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Publication numberCN102863472 A
Publication typeApplication
Application numberCN 201210388825
Publication dateJan 9, 2013
Filing dateOct 15, 2012
Priority dateOct 15, 2012
Also published asCN102863472B
Publication number201210388825.6, CN 102863472 A, CN 102863472A, CN 201210388825, CN-A-102863472, CN102863472 A, CN102863472A, CN201210388825, CN201210388825.6
Inventors王鹏, 李静, 韩福国, 戚欣, 李明
Applicant中国海洋大学
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Combretastatin A-4 analogue, preparation method of combretastatin A-4 analogue and application of combretastatin A-4 analogue in preparing anti-tumor drugs
CN 102863472 A
Abstract
The invention provides a combretastatin A-4 analogue. The structure of the combretastatin A-4 analogue is represented by general formula (I), wherein R1 represents -H, OH or a metal phosphate substituent group, R2 represents -OH or the metal phosphate substituent group, and the metal phosphate substituent group is -OP(O)(ONa)2, -OP(O)(OK)2, -OP(O)(OLi)2, -OP(O) O2Zn or -OP(O) O2Ca. A pharmacology experiment shows that the combretastatin A-4 analogue can inhibit polymerization of endothelial cell tubulin, damage forming of lumens and lead to tumour organization center necrosis, and the combretastatin A-4 analogue can be applied in anti-solid tumor drugs or in tumor vessel breakers and is wide in application prospects.
Claims(10)  translated from Chinese
1. 一种考布他汀A-4类似物,其特征在于:其结构如通式(I)所示: A combretastatin A-4 analogs, characterized in that: the structure of the general formula (I) below:
Figure CN102863472AC00021
其中R1= -H、OH或金属磷酸盐取代基,R2= -OH或金属磷酸盐取代基,所述金属磷酸盐取代基为-OP (O) (ONa)2, -OP (O) (OK)2, -OP (O) (OLi)2, -OP (O) O2Zn 或-OP (O) 02Ca。 Wherein R1 = -H, OH or a metal phosphate substituent, R2 = -OH substituent or a metal phosphate, a metal phosphate substituent is -OP (O) (ONa) 2, -OP (O) (OK ) 2, -OP (O) (OLi) 2, -OP (O) O2Zn or -OP (O) 02Ca.
2.根据权利要求I所述的考布他汀A-4类似物,其特征在于:所述R1和R2中至少有一个为金属磷酸盐取代基。 2. I said combretastatin A-4 analogs claim, wherein: said R1 and R2 is at least one of a metal phosphate substituents.
3.包含权利要求I所述的考布他汀A-4类似物的药物组合物。 3. The claim contains I said combretastatin A-4 pharmaceutical composition analogs.
4.含有有效剂量的权利要求3所述的考布他汀A-4类似物和可药用赋形剂的药物组合物。 3 test cloth according to any preceding claim containing an effective dose of the statin A-4 analogs and a pharmaceutically acceptable excipient pharmaceutical composition.
5.根据权利要求I所述的考布他汀A-4类似物的制备方法,其特征在于包括以下步骤: 将4-(3' ,4' ,5'-三甲氧基苯基)-5-(2〃,3" - 二羟基_4"-甲氧基苯基)-噁唑溶于N,N-二甲基甲酰胺与乙腈的混合溶剂中,在惰性气体保护、低温条件下,依次添加四氯化碳、二甲氨基吡啶以及亚磷酸二苄酯反应制备噁唑类化合物的磷酸衍生物,所述的4-(3',4',5'-三甲氧基苯基)-5-(2〃,3" - 二羟基_4"-甲氧基苯基)-噁唑、四氯化碳、二甲氨基吡啶、亚磷酸二苄酯的摩尔比分别是I :5-15 :0. 1-0. 5 :2-8 ; 然后利用三甲基溴硅烷脱除苄基,再与甲醇钠、氢氧化钾、氢氧化锂、醋酸锌和氢氧化钙中一种或多种反应得到噁唑类化合物的磷酸盐粗品,所述的噁唑类化合物的磷酸衍生物与三甲基溴硅烷的摩尔比是I :4-8 ;所述的噁唑类化合物的磷酸衍生物与甲醇钠、氢氧化钾、氢氧化锂的摩尔比为1:1-5 ;所述的噁唑类化合物的磷酸衍生物与醋酸锌、氢氧化钙的摩尔比为1:1-3; 将所述磷酸盐粗品在水/丙酮中沉出,再在水与乙醇中结晶即得噁唑类化合物的磷酸盐。 5. I according to claim test cloth preparation method statin A-4 analogs, comprising the steps of: 4- (3 ', 4', 5'-trimethoxyphenyl) -5- (2 〃, 3 '- dihydroxy _4 "- methoxyphenyl) - oxazole was dissolved in N, N- mixed solvent of dimethylformamide and acetonitrile, under an inert gas, low temperature, followed by Add carbon tetrachloride, dimethylaminopyridine dibenzyl phosphite and phosphate ester derivative prepared oxazole compounds, the 4- (3 ', 4', 5'-trimethoxyphenyl) -5 - (2 〃, 3 '- dihydroxy _4' - methoxyphenyl) - oxazole, carbon tetrachloride, dimethylaminopyridine, molar ratio of dibenzyl phosphite ester are I: 5-15: 0. 1-0 5: 2-8; trimethyl-silane is then removed utilizing a benzyl group, and then with sodium methoxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, zinc acetate, and the one or more reaction oxazole obtained crude phosphate compound, the molar ratio of phosphoric acid derivatives of the oxazole compounds and trimethylbromosilane is I: 4-8; oxazole derivatives of phosphoric acid compounds and methanol The molar ratio of sodium, potassium, lithium hydroxide is 1: 1-5; and the molar ratio of phosphoric acid derivative zinc acetate, calcium hydroxide of the oxazole compound is 1: 1-3; the The crude phosphate in water / acetone precipitated, and then in water and crystallized from ethanol to give the phosphate oxazole compound.
6.根据权利要求5所述的考布他汀A-4类似物的制备方法,其特征在于:将所述粗品溶于水中,加入丙酮沉出3次,所需丙酮与水的体积比为3-5 :1,所得粗品在水与乙醇中结晶,水与乙醇的体积比为I :3-6。 Cobb according to claim 5, wherein the statin production method A-4 analogs, characterized in that: the crude product was dissolved in water, precipitated by adding acetone three times, the desired volume ratio of acetone to water is 3 -5: 1, the obtained crude product was crystallized in water and ethanol, water and ethanol in a volume ratio of I: 3-6.
7.根据权利要求I所述的考布他汀A-4类似物在制备抑制微管蛋白聚合或抗肿瘤药物中的用途。 According to claim I said combretastatin A-4 in the preparation of analogs inhibiting tubulin polymerization or in the use of antineoplastic agents.
8.权利要求3所述的药物组合物在制备抑制微管蛋白聚合或抗肿瘤药物中的用途。 3 The pharmaceutical composition of claim 1 in the manufacture of inhibiting tubulin polymerization or antineoplastic use.
9.根据权利要求7或8所述的制备抑制微管蛋白聚合或抗肿瘤药物中的用途,其特征在于:所述肿瘤是实体肿瘤,所述实体肿瘤是肺癌、肾癌、乳腺癌、胃癌、卡波氏肉瘤、结肠癌、肝癌、前列腺癌、甲状腺癌、神经母细胞瘤、卵巢癌或头颈部鳞癌、鼻咽癌。 9. Preparation of 7 or claim 8, wherein the tubulin polymerization inhibitory or antineoplastic use, characterized in that: the tumor is a solid tumor, said solid tumor is a lung, kidney, breast, stomach , Kaposi's sarcoma, colon cancer, liver cancer, prostate cancer, thyroid cancer, neuroblastoma, ovarian cancer, or head and neck squamous cell carcinoma, nasopharyngeal carcinoma.
10.根据权利要求7或8所述的制备抑制微管蛋白聚合或抗肿瘤药物中的用途,其特征在于:其中抗肿瘤的机理是抑制内皮细胞微管蛋白聚合,或通过破坏肿瘤既成血管进行作用。 7 or 10. The preparation as claimed in claim 8, wherein the inhibiting tubulin polymerization or antineoplastic use, wherein: wherein the anti-tumor mechanism is inhibiting tubulin polymerization endothelial cells, or by the de facto destruction of tumor blood vessels effect.
Description  translated from Chinese

考布他汀A-4类似物及其制备方法和在制备抗肿瘤药物中的应用 Combretastatin A-4 analogs and preparation method and in the preparation of antineoplastic

技术领域 Technical Field

[0001] 本发明属于药物领域,尤其涉及了考布他汀A-4类似物及其制备方法和在制备抗肿瘤药物中的应用。 [0001] The present invention belongs to the pharmaceutical field, and more particularly to a combretastatin A-4 analogs and preparation method and in the preparation of anti-tumor drugs.

背景技术 Background

[0002]目前靶向肿瘤血管系统的药物主要分为两种:一种是通过抑制肿瘤的新生血管生成而有效阻止肿瘤生长和转移的药物,称为肿瘤新生血管生成抑制剂(tumorangiogenesis inhibtor, TAI),另一种是通过破坏肿瘤内部血管而导致肿瘤坏死的药物,称为血管破坏剂(Vascular Disrupting Agent, VDA)。 [0002] There are currently targeting tumor vasculature drugs are divided into two types: one is via inhibition of tumor angiogenesis and tumor growth and metastasis effectively prevent drugs called angiogenesis inhibitors (tumorangiogenesis inhibtor, TAI ), the other is by destroying the tumor blood vessels and lead to tumor necrosis internal drug, called vascular disrupting agents (Vascular Disrupting Agent, VDA).

[0003] 血管破坏剂是基于实体瘤血管网络混乱、分级不明显、血管内皮细胞形状不规则,相互之间联系松散等特点而开发的一类抗肿瘤药物,它可以快速、选择性的破坏既存的肿瘤血管网络,从而引发肿瘤的坏死。 [0003] The vascular disrupting agent is based on a solid tumor vascular network chaos, grading obvious, vascular endothelial cells of irregular shape, the links between each other loose, etc. and the development of a class of anticancer drugs, it can quickly and selectively destroy existing network of tumor blood vessels, causing tumor necrosis. 在作用机理上,血管破坏剂是通过抑制实体瘤血管内皮细胞微管蛋白聚合,改变细胞骨架结构,从而引起肿瘤血管内皮细胞变形,导致肿瘤内部血栓形成,阻断肿瘤内部氧气和营养的供应以及细胞代谢废物的排出,进而引起实体瘤内部肿瘤细胞的大面积坏死。 On the mechanism of action, a vascular disrupting agent is a solid tumor by inhibiting vascular endothelial cell tubulin polymerization, changes in cytoskeletal structure causing deformation tumor vascular endothelial cells, leading to internal tumor thrombosis, blocking tumor internal supply of oxygen and nutrients and a large area of the discharge cell metabolic waste, thereby causing solid tumor necrosis within the tumor cells. 目前,在欧美进入临床研究的众多血管破坏剂中,考布他汀A-4的磷酸钠盐(CA4P)和考布他汀AI的磷酸钠盐(CAlP)显示出非常好的开发前景。 Currently, clinical studies in Europe and a number of vascular disrupting agent, combretastatin A-4 of the sodium salt (CA4P) and combretastatins AI of sodium salt (CAlP) shows very good development prospects. CA4P具有优良的抗血管活性,对甲状腺癌、肝癌、肺癌等多种实体肿瘤具有显著疗效,已被美国FDA批准为治疗低分化甲状腺癌的孤儿药物;CA1P是其进一步改构的化合物,已进入临床研究阶段。 CA4P has excellent anti-vascular activity against a variety of solid tumors, thyroid cancer, liver cancer, lung cancer has a significant effect, has been approved by the US FDA for the treatment of poorly differentiated thyroid cancer, orphan drugs; CA1P is further modified structure of the compound, has entered clinical research stage. 因此开发新型的、相比CA4P更高效的肿瘤血管破坏剂仍然具有十分重要的意义。 Therefore, the development of new, more efficient compared to CA4P tumor vascular disrupting agent still has great significance.

发明内容 DISCLOSURE

[0004] 针对现有技术中抗肿瘤药物存在的不足和缺陷,本发明提供了考布他汀A-4类似物及其制备方法和在制备抗肿瘤药物中的应用,本发明依据考布他汀类血管破坏剂的结构特点,提供CA4的结构类似物,并将其制备成磷酸盐,该系列磷酸盐衍生物的水溶性好,生物利用度高,能够作为抑制微管蛋白聚合、靶向肿瘤血管的抗肿瘤药物。 [0004] For the prior art antineoplastic existing problems and deficiencies, the present invention provides a combretastatin A-4 analogs and preparation method and in the preparation of anti-tumor drugs, according to the present invention combretastatins category the structural characteristics of vascular disrupting agents, there is provided a structural analogs CA4, and prepared into a phosphate, a water-soluble phosphate derivative of the series of good bioavailability, can be used as the polymerization inhibiting tubulin targeting tumor vasculature anticancer drugs.

[0005] 为实现上述发明目的,本发明采用下述技术方案予以实现: [0005] To achieve the above object of the invention, the present invention adopts the following technical scheme to be realized:

[0006] 一种考布他汀A-4类似物,其结构如通式(I)所示: [0006] A combretastatin A-4 analogs, such as the structure of formula (I) below:

[0007] [0007]

Figure CN102863472AD00041

[0008] 其中R1=-H' OH或金属磷酸盐取代基,R2=-OH或金属磷酸盐取代基,所述金属磷酸盐取代基为-OP (O) (ONa)2, -OP (O) (OK)2, -OP (O) (OLi)2, -OP (O) O2Zn 或-OP (O) O2Ca0 [0008] wherein R1 = -H 'OH or a metal phosphate substituent, R2 = -OH substituent or a metal phosphate, a metal phosphate substituent is -OP (O) (ONa) 2, -OP (O ) (OK) 2, -OP (O) (OLi) 2, -OP (O) O2Zn or -OP (O) O2Ca0

[0009] 对上述技术方案的进一步改进:所述R1和R2中至少有一个为金属磷酸盐取代基。 [0009] The further improvement of the above aspect: the R1 and R2 at least one of a metal phosphate substituents.

[0010] 本发明还提供了包含所述的考布他汀A-4类似物的药物组合物。 [0010] The present invention also provides pharmaceutical compositions comprising a combretastatin A-4 analogs.

[0011] 本发明还提供了含有有效剂量的所述的考布他汀A-4类似物和可药用赋形剂的药物组合物。 [0011] The present invention also provides a test cloth containing an effective dose of the statin A-4 analogs and a pharmaceutically acceptable excipient composition.

[0012] 本发明还提供了所述的考布他汀A-4类似物的制备方法,它包括以下步骤: [0012] The present invention also provides a method for the preparation of combretastatin A-4 analogs, which comprises the following steps:

[0013] 将4-(3',4',5'-三甲氧基苯基)-5-(2",3" - 二羟基_4"-甲氧基苯基)_噁唑溶于N,N- 二甲基甲酰胺与乙腈的混合溶剂中,在惰性气体保护、低温条件下,依次添加四氯化碳、二甲氨基吡啶以及亚磷酸二苄酯反应制备噁唑类化合物的磷酸衍生物,所述的4-(3',4',5'-三甲氧基苯基)-5-(2〃,3" - 二羟基_4"-甲氧基苯基)-噁唑、四氯化碳、二甲氨基吡啶、亚磷酸二苄酯的摩尔比分别是I :5-15 :0. 1-0. 5 :2-8 ; [0013] 4- (3 ', 4', 5'-trimethoxyphenyl) -5- (2 ', 3' - dihydroxy _4 "- methoxyphenyl) oxazole was dissolved in N _ , a mixed solvent of N- dimethylformamide and acetonitrile, under inert gas protection, low temperature, followed by addition of carbon tetrachloride, dimethylaminopyridine and dibenzyl phosphite phosphorylation reaction of compounds prepared oxazole derivative thereof, said 4- (3 ', 4', 5'-trimethoxyphenyl) -5- (2 〃, 3 '- dihydroxy _4' - methoxyphenyl) - oxazole, four CFC, dimethylaminopyridine, molar ratio of dibenzyl phosphite ester are I: 5-15: 0 1-0 5: 2-8;..

[0014] 然后利用三甲基溴硅烷脱除苄基,再与甲醇钠、氢氧化钾、氢氧化锂、醋酸锌和氢氧化钙中一种或多种反应得到噁唑类化合物的磷酸盐粗品,所述的噁唑类化合物的磷酸衍生物与三甲基溴硅烷的摩尔比是I :4-8 ;所述的噁唑类化合物的磷酸衍生物与甲醇钠、氢氧化钾、氢氧化锂的摩尔比为1:1-5 ;所述的噁唑类化合物的磷酸衍生物与醋酸锌、氢氧化钙的摩尔比为1:1-3 ; [0014] trimethyl-silane is then removed utilizing a benzyl group, and then with sodium methoxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, zinc acetate, and one or more compounds obtained by reacting an oxazole crude phosphate , the molar ratio of the phosphoric acid derivative oxazole compounds and trimethylsilyl bromide is I: 4-8; phosphoric acid derivative of the oxazole compounds with sodium methoxide, potassium hydroxide, lithium hydroxide The molar ratio of 1: 1-5; derivative of the acid with zinc acetate oxazole compounds, calcium hydroxide molar ratio of 1: 1-3;

[0015] 将所述磷酸盐粗品在水/丙酮中沉出,再在水与乙醇中结晶即得噁唑类化合物的磷酸盐。 [0015] The crude product of the phosphate in water / acetone precipitated, and then in water and crystallized from ethanol to give the phosphate oxazole compound.

[0016] 对上述技术方案的进一步改进:将所述粗品溶于水中,加入丙酮沉出3次,所需丙酮与水的体积比为3-5 :1,所得粗品在水与乙醇中结晶,水与乙醇的体积比为I :3-6。 [0016] A further modification of the above-mentioned technical solution: The crude product was dissolved in water, precipitated by adding acetone 3 times, acetone and water required 3-5 volume ratio of: 1, the resultant crude crystals in water and ethanol, the volume ratio of water and ethanol I: 3-6.

[0017] 本发明还提供了所述的考布他汀A-4类似物在制备抑制微管蛋白聚合或抗肿瘤药物中的用途。 [0017] The present invention also provides a Cobb said statin analogs in the manufacture of A-4 inhibiting tubulin polymerization or in the use of antineoplastic agents.

[0018] 本发明还提供了所述的药物组合物在制备抑制微管蛋白聚合或抗肿瘤药物中的用途。 [0018] The present invention also provides a pharmaceutical composition in the preparation of inhibiting tubulin polymerization or in the use of antineoplastic agents.

[0019] 对上述技术方案的进一步改进:所述肿瘤是实体肿瘤,所述实体肿瘤是肺癌、肾癌、乳腺癌、胃癌、卡波氏肉瘤、结肠癌、肝癌、前列腺癌、甲状腺癌、神经母细胞瘤、卵巢癌或头颈部鳞癌、鼻咽癌。 [0019] Further improvements to the above aspect: the tumor is a solid tumor, said solid tumor is lung cancer, renal cancer, breast cancer, stomach cancer, Kaposi's sarcoma, colon cancer, liver cancer, prostate cancer, thyroid cancer, nerve neuroblastoma, ovarian cancer, or head and neck squamous cell carcinoma, nasopharyngeal carcinoma.

[0020] 对上述技术方案的进一步改进:其中抗肿瘤的机理是抑制内皮细胞微管蛋白聚合,或通过破坏肿瘤既成血管进行作用。 [0020] Further improvement of the technical scheme: wherein the anti-tumor mechanism of inhibition of endothelial cell tubulin polymerization, or by the de facto destruction of tumor blood vessels effect.

[0021] 与现有技术相比,本发明的优点和积极效果是: [0021] Compared with the prior art, the advantages and the positive effect of the present invention are:

[0022] 本发明提供了考布他汀A-4类似物,它通过4_(3',4',5'-三甲氧基苯基)-5-(2",3" - 二羟基-4"-甲氧基苯基)_噁唑与亚磷酸二苄酯反应制备得到。该系列磷酸盐衍生物的水溶性好,生物利用度高,能够作为抑制微管蛋白聚合、靶向肿瘤血管的抗肿瘤药物。 [0022] The present invention provides a combretastatin A-4 analogs through 4_ (3 ', 4', 5'-trimethoxyphenyl) -5- (2 ', 3' - dihydroxy-4 " - methoxyphenyl) _ oxazole and phosphorous acid benzyl ester prepared by the series of water-soluble phosphate derivatives of good bioavailability, resistant to inhibition of tubulin polymerization as targeting tumor blood vessels. cancer drug.

[0023] 本发明将药物分子与磷酸基团相连形成磷酸盐衍生物,有助于药物分子向细胞内转运,并且在进入药物靶点前具有很好的稳定性和较长的半衰期;磷酸盐前药在体内可被内源性的磷酸酯酶水解为母药释放出来,而癌细胞表面磷酸酯酶含量较高使水解具有选择性。 [0023] The present invention the drug molecules and phosphate groups linked to the formation of phosphate derivatives, to help drug molecules to intracellular transport, and before entering the drug target has good stability and long half-life; phosphate phosphate prodrug in vivo enzymatic hydrolysis by endogenous release of the parent drug, while higher levels of cell surface phosphatase hydrolysis selective. 通过磷酸盐前药给药可以提高药物分子的水溶性、选择性以及降低药物的毒副作用和不良反应。 By phosphate prodrug of a water-soluble drug molecules can improve selectivity and reduce drug side effects and adverse reactions. [0024] 本发明通过实验表明结构类似考布他汀A4的化合物能用于制备抑制微管蛋白聚合或抗肿瘤药物,应用前景广阔。 [0024] The present invention is structurally similar experiments showed that statins A4 test compound cloth can be used for the preparation of inhibiting tubulin polymerization or anticancer drugs, application prospect.

[0025] 结合附图阅读本发明的具体实施方式后,本发明的其他特点和优点将变得更加清楚。 [0025] After DRAWINGS particular embodiment of the present invention, other features and advantages of the present invention will become more apparent.

附图说明 Brief Description

[0026] 图I为本发明中CA-IH对微管蛋白聚合的抑制作用。 [0026] FIG. I of the present invention in CA-IH inhibition of tubulin polymerization.

[0027] 图2为本发明中CA-IH对HUVEC细胞形态的影响。 [0027] FIG. 2 is a schematic affect the CA-IH on HUVEC cell morphology.

[0028] 图3为本发明中免疫荧光检测药物对HUVEC微管的影响图,其中上左为空白对照,上右为溶剂对照,下左为CA4,下右为CA-1H。 [0028] FIG. 3 of the present invention in immunofluorescence drugs on HUVEC microtubules influence diagram, which is blank on the left, on the right for the solvent control, the left as CA4, under the right of CA-1H.

[0029] 图4为本发明中免疫荧光检测药物对HUVEC微丝的影响图,其中上左为空白对照,上右为溶剂对照,下左为CA4,下右为CA-1H。 [0029] FIG. 4 of the present invention in immunofluorescence drugs on HUVEC microfilaments influence diagram, which is blank on the left, on the right for the solvent control, the left as CA4, under the right of CA-1H.

[0030] 图5为本发明中CA-IH对HUVEC既成管腔的破坏图。 [0030] FIG. 5 of the present invention in CA-IH lumen of HUVEC de facto destruction of FIG.

[0031] 图6为本发明中CA-IH对HUVEC既成管腔在各个时间点的破坏率统计图。 [0031] FIG. 6 of the present invention in CA-IH de facto lumen of HUVEC at various points in time destroy the rate chart.

[0032] 图7为本发明中Western blotting检测CA-1HP对HUVEC内微管蛋白聚合的影响图。 [0032] FIG. 7 in the present invention by Western blotting CA-1HP within HUVEC tubulin polymerization influence diagram.

[0033] 图8为本发明中CA-IHP引发NCI-H1975裸小鼠移植瘤组织内部坏死图。 [0033] FIG. 8 of the present invention in CA-IHP initiated NCI-H1975 xenografts in nude mice within the organization necrosis Fig.

[0034] 图9为本发明中CA-IHP引发NCI-H1975裸小鼠移植瘤组织内部坏死统计图。 [0034] FIG. 9 of the present invention in CA-IHP initiated NCI-H1975 xenografts in nude mice necrosis within the organization chart.

具体实施方式 DETAILED DESCRIPTION

[0035] 下面结合附图和具体实施方式对本发明的技术方案作进一步详细的说明。 [0035] below in conjunction with the accompanying drawings and detailed description of the technical aspect of the present invention will be further described in detail.

[0036] 实施例I [0036] Example I

[0037] 本发明的结构类似考布他汀A4的化合物通过4_(3',4',5'-三甲氧基苯基)-5-(2",3" - 二羟基-4"-甲氧基苯基)_噁唑与亚磷酸二苄酯反应进行制备,具体步骤如下: [0037] The structure of the present invention is similar to cloth test compound by statin A4 4_ (3 ', 4', 5'-trimethoxyphenyl) -5- (2 ', 3' - dihydroxy-4 "- methoxy phenyl) _ oxazole and phosphorous acid benzyl ester prepared, follow these steps:

[0038] [0038]

Figure CN102863472AD00061

[0039] 本发明中式(I)中当札、R2为-OH时,名称为4- (3' ,4' ,5'-三甲氧基苯基)-5- (2〃,3" - 二羟基-4"-甲氧基苯基)-噁唑,简称为CA-1H,分子式为C19H19NO7,分子量为373. 36,为淡黄色固体;其结构式如(II)所示: [0039] The present invention is Chinese (I), when Sapporo, R2 is -OH, the name is 4- (3 ', 4', 5'-trimethoxyphenyl) -5- (2 〃 3 "- two hydroxy-4 '- methoxyphenyl) - oxazole, abbreviated as CA-1H, molecular formula is C19H19NO7, molecular weight of 373.36, as a pale yellow solid; such as structural formula (II) shown below:

[0040] [0040]

Figure CN102863472AD00071

[0041] 式(I)中当R2为-OPO3Na2时,名称为4-(3 ' ,4' ,5'-三甲氧基苯基)-5-(4"-甲氧基苯基)-噁唑-2",3" -0,0-二磷酸四钠盐,简称为CA-1HP,分子式为C19H17NO13Na4P2,分子量为621. 24,为灰白色固体;其结构式如(III)所示: [0041] The formula (I), when R2 is -OPO3Na2, the name is 4- (3 ', 4', 5'-trimethoxyphenyl) -5- (4 '- methoxyphenyl) - Evil oxazol-2 ", 3" -0,0-diphosphate tetrasodium salt, abbreviated as CA-1HP, formula C19H17NO13Na4P2, a molecular weight of 621.24, as an off-white solid; its structural formula (III) shown below:

[0042] [0042]

Figure CN102863472AD00072

[0043] [0043]

(III) (III)

[0044] —、本发明磷酸钠衍生物的制备 [0044] -, sodium phosphate derivative of the present invention prepared

[0045]将0.7臟01的4-(3' ,4' ,5'-三甲氧基苯基)-5-(2",3" - 二羟基_4"-甲氧基苯基)-噁唑溶于6mL N, N- 二甲基甲酰胺与6mL乙腈的混合溶剂中,在氩气保护下置于-10C的低温反应装置中,滴加7mmol的四氯化碳,搅拌10分钟后,加入O. 15mmol 二甲氨基吡啶,在搅拌5分钟后缓慢滴加4. 2mmol亚磷酸二苄酯反应,继续反应2小时,并于-5C再反应2小时,加入IOmL磷酸二氢钾溶液(O. 5mol/L)终止反应,反应液用乙酸乙酯萃取(3 X 50mL),萃取液用无水硫酸钠干燥,减压浓缩,硅胶柱层析(石油醚/乙酸乙酯=2/1)得O. 5mmol的白色固体二磷酸四苄酯衍生物。Rf = O. 2 (石油醚/乙酸乙酯=2/1) ; 1HNMR (CDCl3, 600MHz) δ 7. 93 (s, 1H, H_2),7. 19-7. 28 (m, 17H, Ph-H),7. 04-7. 06 (m, 4H, Ph-H), [0045] The dirty 0.7 01 4- (3 ', 4', 5'-trimethoxyphenyl) -5- (2 ", 3" - dihydroxy _4 "- methoxyphenyl) - Evil azole dissolved in 6mL N, N- dimethylformamide and mixed solvents 6mL acetonitrile, placed under argon in -10 C low temperature reaction apparatus, dropping 7mmol of carbon tetrachloride, stirred for 10 minutes After O. 15mmol dimethylaminopyridine was added slowly dropwise 4. 2mmol dibenzyl phosphite reaction was stirred for 5 minutes, the reaction was continued for 2 hours and then at -5 C for 2 hours, was added IOmL dihydrogen phosphate potassium solution (O. 5mol / L) to terminate the reaction, the reaction solution was extracted with ethyl acetate (3 X 50mL), the extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, silica gel column chromatography (petroleum ether / ethyl acetate = 2/1) to give a white solid O. 5mmol tetrabenzyl diphosphate ester derivative .Rf = O. 2 (petroleum ether / ethyl acetate = 2/1); 1HNMR (CDCl3, 600MHz) δ 7. 93 (s, 1H, H_2), 7. 19-7. 28 (m, 17H, Ph-H), 7. 04-7. 06 (m, 4H, Ph-H),

6. 90 (d, J=8. 8Hz, 1H, Ph-H), 6. 8 8 (s, 2H, Ph-H),5. 14-5. 19 (m, 4H, Ph-CH2),4. 78-4. 81 (m, 2H, Ph-CH2),4. 69-4. 72 (m, 2H, Ph-CH2),3. 86 (s, 3H, OCH3),3. 76 (s, 3H, OCH3),3. 69 (s, 6H, OCH3X 2) ;13C NMR (D2O, 150MHz) δ 153. 8(C_3'),153. 2(C_5'),150. 2(C_2), 141. 2,137. 7,136. 2,135. 7,135. 7,135. 3,135. 2,128. 4,128. 4,128. 4,128. I, 127. 9,127. 8,116. 2,109. 6 (C_l”),103. 8(C-2',C-6'),69. 8(Ph-CH2), 60. 8(0CH3-4'),56. 5(0CH3-4”),56. 0(0CH3-3',0CH3-5')。 6. 90 (d, J = 8. 8Hz, 1H, Ph-H), 6. 8 8 (s, 2H, Ph-H), 5. 14-5. 19 (m, 4H, Ph-CH2), 4. 78-4. 81 (m, 2H, Ph-CH2), 4. 69-4. 72 (m, 2H, Ph-CH2), 3. 86 (s, 3H, OCH3), 3. 76 (s , 3H, OCH3), 3 69 (s, 6H, OCH3X 2);.. 13C NMR (D2O, 150MHz) δ 153. 8 (C_3 '.), 153 2 (C_5'), 150 2 (C_2), 141 . 2,137. 7,136. 2,135. 7,135. 7,135. 3,135. 2,128. 4,128. 4,128. 4,128. I, 127. 9,127. 8 , 116. 2,109. 6 (C_l "), 103. 8 (C-2 ', C-6'), 69. 8 (Ph-CH2), 60. 8 (0CH3-4 '), 56. 5 (0CH3-4 "), 56. 0 (0CH3-3 ', 0CH3-5').

[0046] 将0.5mmol的所述二磷酸四苄酯衍生物溶于IOmL 二氯甲烷中,冰浴下滴加 [0046] to the diphosphate derivative 0.5mmol four-benzyl ester was dissolved in IOmL of dichloromethane, was added dropwise under ice-

3. Ommol的三甲基溴硅烷,反应45分钟,减压蒸馏的白色固体用石油醚(3X30mL)洗涤,将白色固体溶于IOmL无水乙醇,加入2mL新鲜制备的甲醇钠(lmol/L),减压浓缩,将所得的固体溶于IOmL水,加入40mL丙酮,析出固体物质过滤,将所得物再用水-乙醇(体积比为I :3-6)结晶得到本发明的磷酸钠衍生物(CA-IHP)151H NMR(CDCl3, 600MHz) δ 8. 24(s, 1H,H_2), 3. Ommol of trimethylsilyl bromide, the reaction for 45 minutes and distilled under reduced pressure a white solid with petroleum ether (3X30mL), dried IOmL white solid was dissolved in absolute ethanol, was added 2mL freshly prepared sodium methoxide (lmol / L) , concentrated under reduced pressure, and the resulting solid was dissolved in IOmL of water, 40mL of acetone was added, the precipitated solid material was filtered, and then the resultant was washed with water - ethanol (volume ratio of I: 3-6) to give the crystalline sodium phosphate derivatives of the present invention ( CA-IHP) 151H NMR (CDCl3, 600MHz) δ 8. 24 (s, 1H, H_2),

6. 91 (s, 1H, Ph-H),6. 83 (d, J=8. 8Hz, 1H, Ph-H),6. 78 (s, 1H, Ph-H),6. 73 (t, J=8. 8Hz, 1H, Ph-H),3. 86 (s, 3H, OCH3),3. 72 (s, 3H, OCH3), 3. 71 (s, 3H, OCH3),3. 66 (d, J = 5. 5Hz, 3H, OCH3)。 6. 91 (s, 1H, Ph-H), 6. 83 (d, J = 8. 8Hz, 1H, Ph-H), 6. 78 (s, 1H, Ph-H), 6. 73 (t , J = 8. 8Hz, 1H, Ph-H), 3. 86 (s, 3H, OCH3), 3. 72 (s, 3H, OCH3), 3. 71 (s, 3H, OCH3), 3. 66 (d, J = 5. 5Hz, 3H, OCH3).

[0047] 二、本发明磷酸钠衍生物的药理实验 [0047] Second, the phosphate derivative of the present invention pharmacological experiments

[0048] I、CA-IH体外抑制微管蛋白聚合活性实验 [0048] I, CA-IH vitro inhibition of tubulin polymerization activity tests

[0049] 微管蛋白溶液在0-4 C是无色透明液体,在37 C时可以聚合成微管,其溶液在340nm的吸光度(0D值)随时间升高,并在一定时间内达到坪值。 [0049] tubulin solution at 0-4 C is colorless, transparent liquid at 37 C when you can be polymerized into microtubules, its solution absorbance at 340nm (0D value) increased over time, and in a certain period of time to plateau. 干扰微管聚合的药物可以影响微管溶液OD值的变化。 Interfere with microtubule polymerization of tubulin drugs can affect change solution OD values.

[0050] 本发明实验中采用的微管蛋白提取于猪脑。 [0050] The present invention used in the experiment tubulin extracted from pig's brain. 聚合体系为:微管蛋白用甘油一MES溶液(O. ImM MES, ImM EGTA,0. 5mM MgCl2, ImM GTP现加,4M甘油)稀释成浓度12 μ M,化合物的终浓度为10 μ M,I μ M,O. I μ M,同时做溶剂对照和阳性对照。 The polymerization system is: tubulin was diluted to a concentration of 12 μ M MES solution with glycerol (O. ImM MES, ImM EGTA, 0 5mM MgCl2, ImM GTP now added, 4M glycerol.), The compound at a final concentration 10 μ M, I μ M, O. I μ M, at the same time as a solvent and positive controls. 设置酶标仪的温度为37C,检测波长为340nm,每分钟混匀读取一次,连续读取30min。 Set microplate temperature of 37 C, detection wavelength of 340nm, mix read once per minute, continuous reading 30min. 实验结果如图I所示,表明CA-IH对微管蛋白聚合具有明显的抑制作用。 The results are shown in Figure I, it shows that CA-IH tubulin polymerization significantly inhibited.

[0051] 2、CA-IH对HUVEC形态的影响 [0051] 2 and CA-IH morphology of HUVEC

[0052] 消化HUVEC,以2000个细胞/孔种于96孔板;24小时细胞贴壁后加药,药物浓度为ΙμΜ,设正常组、溶剂对照组(DMS0 O. 1%)、CA4阳性药对照组;加药O. 5小时、I小时、2小时后开始在显微镜下观察细胞形态并拍照。 [0052] digestion HUVEC, to 2000 cells / well were seeded in 96-well plates; adherent cells 24 hours dosing, the drug concentration ΙμΜ, set the normal group, solvent control group (DMS0 O. 1%), CA4 positive drug in the control group; dosing O. 5 小时, I hour, two hours after the start of cell morphology was observed under a microscope and photographed. 结果见图2。 The results shown in Figure 2.

[0053] 从图2中可以看出正常组细胞呈铺路石状伸展,给药O. 5小时后细胞开始收缩变圆,I小时后、2小时后细胞收缩更明显,表明所述CA-IH能够明显影响HUVEC的细胞形态。 [0053] As can be seen from Figure 2, normal cells were cobblestone stretch, O. 5 hours after administration of the cells began to shrink round, I hour, two hours after the cells shrink more significantly, indicating that the CA-IH It can significantly affect cell morphology of HUVEC.

[0054] 3、CA-IH对内皮细胞骨架的影响 [0054] 3, the impact of CA-IH endothelial cytoskeleton

[0055] 铺玻片到24孔板,以血清在37C包被30min ;消化HUVEC,以2 X IO4/孔种到玻片上;细胞贴壁后加入药物,药物浓度为I μ Μ,设空白对照、溶剂对照和阳性药CA4对照。 [0055] shop slides to 24-well plates in serum was 30min at 37 C packages; digestion HUVEC, with 2 X IO4 / hole kind to the slide; adherent cells were added to the drug, the drug concentration I μ Μ, set blank control, solvent control and positive control drug CA4. 药物作用30min后,吸去培养基,用PBS洗3次;4%多聚甲醛固定30min,吸去多聚甲醛,PBS洗3次;0. 1% Triton-100 打孔IOmin,吸去,PBS 洗3 次;加入1%BSA 封闭30min,吸去,PBS 洗3次;加入Tubulin抗体(Sigma公司产品,1:500稀释),4C过夜;加入actin抗体(Sigma公司产品,1:500稀释)和Tubulin 二抗CY3( Sigma公司产品,1:1000稀释),室温放置30min,用激光共聚焦显微镜观察拍照。 30min after drugs, the medium was aspirated, washed 3 times with PBS; 4% paraformaldehyde 30min, absorb paraformaldehyde, PBS washed 3 times;. 0 1% Triton-100 drilling IOmin, absorb, PBS washed 3 times; adding 1% BSA blocking 30min, absorb, PBS washed 3 times; adding Tubulin antibody (Sigma Products, 1: 500 dilution), 4 C overnight; adding actin antibody (Sigma Products, 1: 500 dilution ) and Tubulin secondary antibodies CY3 (Sigma Products, 1: 1000 dilution), at room temperature 30min, with a laser scanning confocal microscope photographs. 结果见图3、图4。 The results shown in Figure 3, Figure 4.

[0056] 图3为药物对细胞微管的影响,图4为药物对细胞微丝的影响。 [0056] FIG. 3 is the impact of drugs on cell microtubules, Figure 4 is the impact of drugs on cell microfilaments. 从图3中可以看出,正常细胞中微管成丝状结构,药物作用30min后细胞的微管网络结构遭到不同程度的破坏,呈现弥散、点状分布,荧光强度也减弱。 As can be seen from Figure 3, the normal cells microtubule filaments, 30min after drugs microtubule network structure of the cell have been varying degrees of damage, showing diffuse, punctate distribution of fluorescence intensity is decreased. 从图4中可以看出,正常细胞中微丝分布均匀,少量微丝横跨整个细胞,在细胞周边有聚集。 As can be seen from Figure 4, microfilament distribution in normal cells, a small amount of actin across the cells, in a cell surrounded by aggregation. 加入药物后,微丝的分布显著不同,大量微丝形成应力纤维聚集在细胞周边,使这一部位的荧光明显增强。 After addition of the drug, the distribution of actin is significantly different from the formation of a large number of actin stress fibers gathered at the cell periphery, making this part of the fluorescence significantly enhanced. 表明CA-IH可以破坏内皮细胞的骨架结构。 Show CA-IH can destroy the skeleton structure of endothelial cells.

[0057] 4、CA-IH对HUVEC既成管腔的破坏实验 [0057] 4, CA-IH lumen de facto destruction of HUVEC experiments

[0058] HUVEC能够在Matrigel上形成管腔,用以模拟肿瘤组织的血管。 [0058] HUVEC lumen can be formed on Matrigel, to simulate blood vessels in tumor tissue. 将内皮细胞加入到含有Matrigel (BD Biosciences公司产品)的96孔板孔中,每孔I. 8 X IO5个细胞,37C培养12小时形成完整管腔,加入药物浓度为IuM作用后,在每一时间点选取统一视野拍照,统计管腔数,管腔形成的抑制率以下列公式计算: After the endothelial cells were added to 96-well plate wells containing Matrigel (BD Biosciences Company) in each well I. 8 X IO5 cells, 37 C for 12 hours for complete lumen, the drug was added at a concentration of IuM role, in Each time select a unified vision camera, the number of statistical lumen, lumen formation inhibition rate to the following formula:

[0059] 抑制率(%)=(管腔数对照孔一管腔数给药孔)/管腔数对照孔X 100%,此对照为相应时间点的对照组管腔数。 [0059] inhibition rate (%) = (Number of control wells lumen a number of administration lumen hole) / lumen number of control wells X 100%, this comparison to the corresponding point in time in the control group the number of lumens.

[0060] 结果见图5、图6。 [0060] The results shown in Figure 5, Figure 6. 表明CA-IH能够破坏HUVEC形成的管腔,作用9小时破坏率达83. 59%ο Show CA-IH HUVEC lumen formation can undermine the role of nine hours destruction rate 83. 59% ο

[0061] 5、CA-IHP对HUVEC内微管蛋白聚合的影响 [0061] 5, CA-IHP within HUVEC tubulin polymerization

[0062] 取对数生长期的HUVEC,接种于6孔板中,细胞贴壁过夜后,分别加入浓度为10 μ MU μ Μ、0 I μ M的CA-IHP,设空白对照、CA4P阳性对照。 [0062] logarithmic growth phase HUVEC, seeded in 6-well plates, after overnight adherent cells were added at a concentration of 10 μ MU μ Μ, 0 I μ M of CA-IHP, blank control, CA4P positive controls. 2小时后,每孔加入100 μ L裂解液(ImM EGTA, ImM MgSO4, 30% 甘油,5%DMS0,5mM GTP, 1% NP-40,0. IM PIPES pH 6.9),用细胞刮刀收集至离心管中,37C 180,OOOg离心lh,聚合的微管蛋白被沉淀下来。 After 2 hours, each well was added 100 μ L lysis buffer (ImM EGTA, ImM MgSO4, 30% glycerol, 5% DMS0,5mM GTP, 1% NP-40,0. IM pH PIPES 6.9), collected with a cell scraper to centrifugation tube, 37 C 180, OOOg centrifugal lh, polymerized tubulin was precipitated. 将上清转移至对应离心管中,每管加入30 μ L 4\303上样缓冲液(2001111 Tris pH 6. 8,400mMDTT, 8%SDS ' O. 4%溴酚蓝,40%甘油),沉淀中加入130 μ L IX SDS上样缓冲液,混匀后沸水浴中加热lOmin。 The supernatant was transferred to the corresponding tubes, each tube by adding 30 μ L 4 \ 303 sample buffer (2001111 Tris pH 6. 8,400mMDTT, 8% SDS 'O. 4% bromophenol blue, 40% glycerol), precipitation added loaded onto 130 μ L IX SDS buffer, mix boiling water bath heated lOmin. 将上清和沉淀裂解液分别取等量进行Western blot检测tubulin聚合情况。 The lysate supernatant and precipitation were detected by Western blot equal amount of tubulin polymerization conditions. 结果见图7,P代表沉淀中的聚合的微管蛋白,S代表上清液中的解聚的微管蛋白。 The results shown in Figure 7, P on behalf of precipitation polymerization of tubulin, S on behalf of the supernatant tubulin depolymerization.

[0063] 如图7所示,与空白对照组相比,CA-IHP能使P型微管明显减少,S型微管增多,表明CA-IHP可以剂量依赖性地引起细胞内聚合形式的微管蛋白解聚成游离形式的微管蛋白。 [0063] 7, compared with the control group, CA-IHP make P-type microtubules decreased, increased S-type microtubules, suggesting that CA-IHP dose-dependent manner in the form of intracellular polymeric micro tubulin depolymerization into the free form of tubulin.

[0064] 6、CA-IHP引发肿瘤组织内部坏死 [0064] 6, CA-IHP internal trigger tumor necrosis

[0065] 非小细胞肺癌易瑞沙耐药细胞株NCI-H1975接种于裸小鼠右腋下,待肿瘤体积生长至约IOOmm3时,随机分组给药,并设置生理盐水空白对照组、CA4P阳性药组,给药后24小时后脱颈处死小鼠,取出NCI-H1975瘤组织;将瘤组织以OCT包埋,_20C冰冻切片,HE染色(苏木素为国药集团化学试剂公司产品,曙红Y为上海三爱思试剂有限公司产品)。 [0065] non-small cell lung cancer drug Iressa cell line NCI-H1975 nude mice inoculated in the right armpit, the tumor volume to grow to about IOOmm3, the randomized administration, and set the saline control group, CA4P positive drug group, 24 hours after administration after the mice were sacrificed by cervical removed NCI-H1975 tumor; the tumor tissue with OCT embedding, _20 C frozen sections, HE staining (hematoxylin as Sinopharm Chemical Reagent Company products, eosin Y is Shanghai three Elsevier Reagent Co., Ltd.). 显微镜下观察并拍照。 Under the microscope and photographed. 结果见图8、图9。 The results shown in Figure 8, Figure 9.

[0066] 如图所示,随着CA-IH给药剂量的增加肿瘤组织坏死面积增加,给药浓度为100mg/kg时,肿瘤组组织坏死面积占比为80. 5%,细胞核碎裂、溶解,与CA4P相比,CA-IHP更能够杀死肿瘤组织的边缘细胞。 [0066] As shown, the increase with the increase of tumor necrosis area CA-IH administered dose, administered at a concentration of 100mg / kg, the tumor necrosis area group accounted for 80.5%, nuclear fragmentation, dissolution, compared with CA4P, CA-IHP more capable of killing tumor cells in tissue edge. N= “坏死”,V= “存活”。 N = "necrosis", V = "survival."

[0067] 本发明式(I)化合物可以为结晶或定形物形式。 [0067] The compounds of the invention of formula (I) may be in the form of a crystalline or amorphous substance. 式(I)化合物的某些结晶形式可以以包括在本发明范围内的多晶型物形式存在。 Some of the crystalline forms of the compounds of formula (I) may be in the form of polymorph included within the scope of the present invention is present. 本发明还涉及含有有效剂量的本发明化合物和可药用赋形剂例如载体或稀释剂的药物组合物。 The present invention also relates to a compound and a pharmaceutically acceptable excipient such as a carrier or diluent, a pharmaceutical composition comprising an effective amount of the present invention.

[0068] 本发明化合物的相应制剂可用于治疗多种疾病和病症,包括微管蛋白聚合和各种肿瘤,尤其用于治疗各种实体肿瘤和抑制内皮细胞微管蛋白聚合。 [0068] The corresponding preparations of the present compounds are useful for treating a variety of diseases and disorders, including tubulin polymerization and a variety of tumors, in particular for the treatment of various solid tumors and inhibition of endothelial cell tubulin polymerization. 所述实体肿瘤是指肺癌、肾癌、乳腺癌、胃癌、卡波氏肉瘤、结肠癌、肝癌、前列腺癌、甲状腺癌、神经母细胞瘤、卵巢癌及头颈部鳞癌、鼻咽癌,包括但不限于实体肿瘤。 The solid tumor refers to lung cancer, kidney cancer, breast cancer, stomach cancer, Kaposi's sarcoma, colon cancer, liver cancer, prostate cancer, thyroid cancer, neuroblastoma, ovarian cancer and head and neck squamous cell carcinoma, nasopharyngeal carcinoma, including but not limited to solid tumors.

[0069] 总之,本发明提供了结构类似考布他汀A4的化合物,并将其制备成二磷酸盐,该系列磷酸盐衍生物的水溶性好,生物利用度高,能够作为抑制微管蛋白聚合、靶向肿瘤血管的抗肿瘤药物。 [0069] In summary, the present invention provides a structure similar combretastatin A4 compound and prepared diphosphate, the water-soluble phosphate derivatives of the series well, bioavailability, can be used as inhibiting tubulin polymerization , anticancer drugs targeting tumor vasculature.

[0070] 以上实施例仅用以说明本发明的技术方案,而非对其进行限制;尽管参照前述实施例对本发明进行了详细的说明,对于本领域的普通技术人员来说,依然可以对前述实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或替换,并不使相应技术方案的本质脱离本发明所要求保护的技术方案的精神和范围。 Implementation [0070] above example only describing the technical solutions of the present invention, but not intended to be limiting; although reference to the embodiments of the present invention has been described in detail, those of ordinary skill in the art that the foregoing can still technical solutions described in Example modify, or for some technical features equivalent replacements; and such modifications or replacements do not make the essence of corresponding technical solutions depart from the spirit and scope of the invention claimed technical solution.

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Referenced by
Citing PatentFiling datePublication dateApplicantTitle
CN104817519A *May 11, 2015Aug 5, 2015中国药科大学CA-4 derivatives as well as preparation method and medical application of CA-4 derivatives
CN104817519B *May 11, 2015Nov 16, 2016中国药科大学一类ca-4的衍生物、其制法及其医药用途
Classifications
International ClassificationA61P35/00, A61K31/675, C07F9/653
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