新型喹唑啉类衍生物合成及生物活性研究
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摘要
近几年来，喹唑啉类农药和医药表现出良好的生物活性，成为化学界和生物学界学者们研究的热点之一。在医药方面，其对EGF受体(EGFR)产生抑制作用，进而表现出抗癌活性。此外，喹唑啉类化合物还具有抗疟、抗肿瘤和抗HIV活性；还可用于治疗良性前列腺增生和肥大；作为α-受体阻滞剂，在心血管疾病的防治中占据较为重要的作用；可预防动脉粥样硬化和冠心病。农药方面，特别是喹唑啉肟醚类化合物具有抗烟草花叶病毒(TMV)、黄瓜花叶病毒(CMV)的活性及抗植物病菌活性。
为了创制高效的抗癌或抑菌活性的药物，寻找治疗癌症或植物病菌的新靶点，指导开发治疗癌症或抗植物病菌的新靶标药物，本论文以PD 153035为先导化合物，设计合成了四类新型喹唑啉类化合物，进行医药和农药的联合开发。对四类目标化合物的合成方法进行了研究：(Ⅰ)第一类：以邻氨基苯甲酸为原料，经甲酰胺闭环，五氯化磷和三氯氧磷氯化，经芳香胺的4-位胺化反应，合成了N-取代-4-胺基喹唑啉类化合物15个(编号：Ⅰ)，经IR、MS、~1H NMR、~(13)C NMR和元素分析确证了化合物结构。(Ⅱ)第二类：从邻氨基苯甲酸出发，经单氯化或双氯化，合成5-氯2-氨基苯甲酸或3，5-二氯-2-氨基苯甲酸，经甲酰胺闭环，五氯化磷和三氯氧磷氯化，经芳香胺的4-位胺化反应，合成了氯代-N-取代4-胺基喹唑啉类化合物6个(编号：Ⅱ)，经IR、MS、~1H NMR、~(13)C NMR和元素分析确证了化合物结构。(Ⅲ)第三类：从没食子酸出发，经硫酸二甲酯醚化、甲醇酯化、硝酸硝化、碱性水解、二氯化锡还原、甲酰胺闭环、三氯化磷氯化、芳香胺的4-位胺化等八步骤，合成了6，7，8-三甲氧基-4-胺基取代喹唑啉类化合物19个(编号：Ⅲ)，经IR、~1H NMR、~(13)C NMR和元素分析确证了化合物结构。(Ⅳ)第四类：以4-氯代喹唑啉类化合物与芳香硫酚在碳酸钾存在下，丙酮中回流反应，合成了S-取代-4-硫醚类喹唑啉化合物7个(编号：Ⅳ)，经IR、~1H NMR、~(13)C NMR和元素分析确证了化合物结构。共合成了目标化合物47个。
对中间体和目标化合物的合成方法进行了合成条件筛选，特别是对关键中间体2-氨基-3，4，5-三甲氧基苯甲酸的合成方法进行了研究，另外还对2-甲基-6，7，8-三甲氧基喹唑啉-4-酮类化合物作了初步合成探讨。
采用微波辐射催化的绿色合成方法对部分化合物的胺化取代一步与传统的合成方法做了对比，结果表明，微波催化下能很好的促进胺化取代反应的进行，缩短了反应时间，提高了产率。从传统方法的反应时间12h缩短到20min，产率从24.4～51.3％提高到79.1～96.5％。
目标化合物及中间体采用生长速率法，以小麦赤霉病菌(Fusarium graminearum)、苹果腐烂病菌(Cytospora mandshurica)和辣椒枯萎病菌(Fusarium oxysporum)为测试对象，对目标化合物进行了初步抗植物病菌活性筛选。结果表明，部分目标化合物具有一定的抑菌活性，如化合物Ⅰ_(12)在药剂浓度为500μg／mL下，对小麦赤霉病菌、苹果腐烂病菌、辣椒枯萎病菌的抑制率分别为89.08％、72.21％、76.68％，与对照药剂恶霉灵在相同药剂浓度下的抑制率相当；目标化合物Ⅰ_1在药剂浓度为50μg／mL时，对小麦赤霉病菌的抑制率为47.94％，与对照药剂恶霉灵在相同药剂浓度下的抑制率相当，但在此药剂浓度下对苹果腐烂病菌和辣椒枯萎病菌的抑制率分别为：60.06％和71.99％，均优于对照药剂恶霉灵在相同药剂浓度下的抑制率：目标化合物Ⅳ_7在药剂浓度为50μg／mL下，对三种植物病菌的抑制率均优于对照药剂恶霉灵在相同药剂浓度下的抑制率。选定化合物Ⅳ_7对辣椒枯萎病菌，测定了对病菌的毒力(EC_(50))，建立了其线性回归方程，并对药剂处理后辣椒枯萎病菌体细胞中的可溶性蛋白含量、还原糖含量、几丁糖含量、几丁质酶活性进行了测定。结果表明，目标化合物Ⅳ_7对辣椒枯萎菌丝细胞的蛋白合成没有影响；在所设定的时间内，菌体内还原糖含量、几丁糖含量、几丁质酶活性一直低于对照。可以初步推测，目标化合物Ⅳ_7处理后对辣椒枯萎菌丝的作用方式为抑制菌丝体内几丁质酶的活性，进而影响菌体内还原糖含量、几丁糖含量，
In recent years, quinazoline compounds take on good biological activity in medicine and pesticide aspect. With synthesis and bioactivity study of quinazoline compounds developing, it's become one of a focuses studied field to chemicals and biological scholars. In medicine aspect, quinazoline compounds have inhibition on EGF receptor (EGFR), and then demonstrate the anticancer activation. In addition, quinazoline compounds still resist malaria and HIV, treat benign prostate gland hyperplasia and loose. In pesticide respect, quinazoline oxime ether compounds have good biological activity to anti-TMV, CMV and fungal.
In order to create more high-efficient anticancer medicine or fungicide, look for the new target which treats cancer or plant fungicide, guide and develop the new target medicine or pesticide to treat cancer or plant fungicide, regarding PD 153035 as the leading compound, we design and synthesize four kinds of new-type quinazoline compounds: (Ⅰ) Anthranilic acid taken as raw materials, cycled by fonnamide, chlorined by phosphorus pentachloride and phosphorus oxychloride, and then reacted with aryl amine to get N-substituted-4-aminequianzoline, 15 compounds are synthesized. The structure of all 15 compounds is characterized by IR, MS, ~1H NMR, ~(13)C NMR and elemental analysis. (Ⅱ) Take anthranilic acid as raw materials, we get 5-chlorine-2-aminobenzoic acid or 3,5-dichlorine-2-aminobenzoic acid after single chlorination or double chlorination. Then, the 5-chlorine-2-aminobenzoic acid or 3,5-dichlorine-2-aminobenzoic acid through cycled by formamide, chlorined by phosphorus pentachloride and phosphorus oxychloriden, and then reacted with aryl amine to get chlorine substituted N-substituted-4-aminequianzoline. Finally, 6 compounds are synthesized. The structure of all 6 compounds is characterized by IR, MS, ~1H NMR, ~(13)C NMR and elemental analysis. (Ⅲ) Gallic acid taken as raw materials, ethered by dimethyl sulfate, estered by menthol, nitrated by nitric acid, hydrolized in base, reduced by tin dichlorine, cycled by formamide, chlorined by phosphorus oxychloride, and reacted with aryl amine to get 6,7,8-trimethoxyl N-substituted-4-aminequianzoline, 19 compounds are synthesized. The structure of all 18 compounds is characterized by IR, ~1H NMR, ~(13)C NMR and elemental analysis. (Ⅳ) 4-Chlorine quinazoline compound reacted with sulphur aryl phenol in potassium carbonate and acetone, S-substituted-4-sulphur ether quinazoline are synthesized. The structure of all 7 compounds is characterized by IR, ~1H NMR, ~(13)C NMR and elemental analysis. 47 title compounds are synthesized in total.
The synthetic methods of the intermediate and title compounds are decrepit. Particularly, the synthesis of key intermediate 2-amino-3,4,5-trimethoxyl benzoic acid is explained in detail. In addition, we explore 2-methyI-6,7,8-trimethoxyl-quinazolin-4-one via the reaction of 2-amino-3,4,5-trimethoxyl benzoic acid with acetic anhydride, through 6,7,8-trimethoxy-2-methyl-benzo [d][1,3]oxazin-4-one.
The present new method of the formation of N-substituted-4-aminoquinazoline derivatives under microwave irradiation offers several advantages: faster reaction rates and higher yields, which involves a reduction of reaction time from 12 h to 20 min and a raise in yields from 24.4~51.3% to 79.1~96.5%, compared with the classical method.
Some title compounds and intermediate suppressing fungicide such as Fusarium graminearum, Cytospora mandshurica and Fusarium oxysporum is tested. The result indicates that some compounds have good activation of suppressing antifungal activities respectively such as I_(12). When the medicament concentration is 500 μg/mL, suppression ratio of the compound I_(12) is
为了创制高效的抗癌或抑菌活性的药物，寻找治疗癌症或植物病菌的新靶点，指导开发治疗癌症或抗植物病菌的新靶标药物，本论文以PD 153035为先导化合物，设计合成了四类新型喹唑啉类化合物，进行医药和农药的联合开发。对四类目标化合物的合成方法进行了研究：(Ⅰ)第一类：以邻氨基苯甲酸为原料，经甲酰胺闭环，五氯化磷和三氯氧磷氯化，经芳香胺的4-位胺化反应，合成了N-取代-4-胺基喹唑啉类化合物15个(编号：Ⅰ)，经IR、MS、~1H NMR、~(13)C NMR和元素分析确证了化合物结构。(Ⅱ)第二类：从邻氨基苯甲酸出发，经单氯化或双氯化，合成5-氯2-氨基苯甲酸或3，5-二氯-2-氨基苯甲酸，经甲酰胺闭环，五氯化磷和三氯氧磷氯化，经芳香胺的4-位胺化反应，合成了氯代-N-取代4-胺基喹唑啉类化合物6个(编号：Ⅱ)，经IR、MS、~1H NMR、~(13)C NMR和元素分析确证了化合物结构。(Ⅲ)第三类：从没食子酸出发，经硫酸二甲酯醚化、甲醇酯化、硝酸硝化、碱性水解、二氯化锡还原、甲酰胺闭环、三氯化磷氯化、芳香胺的4-位胺化等八步骤，合成了6，7，8-三甲氧基-4-胺基取代喹唑啉类化合物19个(编号：Ⅲ)，经IR、~1H NMR、~(13)C NMR和元素分析确证了化合物结构。(Ⅳ)第四类：以4-氯代喹唑啉类化合物与芳香硫酚在碳酸钾存在下，丙酮中回流反应，合成了S-取代-4-硫醚类喹唑啉化合物7个(编号：Ⅳ)，经IR、~1H NMR、~(13)C NMR和元素分析确证了化合物结构。共合成了目标化合物47个。
对中间体和目标化合物的合成方法进行了合成条件筛选，特别是对关键中间体2-氨基-3，4，5-三甲氧基苯甲酸的合成方法进行了研究，另外还对2-甲基-6，7，8-三甲氧基喹唑啉-4-酮类化合物作了初步合成探讨。
采用微波辐射催化的绿色合成方法对部分化合物的胺化取代一步与传统的合成方法做了对比，结果表明，微波催化下能很好的促进胺化取代反应的进行，缩短了反应时间，提高了产率。从传统方法的反应时间12h缩短到20min，产率从24.4～51.3％提高到79.1～96.5％。
目标化合物及中间体采用生长速率法，以小麦赤霉病菌(Fusarium graminearum)、苹果腐烂病菌(Cytospora mandshurica)和辣椒枯萎病菌(Fusarium oxysporum)为测试对象，对目标化合物进行了初步抗植物病菌活性筛选。结果表明，部分目标化合物具有一定的抑菌活性，如化合物Ⅰ_(12)在药剂浓度为500μg／mL下，对小麦赤霉病菌、苹果腐烂病菌、辣椒枯萎病菌的抑制率分别为89.08％、72.21％、76.68％，与对照药剂恶霉灵在相同药剂浓度下的抑制率相当；目标化合物Ⅰ_1在药剂浓度为50μg／mL时，对小麦赤霉病菌的抑制率为47.94％，与对照药剂恶霉灵在相同药剂浓度下的抑制率相当，但在此药剂浓度下对苹果腐烂病菌和辣椒枯萎病菌的抑制率分别为：60.06％和71.99％，均优于对照药剂恶霉灵在相同药剂浓度下的抑制率：目标化合物Ⅳ_7在药剂浓度为50μg／mL下，对三种植物病菌的抑制率均优于对照药剂恶霉灵在相同药剂浓度下的抑制率。选定化合物Ⅳ_7对辣椒枯萎病菌，测定了对病菌的毒力(EC_(50))，建立了其线性回归方程，并对药剂处理后辣椒枯萎病菌体细胞中的可溶性蛋白含量、还原糖含量、几丁糖含量、几丁质酶活性进行了测定。结果表明，目标化合物Ⅳ_7对辣椒枯萎菌丝细胞的蛋白合成没有影响；在所设定的时间内，菌体内还原糖含量、几丁糖含量、几丁质酶活性一直低于对照。可以初步推测，目标化合物Ⅳ_7处理后对辣椒枯萎菌丝的作用方式为抑制菌丝体内几丁质酶的活性，进而影响菌体内还原糖含量、几丁糖含量，
In recent years, quinazoline compounds take on good biological activity in medicine and pesticide aspect. With synthesis and bioactivity study of quinazoline compounds developing, it's become one of a focuses studied field to chemicals and biological scholars. In medicine aspect, quinazoline compounds have inhibition on EGF receptor (EGFR), and then demonstrate the anticancer activation. In addition, quinazoline compounds still resist malaria and HIV, treat benign prostate gland hyperplasia and loose. In pesticide respect, quinazoline oxime ether compounds have good biological activity to anti-TMV, CMV and fungal.
In order to create more high-efficient anticancer medicine or fungicide, look for the new target which treats cancer or plant fungicide, guide and develop the new target medicine or pesticide to treat cancer or plant fungicide, regarding PD 153035 as the leading compound, we design and synthesize four kinds of new-type quinazoline compounds: (Ⅰ) Anthranilic acid taken as raw materials, cycled by fonnamide, chlorined by phosphorus pentachloride and phosphorus oxychloride, and then reacted with aryl amine to get N-substituted-4-aminequianzoline, 15 compounds are synthesized. The structure of all 15 compounds is characterized by IR, MS, ~1H NMR, ~(13)C NMR and elemental analysis. (Ⅱ) Take anthranilic acid as raw materials, we get 5-chlorine-2-aminobenzoic acid or 3,5-dichlorine-2-aminobenzoic acid after single chlorination or double chlorination. Then, the 5-chlorine-2-aminobenzoic acid or 3,5-dichlorine-2-aminobenzoic acid through cycled by formamide, chlorined by phosphorus pentachloride and phosphorus oxychloriden, and then reacted with aryl amine to get chlorine substituted N-substituted-4-aminequianzoline. Finally, 6 compounds are synthesized. The structure of all 6 compounds is characterized by IR, MS, ~1H NMR, ~(13)C NMR and elemental analysis. (Ⅲ) Gallic acid taken as raw materials, ethered by dimethyl sulfate, estered by menthol, nitrated by nitric acid, hydrolized in base, reduced by tin dichlorine, cycled by formamide, chlorined by phosphorus oxychloride, and reacted with aryl amine to get 6,7,8-trimethoxyl N-substituted-4-aminequianzoline, 19 compounds are synthesized. The structure of all 18 compounds is characterized by IR, ~1H NMR, ~(13)C NMR and elemental analysis. (Ⅳ) 4-Chlorine quinazoline compound reacted with sulphur aryl phenol in potassium carbonate and acetone, S-substituted-4-sulphur ether quinazoline are synthesized. The structure of all 7 compounds is characterized by IR, ~1H NMR, ~(13)C NMR and elemental analysis. 47 title compounds are synthesized in total.
The synthetic methods of the intermediate and title compounds are decrepit. Particularly, the synthesis of key intermediate 2-amino-3,4,5-trimethoxyl benzoic acid is explained in detail. In addition, we explore 2-methyI-6,7,8-trimethoxyl-quinazolin-4-one via the reaction of 2-amino-3,4,5-trimethoxyl benzoic acid with acetic anhydride, through 6,7,8-trimethoxy-2-methyl-benzo [d][1,3]oxazin-4-one.
The present new method of the formation of N-substituted-4-aminoquinazoline derivatives under microwave irradiation offers several advantages: faster reaction rates and higher yields, which involves a reduction of reaction time from 12 h to 20 min and a raise in yields from 24.4~51.3% to 79.1~96.5%, compared with the classical method.
Some title compounds and intermediate suppressing fungicide such as Fusarium graminearum, Cytospora mandshurica and Fusarium oxysporum is tested. The result indicates that some compounds have good activation of suppressing antifungal activities respectively such as I_(12). When the medicament concentration is 500 μg/mL, suppression ratio of the compound I_(12) is
引文
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