CN103664991B - Thiophene [2,3 d] pyrimidine derivatives, Its Preparation Method And Use - Google Patents

Thiophene [2,3 d] pyrimidine derivatives, Its Preparation Method And Use Download PDF

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CN103664991B
CN103664991B CN201210349508.3A CN201210349508A CN103664991B CN 103664991 B CN103664991 B CN 103664991B CN 201210349508 A CN201210349508 A CN 201210349508A CN 103664991 B CN103664991 B CN 103664991B
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CN103664991A (en
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卢灿忠
雍建平
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Fujian Institute of Research on the Structure of Matter of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Abstract

The present invention provides the thiophene containing isoxazole heterocycle [2, the 3 d] pyrimidine derivatives shown in a kind of formula (I), or its pharmaceutically acceptable salt, wherein R1And R2It is each independently selected from hydrogen, C1‑6Alkyl, C1‑6Alkoxyl, halo C1‑6Alkyl or halo C1‑6Alkoxyl, optionally by R7Substituted aryl or optionally by R8Substituted heteroaryl；Or R1And R2Coupled carbon atom forms 4 to 6 yuan of carbocyclic rings or heterocycle together；Z is NR5‑,C(R6)2, S or O；R3Selected from hydrogen, halogen, C1‑6Alkyl, C1‑6Alkoxyl, halo C1‑6Alkyl or halo C1‑6Alkoxyl, n is the integer of 0～5;R4Selected from hydrogen, C1‑6Alkyl, C1‑6Alkoxyl or halo C1‑6Alkyl, optionally by R9Substituted aryl or optionally by R10Substituted heteroaryl.The present invention also provides for formula (I) compound and the preparation method of its pharmaceutically acceptable salt and medical usage, and this compounds can be as the medicine of the treatment disease such as tumor, cancer or lead compound.

Description

Thiophene [2,3-d] pyrimidine derivatives, Its Preparation Method And Use
Technical field
The present invention relates to novel [2,3-d] pyrimidine derivatives of the thiophene containing isoxazole heterocycle of a class formation and spread out containing such Biological medical composition and its use, specifically: such thiophene [2,3-d] pyrimidine derivatives or its pharmaceutical composition have Suppression colorectal cancer cell lines (HCT-116) and human lung carcinoma cell line (A549), can be as swell relevant with tyrosine kinase for the treatment of The medicine of the disease such as tumor, cancer or lead compound.
Background technology
Epidermal growth factor (Epidermal Growth Factor, EGF) and EGF-R ELISA (Epidermal Growth Factor Receptor, EGFR) combine the activity that can activate tyrosine kinase, and therefore activation causes cell to increase The reaction grown.The overexpression of EGFR and increased activity all will cause uncontrollable cell division.
Epidermal growth factor recipient tyrosine kinase (EGFR-TK) is the protein tyrosine kinase found the earliest, widely Being distributed on the cell membrane that human body is respectively organized, it is in most of tumors (such as: bladder cancer, nonsmall-cell lung cancer, ovarian cancer, mammary gland Cancer, gastric cancer, esophageal carcinoma etc.) in process LAN, the intracellular region of EGFR has the binding site of adenosine triphosphate (ATP), EGFR inhibitor Emulative can combine with ATP-binding site, thus suppress the phosphorylation of EGFR, block the conduction of downstream signal, and then Suppress the growth of tumor cell, break up and shift.Carrying out targeting therapy on tumor with EGFR receptor for target spot is current treatment of cancer One of field that middle research is the most active, the most also achieved with significant curative effect.
Patent WO2009/104027 discloses a series of thiophene [2,3-d] pyrimidine derivates and has suppression tyrosine kinase work Property；Patent WO2009/104026 discloses the 4-bit strip of thiophene [2,3-d] pyrimidine phenylamino some thiophene substituted [2,3- D] pyrimidine derivatives has active anticancer.Above-mentioned references cited therein is as reference.
Isoxazole heterocycle, based on patent WO2009/104027 and patent WO2009/104026, is introduced thiophene by the present invention [2,3-d] pyrimidine parent nucleus, has synthesized a series of thiophene containing isoxazole heterocycle [2,3-d] pyrimidine derivatives, vitro inhibition large intestine JEG-3 (HCT-116) and human lung carcinoma cell line (A549) activity show that this compounds is 1 × 10-4Have relatively under M concentration Strong presses down colorectal cancer cell lines (HCT-116) and human lung carcinoma cell line (A549) activity.Can be as anticancer, the candidate of tumour medicine Compound or lead compound.
Summary of the invention
It is an object of the invention to, it is provided that the thiophene containing isoxazole heterocycle [2,3-d] the pyrimidine chemical combination as shown in formula (I) Thing.Show have using this compound as active component and press down colorectal cancer cell lines (HCT-116) and people's pulmonary carcinoma through activity research Cell strain (A549) activity.The present invention is achieved through the following technical solutions:
A kind of thiophene containing isoxazole heterocycle [2,3-d] pyrimidine derivatives shown in formula (I), or it is pharmaceutically acceptable Salt, or solvate:
Wherein: R1And R2Can be identical or different, it is each independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkane Base, halo C1-6Alkoxyl or the substituted C of hydroxyl1-6Alkyl, optionally by R7Substituted aryl or optionally by R8Substituted heteroaryl Base；
Or R1And R2Coupled carbon atom forms 4 to 6 yuan of carbocyclic rings or heterocycle together, and described carbocyclic ring or heterocycle are optional By R11Replace；Described heterocycle contains at least 1 hetero atom selected from N, O or S；
Z is-NR5-,C(R6)2,-S-or-O-, wherein R5For hydrogen or C1-6Alkyl, R6Identical or different, selected from hydrogen, C1-6's Alkyl, halo C1-6Alkyl or the substituted C of hydroxyl1-6Alkyl；
R3Selected from hydrogen, halogen, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, halo C1-6Alkoxyl or hydroxyl are substituted C1-6Alkyl, n is the integer of 0 ~ 5;
R4Selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl or halo C1-6Alkoxyl, optionally by R9Substituted virtue Base or optionally by R10Substituted heteroaryl；
R7、R8、R9、R10Or R11It is each independently selected from hydrogen, hydroxyl, sulfydryl, cyano group, amino, C1-6Alkyl amino, two (C1-6Alkyl) amino, nitro, halogen, C1-6Alkyl, C1-6Alkoxyl, C1-6Alkylthio group, carboxyl, halo C1-6Alkyl, halo C1-6 Alkoxyl, halo C1-6Alkylthio group, the substituted C of hydroxyl1-6Alkyl.
According to the preferred technical solution of the present invention, in formula (I):
R1And R2Can be identical or different, it is each independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, halogen For C1-6Alkoxyl, aryl or by R7Substituted aryl, or
R1And R2Coupled carbon atom forms 4 to 6 yuan of carbocyclic rings together, and described carbocyclic ring is optionally by hydrogen, C1-6Alkyl, halogen Element, nitro or amino replace；
Z is-NR5-,C(R6)2,-S-or-O-, wherein R5For hydrogen or C1-3Alkyl, R6Identical or different, selected from hydrogen, C1-3's Alkyl, or the substituted C of hydroxyl1-3Alkyl；
R3Selected from hydrogen, halogen, C1-6Alkyl, C1-6Alkoxyl or halo C1-6Alkyl or halo C1-6Alkoxyl, n is 0-5's Integer；
R4Selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, aryl or by R9Substituted aryl.
According to the preferred technical solution of the present invention, in formula (I):
R1And R2Can be identical or different, it is each independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, halogen For C1-6Alkoxyl, phenyl or by R7Substituted phenyl, or
Or R1And R2Coupled carbon atom forms 4 to 6 yuan of carbocyclic rings together；
R4Selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, phenyl or by R9Substituted phenyl.
According to the preferred version of the present invention, R1And R2It is each independently selected from hydrogen, C1-3Alkyl, phenyl or by R7Substituted benzene Base, more preferably hydrogen, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group or phenyl；
Z is-NH-, CH2Or-O-;
R3Selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group or trifluoromethyl, n is preferably 1-4, more preferably 2-3.
R4Selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl or halo C1-6Alkyl, phenyl or substituted-phenyl.
According to the more preferably scheme of the present invention, R1And R2Can be identical or different, it is each independently selected from C1-6Alkyl, phenyl Or by R7Substituted phenyl, more preferably hydrogen, methyl, ethyl, the tert-butyl group, phenyl,；
Z is-NH-or-O-,
R3Preferably in ortho position or the para-position of isoxazole ring, more preferably 4-fluorine, 4-chlorine, 2-chlorine, 4-bromine, 2,4-dichloro, 4- Methyl, 4-methoxyl group, hydrogen, 4-trifluoromethyl or 2,4-dimethoxy；
R4Selected from hydrogen, methyl or phenyl.
According to the present invention, more preferably R1Selected from hydrogen, methyl, phenyl；R2Selected from hydrogen, methyl, ethyl or the tert-butyl group.
According to the preferred technical solution of the present invention, wherein:
R7、R8、R9Or R10It is each independently selected from hydrogen, hydroxyl, cyano group, amino, C1-6Alkyl amino, two (C1-6Alkyl) ammonia Base, halogen, C1-6Alkyl, C1-6Alkoxyl, C1-6Alkylthio group, carboxyl, halo C1-6Alkyl, halo C1-6Alkoxyl or for C1-6Alkane sulfur Base.
Further, R7、R8、R9Or R10It is each independently selected from hydrogen, hydroxyl, sulfydryl, cyano group, amino, halogen, C1-6Alkane Base, C1-6Alkoxyl, C1-6Alkylthio group, carboxyl.Further, R7、R8、R9Or R10It is each independently selected from hydrogen, hydroxyl, cyano group, Amino, halogen, C1-6Alkyl, C1-6Alkoxyl, C1-6Alkylthio group or carboxyl.
According to the present invention, thiophene [2, the 3-d] pyrimidine compound shown in described formula (I) is selected from any one compound following:
The thiophene containing isoxazole heterocycle [2,3-d] pyrimidine compound shown in formula (I), can select respectively and pharmaceutically may be used The acid accepted forms pharmaceutically acceptable salt.Wherein term " pharmaceutically acceptable salt " includes but not limited to and mineral acid shape The salt become, example hydrochloric acid salt, phosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate and class thereof are saloid, excellent Select hydrochlorate, nitrate, sulfate or phosphate.Also the salt formed with organic acid is included, such as lactate, oxalates, malic acid Salt, maleate, fumarate, tartrate, succinate, citrate, sulfonate, tosilate, 2-ethoxy Sulfonate, benzoate, salicylate, stearate, trifluoroacetic acid or aminoacid；Alkanoate such as formates, acetate etc., Or HOOC-(CH2) n-COOH wherein n is the salt of 0-4, and class is saloid.Preferably acylate is selected from formates, acetic acid Salt, oxalates, citrate, fumarate, maleate, malate, lactate, tartrate, tosilate, three Fluoroacetate or amino acid salts.Similarly, pharmaceutically acceptable cation includes but not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.
Term " solvate " includes hydrate and alcohol adduct.
The present invention also provides for a kind of pharmaceutical composition, and it includes thiophene [2,3-d] the pyrimidine chemical combination shown in aforesaid formula (I) Thing, or its pharmaceutically acceptable salt or solvate, and at least one pharmaceutically acceptable, inert, nontoxic tax Shape agent or carrier or diluent.
According to described pharmaceutical composition, it is characterised in that described pharmaceutical composition also comprises one or more selected from filling out Fill the pharmaceutically acceptable auxiliary material of agent, disintegrating agent, lubricant, fluidizer, effervescent, correctives, preservative and coating material Material.
The present invention also provides for a kind of pharmaceutical preparation, and it comprises thiophene [2,3-d] the pyrimidine chemical combination shown in aforesaid formula (I) Thing, or its pharmaceutically acceptable salt or solvate, and at least one pharmaceutically acceptable, inert, nontoxic tax Shape agent or carrier or diluent.
Pharmaceutical preparation according to the present invention, it is characterised in that described preparation is preferably solid orally ingestible, liquid port system of mourning Agent or injection.
According to the pharmaceutical preparation of the present invention, described preparation is selected from tablet, dispersible tablet, enteric coatel tablets, chewable tablet, oral cavity disintegration tablet, glue Capsule, granule, oral solution, injection liquid drugs injection, injection freeze-dried powder, infusion solutions or primary infusion.
The present invention also provides for thiophene [2,3-d] the pyrimidine chemical combination shown in formula (I) of a kind of claim 1-4 as medicine Thing or its pharmaceutically acceptable salt, a kind of medicine being effective to treat lesion/cancer disease.
The present invention also provide for the aforementioned any one as medicine thiophene [2,3-d] pyrimidine compound shown in formula (I) or Its pharmaceutically acceptable salt or solvate, especially a kind of for treating for suppression EGFR transition expression and/or activity The medicine of too high effective tumor.
The present invention also provides for thiophene [2,3-d] pyrimidine compound shown in formula (I) or its pharmacy of a kind of aforementioned any one Upper acceptable salt or solvate application in preparation is used for antitumor or cancer drug.
According to application of the present invention, wherein said tumor or cancer are selected from: bladder cancer, nonsmall-cell lung cancer, ovum Nest cancer, breast carcinoma, gastric cancer, esophageal carcinoma, pulmonary carcinoma, head and neck cancer, colon cancer, pharyngeal cancer and cancer of pancreas etc., more preferably nonsmall-cell lung cancer.
According to the present invention, also provide for thiophene [2, the 3-d] pyrimidine shown in formula (I) any one of a kind of claim 1-8 Compound and/or pharmaceutically acceptable salt are in the transition expression of preparation suppression EGFR and/or the inhibitor of hyperactivity Application.
Present invention also offers thiophene [2,3-d] pyrimidine compound shown in formula (I) and/or the medicine of a kind of aforementioned any one On, acceptable salt or solvate are used for pressing down colorectal cancer cell lines (HCT-116) and human lung carcinoma cell line (A549) in preparation Application in the medicine of activity.
Present invention also offers the system of the thiophene containing isoxazole heterocycle [2,3-d] pyrimidine compound shown in a kind of formula (I) Preparation Method, it is characterised in that described method comprises the steps:
5,6-bis-replacement-4-chloro-thiophene [2,3-d] pyrimidine shown in Formula II and the 3-substituted-phenyl-5-hydroxyl shown in formula III 3-substituted-phenyl-5-aminomethyl-isoxazole shown in methyl-isoxazole or formula IV, ties up acid at dry organic solvent and alkalescence Agent system is reacted and prepares the compound shown in formula (I-1) or formula (I-2):
Simultaneously for the formula (I) compound that Z is other substituent groups, such as R5-NR for other substituent groups5, C (R6)2, S Time, (II) and-NH(R can be used5) or Cl-C (R6)2Or 3-substituted-phenyl-5-sulfydryl isoxazole is by corresponding coupling reaction system Standby, wherein 3-substituted-phenyl-5-sulfydryl isoxazole is with propine mercaptan as raw material, uses the building-up process of formula (III) to prepare.
According to the present invention, described reaction temperature be-20 DEG C to counterflow condition, preferably room temperature is to counterflow condition.
According to the present invention, described organic solvent is aromatic hydrocarbons, halogenated hydrocarbons, C1-C6Lower alcohols, oxolane or dimethyl are sub- Sulfone (DMF).Preferably, described solvent is selected from benzene,toluene,xylene, dichloromethane, chloroform, isopropanol, oxolane or DMF, More preferably isopropanol.
According to the present invention, described alkaline acid binding agent is organic base or inorganic base, described organic base selected from triethylamine, three Propylamine, DMAP, potassium tert-butoxide etc.；Described inorganic base is selected from potassium carbonate, sodium hydride, sodium carbonate etc..Preferably acid binding agent is three Ethamine.
According to the present invention, the intermediate 3-substituted-phenyl 5-methylol-isoxazole of described formula (III) is by following method Preparation:
(1) substituted benzaldehyde and azanol or hydroxylamine hydrochloride are in methanol/water system, and under the catalysis of sodium carbonate, reaction is raw Become corresponding benzaldoxime；
(2) benzaldoxime and propilolic alcohol step (1) prepared is at N-bromo-succinimide (NCS) and alkaline acid binding agent Formula (III) isoxazole compound is formed by 1,3-Dipolar Cycloaddition under effect.
In accordance with the present invention it is preferred that, described alkaline acid binding agent is selected from organic base or inorganic base, and described organic base is selected from three Ethamine, tripropyl amine (TPA), DMAP, DMF, N-methylmorpholine etc.；Described inorganic base is selected from potassium carbonate, sodium hydride, sodium carbonate etc..More excellent The alkaline acid binding agent of choosing is triethylamine.
Described reaction temperature be 0 degree to reflux temperature, be preferably room temperature to reflux temperature.
According to the present invention, the intermediate 3-substituted-phenyl 5-aminomethyl-isoxazole of described formula (IV) is by following method Preparation:
(3) the isoxazole compound (preferably being obtained by preceding method) of formula (III) and sulfonic acid chloride react acquisition formula V Compound,；
According to the preferred technical solution of the present invention, in step (3), described sulfonic acid chloride is selected from: mesyl chloride, benzene sulfonyl chloride, Substituted phenylsulfonyl chloride (such as halogeno-benzene sulfonic acid chloride, alkylbenzene sulfonyl chloride) etc., more preferably mesyl chloride.Described reaction temperature is-5 Degree is to reflux temperature, and preferably room temperature is to reflux temperature.Described reaction dissolvent selected from benzene, toluene, halogenated aryl hydrocarbon, halogenated alkane (as Chloroform or dichloromethane), oxolane, acetonitrile and ionic liquid.It is highly preferred that described reaction refluxes in dichloromethane system Reaction.
(4) formula V compound and reaction of sodium azide, preferably in DMF system, at a temperature of 60 DEG C, reaction obtains formula (VI) Compound；
(5) formula (VI) compound and ammonium chloride and zinc powder, iron powder or palladium carbon catalysis reduction preparation formula (IV) compound, preferably Described catalyst is catalyzed under the conditions of mineral acid, preferably hydrochloric acid or sulphuric acid, and described catalyst is preferably zinc powder and chlorination Ammonium.
In step (5) preferred reaction dissolvent be water or organic solvent (such as alcohols, halogenated hydrocarbon, aromatic hydrocarbons etc.) or its Mixture, the preferably reaction system of second alcohol and water.
Preferably synthetic route is as follows:
It is highly preferred that described preparation method is as shown in following flow process:
Simultaneously for the formula (III) that Z is other substituent groups or (IV) compound, such as R5-NR for other substituent groups5, C (R6)2, during S, corresponding propinyl chlorine can be used, prepared by propine mercaptan.
According to the present invention, 5 shown in described Formula II, 6-bis-replacement-4-chloro-thiophene [2,3-d] pyrimidine is by following mistake Prepared by journey:
(1) shape under the effect of reagent 1 by 3-amino 4,5-bis-substituted thiophene-2-methyl formate (VII) and formamidine acetate Become 5,6-dibasic Thienopyrimidine ketonic compound (VIII), it is preferable that described reaction temperature be 0 degree to reflux temperature, more It is preferably room temperature to reflux temperature；
(2) compound (VIII) forms the chloro-thiophene of the 5,6-bis-replacement-4-[2,3-d] shown in Formula II under reagent 2 acts on Pyrimidine, it is preferable that described reaction temperature be 0 degree to reflux temperature, more preferably room temperature is to reflux temperature.
Specifically can see below reaction equation
Wherein, Reagent 1 is selected from: benzene, toluene, glycol monoethyl ether, glycol dimethyl ether, ethylene glycol monoethyl ether, second Glycol diethyl ether, ethanol, 1,2-dichloroethanes and ionic liquid etc.；Reagent 2 is selected from: thionyl chloride, phosphorus oxychloride, pentachloro- Change phosphorus chlorine and replace reagent etc..
According to the present invention, it is provided that the system of the thiophene containing isoxazole heterocycle [2, the 3-d] pyrimidine compound shown in a kind of formula (I) Preparation Method, it is characterised in that described method comprises the steps:
(1) substituted benzaldehyde and azanol or hydroxylamine hydrochloride are in methanol/water system, under the catalysis of sodium carbonate, preferably Room temperature generates corresponding benzaldoxime to reaction under reflux temperature；
(2) benzaldoxime step (1) prepared and propilolic alcohol are in N-bromo-succinimide (NCS) and the effect of triethylamine Under by 1,3-Dipolar Cycloaddition formed formula (III) isoxazole compound；
(3) the isoxazole compound of formula (III) reacts with mesyl chloride, preferably in dichloromethane system, obtain under room temperature Obtain formula V compound；
(4) formula V compound and reaction of sodium azide, preferably in DMF system, at a temperature of 60 DEG C, reaction obtains formula (VI) Compound；
(5) formula (VI) compound is under zinc powder and ammonium chloride are catalyzed, backflow preparation formula (IV) chemical combination in ethanol/water system Thing；
(6) 3-amino 4,5-bis-substituted thiophene-2-methyl formate (VII) and formamidine acetate are formed under the effect of reagent 1 5,6-dibasic Thienopyrimidine ketonic compound (VIII)；
(7) compound (VIII) forms the chloro-thiophene of the 5,6-bis-replacement-4-[2,3-d] shown in Formula II under reagent 2 acts on Pyrimidine,
(8) the chloro-thiophene of the replacement-4-of 5,6-bis-shown in Formula II [2,3-d] pyrimidine and the 3-substituted-phenyl-5-shown in formula III 3-substituted-phenyl-5-aminomethyl-isoxazole shown in methylol-isoxazole or formula IV, ties up at dry organic solvent and alkalescence In acid agent system, reaction prepares the compound shown in formula (I-1) or formula (I-2).
It is possible if desired to form pharmaceutically acceptable salt or the solvate of formula (I) compound.
According to the present invention, described compound of formula I, include but not limited to: their optical isomer, racemic modification and Mixture.
According to the present invention, described halogen or halogen atom are selected from fluorine, chlorine or bromine.
According to the present invention, described alkyl is straight or branched alkyl, such as C1-6Alkyl, preferably C1-3Alkyl, including but do not limit In methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl, n-hexyl etc..
According to the present invention, 4 to 6 yuan of described carbocyclic rings are selected from cyclobutyl, cyclopenta, cyclohexyl.It is preferably cyclopenta or ring Hexyl.
According to the present invention, described is selected from oxolane, tetrahydrochysene thiophene containing at least one selected from N, the heteroatomic heterocycle of O, S Fen, azetidine, pyrrolidinyl, acridine, nafoxidine, 1,3-thiazoline, 1,3-dihydro azoles, piperidines, piperazine, Quinoline, thiomorpholine, thiazine, preferably piperazinyl, morpholinyl or piperidyl.
According to the present invention, described aryl is monocycle or Bicyclic alkyl, such as C6-14Aryl, described aryl is preferably benzene Base or naphthyl, more preferably phenyl.
According to the present invention, described heteroaryl is monocycle or the miscellaneous aryl radical of dicyclo, is wherein preferably 5 members containing heteroatomic ring Or 6 Yuans heteroaryls, it contains at least one, preferably has 1-4 the heteroatomic aromatic rings of N, S or O, and described heteroaryl is preferably pyrrole Piperidinyl, pyrimidine radicals, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, indyl, pyrrole radicals, thienyl, furyl, benzene And furyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, furazanyl, thiadiazolyl group, four Oxazolyl etc., more preferably pyrrole radicals, thienyl, furyl, indyl, benzofuranyl.
Term " effective dose " refers to: at least one compound described and/or at least one pharmaceutically acceptable salt pair In can effectively " treatment ' individual a kind of disease or the consumption of discomfort.If during cancer, effective dose can reduce cancer or tumor The number of cell；Reduce the size of tumor；Suppression or the prevention tumor cell intrusion to peripheral organs.Such as: tumor spread into In soft tissue or skeleton；Suppression or the transfer of prevention tumor；Suppression or the growth of prevention tumor；Alleviate to a certain extent one or The multiple symptom relevant to cancer；Reduce M & M；Improve the quality of living；Or the combination of the effect above.Have Effect amount can be to be reduced the consumption of disease symptoms by suppression activity of EGFR.For treatment of cancer, the effect of experiment in vivo can With by assessing such as survival period, disease developing time (Time to Disease Progression, TTP), response rate (response Rates, RR) sustained response phase and/or quality of life measure.Professional is it has been realized that effective dose can With along be administered approach, the consumption of excipient and with share of other drug and change.
Term " effective dose " also can refer to be at least one compound described and/or its at least one pharmaceutically acceptable Salt overexpression and/or the effective dosage of hyperactivity to suppressing EGFR.
The compound of the present invention is respectively provided with antitumor, active anticancer, especially has anti-colorectal cancer cells pearl (HCT-116) Active and anti-human lung cell A549 activity.The compound of the present invention is 1 × 10-4Inhibitory activity, embodiment it is respectively provided with under M concentration The activity of compound can reach more than 50%, preferably more than 60%, more preferably more than 80%.Wherein most compounds is to large intestine Cancerous cell pearl (HCT-116) and human lung cancer cell A549 have stronger inhibitory activity simultaneously.Such as compound S-101 1 × 10-4Under M concentration, the suppression ratio to colorectal cancer cells pearl (HCT-116) is 68.8%, and the suppression ratio to human lung cancer cell A549 Being 88%, compound S-3 is 1 × 10-4Under M concentration, the suppression ratio to colorectal cancer cells pearl (HCT-116) is 70%, and to people's lung The suppression ratio of cancerous cell A549 is 86.4%, and compound S-83 is 1 × 10-4Under M concentration, the suppression ratio to human lung cancer cell A549 is high Reach 89.4%.Thus the compound of the present invention can be used as treating tumor, the drug candidate of cancer or lead compound.
Specific embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that embodiment compound is not right The restriction of scope, any improvement made on the basis of the present invention and change are all without prejudice to the spirit of the present invention.
Wherein, the building-up process of intermediate and target compound all illustrates with the representative in embodiment, remaining intermediate The same representation compound with the building-up process of target compound.
Instrument and reagent
AVANCE III nuclear magnetic resonance analyser (400MHz, DMSO-d6, TMS is internal standard), ion trap liquid matter is used in conjunction instrument (DECAX-30000LCQ Deca XP), Shimadzu FTIR-8400S (Shimadzu Corporation of Japan produces), XT5 numerical monitor shows Micro-melting point detector (tech electric light instrument plant of Beijing manufacture, temperature is the most calibrated), wavelengthtunable declines orifice plate microplate reader (Molecular Devies SPECTRAMAX190).Chemical reagent is commercially available analytical pure or chemically pure reagent, RPMI1640 is purchased from Gibco company, and Sulforhodamine B (SulforodamineB, SRB) is purchased from Sigma company, trichloroacetic acid (TCA), acetic acid and Tris base unbuffer are domestic analytical reagent.
Embodiment 1 formula (III) intermediate 3-substituted-phenyl-5-methylol-isoxazole and formula (IV) intermediate 3-substituted benzene The synthesis of base 5-aminomethyl-isoxazole
Wherein with R3For H as example:
(1) synthesis of benzaldoxime
10.0mmol dissolution of benzaldehyde is at 30mL 30%CH3OH and H2In O solution, it is equipped with the triangle of magnetic stirring apparatus In Ping, stirring is lower adds 10.0mmol oxammonium hydrochloride, waits oxammonium hydrochloride to be slowly added to 5.0mmol after dissolving and is dried finely ground carbonic acid Sodium.Room temperature reaction, after TLC detection reaction completes, after system removes methanol under reduced pressure, adds 30mL H2O, dichloromethane (3 × 30mL) extraction, merges organic layer, and anhydrous sodium sulfate is dried organic layer. and desolventizing i.e. obtains benzaldoxime crude product, yield 86.2%. This crude product isolated and purified need not directly carry out the next step.
(2) 3-phenyl-5-methylol-isoxazole
Dichloromethane 10.0mmol benzaldoxime and 30mL being dried adds in 250mL single necked round bottom flask, under stirring Add 1.60g (12.0mmol) N-chlorosuccinamide (NCS), be slightly heated to after NCS all dissolves, dripping 0.56g (10.0mmol) 2-propine-1-alcohol, is slowly added dropwise into 20mL molten containing the dichloromethane of 10.1g (10.0mmol) triethylamine subsequently Liquid, after adding the backflow .TLC detection of rear system reaction completing, mother solution is washed, and anhydrous sodium sulfate is dried, and post separates (VPetroleum ether:VEthyl acetate 5:1-2:1) i.e. obtain 3-phenyl-5-methylol-isoxazole, yield 76.8%.
(3) 3-phenyl-5-aminomethyl-isoxazole
Dichloromethane 10.0mmol 5-methylol-3-phenyl-isoxazole and 30mL being dried adds 250mL single port circle In end flask, in the lower 20mL dichloromethane solution addition system that will contain 1.01g (10.0mmol) triethylamine of ice bath stirring, then To be slowly added dropwise in system dissolved with the 5mL dichloromethane solution of 1.37g (12.0mmol) mesyl chloride (MsCl), ice bath reacts After 2h, room temperature reaction.After TLC detection reaction completes, mother solution is washed, and the sodium bicarbonate solution of 5% is washed, washing, and anhydrous sodium sulfate is done Dry, decompression desolventizing obtains crude product 5-methanesulfonic acid-3-phenyl-isoxazole-5-methanol ester, yield 68.0%.Crude product need not purification Directly carry out the next step.
5.0mmol 5-methanesulfonic acid-3-phenyl-isoxazole-5-methanol ester is dissolved in the DMF that 20mL is dried, adds 0.34g (5.20mmol) Hydrazoic acid,sodium salt, after dissolving is stirred at room temperature, is placed in 45 DEG C of-50 DEG C of oil baths reaction, and TLC Indicator Reaction is complete Cheng Hou, filter, filter cake with ether (2 × 30mL) wash, merge organic layer, in organic layer, add 100mL water, with ether (5 × 30mL) extraction, merges organic layer, and organic layer is washed 2 times, and anhydrous sodium sulfate is dried, and obtains crude product 3-phenyl-5-and fold after desolventizing N-methyl-isoxazole, yield 90%, crude product directly carries out following reduction reaction.
5.0mmol 5-azido-methyl-3-phenyl-isoxazole is dissolved in the mixed solution of 80mL ethanol and 20mL water, will The zinc powder of 0.17g (2.6mmol) and the NH of 0.28g (5.2mmol)4Cl adds system, and reflux 1h, and vacuum sloughs ethanol, Xiang Ti System adds 20mL water, is adjusted to pH value to 12 with the sodium hydroxide solution of 20%, addition 50mL DCM in system, after stirring, Filtering, filtering residue, with a small amount of water dissolution, filters, merges the filtrate of twice, separates organic layer, organic layer, washing, anhydrous slufuric acid Sodium is dried, vacuum desolvation agent, and residue post separates (VDichloromethane: VMethanol, 10:1) and obtain product 3-phenyl-5-aminomethyl-isoxazole, yield 75%. light yellow solids, m.p:39-40 DEG C,1H-NMR(400MHz,CDCl3, TMS), δ ppm:1.60(s, 2H, NH2), 3.91 (s,2H,CH2), 6.40 (s, 1H), 7.39 (m, 2H, Ar-H), 7.76 (m, 2H, Ar-H).
Embodiment 2
The synthesis (illustrating as a example by the synthesis of the 6-tert-butyl group-4-chloro-thiophene [2,3-d] pyrimidine) of intermediate (II):
2.13g (10mmol) 3-amino-5-tert-butyl group-thiophene-2-carboxylic acid methyl ester is added 250mL round bottom single neck round bottom burn In Ping, it is subsequently added into 100mL ethylene glycol monoethyl ether and 2.14g (20mmol) formamidine acetate, system under agitation back flow reaction, After TLC detection reaction completes, system cools down, and then decompression distillation has 30mL to ethylene glycol monoethyl ether, system cold preservation a few hours, has Substantial amounts of solid separates out, and filters, and the ether of filter cake cold preservation washs for several times, is directly used in the next step after filter cake vacuum drying.
Weigh above-mentioned crude product 5 grams to add in 100mL round bottom single necked round bottom flask, be slowly added dropwise the phosphorus oxychloride of 3 DMF Solution 20mL, after system back flow reaction 6h, after removing the phosphorus oxychloride of excess under reduced pressure, mixes silica gel after cooling, post separates (V (oil Ether): V (ethyl acetate)=4:1-1:1) i.e. obtain the target compound 6-tert-butyl group-4-chloro-thiophene [2,3-d] pyrimidine, light yellow solid Body, 1H-NMR (400MHz, CDCl3, TMS), δ ppm:1.43(s, 9H, 3CH3), 7.19 (s, 1H), 8.84 (s, 1H).
Embodiment 3
The synthesis of 5-methyl-4-[(3-phenyl-isoxazole-5-base)-methoxyl group-]-thiophene [2,3-d] pyrimidine
Being dissolved in the isopropanol that 5mL is dried by 4-chloro-thiophene [2, the 3-d] pyrimidine of 0.184g (1mmol), stirring is lower will 5mL aqueous isopropanol dissolved with 0.175g (1mmol) 5-methylol-3-phenyl-isoxazole is slowly added dropwise into reaction system, then Add the triethylamine that 0.101g (1mmol) newly steams, after system is stirred at room temperature 30min, 60 DEG C of reactions, after TLC detection reaction completes, Reactant liquor is concentrated in vacuo, and the direct post of residue separates V(petroleum ether): V(ethyl acetate)=9:1-4:1) i.e. obtain target compound 5-methyl-4- [(3-phenyl-isoxazole-5-base)-methoxyl group-]-thiophene [2,3-d] pyrimidine (following table S-1).Remaining compound is according to 5-first The building-up process synthesis of base-4-[(3-phenyl-isoxazole-5-base)-methoxyl group-]-thiophene [2,3-d] pyrimidine.Its structure is the most logical Cross IR,1H NMR, ESI-MS etc. points of analysis methods are characterized.The Physical Constants of the compound preferably gone out and spectroscopic data are with row The form of table illustrates:
The structure of compound, code name and MS data are as shown in the table:
The preferred compound of table 1-
The states of matter of table 2-table 1 compound and IR data
Numbering States of matter IR/cm-1
S-1 White solid 3103,1567,1546,1442,1309,1026,770
S-2 White solid 3107,1567,1548,1457,1444,1312,1028,817
S-3 White solid 3107,1567,1548,1457,1444,1312,1028,821
S-4 White solid 3107,1567,1548,1457,1444,1312,1028,836
S-5 White solid 3107,1567,1548,1457,1444,1312,1028,829
S-6 White solid 3107,1567,1548,1457,1444,1312,1028,817
S-7 White solid 3107,1567,1548,1457,1444,1312,1028,845
S-8 White solid 3107,1567,1548,1457,1444,1312,1028,847
S-9 White solid 3107,1567,1548,1457,1444,1312,1028,817
S-10 White solid 3107,1567,1548,1457,1444,1312,1028,816
S-11 White solid 3237,3103,1567,1546,1442,1309,1026,770
S-12 White solid 3230,3107,1567,1548,1457,1444,1312,1028,817
S-13 White solid 3368,3107,1567,1548,1457,1444,1312,1028,821
S-14 White solid 3228,3107,1567,1548,1457,1444,1312,1028,836
S-15 White solid 3231,3107,1567,1548,1457,1444,1312,1028,829
S-16 White solid 3238,3107,1567,1548,1457,1444,1312,1028,817
S-17 White solid 3210,3107,1567,1548,1457,1444,1312,1028,845
S-18 White solid 3218,3107,1567,1548,1457,1444,1312,1028,847
S-19 White solid 3228,3107,1567,1548,1457,1444,1312,1028,817
S-20 White solid 3218,3107,1567,1548,1457,1444,1312,1028,816
S-21 White solid 3107,1567,1548,1457,1444,1312,1028,756
S-22 White solid 3105,1567,1545,1457,1441,1312,1028,817
S-23 White solid 3107,1567,1545,1457,1440,1312,1028,820
S-24 White solid 3107,1565,1548,1457,1444,1312,1028,815
S-25 White solid 3107,1567,1548,1457,1444,1312,1028,830
S-26 White solid 3107,1566,1548,1456,1443,1312,1028,835
S-27 White solid 3107,1567,1548,1457,1444,1312,1028,817
S-28 White solid 3107,1567,1548,1457,1444,1312,1028,817
S-29 White solid 3107,1567,1548,1457,1444,1312,1028,817
S-30 White solid 3107,1567,1548,1457,1444,1312,1028,817
S-31 White solid 3237,3103,1567,1546,1442,1309,1026,770
S-32 White solid 3237,3103,1567,1546,1442,1309,1026,770
S-33 White solid 3237,3103,1567,1546,1442,1309,1026,770
S-34 White solid 3237,3103,1567,1546,1442,1309,1026,770
S-35 White solid 3237,3103,1567,1546,1442,1309,1026,770
S-36 White solid 3237,3103,1567,1546,1442,1309,1026,770
S-37 White solid 3237,3103,1567,1546,1442,1309,1026,770
S-38 White solid 3237,3103,1567,1546,1442,1309,1026,770
S-39 White solid 3237,3103,1567,1546,1442,1309,1026,770
S-40 White solid 3237,3103,1567,1546,1442,1309,1026,770
S-41 White solid 3103,1567,1546,1442,1309,1026,770
S-42 White solid 3103,1567,1546,1442,1309,1026,812
S-43 White solid 3103,1567,1546,1442,1309,1026,835
S-44 White solid 3103,1567,1546,1442,1309,1026,850
S-45 White solid 3103,1567,1546,1442,1309,1026,832
S-46 White solid 3103,1567,1546,1442,1309,1026,867
S-47 White solid 3103,1567,1546,1442,1309,1026,856
S-48 White solid 3103,1567,1546,1442,1309,1026,834
S-49 White solid 3103,1567,1546,1442,1309,1026,865
S-50 White solid 3103,1567,1546,1442,1309,1026,823
S-51 White solid 3237,3103,1567,1546,1442,1309,1026,770
S-52 White solid 3237,3103,1567,1546,1442,1309,1026,815
S-53 White solid 3237,3103,1567,1546,1442,1309,1026,834
S-54 White solid 3237,3103,1567,1546,1442,1309,1026,850
S-55 White solid 3237,3103,1567,1546,1442,1309,1026,867
S-56 White solid 3237,3103,1567,1546,1442,1309,1026,834
S-57 White solid 3237,3103,1567,1546,1442,1309,1026,821
S-58 White solid 3237,3103,1567,1546,1442,1309,1026,845
S-59 White solid 3237,3103,1567,1546,1442,1309,1026,860
S-60 White solid 3237,3103,1567,1546,1442,1309,1026,835
S-61 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,775
S-62 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,810
S-63 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,823
S-64 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,835
S-65 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,840
S-66 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,860
S-67 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,851
S-68 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,875
S-69 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,835
S-70 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,832
S-71 White solid 3237,3103,1567,1546,1442,1309,1026,775
S-72 White solid 3237,3103,1567,1546,1442,1309,1026,821
S-73 White solid 3237,3103,1567,1546,1442,1309,1026,835
S-74 White solid 3237,3103,1567,1546,1442,1309,1026,845
S-75 White solid 3237,3103,1567,1546,1442,1309,1026,835
S-76 White solid 3237,3103,1567,1546,1442,1309,1026,851
S-77 White solid 3237,3103,1567,1546,1442,1309,1026,823
S-78 White solid 3237,3103,1567,1546,1442,1309,1026,853
S-79 White solid 3237,3103,1567,1546,1442,1309,1026,835
S-80 White solid 3237,3103,1567,1546,1442,1309,1026,843
S-81 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,775
S-82 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,845
S-83 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,845
S-84 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,845
S-85 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,845
S-86 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,845
S-87 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,845
S-88 White solid 3111,1571,1548,1512,1461,1429,1372,1322,1036,846
S-89 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,845
S-90 White solid 3109,1571,1549,1510,1461,1431,1363,1322,1036,827
S-91 White solid 3237,3109,1571,1549,1461,1431,1363,1322,1036,775
S-92 White solid 3230,3109,1571,1549,1461,1431,1363,1322,1036,845
S-93 White solid 3368,3109,1571,1549,1461,1431,1363,1322,1036,845
S-94 White solid 3228,3109,1571,1549,1461,1431,1363,1322,1036,845
S-95 White solid 3231,3109,1571,1549,1461,1431,1363,1322,1036,845
S-96 White solid 3238,3109,1571,1549,1461,1431,1363,1322,1036,845
S-97 White solid 3210,3109,1571,1549,1461,1431,1363,1322,1036,845
S-98 White solid 3218,3111,1571,1548,1461,1429,1372,1322,1036,,846
S-99 White solid 3228,3109,1571,1549,1461,1431,1363,1322,1036,845
S-100 White solid 3218,3109,1571,1549,1461,1431,1363,1322,1036,827
S-101 White solid 3103,1567,1546,1442,1309,1026,770
S-102 White solid 3107,1567,1548,1457,1444,1312,1028,817
S-103 White solid 3107,1567,1548,1457,1444,1312,1028,821
S-104 White solid 3107,1567,1548,1457,1444,1312,1028,836
S-105 White solid 3107,1567,1548,1457,1444,1312,1028,829
S-106 White solid 3107,1567,1548,1457,1444,1312,1028,817
S-107 White solid 3107,1567,1548,1457,1444,1312,1028,845
S-108 White solid 3107,1567,1548,1457,1444,1312,1028,847
S-109 White solid 3107,1567,1548,1457,1444,1312,1028,817
S-110 White solid 3107,1567,1548,1457,1444,1312,1028,816
S-111 White solid 3237,3103,1567,1546,1442,1309,1026,770
S-112 White solid 3230,3107,1567,1548,1457,1444,1312,1028,817
S-113 White solid 3368,3107,1567,1548,1457,1444,1312,1028,821
S-114 White solid 3228,3107,1567,1548,1457,1444,1312,1028,836
S-115 White solid 3231,3107,1567,1548,1457,1444,1312,1028,829
S-116 White solid 3238,3107,1567,1548,1457,1444,1312,1028,817
S-117 White solid 3210,3107,1567,1548,1457,1444,1312,1028,845
S-118 White solid 3218,3107,1567,1548,1457,1444,1312,1028,847
S-119 White solid 3228,3107,1567,1548,1457,1444,1312,1028,817
S-120 White solid 3218,3107,1567,1548,1457,1444,1312,1028,816
S-121 White solid 3109,1561,1531,1510,1455,1434,1386,1311,1028,826
S-122 White solid 3124,2957,1613,1571,1562,1460,1396,1311,1075,1058,888
S-123 White solid 3124,2957,1613,1571,1562,1460,1396,1311,1075,1058,888
S-124 White solid 3124,2957,1613,1571,1562,1460,1432,1311,1075,1058,888
S-125 White solid 3124,2957,1613,1571,1562,1460,1432,1311,1075,1058,888
S-126 White solid 3124,2957,1613,1571,1562,1460,1396,1311,1075,1058,888
S-127 White solid 3124,2957,1613,1571,1562,1460,1396,1311,1075,1058,888
S-128 White solid 3124,2957,1613,1571,1562,1460,1432,1311,1075,1058,888
S-129 White solid 3124,2957,1613,1571,1562,1460,1432,1311,1075,1058,888
S-130 White solid 3124,2957,1613,1571,1562,1460,1432,1311,1075,1058,888
S-131 White solid 3237,3109,1561,1531,1510,1455,1434,1386,1028,826
S-132 White solid 3230,3124,2957,1613,1571,1562,1460,1396,1311,1075,888
S-133 White solid 3368,3124,2957,1613,1571,1562,1460,1432,1396,888
S-134 White solid 3228,3124,2957,1613,1571,1562,1460,1432,1396,888
S-135 White solid 3231,3124,2957,1613,1571,1562,1460,1432,1396,1075
S-136 White solid 3238,3124,2957,1613,1571,1562,1460,1432,1396,1075
S-137 White solid 3210,3124,2957,1613,1571,1562,1460,1432,1396,1311
S-138 White solid 3218,3124,2957,1613,1571,1562,1460,1432,1396,1075
S-139 White solid 3228,3124,2957,1613,1571,1562,1460,1432,1396,1311,1057
S-140 White solid 3218,3124,2957,1613,1571,1562,1460,1432,1396,1311
Compound in table 3-table 11HNMR data
The preparation of embodiment 4 the compounds of this invention pharmaceutically acceptable salt
Hydrochlorate and vinegar with 5-methyl-4-[(3-phenyl-isoxazole-5-base)-methoxyl group-]-thiophene [2,3-d] pyrimidine The preparation of hydrochlorate illustrates it, and the preparation of the salt of remaining compound is with this process.
(1) system of 5-methyl-4-[(3-phenyl-isoxazole-5-base)-methoxyl group-]-thiophene [2,3-d] pyrimidine hydrochloride Standby
5-methyl-4-[(3-phenyl-isoxazole-5-base)-methoxyl group-]-thiophene [2,3-d] pyrimidine of 0.5mmol is added Entering in hydrochloric acid solution and the methanol mixed solution of 20mL (V:V, 1:1) 5%, after slight fever stirring makes it dissolve, room temperature slow evaporation is tied Crystalline substance i.e. obtains 5-methyl-4-[(3-phenyl-isoxazole-5-base)-methoxyl group-]-thiophene [2,3-d] pyrimidine hydrochloride, white solid, Yield: 72%.
(2) system of 5-methyl-4-[(3-phenyl-isoxazole-5-base)-methoxyl group-]-thiophene [2,3-d] pyrimidine acetate Standby:
0.5mmol 5-methyl-4-[(3-phenyl-isoxazole-5-base)-methoxyl group-]-thiophene [2,3-d] pyrimidine is added Fill in the 50mL single necked round bottom flask of 10mL dry methylene chloride, the lower 2mL glacial acetic acid that adds of stirring, 30 DEG C-40 DEG C stirring 1- 2h, after cooling cold preservation crystallization, filter, i.e. obtain after vacuum drying 5-methyl-4-[(3-phenyl-isoxazole-5-base)-methoxyl group-]- Thiophene [2,3-d] pyrimidine acetic acid salt, colorless solid, yield: 58%.
Embodiment 5
Srb assay is used to carry out anti-colorectal cancer cell lines (HCT-116) and human lung carcinoma cell line (A549) screening active ingredients, sieve Select process list of references (Li M.H.;Miao Z.H.;Tan W.F.et al.Clin.Cancer Res.2004,10(24): 8266-8274)。
Concrete experimental procedure is as follows:
(1) according to the growth rate of tumor cell, the colorectal cancer cell lines (HCT-116) being in exponential phase is inoculated In 96 well culture plates, adherent growth is after 24 hours, by 1 × 10-4The medicine of M adds, and its concentration sets 3 multiple holes, and sets the denseest The saline control of degree and acellular zeroing hole, lesion/cancer cell 37 DEG C, cultivate 72 hours under the conditions of 5%CO2；(2) take Going out culture plate, cell is fixed with 10% cold triacetic acid (TCA) solution in every hole, places 1 hour for 4 DEG C；(3) abandon fixative, use distilled water Wash 5 times, natural drying in air；(4) being subsequently adding the SRB solution prepared by the glacial acetic acid of 1%, room temperature dyes 15 minutes； (5) removing supernatant, the acetum with 1% washs 5 times, and air is dried；(6) Tris solution it is eventually adding, on plate shaker Shake 5 minutes.Absorbance (the A under 560nm wavelength is surveyed by the wavelengthtunable orifice plate microplate reader that declines560).Use formula below Calculate enzyme inhibition rate.
Record the compound or its salt shown in formula (I) 1 × 10-4Under M concentration suppress colorectal cancer cells pearl (HCT-116) and The activity of human lung cancer cell A549.Experimental result see table 5 and table 6.
Section Example compound suppression colorectal cancer cells pearl (HCT-116) active testing result in table 5-formula (I)
Compound number Suppression ratio (%) Compound number Suppression ratio (%)
S-3 70.0 S-101 68.8
S-83 69.6 S-102 62.9
S-87 72.7 S-103 71.1
S-88 60.9 S-107 72.9
The active testing result of section Example compound suppression human lung cancer cell A549 in table 6-formula (I)
Compound number Suppression ratio (%) Compound number Suppression ratio (%)
S-1 85.0 S-8 85.9
S-2 80.0 S-83 89.4
S-3 86.4 S-101 88.0
S-5 80.8 S-106 71.6
S-6 75.6 S-121 54.1

Claims (20)

1. thiophene [2, the 3-d] pyrimidine derivatives shown in a formula (I) or its pharmaceutically acceptable salt,
Wherein:
R1And R2Can be identical or different, it is each independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, halo C1-6Alkoxyl or the substituted C of hydroxyl1-6Alkyl；
Or R1And R2Coupled carbon atom forms 4 to 6 yuan of carbocyclic rings together, and described carbocyclic ring is optionally by R11Replace；
Z is-NR5-,C(R6)2,-S-or-O-, wherein R5For hydrogen or C1-6Alkyl, R6Identical or different, selected from hydrogen, C1-6Alkyl, halogen For C1-6Alkyl or the substituted C of hydroxyl1-6Alkyl；
R3Selected from hydrogen, halogen, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, halo C1-6Alkoxyl or the substituted C of hydroxyl1-6Alkane Base, n is the integer of 0～5；
R4Selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl；
R11It is each independently selected from hydrogen, hydroxyl, amino, C1-6Alkyl amino, two (C1-6Alkyl) amino, nitro, halogen, C1-6Alkane Base, C1-6Alkoxyl, C1-6Alkylthio group, halo C1-6Alkyl, halo C1-6Alkoxyl.
Thiophene the most according to claim 1 [2,3-d] pyrimidine derivatives or its pharmaceutically acceptable salt, wherein
R1And R2Can be identical or different, it is each independently selected from hydrogen, C1-3Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, halo C1-6Alkoxyl, or
R1And R2Coupled carbon atom forms 4 to 6 yuan of carbocyclic rings together, and described carbocyclic ring is optionally by hydrogen, C1-6Alkyl, halogen, nitre Base or amino replace；
R4Selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl.
3. according to thiophene [2,3-d] pyrimidine derivatives or its pharmaceutically acceptable salt of claim 1 or 2, wherein
R1And R2It is each independently selected from hydrogen, C1-3Alkyl；
Z is-NH-, CH2Or-O-；
R3Selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group or trifluoromethyl, n is 1-4；
R4Selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl.
Fen the most according to claim 3 [2,3-d] pyrimidine derivatives or its pharmaceutically acceptable salt, wherein
R1And R2Can be identical or different, it is each independently selected from C1-6Alkyl,
Z is-NH-or-O-,
R3Ortho position or para-position at isoxazole ring；
R4Selected from hydrogen, methyl.
Fen the most according to claim 3 [2,3-d] pyrimidine derivatives or its pharmaceutically acceptable salt, wherein
R1And R2It is each independently selected from hydrogen, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group；
N is 2-3.
Fen the most according to claim 4 [2,3-d] pyrimidine derivatives or its pharmaceutically acceptable salt, wherein
R1And R2It is each independently selected from hydrogen, methyl, ethyl, the tert-butyl group.
Fen the most according to claim 4 [2,3-d] pyrimidine derivatives or its pharmaceutically acceptable salt, wherein
R1Selected from hydrogen, methyl；
R2Selected from hydrogen, methyl, ethyl or the tert-butyl group；
R3Selected from 4-fluorine, 4-chlorine, 2-chlorine, 4-bromine, 2,4-dichloro, 4-methyl, 4-methoxyl group, hydrogen, 4-trifluoromethyl or 2,4-diformazan Epoxide；
R4Selected from hydrogen, methyl.
8., according to thiophene [2,3-d] pyrimidine derivatives or its pharmaceutically acceptable salt of any one of claim 1-2, it is selected from:
9. a pharmaceutical composition, it includes thiophene [2, the 3-d] pyrimidine compound shown in claim 1-8 any one formula (I), Or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable, inert, nontoxic excipient.
10. a pharmaceutical composition, it includes thiophene [2,3-d] the pyrimidine chemical combination shown in claim 1-8 any one formula (I) Thing, or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable, inert, nontoxic carrier.
11. 1 kinds of pharmaceutical compositions, it includes thiophene [2,3-d] the pyrimidine chemical combination shown in claim 1-8 any one formula (I) Thing, or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable, inert, nontoxic diluent.
12. according to the pharmaceutical composition of any one of claim 9-11, it is characterised in that described pharmaceutical composition also comprises one Or the multiple pharmacy selected from filler, disintegrating agent, lubricant, fluidizer, effervescent, correctives, preservative and coating material can The auxiliary material accepted.
13. according to the pharmaceutical composition described in any one of claim 9-11, it is characterised in that described pharmaceutical composition is preparation Form.
14. pharmaceutical compositions according to claim 13, it is characterised in that described pharmaceutical composition is solid orally ingestible, liquid Body oral formulations or injection.
15. pharmaceutical compositions according to claim 14, it is characterised in that described preparation is selected from dispersible tablet, enteric coatel tablets, chews Sheet, oral cavity disintegration tablet, capsule, granule, oral solution, injection liquid drugs injection, injection freeze-dried powder, infusion solutions or primary infusion.
Thiophene [2,3-d] pyrimidine compound shown in formula (I) of 16. 1 kinds of any one of claim 1-8 or its pharmaceutically can connect The application in antitumor or cancer drug prepared by the salt being subject to.
17. application according to claim 16, it is characterised in that described tumor or cancer are selected from: bladder cancer, ovarian cancer, breast Adenocarcinoma, gastric cancer, esophageal carcinoma, pulmonary carcinoma, head and neck cancer, colon cancer, pharyngeal cancer and cancer of pancreas.
18. application according to claim 17, it is characterised in that described tumor or cancer are selected from nonsmall-cell lung cancer.
Thiophene [2,3-d] pyrimidine compound shown in formula (I) any one of 19. 1 kinds of claim 1-8 or pharmaceutically can connect The salt being subject to application in the transition expression of preparation suppression EGFR and/or the inhibitor of hyperactivity.
Thiophene [2,3-d] pyrimidine compound or pharmaceutically acceptable shown in formula (I) of 20. 1 kinds of any one of claim 1-8 The preparation method of salt, it is characterised in that described method comprises the steps:
2,5,6-tri-replacement-4-chloro-thiophene [2,3-d] pyrimidine (Formula II) and 3-substituted-phenyl-5-methylol-isoxazole (formula III) or 3-substituted-phenyl-5-aminomethyl-isoxazole (Formula IV) is raw material, in dry organic solvent and alkalescence acid binding agent system Middle reaction preparation:
If it is required, form the pharmaceutically acceptable salt of compound of formula I.
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