CN1314351A - 喹唑啉酮合成方法及具有抗癌作用的一类喹唑啉酮化合物 - Google Patents
喹唑啉酮合成方法及具有抗癌作用的一类喹唑啉酮化合物 Download PDFInfo
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- 230000002194 synthesizing effect Effects 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 10
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical class NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 5
- 239000000463 material Substances 0.000 claims abstract description 3
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 claims description 15
- 230000000259 anti-tumor effect Effects 0.000 claims description 10
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- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 238000006901 Niementowski synthesis reaction Methods 0.000 abstract description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract 2
- 239000000243 solution Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 235000015097 nutrients Nutrition 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 2
- 238000011047 acute toxicity test Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- KDNIOKSLVIGAAN-UHFFFAOYSA-N 2-sulfamoylbenzoic acid Chemical class NS(=O)(=O)C1=CC=CC=C1C(O)=O KDNIOKSLVIGAAN-UHFFFAOYSA-N 0.000 description 1
- RUCHWTKMOWXHLU-UHFFFAOYSA-N 5-nitroanthranilic acid Chemical compound NC1=CC=C([N+]([O-])=O)C=C1C(O)=O RUCHWTKMOWXHLU-UHFFFAOYSA-N 0.000 description 1
- MOBNCKURXDGQCB-UHFFFAOYSA-N 6-nitro-1h-quinazolin-4-one Chemical compound N1C=NC(=O)C2=CC([N+](=O)[O-])=CC=C21 MOBNCKURXDGQCB-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
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- 244000309466 calf Species 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- UTVVREMVDJTZAC-UHFFFAOYSA-N furan-2-amine Chemical compound NC1=CC=CO1 UTVVREMVDJTZAC-UHFFFAOYSA-N 0.000 description 1
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- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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Abstract
本发明涉及喹唑啉酮合成方法及具有抗癌作用的一类喹唑啉酮化合物。本发明喹唑啉酮合成方法,用如化合物通式(1)或(2)所示的邻氨基苯甲酸衍生物作为原料,加入到过量甲酰胺中,滴加三氯氧磷作为脱水剂,反应温度为0℃～150℃,得喹唑啉酮。具有抗癌作用的喹唑啉酮化合物为6,7－二取代基－1－呋喃甲基－4(1H)喹唑啉酮。本发明在v.Niementowski反应的基础上,加入脱水剂,可使反应条件较为温和。
Description
本发明涉及一种喹唑啉酮合成方法及具有抗癌作用的一类喹唑啉酮化合物。
早在1895年v.Niementowski就报道了合成喹唑啉酮的方法[v.Niementowski,J.prakt.chem.,[2]51,564(1895)]，反应式为：
该反应的缺点是反应温度高，当苯环上或氨基上有取代基时，反应所要求的温度更高，有些情况下反应不能进行，例如：
本发明的目的是提出一种喹唑啉酮合成方法及具有抗癌作用的一类喹唑啉酮化合物。
本发明的喹唑啉酮合成方法，用如化合物通式(1)或(2)所示的邻氨基苯甲酸衍生物作为原料，加入到过量甲酰胺中，使原料溶解，搅拌下滴加过量三氯氧磷作为脱水剂，反应温度为0℃～150℃，反应液倒入冰水中，待沉淀完全折出，过滤，重结晶，得喹唑啉酮，
化合物通式(1)为：
化合物通式(2)为：反应式为
R1、R2、R3可以是氢、吸电子及供电子基团，如硝基、磺酰胺基、卤素、腈基、甲基、甲氧基，R4可以是C1～C4的烷基、芳香基、呋喃甲基。
具有抗癌作用的一类喹唑啉酮化合物为6,7-二取代基-1-呋喃甲基-4(1H)喹唑啉酮，该类化合物的通式(3)如下：
R5可以是-F,-Cl,-Br,-I,-CF3,-CN,-N(CN)2,-C(CN)3,R6可以是-SO2NH2,-COOH,-SO3H,-PO(OH)NH2,-PO(OH)OEt,-CONHCN。
本发明在v.Niementowski反应的基础上，可以用苯环上或氨基上带有取代基的邻氨基苯甲酸作为原料合成喹唑啉酮，加入脱水剂，可使反应条件较为温和。本发明提出并合成了一类具有抗癌作用的喹唑啉酮化合物。
实施例1：
1-呋喃甲基-6-磺酰胺基-7-氯-4-(1H)喹唑啉酮的合成方法：将2-呋喃甲胺基-4-氯-5磺酰胺基苯甲酸10克溶于60毫升甲酰胺中，冷却至0℃，于搅拌下滴加POCl3(三氯氧磷)15毫升，滴毕，继续搅拌40分钟，将反应液倒入冰水中，等沉淀完全折出，过滤，得粗品8克，用15％甲酰胺水溶液重结晶即得纯品，熔点mp.208℃～210℃。
实施例2：
6-硝基-4(3H)喹唑啉酮的合成方法：取2-氨基-5-硝基苯甲酸20克加入到150毫升甲酰胺中，85℃水浴加热，至原料完全溶解，于激烈搅拌下滴加三氯氧磷40毫升，温度控制在85℃～90℃，滴毕，继续搅拌30分钟，冷却到室温，将反应液倒入冰水中，等沉淀完全折出，过滤，冰水洗涤得粗品18.6克，产率60.4％，水重结晶，熔点mp.275℃～276℃。
实施例3：
1-呋喃甲基-6-磺酰胺基-7-氯-4-(1H)喹唑啉酮的抗癌作用与急性毒性试验：
(1)抗癌作用试验，将SMMC-7721肝癌细胞接种于96孔培养板，每孔103～104个细胞，每孔体积200微升，培养液为含10％胎牛血清的RPMI1640培养液，待细胞贴壁后，弃去培养液，加入含药物1-呋喃甲基-6-磺酰胺基-7-氯-4-(1H)喹唑啉酮的培养液200微升，每6孔为一药物剂量组，药物剂量范围为0.001μmol/l～50μmol/l。并设空白对照，将培养板移入二氧化碳贮箱中，在37℃,5％CO2及饱和湿度条件下，培养3天后，每孔加入MTT溶液(5mg/ml)20微升，37℃继续孵育4小时，终止培养，小心吸弃孔内培养上清液，每孔加入150微升DMSO(二甲基亚砜)，振荡10分钟，选择490nm，在酶联免疫检测仪上测定各孔光吸收值，记录结果。经计算1-呋喃甲基-6-磺酰胺基-7-氯-4-(1H)喹唑啉酮对SMMC-7721的IC50为15μmol/l。40μmol/l时细胞全部死亡。
(2)急性毒性试验，18～22克昆明种小鼠50只，随机分为5组，每组10只，以0.2ml/10g的容量分别一次性灌胃给予50只小鼠，剂量分别为0.8mg/Kg,8mg/Kg,80mg/Kg,320mg/Kg,800mg/Kg，结果，在给予剂量达800mg/Kg时，小鼠亦未见死亡，全部小鼠经尸体解剖后肉眼观察，心、肝、脾、肺、肾等主要脏器未见明显病理改变。
参见南京药学院主编《药物化学》1978年8月第一版51页，根据生物电子等排原理，在具有生物活性或代谢物中的某些原子或基团，被其电子数和电子排列相同或相似的原子或基团取代(交换)时，仍能保持原有的活性(相对的)。如李正化主编《药物化学》第三版，人民卫生出版社，1993,97～98页，例举了一些存在生物电子等排现象，可相互更换的基团，本发明中具有抗癌作用的1-呋喃甲基-6-磺酰胺基-7-氯-4-(1H)喹唑啉酮中的-SO2NH2取代基可与下列基团互换：-COOH,-SO3H,-PO(OH)NH2,-PO(OH)OEt,-CONHCN,其中-Cl取代基可与下列基团互换：-F,-Br,-I,-CF3,-CN,-N(CN)2,-C(CN)3，因此6,7-二取代基-1-呋喃甲基-4(1H)喹唑啉酮应具有抗癌作用，该类化合物的通式(3)如下：
R5可以是-F,-Cl,-Br,-I,-CF3,-CN,-N(CN)2,-C(CN)3,R6可以是-SO2NH2,-COOH,-SO3H,-PO(OH)NH2,-PO(OH)OEt,-CONHCN。
Claims (2)
1、喹唑啉酮合成方法，用如化合物通式(1)或(2)所示的邻氨基苯甲酸衍生物作为原料，加入到过量甲酰胺中，使原料溶解，其特征在于：搅拌下滴加过量三氯氧磷作为脱水剂，反应温度为0℃～150℃，反应液倒入冰水中，待沉淀完全折出，过滤，重结晶，得喹唑啉酮，
化合物通式(1)为：
化合物通式(2)为：
反应式为
其中R1、R2、R3可以是氢、吸电子及供电子基团，如硝基、磺酰胺基、卤素、腈基、甲基、甲氧基，R4可以是C1～C4的烷基、芳香基、呋喃甲基。
2、具有抗癌作用的一类喹唑啉酮化合物，其特征在于：该类化合物为6,7-二取代基-1-呋喃甲基-4(1H)喹唑啉酮，该类化合物的通式(3)如下：
R5可以是-F,-Cl,-Br,-I,-CF3,-CN,-N(CN)2,-C(CN)3,R6可以是-SO2NH2,-COOH,-SO3H,-PO(OH)NH2,-PO(OH)OEt,-CONHCN。
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| Application Number | Priority Date | Filing Date | Title |
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| CN01106796A CN1314351A (zh) | 2001-03-22 | 2001-03-22 | 喹唑啉酮合成方法及具有抗癌作用的一类喹唑啉酮化合物 |
| PCT/CN2002/000185 WO2002096889A1 (en) | 2001-03-22 | 2002-03-22 | Quinazolinone compound and method of preparation and use thereof in preparing anticancerous medicament |
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| CN01106796A CN1314351A (zh) | 2001-03-22 | 2001-03-22 | 喹唑啉酮合成方法及具有抗癌作用的一类喹唑啉酮化合物 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102757661A (zh) * | 2012-08-03 | 2012-10-31 | 康爱特维迅（蓬莱）化学有限公司 | 一种4-氯-2-取代喹唑啉酮制备方法及其应用 |
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| CA2669117A1 (en) | 2006-10-26 | 2008-05-02 | Gary A. Flynn | Aquaporin modulators and methods of using them for the treatment of edema and fluid imbalance |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3825542A (en) * | 1972-10-12 | 1974-07-23 | Merck & Co Inc | 2-hetro substituted 4(3h)-quinazolinones |
| US3816631A (en) * | 1972-10-12 | 1974-06-11 | Merck & Co Inc | 6-sulfamoyl-7-substituted-4(3h)-quinazolinones for decreasing uric acid concentration |
| RU2214405C2 (ru) * | 1998-02-18 | 2003-10-20 | НьюроСёрч А/С | Новые соединения и их применение в качестве положительных модуляторов амра-рецепторов |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102757661A (zh) * | 2012-08-03 | 2012-10-31 | 康爱特维迅（蓬莱）化学有限公司 | 一种4-氯-2-取代喹唑啉酮制备方法及其应用 |
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