CN105061461B - Tetrahydro benzo [4,5] thieno [2,3 d] pyrimidines and its application containing benzylamine structure - Google Patents
Tetrahydro benzo [4,5] thieno [2,3 d] pyrimidines and its application containing benzylamine structure Download PDFInfo
- Publication number
- CN105061461B CN105061461B CN201510506984.5A CN201510506984A CN105061461B CN 105061461 B CN105061461 B CN 105061461B CN 201510506984 A CN201510506984 A CN 201510506984A CN 105061461 B CN105061461 B CN 105061461B
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- CN
- China
- Prior art keywords
- thieno
- compound
- pyrimidine
- pharmaceutically acceptable
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000003230 pyrimidines Chemical class 0.000 title abstract 3
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- DDWBRNXDKNIQDY-UHFFFAOYSA-N thieno[2,3-d]pyrimidine Chemical compound N1=CN=C2SC=CC2=C1 DDWBRNXDKNIQDY-UHFFFAOYSA-N 0.000 claims description 16
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- 244000061458 Solanum melongena Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 235000011941 Tilia x europaea Nutrition 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- VCJCJLZVNOZZLS-UHFFFAOYSA-N [1]benzothiolo[2,3-d]pyrimidine Chemical compound C1=NC=C2C3=CC=CC=C3SC2=N1 VCJCJLZVNOZZLS-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 229950005953 camsilate Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 description 1
- 229950004783 cipionate Drugs 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000011340 peptidyl-tyrosine autophosphorylation Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- DAUYIKBTMNZABP-UHFFFAOYSA-N thiophene-3-carboxamide Chemical class NC(=O)C=1C=CSC=1 DAUYIKBTMNZABP-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical compound CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention belongs to pharmaceutical technology field, it is related to tetrahydro benzo [4, the 5] thieno [2,3 containing benzylamine structure‑d] pyrimidines and its as epidermal growth factor recipient tyrosine kinase inhibitor application, and preparation method thereof.Tetrahydro benzo [4,5] thieno [2,3 containing benzylamine structure‑d] pyrimidines and pharmaceutically acceptable salt, and its pharmaceutically compatibility acceptable carrier or diluent as epidermal growth factor recipient tyrosine kinase inhibitor.Its general structure is as follows：R1It is H or C1‑C4Alkyl；R2It is independent selected from H, halogen, C1‑C4Alkoxy.The simple synthetic method of this kind of compound of the invention, it is suitable to industrialized production, biological activity test shows that such compound has and suppresses EGF, Human Lung Cancer cell line A549, the activity of human ovarian cancer cell's strain SKOV3 and human osteosarcoma cell U2OS EGFP 4A12G, is a kind of epidermal growth factor recipient tyrosine kinase inhibitor with antitumor action.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to tetrahydro benzo [4,5] thieno [2,3-d] containing benzylamine structure phonetic
Pyridine class compound and preparation method thereof, further relates to it as the application in epidermal growth factor recipient tyrosine kinase inhibitor.
Background technology
According to the differentiation degree and morphological feature of cancer cell, lung cancer can be divided into non-small cell lung cancer and ED-SCLC.Grind
Study carefully discovery, imbalance and the EGF-R ELISA junket ammonia of substantial amounts of EGF signal transduction are there is in patients with lung cancer
The overexpression of acid kinase.
EGF-R ELISA (EGFR) is with the outer ligand receptor binding domain of film and intracellular tyrosine kinase activity
A kind of transmembrane protein in domain.EGFR has 4 types HER-1, HER-2, HER-3 and HER-4, when smaller ligand and EGFR are tied
Close, activate EGFR, and then the EGFR-TK area of EGFR activates, and recognizes the substrates enzymes of albumen, will be by the incoming cell of signal
Interior, while can also activate the phosphorylation of many downstream signaling molecules after EGFR activation, enabling signal Signal Transduction Pathways, final influence is thin
Born of the same parents are survived and cell propagation.Because receptor type tyrosine kinase Main Differences are extracellular ligand binding domain, and the tyrosine of intracellular
Kinase domain has homology higher, it is contemplated that synthesize the smaller ligand that extracellular ligand binding domain is well combined,
So as to suppress intracellular tyrosine kinase activity area, the catalysis activity and tyrosine autophosphorylation of inhibitory enzyme, and then suppress cell week
Transfer of phase process, angiogenesis and tumour etc..
Existing epidermal growth factor recipient tyrosine kinase inhibitor, such as Gefitinib, Tarceva, Lapatinib
Deng, the dermoreactions such as diarrhoea, fash, itch are there is, and possible headache, heart QT intervals extension and bioavilability drop
It is low.
Compound of the present invention has as the epidermal growth factor recipient tyrosine kinase inhibitor of brand new type
There is the characteristics of structure type is novel, and drug action is obvious.Can be used to treat or prevent and EGF-R ELISA signal transduction
The relevant disease such as ED-SCLC that imbalance causes, squamous carcinoma, gland cancer, large cell carcinoma, colorectal cancer, breast cancer, oophoroma, kidney
Cell cancer, bronchial astehma, with good application value and development prospect.
The content of the invention
Technical problem solved by the invention is to provide a kind of compound shown in formula I, its pro-drug and medicine and lives
Property metabolin and its pharmaceutically acceptable salt, and there is provided it to prepare prevention and treatment EGFR signal transduction imbalances related
Disease medicine in application.
Wherein
R1It is H or C1-C4Alkyl；
R2It is independent selected from H, halogen, C1-C4Alkoxy.
Preferably,
R1It is H or ethyl；
R2It is independent selected from H, fluorine, chlorine, methoxyl group.
" pharmaceutically acceptable salt " refers to the biopotency and property for remaining compound of formula I, and has with suitable non-toxic
Conventional acid addition salts or base addition salts that machine or inorganic acid or organic or inorganic alkali are formed.The example of acid-addition salts includes acetic acid
Salt, adipate, alginates, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, camphor
Hydrochlorate, camsilate, cipionate, digluconate, lauryl sulfate, esilate, fumarate, Portugal heptan
Sugar lime, glycerophosphate, Hemisulphate, enanthate, caproate, hydrogen chlorate, hydrobromate, hydriodate, 2- hydroxyl second
Sulfonate, lactate, maleate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oxalates, pamoate, pectin ester
Hydrochlorate, persulfate, 3- phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, sulfate, tartrate,
Rhodanate, toluene fulfonate and undecylate.Alkali salt include ammonium salt, alkali metal salt, such as sodium and sylvite, alkali salt,
The salt of such as calcium and magnesium salts, such as salt of organic base, dicyclohexyl amine salt, N- methyl-D-glucamine salts, and amino acid, such as essence
Propylhomoserin, lysine etc., and, Basic nitrogen-containing groups can be quaternized with such reagent, such as elementary alkyl halide, such as first
The chlorine of base, ethyl, propyl group and butyl, bromine and iodide；Dialkyl sulfate, such as dimethyl suflfate, diethylester, dibutyl ester and two
Pentyl ester；The chlorine of long chain halide, such as decyl, lauryl, myristyl and stearyl, bromine and iodide；Aralkyl halide,
Such as bromide of benzyl and phenethyl.The acid for being preferred for generating acid-addition salts includes hydrochloric acid and acetic acid.
" pharmaceutically acceptable " carrier, excipient, pro-drug such as pharmaceutically acceptablely, refers to and can pharmacologically connect
It is receiving and substantially non-toxic to the patient of particular compound is administered.
" pharmaceutical active metabolin " refers to the metabolite of pharmaceutically acceptable and effective compound of formula I.
Pharmaceutical composition the present invention also relates to suppress epidermal growth factor recipient tyrosine kinase, said composition contains formula
I or derivative or its pharmaceutically useful acid-addition salts and pharmaceutically useful carrier.
The compounds of this invention can be taken by different methods to patient, such as oral with capsule or tablet, with nothing
Bacterium solution or suspensions administration, and in some cases, can be injected intravenously with solution form.Can will be of the invention
Free alkali compound is prepared and taken with its pharmaceutically useful acid addition salt form thereof.
Specific embodiment
Reaction process 1 summarises the synthesis step for preparing the compounds of this invention.
The present invention is described in detail with following examples.But, it should be clearly that, the invention is not restricted to following realities of specific narration
Example.
Embodiment 1：7- (4- ethoxyl phenenyls) -4- benzamido group -5,6,7,8- tetrahydro benzo [4,5] thieno [2,3-d]
The preparation of pyrimidine (compound number 01)
Step A：The preparation of 4- (4- ethoxyl phenenyls) cyclohexanone
Successively by 4- (4- hydroxy phenyls) cyclohexanone 15.0g (79.0mmol), Anhydrous potassium carbonate 109.0g
(789.5mmol), acetone 200mL, dithyl sulfate 24.4g (157.9mmol) are put into 500mL eggplants type bottle, are heated to reflux stirring
After mixing 6h, evaporated under reduced pressure solvent, to water 500mL is added in residue, stirs 2h at room temperature, and suction filtration is washed 2 times, after drying
Obtain white solid 16.6g, yield 96.5%, m.p.：70-72℃.
Step B：The preparation of 2- amino -6- (4- ethoxyl phenenyls) -4,5,6,7- tetrahydro benzos [b] thiophene -3- formamides
To sequentially adding 4- (4- ethoxyl phenenyls) cyclohexanone 2.0g (9.2mmol), cyanoacetamide in 100mL three-necked bottles
0.8g (9.2mmol), sulphur powder (distillation) 0.3g (9.2mmol), absolute ethyl alcohol 6.0mL, are so dropwise added dropwise piperidines 0.8g
(9.2mmol), and 45-50 DEG C of temperature control, drip after stirring reaction 5h under said temperature.After completion of the reaction, by reaction solution ice
Freeze 2h, the solid that suction filtration is separated out, ethanol is washed 2 times, petroleum ether 1 time obtains Orange red solid 1.6g, yield after natural air drying
56.1%.m.p.：219-221℃；IR:(KBr,cm-1)3458(m),3291(d),2912(m),1632(s),1559(s),
1510(s),1474(s),1414(s),1234(s),1179(s),1114(s),1043(s),824(s)；1H-NMR(400MHz,
DMSO-d6):δ1.31(t,3H,CH3),1.73-1.84(m,1H,CH2),1.91-1.95(m,1H,CH2),2.53-2.58(m,
1H,CH2),2.63-2.80(m,3H,CH2),2.81-2.90(m,1H,CH),3.99(m,2H,CH2-O),6.53(brs,2H,
NH2), 6.85 (d, 2H, Ar-H, J=8.8Hz), 6.94 (s, 2H, NH2), 7.19 (d, 2H, Ar-H, J=8.8Hz)；ESI-MS
(m/z):317.3([M+H]+)。
Step C：7- (4- ethoxyl phenenyls) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine -4 (3H) -
The preparation of ketone
To addition 2- amino -6- (4- ethoxyl phenenyls) -4,5,6,7- tetrahydro benzos [b] thiophene -3- in 50mL eggplant-shape bottles
Formamide 1.0g (3.2mmol) and formamide 5.7g (126.4mmol), in after stirring reaction 6h at 165 DEG C, is cooled to room temperature,
After isopropanol 5mL is added after its a large amount of solid of precipitation, 1h is stirred at room temperature, suction filtration, isopropanol is washed 1 time, after natural air drying
Obtain brown solid 0.7g, yield 66.0%.m.p.：239-240℃；IR:(KBr,cm-1)3430(m),2925(s),2880(s),
1657(s),1592(s),1511(s),1370(s),1247(d),1175(s),834(s)；1H-NMR(400MHz,DMSO-d6):
δ1.31(t,3H,CH3),1.87-1.94(m,1H,CH2),1.97-2.03(m,1H,CH2),2.78-2.86(m,2H,CH2),
2.96-3.01(m,2H,CH2),3.12-3.18(m,1H,CH2),4.00(m,2H,CH2- O), 6.87 (d, 2H, Ar-H, J=
8.8Hz), 7.23 (d, 2H, Ar-H, J=8.8Hz), 8.02 (s, 1H, Ar-H), 12.34 (brs, 1H, NH)；ESI-MS(m/z):
327.4([M+H]+)。
Step D：The chloro- 7- of 4- (4- ethoxyl phenenyls) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine
Prepare
To sequentially adding 7- (4- ethoxyl phenenyls) -5,6,7,8- tetrahydro benzos [4,5] thieno in 100mL eggplant-shape bottles
[2,3-d] pyrimidine -4 (3H) -one 10.0g (31.0mmol) and POCl3 30mL (315.3mmol), are heated to reflux stirring, treat
After solid all dissolves, then the 10min that flows back, evaporated under reduced pressure solvent, obtain brownish black crude oil.Through column chromatography for separation (petroleum ether:
Ethyl acetate=2:1) light yellow crystal 9.4g, yield 88.3% are obtained.m.p.：166-169℃；IR:(KBr,cm-1)3442
(m),2974(s),2924(d),2875(s),1515(s),1493(s),1428(s),1383(s),1253(s),1122(s),
1046(s),838(s)；1H-NMR(400MHz,CDCl3):δ1.42(t,3H,CH3),1.96-2.06(m,1H,CH2),2.23-
2.29(m,1H,CH2),2.98-8.15(m,4H,CH2),3.36-3.42(m,1H,CH),4.04(m,2H,CH2-O),6.89(d,
2H, Ar-H, J=8.4Hz), 7.19 (d, 2H, Ar-H, J=8.4Hz), 8.74 (s, 1H, Ar-H)；ESI-MS(m/z):345.3
([M+H]+)。
Step E：7- (4- ethoxyl phenenyls) -4- benzamido group -5,6,7,8- tetrahydro benzo [4,5] thieno [2,3-d] is phonetic
The preparation of pyridine (compound number 01)
By the chloro- 7- of 4- (4- ethoxyl phenenyls) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine 0.5g
(1.5mmol) puts into 50mL eggplant-shape bottles with benzylamine 0.2g (1.5mmol), adds n-butanol 4.8mL, adds triethylamine 0.4g
(4.5mmol), heating reflux reaction 5h, cooling separates out solid, and suction filtration is natural with water 100mL and ethanol 30mL respectively washing 1 time
Faint yellow solid 0.5g, yield 85.0% are obtained after air-drying.m.p.:194-196℃；IR:(KBr,cm-1)3427(m),2920
(s),2852(s),1641(m),1572(s),1512(s),1384(s),1242(s),1115(m),825(s),782(s),747
(s),697(s),620(s)；1H-NMR(400MHz,CDCl3):δ1.41(t,3H,CH3),1.96-2.06(m,1H,CH2),
2.16-2.21(m,1H,CH2),2.88-3.11(m,5H,2×CH2,CH),4.03(m,2H,CH2),4.82(d,2H,CH2-N),
5.56 (t, 1H, NH), 6.86 (d, 2H, Ar-H, J=8.4Hz), 7.16 (d, 2H, Ar-H, J=8.4Hz), 7.28-7.38 (m,
5H,Ar-H),8.45(s,1H,Ar-H)；ESI-MS(m/z):416.1([M+H]+)。
Embodiment 2：7- (4- ethoxyl phenenyls) -4- (2- benzyl chlorides amido) -5,6,7,8- tetrahydro benzos [4,5] thieno
The preparation of [2,3-d] pyrimidine (compound number 02)
With reference to the method for example 1,7- (4- ethoxyl phenenyls) -4- (2- benzyl chlorides amido) -5,6,7,8- tetrahydro benzos are obtained
[4,5] thieno [2,3-d] pyrimidine (compound number 02) 0.4g, yield 63.1%.m.p.:167-169℃；IR:(KBr,
cm-1)3441(m),2921(s),2851(s),1640(m),1571(s),1512(s),1384(s),1245(s),1115(m),
1044(s),826(s),761(s),620(s)；1H-NMR(400MHz,CDCl3):δ1.41(t,3H,CH3),1.98-2.08(m,
1H,CH2),2.21-2.25(m,1H,CH2),2.87-2.95(m,1H,CH2),3.00-3.09(m,4H,CH2,CH),4.03(m,
2H,CH2),4.90(t,2H,CH2- N), 5.86 (t, 1H, NH), 6.87 (d, 2H, Ar-H, J=8.8Hz), 7.17 (d, 2H, Ar-
H, J=8.8Hz), 7.23-7.25 (m, 2H, Ar-H), 7.38-7.41 (m, 1H, Ar-H), 7.50-7.53 (m, 1H, Ar-H),
8.42(s,1H,Ar-H)；ESI-MS(m/z):450.0([M+H]+)。
Embodiment 3：7- (4- ethoxyl phenenyls) -4- (4- fluorin benzyl amines base) -5,6,7,8- tetrahydro benzos [4,5] thieno
The preparation of [2,3-d] pyrimidine (compound number 03)
With reference to the method for example 1,7- (4- ethoxyl phenenyls) -4- (4- fluorin benzyl amines base) -5,6,7,8- tetrahydro benzos are obtained
[4,5] thieno [2,3-d] pyrimidine (compound number 03) 0.4g, yield 65.1%.m.p.:208-210℃；IR:(KBr,
cm-1)3429(m),2921(s),2851(s),1640(m),1571(s),1511(s),1384(s),1243(d),1115(m),
830(s),780(s),620(s)；1H-NMR(400MHz,CDCl3):δ1.41(t,3H,CH3),1.97-2.07(m,1H,CH2),
2.19-2.22(m,1H,CH2),2.92-3.11(m,5H,2×CH2,CH),4.03(m,2H,CH2),4.79(d,2H,CH2-N),
5.54 (t, 1H, NH), 6.86 (d, 2H, Ar-H, J=8.8Hz), 7.04 (t, 2H, Ar-H), 7.16 (d, 2H, Ar-H, J=
8.8Hz),7.33-7.37(m,2H,Ar-H),8.44(s,1H,Ar-H)；ESI-MS(m/z):434.1([M+H]+)。
Embodiment 4：7- (4- ethoxyl phenenyls) -4- (4- methoxybenzyls amido) -5,6,7,8- tetrahydro benzos [4,5] thiophene
And the preparation of [2,3-d] pyrimidine (compound number 04)
With reference to the method for example 1,7- (4- ethoxyl phenenyls) -4- (4- methoxybenzyls amido) -5,6,7,8- tetrahydrochysenes are obtained
Benzo [4,5] thieno [2,3-d] pyrimidine (compound number 04) 0.4g, yield 66.2%.m.p.：190-192℃；IR:
(KBr,cm-1)3437(m),2921(s),2851(s),1640(m),1570(s),1512(s),1384(s),1245(d),1178
(s),1115(m),823(s),781(s),620(s)；1H-NMR(400MHz,CDCl3):δ1.41(t,3H,CH3),1.98-
2.05(m,1H,CH2),2.17-2.20(m,1H,CH2),2.93-3.09(m,5H,2×CH2,CH),3.81(s,3H,CH3-O),
4.02(m,2H,CH2),4.73(d,2H,CH2-N),5.48(brs,1H,NH),6.85-6.91(m,4H,Ar-H),7.15(d,
2H, Ar-H, J=8.4Hz), 7.31 (d, 2H, Ar-H, J=8.4Hz), 8.45 (s, 1H, Ar-H)；ESI-MS(m/z):446.1
([M+H]+)。
Embodiment 5：7- (4- hydroxy phenyls) -4- benzamido group -5,6,7,8- tetrahydro benzo [4,5] thieno [2,3-d] is phonetic
The preparation of pyridine (compound number 05)
Step A：The system of the chloro- 7- of 4- (4- hydroxy phenyls) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine
It is standby
By the chloro- 7- of 4- (4- ethoxyl phenenyls) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine 2.5g
(7.2mmol) and aluminum trichloride (anhydrous) 2.9g (21.6mmol) put into 100mL eggplant-shape bottles, add toluene 50mL, are heated to reflux stirring
Mix, after reaction 30min, stop reaction, to water 100mL is added in reaction system, 3h, suction filtration, natural air drying, warp are stirred at room temperature
Column chromatography (methyl alcohol：Dichloromethane=1:40) isolated yellow solid 1.1g, yield 48.5%.m.p.：202-204℃；IR:
(KBr,cm-1)3261(m),2907(m),1561(s),1540(s),1513(s),1487(s),1384(s),1221(s),1171
(s),1131(s),845(s)；1H-NMR(400MHz,DMSO):δ1.91-2.00(m,1H,CH2),2.09-2.14(m,1H,
CH2),2.93-3.08(m,3H,CH2),3.13-3.17(m,1H,CH2),3.25(brs,1H,CH),6.72(d,2H,Ar-H,J
=8.4Hz), 7.14 (d, 2H, Ar-H, J=8.4Hz), 8.84 (s, 1H, Ar-H), 9.22 (s, 1H, Ar-OH)；ESI-MS(m/
z):317.2([M+H]+)。
Step B：7- (4- hydroxy phenyls) -4- benzamido group -5,6,7,8- tetrahydro benzo [4,5] thieno [2,3-d] pyrimidine
The preparation of (compound number 05)
By the chloro- 7- of 4- (4- hydroxy phenyls) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine 0.5g
In (1.6mmol) and benzylamine 0.2g (1.6mmol) input 50mL eggplant-shape bottles, triethylamine 0.5g (4.8mmol) is added, add positive fourth
Alcohol 4mL, heating stirring backflow 5h, reaction terminate after cool down separate out crystal, suction filtration, with water 10mL and ethanol 10mL respectively washing 1 time,
White solid 0.5g, yield 65.6% are obtained after natural air drying.m.p.：191-193℃；IR:(KBr,cm-1)3454(m),2920
(s),2851(s),1642(m),1575(s),1513(s),1384(s),1111(m),830(s),782(s),620(s)；1H-
NMR(400MHz,CDCl3):δ1.97-2.06(m,1H,CH2),2.17-2.21(m,1H,CH2),2.88-2.95(m,1H,
CH2),3.00-3.10(m,4H,CH2,CH),4.82(d,2H,CH2-N),4.93(brs,1H,Ar-OH),5.57(brs,1H,
), NH 6.81 (d, 2H, Ar-H, J=8.4Hz), 7.12 (d, 2H, Ar-H, J=8.4Hz), 7.29-7.35 (m, 1H, Ar-H),
7.37-7.38(m,4H,Ar-H),8.45(s,1H,Ar-H)；ESI-MS(m/z):388.0([M+H]+)。
Embodiment 6：7- (4- hydroxy phenyls) -4- (2- benzyl chlorides amido) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,
3-d] pyrimidine (compound number 06) preparation
With reference to the method for example 5, prepared 7- (4- hydroxy phenyls) -4- (2- benzyl chlorides amido) -5,6,7,8- tetrahydro benzos [4,
5] thieno [2,3-d] pyrimidine (compound number 06) 0.5g, yield 68.7%.m.p.：148-150℃；IR:(KBr,cm-1)
3454(m),2920(s),2851(s),1639(m),1574(s),1513(s),1384(s),1111(m),831(s),754
(s),620(s)；1H-NMR(600MHz,CDCl3):δ2.01-2.06(m,1H,CH2),2.22-2.25(m,1H,CH2),2.89-
2.93(m,1H,CH2),3.02-3.08(m,4H,CH2,CH),3.49(s,1H,NH),4.90-4.92(m,2H,CH2-N),5.30
(s, 1H, Ar-OH), 6.81 (d, 2H, Ar-H, J=8.4Hz), 7.13 (d, 2H, Ar-H, J=8.4Hz), 7.24-7.26 (m,
2H,Ar-H),7.39-7.41(m,1H,Ar-H),7.51-7.54(m,1H,Ar-H),8.45(brs,1H,Ar-H)；ESI-MS
(m/z):422.1([M+H]+)。
Embodiment 7：7- (4- hydroxy phenyls) -4- (4- fluorin benzyl amines base) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,
3-d] pyrimidine (compound number 07) preparation
With reference to the method for example 5, prepared 7- (4- hydroxy phenyls) -4- (4- fluorin benzyl amines base) -5,6,7,8- tetrahydro benzos [4,
5] thieno [2,3-d] pyrimidine (compound number 07) 0.5g, yield 71.9%.m.p.：165-167℃；IR:(KBr,cm-1)
3456(m),2921(s),2851(s),1640(m),1575(s),1512(s),1383(s),1222(s),1109(m),828
(s),785(s),620(s)；1H-NMR(600MHz,CDCl3):δ1.99-2.03(m,1H,CH2),2.18-2.23(m,1H,
CH2),2.89-2.94(m,1H,CH2),3.00-3.09(m,4H,CH2,CH),3.66(t,1H,NH),4.78-4.80(m,2H,
CH2- N), 5.56 (s, 1H, Ar-OH), 6.81 (d, 2H, Ar-H, J=8.4Hz), 7.04 (t, 2H, Ar-H), 7.12 (d, 2H,
Ar-H, J=8.4Hz), 7.34-7.36 (m, 2H, Ar-H), 8.44 (s, 1H, Ar-H)；ESI-MS(m/z):406.1([M+H
]+)。
Embodiment 8：7- (4- hydroxy phenyls) -4- (4- methoxybenzyls amido) -5,6,7,8- tetrahydro benzos [4,5] thieno
The preparation of [2,3-d] pyrimidine (compound number 08)
With reference to the method for example 5, the tetrahydrochysene benzene of 7- (4- hydroxy phenyls) -4- (4- methoxybenzyls amido) -5,6,7,8- is obtained
And [4,5] thieno [2,3-d] pyrimidine (compound number 08) 0.6g, yield 91.4%.m.p.：74-76℃；IR:(KBr,
cm-1)3458(m),2921(s),2851(s),1613(s),1574(s),1513(s),1383(s),1247(s),1175(s),
1109(m),1033(s),831(s),789(d),619(s)；1H-NMR(400MHz,CDCl3):δ1.97-2.02(m,1H,
CH2),2.16-2.20(m,1H,CH2),2.89-3.05(m,5H,2×CH2,CH),3.81(s,3H,-OCH3),4.74(d,2H,
CH2- N), 5.16 (s, 1H, NH), 5.53 (s, 1H, Ar-OH), 6.81 (d, 2H, Ar-H, J=8.4Hz), 6.90 (d, 2H, Ar-
H, J=8.8Hz), 7.11 (d, 2H, Ar-H, J=8.4Hz), 7.31 (d, 2H, Ar-H, J=8.8Hz), 8.45 (s, 1H, Ar-
H)；ESI-MS(m/z):418.1([M+H]+)。
The above, is only presently preferred embodiments of the present invention, is not the limitation for making other forms to the present invention, is appointed
What those skilled in the art changed possibly also with the technology contents of the disclosure above or be modified as equivalent variations etc.
Effect embodiment.But it is every without departing from technical solution of the present invention content, according to technical spirit of the invention to above example institute
Any simple modification, equivalent variations and the remodeling made, still fall within the protection domain of technical solution of the present invention.
Pharmacological Examples
Embodiment 9：
EGF (EGFR) active determination in vitro
According to the method that Mowafy etc. (Eur.J.Med.Chem, 2013,61,132-145) is introduced, this measure is carried out.
This measure uses the luminous kinase assay kits of Kinase-Glo Plus.It is after measuring kinase reaction
The amount of ATP evaluates kinase activity in solvent.Luminous signal power is directly proportional to the amount of ATP and is inversely proportional with kinase activity.Will
Test compound is diluted to 100 μM in 10%DMSO, and the dilution for then taking out 5 μ l is added in the reaction of 50 μ l to ensure
The ultimate density of DMSO is 1% in all reactions.All of enzymatic reaction reacts 40min at 30 DEG C.In the anti-of 50 μ l
Answer the trishydroxymethylaminomethane (Tris) comprising 40mM, the MgCl of 10mM in mixture2, the bovine serum albumin(BSA) of 0.1mg/mL
(BSA), the composite interstitial substance (Glu, Tyr) of 0.2mg/mL, 10 μM of ATP and EGFR, and control pH to be maintained at 7.4.It is anti-in enzymatic
After should terminating, to the luminous kinase assay solvents of Kinase-Glo Plus that 50 μ l are added in each reaction and then at room temperature
Cultivate 5min.Luminous signal is determined by the unlimited M1000 types ELIASA of Tecan companies.
IC50The measure of value is completed by using ADP-GloTM detection kits.It determines ADP by protein kinase
Generation, with kinase reaction and the ADP that generates the luminous signal can be caused to strengthen in mentioned reagent box.First, it is reaction is mixed
Compound is placed in 96 orifice plates in 30min is cultivated at 30 DEG C, is then added thereto to the ADP-GloTM reagents of 25 μ l.Rock this 96
Orifice plate, then continues to cultivate 40min at room temperature.The kinase assay reagent of 50 μ l is eventually adding, the result of subsequent 96 orifice plate is led to
GloMax ELIASAs are crossed to read.The test method of blank group is substantially parallel consistent with sample sets.Finally, the activity of protein kinase
Numerical value is corrected by reducing the numerical value of blank group.
According to the method described above, the combination of representative compound of the present invention and EGFR, IC are tested50The result of value is shown in table 1.
Table 1
Embodiment 10：A-549 cell proliferating determinings
According to the method that Stockert etc. (Acta Histochemica, 2012,114 (8), 785-796) is introduced, carry out
This measure.
This measure evaluates the antitumor of invention representative compound using mtt assay and using Human Lung Cancer cell line A549
Increment activity.A549 cell lines are cultivated on the improved Eagle culture mediums (DMEM) of DulbeccoShi, and the culture medium is included
10% calf serum (FBS), the penicillin of 100U/mL and the streptomysin of 100g/mL.Make when cell is bred to 80~90%
It merges the Secondary Culture then carried out no more than 20 generations, then them is adapted to environment before next step disposal and reaches 24h.Will
These cells are placed in (8 × 10 on 96 orifice plates4/ mL), then containing 5%CO2Moist environment in overnight incubation and temperature control 37
℃.20 μM/50 μM of invention representative compound is added after 24h.Again by the culture of 24h, MTT (5mg/ are added thereto to
ML) and continue cultivate 4h.Remove culture matrix, by dissolution of crystals in DMSO, using ELIASA (TECAN SPECTRA,
Wetzlar, Germany) measure absorbance under 490nm wavelength.Inhibitory action passes through inhibiting rate and IC50Value is represented.
Representative compound of the present invention is determined according to the method described above, is as a result shown in table 2.
Table 2
Embodiment 11：Effect to Proliferation of ovarian cancer cell SKOV 3
After exponential phase cell is digested with pancreatin, with 6 × 103Individual/hole cell number adds the well culture plate of people 96, put 37 DEG C,
5%CO2Cultivated in incubator, most cells 4 DEG C of insulating box 1h of adherent rearmounted people are treated within the 2nd day, to facilitate cells Synchronous metaplasia
It is long.Supernatant is sucked, plus people contains 10% newborn calf serum (FCS) RPMI RPMI-1640s, 200 μ L/ holes are empirically designed
Packet.The compound injection liquid that SPSS is prepared is added in 96 holes, and 200 μ L are added in every hole, makes the medicine in every hole
Concentration is respectively 1mg/mL, 2mg/mL and 5mg/mI, with 0mg/mL as negative control group.After continuing culture 24,48,72h, each hole
Respectively plus μ L MTT solution (concentration is 5mg/mL) of people 20, gently concussion and cultivate plate, puts back in incubator and is incubated 4h again, then inhales
Supernatant, in the μ L of each Kong Zhongjia dimethyl sulfoxides 200, puts and 5-10min is shaken on oscillator to the greatest extent, in measuring every hole with enzyme mark luminosity
Wavelength is the light absorption value (A=580) of 580nm, and A=580 values are directly proportional to living cells quantity.
Representative compound of the present invention is determined according to the method described above, is as a result shown in table 3.
Table 3
Embodiment 12：Effect to osteosarcoma U 2OS-EGFP-4A12G propagation
After exponential phase cell is digested with pancreatin, trypan blue is counted, and is configured to cell density for 1 × l04Individual/mL's is thin
Born of the same parents' suspension, is inoculated in 96 orifice plates, per the μ L of hole 200, per hole about 2 × 103Individual cell, preculture 24h, matches somebody with somebody SPSS
The compound injection liquid of system is added in 96 holes, and 200 μ L are added in every hole, makes drug concentration respectively 1mg/mL, the 2mg/ in every hole
ML and 5mg/mI, with 0mg/mL as negative control group.MTT solution is added per hole after culture 0h, 12h, 24h and 48h respectively
(5mg/mL) 20 μ L, continue to be incubated 4h, terminate culture.The supernatant abandoned in culture hole is carefully inhaled, the diformazan of 150 μ L is added per hole
Base sulfoxide (DMSO), shakes 10min, makes the cured abundant dissolving of first, selects 490nm wavelength, determines each on enzyme-linked immunosorbent assay instrument
Hole absorbance value (A values), duplicate detection 5 times.
Representative compound of the present invention is determined according to the method described above, is as a result shown in table 4.
Table 4
Example of formulations
Following example of formulations only illustrates protection scope of the present invention, but constitutes restriction never in any form.
Embodiment 13：Gelatine capsule
The preparation of hard gelatin capsule is used：
Above-mentioned preparation can be improved according to the reasonable change for being provided.
Embodiment 14：Tablet
The preparation of tablet is used
Said components are mixed and tabletted.
Embodiment 15：Tablet
The tablet containing 2.5-1000mg active components prepares as follows in every：
Active component, starch and cellulose is set to pass through No. 45 mesh sieves and be thoroughly mixed.By polyvinylpyrrolidonesolution solution with
Gained powder mixes, through No. 14 mesh sieves after.The particle of generation is dried at 50-60 DEG C and through No. 18 mesh sieves.To pass through in advance
Cross No. 60 sodium carboxymethylcelluloses of mesh sieve, magnesium stearate and talcum powder to be added in above-mentioned particle, then mixing, in tablet press machine
Upper compacting obtains tablet.
Embodiment 16：Suspension
The suspension preparation for containing 0.1-1000mg medicines per 5ml is as follows：
Medicine is made to be mixed to form smooth paste through No. 45 mesh sieves and with sodium carboxymethylcellulose and syrup.Benzoic acid is molten
Liquid, flavouring and colouring agent are diluted with some water and add aforesaid paste under agitation.Enough water is subsequently added to reach
The volume for needing.
Embodiment 17：Combined tablet-preparation
Active component, starch and cellulose is set to pass through No. 45 mesh sieves and be thoroughly mixed.By polyvinylpyrrolidonesolution solution with
Gained powder mixes, through No. 14 mesh sieves after.The particle of generation is dried at 50-60 DEG C and through No. 18 mesh sieves.To pass through in advance
Cross No. 60 sodium carboxymethylcelluloses of mesh sieve, magnesium stearate and talcum powder to be added in above-mentioned particle, then mixing, in tablet press machine
Upper compacting obtains tablet.
For described above, those skilled in the art are readily understood by essential feature of the invention, without departing substantially from the present invention
Spirit and scope, the present invention can carry out various changes and improve to adapt to different application and conditions.
Claims (9)
1. a kind of compound of formula I or its pharmaceutically acceptable salt, the compound of formula I structure are as follows：
Wherein
R1It is H or C1-C4Alkyl；
R2It is independent selected from H, halogen, C1-C4Alkoxy.
2. the compound of formula as claimed in claim 1 I or its pharmaceutically acceptable salt：
Wherein, R1It is H or ethyl.
3. the compound of formula as claimed in claim 1 or 2 I or its pharmaceutically acceptable salt：
Wherein, R2Selected from H, fluorine, chlorine, methoxyl group.
4. the compound of Formulas I as claimed in claim 1 or its pharmaceutically acceptable salt, are selected from：
7- (4- ethoxyl phenenyls) -4- benzamido group -5,6,7,8- tetrahydro benzo [4,5] thieno [2,3-d] pyrimidine；
7- (4- ethoxyl phenenyls) -4- (2- benzyl chlorides amido) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine；
7- (4- ethoxyl phenenyls) -4- (4- fluorin benzyl amines base) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine；
7- (4- ethoxyl phenenyls) -4- (4- methoxybenzyls amido) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] is phonetic
Pyridine；
7- (4- hydroxy phenyls) -4- benzamido group -5,6,7,8- tetrahydro benzo [4,5] thieno [2,3-d] pyrimidine；
7- (4- hydroxy phenyls) -4- (2- benzyl chlorides amido) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine；
7- (4- hydroxy phenyls) -4- (4- fluorin benzyl amines base) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine；
7- (4- hydroxy phenyls) -4- (4- methoxybenzyls amido) -5,6,7,8- tetrahydro benzos [4,5] thieno [2,3-d] pyrimidine.
5. a kind of pharmaceutical composition, the compound comprising the formula I described in claim 1-4 any one or its is pharmaceutically acceptable
Salt as active component and pharmaceutically acceptable carrier.
6. described in type I compound described in claim 1-4 any one or its pharmaceutically acceptable salt or claim 5
Application of the pharmaceutical composition in treatment non-small cell lung cancer drug is prepared.
7. described in type I compound described in claim 1-4 any one or its pharmaceutically acceptable salt or claim 5
Pharmaceutical composition answering in the prevention and treatment disease medicament related to the imbalance of EGF-R ELISA signal transduction is prepared
With.
8. application according to claim 7, it is characterised in that：The EGF-R ELISA be HER-1, HER-2,
HER-3 or HER-4.
9. application according to claim 7, it is characterised in that：Wherein described EGF-R ELISA signal transduction loses
The relevant disease of tune is squamous carcinoma, and gland cancer, large cell carcinoma, colorectal cancer, breast cancer, oophoroma, clear-cell carcinoma or bronchus are roared
Breathe heavily.
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| CH530412A (en) * | 1968-07-15 | 1972-11-15 | Ciba Geigy Ag | Process for the preparation of (1) benzothieno- (2,3-d) pyrimidines |
| ES2280040T3 (en) * | 2003-07-24 | 2007-09-01 | Bayer Pharmaceuticals Corporation | TETRAHYDROBENZOTIENOPIRIMIDINAMINE COMPOUNDS USEFUL REPLACED TO TREAT HYPERPROLIFERATIVE DISORDERS. |
| WO2006055268A2 (en) * | 2004-10-27 | 2006-05-26 | Bayer Pharmaceuticals Corporation | Pyrimidothienoindazoles capable of inhibiting tyrosine kinases of the epidermal growth factor |
| CN102014627B (en) * | 2008-04-30 | 2014-10-29 | 国家卫生研究院 | Fused bicyclic pyrimidine compounds as aurora kinase inhibitors |
| WO2010054285A2 (en) * | 2008-11-10 | 2010-05-14 | National Health Research Institutes | Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors |
| CN102464667B (en) * | 2010-11-03 | 2014-06-04 | 中国科学院上海药物研究所 | Five-membered heterocycle pyrimidine compounds, preparation method and application thereof |
| EP2663312B1 (en) * | 2011-01-10 | 2017-10-11 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
| CN103664991B (en) * | 2012-09-19 | 2016-12-28 | 中国科学院福建物质结构研究所 | Thiophene [2,3 d] pyrimidine derivatives, Its Preparation Method And Use |
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