CN107344925B - Deuterated diphenylamino-trifluoromethylpyrimidine compounds - Google Patents
Deuterated diphenylamino-trifluoromethylpyrimidine compounds Download PDFInfo
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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Abstract
The invention belongs to the field of medicines, and relates to a deuterated diphenylamino-trifluoromethylpyrimidine compound or a pharmaceutically acceptable salt thereof, in particular to a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition thereof and application thereof in treating cell proliferative diseases.
Description
Technical Field
The invention belongs to the field of medicines, and relates to a deuterated diphenylamino-trifluoromethylpyrimidine compound or a pharmaceutically acceptable salt thereof, in particular to a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition thereof and application thereof in treating cell proliferative diseases.
Background
Lung cancer is a serious disease seriously threatening human health, is one of the most common malignant tumors in the world, and has become the 1st cause of death of malignant tumors in urban population in China. Non-small cell lung cancer (NSCLC) accounts for over 85% of all types of lung cancer. EGFR (Epidermal Growth Factor Receptor) is a Receptor for cell proliferation and signaling of the Epithelial Growth Factor (EGF), also known as HER1, erbB1.EGFR belongs to the ErbB receptor family, which includes EGFR (ErbB-1), HER2/c-neu (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4). EGFR is a glycoprotein belonging to tyrosine kinase type receptor, and has a penetrating cell membrane and a molecular weight of 170KDa.
EGFR inhibitors Iressa (Gefinitib) and Tarceva (Erlotinib) have been used with great success in the clinical treatment of patients with non-small cell lung cancer, but the resistance problem is also increasing, and the main reason for the resistance is EGFR-T790M mutation, which accounts for about 50% of the total number of patients with drug resistance. At present, second-generation EGFR (epidermal growth factor receptor) irreversible inhibitors (Canertinib, afatinib, neratinib, pelitinib and the like) enter clinical tests, but the selectivity of the molecules to EGFR-T790M mutant is poor, so that the clinical tolerance dose of the drug is low, and the drug cannot reach the effective concentration in vivo under the maximum tolerance dose, so that the drug is ineffective for most drug-resistant patients. Most clinical trials have also been forced to terminate. In addition, rash and diarrhea are the most significant toxic side effects caused by wt-EGFR inhibitors. Therefore, the development of EGFR-T790M mutant inhibitors with high specificity has become an important strategy for solving the current drug resistance problem.
5/20/2014, clovis tumor Inc. (Clovis Oncology) announced that the US FDA granted its test drug Rocilletinib (CO-1686, AVL-301) a breakthrough treatment drug eligibility as a single-drug second line for the treatment of EGFR mutant non-small cell lung cancer (NSCLC) in T790M mutant patients.
CO-1686 is useful for treating EGFR mutant NSCLC that selectively inhibits T790M mutant EGFR while sparing wild-type EGFR signaling. The drug was developed for treatment of NSCLC patients carrying the initial activation of mutant EGFR and T790M mutant EGFR, all at different dose levels showing good response and long-lasting benefit.
The deuterium modification is a novel drug development technology with great potential for improving the metabolic property of the drug. In this method, it is sought to slow CYP-mediated drug metabolism or reduce the production of undesirable metabolites by substituting one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope that can form a stronger bond with carbon than hydrogen. In some cases, the increased bond strength formed by deuterium can positively affect the ADME properties of a drug, and as a result, it is possible to significantly prolong its drug metabolic cycle, reduce the production of toxic metabolites and drug-drug interactions, increase safety, and achieve better therapeutic efficacy.
Even if deuterium atoms are incorporated at known metabolic positions, the effect of deuterium modification on the metabolic properties of a drug is still unpredictable. Therefore, the practical preparation and testing of deuterated molecules must be carried out to determine the metabolic difference between deuterated and non-deuterated drugs.
Although CO-1686 is effective against the T790M resistant mutation while inhibiting wt-EGFR little and without associated dose limiting toxicity, it is challenging to find novel compounds with good oral bioavailability and druggability for the treatment of cell proliferative diseases (such as non-small cell lung cancer).
Accordingly, there remains a need in the art to develop compounds having selective inhibitory activity or better pharmacodynamics/pharmacokinetics for mutant EGFR kinases that are useful as therapeutic agents.
Disclosure of Invention
The invention aims to provide a novel compound with selective inhibitory activity on mutant EGFR kinase and better pharmacodynamic/pharmacokinetic performance and application thereof.
In one aspect, the invention provides a deuterated compound represented by formula (i) or a pharmaceutically acceptable salt thereof:
wherein:
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and R 26 Each independently is hydrogen or deuterium;
R 8 is trifluoromethyl;
R 9 is hydrogen;
with the proviso that R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 And R 26 Is deuterium, and compounds shown below are excluded:
in some embodiments of the invention, examples of compounds of formula (I) are as follows:
in another aspect of the present invention there is provided a method of treating EGFR mediated diseases comprising administering a therapeutically effective amount of a compound of formula (i) or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides the use of a compound of formula (i), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an EGFR-mediated disease.
In some embodiments of the invention, the EGFR-mediated disease is selected from the group consisting of EGFR-T790M activating mutation-mediated diseases.
In some embodiments of the invention, the EGFR-mediated disease is cancer; the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumors, thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma; the lung cancer may be selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma.
In another aspect of the invention there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (i) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention or a salt thereof with a suitable pharmaceutically acceptable carrier, and can be formulated, for example, into solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.
Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid excipients, the resulting mixture is optionally milled, if desired with further suitable auxiliaries, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents and the like. Such as microcrystalline cellulose, glucose solutions, gum arabic syrups, gelatin solutions, sucrose and starch pastes; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol, or dicalcium phosphate; silicon dioxide; croscarmellose sodium, pregelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose, crospovidone, and the like. The dragee cores may optionally be coated, in particular with enteric coatings, according to methods well known in normal pharmaceutical practice.
The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
The compounds of formula (i) or pharmaceutically acceptable salts thereof according to the invention may be administered by any suitable route and method, for example orally or parenterally (e.g. intravenously). A therapeutically effective amount of a compound of formula (I) is from about 0.0001 to 20mg/Kg body weight/day, for example from 0.001 to 10mg/Kg body weight/day.
The frequency of dosage of the compounds of formula (I) is determined by the individual requirements of the patient, for example 1 or 2 times per day, or more times per day. Administration may be intermittent, for example, wherein a patient receives a daily dose of a compound of formula (i) over a period of several days, followed by a period of several days in which the patient does not receive a daily dose of a compound of formula (i).
The compound of formula (I) or the pharmaceutically acceptable salt thereof can also be used for preparing medicines for treating cardiovascular diseases, inflammation, infection, immune diseases, cell proliferation diseases, viral diseases, metabolic diseases or organ transplantation.
The compounds of formula (i) or pharmaceutically acceptable salts thereof of the present invention may also be used in combination with other therapeutic agents, including but not limited to: <xnotran> 5- , FOLFOX, (avastin, bevacizumab), (bexarotene), (bortezomib), (calcitriol), (canertinib), (capecitabine), (gemcitabine), (carboplatin), (celecoxib), (cetuximab), (cisplatin), (dasatinib), (digoxin), (Erlotinib), (etoposide), (everolimus), (fulvestrant), (gefitinib) (genistein), (imatinib), (irinotecan), (lapatinib), (lenalidomide), (letrozole), (leucovorin), (matuzumab) (oxaliplatin), (paclitaxel), (doxetaxel), (panitumumab), PEG (pegfilgrastin), PEG α - (peglated alfa-interferon), (pemetrexed), (satraplatin), (sirolimus), (sunitinib), (sulindac), (taxotere), (temozomolomide), (Torisel), (temsirolimus), </xnotran> Tipifarnib (tipifarnib), trastuzumab (trastuzumab), valproic acid (valproic acid), vinflunine (vinflunine), sorafenib (sorafenib), crizotinib (crizotinib), icotinib (lcotinib), lapatinib (lapatinib), tofacitinib (tofacitinib), PD-0332991 (palbociclib), ambrisentan (ambrisentan), CD40 and/or CD154 specific antibodies, fusion proteins, NF-kB inhibitors, non-steroidal anti-inflammatory drugs, coagulation factor FXa inhibitors (such as rivaroxaban and the like), anti-TNF antibodies, antibiotic drugs such as calicheamicin (calicheamicin), actinomycin (actimycin), doxorubicin (doruxobicin) and the like.
Related definitions:
the term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Examples of the pharmaceutically acceptable salt include a salt with an inorganic acid, a salt with an organic acid, and a salt with an acidic amino acid. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, 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 and the like; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, etc.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water or an organic solvent or a mixture of the two.
Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous form.
Any atom of the labeled synthetic compounds of the present invention may represent any stable isotope of that atom, if not specifically designated. Unless otherwise indicated, when a position in a structure is defined as H, i.e., hydrogen (H-1), that position contains only the amount of the naturally occurring isotope. Likewise, unless otherwise specified, when a position in a structure is defined as D, i.e., deuterium (H-2), that position contains an isotopic amount that is at least 3340 times greater (i.e., at least 50.1% of the deuterium isotope) than the amount of the naturally occurring isotope (0.015%).
The deuteration ratio of a labeled synthetic compound in the present invention refers to the ratio of the content of the labeled synthetic isotope to the amount of the naturally occurring isotope. The deuteration rate per designated deuterium atom of the labeled synthetic compounds of the present invention can be at least 3500 times (52.5%), at least 4000 times (60%), at least 4500 times (67.5%), at least 5000 times (75%), at least 5500 times (82.5%), at least 6000 times (90%), at least 6333.3 times (95%), at least 6466.7 times (97%), at least 6566.7 times (98.5%), at least 6600 times (99%), at least 6633.3 times (99.5%).
Isotopologues in the present invention mean compounds which differ only in isotopic composition in terms of chemical structure. The labeled synthetic compounds of the present invention have the same chemical structure, with only isotopic variations in the atomic composition of the molecule. Thus, a compound labeled as synthesized in the present invention that contains deuterium at a particular position will likewise contain very little hydrogen isotopes at that position, the amount of hydrogen isotopes at a position in the compound labeled as synthesized in the present invention depending upon a number of factors, including the deuterated reagent (D) 2 O、D 2 、NaBD 4 、LiAlD 4 Etc.) and the effectiveness of the synthetic methods for introducing deuterium isotopes. However, as previously describedThe total number of hydrogen isotopologues at such a location will be less than 49.9%. The total amount of hydroisomesomes at a position in the labeled synthetic compound of the invention will be less than 47.5%, 40%, 32.5%, 25%, 17.5%, 10%, 5%, 3%, 1%, or 0.5%.
In the present invention, any individual atom not designated as deuterium is present in its natural isotopic abundance.
The term "pharmaceutically acceptable carrier" refers to those carriers which do not have a significant irritating effect on the organism and which do not impair the biological activity and performance of the active compound. By "pharmaceutically acceptable carrier" is meant an inert substance which facilitates administration of the active ingredient in conjunction with administration of the active ingredient, including, but not limited to, any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier acceptable for use in humans or animals (e.g., livestock) as permitted by the national food and drug administration. Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols, and the like. For additional information on The vector, reference may be made to Remington, the Science and Practice of Pharmacy,21st Ed, lippincott, williams & Wilkins (2005), the contents of which are incorporated herein by reference.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition.
The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is not toxic but yet achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in a case may be determined by a person skilled in the art in the light of routine tests.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
In the invention, the compound shown in the formula I has excellent selective inhibitory activity on mutant EGFR kinase and simultaneously shows excellent pharmacokinetic properties. The pharmacokinetic properties may be obtained by experimental methods known in the art, such as, but not limited to, in vitro liver microsome experiments, in vivo rat pharmacokinetic experiments, and the like.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.
All solvents used in the present invention are commercially available and can be used without further purification. All procedures involving experiments sensitive to water and/or oxygen were performed in a pre-dried glass apparatus under nitrogen atmosphere. All starting materials were commercial starting materials unless otherwise indicated and were not further purified prior to use. The column chromatography adopted by the invention is silica gel (200-300 meshes) produced by Qingdao ocean chemical industry. Thin layer chromatography was performed using merck (e.merck) precoated chromatography plates (silica gel 60pf254,0.25 mm). The instrument used for nuclear magnetic resonance spectroscopy is a Valian VNMRS-400 resonance spectrometer, the chemical shift takes tetramethylsilane (TMS = delta 0.00) as an internal standard, and the recording format of nuclear magnetic resonance hydrogen spectrum data is as follows: proton number, peak type (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant (in hertz Hz).
The invention employs the following abbreviations: DCM represents dichloromethane; DIPEA stands for diisopropylethylamine; PE represents petroleum ether; EA represents ethyl acetate; DMSO represents dimethyl sulfoxide; DMA represents N, N-dimethylacetamide; TFA represents trifluoroacetic acid.
The compounds are prepared by hand or
The software names, and the commercial compounds are under the supplier catalog name.
Detailed Description
The following examples illustrate the invention in more detail, but do not limit the invention in any way.
EXAMPLE 1 preparation of the Compound of formula I-1
Step 1: preparation of Compound (d 3-m-phenylenediamine) of formula 2
M-phenylenediamine (700mg, 6.47mmol) and heavy water (8.8mL, 485mmol) were weighed in a 35mL microwave reaction tube, and Ru was added after dissolution and clarification 3 (CO) 12 Reacting the catalyst (11mg, 16.2 umol) at 150 deg.C for 1hr, vacuum filtering to remove catalyst, evaporating solvent, and repeating the above steps to obtain 710mg of title compound;
MS(ESI,[M+H]+)：112.0944；
1H‐NMR(300M，D2O)：7.05(s，1H)。
step 2: preparation of compound of formula 4 (1- (4- (4- (2, 4, 6-d-3-aminophenylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -3-methoxyphenyl) piperazin-1-yl) ethanone)
Compound of formula 3 (710mg, 1.65mmol), d 3-m-phenylenediamine (184mg, 1.65mmol), etOH 20mL, were weighed in a 35mL microwave reaction tube, reacted at 100 ℃ for 90min, the starting material point was monitored by hplc to disappear, the reaction solution was made into sand, and DCM-MeOH eluted (50;
MS(ESI,[M+H]+)：505.2498；
1H-NMR(500M，DMSO-d6)：8.23(s，1H)，8.10(s，1H)，8.08(s，1H)，7.55(s，1H)，6.94(s，1H)，4.94(s，2H)，3.78(s，3H)，3.58-3.57(d，4H)，3.29(s，2H)，3.12-3.06(d，4H)，2.05(s，3H)。
and step 3: preparation of Compounds of formula I-1
In a reaction flask, the compound of formula 4 (470mg, 0.93mmol) was weighed, THF was freshly distilled to 10mL of the clear solution, and triethylamine (141mg, 1.40mmol), N 2 Under protection, dropwise adding acryloyl chloride (1699 mg, 1.86mmol), dropping the plate raw material after 3hr, performing rotary evaporation on the reaction solution, adding water EA to the residue for extraction, performing drying and rotary evaporation to obtain 320mg, preparing sand from the reaction solution, and eluting with DCM-MeOH to obtain a title compound (210mg, 0.38mmol);
MS(ESI,[M+H]+)：559.2978；
1H-NMR(500M，DMSO-d6)：10.1(s，1H)，8.63(s，1H)，8.28(s，1H)，8.07(s，1H)，7.49～7.55(t，J＝9.69Hz，2H)，7.24～7.29(t，J＝8.01Hz，1H)，7.15～7.17(be，1H)，6.40～6.49(dd，1H)，6.28～6.29(d，J＝1.98Hz，1H)，5.74～5.78(dd，1H)，3.77(s，3H)，3.57(s，4H)，3.07-3.01(d，4H)，2.04(s，3H)。
EXAMPLE 2 preparation of Compounds of formula I-2
Step 1: preparation of the Compound of formula 7 (2-methoxy-3, 5, 6-d-4-piperazinylaniline)
The compound of formula 6 (2.5g, 10.03mmol) was added to a heavy aqueous solution of trifluoroacetic anhydride (2.5g, 11.90mmol). Heating the mixture in a sealed tube oil bath at 120 ℃ for reaction overnight, and adding potassium carbonate solid into the reaction solution at 0 ℃ for alkali adjustment after the TLC detection reaction is finished. Extracting the reaction solution with dichloromethane, combining the organic phases, washing with saturated saline, and carrying out reduced pressure rotary evaporation to obtain 2.35g of a title compound;
HRMS(ESI,[M+H]+)m/z：211.1638。
step 2: preparation of the Compound of formula 9 (1- (4- (2, 5, 6-d-3-methoxy-4-aminophenyl) piperazin-1-yl) ethanone)
To a solution of the compound of formula 7 (1.03g, 4.7 mmol) in dichloromethane was added the compound of formula 8 (0.52g, 2.3mmol). Stirring at room temperature overnight under nitrogen protection, detecting by TLC, adding saturated potassium carbonate solution into the reaction, quenching, extracting the reaction solution with dichloromethane, mixing the organic phases, washing with saturated salt solution, and performing column chromatography to obtain 0.53g of the title compound;
HRMS(ESI,[M+H]+)m/z：253.1770。
and step 3: preparation of the Compound of formula I-2.
Adding the compound of formula 10 (374mg, 1.1mmol) and trifluoroacetic acid (130mg, 1.1mmol) to a solution of the compound of formula 9 (330mg, 1.3mmol) in 1, 4-dioxane, heating in an oil bath under nitrogen protection to 50 ℃ for overnight reaction, monitoring the completion of the reaction by HPLC, adding a heavy aqueous solution of sodium methoxide to the reaction solution to adjust the alkali, extracting the reaction solution with DCM, combining the organic phases, washing with saturated common salt water, and separating by column chromatography to obtain the title compound 269mg;
HRMS(ESI,[M+H]+)m/z：558.2140；
1H‐NMR(300M，DMSO‐d6)：10.164(s,1H),8.663(br,1H),8.291(s,1H),8.089(s,1H),7.753(br,1H),7.538‐7.554(d,1H),7.257‐7.289(t,1H),7.166(br,1H),6.919(s,1H),6.420‐6.474(q,1H),6.246‐6.250(dd,1H),5.754‐5.777(dd,1H),3.779(s,3H),3.548‐3.583(br,4H),3.007‐3.070(br,4H),2.053(s,3H)。
experimental example 1: epidermal Growth Factor Receptor (EGFR) and oncogenic driver ALK inhibitory activity.
The preparation method comprises the following steps: all the above samples were made up in 10mM stock solution in DMSO. When in use, the culture solution is prepared to the required concentration.
Cell lines: NCI-H292 cells were purchased from Shanghai Life sciences cell Bank of Chinese academy of sciences; NCI-H3122 is from the American NCI. The cells were cultured in RPMI 1640 medium containing 10% Fetal Bovine Serum (FBS).
Reagents and instruments: RPMI-1640 was purchased from Gibco BRL; fetal bovine serum was purchased from Gibco; multifunctional microplate readers were purchased from BioTek corporation; SRB was purchased from Sigma.
Test method (SRB method): sulforhodamine B protein staining method (SRB) is used for detecting the inhibition effect of the drug on the proliferation and growth of tumor cells. The method mainly comprises the following steps: cells in logarithmic growth phase are inoculated in a 96-well culture plate, drugs with different concentrations are added, each concentration is provided with 3 multiple wells, and simultaneously, a solvent control with corresponding concentration is arranged. Tumor cells at 37 ℃ and 5% CO 2 Cultured under the conditions for 72 hours. The cells were stained with SRB at room temperature, and finally dissolved in Tris solution, OD was measured at 510nm using a microplate reader (BioTek), and the cell growth inhibition rate was calculated according to the following formula:
inhibition rate = (OD value) Control well OD value Medicine feeding hole ) OD value Control well ×100％。
Calculating half inhibition concentration IC according to each concentration inhibition rate and a nonlinear regression method 50 。
Experimental example 2: effect on proliferation of human lung adenocarcinoma H1975 (T790M) cells cultured in vitro.
Cell line: h1975 cells were purchased from cell banks of Shanghai Life sciences of Chinese academy of sciences and cultured in PRIM 1640 medium containing 10% Fetal Bovine Serum (FBS).
Reagents and instruments: PRIM 1640 from Gibco BRL; fetal bovine serum was purchased from Hyclone; a multifunctional microplate reader was purchased from BioTek corporation; SRB was purchased from Sigma.
Test method (SRB method): the inhibition effect of the drug on the proliferation and growth of tumor cells is detected by a Sulforhodamine B (SRB) protein staining method. The method mainly comprises the following steps:
inoculating cells in logarithmic growth phase into 96-well culture plate, adding drugs with different concentrations (1-10000 nM), setting 3 multiple wells for each concentration, and setting corresponding concentrationVehicle control. Tumor cells at 37 deg.C, 5% 2 Cultured under the conditions for 72 hours. The cells were stained with SRB at room temperature, and finally dissolved in Tris solution, and OD was measured at a wavelength of 510nm using a microplate reader (BioTek), and the cell growth inhibition rate was calculated according to the following formula:
inhibition rate = (OD value) Control well OD value Medicine feeding hole ) OD value Control well ×100％。
Calculating half inhibition concentration IC according to each concentration inhibition rate and a nonlinear regression method 50 。
Claims (2)
1. Use of a compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a cancer selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, hepatocellular cancer, gastrointestinal stromal tumors, thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma,
2. use of a compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a cancer selected from lung cancer selected from small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma,
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| WO2015117547A1 (en) * | 2014-02-04 | 2015-08-13 | Jiangsu Medolution Limited | Substituted pyrimidines useful as egfr-t790m kinase inhibitors |
| CN106146406A (en) * | 2016-02-23 | 2016-11-23 | 深圳市塔吉瑞生物医药有限公司 | A kind of substituted diaminopyrimidines and the compositions comprising this compound and application thereof |
| CN106554318A (en) * | 2015-09-25 | 2017-04-05 | 正大天晴药业集团股份有限公司 | Deuterated diphenyl amino pyrimidine compound |
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| WO2015117547A1 (en) * | 2014-02-04 | 2015-08-13 | Jiangsu Medolution Limited | Substituted pyrimidines useful as egfr-t790m kinase inhibitors |
| CN106554318A (en) * | 2015-09-25 | 2017-04-05 | 正大天晴药业集团股份有限公司 | Deuterated diphenyl amino pyrimidine compound |
| CN106146406A (en) * | 2016-02-23 | 2016-11-23 | 深圳市塔吉瑞生物医药有限公司 | A kind of substituted diaminopyrimidines and the compositions comprising this compound and application thereof |
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| Title |
|---|
| 氘代作用在药物研究中的应用;江文峰，等;《齐鲁药事》;20101231;第29卷(第11期);第682-684页 * |
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