidine et composition comprenant ceux-ci

Country Status (2)

Country Link
CN (3) CN108948082A (fr)
WO (1) WO2017092413A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11530218B2 (en) 2020-01-20 2022-12-20 Incyte Corporation Spiro compounds as inhibitors of KRAS
US11739102B2 (en) 2020-05-13 2023-08-29 Incyte Corporation Fused pyrimidine compounds as KRAS inhibitors
US11767320B2 (en) 2020-10-02 2023-09-26 Incyte Corporation Bicyclic dione compounds as inhibitors of KRAS
US11939328B2 (en) 2021-10-14 2024-03-26 Incyte Corporation Quinoline compounds as inhibitors of KRAS
US11999752B2 (en) 2020-08-28 2024-06-04 Incyte Corporation Vinyl imidazole compounds as inhibitors of KRAS
US12030884B2 (en) 2022-09-30 2024-07-09 Incyte Corporation Pyrazoloquinoline KRAS inhibitors

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3381925B1 (fr) * 2015-11-27 2020-12-16 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Dérivés de brigatinib modifiés par deutérium, compositions pharmaceutiques les contenant et utilisation correspondante
CN106220608B (zh) 2016-07-25 2018-11-27 安润医药科技（苏州）有限公司 二苯氨基嘧啶及三嗪化合物、其药用组合物及用途
WO2019007293A1 (fr) * 2017-07-01 2019-01-10 浙江同源康医药股份有限公司 Composé utilisé comme inhibiteur de la kinase alk et son utilisation
WO2019134573A1 (fr) * 2018-01-04 2019-07-11 深圳市塔吉瑞生物医药有限公司 Procédé de préparation d'un composé de diphénylaminopyrimidine deutéré et forme cristalline de celui-ci
CN109851638B (zh) * 2018-02-07 2022-05-31 深圳市塔吉瑞生物医药有限公司 取代的二氨基嘧啶化合物
US20230026840A1 (en) * 2019-11-21 2023-01-26 Tyk Medicines, Inc. Compound used as egfr kinase inhibitor and use thereof
WO2024083182A1 (fr) * 2022-10-20 2024-04-25 西藏海思科制药有限公司 Procédé de préparation d'un dérivé phosphonyle

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009045476A1 (fr) * 2007-10-02 2009-04-09 Concert Pharmaceuticals, Inc. Dérivés de pyrimidinedione
WO2009143389A1 (fr) * 2008-05-21 2009-11-26 Ariad Pharmaceuticals, Inc. Dérivés phosphorés servant d'inhibiteurs de kinase

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014100431A1 (fr) * 2012-12-20 2014-06-26 Concert Pharmaceuticals, Inc. Inhibiteurs alk deutérés
CN103965114B (zh) * 2013-01-28 2016-01-06 苏州泽璟生物制药有限公司 氘代的苯基氨基嘧啶化合物以及包含该化合物的药物组合物
CN104109149B (zh) * 2013-04-22 2018-09-28 苏州泽璟生物制药有限公司 氘代的二氨基嘧啶化合物以及包含该化合物的药物组合物
CN104327053A (zh) * 2014-08-06 2015-02-04 北京凯悦宁医药科技有限公司 氘代克里唑蒂尼及其衍生物、制备方法及应用
CN111170998B (zh) * 2014-11-05 2023-04-11 益方生物科技(上海)股份有限公司 嘧啶或吡啶类化合物、其制备方法和医药用途
CN105061506B (zh) * 2015-07-27 2017-08-29 苏州明锐医药科技有限公司 抗肿瘤药物ap26113的制备方法
EP3381925B1 (fr) * 2015-11-27 2020-12-16 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Dérivés de brigatinib modifiés par deutérium, compositions pharmaceutiques les contenant et utilisation correspondante

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009045476A1 (fr) * 2007-10-02 2009-04-09 Concert Pharmaceuticals, Inc. Dérivés de pyrimidinedione
WO2009143389A1 (fr) * 2008-05-21 2009-11-26 Ariad Pharmaceuticals, Inc. Dérivés phosphorés servant d'inhibiteurs de kinase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ALLA, KATSNELSON.: "Heavy drugs draw heavy interest from pharma backers", NATURE MEDICINE, vol. 19, no. 6, 30 June 2013 (2013-06-30), pages 656, XP055387255 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11530218B2 (en) 2020-01-20 2022-12-20 Incyte Corporation Spiro compounds as inhibitors of KRAS
US11739102B2 (en) 2020-05-13 2023-08-29 Incyte Corporation Fused pyrimidine compounds as KRAS inhibitors
US11999752B2 (en) 2020-08-28 2024-06-04 Incyte Corporation Vinyl imidazole compounds as inhibitors of KRAS
US11767320B2 (en) 2020-10-02 2023-09-26 Incyte Corporation Bicyclic dione compounds as inhibitors of KRAS
US11939328B2 (en) 2021-10-14 2024-03-26 Incyte Corporation Quinoline compounds as inhibitors of KRAS
US12030883B2 (en) 2022-09-20 2024-07-09 Incyte Corporation Hetero-tricyclic compounds as inhibitors of KRAS
US12030884B2 (en) 2022-09-30 2024-07-09 Incyte Corporation Pyrazoloquinoline KRAS inhibitors

Also Published As

Publication number Publication date
CN108948082A (zh) 2018-12-07
CN106188138B (zh) 2018-07-24
CN106188138A (zh) 2016-12-07
CN113912648A (zh) 2022-01-11

Similar Documents

Publication Publication Date Title
WO2017092413A1 (fr) Composés diaminopyrimidine et composition comprenant ceux-ci
JP7383652B2 (ja) Ｂ－ｒａｆキナーゼのマレイン酸塩、結晶形、調整方法、及びその使用
TWI585088B (zh) 作爲激酶抑制劑之咪唑并［１，２－ｂ］嗒衍生物
EP3873477A1 (fr) Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)
US10822334B2 (en) ErbB receptor inhibitors
US20220227729A1 (en) Identification and use of kras inhibitors
CN103732596A (zh) 新的吡咯并嘧啶衍生物
CN113453681A (zh) 经取代的3-((3-氨基苯基)氨基)哌啶-2，6-二酮化合物、其组合物及使用它们的治疗方法
WO2020114388A1 (fr) Composé pyrazolo[1,5-a]pyridine substitué, composition le contenant et utilisation associée
KR20160140739A (ko) 마크로사이클릭 피리미딘 유도체
BR112015017963B1 (pt) Composto de fenil amino pirimidina deuterado, método para preparar a composição farmacêutica, composição farmacêutica e uso do composto
WO2022166570A1 (fr) Composés pour induire simultanément la dégradation de protéines egfr et parp, leur procédé de préparation et leur utilisation
BR112013008523B1 (pt) Compostos de piridazina carboxamida substituídos e usos dos mesmos para tratar câncer, uma doença de proliferação, uma doença neurológica, uma doença psiquiátrica, obesidade, diabetes ou doença cardiovascular
JP2020506171A (ja) Ｊａｋ１選択的阻害剤
JP2019526605A (ja) 置換２−ｈ−ピラゾール誘導体の結晶形、塩型及びその製造方法
JP7201800B2 (ja) Ｆｌｔ３およびａｘｌの阻害剤としての３，９－ジアザスピロ［５，５］ウンデカン系化合物
CN110903283B (zh) 一种取代的喹唑啉类化合物、包含该化合物的药物组合物和该化合物的用途
WO2021129841A1 (fr) Composé utilisé comme inhibiteur de kinase ret et son application
WO2020098716A1 (fr) Inhibiteur de la tyrosine kinase de bruton
JP2023036957A (ja) ジアリールピラゾール化合物、該化合物を含む組成物およびその使用
CN118176195A (zh) 吡唑[3,4-d]嘧啶-3-酮类化合物及其医药用途
ES2904513T3 (es) 1,4-Benzodiazepinas biheteroarilo sustituidas y usos de las mismas para el tratamiento del cáncer
WO2019096112A1 (fr) Composé de benzimidazole substitué et composition le comprenant
US20240140947A1 (en) Compound for the treatment of cancer
JP7053654B2 (ja) ＰＩ３Ｋβ阻害剤としてのキノキサリン及びピリドピラジン誘導体

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: 16869724

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: 16869724

Country of ref document: EP

Kind code of ref document: A1