CN105037385A - Piperazine-structure-containing tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine compounds and application thereof - Google Patents

Piperazine-structure-containing tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine compounds and application thereof Download PDF

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CN105037385A
CN105037385A CN201510509155.2A CN201510509155A CN105037385A CN 105037385 A CN105037385 A CN 105037385A CN 201510509155 A CN201510509155 A CN 201510509155A CN 105037385 A CN105037385 A CN 105037385A
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phenyl
thieno
pyrimidine
methoxy
base
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CN105037385B (en
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胡春
孙冰
邓新山
张富荣
黄钰淑
尹秀娥
金辄
刘晓平
黄二芳
王金辉
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Shenyang Pharmaceutical University
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    • 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
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Abstract

The invention belongs to the technical field of medicine, and relates to piperazine-structure-containing tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine compounds and application thereof as an epidermal growth factor receptor tyrosine kinase inhibitor, and a preparation method of the compounds. The piperazine-structure-containing tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine compounds and pharmaceutically acceptable salts thereof, and a pharmaceutically compatibility-acceptable carrier or diluter can be used as an epidermal growth factor receptor tyrosine kinase inhibitor. The structural general formula is disclosed in the specification, wherein R1, R2 and R3 are disclosed in the specification. The compounds are simple in synthesis method and suitable for industrial production. The bioactivity test shows that the compounds have the activity of inhibiting epidermal growth factor, human lung cancer cell strain A549, human oophoroma cell strain SKOV3 and human osteosarcoma cell U2OS-EGFP-4A12G, and are an epidermal growth factor receptor tyrosine kinase inhibitor with antitumor function.

Description

Tetrahydro benzo [4,5] thieno-[2,3-d] pyrimidines containing piperazine structure and application thereof
Technical field
The invention belongs to medical art, relate to tetrahydro benzo [4,5] thieno-[2,3-d] pyrimidines containing piperazine structure and preparation method thereof, also relate to it as the application in epidermal growth factor recipient tyrosine kinase inhibitor.
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;
R 3for H, halogen.
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;
More preferably,
R 3for H, fluorine or chlorine.
" 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, excipient, 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 1:7-[4-(4-morpholinyl) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 01)
The preparation of steps A: 4-(4-ethoxyl phenenyl) pimelinketone
Successively by 4-(4-hydroxy phenyl) pimelinketone 15.0g (79.0mmol), Anhydrous potassium carbonate 109.0g (789.5mmol), acetone 200mL, ethyl sulfate 24.4g (157.9mmol) puts into 500mL eggplant type bottle, after reflux stirs 6h, evaporated under reduced pressure solvent, adds water 500mL in residuum, in stirred at ambient temperature 2h, suction filtration, washes 2 times, obtains white solid 16.6g after drying, yield 96.5%, m.p.:70-72 DEG C.
The preparation of step B:2-amino-6-(4-ethoxyl phenenyl)-4,5,6,7-tetrahydro benzo [b] thiophene-3-methane amide
4-(4-ethoxyl phenenyl) pimelinketone 2.0g (9.2mmol) is added successively in 100mL three-necked bottle, Malonamide nitrile 0.8g (9.2mmol), sulphur powder (distillation) 0.3g (9.2mmol), dehydrated alcohol 6.0mL, so dropwise drip piperidines 0.8g (9.2mmol), and temperature control 45-50 DEG C, after dripping under said temperature stirring reaction 5h.After completion of the reaction, by freezing for reaction solution 2h, the solid that suction filtration is separated out, washing with alcohol 2 times, petroleum ether 1 time, obtains Orange red solid 1.6g after natural air drying, yield 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-d 6):δ1.31(t,3H,CH 3),1.73-1.84(m,1H,CH 2),1.91-1.95(m,1H,CH 2),2.53-2.58(m,1H,CH 2),2.63-2.80(m,3H,CH 2),2.81-2.90(m,1H,CH),3.99(m,2H,CH 2-O),6.53(brs,2H,NH 2),6.85(d,2H,Ar-H,J＝8.8Hz),6.94(s,2H,NH 2),7.19(d,2H,Ar-H,J＝8.8Hz)；ESI-MS(m/z):317.3([M+H] +)。
The preparation of step C:7-(4-ethoxyl phenenyl)-5,6,7,8-tetrahydro benzo [4,5] thieno-[2,3-d] pyrimidine-4 (3H)-one
2-amino-6-(4-ethoxyl phenenyl)-4 is added in 50mL eggplant-shape bottle, 5,6,7-tetrahydro benzo [b] thiophene-3-methane amide 1.0g (3.2mmol) and methane amide 5.7g (126.4mmol), at 165 DEG C after stirring reaction 6h, be cooled to room temperature, separate out after a large amount of solid until it and add Virahol 5mL, in stirred at ambient temperature 1h, suction filtration, washed with isopropyl alcohol 1 time, obtains brown solid 0.7g after natural air drying, 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-d 6):δ1.31(t,3H,CH 3),1.87-1.94(m,1H,CH 2),1.97-2.03(m,1H,CH 2),2.78-2.86(m,2H,CH 2),2.96-3.01(m,2H,CH 2),3.12-3.18(m,1H,CH 2),4.00(m,2H,CH 2-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] +)。
The preparation of the chloro-7-of step D:4-(4-ethoxyl phenenyl)-5,6,7,8-tetrahydro benzo [4,5] thieno-[2,3-d] pyrimidine
7-(4-ethoxyl phenenyl)-5 is added successively in 100mL eggplant-shape bottle, 6,7,8-tetrahydro benzo [4,5] thieno-[2,3-d] pyrimidine-4 (3H)-one 10.0g (31.0mmol) and phosphorus oxychloride 30mL (315.3mmol), reflux stirs, after solid all dissolves, then the 10min that refluxes, evaporated under reduced pressure solvent, obtains brownish black crude oil.Light yellow crystal 9.4g is obtained, yield 88.3% through column chromatography for separation (sherwood oil: ethyl acetate=2:1).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,CDCl 3):δ1.42(t,3H,CH 3),1.96-2.06(m,1H,CH 2),2.23-2.29(m,1H,CH 2),2.98-8.15(m,4H,CH 2),3.36-3.42(m,1H,CH),4.04(m,2H,CH 2-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] +)。
The preparation of step e: 7-(4-ethoxyl phenenyl)-4-(4-phenylpiperazine-1-base)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine
By chloro-for 4-7-(4-ethoxyl phenenyl)-5,6,7,8-tetrahydro benzo [4,5] thieno-[2,3-d] pyrimidine 0.5g (1.5mmol) and 1-php hydrochloride 0.4g (1.7mmol) drop into 50mL eggplant-shape bottle, add propyl carbinol 4.8mL, add triethylamine 0.4g (4.5mmol), heating reflux reaction 5h, solid is separated out in cooling, suction filtration, respectively wash 1 time with water 10mL and ethanol 5mL, after natural air drying, namely obtain greenish yellow solid 0.6g, yield 88.2%.m.p.：180-182℃；IR:(KBr,cm -1)3425(m),2924(m),2677(s),1534(s),1513(s),1495(s),1436(s),1368(s),1266(s),826(s),768(s),697(s)； 1H-NMR(400MHz,CDCl 3):δ1.42(t,3H,CH 3),1.84-1.94(m,1H,CH 2),2.15-2.20(m,1H,CH 2),2.94-3.00(m,2H,CH 2),3.10-3.25(m,3H,CH 2,CH),3.30-3.35(m,2H,CH 2-N),3.40-3.45(m,2H,CH 2-N),3.49-3.54(m,2H,CH 2-N),3.62-3.68(m,2H,CH 2-N),4.04(m,2H,CH 2-O),6.87-6.92(m,3H,Ar-H),6.99(d,2H,Ar-H,J＝8.0HZ),7.19(d,2H,Ar-H,J＝8.8HZ),7.28-7.32(m,2H,Ar-H),8.59(s,1H,Ar-H)；ESI-MS(m/z):471.6([M+H] +)。
The preparation of step F: 7-(4-hydroxy phenyl)-4-(4-phenylpiperazine-1-base)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine
By 7-(4-ethoxyl phenenyl)-4-(4-phenylpiperazine-1-base)-5,6,7,8-tetrahydro benzo [4,5] thieno-[2,3-d] pyrimidine 0.5g (1.1mmol), and aluminum trichloride (anhydrous) 0.7g (5.5mmol) drops into 100mL eggplant-shape bottle, add toluene 8mL, reflux stirs, after reaction 1h, and stopped reaction, water 30mL is added in reaction system, stirred at ambient temperature 3h, suction filtration, natural air drying, product obtains off-white color solid 0.4g, yield 87.2% through column chromatography (methyl alcohol: methylene dichloride=1:30).m.p.：190-192℃；IR:(KBr,cm -1)3454(m),2920(s),2850(s),1534(s),1500(s),1445(s),1384(s),1233(s),1116(m),829(s),761(s),693(s)； 1H-NMR(400MHz,CDCl 3):δ1.85-1.93(m,1H,CH 2),2.15-2.19(m,1H,CH 2),2.93-3.00(m,2H,CH 2),3.10-3.16(m,2H,CH 2),3.19-3.21(m,1H,CH),3.30-3.35(m,2H,CH 2-N),3.40-3.45(m,2H,CH 2-N),3.49-3.54(m,2H,CH 2-N),3.62-3.68(m,2H,CH 2-N),4.83(s,1H,Ar-OH),6.82(d,2H,Ar-H,J＝8.4Hz),6.90(t,1H,Ar-H),6.99(d,2H,Ar-H,J＝8.0Hz),7.16(d,2H,Ar-H,J＝8.4Hz),7.28-7.32(m,2H,Ar-H),8.59(s,1H,Ar-H)；ESI-MS(m/z):443.2([M+H] +)。
The preparation of step G:7-[4-(4-morpholinyl) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine (compound number 01)
By 7-(4-hydroxy phenyl)-4-(4-phenylpiperazine-1-base)-5, 6, 7, 8-tetrahydro benzo [4, 5] thieno-[2, 3-d] pyrimidine 0.5g (1.1mmol), Anhydrous potassium carbonate 1.6g (11.0mmol), potassiumiodide 0.2g (0.6mmol), acetone 50mL and 4-chloracetyl morpholine 0.2g (1.1mmol) 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 (sherwood oil: ethyl acetate=2:1) is separated and obtains yellow solid 0.2g, yield 23.3%.m.p.:177-178℃；IR:(KBr,cm -1)3452(m),2920(s),2851(s),1643(s),1442(m),1384(s),1116(s),847(s),760(s),620(s)； 1H-NMR(400MHz,CDCl 3):δ1.84-1.94(m,1H,CH 2),2.15-2.19(m,1H,CH 2),2.93-3.00(m,2H,CH 2),3.11-3.25(m,3H,CH 2,CH),3.30-3.35(m,2H,CH 2-N),3.40-3.45(m,2H,CH 2-N),3.49-3.54(m,2H,CH 2-N),3.62-3.69(m,10H,3×CH 2-N,2×CH 2-O),4.70(s,2H,CH 2-O),6.88-6.94(m,3H,Ar-H),6.99(d,2H,Ar-H,J＝8.0Hz),7.21(d,2H,Ar-H,J＝8.8Hz),7.28-7.32(m,2H,Ar-H),8.60(s,1H,Ar-H)；ESI-MS(m/z):570.4([M+H] +)。
The preparation of embodiment 2:7-[4-(piperidino) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-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 7-[4-(piperidino) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 02) 0.3g, yield 25.0%.m.p.:152-154℃；IR:(KBr,cm -1)3446(m),2920(s),2851(s),1656(s),1532(s),1498(s),1443(s),1371(s),1232(s),827(s),755(s),691(s)； 1H-NMR(400MHz,CDCl 3):δ1.53-1.69(m,6H,CH 2),1.84-1.93(m,1H,CH 2),2.15-2.19(m,1H,CH 2),2.92-3.00(m,2H,CH 2),3.11-3.24(m,3H,CH 2,CH),3.29-3.35(m,2H,CH 2-N),3.40-3.45(m,2H,CH 2-N),3.49-3.58(m,6H,3×CH 2-N),3.62-3.67(m,2H,CH 2-N),4.68(s,2H,CH 2-O),6.88-6.95(m,3H,Ar-H),6.99(d,2H,Ar-H,J＝7.6Hz),7.20(d,2H,Ar-H,J＝8.8Hz),7.27-7.31(m,2H,Ar-H),8.58(s,1H,Ar-H)；ESI-MS(m/z):568.1([M+H] +)。
The preparation of embodiment 3:7-(4-diethylin formyl radical p-methoxy-phenyl)-4-(4-phenylpiperazine-1-base)-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 7-(4-diethylin formyl radical p-methoxy-phenyl)-4-(4-phenylpiperazine-1-base)-5,6; 7,8-tetrahydro benzo [4,5] thieno-[2; 3-d] pyrimidine (compound number 03) 0.3g, yield 45.5%.m.p.:124-126 ℃C；IR:(KBr,cm -1)3457(m),2921(s),2851(s),1645(s),1533(s),1510(s),1439(s),1384(s),1234(s),1114(s),830(s),760(s),693(s)； 1H-NMR(400MHz,CDCl 3):δ1.15(t,3H,CH 3),δ1.23(t,3H,CH 3),1.83-1.93(m,1H,CH 2),2.15-2.18(m,1H,CH 2),2.92-3.00(m,2H,CH 2),3.10-3.24(m,3H,CH 2,CH),3.29-3.34(m,2H,CH 2-N),3.37-3.45(m,6H,3×CH 2-N),3.48-3.54(m,2H,CH 2-N),3.62-3.67(m,2H,CH 2-N),4.67(s,2H,CH 2-O),6.88-6.94(m,3H,Ar-H),6.99(d,2H,Ar-H,J＝8.0Hz),7.20(d,2H,Ar-H,J＝8.8Hz),7.26-7.31(m,2H,Ar-H),8.58(s,1H,Ar-H)；ESI-MS(m/z):556.2([M+H] +)。
The preparation of embodiment 4:7-(4-anilino formyl radical p-methoxy-phenyl)-4-(4-phenylpiperazine-1-base)-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 7-(4-anilino formyl radical p-methoxy-phenyl)-4-(4-phenylpiperazine-1-base)-5,6; 7,8-tetrahydro benzo [4,5] thieno-[2; 3-d] pyrimidine (compound number 04) 0.3g, yield 46.2%.m.p.:164-166℃；IR:(KBr,cm -1)3453(m),2920(s),2850(s),1643(s),1600(s),1534(s),1508(s),1442(s),1384(s),1234(s),1113(s),829(s),755(s),693(s)； 1H-NMR(400MHz,CDCl 3):δ1.86-1.96(m,1H,CH 2),2.17-2.21(m,1H,CH 2),2.94-3.01(m,2H,CH 2),3.14-3.27(m,3H,CH,CH 2),3.30-3.35(m,2H,CH 2-N),3.41-3.45(m,2H,CH 2-N),3.49-3.54(m,2H,CH 2-N),3.63-3.68(m,2H,CH 2-N),4.62(s,2H,CH 2-O),6.90(t,1H,Ar-H),6.99(d,4H,J＝8.8Hz),7.16(t,1H,Ar-H),7.28-7.32(m,3H,Ar-H),7.34-7.38(m,3H,Ar-H),7.59(d,2H,J＝8.0Hz),8.28(s,1H,NH),8.59(s,1H,Ar-H)；ESI-MS(m/z):576.5([M+H] +)。
Embodiment 5:7-[4-(4-fluoroanilino) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 05)
With reference to the method for example 1; obtained 7-[4-(4-fluoroanilino) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 05) 0.1g, yield 21.0%.m.p.:197-199℃；IR:(KBr,cm -1)3444(m),2919(s),2850(s),1641(m),1535(s),1509(s),1441(m),1384(s),1233(s),1117(s),833(s),757(s),620(s)； 1H-NMR(400MHz,CDCl 3):δ1.86-1.96(m,1H,CH2),2.17-2.21(m,1H,CH 2),2.94-3.01(m,2H,CH 2),3.14-3.35(m,5H,CH 2,CH,CH 2-N),3.40-3.46(m,2H,CH 2-N),3.49-3.54(m,2H,CH 2-N),3.63-3.68(m,2H,CH 2-N),4.62(s,2H,CH 2-O),6.90(s,1H,Ar-H),6.97-7.00(m,4H,Ar-H),7.06(t,2H,Ar-H),7.28-7.32(m,4H,Ar-H),7.55-7.58(m,2H,Ar-H),8.26(s,1H,NH),8.59(s,1H,Ar-H)；ESI-MS(m/z):594.3([M+H] +)。
Embodiment 6:7-[4-(4-chloroanilino) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 06)
With reference to the method for example 1; obtained 7-[4-(4-chloroanilino) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 06) 0.3g, yield 36.2%.m.p.:194-195℃；IR:(KBr,cm -1)3452(m),2920(s),2850(s),1598(m),1532(s),1507(s),1440(m),1383(s),1234(s),1116(s),829(s),758(s),620(s)； 1H-NMR(400MHz,CDCl 3):δ1.86-1.96(m,1H,CH 2),2.17-2.21(m,1H,CH 2),2.94-3.01(m,2H,CH 2),3.14-3.27(m,3H,CH 2,CH),3.29-3.35(m,2H,CH 2-N),3.41-3.45(m,2H,CH 2-N),3.50-3.56(m,2H,CH 2-N),3.64-3.68(m,2H,CH 2-N),4.61(s,2H,CH 2-O),6.90(t,1H,Ar-H),6.97-7.00(m,4H,Ar-H),7.28-7.33(m,6H,Ar-H),7.56(d,2H,Ar-H,J＝8.8Hz),8.29(s,1H,NH),8.59(s,1H,Ar-H)；ESI-MS(m/z):610.5([M+H] +)。
Embodiment 7:7-[4-(4-bromobenzene amido) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 07)
With reference to the method for example 1; obtained 7-[4-(4-bromobenzene amido) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 07) 0.2g, yield 32.4%.m.p.:176-178℃；IR:(KBr,cm -1)3452(m),2920(s),2851(s),1642(m),1533(s),1508(s),1441(m),1384(s),1234(s),1114(s),828(s),758(s),620(s)； 1H-NMR(400MHz,CDCl 3):δ1.85-1.96(m,1H,CH 2),2.17-2.21(m,1H,CH 2),2.93-3.01(m,2H,CH 2),3.14-3.35(m,5H,CH 2,CH,CH 2-N),3.40-3.45(m,2H,CH 2-N),3.49-3.54(m,2H,CH 2-N),3.63-3.68(m,2H,CH 2-N),4.61(s,2H,CH 2-O),6.90(t,1H,Ar-H),6.97-7.00(m,4H,Ar-H),7.26-7.32(m,4H,Ar-H),7.46-7.53(m,4H,Ar-H),8.27(s,1H,NH),8.59(s,1H,Ar-H)；ESI-MS(m/z):653.8([M+H] +)。
Embodiment 8:7-[4-(1-pyrrolidyl) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 08)
With reference to the method for example 1; obtained 7-[4-(1-pyrrolidyl) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 08) 0.4g, yield 55.6%.m.p.:210-212℃；IR:(KBr,cm -1)3452(m),2920(s),2851(s),1659(s),1532(s),1500(m),1442(m),1384(s),1234(s),1114(s),828(s),755(s),620(s)； 1H-NMR(400MHz,CDCl 3):δ1.83-1.91(m,3H,CH 2),1.94-2.01(m,2H,CH 2),2.15-2.19(m,1H,CH 2),2.92-3.00(m,2H,CH 2),3.11-3.26(m,3H,CH 2,CH),3.29-3.35(m,2H,CH 2-N),3.40-3.45(m,2H,CH 2-N),3.49-3.55(m,6H,CH 2-N,2×CH 2),3.63-3.67(m,2H,CH 2-N),4.63(s,2H,CH 2-O),6.88-6.95(m,3H,Ar-H),6.99(d,2H,Ar-H,J＝8.4Hz),7.20(d,2H,Ar-H,J＝8.8Hz),7.30(t,2H,Ar-H),8.59(s,1H,Ar-H)；ESI-MS(m/z):554.0([M+H] +)。
Embodiment 9:7-[4-(4-morpholinyl) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 09)
With reference to the method for example 1; obtained 7-[4-(4-morpholinyl) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 09) 0.2g, yield 28.1%.m.p.:204-206℃；IR:(KBr,cm -1)3452(m),2920(s),2851(s),1652(m),1511(s),1440(s),1384(s),1233(s),1115(s),979(s),828(s),620(s)； 1H-NMR(400MHz,CDCl 3):δ1.85-1.94(m,1H,CH 2),2.15-2.23(m,1H,CH 2),2.93-3.00(m,2H,CH 2),3.12-3.26(m,5H,CH 2,CH,CH 2-N),3.32-3.37(m,2H,CH 2-N),3.48-3.53(m,2H,CH 2-N),3.63-3.68(m,10H,3×CH 2-N,2×CH 2-O),4.70(s,2H,CH 2-O),6.92-7.01(m,6H,Ar-H),7.21(d,2H,Ar-H,J＝8.4Hz),8.59(s,1H,Ar-H)；ESI-MS(m/z):588.4([M+H] +)。
Embodiment 10:7-[4-(piperidino) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 10)
With reference to the method for example 1; obtained 7-[4-(piperidino) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 10) 0.3g, yield 53.1%.m.p.:184-186℃；IR:(KBr,cm -1)3452(m),2921(s),2852(s),1655(m),1511(s),1442(s),1384(s),1234(s),1115(s),981(s),828(s),713(s),620(s)； 1H-NMR(400MHz,CDCl 3):δ1.53-1.67(m,6H,3×CH 2),1.84-1.93(m,1H,CH 2),2.15-2.18(m,1H,CH 2),2.92-3.00(m,2H,CH 2),3.10-3.26(m,5H,CH 2,CH,CH 2-N),3.31-3.37(m,2H,CH 2-N),3.48-3.53(m,4H,2×CH 2-N),3.57(t,2H,CH 2-N),3.61-3.67(m,2H,CH 2-N),4.68(s,2H,CH 2-O),6.92-7.01(m,6H,Ar-H),7.21(d,2H,Ar-H,J＝8.4Hz),8.58(s,1H,Ar-H)；ESI-MS(m/z):586.6([M+H] +)。
Embodiment 11:7-(4-diethylin formyl radical p-methoxy-phenyl)-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 11)
With reference to the method for example 1; obtained 7-(4-diethylin formyl radical p-methoxy-phenyl)-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 11) 0.4g, yield 65.1%.m.p.:143-145℃；IR:(KBr,cm -1)3450(m),2921(s),2850(s),1655(m),1511(s),1439(s),1384(s),1235(s),1115(m),983(s),828(s),715(s),620(s)； 1H-NMR(400MHz,CDCl 3):δ1.15(t,3H,CH 3),δ1.23(t,3H,CH 3),1.83-1.93(m,1H,CH 2),2.15-2.18(m,1H,CH 2),2.92-3.00(m,2H,CH 2),3.10-3.26(m,5H,CH 2,CH,CH 2-N),3.31-3.44(m,6H,3×CH 2-N),3.47-3.53(m,2H,CH 2-N),3.61-3.67(m,2H,CH 2-N),4.68(s,2H,CH 2-O),6.92-7.01(m,6H,Ar-H),7.20(d,2H,Ar-H,J＝8.8Hz),8.58(s,1H,Ar-H)；ESI-MS(m/z):574.7([M+H] +)。
Embodiment 12:7-(4-anilino formyl radical p-methoxy-phenyl)-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 12)
With reference to the method for example 1; obtained 7-(4-anilino formyl radical p-methoxy-phenyl)-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 12) 0.4g, yield 58.5%.m.p.:176-178℃；IR:(KBr,cm -1)3452(m),2919(s),2850(s),1641(m),1534(s),1510(s),1442(s),1384(s),1234(s),1114(m),983(s),828(s),756(s),694(s),620(s)； 1H-NMR(400MHz,CDCl 3):δ1.86-1.96(m,1H,CH2),2.18-2.21(m,1H,CH 2),2.93-3.01(m,2H,CH 2),3.15-3.26(m,5H,CH 2,CH,CH 2-N),3.32-3.37(m,2H,CH 2-N),3.48-3.54(m,2H,CH 2-N),3.62-3.68(m,2H,CH 2-N),4.63(s,2H,CH 2-O),6.92-7.02(m,6H,Ar-H),7.17(t,1H,Ar-H),7.27(d,2H,J＝8.4Hz),7.37(t,2H,Ar-H),7.59(d,2H,J＝7.6Hz),8.26(s,1H,NH),8.59(s,1H,Ar-H)；ESI-MS(m/z):594.6([M+H] +)。
Embodiment 13:7-[4-(4-fluoroanilino) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 13)
With reference to the method for example 1; obtained 7-[4-(4-fluoroanilino) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 13) 0.3g, yield 43.3%.m.p.:174-175℃；IR:(KBr,cm -1)3388(m),2919(s),2849(s),1684(s),1534(s),1510(s),1439(s),1384(s),1233(m),1114(m),982(s),830(s),712(s),694(s),620(s)； 1H-NMR(400MHz,CDCl 3):δ1.86-1.96(m,1H,CH 2),2.18-2.21(m,1H,CH 2),2.93-3.01(m,2H,CH 2),3.14-3.26(m,5H,CH 2,CH,CH 2-N),3.32-3.37(m,2H,CH 2-N),3.48-3.54(m,2H,CH 2-N),3.63-3.68(m,2H,CH 2-N),4.62(s,2H,CH 2-O),6.92-7.02(m,6H,Ar-H),7.06(t,2H,Ar-H),7.27(d,2H,Ar-H,J＝9.2Hz),7.54-7.58(m,2H,Ar-H),8.25(s,1H,NH),8.59(s,1H,Ar-H)；ESI-MS(m/z):612.6([M+H] +)。
Embodiment 14:7-[4-(4-chloroanilino) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 14)
With reference to the method for example 1; obtained 7-[4-(4-chloroanilino) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 14) 0.2g, yield 27.9%.m.p.:202-204℃；IR:(KBr,cm -1)3444(m),2919(s),2850(s),1681(m),1534(s),1509(s),1439(s),1384(s),1234(s),1117(m),983(s),829(s),717(s),620(s)； 1H-NMR(400MHz,CDCl 3):δ1.85-1.96(m,1H,CH 2),2.17-2.21(m,1H,CH 2),2.94-3.01(m,2H,CH 2),3.14-3.26(m,5H,CH 2,CH,CH 2-N),3.32-3.37(m,2H,CH 2-N),3.48-3.54(m,2H,CH 2-N),3.63-3.68(m,2H,CH 2-N),4.62(s,2H,CH 2-O),6.92-7.02(m,6H,Ar-H),7.27(d,2H,Ar-H,J＝9.2Hz),7.32(d,2H,Ar-H,J＝8.8Hz),7.56(d,2H,Ar-H,J＝8.8Hz),8.28(s,1H,NH),8.59(s,1H,Ar-H)；ESI-MS(m/z):628.4([M+H] +)。
Embodiment 15:7-[4-(4-bromobenzene amido) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 15)
With reference to the method for example 1; obtained 7-[4-(4-bromobenzene amido) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 15) 0.1g, yield 13.7%.m.p.:119-120℃；IR:(KBr,cm -1)3450(m),2919(s),2850(s),1687(m),1532(s),1508s),1440(s),1384(s),1234(s),1117(m),983(s),826(s),713(s),620(s)； 1H-NMR(400MHz,CDCl 3):δ1.85-1.96(m,1H,CH 2),2.17-2.22(m,1H,CH 2),2.93-3.01(m,2H,CH 2),3.17-3.26(m,5H,CH 2,CH,CH 2-N),3.32-3.37(m,2H,CH 2-N),3.48-3.54(m,2H,CH 2-N),3.62-3.68(m,2H,CH 2-N),4.62(s,2H,CH 2-O),6.92-7.02(m,6H,Ar-H),7.27(d,2H,Ar-H,J＝8.8Hz),7.46-7.52(m,4H,Ar-H),8.27(s,1H,NH),8.59(s,1H,Ar-H)；ESI-MS(m/z):672.4([M+H] +)。
Embodiment 16:7-[4-(1-pyrrolidyl) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 16)
With reference to the method for example 1; obtained 7-[4-(1-pyrrolidyl) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 16) 0.2g, yield 29.0%.m.p.:227-229℃；IR:(KBr,cm -1)3454(m),2920(s),2850(s),1656(m),1510(s),1441(m),1384(s),1235(s),1116(s),981(s),828(s),777(s),620(s)； 1H-NMR(400MHz,CDCl 3):δ1.85-1.99(m,5H,CH 2),2.15-2.22(m,1H,CH 2),2.91-3.00(m,2H,CH 2),3.11-3.36(m,7H,CH 2,CH),3.48-3.66(m,8H,CH 2-N),4.63(s,2H,CH 2-O),6.93-7.01(m,6H,Ar-H),7.20(d,2H,Ar-H,J＝8.4Hz),8.58(s,1H,Ar-H)；ESI-MS(m/z):572.3([M+H] +)。
Embodiment 17:7-[4-(4-morpholinyl) formyl radical p-methoxy-phenyl]-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 17)
With reference to the method for example 1; obtained 7-[4-(4-morpholinyl) formyl radical p-methoxy-phenyl]-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 17) 0.2g, yield 31.6%.m.p.:188-190℃；IR:(KBr,cm -1)3452(m),2919(s),2851(s),1649(m),1533(s),1497(s),1439(s),1384(s),1234(s),1116(s),980(s),825(m),620(s)； 1H-NMR(400MHz,DMSO):δ1.82-1.88(m,1H,CH 2),2.05-2.10(m,1H,CH 2),2.90-3.04(m,2H,CH 2),3.12-3.16(m,3H,CH 2,CH),3.25-3.28(m,2H,CH 2-N),3.39-3.46(m,8H,4×CH 2-N),3.56-3.60(m,6H,CH 2-N,2×CH 2-O),4.80(s,2H,CH 2-O),6.90(d,2H,Ar-H,J＝7.2Hz),7.02(d,2H,Ar-H,J＝7.6Hz),7.26(d,2H,Ar-H,J＝7.6Hz),8.55(s,1H,Ar-H)；ESI-MS(m/z):604.1([M+H] +)。
Embodiment 18:7-[4-(piperidino) formyl radical p-methoxy-phenyl]-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 18)
With reference to the method for example 1; obtained 7-[4-(piperidino) formyl radical p-methoxy-phenyl]-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 18) 0.1g, yield 10.5%.m.p.:178-180℃；IR:(KBr,cm -1)3454(m),2922(s),2852(s),1647(s),1533(s),1497(s),1443(s),1384(s),1235(s),1116(m),981(s),824(m),620(s)； 1H-NMR(400MHz,DMSO):δ1.53-1.60(m,6H,3×CH 2),1.81-1.88(m,1H,CH 2),2.05-2.10(m,1H,CH 2),3.12-3.16(m,4H,2×CH 2),3.26-3.30(m,3H,CH,CH 2-N),3.37-3.43(m,10H,5×CH 2-N),4.76(s,2H,CH 2-O),6.88(d,2H,Ar-H,J＝8.4Hz),7.02(d,2H,Ar-H,J＝8.4Hz),7.26(d,2H,Ar-H,J＝8.4Hz),8.55(s,1H,Ar-H)；ESI-MS(m/z):602.2([M+H] +)。
Embodiment 19:7-(4-diethylin formyl radical p-methoxy-phenyl)-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 19)
With reference to the method for example 1; obtained 7-(4-diethylin formyl radical p-methoxy-phenyl)-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 19) 0.04g, yield 5.4%.m.p.:164-166℃；IR:(KBr,cm -1)3455(m),2970(s),2921(s),2850(s),1645(m),1533(s),1497(s),1439(s),1383(s),1234(s),981(s),825(m),620(s)； 1H-NMR(400MHz,DMSO):δ1.53-1.60(m,6H,3×CH 2),1.81-1.88(m,1H,CH 2),2.05-2.10(m,1H,CH 2),3.12-3.16(m,4H,2×CH 2),3.26-3.30(m,3H,CH,CH 2-N),3.37-3.43(m,10H,5×CH 2-N),4.76(s,2H,CH 2-O),6.88(d,2H,Ar-H,J＝8.4Hz),7.02(d,2H,Ar-H,J＝8.4Hz),7.26(d,2H,Ar-H,J＝8.4Hz),8.55(s,1H,Ar-H)；ESI-MS(m/z):590.3([M+H] +)。
Embodiment 20:7-(4-anilino formyl radical p-methoxy-phenyl)-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 20)
With reference to the method for example 1; obtained 7-(4-anilino formyl radical p-methoxy-phenyl)-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 20) 0.2g, yield 31.2%.m.p.:181-183℃；IR:(KBr,cm -1)3450(m),2919(s),2850(s),1654(s),1534(s),1497(s),1442(s),1384(s),1236(s),1118(m),984(s),755(m),620(s)； 1H-NMR(400MHz,DMSO):δ1.79-1.86(m,1H,CH 2),2.05-2.09(m,1H,CH 2),2.91-3.05(m,2H,CH 2),3.12-3.17(m,3H,CH 2,CH),3.25-3.29(m,2H,CH 2-N),3.37-3.45(m,4H,2×CH 2-N),3.54-3.60(m,2H,CH 2-N),4.69(s,2H,CH 2-O),6.96-7.03(m,4H,Ar-H),7.08(t,1H,Ar-H),7.25-7.32(m,6H,Ar-H),7.63-7.65(d,2H,Ar-H,J＝7.6Hz),8.55(s,1H,Ar-H),10.07(s,1H,NH)；ESI-MS(m/z):610.0([M+H] +)。
Embodiment 21:7-[4-(4-fluoroanilino) formyl radical p-methoxy-phenyl]-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 21)
With reference to the method for example 1; obtained 7-[4-(4-fluoroanilino) formyl radical p-methoxy-phenyl]-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 21) 0.3g, yield 41.8%.m.p.:119-121℃；IR:(KBr,cm -1)3444(m),2919(s),2850(s),1657(m),1534(s),1508(s),1441(s),1383(s),1233(s),1126(m),982(s),831(s),620(s)； 1H-NMR(400MHz,DMSO):δ1.80-1.88(m,1H,CH 2),2.06-2.10(m,1H,CH 2),2.90-3.07(m,2H,CH 2),3.13-3.16(m,3H,CH 2,CH),3.25-3.29(m,2H,CH 2-N),3.38-3.43(m,4H,2×CH 2-N),3.57-3.60(m,2H,CH 2-N),4.68(s,2H,CH 2-O),6.97-7.03(m,4H,Ar-H),7.16(t,2H,Ar-H),7.25-7.31(m,4H,Ar-H),7.65-7.66(m,2H,Ar-H),8.55(s,1H,Ar-H),10.12(s,1H,NH)；ESI-MS(m/z):628.0([M+H] +)。
Embodiment 22:7-[4-(4-bromobenzene amido) formyl radical p-methoxy-phenyl]-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5; 6,7,8-tetrahydro benzo [4; 5] preparation of thieno-[2,3-d] pyrimidine (compound number 22)
With reference to the method for example 1; obtained 7-[4-(4-bromobenzene amido) formyl radical p-methoxy-phenyl]-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5; 6; 7; 8-tetrahydro benzo [4; 5] thieno-[2,3-d] pyrimidine (compound number 22) 0.1g, yield 12.6%.m.p.:126-128℃；IR:(KBr,cm -1)3452(m),2920(s),2850(s),1642(m),1532(s),1507(d),1440(s),1383(s),1234(s),1116(m),982(s),823(s),620(s)； 1H-NMR(400MHz,DMSO):δ1.82-1.85(m,1H,CH 2),2.05-2.09(m,1H,CH 2),2.90-2.98(m,2H,CH 2),3.13-3.17(m,3H,CH 2,CH),3.36-3.43(m,6H,3×CH 2-N),3.57-3.60(m,2H,CH 2-N),4.69(s,2H,CH 2-O),6.96-7.03(m,4H,Ar-H),7.25-7.31(m,4H,Ar-H),7.51(d,2H,Ar-H,J＝8.4Hz),7.63(d,2H,Ar-H,J＝8.4Hz).8.55(s,1H,Ar-H),10.20(s,1H,NH)；ESI-MS(m/z):688.4([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 23:
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 24: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 25: 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 26: 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 27: gelatine capsule
The preparation of hard gelatin capsule adopts:
Above-mentioned preparation can be improved according to provided reasonable change.
Embodiment 28: tablet
The preparation of tablet adopts
Said components is mixed and is pressed into tablet.
Embodiment 29: 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 30: 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 31: 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. a compound for formula I, its prodrug and pharmaceutical active metabolite, and above-claimed cpd pharmacy acceptable salt:
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;
R 3for H, halogen.
2. the compound of formula I 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:
Wherein, R 3for H, fluorine or chlorine.
4., as the compound of the formula I of claim 1-3 as described in any one, its prodrug and pharmaceutical active metabolite, and above-claimed cpd pharmacy acceptable salt, be selected from:
7-[4-(4-morpholinyl) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
7-[4-(piperidino) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
7-(4-diethylin formyl radical p-methoxy-phenyl)-4-(4-phenylpiperazine-1-base)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
7-(4-anilino formyl radical p-methoxy-phenyl)-4-(4-phenylpiperazine-1-base)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3- d] pyrimidine;
7-[4-(4-fluoroanilino) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3- d] pyrimidine;
7-[4-(4-chloroanilino) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3- d] pyrimidine;
7-[4-(4-bromobenzene amido) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3- d] pyrimidine;
7-[4-(1-pyrrolidyl) formyl radical p-methoxy-phenyl]-4-(4-phenylpiperazine-1-base)-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
7-[4-(4-morpholinyl) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3- d] pyrimidine;
7-[4-(piperidino) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3- d] pyrimidine;
7-(4-diethylin formyl radical p-methoxy-phenyl)-4-[4-(4-fluorophenyl) piperazine-1-base]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
7-(4-anilino formyl radical p-methoxy-phenyl)-4-[4-(4-fluorophenyl) piperazine-1-base]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3- d] pyrimidine;
7-[4-(4-fluoroanilino) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3- d] pyrimidine;
7-[4-(4-chloroanilino) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3- d] pyrimidine;
7-[4-(4-bromobenzene amido) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3- d] pyrimidine;
7-[4-(1-pyrrolidyl) formyl radical p-methoxy-phenyl]-4-[4-(4-fluorophenyl) piperazine-1-base]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
7-[4-(4-morpholinyl) formyl radical p-methoxy-phenyl]-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3- d] pyrimidine;
7-[4-(piperidino) formyl radical p-methoxy-phenyl]-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3- d] pyrimidine;
7-(4-diethylin formyl radical p-methoxy-phenyl)-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3-d] pyrimidine;
7-(4-anilino formyl radical p-methoxy-phenyl)-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3- d] pyrimidine;
7-[4-(4-fluoroanilino) formyl radical p-methoxy-phenyl]-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3- d] pyrimidine;
7-[4-(4-bromobenzene amido) formyl radical p-methoxy-phenyl]-4-[4-(4-chloro-phenyl-) piperazine-1-base]-5,6,7,8-tetrahydro benzos [4,5] thieno-[2,3- d] pyrimidine.
5. a pharmaceutical composition, comprises the compound of the formula I of claim 1-4 described in any one, its prodrug and pharmaceutical active metabolite, and above-claimed cpd pharmaceutically acceptable salt as activeconstituents and medicine acceptable carrier.
6. the type I compound of claim 1-4 described in any one or the application of pharmaceutical composition according to claim 5 in preparation treatment non-small cell lung cancer drug.
7. the type I compound of claim 1-4 described in any one or the pharmaceutical composition according to claim 5 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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