CN108467385A - Deuterated difficult to understand this of one kind replacing Buddhist nun's derivative and its application - Google Patents
Deuterated difficult to understand this of one kind replacing Buddhist nun's derivative and its application Download PDFInfo
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- CN108467385A CN108467385A CN201810671774.5A CN201810671774A CN108467385A CN 108467385 A CN108467385 A CN 108467385A CN 201810671774 A CN201810671774 A CN 201810671774A CN 108467385 A CN108467385 A CN 108467385A
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- 0 CN(C)CCN(*=*)c(c(NC(C=C)=O)c1)cc(OC)c1NC(N)=NC=C(*)C(c1c[n](C)c2ccccc12)=C Chemical compound CN(C)CCN(*=*)c(c(NC(C=C)=O)c1)cc(OC)c1NC(N)=NC=C(*)C(c1c[n](C)c2ccccc12)=C 0.000 description 2
- BBLXIJVUTCNVGB-UHFFFAOYSA-N CN(C)CCN(C)c(c(NC(C=C)=O)c1)cc(OC)c1Nc1nc(C2=CCN(C)c3c2cccc3)ccn1 Chemical compound CN(C)CCN(C)c(c(NC(C=C)=O)c1)cc(OC)c1Nc1nc(C2=CCN(C)c3c2cccc3)ccn1 BBLXIJVUTCNVGB-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses deuterated difficult to understand these shown in a kind of formula I to replace Buddhist nun (Osimertinib) derivative, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, and each symbol therein is as defined in the claims.Deuterated difficult to understand this of the present invention replaces Buddhist nun's derivative that can inhibit activation or the resistant mutation of one or more EGFR, can be used for the treatment of EGFR sensitive mutant cancers, is a kind of medicine being preferably mutated caused disease by EGFR.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to deuterated difficult to understand this for being used as EGFR inhibitor replaces Buddhist nun
(Osimertinib) derivative and its prepare for adjust EGFR tyrosine kinase activities or treatment EGFR relevant diseases, especially
It is the application in the drug of non-small cell lung cancer.
Background technology
EGF-R ELISA EGFR (Epidermal Growth Factor Receptor) is erbB receptor families
Transmembrane protein tyrosine kinases one kind, when it is combined with growth factor ligand (such as epidermal growth factor (EGF)), by
Homologous dimerization can occur with additional EGFR molecules for body, or with another family member (such as erbB2 (HER2), erbB3
(HER3) or erbB4 (HER4)) occur heterodimeric.The homologous dimerization and/or heterodimeric of erbB receptors lead to Intracellular domain
The phosphorylation of middle key tyrosine residue, and lead to many Cellular Signaling Transduction Mediated accesses to participating in cell Proliferation and existence
Stimulation.The imbalance of erbB families signal transduction promotes proliferation, intrusion, transfer, angiogenesis and tumour cell existence, and
(including lung cancer, incidence cancer and breast cancer etc.) is described in many human cancers.
Lung cancer is the highest cancer of global incidence, first in lung cancer in China incidence occupies all cancers, and
The Chinese highest cancer of morbidity and mortality.In the lung cancer patient of China, about 30% patient is mutated with EGFR,
Middle L858R and 9 deletion mutation of exons 1 account for about 90% or more, and this kind of patient is more sensitive to EGFR inhibitor.It is existing on
City's first generation EGFR inhibitor such as Tarceva, Gefitinib etc. has a better effect this kind of patient, can make wherein 60%
Above patient's tumor regression, hence it is evident that extend the progression free survival phase of patient.But most humans can be obtained at 6-12 months
Drug resistance, this drug resistance pattern are the further mutation of EGFR, and this reduces its sensibility to first generation EGFR inhibitor.This
Most commonly so-called " gatekeeper " mutation T 790M in a little mutation (Science, 2004, Vol.304,1497-1500；
New England Journal of Medicine 2004,350,2129-2139), by originally in the L-threonine in the site
(T) it is that l-methionine (M) substitutes, the EGF tyrosine kinase R after variation is no longer combined with Gefitinib, Tarceva, to
Make first generation EGFR inhibitor that will no longer work, this kind of patient is caused to be currently in the available state of no medicine.Clinical discovery pair
Generation EGFR inhibitor, which generates, has 50% detection to have EGFR T790M mutation in drug resistant patient.In T790M mutational cell lines
In H1975, first generation EGFR inhibitor is all higher than 3 μM such as Gefitinib and Tarceva, basic without activity.
In order to improve the inhibitory activity to mutation such as drug resistance EGFR T790M, WO2013014448, which is disclosed, can be used as EGFR
The pyrimidine derivatives of inhibitor and its purposes for the treatment of cancer, structure is as shown in formula A, wherein G is selected from 4,5,6,7- tetrahydro-pyrazoles
And [1,5-a] pyridin-3-yl, 1H- indol-3-yls, 1- Methyl-1H-indole -3- bases or pyrazolo [1,5-a] pyridin-3-yl,
R2For methyl or methoxy；
The structural formula of compound (AZD9291) of listing of having succeeded in WO2013014448 is：
U.S. FDA is obtained on November 13rd, 2015 accelerates approval (trade name TagAsso, AZD9291, Osimertinib)
Listing, the patients with advanced NSCLC positive for treating EGF-R ELISA EGFR T790M mutation.But
The half-life period of Osimertinib (AZD9291, TagAsso) is shorter, and dosage is higher, some metabolites are due to wild
The excessive inhibition or activation of type EGFR, in process of clinical application, leads to adverse reaction, most common adverse reaction (≤25%)
For diarrhea, fash, dry skin and nail toxicity.It is less sensitive to some which also limits the treatment window of this drug of application
Patient due to treating the limitation of window, and causes therapeutic effect poor.Meanwhile for some too sensitive patients, due to excessive
Side effect, and lead to that this drug therapy cannot be used.Therefore, it is highly desirable to optimize the structure of the medicine, increases by half
It declines the phase, reduces drug toxicity, increase treatment window, to allow more patients to be benefited.
So far, CN104140418B discloses deuterated difficult to understand this of some methyl and replaces Buddhist nun (AZD9291) compound, structure
Formula is as shown in formula B, wherein R1、R2、R3、R4And R5For methyl or deuterated methyl,
Although these compounds disclosed in CN104140418B improve difficult to understand this and replace half-life period of Buddhist nun (Osimertinib),
But by have document report and ours the study found that Osimertinib and target spot EGFR kinases binding pattern
In, pyrimidine loop section is combined (hige-binding) with the hinge area of EGFR kinases, once pyrimidine loop section is metabolised to other
Form, the combination that may result in Osimertinib and EGFR kinases die down or cannot in conjunction with and lose activity.CN105153122
Report that methyl is deuterated and the complete deuterated AZD9291 compounds of indole ring, although such compound can also increase Osimertinib
Half-life period, but since deuterated site is too many, produce prepare when, it is inevitable at high price, increase R＆D and production cost,
Increase so as to cause the expenditure of patient.CN105237515 discloses the Osimertinib compounds of only deuterated pyrimidine ring, we
The study found that the compound shown in production C after the methyl on indoles is metabolized,
Although this compound still has inhibition activity of EGFR, it cannot be by blood-brain barrier, into brain, to brain
The tumor patient of portion's transfer loses effect.
Therefore, it is necessary to develop can increase Osimertinib half-life period reduce well not only toxic side effect but also
Blood-brain barrier can be penetrated, into brain, to the effective drug of patient of brain tumor transfer.
Invention content
The present invention provides such as I compound represented of formula or its pharmaceutically acceptable salt, stereoisomer, solvations
Object or prodrug：
Wherein：
R1、R2、R3、R4、R5It is each independently selected from methyl or deuterated methyl；
R6Selected from H or deuterium.
Preferably, the deuterated methyl is-CD3.The R1、R2、R3、R4、R5It is each independently selected from methyl or-CD3。
The R1、R2、R3、R4、R5In it is at least one be-CD3。
The R1、R2、R3、R4、R5In have 1~3 be-CD3。
I compound represented of formula or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, wherein
The compound that the compound is optionally indicated from following structural formula：
Wherein, the pharmaceutically acceptable salt is inorganic acid salt or acylate, and the inorganic acid salt is selected from hydrochloric acid
Salt, hydrobromate, hydriodate, sulfate, disulfate, nitrate, phosphate, acid phosphate；The acylate choosing
From formates, acetate, trifluoroacetate, propionate, acetonate, oxyacetate, oxalate, malonate, fumaric acid
Salt, maleate, lactate, malate, citrate, tartrate, mesylate, esilate, benzene sulfonate, bigcatkin willow
Hydrochlorate, picrate, glutamate, ascorbate, camphor hydrochlorate, camsilate.
Preferably, the inorganic acid salt is hydrochloride or sulfate；The acylate is mesylate.
Another technical solution provided by the invention is：A kind of pharmaceutical composition, including compound shown in above-mentioned formula I and
Pharmaceutically acceptable carrier.
Deuterated difficult to understand this provided by the invention replaces Buddhist nun's derivative, is I compound represented of formula or its is pharmaceutically acceptable
Salt, stereoisomer, solvate or prodrug, the compound can inhibit activation or the resistant mutation of one or more EGFR,
Such as L858R activated mutants body, Exon19 missing EGFR activated mutants body, T790M resistant mutants；The compound improves pair
The inhibitory activity of the mutation such as drug resistance EGFR T790M can be used for out and at the same time reducing the inhibitory activity to Wild type EGFR
The active higher of hair, selective more preferable, the lower third generation EGFR mutant selective depressants of toxicity.
Solvate mentioned in the present invention refers to the complex that the compound of the present invention is formed with solvent.They or
Reaction either Precipitation or is crystallized out from solvent in a solvent.For example, the complex formed with water is known as hydrate；
Other further include alcohol adduct, ketone conjunction object etc..Solvate of the present invention include I compound represented of formula and its
The solvate of salt, stereoisomer.
Stereoisomer mentioned by the present invention, which refers to I compound represented of Chinese style of the present invention, can contain one or more
Chiral centre, and exist with different optical active forms.When compound contains there are one when chiral centre, compound includes mapping
Isomers.The present invention includes the mixture of both isomers and isomers, such as racemic mixture.Enantiomter can lead to
Cross methods known in the art fractionation, such as the methods of crystallization and chiral chromatogram.When I compound represented of formula contain it is more
When a chiral centre, may exist non-corresponding isomers.The present invention stereoisomer include split it is optically pure
The mixture of specific isomers and non-corresponding isomers.Diastereoisomer can be split by method known in the art,
For example crystallize and prepare chromatography.
Prodrug mentioned by the present invention refer to include known amino protecting group and carboxyl-protecting group, in physiological conditions by
Hydrolysis or the parent compound discharged via enzyme reaction.Medicament preparation can refer to the prior art before specific
(Saulnier, M.G.；Frennesson, D.B.；Deshpande, M.S.；Hansel, S.B and Vysa,
D.M.Bioorg.Med.ChemLett.1994,4,1985-1990；And Greenwald, R.B.；Choe, Y.H.；Conover,
C.D.；Shum, K.；Wu, D.；Royzen, M.J.Med.Chem.2000,43,475.).
It in practical applications, can be by the type I compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, molten
Agent compound or prodrug are made suitable dosage form with one or more pharmaceutical carriers and apply.These dosage forms include being suitable for taking orally, being straight
Enteral administration, local administration are administered in mouth and other parenteral routes application (for example, subcutaneous, muscle, vein etc.) etc..
The pharmaceutical composition of the present invention can be prepared in a manner of meeting medical practice specification, quantitative and administration.Giving
" effective quantity " of object is closed by specific illness to be treated, the target spot and administering mode of the individual for the treatment of, the cause of illness, drug
Etc. factors determine.
Deuterated difficult to understand this provided by the invention replaces Buddhist nun's derivative, can be used for preparing regulation and control EGFR tyrosine kinase activities or treatment
Drug in terms of EGFR relevant diseases, such as cancer, diabetes, disease of immune system, neurodegenerative disease or angiocardiopathy
Deng being particularly suitable for being mutated by EGFR, including sensitive mutant (such as L858R is mutated or the aobvious factor 19 lacks outside) and drug resistance are dashed forward
Become (such as EGFR T790M mutation), the medicine of caused non-small cell lung cancer.
Therefore, on the other hand, the present invention provides the type I compound of the present invention or its pharmaceutically acceptable salt, solids
Isomers, solvate or prodrug are being prepared for regulating and controlling EGFR tyrosine kinase activities or treating the drug of EGFR relevant diseases
The application of aspect.
In one embodiment, the regulation and control EGFR tyrosine kinase activities or treatment EGFR relevant diseases refer to treatment
Cancer, diabetes, disease of immune system, neurodegenerative disease or angiocardiopathy.
In another embodiment, the present invention provides the type I compound of the present invention or its is pharmaceutically acceptable
The application of salt, stereoisomer, solvate or prodrug in terms of the drug for preparing treatment non-small cell lung cancer.The deuterium of the present invention
Dai Aosi is particularly suitable for preparing treating cancer for Buddhist nun's derivative, such as the drug of non-small cell lung cancer.
The type I compound or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug of the present invention, anti-
Cancer treatment in can be used as monotherapy medicinal application, or in addition to this can also with routine operation or radiotherapy or
Chemotherapy or immunotherapy use in conjunction.Above-mentioned therapy with the present invention EGFR inhibitor can side by side, simultaneously, it is sequential
Ground is respectively administered.
The drug for regulating and controlling EGFR tyrosine kinase activities or treatment EGFR relevant diseases of the present invention, except the present invention's
Can also include any one or more in following drug except EGFR inhibitor：Gefitinib, angstrom gram replaces Tarceva
Buddhist nun, Lapatinib, XL647, NVP-AEE-788, ARRY-334543, Vande Thani, PF00299804, Cetuximab, Pa Ni
Prominent monoclonal antibody, pricks Shandong wood monoclonal antibody, Buddhist nun's trastuzumab, MDX-214, CDX-110, IMC-11F8, CNF2024, smooth spiral shell at handkerchief trastuzumab
Revolve mycin, Ah's spiramvcin, IPI-504, NVP-AUY922.
Specific implementation mode
Technical scheme of the present invention is further described with reference to specific embodiment.
Embodiment 1
Target compound 1, structural formula are：
Synthetic route is：
Specific synthesis step is as follows：
1) synthesis of compound TRN158-a：Under nitrogen protection, 18 grams of 5- bromo- 2 are sequentially added into 1 liter of there-necked flask,
4- dichloro pyrimidines and 180 milliliters of anhydrous tetrahydro furans, are down to -60 DEG C, and 393 milli of tetrahydrofuran solution of isopropylmagnesium chloride is added dropwise
It rises, 40 minutes used times；It is warming up to -30 DEG C later to react 1 hour, 20 milliliters of the deuterium-oxide of dropwise addition at -30 DEG C, 20 minutes used times, it
After be slowly increased to room temperature reaction 1 hour；After reaction, add 1 liter of ethyl acetate to stir 10 minutes into reaction solution, filter, filter
Liquid is spin-dried for；Gained crude product obtains 3.07g white solids through silica gel column chromatography；MS+1：151.
2) synthesis of compound TRN158-b：Under nitrogen protection, 4 grams of sodium hydrogen and 600 are sequentially added into 1 liter of there-necked flask
Milliliter anhydrous tetrahydro furan, is cooled to 0 DEG C, and 60 milliliters of the tetrahydrofuran solution of 9.75 grams of indoles is added dropwise into reaction solution, is added dropwise
After be gradually heating to room temperature, stir 1 hour；It is cooled to 0 DEG C, 14.5 grams of deuterated iodomethane, drop are added dropwise into reaction solution
It is gradually heating to be stirred overnight at room temperature after adding；TLC detects raw material and disappears, and ice water is added to reaction solution and EA, water layer are used again
EA is washed 2 times, is then combined with EA layer saturated common salts water washing 2 times, and then drying is spin-dried for organic layer；It crosses pillar and obtains 10.5 grams
Colourless liquid；The analysis data of the compound are as follows：
1H-NMR (400MHz, CDCl3)δ：7.63 (d, J=8.64,1H)；7.30 (dd, J=0.76, J=9.0,1H)；
7.21 (t, J=16.24,1H)；7.09 (t, J=15.88,1H)；7.00(d,3.08,1H)；6.46 (dd, J=0.76, J=
3.84,1H)；MS+1：135.
3) synthesis of compound TRN15801-1：Under nitrogen protection, 3.76 grams are sequentially added into 100 milliliters of single port bottles
TRN158-a, 40 milliliters of DME, 4.06 grams of anhydrous ferric chlorides and 2.8 grams of TRN158-b react overnight at 60 DEG C；TLC is detected
TRN158-b disappears, and reaction solution is dropped to room temperature, is poured into the mixed liquor of ice water and EA, water layer is washed 2 times with EA again, is then closed
And EA layers are used saturated common salt water washing 2 times, then drying is spin-dried for organic layer；It crosses pillar and obtains 0.746 gram of yellow solid；The chemical combination
The analysis data of object are as follows：
1H-NMR (400MHz, CDCl3)：δ：8.42(s,1H)；8.28-8.34 (m, J=22.76,1H)；7.92(s,1H)；
7.30-7.40 (m, J=41.32,3H)；MS+1：248.
4) synthesis of target compound 1：Under nitrogen protection, 540 milligrams are sequentially added into 100 milliliters of single port bottles
TRN15801-1,574 milligrams of TRN158-c, 30 milliliters of DCE, 20 milliliters of 2- amylalcohols and 374 milligrams of p-methyl benzenesulfonic acid, oil bath heating
Overnight to 80 DEG C of reactions；TLC detects TRN158-c and disappears, and reaction solution drops to room temperature, pours into the mixed liquor of ice water and DCM, water
Layer is washed 2 times with DCM again, is then combined with DCM layer saturated common salts water washing 2 times, and then drying is spin-dried for organic layer；Pillar is crossed to obtain
Analysis data to 200 milligrams of brown solids, the compound are as follows：
1H-NMR (400MHz, CDCl3)：δ：10.18(br,1H)；9.85(s,1H)；9.12(br,1H)；8.38(s,1H)；
8.06 (dd, J=2.92, J=8.64,1H)；7.72(s,1H)；7.39 (dd, J=1.84, J=9.24,1H)；7.23-7.30
(m,2H)；6.79(s,1H)；6.33-6.48(m,,2H)；5.71 (dd, J=2.20, J=11.92,1H)；3.88(s,3H)；
2.89 (t, J=11.2,2H)；2.70(s,3H)；2.26-2.29(m,8H)；MS+1：504, it is target compound 1.
Embodiment 2
Target compound 2, structural formula is as follows：
Synthetic route is as follows：
The synthesis of compound TRN15802-2：
Compound TRN15801-1 (500mg, 2.02mmol) is added in reaction bulb, 10 milliliters of isopropyls are then added
Alcohol adds the hydration p-methyl benzenesulfonic acid of TRN158-d (416mg, 2.2mmol) and one (475mg, 2.5mmol), and then argon gas is protected
Under shield, back flow reaction is added and stays overnight.Reaction solution is dropped into room temperature, partial solvent is fallen in then concentration, is then placed in ice bath, stands
Crystallization, filtering, filter cake are washed 2 times with acetonitrile, are dried to obtain 524mg products.MS+1：401.3.
The synthesis of compound TRN15802-3：
By compound TRN15802-2 (520mg, 1.3mmol), N, N, N '-trimethyl ethylenediamine (265mg, 2.6mmol)
It is added in reaction bulb with potassium carbonate (359mg, 2.6mmol), then adds 10 milliliters of N-Methyl pyrrolidones, 120 degree anti-
It answers 5 hours, the near room temperature of reaction solution is subsequently poured into ice water, stir 30 minutes, then filter, collect filter cake, use methyl- tert
Butyl ether washes twice, dry, obtains 500mg products.MS+1:483.3.
The synthesis of compound TRN15802-4：
Compound TRN15802-3 (500mg, 1.03mmol) is added in there-necked flask, 10 milliliters of ethyl alcohol is then added
With 10 milliliters of saturated aqueous ammonium chloride, iron powder (560mg, 10mmol) is then added.Heating reflux reaction 8 hours, then
Reaction solution is cooled to room temperature, is filtered, filtrate concentration is dry, and 50 milliliters of dichloromethane are added, are then washed with water one time, with saturation
Brine It one time, dry organic phase, organic phase concentration obtain 420mg products.MS+1：453.3.
The synthesis of compound TRN15802：
Compound TRN15802 (400mg, 0.88mmol) is added in there-necked flask, 20 milliliters of anhydrous dichloro is added
Methane and diisopropylethylamine (206mg, 1.6mmol) cool to 0 degree, acryloyl chloride are then added dropwise then under argon gas protection
5 milliliters of the anhydrous methylene chloride solution of (90mg, 1mmol) adds, after adding, automatically ramps up to ambient temperature overnight for about 30 minutes.It will
Reaction solution pours into ice water, then three times (20 milliliters of dichloromethane every time) with dichloromethane extraction, merges organic phase, organic phase
With saturated common salt water washing one time, organic phase drying, concentrated pillar obtains 245mg products.The analysis data of the compound are such as
Under：
1H-NMR (400MHz, CDCl3)：δ：10.18(br,1H)；9.85(s,1H)；9.12(br,1H)；8.38(s,1H)；
8.06 (dd, J=2.92, J=8.64,1H)；7.72(s,1H)；7.39 (dd, J=1.84, J=9.24,1H)；7.23-7.30
(m,2H)；6.79(s,1H)；6.33-6.48(m,,2H)；5.71 (dd, J=2.20, J=11.92,1H)；2.89 (t, J=
11.2,2H)；2.70(s,3H)；2.26-2.29(m,8H)；MS+1：507.3.
The preparation method of the synthesized reference patent document CN105237515B of compound TRN158-d synthesizes.
Embodiment 3
Target compound 3, structural formula is as follows：
Synthetic route is as follows：
Intermediate TRN158-e is purchased from lark prestige Reagent Company.
The synthetic route of intermediate TRN158-f is as follows：
The synthesis of compound 3：
Compound 1 (5g, 71mmol) is added in there-necked flask, then under 0 degree, 100 milliliters of ethyl alcohol, three second are added
Amine (7.2g, 71mmol), benzaldehyde (7.5g, 71mmol).Tetraisopropyl titanate (21.6g, 76mmol) is added dropwise under 0 degree, adds
After complete, it is slowly increased to ambient temperature overnight.It is 2 small that sodium borohydride (2.8g, 74mmol) is added portionwise near 0 degree of reaction solution by next day
When it is interior add, after adding, at 0 degree, the reaction was continued 4 hours, saturated aqueous ammonium chloride is added, reaction is quenched, filtering, filtrate is dense
Then three times with dichloromethane extraction contracting merges organic phase, then cross pillar and obtain 4.6g grease products.MS+1:125.1.
The synthesis of compound 5：
Compound 3 (4.6g, 36.8mmol) and compound 4 (5.3g, 36.8mmol) are added in reaction bulb, then again
30 milliliters of ethyl alcohol are added, 30 milliliters of sodium hydrate aqueous solution (1.5g, 36.9mmol) is added dropwise under 0 degree, after adding, will react
Liquid is heated slowly to flow back, and reacts 3 hours.Near room temperature will be reacted, then concentration of reaction solution, be extracted with dichloromethane, it is organic
Mutually dry, crude product is crossed pillar and obtains 3.1g oil products by concentration.MS+1：196.2.
The synthesis of compound TRN158-f：
Compound 5 (3.1g, 15.8mmol) is added in reaction bulb, 100 milligrams of wet palladium carbon is then added, then exists
It reacts overnight, reaction solution is filtered, filtrate is spin-dried for obtaining 1.2g oil products under atmosphere of hydrogen.MS+1：106.1.
Compound TRN15803-2, TRN15803-3, the synthetic operation process of TRN15803-4 and TRN15803 is with reference to real
The corresponding steps applied in example 2 are synthesized.The analysis data of the target compound TRN15803 of synthesis are as follows：
1H-NMR (400MHz, CDCl3)：δ：10.18(br,1H)；9.85(s,1H)；9.12(br,1H)；8.38(s,1H)；
8.06 (dd, J=2.92, J=8.64,1H)；7.72(s,1H)；7.39 (dd, J=1.84, J=9.24,1H)；7.23-7.30
(m,2H)；6.79(s,1H)；6.33-6.48(m,,2H)；5.71 (dd, J=2.20, J=11.92,1H)；3.88(s,3H)；
2.89 (t, J=11.2,2H)；2.26-2.29(m,8H)；MS+1：507.3.
Embodiment 4
Target compound 4, structural formula are：
Synthetic route is：
Preparation method synthesis of the synthesis of intermediate TRN158-g with reference to patent CN105237515B.
Compound TRN15804-2, TRN15804-3, the synthetic operation of TRN15804-4 and TRN15804 is with reference to embodiment
Corresponding steps in 2 are synthesized.The analysis data of the target compound TRN15804 of synthesis are as follows：
1H-NMR (400MHz, CDCl3)：δ：10.18(br,1H)；9.85(s,1H)；9.12(br,1H)；8.38(s,1H)；
8.06 (dd, J=2.92, J=8.64,1H)；7.72(s,1H)；7.39 (dd, J=1.84, J=9.24,1H)；7.23-7.30
(m,2H)；6.79(s,1H)；6.33-6.48(m,,2H)；5.71 (dd, J=2.20, J=11.92,1H)；3.88(s,3H)；
2.89 (t, J=11.2,2H)；2.70(s,3H)；2.26-2.29(m,2H)；MS+1：510.3.
With reference to the synthetic method of above-described embodiment, it is divided into and is not prepared for a series of specific compounds.It is shown in Table 1.
Embodiment 5- embodiments 12
The target compound and its characterize data of embodiment 5-12 synthesis, are specifically shown in Table 1.
Table 1
Embodiment 13
The mesylate of compound TRN15801 is synthesized, synthetic route is as follows：
Specific operation process：Compound TRN15801 (100mg, 0.2mmol) is added in reaction bulb, is then added 10
The acetonitrile of milliliter, adds methanesulfonic acid (20mg), then heating reflux reaction 3 hours, are then down to room temperature, filter to obtain product 96
Milligram.
Effect experimental examples
Experimental example 1
The compound provided using above example, to the activity inhibition of Wild type EGFR and mutant egf R kinases
It is detected.
Determinand is determined to double-mutant EGFR kinases (EGFR T790M/L858R kinases), Wild type EGFR kinases
(EGFR WT) active inhibiting effect.Wild type EGFR used in detection and mutant egf R (T790M/L858R) kinases are equal
Purchased from Carna Bioscience (card receive bioscience).
Experimentation is as follows：
One, the preparation of untested compound
1, compound to be measured is configured to the DMSO solution of 10mM (mmol/L), control sample compound AZD9291 respectively
It is configured to the DMSO solution of 1mM (mmol/L)；
2, it is diluted by 3- times, by testing compound solution serial dilution to 12 concentration, (or other required test is dense
Degree) on 384 orifice plates of TECAN EVO200；
3, using (Coring3570) on Echo550 transfer 20nL testing compound solutions to 384 orifice plates.Made using DMSO
For blank control.
Two, enzyme test is carried out
1, prepare the 1.3X enzyme solutions containing enzyme, matrix, co-factor, as shown in table 2 below；
2, at room temperature, the 1.3X enzyme solutions culture of 15 μ L 30 minutes is added in the hole of each orifice plate；
3, the 4X ATP solution that 5 μ L are added starts test reaction, and the liquor capacity in final each hole should be 20 μ L, contain
Ingredient it is as shown in table 2 below；
4, orifice plate is cultivated 90 minutes at room temperature, and the stop buffer (containing 0.5M EDTA) that 40 μ L are then added terminates
Test reaction；
5, the experimental data in each hole is tested and analyzed using EZ.
Enzyme solutions parameter list in the test of 2 enzyme of table
Three, data analysis
1, using read conversion ratios (CR), inhibition ratio is calculated according to following formula：
2, according to following formula, IC50 and Ki values are calculated using XLFit (equation 201),
The testing result of part of compounds is as shown in table 3 below.
The activity suppression testing result of 3 Wild type EGFR of table and mutant egf R kinases
Each detection compound difference is as follows in table 3.
1 structural formula of compound of the embodiment of the present invention is：
Control compound 2 is that Authorization Notice No. is compound disclosed in CN105237515B, and structural formula is：
Control compound 3 is that Authorization Notice No. is compound disclosed in CN104140418B, and structural formula is：
Control compound 1 (AZD9291, trade name：Ao Si replaces Buddhist nun) structure is as follows：
The compound of the embodiment of the present invention 1 is can be seen that than control compound 1, control compound from the detection data of table 3
2 and control compound 3 have better kinase activity.
Experimental example 2
Compounds on cell growth inhibitory activity is tested.Test method and step use side well known to those skilled in the art
Method carries out, and agents useful for same is commercially available in method obtains.
Test method：
2.1 experimental procedure：
(1) take 40nL testing compound solutions to test board using Echo (contactless nanoliter level sound wave liquor-transferring system).
(2) cell is configured to the solution of 25000cell/mL, is then taken on 40 μ L to 384 specified hole test boards.
(3) culture plate is at 37 DEG C, 5% carbon dioxide, is cultivated 72 hours under 95% humidity.
(4) it is added 40 μ L's in every holeReagent.
(5) at room temperature by test board, it is incubated 30 minutes, with stabilized illumination signal.
(6) sealing test plate removes bubble removing with 1000 revs/min of centrifugal speed.
(7) test board is shaken 1 minute on shaking table.
(8) read test plate data.
2.2 data processing
(1) residual rate is calculated using following formula：
S：Test sample is read；
V：Blank sample is read；
M：AZD9291 test specimens (1 μM is used to test PC-9 and H1975, and 30 μM are tested for A431) reading；
IC50 is calculated using XLFIT (V5.3.1.3) software.
Testing result is as shown in table 4：
4 compound on intracellular inhibitory activity of table
Respective compound in the structural formula and table 3 of control compound 1, control compound 2 and control compound 3 in table 4
It is identical.
From table 4, it can be seen that 1 compound of the embodiment of the present invention shows EGFR mutant cells (H1975, PC-9)
Stronger inhibitory activity, compared with control compound 1 and control compound 2 and control compound 3, the compound of the present invention pair
The growth of EGFR mutant cells has higher inhibitory activity.
Experimental example 3
Compound ira vitro metabolic stability experimental study, test method and step use side well known to those skilled in the art
Method carries out, and agents useful for same is commercially available in method obtains.
Test method：
3.1 experimental design：
(1) main solution of this experiment is configured according to following table.
Table 5
(2) two test experiments are carried out respectively as follows：
A) reduced Coenzyme II (NADPH) is needed：Take 20 milligrams every milliliter of 10 microlitres of liver particle with 10 mMs also
Prototype codehydrogenase Ⅱ (NADPH) mixing hatching.Finally the concentration of liver particle and reduced Coenzyme II (NADPH) is set separately
0.5 milligram every milliliter and 1 mM.
B) reduced Coenzyme II (NADPH) is not needed：Take 20 milligrams every milliliter of 10 microlitres of liver particle super with 40 microlitres
Pure water is added to hatches together.The ultimate density of liver particle is 0.5 milligram every milliliter.
(3) 4 microlitres of 200 micromolar internal control compounds are separately added into or compound to be tested is needed to start test in fact
It tests.In our current research, sample is controlled using verapamil (Verapamil) as the positive.The compound that need to test or internal control compound
Concentration is finally 2 micromoles.
(4) at 0,15,30,45 and 60 minute, take a small amount of incubation fluid for testing.By 4 times of bodies of a small amount of incubation fluid taken
Long-pending cold dilution in acetonitrile, with IS (100 nanomole alprazolams (alprazolam), 200 nanomoles labetalol
(labetalol), 200 nanomole caffeines (caffeine) and 2 micromolar Ketoprofens (ketoprofen)) stop this instead
It answers.Sample centrifuges 40 minutes, takes 100 microlitres of a small amount of filtrates and 100 microlitres of ultra-pure water mixing, then uses liquid matter/mass spectrum point
Analysis.
(5) data analysis
All record data are all recorded in Microsoft's excel tables.
Peak area is determined from the chromatography of ions figure of extraction.Slope value K is by the natural logrithm of parent drug retained percentage
What the linear regression with incubation time curve determined.
(in vitro) half-life period (in vitro t in vitro1/2) calculated by following formula：
Vitro half-lives=- (0.693/k).
External t1/2(min) it is converted into external intrinsic clearance (external CLint(in vitro CLint), μ L/min/mg eggs
Following equation (average value of replication) is used to carry out in vain)：
By external t1/2(min) it is converted into inherent clearance rate (the amplification CL of amplificationint, with mL/min/kg) and use following side
Journey (average value of replication)：
The conversion coefficient of 6 liver particle internal clearance rate of table prediction
A.Iwatsubo etc., Davies and Morris, 1993,10 (7) pp 1093-1095
B.Barter etc., 2007, Curr Drug Metab, 8 (1), pp 33-45；Iwatsubo etc., 1997, JPET,
283pp
462-469.
3.2 experimental result
External liver particle metabolic stability experimental result is as shown in table 7 below：
7 Compound ira vitro liver particle metabolic stability of table
Control compound 2,3 structural formula of control compound in table 7 is the same as respective compound in table 3.
Can significantly it find out from the experimental data of table 7, the compound ratio AZD9291 of embodiment 1 and right in the present invention
There is better metabolic stability in people's liver particle according to compound 2 and control compound 3.This just implies the change in the present invention
Close object has better medicine for stability and activity in vivo in human body, is very suitable for carrying out subsequent medicament research and development.
The compound that above example of the present invention is provided can be used for preparing EGFR inhibitor.
The compound that the embodiment of the present invention is provided can be used for preparing regulation and control EGFR tyrosine kinase activities or treatment
The drug of EGFR relevant diseases.Wherein, EGFR relevant diseases are selected from cancer, diabetes, disease of immune system, nervus retrogression disease
Disease and angiocardiopathy.
The compound that the embodiment of the present invention is provided can be used for preparing the drug for the treatment of non-small cell lung cancer.
The compound that the embodiment of the present invention is provided can be mixed with pharmaceutically acceptable carrier, be prepared into a kind of drug
Composition.
Example the above is only the implementation of the present invention is not intended to limit the scope of the invention, every to utilize this hair
Equivalent transformation made by bright description, is applied directly or indirectly in other relevant technical fields, and is included in this hair
In bright scope of patent protection.
Claims (12)
1. I compound represented of formula or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug：
Wherein：
R1、R2、R3、R4、R5It is each independently selected from methyl or deuterated methyl；
R6Selected from H or deuterium.
2. compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvate or preceding
Medicine, which is characterized in that the R1、R2、R3、R4、R5It is each independently selected from methyl or-CD3。
3. compound according to claim 2 or its pharmaceutically acceptable salt, stereoisomer, solvate or preceding
Medicine, which is characterized in that the R1、R2、R3、R4、R5In it is at least one be-CD3。
4. compound according to claim 3 or its pharmaceutically acceptable salt, stereoisomer, solvate or preceding
Medicine, which is characterized in that the R1、R2、R3、R4、R5In have 1~3 be-CD3。
5. compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvate or preceding
Medicine, which is characterized in that the compound that the compound is optionally indicated from following structural formula：
6. according to any compounds of claim 1-5, wherein the pharmaceutically acceptable salt be inorganic acid salt or
Acylate, the inorganic acid salt are selected from hydrochloride, hydrobromate, hydriodate, sulfate, disulfate, nitrate, phosphoric acid
Salt, acid phosphate；The acylate is selected from formates, acetate, trifluoroacetate, propionate, acetonate, oxyacetic acid
Salt, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methylsulphur
Hydrochlorate, esilate, benzene sulfonate, salicylate, picrate, glutamate, ascorbate, camphor hydrochlorate, camphor sulphur
Hydrochlorate.
7. compound according to claim 6, wherein the inorganic acid salt is hydrochloride or sulfate；Described has
Machine hydrochlorate is mesylate.
8. a kind of pharmaceutical composition, including the compound described in any one of claim 1-7 and pharmaceutically acceptable load
Body.
9. application of the compound in preparing EGFR inhibitor described in any one of claim 1-7.
10. the compound described in any one of claim 1-7 is being prepared for regulating and controlling EGFR tyrosine kinase activities or treatment
Application in the drug of EGFR relevant diseases.
11. application according to claim 10, wherein the disease is selected from cancer, diabetes, disease of immune system, god
Through degenerative disease and angiocardiopathy.
12. compound the answering in preparing the drug for treating non-small cell lung cancer described in any one of claim 1-7
With.
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| CN110003183A (en) * | 2019-04-09 | 2019-07-12 | 河南真实生物科技有限公司 | 2-(2,4,5- replace phenylaminos) pyrimidine derivatives and its crystal form B |
| CN110903283A (en) * | 2018-09-17 | 2020-03-24 | 南京雷正医药科技有限公司 | Substituted quinazoline compound, pharmaceutical composition containing compound and application of compound |
| 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 |
| WO2021037198A1 (en) * | 2019-08-30 | 2021-03-04 | 润佳（苏州）医药科技有限公司 | Deuterated compound and use thereof in cancer treatment |
| 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 |
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| 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 |
| CN110003183A (en) * | 2019-04-09 | 2019-07-12 | 河南真实生物科技有限公司 | 2-(2,4,5- replace phenylaminos) pyrimidine derivatives and its crystal form B |
| WO2021037198A1 (en) * | 2019-08-30 | 2021-03-04 | 润佳（苏州）医药科技有限公司 | Deuterated compound and use thereof in cancer treatment |
| 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 |
| 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 |
| CN114380783A (en) * | 2022-01-18 | 2022-04-22 | 梯尔希（南京）药物研发有限公司 | Preparation method of olopatadine deuterium labeled metabolite |
| CN114380783B (en) * | 2022-01-18 | 2023-02-10 | 梯尔希（南京）药物研发有限公司 | Preparation method of olopatadine deuterium labeled metabolite |
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