WO2023016075A1 - 一种二氢-2h-异吲哚酯类化合物 - Google Patents

一种二氢-2h-异吲哚酯类化合物 Download PDF

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WO2023016075A1
WO2023016075A1 PCT/CN2022/097865 CN2022097865W WO2023016075A1 WO 2023016075 A1 WO2023016075 A1 WO 2023016075A1 CN 2022097865 W CN2022097865 W CN 2022097865W WO 2023016075 A1 WO2023016075 A1 WO 2023016075A1
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dihydro
isoindole
compound
ester compound
drug
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PCT/CN2022/097865
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French (fr)
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史命锋
郭晔堃
胡翔
黄杜坚
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上海贵之言医药科技有限公司
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Priority to KR1020247004292A priority Critical patent/KR20240046174A/ko
Priority to CA3227575A priority patent/CA3227575A1/en
Priority to AU2022327355A priority patent/AU2022327355A1/en
Publication of WO2023016075A1 publication Critical patent/WO2023016075A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • the invention belongs to the technical field of medicine, and in particular relates to a dihydro-2H-isoindole ester compound.
  • Multiple myeloma (multiple myeloma, MM) is a malignant tumor with poor prognosis, mainly in the elderly. It is caused by the massive proliferation of monoclonal plasma cells in the bone marrow, which leads to the severe decline or even failure of the bone marrow hematopoietic function in patients, and finally leads to multiple skeletal lesions in the body. destroy.
  • Chemotherapy is currently the main treatment for multiple myeloma.
  • the "Guidelines for the Diagnosis and Treatment of Multiple Myeloma in China (2020 Edition)” pointed out that the current induction therapy is mainly based on a three-drug combination regimen of proteasome inhibitors combined with immunomodulators and dexamethasone, and commonly used regimens include bortezomib/ Thalidomide/dexamethasone (BTD), lenalidomide/bortezomib/dexamethasone (RVD), thalidomide/cyclophosphamide/dexamethasone (TCD), etc.
  • BTD Thalidomide/dexamethasone
  • RVD lenalidomide/bortezomib/dexamethasone
  • TCD thalidomide/cyclophosphamide/dexamethasone
  • Thalidomide thalidomide
  • lenalidomide lenalidomide
  • pomalidomide pomalidomide
  • the known mechanisms of action of the above-mentioned immunomodulators include anti-tumor, anti-angiogenesis, erythropoiesis-stimulating, and immune-regulating properties. It is believed that they can attack the plasma cell microenvironment with multiple targets, induce apoptosis, and have immune-regulating and angiogenesis-inhibiting properties. dual role.
  • neutropenia and thrombocytopenia have emerged as major dose-limiting toxicities.
  • the first aspect of the present invention provides a dihydro-2H-isoindole ester compound, the structure of which is shown in the following general formula (I):
  • R is selected from: -CH(CH 3 ) 2 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH 2 CH(CH 3 ) 2 , -(CH 2 ) 5 CH 3 , -(CH 2 ) 7 CH 3 , -(CH 2 ) 10 CH 3 , -(CH 2 ) 17 CH 3 , -CH 2 CH(C 2 H 5 ) 2 , -CH(C 2 H 5 ) 2 , - CH(CH( CH3 ) 2 ) 2 , and -CH2Ph .
  • the second aspect of the present invention provides the preparation method of the dihydro-2H-isoindole ester compound:
  • R is selected from: -CH(CH 3 ) 2 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH 2 CH(CH 3 ) 2 , -(CH 2 ) 5 CH 3 , -(CH 2 ) 7 CH 3 , -(CH 2 ) 10 CH 3 , -(CH 2 ) 17 CH 3 , -CH 2 CH(C 2 H 5 ) 2 , -CH(C 2 H 5 ) 2 , - CH(CH(CH 3 ) 2 ) 2 , and -CH 2 Ph;
  • R' is H or nitro.
  • the third aspect of the present invention provides the use of the dihydro-2H-isoindole ester compound for preparing a drug for treating multiple myeloma.
  • the permeability of the dihydro-2H-isoindole ester compound of the present invention is better than that of the existing drugs. After oral administration, it can be absorbed stably and hydrolyzed into active metabolites, so as to continuously exert its medicinal effect. Due to the different absorption and metabolism behaviors, the pharmacokinetic properties of the compounds of the present invention are more suitable for clinical needs than existing drugs.
  • the AUC of the active metabolites of the dihydro-2H-isoindole ester compounds of the present invention is equivalent to about 40-60% of the amount of the same substance of the existing drug, but its advantage is that the peak time is up to 7h, The average residence time is 4 to 9 hours, both of which are better than 0.7 hours and 3 hours of existing drugs.
  • the AUC of the active metabolite of compound 1 is equivalent to 45% of the dosage of the same substance of the existing drug, the peak time is 0.8h, and the average residence time is 4.5h;
  • the AUC of the active metabolite of compound 3 is equivalent to that of the existing drug 40% of the dose of the same substance of the drug, the time to peak is 5h, and the average residence time is 5.6h;
  • the AUC of the active metabolite of compound 6 is equivalent to 61% of the dose of the same substance of the existing drug, and the time to peak is 5h. 7h, the average residence time is 8.6h.
  • the AUC of the active metabolite of compound 6 is equivalent to 61% of the amount of the same substance of the existing drug, the peak time is 7h, and the average residence time is 8.6h, and the peak time and average residence time are far better than the existing ones. drug.
  • the dihydro-2H-isoindole ester compounds of the present invention can provide more stable blood drug concentration and long-lasting action duration.
  • Figure 1 shows the drug-time curve of the control drug after intragastric administration to rats.
  • Figure 2 shows the drug-time curve of the active metabolite of compound 1 after intragastric administration to rats.
  • Figure 3 shows the drug-time curve of the active metabolite of compound 3 after intragastric administration to rats.
  • Figure 4 shows the drug-time curve of the active metabolite of compound 6 after intragastric administration to rats.
  • Plasma drug concentration refers to the total concentration of the drug in plasma after absorption, including the drug bound to plasma protein or free in plasma, and sometimes generally refers to the concentration of the drug in whole blood.
  • the strength of the drug's action is directly proportional to the concentration of the drug in the blood plasma, which varies with time in the body.
  • Peak time refers to the time after a single dose, the blood concentration reaches the peak value. At this time point, the blood concentration is the highest. Used to analyze reasonable medication time.
  • AUC is the abbreviation of the area under the plasma concentration-time curve. In the study of modern pharmacokinetics, AUC is an important parameter in the body of the drug. Calculate the bioavailability of a drug.
  • the terminal elimination half-life is the time required for the plasma concentration of a drug to decrease by 50% after reaching equilibrium of distribution.
  • distill 80g of tetrahydrofuran then add 50g of ethanol, beat at 70°C, cool down to 20-25°C, filter, and collect the filter cake; filter cake is again beaten with 50g of ethanol at 70°C, and then cooled to 20-25°C, Filter, collect the filter cake, and dry to obtain 12.0 g of the product, with a yield of 75%.
  • the preparation steps were the same as in Example 1, except that 15 g of raw materials were added, and a corresponding amount of isobutyl chloroformate was used instead of isopropyl chloroformate to obtain 14.9 g of the target compound with a yield of 71.6%.
  • Example 2 The preparation steps are the same as in Example 1, the difference is that 5eq. n-octanol and 7.5eq. triethylamine and 2.5eq. triphosgene are used to prepare the n-octyl chloroformate crude product, and the crude product directly replaces the isopropyl chloroformate in Example 1, After the reaction, column chromatography obtained 4.20 g of the target compound, with a yield of 52.4%.
  • Example 2 The preparation steps are the same as in Example 1, except that 5eq.2-ethylbutanol and 7.5eq.triethylamine and 2.5eq.triphosgene are used to prepare the crude product of 2-ethylbutanol chloroformate, which is directly substituted in Example 1
  • the isopropyl chloroformate was obtained by column chromatography after the reaction to obtain 3.9 g of the target compound, with a yield of 52.5%.
  • Embodiment 11 compound pharmacokinetic detection
  • Chromatographic conditions chromatographic column 2.1 x 50mm (1.7um, BEH C18, Waters), column temperature 45°C.
  • the mobile phase consists of 0.1% formic acid aqueous solution (A) and acetonitrile, and the gradient is shown in the following table:
  • Mass spectrometry conditions Positive ion multiple reaction monitoring (MRM) mode, Curtain Gas and Gas1, Gas2 are set to 45psi, ion source temperature 500 °C, ion source voltage 5000V, parent ion (Q1), product ion (Q3) and The collision energy (CE) is shown in the table below:
  • mice Male SD rats, 6 in each group, weighing 200-220 grams, fasted overnight before the experiment.
  • Drug preparation accurately weigh the control drug lenalidomide and each test compound (compound 1-10), and disperse in 0.5% CMC-Na solution to prepare a suspension.
  • Animal administration and blood collection intragastric administration of rats, 100 ⁇ l of blood was taken before administration and at 10min, 20min, 40min, 1h, 1.5h, 2h, 3h, 5h, 8h, 12h, 21h, 24h, and 30h after administration, Place on an ice bath, centrifuge to prepare plasma, and freeze.
  • the blood drug concentration data was processed by MultiQuan3.0 (Sciex), and the pharmacokinetic parameters were calculated using DAS 2.0 software for analysis, and the blood drug concentration unit was ug/L.
  • Figures 1 to 4 respectively show the relationship between blood concentration and time of the control group and compound 1, 3, and 6 test groups, and Table 2 shows the pharmacokinetic test results.
  • the compound of the present invention exerts drug effect in plasma after oral absorption, and the active metabolites of compounds 1, 3, 6, etc. are the same as existing drugs.
  • the AUC of the amount of substance administered is basically the same, but the peak value of the blood drug concentration of the compound of the present invention becomes smaller, the peak time is delayed, the average residence time is longer, and the pharmacokinetic characteristics are more suitable for clinical needs.

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Abstract

本发明公开了一种二氢-2H-异吲哚酯类化合物，其结构通式如（I）本发明还提供了所述二氢-2H-异吲哚酯类化合物的制备方法及其用于制备多发性骨髓瘤的药物的应用。本发明的二氢-2H-异吲哚酯类化合物的渗透性较好，口服吸收后平稳吸收并发挥药效。由于吸收代谢行为不同，本发明所述化合物的药代动力学特性较现有药物更适合临床需求。

Description

一种二氢-2H-异吲哚酯类化合物 技术领域
本发明属于医药技术领域，具体地说，是关于一种二氢-2H-异吲哚酯类化合物。
背景技术
多发性骨髓瘤(multiple myeloma，MM)多发于老年，是一种预后不佳的恶性肿瘤，为骨髓中单克隆浆细胞大量增生，引发患者骨髓造血功能严重下降甚至衰竭，最终导致机体多发性骨骼破坏。
化疗为现阶段多发性骨髓瘤的主要治疗手段。《中国多发性骨髓瘤诊断和治疗指南(2020年版)》中指出，目前诱导治疗多以蛋白酶体抑制剂联合免疫调节剂及***的3药联合方案为主，常用方案包括硼替佐米/沙利度胺/***(BTD)、来那度胺/硼替佐米/***(RVD)、沙利度胺/环磷酰胺/***(TCD)等。
沙利度胺(thalidomide)、来那度胺(lenalidomide)和泊马度胺(pomalidomide)是临床应用较多的免疫调节剂，在结构上均为二氢-2H-异吲哚连接哌啶二酮的骨架：
Figure PCTCN2022097865-appb-000001
上述免疫调节剂己知的作用机制包括抗肿瘤、抗血管生成、促红细胞生成和免疫调节等特性，被认为可多靶位攻击浆细胞微环境，使细胞凋亡，具有免疫调节和抑制血管生成的双重作用。
随着度胺类药物的研究不断深入，上述三药的适用范围也在不断扩大，逐渐成为泛癌种的抗肿瘤药物。
在使用过程中，血液学毒性(中性粒细胞减少和血小板减少)和静脉血栓(深静脉血栓和肺栓塞)是三个药物共有的不良反应。尤其是中性粒细胞减少和血小板减少已成为主要的剂量限制性毒性。
以来那度胺为例，临床研究显示所有接受50mg/day治疗的患者在第28天后均 出现3级骨髓抑制，降低剂量至25mg/day耐受较好，此剂量也被视为最大耐受剂量(MTD)。研究显示，严重骨髓抑制(3级或更高)与剂量有关，如出现中性粒细胞减少或血小板减少等骨髓抑制毒副作用时应下调剂量。
临床药代动力学研究显示，度胺类药物的吸收和代谢均较快，血药浓度变化幅度较大。较高的血药浓度峰值成为使用剂量的限制因素。
发明内容
有鉴于度胺类药物在实际使用中所存在的上述缺点和不足，本案发明人对结构做了一系列的改造，并对改造后的各化合物的药物动力学等进行了研究，并从中成功地找到了一类二氢-2H-异吲哚酯类化合物。
因此，本发明的第一个方面，提供了一种二氢-2H-异吲哚酯类化合物，其结构如以下通式(I)所示：
Figure PCTCN2022097865-appb-000002
其中，R选自：-CH(CH 3) 2，-(CH 2) 2CH 3，-(CH 2) 3CH 3，-CH 2CH(CH 3) 2，-(CH 2) 5CH 3，
Figure PCTCN2022097865-appb-000003
-(CH 2) 7CH 3，-(CH 2) 10CH 3，-(CH 2) 17CH 3，-CH 2CH(C 2H 5) 2，-CH(C 2H 5) 2，-CH(CH(CH 3) 2) 2，以及-CH 2Ph。
本发明的第二个方面，提供了所述二氢-2H-异吲哚酯类化合物的制备方法：
方法一、以可市售的3-(4-氨基-1-氧-1,3-二氢-2H-异吲哚-2-基)哌啶-2,6-二酮为原料，与相应的氯甲酸酯反应而得到目标化合物：
Figure PCTCN2022097865-appb-000004
或
方法二、同样的原料先与氯甲酸苯酯(或氯甲酸对硝基苯酯)反应得到苯酯(或 对硝基苯酯)化合物，再与相应的醇进行酯交换得到目标化合物：
Figure PCTCN2022097865-appb-000005
其中：
R选自：-CH(CH 3) 2，-(CH 2) 2CH 3，-(CH 2) 3CH 3，-CH 2CH(CH 3) 2，-(CH 2) 5CH 3，
Figure PCTCN2022097865-appb-000006
-(CH 2) 7CH 3，-(CH 2) 10CH 3，-(CH 2) 17CH 3，-CH 2CH(C 2H 5) 2，-CH(C 2H 5) 2，-CH(CH(CH 3) 2) 2，以及-CH 2Ph；
R’为H或硝基。
本发明的第三个方面，提供了所述二氢-2H-异吲哚酯类化合物用于制备治疗多发性骨髓瘤的药物的应用。
本发明具有以下有益效果：
1、本发明的二氢-2H-异吲哚酯类化合物的渗透性优于现有药物，口服吸收后平稳吸收并水解为活性代谢产物，持续发挥药效。由于吸收代谢行为不同，本发明所述化合物的药代动力学特性较现有药物更适合临床需求。
2、本发明的二氢-2H-异吲哚酯类化合物活性代谢产物的AUC相当于现有药物同物质的量给药的40-60％左右，但其优势在于达峰时间最高达7h，平均滞留时间达4～9h，均优于现有药物的0.7h和3h。
其中化合物1的活性代谢产物的AUC相当于现有药物同物质的量给药的45％，达峰时间为0.8h，平均滞留时间为4.5h；化合物3的活性代谢产物的AUC相当于现有药物同物质的量给药的40％，达峰时间为5h，平均滞留时间为5.6h；化合物6的活性代谢产物的AUC相当于现有药物同物质的量给药的61％，达峰时间为7h，平均滞留时间为8.6h。
其中化合物6的活性代谢产物的AUC相当于现有药物同物质的量给药的61％，达峰时间为7h，平均滞留时间为8.6h，达峰时间和平均滞留时间均远优于现有药物。
3、本发明的二氢-2H-异吲哚酯类化合物可提供更平稳的血药浓度和持久的作用时长。
附图说明
图1显示了对照药物大鼠灌胃给药后的药时曲线。
图2显示了化合物1大鼠灌胃给药后的活性代谢产物药时曲线。
图3显示了化合物3大鼠灌胃给药后的活性代谢产物药时曲线。
图4显示了化合物6大鼠灌胃给药后的活性代谢产物药时曲线。
具体实施方式
下面结合附图，以具体实施例对本发明的技术方案进行清楚、完整地描述。应理解，所描述的实施例仅是本发明的一部分实施例，而不是全部的实施例。基于本发明的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明的范围。
本发明的上下文中，所涉及的术语的定义如下：
血药浓度：血药浓度系指药物吸收后在血浆内的总浓度，包括与血浆蛋白结合的或在血浆游离的药物，有时也可泛指药物在全血中的浓度。药物作用的强度与药物在血浆中的浓度成正比，药物在体内的浓度随着时间而变化。
达峰时间：指单次服药以后，血药浓度达到峰值的时间。这个时间点，血药浓度最高。用来分析合理的服药时间。
AUC是血药浓度-时间曲线下的面积的简写，在现代药物动力学的研究中，AUC是药物体内的一个重要参数，该面积代表一次服药后某时间内的药物吸收总量，而且可用来计算药物的生物利用度。
终末消除半衰期是药物达到分布平衡后的血药浓度减少50％所需的时间。
本发明的上下文中，所涉及的结构通式(I)的化合物，其编号与R基的对应关系如以下表1所示：
表1
Figure PCTCN2022097865-appb-000007
Figure PCTCN2022097865-appb-000008
实施例1、化合物1的制备
在250ml三口瓶中加入3-(4-氨基-1-氧-1,3-二氢-2H-异吲哚-2-基)哌啶-2,6-二酮12g，然后加四氢呋喃100g，升温至回流；然后加入5.7g的氯甲酸异丙酯，回流状态反应4h；然后补加氯甲酸异丙酯3.6g，继续反应4h；再次补加氯甲酸异丙酯2.7g，反应4h；TLC监控至几乎无原料点时停止反应。
反应结束后，蒸馏出80g四氢呋喃，然后加入50g乙醇，于70℃打浆，降温至20～25℃过滤，收集滤饼；滤饼再次用50g乙醇于70℃打浆，然后降温至20～25℃，过滤，收集滤饼，烘干得到产品12.0g，收率75％。
1H NMR(300MHz,DMSO-d 6)δ11.01(s,1H),9.45(s,1H),7.76(dt,J＝7.4,3.7Hz,1H),7.54–7.42(m,2H),5.13(dd,J＝13.2,5.1Hz,1H),4.91(hept,J＝6.3Hz,1H),4.53–4.26(m,2H),2.92(ddd,J＝17.2,13.5,5.4Hz,1H),2.69–2.55(m,1H),2.36(qd,J＝13.2,4.4Hz,1H),2.03(ddd,J＝9.6,5.1,2.4Hz,1H),1.27(d,J＝6.2Hz,6H). 13C NMR(75MHz,DMSO-d 6)δ173.34,171.48,168.30,153.88,134.49,133.52,133.22,129.16,124.77,118.81,68.47,52.07,46.78,31.69,23.06,22.40。
质谱测得[M+H] +＝346.1，与分子式相符。
实施例2、化合物2的制备
制备步骤与实施例1相同，差别在于以氯甲酸丙酯替代氯甲酸异丙酯，得目标化 合物13.4g，收率83.6％。
1H NMR(300MHz,DMSO-d 6)δ11.01(s,1H),9.51(s,1H),7.76(dt,J＝7.4,3.7Hz,1H),7.56–7.43(m,2H),5.13(dd,J＝13.2,5.1Hz,1H),4.54–4.28(m,2H),4.06(t,J＝6.7Hz,2H),2.92(ddd,J＝18.1,13.4,5.3Hz,1H),2.74–2.55(m,1H),2.36(qd,J＝13.3,4.5Hz,1H),2.15–1.91(m,1H),1.65(q,J＝7.1Hz,2H). 13C NMR(75MHz,DMSO-d 6)δ173.33,171.48,168.28,154.39,134.42,133.56,133.23,129.20,124.79,118.89,66.57,52.06,46.75,31.68,23.07,22.34,10.72。
质谱测得[M+H] +＝346.1与分子式相符。
实施例3、化合物3的制备
制备步骤与实施例1相同，差别在于以氯甲酸丁酯替代氯甲酸异丙酯，得目标化合物12.0g，收率72.1％。
1H NMR(300MHz,DMSO-d 6)δ11.01(s,1H),9.50(s,1H),7.76(dt,J＝7.3,3.6Hz,1H),7.49(d,J＝3.0Hz,2H),5.13(dd,J＝13.2,5.1Hz,1H),4.56–4.23(m,2H),4.11(t,J＝6.6Hz,2H),2.92(ddd,J＝18.4,13.6,5.4Hz,1H),2.61(d,J＝16.9Hz,1H),2.35(qd,J＝13.1,4.3Hz,1H),2.03(dtd,J＝10.2,7.9,6.5,3.5Hz,1H),1.62(tt,J＝8.4,6.4Hz,2H),1.49–1.27(m,2H),0.92(t,J＝7.3Hz,3H). 13C NMR(75MHz,DMSO-d 6)δ173.33,171.48,168.29,154.39,134.44,133.52,133.23,129.18,124.74,118.87,64.77,52.07,46.76,31.69,31.02,23.09,19.07,14.04。
质谱测得[M+H] +＝360.1与分子式相符。
实施例4、化合物4的制备
制备步骤与实施例1相同，差别在于投入15g原料，并以相应量的氯甲酸异丁酯替代氯甲酸异丙酯，得目标化合物14.9g，收率71.6％。
1H NMR(300MHz,DMSO-d 6)δ11.01(s,1H),9.51(s,1H),7.77(dt,J＝7.4,3.7Hz,1H),7.56–7.42(m,2H),5.13(dd,J＝13.2,5.1Hz,1H),4.57–4.25(m,2H),3.90(d,J＝6.7Hz,2H),2.92(ddd,J＝18.1,13.4,5.4Hz,1H),2.61(d,J＝17.2Hz,1H),2.36(qd,J＝13.2,4.5Hz,1H),2.13–1.96(m,1H),1.94(dp,J＝13.4,6.8Hz,1H),0.94(d,J＝6.7Hz,6H). 13C NMR(75MHz,DMSO-d 6)δ173.33,171.49,168.28,154.42,134.42,133.56,133.23,129.20,124.80,118.90,70.96,52.05,46.73,31.69,28.03,23.08,19.36。
质谱测得[M+H] +＝360.1与分子式相符。
实施例5、化合物5的制备
制备步骤与实施例1相同，差别在于以氯甲酸正己酯替代氯甲酸异丙酯，得目标化合物11.0g，收率62.5％。
1H NMR(300MHz,DMSO-d 6)δ11.01(s,1H),9.50(s,1H),7.76(dt,J＝7.4,3.7Hz,1H),7.57–7.35(m,2H),5.13(dd,J＝13.2,5.1Hz,1H),4.55–4.25(m,2H),4.10(t,J＝6.6Hz,2H),2.92(ddd,J＝17.8,13.4,5.3Hz,1H),2.61(d,J＝17.6Hz,1H),2.35(qd,J＝13.2,4.4Hz,1H),2.03(dtd,J＝12.0,5.1,4.6,1.9Hz,1H),1.74–1.52(m,2H),1.46–1.20(m,6H),0.88(t,J＝6.8Hz,3H). 13C NMR(75MHz,DMSO-d 6)δ173.31,171.47,168.28,154.38,134.44,133.52,133.23,129.18,124.75,118.87,65.07,52.06,46.74,31.69,31.39,28.95,25.51,23.09,22.51,14.34。
质谱测得[M+H] +＝388.2与分子式相符。
实施例6、化合物6的制备
在1L单口瓶中加入3-(4-氨基-1-氧-1,3-二氢-2H-异吲哚-2-基)哌啶-2,6-二酮17g，氯甲酸对硝基苯酯19.8g，250mL四氢呋喃，于65℃加热搅拌3h，TLC监控原料反应完毕时，旋干，加入200mL乙酸乙酯打浆，过滤得到24g白色固体。
在500mL三口瓶中加入上步所得白色固体19g，4-(羟甲基)-5-甲基-[1,3]二氧杂环戊烯-2-酮9.7g，三乙胺7.6g和250mL DMF，于25℃搅拌24h，TLC监控原料反应完毕时，将反应液倒入冰水中，用1L乙酸乙酯萃取，无水硫酸钠干燥，旋干；柱层析石油醚:乙酸乙酯＝1:1～0:1，层析液浓缩得到油状物约7g，加正庚烷(200mL)打浆，过滤得到得目标化合物白色固体4.4g，纯度93.6％。
1H NMR(300MHz,DMSO-d 6)δ11.01(s,1H),9.78(s,1H),7.77(dt,J＝7.7,3.8Hz,1H),7.59–7.45(m,2H),5.13(dd,J＝13.2,5.1Hz,1H),5.05(s,2H),4.56–4.24(m,2H),2.92(ddd,J＝18.0,13.4,5.3Hz,1H),2.69–2.56(m,1H),2.34(qd,J＝13.2,4.4Hz,1H),2.20(s,3H),2.10–1.95(m,1H). 13C NMR(76MHz,DMSO-d 6)δ173.33,171.47,168.20,153.57,152.36,140.61,134.16,133.94,133.77,133.31,129.31,124.95,119.30,54.77,52.08,46.68,31.68,23.07,9.32。
质谱测得[M+H] +＝416.1，与分子式相符。
实施例7、化合物7的制备
制备步骤与实施例1相同，差别在于用5eq.正辛醇和7.5eq.三乙胺及2.5eq.三光气制备氯甲酸正辛酯粗品，粗品直接替代实施例1中的氯甲酸异丙酯，反应后柱层析得目标化合物4.20g，收率52.4％。
1H NMR(400MHz,DMSO-d 6)δ11.01(s,1H),9.51(s,1H),7.76(dt,J＝7.1,3.5Hz,1H),7.62–7.36(m,2H),5.12(dd,J＝13.2,5.1Hz,1H),4.40(dd,J＝36.2,17.6Hz,2H),4.19–4.01(m,2H),3.00–2.84(m,1H),2.66(dd,J＝36.3,20.1Hz,1H),2.35(qd,J＝13.2,4.4Hz,1H),2.07–1.94(m,1H),1.75–1.41(m,2H),1.31–1.26(m,10H),0.86(t,J＝6.8Hz,3H).
质谱测得[M+H] +＝416.23与分子式相符。
实施例8、化合物8的制备
制备步骤与实施例1相同，差别在于用5eq.正十一醇和7.5eq.三乙胺及2.5eq.三光气制备氯甲酸正十一醇酯粗品，粗品直接替代实施例1中的氯甲酸异丙酯，反应后柱层析得目标化合物5.6g，收率63.2％。
1H NMR(400MHz,DMSO-d 6)δ11.01(s,1H),9.49(s,1H),7.76(dt,J＝7.1,3.5Hz,1H),7.58–7.39(m,2H),5.12(dd,J＝13.3,5.1Hz,1H),4.39(q,J＝17.6Hz,2H),4.08(t,J＝6.6Hz,2H),3.00–2.83(m,1H),2.63(t,J＝16.4Hz,1H),2.34(qd,J＝13.2,4.4Hz,1H),2.02(ddd,J＝13.2,6.5,4.5Hz,1H),1.77–1.41(m,2H),1.40–1.15(m,16H),0.85(t,J＝6.8Hz,3H).
质谱测得[M+H] +＝458.29与分子式相符。
实施例9、化合物9的制备
制备步骤与实施例1相同，差别在于用5eq.正十八醇和7.5eq.三乙胺及2.5eq.三光气制备氯甲酸正十八醇酯粗品，粗品直接替代实施例1中的氯甲酸异丙酯，反应后柱层析得目标化合物6.4g，收率60.1％。
1H NMR(400MHz,DMSO-d 6)δ11.00(s,1H),9.49(s,1H),7.76(dd,J＝5.9,2.3Hz,1H),7.48(dd,J＝8.6,5.0Hz,2H),5.12(dd,J＝13.2,5.0Hz,1H),4.39(q,J＝17.6Hz,2H),4.08(t,J＝6.6Hz,2H),3.02–2.81(m,1H),2.60(d,J＝17.0Hz,1H),2.34(qd,J＝13.2,4.3Hz,1H),1.99(dd,J＝27.4,21.9Hz,1H),1.57(dt,J＝69.7,34.9Hz,2H),1.41–0.95(m,30H),0.85(t,J＝6.6Hz,3H).
质谱测得[M+H] +＝556.39与分子式相符。
实施例10、化合物10的制备
制备步骤与实施例1相同，差别在于用5eq.2-乙基丁醇和7.5eq.三乙胺及2.5eq.三光气制备氯甲酸2-乙基丁醇酯粗品，粗品直接替代实施例1中的氯甲酸异丙酯，反应后柱层析得目标化合物3.9g，收率52.5％。
1H NMR(400MHz,DMSO-d 6)δ11.01(s,1H),9.47(s,1H),7.75(dt,J＝33.1,16.5Hz,1H),7.61–7.27(m,2H),5.13(dd,J＝13.2,5.1Hz,1H),4.40(q,J＝17.6Hz,2H),4.03(d,J＝5.9Hz,2H),3.00–2.83(m,1H),2.61(d,J＝16.9Hz,1H),2.35(qd,J＝13.2,4.4Hz,1H),2.10–1.94(m,1H),1.58–1.47(m,1H),1.45–1.28(m,4H),0.88(t,J＝7.4Hz,6H).
质谱测得[M+H] +＝388.19与分子式相符。
实施例11、化合物药代动力学检测
仪器：超高压液相色谱(Acquity UPLC,Waters)、三重四极杆质谱(Qtrap 5500，Sciex)、高速冷冻离心机(5430R,Eppendorf)。
色谱条件：色谱柱2.1 x 50mm(1.7um，BEH C18，Waters)，柱温45℃。流动相由0.1％甲酸水溶液(A)和乙腈构成，梯度见下表：
Gradient Table      
Time Flow ％A ％B
initial 0.400 95.0 5.0
1.00 0.400 95.0 5.0
2.80 0.400 38.0 62.0
2.90 0.400 0.0 100.0
3.90 0.400 0.0 100.0
4.00 0.400 95.0 5.0
质谱条件：正离子多反应监测(MRM)模式，Curtain Gas及Gas1、Gas2均设为45psi，离子源温度500℃，离子源电压5000V，部分化合物的母离子(Q1)、子离子(Q3)及碰撞能量(CE)见下表：
  Q1 Mass(Da) Q3 Mass(Da) Time(msec) ID CE(volts)
1 260.100 149.100 100.0 Lenalidomide 20.000
2 388.200 277.200 100.0 化合物5 30.000
3 416.100 193.100 100.0 化合物6 25.000
4 274.100 84.000 100.0 IS 20.000
实验动物：雄性SD大鼠，每组6只，体重200-220克，实验前禁食过夜。
药物配制：精确称量对照药物来那度胺和各供试化合物(化合物1-10)，分散于0.5％CMC-Na溶液中制备成混悬液。
动物给药取血：大鼠灌胃给药，给药前及给药后10min，20min，40min，1h，1.5h，2h，3h，5h，8h，12h，21h、24h、30h取血100μl，置于冰浴上，离心制备血浆，冻存。
血药浓度数据及药代动力学参数计算：
血药浓度数据由MultiQuan3.0(Sciex)处理，药代动力学参数计算采用DAS 2.0软件进行分析，血药浓度单位为ug/L。
图1至图4分别显示了对照组以及化合物1、3、6测试组的血药浓度与时间的关系图，表2显示了药代动力学的试验结果。
由图1至图4以及表2的药代动力学试验结果可知，本发明的所述化合物口服吸收后在血浆中发挥药效，化合物1、3、6等的活性代谢产物与现有药物同物质的量给药的AUC基本相当，但本发明的化合物的血药浓度峰值变小、达峰时间延后、平均滞留时间更长，药代动力学特性更适合临床需求。
Figure PCTCN2022097865-appb-000009

Claims (6)

  1. 一种二氢-2H-异吲哚酯类化合物，其特征在于，所述化合物的结构通式如下：
    Figure PCTCN2022097865-appb-100001
    其中，R选自：-CH(CH 3) 2，-(CH 2) 2CH 3，-(CH 2) 3CH 3，-CH 2CH(CH 3) 2，-(CH 2) 5CH 3，
    Figure PCTCN2022097865-appb-100002
    -(CH 2) 7CH 3，-(CH 2) 10CH 3，-(CH 2) 17CH 3，-CH 2CH(C 2H 5) 2，-CH(C 2H 5) 2，-CH(CH(CH 3) 2) 2，以及-CH 2Ph。
  2. 根据权利要求1所述的二氢-2H-异吲哚酯类化合物，其特征在于，所述R选自：-CH(CH 3) 2、-(CH 2) 3CH 3、以及
    Figure PCTCN2022097865-appb-100003
  3. 根据权利要求2所述的二氢-2H-异吲哚酯类化合物，其特征在于，所述R为
    Figure PCTCN2022097865-appb-100004
  4. 权利要求1～3中任一项所述的二氢-2H-异吲哚酯类化合物的制备方法，其特征在于，所述方法以3-(4-氨基-1-氧-1,3-二氢-2H-异吲哚-2-基)哌啶-2,6-二酮为原料，与相应的氯甲酸酯反应而得到目标化合物，反应式如下：
    Figure PCTCN2022097865-appb-100005
    其中，R选自：-CH(CH 3) 2，-(CH 2) 2CH 3，-(CH 2) 3CH 3，-CH 2CH(CH 3) 2，-(CH 2) 5CH 3，
    Figure PCTCN2022097865-appb-100006
    -(CH 2) 7CH 3，-(CH 2) 10CH 3，-(CH 2) 17CH 3，-CH 2CH(C 2H 5) 2，-CH(C 2H 5) 2，-CH(CH(CH 3) 2) 2，以及-CH 2Ph。
  5. 权利要求1～3中任一项所述的二氢-2H-异吲哚酯类化合物的制备方法，其特征在于，所述方法以3-(4-氨基-1-氧-1,3-二氢-2H-异吲哚-2-基)哌啶-2,6-二酮为原料，先与氯甲酸苯酯(或氯甲酸对硝基苯酯)反应得到苯酯(或对硝基苯酯)化合物，再与相应的醇进行酯交换得到目标化合物，具体反应式如下：
    Figure PCTCN2022097865-appb-100007
    其中：
    R选自：-CH(CH 3) 2，-(CH 2) 2CH 3，-(CH 2) 3CH 3，-CH 2CH(CH 3) 2，-(CH 2) 5CH 3，
    Figure PCTCN2022097865-appb-100008
    -(CH 2) 7CH 3，-(CH 2) 10CH 3，-(CH 2) 17CH 3，-CH 2CH(C 2H 5) 2，-CH(C 2H 5) 2，-CH(CH(CH 3) 2) 2，以及-CH 2Ph；
    R’为H或硝基。
  6. 权利要求1～3中任一项所述的二氢-2H-异吲哚酯类化合物的应用，其特征在于，用于制备治疗多发性骨髓瘤的药物。
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CN103396397A (zh) * 2013-08-14 2013-11-20 中国人民解放军军事医学科学院毒物药物研究所 来那度胺衍生物及其作为药物的用途
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CN103396397A (zh) * 2013-08-14 2013-11-20 中国人民解放军军事医学科学院毒物药物研究所 来那度胺衍生物及其作为药物的用途
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