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CN101747329A - A class of 4-arylthioquinazoline derivatives and its preparation method and medical use - Google Patents

A class of 4-arylthioquinazoline derivatives and its preparation method and medical use Download PDF

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CN101747329A
CN101747329A CN200910265062A CN200910265062A CN101747329A CN 101747329 A CN101747329 A CN 101747329A CN 200910265062 A CN200910265062 A CN 200910265062A CN 200910265062 A CN200910265062 A CN 200910265062A CN 101747329 A CN101747329 A CN 101747329A
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quinazoline
methyl
hydrogen
arylthio
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杨胜勇
杨黎
赵瀛兰
余洛汀
魏于全
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Sichuan University
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Sichuan University
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Abstract

本发明公开了一类4-芳硫基喹唑啉新衍生物和其制备方法及在制备治疗急性髓细胞白血病药物组合物中的用途，发明人经过研究发现4-芳硫基喹唑啉衍生物，具有很强的FLT3抑制活性，该制备方法具有反应步骤简短，所需原料试剂廉价易得，不需要柱层析纯化，整个过程只需1次重结晶，即可得到高纯度的目标产物。The invention discloses a new class of 4-arylthioquinazoline derivatives and its preparation method and its use in the preparation of pharmaceutical compositions for the treatment of acute myeloid leukemia. It has strong FLT3 inhibitory activity, the preparation method has short reaction steps, the required raw material reagents are cheap and easy to obtain, no column chromatography purification is required, and the whole process only needs one recrystallization to obtain the target product with high purity .

Description

One class 4-arylthio quinazoline derivant and preparation method and medicinal use
Technical field
The present invention relates to treat novel 4-arylthio quinazoline derivant and its preparation method and the purposes in preparation treatment acute myelocytic leukemia pharmaceutical composition of a class of acute myelocytic leukemia.
Background technology
Acute myelocytic leukemia (AML) is that hemopoietic stem cell is cloned a kind of malignant neoplastic disease that hyperplasia causes unusually, is modal type in adult's acute leukemia; Its sickness rate height, according to statistics, the annual morbidity of China AML is 1.62/100000, also has the trend that rises year by year in recent years.And show according to the recent statistics of national cancer institute, the overall sickness rate of 2001～2005 years U.S. AML is 3.6/100000, mortality ratio is 2.8/100000, and the meta age of onset is 67 years old, and over-65s patient sickness rate is 15.3/100000-18.1/100000.
Chemotherapy is the main treatment means of AML, and chemotherapeutics commonly used comprises anthracycline drug, and for example daunorubicin, and nucleoside analog draws as fluorine to reach shore, Clofarabine, Sapacitabine and Troxacytabine etc.Single medicine is used anthracene nucleus medicament treatment AML, and complete remission rate has only 30%～50%, as the associating cytosine arabinoside, can improve complete remission rate to a certain extent.But refractory, recurrence, old AML are still the difficult point of current clinical treatment.Exception, traditional chemotherapeutics target is poor, toxicity is big.Therefore, the specific molecular target chemotherapy medicine is the developing direction of following treatment AML medicine.
FLT3 (Fms-like tyrosine kinase, the Tyrosylprotein kinase 3 of FMS sample) is a kind of receptor tyrosine kinase, and it is playing an important role aspect the propagation of hemopoietic stem cell and the differentiation.Molecular biology research in recent years finds that among about 1/3rd the acute myelocytic leukemia patient, FLT3 sudden change or high expression level appear in its hemopoietic stem cell.Many studies show that has the AML patient that FLT3 suddenlys change, easily recurrence and poor prognosis.At present, as the critical treatment target spot of treatment AML, its specific inhibitor is considered to the molecular targeted agents of the most promising current treatment AML to FLT3.
Summary of the invention
The contriver has very strong FLT3 and suppresses active through discovering 4-arylthio quinazoline derivant, and its structural formula is as follows:
Figure G2009102650624D00021
In the formula, R 1Be ethylamino-or the Propylamino that methyl, methoxy ethyl, N replace, R 2Be methyl, methoxy ethyl.X 1=X 2During=CH, R 3Be hydrogen; X 1=N, X 2During=CH, R 3Be hydrogen, methyl or 4-CH 3-5-CH 2CONHR 4(R 4For replacing or unsubstituted phenyl or benzyl); X 1=X 2During=N, R 3Be hydrogen, 5-NHCONHR 4(R 4For replacing or unsubstituted phenyl).
General reactions steps is as follows:
Figure G2009102650624D00022
In the formula, R 1Be ethylamino-or the Propylamino that methyl, methoxy ethyl, N replace, R 2Be methyl, methoxy ethyl.X 1=X 2During=CH, R 3Be hydrogen; X 1=N, X 2During=CH, R 3Be hydrogen, methyl or 4-CH 3-5-CH 2CONHR 4(R 4For replacing or unsubstituted phenyl or benzyl); X 1=X 2During=N, R 3Be hydrogen, 5-NHCONHR 4(R 4For replacing or unsubstituted phenyl).
And the contriver further finds compound 6 under study for action, 7-dimethoxy-4-(thiazol-2-ylthio) quinazoline (1), and this compound has very strong restraining effect, IC to the FLT3 kinases 50(half-inhibition concentration) is 7nM, and leukemia cell line MV-4-11 and RS-4-11 that FLT3 is suddenlyd change have the obvious suppression effect.The relative molecular mass of this compound is 305.38, is white powder, and is water-soluble relatively poor, dissolves in dimethyl sulfoxide (DMSO) (DMSO) and ethanol equal solvent.Its structural formula is as follows:
Figure G2009102650624D00031
Its chemistry is by name: C 13H 11N 3O 2S 2, English name: 6,7-dimethoxy-4-(thiazol-2-yl thio) quinazoline, Chinese named: 6,7-dimethoxy-4 '-(thiazole-2-sulfenyl) quinazoline.
The preparation method of compound 1 is:
Figure G2009102650624D00032
This preparation method's advantage is: reactions steps is brief, and desired raw material reagent is cheap and easy to get, does not need column chromatography purification, and whole process only needs 1 recrystallization, can obtain target product with high purity.
Also there is not medicinal use report at present about the derivative of this compound and other 4-arylthio quinazoline.
Second technical problem to be solved by this invention provides a kind of anti-tumor small molecular targeted drug.The contriver has the kinase whose activity of the FLT3 of inhibition through discovering 4-arylthio quinazoline derivant, particularly 6,7-dimethoxy-4-(thiazol-2-ylthio) quinazoline (1) can be used for preparation treatment acute myelocytic leukemia small molecules targeted drug.
The anti-tumor small molecular targeted drug is to be that main active ingredient is added pharmaceutically acceptable complementary composition and is prepared from the 4-arylthio quinazoline derivant shown in the formula I.
Beneficial effect of the present invention is, has creatively proved that by experiment in vivo and vitro 4-arylthio quinazoline derivant has favorable anti-tumor effect, can be used to prepare antineoplastic pharmaceutical compositions.For the antitumor drug preparation field provides a kind of new selection, have good market outlook.
Description of drawings
Fig. 1 embodiment 1 compound is to the active variation of increasing with compound concentration of the kinase whose inhibition of FLT3
The variation that Fig. 2 embodiment 1 compound increases with compound concentration the inhibited proliferation of different people tumor cell line
The variation that Fig. 3 embodiment 10 compounds increase with compound concentration the inhibited proliferation of different people tumor cell line
The variation that Fig. 4 embodiment 16 compounds increase with compound concentration the inhibited proliferation of different people tumor cell line
Embodiment
Below in conjunction with embodiment the present invention is further set forth but be not limitation of the present invention; All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 16, the preparation of 7-dimethoxy-4 '-(thiazole-2-sulfenyl) quinazoline
The general reactions steps of preparation 4-arylthio quinazoline derivant is as follows:
1, with quinazolinone A (48.5mmol) and POCl 3(42ml, 458.8mmol) the stirring and refluxing reaction is 2 hours, and the question response liquid cooling is poured in the frozen water to room temperature, transfers pH to neutral with 20%NaOH, adds methylene dichloride (DCM) extraction separatory, and organic phase is spin-dried for and obtains white solid B, is directly used in next step reaction.
2, under the stirring at room, in butanone (30ml) suspension of C (2.8mmol), add K 2CO 3(8.0mmol), stirring reaction is 10 minutes under the room temperature, adds B (2.7mmol) again, is warming up to 80-85 ℃ of reaction 4 hours, the cooling reaction solution, and water and methylene dichloride (DCM) extraction separatory is spin-dried for organic layer and obtains 4-arylthio quinazoline derivant head product.Obtain pure product with ethanol (30ml) recrystallization.
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6,7-dimethoxyquinazoline-4-ketone, and C is the 2-thyroidan, makes crude product (1) 810mg, the crude product productive rate is 99.3%.Obtain 700mg, recrystallization productive rate 85.8% with ethanol (30ml) recrystallization.
1H?NMR(400MHz，DMSO-d 6)：δ8.88(s，1H)，8.06(d，J＝3.2Hz，1H)，8.03(d，J＝3.2Hz，1H)，7.40(s，1H)，7.29(s，1H)，4.00(s，6H)ppm；
13C?NMR(100MHz，DMSO-d 6)：δ162.4，156.1，153.8，151.6，150.5，146.0，143.0，125.3，117.4，107.1，100.7，56.3，56.1ppm；
ESI-MS(m/z，％)306.1(M+H) +。
Embodiment 26, the preparation of 7-dimethoxy-4 '-(thiophene-2-sulfenyl) quinazoline
Figure G2009102650624D00051
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6,7-dimethoxyquinazoline-4-ketone, and C is the 2-mercapto-thiophene, makes crude product (2) 410mg, productive rate is 92.0%.Obtain 360mg with ethyl alcohol recrystallization, recrystallization productive rate 80.5%.
1H?NMR(400MHz，DMSO-d 6)：δ8.74(s，1H)，7.95(d，J＝5.2Hz，1H)，7.47(d，J＝3.6Hz，1H)，7.35(s，1H)，7.31(s，1H)，7.25(t，J＝4.4Hz，1H)，3.99(s，6H)ppm；
13C?NMR(100MHz，DMSO-d 6)：δ165.6，155.8，152.2，150.3，145.8，137.7，133.9，128.2，123.3，117.4，107.0，100.6，56.2，56.0ppm；
ESI-MS(m/z，％)305.0(M+H) +。
Embodiment 36, the preparation of 7-dimethoxy-4 '-(1,3,4-thiadiazoles-2-sulfenyl) quinazoline
Figure G2009102650624D00052
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6, and 7-dimethoxyquinazoline-4-ketone, C are 2-sulfydryl-1,3, and the 4-thiadiazoles makes crude product (3) 350mg, and productive rate is 85.5%.Obtain 200mg with ethyl alcohol recrystallization, recrystallization productive rate 48.9%.
1H?NMR(400MHz，CDCl 3)：δ9.33(s，1H)，8.97(s，1H)，7.37(s，1H)，7.23(s，1H)，4.09(d，J＝5.6Hz，6H)ppm；
ESI-MS(m/z，％)307.2(M+H) +。
Embodiment 46, the preparation of 7-dimethoxy-4 '-(4-methylthiazol-2-sulfenyl) quinazoline
Figure G2009102650624D00061
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6, and 7-dimethoxyquinazoline-4-ketone, C are 4-methyl-2-thyroidan, make crude product (4) 300mg, and productive rate is 82.2%.Obtain 150mg with ethyl alcohol recrystallization, recrystallization productive rate 41.9%.
1H?NMR(400MHz，CDCl 3)：δ8.88(s，1H)，7.29(s，1H)，7.24(s，1H)，7.15(d，J＝1.2Hz，1H)，4.05(s，6H)，2.53(d，J＝0.8Hz，3H)ppm；
ESI-MS(m/z，％)318.3(M+H) +。
The preparation of embodiment 5 7-methoxyl group-6-(2-piperidines oxyethyl group)-4-(thiazole-2-sulfenyl) quinazoline
Figure G2009102650624D00062
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 7-methoxyl group-6-(2-(piperidino) oxyethyl group) quinazoline-4-one, and C is the 2-thyroidan, makes solid (5) 187mg, and overall yield is 54.2%.
1H?NMR(400MHz，DMSO-d 6)：δ8.88(s，1H)，8.06(d，J＝3.2Hz，1H)，8.03(d，J＝3.2Hz，1H)，7.40(s，1H)，7.38(s，1H)，4.31(t，J＝6.0Hz，2H)，4.00(s，3H)，2.75(t，J＝5.8Hz，2H)，2.48(broad，3H)，1.84(s，1H)，1.50-1.55(m，4H)，1.39-1.40(m，2H)ppm；
ESI-MS(m/z，％)403.03(M+H) +。
The preparation of embodiment 67-methoxyl group-6-(2-morpholine oxyethyl group)-4-(thiazole-2-sulfenyl) quinazoline
Figure G2009102650624D00071
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 7-methoxyl group-6-(2-morpholinyl oxyethyl group) quinazoline-4-one, and C is the 2-thyroidan, obtains solid (6) 100mg, and overall yield is 36.8%.
1H?NMR(400MHz，DMSO-d 6)：δ8.88(s，1H)，8.06(d，J＝3.6Hz，1H)，8.03(d，J＝3.2Hz，1H)，7.40(s，1H)，7.36(s，1H)，4.33(t，J＝5.8Hz，2H)，4.00(s，3H)，3.61(t，J＝4.4Hz，4H)，2.80(t，J＝5.8Hz，2H)，2.51(t，J＝1.8Hz，4H)ppm；
ESI-MS(m/z，％)405.01(M+H) +。
The preparation of embodiment 77-methoxyl group-6-(2-tetramethyleneimine oxyethyl group)-4-(thiazole-2-sulfenyl) quinazoline
Figure G2009102650624D00072
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 7-methoxyl group-6-(2-(1-Pyrrolidine base) oxyethyl group) quinazoline-4-one, and C is the 2-thyroidan
According to embodiment 1 same procedure, obtain solid (7) 92mg, overall yield is 42.0%.
1H?NMR(400MHz，DMSO-d 6)：δ8.88(s，1H)，8.06(d，J＝3.2Hz，1H)，8.03(d，J＝3.2Hz，1H)，7.41(s，1H)，7.36(s，1H)，4.31(t，J＝5.6Hz，2H)，4.01(s，3H)，2.91(t，J＝5.6Hz，2H)，2.59(s，4H)，1.71(s，4H)ppm；
ESI-MS(m/z，％)388.99(M+H) +。
The preparation of embodiment 87-methoxyl group-6-(3-(N, N-dimethyl) propoxy-)-4-(thiazole-2-sulfenyl) quinazoline
Figure G2009102650624D00081
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6-(3-dimethylamino propoxy-)-7-methoxyl group quinazoline-4-one, and C is the 2-thyroidan, obtains solid (8) 90mg, and overall yield is 46.0%.
1H?NMR(400MHz，DMSO-d 6)：δ8.87(s，1H)，8.06(d，J＝3.2Hz，1H)，8.03(d，J＝3.2Hz，1H)，7.39(s，1H)，7.28(s，1H)，4.22(t，J＝6.6Hz，2H)，4.01(s，3H)，2.41(t，J＝7.0Hz，2H)，2.18(s，6H)，1.96(m，J＝6.8Hz，2H)ppm；
ESI-MS(m/z，％)376.99(M+H) +。
Embodiment 96, the preparation of 7-two (2-methoxy ethoxy)-4-(thiazole-2-sulfenyl) quinazoline
Figure G2009102650624D00082
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6,7-dimethoxy oxyethyl group quinazoline-4-ketone, and C is the 2-thyroidan, makes crude product (9) 200mg, productive rate is 74.5%.Obtain 135mg with ethyl alcohol recrystallization, recrystallization productive rate 50.5%.
1H?NMR(400MHz，CDCl 3)：δ8.89(s，1H)，7.97(d，J＝3.2Hz，1H)，7.61(d，J＝3.2Hz，1H)，7.33(s，1H)，4.33(m，J＝2.2Hz，4H)，3.89(m，J＝4.4Hz，4H)，3.50(d，J＝7.6Hz，6H)ppm；
ESI-MS(m/z，％)393.89(M+H) +。
Embodiment 106, the preparation of 7-two (2-methoxy ethoxy)-4-(1,3,4-thiadiazoles-2-sulfenyl) quinazoline
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6,7-dimethoxy oxyethyl group quinazoline-4-ketone, and C is a 2-sulfenyl-1,3, and the 4-thiadiazoles makes crude product (10) 300mg, and productive rate is 79.3%.Obtain 165mg with ethyl alcohol recrystallization, recrystallization productive rate 43.6%.
1H?NMR(400MHz，CDCl 3)：δ9.86(s，1H)，8.94(s，1H)，7.46(s，1H)，7.40(s，1H)，4.38(q，J＝4.4Hz，4H)，3.78(q，J＝4.8Hz，4H)，3.37(d，J＝7.6Hz，6H)ppm；
ESI-MS(m/z，％)417.08(M+Na) +。
The preparation of embodiment 112-(4-(6, the 7-dimethoxyquinazoline) sulfenyl)-4-methylthiazol-5-(N-(3-chloro-phenyl-)) ethanamide
Figure G2009102650624D00092
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6, and 7-dimethoxyquinazoline-4-ketone, C are N-(3-chloro-phenyl-)-2-(2-sulfydryl-4-methylthiazol-5-yl) ethanamide, obtain target product (11) 167mg, productive rate is 51.8%.
1H?NMR(400MHz，DMSO-d 6)：δ10.52(s，1H)，8.86(s，1H)，7.82(s，1H)，7.45(d，J＝8.4Hz，1H)，7.34-7.39(m，2H)，7.29(s，1H)，7.13(d，J＝7.6Hz，1H)，4.00(s，8H)，2.39(s，3H)ppm；
ESI-MS(m/z，％)485.00(M-H) -.
The preparation of embodiment 12 2-(4-(6, the 7-dimethoxyquinazoline) sulfenyl)-4-methylthiazol-5-(N-(3-trifluoromethyl)) ethanamide
Figure G2009102650624D00101
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6, and 7-dimethoxyquinazoline-4-ketone, C are 2-(2-sulfydryl-4-methylthiazol-5-yl)-N-(3-trifluoromethyl) ethanamide, obtain product (12) 153mg, productive rate is 44.5%.
1H?NMR(400MHz，DMSO-d 6)：δ10.67(s，1H)，8.87(s，1H)，8.11(s，1H)，7.78(d，J＝7.6Hz，1H)，7.58(t，J＝8.0Hz，1H)，7.40-7.44(m，2H)，7.29(s，1H)，4.04(s，2H)，4.00(s，6H)，2.40(s，3H)ppm；
ESI-MS(m/z，％)519.00(M-H) -。
The preparation of embodiment 13 2-(4-(6, the 7-dimethoxyquinazoline) sulfenyl)-4-methylthiazol-5-(N-(4-phenyl methyl ketone amino)) ethanamide
Figure G2009102650624D00111
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6, and 7-dimethoxyquinazoline-4-ketone, C are N-(4-acetamido phenyl)-2-(2-sulfydryl-4-methylthiazol-5-yl) ethanamide, obtain product (13) 232mg, productive rate is 57.0%.
1H?NMR(400MHz，DMSO-d 6)：δ10.27(s，1H)，9.90(s，1H)，8.86(s，1H)，7.51(s，4H)，7.39(s，1H)，7.28(s，1H)，4.00(s，6H)，3.96(s，2H)，2.40(s，3H)，2.02(s，3H)ppm；
ESI-MS(m/z，％)508.00(M-H) -。
The preparation of embodiment 14 2-(4-(6, the 7-dimethoxyquinazoline) sulfenyl)-4-methylthiazol-5-(N-(4-benzyl chloride amido)) ethanamide
Figure G2009102650624D00112
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6, and 7-dimethoxyquinazoline-4-ketone, C are N-(4-benzyl chloride base)-2-(2-sulfydryl-4-methylthiazol-5-yl) ethanamide, obtain product (14) 153mg, productive rate is 48.0%.
1H?NMR(400MHz，DMSO-d 6)：δ8.85(s，1H)，8.77(s，1H)，7.39(d，J＝7.2Hz，3H)，7.30(d，J＝8.0Hz，3H)，4.30(d，J＝4.8Hz，2H)，4.00(s，6H)，3.81(s，2H)，2.35(s，3H)ppm；
ESI-MS(m/z，％)500.96(M+H) +。
The preparation of embodiment 152-(4-(6, the 7-dimethoxyquinazoline) sulfenyl)-4-methylthiazol-5-(N-(3, the 5-dichlorophenyl)) ethanamide
Figure G2009102650624D00121
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6,7-dimethoxyquinazoline-4-ketone, C is N-(3, the 5-dichlorophenyl)-and 2-(2-sulfydryl-4-methylthiazol-5-yl) ethanamide, obtain product (15) 110mg, productive rate is 32.3%.
1H?NMR(400MHz，DMSO-d 6)：δ10.68(s，1H)，8.87(s，1H)，7.67(s，2H)，7.40(s，1H)，7.30(d，J＝8.4Hz，2H)，4.01(d，J＝7.6Hz，8H)，3.96(s，2H)，2.39(s，3H)ppm；
ESI-MS(m/z，％)520.91(M+H) +。
The preparation of embodiment 16 2-(4-(6,7-two (2-methoxy ethoxy) quinazoline) sulfenyl)-4-methylthiazol-5-(N-(3-trifluoromethyl)) ethanamide
Figure G2009102650624D00122
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6, and 7-dimethoxy oxyethyl group quinazoline-4-ketone, C are 2-(2-sulfydryl-4-methylthiazol-5-yl)-N-(3-trifluoromethyl) ethanamide, obtain product (16) 119mg, productive rate is 36.8%.
1H?NMR(400MHz，DMSO-d 6)：δ10.67(s，1H)，8.86(s，1H)，8.11(s，1H)，7.78(d，J＝8.0Hz，1H)，7.58(t，J＝8.0Hz，1H)，7.43(d，J＝6.8Hz，2H)，7.35(s，1H)，4.36(t，J＝2.2Hz，4H)，4.03(s，2H)，3.77(q，J＝2.2Hz，4H)，3.36(d，J＝5.6Hz，6H)，2.40(s，3H)ppm；
ESI-MS(m/z，％)607.22(M-H) -。
The preparation of embodiment 17 2-(4-(6,7-two (2-methoxy ethoxy) quinazoline) sulfenyl)-4-methylthiazol-5-(N-(4-trifluoromethyl)) ethanamide
Figure G2009102650624D00131
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6, and 7-dimethoxy oxyethyl group quinazoline-4-ketone, C are 2-(2-sulfydryl-4-methylthiazol-5-yl)-N-(4-trifluoromethyl) ethanamide, obtain product (17) 160mg, productive rate is 49.0%.
1H?NMR(400MHz，DMSO-d 6)：δ10.69(s，1H)，8.85(s，1H)，7.82(d，J＝8.4Hz，2H)，7.70(d，J＝8.8Hz，2H)，7.42(s，2H)，7.35(s，1H)，4.36(d，J＝4.4Hz，4H)，4.05(s，2H)，3.77(q，J＝4.0Hz，4H)，3.36(d，J＝6.0Hz，6H)，2.40(s，3H)ppm；
ESI-MS(m/z，％)607.22(M-H) -。
The preparation of embodiment 18 2-(4-(6,7-two (2-methoxy ethoxy) quinazoline) sulfenyl)-4-methylthiazol-5-(N-(3-chloro-phenyl-)) ethanamide
Figure G2009102650624D00132
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6, and 7-dimethoxy oxyethyl group quinazoline-4-ketone, C are 2-(2-sulfydryl-4-methylthiazol-5-yl)-N-(3-chloro-phenyl-) ethanamide, obtain product (18) 200mg, productive rate is 62.3%.
1H?NMR(400MHz，DMSO-d 6)：δ10.52(s，1H)，8.85(s，1H)，7.82(t，J＝1.8Hz，1H)，7.42-7.46(m，2H)，7.38(s，1H)，7.34-7.36(m，1H)，7.13(dd，J＝0.8Hz，1H)，4.35(m，J＝2.9Hz，4H)，4.01(s，2H)，3.77(m，J＝3.2Hz，4H)，3.36(d，J＝6.0Hz，6H)，2.39(s，3H)ppm；
ESI-MS(m/z，％)573.02(M-H) -。
The preparation of embodiment 19 2-(4-(6,7-two (2-methoxy ethoxy) quinazoline) sulfenyl)-4-methylthiazol-5-(N-(3, the 5-xylyl)) ethanamide
Figure G2009102650624D00141
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6,7-dimethoxy oxyethyl group quinazoline-4-ketone, C is 2-(2-sulfydryl-4-methylthiazol-5-yl)-N-(3, the 5-3,5-dimethylphenyl) ethanamide obtains product (19) 210mg, and productive rate is 68.6%.
1H?NMR(400MHz，DMSO-d 6)：δ10.17(s，1H)，8.85(s，1H)，7.42(s，2H)，7.35(s，1H)，7.22(s，2H)，6.71(s，1H)，4.36(d，J＝4.0Hz，4H)，3.96(s，2H)，3.77(d，J＝4.0Hz，4H)，3.36(d，J＝6.0Hz，6H)，2.39(s，3H)，2.23(s，6H)ppm；
ESI-MS(m/z，％)567.02(M-H) -。
The preparation of embodiment 20 2-(4-(6,7-two (2-methoxy ethoxy) quinazoline) sulfenyl)-5-(N-(3-chloro-phenyl-) urea) thiadiazoles
Figure G2009102650624D00142
By the method for preparing the general reactions steps of 4-arylthio quinazoline derivant, wherein A is 6,7-dimethoxy oxyethyl group quinazoline-4-ketone, C is 1-(3-chloro-phenyl-)-3-(5-sulfydryl-1,3,4-thiadiazoles-2-yl) urea, obtain product (20) 85mg, productive rate is 15.7%.
1H?NMR(400MHz，DMSO-d 6)：δ11.41(s，1H)，9.34(s，1H)，8.89(s，1H)，7.73(s，1H)，7.45(s，1H)，7.38(broad，3H)，7.14(s，1H)，4.38(d，J＝4.4Hz，4H)，3.78(q，J＝4.8Hz，4H)，3.37(d，J＝7.6Hz，6H)ppm；
ESI-MS(m/z，％)563.00(M-H) -。
The FLT3 kinase inhibiting activity test experience of embodiment 21 compounds 1
1, experimental technique
Compound 1 is dissolved in gradient concentration among 100% the DMSO as sample to be tested, then, the FLT3 of the sample to be tested of different concns and 5-10mU (people source) is blended in (working fluid composition: 8mM MOPS, 0.2mM EDTA in the 25ul working fluid, 50 μ M EAIYAAPFAKKK (small peptide), pH7.0).Behind the concussion mixing, add Mg[γ-33P-ATP] begin reaction behind the mixture.At room temperature hatched 40 minutes, and added 3% phosphoric acid solution termination reaction, reaction solution is dropped on the P30 filter membrane pad again, and with 75mM phosphoric acid solution wash-out three times (each 5 minutes).At last, dry after embathing with methyl alcohol and carry out the radioactivity scintillation counting and detect.Detected result sees Table 1 and Fig. 1.
2. result
1 couple of FLT3 of table 1 compound and the active (IC of other common kinase whose inhibition 50)
Kinases ??IC 50(nM) Kinases ??IC 50(nM)
??FLT3 ??7 ??Lck ??＞10000
??KIT ??＞10000 ??Met ??＞10,000
??FMS ??10,180 ??RAF1 ??＞10,000
??PDGFR ??＞10,000 ??Syk ??＞10000
??PDGFR ??＞10,000 ??Pim-1 ??＞10,000
??FLT1 ??9,046 ??PLK1 ??＞10,000
??KDR ??5880 ??PLK3 ??＞10,000
??FLT4 ??3,548 ??EGFR ??＞10000
??Aurora?A ??3874 ??CDK1 ??＞10000
??Aurora?B ??993 ??CDK2 ??＞10000
??IGF-1R ??＞10000 ??CHK1 ??＞10000
Activity data shows in the table 1, the half-inhibition concentration (IC of 1 couple of FLT3 of compound 50) 7nM, lower or almost do not have an activity (IC to other common kinase whose inhibition activity 50＞10000nM).Show further also that by Fig. 1 along with drug level increases, the inhibition activity of 1 couple of FLT3 of compound is obvious more, has tangible dose-dependently.
The tumor cell in vitro proliferation inhibition test of embodiment 224-arylthio quinazoline derivant
1, experiment material
1.1 main agents
(InvitrogenCorporation, USA), the IMDM substratum is available from ATCC (American Type CultureCollection) available from Gibco BRL company for RPMI-1640, DMEM, foetal calf serum, pancreatin etc.Thiazole bromide blue tetrazolium (MTT), dimethyl sulfoxide (DMSO) (DMSO) are Sigma company (USA) product.4-arylthio quinazoline series derivates is synthetic by the contriver, is mixed with the 20mg/ml storage liquid with 100%DMSO during experiment in vitro, puts-20 ℃ of refrigerators and keeps in Dark Place standbyly, faces the time spent to be diluted to desired concn with complete culture solution.
1.2 clone and cultivation
Used human hepatoma cell strain (HepG2), Human Prostate Cancer Cells strain (PC-3), human lung carcinoma cell line (A549), human colon cancer cell strain (HCT-116), people's chronic myelogenous leukemia cell strain (K562), human breast cancer cell strain (MCF-7), person monocytic cell's leukemia cell line (Raji), people's malignant melanoma cell strain (A375), the people's acute myeloid leukaemia cell strain (MV4-11) of this experiment all purchased the ATCC company in the U.S., preserved by this laboratory.
Human hepatoma cell strain (HepG2), Human Prostate Cancer Cells strain (PC-3), human colon cancer cell strain (HCT-116) and human breast cancer cell strain (MCF-7) are with containing the DMEM perfect medium of 10% foetal calf serum, 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates at 5%CO 2, cultivate under 37 ℃ of conditions.Human lung carcinoma cell line (A549), people's chronic myelogenous leukemia cell strain (K562), person monocytic cell's leukemia cell line (Raji) and people's malignant melanoma cell strain (A375) are with containing the RPMI-1640 perfect medium of 10% foetal calf serum, 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates at 5%CO 2, under 37 ℃ of conditions.People's acute myeloid leukaemia cell strain (MV4-11) (annotate: MV4-11 is the FLT3-ITD mutant clone, and other cell strains all do not have the FLT3-ITD sudden change) is with containing the IMDM perfect medium of 10% foetal calf serum, 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates at 5%CO 2, under 37 ℃ of conditions.
2 experimental techniques and result
2.1 experimental technique (mtt assay)
Adjusting cell concn with complete culture solution is 1-2 * 10 4The cell suspension of individual/ml, be inoculated in 96 orifice plates, every hole 200 μ l cell suspensions, overnight incubation, handle cell with the 4-arylthio quinazoline derivant of gradient concentration respectively and (directly use the substratum suspendible cell that contains the different concns compound for suspension cell next day, and the 3-10 that its cell starting point concentration is an attached cell doubly), establish the negative control group and the isopyknic solvent control group that do not contain medicine simultaneously, DMSO concentration is 0.1%, and each dosage group is established 3 multiple holes, at 37 ℃, 5%CO 2Cultivate under the condition.After 48 hours, every hole adds 5mg/ml MTT reagent 20 μ l, continues to cultivate 2-4h, abandons supernatant, adds DMSO150 μ L again, vibration mixing 15min, and (λ=570nm) measure absorbancy (A) value (the A value is directly proportional with viable count) gets its mean value with microplate reader.Relative cell proliferation inhibition rate=(control group A 570-experimental group A570)/control group A 570 * 100%.Experiment repeats 3 times at least.Experimental data represents that with mean the data statistics data adopts the t check, and there is statistical significance P＜0.05 for difference.Below each compound on cell proliferation restraining effect all represent with IC50 or inhibiting rate.Detected result sees Table 2 and Fig. 2, Fig. 3 and Fig. 4.
2.2 experimental result
The on cell proliferation restraining effect of the compound of table 2 embodiment 1-20 on different tumor cell lines
Figure G2009102650624D00171
Figure G2009102650624D00181
Experimental result shows that most of cell strain MV4-11 to FLT3 sudden change high expression level has obvious growth to suppress IC among the compound 1-20 50Generally below 2M.And they are more weak or unrestraint is active to the restraining effect of other five kinds of tumor cell lines, show the cell strain MV4-11 selective restraining effect of these compounds to FLT3 sudden change high expression level.Show further also that by Fig. 2, Fig. 3, Fig. 4 along with drug level increases, cell inhibitory effect is obvious more, and obviously the FLT3 mutant cell had selectivity and a dose-dependently.

Claims (3)

1.一种4-芳硫基喹唑啉衍生物，其结构式如式I所示：1. a kind of 4-arylthioquinazoline derivatives, its structural formula is as shown in formula I:
Figure F2009102650624C00011
Figure F2009102650624C00011
 式中，R1为甲基、甲氧基乙基、N取代的乙胺基或丙胺基，R2为甲基、甲氧基乙基。X1＝X2＝CH时，R3为氢；X1＝N，X2＝CH时，R3为氢、甲基或4-CH3-5-CH2CONHR4(R4为取代或未取代的苯基或苄基)；X1＝X2＝N时，R3为氢、5-NHCONHR4(R4为取代或未取代的苯基)。In the formula, R1 is methyl, methoxyethyl, N-substituted ethylamino or propylamino, and R2 is methyl or methoxyethyl. When X 1 =X 2 =CH, R 3 is hydrogen; when X 1 =N, X 2 =CH, R 3 is hydrogen, methyl or 4-CH 3 -5-CH 2 CONHR 4 (R 4 is substituted or unsubstituted phenyl or benzyl); when X 1 =X 2 =N, R 3 is hydrogen, 5-NHCONHR 4 (R 4 is substituted or unsubstituted phenyl). 2.如权利要求1所述的衍生物I的制备方法，其反应方程式如下：2. the preparation method of derivative I as claimed in claim 1, its reaction equation is as follows:
Figure F2009102650624C00012
Figure F2009102650624C00012
 式中，R1为甲基、甲氧基乙基、N取代的乙胺基或丙胺基，R2为甲基、甲氧基乙基。X1＝X2＝CH时，R3为氢；X1＝N，X2＝CH时，R3为氢、甲基或4-CH3-5-CH2CONHR4(R4为取代或未取代的苯基或苄基)；X1＝X2＝N时，R3为氢、5-NHCONHR4(R4为取代或未取代的苯基)。In the formula, R1 is methyl, methoxyethyl, N-substituted ethylamino or propylamino, and R2 is methyl or methoxyethyl. When X 1 =X 2 =CH, R 3 is hydrogen; when X 1 =N, X 2 =CH, R 3 is hydrogen, methyl or 4-CH 3 -5-CH 2 CONHR 4 (R 4 is substituted or unsubstituted phenyl or benzyl); when X 1 =X 2 =N, R 3 is hydrogen, 5-NHCONHR 4 (R 4 is substituted or unsubstituted phenyl). 3.一种式I衍生物作为活性成分在制备用于治疗肿瘤的药物组合物的用途，其特征在于添加药学上可接受的辅助性成分制备而成：3. The use of a derivative of formula I as an active ingredient in the preparation of a pharmaceutical composition for treating tumors, characterized in that it is prepared by adding pharmaceutically acceptable auxiliary ingredients:
Figure F2009102650624C00013
Figure F2009102650624C00013
 式中，R1为甲基、甲氧基乙基、N取代的乙胺基或丙胺基，R2为甲基、甲氧基乙基。X1＝X2＝CH时，R3为氢；X1＝N，X2＝CH时，R3为氢、甲基或4-CH3-5-CH2CONHR4(R4为取代或未取代的苯基或苄基)；X1＝X2＝N时，R3为氢、5-NHCONHR4(R4为取代或未取代的苯基)。In the formula, R1 is methyl, methoxyethyl, N-substituted ethylamino or propylamino, and R2 is methyl or methoxyethyl. When X 1 =X 2 =CH, R 3 is hydrogen; when X 1 =N, X 2 =CH, R 3 is hydrogen, methyl or 4-CH 3 -5-CH 2 CONHR 4 (R 4 is substituted or unsubstituted phenyl or benzyl); when X 1 =X 2 =N, R 3 is hydrogen, 5-NHCONHR 4 (R 4 is substituted or unsubstituted phenyl).
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103232401A (en) * 2013-04-12 2013-08-07 浙江工业大学 New synthetic method of 4-arylthio quinazoline compound shown in the formula (I)
WO2015077375A1 (en) 2013-11-20 2015-05-28 Signalchem Lifesciences Corp. Quinazoline derivatives as tam family kinase inhibitors
CN112209888A (en) * 2020-10-14 2021-01-12 河南中医药大学 4-arylmercapto quinazoline compound, preparation method and medical application

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103232401A (en) * 2013-04-12 2013-08-07 浙江工业大学 New synthetic method of 4-arylthio quinazoline compound shown in the formula (I)
CN103232401B (en) * 2013-04-12 2015-11-04 浙江工业大学 A kind of synthetic method of 4-arylthioquinazoline compound
WO2015077375A1 (en) 2013-11-20 2015-05-28 Signalchem Lifesciences Corp. Quinazoline derivatives as tam family kinase inhibitors
CN112209888A (en) * 2020-10-14 2021-01-12 河南中医药大学 4-arylmercapto quinazoline compound, preparation method and medical application
CN112209888B (en) * 2020-10-14 2024-02-02 河南中医药大学 4-arylmercapto quinazoline compound, preparation method and medical application

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