CN102219811A - CA-4 derivatives and preparation method and medicinal application thereof - Google Patents

CA-4 derivatives and preparation method and medicinal application thereof Download PDF

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CN102219811A
CN102219811A CN 201110093276 CN201110093276A CN102219811A CN 102219811 A CN102219811 A CN 102219811A CN 201110093276 CN201110093276 CN 201110093276 CN 201110093276 A CN201110093276 A CN 201110093276A CN 102219811 A CN102219811 A CN 102219811A
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derivatives
preparation
method
diseases
treating
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CN102219811B (en )
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何书英
何广卫
卞金磊
司崇静
吴梦茜
孙丽
屠哲玮
徐云根
戴宇驰
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中国药科大学
合肥医工医药有限公司
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Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to CA-4 derivatives (I) and a preparation method thereof, and the inhibitory effect of the CA-4 derivatives on tumor blood vessels. Pharmacological experiments prove that the compounds can be used for treating angiogenesis-related diseases such as various cancers and chronic inflammation, and other angiogenic diseases.

Description

CA-4衍生物、其制法及其医药用途 CA-4 derivatives, their preparation, and pharmaceutical use

技术领域 FIELD

[0001] 本发明涉及药物化学领域,具体涉及一类Combretastatin A-4衍生物、它们的制备方法、以及对肿瘤血管抑制作用。 [0001] The present invention relates to pharmaceutical chemistry, specifically relates to a class of Combretastatin A-4 derivatives, their preparation, and inhibition of tumor angiogenesis.

背景技术 Background technique

[0002] Combretastatin A-4 (简称CA-4)是Combretastatins 类化合物中抗肿瘤活性最好的物质之一,它是从南非树木Combretum Caffnom中分离出来的,能利用肿瘤组织与正常组织内皮细胞的生理差异,选择性地抑制肿瘤微管蛋白活性,改变其内皮细胞的骨架结构与形态,增强其血管渗透性、扰乱血流,从而引起肿瘤血管内皮细胞凋亡,导致次级肿瘤细胞死亡。 [0002] Combretastatin A-4 (referred to as CA-4) is one of the active antitumor compounds Combretastatins best material, which is isolated from the South African tree Combretum Caffnom, can use the tumor tissue and normal tissue endothelial cells physiological differences, selectively inhibiting tubulin tumor activity, change their backbone structure and morphology of endothelial cells, vascular permeability enhancing its disrupt blood flow, causing apoptosis of tumor vascular endothelial cells, leading to secondary tumor cell death. 然而CA-4的水溶性非常差,限制了其临床应用。 However, water-soluble CA-4 is very poor, limiting its clinical application. 而其水溶性前药CA-4磷酸二钠盐(CA-4P)已进入III期临床阶段。 And its water-soluble prodrugs CA-4 disodium phosphate (CA-4P) has entered Phase III clinical.

[0003] [0003]

Figure CN102219811AD00041

[0004] 根据作用机制,目前临床使用的抗肿瘤药物主要有以下四类:①直接作用于DNA 的药物;②干扰DNA合成的药物;③抗有丝分裂的药物;④基于肿瘤信号传导通路的药物。 [0004] The mechanism of action, the current clinically used anticancer drugs are the following four categories: ① direct role in DNA pharmaceutical; ② interfere with DNA synthesis of drugs; ③ antimitotic drugs; drugs ④ tumor signaling based path. 前两种药物的作用强,但缺乏选择性,毒副作用大。 The role of the first two drugs is strong, but the lack of selectivity, toxic side effects. 抗有丝分裂药物作用于微管蛋白,微管蛋白抑制剂(如:长春碱和紫杉醇类)作为抗肿瘤药物在临床上取得了良好的疗效,但也存在抗瘤谱窄、毒性较大、较易产生耐药性等缺点。 Antimitotic drugs tubulin, tubulin inhibitors (such as: taxol and vinblastine) as anticancer drugs achieved good clinical efficacy, but there is also a narrow spectrum anti-tumor, greater toxicity, easier generate drawback drug resistance. 但某些微管蛋白抑制剂在使用间隙或停药后,原本受到抑制的正常细胞在药物代谢或清除后可恢复细胞周期,而在某些肿瘤细胞由于突变损害过早地灭活纺锤体检查点而使肿瘤细胞停止分裂,从而显示出一定的选择性。 But some tubulysins gap after use or withdrawal, had been restored to normal cells inhibited cell cycle after drug metabolism or clearance, and in certain tumor cell damage due to mutations that prematurely inactivate spindle checkpoint the tumor cells to stop dividing, to display a certain selectivity. 基于肿瘤信号传导机制(靶向)的抗肿瘤药物具有毒性低、副作用少等优点。 Tumor based signaling mechanisms (targeting) antineoplastic agents have low toxicity, less side effects and other advantages. 但由于存在血管生成援救反应以及癌症基因突变的易发性和复杂性,导致目前已有的基于肿瘤信号传导通路的单靶点或多靶点TAI易产生耐药性,从而影响它们的临床使用效果。 However, due to the presence of the reaction angiogenic rescue mutations and cancer-prone and complex, have led to the current based on a single target or targets signal transduction pathway of tumor TAI easy to produce drug resistance, thereby affecting their clinical use effect. 因此,开发基于不同作用机制的多靶点血管生成抑制剂,有可能获得高效、低毒、低耐药性的新型抗肿瘤药物。 Thus, the development of multi-target vessel based on different mechanisms of action production inhibitor, it is possible to obtain high efficiency, low toxicity, low resistance new anticancer drugs.

发明内容 SUMMARY

[0005] 本发明公开了一类通式I的化合物及其水合物,其结构特征是CA-4分子中的羟基通过丁二酸(或丙二酸、戊二酸或己二酸)连接臂与氨基糖分子中的氨基偶联,得到多靶点血管生成抑制剂。 [0005] The present invention discloses a class of compounds of formula I and hydrates thereof, wherein the structure is CA-4 hydroxyl molecules via connecting arms acid (or malonic acid, glutaric acid, or adipic acid) amino sugar molecule and the amino coupling, to give multi-target angiogenesis inhibitors. 药理实验显示,本发明的化合物对人脐静脉内皮细胞增殖具有较强的抑制作用。 Pharmacological experiments show that the compounds of the present invention on the proliferation of human umbilical vein endothelial cells have a strong inhibitory effect. 因此,本发明的式I化合物及其含结晶水的化合物可以用于治疗各种与血管生成相关的疾病,这些疾病包括各种癌症和慢性炎症,以及其它血管原性的疾病。 Thus, compounds of formula I of the present invention and a compound containing water of crystallization can be used for treating various diseases associated with angiogenesis, such diseases include various cancers and chronic inflammation, and other angiogenic diseases.

[0006] 本发明的化合物通式I如下: [0006] The compounds of formula I of the invention as follows:

[0007] [0007]

Figure CN102219811AD00051

[0008] 其中G-NH-代表以下任一结构: [0008] wherein any one of the representatives of a G-NH- structure:

[0009] [0009]

Figure CN102219811AD00052

[0010] 其中G-NH-优选代表以下任一结构: [0010] wherein G-NH- preferably represents any of the following structures:

[0011] [0011]

Figure CN102219811AD00053

[0012] [0012]

[0013] G-NH-进一步优选代表以下任一结构: [0013] more preferably represents any of G-NH- following structure:

[0014] [0014]

Figure CN102219811AD00061

[0015] 其中η代表:0、1、2或3。 [0015] Representative wherein η: 2 or 3.

[0016] η优选代表:1或2。 [0016] η preferably represents: 1 or 2.

[0017] η进一步优选代表:1。 [0017] η more preferably represents: 1.

[0018] 本发明化合物的水合物也具有与化合物同样的疗效,其中的水合物以结晶水的形式存在,结晶水的摩尔当量从0. 5到10。 [0018] Hydrates of compounds of the present invention has the same effect of the compound, wherein the hydrate water of crystallization in the form of water of crystallization molar equivalents of from 0.5 to 10.

[0019] 本发明部分化合物是: [0019] Some compounds of the present invention are:

[0020] Ν-(2,3,4,6-四_0_乙酰基脱氧-β _D_吡喃葡萄糖基)_3_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-3_氧代丙酰胺(II) [0020] Ν- (2,3,4,6- four _0_ -β _D_ acetyl-deoxy-glucopyranosyl) _3 _ ((Z) 2, - methoxy - 5 - (3 ", 4 "5" _ trimethoxy styryl) phenoxy) -3_ oxo-propanamide (II)

[0021] N-(2,3,4,6-四_0_乙酰基脱氧-β _D_吡喃葡萄糖基)_4_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-4_氧代丁酰胺(1-2) [0021] N- (2,3,4,6- four _0_ -β _D_ acetyl-deoxy-glucopyranosyl) _4 _ ((Z) 2, - methoxy - 5 - (3 ", 4 "5" _ trimethoxy styryl) phenoxy) -4_ oxobutanamide (1-2)

[0022] N-(2,3,4,6-四_0_乙酰基脱氧-β _D_吡喃葡萄糖基)_5_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-5_氧代戊酰胺(1-3) [0022] N- (2,3,4,6- four _0_ -β _D_ acetyl-deoxy-glucopyranosyl) _5 _ ((Z) 2, - methoxy - 5 - (3 ", 4 "5" _ trimethoxy styryl) phenoxy) -5_ oxopentanamide (1-3)

[0023] N-(2,3,4,6-四_0_乙酰基脱氧-β _D_吡喃半乳糖基)_3_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)3_氧代丙酰胺(1-4) [0023] N- (2,3,4,6- four _0_ acetyl-deoxy-galactopyranosyl -β _D_) _3 _ ((Z) 2, - methoxy - 5 - (3 ', 4 ", 5" _ trimethoxy styryl) phenoxy) 3_ oxo-propanamide (1-4)

[0024] N-(2,3,4,6_四_0_乙酰基脱氧-β _D_吡喃半乳糖基)_4_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-4_氧代丁酰胺(1-5) [0024] N- (2,3,4,6_ four _0_ acetyl-deoxy-galactopyranosyl -β _D_) _4 _ ((Z) 2, - methoxy - 5 - (3 ', 4 ", 5" _ trimethoxy styryl) phenoxy) -4_ oxobutanamide (1-5)

[0025] N-(2,3,4,6-四_0_乙酰基脱氧-β _D_吡喃半乳糖基)_5_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-5_氧代戊酰胺(1-6) [0025] N- (2,3,4,6- four _0_ acetyl-deoxy-galactopyranosyl -β _D_) _5 _ ((Z) 2, - methoxy - 5 - (3 ', 4 ", 5" _ trimethoxy styryl) phenoxy) -5_ oxopentanamide (1-6)

[0026] N-(l,3,4,6-四_0_乙酰基_2_脱氧-β-D-吡喃葡萄糖基)_4_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-4_氧代丁酰胺(1-7) [0026] N- (l, 3,4,6- four _0_ _2_ deoxy-acetyl -β-D- glucopyranosyl) _4 _ ((Z) 2, - methoxy - 5 - ( 3 ", 4", 5 "_ trimethoxy styryl) phenoxy) -4_ oxobutanamide (1-7)

[0027] N-(l,3,4,6-四_0_乙酰基_2_脱氧-β-D-吡喃葡萄糖基)_5_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-5_氧代戊酰胺(1-8) [0027] N- (l, 3,4,6- four _0_ _2_ deoxy-acetyl -β-D- glucopyranosyl) _5 _ ((Z) 2, - methoxy - 5 - ( 3 ", 4", 5 "_ trimethoxy styryl) phenoxy) -5_ oxopentanamide (1-8)

[0028] N-(l,3,4,6-四_0_乙酰基_2_脱氧-β-D-吡喃葡萄糖基)_6_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-6_氧代己酰胺(1-9) [0028] N- (l, 3,4,6- four _0_ _2_ deoxy-acetyl -β-D- glucopyranosyl) _6 _ ((Z) 2, - methoxy - 5 - ( 3 ", 4", 5 "_ trimethoxy styryl) phenoxy) -6_ oxo-hexanamide (1-9)

[0029] N-(l,3,4,6-四_0_乙酰基_2_脱氧-β-D-吡喃半乳糖基)_4_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-4_氧代丁酰胺(1-10) [0029] N- (l, 3,4,6- four _0_ _2_ deoxy-acetyl -β-D- galactopyranosyl) _4 _ ((Z) 2, - methoxy - 5 - (3 ", 4", 5 "_ trimethoxy styryl) phenoxy) -4_ oxobutanamide (1-10)

[0030] N-(l,3,4,6-四_0_乙酰基_2_脱氧-β-D-吡喃半乳糖基)_5_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-5_氧代戊酰胺(I-Il) [0030] N- (l, 3,4,6- four _0_ _2_ deoxy-acetyl -β-D- galactopyranosyl) _5 _ ((Z) 2, - methoxy - 5 - (3 ", 4", 5 "_ trimethoxy styryl) phenoxy) -5_ oxopentanamide (I-Il)

[0031] N-(l,3,4,6-四_0_乙酰基_2_脱氧-β-D-吡喃半乳糖基)_6_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-6_氧代己酰胺(1-12) [0031] N- (l, 3,4,6- four _0_ _2_ deoxy-acetyl -β-D- galactopyranosyl) _6 _ ((Z) 2, - methoxy - 5 - (3 ", 4", 5 "_ trimethoxy styryl) phenoxy) -6_ oxo-hexanamide (1-12)

[0032] Ν-(6_脱氧-3-0-吡喃葡萄糖基)-4_((2)2,-甲氧基_5,_ (3”,4”,5” -三甲氧基苯乙烯基)苯氧基)-4-氧代丁酰胺(1-13) [0032] Ν- (6_ -3-0- deoxy-glucopyranosyl) -4 _ ((2) 2, - methoxy _5, _ (3 ", 4", 5 "- trimethoxy styrene yl) phenoxy) -4-oxo-butyramide (1-13)

[0033] N-(6-脱氧-aD-吡喃半乳糖基)-4-((Z) 2,-甲氧基_5,_ (3”,4”,5” -三甲氧基苯乙烯基)苯氧基)-4-氧代丁酰胺(1-14) [0033] N- (6- deoxy--aD- galactopyranosyl) -4 - ((Z) 2, - methoxy _5, _ (3 ", 4", 5 "- trimethoxy styrene yl) phenoxy) -4-oxo-butyramide (1-14)

[0034] N-(l-脱氧-3-0-吡喃葡萄糖基)-4_((2)2,-甲氧基_5,_ (3”,4”,5” -三甲氧基苯乙烯基)苯氧基)-4-氧代丁酰胺(1-15) [0034] N- (l- -3-0- deoxy-glucopyranosyl) -4 _ ((2) 2, - methoxy _5, _ (3 ", 4", 5 "- trimethoxy styrene yl) phenoxy) -4-oxo-butyramide (1-15)

[0035] N-(1-脱氧-β-D-吡喃葡萄糖基)-5-((Z) 2' -甲氧基_5,_(3”,4”,5”-三甲氧基苯乙烯基)苯氧基)-5-氧代戊酰胺(1-16) [0035] N- (1- deoxy -β-D- glucopyranosyl) -5 - ((Z) 2 '- methoxy _5, _ (3 ", 4", 5 "- trimethoxybenzene ethenyl) phenoxy) -5-oxo-pentanamide (1-16)

[0036] N-(1-脱氧-β-D-吡喃葡萄糖基)-6-((Z) 2' -甲氧基_5,_(3”,4”,5”-三甲氧基苯乙烯基)苯氧基)-6_氧代己酰胺(1-17) [0036] N- (1- deoxy -β-D- glucopyranosyl) -6 - ((Z) 2 '- methoxy _5, _ (3 ", 4", 5 "- trimethoxybenzene ethenyl) phenoxy) -6_ oxo-hexanamide (1-17)

[0037] N-(1-脱氧-β-D-吡喃半乳糖基)-4-((Z) 2,-甲氧基_5,_(3”,4”,5”-三甲氧基苯乙烯基)苯氧基)-4-氧代丁酰胺(1-18) [0037] N- (1- deoxy -β-D- galactopyranosyl) -4 - ((Z) 2, - methoxy _5, _ (3 ", 4", 5 "- trimethoxy styryl) phenoxy) -4-oxo-butyramide (1-18)

[0038] N-(1-脱氧-β-D-吡喃半乳糖基)-5-((Z) 2,-甲氧基_5,_(3”,4”,5”-三甲氧基苯乙烯基)苯氧基)-5-氧代戊酰胺(1-19) [0038] N- (1- deoxy -β-D- galactopyranosyl) -5 - ((Z) 2, - methoxy _5, _ (3 ", 4", 5 "- trimethoxy styryl) phenoxy) -5-oxo-pentanamide (1-19)

[0039] N-(2-脱氧-β-D-吡喃葡萄糖基)-4-((Z) 2,-甲氧基_5,_(3”,4”,5”-三甲氧基苯乙烯基)苯氧基)-4_氧代丁酰胺(1-20) [0039] N- (2- deoxy--β-D- glucopyranosyl) -4 - ((Z) 2, - methoxy _5, _ (3 ", 4", 5 "- trimethoxybenzene ethenyl) phenoxy) -4_ oxobutanamide (1-20)

[0040] N-(2-脱氧-β-D-吡喃葡萄糖基)-5-((Z) 2' -甲氧基_5,_(3”,4”,5”-三甲氧基苯乙烯基)苯氧基)-5_氧代戊酰胺(1-21) [0040] N- (2- deoxy--β-D- glucopyranosyl) -5 - ((Z) 2 '- methoxy _5, _ (3 ", 4", 5 "- trimethoxybenzene ethenyl) phenoxy) -5_ oxopentanamide (1-21)

[0041] N-(2-脱氧-β-D-吡喃半乳糖基)-4-((Z) 2,-甲氧基_5,_(3”,4”,5”-三甲氧基苯乙烯基)苯氧基)-4-氧代丁酰胺(1-22) [0041] N- (2- deoxy--β-D- galactopyranosyl) -4 - ((Z) 2, - methoxy _5, _ (3 ", 4", 5 "- trimethoxy styryl) phenoxy) -4-oxo-butyramide (1-22)

[0042] N-(2-脱氧-β-D-吡喃半乳糖基)-5-((Z) 2,-甲氧基_5,_(3”,4”,5”-三甲氧基苯乙烯基)苯氧基)-5-氧代戊酰胺(1-23) [0042] N- (2- deoxy--β-D- galactopyranosyl) -5 - ((Z) 2, - methoxy _5, _ (3 ", 4", 5 "- trimethoxy styryl) phenoxy) -5-oxo-pentanamide (1-23)

[0043] N-(l,2,3,4-四_0_乙酰基_6_脱氧-β-D-吡喃葡萄糖基)_4_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-4_氧代丁酰胺(1-24) [0043] N- (l, 2,3,4- four _0_ acetyl _6_ deoxy -β-D- glucopyranosyl) _4 _ ((Z) 2, - methoxy - 5 - ( 3 ", 4", 5 "_ trimethoxy styryl) phenoxy) -4_ oxobutanamide (1-24)

[0044] N-(l,2,3,4-四_0_乙酰基_6_脱氧-α-D-吡喃半乳糖基)_4_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-4_氧代丁酰胺(1-25) [0044] N- (l, 2,3,4- four _0_ acetyl _6_ deoxy -α-D- galactopyranosyl) _4 _ ((Z) 2, - methoxy - 5 - (3 ", 4", 5 "_ trimethoxy styryl) phenoxy) -4_ oxobutanamide (1-25)

[0045] 本发明通式化合物(I)的制备方法如下: [0045] The production method of the present invention compounds of general formula (I) as follows:

[0046] 其中关键中间体2的制备方法如下: [0046] The key intermediate 2 is prepared as follows:

[0047] [0047]

Figure CN102219811AD00071

[0048] (a)溶剂为乙酸酐;催化剂为三乙胺。 [0048] (a) the solvent is acetic anhydride; the catalyst is triethylamine.

[0049] (b)溶剂为喹啉;催化剂为铜粉。 [0049] (b) the solvent is quinoline; catalyst is copper powder.

[0050] (c)反应物为丙二酸酐、丁二酸酐、戊二酸酐或己二酸酐;溶剂为丙酮、乙腈或四氢呋喃;催化剂为三乙胺、碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、氢氧化钾、氢氧化钠、氢化钠或氨基钠。 [0050] (c) the reaction product of malonic anhydride, succinic anhydride, glutaric anhydride or adipic anhydride; solvent is acetone, acetonitrile or tetrahydrofuran; the catalyst is triethylamine, potassium carbonate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydroxide, sodium hydroxide, sodium hydride or sodium amide.

[0051] 目标化合物I的制备方法如下: Preparation Method [0051] The object compound I are as follows:

[0052] (1)当G-NH2 = G1-NH2 〜G6-NH2 时,合成路线如下: [0052] (1) when G-NH2 = G1-NH2 ~G6-NH2, the following synthetic route:

[0053] [0053]

Figure CN102219811AD00081

[0054] (d)反应物为草酰氯,或二氯亚砜,或三乙胺和EDCI/HOBt ;溶剂为DMF。 [0054] (d) reaction of oxalyl chloride, or thionyl chloride, or triethylamine, and EDCI / HOBt; the solvent is DMF.

[0055] (2)当G-NH2 = G7-NH2 〜Gltl-NH2 时,合成路线如下: [0055] (2) when G-NH2 = G7-NH2 ~Gltl-NH2, the following synthetic route:

[0056] [0056]

Figure CN102219811AD00082

[0057] (e)反应物为甲醇钠或乙醇钠;溶剂为甲醇或乙醇。 [0057] (e) The reaction is sodium methoxide or sodium ethoxide; the solvent is methanol or ethanol.

[0058] (3)当G-NH2 = Gn-NH2 〜G12-NH2 时,合成路线如下: [0058] (3) when G-NH2 = Gn-NH2 ~G12-NH2, the following synthetic route:

[0059] [0059]

Figure CN102219811AD00083

[0060] (f)反应物为醋酐,三乙胺和4-DMAP ;溶剂为吡啶或三乙胺。 [0060] (f) reaction of acetic anhydride, triethylamine and 4-DMAP; the solvent is pyridine or triethylamine.

[0061] 以下是本发明部分化合物的药理试验及结果。 [0061] The following are the results of pharmacological tests and of the compound of the present invention.

[0062] 本发明部分化合物在常氧状态下对血管内皮细胞增殖抑制活性的测试方法如下: [0062] The compounds of the invention section of vascular endothelial cell proliferation inhibitory activity under normoxic conditions the following test methods:

[0063] 材料:人脐静脉内皮细胞(HUVEC)细胞株。 [0063] Materials: Human umbilical vein endothelial cells (HUVEC) cell lines.

[0064] 检测原理: [0064] Detection principle:

[0065] 活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为水不溶性的蓝紫色结晶甲瓒(Formazan)并沉积在细胞中,而死细胞无此功能。 [0065] The living cells mitochondrial succinate dehydrogenase reduction of MTT can exogenous violet water insoluble formazan crystals (of formazan for) and deposited in the cells, dead cells can not. 二甲基亚砜(DMSO)能溶解细胞中的甲瓒,用酶联免疫检测仪在570nm波长处测定其光吸收值,可间接反映活细胞数量。 Dimethylsulfoxide (DMSO) can dissolve formazan cells, absorbance was measured at 570nm wavelength using ELISA to, it can reflect the number of viable cells. 吸光值越小说明被测化合物对人脐静脉内皮细胞(HUVEC)抑制作用越强,活性越好。 Absorbance smaller the test compound, the stronger the inhibition of human umbilical vein endothelial cells (HUVEC), the better the activity.

[0066] 溶液配制: [0066] The solution preparation:

[0067] (I)PBS 溶液 [0067] (I) PBS solution of

[0068] NaCl 8. 00g, KCl 0. 20g, Na2HPO4 · 12H20 3. 49g, KH2PO4O. 20g,加三蒸水溶解后,定容至1000ml,高压灭菌后4°C保存备用。 After [0068] NaCl 8. 00g, KCl 0. 20g, Na2HPO4 · 12H20 3. 49g, KH2PO4O. 20g, triple-distilled water was added to dissolve, the volume to 1000ml, after autoclaving at 4 ° C for use.

[0069] (2)0. 25%胰蛋白酶溶液 [0069] (2) 0.25% trypsin solution

[0070] 称取胰蛋白酶0. 25g,加入PBS溶液液,磁力搅拌器上搅拌使其完全溶解,定容至100ml,过滤除菌后_20°C保存备用。 [0070] said spare storage _20 ° C after taking trypsin 0. 25g, PBS was added to the solution, and completely dissolved with stirring on a magnetic stirrer, a constant volume of 100ml, filtered sterilization.

[0071] (3)噻唑兰(MTT)溶液 [0071] (3) thiazol tetrazolium (MTT) solution of

[0072] 称取MTT 50mg,加入PBS使其终体积为10ml,磁力搅拌器上搅拌使其完全溶解后, 过滤除菌,4°C避光保存,两周内使用有效。 [0072] Weigh MTT 50mg, PBS was added to a final volume of 10ml, the magnetic stirrer so that it completely dissolved, filter sterilized, 4 ° C protected from light, effective use within two weeks.

[0073] 稀释方法:使用前用二甲亚砜(DMSO)将所有被测化合物粉末均配制为10_2M的浓度的母液,临用前用细胞培养液配成所需浓度。 [0073] dilution: Before use the powder were all formulated test compound concentration of the mother liquor 10_2M with dimethyl sulfoxide (DMSO), immediately prior to cell culture medium formulated with the desired concentration.

[0074] 操作流程: [0074] Protocol:

[0075] 使用噻唑兰(MTT)法进行测定,主要步骤如下: [0075] performed using the MTT assay (MTT) method, the following main steps:

[0076] (1)取处于指数生长期状态良好的人静脉内皮细胞(HUVEC) —瓶,加入0. 25%胰蛋白酶消化液,消化1〜2min,倒置显微镜下可见胞质回缩、细胞变圆、细胞间隙清晰时,立即翻转培养瓶,加入少许含10%新生牛血清的DMEM培养液终止消化,缓缓吹下瓶壁的细胞,制成细胞悬液。 [0076] (1) taking in a good state of the exponential growth phase of human umbilical vein endothelial cells (HUVEC) - bottle was added 0.25% trypsin digestion solution, digestion 1~2min, visible cytoplasm retracted under inverted microscope, the cell becomes round, when the cell gap clear, immediately inverting flask, was added DMEM culture medium containing a little 10% newborn calf serum to terminate the digestion, cells slowly blowing the bottle wall, cell suspension.

[0077] (2)取细胞悬液接种于96孔板上,100 μ 1/孔,每孔约5000个细胞,置恒温C02培 [0077] (2) cell suspension were seeded in 96-well plates, 100 μ 1 / hole, about 5000 cells per well, cultured home thermostat C02

养箱中培养24小时。 Raising box for 24 hours.

[0078] (3)将细胞对照组(含10%胎牛血清的DMEM)、加药组(含10%胎牛血清的DMEM 和最终浓度分别为10-5mol/L、10-6 μ mol/L、10_7 μ mol/L的待检测药物),100 μ 1/孔,培养24小时。 [0078] (3) a cell control (DMEM containing 10% fetal bovine serum), dosing group (DMEM containing 10% fetal bovine serum and final concentrations of 10-5mol / L, 10-6 μ mol / L, 10_7 μ mol / L of the drug to be detected), 100 μ 1 / well and cultured for 24 hours.

[0079] (4)每孔加入5mg/ml 的MTT 溶液20 μ 1,37°C孵育4h。 [0079] (4) added to each well 5mg / ml MTT solution in 20 μ 1,37 ° C incubation 4h.

[0080] (5)吸去上清液,加入DMS0,150 μ 1/孔,平板床上振摇5分钟。 [0080] (5) aspirate supernatant was DMS0,150 μ 1 / hole, the bed plate shaken for 5 minutes.

[0081] (6)用酶联免疫检测仪在波长为570nm处测定每孔的吸光值。 [0081] (6) measured by ELISA to the absorbance of each well at a wavelength of 570nm.

[0082] 表1.本发明部分化合物抑制人脐静脉内皮细胞(HUVEC)增殖的IC5tl(mol/L) [0082] Table 1. Some compounds of the invention inhibit IC5tl human umbilical vein endothelial cells (HUVEC) proliferation (mol / L)

[0083] [0083]

Figure CN102219811AD00091

[0084] 表1中化合物代号对应的化学结构同实施例。 [0084] Table 1 compound with a chemical structure corresponding to the code embodiment.

[0085] 药理测试结果表明,本发明的部分化合物,如1-2、1-5、1-7、1-10、1-13和1-14对人脐静脉内皮细胞(HUVEC)的增殖有明显的抑制作用,并且药效优于CA-4。 [0085] The pharmacological test results indicated that some compounds of the invention, such as proliferation 1-2,1-5,1-7,1-10,1-13 and 1-14 of human umbilical vein endothelial cells (HUVEC) are significantly inhibited, and better efficacy than the CA-4.

[0086] 本发明还提供了一种治疗与血管生成相关的疾病的药物组合物,其中含有治疗有效量的通式I化合物和药学上可接受的载体。 [0086] The present invention further provides a method of treating a disease associated with angiogenesis is a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier. 所述药物组合物可以是普通片剂或胶囊、缓释片剂或胶囊、控释片剂或胶囊、口服液、注射剂等制剂学上常规的制剂形式。 The pharmaceutical composition may be an ordinary tablet or capsule, sustained release tablet or capsule, controlled release tablet or capsule, oral solution, injectable on conventional formulations like pharmaceutics.

[0087] 一般地,本发明的CA-4衍生物用于治疗时,人用剂量范围为Img〜5000mg/天。 When [0087] Generally, CA-4 derivatives of the present invention for the treatment, the human dose range Img~5000mg / day. 也可根据剂型的不同和疾病严重程度,使用剂量超出该范围。 It may be different according to the severity of disease and dosage forms, doses outside this range.

具体实施方式 detailed description

[0088] 实施例1 [0088] Example 1

[0089] N-(2,3,4,6_四_0_乙酰基脱氧-β _D_吡喃葡萄糖基)_4_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-4_氧代丁酰胺(1-2)的制备 [0089] N- (2,3,4,6_ four _0_ -β _D_ acetyl-deoxy-glucopyranosyl) _4 _ ((Z) 2, - methoxy - 5 - (3 ", 4 preparation ", 5" _ trimethoxy styryl) phenoxy) -4_ oxobutanamide (1-2)

[0090] (E)-3-(3,-羟基-4,-甲氧基)苯基-2-(3”,4”,5”-三-甲氧基)苯基-丙烯酸⑴ [0090] (E) -3- (3, - hydroxy - 4 - methoxy) phenyl-2- (3 ', 4', 5 '- tris - methoxy) phenyl - acrylic ⑴

[0091] 在500ml三颈瓶中加入3,4,5_三甲氧基苯乙酸(50g,0. 22mol)、3_羟基_4_甲氧基苯甲醛(34g,0. 22mol)、62. 5ml三乙胺和150ml乙酸酐,搅拌升温至140°C,反应4h, 停止加热,冷却至10°C,缓慢滴加浓盐酸200ml,室温下过夜。 [0091] Add 3,4,5_ trimethoxy acid (50g, 0. 22mol) in 500ml three-necked flask, 3_ _4_ hydroxy-methoxybenzaldehyde (34g, 0. 22mol), 62. 5ml of triethylamine and 150ml of acetic anhydride was stirred warmed to 140 ° C, the reaction 4h, heating was stopped, cooled to 10 ° C, 200ml of concentrated hydrochloric acid was slowly added dropwise, at room temperature overnight. 有土黄色固体析出,停止反应过滤出固体,用约IOOml乙醇重结晶,得黄色针状物纯品47. 5g,产率为61%,mp 184〜 1860C (文献值:184 〜186°C [Bioorg. Med. Chem. ,2005,13(11) :3853_3864]) There khaki solid precipitated solid was filtered off and the reaction was stopped with about IOOml recrystallized from ethanol to give yellow needles of pure 47. 5g, yield 61%, mp 184~ 1860C (literature value: 184 ~186 ° C [ .. Bioorg Med Chem, 2005,13 (11):. 3853_3864])

[0092] 1HNMR(300MHz, DMSO), δ (ppm) :12. 42 (1Η, s, C00H) ,8. 95 (1Η, s, OH), 7. 57 (1H, s, =CH),6. 81(1H,d, J = 8. 7Hz,5,-ArH),6. 61 (1H, dd, J = 2. IHz, J = 8. 4Hz,6,-ArH), 6. 54 (1H, d, J = 2. lHz,2,-ArH), 6. 44 (2H, s,2” &6”-ArH),3. 73 (3H, s, OCH3),3. 72 (3H, s, OCH3),3. 69 (6H, s,2 X OCH3). [0092] 1HNMR (300MHz, DMSO), δ (ppm):.. 12 42 (1Η, s, C00H), 8 95 (1Η, s, OH), 7. 57 (1H, s, = CH), 6 . 81 (1H, d, J = 8. 7Hz, 5, -ArH), 6. 61 (1H, dd, J = 2. IHz, J = 8. 4Hz, 6, -ArH), 6. 54 (1H , d, J = 2. lHz, 2, -ArH), 6. 44 (2H, s, 2 "& 6" -ArH), 3. 73 (3H, s, OCH3), 3. 72 (3H, s, OCH3), 3. 69 (6H, s, 2 X OCH3).

[0093] (Z)-3”,4,,4”,5”-四甲氧基-3,_ 羟基二苯乙烯(CA-4) [0093] (Z) -3 ", 4,, 4", 5 "- tetramethyl-3, _ hydroxy stilbene (CA-4)

[0094] 在装有温度计、回流冷凝管、干燥管的500mL三颈瓶中加入1(7. 2g,20mmol),铜粉6. 6g (0. 103mol),喹啉72ml,反应加热至200°C,搅拌3h。 [0094] equipped with a thermometer, a reflux condenser, drying tube 500 mL three-necked flask was added 1 (7. 2g, 20mmol), copper powder 6. 6g (0. 103mol), quinoline 72 ml, the reaction was heated to 200 ° C, stirred for 3h. 反应完毕后加入乙醚适量,用硅藻土滤除铜粉。 After the reaction, an appropriate amount of diethyl ether was added, the copper powder was filtered off through celite. 用300ml 5MHC1把吡啶洗掉,用乙醚150ml萃取,将分出的水层用乙醚洗(3 X 150ml),合并有机层。 Pyridine wash with 300ml 5MHC1 and extracted with diethyl ether 150ml, the separated aqueous layer was washed with ether (3 X 150ml), the organic layers combined. 有机层分别用500ml水洗一次,饱和Na2CO3 (2 X 300ml)洗两次,饱和NaCl (2 X 300ml)洗两次,无水Na2SO4干燥过夜。 The organic layers were once with saturated Na2CO3 (2 X 300ml) were washed twice with saturated NaCl (2 X 300ml) were washed twice, and dried over anhydrous Na2SO4 overnight and washed with 500ml. 滤去硫酸钠,减压旋掉2/3体积的乙醚,有微黄色固体析出,滤出固体并用适量乙醚洗涤,回收母液,再除去部分溶剂,将析出的固体滤出,共得产物5. 0g,产率79%,mp 116〜117°C (文献值:116°C [J. Org. Chem., 2001,66(24) :8135-8138]) Sodium sulfate was filtered off, spin off under reduced pressure to 2/3 volume of ether, yellowish solid has precipitated solid was filtered off and washed with an appropriate amount of diethyl ether, recovered mother liquor, and removing part of the solvent, the precipitated solid was filtered off, the product to give a total of 5. 0g, yield 79%, mp 116~117 ° C (literature value: 116 ° C [. J. Org Chem, 2001,66 (24):. 8135-8138])

[0095] 1H 匪R(300Hz,CDCl3) : δ 6. 92(lH,d, J = 2. 1Hz, 2'-ArH), 6. 82 (1H, dd, J = 8. 4Hz, [0095] 1H bandit R (300Hz, CDCl3): δ 6. 92 (lH, d, J = 2. 1Hz, 2'-ArH), 6. 82 (1H, dd, J = 8. 4Hz,

2. 1Ηζ,6,-ArH), 6. 74 (1H, d, J = 8. 1Ηζ,5,-ArH), 6. 53 (2H, s,2” &6”-ArH),6. 47 (1H, d, J =12. 6Hz,la-H),6. 41(lH,d,J = 12. 6,la,-H),5. 68 (1H,s,OH),3. 87(3H,s,4,-ArOCH3), 2. 1Ηζ, 6, -ArH), 6. 74 (1H, d, J = 8. 1Ηζ, 5, -ArH), 6. 53 (2H, s, 2 "& 6" -ArH), 6. 47 ( 1H, d, J = 12. 6Hz, la-H), 6. 41 (lH, d, J = 12. 6, la, -H), 5. 68 (1H, s, OH), 3. 87 ( 3H, s, 4, -ArOCH3),

3. 84 (3H,s,4 ” -ArOCH3),3. 70 (6H,s,3 ” &5 ” -ArOCH3) · 3. 84 (3H, s, 4 "-ArOCH3), 3. 70 (6H, s, 3" & 5 "-ArOCH3) ·

[0096] (Z)-4 (2,-甲氧基-5,_(3”,4”,5”-三甲氧基苯乙烯基)苯氧基)_4_氧代丁酸(2b) [0096] (Z) -4 (2, - methoxy - 5, _ (3 ", 4", 5 "- trimethoxy styryl) phenoxy) _4_ oxobutanoate (2b)

[0097] 冰浴下将三乙胺1. 8ml (12. 8mmol)缓慢滴入8ml丙酮中,再加入CA-4 (lg, 3. 2mmol)和丁二酸酐(1. 2g,12mmol),使反应温度保持在15 °C,搅拌,反应24h,停止反应,旋去丙酮,加适量乙酸乙酯,用l.Omol/L HCl (13ml)洗有机层,并用20ml水洗一遍, 饱和NaCl (2 X 20ml)洗,无水MgSO4干燥2h,过滤,旋干溶剂,用乙醚溶解粗品,滤除不溶物,旋去溶剂,将析出的固体过滤,用少量乙醚洗涤,得类白色固体粉末0. 8g,产率60.0%, m. ρ· 107 〜110°C。 [0097] The ice-bath Triethylamine 1. 8ml (12. 8mmol) 8ml of acetone was slowly added dropwise, added CA-4 (lg, 3. 2mmol) and succinic anhydride (1. 2g, 12mmol), so that the reaction temperature was maintained at 15 ° C, with stirring, the reaction 24h, the reaction was stopped, acetone was removed by rotary evaporation, add appropriate amount of ethyl acetate, the organic layer was washed with l.Omol / L HCl (13ml), and once with 20ml water, saturated NaCl (2 X 20ml) wash, dried over anhydrous MgSO4 2h, filtered, and rotary evaporation, the crude product dissolved in diethyl ether, insoluble material was filtered off, the solvent removed by rotary evaporation, and the precipitated solid was filtered, washed with a little ether to give an off-white solid powder 0. 8g, yield 60.0%, m. ρ · 107 ~110 ° C.

[0098] 1H NMR(300Hz, CDCl3) : δ 7. 11 (1Η, dd, J = 8. 4Hz, 1. 8Hz,4,-ArH), 6. 97 (1H, d, J =1. 2Hz,6,-ArH), 6. 84(lH,d,J = 8. 4Hz,3,-ArH), 6. 46 (2H,s,2” &6”-ArH),6. 42(2H,s, la &la,-H),3. 91 (3H, s,2,-ArOCH3),3. 85 (3H, s,4”-ArOCH3),3. 71 (6H, s,3”&5”-ArOCH3), [0098] 1H NMR (300Hz, CDCl3): δ 7. 11 (1Η, dd, J = 8. 4Hz, 1. 8Hz, 4, -ArH), 6. 97 (1H, d, J = 1 2Hz,. 6, -ArH), 6. 84 (lH, d, J = 8. 4Hz, 3, -ArH), 6. 46 (2H, s, 2 "& 6" -ArH), 6. 42 (2H, s, la & la, -H), 3. 91 (3H, s, 2, -ArOCH3), 3. 85 (3H, s, 4 "-ArOCH3), 3. 71 (6H, s, 3" & 5 "-ArOCH3) ,

2. 85 (2H, t, J = 6. 0HzC0CH2CH2C00H),2. 76 (2H, t, J = 6. OHz COC压CH2COOH) · 2. 85 (2H, t, J = 6. 0HzC0CH2CH2C00H), 2. 76 (2H, t, J = 6. OHz COC pressure CH2COOH) ·

[0099] N-(2,3,4,6_四_0_乙酰基脱氧-β _D_吡喃葡萄糖基)_4_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-4_氧代丁酰胺(1-2) [0099] N- (2,3,4,6_ four _0_ -β _D_ acetyl-deoxy-glucopyranosyl) _4 _ ((Z) 2, - methoxy - 5 - (3 ", 4 "5" _ trimethoxy styryl) phenoxy) -4_ oxobutanamide (1-2)

[0100]将 G1-NH2-HCl(OJTgJmmol)溶于DMF(7ml),缓慢滴加干燥的三乙胺(0.28ml, 2mmol),然后依次分批加入2b (0. 83g, 2mmol),EDCI (0. 38g, 2mmol),HOBt (0. 27g, 2mmol), 室温搅拌24h。 [0100] The G1-NH2-HCl (OJTgJmmol) was dissolved in DMF (7ml), was slowly added dropwise dry triethylamine (0.28ml, 2mmol), followed by portionwise addition of 2b (0. 83g, 2mmol), EDCI ( 0. 38g, 2mmol), HOBt (0. 27g, 2mmol), stirred at room temperature 24h. 反应液加入二氯甲烷(70ml),饱和食盐水洗(3X 70ml),干燥,抽滤,减压蒸除溶剂,硅胶柱层析(石油醚/乙酸乙酯=3/2),得微黄色固体0.86g,收率57.7%, m. ρ· 83-85 0C ; The reaction mixture was added methylene chloride (70 ml of), washed with brine (3X 70ml), dried, filtered off with suction, the solvent was distilled off under reduced pressure, silica gel column chromatography (petroleum ether / ethyl acetate = 3/2) to give a yellowish solid 0.86g, yield 57.7%, m ρ · 83-85 0C.;

[0101] 1H-WrGOOMHz, CDCl3) δ (ppm) :7. 11 (1H, dd, J = 8. 4Hz, J = 1·8Ηζ,4,-ArH), 7. 00(lH,d,J = 1. 8Hz,6,-ArH),6· 82(lH,d,J = 8. 7Hz,3,-ArH),6. 49 (2H,s,2”&6”_ArH), [0101] 1H-WrGOOMHz, CDCl3) δ (ppm):. 7 11 (1H, dd, J = 8. 4Hz, J = 1 · 8Ηζ, 4, -ArH), 7. 00 (lH, d, J = 1. 8Hz, 6, -ArH), 6 · 82 (lH, d, J = 8. 7Hz, 3, -ArH), 6. 49 (2H, s, 2 "& 6" _ArH),

6. 45 (2H, s, laH&la'H),6. 34 (1H, d, J = 9Hz,NH),5. 33 〜5. 33 (2H,m, HI,H_3),5. 06 (1H, t, J = 9. 9Hz,H-2),4. 92(lH,t,J = 9. 6Hz,H_4),4. 30(lH,dd,J = 4. 2Hz, J = 12. 6Hz,H_6a), 4. 08 (1H, dd, J = 1. 2Hz,J = 12. 3Hz,H_6b),3. 92 〜3,90 (lH,m,H_5),3. 87 (3H, s,2,-OCH3), 6. 45 (2H, s, laH & la'H), 6. 34 (1H, d, J = 9Hz, NH), 5. 33 ~5. 33 (2H, m, HI, H_3), 5. 06 (1H , t, J = 9. 9Hz, H-2), 4. 92 (lH, t, J = 9. 6Hz, H_4), 4. 30 (lH, dd, J = 4. 2Hz, J = 12. 6Hz , H_6a), 4. 08 (1H, dd, J = 1. 2Hz, J = 12. 3Hz, H_6b), 3. 92 ~3,90 (lH, m, H_5), 3. 87 (3H, s, 2, -OCH3),

3. 84(3H,s,4”-0CH3),3· 70(6H,s,3”&5”_0CH3),2. 95 〜2. 76 (2H,m, NHCH2CHaCOOH), 2. 57 〜 2. 52 (2H, m, CONHCHaCH2COOH), 2. 17, 2. 07, 2. 05, 2. 03 (each 3H, each s,4X0Ac); 3. 84 (3H, s, 4 "-0CH3), 3 · 70 (6H, s, 3" & 5 "_0CH3), 2. 95 ~2. 76 (2H, m, NHCH2CHaCOOH), 2. 57 ~ 2. 52 (2H, m, CONHCHaCH2COOH), 2. 17, 2. 07, 2. 05, 2. 03 (each 3H, each s, 4X0Ac);

[0102] IR(cm-1) :3357 (NH),2944 (CH),2360,2336,1754 (ester, C = O), 1680 (amide, C = 0),1509,1232 (OCH3),1129 (OAc),1039 (OCH3) [0102] IR (cm-1): 3357 (NH), 2944 (CH), 2360,2336,1754 (ester, C = O), 1680 (amide, C = 0), 1509,1232 (OCH3), 1129 (OAc), 1039 (OCH3)

[0103] MS (ESI(+)70eV, m/z) :763. 4[M+NH4]+; [0103] MS (ESI (+) 70eV, m / z): 763 4 [M + NH4] +;.

[0104] MS (ESI (-) 70V, m/z) :780. 5 [M+Cl]- [0104] MS (ESI (-) 70V, m / z):. 780 5 [M + Cl] -

[0105] 实施例2 [0105] Example 2

[0106] N-(2,3,4,6_四_0_乙酰基脱氧-β _D_吡喃半乳糖基)_4_((Z) 2,-甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-4_氧代丁酰胺(1-5)的制备 [0106] N- (2,3,4,6_ four _0_ acetyl-deoxy-galactopyranosyl -β _D_) _4 _ ((Z) 2, - methoxy - 5 - (3 ', preparation of 4 ", 5" _ trimethoxy styryl) phenoxy) -4_ oxobutanamide (1-5)

[0107]将 G2-NH2 (0. 8g,2. 3mmol)溶于DMF (12ml)。 [0107] The G2-NH2 (0. 8g, 2. 3mmol) was dissolved in DMF (12ml). 然后依次分批加入2b (0. 92g, 2. 3mmol),EDCI (0. 44g,2. 3mmol),HOBt (0. 31g,2. 3mmol),室温搅拌24h。 Was added portionwise followed 2b (0. 92g, 2. 3mmol), EDCI (0. 44g, 2. 3mmol), HOBt (0. 31g, 2. 3mmol), stirred at room temperature 24h. 反应液加入二氯甲烷(80ml),水洗(2 X 100ml),饱和食盐水洗(3 X 100ml),干燥,抽滤,减压蒸除溶剂,硅胶柱层析(石油醚/乙酸乙酯=3/2),得微黄色固体1.088,收率63.0%,!11.?. 85-87°C ; The reaction mixture was added methylene chloride (in 80 ml of), washed with water (2 X 100ml), washed with brine (3 X 100ml), dried, filtered off with suction, the solvent was distilled off under reduced pressure, silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 2) to give 1.088 yellowish solid, yield 63.0% ,! 11 85-87 ° C.?.;

[0108] 1H-WrGOOMHz, CDCl3) δ (ppm) :7. 12 (1H, dd, J = 8. 4Hz, J=L 8Hz,4,-ArH), [0108] 1H-WrGOOMHz, CDCl3) δ (ppm):. 7 12 (1H, dd, J = 8. 4Hz, J = L 8Hz, 4, -ArH),

7. 01(lH,d,J = 1. 8Hz,6,-ArH),6· 83(lH,d,J = 8. 7Hz,3,-ArH),6. 50 (2Η,s,2”&6”_ArH), 6. 45 (2H, s, laH&la,H),6. 38 (1H, d, J = 8. 7Hz,NH),5. 44 (1H, s,H_4),5. 30 〜5. 13(3H,m, HI,H-2and H_3),4. 11 〜4. 03 (3H,m,H_5,H_6a and H_6b),3. 84 (3H,s,2,-OCH3),3. 80 (3H, s,4 ”-OCH3),3· 70 (6H,s,3 ”&5 ”-OCH3),2. 99 〜2. 84 (2Η,m,NHCH2CH2COOH),2. 58 〜2. 54 (2H, m, CONHCHaCH2COOH), 2. 07, 2. 04,1. 99,1. 98 (each 3H, each s,4X0Ac);[0109] IR(cm-1) :3369 (NH), 2944 (CH), 1751 (ester, C = 0),1699 (amide,C = 0),1508, 1229 (OCH3), 1129 (OAc),1054 (OCH3) 7. 01 (lH, d, J = 1. 8Hz, 6, -ArH), 6 · 83 (lH, d, J = 8. 7Hz, 3, -ArH), 6. 50 (2Η, s, 2 " & 6 "_ArH), 6. 45 (2H, s, laH & la, H), 6. 38 (1H, d, J = 8. 7Hz, NH), 5. 44 (1H, s, H_4), 5. 30 ~ 5. 13 (3H, m, HI, H-2and H_3), 4. 11 ~4. 03 (3H, m, H_5, H_6a and H_6b), 3. 84 (3H, s, 2, -OCH3), 3 . 80 (3H, s, 4 "-OCH3), 3 · 70 (6H, s, 3" & 5 "-OCH3), 2. 99 ~2. 84 (2Η, m, NHCH2CH2COOH), 2. 58 ~2. .. 54 (2H, m, CONHCHaCH2COOH), 2. 07, 2. 04,1 99,1 98 (each 3H, each s, 4X0Ac); [0109] IR (cm-1): 3369 (NH), 2944 (CH), 1751 (ester, C = 0), 1699 (amide, C = 0), 1508, 1229 (OCH3), 1129 (OAc), 1054 (OCH3)

[0110] MS (ESI(+)70eV, m/z) :763. 4[M+NH4]+; [0110] MS (ESI (+) 70eV, m / z): 763 4 [M + NH4] +;.

[0111] MS (ESI (-) 70V, m/z) :780. 6 [M+Cl]- [0111] MS (ESI (-) 70V, m / z):. 780 6 [M + Cl] -

[0112] 实施例3 [0112] Example 3

[0113] N-(l,3,4,6-四_0_乙酰基_2_脱氧-β _D_吡喃葡萄糖基)_4_((Z) 2' -甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-4_氧代丁酰胺(1-7)的制备 [0113] N- (l, 3,4,6- four _0_ acetyl -β _D_ _2_ deoxy-glucopyranosyl) _4 _ ((Z) 2 '- methoxy - 5 - (3 preparation ", 4", 5 "_ trimethoxy styryl) phenoxy) -4_ oxobutanamide (1-7)

[0114]将 G3-NH2. HCl (0. 77g,2_ol)溶于DMF(IOml)。 [0114] The G3-NH2. HCl (0. 77g, 2_ol) was dissolved in DMF (IOml). 缓慢滴加干燥的三乙胺(0. 28ml, 2mmol)。 Dried slowly added dropwise triethylamine (0. 28ml, 2mmol). 然后先后分批加入2b (0. 83g, 2mmol),EDCI (0. 38g, 2mmol),HOBt (0. 27g, 2mmol), 室温搅拌24h。 It was then added portionwise successively 2b (0. 83g, 2mmol), EDCI (0. 38g, 2mmol), HOBt (0. 27g, 2mmol), stirred at room temperature 24h. 反应液加入二氯甲烷(80ml),水洗(2X 100ml),饱和食盐水洗(3X 100ml), 干燥,抽滤,减压蒸除溶剂,硅胶柱层析(石油醚/乙酸乙酯=2/1),得白色固体0. 82g,收率55. 0%,m. ρ· 78-790C ; The reaction mixture was added methylene chloride (in 80 ml of), washed with water (2X 100ml), washed with brine (3X 100ml), dried, filtered off with suction, the solvent was distilled off under reduced pressure, silica gel column chromatography (petroleum ether / ethyl acetate = 2/1 ), as a white solid 0. 82g, yield of 55. 0%, m ρ · 78-790C.;

[0115] 1H-WrGOOMHz, CDCl3) δ (ppm) :7. 12 (1H, dd, J = 8. 4Hz, J=L 8Hz,4,-ArH), 6. 98(lH,d,J = 1. 8Hz,6,-ArH),6· 82(lH,d,J = 8. 4Hz,3,-ArH),6. 49 (2Η,s,2”&6”_ArH), 6. 45(2H,s,laH&la'H) ,5. 73 〜5. 68 (2H,m,NH,H_l),5. 18 〜5. 12 (2H,m,H_3,H_4),4· 29 〜 [0115] 1H-WrGOOMHz, CDCl3) δ (ppm):. 7 12 (1H, dd, J = 8. 4Hz, J = L 8Hz, 4, -ArH), 6. 98 (lH, d, J = 1 . 8Hz, 6, -ArH), 6 · 82 (lH, d, J = 8. 4Hz, 3, -ArH), 6. 49 (2Η, s, 2 "& 6" _ArH), 6. 45 (2H, s, laH & la'H), 5. 73 ~5. 68 (2H, m, NH, H_l), 5. 18 ~5. 12 (2H, m, H_3, H_4), 4 · 29 ~

4. 24 (2H, m, H_2and H_6a),4. 13 〜4· 09 (2H,m, H_6b and H_5),3. 84 (3H,s,2,-OCH3), 4. 24 (2H, m, H_2and H_6a), 4. 13 ~4 · 09 (2H, m, H_6b and H_5), 3. 84 (3H, s, 2, -OCH3),

3. 79(3H,s,4”-0CH3),3. 70(6H,s,3”&5”_0CH3),2. 89 〜2. 85 (2H,m, NHCH2CE,C00H), 2. 49 〜 3. 79 (3H, s, 4 "-0CH3), 3. 70 (6H, s, 3" & 5 "_0CH3), 2. 89 ~2. 85 (2H, m, NHCH2CE, C00H), 2. 49 ~

2. 42 (2H, m, CONHCHaCH2COOH), 2. 15, 2. 09, 2. 03,1. 97 (each 3H, each s,4X0Ac); . 2. 42 (2H, m, CONHCHaCH2COOH), 2. 15, 2. 09, 2. 03,1 97 (each 3H, each s, 4X0Ac);

[0116] IR(cm-1) :3375 (NH), 2944 (CH), 1756 (ester, C = 0), 1676 (amide, C = 0),1510, 1225 (OCH3), 1129 (OAc),1075 (OCH3),1038 [0116] IR (cm-1): 3375 (NH), 2944 (CH), 1756 (ester, C = 0), 1676 (amide, C = 0), 1510, 1225 (OCH3), 1129 (OAc), 1075 (OCH3), 1038

[0117] MS (ESI (+) 70eV, m/z) :763. 4 [M+NHj + ; . [0117] MS (ESI (+) 70eV, m / z): 763 4 [M + NHj +;

[0118] MS (ESI (-) 70V, m/z) :780. 7 [M+Cl]-; . [0118] MS (ESI (-) 70V, m / z): 780 7 [M + Cl] -;

[0119] 实施例4 [0119] Example 4

[0120] N-(l,3,4,6_四_0_乙酰基_2_脱氧-β _D_吡喃半乳糖基)_4_((Z) 2' -甲氧基-5,-(3”,4”,5”_三甲氧基苯乙烯基)苯氧基)-4_氧代丁酰胺(1-10)的制备 [0120] N- (l, 3,4,6_ four _0_ _2_ acetyl-deoxy-galactopyranosyl -β _D_) _4 _ ((Z) 2 '- methoxy - 5 - ( preparation 3 ", 4", 5 "_ trimethoxy styryl) phenoxy) -4_ oxobutanamide (1-10)

[0121]将 G4-NH2. HCl (0. 77g,2_ol)溶于DMF(IOml)。 [0121] The G4-NH2. HCl (0. 77g, 2_ol) was dissolved in DMF (IOml). 缓慢滴加干燥的三乙胺(0. 28ml, 2mmol)。 Dried slowly added dropwise triethylamine (0. 28ml, 2mmol). 然后先后分批加入2b (0. 83g, 2mmol),EDCI (0. 38g, 2mmol),HOBt (0. 27g, 2mmol), 室温搅拌24h。 It was then added portionwise successively 2b (0. 83g, 2mmol), EDCI (0. 38g, 2mmol), HOBt (0. 27g, 2mmol), stirred at room temperature 24h. 反应液加入二氯甲烷(80ml),水洗(2X 100ml),饱和食盐水洗(3X 100ml), 干燥,抽滤,减压蒸除溶剂,硅胶柱层析(石油醚/乙酸乙酯=2/1),得微黄色固体0. 65g, 收率43. 6%, mp 66-68°C ; The reaction mixture was added methylene chloride (in 80 ml of), washed with water (2X 100ml), washed with brine (3X 100ml), dried, filtered off with suction, the solvent was distilled off under reduced pressure, silica gel column chromatography (petroleum ether / ethyl acetate = 2/1 ) to give a slightly yellow solid 0. 65g, yield 43. 6%, mp 66-68 ° C;

[0122] 1H-WrGOOMHz, CDCl3) δ (ppm) :7. 12 (1H, dd, J = 8. 4Hz, J=L 8Hz,4,-ArH), 6. 98(lH,d,J = 1. 8Hz,6,-ArH),6· 82(lH,d,J = 8. 7Hz,3,-ArH),6. 49 (2Η,s,2”&6”_ArH), 6. 45 (2H, s, laH&la,H),5. 80 (1H, d,J = 9. 3Hz, NH),5. 73 (1H, d,J = 8. 7Hz, H_l), [0122] 1H-WrGOOMHz, CDCl3) δ (ppm):. 7 12 (1H, dd, J = 8. 4Hz, J = L 8Hz, 4, -ArH), 6. 98 (lH, d, J = 1 . 8Hz, 6, -ArH), 6 · 82 (lH, d, J = 8. 7Hz, 3, -ArH), 6. 49 (2Η, s, 2 "& 6" _ArH), 6. 45 (2H, s, laH & la, H), 5. 80 (1H, d, J = 9. 3Hz, NH), 5. 73 (1H, d, J = 8. 7Hz, H_l),

5. 14 (1H,s, H-4), 5. 12 (1H, dd, J = 8. 7Hz, J = 2. 7Hz, H_3),4. 46 〜4. 36 (1H, m, H_2), 5. 14 (1H, s, H-4), 5. 12 (1H, dd, J = 8. 7Hz, J = 2. 7Hz, H_3), 4. 46 ~4. 36 (1H, m, H_2) ,

4. 20 〜4· 08 (3H, m, H_5,H_6a and H_6b),3. 84 (3H,s,2,-OCH3),3. 79 (3H,s,4 ” -OCH3), 4. 20 ~4 · 08 (3H, m, H_5, H_6a and H_6b), 3. 84 (3H, s, 2, -OCH3), 3. 79 (3H, s, 4 "-OCH3),

3. 70 (6H,s,3 ” &5 ” -OCH3),2. 87 (2H,t,J = 6. 3Hz,NHCH2CHaCOOH),2. 46 (2H,t,J = 6. 3Hz, ConhCh2Ch2Cooh),2. 16 (3H,S, OAc),2. 09 (6H, s,2X0Ac),I. 93 (3H,S, OAc); 3. 70 (6H, s, 3 "& 5" -OCH3), 2. 87 (2H, t, J = 6. 3Hz, NHCH2CHaCOOH), 2. 46 (2H, t, J = 6. 3Hz, ConhCh2Ch2Cooh), .. 2. 16 (3H, S, OAc), 2 09 (6H, s, 2X0Ac), I 93 (3H, S, OAc);

[0123] IR(cm-1) :3363 (NH), 2944 (CH), 1751 (ester, C = 0), 1685 (amide, C = 0),1510, 1224 (OCH3), 1128 (OAc),1075 (OCH3),1042 ;[0124] MS (ESI (+) 70eV, m/z) :763. 3 [M+NHj + ; [0123] IR (cm-1): 3363 (NH), 2944 (CH), 1751 (ester, C = 0), 1685 (amide, C = 0), 1510, 1224 (OCH3), 1128 (OAc), 1075 (OCH3), 1042; [0124] MS (ESI (+) 70eV, m / z):. 763 3 [m + NHj +;

[0125] MS (ESI (-) 70V, m/z) :780. 6 [M+Cl]-; . [0125] MS (ESI (-) 70V, m / z): 780 6 [M + Cl] -;

[0126] 实施例5 [0126] Example 5

[0127] N-(6_脱氧-3-0-吡喃葡萄糖基)-4_((2)2,-甲氧基_5,_ (3”,4”,5” -三甲氧基苯乙烯基)苯氧基)-4-氧代丁酰胺(1-13) [0127] N- (6_ -3-0- deoxy-glucopyranosyl) -4 _ ((2) 2, - methoxy _5, _ (3 ", 4", 5 "- trimethoxy styrene yl) phenoxy) -4-oxo-butyramide (1-13)

[0128]将 G5-NH2 (0. 5g,2. 6mmol)溶于DMF(IOml)。 [0128] The G5-NH2 (0. 5g, 2. 6mmol) was dissolved in DMF (IOml). 然后依次分批加入2b (1. 08g, 2. 6mmol),EDCI (0. 50g, 2. 6mmol),HOBt (0. 35g, 2. 6mmol),室温搅拌24h。 Was added portionwise followed 2b (1. 08g, 2. 6mmol), EDCI (0. 50g, 2. 6mmol), HOBt (0. 35g, 2. 6mmol), stirred at room temperature 24h. 反应液于80 "C 下减压蒸除溶剂,剩余物硅胶柱层析(二氯甲烷/甲醇=20/1),得白色固体0. 55g,收率35. 9%, m. ρ· 153 〜156°C。 The reaction solution at 80 "C the solvent was distilled off under reduced pressure, the residue was silica gel column chromatography (dichloromethane / methanol = 20/1) to give a white solid 0. 55g, yield of 35. 9%, m. Ρ · 153 ~156 ° C.

[0129] 实施例6 [0129] Example 6

[0130] N-(6-脱氧-aD-吡喃半乳糖基)-4-((Z) 2,-甲氧基_5,_ (3”,4”,5” -三甲氧基苯乙烯基)苯氧基)-4_氧代丁酰胺(1-14) [0130] N- (6- deoxy--aD- galactopyranosyl) -4 - ((Z) 2, - methoxy _5, _ (3 ", 4", 5 "- trimethoxy styrene yl) phenoxy) -4_ oxobutanamide (1-14)

[0131]将 G6-NH2 (0. 5g,2. 6mmol)溶于DMF(IOml)。 [0131] The G6-NH2 (0. 5g, 2. 6mmol) was dissolved in DMF (IOml). 然后依次分批加入2b (1. 08g, 2. 6mmol),EDCI (0. 50g, 2. 6mmol),HOBt (0. 35g, 2. 6mmol),室温搅拌24h。 Was added portionwise followed 2b (1. 08g, 2. 6mmol), EDCI (0. 50g, 2. 6mmol), HOBt (0. 35g, 2. 6mmol), stirred at room temperature 24h. 反应液于80 "C 下减压蒸除溶剂,剩余物硅胶柱层析(二氯甲烷/甲醇=20/1),得淡黄色固体0. 4g,收率26%, m. ρ· 136 〜139°C。 The reaction solution at 80 "C the solvent was distilled off under reduced pressure, the residue was silica gel column chromatography (dichloromethane / methanol = 20/1) to give a pale yellow solid 0. 4g, 26% yield in addition, m. Ρ · 136 ~ 139 ° C.

[0132] 实施例7 [0132] Example 7

[0133] 片剂 [0133] Tablets

[0134] 取实施例7中所得化合物0. 5g,淀粉2g,糊精Ig混合,用适量30%乙醇作湿润剂, 制粒,压片。 [0134] the compound obtained in Example 7 taken embodiment 0. 5g, starch 2g, dextrin Ig mixed with an appropriate amount of 30% ethanol as wetting agents, granulating, tabletting.

Claims (7)

  1. 1.通式(I)的化合物或其水合物: 1. A compound of formula (I) or a hydrate thereof:
    Figure CN102219811AC00021
    其中G-NH-代表: Representative G-NH- wherein:
    Figure CN102219811AC00022
    η代表0、1、2或3。 η represents 0, 1 or 3.
  2. 2.权利要求1的化合物或其水合物,其中G-NH-代表: 2. A compound, or a hydrate thereof as claimed in claim 1, wherein G-NH- Representative:
    Figure CN102219811AC00023
    η代表1或2。 η represents 1 or 2.
  3. 3.权利要求2的化合物或其水合物,其中G-NH-代表: 3. The compound of claim 2, or a hydrate thereof, wherein G-NH- Representative:
    Figure CN102219811AC00024
    η代表1。 η represents 1.
  4. 4.权利要求1至3中任一项的化合物或其水合物,其中的水合物以结晶水的形式存在, 结晶水的摩尔当量从0. 5到10。 1 to 3 or a hydrate thereof according to any one of the compound of claim 1, wherein the hydrate crystalline form of water, water of crystallization molar equivalent of from 0.5 to 10.
  5. 5. 一种药物组合物,其中含有权利要求1至3中任一项的化合物或其水合物和药学上可接受的载体。 A pharmaceutical composition which comprises a compound as claimed in claim or a hydrate thereof and a pharmaceutically acceptable carrier according to any one of 1 to 3.
  6. 6.权利要求1至3中任一项的化合物或其水合物在制备治疗血管生成性疾病的药物中的用途。 To 3 or a hydrate of a compound of any use of a medicament for treating an angiogenic disease in claim.
  7. 7.权利要求6的用途,其中血管生成性疾病是肿瘤或慢性炎症。 The use of claim 6, wherein the angiogenic disorder is cancer or chronic inflammation.
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