CN105061462A - Tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidines compound containing amide and application thereof - Google Patents
Tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidines compound containing amide and application thereof Download PDFInfo
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- thieno
- pyrimidine
- phenylsulfanvl
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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 invention belongs to the technical field of medicine, and relates to a tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidines compound containing amide, an application of the compound as an epidermal growth factor receptor tyrosine kinase inhibitor and a preparation method of the compound. The tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidines compound containing amide, pharmaceutically acceptable salts and pharmaceutically compatibility acceptable carriers or diluent are used as the epidermal growth factor receptor tyrosine kinase inhibitor. The general structural formula is shown as follows (please see the specification for the formula). R1 and R2 are independently selected from hydrogen, C1-C4 alkyl groups, and phenyl groups substituted or unsubstituted by halogen; or the R1, the R2 and nitrogen atoms connected with the R1 and the R2 constitute pyrrolidinyl, piperidyl and morpholinyl together. The synthetic method of the compound is simple, convenient and suitable for industrial production. Biological activity tests show that the compound has the effect of restraining epidermal growth factors. The compound is the epidermal growth factor receptor tyrosine kinase inhibitor with an anti-tumor effect.
Description
Technical field
The invention belongs to medical art, relate to tetrahydro benzo [4,5] thieno-[2, the 3-d] pyrimidines containing acid amides and apply as epidermal growth factor recipient tyrosine kinase inhibitor, and preparation method thereof.
Background technology
According to differentiation degree and the morphological specificity of cancer cells, lung cancer can be divided into nonsmall-cell lung cancer and small cell lung cancer.Research finds, there is a large amount of imbalances of Urogastron signal transduction and the overexpression of epidermal growth factor recipient tyrosine kinase in patients with lung cancer.
EGF-R ELISA (EGFR) is a kind of transmembrane protein with the outer ligand receptor binding domain of film and the active territory of intracellular tyrosine kinase.EGFR has 4 type HER-1, HER-2, HER-3 and HER-4, when smaller ligand is combined with EGFR, EGFR is activated, and then the Tyrosylprotein kinase district of EGFR activates, identify the substrates enzymes of albumen, will signal be imported in cell, after EGFR activation simultaneously, also can activate the phosphorylation of many downstream signaling molecules, initiating signal Signal Transduction Pathways, finally affects cell survival and cell proliferation.Because receptor type tyrosine kinase Main Differences is the outer ligand binding domains of born of the same parents, and the tyrosine kinase domain in born of the same parents has higher homology, the present invention is intended to the outer ligand binding domain of synthesis born of the same parents in conjunction with good smaller ligand, thus suppress Bao Nei tyrosine kinase activity district, the catalytic activity of inhibitory enzyme and tyrosine autophosphorylation, and then the transfer etc. of T suppression cell cycle progression, vasculogenesis and tumour.
Existing epidermal growth factor recipient tyrosine kinase inhibitor, as Gefitinib, Tarceva, lapatinibditosylate etc., all also exists the skin reactions such as diarrhoea, fash, itch, and possible headache, heart QT intervals prolongation and bioavailability reduction etc.
Compound of the present invention, as the epidermal growth factor recipient tyrosine kinase inhibitor of brand new type, has structure type novelty, the obvious feature of drug action.Can be used for treating or prevention and EGF-R ELISA signal transduction lack of proper care the relative disease that causes as small cell lung cancer, squama cancer, gland cancer, large cell carcinoma, colorectal carcinoma, mammary cancer, ovarian cancer, renal cell carcinoma, bronchial asthma, has good using value and development prospect.
Summary of the invention
Technical problem solved by the invention is to provide a kind of such as formula the compound shown in I, its prodrug and pharmaceutical active metabolite and its pharmacy acceptable salt, and provides its application in the medicine preparing the relevant disease of prevention and therapy EGFR signal transduction imbalance.
Wherein
R
1, R
2separately be selected from hydrogen, C
1-C
4alkyl, halogen substiuted or unsubstituted phenyl or R
1, R
2pyrrolidyl is formed, piperidyl, morpholinyl together with the nitrogen-atoms that they are connected.
Preferably,
R
1, R
2separately be selected from hydrogen, ethyl, phenyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, or R
1, R
2pyrrolidyl is formed, piperidyl, morpholinyl together with the nitrogen-atoms that they are connected.
" the acceptable salt of medicine " refers to the biopotency and the character that remain formula I, and with the acid of suitable non-toxic organic or inorganic or the conventional acid addition salts that formed of organic or inorganic alkali or base addition salt.The example of acid salt comprises acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, camsilate, cipionate, digluconate, dodecyl sulfate, esilate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrogen chlorate, hydrobromate, hydriodate, 2-isethionate, lactic acid salt, maleate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinic acid salt, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, vitriol, tartrate, thiocyanate-, tosylate and undecylate.Alkali salt comprises ammonium salt, an alkali metal salt, such as sodium and sylvite, alkaline earth salt, such as calcium and magnesium salts, the salt of organic bases, such as dicyclohexyl amine salt, N-methyl-D-glucamine salt, and amino acid whose salt, such as arginine, Methionin etc., and, Basic nitrogen-containing groups can be quaternized with such reagent, and such as elementary alkyl halide, as methyl, ethyl, the chlorine of propyl group and butyl, bromine and iodide; Dialkyl sulfate, as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long chain halide, as decyl, lauryl, the chlorine of myristyl and stearyl-, bromine and iodide; Aralkyl halide, as the bromide etc. of benzyl and styroyl.The acid being preferred for generating acid salt comprises hydrochloric acid and acetic acid.
" pharmaceutically acceptable ", as pharmaceutically acceptable ground carrier, vehicle, prodrug etc., refers to pharmacologically acceptable and to the essentially no toxicity of the patient of administration particular compound.
" pharmaceutical active metabolite " refers to the meta-bolites of pharmaceutically acceptable and effective formula I.
The present invention also relates to the medicinal compositions suppressing epidermal growth factor recipient tyrosine kinase, said composition contains the acid salt that formula I or derivative or its are pharmaceutically suitable for and the carrier be pharmaceutically suitable for.
The compounds of this invention can be taken to patient by diverse ways, such as with capsule or tablet oral, with sterile solution agent or suspensoid administration, and in some cases, can with solution form intravenous injection.Free alkali compound of the present invention can be carried out preparing and taking with its acid addition salt form thereof be pharmaceutically suitable for.
Embodiment
Reaction process 1 summarises the synthesis step preparing the compounds of this invention.
Reaction process 1
The present invention is described in detail with following example.But, should be clear and definite, the invention is not restricted to the concrete following example described.
The preparation of embodiment 1:4-[2-(4-morpholinyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 01)
The preparation of amino-4,5,6,7-tetrahydro benzo [b] thiophene-3-methane amides of steps A: 2-
Malonamide nitrile 10.1g (120mmol) is added successively in 250mL three-necked bottle, elemental sulfur 3.8g (120mmol), pimelinketone 11.8g (120mmol) and dehydrated alcohol 38mL, diethylamine 8.8g (120mmol) is slowly dropped to above-mentioned mixed solution, control temperature 40 ~ 50 DEG C, stirring reaction 5h, cooling crystallization, suction filtration, obtain a small amount of dehydrated alcohol of yellow-brown solid and wash 2 times, natural air drying, obtain yellow solid powder 11.7g, yield 49.6%, m.p.:186-188 DEG C.
The preparation of step B:5,6,7,8-tetrahydro benzo thieno-[2,3-d] pyrimidine-4 (3H)-one
By 2-amino-4,5,6,7-tetrahydro benzo [b] thiophene-3-methane amide 11.6g (59.2mmol) and methane amide (46.4g, 1031mmol) drop in 250mL eggplant-shape bottle, are heated to 165 DEG C of stirring and refluxing 6h, Virahol 110mL is added after reaction terminates, suction filtration after stirring, then use Virahol, wash each 1 time, natural air drying, obtain yellow-brown solid powder 9.7g, yield 80.0%, m.p.:255-257 DEG C.
The preparation of chloro-5,6,7, the 8-tetrahydrochysene-1-thionaphthenes of step C:4-also [2,3-d] pyrimidine
By 5,6,7,8-tetrahydro benzo thieno-[2,3-d] pyrimidine-4 (3H)-one 8.7g (42.0mmol) and phosphorus oxychloride 70.9g (467.1mmol) drops into 250mL eggplant-shape bottle, reflux 2h, column chromatography (sherwood oil: ethyl acetate=2:1), obtain yellow solid 6.7g, yield 70.5%, m.p.:97-99 DEG C.
The preparation of step D:4-(2-Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzo [4,5] thieno-[2,3-d] pyrimidine
By chloro-for 4-5,6,7,8-tetrahydrochysene-1-thionaphthene also [2,3-d] pyrimidine 5.0g (22.3mmol) drops into 250mL eggplant-shape bottle with 2-methoxybenzenethiol 3.4g (24.5mmol) respectively, and add propyl carbinol 64mL, add triethylamine 6.8g (66.9mmol), heating reflux reaction 1h, cooling crystallize out, suction filtration, respectively washs 1 time with water 10mL and ethanol 10mL, yellow crystalline powder 6.9g is obtained, yield 94.5% after natural air drying.m.p.:160-162℃；IR:(KBr,cm
-1):2936(s),1643(m),1584(s),1496(s),1415(s),1168(s),1129(s),832(s)；
1H-NMR(600MHz,CDCl
3):1.92-1.96(m,4H,2×CH
2),2.87(s,2H,CH
2),3.24(s,2H,CH
2),3.79(s,3H,OCH
3),7.01-7.07(m,2H,Ar-H),7.49(t,1H,Ar-H,J＝7.9Hz),7.55(dd,1H,Ar-H,J
1＝7.5,J
2＝1.6Hz),δ8.49(s,1H,Ar-H)；ESI-MS(m/z):329.3([M+H]
+)。
The preparation of step e: 4-(2-hydroxybenzene sulfenyl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine
By 4-(2-Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzo [4,5] thieno-[2,3-d] pyrimidine 3.3g (9.9mmol) and aluminum trichloride (anhydrous) 4.0g (29.8mmol) drops into 250mL eggplant-shape bottle, adds toluene 70mL, and reflux stirs, after reaction 1h, stopped reaction, adds water 100mL in reaction system, stirred at ambient temperature 3h, suction filtration, natural air drying, product obtains off-white color crystalline powder 1.8g, yield 58.3% through column chromatography (methyl alcohol: methylene dichloride=1:100).m.p.:175-176℃；IR:(KBr,cm
-1):3421(m),2932(m),1632(m),1596(m),1473(s),1409(s),1384(s),1142(s),830(m)；
1H-NMR(400MHz,CDCl
3):1.95-1.99(m,4H,CH
2),2.90(s,2H,CH
2),3.23(s,2H,CH
2),6.94(t,J＝8.2Hz,1H),7.17(dd,J
1＝8.1,J
2＝1.0Hz,1H),7.42(t,J＝7.7Hz,1H),7.49(dd,J
1＝7.8,J
2＝1.4Hz,1H),δ8.61(s,1H)；ESI-MS(m/z):315.3([M+H]
+)。
The preparation of step F: 4-[2-(4-morpholinyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 01)
By 4-(2-hydroxybenzene sulfenyl)-5, 6, 7, 8-tetrahydro benzo [4, 5] thieno-[2, 3-d] pyrimidine 0.5g (1.6mmol), Anhydrous potassium carbonate 2.2g (15.9mmol), potassiumiodide 0.1g (0.8mmol), acetone 50mL and 4-chloracetyl morpholine 0.3g (1.8mmol) drop in 100mL eggplant type bottle successively, reflux stirs 12h, remove solvent under reduced pressure after completion of the reaction, then in residuum, add methylene dichloride 50mL and water 50mL extract, the saturated NaCl solution washing of organic phase 100mL 1 time, collect organic phase and use anhydrous magnesium sulfate drying 30min, filter, column chromatography (methyl alcohol: methylene dichloride=1:50) is separated and obtains yellow solid 0.6g, yield 78.6%.m.p.:164-165℃；IR:(KBr,cm
-1)3441(m),2943(s),1643(s),1626(s),1557(s),1504(s),1471(s),1436(s),1305(s),1198(s),1115(s),1070(s),977(s),777(s)；
1H-NMR(400MHz,CDCl
3):δ1.94-1.95(m,4H,2×CH
2),2.90(m,2H,CH
2),3.13(m,2H,CH
2),3.32(t,2H,CH
2-N),3.50(t,2H,CH
2-N),3.54-3.57(m,2H,CH
2-O),3.60-3.62(m,2H,CH
2-O),3.65(s,2H,CH
2-O),7.20(dd,1H,Ar-H,J
1＝8.0Hz,J
2＝1.2Hz),7.28-7.32(m,1H,Ar-H),7.35-7.40(m,1H,Ar-H),(dd,1H,Ar-H,J
1＝8.0Hz,J
2＝1.2Hz),8.45(s,1H,Ar-H)；ESI-MS(m/z):442.4([M+H]
+)。
The preparation of embodiment 2:4-[2-(piperidino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 02)
With reference to the method for example 1, obtained 4-[2-(piperidino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine 0.5g, yield 85.7%.m.p.:127-129℃；IR:(KBr,cm
-1)3426(m),2939(s),2856(s),1642(s),1624(s),1556(s),1506(s),1471(s),1390(s),1309(s),1193(s),1138(s),1070(s),978(s),774(s)；
1H-NMR(400MHz,CDCl
3):δ1.40-1.52(m,4H,2×CH
2),1.55-1.60(m,2H,CH
2),1.92-1.97(m,4H,2×CH
2),2.89(m,2H,CH
2),3.14(m,2H,CH
2),3.25(t,2H,CH
2-N),3.49(t,2H,CH
2-N),3.68(s,2H,CH
2-O),7.19(dd,1H,Ar-H,J
1＝7.6Hz,J
2＝1.6Hz),7.27-7.37(m,2H,Ar-H),7.64(dd,1H,Ar-H,J
1＝7.6Hz,J
2＝1.6Hz),8.45(s,1H,Ar-H)；ESI-MS(m/z):440.2([M+H]
+)。
The preparation of embodiment 3:4-(2-diethylin formyl radical Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 03)
With reference to the method for example 1, obtained 4-(2-diethylin formyl radical Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 03) 0.4g, yield 72.2%.m.p.:117-119℃；IR:(KBr,cm
-1)3428(m),2936(s),1649(s),1559(s),1503(s),1466(s),1390(s),1309(s),1193(s),1136(s),1069(s),974(s),781(s)；
1H-NMR(400MHz,CDCl
3):δ1.06-1.10(m,6H,2×CH
3),1.91-1.96(m,4H,2×CH
2),2.88-2.91(m,2H,CH
2),3.12-3.15(m,2H,CH
2),3.18-3.24(m,2H,CH
2-N),3.31-3.36(m,2H,CH
2-N),3.66(s,2H,CH
2-O),7.19(dd,1H,Ar-H,J
1＝8.0Hz,J
2＝1.6Hz),7.26-7.30(m,1H,Ar-H),7.33-7.37(m,1H,Ar-H),7.62(dd,1H,Ar-H,J
1＝8.0Hz,J
2＝1.6Hz),8.45(s,1H,Ar-H)；ESI-MS(m/z):428.2([M+H]
+)。
The preparation of embodiment 4:4-[2-(1-pyrrolidyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 04)
With reference to the method for example 1, obtained 4-[2-(1-pyrrolidyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 04) 0.6g, yield 80.9%.m.p.:146-147℃；IR:(KBr,cm
-1)3432(m),2937(s),2878(m),1646(s),1628(s),1557(s),1506(s),1471(s),1435(s),1391(s),1307(s),1194(s),1070(s),977(s),776(s)；
1H-NMR(400MHz,CDCl
3):δ1.77-1.88(m,4H,2×CH
2),1.91-1.99(m,4H,2×CH
2),2.89(m,2H,CH
2),3.13(m,2H,CH
2),3.32(t,2H,CH
2-N),3.43(t,2H,CH
2-N),3.60(s,2H,CH
2-O),7.19(dd,1H,Ar-H,J
1＝7.6Hz,J
2＝1.6Hz),7.27-7.36(m,2H,Ar-H),7.66(dd,1H,Ar-H,J
1＝7.6Hz,J
2＝1.6Hz),8.45(s,1H,Ar-H)；ESI-MS(m/z):426.0([M+H]
+)。
The preparation of embodiment 5:4-(2-anilino formyl radical Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 05)
With reference to the method for example 1, obtained 4-(2-anilino formyl radical Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 05) 0.3g, yield 57.9%.m.p.:187-189℃；IR:(KBr,cm
-1)3440(m),3256(d),2936(d),1659(s),1604(s),1552(s),1502(s),1470(s),1390(s),1334(s),1306(s),1194(s),1067(s),974(s),767(m)；
1H-NMR(400MHz,CDCl
3):δ1.92-1.96(m,4H,2×CH
2),2.88-2.90(m,2H,CH
2),3.12-3.14(m,2H,CH
2),3.69(s,2H,CH
2-O),7.08-7.12(m,1H,Ar-H),7.20(dd,1H,Ar-H,J
1＝8.0Hz,J
2＝1.2Hz),7.25-7.38(m,6H,Ar-H),7.46(dd,1H,Ar-H,J
1＝8.0Hz,J
2＝1.2Hz),8.37(s,1H,Ar-H),8.53(s,1H,NH)；ESI-MS(m/z):448.1([M+H]
+)。
The preparation of embodiment 6:4-[2-(4-fluoroanilino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 06)
With reference to the method for example 1, obtained 4-[2-(4-fluoroanilino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 06) 0.2g, yield 39.0%.m.p.:122-124℃；IR:(KBr,cm
-1)3275(m),2934(s),1670(s),1556(s),1508(s),1469(s),1436(s),1390(s),1305(s),1197(s),1067(s),974(s),835(s),777(s)；
1H-NMR(400MHz,CDCl
3):δ1.92-1.96(m,4H,2×CH
2),2.89(m,2H,CH
2),3.12(m,2H,CH
2),3.69(s,2H,CH
2-O),6.96(t,2H,Ar-H),7.19-7.29(m,4H,Ar-H),7.34-7.39(m,1H,Ar-H),7.45(dd,1H,Ar-H,J
1＝8.0Hz,J
2＝1.6Hz),8.32(s,1H,Ar-H),8.56(s,1H,NH)；ESI-MS(m/z):488.1([M+H]
+)。
The preparation of embodiment 7:4-[3-(4-morpholinyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 07)
With reference to the method for example 1, obtained 4-[3-(4-morpholinyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 07) 0.5g, yield 87.5%.m.p.:117-119℃；IR:(KBr,cm
-1)3444(m),2929(s),2857(s),1679(s),1659(s),1591(s),1496(s),1468(s),1416(s),1382(s),1219(s),1112(s),1031(s),831(s),773(s),684(s)；
1H-NMR(400MHz,CDCl
3):δ1.92-1.96(m,4H,2×CH
2),2.87-2.89(m,2H,CH
2),3.17-3.19(m,2H,CH
2),3.60-3.68(m,8H,2×CH
2-N,2×CH
2-O),4.72(s,2H,CH
2-O),7.06(dd,1H,Ar-H,J
1＝7.6Hz,J
2＝2.8Hz),7.18(t,1H,Ar-H),7.23(d,1H,Ar-H,J＝8.0Hz),7.39(t,1H,Ar-H),8.53(s,1H,Ar-H)；ESI-MS(m/z):441.9([M+H]
+)。
The preparation of embodiment 8:4-[3-(1-pyrrolidyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 08)
With reference to the method for example 1, obtained 4-[3-(1-pyrrolidyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 08) 0.2g, yield 30.9%.m.p.:103-105℃；IR:(KBr,cm
-1)3422(m),2932(m),2867(s),1678(s),1574(s),1493(s),1407(s),1352(s),1281(s),1227(s),1092(s),829(s),789(s),689(s)；
1H-NMR(400MHz,CDCl
3):δ1.83-2.00(m,8H,4×CH
2),2.88(m,2H,CH
2),3.18(m,2H,CH
2),3.53(t,4H,CH
2-N),4.64(s,2H,CH
2-O),7.06(dd,1H,Ar-H,J
1＝8.4Hz,J
2＝2.0Hz),7.20(t,2H,Ar-H),7.38(t,1H,Ar-H),8.54(s,1H,Ar-H)；ESI-MS(m/z):426.1([M+H]
+)。
The preparation of embodiment 9:4-(3-anilino formyl radical Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 09)
With reference to the method for example 1, obtained 4-(3-anilino formyl radical Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 09) 0.1g, yield 18.3%.m.p.:123-125℃；IR:(KBr,cm
-1)3375(s),2929(s),2855(s),1685(s),1603(s),1544(s),1493(s),1444(s),1407(s),1319(s),1226(s),1129(s),832(s),764(s),689(s)；
1H-NMR(400MHz,CDCl
3):δ1.94-1.96(m,4H,2×CH
2),2.88-2.90(m,2H,CH
2),3.17-3.19(m,2H,CH
2),4.65(s,2H,CH
2-O),7.10(dd,1H,Ar-H,J
1＝8.4Hz,J
2＝2.0Hz),7.16(t,1H,Ar-H),7.28(t,1H,Ar-H),7.36(t,3H,Ar-H),7.44(t,1H,Ar-H),7.58(d,2H,J＝7.6Hz),8.25(s,1H,NH),8.49(s,1H,Ar-H)；ESI-MS(m/z):448.3([M+H]
+)。
The preparation of embodiment 10:4-[3-(4-fluoroanilino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 10)
With reference to the method for example 1, obtained 4-[3-(4-fluoroanilino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 10) 0.6g, yield 85.1%.m.p.:151-152℃；IR:(KBr,cm
-1)3406(s),2944(m),1689(s),1589(s),1509(m),1408(s),1223(s),1058(s),829(s),793(s),687(s)；
1H-NMR(400MHz,CDCl
3):δ1.92-1.99(m,4H,2×CH
2),2.88-2.90(m,2H,CH
2),3.17-3.19(m,2H,CH
2),4.65(s,2H,CH
2-O),7.03-7.10(m,3H,Ar-H),7.25-7.30(m,2H,Ar-H),7.44(t,1H,Ar-H,),7.52-7.57(m,2H,Ar-H),8.23(s,1H,NH),8.51(s,1H,Ar-H)；ESI-MS(m/z):466.1([M+H]
+)。
The preparation of embodiment 11:4-[4-(4-morpholinyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 11)
With reference to the method for example 1, obtained 4-[4-(4-morpholinyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 11) 0.6g, yield 78.6%.m.p.:141-144℃；IR:(KBr,cm
-1)3442(m),2932(s),2857(s),1650(s),1591(s),1492(s),1440(s),1409(s),1380(s),1236(s),1110(s),1031(s),829(s),731(s)；
1H-NMR(600MHz,CDCl
3):δ1.92-1.96(m,4H,2×CH
2),2.87-2.88(m,2H,CH
2),3.18-3.19(m,2H,CH
2),3.61-3.63(m,2H,CH
2-N),3.65-3.66(m,2H,CH
2-N),3.68-3.70(m,4H,CH
2-O),4.75(s,2H,CH
2-O),7.04(d,2H,Ar-H,J＝8.4Hz),7.50(d,2H,Ar-H,J＝8.4Hz),8.52(s,1H,Ar-H)；ESI-MS(m/z):442.0([M+H]
+)。
The preparation of embodiment 12:4-[4-(piperidino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 12)
With reference to the method for example 1, obtained 4-[4-(piperidino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 12) 0.6g, yield 91.4%.m.p.:84-86℃；IR:(KBr,cm
-1)3443(m),2935(s),2855(s),1639(s),1592(s),1493(s),1383(s),1241(s),1178(s),1128(s),1036(m),826(s),727(s)；
1H-NMR(400MHz,CDCl
3):δ1.58-1.66(m,6H,3×CH
2),1.91-1.97(m,4H,2×CH
2),2.86-2.88(m,2H,CH
2),3.19(brs,2H,CH
2),3.50(t,2H,CH
2-N),3.58(t,2H,CH
2-N),4.73(s,2H,CH
2-O),7.04(d,2H,Ar-H,J＝8.4Hz),7.49(d,2H,Ar-H,J＝8.4Hz),8.51(s,1H,Ar-H)；ESI-MS(m/z):440.5([M+H]
+)。
The preparation of embodiment 13:4-(4-diethylin formyl radical Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 13)
With reference to the method for example 1, obtained 4-(4-diethylin formyl radical Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 13) 0.6g, yield 90.8%.m.p.:88-91℃；IR:(KBr,cm
-1)3577(s),3489(s),2971(s),2934(s),1647(s),1614(s),1594(s),1494(s),1410(s),1250(s),1078(s),835(s),728(s),616(s)；
1H-NMR(400MHz,CDCl
3):δ1.16(t,3H,CH
3),1.24(t,3H,CH
3),1.94(t,4H,CH
2),2.87(t,2H,CH
2),3.18(t,2H,CH
2),3.41(m,4H,2×CH
2-N),4.72(s,2H,CH
2-O),7.04(d,2H,Ar-H,J＝8.8Hz),7.49(d,2H,Ar-H,J＝8.8Hz),8.52(s,1H,Ar-H)；ESI-MS(m/z):428.2([M+H]
+)。
The preparation of embodiment 14:4-[4-(1-pyrrolidyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 14)
With reference to the method for example 1, obtained 4-[4-(1-pyrrolidyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 14) 0.6g, yield 83.8%.m.p.:125-127℃；IR:(KBr,cm
-1)3556(s),3476(s),2936(s),2882(s),1649(s),1595(s),1494(s),1410(s),1251(s),1175(s),833(s),720(s)；
1H-NMR(400MHz,CDCl
3):δ1.84-2.02(m,8H,4×CH
2),2.87(t,2H,CH
2),3.19(t,2H,CH
2),3.55(t,4H,2×CH
2-N),4.67(s,2H,CH
2-O),7.04(d,2H,Ar-H,J＝8.8Hz),7.49(d,2H,Ar-H,J＝8.8Hz),8.52(s,1H,Ar-H)；ESI-MS(m/z):426.1([M+H]
+)。
The preparation of embodiment 15:4-(4-anilino formyl radical Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 15)
With reference to the method for example 1, obtained 4-(4-anilino formyl radical Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 15) 0.6g, yield 77.5%.m.p.:196-198℃；IR:(KBr,cm
-1)3374(s),2929(s),1684(s),1599(s),1534(s),1492(s),1438(s),1408(s),1244(d),1180(s),820(s),761(s),695(s)；
1H-NMR(400MHz,CDCl
3):δ1.94-1.95(m,4H,2×CH
2),2.88(s,2H,CH
2),3.19(s,2H,CH
2),4.68(s,2H,CH
2-O),7.10(d,2H,Ar-H,J＝8.8Hz),7.18(t,1H,Ar-H),7.38(t,2H,Ar-H),7.56-7.61(m,4H,Ar-H),8.24(s,1H,NH),8.52(s,1H,Ar-H)；ESI-MS(m/z):448.1([M+H]
+)。
The preparation of embodiment 16:4-[4-(4-fluoroanilino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 16)
With reference to the method for example 1, the obtained 1-(bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-ethoxyl phenenyl) piperazine (compound number 16) 0.6g, yield 85.1%.m.p.:195-197℃；IR:(KBr,cm
-1)3270(s),2929(s),1680(s),1537(s),1510(d),1412(s),1257(s),1216(s),827(s)；
1H-NMR(400MHz,CDCl
3):δ1.95(t,4H,2×CH
2),2.88(s,2H,CH
2),3.19(s,2H,CH
2),4.67(s,2H,CH
2-O),7.05-7.10(m,4H,Ar-H),7.55-7.58(m,4H,Ar-H),8.22(s,1H,NH),8.52(s,1H,Ar-H)；ESI-MS(m/z):466.2([M+H]
+)。
The preparation of embodiment 17:4-[4-(4-chloroanilino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 17)
With reference to the method for example 1, obtained 4-[4-(4-chloroanilino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 17) 0.3g, yield 41.0%.m.p.:208-210℃；IR:(KBr,cm
-1)3262(s),2926(s),1682(s),1593(s),1532(s),1492(s),1413(s),1258(s),1090(s),827(s)；
1H-NMR(600MHz,CDCl
3):δ1.92-1.95(m,4H,2×CH
2),2.86-2.88(m,2H,CH
2),3.17-3.19(m,2H,CH
2),4.66(s,2H,CH
2-O),7.08(d,2H,Ar-H,J＝8.4Hz),7.33(d,2H,Ar-H,J＝8.4Hz),7.56(d,4H,Ar-H,J＝8.4Hz),8.24(s,1H,NH),8.51(s,1H,Ar-H)；ESI-MS(m/z):482.1([M+H]
+)。
The preparation of embodiment 18:4-[4-(4-bromobenzene amido) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 18)
With reference to the method for example 1, obtained 4-[4-(4-bromobenzene amido) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 18) 0.1g, yield 10.0%.m.p.:198-199℃；IR:(KBr,cm
-1)3261(s),2925(s),1682(s),1654(s),1531(s),1492(s),1412(s),1255(s),1071(s),813(d)；
1H-NMR(400MHz,CDCl
3):δ1.95(s,4H,2×CH
2),2.88(s,2H,CH
2),3.19(s,2H,CH
2),4.66(s,2H,CH
2-O),7.08(d,2H,Ar-H,J＝8.4Hz),7.47-7.59(m,6H,Ar-H),8.24(s,1H,NH),8.52(s,1H,Ar-H)；ESI-MS(m/z):426.4([M+H]
+)。
The above is only preferred embodiment of the present invention, and be not restriction the present invention being made to other form, any those skilled in the art may utilize the technology contents of above-mentioned announcement to be changed or be modified as the Equivalent embodiments of equivalent variations.But everyly do not depart from technical solution of the present invention content, any simple modification, equivalent variations and the remodeling done above embodiment according to technical spirit of the present invention, still belong to the protection domain of technical solution of the present invention.
Pharmacological Examples
Embodiment 19:
Urogastron (EGFR) active determination in vitro
According to the method that (Eur.J.Med.Chem, 2013,61,132-145) such as Mowafy are introduced, carry out this and measure.
This mensuration uses the luminous kinase assay test kit of Kinase-GloPlus.It evaluates kinase activity by the amount of ATP in solvent after measurement kinase reaction.Luminous signal power is directly proportional to the amount of ATP and is inversely proportional to kinase activity.Test compounds is diluted to 100 μMs in 10%DMSO, the diluent then taking out 5 μ l join in the reaction of 50 μ l with ensure the ultimate density of the middle DMSO that responds be 1%.All enzymatic reactions all react 40min at 30 DEG C.The Tutofusin tris (Tris) of 40mM is comprised, the MgCl of 10mM in the reaction mixture of 50 μ l
2, the bovine serum albumin (BSA) of 0.1mg/mL, the composite interstitial substance (Glu, Tyr) of 0.2mg/mL, ATP and EGFR of 10 μMs, and control pH remains on 7.4.After enzymatic reaction terminates, in each reaction, add the luminous kinase assay solvent of Kinase-GloPlus of 50 μ l and at room temperature cultivate 5min subsequently.Luminous signal is measured by the unlimited M1000 type microplate reader of Tecan company.
IC
50the mensuration of value has been come by using ADP-GloTM detection kit.It measures the generation of ADP by protein kinase, and the ADP generated with kinase reaction in mentioned reagent box can cause luminous signal to strengthen.First, reaction mixture is placed in 96 orifice plates and cultivates 30min at 30 DEG C, subsequently to the ADP-GloTM reagent wherein adding 25 μ l.Rock this 96 orifice plate, then continue to cultivate 40min under room temperature.Finally add the kinase assay reagent of 50 μ l, the result of 96 orifice plates is read by GloMax microplate reader subsequently.The test method of blank group is complete parallel consistent with sample sets.Finally, the activity value of protein kinase is corrected by the numerical value reducing blank group.
According to the method described above, the combination of representative compound of the present invention and EGFR is tested, IC
50the result of value is shown in table 1.
Table 1
Embodiment 20:A-549 cell proliferating determining
According to the method that (ActaHistochemica, 2012,114 (8), 785-796) such as Stockert are introduced, carry out this and measure.
This mensuration uses mtt assay and utilizes Human Lung Cancer cell line A549 active to the antitumor increment evaluating invention representative compound.The Eagle substratum (DMEM) that A549 cell strain improves at DulbeccoShi is cultivated, and this substratum comprises 10% calf serum (FBS), the penicillin of 100U/mL and the Streptomycin sulphate of 100g/mL.Make when cell proliferation to 80 ~ 90% it merge the Secondary Culture carrying out being no more than 20 generations subsequently, then before next step is disposed, make them conform and reach 24h.These cells to be placed on 96 orifice plates (8 × 10
4/ mL), then containing 5%CO
2moist environment in overnight incubation temperature control at 37 DEG C.The invention representative compound of 20 μMs/50 μMs is added after 24h.Again through the cultivation of 24h, add MTT (5mg/mL) wherein and continue to cultivate 4h.Remove culture medium, by dissolution of crystals in DMSO, utilize microplate reader (TECANSPECTRA, Wetzlar, Germany) to measure absorbancy under 490nm wavelength.Restraining effect is by inhibiting rate and IC
50value represents.
Measure representative compound of the present invention according to the method described above, result is shown in table 2.
Table 2
Embodiment 21: to the effect of Proliferation of ovarian cancer cell SKOV 3
After the trysinization of logarithmic phase cell, with 6 × 10
3individual/porocyte number adds people 96 well culture plate, puts 37 DEG C, 5%CO
2cultivate in incubator, within the 2nd day, treat the adherent rearmounted people of most cells 4 DEG C of thermostat container 1h, grow to facilitate cell synchronization.Suck supernatant liquor, add people containing 10% newborn calf serum (FCS) RPMI1640 nutrient solution, 200 μ L/ holes, empirically design grouping.The compound injection liquid of stroke-physiological saline solution preparation is added in 96 holes, and adding 200 μ L in every hole, make the drug level in every hole be respectively 1mg/mL, 2mg/mL and 5mg/mI, take 0mg/mL as negative control group.Continue cultivation 24,48, after 72h, each hole adds people 20 μ LMTT solution (concentration is 5mg/mL) respectively, shake culture plate gently, put back in incubator and hatch 4h again, then exhaust supernatant liquor, in each hole, add methyl-sulphoxide 200 μ L, put on oscillator and shake 5-10min, measure with enzyme mark photometer the light absorption value (A=580) that every hole medium wavelength is 580nm, A=580 value is directly proportional to viable cell quantity.
Measure representative compound of the present invention according to the method described above, result is shown in table 3.
Table 3
Embodiment 22: the effect that osteosarcoma U 2OS-EGFP-4A12G is bred
After the trysinization of logarithmic phase cell, trypan blue counts, and being mixed with cell density is 1 × l0
4the cell suspension of individual/mL, is inoculated in 96 orifice plates, every hole 200 μ L, every hole about 2 × 10
3individual cell, preculture 24h, the compound injection liquid of stroke-physiological saline solution preparation is added in 96 holes, and adding 200 μ L in every hole, make the drug level in every hole be respectively 1mg/mL, 2mg/mL and 5mg/mI, take 0mg/mL as negative control group.After cultivating 0h, 12h, 24h and 48h respectively, every hole adds MTT solution (5mg/mL) 20 μ L, continues to hatch 4h, stops cultivating.The supernatant liquor in culture hole is abandoned in careful suction, and every hole adds the dimethyl sulfoxide (DMSO) (DMSO) of 150 μ L, concussion 10min, make the cured abundant dissolving of first, select 490nm wavelength, enzyme-linked immunosorbent assay instrument measures each hole absorbance value (A value), duplicate detection 5 times.
Measure representative compound of the present invention according to the method described above, result is shown in table 4.
Table 4
Example of formulations
Following example of formulations only illustrates protection scope of the present invention, but forms restriction never in any form.
Embodiment 23: gelatine capsule
The preparation of hard gelatin capsule adopts:
Above-mentioned preparation can be improved according to provided reasonable change.
Embodiment 77: tablet
The preparation of tablet adopts
Said components is mixed and is pressed into tablet.
Embodiment 24: tablet
Tablet containing 2.5-1000mg active ingredient in every sheet is prepared as follows:
Make activeconstituents, starch and Mierocrystalline cellulose by No. 45 mesh sieves and thoroughly mixing.Polyvinylpyrrolidonesolution solution is mixed with gained powder, with after through No. 14 mesh sieves.The particle that generates is dry and through No. 18 mesh sieves at 50-60 DEG C.Xylo-Mucine in advance through No. 60 mesh sieves, Magnesium Stearate and talcum powder are joined in above-mentioned particle, mix subsequently, on tabletting machine, compacting obtains tablet.
Embodiment 25: suspension
The suspension that every 5ml contains 0.1-1000mg medicine is prepared as follows:
Make medicine through No. 45 mesh sieves and be mixed to form level and smooth paste with Xylo-Mucine and syrup.Some water dilution of benzoic acid solution, correctives and tinting material is also under agitation added aforesaid paste.Add enough water subsequently to reach required volume.
Embodiment 26: combined tablet-preparation
Make activeconstituents, starch and Mierocrystalline cellulose by No. 45 mesh sieves and thoroughly mixing.Polyvinylpyrrolidonesolution solution is mixed with gained powder, with after through No. 14 mesh sieves.The particle that generates is dry and through No. 18 mesh sieves at 50-60 DEG C.Xylo-Mucine in advance through No. 60 mesh sieves, Magnesium Stearate and talcum powder are joined in above-mentioned particle, mix subsequently, on tabletting machine, compacting obtains tablet.
For above-mentioned explanation, those skilled in the art can easily understand essential feature of the present invention, do not deviate from the spirit and scope of the present invention, and the present invention can carry out various changes and improvements to adapt to different application and condition.
Claims (10)
1. the compound of a formula I:
Wherein
R
1, R
2separately be selected from hydrogen, C
1-C
4alkyl, halogen substiuted or unsubstituted phenyl or R
1, R
2pyrrolidyl is formed, piperidyl, morpholinyl together with the nitrogen-atoms that they are connected.
2. compound as claimed in claim 1, its prodrug and pharmaceutical active metabolite, and above-claimed cpd pharmacy acceptable salt, wherein:
R
1, R
2separately be selected from hydrogen, ethyl, phenyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, or R
1, R
2pyrrolidyl is formed, piperidyl, morpholinyl together with the nitrogen-atoms that they are connected.
3. the compound of formula I as claimed in claim 1 or 2, its prodrug and pharmaceutical active metabolite, and above-claimed cpd pharmacy acceptable salt, be selected from:
4-[2-(4-morpholinyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-[2-(piperidino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-(2-diethylin formyl radical Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-[2-(1-pyrrolidyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-(2-anilino formyl radical Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-[2-(4-fluoroanilino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-[3-(4-morpholinyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-[3-(1-pyrrolidyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-(3-anilino formyl radical Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-[3-(4-fluoroanilino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-[4-(4-morpholinyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-[4-(piperidino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-(4-diethylin formyl radical Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-[4-(1-pyrrolidyl) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-(4-anilino formyl radical Methoxv-phenylsulfanvl)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-[4-(4-fluoroanilino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-[4-(4-chloroanilino) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
4-[4-(4-bromobenzene amido) formyl radical Methoxv-phenylsulfanvl]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine.
4. a pharmaceutical composition, comprises the compound of the formula I of claim 1-3 described in any one, its prodrug and pharmaceutical active metabolite, and above-claimed cpd pharmaceutically acceptable salt as activeconstituents and medicine acceptable carrier.
5. the type I compound of claim 1-3 described in any one or pharmaceutical composition according to claim 4 are preparing the application in antitumor drug.
6. the type I compound of claim 1-3 described in any one or the application of pharmaceutical composition according to claim 4 in preparation treatment non-small cell lung cancer drug.
7. the type I compound of claim 1-3 described in any one or the pharmaceutical composition according to claim 4 application preparing prevention and therapy and lack of proper care in relevant disease medicament to EGF-R ELISA signal transduction.
8. application according to claim 7, is characterized in that: described EGF-R ELISA is HER-1, HER-2, HER-3 or HER-4.
9. application according to claim 6, is characterized in that, described cell is epithelial cell, glandular epithelium and embryonic cell except vascular tissue and hemopoietic system, all adult tissue cells except renal glomerulus and peripheral nerve.
10. application according to claim 7, is characterized in that: the relative disease of wherein said EGF-R ELISA signal transduction imbalance is squama cancer, gland cancer, large cell carcinoma, colorectal carcinoma, mammary cancer, ovarian cancer, renal cell carcinoma or bronchial asthma.
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| CN102264745A (en) * | 2008-11-10 | 2011-11-30 | 财团法人卫生研究院 | Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors |
| WO2012080729A2 (en) * | 2010-12-14 | 2012-06-21 | Electrophoretics Limited | CASEIN KINASE 1δ (CK1δ) INHIBITORS |
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| JP2022535383A (en) * | 2019-05-29 | 2022-08-08 | ▲賽▼▲爾▼瑞成（北京）生命科学技▲術▼有限公司 | RORγt ACTIVITY INHIBITOR COMPOUND, PREPARATION AND APPLICATION THEREOF |
| JP7263560B2 (en) | 2019-05-29 | 2023-04-24 | ▲賽▼▲爾▼瑞成（北京）生命科学技▲術▼有限公司 | RORγt ACTIVITY INHIBITOR COMPOUND, PREPARATION AND APPLICATION THEREOF |
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