CN105153122A - [(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative and its salt, preparation method of derivative, and application of derivative and salt - Google Patents

[(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative and its salt, preparation method of derivative, and application of derivative and salt Download PDF

Info

Publication number
CN105153122A
CN105153122A CN201510534307.4A CN201510534307A CN105153122A CN 105153122 A CN105153122 A CN 105153122A CN 201510534307 A CN201510534307 A CN 201510534307A CN 105153122 A CN105153122 A CN 105153122A
Authority
CN
China
Prior art keywords
formula
compound
derivative
present
mesylate
Prior art date
Legal status (The legal status 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 status listed.)
Granted
Application number
CN201510534307.4A
Other languages
Chinese (zh)
Other versions
CN105153122B (en
Inventor
彭快
郑飞鸣
傅勇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Henan inno Medicine Technology Co.,Ltd.
Original Assignee
Shanghai Sheng Kao Pharmaceutical Technology Co Ltd
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 Shanghai Sheng Kao Pharmaceutical Technology Co Ltd filed Critical Shanghai Sheng Kao Pharmaceutical Technology Co Ltd
Priority to CN201510534307.4A priority Critical patent/CN105153122B/en
Publication of CN105153122A publication Critical patent/CN105153122A/en
Application granted granted Critical
Publication of CN105153122B publication Critical patent/CN105153122B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The invention provides a [(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative and its salt, a preparation method of the derivative, and application of the derivative and the salt. The [(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative has a structure shown in the formula I below. Deuterium-carbon bonds in the derivative enable the derivative to decompose slowly in a human body, a medicament of the derivative has a longer half-life period and a higher concentration in blood, the dosage of the medicament is finally reduced, and toxic and side effects of the medicament are decreased. Experiments show that compared with AZD 9291 mesylates, AZD 929-D9 mesylate of the deuterium-substituted derivative has Cmax which is 1.32 times as high as that of AZD 9291, exposed dose 1.41 times as high as that of AZD 9291, and elimination half-life 1.31 times as long as that of AZD 9291.

Description

[(indol-3-yl) pyrimidine-2-base] aminophenyl third-2-alkenylamide derivative and salt, preparation method, application
Technical field
The present invention relates to field of pharmaceutical chemistry technology, particularly relate to [(indol-3-yl) pyrimidine-2-base] aminophenyl third-2-alkenylamide derivative and salt thereof, its preparation method, application.
Background technology
In worldwide, the malignant tumour that sickness rate and mortality ratio all rank the first is lung cancer, and wherein the most common is nonsmall-cell lung cancer.EGF-R ELISA-1 (epidermalgrowthfactorreceptor, EGFR) is expressed usually at nonsmall-cell lung cancer tumor cell surface; With its ligand binding or after forming heterodimer with other EGF-R ELISA (HER2, EGFR3), can activating cells downstream signal transduction approach, cause the abnormality proliferation of cell.Visible for nonsmall-cell lung cancer, EGFR is a very important therapy target.Particularly, in fraction of nonsmall cell lung cancer, as non-squamous cell carcinoma, there is the 19 exon point mutation of EGFR and the L858R deletion mutantion of 21 exons.Tyrosine kinase inhibitor (the tyrosinekinaseinhibitor of anti-like this EGFR, TKI), if Gefitinib (Gefitinib), Erlotinib (Erlotinib), Ah method are for Buddhist nun (Afatinib), effective especially to this type of patient.Simultaneously relative to chemotherapy, this three kinds of medicines efficient higher, longer without the progression of disease phase, and also toxicity is taught little.
But use this kind of TKI to carry out in the process for the treatment of, can there is the secondary mutation of EGFR the 20th outer display T790M in the tumour carrying EGFR sensitizing mutation, cause the secondary resistance to this kind of TKI, and the incidence of this secondary mutation is about 50%.In addition, some patients is also had to carry the sudden change of the EGFRT790M of former, to this kind of TKI resistance.Therefore, in order to the secondary and initial drug-resistant that overcome EGFRT790M cause to Gefitinib (Gefitinib), Erlotinib (Erlotinib), Ah method is for the resistance of Buddhist nun (Afatinib), have developed a kind of irreversible EGFR tyrosine kinase inhibitor, the T790M of EGFR is suddenlyd change, the nonsmall-cell lung cancer of 19 exon point mutation and L858R point mutation all has good inhibition, Gefitinib (Gefitinib) may be become, Erlotinib (Erlotinib), Ah method is for the second line treatment medicine after Buddhist nun (Afatinib) resistance.
In prior art, AZD-9291 is efficient selective EGFR mutant inhibitor; Its molecular formula is C 28h 33n 7o 2; Its structural formula is for shown in formula 1:
The IC50 of AZD9291 to exon 19 absence type EGFR, L858R/T790MEGFR and Wild type EGFR is respectively 12.92nM, 11.44nM and 493.8nM.But the transformation period of AZD9291 is shorter, and using dosage is higher, cause bad metabolism, as higher diarrhoea, fash and nauseating incidence, therefore, be necessary to be optimized the structure of this medicine, increase the transformation period, to reduce the dosage of medicine, reduce drug toxicity.
Summary of the invention
In view of this, the object of the present invention is to provide [(indol-3-yl) pyrimidine-2-base] aminophenyl third-2-alkenylamide derivative and salt thereof, its preparation method, application, the transformation period of [(indol-3-yl) pyrimidine-2-base] provided by the invention aminophenyl third-2-alkenylamide derivative increases, reduce the dosage of medicine, reduce drug toxicity.
The invention provides [(indol-3-yl) pyrimidine-2-base] aminophenyl third-2-alkenylamide derivative, there is formula I structure:
In formula I, described R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19and R 20be hydrogen or deuterium independently.
Preferably, in described formula I, the number of D atom is 9 ~ 29.
Preferably, described derivative has formula 101, formula 102, formula 103 or formula 104 structure:
The invention provides the mesylate of derivative described in technique scheme, there is formula II structure:
The invention provides the preparation method of derivative described in technique scheme, comprise the following steps:
The compound with formula III structure is reacted with the compound with formula IV structure, obtains the compound with formula V structure;
The described compound with formula V structure is carried out reducing and amidation successively, obtains the derivative with formula I structure;
Described R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19and R 20independently selected from hydrogen or deuterium;
In formula III, described M is F, Cl, Br or I.
Preferably, the compound described in formula III structure is obtained by following preparation method:
The compound with formula VI structure is reacted with the compound with formula VII structure, obtains the compound with formula III structure;
Described R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19and R 20independently selected from hydrogen or deuterium;
In formula VI, described R is F, Cl, Br or I.
Preferably, the temperature of the compound described in formula VI structure and the reaction of the compound with formula VII structure is 90 DEG C ~ 100 DEG C; Reaction times is 18 ~ 22h.
Preferably, the temperature of the compound described in formula III structure and the reaction of the compound with formula IV structure is 93 ~ 98 DEG C; Reaction times is 5.5 ~ 6.5h.
The invention provides the application of derivative in the medicine of preparation treatment tumour that described in the mesylate of derivative described in derivative, technique scheme described in a kind of technique scheme or technique scheme prepared by preparation method.
Preferably, described tumour is malignant tumour.
The invention provides [(indol-3-yl) pyrimidine-2-base] aminophenyl third-2-alkenylamide derivative, there is formula I structure.Deuterium-carbon bond in [(indol-3-yl) pyrimidine-2-base] provided by the invention aminophenyl third-2-alkenylamide derivative makes it, and decomposition rate is slow in vivo, extend the transformation period of medicine, add the Plasma Concentration of medicine, finally reduce its using dosage, reduce its toxic side effect.Experimental result shows: deuterated derivative AZD9291-D9 mesylate provided by the invention compares AZD9291 mesylate, C maxit is 1.32 times of AZD9291 mesylate; Its exposed amount (AUC 0-t) be 1.41 times of AZD9291 mesylate; It eliminates transformation period t 1/2be 1.31 times of AZD9291 mesylate, namely extend 31%,
Accompanying drawing explanation
Fig. 1 is the reaction scheme figure of the embodiment of the present invention 1;
Fig. 2 is the LC-MS detection figure of the brown solid that the embodiment of the present invention 1 step 9 prepares;
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of the brown solid that the embodiment of the present invention 1 step 9 prepares;
Fig. 4 is the carbon-13 nmr spectra figure of the brown solid that the embodiment of the present invention 1 step 9 prepares;
Fig. 5 is the LC-MS detection figure of the off-white color solid that the embodiment of the present invention 1 step 10 prepares;
Fig. 6 is the hydrogen nuclear magnetic resonance spectrogram of the off-white color solid that the embodiment of the present invention 1 step 10 prepares;
Fig. 7 is that the mesylate drug prepared of the embodiment of the present invention and comparative example is to the test result of nude mice;
Fig. 8 is that the mesylate drug prepared of the embodiment of the present invention and comparative example is to the nude mice test result of 40 ~ 120 days.
Embodiment
The invention provides [(indol-3-yl) pyrimidine-2-base] aminophenyl third-2-alkenylamide derivative, there is formula I structure:
In formula I, described R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19and R 20be hydrogen or deuterium independently.
In the present invention, in described formula I, the number of D atom is preferably 9 ~ 29; In a particular embodiment of the present invention, in described formula I, the number of D atom is specially 9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28 or 29.
In the present invention, described derivative preferably has formula II, formula III, formula IV or formula V structure:
The invention provides the mesylate of derivative described in a kind of technique scheme, there is formula II structure:
In the present invention, in described formula II, the number of D atom is preferably 9 ~ 29; In a particular embodiment of the present invention, in described formula II, the number of D atom is specially 9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28 or 29.
In the present invention, the mesylate of described derivative preferably has formula 201, formula 202, formula 203 or formula 204 structure:
The invention provides the preparation method of derivative described in a kind of technique scheme, comprise the following steps:
The compound with formula III structure is reacted with the compound with formula IV structure, obtains the compound with formula V structure;
The described compound with formula V structure is carried out reducing and amidation successively, obtains the derivative with formula I structure;
Described R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19and R 20independently selected from hydrogen or deuterium;
In formula III, described M is F, Cl, Br or I.
The compound with formula VI structure reacts with the compound with formula VII structure by the present invention, obtains the compound with formula V structure.
In the present invention, the compound described in formula III structure is obtained by following preparation method:
The compound with formula VI structure is reacted with the compound with formula VII structure, obtains the compound with formula III structure;
Described R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19and R 20independently selected from hydrogen or deuterium;
In formula VI, described R is F, Cl, Br or I.
The present invention does not have special restriction to the described source with the compound of formula VI structure, adopt the compound with formula VI structure well known to those skilled in the art, as adopted its commercial goods, the technical scheme that also preparation well known to those skilled in the art can be adopted to have the compound of formula VI structure is prepared voluntarily.In the present invention, the compound described in formula VI structure obtains preferably by following methods:
By the deuterated iodomethane reaction of compound and three with formula VII structure, obtain the compound with formula VI structure;
The present invention does not have special restriction to the described source with the compound of formula VII structure, adopt the compound with formula VII structure well known to those skilled in the art, as adopted its commercial goods, the technical scheme that also preparation well known to those skilled in the art can be adopted to have the compound of formula VII structure is prepared voluntarily.In the present invention, the compound described in formula VII structure is preferably obtained by following preparation method:
By there is the compound of formula VIII structure and there is the compound reaction of formula IX structure, obtain the compound with formula VII structure;
In the present invention, the compound described in formula VIII structure is preferably specially shown in formula 301:
In the present invention, the compound described in formula IX structure is preferably specially shown in formula 302:
The present invention preferably will have the compound dissolution of formula VIII structure in methylene dichloride, obtains the compound solution with formula VIII structure.The volume ratio of the described amount of substance and methylene dichloride with the compound of formula VIII structure is preferably 0.13 ~ 0.16mol:500mL.The present invention is preferably at AlCl 3existence under carry out the reaction of the compound of formula VIII structure and the compound of formula IX structure; Described AlCl 30.15 ~ 0.2:0.13 ~ 0.15 is preferably with the amount of substance ratio of the compound of formula VIII structure.
In the present invention, the amount of substance of the compound of described formula VIII structure and the compound of formula IX structure is than being preferably 1:1; The temperature of the compound of formula VIII structure and the compound reaction of formula IX structure is preferably 20 DEG C ~ 30 DEG C; The time of the compound of formula VIII structure and the compound reaction of formula IX structure is preferably 12 ~ 15h.Reaction solution preferably extracts by the present invention.The present invention preferably adopts ethyl acetate EtOAc to extract; The number of times of described extraction is preferably 3 times.
The present invention preferably carries out having the compound of formula VII structure and the reaction of three deuterated methyl iodide in a nitrogen atmosphere.The present invention preferably carries out having the compound of formula VII structure and the reaction of three deuterated methyl iodide under the existence of NaH and tetrahydrofuran (THF).In the present invention, the compound of described NaH, formula VII structure and the amount of substance of three deuterated methyl iodide are than being preferably (6.7 ~ 6.8): (5.5 ~ 5.6): (6.6 ~ 6.7), are more preferably (6.73 ~ 6.78): (5.53 ~ 5.55): (6.63 ~ 6.68).In the present invention, the temperature of the compound and three deuterated iodomethane reactions described in formula VII structure is preferably 0 DEG C; The time of the described compound and three deuterated iodomethane reactions with formula VII structure is preferably 1.5 hours.The reaction solution that the deuterated iodomethane reaction of compound and three with formula VII structure obtains preferably extracts by the present invention.The present invention preferably adopts ethyl acetate EtOAc to extract; The number of times of described extraction is preferably 3 times.The present invention preferably washs extracting the organic phase obtained.The present invention preferably adopts saturated brine to wash; The number of times of described washing is preferably 3 times.Washed product is preferably carried out drying by the present invention; The present invention preferably adopts anhydrous sulfate to carry out drying; Described anhydrous sulfate is preferably anhydrous sodium sulphate.
In the present invention, the compound described in formula VI structure is preferably specially shown in formula 303:
The source of the present invention to the compound with formula VII structure does not have special restriction, adopts the compound of formula VII structure well known to those skilled in the art, as adopted its commercial goods.In the present invention, the compound described in formula VII structure is preferably specially shown in formula 304:
The present invention preferably carries out having the compound of formula VI structure and has the reaction of compound of formula VII structure under the existence of tosic acid and sec.-amyl alcohol.In the present invention, there is described in the compound of formula VI structure, there is the amount of substance of the compound of formula VII structure and tosic acid than being preferably 1:1:1.15 ~ 1.2; The volume of described sec.-amyl alcohol and the amount of substance of tosic acid are than being preferably (23 ~ 26) mL:(1.15 ~ 1.2) mol.In the present invention, described in have formula VI structure compound and have formula VII structure compound reaction temperature be preferably 90 DEG C ~ 100 DEG C, be more preferably 95 DEG C; The time of the described compound with formula VI structure and the compound reaction with formula VII structure is preferably 18 ~ 22h, is more preferably 20h.The reaction solution that the compound with formula VI structure and the compound with formula VII structure are obtained by reacting preferably is cooled to room temperature by the present invention, has solid to separate out.The solid obtained preferably is carried out suction filtration, washing and drying by the present invention successively.The present invention preferably adopts sec.-amyl alcohol and water to wash successively.The present invention preferably adopts vacuum-drying.
In the present invention, the compound described in formula III structure is preferably specially shown in formula 305:
The present invention does not have special restriction to the described source with the compound of formula IV structure, preparation well known to those skilled in the art is adopted to have the compound of formula IV structure, as adopted its commercial goods, the technical scheme that also preparation well known to those skilled in the art can be adopted to have the compound of formula IV structure is prepared voluntarily.In the present invention, the preparation method described in the compound of formula IV structure preferably includes following steps:
To compound and the reaction of deuterated dimethylamine of formula X structure be had, obtain the compound with formula XI structure;
To the compound reduction of formula XI structure be had, obtain the compound with formula IV structure;
The present invention will have compound and the reaction of deuterated dimethylamine of formula X structure, obtain the compound with formula XI structure.In the present invention, the compound described in formula X structure is preferably specially shown in formula 306:
In the present invention, described deuterated dimethylamine preferably participates in anti-with the hydrochloride form of deuterated dimethylamine; The amount of substance ratio of the described compound and deuterated dimethylamine with formula X structure is preferably 34 ~ 35:22 ~ 23.In the present invention, the temperature of the compound and the reaction of deuterated dimethylamine described in formula X structure is preferably 20 DEG C ~ 30 DEG C; The time of the described compound and the reaction of deuterated dimethylamine with formula X structure is preferably 20 ~ 24h.
After obtaining having the compound of formula XI structure, the present invention will have the compound reduction of formula XI structure, obtain the compound with formula IV structure.
The present invention preferably adopts tetrahydrochysene lithium aluminium to carry out the reduction of the compound with formula IV structure.In the present invention, described tetrahydrochysene lithium aluminium is preferably 9 ~ 11:1 with the amount of substance ratio of the compound with formula IV structure, is more preferably 10:1.The present invention preferably carries out above-mentioned reduction under the existence of anhydrous tetrahydro furan.In the present invention, the temperature of described reduction is preferably 0 ~ 5 DEG C; The time of described reduction is preferably 5.5 ~ 6.5h.The present invention preferably carries out cancellation, filtration, the adjustment of pH value, extraction and drying to reaction solution.The present invention preferably adopts water to carry out cancellation.The pH value of reaction solution is preferably adjusted to 2 ~ 3 by the present invention.Reaction solution after pH value preferably regulates by the present invention and water mixing, then extract, obtain aqueous phase.Described aqueous phase preferably adopts cryodesiccated mode to carry out drying by the present invention.
In the present invention, the compound described in formula IV structure is preferably specially shown in formula 307:
In the present invention, the reaction of the compound described in formula III structure and the compound with formula IV structure is preferably carried out under the existence of DIPEA (DIEA) and N,N-dimethylacetamide (DMAC).In the present invention, the temperature of the compound described in formula III structure and the reaction of the compound with formula IV structure is preferably 93 ~ 98 DEG C; The time of the described compound with formula III structure and the compound reaction with formula IV structure is preferably 5.5 ~ 6.5h.In the present invention, the amount of substance of the compound described in formula III structure and the compound with formula IV structure is than being preferably 7 ~ 9:10.
The reaction solution that the compound with formula III structure and the compound with formula IV structure are obtained by reacting preferably is cooled to 20 ~ 30 DEG C by the present invention.The present invention preferably by the reaction solution of cooling and water mixing, stirs, separates out solid.The reaction solution suction filtration that the present invention preferably will have solid to separate out, obtains filter cake; Described filter cake is washed; Described filtrate carried out successively extract, wash, dry and concentrated, obtain solid product; By solid product and filter cake mixing, obtain the compound with formula V structure.
After obtaining having the compound of formula V structure, the compound with formula V structure carries out reducing and amidation by the present invention successively, obtains the derivative with formula I structure.The present invention preferably carries out the reduction of the compound of formula V structure under the existence of iron powder and ammonium chloride.The present invention preferably carries out the reduction of the compound of formula V structure in the mixing solutions of second alcohol and water.The compound of formula V structure is preferably warming up to backflow and reacts by the present invention; The time of the compound reduction of described formula V structure is preferably 2.5 ~ 3.5h, is more preferably 3h.The present invention preferably the compound of formula V structure is reduced obtain reaction solution cooling and filter; The filtrate obtained is concentrated, enriched material is purified, obtain reduzate.
The present invention, by reduzate amidation, obtains the derivative with formula I structure.The present invention preferably adopts 3-chlorpromazine chloride and NaOH to carry out the amidation of reduzate.The present invention is reduzate is first and 3-chlorpromazine chloride reaction preferably, obtains intermediate; Described intermediate is reacted with NaOH again, obtains the derivative with formula I structure.The present invention preferably carries out amidation under the mixed solvent of tetrahydrofuran (THF) and water.In the present invention, the amount of substance of described reduzate and 3-chlorpromazine chloride is than being preferably 0.8 ~ 0.9:1.In the present invention, described amidated temperature is preferably 0 DEG C; The described amidated time is preferably 9 ~ 11h.Amidated products is preferably cooled to room temperature by the present invention, then mixes with water, obtains mixed solution; Described mixed solution is extracted, obtains organic phase; Described organic phase is carried out successively wash, dry, concentrating under reduced pressure and purification.The present invention preferably adopts ethyl acetate to extract.The present invention preferably adopts anhydrous sulfate to carry out drying.The present invention preferably adopts volume ratio to be that the methyl alcohol of 1:10 and methylene dichloride are purified as elutriant.
In the present invention, the mesylate of described derivative, has formula II structure.The preparation method of the present invention to the mesylate of derivative does not have special restriction, adopts the salify mode of mesylate well known to those skilled in the art.In the present invention, the preparation method of the mesylate of described derivative preferably includes following steps:
By derivative described in technique scheme and methylsulfonic acid reaction, obtain the mesylate of derivative.
Described derivative is preferably first dissolved in the mixing solutions of acetone and water by the present invention, obtains derivative solution.In the present invention, the amount of substance of described derivative and the volume ratio of mixing solutions are preferably (0.07 ~ 0.09) mol:(0.4 ~ 0.5) mL, be more preferably 0.08mol:0.44mL; The volume ratio of described acetone and water is preferably 10:1.In the present invention, described methylsulfonic acid preferably participates in reaction with the acetone soln of methylsulfonic acid; The volume ratio of described methylsulfonic acid and amount of substance and acetone is preferably (0.07 ~ 0.09) mmol:(0.045 ~ 0.055) mL, be more preferably 0.08mmol:0.05mL.
In the present invention, the temperature of described derivative and methylsulfonic acid reaction is 55 ~ 65 DEG C; The time of described derivative and methylsulfonic acid reaction is preferably 1 ~ 5 hour.
The reaction solution that derivative and methylsulfonic acid are obtained by reacting preferably carries out being cooled to 20 DEG C ~ 30 DEG C by the present invention, and adularescent solid is separated out.The present invention, preferably by the reacting liquid filtering of cooling, to solid methyl tertiary butyl ether (MTBE) washing obtained, obtains the mesylate of derivative.
In the present invention, the pharmacy acceptable salt of described derivative, crystalline hydrate, solvate, prodrug, monocrystalline type thing or polymorphic form are all in protection scope of the present invention.
Present invention also offers the application of derivative in the medicine of preparation treatment tumour that described in the mesylate of derivative described in derivative, technique scheme described in a kind of technique scheme or technique scheme prepared by preparation method.
In the present invention, described tumour is preferably malignant tumour; Described malignant tumour preferably include medullary thyroid carcinoma, nonsmall-cell lung cancer, carcinoma of the pancreas, kidney, metastatic renal cell cancer, bladder cancer, ovarian cancer, the cancer of the brain, mammary cancer prostate cancer, multiple myeloma, soft tissue sarcoma, melanoma cancer, recurrence/transitivity Merkel cell carcinoma, carcinoma of endometrium, plexiform neurofibroma, liver cancer, late period cholangiocellular carcinoma, adult glioblastoma multiforme, transitivity tie straight cancer or acute myelocytic leukemia.More preferably medullary thyroid carcinoma or prostate cancer or liver cancer or kidney.In some embodiments of the invention, for malignant tumour be nonsmall-cell lung cancer.
In the present invention, the mesylate of described derivative or derivative, when the medicine as treatment tumour, also comprises pharmaceutically acceptable auxiliary material.In the present invention, described pharmaceutically acceptable auxiliary material comprises: one or more in pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle.
Can be used as pharmaceutically acceptable carrier substance to include, but are not limited to: sugar, as lactose, dextrose plus saccharose; Starch is as W-Gum and potato starch; Serum protein, as human serum protein; Cellulose and its derivates as Xylo-Mucine, ethyl cellulose and rhodia; Buffer substance, as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate; Ion-exchanger, aluminum stearate Yelkin TTS; The partial glyceride mixtures of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, sodium-chlor, Sodium phosphate dibasic, polyvinylpyrrolidone, colloidal silicon, potassium hydrogen phosphate, Magnesium Trisilicate, polyacrylate, zinc salt, lanolin, polyethylene-polyoxypropylene-blocking-up polymer; Natural gum powder; Fructus Hordei Germinatus; Gelatin; Talcum powder; Auxiliary material is as cocoa butter and suppository wax; Oily as peanut oil, Thistle oil, oleum gossypii seminis, sesame oil, sweet oil, soya-bean oil and Semen Maydis oil; Glycol compound, as propylene glycol and polyoxyethylene glycol; Ester class is as ethyl oleate and Ethyl Lauroyl acid esters; Agar; Buffer reagent is as aluminium hydroxide and magnesium hydroxide; Lalgine; Pyrogen-free water; Isotonic salt; Lin Ge (family name) solution; Ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, coating agents, sweeting agent, seasonings and spices, sanitas and antioxidant.
In the present invention, the tumour medicine for preparing of the mesylate of described derivative or derivative can oral administration administration, drug administration by injection, Aerosol inhalation administration, topical, per rectum administration, nose administration, containing taking administration, vagina administration or by the administration of implantable medicine box.In the present invention, described drug administration by injection comprise in subcutaneous, vein, intramuscular, IA, synovial membrane (chamber), intrasternal, film, intraocular, in liver, intralesional, the injection of encephalic or infusion techniques.In the present invention, pharmaceutical administration is preferably oral administration, to Intraperitoneal medication or intravenous injection.In the present invention, the aseptic injection system of medicine can be water or oleaginous suspension, and these suspension can adopt suitable dispersion agent, wetting agent and suspension agent to manufacture by formula according to known technology.Aseptic injection can be aseptic parenteral solution or suspension, injects nontoxic acceptable thinner or solvent, as 1,3 butylene glycol solution.These acceptable vehicle and solvent can be water, sodium chloride solution and Ringer's solution etc.Further, aseptic nonvolatile oil by convention can as solvent or suspension medium.
The solid dosage of oral administration can comprise tablet, capsule, pulvis, granula and pill.Further, in these formulations, active compound and the pharmaceutically acceptable inert excipient of at least one or carrier or filling agent mix, as Trisodium Citrate, calcium phosphate.Weighting agent as lactose, starch, glucose, N.F,USP MANNITOL, sucrose or silicic acid; Tackiness agent as alginate, carboxymethyl cellulose, sucrose, Povidone, gelatin, or gum arabic; Absorption agent is as bentonite or white bole; Wetting Agent for Printing Inks is as glycerine; Disintegrating agent as calcium carbonate, potato starch, Lalgine, agar, tapioca (flour), some silicate or sodium carbonate; Absorption enhancer is as quaternary ammonium compounds; Wetting agent is as hexadecanol and glyceryl monostearate; Lubricant as solid polyethylene glycol, Magnesium Stearate, calcium stearate, talcum powder, Sulfuric acid,monododecyl ester, sodium salt, and their mixture; Retarding agent solution is as paraffin; Buffer reagent can be comprised as formulations such as tablet, capsule or pills.
Solid dosage can comprise sugar-pill, tablet, granule, pill or capsule etc., can adopt dressing or the preparation of shell material, as casing or other material well known in the art.And active compound can discharge by the mode postponed in such composition, be released in certain part in digestive tube.Further, active compound can form microencapsulation form with one or more in above-mentioned vehicle.
Tumour medicine can also be incorporated in suitable delivery vector, and such delivery vector can provide and controls and/or discharge compound continuously, also can be used as targeting moiety.The Non-limiting examples ground of delivery vector comprises adjuvant, synthetic adjuvant, microcapsule, particulate, liposome and yeast cell wall particle.The wall of yeast cell can differently process optionally to remove protein component, dextran or mannosans layer.
Tumour medicine can be carry out oral administration with any acceptable oral dosage form, comprising but be not limited to: capsule, tablet, water suspension or water solution.Orally use about tablet and enteric coated tablet formulation, weighting agent generally comprises lactose, sucrose, W-Gum, lactose, glucose, silicic acid, Trisodium Citrate, N.F,USP MANNITOL, Si Liaodengji dicalcium phosphate feed grade; Binding is as starch, derivatived cellulose, gel, Polyvinylpyrolidone (PVP) (pvp), sucrose; Lubricant is as glycerine; Disintegrating agent is as agar, calcium carbonate, potato, tapioca (flour), Lalgine or croscarmellose sodium; Lubricant such as Magnesium Stearate and glycerine are all typically added.For capsule oral administration, suitable thinner comprises lactose and dry W-Gum.When oral administration is water suspension, its effective constituent is made up of emulsifying agent and suspension agent.When preparing these formulations, pharmaceutically acceptable sweeting agent, seasonings or tinting material also can be added.
In the present invention, the dosage of the medicine of tumour that the mesylate of described derivative or derivative prepares should consider the factor such as route of administration, patient health situation.In the present invention, for the people of 60kg body weight, day dosage be preferably 1 ~ 1000mg, be more preferably 5 ~ 100mg.
In order to further illustrate the present invention; below in conjunction with embodiment, [(indol-3-yl) pyrimidine-2-base] aminophenyl third-2-alkenylamide derivative provided by the invention and salt thereof, its preparation method, application are described in detail, but they can not be interpreted as limiting the scope of the present invention.
Embodiment 1
Reaction scheme as shown in Figure 1, Fig. 1 is the reaction scheme figure of the embodiment of the present invention 1:
Step one: preparation 3-(2-chloropyrimide-4-base)-1H-indoles
N 2under atmosphere, in methylene dichloride (500mL) solution of compound 1 (21g, 0.14mol), add AlCl in batches 3(22.5g, 0.17mol), finishes for 10 minutes.After gained suspension liquid at room temperature stirs 10 minutes, reaction system is clarified substantially.Under room temperature, in above-mentioned reaction solution, add compound 2 (16.5g, 0.14mol) in batches, within 10 minutes, add.Gained brown suspension, spends the night under stirring at room temperature; React through TLC monitoring, when compound 1 consumes completely, poured into by reaction solution under stirring in frozen water (500mL), this system extracts 3 times through EtOAc (300mL).Merge organic phase, and with salt water washing (200mL) 2 times, after anhydrous sodium sulfate drying, concentrating under reduced pressure obtains 38g viscous brown crude product.This thick product is purified (elutriant n-hexane:EtOAc=5:1 to 3:1) through silica gel column chromatography, obtains 16g target compound 3, yellow solid, yield 49%.
The LC-MS test result of compound 3 is: LCMS (ESI+): m/z230.15 (M+H); 1h-NMR (300MHz, DMSO-d6) δ 12.09 (brs, 1H), 8.59-8.54 (m, 2H), 8.44-8.40 (m, 1H), (7.92 d, J=5.4Hz, 1H), 7.52-7.50 (m, 1H), 7.34-7.20 (m, 2H).
Step 2: preparation 3-(2-chloropyrimide-4-base) the deuterated Methvl-indole of-1-three
Under nitrogen atmosphere, under ice bath cooling, to 3-(2-chloropyrimide-4-base)-1H-indoles 3 (1.27g, in THF (50mL) solution 5.53mmol), add 60%NaH (0.27g, 6.75mmol), 20min finishes in batches, this reaction solution stirs 0.5 hour at 0 DEG C, in above-mentioned reaction system, drip three deuterated methyl iodide (0.96g, 6.64mmol), 10min drips complete, and 0 DEG C of reaction 1.5 hours, TLC monitored reaction; When raw material 3 is exhausted, reaction terminates, and slowly drips saturated sodium bicarbonate solution (10mL) cancellation reaction in reaction solution.Gained mixture EtOAc (40mL) is extracted 3 times, merges organic phase, and wash (40mL) 3 times with saturated brine; After anhydrous sodium sulfate drying, concentrating under reduced pressure obtains 1.29g yellow solid 4, yield 94.9%, and this compound 4, without further purification, is directly used in next step.
The test result of compound 4 is: HPLC:96.8%; LCMS (ESI+): m/z247.16 (M+H); 1h-NMR (300MHz, CDCl 3) δ 8.46-8.42 (m, 1H), 8.38-8.31 (m, 1H), 7.95 (s, 1H), 7.50-7.46 (m, 1H), 7.40-7.28 (m, 3H).
Step 3: preparation N-(4-fluoro-2-methoxyl group-5-nitrophenyl)-4-(the deuterated Methvl-indole-3-of I-tri-certain) pyrimidine-2-amine
By compound 4 (1.19g, 4.82mmol) under room temperature, compound 5 (0.90g, 4.82mmol) and p-TsOH .h 2o (1.1g, 5.72mmol) adds in sec.-amyl alcohol (24mL), and gained suspension liquid, through nitrogen replacement 3 times, stirs after 5 minutes, is warming up to 95 DEG C of reactions.HPLC monitors reaction.After 20 hours, HPLC shows starting compound 4 completely dissolve, and reaction terminates.After reaction solution is down to room temperature, stirs 1 hour, have solid to separate out.Suction filtration, filter cake uses sec.-amyl alcohol (2mL) and water (2mL) washing successively.Gained solid obtains 1.8g yellow solid compound 6 through vacuum-drying.This product, without further purification, is directly used in next step.
The test result of compound 6 is: HPLC:94.8% (deduction p-TsOH); LCMS (ESI+): m/z397.11 (M+H); 1h-NMR (300MHz, DMSO-d6) δ 9.84 (brs, 1H), 8.75 (d, J=8.1Hz, 1H), 8.69 (t, J=2.1Hz, 1H), 8.32 (d, J=6.6Hz, 1H), 8.20 (d, J=7.2Hz, 1H), 7.59 (t, J=8.1Hz, 1H), 7.53-7.47 (m, 2H), 7.31 (t, J=7.5Hz, 1H), 7.13 (t, J=8.1Hz, 1H), 4.00 (s, 3H) (thick product, the TsOH containing about 25%).
Step 4: prepare intermediate 7-2
7 (10g, 0.13mol, 1.0eq), 50mL water and 50mL (1mol/L) aqueous sodium hydroxide solution is added in reaction flask.Be cooled to 0 ~ 5 DEG C with ice-water bath after stirring clarification, then drip 7-1 (14.4g, 0.13mol, toluene solution (30mL) 1.0eq), the while of in dropping process, hydrogen make-up aqueous solution of sodium oxide (1M, 216mL), makes system pH remain between 8 ~ 10.Move to room temperature after adding and stir 30 minutes.Add 500mL water dilute reaction solution, extracting (250mLx3) with EtOAc.Collect aqueous phase and dilute hydrochloric acid (1mol/L) be adjusted to PH to 3 ~ 4, aqueous phase extracts three times (250mLx3) with extracting EtOAc again.EtOAc phase Na 2sO 4drying, filtering and concentrating obtains compound 7-2.
1HNMR(300MHz,CDCl 3)δ5.28(s,2H),4.20-4.15(m,2H),4.13-4.02(m,2H),1.27(t,3H,J＝7.2Hz)。
Step 5: prepare intermediate 7-3
Under room temperature, to Pvi-Cl (4.13g, 34.27mmol, 1.5eq) with TEA (4.0g, 39.53mmol, 1.7eq) chloroform (55mL) solution in, slowly drip compound 7-2 (5.04g, 34.27mmol, 1.5eq) chloroformic solution (55mL).After dropwising, more under nitrogen protection, stirring at room temperature 1.5 hours.Under nitrogen protection, add the hydrochloride (2.0g, 22.84mmol, 1.0eq) of deuterated dimethylamine, then stirring at room temperature 22 hours under enclosed system.Add 100mL water, at room temperature stir 1 hour, then add 40mL chloroform, organic phase with 100mL water washing once, then use the aqueous sodium carbonate of 100mL (1mol/L) to wash 3 times, then the water washing using 100mL is once.Chloroform uses Na mutually 2sO 4drying, filters, and crosses column purification, obtain compound 7-3 (3.0g, productive rate: 72%) after concentrated;
1HNMR(300MHz,CDCl 3)δ5.68(s,1H),4.21-4.10(m,2H),4.02-3.98(m,2H),1.27(t,3H,J＝7.2Hz).
Step 6: preparation N-methyl-N ', N '-two (three deuterated methyl) 1，2-diaminoethane 8
Compound 7-3 (3.0g, 16.6mmol, 1.0eq) is dissolved in the anhydrous THF of 100mL.Be cooled to 0 ~ 5 DEG C with ice-water bath under nitrogen protection, then slowly add tetrahydrochysene lithium aluminium (7.0g, 166mmol, 10eq) in batches, after stablizing and there is no bubble formation, be slowly warming up to micro-backflow.After 6 hours, reaction terminates.After system is down to room temperature, be cooled to 0 ~ 5 DEG C with ice-water bath, dropwise slowly add 7mL shrend and go out, more dropwise slowly add the aqueous sodium hydroxide solution of 7mL20%, more dropwise slowly add 7mL water.Stirring at room temperature is after 30 minutes, filters, and with THF washing leaching cake three times, collects filtrate, with after dilute hydrochloric acid adjustment pH2-3 by solution evaporate to dryness, then add water (150mL), extract three times with EtOAc (150mLx3).Aqueous phase is dry through freeze-drying, obtains compound 8 (2.6g, productive rate: 86%).
The test result of compound 8 is: 1hNMR (300MHz, D 2o) δ 3.51-3.42 (m, 4H), 2.74 (s, 3H).
Step 7: preparation N '-(2-[two (three deuterated methyl) is amino] ethyl)-2-methoxyl group-N '-methyl-N-[4-(1-tri-deuterium methyl draws diindyl-3-base) pyrimidine-2-base]-5-nitre benzene-Isosorbide-5-Nitrae-diamines 9
Under room temperature, by compound 6 (300mg, 0.76mmol), compound 8 (170.0mg, 0.94mmol) and DIEA (440.0mg, 3.4mmol) add in DMAC (3mL), in vexed tank, be warming up to 95 DEG C of reactions, HPLC monitors reaction, after 6 hours, HPLC shows raw material 6 completely dissolve, and reaction terminates; Reaction solution is down to room temperature, adds water (3mL), stirring at room temperature 2 hours, has solid to separate out, suction filtration, and filter cake use water (2mL) washs; Filtrate extracts 3 times with EtOAc (30mL), merges organic phase, and washes 6 times (30mL) with water to remove DMAC.Through anhydrous sodium sulfate drying, obtain brick-red solid compound 9 after concentrating under reduced pressure, yield 73%.This product, without further purification, is directly used in next step.
The test result of compound 9 is: LCMS (ESI+): m/z485.33 (M+H); 1h-NMR (crude product 300MHz, CDCl 3) δ 9.59 (s, 1H), 8.41-8.18 (m, 4H), 7.63 (s, 1H), 7.41-7.20 (m, 2H), 7.20 (d, J=5.1Hz, 1H), 6.82 (s, 1H), 4.04 (s, 3H), 3.30 (t, J=6.9Hz, 2H), 3.0 (s, 3H), 2.60 (t, J=6.9Hz, 2H).
Step 8: preparation N 1-(2-[two (three deuterated methyl) is amino] ethyl)-5-methoxyl group-N 1-methyl-N 4-[4-(1-tri-deuterium methyl draws diindyl-3-base) pyrimidine-2-base] benzene-1,2,4-triamine 10
By compound 9 (1.08g, 2.23mmol) under room temperature, iron powder (0.750g, 13.38mmol) and NH 4cl (0.084g, 1.57mmol) adds to EtOH/H 2in O (60mL/20mL), and be warming up to backflow.After 3 hours, TLC shows raw material 9 completely dissolve, and reaction terminates; Reaction solution is down to room temperature, filters; Filter cake ethanol (10mL) washs 3 times, filtrate reduced in volume, and gained residue by silicagel column chromatography (elutriant MeOH:DCM=1:10,1% ammoniacal liquor) is purified, and obtains 790mg beige solid compound 10, yield 78%.
The test result of compound 10 is: HPLC:98.1%; LCMS (ESI+): m/z455.33 (M+H); 1h-NMR (300MHz, CDCl 3) δ 8.48-8.46 (m, 1H), 8.34 (d, J=5.1Hz, 1H), 8.20 (s, 1H), 7.82 (s, 1H), 7.64 (s, 1H), 7.39-7.28 (m, 3H), 7.05 (d, J=5.1Hz, 1H), 6.67 (s, 1H), 3.86 (s, 3H), 3.49 (s, 2H), 3.30 (t, J=5.7Hz, 2H), 3.08 (d, J=5.7Hz, 2H), 2.72 (s, 3H)
Step 9: preparation N-(2-{2-[two (three deuterated methyl) is amino] ethyl-(methyl) is amino }-4-methoxyl group-5-{ [4-(1-tri-deuterated skatole-3-base) pyrimidine-2-base] amino } phenyl) the third-2-alkene acid amides (AZD9291-d9)
Under ice bath cooling, to the THF/H of compound 10 (0.7g, 1.54mmol) 2drip 3-chlorpromazine chloride (0.24g, 1.85mmoL) in O (6mL/0.6mL) solution, within 10 minutes, drip and finish; This reaction solution continues to stir at 0 DEG C.After 1 hour, TLC and LCMS shows raw material 10 and is exhausted; NaOH (0.25g, 6.15mmoL) is added in above-mentioned reaction solution, and is warming up to backflow.After 9 hours, it is complete that LCMS and TLC shows intermediate primitive reaction, room temperature is down in reaction, adds water (1mL), and extract 3 times with EtOAc (30mL), merges organic phase, washes (10mL) with water 3 times.Through anhydrous sodium sulfate drying, concentrating under reduced pressure obtains 0.9g viscous brown thing crude product.This crude product is purified through silica gel column chromatography (elutriant MeOH:DCM=1:10), obtains 0.61g spumescence brown solid compound 11, yield 78%.
The present invention carries out LC-MS detection to the compound that step 9 obtains, detected result as shown in Figure 2, Fig. 2 is the LC-MS detection figure of the brown solid that the embodiment of the present invention 1 step 9 prepares, as seen from Figure 2: LCMS (ESI+): m/z509.30 (M+H);
The present invention carries out proton nmr spectra detection to the compound that step 9 obtains, and as shown in Figure 3, Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of the brown solid that the embodiment of the present invention 1 step 9 prepares to detected result, as seen from Figure 3: 1h-NMR (300MHz, CDCl 3) δ 10.21 (brs, 1H), 9.87 (s, 1H), 9.14 (s, 1H), 8.40 (d, J=5.4Hz, 1H), 8.09-8.07 (m, 1H), 7.74 (s, 1H), 7.43-7.40 (m, 1H), 7.32-7.23 (m, 2H), 7.22 (d, J=5.4Hz, 1H), 6.82 (s, 1H), 6.52-6.35 (m, 2H), 5.72 (dd, J 1=2.4Hz, J 2=9.6Hz, 1H), 3.96 (s, 3H), 2.91 (t, J=5.4Hz, 2H), 2.73 (s, 3H), 2.30-2.28 (m, 2H).
The present invention carries out carbon-13 nmr spectra test to the compound that step 9 obtains, and as described in Figure 4, Fig. 4 is the carbon-13 nmr spectra figure of the brown solid that the embodiment of the present invention 1 step 9 prepares to test result.
Step 10: preparation N-(2-{2-[two (three deuterated methyl) is amino] ethyl-(methyl) is amino }-4-methoxyl group-5-{ [4-(1-tri-deuterated skatole-3-base) pyrimidine-2-base] amino } phenyl) the third-2-alkene amide mesylate (AZD9291-d9 mesylate)
By compound 11 (40mg, 0.08mmol) be dissolved in acetone/water (0.4mL/0.04mL), and be warming up to 60 DEG C, disposable acetone (0.05mL) solution adding methylsulfonic acid (7.6mg, 0.08mmoL), this reaction solution continues stirring at 60 DEG C and naturally cools to room temperature after 1.5 hours, off-white color solid is had to separate out, filter, with MTBE (1mL) washing, dry 44.6mg white solid 12 (AZD9291-d9 mesylate); The productive rate of off-white color solid AZD9291-d9 mesylate is 94%.
Chemical purity >98%, deuterated purity >99%;
The present invention carries out LC-MS detection to the off-white color solid that embodiment 1 step 10 obtains, detect figure as shown in Figure 5, Fig. 5 is the LC-MS detection figure of the off-white color solid AZD9291-d9 mesylate that the embodiment of the present invention 1 step 10 prepares, as can be seen from Figure 5: LCMS (ESI+): m/z509 (M-OMs);
The present invention carries out proton nmr spectra test to the off-white color solid that step 10 obtains, and as shown in Figure 6, Fig. 6 is the hydrogen nuclear magnetic resonance spectrogram of the off-white color solid AZD9291-d9 mesylate that the embodiment of the present invention 1 step 10 prepares to test result.
As can be seen from Figure 6: 1h-NMR (300MHz, DMSO-d6) δ 9.60 (s, 1H), 9.18 (s, 1H), 8.78 (s, 1H), 8.54 (s, 1H), 8.32 (d, J=5.7Hz, 2H), 7.96 (s, 1H), 7.53 (d, J=8.1Hz, 1H), 7.27-7.13 (m, 3H), 7.02 (s, 1H), 6.69 (dd, J 1=9.9Hz, J 2=16.5Hz, 1H), 6.33 (d, J=16.5Hz, 1H), 5.82 (d, J=10.2Hz, 1H), 3.91 (s, 3H), 3.28 (brs, 4H), 2.63 (s, 3H), 2.09 (s, 3H).
The experiment in vitro of 1.1 deuterated derivative AZD9291-D9 mesylates
The AZD9291-D9 mesylate that Example 1 prepares, investigates its lethal effect to PC-9 and PC-9 persister cell, and using AZD9291 mesylate and Gefitinib as positive control, PBS is as blank.
Respectively by each 20000 of PC-9 and PC-9 persister two kinds of cells, be inoculated into 7 75cm 2tissue Culture Flask, carries out cell cultures.Passage is incubated at 37 DEG C, 5% CO2gas incubator, counting, centrifugal 5 minutes of 1000rpm, adjusts cell density with substratum, according to 2000/100 μ L/ holes, and inoculating cell in 96 orifice plates; Second day, agent-feeding treatment respectively, 100 μ g/mL, 30 μ g/mL, 10 μ g/mL, 3 μ g/mL, 1 μ g/mL, 0.3 μ g/mL, 0.1 μ g/mL, 0.03 μ g/mL, 0.01 μ g/mL, according to above-mentioned cell doubling time, carry out cultivating for 3 days respectively to the PC-9 cell after dosing, PC-9 persister carries out cultivating for 5 days.In detection day, the CCK8 reagent (Japanese colleague's chemistry) of 100 μ L is added in each cell culture well, put into incubator and leave standstill 1 hour, light absorption value is measured at 450nm with Beijing Pu Lang company microplate reader (model DNM9602), application GraphPad software, calculate IC50, testing sample to PC-9 and PC-9 persister lethal effect detected result, in table 1; And Gefitinib is to PC-9 persister lethal effect detected result, in table 2:
Table 1 testing sample is to PC-9 and PC-9 persister lethal effect detected result
Table 2 Gefitinib is to PC-9 persister lethal effect detected result
As known from Table 1, experimental group and positive controls testing sample to the lethal effect of PC-9 persister cell quite, growth half-inhibition concentration IC 50quite, difference is not remarkable, (P > 0.05), the suitable to the lethal effect of cancer cell of the deuterated AZD9291-D9 mesylate that the embodiment of the present invention 1 prepares and AZD9291 mesylate is described, namely by after deuterated for AZD9291 mesylate, its Bioactivity can not be changed.
The Pharmacokinetic Evaluation of 1.2 deuterated derivative AZD9291-D9
The deuterated AZD9291-D9 mesylate that Example 1 prepares, carry out pharmacokinetic studies to it, using AZD9291 mesylate as positive control, PBS is as blank.
Animal subject is: male CD1 mouse, body weight 18 ~ 22g, and tested by the medicine of Shanghai, animal center provides, occupancy permit SYXK (Shanghai) 2010-0049.Animal subject should carry out adaptability raising in test site in 3 ~ 7 days a few days ago in test, and male CD1 mouse, is divided into 2 groups at random, and gavage gives by test agent respectively, and before test, fasting 12 hours, freely drinks water, and administration is unified feed after 2 hours; Single oral gavage gives the testing sample of 25mg/kg dosage, and the testing sample of experimental group and positive controls all uses 0.5%w/v Vltra tears (HPMC);
The aqueous dissolution of 0.1%w/v tween; 0.25h, 0.5h, 1.0h, 2.0h, 3.0h, 5.0h, 8.0h, 10h and 24h sampling upon administration respectively; Each time point 3 mouse, through eyeball of mouse rear vein beard extracting vein blood 0.3mL after above setting-up time point Animal Anesthesia, put in heparinised tubes, centrifugal 5 minutes of 11000g, separated plasma, freezes in-20 DEG C of refrigerator and cooled; During sample detection, plasma sample adopts LC-MS/MS method to measure the concentration of compd A ZD9291 mesylate and deuterated AZD9291-D9 mesylate in blood plasma after methanol extraction albumen, and linearity range is 30.0 ~ 30000ng/mL.
Adopt the main pharmacokinetic parameters (T after the administration of WinNonlin6.3 computed in software mouse stomach max, C max, AUC, MRT and t 1/2).Wherein, peak concentration C is reached maxwith peak time T maxfor measured value.
Lower area of blood concentration-time curve AUC 0-tvalue: adopt trapezoidal method to calculate.
AUC 0-∞＝AUC 0-t+C t/k e，
C tfor last can record the Plasma Concentration of time point, k efor elimination rate constant;
Eliminate transformation period t 1/2=0.693/k e;
Average retention time MRT=AUMC/AUC.
Mouse is after gavage gives 25mg/kgAZD9291-D9 mesylate and AZD9291 mesylate respectively, and the pharmacokinetic parameters of medicine is in table 3, and table 3 is the medicine kinetic parameter of mouse respectively after gavage 25mg/kg medicine:
Medicine kinetic parameter after table 3 mouse difference gavage 25mg/kg medicine
From table 3, experimental data is known, the C of the deuterated AZD9291-D9 mesylate that the preparation method that embodiment 1 provides prepares maxit is 1.32 times of AZD9291 mesylate; Its exposed amount (AUC 0-t) be 1.41 times of AZD9291 mesylate; It eliminates transformation period t 1/2be 1.31 times of AZD9291 mesylate, namely extend 31%, the deuterated AZD9291-D9 mesylate that the present invention prepares is described, compares AZD9291 mesylate, significantly improve Plasma Concentration, extend drug half-life, significant difference.
Embodiment 2
Preparation N-(2-{2-[two (three deuterated methyl) is amino] ethyl-(methyl) is amino }-4-methoxyl group-5-{ [4-(the deuterated methyl-2 of 1-tri-, 4,5, the deuterated indol-3-yl of 6,7-five) pyrimidine-2-base] amino phenyl) the third-2-alkene amide mesylate (AZD9291-D14 mesylate)
The present embodiment 2 is according to the method preparation described in example 1, and difference is: replace 1H-indoles with 1H-indoles-2,3,4,5,6,7-d6 thus obtained target product.
After tested: chemical purity >98%, deuterated purity >98%; LCMS (ESI+): m/z514 (M-OMs).
Comparative example 1
Preparation N-(2-{2-[two (three deuterated methyl) is amino] ethyl-(methyl) is amino }-4-methoxyl group-5-{ [4-(1-skatole-3-base) pyrimidine-2-base] amino } phenyl) the third-2-alkene amide mesylate (AZD9291-D6 mesylate):
The method described in example 1 is pressed in preparation, and difference is: replace three deuterated methyl iodide with methyl iodide, thus obtained target product.
Chemical purity >98%, deuterated purity >99%; LCMS (ESI+): m/z506 (M-OMs).
Comparative example 2
Preparation N-(2-{2-dimethyl aminoethyl-(methyl) is amino }-4-methoxyl group-5-{ [4-(methyl-2,4,5, the deuterated indoles indol-3-yl of 6,7-five) pyrimidine-2-base] amino phenyl) the third-2-alkene amide mesylate (AZD9291-D5 mesylate):
The method described in example 1 is pressed in preparation, and difference is: replace three deuterated methyl iodide with methyl iodide, with N-methyl-N ', N '-dimethyl-1,2-quadrol replaces N-methyl-N ', N '-two (three deuterated methyl) 1，2-diaminoethane, with 1H-indoles-2,3,4,5,6,7-d6 replaces 1H-indoles thus obtained target product.
Chemical purity >98%, deuterated purity >99%; LCMS (ESI+): m/z508 (M-OMs).
Comparative example 3
Preparation N-(2-{2-dimethyl aminoethyl-(methyl) is amino }-4-methoxyl group-5-{ [4-(1-tri-deuterated skatole-3-base) pyrimidine-2-base] amino } phenyl) the third-2-alkene amide mesylate (AZD9291-D3 mesylate):
The method described in example 1 press in preparation, and difference is: with N-methyl-N ', and N '-dimethyl-1，2-diaminoethane replaces N-methyl-N ', N '-two (three deuterated methyl) 1，2-diaminoethane 8 thus obtain target product.
Chemical purity >98%, deuterated purity >99%; LCMS (ESI+): m/z503 (M-OMs).
The experiment of nude mouse of the mesylate of the deuterated derivative of embodiment 3:
PC-9 lung carcinoma cell RPMI1640 culture medium culturing, gets 5 × 10 6(volume: 0.1mL) cell is inoculated in BALB/C-NU nude mice by subcutaneous, and grows 4 months; The situation of growth of xenografted is measured for every 2 weeks, and calculates gross tumor volume, as transplanted tumor volume growth to 0.2 ~ 0.4cm 3time, mouse is carried out at random, being divided into treatment group and placebo group respectively according to tumor size.Intragastrically daily/placebo, measure the mean change of volume of tumour, add up with bilateral T inspection.
Build Transplanted tumor model, the AZD9291-D5 using the AZD9291 of 2mg/kg body weight, the AZD9291-D3 of comparative example 1 preparation, comparative example 2 to prepare respectively, AZD9291-D6, the AZD9291-D9 of embodiment 1 preparation, AZD9291-D14 and the PBS negative control gavage feeding of embodiment 2 preparation prepared by comparative example 1, often organize 6, at the volume of different point in time measurement tumours, the volume unit of tumour is cm 3.
7 treated animals are set, PC-9 cell nude mice model: blank group, AZD9291 mesylate, AZD9291-D3 mesylate, AZD9291-D5 mesylate, AZD9291-D6 mesylate, AZD9291-D9 mesylate and AZD9291-D14 mesylate drug concentration be 2mg/kg.
To the test result of nude mice as shown in Figure 7, Fig. 7 is that the mesylate drug prepared of the embodiment of the present invention and comparative example is to the test result of nude mice; Wherein, for blank group to the test curve of nude mice, for AZD9291 mesylate is to the test curve of nude mice, for AZD9291-D5 mesylate is to the test curve of nude mice, for AZD9291-D3 is to the test curve of nude mice, for AZD9291-D6 mesylate is to the test curve of nude mice, for AZD9291-D9 mesylate is to the test curve of nude mice, for AZD9291-D14 mesylate is to the test curve of nude mice.Fig. 8 is the enlarged view of partial trace in Fig. 7, Fig. 8 be the mesylate prepared of the embodiment of the present invention and comparative example to the nude mice test result of 40 ~ 120 days, wherein, for AZD9291 mesylate is to the test curve of nude mice, for AZD9291-D3 is to the test curve of nude mice, for AZD9291-D6 mesylate is to the test curve of nude mice, for AZD9291-D9 mesylate is to the test curve of nude mice, for AZD9291-D14 mesylate is to the test curve of nude mice, for AZD9291-D5 mesylate is to the test curve of nude mice.
The known rejection ability to tumor bearing nude mice tumour of experimental data from Fig. 7 and Fig. 8, the blank group of AZD9291-D14=AZD9291-D9>AZD9291-D6GreatT.Gr eaT.GTAZD9291-D3>AZD9291-D5> AZD9291>; AZD9291-D9 is 1.5 times of AZD9291-D6, is 1.8 times of AZD9291-D3; It is 2 times of AZD9291.By contrast, the rejection ability of AZD9291-D14 and AZD9291-D9 to tumor bearing nude mice tumour is the strongest.
The mesylate of deuterated derivative provided by the invention considerably increases the transformation period of medicine, extends the time that medicine is detained in body; Improve the concentration of blood Chinese traditional medicine simultaneously, thus reach better curative effect; Compare AZD9291 mesylate, the using dosage of the mesylate of deuterated derivative provided by the invention is less, and then can eliminate the bad metabolic problems of medicine further, reduces drug toxicity and other side effects.
As seen from the above embodiment, the invention provides [(indol-3-yl) pyrimidine-2-base] aminophenyl third-2-alkenylamide derivative, there is formula I structure.Deuterium-carbon bond in [(indol-3-yl) pyrimidine-2-base] provided by the invention aminophenyl third-2-alkenylamide derivative makes it, and decomposition rate is slow in vivo, extend the transformation period of medicine, add the Plasma Concentration of medicine, finally reduce its using dosage, reduce its toxic side effect.
In addition, derivative provided by the invention is more stable in vivo, decreases it in enteron aisle inwall and the metabolism in liver, reduces the bad metabolism of medicine, reduces drug toxicity and other side effects further.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.

Claims (10)

1. [(indol-3-yl) pyrimidine-2-base] aminophenyl third-2-alkenylamide derivative, has formula I structure:
In formula I, described R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19and R 20be hydrogen or deuterium independently.
2. derivative according to claim 1, is characterized in that, in described formula I, the number of D atom is 9 ~ 29.
3. derivative according to claim 1, is characterized in that, described derivative has formula 101, formula 102, formula 103 or formula 104 structure:
4. the mesylate of derivative described in claims 1 to 3 any one, has formula II structure:
5. the preparation method of derivative described in claims 1 to 3 any one, comprises the following steps:
The compound with formula III structure is reacted with the compound with formula IV structure, obtains the compound with formula V structure;
The described compound with formula V structure is carried out reducing and amidation successively, obtains the derivative with formula I structure;
Described R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19and R 20independently selected from hydrogen or deuterium;
In formula III, described M is F, Cl, Br or I.
6. preparation method according to claim 5, is characterized in that, described in there is formula III structure compound obtained by following preparation method:
The compound with formula VI structure is reacted with the compound with formula VII structure, obtains the compound with formula III structure;
Described R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19and R 20independently selected from hydrogen or deuterium;
In formula VI, described R is F, Cl, Br or I.
7. preparation method according to claim 6, is characterized in that, described in have formula VI structure compound and have formula VII structure compound reaction temperature be 90 DEG C ~ 100 DEG C; Reaction times is 18 ~ 22h.
8. preparation method according to claim 5, is characterized in that, described in have formula III structure compound and have formula IV structure compound reaction temperature be 93 ~ 98 DEG C; Reaction times is 5.5 ~ 6.5h.
9. the application of derivative in the medicine of preparation treatment tumour prepared of preparation method described in the mesylate of derivative described in derivative, claim 4 ~ 6 any one described in a claims 1 to 3 any one or claim 7 ~ 8 any one.
10. application according to claim 9, is characterized in that, described tumour is malignant tumour.
CN201510534307.4A 2015-08-27 2015-08-27 [(indol-3-yl) pyrimidine -2-base] aminophenyl propyl- 2- alkenylamide derivatives and salt, preparation method, application Active CN105153122B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510534307.4A CN105153122B (en) 2015-08-27 2015-08-27 [(indol-3-yl) pyrimidine -2-base] aminophenyl propyl- 2- alkenylamide derivatives and salt, preparation method, application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510534307.4A CN105153122B (en) 2015-08-27 2015-08-27 [(indol-3-yl) pyrimidine -2-base] aminophenyl propyl- 2- alkenylamide derivatives and salt, preparation method, application

Publications (2)

Publication Number Publication Date
CN105153122A true CN105153122A (en) 2015-12-16
CN105153122B CN105153122B (en) 2018-07-20

Family

ID=54794213

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510534307.4A Active CN105153122B (en) 2015-08-27 2015-08-27 [(indol-3-yl) pyrimidine -2-base] aminophenyl propyl- 2- alkenylamide derivatives and salt, preparation method, application

Country Status (1)

Country Link
CN (1) CN105153122B (en)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017117070A1 (en) 2015-12-27 2017-07-06 NeuForm Pharmaceuticals, Inc. Deuterated compounds for treating cancer and related diseases and conditions, and compositions and methods thereof
CN107043369A (en) * 2016-02-06 2017-08-15 焦玉奇 2 (2,4,5 substituted aniline) pyrimidine derivatives
CN107192773A (en) * 2017-05-17 2017-09-22 江苏斯威森生物医药工程研究中心有限公司 A kind of detection is difficult to understand uncommon for Buddhist nun's content and the high-efficient liquid phase technique about material
CN107522690A (en) * 2016-06-20 2017-12-29 江苏先声药业有限公司 A kind of Osimertinib preparation method
CN108047205A (en) * 2016-12-14 2018-05-18 河南美泰宝生物制药有限公司 2- (2,4,5- substitution phenylamino) pyrimidine derivatives, its preparation method and its application in antitumor drug is prepared
CN108530429A (en) * 2016-01-22 2018-09-14 焦玉奇 2- (2,4,5- substituted anilines) pyrimidine derivatives
CN108558835A (en) * 2017-05-24 2018-09-21 浙江同源康医药股份有限公司 A kind of crystal form, the Preparation method and use of deuterated AZD9291
CN108675993A (en) * 2018-06-14 2018-10-19 纽瑞森生物科技（北京）有限公司 Deuterated pyrimidines, preparation method, pharmaceutical composition, preparation and purposes
US10179784B2 (en) 2014-11-05 2019-01-15 Inventisbio Shanghai Ltd. Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof
US10513509B2 (en) 2016-05-26 2019-12-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
CN110950847A (en) * 2018-09-27 2020-04-03 浙江同源康医药股份有限公司 Novel crystal form of deuterated AZD9291 compound and application thereof
CN111285852A (en) * 2020-04-02 2020-06-16 广州博济医药生物技术股份有限公司 Crystal form of deuterated oxitinib medicinal salt and preparation method thereof
CN111362924A (en) * 2020-04-21 2020-07-03 南京雷正医药科技有限公司 Deuterated pyrimidine derivatives and uses thereof
CN111909135A (en) * 2020-08-15 2020-11-10 天津大学 AZD9291 deutero-mesylate new salt form and preparation method thereof
CN113582976A (en) * 2021-08-24 2021-11-02 郑州大学 Deuterated 2-substituted aniline-4-indolyl pyrimidine derivative and preparation method and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104140418A (en) * 2014-08-15 2014-11-12 朱孝云 Novel 2-(2, 4, 5-subsituted aniline) pyrimidine derivatives and use thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104140418A (en) * 2014-08-15 2014-11-12 朱孝云 Novel 2-(2, 4, 5-subsituted aniline) pyrimidine derivatives and use thereof

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11498921B1 (en) 2014-11-05 2022-11-15 InventisBio Co., Ltd. Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof
US11203589B2 (en) 2014-11-05 2021-12-21 InventisBio Co., Ltd. Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof
US10179784B2 (en) 2014-11-05 2019-01-15 Inventisbio Shanghai Ltd. Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof
CN108779102A (en) * 2015-12-27 2018-11-09 纽弗姆制药有限公司 For treating cancer and relevant disease and the deuterated compound of the patient's condition and combinations thereof and method
KR102029135B1 (en) * 2015-12-27 2019-10-07 뉴폼 파마슈티컬스, 아이엔씨. Deuterated compounds, compositions and methods thereof for treating cancer and related diseases and conditions
KR20180090899A (en) * 2015-12-27 2018-08-13 뉴폼 파마슈티컬스, 아이엔씨. Dehydrogenated compounds for the treatment of cancer and related diseases and conditions, compositions and methods thereof
WO2017117070A1 (en) 2015-12-27 2017-07-06 NeuForm Pharmaceuticals, Inc. Deuterated compounds for treating cancer and related diseases and conditions, and compositions and methods thereof
JP2019500408A (en) * 2015-12-27 2019-01-10 ノイフォルム・ファーマシューティカルズ・インコーポレイテッドＮｅｕｆｏｒｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． Deuterium compounds for treating cancerous conditions
CN108779102B (en) * 2015-12-27 2020-04-21 纽弗姆制药有限公司 Deuterated compounds, compositions thereof, and methods for treating cancer and related diseases and conditions
CN108530429A (en) * 2016-01-22 2018-09-14 焦玉奇 2- (2,4,5- substituted anilines) pyrimidine derivatives
CN108610331A (en) * 2016-01-22 2018-10-02 焦玉奇 2- (2,4,5- substituted anilines) pyrimidine derivatives
CN108530429B (en) * 2016-01-22 2021-04-27 焦玉奇 2- (2,4, 5-substituted aniline) pyrimidine derivatives
CN107043369A (en) * 2016-02-06 2017-08-15 焦玉奇 2 (2,4,5 substituted aniline) pyrimidine derivatives
US10513509B2 (en) 2016-05-26 2019-12-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
US11098030B2 (en) 2016-05-26 2021-08-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
CN107522690B (en) * 2016-06-20 2022-08-05 海南先声药业有限公司 Preparation method of Osimetinib
CN107522690A (en) * 2016-06-20 2017-12-29 江苏先声药业有限公司 A kind of Osimertinib preparation method
CN108047205B (en) * 2016-12-14 2019-08-27 河南真实生物科技有限公司 2- (2,4,5- replace phenylamino) pyrimidine derivatives, preparation method and its application in preparation of anti-tumor drugs
CN108047205A (en) * 2016-12-14 2018-05-18 河南美泰宝生物制药有限公司 2- (2,4,5- substitution phenylamino) pyrimidine derivatives, its preparation method and its application in antitumor drug is prepared
CN107192773B (en) * 2017-05-17 2019-09-27 张家港威胜生物医药有限公司 A kind of detection is difficult to understand uncommon for Buddhist nun's content and the high-efficient liquid phase technique in relation to substance
CN107192773A (en) * 2017-05-17 2017-09-22 江苏斯威森生物医药工程研究中心有限公司 A kind of detection is difficult to understand uncommon for Buddhist nun's content and the high-efficient liquid phase technique about material
CN108558835A (en) * 2017-05-24 2018-09-21 浙江同源康医药股份有限公司 A kind of crystal form, the Preparation method and use of deuterated AZD9291
US10882845B2 (en) 2017-05-24 2021-01-05 TYK Medicines Inc. Crystal form of deuterated AZD9291, preparation method therefor, and use thereof
CN108675993A (en) * 2018-06-14 2018-10-19 纽瑞森生物科技（北京）有限公司 Deuterated pyrimidines, preparation method, pharmaceutical composition, preparation and purposes
CN110950847A (en) * 2018-09-27 2020-04-03 浙江同源康医药股份有限公司 Novel crystal form of deuterated AZD9291 compound and application thereof
CN110950847B (en) * 2018-09-27 2022-11-01 浙江同源康医药股份有限公司 Novel crystal form of deuterated AZD9291 compound and application thereof
CN111285852A (en) * 2020-04-02 2020-06-16 广州博济医药生物技术股份有限公司 Crystal form of deuterated oxitinib medicinal salt and preparation method thereof
CN111362924B (en) * 2020-04-21 2021-05-28 南京雷正医药科技有限公司 Deuterated pyrimidine derivatives and uses thereof
CN111362924A (en) * 2020-04-21 2020-07-03 南京雷正医药科技有限公司 Deuterated pyrimidine derivatives and uses thereof
CN111909135A (en) * 2020-08-15 2020-11-10 天津大学 AZD9291 deutero-mesylate new salt form and preparation method thereof
CN113582976A (en) * 2021-08-24 2021-11-02 郑州大学 Deuterated 2-substituted aniline-4-indolyl pyrimidine derivative and preparation method and application thereof

Also Published As

Publication number Publication date
CN105153122B (en) 2018-07-20

Similar Documents

Publication Publication Date Title
CN105153122A (en) [(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative and its salt, preparation method of derivative, and application of derivative and salt
CN111647000B (en) Pyrazine derivative and application thereof in inhibition of SHP2
CN102190616B (en) A kind of deuterated synthesis of ω-diphenyl urea and the Method and process of production
CN104603123B (en) Solid-state form of bent Ge Lieting and its production and use
CN102731485A (en) 4-(substituted phenylamino)quinazoline derivative, its preparation method, pharmaceutical composition and application
CN107759600A (en) Crystallization as the Pyrrolopyrimidine compounds of JAK inhibitor
CN101967140A (en) Deuterated crizotinib as well as derivant, preparation method and application thereof
CN106146583A (en) Novel cytidine derivatives and application thereof
CN106478605A (en) Pyrimidines, its preparation method and medical usage
WO2020233641A1 (en) Compound used as ret kinase inhibitor and application thereof
CN104003925B (en) Oxindole compounds or derivatives thereof and uses thereof
WO2021121146A1 (en) Crystal form a of aminopyrimidine mesylate compound, preparation method therefor, and application thereof
CN103936762B (en) Morpholine quinolines, Preparation Method And The Use
CN103044395B (en) Desloratadine-containing amino acid derivative as well as preparation method and application thereof
CN112867717A (en) Compounds useful as kinase inhibitors and uses thereof
CN103965175A (en) 4-(substituted phenylamino)quinazoline compounds, and preparation method and application thereof
CN104557913B (en) Pyridopyrimidine compounds as well as preparation method and application thereof
CN104292211A (en) Desloratadine nitric oxide donor, and preparation method and application thereof
CN108822126B (en) Thienopyran formyl piperazine compound and medical application thereof
CA3159749A1 (en) Salts and forms of an estrogen receptor modulator
CN102267952B (en) Quinazoline compound and preparation method and application thereof
JP2022507558A (en) Potassium salt monohydrate of thienopyridone derivative and its preparation method
CN102786458B (en) Pyrrole formamide derivative, and preparation method and application thereof
CN104788372B (en) A kind of deuterated card is rich to replace Buddhist nun's derivative, its preparation method, application and its intermediate
WO2019001307A1 (en) Amide compound, composition containing same, and use thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20210330

Address after: 450000 no.957, block a, Newton international, middle Yangjin Road, Jinshui District, Zhengzhou City, Henan Province

Patentee after: Henan inno Medicine Technology Co.,Ltd.

Address before: Room a-758, building 1, 1758, Luchaogang Road, Nanjiang new town, Pudong New Area, Shanghai, 200120

Patentee before: SHANGHAI SHENGKAO PHARMACEUTICAL TECHNOLOGY Co.,Ltd.

CB03 Change of inventor or designer information
CB03 Change of inventor or designer information

Inventor after: Zhang Huizhen

Inventor after: Peng Kuai

Inventor after: Zheng Feiming

Inventor after: Fu Yong

Inventor before: Peng Kuai

Inventor before: Zheng Feiming

Inventor before: Fu Yong