CN107344925A - Deuterated diphenyl amino-trifluoromethyl pyrimidine compound - Google Patents
Deuterated diphenyl amino-trifluoromethyl pyrimidine compound Download PDFInfo
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- CN107344925A CN107344925A CN201610286806.0A CN201610286806A CN107344925A CN 107344925 A CN107344925 A CN 107344925A CN 201610286806 A CN201610286806 A CN 201610286806A CN 107344925 A CN107344925 A CN 107344925A
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- 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
Abstract
The invention belongs to field of medicaments, it is related to deuterated diphenyl amino trifluoromethyl pyrimidine compound or its pharmaceutically acceptable salt, and in particular to compound shown in formula (I) or its pharmaceutically acceptable salt, its preparation method, its pharmaceutical composition and its purposes in cell proliferation disorders are treated.
Description
Technical field
The invention belongs to field of medicaments, is related to deuterated diphenyl amino-trifluoromethyl pyrimidine compound or its is pharmaceutically acceptable
Salt, and in particular to compound shown in formula (I) or its pharmaceutically acceptable salt, its preparation method, its pharmaceutical composition and its
Purposes in cell proliferation disorders are treated.
Background technology
Lung cancer is the major disease of serious threat human health, is one of most common malignant tumour in the world, it has also become China city
The 1st of city's population Death Cause for Malignant Tumors.Non-small cell lung cancer (NSCLC) accounts for more than the 85% of all types lung cancer.
EGFR (Epidermal Growth Factor Receptor) be epidermal growth factor (EGF) cell propagation and signal transduction by
Body, also referred to as HER1, ErbB1.EGFR belongs to one kind of ErbB receptor family, and the family includes EGFR (ErbB-1),
HER2/c-neu (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4).EGFR is a kind of glycoprotein, belongs to tyrosine-kinase
Enzyme receptor, cell membrane insertion, molecular weight 170KDa.
EGFR inhibitor Iressa (Gefinitib) and Erlotinib (Erlotinib) etc. are in clinical treatment non-small cell lung carninomatosis
Immense success is obtained in people, but its resistance problems also becomes increasingly conspicuous, be EGFR-T790M mutation the main reason for resistance, account for
The 50% of resistance patient sum.Though at present have the non-reversible inhibitor of second generation EGFR (Canertinib, Afatinib, Neratinib,
Pelitinib etc.) enter clinical test, but these molecules cause clinical drug to the poor selectivity of EGFR-T790M mutant
Tolerance dose is relatively low, and under its maximum tolerated dose, medicine can not reach its valid density in vivo and cause to most multidrug resistant diseases
People is invalid.Most clinical tests have also been forced to terminate.In addition, fash and diarrhoea are most notable poison caused by wt-EGFR inhibitor
Side effect.Therefore exploitation turns into the weight for solving current drug resistance problems with high specific EGFR-T790M mutant inhibitor
Will strategy.
On May 20th, 2014, Clovis tumour company (Clovis Oncology) announce that U.S. FDA authorizes its experiment
The breakthrough medicine qualifications of medicine Rociletinib (CO-1686, AVL-301), it is used to treat as single medicine two wires
T790M mutation patient EGFR mutation non-small cell lung cancers (NSCLC).
CO-1686 can be used for treatment EGFR saltant type NSCLC, and it is capable of selective depression T790M mutant egfs R's
Wild type EGFR signal is set to leave unused simultaneously.The medicine is developed for carrying initial activation mutation EGFR and T790M mutation EGFR
NSCLC patient treatment, all various dose water average energies show sound response and permanent benefit.
Deuterated modification is to improve a kind of very potential new drug development technology of pharmacokinetic properties.In the method, try to lead to
Cross and substitute one or more hydrogen atom D-atoms so as to slow down the drug metabolism of CYP mediations or reduce undesirable metabolin
Generation.Deuterium is safe and stable, without radioactive isotope, and compared with hydrogen, deuterium can form stronger key with carbon.
In some cases, the increased bond strength formed by deuterium can be with the ADME properties of actively impact medicine, as a result may be obvious
Interaction, raising security and the acquisition that ground extends between its drug metabolism circulation, the generation for reducing toxic metabolite and medicine
More preferably the effect of.
Even if D-atom is mixed with known metabolism site, influence of the deuterium modification for the metabolisming property of medicine is still unpredictable
's.Therefore the actual preparation and test of deuterated molecule are had to pass through, just can determine that deuterated medicine with non-deuterated medicine in terms of metabolism
Difference.
Although CO-1686 can be reasonably resistant to T790M resistant mutations, while hardly suppressing wt-EGFR and nothing
Related dose-limiting toxicity, however, it was found that with treatment cell proliferation disease (such as non-small cell lung cancer) and with very well
Oral administration biaavailability and have the new compound of druggability or challenging work.
Therefore, this area, which stills need exploitation, has selective inhibitory activity or more to the mutant egf R kinases that is suitable for therapeutic agent
The compound of good pharmacodynamics/pharmacokinetics.
The content of the invention
It is an object of the invention to provide it is a kind of it is new to mutant egf R kinases with selective inhibitory activity and with more preferable medicine
Imitate compound of/pharmacokinetics performance and application thereof.
One aspect of the present invention provides the deuterated compound or its pharmaceutically acceptable salt shown in a kind of formula (I)：
Wherein：
R1、R2、R3、R4、R5、R6、R7、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、
R21、R22、R23、R24、R25And R26It is each independently hydrogen or deuterium；
R8For trifluoromethyl；
R9For hydrogen；
Additional conditions are R1、R2、R3、R4、R5、R6、R7、R10、R11、R12、R13、R14、R15、R16、R17、
R18、R19、R20、R21、R22、R23、R24、R25And R26In it is at least one be deuterium, and exclude compound as follows：
In some embodiments of the present invention, the example of compound is as follows shown in formula (I)：
Another aspect provides a kind of method for the disease for treating EGFR mediations, methods described has including giving treatment
Formula (I) compound of effect amount or its pharmaceutically acceptable salt.
Another aspect of the present invention provides formula (I) compound or its pharmaceutically acceptable salt and is preparing treatment EGFR
Purposes in the medicine of the disease of mediation.
In some embodiments of the present invention, the disease of the EGFR mediations mediates selected from EGFR-T790M activated mutants
Disease.
In some embodiments of the present invention, the disease of the EGFR mediations is cancer；The cancer is selected from oophoroma, palace
Neck cancer, colorectal cancer, breast cancer, cancer of pancreas, glioma, glioblastoma, melanoma, prostate cancer, white blood
Disease, lymthoma, NHL, stomach cancer, lung cancer, hepatocellular carcinoma, stomach cancer, gastrointestinal stromal tumor, thyroid cancer,
It is cholangiocarcinoma, carcinoma of endometrium, kidney, primary cutaneous type, acute myelocytic leukemia, Huppert's disease, black
Melanoma, celiothelioma；The lung cancer can be selected from non-small cell lung cancer, ED-SCLC, adenocarcinoma of lung, lung squamous cancer.
Another aspect provides a kind of pharmaceutical composition, and it includes formula (I) compound or its medicine of therapeutically effective amount
Acceptable salt and one or more pharmaceutically acceptable carriers or excipient on.
The pharmaceutical composition of the present invention can be by the way that the compound or its salt of the present invention be combined with suitable pharmaceutically acceptable carrier
And prepare, such as solid-state, semisolid, liquid or gaseous state preparation can be configured to, as tablet, pill, capsule, pulvis,
Granula, paste, emulsion, suspending agent, solution, suppository, injection, inhalant, gel, microballoon and aerosol etc..
Give compound of the invention or its pharmaceutically acceptable salt or the classical pathway of its pharmaceutical composition includes but is not limited to mouth
Clothes, rectum, saturating mucous membrane, through enteral administration, or local, percutaneous, suction, parenteral, sublingual, intravaginal, intranasal, eye
Interior, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical composition of the present invention can use method well-known in the art to manufacture, such as conventional mixing method, dissolution method,
Granulation, dragee method processed, levigate method, emulsion process, freeze-drying etc..
, can be by the way that reactive compound be mixed to prepare with pharmaceutically acceptable carrier well known in the art for being administered orally
The pharmaceutical composition.These carriers can make the present invention compound be formulated into tablet, pill, lozenge, sugar-coat agent, capsule,
Liquid, gel, slurry agent, suspending agent etc., for the oral administration to patient.
Solid oral composition can be prepared by mixing, filling or the tabletting method of routine.For example, following methods can be passed through
Obtain：Described reactive compound is mixed with solid excipient, the mixture for gained of optionally milling, added if necessary
Other suitable assistant agents, are then processed into particle by the mixture, have obtained the core of tablet or sugar-coat agent.Suitable accessory package
Include but be not limited to：Adhesive, diluent, disintegrant, lubricant, glidant, sweetener or flavouring etc..Such as microcrystalline cellulose
Element, glucose solution, mucialga of arabic gummy, gelatin solution, sucrose and gelatinized corn starch；Talcum, starch, magnesium stearate, stearic acid
Calcium or stearic acid；Lactose, sucrose, starch, mannitol, D-sorbite or Dicalcium Phosphate；Silica；Cross-linked carboxymethyl
Sodium cellulosate, pre-paying starch, primojel, alginic acid, cornstarch, farina, methylcellulose, agar,
Carboxymethyl cellulose, PVPP etc..Can be according to known method in usual medicinal practice optionally to sugar-coat
The core of agent is coated, especially using enteric coating.
Pharmaceutical composition could be applicable to parenteral, such as the sterile solution agent of suitable unit dosage forms, supensoid agent or lyophilized production
Product.
Formula (I) compound of the present invention or its pharmaceutically acceptable salt can be given by any applicable approaches and methods
Medicine, such as orally or parenterally (for example, intravenous) administration.The therapeutically effective amount of formula (I) compound is from about 0.0001
To 20mg/Kg body weight/days, such as from 0.001 to 10mg/Kg body weight/days.
The dose frequency of formula (I) compound determines by the demand of individual patients, for example, 1 time a day or 2 times, or daily more
Repeatedly.Administration can be intermittent, for example, wherein in a period of some days, patient receives the every of formula (I) compound
Daily dose, then during some days, patient does not receive the daily dosage of formula (I) compound.
The present invention formula (I) compound or its pharmaceutically acceptable salt can also be used for prepare treatment angiocardiopathy, inflammation,
Infection, immunity disease, cell proliferation disease, viral disease, metabolic disease or organ transplant medicine in purposes.
Formula (I) compound of the present invention or its pharmaceutically acceptable salt also can treat above-mentioned disease with other treatment drug combination
Disease or progress or the morbidity for delaying the disease, described other treatment medicine include but is not limited to：5 FU 5 fluorouracil,
FOLFOX, Avastin (avastin, bevacizumab), bexarotene (bexarotene), bortezomib (bortezomib),
Calcitriol (calcitriol), Canertinib (canertinib), capecitabine (capecitabine), gemcitabine (gemcitabine),
Carboplatin (carboplatin), celecoxib (celecoxib), Cetuximab (cetuximab), cis-platinum (cisplatin), reach
Sand for Buddhist nun (dasatinib), digoxin (digoxin), Erlotinib (Erlotinib), etoposide (etoposide), according to dimension
Take charge of (everolimus), fulvestrant (fulvestrant), Gefitinib (gefitinib) Genistein (genistein),
Imatinib (imatinib), Irinotecan (irinotecan), Lapatinib (lapatinib), lenalidomide (lenalidomide),
Letrozole (letrozole), folinic acid (leucovorin), matuzumab (matuzumab) oxaliplatin (oxaliplatin),
Taxol (paclitaxel), docetaxel (doxetaxel), Victibix (panitumumab), the granulocyte collection of PEGylation
Fall stimulating factor (pegfilgrastin), alpha-interferon (peglated alfa-interferon), the pemetrexed of PEGylation
(pemetrexed), Sha Bai (satraplatin), sirolimus (sirolimus), Sutent (sunitinib), sulindac
(sulindac), taxotere (taxotere), Temozolomide (temozomolomide), temsirolimu (Torisel), for western sieve
Take charge of (temsirolimus), for pyrrole method Buddhist nun (tipifarnib), trastuzumab (trastuzumab), valproic acid (valproic acid),
Vinflunine (vinflunine), Sorafenib (sorafenib), gram azoles for Buddhist nun (crizotinib), Conmana (lcotinib),
Lapatinib (lapatinib), tropsch imatinib (tofacitinib), PD-0332991 (palbociclib), BSF208075
(ambrisentan), CD40 and/or CD154 specific antibodies, fusion protein, NF-kB inhibitor, NSAIDs,
For example perverse p0-357 (calicheamicin) of Factor Xa inhibitor (such as razaxaban), anti-TNF antibody, antibiotic medicine,
D actinomycin D (actinomycin), adriamycin (doxorubicin) etc..
Relevant definition：
Term " pharmaceutically acceptable ", it is that they are reliable for those compounds, material, composition and/or formulation
Medical judgment within the scope of, contact use suitable for the tissue with human and animal, without excessive toxicity, excitant,
Allergic reaction or other problems or complication, match with rational interests/Hazard ratio.
As pharmaceutically acceptable salt, for example, the salt formed with inorganic acid, the salt and acidic amino acid that are formed with organic acid
Salt of formation etc..Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferable salt is the compounds of this invention and sour shape
Into salt.The acid for suitably forming salt includes but is not limited to：The nothings such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid
Machine acid；Formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, butanedioic acid, fumaric acid, maleic acid, lactic acid, apple
Tartaric acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, naphthalene sulfonic acids
Deng organic acid；And the amino acid such as proline, phenylalanine, aspartic acid, glutamic acid.
The pharmaceutically acceptable salt of the present invention can be synthesized by the parent compound containing acid group or base by conventional chemical processes.
Generally, the preparation method of such salt is：In the mixture of water or organic solvent or both, via free alkali form
These compounds and the appropriate acid reaction of stoichiometry prepare.
Some compounds of the present invention can exist with nonsolvated forms or solvation form, including hydrate forms.Typically
For, solvation form is suitable with non-solvated form, is intended to be included within the scope.Some chemical combination of the present invention
Thing can exist with polycrystalline or amorphous form.
If any atom of the compound of institute's labelled synthesis does not specify in the present invention, any one that can represent the atom is steady
Fixed isotope.Unless stated otherwise, when a certain position is defined as H i.e. hydrogen (H-1) in structure, the position, which only contains, naturally deposits
Isotopic mass.Equally, unless stated otherwise, when a certain position is defined as D i.e. deuterium (H-2) in structure, the position contains
Isotopic mass is at least bigger than naturally occurring isotopic mass (0.015%) 3340 times (i.e. at least can 50.1% deuterium isotope).
The deuterated rate of the compound of institute's labelled synthesis refers to the isotopic content of labelled synthesis and naturally occurring isotope in the present invention
The ratio of amount.The deuterated rate of each specified D-atom of the compound of institute's labelled synthesis can be at least 3500 times in the present invention
(52.5%), it is at least 4000 times (60%), is at least 4500 times (67.5%), is at least 5000 times (75%), at least
For 5500 times (82.5%), be at least 6000 times (90%), be at least 6333.3 times (95%), be at least 6466.7 times (97%),
At least 6566.7 times (98.5%), it is at least 6600 times (99%), is at least 6633.3 times (99.5%).
Isotopic body (isotopologues) in the present invention refers to chemical combination different only in isotopics in terms of chemical constitution
Thing.The compound of institute's labelled synthesis has identical chemical constitution, the only isotope in the atom composition of its molecule in the present invention
Change.Therefore, the present invention in institute's labelled synthesis the hydrogen that can similarly contain the considerably less position containing deuteride in ad-hoc location
Isotopic body, the hydrogen isotope body of certain position in the present invention in the compound of institute labelled synthesis measure certainly many factors, wherein
Including deuterated reagent (D2O、D2、NaBD4、LiAlD4Deng) deuterium isotopic purity and introduce deuterium isotope synthetic method
Validity.However, the amount sum of the hydrogen isotope body of certain this position will be less than 49.9% as previously described.Marked in the present invention
Remember synthesis compound in certain position hydrogen isotope body amount sum will be less than 47.5%, 40%, 32.5%, 25%, 17.5%,
10%th, 5%, 3%, 1% or 0.5%.
In the present invention, any each atom for being not designated as deuterium exists with its natural isotopic abundance.
Term " pharmaceutically acceptable carrier " refers to act on organism without obvious stimulation, and will not damage the reactive compound
Bioactivity and performance those carriers." pharmaceutically acceptable carrier " refer to it is being together administered with active ingredient, be advantageous to
Active ingredient administration inert substance, including but not limited to State Food and Drug Administration license it is acceptable be used for people or
Any glidant, sweetener, diluent, preservative, dyestuff/colouring agent, flavoring reinforcing agent, the table of animal (such as domestic animal)
Face activating agent, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifying agent.The carrier
Non-limiting examples include calcium carbonate, calcium phosphate, various sugared and each kind of starch, cellulose derivative, gelatin, vegetable oil and
Polyethylene glycol etc..On the other information of carrier, Remington may be referred to:The Science and Practice of Pharmacy,
21st Ed., Lippincott, Williams＆Wilkins (2005), the content of the document are incorporated herein by reference.
Term " excipient " typically refers to carrier, diluent and/or medium required for preparing drug composition effective.
For medicine or pharmacologically active agents, term " effective dose " or " therapeutically effective amount " refer to nontoxic but can reached expected
The medicine of effect or enough dosages of medicament.For the peroral dosage form in the present invention, " effective dose " of a kind of active material in composition
For the required dosage that produces a desired effect when referring to be combined with another active material in said composition.The determination of effective dose because
People and different, age and ordinary circumstance depending on acceptor, specific active material is also depended on, suitable effective dose can in case
To be determined by those skilled in the art according to routine test.
Term " active component ", " therapeutic agent ", " active material " or " activating agent " refer to a kind of chemical entities, and it can effectively be controlled
Treat disorderly target, disease or illness.
In the present invention, the tool of compound shown in formula I has excellent selective inhibitory activity to mutant egf R kinases, simultaneously
Show excellent pharmacokinetic property.The pharmacokinetic property can be obtained by experimental method known in the art,
Such as but be not limited only to external liver microsomal assay, Pharmacokinetics in Rat experiment etc..
The compound of the present invention can be prepared by a variety of synthetic methods well-known to those skilled in the art, including be set forth below
Embodiment, itself and other chemical synthesis process the combination embodiment and art technology that are formed on personnel institute
Well known equivalent substitution mode, preferred embodiment include but is not limited to embodiments of the invention.
All solvents used in the present invention are commercially available, be can be used without being further purified.It is related to water and/or oxygen sensitive
All operations of experiment all carried out in predrying glass apparatus under blanket of nitrogen.Unless otherwise indicated, all raw materials are business
Industry raw material, and be not further purified using preceding.Column chromatography used in the present invention is produced using Qingdao Haiyang chemical industry
Silica gel (200-300 mesh).Thin-layer chromatography using Merck ＆ Co., Inc. (E.Merck) precoating chromatosheet (silica gel 60PF254,0.25
Millimeter).The instrument that nuclear magnetic resonance spectroscopy uses is Varian VNMRS-400 resonance light spectrometers, and chemical shift is with tetramethyl
Silane (TMS=δ 0.00) is internal standard, and the record format of hydrogen nuclear magnetic resonance modal data is：Proton number, and peak type (s, it is unimodal；D,
Doublet；T, triplet；Q, quartet；M, multiplet), coupling constant (in units of hertz Hz).
The present invention uses following initialisms：DCM represents dichloromethane；DIPEA represents diisopropyl ethyl amine；PE represents stone
Oily ether；EA represents ethyl acetate；DMSO represents dimethyl sulfoxide；DMA represents DMAC N,N' dimethyl acetamide；TFA is represented
Trifluoroacetic acid.
Compound manually orSoftware is named, and commercial compound uses supplier's directory name.
Embodiment
The present invention can be described in more detail in the following examples, but the invention is not limited in any way.
The preparation of the compound of 1 formula of embodiment I -1
Step 1：The preparation of the compound of formula 2 (d3- m-phenylene diamine (MPD)s)
The weighing m-phenylene diamine (MPD) (700mg, 6.47mmol) in 35mL microwave reaction pipes, heavy water (8.8mL, 485mmol),
Add Ru after dissolved clarification3(CO)12Catalyst (11mg, 16.2umol), 150 DEG C of reaction 1hr of microwave, suction filtration remove catalyst, rotated
Repeat operation after dry solvent, secondary deuterated 710mg title compounds；
MS(ESI,[M+H]+)：112.0944；
1H-NMR (300M, D2O)：7.05 (s, 1H).
Step 2：The compound of formula 4 (1- (4- (4- (4- (2,4,6-d-3- aminophenyiaminos)-5- (trifluoromethyl) pyrimidine -2 --amino)-3-
Methoxyphenyl) piperazine -1- bases) ethyl ketone) and preparation
The compound of weighing type 3 (710mg, 1.65mmol) in 35mL microwave reaction pipes, d3- m-phenylene diamine (MPD)s (184mg,
1.65mmol), EtOH 20mL, 100 DEG C of reaction 90min, HPLC monitoring raw material points of microwave disappear, reaction solution sand,
DCM-MeOH elutions (50:1 to 20：1) title compound (500mg, 0.99mmol) is obtained；
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)。
Step 3：The preparation of the compound of formula I -1
The compound of weighing type 4 (470mg, 0.93mmol) in reaction bulb, it is new to steam THF 10mL dissolved clarifications, add triethylamine (141mg,
1.40mmol), N2Protection is lower to be added dropwise acryloyl chloride (169mg, 1.86mmol), and putting board raw material after 3hr disappears, and revolving is anti-
Liquid is answered, residue adds water EA to extract, and it is dry that 320mg, reaction solution sand, DCM-MeOH elute titled to dry revolving
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)。
The preparation of the compound of 2 formula of embodiment I -2
Step 1：The preparation of the compound of formula 7 (2- methoxyl group -3,5,6-d-4- piperazines aniline)
The compound of formula 6 (2.5g, 10.03mmol) is added in the heavy aqueous solution of TFAA (2.5g, 11.90mmol).
Overnight, TLC is detected after completion of the reaction the 120 DEG C of reactions of seal pipe oil bath heating, and adding potash solid into reaction solution at 0 DEG C adjusts
Alkali.With dichloromethane extractive reaction liquid, organic phase merging is washed with saturated common salt, and title compound 2.35g is obtained after vacuum rotary steam；
HRMS(ESI,[M+H]+)m/z：211.1638.
Step 2：The preparation of the compound of formula 9 (1- (4- (2,5,6-d-3- methoxyl group -4- aminophenyls) piperazine -1- bases) ethyl ketone)
The compound of formula 8 (0.52g, 2.3mmol) is added into the dichloromethane solution of the compound of formula 7 (1.03g, 4.7mmol).
It is stirred overnight at room temperature under nitrogen protection, TLC detections add unsaturated carbonate potassium solution into reaction after completion of the reaction and reaction is quenched, and use
Dichloromethane extractive reaction liquid, organic phase merging are washed with saturated common salt, and column chromatography obtains title compound 0.53g；
HRMS(ESI,[M+H]+)m/z：253.1770.
Step 3：The preparation of the compound of formula I -2.
By the compound of formula 10 (374mg, 1.1mmol) and trifluoroacetic acid (130mg, 1.1mmol) add the compound of formula 9 (330mg,
In Isosorbide-5-Nitrae-dioxane solution 1.3mmol), the lower oil bath heating of nitrogen protection to 50 DEG C of reactions overnight, reacted by HPLC monitorings
Finish, the heavy aqueous solution alkali tune of sodium methoxide is added into reaction solution, with DCM extractive reaction liquid, organic phase merging saturated aqueous common salt
Wash, column chromatography for separation obtains 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：EGF-R ELISA (epidermal growth factor receptor, EGFR) and carcinogenic driving Gene A LK
Inhibitory activity.
Compound method：Above sample is made into 10mM stoste with DMSO.During use required concentration is made into nutrient solution.
Cell line：NCI-H292 cells are purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences cell bank；NCI-H3122 comes from the U.S.
NCI.With the medium cultures of RPMI 1640 containing 10% hyclone (FBS).
Reagent and instrument：RPMI-1640 is purchased from Gibco BRL companies；Hyclone is purchased from Gibco companies；Multifunctional enzyme mark
Instrument is purchased from BioTek companies；SRB is purchased from Sigma companies.
Test method (srb assay)：Medicine is detected using Sulforhodamine B protein stainings method (Sulforhodamine B, SRB)
To the inhibitory action of tumor cell proliferation growth.Key step is as follows：Exponential phase cell is inoculated with 96 well culture plates, is added
The medicine of various concentrations, each concentration sets 3 multiple holes, while sets the Vehicle controls of respective concentration.Tumour cell is in 37 DEG C, 5%CO2
Under the conditions of cultivate 72 hours.Cell is dyed with SRB room temperatures, is eventually adding the dissolving of Tris solution, ELIASA (BioTek)
OD values are determined under 510nm wavelength, inhibitory rate of cell growth is calculated with following equation：
Inhibiting rate=(OD valuesControl wells- OD is worthDosing holes)/OD valuesControl wells× 100%.
According to each concentration inhibiting rate, according to non-linear regression method calculation of half inhibitory concentration IC50。
Experimental example 2：Influence in vitro culture human lung adenocarcinoma H1975 (T790M) cell propagation.
Cell line：H1975 cells are purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences cell bank, with containing 10% hyclone (FBS)
The medium cultures of PRIM 1640.
Reagent and instrument：PRIM 1640 is purchased from Gibco BRL companies；Hyclone is purchased from Hyclone companies；Multifunctional enzyme
Mark instrument is purchased from BioTek companies；SRB is purchased from Sigma companies.
Test method (srb assay)：Medicine is detected using Sulforhodamine B (Sulforhodamine B, SRB) protein staining method
To the inhibitory action of tumor cell proliferation growth.Key step is as follows：
Exponential phase cell is inoculated with to set in 96 well culture plates, the medicine of addition various concentrations (1-10000nM), each concentration
3 multiple holes, while set the Vehicle controls of respective concentration.Tumour cell is in 37 DEG C, 5%CO2Under the conditions of cultivate 72 hours.Carefully
Born of the same parents are dyed with SRB room temperatures, are eventually adding the dissolving of Tris solution, OD values are determined under ELIASA (BioTek) 510nm wavelength,
Inhibitory rate of cell growth is calculated with following equation：
Inhibiting rate=(OD valuesControl wells- OD is worthDosing holes)/OD valuesControl wells× 100%.
According to each concentration inhibiting rate, according to non-linear regression method calculation of half inhibitory concentration IC50。
Claims (5)
1. deuterated compound or its pharmaceutically acceptable salt shown in formula (I)：
Wherein：
R1、R2、R3、R4、R5、R6、R7、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、
R21、R22、R23、R24、R25And R26It is each independently hydrogen or deuterium；
R8For trifluoromethyl；
R9For hydrogen；
Additional conditions are R1、R2、R3、R4、R5、R6、R7、R10、R11、R12、R13、R14、R15、R16、R17、
R18、R19、R20、R21、R22、R23、R24、R25And R26In it is at least one be deuterium, and exclude change as follows
Compound：
2. deuterated compound or its pharmaceutically acceptable salt shown in formula (I) as claimed in claim 1, it is characterised in that choosing
From following compounds：
3. the compound or its pharmaceutically acceptable salt described in claim any one of 1-2 are preparing the disease for the treatment of EGFR mediations
Purposes in medicine.
4. purposes according to claim 3, the disease of the EGFR mediations is selected from cancer.
5. pharmaceutical composition, it includes formula (I) compound or its pharmaceutically acceptable salt and one or more medicines of therapeutically effective amount
Acceptable carrier or excipient on.
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| CN111099955A (en) * | 2019-12-30 | 2020-05-05 | 西安瑞联新材料股份有限公司 | Method and device for producing deuterated aromatic ring compound safely, environmentally and cheaply |
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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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| CN111099955A (en) * | 2019-12-30 | 2020-05-05 | 西安瑞联新材料股份有限公司 | Method and device for producing deuterated aromatic ring compound safely, environmentally and cheaply |
| CN111099955B (en) * | 2019-12-30 | 2022-09-02 | 西安瑞联新材料股份有限公司 | Method and device for producing deuterated aromatic ring compound safely, environmentally and cheaply |
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