CN106188041A - [1,2,4]三唑并[1,5‑a]吡啶衍生物 - Google Patents
[1,2,4]三唑并[1,5‑a]吡啶衍生物 Download PDFInfo
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- CN106188041A CN106188041A CN201610514454.XA CN201610514454A CN106188041A CN 106188041 A CN106188041 A CN 106188041A CN 201610514454 A CN201610514454 A CN 201610514454A CN 106188041 A CN106188041 A CN 106188041A
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- LENLQGBLVGGAMF-UHFFFAOYSA-N tributyl([1,2,4]triazolo[1,5-a]pyridin-6-yl)stannane Chemical compound C1=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=NN21 LENLQGBLVGGAMF-UHFFFAOYSA-N 0.000 title abstract description 13
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 12
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
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- 239000000047 product Substances 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
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- WEKACLANHIIGOO-UHFFFAOYSA-N C(C(C=C1)=CC=C1N1N=CN=C1)N1CCOCC1 Chemical compound C(C(C=C1)=CC=C1N1N=CN=C1)N1CCOCC1 WEKACLANHIIGOO-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
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- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
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- FHIVAFMUCKRCQO-UHFFFAOYSA-N diazinon Chemical compound CCOP(=S)(OCC)OC1=CC(C)=NC(C(C)C)=N1 FHIVAFMUCKRCQO-UHFFFAOYSA-N 0.000 description 2
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- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 1
- HHIZISRHAQPAMY-UHFFFAOYSA-N 5-bromo-1h-1,2,4-triazole Chemical compound BrC1=NC=NN1 HHIZISRHAQPAMY-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241001044369 Amphion Species 0.000 description 1
- JYNQKCFJPQEXSL-UHFFFAOYSA-N CCC(C(C)C)N Chemical compound CCC(C(C)C)N JYNQKCFJPQEXSL-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 101000905241 Mus musculus Heart- and neural crest derivatives-expressed protein 1 Proteins 0.000 description 1
- UAVNOTTVADRBEI-UHFFFAOYSA-N NN1N=C(C2=CC=C(CN3CCOCC3)C=C2)N=C1 Chemical compound NN1N=C(C2=CC=C(CN3CCOCC3)C=C2)N=C1 UAVNOTTVADRBEI-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
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- 239000003513 alkali Substances 0.000 description 1
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- 125000000217 alkyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- -1 and is dried Substances 0.000 description 1
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- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical group O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了式(Ⅰ)所示的[1,2,4]三唑并[1,5‑a]吡啶衍生物。本发明提供的化合物对肿瘤细胞具有显著的抑制作用,可以用于预防和/或治疗肿瘤相关疾病,尤其是肺癌,具有广泛的应用前景。
Description
技术领域
本发明涉及[1,2,4]三唑并[1,5-a]吡啶衍生物。
背景技术
目前,肺癌是发病率和死亡率增长最快,对人群健康和生命威胁最大的恶性肿瘤之一。
然而,尽管市场上已经存在多种治疗肺癌的药物,但是都存在着各种缺陷,例如生物利用度不高、专属性不强、毒副作用大等问题。而这些缺陷,往往是由于化合物本身的结构特点及其作用靶标所带来的,难以在进一步的研究开发中克服。
因此,本领域人员都希望合成出结构各异的多种化合物以及探索到新的作用靶标以克服前述缺陷。
发明内容
为解决上述问题,本发明提供了一种全新结构的[1,2,4]三唑并[1,5-a]吡啶衍生物。
本发明提供了式(Ⅰ)所示的化合物或其药学上可接受的盐、或其溶剂合物:
其中,
R1表示卤原子、-CN、-OH、-NH2、-NH(C1-C4烷基)或者-N(C1-C4烷基)2;
R2和R3分别独立地表示无或其所连接环上的一个或多个卤原子,或一个或多个C1-C4烷基;
R4和R5分别独立地表示氢、卤原子或C1-C4烷基;或者,R4和R5与所其连接的氮原子一起形成包含0-1个氧原子或硫原子的5-7元杂环,所述杂环上的碳原子任选进一步被C1-C4烷基所取代;
n表示1、2或3。
进一步地,R1表示Cl、Br、I、-CN或-NH2。
进一步地,R2和R3均表示无。
进一步地,R4和R5与所其连接的氮原子一起形成包含0-1个氧原子的5-7元杂环。
进一步地,所述杂环为吗啉环。
进一步地,n为1。
进一步地,所述化合物为如下化合物之一:
本发明还提供了一种制备所述式(Ⅰ)所述化合物的方法,包括下述步骤:
其中,R1表示Cl、Br或I,R2-R5如权利要求1中所定义,且R4和R5不同时为氢;
以式(Ⅰa)所示化合物为原料,经氨基重氮化反应,卤代反应后制备得到式(Ⅰb)所示化合物;
或者,
R1表示氰基,R2-R5如权利要求1中所定义,
以式(Ⅰc)所示化合物为原料,与CuCN反应制备得到式(Ⅰd)所示化合物。
本发明还提供了所述的化合物、或其溶剂合物、或其药学上可接受的盐在制备JAK激酶抑制剂类药物中的用途。
本发明还提供了所述的化合物、或其溶剂合物、或其药学上可接受的盐在制备抗肿瘤药物中的用途。
进一步地,所述药物是治疗肺癌的药物。
进一步地,所述肺癌是非小细胞肺癌。
本发明还提供了一种药物组合物,它是以前述的化合物、或其溶剂合物、或其药学上可接受的盐为活性成分,加上药学上可接受的辅料制备而成的制剂。
本发明中,所述C1-C4的烷基是指C1、C2、C3、C4的烷基,即具有1~4个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基等等。
本发明中,“治疗”也包括复发性(relapse)预防或阶段性(phase)预防,以及急性或慢性体征、症状和/或功能失常的治疗。治疗可以是对症治疗,例如抑制症状。它可以在短期内实现,在中期内调整,或者可以说是长期治疗,例如在维持疗法里面。
本发明中,“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
本发明中,“盐”是将化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
试验结果显示,本发明的化合物对肺癌细胞株A549和H1299具有明显的抑制作用,具有广阔的市场前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
下述实施例所用试剂来源如下:
实施例1 2-氨基-5-[4-(4-吗啉基甲基)苯基]-[1,2,4]三唑并[1,5-a]吡啶(化合物1)的制备
在25ml圆底烧瓶中加入2ml水、10ml 1,4-二氧六环,充分搅拌混匀,再依次加入4-(4-吗啉甲基)苯硼酸频哪酯2.85g(9.40mmol)、K2CO3 1.30g(0.63mmol)、PdCl2dppf0.34g(0.46mmol)、5-溴-[1,2,4]三唑[1,5-a]吡啶-2-胺2g(9.29mmol),室温搅拌10分钟,反应液呈黄色;将反应瓶转移至油浴锅90℃回流,1小时后反应液由黄变黑,继续反应3-5小时,TLC检测至反应结束(展开剂:5%CH3OH/CH2Cl2);然后想烧瓶中加入10ml水终止反应,转移至50ml烧杯,CH2Cl2萃取(3×50ml),合并有机相,加入1g无水硫酸镁,过滤,浓缩,干燥,硅胶层析柱分离(硅胶10g,洗脱:0%→2.0%CH3OH/CH2Cl2)。产物为淡黄色固体,产量及收率:2.65g(92%)。
结构表征数据如下:
m/z calcd for[M+H]+,309.195;found,309.19.
1H NMRδ7.87(d,J=8.1Hz,2H),7.51(d,J=8.0Hz,2H),7.47(dd,J=8.5,7.4Hz,1H),7.40(d,J=8.7Hz,1H),6.90(d,J=7.2Hz,1H),4.59(s,2H),3.76(t,J=4.4Hz,4H),3.59(s,2H),2.52(s,4H).
13C NMR(600MHz,CDCl3):δ53.68,63.06,66.97,112.16,112.29,128.86,129.22,129.28,131.61,139.84,152.03,164.84.
实施例2 2-碘-5-[4-(4-吗啉基甲基)苯基]-[1,2,4]三唑并[1,5-a]吡啶(化合物2)的制备
在25mL圆底烧瓶中加入2-胺-5-[4-(4-吗啉基甲基)苯基]-[1,2,4]三唑并[1,5-a]吡啶100mg(0.32mmol)和8mL乙腈,待底物室温搅拌溶解后,加入亚硝酸钠500mg(7.25mmol),搅拌1分钟,再缓慢滴加由0.5mL 45%的HI溶液和2mL乙腈溶液配制的混合溶液,有红棕色气体生成,室温搅拌2小时后,再加入相同量的HI乙腈溶液继续反应2-3小时,TCL监测指反应结束(展开剂:5%CH3OH/CH2Cl2)。将反应液转移至50mL烧杯,用K2CO3溶液(1g/8mL)调节至中性,溶液颜色由黑色变为黄色。CH2Cl2萃取有机相(3×20mL),合并有机相,加入1g无水硫酸镁,过滤,浓缩,干燥,硅胶层析柱分离(硅胶10g,洗脱:0%→1.0%CH3OH/CH2Cl2)。产物为淡黄色固体,产量及收率:101mg(75%)。
结构表征数据如下:
m/z calcd for[M+H]+,421.0525;found,421.0548.
1H NMR(600MHz,CDCl3):δ7.83(d,J=8.2Hz,2H),7.61(dd,J=8.9,1.2Hz,1H),7.52(dd,J=8.8,7.2Hz,1H),7.46(d,J=7.9Hz,2H),7.01(dd,J=7.3,1.2Hz,1H),3.69(s,4H),3.53(s,2H),2.45(s,4H).
13C NMR(600MHz,CDCl3):δ53.67,63.00,66.95,113.97,114.00,116.39,129.06,129.37,130.28,140.45,153.04.
实施例3 2-氰基-5-[4-(4-吗啉基甲基)苯基]-[1,2,4]三唑并[1,5-a]吡啶(化合物3)的制备
在25mL圆底烧瓶中依次加入40mg CuCN(0.45mmol)、5mL吡啶和2-碘-5-[4-(4-吗啉基甲基)苯基]-[1,2,4]三唑并[1,5-a]吡啶100mg(0.24mmol),室温搅拌,溶液呈浅黄色乳浊液液;烧瓶转移至油浴锅,110℃回流1.5小时;10mL CH2Cl2稀释反应液,随后分别用1mol/L NH3·H2O(2×5mL)、0.5mol/L HCl(3×10mL)处理反应液,CH2Cl2萃取,合并有机层,加入1g无水硫酸镁,过滤,浓缩,干燥,硅胶层析柱分离(硅胶10g,洗脱:0%→1.0%CH3OH/CH2Cl2)。产物为淡黄色稠状体,产量及收率:35mg(46%)。
结构表征数据如下:
m/z calcd for[M+H]+,320.1512;found,320.1609.
1H NMR(600MHz,CDCl3):δ7.89(d,J=7.8Hz,2H),7.83(d,J=8.9Hz,1H),7.76(dd,J=8.9,7.2Hz,1H),7.62(d,J=8.1Hz,2H),7.31(dd,J=7.5,1.8Hz,1H),3.82(s,4H),3.73(s,2H),2.63(s,4H).
实施例3 2-溴-5-[4-(4-吗啉基甲基)苯基]-[1,2,4]三唑并[1,5-a]吡啶(化合物4)的制备
在25mL圆底烧瓶中加入2-胺-5-[4-(4-吗啉基甲基)苯基]-[1,2,4]三唑并[1,5-a]吡啶150mg(0.48mmol)和10mL乙腈,冰浴搅拌溶解,加入亚硝酸钠500mg(7.25mmol),搅拌1分钟,再缓慢滴加由0.5mL 47%的HBr溶液和2mL乙腈溶液配制的混合溶液,搅拌反应2-3分钟,TCL监测指反应结束(展开剂:5%CH3OH/CH2Cl2)。将反应液转移至50mL烧杯,用K2CO3溶液(1g/8mL)调节至中性。CH2Cl2萃取有机相(3×20mL),合并有机相,加入1g无水硫酸镁,过滤,浓缩,干燥,硅胶层析柱分离(硅胶10g,洗脱:0%→3.0%CH3OH/CH2Cl2)。产物为黄棕色粘稠固体,产量及收率:165mg(91%)。
结构表征数据如下:
m/z calcd for[M+H]+,373.0664;found,373.0599.
1H NMR(600MHz,CDCl3):δ7.89(d,J=8.2Hz,2H),7.66(ddd,J=16.0,8.9,4.2Hz,2H),7.53(d,J=8.1Hz,2H),7.13(dd,J=7.1,1.4Hz,1H),3.75(t,J=4.6Hz,4H),3.60(s,2H),2.52(s,4H).
13C NMR(600MHz,CDCl3):δ29.70,53.68,63.01,63.97,114.16,114.21,129.02,129.37, 130.38,130.60,140.76,144.66,152.52.
实施例5 2-氯-5-[4-(4-吗啉基甲基)苯基]-[1,2,4]三唑并[1,5-a]吡啶(化合物5)的制备
在25mL圆底烧瓶中加入2-胺-5-[4-(4-吗啉基甲基)苯基]-[1,2,4]三唑并[1,5-a]吡啶250mg(0.80mmol)和8mL乙腈,冰浴搅拌溶解,加入亚硝酸钠50mg(0.73mmol),搅拌1分钟,再缓慢滴加由0.2mL 37%的HCl水溶液,搅拌反应10-15分钟,有白色重氮盐沉淀生成,TCL监测至原料彻底消失(展开剂:5%CH3OH/CH2Cl2);再加入0.5mL37%的HCl水溶液溶解重氮盐,溶液显黄褐色透明液,将烧瓶移至油浴锅80℃回流1.5-2小时,观测至无气体生成;将反应液转移至50mL烧杯,加入5mL水稀释反应液,再用饱和Na2CO3溶液调节PH至中性。CH2Cl2萃取有机相(3×20mL),合并有机相,加入1g无水硫酸镁,过滤,浓缩,干燥,硅胶层析柱分离(硅胶12g,洗脱:0%→2%CH3OH/CH2Cl2)。产物为黄绿色固体,产量及收率:220mg(83%)。
结构表征数据如下:
m/z calcd for[M+H]+,329.1169;found,329.1156.
1H NMR(600MHz,CDCl3):δ7.88(d,J=8.1Hz,2H),7.69–7.63(m,2H),7.53(d,J=8.0Hz,2H),7.15(dd,J=5.7,2.8Hz,1H),3.75(t,J=4.4Hz,4H),3.60(s,2H),2.52(s,4H).
13C NMR(600MHz,CDCl3):δ29.70,53.67,63.00,63.97,114.26,114.28,129.00,129.38,130.36,130.66,140.85,152.12,156.03.
实施例6 2-氟-5-[4-(4-吗啉基甲基)苯基]-[1,2,4]三唑并[1,5-a]吡啶(化合物6)的制备
在25mL塑料烧杯中加入2-胺-5-[4-(4-吗啉基甲基)苯基]-[1,2,4]三唑并[1,5-a]吡啶 100mg(0.32mmol)和5mL吡啶,冰浴搅拌溶解,加入亚硝酸钠(50mg,0.73mmol)的水溶液1mL,冰浴搅拌2分钟,再缓慢滴加由0.2mL 40%的HF水溶液,搅拌反应30分钟后,移至室温搅拌24小时,TCL监测至产物不再变化(展开剂:5%CH3OH/CH2Cl2);加入5mL水稀释反应液,再用饱和K2CO3溶液调节至中性。CH2Cl2萃取有机相(3×20mL),合并有机相,加入1g无水硫酸镁,过滤,浓缩,干燥,硅胶层析柱分离(硅胶6g,洗脱:0%→2%CH3OH/CH2Cl2)。产物为红棕色固体,产量及收率:10mg(10%)。
实施例7本发明化合物的药效试验
采用MTT检测法,其为黄色化合物,是一种接受氢离子的染料,可作用于活细胞线粒体中的呼吸链,在琥珀酸脱氢酶和细胞色素C的作用下tetrazolium环开裂,生成蓝色的formanzan结晶,formazan结晶的生成量仅与活细胞数目成正比,还原生成的formanzan结晶可在二甲亚砜(DMSO)中溶解,利用酶标仪测定490nm处的光密度值(OD)值,即可反应出活细胞数量。
一、实验步骤
肺癌细胞株:A549和H1299。
实验用品:肺癌细胞株、细胞培养所需工具、MTT以及化合物母液为10mmol/L。
1、具体方法。
(3-1)复苏A549和H1299细胞,待状态良好时,即传代一次后细胞长到80%左右(即对数生长期)进行铺板(96孔板)。
(3-2)首先,收集细胞,通过计数板调整细胞悬液浓度,以每孔1000—10000个细胞接种到96孔板,具体每孔的细胞数依据不同细胞的生长速度和药物作用时间来确定,549铺5000和1299铺5000,每孔200ul(100ul的细胞悬液+100ul的不同浓度梯度的药物稀释液),边孔(36个)加200ul的双无培养基,(为了防止边缘效应)。
(3-3)铺板加药后,根据24h、48h、72h处理,然后呈色,每孔加含20ulMTT溶液(5mg/mL)的培养液200ul,继续培养1-4h,终止培养,小心吸弃孔内培养上清液,对于悬浮细胞需要离心后再吸弃孔内的培养上清液。每孔加150ulDMSO,在摇床上震荡15~20min,使结晶物充分溶解。
(3-4)比色:在酶标仪上测定,选择490或者570nm波长,从而测定各孔的光吸收值,记录结果。
(3-5)计算
抑制率=(对照-给药)/对照×100%
IC50(半数抑制浓度)时可根据不同浓度的抑制率用spass软件求算。
三、实验结果
A549每孔铺5000,作用48h,结果如下表1所示:
表1本发明化合物1~3对A549的抑制作用
H1299每孔铺5000,作用48h,结果如下表2所示:
表2本发明化合物1~3对H1299的抑制作用
综上所述,本发明提供的化合物对肿瘤细胞具有显著的抑制作用,可以用于预防和/或治疗肿瘤相关疾病,尤其是肺癌,具有广泛的应用前景。
Claims (10)
1.式(Ⅰ)所示的化合物或其药学上可接受的盐、或其溶剂合物:
其中,
R1表示卤原子、-CN、-OH、-NH2、-NH(C1-C4烷基)或者-N(C1-C4烷基)2;
R2和R3分别独立地表示无或其所连接环上的一个或多个卤原子,或一个或多个C1-C4烷基;
R4和R5分别独立地表示氢、卤原子或C1-C4烷基;或者,R4和R5与所其连接的氮原子一起形成包含0-1个氧原子或硫原子的5-7元杂环,所述杂环上的碳原子任选进一步被C1-C4烷基所取代;
n表示1、2或3。
2.根据权利要求1所述的化合物,其特征在于:R1表示Cl、Br、I、-CN或-NH2。
3.根据权利要求1或2所述的化合物,其特征在于:R2和R3均表示无。
4.根据权利要求1-3任一项所述的化合物,其特征在于:R4和R5与所其连接的氮原子一起形成包含0-1个氧原子的5-7元杂环。
5.根据权利要求4所述的化合物,其特征在于:所述杂环为吗啉环。
6.根据权利要求1-5任一项所述的化合物,其特征在于:n为1。
7.根据权利要求1所述的化合物,所述化合物为如下化合物之一:
8.一种制备权利要求1所述式(Ⅰ)化合物的方法,其特征在于:包括下述步骤:
其中,R1表示Cl、Br或I,R2-R5如权利要求1中所定义,且R4和R5不同时为氢;
以式(Ⅰa)所示化合物为原料,经氨基重氮化反应,卤代反应后制备得到式(Ⅰb)所示化合物;
或者,
R1表示氰基,R2-R5如权利要求1中所定义,
以式(Ⅰc)所示化合物为原料,与CuCN反应制备得到式(Ⅰd)所示化合物。
9.权利要求1-7任一项所述的化合物、或其溶剂合物、或其药学上可接受的盐在制备抗肿瘤药物中的用途;优选的,所述药物是治疗肺癌的药物;更优选的,所述肺癌是非小细胞肺癌。
10.一种药物组合物,其特征在于:它是以权利要求1-7任一项所述的化合物、或其溶剂合物、或其药学上可接受的盐为活性成分,加上药学上可接受的辅料制备而成的制剂。
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CN108516976A (zh) * | 2018-04-27 | 2018-09-11 | 四川大学华西医院 | 一种7-脱氮嘌呤衍生物及其四元环超分子结构 |
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