CN101575314B - Dihydropyridine compounds and application thereof on preparing drugs for curing and/or preventing virus diseases - Google Patents
Dihydropyridine compounds and application thereof on preparing drugs for curing and/or preventing virus diseasesDownload PDFInfo
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Abstract
Description
Translated fromChinese技术领域technical field
本发明涉及通式(I)的二氢吡啶类化合物及其制备方法，包含上述化合物的药物组合物，以及该类化合物或其异构体或其可药用盐或水合物作为药物例如抗病毒药物的用途，尤其是作为用于治疗和/或预防乙型肝炎的药物的用途。The present invention relates to a dihydropyridine compound of general formula (I) and a preparation method thereof, a pharmaceutical composition comprising the above-mentioned compound, and the compound or its isomer or its pharmaceutically acceptable salt or hydrate as medicine such as antiviral Use of a medicament, especially as a medicament for the treatment and/or prophylaxis of hepatitis B.
背景技术Background technique
慢性乙型肝炎是由乙型肝炎病毒(HBV)引起的，世界范围内广泛流行的一种严重传染病，与肝硬化和肝癌的发生密切相关。我国是乙型肝炎高发区，1992-1995年全国病毒性肝炎血清流行病学调查结果表明，我国人群乙型肝炎病毒表面抗原(HBsAg)携带率为9.7％，估计约1.3亿人为HBV携带者。对我国病毒性肝炎流行现状的研究发现，乙型肝炎年报告发病率从1990年的21.9/10万升高到2003年的53.3/10万，呈明显上升趋势(王晓军，张荣珍，胡苑笙等疾病监测，2004，19(8)：290-292)。慢性乙型肝炎不仅严重影响人体健康，而且给家庭、社会造成沉重的经济负担，慢性乙型肝炎已成为我国重大的公共卫生问题之一。Chronic hepatitis B is caused by hepatitis B virus (HBV), a serious infectious disease that is widely prevalent in the world, and is closely related to the occurrence of liver cirrhosis and liver cancer. my country is a high-incidence area of hepatitis B. The results of national viral hepatitis serum epidemiological surveys from 1992 to 1995 showed that the carrier rate of hepatitis B virus surface antigen (HBsAg) in the Chinese population was 9.7%, and it was estimated that about 130 million people were HBV carriers. The research on the epidemic situation of viral hepatitis in my country found that the annual reported incidence of hepatitis B increased from 21.9/100,000 in 1990 to 53.3/100,000 in 2003, showing a clear upward trend (Wang Xiaojun, Zhang Rongzhen, Hu Yuansheng and other disease monitoring , 2004, 19(8): 290-292). Chronic hepatitis B not only seriously affects human health, but also causes a heavy economic burden to families and society. Chronic hepatitis B has become one of the major public health problems in my country.
用于治疗慢性乙肝的药物主要有两类——免疫调节剂和核苷类DNA聚合酶抑制剂(Loomba R.，Liang T.J.，Antivir.Ther.，2006，11(1)：1-15)。前者包括：干扰素-α2b(IFN-α2b，Intron A)和聚乙二醇干扰素-α2a(peg-IFN-α2a，Pegasys
二氢吡啶类化合物具有广泛的生理活性，如可作为N型钙离子通道拮抗剂(US6350762)和L型钙离子通道拮抗剂(US6001857)。同时3-[4-(2-甲咪唑基[4，5-c]吡啶)戊酸]-5-(N-吡啶-2-氨甲酰基)-1，4-二氢吡啶类化合物具有抗过敏、抗炎作用(US4904671)。但未见1，4-二氢吡啶类化合物抗乙型肝炎病毒的相关报道。Dihydropyridine compounds have a wide range of physiological activities, such as N-type calcium ion channel antagonists (US6350762) and L-type calcium ion channel antagonists (US6001857). At the same time, 3-[4-(2-methylimidazolyl[4,5-c]pyridine)pentanoic acid]-5-(N-pyridine-2-carbamoyl)-1,4-dihydropyridine compounds have anti Allergic, anti-inflammatory effects (US4904671). But there is no relevant report on the anti-hepatitis B virus of 1,4-dihydropyridine compounds.
发明内容Contents of the invention
本发明人发现，本发明提供的一类新颖的通式(I)的二氢吡啶化合物具有有效的抗病毒作用特别是抗乙型肝炎病毒的作用，本发明基于上述发现而得以完成。The present inventors found that a class of novel dihydropyridine compounds of general formula (I) provided by the present invention has effective antiviral effect, especially anti-hepatitis B virus effect, and the present invention is completed based on the above findings.
发明概述：Summary of the invention:
本发明第一方面提供了通式(I)化合物，The first aspect of the present invention provides a compound of general formula (I),
其中：in:
R1代表氢、(C1-C6)-烷基、(C2-C6)-链烯基、(C1-C6)-酰基、磺酰基；R1 represents hydrogen, (C1 -C6 )-alkyl, (C2 -C6 )-alkenyl, (C1 -C6 )-acyl, sulfonyl;
R2代表(C1-C6)-烷基；R2 represents (C1 -C6 )-alkyl;
R3代表芳基或杂芳基，其任选被一个或多个各自独立地选自以下的取代基取代：氢、卤素、三氟甲基、三氟甲氧基、三氟甲磺酰基、硝基、氰基、羧基、羟基、氨基、(C1-C6)-烷基氨基、(C1-C6)-二烷基氨基，(C1-C6)-酰氨基、(C1-C6)-烷基、(C1-C6)-烷氧基、(C1-C6)-烷氧羰基、(C1-C6)-氨甲酰基，其中所述烷基可被具有6-10个碳原子的芳基、卤素、(C1-C6)-烷氧基、(C1-C6)-烷基氨基、酰胺基取代；R represents aryl or heteroaryl, which is optionally substituted by one or more substituents each independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyl, Nitro, cyano, carboxyl, hydroxyl, amino, (C1 -C6 )-alkylamino, (C1 -C6 )-dialkylamino, (C1 -C6 )-amido, (C1 -C6 )-alkyl, (C1 -C6 )-alkoxy, (C1 -C6 )-alkoxycarbonyl, (C1 -C6 )-carbamoyl, wherein the alkyl Can be substituted by aryl, halogen, (C1 -C6 )-alkoxy, (C1 -C6 )-alkylamino, amido having 6-10 carbon atoms;
R4代表芳基或杂芳基，其任选被一个或多个各自独立地选自以下的取代基取代：氢、卤素、羟基、氰基、羧基、三氟甲基、硝基、苄基、(C1-C6)-烷基、(C1-C6)-烷氧基、(C1-C6)-烷硫基、(C1-C6)-烷氧羰基、(C1-C6)-酰氧基、氨基、(C1-C6)-烷基氨基或(C1-C6)-二烷基氨基、(C1-C6)-酰基氨基、(C1-C6)-氨甲酰基，R represents aryl or heteroaryl, which is optionally substituted by one or more substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, carboxyl, trifluoromethyl, nitro, benzyl , (C1 -C6 )-alkyl, (C1 -C6 )-alkoxy, (C1 -C6 )-alkylthio, (C1 -C6 )-alkoxycarbonyl, (C1 -C6 )-acyloxy, amino, (C1 -C6 )-alkylamino or (C1 -C6 )-dialkylamino, (C1 -C6 )-acylamino, (C1 -C6 )-carbamoyl,
或其异构体、可药用盐或水合物。or its isomers, pharmaceutically acceptable salts or hydrates.
根据本发明第一方面的通式(I)化合物，其中：According to the compound of general formula (I) of the first aspect of the present invention, wherein:
R1代表氢、(C1-C3)-烷基、甲酰基、乙酰基、苯甲酰基、甲磺酰基、苯甲磺酰基、对甲苯磺酰基；R1 represents hydrogen, (C1 -C3 )-alkyl, formyl, acetyl, benzoyl, methanesulfonyl, phenylmethylsulfonyl, p-toluenesulfonyl;
R2代表(C1-C4)-烷基；R2 represents (C1 -C4 )-alkyl;
R3代表芳基或杂芳基，其任选被一个或多个各自独立地选自以下的取代基取代：氢、卤素、三氟甲基、三氟甲氧基、三氟甲磺酰基、硝基、氰基、羧基、羟基、氨基、(C1-C4)-烷基氨基、(C1-C4)-二烷基氨基，(C1-C4)-酰氨基、(C1-C4)-烷氧基羰基、(C1-C4)-烷氧基、(C1-C4)-烷基、(C1-C4)-氨甲酰基；R represents aryl or heteroaryl, which is optionally substituted by one or more substituents each independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyl, Nitro, cyano, carboxyl, hydroxyl, amino, (C1 -C4 )-alkylamino, (C1 -C4 )-dialkylamino, (C1 -C4 )-amido, (C1 -C4 )-alkoxycarbonyl, (C1 -C4 )-alkoxy, (C1 -C4 )-alkyl, (C1 -C4 )-carbamoyl;
R4代表芳基或杂芳基，其任选被一个或多个各自独立地选自以下的取代基取代：氢、卤素、硝基、氰基、羟基、三氟甲基、羧基、(C1-C3)-烷基、(C1-C3)-烷氧基、(C1-C3)-烷氧羰基、氨基、(C1-C3)-烷基氨基、(C1-C3)-二烷基氨基、(C1-C3)-酰基氨基、(C1-C3)-氨甲酰基。R represents aryl or heteroaryl, which is optionally substituted by one or more substituents each independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, trifluoromethyl, carboxy, (C1 -C3 )-Alkyl, (C1 -C3 )-Alkoxy, (C1 -C3 )-Alkoxycarbonyl, Amino, (C1 -C3 )-Alkylamino, (C1 -C3 )-dialkylamino, (C1 -C3 )-acylamino, (C1 -C3 )-carbamoyl.
或其异构体、可药用盐或水合物。or its isomers, pharmaceutically acceptable salts or hydrates.
根据本发明第一方面的通式(I)化合物，其中：According to the compound of general formula (I) of the first aspect of the present invention, wherein:
R1代表氢、甲基、甲酰基、乙酰基、甲磺酰基、苯甲酰基；R represents hydrogen, methyl, formyl, acetyl, methanesulfonyl, benzoyl;
R2代表甲基、乙基、丙基、异丙基；R represents methyl, ethyl, propyl, isopropyl;
R3代表芳基或杂芳基，其任选被一个或多个各自独立地选自以下的取代基取代：氢、氟、氯、溴、三氟甲基、三氟甲氧基、三氟甲磺酰基、硝基、氰基、羧基、羟基、氨基、甲氨基、二甲氨基、甲酰胺基、乙酰胺基、乙氨基、甲氧基羰基、甲氧基、乙氧基、甲基、乙基、丙基；R represents aryl or heteroaryl, which is optionally substituted by one or more substituents each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, trifluoro Methylsulfonyl, nitro, cyano, carboxyl, hydroxyl, amino, methylamino, dimethylamino, formamido, acetamido, ethylamino, methoxycarbonyl, methoxy, ethoxy, methyl, Ethyl, propyl;
R4代表芳基或杂芳基，其任选被一个或多个各自独立地选自以下的取代基取代：氢、氟、氯、溴、甲基、乙基、丙基、异丙基、羟基、羧基、甲氧基、乙氧基、甲氧羰基、乙氧羰基、硝基、氨基、甲氨基、二甲氨基、甲酰胺基、乙氨基、乙酰胺基。R represents aryl or heteroaryl, which is optionally substituted by one or more substituents each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, Hydroxyl, carboxyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, nitro, amino, methylamino, dimethylamino, formamido, ethylamino, acetamido.
或其异构体、可药用盐或水合物。or its isomers, pharmaceutically acceptable salts or hydrates.
根据本发明第一方面的通式(I)化合物，其中：According to the compound of general formula (I) of the first aspect of the present invention, wherein:
R1代表氢、乙酰基；R1 represents hydrogen, acetyl;
R2代表甲基、乙基；R represents methyl, ethyl;
R3代表单取代或多取代任选自下述基团的相同或不同取代基的芳基：氢、氯、氟、溴、三氟甲基、甲基、甲氧基、羧基、氰基、羟基；R3 represents mono-substituted or multi-substituted aryl with the same or different substituents optionally selected from the following groups: hydrogen, chlorine, fluorine, bromine, trifluoromethyl, methyl, methoxy, carboxyl, cyano, Hydroxy;
R4代表单取代或多取代任选自下述基团的相同或不同取代基的苯基、噻吩基、噻唑基：氢、氟、甲基、羟基、甲氧基、甲氧羰基、硝基、氨基、甲氨基、甲酰胺基、乙酰胺基。R4 represents phenyl, thienyl, thiazolyl, mono-substituted or multi-substituted, optionally selected from the following groups with the same or different substituents: hydrogen, fluorine, methyl, hydroxyl, methoxy, methoxycarbonyl, nitro , amino, methylamino, formamido, acetamido.
或其异构体、可药用盐或水合物。or its isomers, pharmaceutically acceptable salts or hydrates.
根据本发明第一方面的通式(I)化合物，其选自：According to the compound of general formula (I) of the first aspect of the present invention, it is selected from:
(1)2-甲基-4-苯基-5-硝基-6-(4-甲基苯基)-1，4-二氢吡啶-3-羧酸乙酯；(1) 2-methyl-4-phenyl-5-nitro-6-(4-methylphenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(2)2-甲基-4-(2-氯苯基)-5-硝基-6-(4-甲基苯基)-1，4-二氢吡啶-3-羧酸乙酯；(2) 2-methyl-4-(2-chlorophenyl)-5-nitro-6-(4-methylphenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(3)2-甲基-4-(3-氯苯基)-5-硝基-6-(4-甲基苯基)-1，4-二氢吡啶-3-羧酸乙酯；(3) 2-methyl-4-(3-chlorophenyl)-5-nitro-6-(4-methylphenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(4)2-甲基-4-(2-氯苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸乙酯；(4) 2-methyl-4-(2-chlorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(5)2-甲基-4-(3-氯苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸乙酯；(5) 2-methyl-4-(3-chlorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(6)2-甲基-4-(2-氯苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；(6) 2-methyl-4-(2-chlorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(7)2-甲基-4-(4-氟苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；(7) 2-methyl-4-(4-fluorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(8)2-甲基-4-(2-甲氧基苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；(8) 2-methyl-4-(2-methoxyphenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(9)2-甲基-4-(2-溴苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；(9) 2-methyl-4-(2-bromophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(10)2-甲基-4-(3-氯苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；(10) 2-methyl-4-(3-chlorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(11)2-甲基-4-(4-氯苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；(11) 2-methyl-4-(4-chlorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(12)2-甲基-4-(2-氯-4-氟苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；(12) 2-Methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester ;
(13)2-甲基-4-(2-甲氧基苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸乙酯；(13) 2-methyl-4-(2-methoxyphenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine-3- ethyl carboxylate;
(14)2-甲基-4-(2-溴苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸乙酯；(14) 2-methyl-4-(2-bromophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(15)2-甲基-4-(2-氯-4-氟苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸乙酯；(15) 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine- 3-Ethyl carboxylate;
(16)2-甲基-4-(4-氯苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸乙酯；(16) 2-methyl-4-(4-chlorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(17)2-甲基-4-(2-氯-4-氟苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸甲酯；(17) 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine- 3-Carboxylic acid methyl ester;
(18)2-甲基-4-(2-甲基苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸乙酯；(18) 2-methyl-4-(2-methylphenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine-3-carboxyl ethyl acetate;
(19)2-甲基-4-(2-甲基苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；和(19) ethyl 2-methyl-4-(2-methylphenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylate; and
(20)1-乙酰基-2-甲基-4-(2-甲基苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯，(20) 1-acetyl-2-methyl-4-(2-methylphenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester,
或其异构体、可药用盐或水合物。or its isomers, pharmaceutically acceptable salts or hydrates.
本发明第二方面提供了制备本发明第一方面任一项所述通式(I)化合物的方法，其包括：The second aspect of the present invention provides a method for preparing a compound of general formula (I) according to any one of the first aspect of the present invention, comprising:
步骤A)在加入或不加入碱或酸的情况下，在适当的惰性溶剂中，通式(II)的烯胺类化合物Step A) In a suitable inert solvent, the enamine compound of general formula (II) is added or not added under the condition of alkali or acid
与通式(III)的醛With the aldehyde of general formula (III)
R3CHO (III)R3 CHO (III)
以及通式(IV)的化合物反应，And the compound reaction of general formula (IV),
得到其中的R1为氢的通式(I)化合物；和，任选的to obtain a compound of general formula (I) whereinR is hydrogen; and, optionally
步骤B)在碱性条件下，在适当的惰性溶剂中，上述步骤A)的产物与式R1X表示的化合物反应，得到通式(I)化合物，Step B) under basic conditions, in a suitable inert solvent, the product of the above step A) is reacted with the compound represented by the formula R1 X to obtain the compound of the general formula (I),
其中，X表示卤素(例如氟、氯、溴和碘)，R1、R2、R3、和R4各自同本发明第一方面任一项所述通式(I)化合物中的定义。Wherein, X represents halogen (such as fluorine, chlorine, bromine and iodine), and R1 , R2 , R3 , and R4 are each as defined in the compound of general formula (I) described in any one of the first aspect of the present invention.
本发明第三方面提供了一种药物组合物，其包含治疗和/或预防有效量的本发明第一方面任一项所述的通式(I)的化合物，任选的可药用的载体，以及任选的其它药物活性化合物。The third aspect of the present invention provides a pharmaceutical composition, which comprises a therapeutically and/or preventively effective amount of the compound of general formula (I) described in any one of the first aspect of the present invention, optionally a pharmaceutically acceptable carrier , and optionally other pharmaceutically active compounds.
本发明第四方面提供了本发明第一方面任一项所述的通式(I)的化合物在制备用于治疗和/或预防急性或慢性病毒性疾病的药物中的用途。The fourth aspect of the present invention provides the use of the compound of general formula (I) described in any one of the first aspect of the present invention in the preparation of medicines for treating and/or preventing acute or chronic viral diseases.
本发明第五方面提供了本发明第一方面任一项所述的通式(I)的化合物在制备用于治疗和/或预防急性或慢性乙型肝炎病毒感染的药物中的用途。The fifth aspect of the present invention provides the use of the compound of general formula (I) described in any one of the first aspect of the present invention in the preparation of a medicament for treating and/or preventing acute or chronic hepatitis B virus infection.
本发明第六方面提供了治疗和/或预防急性或慢性病毒性疾病的方法，其包括给有需要的受试者施用治疗和/或预防有效量的本发明第一方面任一项所述的通式(I)的化合物。The sixth aspect of the present invention provides a method for treating and/or preventing acute or chronic viral diseases, which includes administering to a subject in need a therapeutically and/or preventively effective amount of any one of the compounds described in the first aspect of the present invention. Compounds of formula (I).
本发明第七方面提供了治疗和/或预防急性或慢性乙型肝炎病毒感染的方法，其包括给有需要的受试者施用治疗和/或预防有效量的本发明第一方面任一项所述的通式(I)的化合物。The seventh aspect of the present invention provides a method for treating and/or preventing acute or chronic hepatitis B virus infection, which includes administering a therapeutically and/or preventively effective amount of any one of the first aspects of the present invention to a subject in need. The compound of general formula (I) mentioned above.
发明详述：Detailed description of the invention:
本发明所引述的所有文献，它们的全部内容通过引用并入本文，并且如果这些文献所表达的含义与本发明不一致时，以本发明的表述为准。此外，本发明使用的各种术语和短语具有本领域技术人员公知的一般含义，即便如此，本发明仍然希望在此对这些术语和短语作更详尽的说明和解释，提及的术语和短语如有与公知含义不一致的，以本发明所表述的含义为准。All the documents cited in the present invention are incorporated herein by reference in their entirety, and if the meaning expressed in these documents is inconsistent with the present invention, the expression of the present invention shall prevail. In addition, various terms and phrases used in the present invention have common meanings known to those skilled in the art. Even so, the present invention still hopes to make a more detailed description and explanation of these terms and phrases here. The terms and phrases mentioned are as follows: If there is any inconsistency with the known meaning, the meaning expressed in the present invention shall prevail.
本发明说明书中，术语“卤素”或“卤代”是指氟、氯、溴、和碘。In the present specification, the term "halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine.
本发明说明书中，术语“(C2-C6)-链烯基”是指具有2-6个碳原子的直链或支链烯基，优选3-4个碳原子的直链或支链烯基，包括但是并不局限于乙烯基、丙烯基、正戊烯基、正己烯基。In the description of the present invention, the term "(C2 -C6 )-alkenyl" refers to a straight chain or branched chain alkenyl group with 2-6 carbon atoms, preferably a straight chain or branched chain group with 3-4 carbon atoms Alkenyl includes, but is not limited to, ethenyl, propenyl, n-pentenyl, n-hexenyl.
本发明说明书中，术语“(C1-C6)-酰基”是指具有1-6个碳原子的直链或支链酰基，优选具有2-4个碳原子的直链或支链酰基。In the specification of the present invention, the term "(C1 -C6 )-acyl" refers to a straight-chain or branched acyl group having 1-6 carbon atoms, preferably a straight-chain or branched acyl group having 2-4 carbon atoms.
本发明说明书中，术语“芳基”通常是指5-14元的芳环系统，或可能包含稠合的双环或三环的芳环系统，包括但是并不局限于苯基和萘基。In the description of the present invention, the term "aryl" generally refers to a 5-14 membered aromatic ring system, or an aromatic ring system that may contain fused bicyclic or tricyclic rings, including but not limited to phenyl and naphthyl.
本发明说明书中，术语“杂芳基”通常是指含杂原子N、O、S等的5-14元芳环系统，或可能包含稠合的双环或三环的芳环系统。In the specification of the present invention, the term "heteroaryl" generally refers to a 5-14 membered aromatic ring system containing heteroatoms N, O, S, etc., or an aromatic ring system that may contain fused bicyclic or tricyclic rings.
本发明说明书中，术语“(C1-C6)-烷基”是指直链或支链的含有1-6个碳原子的基团，包括但并不局限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基和叔丁基等。In the description of the present invention, the term "(C1 -C6 )-alkyl" refers to a linear or branched group containing 1-6 carbon atoms, including but not limited to methyl, ethyl, n- Propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, etc.
本发明说明书中，术语“(C1-C6)-烷氧基”是指含有1-6个碳原子的直链或支链烷氧基，优选具有1-4个碳原子的直链或支链烷氧基，包括但并不局限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基和叔丁氧基等。In the description of the present invention, the term "(C1 -C6 )-alkoxy" refers to a straight-chain or branched alkoxy group containing 1-6 carbon atoms, preferably a straight-chain or branched chain alkoxy group having 1-4 carbon atoms. Branched alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert-butoxy.
本发明说明书中，术语“(C1-C6)-烷硫基”是指含有1-6个碳原子的直链或支链烷硫基，优选具有1-4个碳原子的直链或支链烷硫基。In the description of the present invention, the term "(C1 -C6 )-alkylthio" refers to a straight-chain or branched alkylthio group containing 1-6 carbon atoms, preferably a straight-chain or branched chain alkylthio group having 1-4 carbon atoms. Branched chain alkylthio.
本发明说明书中，术语“(C1-C6)-烷氧羰基”是指具有1-6个碳原子的直链或支链烷氧羰基，优选具有1-4个碳原子的直链或支链烷氧羰基，包括但并不局限于甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、丁氧羰基、异丁氧羰基和叔丁氧羰基等。In the description of the present invention, the term "(C1 -C6 )-alkoxycarbonyl" refers to a straight-chain or branched alkoxycarbonyl group with 1-6 carbon atoms, preferably a straight-chain or branched chain alkoxycarbonyl group with 1-4 carbon atoms. Branched alkoxycarbonyl, including but not limited to methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl and tert-butoxycarbonyl, etc.
本发明化合物可以以光学异构体形式存在，所述光学异构体形式之间可呈对映异构体或非对映异构体关系。本发明涉及这些对映异构体或非对映异构体以及它们的混合物。象非对映异构体一样，外消旋体可通过已知方法拆分成光学异构体的单一成分，如利用本发明化合物分子中具有碱性的氮原子同酸性手性拆分试剂成盐的方法进行拆分，该方法具体描述如下：发明化合物和拆分试剂分别用有机溶剂溶解，然后混合，放置，析出固体。分离固体与溶液，分别用碱液处理，有机溶剂提取即得一对对映异构体。The compounds of the present invention may exist in the form of optical isomers, which may exhibit enantiomeric or diastereomeric relationships between them. The present invention relates to these enantiomers or diastereomers and mixtures thereof. Like diastereoisomers, racemates can be resolved into individual components of optical isomers by known methods, such as using a basic nitrogen atom in the molecule of the compound of the present invention with an acidic chiral resolution reagent The salt method is used for resolution, and the method is specifically described as follows: the inventive compound and the resolution reagent are respectively dissolved in an organic solvent, then mixed, placed, and a solid is precipitated. Separation of solid and solution, treatment with lye, organic solvent extraction that is a pair of enantiomers.
酸性手性拆分试剂包括但不局限于R或S构型的樟脑酸、樟脑磺酸，D或L构型的酒石酸、乳酸、苹果酸、天然或非天然氨基酸及其衍生物等。Acidic chiral resolution reagents include, but are not limited to, camphoric acid and camphorsulfonic acid in R or S configuration, tartaric acid, lactic acid, malic acid in D or L configuration, natural or unnatural amino acids and their derivatives, etc.
上述拆分方法所用有机溶剂包括但并不局限于甲醇、乙醇、丙酮、乙酸乙酯、乙醚、石油醚、二氯甲烷、三氯甲烷等。The organic solvents used in the above resolution methods include but are not limited to methanol, ethanol, acetone, ethyl acetate, ether, petroleum ether, dichloromethane, chloroform and the like.
或者在发明化合物的分子中引入另一手性基团，使其成为一对易于分离的非对映异构体，分离纯化后除去引入的手性基团从而得到光学纯的对映异构体，该方法具体描述如下：Or introduce another chiral group into the molecule of the inventive compound to make it a pair of diastereoisomers that are easy to separate, and remove the introduced chiral group after separation and purification to obtain optically pure enantiomers, The method is described in detail as follows:
1)加入碱的情况下，在适当的惰性溶剂中，通式(I)化合物(其中的R1为氢)与分子中至少含一个手性中心的酸的酰氯或酸酐反应，或者通式(I)化合物(其中的R1为氢)与分子中至少含一个手性中心的酸在适当的缩合剂存在下反应，得到通式(V)和(VI)的混合物。在适当的溶剂中重结晶，或经柱层析分离纯化，分别获得纯的(V)和(VI)。1) In the case of adding a base, in a suitable inert solvent, the compound of general formula (I) (whereinR is hydrogen) reacts with the acid chloride or acid anhydride of an acid containing at least one chiral center in the molecule, or the general formula ( I) The compound (wherein R1 is hydrogen) reacts with an acid containing at least one chiral center in the molecule in the presence of a suitable condensing agent to obtain a mixture of general formulas (V) and (VI). Recrystallize in an appropriate solvent, or separate and purify by column chromatography to obtain pure (V) and (VI), respectively.
其中R2、R3、R4定义同上文，R代表至少含一个手性中心的酰基或磺酸基，Wherein R2 , R3 , R4 are as defined above, and R represents an acyl or sulfonic acid group containing at least one chiral center,
2)通式(V)或(VI)在适当的溶剂中与强碱如醇钠反应得通式(I)化合物的一对对映异构体。2) Reaction of the general formula (V) or (VI) with a strong base such as sodium alkoxide in an appropriate solvent to obtain a pair of enantiomers of the compound of the general formula (I).
其中R2、R3、R4定义同上、R1为氢，Wherein R2 , R3 , R4 are as defined above, R1 is hydrogen,
分子中至少含一个手性中心的酸包括但并不局限于R或S构型的樟脑酸、樟脑磺酸、D或L构型的酒石酸、乳酸、苹果酸、天然或非天然氨基酸及其衍生物等。Acids containing at least one chiral center in the molecule include but are not limited to camphoric acid in R or S configuration, camphorsulfonic acid, tartaric acid in D or L configuration, lactic acid, malic acid, natural or unnatural amino acids and their derivatives things etc.
缩合剂包括但并不局限于二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、N，N’-羰基二咪唑(CDI)、1-乙基-3-[3-(二甲胺基)丙基]碳二亚胺(EDCI)、BOP(卡特缩合剂)等。Condensing agents include but are not limited to dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N, N'-carbonyldiimidazole (CDI), 1-ethyl-3- [3-(Dimethylamino)propyl]carbodiimide (EDCI), BOP (Carter condensing agent) and the like.
利用下述反应方案举例说明本发明化合物的手性拆分方法：The following reaction scheme is used to illustrate the chiral resolution method of the compounds of the present invention:
[1][1]
[2][2]
[3][3]
本发明化合物还可以呈盐的形式。其可药用的盐是优选的。The compounds of the invention may also be in the form of salts. Pharmaceutically acceptable salts thereof are preferred.
其中可药用的盐包括但是并不局限于，与无机酸如盐酸、硫酸、磷酸、亚磷酸、氢溴酸和硝酸所成的盐，以及与各种有机酸如马来酸、富马酸、苹果酸、延胡索酸、琥珀酸、酒石酸、柠檬酸、乙酸、乳酸、苯甲酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、棕榈酸等所成的盐。Pharmaceutically acceptable salts include, but are not limited to, salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, hydrobromic acid and nitric acid, and salts with various organic acids such as maleic acid and fumaric acid. , malic acid, fumaric acid, succinic acid, tartaric acid, citric acid, acetic acid, lactic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, palmitic acid, etc.
其可药用的盐还包括但并不局限于本发明化合物的金属盐如钠盐、钾盐、镁盐或钙盐，或与氨或有机胺如乙胺、二乙胺、三乙胺、二乙醇胺、三乙醇胺、二环己基胺、二甲基氨基乙醇、精氨酸、赖氨酸、乙二胺、或2-苯基乙胺等成的铵盐。Its pharmaceutically acceptable salts also include but are not limited to metal salts of the compounds of the present invention such as sodium salts, potassium salts, magnesium salts or calcium salts, or with ammonia or organic amines such as ethylamine, diethylamine, triethylamine, Ammonium salts of diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine, or 2-phenylethylamine.
本发明中的一些化合物可能用水或各种有机溶剂结晶或重结晶，在这种情况下，可能形成各种溶剂化物。本发明包括那些化学计量的溶剂化物，包括水合物，也包括在用低压升华干燥法制备时形成的包含可变量水的化合物。Some compounds of the present invention may be crystallized or recrystallized from water or various organic solvents, in which case various solvates may be formed. The present invention includes those stoichiometric solvates, including hydrates, as well as compounds containing variable amounts of water formed when prepared by low pressure sublimation drying.
虽然在发明概述部分对本发明第一方面的通式(I)化合物进行了明确说明，但申请人仍然在此作进一步的描述。具体地说，本发明定义如下的通式(I)化合物或其异构体及它们的盐或水合物是优选的，Although the compound of the general formula (I) of the first aspect of the present invention has been clearly described in the summary of the invention, the applicant still provides further description here. Specifically, the compounds of general formula (I) or their isomers and their salts or hydrates as defined in the present invention are preferred,
其中：in:
R1代表氢、(C1-C3)-烷基、甲酰基、乙酰基、苯甲酰基、甲磺酰基、苯甲磺酰基、对甲苯磺酰基；R1 represents hydrogen, (C1 -C3 )-alkyl, formyl, acetyl, benzoyl, methanesulfonyl, phenylmethylsulfonyl, p-toluenesulfonyl;
R2代表(C1-C4)-烷基；R2 represents (C1 -C4 )-alkyl;
R3代表芳基或杂芳基，其任选被一个或多个各自独立地选自以下的取代基取代：氢、卤素、三氟甲基、三氟甲氧基、三氟甲磺酰基、硝基、氰基、羧基、羟基、氨基、(C1-C4)-烷基氨基、(C1-C4)-二烷基氨基，(C1-C4)-酰氨基、(C1-C4)-烷氧基羰基、(C1-C4)-烷氧基、(C1-C4)-烷基、(C1-C4)-氨甲酰基；R represents aryl or heteroaryl, which is optionally substituted by one or more substituents each independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyl, Nitro, cyano, carboxyl, hydroxyl, amino, (C1 -C4 )-alkylamino, (C1 -C4 )-dialkylamino, (C1 -C4 )-amido, (C1 -C4 )-alkoxycarbonyl, (C1 -C4 )-alkoxy, (C1 -C4 )-alkyl, (C1 -C4 )-carbamoyl;
R4代表芳基或杂芳基，其任选被一个或多个各自独立地选自以下的取代基取代：氢、卤素、硝基、氰基、羟基、三氟甲基、羧基、(C1-C3)-烷基、(C1-C3)-烷氧基、(C1-C3)-烷氧羰基、氨基、(C1-C3)-烷基氨基、(C1-C3)-二烷基氨基、(C1-C3)-酰基氨基、(C1-C3)-氨甲酰基。R represents aryl or heteroaryl, which is optionally substituted by one or more substituents each independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, trifluoromethyl, carboxy, (C1 -C3 )-Alkyl, (C1 -C3 )-Alkoxy, (C1 -C3 )-Alkoxycarbonyl, Amino, (C1 -C3 )-Alkylamino, (C1 -C3 )-dialkylamino, (C1 -C3 )-acylamino, (C1 -C3 )-carbamoyl.
此外，定义如下的通式(I)化合物或其异构体及它们的盐或水合物是特别优选的，其中：Furthermore, compounds of general formula (I) or their isomers and their salts or hydrates are particularly preferred as defined below, wherein:
R1代表氢、甲基、甲酰基、乙酰基、甲磺酰基、苯甲酰基；R represents hydrogen, methyl, formyl, acetyl, methanesulfonyl, benzoyl;
R2代表甲基、乙基、丙基、异丙基；R represents methyl, ethyl, propyl, isopropyl;
R3代表芳基或杂芳基，其任选被一个或多个各自独立地选自以下的取代基取代：氢、氟、氯、溴、三氟甲基、三氟甲氧基、三氟甲磺酰基、硝基、氰基、羧基、羟基、氨基、甲氨基、二甲氨基、甲酰胺基、乙酰胺基、乙氨基、甲氧基羰基、甲氧基、乙氧基、甲基、乙基、丙基；R represents aryl or heteroaryl, which is optionally substituted by one or more substituents each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, trifluoro Methylsulfonyl, nitro, cyano, carboxyl, hydroxyl, amino, methylamino, dimethylamino, formamido, acetamido, ethylamino, methoxycarbonyl, methoxy, ethoxy, methyl, Ethyl, propyl;
R4代表芳基或杂芳基，其任选被一个或多个各自独立地选自以下的取代基取代：氢、氟、氯、溴、甲基、乙基、丙基、异丙基、羟基、羧基、甲氧基、乙氧基、甲氧羰基、乙氧羰基、硝基、氨基、甲氨基、二甲氨基、甲酰胺基、乙氨基、乙酰胺基。R represents aryl or heteroaryl, which is optionally substituted by one or more substituents each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, Hydroxyl, carboxyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, nitro, amino, methylamino, dimethylamino, formamido, ethylamino, acetamido.
进一步的，定义如下的通式(I)化合物或其异构体及它们的盐或水合物是非常特别优选的，其中：Further, compounds of general formula (I) or their isomers and their salts or hydrates are very particularly preferred as defined below, wherein:
R1代表氢、乙酰基；R1 represents hydrogen, acetyl;
R2代表甲基、乙基；R represents methyl, ethyl;
R3代表单取代或多取代任选自下述基团的相同或不同取代基的芳基：氢、氯、氟、溴、三氟甲基、甲基、甲氧基、羧基、氰基、羟基；R3 represents mono-substituted or multi-substituted aryl with the same or different substituents optionally selected from the following groups: hydrogen, chlorine, fluorine, bromine, trifluoromethyl, methyl, methoxy, carboxyl, cyano, Hydroxy;
R4代表单取代或多取代任选自下述基团的相同或不同取代基的苯基、噻吩基、噻唑基：氢、氟、甲基、羟基、甲氧基、甲氧羰基、硝基、氨基、甲氨基、甲酰胺基、乙酰胺基。R4 represents phenyl, thienyl, thiazolyl, mono-substituted or multi-substituted, optionally selected from the following groups with the same or different substituents: hydrogen, fluorine, methyl, hydroxyl, methoxy, methoxycarbonyl, nitro , amino, methylamino, formamido, acetamido.
本发明特别优选的通式(I)化合物或其异构体或其可药用盐或水合物优选下面的化合物：The particularly preferred compound of general formula (I) or its isomer or pharmaceutically acceptable salt or hydrate of the present invention is preferably the following compound:
(1)2-甲基-4-苯基-5-硝基-6-(4-甲基苯基)-1，4-二氢吡啶-3-羧酸乙酯；(1) 2-methyl-4-phenyl-5-nitro-6-(4-methylphenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(2)2-甲基-4-(2-氯苯基)-5-硝基-6-(4-甲基苯基)-1，4-二氢吡啶-3-羧酸乙酯；(2) 2-methyl-4-(2-chlorophenyl)-5-nitro-6-(4-methylphenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(3)2-甲基-4-(3-氯苯基)-5-硝基-6-(4-甲基苯基)-1，4-二氢吡啶-3-羧酸乙酯；(3) 2-methyl-4-(3-chlorophenyl)-5-nitro-6-(4-methylphenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(4)2-甲基-4-(2-氯苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸乙酯；(4) 2-methyl-4-(2-chlorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(5)2-甲基-4-(3-氯苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸乙酯；(5) 2-methyl-4-(3-chlorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(6)2-甲基-4-(2-氯苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；(6) 2-methyl-4-(2-chlorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(7)2-甲基-4-(4-氟苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；(7) 2-methyl-4-(4-fluorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(8)2-甲基-4-(2-甲氧基苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；(8) 2-methyl-4-(2-methoxyphenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(9)2-甲基-4-(2-溴苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；(9) 2-methyl-4-(2-bromophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(10)2-甲基-4-(3-氯苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；(10) 2-methyl-4-(3-chlorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(11)2-甲基-4-(4-氯苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；(11) 2-methyl-4-(4-chlorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(12)2-甲基-4-(2-氯-4-氟苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；(12) 2-Methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester ;
(13)2-甲基-4-(2-甲氧基苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸乙酯；(13) 2-methyl-4-(2-methoxyphenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine-3- ethyl carboxylate;
(14)2-甲基-4-(2-溴苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸乙酯；(14) 2-methyl-4-(2-bromophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(15)2-甲基-4-(2-氯-4-氟苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸乙酯；(15) 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine- 3-Ethyl carboxylate;
(16)2-甲基-4-(4-氯苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸乙酯；(16) 2-methyl-4-(4-chlorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester;
(17)2-甲基-4-(2-氯-4-氟苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸甲酯；(17) 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine- 3-Carboxylic acid methyl ester;
(18)2-甲基-4-(2-甲基苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-二氢吡啶-3-羧酸乙酯；(18) 2-methyl-4-(2-methylphenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridine-3-carboxyl ethyl acetate;
(19)2-甲基-4-(2-甲基苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯；和(19) ethyl 2-methyl-4-(2-methylphenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylate; and
(20)1-乙酰基-2-甲基-4-(2-甲基苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡啶-3-羧酸乙酯。(20) 1-acetyl-2-methyl-4-(2-methylphenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester.
本发明化合物通式(I)化合物可通过下述方法制备：Compound of the present invention general formula (I) compound can be prepared by following method:
A)在加入或不加入碱或酸的情况下，于20-150℃，在适当的惰性溶剂中，使通式(II)的烯胺类化合物A) In the case of adding or not adding alkali or acid, at 20-150 ° C, in a suitable inert solvent, make the enamine compound of general formula (II)
其中R2定义同上，whereR2 is as defined above,
与通式R3CHO(III)醛With the general formula R3 CHO (III) aldehyde
其中R3定义同上，whereinR3 is as defined above,
以及通式(IV)反应，And the general formula (IV) reaction,
其中R4定义同上，wherein R4 is as defined above,
反应得通式(I)化合物Reaction gets general formula (I) compound
其中R1为氢，whereR is hydrogen,
B)在碱性条件下，在适当的惰性溶剂中，上述步骤产物与通式R1X反应得到通式(I)化合物，其中R1定义同上，X为卤素例如氟、氯、溴、和碘。B) under alkaline conditions, in a suitable inert solvent, the product of the above steps is reacted with the general formula R1 X to obtain a compound of the general formula (I), wherein R1 is as defined above, and X is a halogen such as fluorine, chlorine, bromine, and iodine.
可以利用下述反应方案来举例说明本发明方法：The following reaction scheme can be utilized to illustrate the process of the invention:
对该反应而言，适用的溶剂是所有的惰性有机溶剂。这些溶剂优选包括醇类如乙醇、甲醇、异丙醇，醚类如二氧杂环己烷、乙醚、四氢呋喃、乙二醇一甲醚、乙二醇二甲醚或冰醋酸、二甲基甲酰胺、二甲基亚砜、乙腈、吡啶和六甲基磷酰胺。Suitable solvents for this reaction are all inert organic solvents. These solvents preferably include alcohols such as ethanol, methanol, isopropanol, ethers such as dioxane, diethyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether or glacial acetic acid, dimethyl formaldehyde amides, dimethylsulfoxide, acetonitrile, pyridine, and hexamethylphosphoramide.
反应温度可在较宽的范围内变化。通常该反应在20-150℃进行，但优选在各溶剂的沸点进行。The reaction temperature can be varied within wide ranges. Usually the reaction is carried out at 20-150°C, but preferably at the boiling point of each solvent.
该反应可在常压，但也可在升高的压力下进行。通常该反应在常压下进行。The reaction can be carried out at normal pressure, but also under elevated pressure. Usually the reaction is carried out under normal pressure.
该反应可在加入或不加入碱或酸的条件下进行。有机酸如甲酸、冰醋酸、甲磺酸、对甲苯磺酸，无机酸如盐酸、硫酸、磷酸、硝酸等。但本发明反应优选在相对弱的酸如乙酸或甲酸的存在下进行。The reaction can be carried out with or without the addition of base or acid. Organic acids such as formic acid, glacial acetic acid, methanesulfonic acid, p-toluenesulfonic acid, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc. However, the reaction of the invention is preferably carried out in the presence of a relatively weak acid such as acetic or formic acid.
该反应适用的碱优选包括有机碱如三乙胺、甲基二乙胺、吡啶、六氢吡啶、吗啉，无机碱如碳酸钠、碳酸钾、碳酸氢钠、醋酸纳、氢氧化钠、氢氧化钾。Suitable bases for this reaction preferably include organic bases such as triethylamine, methyldiethylamine, pyridine, hexahydropyridine, morpholine, inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, hydrogen Potassium oxide.
用作起始物质的通式(II)的烯胺在某些情况下是已知的，或者可以按照文献中记载的已知方法制备(参见Mara E.F.B.，Hugo S.B.，Lauri M，et al.Synthesis，1994，898-900)。The enamines of general formula (II) used as starting materials are known in some cases or can be prepared according to known methods described in the literature (see Mara E.F.B., Hugo S.B., Lauri M, et al. Synthesis , 1994, 898-900).
用作起始物质的通式(IV)的是已知的，或者可以按照文献中记载的已知方法制备(David C.Baker，Sterling R.Synthesis，1978，6，478-479.)。The starting materials of the general formula (IV) are known or can be prepared according to known methods described in the literature (David C. Baker, Sterling R. Synthesis, 1978, 6, 478-479.).
本发明通式(I)化合物可以用常规方法单个合成，亦可用组合化学的混-分方法或平行合成的方法以库(每个库中至少含两个，或5-1000个，最好是10-100个化合物)为单位合成，即可以在液相中合成也可以用固相合成方法。The compound of general formula (I) of the present invention can be single-synthesized with conventional method, also can use the mixing-dividing method of combinatorial chemistry or the method for parallel synthesis with library (contain two at least in each library, or 5-1000, preferably 10-100 compounds) can be synthesized as a unit, that is, it can be synthesized in liquid phase or solid phase synthesis method.
关于制备通式(I)化合物更详尽的资料见实施例。More detailed information on the preparation of compounds of general formula (I) is given in the Examples.
本发明化合物的抗病毒作用按Sells等人(M.A.Sells，M.L.Chen，G.Proc.Natl.Acad.Sci.1987，84，1005-1009)和Korba等(B.E.Korba，J.L.Gerin Antiviral Research 1992，19，55-70)描述的方法测定。(M.A.Sells, M.L.Chen, G.Proc.Natl.Acad.Sci.1987,84,1005-1009) and Korba etc. (B.E.Korba, J.L.Gerin Antiviral Research 1992,19 , 55-70) were determined by the method described.
在96孔微量滴定板中进行抗病毒试验。该板的第一竖行只含生长培养基和HepG 2.2.15细胞，用作空白对照。Antiviral assays were performed in 96-well microtiter plates. The first vertical row of the plate contains only growth medium and HepG 2.2.15 cells and serves as a blank control.
首先将试验化合物的贮备液(50毫摩尔)溶解在DMSO中，用HepG 2.2.15细胞生长培养基制备进一步稀释液。通常将本发明的化合物以100μg/ml的试验浓度(第1试验浓度)吸移到微量滴定板第二竖试验排的各孔中，然后用生长培养基加2％胎牛血清(25μl)进行稀释，每次稀释2倍，稀释最高达210倍。Stock solutions (50 mmol) of test compounds were first dissolved in DMSO and further dilutions were prepared in HepG 2.2.15 cell growth medium. Typically, the compounds of the present invention are pipetted into the wells of the second vertical test row of the microtiter plate at a test concentration of 100 μg/ml (the first test concentration), followed by growth medium plus 2% fetal calf serum (25 μl). Dilution, each dilution is 2 times, and the dilution is up to 210 times.
然后将225μl HepG 2.2.15细胞在生长培养基加2％胎牛血清中的悬浮液(5×104个细胞/ml)加到该96孔微量滴定板的每个孔中。225 μl of a suspension of HepG 2.2.15 cells in growth medium plus 2% fetal calf serum (5×104 cells/ml) was then added to each well of the 96-well microtiter plate.
该试验混合物在37℃，5％CO2条件下培育4天。然后吸出上清液并弃去，在各孔中加入225μl新制备的生长培养基。再次加入本发明化合物，溶液体积25μl。将该混合物再培育4天。The assay mixture was incubated for 4 days at 37°C, 5% CO2 . The supernatant was then aspirated and discarded, and 225 μl of freshly prepared growth medium was added to each well. The compound of the present invention was added again, and the volume of the solution was 25 μl. The mixture was incubated for an additional 4 days.
在收获上清液测定抗病毒效果之前用光学显微镜技术或生物化学检测方法(如Alamar Blue染色或Trypan Blue染色)考察HepG2.2.15细胞毒性变化。Before harvesting the supernatant to measure the antiviral effect, use light microscopy or biochemical detection methods (such as Alamar Blue staining or Trypan Blue staining) to examine the cytotoxicity changes of HepG2.2.15.
然后收集上清液，并用真空将其吸收到用尼龙膜盖住的96孔斑点印迹室中(按生产商的使用说明)。The supernatant was then collected and vacuumed into a 96-well dot blot chamber covered with a nylon membrane (per manufacturer's instructions).
细胞毒性测定Cytotoxicity assay
由物质诱发的在HepG 2.2.15细胞中的细胞毒性或抑制细胞的变化可采用例如光学显微镜技术来测定，并以细胞形态的变化表示。这类在HepG 2.2.15细胞中由物质诱发的变化与未经处理的细胞相比是明显的，例如细胞溶解、空泡形成或细胞形态改变。以观察细胞病变为指标，8天显微镜下观察细胞病变，完全破坏为4；75％为3；50％为2；25％为1；无病变为0。计算各浓度下平均细胞病变程度和抑制百分数。按Reed&Muench法计算半数有毒浓度(TC50)，最大无毒浓度(TC0)。Cytotoxic or cytostatic changes induced by substances in HepG 2.2.15 cells can be determined, for example, using light microscopy techniques and expressed as changes in cell morphology. Such substance-induced changes were evident in HepG 2.2.15 cells compared to untreated cells, such as cell lysis, vacuolation or changes in cell morphology. Taking the observation of cell lesions as an index, observe the cell lesions under a microscope after 8 days, 4 for complete destruction; 3 for 75%; 2 for 50%; 1 for 25%; 0 for no lesion. Calculate the average cytopathic degree and inhibition percentage at each concentration. Calculate the half toxic concentration (TC50 ) and the maximum non-toxic concentration (TC0 ) according to the Reed&Muench method.
TC50是指50％的细胞具有与相应的细胞对照相似的形态时的本发明化合物的浓度。TC50 refers to the concentration of the compound of the invention at which 50% of the cells have a morphology similar to the corresponding cell control.
抗病毒活性测定Antiviral activity assay
将上清液转移到斑点装置(参见上文)的尼龙膜上之后，将HepG2.2.15细胞的上清液变性(1.5M NaCl/0.5M NaOH)、中和(3MNaCl/0.5M Tris HCl，pH 7.5)和洗涤(2x SSC)。然后将滤膜在120℃保温2-4小时使DNA被烘烤到该膜上。After transferring the supernatant to the nylon membrane of the dot apparatus (see above), the supernatant of HepG2.2.15 cells was denatured (1.5M NaCl/0.5M NaOH), neutralized (3M NaCl/0.5M Tris HCl, pH 7.5) and wash (2x SSC). The filter was then incubated at 120°C for 2-4 hours to allow the DNA to be baked onto the membrane.
DNA杂交DNA hybridization
通常采用非放射活性地高辛配基标记的乙型肝炎特异性DNA探针来测定尼龙滤膜上处理后的HepG 2.2.15细胞的病毒DNA。其中，每次都是依据生产商的使用说明将所述探针用地高辛配基标记、纯化和杂交。A non-radioactive digoxigenin-labeled hepatitis B-specific DNA probe is usually used to detect viral DNA from treated HepG 2.2.15 cells on nylon filters. Each time, the probes were labeled with digoxigenin, purified and hybridized according to the manufacturer's instructions.
简单地说，预杂化和杂化是在5×SSC、1×封闭剂、0.1％N-月桂酰肌氨酸、0.02％SDS和100μg青鱼精子DNA中进行预杂交和杂交。在60℃进行30分钟预杂交，用20-40ng/ml地高辛配基化的变性HBV特异性DNA进行特异性杂交(14小时，60℃)。然后将过滤膜进行洗涤，进行HBV DNA的地高辛配基抗体检测。Briefly, prehybridization and hybridization were performed in 5×SSC, 1×blocker, 0.1% N-lauroyl sarcosine, 0.02% SDS and 100 μg of herring sperm DNA. Prehybridization was performed at 60°C for 30 minutes, and specific hybridization was performed with 20-40 ng/ml digoxigenated denatured HBV-specific DNA (14 hours, 60°C). Then the filter membrane was washed, and the digoxigenin antibody detection of HBV DNA was carried out.
地高辛配基标记的DNA的免疫学检测按生产商的说明进行。Immunological detection of digoxigenin-labeled DNA was performed according to the manufacturer's instructions.
简单地说，该滤膜用封闭剂进行洗涤和预杂交(按制造商的说明)，然后用事先偶联到碱性磷酸酶上的抗-DIG抗体进行杂交30分钟。洗涤后，加入碱性磷酸酯酶底物CSPD，与滤器一起培养5分钟，然后包在塑料薄膜中，并在37℃再培养15分钟。将过滤器暴露于x-射线膜上测量乙型肝炎特定DNA的化学发光信号(根据信号强度培养10分钟至2小时)，计算半数抑制浓度(IC50)。Briefly, the filters were washed with blocking agent and prehybridized (according to the manufacturer's instructions), followed by hybridization for 30 minutes with anti-DIG antibody previously conjugated to alkaline phosphatase. After washing, the alkaline phosphatase substrate CSPD was added, incubated with the filters for 5 minutes, then wrapped in plastic film and incubated for an additional 15 minutes at 37°C. The filter was exposed to x-ray film to measure the chemiluminescence signal of hepatitis B specific DNA (incubation for 10 minutes to 2 hours according to the signal intensity), and the half maximal inhibitory concentration (IC50 ) was calculated.
半数抑制浓度(IC50)是指与未处理样品相比，使乙型肝炎特异性带减少50％时本发明化合物的浓度。The half inhibitory concentration (IC50 ) refers to the concentration of the compound of the present invention that reduces the hepatitis B-specific band by 50% compared with the untreated sample.
本发明的化合物显示出较强的抗病毒作用。这类化合物对乙型肝炎(HBV)具有出乎预料的抗病毒活性，因此适于用来治疗病毒引起的各种疾病，尤其是急性和慢性持久性HBV病毒感染引起的疾病。由HBV引起的慢性病毒性疾病可以导致各种不同严重程度的综合症状，众所周知，慢性乙型肝炎病毒感染可导致肝硬化和(或)肝细胞癌。The compound of the present invention shows strong antiviral effect. These compounds have unexpected antiviral activity against hepatitis B (HBV), and are therefore suitable for treating various diseases caused by viruses, especially diseases caused by acute and chronic persistent HBV virus infection. Chronic viral diseases caused by HBV can lead to syndromes of varying severity. It is well known that chronic hepatitis B virus infection can lead to liver cirrhosis and/or hepatocellular carcinoma.
可用本发明化合物治疗的适应症的实例有：Examples of indications which may be treated with the compounds of the invention are:
治疗可导致感染性肝炎的急性和慢性病毒感染的，例如乙型肝炎病毒感染。特别优选的是慢性乙型肝炎感染的治疗和急性乙型肝炎病毒感染的治疗。Treatment of acute and chronic viral infections, such as hepatitis B virus infection, that can lead to infectious hepatitis. Particularly preferred are the treatment of chronic hepatitis B infection and the treatment of acute hepatitis B virus infection.
本发明化合物的药物组合物，可以以下方面的任意方式施与：口服、喷雾吸入、直肠给药、鼻腔给药、阴道给药、局部给药、非肠道给药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内或颅内注射或输入，或借助一种外植的储器用药，其中优选口服、肌注、腹膜内或静脉内用药方式。Pharmaceutical compositions of the compounds of this invention may be administered in any of the following ways: oral, inhalation spray, rectal, nasal, vaginal, topical, parenteral e.g. subcutaneous, intravenous, intramuscular , intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or administration via an explanted reservoir, wherein oral administration, intramuscular injection, intraperitoneal administration or intravenous administration are preferred.
本发明化合物或含有本发明化合物的药物组合物可以单位剂量形式给药。给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、埋植剂、贴剂、擦剂等。The compounds of the present invention or pharmaceutical compositions containing the compounds of the present invention may be administered in unit dosage form. The dosage forms for administration may be liquid dosage forms or solid dosage forms. The liquid dosage form can be true solution type, colloid type, particle dosage form, emulsion dosage form, suspension dosage form. Other dosage forms such as tablets, capsules, drop pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powder injections, clathrates, implants, patches, wipes agent etc.
本发明的药物组合物中还可以含有常用的载体，这里所述可药用载体包括但不局限于：离子交换剂，氧化铝，硬脂酸铝，卵磷脂，血清蛋白如人血清蛋白，缓冲物质如磷酸盐，甘油，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜂蜡，羊毛酯等。载体在药物组合物中的含量可以是1％-98％重量，通常大约占到80％重量。为方便起见，局部麻醉剂，防腐剂，缓冲剂等可直接溶于载体中。The pharmaceutical composition of the present invention can also contain commonly used carriers, and the pharmaceutically acceptable carriers described here include but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer Substances such as phosphates, glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts , colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin, etc. The content of the carrier in the pharmaceutical composition can be 1%-98% by weight, usually about 80% by weight. For convenience, local anesthetics, preservatives, buffers, etc. can be directly dissolved in the vehicle.
口服片剂和胶囊可以含有赋形剂如粘合剂，如糖浆，阿拉伯胶，山梨醇，黄芪胶，或聚乙烯吡咯烷酮，填充剂，如乳糖，蔗糖，玉米淀粉，磷酸钙，山梨醇，氨基乙酸，润滑剂，如硬脂酸镁，滑石，聚乙二醇，硅土，崩解剂，如马铃薯淀粉，或可接受的增润剂，如月桂醇钠硫酸盐。片剂可以用制药学上公知的方法包衣。Oral tablets and capsules may contain excipients such as binders such as syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone, fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, amino Acetic acid, lubricants such as magnesium stearate, talc, polyethylene glycol, silica, disintegrants such as potato starch, or acceptable moisturizers such as sodium lauryl sulfate. Tablets can be coated by methods known in pharmacy.
口服液可以制成水和油的悬浮液，溶液，乳浊液，糖浆或酏剂，也可以制成干品，用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂，如悬浮剂，山梨醇，纤维素甲醚，葡萄糖糖浆，凝胶，羟乙基纤维素，羧甲基纤维素，硬脂酸铝凝胶，氢化的食用油脂，乳化剂，如卵磷脂，山梨聚醣单油酸盐，阿拉伯胶；或非水载体(可能包含可食用油)，如杏仁油，油脂如甘油，乙二醇，或乙醇；防腐剂，如对羟基苯甲酸甲酯或丙酯，山梨酸。如需要可添加调味剂或着色剂。Oral solutions can be made into water and oily suspensions, solutions, emulsions, syrups or elixirs, and can also be made into dry products, which must be supplemented with water or other suitable media before use. This liquid preparation may contain conventional additives such as suspending agent, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible Fats, emulsifiers, such as lecithin, sorbitan monooleate, acacia; or non-aqueous vehicles (which may contain edible oils), such as almond oil, fats such as glycerin, glycol, or ethanol; preservatives, Such as methyl or propyl paraben, sorbic acid. Flavoring or coloring agents may be added if desired.
栓剂可包含常规的栓剂基质，如可可黄油或其它甘油酯。Suppositories may contain conventional suppository bases, such as cocoa butter or other glycerides.
对胃外投药，液态剂型通常由化合物和一种消毒的载体制成。载体首选水。依照所选载体和药物浓度的不同，化合物既可溶于载体中也可制成悬浮溶液，在制成注射用溶液时先将化合物溶于水中，过滤消毒后装入封口瓶或安瓿中。For parenteral administration, liquid dosage forms usually consist of the compound and a sterile carrier. The preferred carrier is water. Depending on the selected carrier and the concentration of the drug, the compound can be dissolved in the carrier or made into a suspension solution. When making a solution for injection, the compound is first dissolved in water, filtered and sterilized, and then filled into a sealed bottle or ampoule.
当皮肤局部施用时，本发明化合物可以制成适当的软膏，洗剂，或霜剂的形式，其中活性成分悬浮或溶解于一种或多种的载体中。其中软膏制剂可以使用的载体包括但不局限于：矿物油，液体凡士林，白凡士林，丙二醇，聚氧化乙烯，聚氧化丙烯，乳化蜡和水；洗剂和霜剂可使用的载体包括但不限于：矿物油，脱水山梨糖醇单硬脂酸酯，吐温60，十六烷酯蜡，十六碳烯芳醇，2-辛基十二烷醇，苄醇和水。When applied topically to the skin, the compounds of the invention may be formulated in suitable ointments, lotions, or creams in which the active ingredients are suspended or dissolved in one or more carriers. Carriers that can be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water; carriers that can be used in lotions and creams include, but are not limited to : Mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, hexadecenyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
在上述药物制剂中通式(I)的活性化合物的存在浓度应为该混合物总重量的约0.1～99.5％，优选约0.5～95％(重量)。The active compound of general formula (I) in the above pharmaceutical preparations should be present in a concentration of about 0.1 to 99.5%, preferably about 0.5 to 95% by weight, based on the total weight of the mixture.
上述药物制剂除了包含通式(I)的化合物外，还可进一步包含其它的药物活性化合物。The above-mentioned pharmaceutical preparations may further comprise other pharmaceutically active compounds in addition to the compound of general formula (I).
一般而言，已经证明有利的是无论在人体医药还是在兽医药中，本发明活性化合物的给药总量每24小时为约0.5-500mg，优选1-100mg/kg体重，如果合适的话，分多次单剂量给药，以达到所要求的效果。单剂量中含活性化合物的量优选为约1-80mg，更优选为1-50mg/kg体重，但也可以不按照上述的剂量，即取决于治疗对象的种类和体重、疾病的性质和严重程度、制剂的类型和药物的给药方式，以及给药周期或时间间隔。In general, it has proven to be advantageous whether in human medicine or in veterinary medicine to administer the active compound according to the invention in a total amount of about 0.5-500 mg, preferably 1-100 mg/kg body weight per 24 hours, divided if appropriate. Multiple single doses are administered to achieve the desired effect. The amount of the active compound in a single dose is preferably about 1-80 mg, more preferably 1-50 mg/kg body weight, but may not follow the above-mentioned dosage, that is, depends on the type and body weight of the treatment object, the nature and severity of the disease , the type of preparation and the mode of administration of the drug, as well as the period or time interval of administration.
具体实施方式Detailed ways
下面通过具体的实施例进一步说明本发明，但是，应当理解为，这些实施例仅仅是用于更详细具体地说明之用，而不应理解为用于以任何形式限制本发明。The present invention will be further illustrated by specific examples below, but it should be understood that these examples are only used for more detailed description, and should not be construed as limiting the present invention in any form.
本发明对试验中所使用到的材料以及试验方法进行一般性和/或具体的描述。虽然为实现本发明目的所使用的许多材料和操作方法是本领域公知的，但是本发明仍然在此作尽可能详细描述。本领域技术人员清楚，在下文中，如果未特别说明，本发明所用材料和操作方法是本领域公知的。The present invention provides general and/or specific descriptions of the materials and test methods used in the tests. While many of the materials and methods of manipulation which are employed for the purposes of the invention are well known in the art, the invention has been described here in as much detail as possible. It will be clear to those skilled in the art that in the following, unless otherwise specified, the materials and operation methods used in the present invention are well known in the art.
化合物的熔点由RY-1熔点仪测定，温度计未较正。质谱由Micromass ZabSpec高分辨率质谱仪(分辨率1000)测定。1H NMR由JNM-ECA-400超导NMR仪测定，工作频率1H NMR 400MHz。The melting point of the compound was determined by RY-1 melting point apparatus, and the thermometer was not corrected. Mass spectra were determined by a Micromass ZabSpec high-resolution mass spectrometer (resolution 1000).1 H NMR was measured by a JNM-ECA-400 superconducting NMR instrument, and the working frequency of1 H NMR was 400MHz.
实施例Example
实施例1：2-甲基-4-苯基-5-硝基-6-(4-甲基苯基)-1，4-二氢吡啶Example 1: 2-methyl-4-phenyl-5-nitro-6-(4-methylphenyl)-1,4-dihydropyridine-3-羧酸乙酯-3-Carboxylic acid ethyl ester
步骤1：2-硝基对甲苯乙酮的合成Step 1: Synthesis of 2-nitro-p-methylacetophenone
将5.68g(94mmol)硝基甲烷缓慢滴入0.96gNaH(24mmol)的20ml无水THF溶液中，滴加结束，室温搅拌至不再有气泡冒出，放置备用。Slowly drop 5.68g (94mmol) of nitromethane into a solution of 0.96gNaH (24mmol) in 20ml of anhydrous THF. After the addition is complete, stir at room temperature until no more bubbles emerge, and set aside for later use.
将2.72g对甲苯甲酸(20mmol)、3.89g碳酰二咪唑(24mmol)在50ml无水THF中回流1h，TLC检测反应完全。将反应液缓慢滴加至上述备用液中，滴加结束，回流16h。冷却，过滤，150ml水溶解，盐酸调pH至约3.0。乙酸乙酯萃取数次，合并有机层，浓缩，得到粗品。粗品溶于乙酸乙酯，加入石油醚，析出晶体。过滤干燥即得微黄色结晶1.79g。收率：50％。熔点：145-147℃。2.72g of p-toluic acid (20mmol) and 3.89g of carbonyldiimidazole (24mmol) were refluxed in 50ml of anhydrous THF for 1h, and the reaction was complete as detected by TLC. The reaction solution was slowly added dropwise to the above standby solution, and after the dropwise addition was completed, it was refluxed for 16 hours. Cool, filter, dissolve in 150ml of water, and adjust the pH to about 3.0 with hydrochloric acid. Extracted several times with ethyl acetate, the organic layers were combined and concentrated to obtain a crude product. The crude product was dissolved in ethyl acetate, petroleum ether was added, and crystals were precipitated. It was filtered and dried to obtain 1.79 g of slightly yellow crystals. Yield: 50%. Melting point: 145-147°C.
步骤2：3-氨基-2-丁烯酸乙酯的合成Step 2: Synthesis of ethyl 3-amino-2-butenoate
将13.0g乙酰乙酸乙酯、3.0g蒙脱土k-10加入反应瓶中，室温搅拌。缓慢滴入10.0g氨水，搅拌过夜。二氯甲烷洗涤萃取，加入无水MgSO4干燥。过滤，浓缩，得到微黄色固体10.0g。收率：79.5％。熔点：107℃。Add 13.0 g of ethyl acetoacetate and 3.0 g of montmorillonite k-10 into the reaction flask, and stir at room temperature. Slowly add 10.0 g of ammonia water dropwise, and stir overnight. The extract was washed with dichloromethane and dried by adding anhydrous MgSO4 . It was filtered and concentrated to obtain 10.0 g of a light yellow solid. Yield: 79.5%. Melting point: 107°C.
步骤3：2-甲基-4-苯基-5-硝基-6-(4-甲基苯基)-1，4-二氢吡啶-3-羧Step 3: 2-Methyl-4-phenyl-5-nitro-6-(4-methylphenyl)-1,4-dihydropyridine-3-carboxy酸乙酯的合成Synthesis of ethyl acetate
将2-硝基对甲苯乙酮5mmol、苯甲醛8mmol、β-丙氨酸0.07g加入40ml甲苯中，滴入4ml冰醋酸，搅拌回流。反应3h，浓缩，残留物称重，加入等摩尔量的3-氨基-2-丁烯酸乙酯5mmol，15ml冰醋酸，室温搅拌20h。浓缩，柱层析得黄色结晶0.7g(收率38.9％)。m.p.193-194℃。1H NMR(DMSO-d6)(ppm)：1.169-1.204(3H，t，CH3)，2.311(3H，s，CH3)，2.374(3H，s，ArCH3)，4.070-4.088(2H，m，CH2)，5.312(1H，s，CH)，7.285-7.313(9H，m，ArH)，9.758(1H，s，NH)。MS(FAB)379.1(M+)。Add 5 mmol of 2-nitro-p-methylacetophenone, 8 mmol of benzaldehyde, and 0.07 g of β-alanine into 40 ml of toluene, drop into 4 ml of glacial acetic acid, and stir to reflux. React for 3 hours, concentrate, weigh the residue, add equimolar amount of 3-amino-2-butenoic acid ethyl ester 5mmol, 15ml glacial acetic acid, and stir at room temperature for 20 hours. Concentration, and column chromatography gave 0.7 g of yellow crystals (yield 38.9%). mp193-194°C.1 H NMR (DMSO-d6 ) (ppm): 1.169-1.204 (3H, t, CH3 ), 2.311 (3H, s, CH3 ), 2.374 (3H, s, ArCH3 ), 4.070-4.088 (2H , m,CH2 ), 5.312 (1H, s, CH), 7.285-7.313 (9H, m, ArH), 9.758 (1H, s, NH). MS (FAB) 379.1 (M+ ).
实施例2：2-甲基-4-(2-氯苯基)-5-硝基-6-(4-甲基苯基)-1，4-二氢Example 2: 2-methyl-4-(2-chlorophenyl)-5-nitro-6-(4-methylphenyl)-1,4-dihydro吡啶-3-羧酸乙酯Ethyl pyridine-3-carboxylate
采用实施例1的方法，将其中的苯甲醛改为2-氯苯甲醛，得0.25g黄色结晶，收率12.1％，m.p.205-206℃。1H NMR(DMSO-d6)(ppm)：1.107-1.143(3H，t，CH3)，2.494(3H，s，CH3)，2.498(3H，s，ArCH3)，4.002-4.019(2H，m，CH2)，5.689(1H，s，CH)，7.226-7.353(8H，m，ArH)，9.750(1H，s，NH)。MS(FAB)413.1(M+)。Using the method of Example 1, the benzaldehyde therein was changed to 2-chlorobenzaldehyde to obtain 0.25 g of yellow crystals, yield 12.1%, mp 205-206°C.1 H NMR (DMSO-d6) (ppm): 1.107-1.143 (3H, t, CH3 ), 2.494 (3H, s, CH3 ), 2.498 (3H, s, ArCH3 ), 4.002-4.019 (2H, m,CH2 ), 5.689 (1H, s, CH), 7.226-7.353 (8H, m, ArH), 9.750 (1H, s, NH). MS (FAB) 413.1 (M+ ).
实施例3：2-甲基-4-(3-氯苯基)-5-硝基-6-(4-甲基苯基)-1，4-二氢Example 3: 2-methyl-4-(3-chlorophenyl)-5-nitro-6-(4-methylphenyl)-1,4-dihydro吡啶-3-羧酸乙酯Ethyl pyridine-3-carboxylate
采用实施例1的方法，将其中的苯甲醛改为2-氯苯甲醛，得0.21g黄色结晶，收率10.2％，m.p.141-142℃。1H NMR(DMSO-d6)(ppm)：1.171-1.207(3H，t，CH3)，2.328(3H，s，CH3)，2.376(3H，s，ArCH3)，4.061-4.092(2H，m，CH2)，5.299(1H，s，CH)，7.280-7.316(8H，m，ArH)，9.818(1H，s，NH)。MS(FAB)413.0(M+)。Using the method of Example 1, the benzaldehyde was changed to 2-chlorobenzaldehyde to obtain 0.21 g of yellow crystals, the yield was 10.2%, and the mp was 141-142°C.1 H NMR (DMSO-d6) (ppm): 1.171-1.207 (3H, t, CH3 ), 2.328 (3H, s, CH3 ), 2.376 (3H, s, ArCH3 ), 4.061-4.092 (2H, m,CH2 ), 5.299 (1H, s, CH), 7.280-7.316 (8H, m, ArH), 9.818 (1H, s, NH). MS (FAB) 413.0 (M+ ).
实施例4：2-甲基-4-(2-氯苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-Example 4: 2-methyl-4-(2-chlorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-二氢吡啶-3-羧酸乙酯Ethyl dihydropyridine-3-carboxylate
将2-氯苯甲醛8mmol、2-硝基三氟苯乙酮5mmol、0.07g的β-丙氨酸加入40ml甲苯中，滴入4ml冰醋酸，搅拌回流。反应3h，浓缩，残留物称重，加入等摩尔量的3-氨基-2-丁烯酸乙酯6.7mmol，15ml冰醋酸，室温搅拌20h。浓缩，柱层析得黄色粉末0.4g。收率：17.7％。产物熔点m.p.176-177℃。1H NMR(DMSO-d6)(ppm)：1.111-1.147(3H，t，CH3)，2.497(3H，s，CH3)，4.021-4.039(2H，m，CH2)，5.784(1H，s，CH)，7.329-7.460(6H，m，ArH)，10.081(1H，s，NH)。MS(FAB)453.0(M+)。Add 8 mmol of 2-chlorobenzaldehyde, 5 mmol of 2-nitrotrifluoroacetophenone, and 0.07 g of β-alanine into 40 ml of toluene, drop in 4 ml of glacial acetic acid, and stir to reflux. React for 3 hours, concentrate, weigh the residue, add equimolar amount of 3-amino-2-butenoic acid ethyl ester 6.7mmol, 15ml glacial acetic acid, and stir at room temperature for 20 hours. Concentration and column chromatography gave 0.4 g of yellow powder. Yield: 17.7%. The melting point of the product is mp176-177°C.1 H NMR (DMSO-d6) (ppm): 1.111-1.147 (3H, t, CH3 ), 2.497 (3H, s, CH3 ), 4.021-4.039 (2H, m, CH2 ), 5.784 (1H, s, CH), 7.329-7.460 (6H, m, ArH), 10.081 (1H, s, NH). MS (FAB) 453.0 (M+ ).
实施例5：2-甲基-4-(3-氯苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-Example 5: 2-methyl-4-(3-chlorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-二氢吡啶-3-羧酸乙酯Ethyl dihydropyridine-3-carboxylate
采用实施例4的方法，将其中2-氯苯甲醛改为3-氯苯甲醛，得0.2g桔黄色针状结晶，收率17.8％，m.p.150-151℃。1H NMR(DMSO-d6)(ppm)：1.181-1.217(3H，t，CH3)，2.302(3H，s，CH3)，4.087-4.118(2H，m，CH2)，5.378(1H，s，CH)，7.299-7.354(6H，m，ArH)，10.166(1H，s，NH)。MS(FAB)453.0(M+)。Using the method of Example 4, 2-chlorobenzaldehyde was changed to 3-chlorobenzaldehyde to obtain 0.2 g of orange needle crystals, yield 17.8%, mp 150-151°C.1 H NMR (DMSO-d6) (ppm): 1.181-1.217 (3H, t, CH3 ), 2.302 (3H, s, CH3 ), 4.087-4.118 (2H, m, CH2 ), 5.378 (1H, s, CH), 7.299-7.354 (6H, m, ArH), 10.166 (1H, s, NH). MS (FAB) 453.0 (M+ ).
实施例6：2-甲基-4-(2-氯苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡Example 6: 2-methyl-4-(2-chlorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine啶-3-羧酸乙酯Ethyl pyrene-3-carboxylate
将2-氯苯甲醛8mmol、2-硝基噻吩乙酮5mmol、0.07g的β-丙氨酸加入40ml甲苯中，滴入4ml冰醋酸，搅拌回流。反应3h，浓缩，残留物称重，加入等摩尔量的3-氨基-2-丁烯酸乙酯8mmol，15ml冰醋酸，室温搅拌20h。浓缩，柱层析得桔黄色结晶0.2g。收率：9.9％。产物熔点m.p.146-147℃。1H NMR(DMSO-d6)(ppm)：1.105-1.140(3H，t，CH3)，2.301(3H，s，CH3)，3.990-4.025(2H，q，CH2)，5.682(1H，s，CH)，7.183-7.443(6H，m，ArH，C4H3SH)，7.804-7.820(1H，q，C4H3SH)，9.862(1H，s，NH)。MS(FAB)405.1(M+)。Add 8mmol of 2-chlorobenzaldehyde, 5mmol of 2-nitrothiophenetophenone, and 0.07g of β-alanine into 40ml of toluene, drop in 4ml of glacial acetic acid, and stir to reflux. React for 3 hours, concentrate, weigh the residue, add equimolar amount of 3-amino-2-butenoic acid ethyl ester 8mmol, 15ml glacial acetic acid, and stir at room temperature for 20 hours. Concentration and column chromatography gave 0.2 g of orange crystals. Yield: 9.9%. The melting point of the product is mp146-147°C.1 H NMR (DMSO-d6) (ppm): 1.105-1.140 (3H, t, CH3 ), 2.301 (3H, s, CH3 ), 3.990-4.025 (2H, q, CH2 ), 5.682 (1H, s,CH) , 7.183-7.443 (6H,m , ArH, C4H3SH), 7.804-7.820 (1H, q,C4H3SH ), 9.862 (1H, s, NH). MS (FAB) 405.1 (M+ ).
实施例7：2-甲基-4-(4-氟苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡Example 7: 2-methyl-4-(4-fluorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine啶-3-羧酸乙酯Ethyl pyrene-3-carboxylate
采用实施例6的方法，将其中2-氯苯甲醛改为4-氟苯甲醛，得0.25g黄色结晶，收率12.6％，m.p.145-146℃。1H NMR(DMSO-d6)(ppm)：1.160-1.196(3H，t，CH3)，2.338(3H，s，CH3)，4.075-4.092(2H，m，CH2)，5.294(1H，s，CH)，7.159-7.393(6H，m，ArH，C4H3SH)，7.845-7.858(1H，q，C4H3SH)，9.952(1H，s，NH)。MS(FAB)389.1(M+)。Using the method of Example 6, 2-chlorobenzaldehyde was changed to 4-fluorobenzaldehyde to obtain 0.25 g of yellow crystals, yield 12.6%, mp 145-146°C.1 H NMR (DMSO-d6) (ppm): 1.160-1.196 (3H, t, CH3 ), 2.338 (3H, s, CH3 ), 4.075-4.092 (2H, m, CH2 ), 5.294 (1H, s, CH) , 7.159-7.393 (6H,m , ArH, C4H3SH),7.845-7.858 (1H, q,C4H3SH ), 9.952 (1H, s, NH). MS (FAB) 389.1 (M+ ).
实施例8：2-甲基-4-(2-甲氧基苯基)-5-硝基-6-(2-噻吩基)-1，4-Example 8: 2-methyl-4-(2-methoxyphenyl)-5-nitro-6-(2-thienyl)-1,4-二氢吡啶-3-羧酸乙酯Ethyl dihydropyridine-3-carboxylate
采用实施例6的方法，将其中的2-氯苯甲醛改为2-甲氧基苯甲醛，得0.32g红色结晶，收率16％，m.p.173-174℃。1H NMR(DMSO-d6)(ppm)：1.137-1.173(3H，t，CH3)，2.255(3H，s，CH3)，3.749(3H，s，OCH3)，3.992-4.028(2H，q，CH2)，5.459(1H，s，CH)，7.172-7.219(5H，m，ArH，C4H3SH)，7.310-7.318(1H，d，C4H3SH)，7.797-7.809(1H，d，C4H3SH)，9.807(1H，s，NH)。MS(FAB)401.1(M+)。Using the method of Example 6, 2-chlorobenzaldehyde was changed to 2-methoxybenzaldehyde to obtain 0.32 g of red crystals, yield 16%, mp 173-174°C.1 H NMR (DMSO-d6) (ppm): 1.137-1.173 (3H, t, CH3 ), 2.255 (3H, s, CH3 ), 3.749 (3H, s, OCH3 ), 3.992-4.028 (2H, q, CH2 ), 5.459 (1H, s, CH), 7.172-7.219 (5H, m, ArH, C4 H3 SH), 7.310-7.318 (1H, d, C4 H3 SH), 7.797-7.809 (1H, d,C4H3SH ), 9.807 (1H , s, NH). MS (FAB) 401.1 (M+ ).
实施例9：2-甲基-4-(2-溴苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢吡Example 9: 2-methyl-4-(2-bromophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine啶-3-羧酸乙酯Ethyl pyrene-3-carboxylate
采用实施例6的方法，将其中2-氯苯甲醛改为2-溴苯甲醛，得0.31g红色结晶，收率13.8％，m.p.144-145℃。1H NMR(DMSO-d6)(ppm)：1.106-1.141(3H，t，CH3)，2.295(3H，s，CH3)，4.017-4.035(2H，m，CH2)，5.662(1H，s，CH)，7.167-7.440(5H，m，ArH，C4H3SH)，7.533-7.551(1H，d，C4H3SH)，7.800-7.814(1H，q，C4H3SH)，9.827(1H，s，NH)。MS(FAB)451.0(M+)。Using the method of Example 6, 2-chlorobenzaldehyde was changed to 2-bromobenzaldehyde to obtain 0.31 g of red crystals, yield 13.8%, mp 144-145°C.1 H NMR (DMSO-d6) (ppm): 1.106-1.141 (3H, t, CH3 ), 2.295 (3H, s, CH3 ), 4.017-4.035 (2H, m, CH2 ), 5.662 (1H, s, CH), 7.167-7.440 (5H, m, ArH, C4 H3 SH), 7.533-7.551 (1H, d, C4 H3 SH), 7.800-7.814 (1H, q, C4 H3 SH ), 9.827 (1H, s, NH). MS (FAB) 451.0 (M+ ).
实施例10：2-甲基-4-(3-氯苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢Example 10: 2-methyl-4-(3-chlorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydro吡啶-3-羧酸乙酯Ethyl pyridine-3-carboxylate
采用实施例6的方法，将其中的2-氯苯甲醛改为3-氯苯甲醛，得0.6g红色结晶，收率29.7％，m.p.130-131℃。1H NMR(DMSO-d6)(ppm)：1.174-1.210(3H，t，CH3)，2.346(3H，s，CH3)，4.086-4.119(2H，m，CH2)，5.287(1H，s，CH)，7.264-7.416(6H，m，ArH，C4H3SH)，7.861-7.874(1H，m，C4H3SH)，10.012(1H，s，NH)。MS(FAB)405.0(M+)。Using the method of Example 6, 2-chlorobenzaldehyde was changed to 3-chlorobenzaldehyde to obtain 0.6 g of red crystals, yield 29.7%, mp 130-131°C.1 H NMR (DMSO-d6) (ppm): 1.174-1.210 (3H, t, CH3 ), 2.346 (3H, s, CH3 ), 4.086-4.119 (2H, m, CH2 ), 5.287 (1H, s,CH) , 7.264-7.416 (6H,m , ArH, C4H3SH), 7.861-7.874 (1H, m,C4H3SH ), 10.012 (1H, s, NH). MS (FAB) 405.0 (M+ ).
实施例11：2-甲基-4-(4-氯苯基)-5-硝基-6-(2-噻吩基)-1，4-二氢Example 11: 2-methyl-4-(4-chlorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydro吡啶-3-羧酸乙酯Ethyl pyridine-3-carboxylate
采用实施例6的方法，将其中的2-氯苯甲醛改为4-氯苯甲醛，得0.18g黄色结晶，收率9％，m.p.148-149℃。1H NMR(DMSO-d6)(ppm)：1.162-1.197(3H，t，CH3)，2.339(3H，s，CH3)，4.070-4.088(2H，m，CH2)，5.283(1H，s，CH)，7.280-7.411(6H，m，ArH，C4H3SH)，7.849-7.862(1H，m，C4H3SH)，9.971(1H，s，NH)。MS(FAB)405.1(M+)。Using the method of Example 6, 2-chlorobenzaldehyde was changed to 4-chlorobenzaldehyde to obtain 0.18 g of yellow crystals, yield 9%, mp 148-149°C.1 H NMR (DMSO-d6) (ppm): 1.162-1.197 (3H, t, CH3 ), 2.339 (3H, s, CH3 ), 4.070-4.088 (2H, m, CH2 ), 5.283 (1H, s, CH) , 7.280-7.411 (6H,m , ArH, C4H3SH),7.849-7.862 (1H, m,C4H3SH ), 9.971 (1H, s, NH). MS (FAB) 405.1 (M+ ).
实施例12：2-甲基-4-(2-氯-4-氟苯基)-5-硝基-6-(2-噻吩基)-1，4-Example 12: 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2-thienyl)-1,4-二氢吡啶-3-羧酸乙酯Ethyl dihydropyridine-3-carboxylate
采用实施例6的方法，将其中的2-氯苯甲醛改为2-氯-4-氟苯甲醛，得0.3g红色结晶，收率14.2％，m.p.152-153℃。1H NMR(DMSO-d6)(ppm)：1.109-1.144(3H，t，CH3)，2.305(3H，s，CH3)，3.995-4.031(2H，q，CH2)，5.656(1H，s，CH)，7.162-7.347(4H，m，ArH，C4H3SH)，7.439-7.477(1H，q，C4H3SH)，7.806-7.822(1H，q，C4H3SH)，9.886(1H，s，NH)。MS(FAB)423.1(M+)。Using the method of Example 6, 2-chlorobenzaldehyde was changed to 2-chloro-4-fluorobenzaldehyde to obtain 0.3 g of red crystals, yield 14.2%, mp 152-153°C.1 H NMR (DMSO-d6) (ppm): 1.109-1.144 (3H, t, CH3 ), 2.305 (3H, s, CH3 ), 3.995-4.031 (2H, q, CH2 ), 5.656 (1H, s, CH), 7.162-7.347 (4H, m, ArH, C4 H3 SH), 7.439-7.477 (1H, q, C4 H3 SH), 7.806-7.822 (1H, q, C4 H3 SH ), 9.886 (1H, s, NH). MS (FAB) 423.1 (M+ ).
实施例13：2-甲基-4-(2-甲氧基苯基)-5-硝基-6-(2，4，6-三氟苯Example 13: 2-methyl-4-(2-methoxyphenyl)-5-nitro-6-(2,4,6-trifluorobenzene基)-1，4-二氢吡啶-3-羧酸乙酯base)-1,4-dihydropyridine-3-carboxylic acid ethyl ester
采用实施例4的方法，将其中的2-氯苯甲醛改为2-甲氧基苯甲醛，得0.6g黄色结晶，收率27％，m.p.163-164℃。1H NMR(DMSO-d6)(ppm)：1.131-1.166(3H，t，CH3)，2.231(3H，s，CH3)，3.754(3H，s，OCH3)，3.981-4.016(2H，q，CH2)，5.595(1H，s，CH)，6.849-6.887(1H，t，ArH)，6.955-6.976(1H，d，ArH)，7.173-7.241(2H，m，ArH)，7.351-7.430(2H，q，ArH)，9.948(1H，s，NH)。MS(FAB)449.1(M+)。Using the method of Example 4, the 2-chlorobenzaldehyde was changed to 2-methoxybenzaldehyde to obtain 0.6 g of yellow crystals, yield 27%, mp 163-164°C.1 H NMR (DMSO-d6) (ppm): 1.131-1.166 (3H, t, CH3 ), 2.231 (3H, s, CH3 ), 3.754 (3H, s, OCH3 ), 3.981-4.016 (2H, q, CH2 ), 5.595 (1H, s, CH), 6.849-6.887 (1H, t, ArH), 6.955-6.976 (1H, d, ArH), 7.173-7.241 (2H, m, ArH), 7.351- 7.430 (2H, q, ArH), 9.948 (1H, s, NH). MS (FAB) 449.1 (M+ ).
实施例14：2-甲基-4-(2-溴苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-Example 14: 2-methyl-4-(2-bromophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-二氢吡啶-3-羧酸乙酯Ethyl dihydropyridine-3-carboxylate
采用实施例4的方法，将其中2-氯苯甲醛改为2-溴苯甲醛，得0.63g黄色结晶，收率25％，m.p.173-174℃。1H NMR(DMSO-d6)(ppm)：1.120-1.155(3H，t，CH3)，2.276(3H，s，CH3)，4.050-4.068(2H，m，CH2)，5.760(1H，s，CH)，7.118-7.159(1H，m，ArH)，7.378-7.536(5H，m，ArH)，10.086(1H，s，NH)。MS(FAB)497.0(M+)。Using the method of Example 4, 2-chlorobenzaldehyde was changed to 2-bromobenzaldehyde to obtain 0.63 g of yellow crystals, yield 25%, mp 173-174°C.1 H NMR (DMSO-d6) (ppm): 1.120-1.155 (3H, t, CH3 ), 2.276 (3H, s, CH3 ), 4.050-4.068 (2H, m, CH2 ), 5.760 (1H, s, CH), 7.118-7.159 (1H, m, ArH), 7.378-7.536 (5H, m, ArH), 10.086 (1H, s, NH). MS (FAB) 497.0 (M+ ).
实施例15：2-甲基-4-(2-氯-4-氟苯基)-5-硝基-6-(2，4，6-三氟苯Example 15: 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4,6-trifluorobenzene基)-1，4-二氢吡啶-3-羧酸乙酯base)-1,4-dihydropyridine-3-carboxylic acid ethyl ester
采用实施例4的方法，将其中的2-氯苯甲醛改为2-氯-4-氟苯甲醛，得0.3g黄色结晶，收率13％，m.p.185-186℃。1H NMR(DMSO-d6)(ppm)：1.117-1.153(3H，t，CH3)，2.287(3H，s，CH3)，4.009-4.043(2H，q，CH2)，5.759(1H，s，CH)，7.238-7.245(1H，m，ArH)，7.324-7.493(4H，m，ArH)，10.152(1H，s，NH)。MS(FAB)471.1(M+)。Using the method of Example 4, 2-chlorobenzaldehyde was changed to 2-chloro-4-fluorobenzaldehyde to obtain 0.3 g of yellow crystals, yield 13%, mp 185-186°C.1 H NMR (DMSO-d6) (ppm): 1.117-1.153 (3H, t, CH3 ), 2.287 (3H, s, CH3 ), 4.009-4.043 (2H, q, CH2 ), 5.759 (1H, s, CH), 7.238-7.245 (1H, m, ArH), 7.324-7.493 (4H, m, ArH), 10.152 (1H, s, NH). MS (FAB) 471.1 (M+ ).
实施例16：2-甲基-4-(4-氯苯基)-5-硝基-6-(2，4，6-三氟苯基)-1，4-Example 16: 2-methyl-4-(4-chlorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-二氢吡啶-3-羧酸乙酯Ethyl dihydropyridine-3-carboxylate
采用实施例4的方法，将其中的2-氯苯甲醛分别改为4-氯苯甲醛，得0.15g黄色结晶，收率7％，m.p.160-161℃。1H NMR(DMSO-d6)(ppm)：1.166-1.201(3H，t，CH3)，2.300(3H，s，CH3)，4.053-4.071(2H，m，CH2)，5.366(1H，s，CH)，7.312-7.334(2H，d，ArH)，7.390-7.411(4H，m，ArH)，10.158(1H，s，NH)。MS(FAB)453.1(M+)。Using the method of Example 4, 2-chlorobenzaldehyde was changed to 4-chlorobenzaldehyde respectively to obtain 0.15 g of yellow crystals, yield 7%, mp 160-161°C.1 H NMR (DMSO-d6) (ppm): 1.166-1.201 (3H, t, CH3 ), 2.300 (3H, s, CH3 ), 4.053-4.071 (2H, m, CH2 ), 5.366 (1H, s, CH), 7.312-7.334 (2H, d, ArH), 7.390-7.411 (4H, m, ArH), 10.158 (1H, s, NH). MS (FAB) 453.1 (M+ ).
实施例17：2-甲基-4-(2-氯-4-氟苯基)-5-硝基-6-(2，4，6-三氟苯Example 17: 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4,6-trifluorobenzene基)-1，4-二氢吡啶-3-羧酸甲酯base)-1,4-dihydropyridine-3-carboxylic acid methyl ester
采用实施例4的方法，将其中的2-氯苯甲醛和3-氨基-2-丁烯酸乙酯分别改为2-氯-4-氟苯甲醛2-氨基-2-丁烯酸甲酯，得0.36g黄色结晶。收率16％，m.p.154-155。1HNMR(DMSO-d6)(ppm)：2.284(3H，s，CH3)，3.572(3H，s，CH3)，5.761(1H，s，CH)，7.216-7.265(1H，m，ArH)，7.323-7.484(4H，m，ArH)，10.170(1H，s，NH)。MS(FAB)457.0(M+)。Adopt the method for embodiment 4, change 2-chlorobenzaldehyde and 3-amino-2-butenoic acid ethyl ester into 2-chloro-4-fluorobenzaldehyde 2-amino-2-butenoic acid methyl ester respectively , to obtain 0.36 g of yellow crystals. Yield 16%, mp154-155.1 HNMR (DMSO-d6) (ppm): 2.284 (3H, s, CH3 ), 3.572 (3H, s, CH3 ), 5.761 (1H, s, CH), 7.216-7.265 (1H, m, ArH) , 7.323-7.484 (4H, m, ArH), 10.170 (1H, s, NH). MS (FAB) 457.0 (M+ ).
实施例18：2-甲基-4-(2-甲基苯基)-5-硝基-6-(2，4，6-三氟苯Example 18: 2-methyl-4-(2-methylphenyl)-5-nitro-6-(2,4,6-trifluorobenzene基)-1，4-二氢吡啶-3-羧酸乙酯base)-1,4-dihydropyridine-3-carboxylic acid ethyl ester
采用实施例4的方法，将其中的2-氯苯甲醛改为2-甲基苯甲醛，得0.7g黄色结晶，收率32％，m.p.177-178℃。1H NMR(DMSO-d6)(ppm)：1.122-1.158(3H，t，CH3)，2.291(3H，s，CH3)，2.503-2.567(3H，d，ArCH3)，4.022-4.057(2H，q，CH2)，5.551(1H，s，CH)，7.076-7.447(6H，m，ArH)，10.035(1H，s，NH)。MS(FAB)433.1(M+)。Using the method of Example 4, the 2-chlorobenzaldehyde was changed to 2-methylbenzaldehyde to obtain 0.7 g of yellow crystals, yield 32%, mp 177-178°C.1 H NMR (DMSO-d6) (ppm): 1.122-1.158 (3H, t, CH3 ), 2.291 (3H, s, CH3 ), 2.503-2.567 (3H, d, ArCH3 ), 4.022-4.057 ( 2H, q,CH2 ), 5.551 (1H, s, CH), 7.076-7.447 (6H, m, ArH), 10.035 (1H, s, NH). MS (FAB) 433.1 (M+ ).
实施例19：2-甲基-4-(2-甲基苯基)-5-硝基-6-(2-噻吩基)-1，4-二Example 19: 2-methyl-4-(2-methylphenyl)-5-nitro-6-(2-thienyl)-1,4-di氢吡啶-3-羧酸乙酯Ethyl hydropyridine-3-carboxylate
采用实施例6的方法，将其中的2-氯苯甲醛改为2-甲基苯甲醛，得0.7g黄色结晶，收率36％，m.p.171-172℃。1H NMR(DMSO-d6)(ppm)：1.115-1.151(3H，t，CH3)，2.316(3H，s，CH3)，2.499-2.507(3H，d，ArCH3)，4.012-4.047(2H，q，CH2)，5.457(1H，s，CH)，7.085-7.336(6H，m，ArH)，7.811-7.824(1H，d，C4H3SH)，9.812(1H，s，NH)。MS(FAB)385.1(M+)。Using the method of Example 6, 2-chlorobenzaldehyde was changed to 2-methylbenzaldehyde to obtain 0.7 g of yellow crystals, yield 36%, mp 171-172°C.1 H NMR (DMSO-d6) (ppm): 1.115-1.151 (3H, t, CH3 ), 2.316 (3H, s, CH3 ), 2.499-2.507 (3H, d, ArCH3 ), 4.012-4.047 ( 2H, q, CH2 ), 5.457 (1H, s, CH), 7.085-7.336 (6H, m, ArH), 7.811-7.824 (1H, d, C4 H3 SH), 9.812 (1H, s, NH ). MS (FAB) 385.1 (M+ ).
实施例20：1-乙酰基-2-甲基-4-(2-甲基苯基)-5-硝基-6-(2-噻吩Example 20: 1-Acetyl-2-methyl-4-(2-methylphenyl)-5-nitro-6-(2-thiophene基)-1，4-二氢吡啶-3-羧酸乙酯base)-1,4-dihydropyridine-3-carboxylic acid ethyl ester
将实施例19的产物0.2克溶于无水四氢呋喃5ml中，加入氢化钠22mg，至不再有气泡冒出，加入乙酰氯0.05ml，室温反应1小时，加水终止反应。浓缩，残渣用水、乙酸乙酯分液，有机相用硫酸钠干燥。过滤，浓缩柱层析得淡黄色固体0.18克。收率81％。1H NMR(DMSO-d6)(ppm)：1.12-1.15(3H，t，CH3)，2.04(3H，s，CH3)，2.33(3H，s，CH3)，2.50-2.52(3H，d，ArCH3)，4.02-4.07(2H，q，CH2)，5.46(1H，s，CH)，7.09-7.34(6H，m，ArH)，7.81-7.83(1H，d，C4H3SH)。MS(FAB)426.1(M+)。Dissolve 0.2 g of the product of Example 19 in 5 ml of anhydrous tetrahydrofuran, add 22 mg of sodium hydride until there are no more bubbles, add 0.05 ml of acetyl chloride, react at room temperature for 1 hour, and add water to terminate the reaction. After concentration, the residue was separated with water and ethyl acetate, and the organic phase was dried over sodium sulfate. Filtration, concentration and column chromatography yielded 0.18 g of light yellow solid. Yield 81%.1 H NMR (DMSO-d6) (ppm): 1.12-1.15 (3H, t, CH3 ), 2.04 (3H, s, CH3 ), 2.33 (3H, s, CH3 ), 2.50-2.52 (3H, d, ArCH3 ), 4.02-4.07 (2H, q, CH2 ), 5.46 (1H, s, CH), 7.09-7.34 (6H, m, ArH), 7.81-7.83 (1H, d, C4 H3 SH). MS (FAB) 426.1 (M+ ).
实施例21：化合物的细胞毒性及抗病毒活性测定Example 21: Determination of Cytotoxicity and Antiviral Activity of Compounds
照上文所述方法测定本发明化合物的细胞毒性及抗病毒活性，结果见表1。The cytotoxicity and antiviral activity of the compound of the present invention were measured according to the method described above, and the results are shown in Table 1.
表1：化合物对HBV DNA的抑制作用Table 1: Inhibitory effects of compounds on HBV DNA
＊0.27μg/ml浓度下，化合物对HBV DNA的抑制率。* At the concentration of 0.27μg/ml, the inhibitory rate of the compound on HBV DNA.
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