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CN103421061A - Lenalidomide derivative and preparation method and pharmaceutical application thereof - Google Patents

Lenalidomide derivative and preparation method and pharmaceutical application thereofDownload PDF

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CN103421061A
CN103421061ACN2013103547059ACN201310354705ACN103421061ACN 103421061 ACN103421061 ACN 103421061ACN 2013103547059 ACN2013103547059 ACN 2013103547059ACN 201310354705 ACN201310354705 ACN 201310354705ACN 103421061 ACN103421061 ACN 103421061A
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deoxy
oxoisoindoline
acetyl
amino
tetra
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徐云根
董缙
刘坤
楼影涵
庄毅超
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China Pharmaceutical University
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Abstract

Translated fromChinese

本发明涉及药物化学领域，具体涉及一类来那度胺衍生物(I)，其中G和n的定义同说明书。药理试验证明，本发明化合物对血管内皮细胞增殖具有抑制作用，可用于临床治疗肿瘤或慢性炎症。The present invention relates to the field of medicinal chemistry, in particular to a class of lenalidomide derivatives (I), wherein the definitions of G and n are the same as those in the description. Pharmacological tests prove that the compound of the invention has an inhibitory effect on the proliferation of vascular endothelial cells, and can be used for clinical treatment of tumors or chronic inflammation.

Description

Translated fromChinese
来那度胺衍生物、其制法及其医药用途Lenalidomide derivatives, their preparation methods and their medicinal uses

技术领域technical field

本发明涉及药物化学领域，具体涉及一类来那度胺衍生物、它们的制备方法、以及对血管内皮细胞增殖的抑制作用。 The invention relates to the field of medicinal chemistry, in particular to a class of lenalidomide derivatives, their preparation method and their inhibitory effect on the proliferation of vascular endothelial cells. the

背景技术Background technique

血管的异常生长与包括肿瘤、老年黄斑变性在内的多种疾病的发生发展密切有关。血管的生长取决于促进以及抑制两类因子的相互作用。生理状态下，体内促血管生长因子和血管生成抑制因子这两类因子保持动态平衡；而在病理组织，这两类因子的动态平衡被打破。促进血管生成因子，如血管内皮生长因子(VEGF)，血管生成素(Ang)和成纤维生长因子(FGF)等大量合成并释放，而抑制血管生成的生长因子缺失或失活。于是促血管生成因子占主导地位并作用于内皮细胞，最终导致血管生成。 Abnormal growth of blood vessels is closely related to the occurrence and development of various diseases including tumors and age-related macular degeneration. The growth of blood vessels depends on the interaction of promoting and inhibiting factors. Under physiological conditions, the two types of factors, pro-angiogenic growth factors and angiogenesis inhibitory factors, maintain a dynamic balance; however, in pathological tissues, the dynamic balance of these two types of factors is broken. Promote the synthesis and release of angiogenesis factors, such as vascular endothelial growth factor (VEGF), angiopoietin (Ang) and fibroblast growth factor (FGF), while the growth factors that inhibit angiogenesis are missing or inactivated. Pro-angiogenic factors then dominate and act on endothelial cells, ultimately leading to angiogenesis. the

血管生成抑制剂能够通过破坏或抑制血管生成，有效阻止疾病的发展。由于病理组织的新生血管相较正常血管具有一些独特的性质，血管生成抑制剂至少具有以下两个优点。首先，正常血管通常处于静止状态，而在病理组织血管内皮细胞处于高度生长状态，所以，此类药物具有更高的选择性和更低的毒性。其次，由于血管内皮细胞基因组稳定，新生血管不易对此类药物产生耐药性。 Angiogenesis inhibitors can effectively prevent the development of diseases by destroying or inhibiting angiogenesis. Since new blood vessels in pathological tissues have some unique properties compared with normal blood vessels, angiogenesis inhibitors have at least the following two advantages. First of all, normal blood vessels are usually in a quiescent state, while vascular endothelial cells in pathological tissues are in a state of high growth, so this type of drug has higher selectivity and lower toxicity. Second, due to the stable genome of vascular endothelial cells, new blood vessels are less likely to develop resistance to such drugs. the

目前，已上市或正处于临床试验中的血管生成抑制剂基于其作用机理可分为以下三类：（1）间接血管生成抑制剂，主要通过选择性地抑制一种或几种促血管生成因子，或通过阻断促血管生成因子的下游信号通路而发挥作用，如贝伐单抗，索拉非尼和苏尼替尼等；（2）直接血管生成抑制剂，可直接作用于内皮细胞抑制其增殖、迁移和形成新生血管，如西仑吉肽和内皮抑素等；（3）其他途径血管生成抑制剂，包括作用于多个不同靶点或作用机制尚不明确难以划分入前两类的药物，如沙利度胺、来那度胺等。 At present, the angiogenesis inhibitors that have been marketed or are in clinical trials can be divided into the following three categories based on their mechanism of action: (1) Indirect angiogenesis inhibitors, mainly by selectively inhibiting one or several pro-angiogenic factors , or play a role by blocking the downstream signaling pathways of pro-angiogenic factors, such as bevacizumab, sorafenib and sunitinib; (2) direct angiogenesis inhibitors, which can directly act on endothelial cells to inhibit Its proliferation, migration and formation of new blood vessels, such as cilengitide and endostatin, etc.; (3) other pathways of angiogenesis inhibitors, including acting on multiple different targets or the mechanism of action is not yet clear, it is difficult to divide into the first two categories Drugs such as thalidomide, lenalidomide, etc. the

鉴于血管生成涉及多重信号传导通路，阻断单一信号传导通路不能起到持续的临床治疗效果，多靶点血管生成抑制剂是当前药物研发的热点之一。 In view of the fact that angiogenesis involves multiple signal transduction pathways, blocking a single signal transduction pathway cannot achieve a sustained clinical therapeutic effect, and multi-target angiogenesis inhibitors are currently one of the hot spots in drug development. the

沙利度胺是一种多靶点血管生成抑制剂。其抗血管生成作用可能是通过抑制VEGF和FGF。除此之外，沙利度胺还具有抗TNF-α作用。但由于沙利度胺具有过多的副作用，尤其是周围神经病变，其长期使用受到限制。以沙利度胺为先导化合物已开发出多种沙利度胺的类似物，如来那度胺(lenalidomide,CC-5013)，Actimid(CC-4047)。其中，来那度胺在2005获得FDA批准与地塞米松联合用于骨髓增生异常综合症的治疗。来那度胺的骨髓抑制作用较沙利度胺更强，并且基本没有沙利度胺的神经毒性。目前正在进行实体瘤如前列腺癌和霍奇金 淋巴瘤治疗的II期临床研究。 Thalidomide is a multi-target angiogenesis inhibitor. Its anti-angiogenic effect may be through the inhibition of VEGF and FGF. In addition, thalidomide also has anti-TNF-α effect. However, due to the excessive side effects of thalidomide, especially peripheral neuropathy, its long-term use is limited. Using thalidomide as the lead compound, various thalidomide analogues have been developed, such as lenalidomide (lenalidomide, CC-5013) and Actimid (CC-4047). Among them, lenalidomide was approved by the FDA in 2005 in combination with dexamethasone for the treatment of myelodysplastic syndrome. The myelosuppressive effect of lenalidomide is stronger than that of thalidomide, and it basically has no neurotoxicity of thalidomide. Phase II clinical studies for the treatment of solid tumors such as prostate cancer and Hodgkin's lymphoma are currently underway. the

Figure BDA0000366374840000021
Figure BDA0000366374840000021

发明内容Contents of the invention

本发明公开了一类通式I的化合物及其水合物，经药理实验显示，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。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。 The invention discloses a class of compounds of general formula I and hydrates thereof. Pharmacological experiments show that the compounds of the invention have strong inhibitory effect on the proliferation of human umbilical vein endothelial cells. Therefore, the compound of formula I and the compound containing crystal water of the present invention can be used to treat various diseases related to angiogenesis, these diseases include various cancers and chronic inflammation, and other angiogenic diseases. the

本发明的化合物通式I如下： Compound general formula I of the present invention is as follows:

Figure BDA0000366374840000022
Figure BDA0000366374840000022

其中G-NH-代表： Where G-NH- stands for:

Figure BDA0000366374840000023
Figure BDA0000366374840000023

Figure BDA0000366374840000031
Figure BDA0000366374840000031

其中G-NH-优选代表： Among them, G-NH- preferably represents:

Figure BDA0000366374840000032
Figure BDA0000366374840000032

G-NH-进一步优选代表： G-NH-further preferred representatives:

其中n代表： where n stands for:

2,3或4。 2, 3 or 4. the

n优选代表： n preferably represents:

3或4。 3 or 4. the

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。 The hydrate of the compound of the present invention also has the same curative effect as the compound, wherein the hydrate exists in the form of crystal water, and the molar equivalent of the crystal water is from 0.5 to 10. the

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

N-(2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃葡萄糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-1) N-(2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-glucopyranosyl)-3-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-3-oxopropionamide (I-1) 

N-(2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃葡萄糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-2) N-(2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-glucopyranosyl)-4-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-4-oxobutyramide (I-2) 

N-(2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃葡萄糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺(I-3) N-(2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-glucopyranosyl)-5-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-5-oxopentamide (I-3) 

N-(2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃半乳糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-4) N-(2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-galactopyranosyl)-3-(2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindoline-4-amino)-3-oxopropionamide (I-4) 

N-(2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃半乳糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-5) N-(2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-galactopyranosyl)-4-(2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindoline-4-amino)-4-oxobutanamide (I-5) 

N-(2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃半乳糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺(I-6) N-(2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-galactopyranosyl)-5-(2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindoline-4-amino)-5-oxopentamide (I-6) 

N-(1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃葡萄糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-7) N-(1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosyl)-3-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-3-oxopropionamide (I-7) 

N-(1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃葡萄糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-8) N-(1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosyl)-4-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-4-oxobutyramide (I-8) 

N-(1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃葡萄糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺(I-9) N-(1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosyl)-5-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-5-oxopentamide (I-9) 

N-(1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃半乳糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-10) N-(1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranosyl)-3-(2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindoline-4-amino)-3-oxopropionamide (I-10) 

N-(1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃半乳糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-11) N-(1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranosyl)-4-(2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindoline-4-amino)-4-oxobutyramide (I-11) 

N-(1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃半乳糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺(I-12) N-(1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranosyl)-5-(2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindoline-4-amino)-5-oxopentamide (I-12) 

N-(1,2,3,4-四-O-乙酰基-6-脱氧-β-D-吡喃葡萄糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-13) N-(1,2,3,4-tetra-O-acetyl-6-deoxy-β-D-glucopyranosyl)-3-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-3-oxopropionamide (I-13) 

N-(1,2,3,4-四-O-乙酰基-6-脱氧-β-D-吡喃葡萄糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-14) N-(1,2,3,4-tetra-O-acetyl-6-deoxy-β-D-glucopyranosyl)-4-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-4-oxobutyramide (I-14) 

N-(1,2,3,4-四-O-乙酰基-6-脱氧-β-D-吡喃葡萄糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚 啉-4-胺基)-5-氧代戊酰胺(I-15) N-(1,2,3,4-tetra-O-acetyl-6-deoxy-β-D-glucopyranosyl)-5-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-5-oxopentamide (I-15)

N-(1,2,3,4-四-O-乙酰基-6-脱氧-α-D-吡喃葡萄糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-16) N-(1,2,3,4-tetra-O-acetyl-6-deoxy-α-D-glucopyranosyl)-3-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-3-oxopropionamide (I-16) 

N-(1,2,3,4-四-O-乙酰基-6-脱氧-α-D-吡喃葡萄糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-17) N-(1,2,3,4-tetra-O-acetyl-6-deoxy-α-D-glucopyranosyl)-4-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-4-oxobutyramide (I-17) 

N-(1,2,3,4-四-O-乙酰基-6-脱氧-α-D-吡喃葡萄糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺(I-18) N-(1,2,3,4-tetra-O-acetyl-6-deoxy-α-D-glucopyranosyl)-5-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-5-oxopentamide (I-18) 

N-(1,2,3,4-四-O-乙酰基-6-脱氧-β-D-吡喃半乳糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-19) N-(1,2,3,4-tetra-O-acetyl-6-deoxy-β-D-galactopyranosyl)-3-(2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindoline-4-amino)-3-oxopropionamide (I-19) 

N-(1,2,3,4-四-O-乙酰基-6-脱氧-β-D-吡喃半乳糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-20) N-(1,2,3,4-tetra-O-acetyl-6-deoxy-β-D-galactopyranosyl)-4-(2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindoline-4-amino)-4-oxobutanamide (I-20) 

N-(1,2,3,4-四-O-乙酰基-6-脱氧-β-D-吡喃半乳糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺(I-21) N-(1,2,3,4-tetra-O-acetyl-6-deoxy-β-D-galactopyranosyl)-5-(2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindoline-4-amino)-5-oxopentamide (I-21) 

N-(1,2,3,4-四-O-乙酰基-6-脱氧-α-D-吡喃半乳糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-22) N-(1,2,3,4-tetra-O-acetyl-6-deoxy-α-D-galactopyranosyl)-3-(2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindoline-4-amino)-3-oxopropionamide (I-22) 

N-(1,2,3,4-四-O-乙酰基-6-脱氧-α-D-吡喃半乳糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-23) N-(1,2,3,4-tetra-O-acetyl-6-deoxy-α-D-galactopyranosyl)-4-(2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindoline-4-amino)-4-oxobutyramide (I-23) 

N-(1,2,3,4-四-O-乙酰基-6-脱氧-α-D-吡喃半乳糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺(I-24) N-(1,2,3,4-tetra-O-acetyl-6-deoxy-α-D-galactopyranosyl)-5-(2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindoline-4-amino)-5-oxopentamide (I-24) 

N-(1-脱氧-β-D-吡喃葡萄糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-25) N-(1-deoxy-β-D-glucopyranosyl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-amine Base) -3-oxopropionamide (I-25) 

N-(1-脱氧-β-D-吡喃葡萄糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-26) N-(1-deoxy-β-D-glucopyranosyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-amine Base) -4-oxobutyramide (I-26) 

N-(1-脱氧-β-D-吡喃葡萄糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺(I-27) N-(1-deoxy-β-D-glucopyranosyl)-5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-amine Base) -5-oxopentamide (I-27) 

N-(1-脱氧-β-D-吡喃半乳糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-28) N-(1-deoxy-β-D-galactopyranosyl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4- Amino)-3-oxopropionamide (I-28) 

N-(1-脱氧-β-D-吡喃半乳糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-29) N-(1-deoxy-β-D-galactopyranosyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4- Amino)-4-oxobutyramide (I-29) 

N-(1-脱氧-β-D-吡喃半乳糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺(I-30) N-(1-deoxy-β-D-galactopyranosyl)-5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4- Amino)-5-oxopentamide (I-30) 

N-(2-脱氧-β-D-吡喃葡萄糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-31) N-(2-deoxy-β-D-glucopyranosyl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-amine Base) -3-oxopropionamide (I-31) 

N-(2-脱氧-β-D-吡喃葡萄糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-32) N-(2-deoxy-β-D-glucopyranosyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-amine Base) -4-oxobutanamide (I-32) 

N-(2-脱氧-β-D-吡喃葡萄糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺(I-33) N-(2-deoxy-β-D-glucopyranosyl)-5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-amine Base) -5-oxopentamide (I-33) 

N-(2-脱氧-β-D-吡喃半乳糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-34) N-(2-deoxy-β-D-galactopyranosyl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4- Amino)-3-oxopropionamide (I-34) 

N-(2-脱氧-β-D-吡喃半乳糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-35) N-(2-deoxy-β-D-galactopyranosyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4- Amino)-4-oxobutyramide (I-35) 

N-(2-脱氧-β-D-吡喃半乳糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺(I-36) N-(2-deoxy-β-D-galactopyranosyl)-5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4- Amino)-5-oxopentamide (I-36) 

N-(6-脱氧-β-D-吡喃葡萄糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-37) N-(6-deoxy-β-D-glucopyranosyl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-amine Base) -3-oxopropionamide (I-37) 

N-(6-脱氧-β-D-吡喃葡萄糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-38) N-(6-deoxy-β-D-glucopyranosyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-amine Base) -4-oxobutyramide (I-38) 

N-(6-脱氧-β-D-吡喃葡萄糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺(I-39) N-(6-deoxy-β-D-glucopyranosyl)-5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-amine Base) -5-oxopentamide (I-39) 

N-(6-脱氧-α-D-吡喃葡萄糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-40) N-(6-deoxy-α-D-glucopyranosyl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-amine Base) -3-oxopropionamide (I-40) 

N-(6-脱氧-α-D-吡喃葡萄糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-41) N-(6-deoxy-α-D-glucopyranosyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-amine Base) -4-oxobutyramide (I-41) 

N-(6-脱氧-α-D-吡喃葡萄糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺(I-42) N-(6-deoxy-α-D-glucopyranosyl)-5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-amine Base) -5-oxopentamide (I-42) 

N-(6-脱氧-β-D-吡喃半乳糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-43) N-(6-deoxy-β-D-galactopyranosyl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4- Amino)-3-oxopropionamide (I-43) 

N-(6-脱氧-β-D-吡喃半乳糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-44) N-(6-deoxy-β-D-galactopyranosyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4- Amino)-4-oxobutanamide (I-44) 

N-(6-脱氧-β-D-吡喃半乳糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊 酰胺(I-45) N-(6-deoxy-β-D-galactopyranosyl)-5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4- Amino)-5-oxopentamide (I-45)

N-(6-脱氧-α-D-吡喃半乳糖基)-3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-3-氧代丙酰胺(I-46) N-(6-deoxy-α-D-galactopyranosyl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4- Amino)-3-oxopropionamide (I-46) 

N-(6-脱氧-α-D-吡喃半乳糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-47) N-(6-deoxy-α-D-galactopyranosyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4- Amino)-4-oxobutyramide (I-47) 

N-(6-脱氧-α-D-吡喃半乳糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺(I-48) N-(6-deoxy-α-D-galactopyranosyl)-5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4- Amino)-5-oxopentamide (I-48) 

本发明通式化合物（I）的制备方法如下： The preparation method of general formula compound (I) of the present invention is as follows:

其中关键中间体7的制备方法如下： Wherein the preparation method of key intermediate 7 is as follows:

Figure BDA0000366374840000071
Figure BDA0000366374840000071

关键中间体G-NH2的制备方法如下： The key intermediate G-NH The preparation method is as follows:

（1）2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃氨基葡萄糖（G1-NH2）的合成路线如下： (1) The synthetic route of 2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-glucopyranosamine (G1 -NH2 ) is as follows:

Figure BDA0000366374840000072
Figure BDA0000366374840000072

Figure BDA0000366374840000081
Figure BDA0000366374840000081

2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃氨基半乳糖（G2-NH2）的合成是以D-(+)-半乳糖为原料，方法同G1-NH1； 2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-galactopyranose (G2 -NH2 ) is synthesized from D-(+)-galactose, The method is the same as G1 -NH1 ;

2,3,4-四-O-乙酰基-1-脱氧-β-D-吡喃氨基木糖（G3-NH2）的合成是以D-木糖为原料，方法同G1-NH1； The synthesis of 2,3,4-tetra-O-acetyl-1-deoxy-β-D-pyranylaminoxylose (G3 -NH2 ) is based on D-xylose, and the method is the same as that of G1 -NH1 ;

2,3,4-四-O-乙酰基-1-脱氧-β-D-吡喃氨基阿拉伯糖（G4-NH2）的合成是以D-阿拉伯为原料，方法同G1-NH1； 2,3,4-Tetra-O-acetyl-1-deoxy-β-D-pyranylaminoarabinose (G4 -NH2 ) is synthesized using D-arabino as raw material, and the method is the same as G1 -NH1 ;

2,3,4-四-O-乙酰基-1-脱氧-α-L-吡喃氨基鼠李糖（G5-NH2）的合成是以L-鼠李糖为原料，方法同G1-NH1； The synthesis of 2,3,4-tetra-O-acetyl-1-deoxy-α-L-pyranylaminorhamnose (G5 -NH2 ) is based on L-rhamnose, and the method is the same as G1 -NH1 ;

（2）1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃氨基葡萄糖（G6-NH2）的合成路线如下： (2) The synthetic route of 1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosamine (G6 -NH2 ) is as follows:

Figure BDA0000366374840000082
Figure BDA0000366374840000082

1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃氨基半乳糖（G7-NH2）的合成是以2-氨基半乳糖盐酸盐为原料，方法同G6-NH2。 1,3,4,6-Tetra-O-acetyl-2-deoxy-β-D-galactopyranosamine (G7 -NH2 ) is synthesized from 2-galactosamine hydrochloride, The method is the same as G6 -NH2 .

1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃氨基甘露糖（G8-NH2）的合成是以2-氨基甘露糖盐酸盐为原料，方法同G6-NH2。 The synthesis of 1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-aminopyranose (G8 -NH2 ) is based on 2-aminomannose hydrochloride, The method is the same as G6 -NH2 .

（3）甲基6-氨基-6-脱氧-α-D-吡喃葡萄糖（G9-NH2）和甲基6-氨基-6-脱氧-β-D-吡喃葡萄糖（G10-NH2）的合成路线如下： (3) Methyl 6-amino-6-deoxy-α-D-glucopyranose (G9 -NH2 ) and methyl 6-amino-6-deoxy-β-D-glucopyranose (G10 -NH2 ) The synthetic route is as follows:

Figure BDA0000366374840000091
Figure BDA0000366374840000091

甲基6-氨基-6-脱氧-α-D-吡喃半乳糖（G11-NH2）和甲基6-氨基-6-脱氧-β-D-吡喃半乳糖（G12-NH2）的合成是以D-(+)-半乳糖为原料，方法分别同G9-NH2和G10-NH2. Methyl 6-amino-6-deoxy-α-D-galactopyranose (G11 -NH2 ) and methyl 6-amino-6-deoxy-β-D-galactopyranose (G12 -NH2 ) is synthesized using D-(+)-galactose as raw material, and the method is the same as G9 -NH2 and G10 -NH2 .

目标化合物I的制备方法如下： The preparation method of target compound I is as follows:

（1）当G-NH2=G1-NH2～G12-NH2时，合成路线如下： (1) When G-NH2 =G1 -NH2 ～G12 -NH2 , the synthesis route is as follows:

Figure BDA0000366374840000092
Figure BDA0000366374840000092

（3）当G-NH2=G21-NH2～G24-NH2时，合成路线如下： (3) When G-NH2 =G21 -NH2 ～G24 -NH2 , the synthesis route is as follows:

Figure BDA0000366374840000101
Figure BDA0000366374840000101

其中a～z代表反应条件： Where a~z represent the reaction conditions:

(a)反应物为氯甲酸苄酯；催化剂为碳酸钾或碳酸钠或氢氧化钠。 (a) reactant is benzyl chloroformate; Catalyst is salt of wormwood or sodium carbonate or sodium hydroxide. the

(b)反应物为氯化亚砜；溶剂为甲醇。 (b) reactant is sulfur oxychloride; Solvent is methyl alcohol. the

(c)反应物为H2；催化剂为5%～10%Pd/C；溶剂为甲醇和/或乙酸乙酯。 (c) The reactant is H2 ; the catalyst is 5%-10% Pd/C; the solvent is methanol and/or ethyl acetate.

(d)反应物为液溴或N-溴代丁二酰亚胺，过氧化苯甲酰；溶剂为四氯化碳。 (d) The reactant is liquid bromine or N-bromosuccinimide, benzoyl peroxide; the solvent is carbon tetrachloride. the

(e)反应物为三乙胺；溶剂为乙腈。 (e) reactant is triethylamine; Solvent is acetonitrile. the

(f)反应物为H2；催化剂为5%～10%Pd/C；溶剂为甲醇和/或乙酸乙酯和/或DMF。 (f) The reactant is H2 ; the catalyst is 5%-10% Pd/C; the solvent is methanol and/or ethyl acetate and/or DMF.

(g)反应物为碳酸钾或叔丁醇钾；溶剂为乙腈。 (g) The reactant is potassium carbonate or potassium tert-butoxide; the solvent is acetonitrile. the

(h)反应物为丙二酸酐或丁二酸酐或戊二酸酐；溶剂为DMF。 (h) The reactant is malonic anhydride or succinic anhydride or glutaric anhydride; the solvent is DMF. the

(i)反应物为醋酐；催化剂为氯化锌或醋酸钠。 (i) reactant is acetic anhydride; Catalyst is zinc chloride or sodium acetate. the

(j)反应物为红磷，溴；溶剂为醋酸。 (j) reactant is red phosphorus, bromine; Solvent is acetic acid. the

(k)反应物为叠氮钠；溶剂为丙酮和水。 (k) reactant is sodium azide; Solvent is acetone and water. the

(l)反应物为H2；催化剂为5%～10%Pd/C；溶剂为甲醇和/或乙酸乙酯。 (l) The reactant is H2 ; the catalyst is 5% to 10% Pd/C; the solvent is methanol and/or ethyl acetate.

(m)反应物为苯甲醛；溶剂为氢氧化钠和水。 (m) reactant is benzaldehyde; Solvent is sodium hydroxide and water. the

(n)反应物为醋酐；溶剂为吡啶。 (n) reactant is acetic anhydride; Solvent is pyridine. the

(o)反应物为HCl；溶剂为丙酮。 (o) The reactant is HCl; the solvent is acetone. the

(p)反应物为氯化氢；溶剂为甲醇。 (p) reactant is hydrogen chloride; Solvent is methyl alcohol. the

(q)无水乙醇或含水乙醇。 (q) Absolute ethanol or hydrous ethanol. the

(r)反应物为对甲苯磺酰氯；溶剂为吡啶。 (r) The reactant is p-toluenesulfonyl chloride; the solvent is pyridine. the

(s)反应物为叠氮钠；溶剂为DMF、丙酮和水，或他们之中的两种或两种以上的混合溶剂。 (s) The reactant is sodium azide; the solvent is DMF, acetone and water, or a mixed solvent of two or more of them. the

(t)反应物为H2；催化剂为5%～10%Pd/C；溶剂为甲醇和/或乙酸乙酯。 (t) The reactant is H2 ; the catalyst is 5%-10% Pd/C; the solvent is methanol and/or ethyl acetate.

(u)反应物为草酰氯，或二氯亚砜，或三乙胺和EDCI/HOBt；溶剂为DMF。 (u) The reactant is oxalyl chloride, or thionyl chloride, or triethylamine and EDCI/HOBt; the solvent is DMF. the

(v)反应物为甲醇钠；溶剂为甲醇。 (v) reactant is sodium methylate; Solvent is methyl alcohol. the

(w)反应物为醋酐，三乙胺，和4-DMAP；溶剂为吡啶。 (w) The reactant is acetic anhydride, triethylamine, and 4-DMAP; the solvent is pyridine. the

下面是本发明部分化合物的药理试验及结果。 The following are the pharmacological tests and results of some compounds of the present invention. the

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： The test method of some compounds of the present invention to the proliferation inhibitory activity of vascular endothelial cells under normal oxygen state is as follows:

材料： Material:

细胞株：HUVECs为原代培养的人脐静脉内皮细胞，用含30μg/ml ECGS、10ng/ml EGF和20%胎牛血清的M199培养液培养，细胞经过CD31表面抗原免疫荧光鉴定后使用。 Cell line: HUVECs are primary cultured human umbilical vein endothelial cells, cultured in M199 medium containing 30 μg/ml ECGS, 10 ng/ml EGF and 20% fetal bovine serum, and used after CD31 surface antigen immunofluorescence identification. the

试剂：(1)培养液：M199培养基，为美国GIBCO公司产品。取M199粉末10.4g溶于1000ml灭菌三蒸水中，用NaHCO3调PH值至7.0，圆筒式过滤器过滤除菌、分装，4℃冰箱保存。使用前加入30μg/ml ECGS、10ng/ml EGF、20%胎牛血清、100U/ml的青霉素和100U/ml的链霉素。 Reagents: (1) Culture medium: M199 medium, a product of GIBCO, USA. Dissolve 10.4 g of M199 powder in 1000 ml of sterilized triple-distilled water, adjust the pH value to 7.0 with NaHCO3 , filter and sterilize with a cylindrical filter, pack in aliquots, and store in a refrigerator at 4°C. Add 30μg/ml ECGS, 10ng/ml EGF, 20% fetal bovine serum, 100U/ml penicillin and 100U/ml streptomycin before use.

(2)胎牛血清：美国GIBCO公司产品。经56℃水浴灭活30min，分装并保存于－20℃低温冰箱中。 (2) Fetal bovine serum: the product of American GIBCO Company. After inactivation in a water bath at 56°C for 30 minutes, aliquot and store in a low-temperature refrigerator at -20°C. the

(3)PBS缓冲液：称取NaCl8.0g、KCl0.20g、Na2HPO4·H2O1.56g、KH2PO42.0g，溶于1000ml三蒸水中，高压灭菌，4℃冰箱保存。 (3) PBS buffer solution: Weigh 8.0g of NaCl, 0.20g of KCl, 1.56g of Na2 HPO4 ·H2 O, 2.0g of KH2 PO4 , dissolve in 1000ml triple distilled water, autoclave, store in refrigerator at 4°C .

(4)0.02%EDTA溶液：称取EDTA20mg，溶于100ml PBS缓冲液中，高压灭菌。 (4) 0.02% EDTA solution: Weigh 20 mg of EDTA, dissolve in 100 ml of PBS buffer, and sterilize by autoclaving. the

(5)ECGS：内皮细胞生长添加剂，sigma公司产品。 (5) ECGS: endothelial cell growth supplement, product of sigma company. the

(6)EGF：表皮生长因子，sigma公司产品。 (6) EGF: epidermal growth factor, product of sigma company. the

(7)MTT（methylthiazolyl tetrazolium）溶液：美国Fluka公司产品。称取250mg MTT加到50ml0.01M PBS（pH7.2）溶液中，均匀混合，配成5mg/ml的MTT溶液，微孔滤膜过滤除菌，4℃避光保存。 (7) MTT (methylthiazolyl tetrazolium) solution: product of Fluka Company in the United States. Weigh 250mg of MTT and add it to 50ml of 0.01M PBS (pH7.2) solution, mix evenly to make 5mg/ml of MTT solution, sterilize by filtration with microporous membrane, and store in the dark at 4°C. the

(8)96孔平底细胞培养板，Millipore公司。 (8) 96-well flat-bottomed cell culture plate, Millipore Company. the

(9)0.4%台盼蓝溶液：PBS配制，购置于Sigma公司。 (9) 0.4% trypan blue solution: prepared in PBS, purchased from Sigma Company. the

(10)二甲亚枫DMSO：上海化工有限公司。 (10) Dimethicone DMSO: Shanghai Chemical Co., Ltd. the

(11)人重组VEGF165：美国peprotech公司。 (11) Human recombinant VEGF165 : American peprotech company.

仪器：(1)YJ-875型医用净化工作台：苏州净化设备厂生产。 Instruments: (1) YJ-875 medical purification workbench: produced by Suzhou Purification Equipment Factory. the

(2)XS-402型生物显微镜：江南光电（集团）股份有限公司产品。 (2) XS-402 Biological Microscope: Product of Jiangnan Optoelectronics (Group) Co., Ltd. the

(3)702型超低温冰箱：美国Thermo electron公司产品。 (3) 702 type ultra-low temperature refrigerator: a product of American Thermo electron company. the

(4)YXQ-LS-50SII全自动立式电热压力蒸气灭菌器：上海博迅实业有限公司医疗设备厂产品。 (4) YXQ-LS-50SII automatic vertical electric pressure steam sterilizer: product of Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory. the

(5)DGX-9003型鼓风干燥箱：上海福玛实验设备有限公司产品。 (5) DGX-9003 blast drying oven: product of Shanghai Fuma Experimental Equipment Co., Ltd. the

(6)THZ-312型台式恒温振荡器：上海精宏试验设备有限公司产品。 (6) THZ-312 desktop constant temperature oscillator: a product of Shanghai Jinghong Experimental Equipment Co., Ltd. the

(7)3111型水套式CO2培养箱：美国Thermo Forma公司生产。 (7) Model 3111 water-jacketed CO2 incubator: produced by American Thermo Forma Company.

(8)ELX800酶联免疫检测仪：美国Bio-tech公司生产。 (8) ELX800 enzyme-linked immunoassay instrument: produced by American Bio-tech Company. the

(9)电光分析天平：北京赛多利斯仪器系统有限公司。 (9) Electro-optical analytical balance: Beijing Sartorius Instrument System Co., Ltd. the

(10)LD4-2普通离心机：北京医用离心机厂产品。 (10) LD4-2 Ordinary Centrifuge: Product of Beijing Medical Centrifuge Factory. the

(11)Research型单道可调移液器：德国Eppendorf公司产品。 (11) Research-type single-channel adjustable pipette: a product of Eppendorf, Germany. the

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。 Dilution method: before use, all the test compound powders were prepared as a mother solution with a concentration of 10-2 M with dimethyl sulfoxide (DMSO), and the required concentration was prepared with cell culture medium before use.

操作流程： Operating procedures:

取六孔板，在六孔板板底用记号笔在每孔的中间画一条水平的直线。取对数生长期的HUVEC细胞按适当的浓度接种与六孔平底细胞培养板中，细胞完全贴壁后进行实验（细胞总浓度达到约60%即可）。 Take a six-hole plate and draw a horizontal straight line in the middle of each well with a marker pen at the bottom of the six-hole plate. The HUVEC cells in the logarithmic growth phase were inoculated in a six-well flat-bottomed cell culture plate at an appropriate concentration, and the experiment was carried out after the cells were completely adhered to the wall (the total concentration of the cells should reach about 60%). the

超净台内，弃去含有血清的培养基，用PBS洗2遍，用小的10μl塑料枪头在接单层细胞表面划一条直线（垂直于事先在板底画好的线）。用37℃无血清的培养基小心得洗下所脱离的细胞及细胞碎片，在显微镜下拍照，作为细胞迁移前状态(0h)数据。然后分别加入含1%FBS的M199培养基和20ng/mlVEGF的被测化合物，使给药浓度达到10-5M，阴性对照组用1%FBS的M199培养基培养，阳性对照是1%的M199和20ng/ml VEGF的培养基。放在细胞培养箱中，在给药24h后在显微镜下观察细胞修复痕迹的变化，并拍照记录。拍照的视野固定在预先划线的上下两边。 In the ultra-clean bench, discard the medium containing serum, wash twice with PBS, and use a small 10μl plastic pipette tip to draw a straight line on the surface of the monolayer of cells (perpendicular to the line drawn in advance on the bottom of the plate). The detached cells and cell fragments were carefully washed with a serum-free medium at 37°C, and photographed under a microscope as the data of the pre-migration state (0h). Then add the M199 medium containing 1% FBS and the test compound of 20ng/ml VEGF respectively to make the administration concentration reach 10-5 M. and 20ng/ml VEGF medium. Put it in a cell culture box, observe the changes of cell repair traces under a microscope after administration for 24 hours, and take pictures to record. The field of view for taking pictures is fixed at the upper and lower sides of the pre-marked lines.

使用ImageJ软件处理图片，对划痕区进行细胞计数。结果如下： The images were processed using ImageJ software, and the cells in the scratched area were counted. The result is as follows:

表1.本发明部分化合物抑制细胞迁移作用 Table 1. Some compounds of the present invention inhibit cell migration

Figure BDA0000366374840000121
Figure BDA0000366374840000121

表1中化合物代号对应的化学结构同实施例。 The chemical structures corresponding to the compound codes in Table 1 are the same as in the examples. the

药理测试结果表明，本发明的部分化合物，如I-3和I-8，对人脐静脉内皮细胞（HUVEC）的迁移有一定的抑制作用。 The pharmacological test results show that some compounds of the present invention, such as I-3 and I-8, have a certain inhibitory effect on the migration of human umbilical vein endothelial cells (HUVEC). the

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。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 present invention also provides a pharmaceutical composition for treating diseases related to angiogenesis, which contains a therapeutically effective amount of the compound of general formula I and a pharmaceutically acceptable carrier. The pharmaceutical composition can be in the form of common pharmaceutical preparations such as ordinary tablets or capsules, sustained-release tablets or capsules, controlled-release tablets or capsules, oral liquids, and injections. the

一般地，本发明的来那度胺衍生物用于治疗时，人用剂量范围为1mg～5000mg/天。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。 Generally, when the lenalidomide derivatives of the present invention are used for treatment, the human dose ranges from 1 mg to 5000 mg/day. Depending on the dosage form and the severity of the disease, the dosage may exceed this range. the

具体实施方式Detailed ways

实施例1 Example 1

N-(2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃葡萄糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺1.5水合物(I-2)的制备 N-(2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-glucopyranosyl)-4-(2-(2,6-dioxopiperidine-3- Preparation of -1-oxoisoindoline-4-amino)-4-oxobutyramide 1.5 hydrate (I-2)

N-苄氧羰基-L-谷氨酰胺(1) N-Benzyloxycarbonyl-L-glutamine (1)

将L-谷氨酰胺(58.4g,0.4mo1)溶于K2CO3(82.8g,0.6mol)的水溶液(400ml)。冰水浴下滴加氯甲酸苄酯(85ml,0.5mol)，滴加完毕后，室温搅拌3h。用乙酸乙酯(300ml×3)提取反应液，水层用浓HCl酸化至pH值为2～3(不出现更多白色混浊)，置冰箱中过夜析晶。抽滤，用研钵将滤饼研碎，再将得到的白色固体用水洗涤，红外灯下干燥，得白色固体82.0g，产率73.1%，m.p.132～133(文献值：m.p.133～135℃[Justus Liebigs Annalen der Chemie,1961,640,145-156]) L-glutamine (58.4 g, 0.4 mol) was dissolved in an aqueous solution (400 ml) of K2 CO3 (82.8 g, 0.6 mol). Benzyl chloroformate (85ml, 0.5mol) was added dropwise in an ice-water bath, and after the addition was complete, the mixture was stirred at room temperature for 3h. The reaction solution was extracted with ethyl acetate (300ml×3), the aqueous layer was acidified with concentrated HCl until the pH value was 2-3 (no more white turbidity), and placed in the refrigerator overnight for crystallization. Suction filtration, the filter cake was ground with a mortar, then the white solid obtained was washed with water, and dried under an infrared lamp to obtain 82.0 g of a white solid, with a yield of 73.1%, mp132～133 (literature value: mp133～135 ° C [Justus Liebigs Annalen der Chemie, 1961, 640, 145-156])

1H-NMR(300MHz,DMSO-d6)δ(ppm):12.58(1H,s,COOH),7.58(1H,d,J=8.1Hz,NH),7.36(5H,s,aromatic),7.28(1H,s NHa),6.76(1H,s,NHb),5.03(2H,s,PhCH2),3.94(1H,dd,J=13.2Hz,J=9.3Hz,CHCOOH),2.14(2H,t,J=7.2Hz,NH2COCH2),2.01～1.92(1H,m,CHaHbCHCOOH),1.79～1.67(1H,m,CHaHbCHCOOH). 1 H-NMR(300MHz,DMSO-d6 )δ(ppm):12.58(1H,s,COOH),7.58(1H,d,J=8.1Hz,NH),7.36(5H,s,aromatic),7.28 (1H,s NHa ),6.76(1H,s,NHb ),5.03(2H,s,PhCH2 ),3.94(1H,dd,J=13.2Hz,J=9.3Hz,CH COOH),2.14 (2H,t,J=7.2Hz,NH2 COCH2 ),2.01～1.92(1H,m,CH aHb CHCOOH),1.79～1.67(1H,m,CHaHb CHCOOH).

N-苄氧羰基-L-谷氨酰胺甲酯(2) N-Benzyloxycarbonyl-L-glutamine methyl ester (2)

1(76.5g,272.9mmo1)溶于甲醇(490m1)中，冰水浴下滴加氯化亚砜(43ml,593mmo1)，室温反应2h。减压蒸除部分甲醇(约250m1)，加水(500m1)后搅拌，置冰箱中析晶，过滤，滤饼干燥，得白色固体63.2g，产率78.8%，m.p.139～141℃(文献值：m.p.142～143℃[Bioorg.Med.Chem.,2005,13(3):785-797]) 1 (76.5g, 272.9mmol) was dissolved in methanol (490ml), and thionyl chloride (43ml, 593mmol) was added dropwise in an ice-water bath, and reacted at room temperature for 2h. Evaporate part of the methanol (about 250m1) under reduced pressure, add water (500m1) and stir, put it in the refrigerator to crystallize, filter, and dry the filter cake to obtain 63.2g of white solid with a yield of 78.8%, m.p.139～141℃ (literature value: m.p.142～143℃[Bioorg.Med.Chem.,2005,13(3):785-797]) 

1H-NMR(300MHz,CDCl3)δ(ppm):7.36(5H,s,aromatic),5.88(1H,brs,NH),5.63(1H,d,J=7.8Hz,NH),5.41(1H,brs,NH)5.16(2H,s,PhCH2),4.40～4.39(1H,m,CHCOOCH3),3.75(3H,s,OCH3),2.35～2.22(3H,m,NH2COCH2and CHaHbCHCOOH overlapping),2.04～1.93(1H,m,CHaHbCHCOOH). 1 H-NMR (300MHz, CDCl3 ) δ (ppm): 7.36 (5H, s, aromatic), 5.88 (1H, brs, NH), 5.63 (1H, d, J=7.8Hz, NH), 5.41 (1H ,brs,NH)5.16(2H,s,PhCH2 ),4.40～4.39(1H,m,CH COOCH3 ),3.75(3H,s,OCH3 ),2.35～2.22(3H,m,NH2 COCH2 and CHaHb CHCOOH overlapping),2.04～1.93(1H,m,CHaHb CHCOOH).

L-谷氨酰胺甲酯(3) L-Glutamine Methyl Ester (3)

将2(34.46g,117.0mmo1)溶解于甲醇(350m1)和乙酸乙酯(200ml)的混合溶剂中，搅拌溶解后加 入10%Pd-C(含水1%3.0g)，常压常温氢化搅拌反应24h。滤除催化剂，滤液减压蒸干，得油状物19.52g，不经纯化直接投下步反应。 Dissolve 2 (34.46g, 117.0mmol) in a mixed solvent of methanol (350m1) and ethyl acetate (200ml), stir and dissolve, add 10% Pd-C (1% 3.0g of water), hydrogenation at normal pressure and temperature Reaction 24h. The catalyst was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure to obtain 19.52 g of an oily substance, which was directly put into the next reaction without purification. the

2-溴甲基-3-硝基苯甲酸甲酯(4) Methyl 2-bromomethyl-3-nitrobenzoate (4)

2-甲基-3-硝基苯甲酸甲酯(95.5g,489.5mmo1)悬浮于四氯化碳(480m1)中，搅拌下加入过氧化苯甲酰(15.5g,64.0mmo1)加热回流下缓慢滴加液溴(37.5ml,730.0mmo1)，并用40W白炽灯光照下回流7d。冷却至室温，加入二氯甲烷(500m1)，所得溶液以饱和碳酸氢钠溶液(400ml×3)洗涤，无水硫酸镁干燥。过滤，滤液减压浓缩至200ml，抽滤，得淡黄色固体110.5g，产率82.3%，m.p.57-60℃(文献值：m.p.66～68℃[Bioorg.Med.Chem.,2005,13(3):785-797]); Methyl 2-methyl-3-nitrobenzoate (95.5g, 489.5mmol) was suspended in carbon tetrachloride (480m1), and benzoyl peroxide (15.5g, 64.0mmol) was added under reflux under stirring. Liquid bromine (37.5ml, 730.0mmol) was added dropwise, and refluxed under 40W incandescent light for 7d. After cooling to room temperature, dichloromethane (500 ml) was added, and the resulting solution was washed with saturated sodium bicarbonate solution (400 ml×3), and dried over anhydrous magnesium sulfate. Filtration, the filtrate was concentrated under reduced pressure to 200ml, and suction filtered to obtain 110.5g of a light yellow solid, with a yield of 82.3%, m.p. 3):785-797]);

1H-NMR(300MHz,CDCl3)δ(ppm):8.11(1H,d,J=7.8Hz,aromatic),7.96(1H,d,J=8.1Hz,aromatic),7.54(1H,t,J=8.1Hz,aromatic),5.16(2H,s,CH2Br),4.00(3H,s,OCH3). 1 H-NMR(300MHz,CDCl3 )δ(ppm):8.11(1H,d,J=7.8Hz,aromatic),7.96(1H,d,J=8.1Hz,aromatic),7.54(1H,t,J =8.1Hz,aromatic),5.16(2H,s,CH2 Br),4.00(3H,s,OCH3 ).

N-(4-硝基-1-氧代-1,3-二氢-2H-异氮杂茚-2-基)-L-谷氨酰胺甲酯(5) N-(4-nitro-1-oxo-1,3-dihydro-2H-isozainden-2-yl)-L-glutamine methyl ester (5)

新鲜制备的3(68.0mmol)溶于乙腈(180m1)中，搅拌下加入4(18.6g,68.0mmo1)和三乙胺(28.9ml,20.0mmo1)，加热回流0.5h，加入水(2ml)淬灭反应。反应液减压蒸干，剩余物中加入水(100ml)，搅拌，析出白色固体，过滤，滤饼用水洗涤后干燥，得白色固体5.45g，产率29.2%，m.p.90～92℃(文献值：m.p.100～102℃[中国医药工业杂志,2008,39(12):888-891]) Freshly prepared 3 (68.0mmol) was dissolved in acetonitrile (180m1), 4 (18.6g, 68.0mmol) and triethylamine (28.9ml, 20.0mmol) were added under stirring, heated to reflux for 0.5h, and water (2ml) was added to quench extinction reaction. The reaction solution was evaporated to dryness under reduced pressure, water (100ml) was added to the residue, stirred, a white solid was precipitated, filtered, the filter cake was washed with water and dried to obtain 5.45g of a white solid, with a yield of 29.2%, m.p.90～92°C (literature value : m.p.100～102℃[Chinese Journal of Pharmaceutical Industry, 2008,39(12):888-891]) 

1H-NMR(300MHz,CDCl3)δ(ppm):8.45(1H,d,J=8.4Hz,aromatic),8.19(1H,d,J=7.5Hz,aromatic),7.73(1H,t,J=7.8Hz,aromatic),5.69(1H,brs,NHa),5.34(1H,brs,NHb),5.18～5.08(2H,m,CHCOOCH3and PhCHaHb overlapping),4.92(1H,d,J=19.5Hz,PhCHaHb),3.77(3H,s,OCH3),2.61～2.52(1H,m,CHaHbCOONH2),2.41～2.26(3H,m,CHaHbCOONH2,CH2CHaHbCOONH2overlapping). 1 H-NMR(300MHz,CDCl3 )δ(ppm):8.45(1H,d,J=8.4Hz,aromatic),8.19(1H,d,J=7.5Hz,aromatic),7.73(1H,t,J =7.8Hz,aromatic),5.69(1H,brs,NHa ),5.34(1H,brs,NHb ),5.18～5.08(2H,m,CH COOCH3 and PhCHa Hb overlapping),4.92( 1H,d,J=19.5Hz,PhCHaHb ),3.77(3H,s,OCH3 ),2.61～2.52(1H,m,CHaHb COONH2 ),2.41～2.26(3H,m, CHaHb COONH2 ,CH2 CHa Hb COONH2 overlapping).

N-(4-氨基-1-氧代-1,3-二氢-2H-异氮杂茚-2-基)-L-谷氨酰胺甲酯(6) N-(4-Amino-1-oxo-1,3-dihydro-2H-isozainden-2-yl)-L-glutamine methyl ester (6)

将5(17.80g,55.45mmo1)搅拌溶解于甲醇(200m1)和乙酸乙酯(100ml)的混合溶剂中，加入催化剂10%Pd-C(1.8g)，常温常压搅拌反应4h。滤除催化剂，滤液减压蒸干，剩余物中加入乙酸乙酯(40m1)，搅拌，析出淡黄色固体。过滤，滤饼用乙酸乙酯洗涤后干燥，得淡黄色固体13.11g，产率81.2%，m.p.181～184℃(文献值：m.p.183～185℃[中国医药工业杂志,2008,39(12):888-891]) 5 (17.80g, 55.45mmol) was stirred and dissolved in a mixed solvent of methanol (200ml) and ethyl acetate (100ml), and the catalyst 10%Pd-C (1.8g) was added, and the reaction was stirred at room temperature and pressure for 4h. The catalyst was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure. Ethyl acetate (40 ml) was added to the residue, stirred, and a pale yellow solid was precipitated. Filter, and dry the filter cake after washing with ethyl acetate to obtain 13.11 g of a light yellow solid, with a yield of 81.2%, m.p. :888-891])

1H-NMR(300MHz,DMSO-d6)δ(ppm):7.26(1H,s,aromatic),7.18(1H,t,J=7.8Hz,aromatic),6.89(1H,d,J=7.5Hz,aromatic),6.79(2H,d,J=7.8,CONH2),5.47(2H,brs,PhNH2),4.86(1H,m,CHCOOCH3),4.23(2H,s,PhCH2),3.66(3H,s,OCH3),2.31～2.25(1H,m,CHaHbCOONH),2.09～1.97(3H,m,CHaHbCOONH2,CH2CHaHbCOONH2overlapping). 1 H-NMR(300MHz,DMSO-d6 )δ(ppm):7.26(1H,s,aromatic),7.18(1H,t,J=7.8Hz,aromatic),6.89(1H,d,J=7.5Hz ,aromatic),6.79(2H,d,J=7.8,CONH2 ),5.47(2H,brs,PhNH2 ),4.86(1H,m,CH COOCH3 ),4.23(2H,s,PhCH2 ), 3.66(3H,s,OCH3 ),2.31～2.25(1H,m,CH a H bCOONH) ,2.09～1.97(3H,m,CHaHb COONH2 ,CH2 CHa Hb COONH2 overlapping ).

外消旋3-(4-氨基-1-氧代异吲哚啉-2-基)-哌啶-2,6-二酮(来那度胺) Racemic 3-(4-amino-1-oxoisoindolin-2-yl)-piperidine-2,6-dione (lenalidomide)

6(5.70g,19.4mmo1)溶于乙腈(300m1)中，加入无水碳酸钾(2.68g,19.4mmo1)，加热回流4h，加入水(10m1)，自然降至室温后，减压蒸除乙腈。将残余物悬浮于水(30ml)，过滤，滤饼用水和甲醇洗涤后减压干燥，得淡黄色固体3.94g，产率70.2%，m.p.256～259℃(文献值[8]：m.p.235.5～239℃[WO9803502]) 6 (5.70g, 19.4mmol) was dissolved in acetonitrile (300m1), anhydrous potassium carbonate (2.68g, 19.4mmol) was added, heated to reflux for 4h, water (10m1) was added, and after cooling down to room temperature naturally, the acetonitrile was distilled off under reduced pressure . The residue was suspended in water (30ml), filtered, and the filter cake was washed with water and methanol and dried under reduced pressure to obtain 3.94 g of a light yellow solid, with a yield of 70.2%, mp256～259°C (literature value[8] : mp235.5～ 239°C [WO9803502])

1H-NMR(300MHz,DMSO-d6)δ(ppm):11.01(1H,s,CONHCO),7.19(1H,t,J=7.5Hz,aromatic),6.92(1H,d,J=7.2Hz,aromatic),6.80(1H,d,J=7.8Hz,aromatic),5.43(2H,s,PhNH2),5.11(1H,dd,J=13.2Hz,J=5.1Hz,NCHCO),4.16(2H,dd,J=32.4Hz,J=17.1Hz,PhCH2),2.98～2.86(1H,m,CHaHbCOONH),2.64～2.59(1H,m,CHaHbCOONH),2.38～2.23(1H,m,CHaHbCHaHbCOONH),2.05～2.01(1H,m,CHaHbCHaHbCOONH). 1 H-NMR(300MHz,DMSO-d6 )δ(ppm):11.01(1H,s,CONHCO),7.19(1H,t,J=7.5Hz,aromatic),6.92(1H,d,J=7.2Hz ,aromatic),6.80(1H,d,J=7.8Hz,aromatic),5.43(2H,s,PhNH2 ),5.11(1H,dd,J=13.2Hz,J=5.1Hz,NCHCO),4.16(2H ,dd,J=32.4Hz,J=17.1Hz,PhCH2 ),2.98～2.86(1H,m,CHaHb COONH),2.64～2.59(1H,m,CHaHb COONH),2.38～ 2.23(1H,m,CHaHb CHa Hb COONH),2.05～2.01(1H,m,CHaHb CHa Hb COONH).

4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酸(7-2) 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-amino)-4-oxobutanoic acid (7-2) 

将来那度胺(2.58g,9.8mmol)溶于DMF(30ml)，加入丁二酸酐(1.47g,1.47mmol)，加热到60℃反应24h。将反应液倒入乙醚(300ml)中，搅拌析出大量固体，放置冰箱过夜继续析晶，过滤。乙醚洗，得为淡黄色固体3.45g，产率98.2%；m.p.223～224℃; Lenalidomide (2.58g, 9.8mmol) was dissolved in DMF (30ml), succinic anhydride (1.47g, 1.47mmol) was added, heated to 60°C for 24h. The reaction solution was poured into diethyl ether (300ml), stirred to precipitate a large amount of solid, placed in the refrigerator overnight to continue crystallization, and filtered. After washing with ether, 3.45 g of light yellow solid was obtained, with a yield of 98.2%; m.p.223～224°C;

1H-NMR(300MHz,DMSO-d6)δ(ppm):12.21(1H,brs,COOH),11.70(1H,s,CONHCO),9.92(1H,s,CONH),7.82(1H,d,J=3.6Hz,aromatic),7.50(2H,s,aromatic),5.15(1H,dd,J=13.2Hz,J=4.8Hz,NCHCO),4.35(2H,dd,J=26.4Hz,J=17.7Hz,PhCH2),2.89(1H,s,CONHCHaHbCHaHbCOOH),2.73(1H,s,CONHCHaHbCHaHbCOOH),2.61～2.54(4H,m,CONHCH2CHaHbCOOH and CH2COONH overlapping),2.39～2.32(1H,m,CHaHbCHaHbCOONH),2.05～2.03(1H,m,CHaHbCHaHbCOONH); 1 H-NMR (300MHz, DMSO-d6 ) δ (ppm): 12.21 (1H, brs, COOH), 11.70 (1H, s, CONHCO), 9.92 (1H, s, CONH), 7.82 (1H, d, J=3.6Hz, aromatic),7.50(2H,s,aromatic),5.15(1H,dd,J=13.2Hz,J=4.8Hz,NCHCO),4.35(2H,dd,J=26.4Hz,J=17.7 Hz,PhCH2 ),2.89(1H,s,CONHCHa HbCHa Hb COOH),2.73(1H,s,CONHCHa Hb CHaHb COOH),2.61～2.54(4H,m,CONHCH2 CHa Hb COOH andCH2 COONH overlapping),2.39～2.32(1H,m,CHa Hb CHa Hb COONH),2.05～2.03(1H,m,CHaHb CHa HbCOONH );

IR(cm-1):3404,3198,3086,2914,1708,1663,1602,1540,1425,1290,1237,1186,992,813,759;MS(ESI(-)70V,m/z):358.0[M-H]-. IR(cm-1 ):3404,3198,3086,2914,1708,1663,1602,1540,1425,1290,1237,1186,992,813,759; MS(ESI(-)70V,m/z):358.0[MH]- .

1,2,3,4,6-五-O-乙酰基-α-D-吡喃葡萄糖(8) 1,2,3,4,6-penta-O-acetyl-α-D-glucopyranose (8) 

在三颈瓶中加入ZnCl2(2.0g,14.7mmol)和无水乙酸酐(50.0ml，520mol)，加热30min后氯化锌溶解，分批加入D-葡萄糖粉末(10.0g,56mmol)，充分搅拌。加毕，继续在油浴100℃加热2h。冷却，将混合物倒入200mL冰水中，充分搅拌以分解未反应的醋酐。开始有油状物生成，之后固化成大量白色沉淀，继续搅拌1h，过滤，多次冷水洗涤，红外灯下干燥，得白色固体18.11g(粗产率83.6%)。固体用无水乙醇(70ml)重结晶，得到白色固体，红外灯干燥得15.61g，母液浓缩后又得0.78g，总产率75.60%，m.p.107-109℃。（文献值：m.p.107-110℃[精细化工,2005,22(4):307-310]）。 Add ZnCl2 (2.0g, 14.7mmol) and anhydrous acetic anhydride (50.0ml, 520mol) in the three-necked flask, after heating for 30min, zinc chloride dissolves, and adds D-glucose powder (10.0g, 56mmol) in batches, fully Stir. After addition, continue to heat in an oil bath at 100°C for 2h. After cooling, the mixture was poured into 200 mL of ice water and stirred well to decompose unreacted acetic anhydride. An oily substance was formed at the beginning, and then solidified into a large amount of white precipitate. Stirring was continued for 1 h, filtered, washed with cold water several times, and dried under an infrared lamp to obtain 18.11 g of a white solid (crude yield 83.6%). The solid was recrystallized from absolute ethanol (70ml) to obtain a white solid, which was dried under an infrared lamp to obtain 15.61g, and the mother liquor was concentrated to obtain another 0.78g, with a total yield of 75.60%, mp107-109°C. (Literature value: mp107-110℃[Fine Chemical Industry, 2005,22(4):307-310]).

1-溴代-2,3,4,6-四-O-乙酰基-1-脱氧-α-D-吡喃葡萄糖(9) 1-Bromo-2,3,4,6-tetra-O-acetyl-1-deoxy-α-D-glucopyranose (9) 

在三颈瓶中，将红磷(1.8g,14.5mmol)悬浮于乙酸(20ml)中，充分搅拌，滴加液溴(3.48ml,68mmol），控制温度低于20℃。滴加完毕，室温继续搅拌30min。将8(12.96g,33.2mmol)分批加入上述溴代试剂中。加完，室温搅拌4h，加入氯仿(20ml)。然后将混合物倒入冰水中，过滤，分出有机层，水层用氯仿萃取，有机层分别用水、饱和碳酸氢钠溶液，饱和NaCl溶液洗涤，无水Na2SO4干燥。不高于30℃下减压蒸除溶剂，所得残余物硅胶柱层析(石油醚/乙酸乙酯=2:1-1:1)，得到白色固体8.72g，产率63.84%，m.p.89-90℃(文献值:m.p.88-89℃[精细化工,2005,22(4):307-310])。 In a three-necked flask, suspend red phosphorus (1.8g, 14.5mmol) in acetic acid (20ml), stir well, add liquid bromine (3.48ml, 68mmol) dropwise, and control the temperature below 20°C. After the dropwise addition was completed, stirring was continued at room temperature for 30 min. 8 (12.96g, 33.2mmol) was added in portions to the above brominated reagent. After the addition was complete, stir at room temperature for 4 h, and then add chloroform (20 ml). Then the mixture was poured into ice water, filtered, the organic layer was separated, the aqueous layer was extracted with chloroform, the organic layer was washed with water, saturated sodium bicarbonate solution, and saturated NaCl solution, and dried over anhydrous Na2 SO4 . The solvent was distilled off under reduced pressure at no higher than 30°C, and the obtained residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=2:1-1:1) to obtain 8.72 g of a white solid with a yield of 63.84%, mp89-90 ℃ (literature value: mp88-89℃ [Fine Chemical Industry, 2005, 22(4): 307-310]).

1-叠氮基-2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃葡萄糖(10) 1-azido-2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-glucopyranose (10) 

将9(3.89g,50mmol)溶于丙酮(36mL)，再加入叠氮钠(0.78g,60mmol)的水溶液(9ml)。混合溶液在常温下搅拌反应至经TLC监测原料点消失。待反应液冷却后倾入到含冰水和二氯甲烷的混合溶液中，分出有机层，水层再用二氯甲烷萃取一次，合并有机相后用无水MgSO4干燥过夜。过滤，减压蒸除溶剂，得白色固体混合物3.49g。（不精制直接投入下步反应） 9 (3.89g, 50mmol) was dissolved in acetone (36mL), and an aqueous solution (9ml) of sodium azide (0.78g, 60mmol) was added. The mixed solution was stirred and reacted at room temperature until the starting point disappeared as monitored by TLC. After the reaction solution was cooled, it was poured into a mixed solution containing ice water and dichloromethane, the organic layer was separated, and the aqueous layer was extracted once with dichloromethane, and the combined organic phases were dried overnight with anhydrous MgSO4 . After filtration, the solvent was distilled off under reduced pressure to obtain 3.49 g of a white solid mixture. (Directly put into the next step reaction without refining)

取少量柱层析(PE/EA=2:1)，得亮白色固体粉末，m.p.124-127℃（文献值：m.p.125.5-126.5℃[Tetrahedron,2005,61,8625-8632]）； Take a small amount of column chromatography (PE/EA=2:1) to obtain a bright white solid powder, m.p.124-127°C (literature value: m.p.125.5-126.5°C [Tetrahedron, 2005,61,8625-8632]);

1H-NMR(300MHz,CDCl3)δ(ppm):5.23(1H,t,J=9.6Hz,H-3),5.11(1H,t,J=9.6Hz,H-4),4.96(1H,t,J=9.3Hz,H-2),4.65(1H,d,J=8.7Hz,H-1),4.28(1H,dd,J=4.8Hz,J=12.6Hz,H-6a),4.17(1H,dd,J=1.8Hz,J=12.3Hz,H-6b),3.80(1H,ddd,J=2.4Hz,J=4.8Hz,J=9.9Hz,H-5),2.111,2.086,2.039,2.018(each3H,each s,each CH3). 1 H-NMR (300MHz, CDCl3 ) δ (ppm): 5.23 (1H, t, J=9.6Hz, H-3), 5.11 (1H, t, J=9.6Hz, H-4), 4.96 (1H ,t,J=9.3Hz,H-2),4.65(1H,d,J=8.7Hz,H-1),4.28(1H,dd,J=4.8Hz,J=12.6Hz,H-6a), 4.17(1H,dd,J=1.8Hz,J=12.3Hz,H-6b),3.80(1H,ddd,J=2.4Hz,J=4.8Hz,J=9.9Hz,H-5),2.111,2.086 ,2.039,2.018(each3H,each s,each CH3 ).

2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃氨基葡萄糖盐酸盐(G1-NH2.HCl) 2,3,4,6-Tetra-O-acetyl-1-deoxy-β-D-glucopyranosamine hydrochloride (G1 -NH2 .HCl)

将含有10的混合物(3.49g)溶于乙酸乙酯和甲醇的混合溶液(60ml,甲醇/乙酸乙酯和体积比1/1)中，10%Pd/C(0.35g)加入其中。混合物在常压下氢化6h。用硅藻土助滤过滤得无色液体，减压除去溶剂后得到黄色糖浆状物，加入适量丙酮使其溶解，然后在冰浴下滴加饱和HCl的乙醇溶液至无白色固体析出，pH约为4左右，置于冰箱中约2h。过滤，滤饼用冷丙酮洗涤，红外灯下烘干得白色固体2.82g，产率78.69%，m.p.161-162℃（炭化）。 The mixture containing 10 (3.49 g) was dissolved in a mixed solution of ethyl acetate and methanol (60 ml, methanol/ethyl acetate and volume ratio 1/1), and 10% Pd/C (0.35 g) was added thereto. The mixture was hydrogenated at normal pressure for 6h. Use diatomaceous earth to filter to obtain a colorless liquid, remove the solvent under reduced pressure to obtain a yellow syrup, add an appropriate amount of acetone to dissolve it, and then add a saturated ethanol solution of HCl dropwise in an ice bath until no white solid is precipitated, and the pH is about For about 4, put it in the refrigerator for about 2h. After filtering, the filter cake was washed with cold acetone, and dried under an infrared lamp to obtain 2.82 g of a white solid, with a yield of 78.69%, m.p.161-162°C (charring). the

取少量G1-NH2.HCl，用碳酸氢钠溶液处理得1-氨基-2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃葡萄糖G1-NH2，测定1H-NMR: Take a small amount of G1 -NH2 .HCl and treat it with sodium bicarbonate solution to obtain 1-amino-2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-glucopyranose G1 - NH2 , measure1 H-NMR:

1H-NMR(300MHz,CDCl3)δ(ppm):5.25(1H,t,J=9.3Hz,H-3),5.07(1H,t,J=9.6Hz,H-4),4.84(1H,m,H-2),4.20(3H,m,H-1,6a,6b),3.73(1H,m,H-5),2.10-2.01(2H,br s,NH),2.10-2.10(12H,m,4×CH3). 1 H-NMR (300MHz, CDCl3 ) δ (ppm): 5.25 (1H, t, J=9.3Hz, H-3), 5.07 (1H, t, J=9.6Hz, H-4), 4.84 (1H ,m,H-2),4.20(3H,m,H-1,6a,6b),3.73(1H,m,H-5),2.10-2.01(2H,br s,NH),2.10-2.10( 12H,m,4×CH3 ).

N-(2,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃葡萄糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺1.5水合物(I-2) N-(2,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosyl)-4-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-4-oxobutanamide 1.5 hydrate (I-2) 

将G1-NH2.HCl(1.15g,3mmol)溶于DMF(10ml)。缓慢滴加干燥的三乙胺(0.42ml,3mmol)。然后先后分批加入7-2(1.13g,3mmol),EDCI(0.58g,3mmol),HOBt(0.41g,3mmol)，室温搅拌24h。 反应液加入二氯甲烷(100ml)，饱和食盐水洗(3×100ml)，干燥，抽滤，减压蒸除溶剂，硅胶柱层析(二氯甲烷/甲醇=60/1,40/1,20/1)，得类白色固体0.18g，收率8.7%，m.p.161-162℃; G1 -NH2 .HCl (1.15 g, 3 mmol) was dissolved in DMF (10 ml). Dry triethylamine (0.42ml, 3mmol) was slowly added dropwise. Then 7-2 (1.13g, 3mmol), EDCI (0.58g, 3mmol), HOBt (0.41g, 3mmol) were added in batches successively, and stirred at room temperature for 24h. Add dichloromethane (100ml) to the reaction solution, wash with saturated brine (3×100ml), dry, filter with suction, evaporate the solvent under reduced pressure, perform silica gel column chromatography (dichloromethane/methanol=60/1,40/1,20 /1), 0.18g off-white solid was obtained, yield 8.7%, mp161-162°C;

1H-NMR(300MHz,CDCl3)δ(ppm):9.32(1H,d,J=28.2Hz,CONHCO),8.84(1H,d,J=30.3Hz,NH),7.83(1H,dd,J=16.2Hz,J=7.8Hz,aromatic),7.62(1H,d,J=6.9Hz,aromatic),7.43(1H,t,J=7.5Hz,aromatic),7.15(1H,d,J=9.0Hz,NH),5.34～5.27(2H,m,NCHCO and H-1),5.14～5.03(2H,m,H-2and H-3),4.95(1H,t,J=9.6Hz,H-4),4.35～4.31(3H,m,PhCH2and H-6a),4.06(1H,t,J=11.1Hz,H-6b),3.87～3.85(1H,m,H-5),2.75(2H,s,CONHCH2CH2COOH),2.46(2H,s,CONHCH2CH2COOH),2.31～2.25(2H,m,CH2CH2COONH),2.18～2.12(2H,m,CH2CH2COONH),2.05,2.05,2.02,2.02(each3H,each s,4×OAc); 1 H-NMR (300MHz, CDCl3 ) δ (ppm): 9.32 (1H, d, J=28.2Hz, CONHCO), 8.84 (1H, d, J=30.3Hz, NH), 7.83 (1H, dd, J =16.2Hz,J=7.8Hz,aromatic),7.62(1H,d,J=6.9Hz,aromatic),7.43(1H,t,J=7.5Hz,aromatic),7.15(1H,d,J=9.0Hz ,NH),5.34～5.27(2H,m,NCHCO and H-1),5.14～5.03(2H,m,H-2and H-3),4.95(1H,t,J=9.6Hz,H-4) ,4.35～4.31(3H,m,PhCH2 and H-6a),4.06(1H,t,J=11.1Hz,H-6b),3.87～3.85(1H,m,H-5),2.75(2H, s,CONHCH2CH2 COOH),2.46(2H,s,CONHCH2 CH2 COOH),2.31～2.25(2H,m,CH2CH2 COONH),2.18～2.12(2H,m,CH2 CH2 COONH),2.05,2.05,2.02,2.02(each3H,each s,4×OAc);

IR(cm-1):3457(NH),2944,1749(C=O),1683(C=O),1539,1372,1233,1039,907,754,594; IR(cm-1 ):3457(NH),2944,1749(C=O),1683(C=O),1539,1372,1233,1039,907,754,594;

MS(ESI(-)70V,m/z):723.5[M+Cl]-; MS(ESI(-)70V,m/z):723.5[M+Cl]- ;

Anal.Calcd for C31H36N4O14·1.5H2O:C,52.03,H,5.49,N,7.83.Found:C,52.04,H,5.54,N,7.68. Anal.Calcd for C31 H36 N4 O14 1.5H2 O:C,52.03,H,5.49,N,7.83.Found:C,52.04,H,5.54,N,7.68.

实施例2 Example 2

N-(2,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃葡萄糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺二水合物(I-3)的制备 N-(2,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosyl)-5-(2-(2,6-dioxopiperidine-3- Preparation of -1-oxoisoindoline-4-amino)-5-oxopentamide dihydrate (I-3)

5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酸(7-3) 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-amino)-5-oxopentanoic acid (7-3) 

将来那度胺(3.93g,15mmol)溶于DMF(30ml)，加入戊二酸酐(2.58g,22.5mmol)，加热到60℃反应48h。将反应液倒入乙醚中，搅拌析出大量固体，放置冰箱过夜继续析晶，过滤。乙醚洗，得为淡黄色固体5.15g，产率93.0%，m.p.150～152℃; Lenalidomide (3.93g, 15mmol) was dissolved in DMF (30ml), glutaric anhydride (2.58g, 22.5mmol) was added, heated to 60°C for 48h. Pour the reaction solution into ether, stir to precipitate a large amount of solids, place in the refrigerator overnight to continue crystallization, and filter. After washing with ether, 5.15 g of a light yellow solid was obtained, with a yield of 93.0%, m.p.150-152°C;

1H-NMR(300MHz,DMSO-d6)δ(ppm):12.08(1H,brs,COOH),11.03(1H,s,CONHCO),9.82(1H,s,CONH),7.82(1H,s,aromatic),7.50(2H,s,aromatic),5.15(1H,d,J=11.7Hz,NCHCO),4.34(2H,s,PhCH2),2.92～2.87(2H,m,CONHCH2CH2CH2COOH),2.63～2.53(2H,mCONHCH2CH2CH2COOH),2.40(2H,s,CH2CH2COONH),2.28(2H,m,CH2CH2COONH),2.08～2.04(2H,m,CONHCH2CH2CH2COOH); 1 H-NMR (300MHz, DMSO-d6 ) δ (ppm): 12.08 (1H, brs, COOH), 11.03 (1H, s, CONHCO), 9.82 (1H, s, CONH), 7.82 (1H, s, aromatic), 7.50 (2H, s, aromatic), 5.15 (1H, d, J=11.7Hz, NCHCO), 4.34 (2H, s, PhCH2 ), 2.92～2.87 (2H, m, CONHCH2 CH2CH2 COOH),2.63～2.53(2H,mCONHCH2 CH2 CH2 COOH),2.40(2H, s,CH2CH2 COONH),2.28(2H,m,CH2 CH2 COONH),2.08～ 2.04( 2H,m ,CONHCH2CH2CH2COOH );

IR(cm-1):3434,3339,3180,3080,2844,1728,1692,1665,1599,1544,1433,1352,1234,1193,745,615; IR(cm-1 ):3434,3339,3180,3080,2844,1728,1692,1665,1599,1544,1433,1352,1234,1193,745,615;

MS(ESI(+)70V,m/z):374.1[M+H]+; MS(ESI(+)70V,m/z):374.1[M+H]+ ;

MS(ESI(-)70V,m/z):372.0[M-H]-. MS(ESI(-)70V,m/z):372.0[MH]- .

N-(2,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃葡萄糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺二水合物(I-3) N-(2,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosyl)-5-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-5-oxopentamide dihydrate (I-3) 

将G1-NH2.HCl(1.15g,3mmol)溶于DMF(10ml)。缓慢滴加干燥的三乙胺(0.42ml,3mmol)。然后先后分批加入7-3(1.17g,3mmol),EDCI(0.58g,3mmol),HOBt(0.41g,3mmol)，室温搅拌24h。反应液加入二氯甲烷(100ml)，饱和食盐水洗(3×100ml)，干燥，抽滤，减压蒸除溶剂， 硅胶柱层析(二氯甲烷/甲醇=60/1,40/1,20/1)，得类白色固体0.16g，收率7.6%，m.p.153-155℃; G1 -NH2 .HCl (1.15 g, 3 mmol) was dissolved in DMF (10 ml). Dry triethylamine (0.42ml, 3mmol) was slowly added dropwise. Then 7-3 (1.17g, 3mmol), EDCI (0.58g, 3mmol), HOBt (0.41g, 3mmol) were added in batches successively, and stirred at room temperature for 24h. Add dichloromethane (100ml) to the reaction solution, wash with saturated brine (3×100ml), dry, filter with suction, evaporate the solvent under reduced pressure, and perform silica gel column chromatography (dichloromethane/methanol=60/1,40/1,20 /1), to obtain off-white solid 0.16g, yield 7.6%, mp153-155°C;

1H-NMR(300MHz,CDCl3)δ(ppm):9.00(1H,d,J=28.8Hz,CONHCO),8.62(1H,d,J=50.1Hz,NH),7.91～7.85(1H,m,aromatic),7.68～7.64(1H,m,aromatic),7.46(1H,t,J=6.9Hz,aromatic),6.91(1H,t,J=8.4Hz,NH),5.31(2H,dd,J=19.5Hz,J=9.9Hz,NCHCO and H-1),5.17～5.09(2H,m,H-2and H-3),4.98～4.91(1H,m,H-4),4.37～4.33(2H,m,PhCH2),4.16～4.01(1H,m,H-6a),3.92～3.77(2H,m,H-5and H-6b),2.79(2H,s,CONHCH2CH2CH2COOH),2.47～2.42(2H,s,CONHCH2CH2CH2COOH),2.32～2.29(2H,m,CH2CH2COONH),2.17～2.16(2H,m,CH2CH2COONH),2.06,2.06,2.03,2.03(each3H,each s,4×OAc),1.77(2H,s,CONHCH2CH2CH2COOH); 1 H-NMR (300MHz, CDCl3 ) δ (ppm): 9.00 (1H, d, J=28.8Hz, CONHCO), 8.62 (1H, d, J=50.1Hz, NH), 7.91～7.85 (1H, m ,aromatic),7.68～7.64(1H,m,aromatic),7.46(1H,t,J=6.9Hz,aromatic),6.91(1H,t,J=8.4Hz,NH),5.31(2H,dd,J =19.5Hz, J=9.9Hz, NCHCO and H-1), 5.17～5.09(2H,m,H-2and H-3),4.98～4.91(1H,m,H-4),4.37～4.33(2H ,m,PhCH2 ),4.16～4.01(1H,m,H-6a),3.92～3.77(2H,m,H-5and H-6b),2.79(2H,s,CONHCH2 CH2CH2 COOH ),2.47～2.42(2H,s,CONHCH2 CH2 CH2 COOH),2.32～2.29(2H,m,CH2CH2 COONH),2.17～2.16(2H,m,CH 2CH2 COONH ),2.06,2.06,2.03,2.03(each3H,each s,4×OAc),1.77(2H,s,CONHCH2CH2 CH2 COOH);

IR(cm-1):3381(NH),2938,2354,1752(C=O),1686(C=O),1535,1431,1371,1232,1039,904,751,592; IR(cm-1 ):3381(NH),2938,2354,1752(C=O),1686(C=O),1535,1431,1371,1232,1039,904,751,592;

MS(ESI(+)70V,m/z):703.2[M+H]+; MS(ESI(+)70V,m/z):703.2[M+H]+ ;

MS(ESI(-)70V,m/z):737.4[M+Cl]-; MS(ESI(-)70V,m/z):737.4[M+Cl]- ;

Anal.Calcd for C32H38N4O14·2H2O:C,52.03,H,5.73,N,7.58.Found:C,51.85,H,5.64,N,7.36. Anal.Calcd for C32 H38 N4 O14 2H2 O:C,52.03,H,5.73,N,7.58.Found:C,51.85,H,5.64,N,7.36.

实施例3 Example 3

N-(2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃半乳糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-5)的制备 N-(2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-galactopyranosyl)-4-(2-(2,6-dioxopiperidine-3 Preparation of -yl)-1-oxoisoindoline-4-amino)-4-oxobutyramide (I-5)

1,2,3,4,6-五-O-乙酰基-β-D-吡喃半乳糖(8-2) 1,2,3,4,6-penta-O-acetyl-β-D-galactopyranose (8-2) 

将无水NaOAc(2.5g,30.4mmol)悬浮于Ac2O(35ml)中，加热至回流。控制回流速度，分批加入D-吡喃半乳糖(5.0g，0.029mol)，继续回流1小时。冷却后将反应液倒入碎冰(约250ml)中，搅拌4小时，析出固体。过滤，冷水洗涤，得灰白色固体6.5g，无水乙醇(50ml)重结晶，得白色晶体5g，收率44.2%。m.p.147-149℃。（文献值mp.144-146℃[CN1594342A]） Anhydrous NaOAc (2.5g, 30.4mmol) was suspended inAc2O (35ml) and heated to reflux. Control the reflux speed, add D-galactopyranose (5.0 g, 0.029 mol) in batches, and continue to reflux for 1 hour. After cooling, the reaction solution was poured into crushed ice (about 250 ml), stirred for 4 hours, and a solid was precipitated. Filter and wash with cold water to obtain 6.5 g of off-white solid, recrystallize from absolute ethanol (50 ml) to obtain 5 g of white crystal, yield 44.2%. mp147-149°C. (Literature value mp.144-146°C [CN1594342A])

1-溴代-2,3,4,6-四-O-乙酰基-1-脱氧-α-D-吡喃半乳糖(9-2) 1-bromo-2,3,4,6-tetra-O-acetyl-1-deoxy-α-D-galactopyranose (9-2) 

三颈瓶中，将红磷(0.7g,5.6mmol)悬浮于乙酸(7.7ml)，充分搅拌，缓慢滴加液溴(1.35ml,26.1mmol)，控制温度低于20℃。滴加完毕，室温搅拌30min后，将8-2(5g,12.3mmol)分批加入，加毕，室温搅拌4h，加入氯仿(8ml)稀释。混合物倒入30ml冰水中，过滤，分出有机层，水层用氯仿(30ml×2)萃取，有机层依次快速用水(50ml)，饱和碳酸氢钠溶液(50ml×2)，饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，不高于30℃减压蒸除溶剂，剩余物以石油醚/乙酸乙酯(2：1)硅胶柱层析，真空干燥后得白色固体3.3g，收率63.2%。所得产物不稳定直接进行下一步反应。 In a three-necked flask, suspend red phosphorus (0.7g, 5.6mmol) in acetic acid (7.7ml), stir well, and slowly add liquid bromine (1.35ml, 26.1mmol) dropwise, controlling the temperature below 20°C. After the dropwise addition was completed, after stirring at room temperature for 30 min, 8-2 (5 g, 12.3 mmol) was added in batches. After the addition was complete, the mixture was stirred at room temperature for 4 h, and diluted by adding chloroform (8 ml). The mixture was poured into 30ml of ice water, filtered, and the organic layer was separated. The aqueous layer was extracted with chloroform (30ml×2), and the organic layer was rapidly washed with water (50ml), saturated sodium bicarbonate solution (50ml×2), and saturated sodium chloride solution. Washed and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure at no higher than 30°C. The residue was subjected to silica gel column chromatography with petroleum ether/ethyl acetate (2:1), and after vacuum drying, 3.3 g of a white solid was obtained, with a yield of 63.2%. The resulting product was unstable and directly proceeded to the next reaction. the

叠氮基-2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃半乳糖(10-2) Azido-2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-galactopyranose (10-2) 

将9-2(10g,0.024mol)溶于丙酮(100ml)，再将叠氮钠(3.16g,0.049mol)溶于水(25ml)所形成的溶液加入其中。混合物在常温下过夜搅拌反应。旋出丙酮，晶体析出，过滤，粗品以硅胶柱快速层析(石油醚/乙酸乙酯=2/1)，得白色晶体8.9g，收率99.4%。m.p.99-100℃。（文献值:m.p.99-100℃[有机化学2003,23(4):361-367]） 9-2 (10 g, 0.024 mol) was dissolved in acetone (100 ml), and a solution formed by dissolving sodium azide (3.16 g, 0.049 mol) in water (25 ml) was added thereto. The mixture was stirred and reacted overnight at room temperature. The acetone was spun out, the crystals were precipitated, filtered, and the crude product was flash chromatographed on a silica gel column (petroleum ether/ethyl acetate=2/1) to obtain 8.9 g of white crystals, with a yield of 99.4%. m.p.99-100°C. (Literature value: m.p.99-100℃[Organic Chemistry 2003,23(4):361-367]) 

2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃氨基半乳糖(G2-NH2) 2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-galactopyranosamine (G2 -NH2 )

将1c(1g,2.68mmol)溶于乙酸乙酯/甲醇(1:1,20ml)的混合溶剂中，加入10%Pd/C(0.1g)，常压室温下氢化至经TLC检测原料点消失。硅藻土助滤，旋干，真空干燥得白色泡沫状固体0.85g，收率91.3%。化合物不稳定直接进行下一步反应。 Dissolve 1c (1g, 2.68mmol) in a mixed solvent of ethyl acetate/methanol (1:1, 20ml), add 10%Pd/C (0.1g), and hydrogenate at room temperature until the starting point disappears as detected by TLC . Diatomaceous earth was used as a filter aid, spin-dried, and vacuum-dried to obtain 0.85 g of a white foamy solid, with a yield of 91.3%. The compound is unstable and proceeds directly to the next reaction. the

N-(2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃半乳糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺(I-5) N-(2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-galactopyranosyl)-4-(2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindoline-4-amino)-4-oxobutanamide (I-5) 

将G2-NH2(1.04g,3mmol)溶于DMF(10ml)。然后先后分批加入7-2(1.13g,3mmol),EDCI(0.58g,3mmol),HOBt(0.41g,3mmol)，室温搅拌24h。反应液加入二氯甲烷(100ml)，饱和食盐水洗(3×100ml)，干燥，抽滤，减压蒸除溶剂，硅胶柱层析(二氯甲烷/甲醇=60/1,40/1,20/1)，得类白色固体0.21g，收率9.2%，m.p.173-176℃; G2 -NH2 (1.04 g, 3 mmol) was dissolved in DMF (10 ml). Then 7-2 (1.13g, 3mmol), EDCI (0.58g, 3mmol), HOBt (0.41g, 3mmol) were added in batches successively, and stirred at room temperature for 24h. Add dichloromethane (100ml) to the reaction solution, wash with saturated brine (3×100ml), dry, filter with suction, evaporate the solvent under reduced pressure, perform silica gel column chromatography (dichloromethane/methanol=60/1,40/1,20 /1), 0.21g off-white solid was obtained, yield 9.2%, mp173-176°C;

1H-NMR(300MHz,CDCl3)δ(ppm):9.29(1H,d,J=15.6Hz,CONHCO),8.84(1H,d,J=12.3Hz,NH),7.85(1H,d,J=7.8Hz,aromatic),7.61(1H,d,J=7.2Hz,aromatic),7.40(1H,t,J=7.5Hz,aromatic),6.90～6.85(1H,m,NH),5.44(1H,s,H-4),5.31(1H,s,NCHCO),5.28～5.08(3H,m,H-1,H-2,and H-3),4.30～4.28(2H,m,PhCH2),4.09～4.06(3H,m,H-5,H-6a and H-6b),2.74～2.69(2H,m,CONHCH2CH2COOH),2.67～2.62(2H,m,CONHCH2CH2COOH),2.41(2H,s,CH2CH2COONH),2.14(2H,s,CH2CH2COONH),2.00(12H,s,4×OAc) 1 H-NMR (300MHz, CDCl3 ) δ (ppm): 9.29 (1H, d, J=15.6Hz, CONHCO), 8.84 (1H, d, J=12.3Hz, NH), 7.85 (1H, d, J =7.8Hz, aromatic),7.61(1H,d,J=7.2Hz,aromatic),7.40(1H,t,J=7.5Hz,aromatic),6.90～6.85(1H,m,NH),5.44(1H, s,H-4),5.31(1H,s,NCHCO),5.28～5.08(3H,m,H-1,H-2,and H-3),4.30～4.28(2H,m,PhCH2 ), 4.09～4.06(3H,m,H-5,H-6a and H-6b),2.74～2.69(2H,m,CONHCH2CH2 COOH),2.67～2.62(2H,m,CONHCH2 CH2 COOH),2.41(2H,s,CH2CH2 COONH),2.14(2H,s,CH2 CH2 COONH),2.00(12H,s,4×OAc )

IR(cm-1):3428(NH),2366,1748(C=O),1686(C=O),1531,1372,1232,1078,1048,913,754,597; IR(cm-1 ):3428(NH),2366,1748(C=O),1686(C=O),1531,1372,1232,1078,1048,913,754,597;

MS(ESI(+)70V,m/z):689.1[M+H]+; MS(ESI(+)70V,m/z):689.1[M+H]+ ;

MS(ESI(-)70V,m/z):723.3[M+Cl]-; MS(ESI(-)70V,m/z):723.3[M+Cl]- ;

Anal.Calcd for C31H36N4O14:C,54.07,H,5.27,N,8.14.Found:C,53.73,H,5.63,N,7.97. Anal.Calcd for C31 H36 N4 O14 :C,54.07,H,5.27,N,8.14.Found:C,53.73,H,5.63,N,7.97.

实施例4 Example 4

N-(2,3,4,6-四-O-乙酰基-1-脱氧-β-D-吡喃半乳糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺二水合物(I-6)的制备 N-(2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-galactopyranosyl)-5-(2-(2,6-dioxopiperidine-3 Preparation of -yl)-1-oxoisoindoline-4-amino)-5-oxopentamide dihydrate (I-6)

将G2-NH2(1.04g,3mmol)溶于DMF(10ml)。然后先后分批加入7-3(1.17g,3mmol),EDCI(0.58g,3mmol),HOBt(0.41g,3mmol)，室温搅拌24h。反应液加入二氯甲烷(100ml)，饱和食盐水洗(3×100ml)，干燥，抽滤，减压蒸除溶剂，硅胶柱层析(二氯甲烷/甲醇=60/1,40/1,20/1)，得类白色固体0.22g，收率10.4%，m.p.138-141℃; G2 -NH2 (1.04 g, 3 mmol) was dissolved in DMF (10 ml). Then 7-3 (1.17g, 3mmol), EDCI (0.58g, 3mmol), HOBt (0.41g, 3mmol) were added in batches successively, and stirred at room temperature for 24h. Add dichloromethane (100ml) to the reaction solution, wash with saturated brine (3×100ml), dry, filter with suction, evaporate the solvent under reduced pressure, perform silica gel column chromatography (dichloromethane/methanol=60/1,40/1,20 /1), 0.22g off-white solid was obtained, the yield was 10.4%, mp138-141°C;

1H-NMR(300MHz,CDCl3)δ(ppm):9.20(1H,d,J=12.9Hz,CONHCO),8.81(1H,d,J=16.5Hz, NH),7.81(1H,d,J=8.7Hz,aromatic),7.63(1H,d,J=7.5Hz,aromatic),7.45～7.40(1H,m,aromatic),6.85(1H,dd,J=22.8Hz,J=9.0Hz,NH),5.45(1H,d,J=2.4Hz,H-4),5.31(1H,m,NCHCO),5.14～5.08(3H,m,H-1,H-2,and H-3),4.37～4.29(2H,m,PhCH2),4.22～4.13(1H,m,H-5),4.07～4.02(2H,m,H-6a and H-6b),2.77(2H,s,CONHCH2CH2CH2COOH),2.47～2.45(2H,m,CONHCH2CH2CH2COOH),2.31～2.29(2H,m,CH2CH2COONH),2.22(2H,s,CH2CH2COONH),2.05,2.04,2.03,2.01(each3H,each s,4×OAc)2.01(2H,s,CONHCH2CH2CH2COOH); 1 H-NMR (300MHz, CDCl3 ) δ (ppm): 9.20 (1H, d, J=12.9Hz, CONHCO), 8.81 (1H, d, J=16.5Hz, NH), 7.81 (1H, d, J =8.7Hz, aromatic),7.63(1H,d,J=7.5Hz,aromatic),7.45～7.40(1H,m,aromatic),6.85(1H,dd,J=22.8Hz,J=9.0Hz,NH) ,5.45(1H,d,J=2.4Hz,H-4),5.31(1H,m,NCHCO),5.14～5.08(3H,m,H-1,H-2,and H-3),4.37～ 4.29(2H,m,PhCH2 ),4.22～4.13(1H,m,H-5),4.07～4.02(2H,m,H-6a and H-6b),2.77(2H,s,CONHCH2 CH2CH2 COOH), 2.47～2.45(2H,m,CONHCH2 CH2 CH2COOH ),2.31～2.29(2H,m,CH2CH2 COONH),2.22(2H,s,CH2 CH2 COONH),2.05,2.04,2.03,2.01(each3H,each s,4×OAc)2.01(2H,s,CONHCH2CH2 CH2 COOH);

IR(cm-1):3445(NH),2968,2366,1748(C=O),1685(C=O),1540,1428,1369,1232,1078,910,745,597; IR(cm-1 ):3445(NH),2968,2366,1748(C=O),1685(C=O),1540,1428,1369,1232,1078,910,745,597;

MS(ESI(-)70V,m/z):737.2[M+Cl]-; MS(ESI(-)70V,m/z):737.2[M+Cl]- ;

Anal.Calcd for C32H38N4O14·2H2O:C,52.03,H,5.73,N,7.58.Found:C,52.24,H,5.65,N,7.56. Anal.Calcd for C32 H38 N4 O14 2H2 O:C,52.03,H,5.73,N,7.58.Found:C,52.24,H,5.65,N,7.56.

实施例5 Example 5

N-(1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃葡萄糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺二水合物(I-8)的制备 N-(1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosyl)-4-(2-(2,6-dioxopiperidine-3- Preparation of -1-oxoisoindoline-4-amino)-4-oxobutyramide dihydrate (I-8)

2-亚苄基-1,3,4,6-四羟基-2-脱氧-β-D-吡喃氨基葡萄糖(11) 2-Benzylidene-1,3,4,6-tetrahydroxy-2-deoxy-β-D-glucopyranosamine (11) 

0℃下将1,3,4,6-四羟基-2-脱氧-D-吡喃氨基葡萄糖盐酸盐(50g,230mmol)加入到含有NaOH(11.0g,270mmol)的水溶液(47ml)中，搅拌下缓缓加入苯甲醛(27.0ml,265mmol)，很快析出白色固体，继续搅拌1h后停止反应，0℃下放置12h，过滤，依次用水、V(乙醚)：V(乙醇)＝4：1的混合溶剂洗涤，干燥得白色固体40.50g，不经纯化直接投下步反应。 1,3,4,6-tetrahydroxy-2-deoxy-D-glucopyranosamine hydrochloride (50g, 230mmol) was added to an aqueous solution (47ml) containing NaOH (11.0g, 270mmol) at 0°C, Slowly add benzaldehyde (27.0ml, 265mmol) under stirring, a white solid precipitates out quickly, stop the reaction after continuing to stir for 1h, place it at 0°C for 12h, filter, then water, V (ether): V (ethanol) = 4: 1 mixed solvent, and dried to obtain 40.50 g of white solid, which was directly put into the next reaction without purification. the

2-亚苄基-1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃氨基葡萄糖(12) 2-Benzylidene-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosamine (12) 

将含有中间体11的混合物(40.50g)加入到吡啶(283.2ml)中，冰水浴中搅拌下加入醋酸酐(142.9ml,1.57mol)，升温至35-40℃，保温6h，40-50℃下减压蒸出部分溶剂，将剩余反应液倒入冰水中，有白色固体析出，搅拌1h，过滤，依次用水、石油醚洗涤，干燥得白色固体52.27g，产率79.2%。m.p.153-154.5℃(文献值：m.p.158-160℃[合成化学,2003,11:379-380]) Add the mixture containing intermediate 11 (40.50g) into pyridine (283.2ml), add acetic anhydride (142.9ml, 1.57mol) under stirring in an ice-water bath, heat up to 35-40°C, keep warm for 6h, 40-50°C Part of the solvent was evaporated under reduced pressure, and the remaining reaction solution was poured into ice water. A white solid precipitated out, stirred for 1 h, filtered, washed with water and petroleum ether, and dried to obtain 52.27 g of a white solid, with a yield of 79.2%. m.p.153-154.5℃ (literature value: m.p.158-160℃[Synthetic Chemistry, 2003,11:379-380]) 

1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃氨基葡萄糖盐酸盐(G6-NH2.HCl) 1,3,4,6-Tetra-O-acetyl-2-deoxy-β-D-glucopyranosamine hydrochloride (G6 -NH2 .HCl)

将中间体12(52.27g,120mmol)加入到500mL丙酮中，室温搅拌下缓慢加入含浓HCl4.28g的乙醇溶液(52ml)，很快析出白色固体，反应1h后加入乙醚停止反应，冷却，0℃下保温1h，过滤，滤饼用乙醚洗涤，干燥得白色固体31.38g，产率68.1%。m.p.229℃（碳化）（文献值:m.p.230℃[US 4216208]. Intermediate 12 (52.27g, 120mmol) was added to 500mL of acetone, and an ethanol solution (52ml) containing 4.28g of concentrated HCl was slowly added under stirring at room temperature, and a white solid precipitated out quickly. After reacting for 1h, diethyl ether was added to stop the reaction, cooled, 0 It was kept at ℃ for 1 h, filtered, the filter cake was washed with ether, and dried to obtain 31.38 g of white solid, with a yield of 68.1%. m.p.229°C (carbonization) (literature value: m.p.230°C [US 4216208]. 

N-(1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃葡萄糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺二水合物(I-8) N-(1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosyl)-4-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-4-oxobutanamide dihydrate (I-8) 

将G6-NH2.HCl(1.15g,3mmol)溶于DMF(10ml)。缓慢滴加干燥的三乙胺(0.42ml,3mmol)。 然后先后分批加入7-2(1.13g,3mmol),EDCI(0.58g,3mmol),HOBt(0.41g,3mmol)，室温搅拌24h。反应液加入二氯甲烷(100ml)，饱和食盐水洗(3×100ml)，干燥，抽滤，减压蒸除溶剂，硅胶柱层析(二氯甲烷/甲醇=60/1,40/1,20/1)，得类白色固体0.33g，收率16.0%，m.p.161-162℃; G6 -NH2 .HCl (1.15 g, 3 mmol) was dissolved in DMF (10 ml). Dry triethylamine (0.42ml, 3mmol) was slowly added dropwise. Then 7-2 (1.13g, 3mmol), EDCI (0.58g, 3mmol), HOBt (0.41g, 3mmol) were added in batches successively, and stirred at room temperature for 24h. Add dichloromethane (100ml) to the reaction solution, wash with saturated brine (3×100ml), dry, filter with suction, evaporate the solvent under reduced pressure, perform silica gel column chromatography (dichloromethane/methanol=60/1,40/1,20 /1), 0.33g off-white solid was obtained, the yield was 16.0%, mp161-162°C;

1H-NMR(500MHz,CDCl3)δ(ppm):9.05(1H,d,J=36.2Hz,CONHCO),8.78(1H,brs,NH),7.80(1H,s,aromatic),7.66(1H,d,J=6.4Hz,aromatic),7.45(1H,m,aromatic),6.59(1H,brs,NH),5.84(1H,t,J=8.1Hz,H-1),5.31～5.26(1H,m,NCHCO),5.18(1H,m,H-3),5.08(1H,t,J=9.7Hz,H-4),4.37～4.25(3H,m,PhCH2and H-2),4.19～4.09(2H,m,H-6a and H-6b),3.86(1H,m,H-5),2.81(2H,m,CONHCH2CH2COOH),2.69(2H,m,CONHCH2CH2COOH),2.54(2H,m,CH2CH2COONH),2.17(2H,m,CH2CH2COONH),2.08,2.07,2.03,2.02(each3H,each s,4×OAc); 1 H-NMR (500MHz, CDCl3 ) δ (ppm): 9.05 (1H, d, J=36.2Hz, CONHCO), 8.78 (1H, brs, NH), 7.80 (1H, s, aromatic), 7.66 (1H ,d,J=6.4Hz,aromatic),7.45(1H,m,aromatic),6.59(1H,brs,NH),5.84(1H,t,J=8.1Hz,H-1),5.31～5.26(1H ,m,NCHCO),5.18(1H,m,H-3),5.08(1H,t,J=9.7Hz,H-4),4.37～4.25(3H,m,PhCH2 and H-2),4.19 ~4.09(2H,m,H-6a and H-6b),3.86(1H,m,H-5),2.81(2H,m,CONHCH2CH2 COOH),2.69(2H,m,CONHCH2 CH2 COOH),2.54(2H,m, CH2CH2 COONH),2.17(2H,m,CH2 CH2 COONH),2.08,2.07,2.03,2.02(each3H,each s,4×OAc) ;

IR(cm-1):3457(NH),2944,1749(C=O),1683(C=O),1539,1372,1233,1039,907,754,594; IR(cm-1 ):3457(NH),2944,1749(C=O),1683(C=O),1539,1372,1233,1039,907,754,594;

MS(ESI(-)70V,m/z):687.3[M-H]-; MS(ESI(-)70V,m/z):687.3[MH]- ;

Anal.Calcd for C31H36N4O14·2H2O:C,51.38,H,5.56,N,7.73.Found:C,51.75,H,5.35,N,7.78. Anal.Calcd for C31 H36 N4 O14 2H2 O:C,51.38,H,5.56,N,7.73.Found:C,51.75,H,5.35,N,7.78.

实施例6 Example 6

N-(1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃葡萄糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺二水合物(I-9) N-(1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosyl)-5-(2-(2,6-dioxopiperidine-3- Base)-1-oxoisoindoline-4-amino)-5-oxopentamide dihydrate (I-9) 

将G6-NH2.HCl(1.15g,3mmol)溶于DMF(10ml)。缓慢滴加干燥的三乙胺(0.42ml,3mmol)。然后先后分批加入7-3(1.17g,3mmol),EDCI(0.58g,3mmol),HOBt(0.41g,3mmol)，室温搅拌24h。反应液加入二氯甲烷(100ml)，饱和食盐水洗(3×100ml)，干燥，抽滤，减压蒸除溶剂，硅胶柱层析(二氯甲烷/甲醇=60/1,40/1,20/1)，得类白色固体0.40g，收率19.0%，m.p.153-154℃; G6 -NH2 .HCl (1.15 g, 3 mmol) was dissolved in DMF (10 ml). Dry triethylamine (0.42ml, 3mmol) was slowly added dropwise. Then 7-3 (1.17g, 3mmol), EDCI (0.58g, 3mmol), HOBt (0.41g, 3mmol) were added in batches successively, and stirred at room temperature for 24h. Add dichloromethane (100ml) to the reaction solution, wash with saturated brine (3×100ml), dry, filter with suction, evaporate the solvent under reduced pressure, perform silica gel column chromatography (dichloromethane/methanol=60/1,40/1,20 /1), 0.40g off-white solid was obtained, the yield was 19.0%, mp153-154°C;

1H-NMR(300MHz,CDCl3)δ(ppm):9.35(1H,d,J=15.0Hz,CONHCO),8.83(1H,d,J=30Hz,NH),7.91～7.72(1H,m,aromatic),7.62(1H,s,aromatic),7.48～7.38(1H,m,aromatic),6.79(1H,dd,J=30.0Hz,J=7.8Hz,NH),5.86(1H,dd,J=22.5Hz,J=8.4Hz,H-1),5.35～5.24(1H,m,NCHCO),5.14～5.09(2H,m,H-3and H-4),4.34～4.30(2H,m,PhCH2),4.26～4.23(2H,m,H-2and H-6a),4.16～4.08(1H,m,H-6b),3.90(1H,s,H-5),2.75(2H,m,CONHCH2CH2CH2COOH),2.38(2H,m,CONHCH2CH2CH2COOH),2.18(4H,m,CH2CH2COONH and CH2CH2COONH),2.09,2.09,2.04,2.04(each3H,each s,4×OAc),2.04(2H,s,CONHCH2CH2CH2COOH); 1 H-NMR (300MHz, CDCl3 ) δ (ppm): 9.35 (1H, d, J=15.0Hz, CONHCO), 8.83 (1H, d, J=30Hz, NH), 7.91～7.72 (1H, m, aromatic),7.62(1H,s,aromatic),7.48～7.38(1H,m,aromatic),6.79(1H,dd,J=30.0Hz,J=7.8Hz,NH),5.86(1H,dd,J= 22.5Hz, J=8.4Hz, H-1), 5.35～5.24(1H,m,NCHCO),5.14～5.09(2H,m,H-3and H-4),4.34～4.30(2H,m,PhCH2 ),4.26～4.23(2H,m,H-2and H-6a),4.16～4.08(1H,m,H-6b),3.90(1H,s,H-5),2.75(2H,m,CONHCH2 CH2 CH2 COOH), 2.38(2H,m,CONHCH2CH2 CH2 COOH),2.18(4H,m, CH2 CH2 COONH and CH2 CH2 COONH),2.09,2.09,2.04 ,2.04(each3H,eachs ,4×OAc), 2.04(2H ,s,CONHCH2CH2CH2COOH);

IR(cm-1):3404(NH),3074,2366,1752(C=O),1677(C=O),1541,1370,1230,1074,1040,754,600; IR(cm-1 ):3404(NH),3074,2366,1752(C=O),1677(C=O),1541,1370,1230,1074,1040,754,600;

MS(ESI(-)70V,m/z):701.3[M-H]-; MS(ESI(-)70V,m/z):701.3[MH]- ;

Anal.Calcd for C32H38N4O14·2H2O:C,52.03,H,5.73,N,7.58.Found:C,52.36,H,5.47,N,7.46. Anal.Calcd for C32 H38 N4 O14 2H2 O:C,52.03,H,5.73,N,7.58.Found:C,52.36,H,5.47,N,7.46.

实施例7 Example 7

N-(1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃半乳糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺一水合物(I-11)的制备 N-(1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranosyl)-4-(2-(2,6-dioxopiperidine-3 Preparation of -yl)-1-oxoisoindoline-4-amino)-4-oxobutyramide monohydrate (I-11)

2-亚苄基-1,3,4,6-四羟基-2-脱氧-β-D-吡喃氨基半乳糖(11-2) 2-Benzylidene-1,3,4,6-tetrahydroxy-2-deoxy-β-D-galactopyranosamine (11-2) 

0℃下将1,3,4,6-四羟基-2-脱氧-D-吡喃氨基半乳糖盐酸盐(10g,46mmol)加入到含有NaOH(2.2g,55mmol)的水溶液(47ml)中，机械搅拌下缓缓加入苯甲醛(5.4ml,53mmol)，很快析出白色固体，继续搅拌1h后停止反应，0℃下放置12h，过滤，依次用水、V(乙醚)：V(乙醇)＝4：1的混合溶剂洗涤，红外灯下干燥得白色固体混合物10g，未经纯化直接投下步反应。 1,3,4,6-Tetrahydroxy-2-deoxy-D-galactopyranose hydrochloride (10g, 46mmol) was added to an aqueous solution (47ml) containing NaOH (2.2g, 55mmol) at 0°C , slowly added benzaldehyde (5.4ml, 53mmol) under mechanical stirring, a white solid precipitated out quickly, continued to stir for 1h and then stopped the reaction, placed at 0°C for 12h, filtered, followed by water, V (ether): V (ethanol) = Washed with a 4:1 mixed solvent, and dried under infrared light to obtain 10 g of a white solid mixture, which was directly used for the next reaction without purification. the

2-亚苄基-1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃氨基半乳糖(12-2) 2-Benzylidene-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose (12-2)

将含有中间体11-2的混合物(5g)加入到吡啶(60ml)中，冰水浴中搅拌下加入醋酸酐(42mL,0.46mol)，升温至35℃～40℃，保温6h，将反应液倒入冰水(100ml)中机械搅拌1h，0℃静置过夜，有白色固体析出，过滤，依次用水、石油醚洗涤，阴凉处干燥得白色固体2.9g，未经纯化直接投下步反应。 Add the mixture (5g) containing intermediate 11-2 into pyridine (60ml), add acetic anhydride (42mL, 0.46mol) under stirring in an ice-water bath, heat up to 35°C-40°C, keep warm for 6h, pour the reaction solution Put it into ice water (100ml) and mechanically stir it for 1h, let it stand overnight at 0°C, a white solid precipitated, filtered, washed with water and petroleum ether in turn, and dried in a cool place to obtain 2.9g of white solid, which was directly put into the next reaction without purification. the

1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃氨基半乳糖盐酸盐(G7-NH2.HCl) 1,3,4,6-Tetra-O-acetyl-2-deoxy-β-D-galactopyranosamine hydrochloride (G7 -NH2 .HCl)

将含有中间体12-2的混合物2.9g加入到150mL丙酮中，滤液室温搅拌下缓慢加入含浓HCl2.9g的5mL乙醇溶液，很快析出白色固体，反应1h后加入乙醚停止反应，冷却，0℃下保温1h，过滤，滤饼用乙醚洗涤，红外灯下干燥得白色固体2.2g，产率85.9%。m.p.200-204℃（炭化）（文献值：m.p.204-206℃[Eur.J.Org.Chem.2006,657–671]） Add 2.9 g of the mixture containing intermediate 12-2 into 150 mL of acetone, and slowly add 5 mL of ethanol solution containing 2.9 g of concentrated HCl to the filtrate under stirring at room temperature, and a white solid precipitates out quickly. After reacting for 1 h, diethyl ether is added to stop the reaction, cooled, 0 Incubate at ℃ for 1 h, filter, wash the filter cake with ether, and dry under infrared light to obtain 2.2 g of white solid, with a yield of 85.9%. m.p.200-204°C (carbonization) (literature value: m.p.204-206°C [Eur.J.Org.Chem.2006,657–671])

N-(1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃半乳糖基)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-4-氧代丁酰胺一水合物(I-11) N-(1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranosyl)-4-(2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindoline-4-amino)-4-oxobutyramide monohydrate (I-11) 

将G7-NH2.HCl(1.15g,3mmol)溶于DMF(10ml)。缓慢滴加干燥的三乙胺(0.42ml,3mmol)。然后先后分批加入7-2(1.13g,3mmol),EDCI(0.58g,3mmol),HOBt(0.41g,3mmol)，室温搅拌24h。反应液加入二氯甲烷(100ml)，饱和食盐水洗(3×100ml)，干燥，抽滤，减压蒸除溶剂，硅胶柱层析(二氯甲烷/甲醇=60/1,40/1,20/1)，得类白色固体0.11g，收率5.3%，m.p.172-174℃; G7 -NH2 .HCl (1.15 g, 3 mmol) was dissolved in DMF (10 ml). Dry triethylamine (0.42ml, 3mmol) was slowly added dropwise. Then 7-2 (1.13g, 3mmol), EDCI (0.58g, 3mmol), HOBt (0.41g, 3mmol) were added in batches successively, and stirred at room temperature for 24h. Add dichloromethane (100ml) to the reaction solution, wash with saturated brine (3×100ml), dry, filter with suction, evaporate the solvent under reduced pressure, perform silica gel column chromatography (dichloromethane/methanol=60/1,40/1,20 /1), 0.11g off-white solid was obtained, yield 5.3%, mp172-174°C;

1H-NMR(300MHz,CDCl3)δ(ppm):9.29(1H,brs,CONHCO),8.78(1H,d,J=15.6Hz,CONH),7.76(1H,d,J=6.0Hz,aromatic),7.65(1H,d,J=7.2Hz,aromatic),7.43(1H,t,J=7.5Hz,aromatic),6.66(1H,brs,NH),5.91(1H,d,J=9.6Hz,NH),5.39～5.36(2H,m,H-4and H-3),5.30～5.30(1H,m,NCHCO),5.15(1H,d,J=11.1Hz,H-2),4.33～4.28(2H,m,PhCH2),4.25～4.12(3H,m,H-5,H-6aand H-6b),2.76～2.69(2H,m,CONHCH2CH2COOH),2.52(2H,s,CONHCH2CH2COOH),2.28(2H,m,CH2CH2COONH),2.18,2.04,1.96,1.90(each3H,each s,4×OAc),1.85(2H,s,CH2CH2COONH); 1 H-NMR (300MHz, CDCl3 ) δ (ppm): 9.29 (1H, brs, CONHCO), 8.78 (1H, d, J=15.6Hz, CONH), 7.76 (1H, d, J=6.0Hz, aromatic ),7.65(1H,d,J=7.2Hz,aromatic),7.43(1H,t,J=7.5Hz,aromatic),6.66(1H,brs,NH),5.91(1H,d,J=9.6Hz, NH),5.39～5.36(2H,m,H-4and H-3),5.30～5.30(1H,m,NCHCO),5.15(1H,d,J=11.1Hz,H-2),4.33～4.28( 2H,m,PhCH2 ),4.25～4.12(3H,m,H-5,H-6aand H-6b),2.76～2.69(2H,m,CONHCH2CH2 COOH),2.52(2H,s, CONHCH2 CH2 COOH),2.28(2H,m,CH2CH2 COONH),2.18,2.04,1.96,1.90(each3H,each s,4×OAc),1.85(2H,s,CH 2CH2COONH );

IR(cm-1):3363(NH),2926,1749(C=O),1685(C=O),1541,1428,1370,1230,1075,1043,757,603; IR(cm-1 ):3363(NH),2926,1749(C=O),1685(C=O),1541,1428,1370,1230,1075,1043,757,603;

MS(ESI(-)70V,m/z):723.2[M+Cl]-; MS(ESI(-)70V,m/z):723.2[M+Cl]- ;

Anal.Calcd for C31H36N4O14·H2O:C,52.69,H,5.42,N,7.93.Found:C,52.34,H,5.72,N,7.64. Anal.Calcd for C31 H36 N4 O14 ·H2 O:C,52.69,H,5.42,N,7.93.Found:C,52.34,H,5.72,N,7.64.

实施例8 Example 8

N-(1,3,4,6-四-O-乙酰基-2-脱氧-β-D-吡喃半乳糖基)-5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-胺基)-5-氧代戊酰胺二水合物(I-12)的制备 N-(1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranosyl)-5-(2-(2,6-dioxopiperidine-3 Preparation of -yl)-1-oxoisoindoline-4-amino)-5-oxopentamide dihydrate (I-12)

将G7-NH2.HCl(1.15g,3mmol)溶于DMF(10ml)。缓慢滴加干燥的三乙胺(0.42ml,3mmol)。然后先后分批加入7-3(1.17g,3mmol),EDCI(0.58g,3mmol),HOBt(0.41g,3mmol)，室温搅拌24h。反应液加入二氯甲烷(100ml)，饱和食盐水洗(3×100ml)，干燥，抽滤，减压蒸除溶剂，硅胶柱层析(二氯甲烷/甲醇=60/1,40/1,20/1)，得类白色固体0.40g，收率19.0%，m.p.166-169℃; G7 -NH2 .HCl (1.15 g, 3 mmol) was dissolved in DMF (10 ml). Dry triethylamine (0.42ml, 3mmol) was slowly added dropwise. Then 7-3 (1.17g, 3mmol), EDCI (0.58g, 3mmol), HOBt (0.41g, 3mmol) were added in batches successively, and stirred at room temperature for 24h. Add dichloromethane (100ml) to the reaction solution, wash with saturated brine (3×100ml), dry, filter with suction, evaporate the solvent under reduced pressure, perform silica gel column chromatography (dichloromethane/methanol=60/1,40/1,20 /1), 0.40g off-white solid was obtained, the yield was 19.0%, mp166-169°C;

1H-NMR(300MHz,CDCl3)δ(ppm):9.19(1H,brs,CONHCO),8.65(1H,d,J=14.4Hz,CONH),7.83(1H,dd,J=24.3Hz,J=7.5Hz,aromatic),7.64～7.62(1H,m,aromatic),7.43(1H,dd,J=16.5Hz,J=8.4Hz,aromatic),6.59(1H,brs,NH),5.87(1H,d,J=8.7Hz,NH),5.35(1H,s,H-4),5.30(1H,d,J=13.8Hz,H-3),5.24(1H,d,J=10.8Hz,NCHCO),5.16～5.08(1H,m,H-2),4.44～4.28(2H,m,PhCH2),4.19～4.13(3H,m,H-5,H-6a and H-6b overlapping),2.74(2H,s,CONHCH2CH2CH2COOH),2.39(2H,s,CONHCH2CH2CH2COOH),2.23～2.22(2H,m,CH2CH2COONH),2.18～2.13(2H,m,CH2CH2COONH),2.17,2.13,2.06,1.99(each3H,each s,4×OAc),1.91(2H,s,CONHCH2CH2CH2COOH); 1 H-NMR (300MHz, CDCl3 ) δ (ppm): 9.19 (1H, brs, CONHCO), 8.65 (1H, d, J=14.4Hz, CONH), 7.83 (1H, dd, J=24.3Hz, J =7.5Hz, aromatic),7.64～7.62(1H,m,aromatic),7.43(1H,dd,J=16.5Hz,J=8.4Hz,aromatic),6.59(1H,brs,NH),5.87(1H, d,J=8.7Hz,NH),5.35(1H,s,H-4),5.30(1H,d,J=13.8Hz,H-3),5.24(1H,d,J=10.8Hz,NCHCO) ,5.16～5.08(1H,m,H-2),4.44～4.28(2H,m,PhCH2 ),4.19～4.13(3H,m,H-5,H-6a and H-6b overlapping),2.74( 2H,s,CONHCH2 CH2CH2 COOH),2.39(2H,s,CONHCH2 CH2 CH2 COOH),2.23～2.22(2H,m,CH2CH2 COONH),2.18～2.13( 2H,m,CH2 CH2 COONH),2.17,2.13,2.06,1.99(each3H,each s,4×OAc),1.91(2H,s,CONHCH2CH2 CH2 COOH);

IR(cm-1):3440(NH),2944,1751(C=O),1749(C=O),1678(C=C),1540,1425,1371,1230,1074,1042,750,594; IR(cm-1 ):3440(NH),2944,1751(C=O),1749(C=O),1678(C=C),1540,1425,1371,1230,1074,1042,750,594;

MS(ESI(-)70V,m/z):737.3[M+Cl]-; MS(ESI(-)70V,m/z):737.3[M+Cl]- ;

Anal.Calcd for C32H38N4O14·2H2O:C,52.03,H,5.73,N,7.58.Found:C,52.05,H,5.51,N,7.53. Anal.Calcd for C32 H38 N4 O14 2H2 O:C,52.03,H,5.73,N,7.58.Found:C,52.05,H,5.51,N,7.53.

实施例9 Example 9

片剂 tablet

取实施例7中所得化合物0.5g，淀粉2g,糊精1g混合,用适量30%乙醇作湿润剂,制粒，压片。 Take 0.5 g of the compound obtained in Example 7, mix with 2 g of starch and 1 g of dextrin, use an appropriate amount of 30% ethanol as a wetting agent, granulate, and compress into tablets. the

Claims (7)

Translated fromChinese
1.通式（I）的化合物或其水合物：1. The compound of general formula (I) or its hydrate:其中G-NH-代表：Where G-NH- stands for:
Figure FDA0000366374830000012
Figure FDA0000366374830000012
Figure FDA0000366374830000021
Figure FDA0000366374830000021
其中n代表：2、3或4。where n stands for: 2, 3 or 4.2.权利要求1的化合物或其水合物，其中G-NH-代表：2. The compound of claim 1 or a hydrate thereof, wherein G-NH-represents:
Figure FDA0000366374830000022
Figure FDA0000366374830000022
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-represents:4.权利要求1至4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。4. The compound or hydrate thereof according to any one of claims 1 to 4, wherein the hydrate exists in the form of water of crystallization, and the molar equivalent of water of crystallization is 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 the compound according to any one of claims 1 to 3 or a hydrate thereof and a pharmaceutically acceptable carrier.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。6. Use of the compound according to any one of claims 1 to 3 or a hydrate thereof in the preparation of a medicament for treating angiogenic diseases.7.权利要求7的用途，其中血管生成性疾病是肿瘤或慢性炎症。7. The use according to claim 7, wherein the angiogenic disease is tumor or chronic inflammation.
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