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Publication numberCN102219811 A
Publication typeApplication
Application numberCN 201110093276
Publication dateOct 19, 2011
Filing dateApr 14, 2011
Priority dateApr 14, 2011
Also published asCN102219811B
Publication number201110093276.5, CN 102219811 A, CN 102219811A, CN 201110093276, CN-A-102219811, CN102219811 A, CN102219811A, CN201110093276, CN201110093276.5
Inventors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
Applicant中国药科大学, 合肥医工医药有限公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
CA-4 derivatives and preparation method and medicinal application thereof
CN 102219811 A
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.
Claims(7)  translated from Chinese
1.通式(I)的化合物或其水合物: 1. Formula (I) compound or a hydrate thereof:
Figure CN102219811AC00021
其中G-NH-代表: Where G-NH- representative:
Figure CN102219811AC00022
η代表0、1、2或3。 η on behalf of 2 or 3.
2.权利要求1的化合物或其水合物,其中G-NH-代表: Compound or a hydrate thereof according to claim 1, wherein the G-NH- Representative:
Figure CN102219811AC00023
η代表1或2。 η represents 1 or 2.
3.权利要求2的化合物或其水合物,其中G-NH-代表: Compound or a hydrate thereof according to claim 2, wherein the G-NH- Representative:
Figure CN102219811AC00024
η代表1。 η represents 1.
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。 1-3 or a hydrate thereof A compound according to any preceding claim, wherein the crystalline form of the hydrate water in the presence of water of crystallization molar equivalent of from 0.5 to 10.
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。 5. A pharmaceutical composition, comprising Claim acceptable compound or a hydrate thereof and a pharmaceutically acceptable carrier in any of 1-3.
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。 1-3 A compound or a hydrate thereof for the preparation of any therapeutic angiogenic diseases in claim.
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。 Use according to claim 6, wherein the angiogenic disease is cancer or chronic inflammation.
Description  translated from Chinese

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 Technical 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 the field of pharmaceutical chemistry, in particular to a class of Combretastatin A-4 derivatives, processes for their preparation, as well as the inhibition of tumor angiogenesis.

背景技术 Background

[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 the CA-4) is one of the best material Combretastatins compounds in anti-tumor activity, it is separated from the South African tree Combretum Caffnom out, and can take advantage of the tumor tissue and normal tissue endothelial cells physiological differences, selectively inhibits tumor tubulin activity, changing its skeletal structure and morphology of endothelial cells, enhance its vascular permeability, disrupt blood flow, causing the tumor vascular endothelial cell apoptosis, 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, the 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 prodrug CA-4 disodium phosphate (CA-4P) has entered clinical Phase III.

[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] According to mechanism of action of anticancer drugs currently in clinical use mainly in the following four categories: ① direct role in DNA drugs; ② interfere with DNA synthesis of drugs; ③ antimitotic drugs; ④ drugs based on tumor signal transduction pathway. 前两种药物的作用强,但缺乏选择性,毒副作用大。 Before the role of the 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 act on tubulin, tubulin inhibitors (eg: vinblastine, and paclitaxel) as anticancer drugs achieved good clinical efficacy, but also the presence of anti-tumor spectrum narrow, high toxicity, easier resistance and other shortcomings. 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 tubulin inhibitors using the gap or withdrawal, had been suppressed in normal cells after drug metabolism or clearance to resume the cell cycle, and some tumor cells inactivated prematurely due to mutations damage the spindle checkpoint leaving the tumor cells to stop dividing, thus showing 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。 Anticancer drugs based on tumor signaling mechanisms (targeted) have low toxicity, few 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 angiogenic rescue response, and cancer susceptibility gene mutations and complexity has led to the current target-based single or multi-target tumor signal transduction pathway TAI easy to produce drug resistance, thus 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。 Therefore, the development of multi-target vessel based on different mechanisms of production inhibitor, it is possible to obtain high efficiency, low toxicity, low resistance of new anticancer drugs.

发明内容 DISCLOSURE

[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 their hydrates, their structure is characterized by CA-4 hydroxyl molecules by acid (or propionic acid, glutaric acid or adipic acid) tether and amino sugar molecule amine 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 in human umbilical vein endothelial cells has 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。 Accordingly, the compounds of formula I of the present invention is a compound containing water of crystallization and can be used to treat 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] G-NH- on behalf of any of the following structure:

[0009] [0009]

Figure CN102219811AD00052

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

[0011] [0011]

Figure CN102219811AD00053

[0012] [0012]

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

[0014] [0014]

Figure CN102219811AD00061

[0015] 其中η代表:0、1、2或3。 [0015] where η representative: 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 further 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] The hydrate compounds of the invention also has the same effect with the compound, wherein the hydrate crystalline form of the presence of water, the molar equivalent of water of crystallization 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_ oxo butyramide (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_ oxo-pentanamide (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_ -β _D_ acetyl-deoxy-galactopyranosyl) _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_ -β _D_ acetyl-deoxy-galactopyranosyl) _4 _ ((Z) 2, - methoxy - 5 - (3 ", 4 ", 5" _ trimethoxy styryl) phenoxy) -4_ oxo butyramide (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_ -β _D_ acetyl-deoxy-galactopyranosyl) _5 _ ((Z) 2, - methoxy - 5 - (3 ", 4 ", 5" _ trimethoxy styryl) phenoxy) -5_ oxo-pentanamide (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_ acetyl _2_ deoxy -β-D- glucopyranosyl) _4 _ ((Z) 2, - methoxy -5 - ( 3 ", 4", 5 "_ trimethoxy styryl) phenoxy) -4_ oxo butyramide (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_ acetyl _2_ deoxy -β-D- glucopyranosyl) _5 _ ((Z) 2, - methoxy -5 - ( 3 ", 4", 5 "_ trimethoxy styryl) phenoxy) -5_ oxo-pentanamide (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_ acetyl _2_ deoxy -β-D- glucopyranosyl) _6 _ ((Z) 2, - methoxy -5 - ( 3 ", 4", 5 "_ trimethoxy styryl) phenoxy) -6_ oxo-hexyl amide (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_ acetyl _2_ deoxy -β-D- galactopyranosyl) _4 _ ((Z) 2, - methoxy - 5 - (3 ", 4", 5 "_ trimethoxy styryl) phenoxy) -4_ oxo butyramide (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_ acetyl _2_ deoxy -β-D- galactopyranosyl) _5 _ ((Z) 2, - methoxy - 5 - (3 ", 4", 5 "_ trimethoxy styryl) phenoxy) -5_ oxo-pentanamide (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_ acetyl _2_ deoxy -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- deoxy -3-0- 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-pentyl amide (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 styrene-yl) 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-pentyl amide (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_ oxo butyramide (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_ oxo-pentanamide (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 styrene-yl) 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-pentyl amide (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_ oxo butyramide (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_ oxo butyramide (1-25)

[0045] 本发明通式化合物(I)的制备方法如下: [0045] The present invention is a compound of formula (I) are prepared as follows:

[0046] 其中关键中间体2的制备方法如下: [0046] The key intermediate of Preparation 2 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) reactant is 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 hydroxide, 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 target compound I as follows:

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

[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) reactants is oxalyl chloride, or thionyl chloride, or triethylamine and EDCI / HOBt; solvent is DMF.

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

[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) reactant 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 the G-NH2 = Gn-NH2 ~G12-NH2, synthetic route is as follows:

[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) reactant is 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 some compounds 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] Some compounds of the present invention in 61.72 on vascular endothelial cell proliferation inhibiting activity of the test method is as follows:

[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] mitochondria of living cells to make exogenous succinate dehydrogenase MTT reduction of water-insoluble crystalline blue-purple formazan (Formazan) and deposited in 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。 Dimethyl sulfoxide (DMSO) to dissolve formazan cells, measured by ELISA absorbance detector at 570nm wavelength, 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 values the smaller the test compound on human umbilical vein endothelial cells (HUVEC), the stronger inhibitory activity the better.

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

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

[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4C保存备用。 [0068] NaCl 8. 00g, KCl 0. 20g, Na2HPO4 12H20 3. 49g, KH2PO4O. 20g, plus three dissolved in distilled water, 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_20C保存备用。 [0070] Weigh trypsin 0. 25g, added PBS solution was stirred to dissolve completely on a magnetic stirrer, set the volume to 100ml, filter-sterilized and stored at _20 C.

[0071] (3)噻唑兰(MTT)溶液 [0071] (3) MTT (MTT) solution

[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,4C避光保存,两周内使用有效。 [0072] Weigh MTT 50mg, PBS was added to a final volume of 10ml, on a magnetic stirrer so that after complete dissolution, filter sterilized, 4 C protected from light, the 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 with dimethyl sulfoxide (DMSO) to all tested compounds were formulated as a powder 10_2M concentration of liquor before use with cell culture medium dubbed the desired concentration.

[0074] 操作流程: [0074] flow:

[0075] 使用噻唑兰(MTT)法进行测定,主要步骤如下: [0075] The MTT assay (MTT) were measured in the following 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) to take in the exponential growth phase in good human vein endothelial cells (HUVEC) - bottle, adding 0.25% trypsin digestion, digestion 1~2min, cytoplasmic retraction visible under an inverted microscope, cells become round, when clear cell gap, immediately flip the flask, add a little DMEM culture medium containing 10% fetal bovine serum to terminate digestion, slowly blowing down the sidewall of the cell, 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 / holes with approximately 5000 cells, set the thermostat C02 training

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) The cells in the control group (containing 10% fetal bovine serum DMEM), dosing group (DMEM containing 10% fetal bovine serum and final concentrations 10-5mol / L, 10-6 μ mol / L, 10_7 μ mol / L of the drug to be detected), 100 μ 1 / hole, and cultured for 24 hours.

[0079] (4)每孔加入5mg/ml 的MTT 溶液20 μ 1,37C孵育4h。 [0079] (4) was added to each well 5mg / ml of MTT solution 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, added DMS0,150 μ 1 / hole plate shaken for 5 minutes in bed.

[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) by enzyme-linked immunosorbent assay was measured at a wavelength at 570nm absorbance per well.

[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 human umbilical vein endothelial cells (HUVEC) proliferation IC5tl (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] The chemical structure of the compounds in Table 1 correspond to the same code examples.

[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] Pharmacological test results show that some compounds of the present 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 the efficacy is superior to 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 also provides a method of treating a disease associated with angiogenesis pharmaceutical composition containing 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 compositions may be in conventional tablets or capsules, sustained release tablets or capsules, controlled-release tablets capsules, oral liquid form preparations on conventional injection or the 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。 [0087] In general, CA-4 derivative of the present invention are useful in the treatment, the human dose range of 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。 Can also be different depending on the severity and disease formulations, 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_ oxo butyramide (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140C,反应4h, 停止加热,冷却至10C,缓慢滴加浓盐酸200ml,室温下过夜。 [0091] In a three-necked 500ml flask was added 3,4,5_ trimethoxy phenylacetic acid (50g, 0. 22mol), 3_ _4_ hydroxy-methoxybenzaldehyde (34g, 0. 22mol), 62. 5ml of triethylamine and 150ml of acetic anhydride, warmed with stirring to 140 C, the reaction 4h, heating was stopped, cooled to 10 C, concentrated hydrochloric acid was slowly added dropwise 200ml, 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 〜186C [Bioorg. Med. Chem. ,2005,13(11) :3853_3864]) There khaki solid precipitated solid was filtered off to stop the reaction, with about IOOml recrystallized from ethanol to give yellow needles 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 "- tetramethoxysilane -3, _-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200C,搅拌3h。 [0094] equipped with a thermometer, reflux condenser, 500mL three-necked flask with a drying tube was added 1 (7. 2g, 20mmol), copper powder 6. 6g (0. 103mol), quinoline 72ml, reaction was heated to 200 C, stirring 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 ether was added, filtered through Celite copper. 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。 With 300ml 5MHC1 the pyridine wash was extracted with ether 150ml, the separated aqueous layer washed with ether (3 X 150ml), the combined organic layers. 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 layer once with saturated Na2CO3 (2 X 300ml) were washed twice with saturated NaCl (2 X 300ml) washed twice, dried over anhydrous Na2SO4 overnight and were 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 116〜117C (文献值:116C [J. Org. Chem., 2001,66(24) :8135-8138]) Sodium sulfate was filtered off, spin off under reduced pressure to 2/3 volume of ethyl ether, there is a slightly yellow solid 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 was 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 〜110C。 [0097] ice bath Triethylamine 1. 8ml (12. 8mmol) slowly dropped 8ml acetone, then add CA-4 (lg, 3. 2mmol) and succinic anhydride (1. 2g, 12mmol), so The reaction temperature is maintained at 15 C, with stirring, the reaction 24h, the reaction was stopped, spin off the acetone, plus the amount of ethyl acetate, the organic layer was washed l.Omol / L HCl (13ml), and treated with 20ml water again, saturated NaCl (2 X 20ml) washed, dried over anhydrous MgSO4 2h, filtered, and spin dry the solvent, the crude product was dissolved in ether, insolubles were removed by filtration, the solvent was spin, and the precipitated solid was filtered, washed with a small amount of 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_ oxo butyramide (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), dried triethylamine was slowly added dropwise (0.28ml, 2mmol), followed by portionwise added 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 solution was added dichloromethane (70ml), brine (3X 70ml), drying, filtration, solvent was distilled off under reduced pressure, silica gel column chromatography (petroleum ether / ethyl acetate = 3/2) to give a slightly yellow 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 = 18Ηζ,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_ -β _D_ acetyl-deoxy-galactopyranosyl) _4 _ ((Z) 2, - methoxy - 5 - (3 ", Preparation of 4 ", 5" _ trimethoxy styryl) phenoxy) -4_ oxo butyramide (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.?. 85-87C ; The reaction solution was added dichloromethane (80ml), washed with water (2 X 100ml), brine (3 X 100ml), drying, filtration, 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_ oxo butyramide (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 dropped 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。 Then successively added portionwise 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 solution was added dichloromethane (80ml), washed with water (2X 100ml), brine (3X 100ml), drying, filtration, solvent was distilled off under reduced pressure, silica gel column chromatography (petroleum ether / ethyl acetate = 2/1 ) to give a white solid 0. 82g, yield 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_ acetyl -β _D_ _2_ deoxy-galactopyranosyl) _4 _ ((Z) 2 '- methoxy - 5 - ( 3 ", 4", 5 "_ trimethoxy styryl) phenoxy) butyramide Preparation -4_ oxo (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 dropped 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。 Then successively added portionwise 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 66-68C ; The reaction solution was added dichloromethane (80ml), washed with water (2X 100ml), brine (3X 100ml), drying, filtration, solvent was distilled off under reduced pressure, silica gel column chromatography (petroleum ether / ethyl acetate = 2/1 ) to give a yellowish 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 〜156C。 The reaction was incubated at 80 "C the solvent was distilled off under reduced pressure, the residue was chromatographed on silica gel (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_ oxo butyramide (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 〜139C。 The reaction was incubated at 80 "C the solvent was distilled off under reduced pressure, the residue was chromatographed on silica gel (dichloromethane / methanol = 20/1) to give a pale yellow solid 0. 4g, yield 26%, 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 resulting compound of Example 7 taken embodiment 0. 5g, starch 2g, dextrin Ig mixed with an appropriate amount of 30% ethanol as wetting agents, granulating, tabletting.

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Classifications
International ClassificationA61P35/00, C07H15/12, C07H1/00, A61P29/00, A61K31/7028
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