WO2023045411A1 - 一种吡唑并嘧啶酯类化合物 - Google Patents

一种吡唑并嘧啶酯类化合物 Download PDF

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WO2023045411A1
WO2023045411A1 PCT/CN2022/097873 CN2022097873W WO2023045411A1 WO 2023045411 A1 WO2023045411 A1 WO 2023045411A1 CN 2022097873 W CN2022097873 W CN 2022097873W WO 2023045411 A1 WO2023045411 A1 WO 2023045411A1
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compound
chloroformate
preparation
ester compound
solvent
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PCT/CN2022/097873
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French (fr)
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郭晔堃
黄杜坚
胡翔
史命锋
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上海贵之言医药科技有限公司
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Priority to KR1020247008585A priority Critical patent/KR20240067878A/ko
Priority to CA3230633A priority patent/CA3230633A1/en
Priority to AU2022350120A priority patent/AU2022350120A1/en
Publication of WO2023045411A1 publication Critical patent/WO2023045411A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

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  • the invention belongs to the technical field of medicine, and in particular relates to a pyrazolopyrimidine ester compound.
  • Lymphoma is a cancer of the blood that develops from lymphocytes, a subtype of blood cells produced in the bone marrow and found in blood and lymphoid tissues.
  • the two main types of lymphoma are Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL), with the latter accounting for 80% to 90%.
  • NHL includes a heterogeneous group of malignancies arising from lymphoid tissues, the most common subtypes in China are DLBCL (diffuse large B-cell lymphoma), CLL/SLL (chronic lymphocytic leukemia/small lymphocytic lymphoma) , FL (follicular lymphoma), MZL (lymph node marginal zone B-cell lymphoma) and MCL (mantle cell lymphoma), of which about 85% are B-cell lymphomas according to the origin of different lymphocytes.
  • DLBCL diffuse large B-cell lymphoma
  • CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma
  • FL follicular lymphoma
  • MZL lymph node marginal zone B-cell lymphoma
  • MCL mantle cell lymphoma
  • BTK (Bruton's tyrosine kinase, Bruton's tyrosine kinase) is a non-receptor, cytoplasmic tyrosine protein kinase in the Tec family, involved in the transduction of TLR, BAFF-R, BCR and CXCR4/5 signals , involved in regulating the proliferation, differentiation, apoptosis and migration of B cells.
  • BTK plays an important role in the pathogenesis of malignant B-cell lymphoma, and BTK inhibitors are important drugs for the treatment of B-cell lymphoma.
  • BTK inhibitors have been clearly confirmed in clinical trials that they have the curative effect on malignant B-cell lymphoma, the lymphoma with the highest incidence rate, which surpasses traditional chemotherapy.
  • BTK inhibitors include Ibrutinib, Acalabrutinib, Zanubrutinib, Tirabrutinib and Orelabrutinib, etc. Its structural formula is as follows respectively:
  • ibrutinib is the first BTK inhibitor to be marketed in the world. It has changed the treatment mode of CLL and MCL. It can be treated orally and obtain relatively durable remission.
  • the first aspect of the present invention provides a pyrazolopyrimidine ester compound, the structure of which is shown in general formula (I):
  • R is selected from -C 2 H 5 , -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 , -Bn, -(CH 2 ) 10 CH 3 , -(CH 2 ) 13 CH 3 , -CH(C 2 H 5 ) 2 , -CH(CH(CH 3 ) 2 ) 2 , - (CH 2 ) 7 CH 3 and -CH 2 CH(C 2 H 5 ) 2 .
  • the second aspect of the present invention provides the preparation method of the pyrazolopyrimidine ester compound:
  • R is selected from -C 2 H 5 , -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 ,-Bn,-(CH 2 ) 10 CH 3 ,-(CH 2 ) 13 CH 3 ,-CH(C 2 H 5 ) 2 ,-CH(CH(CH 3 ) 2 ) 2 ,- (CH 2 ) 7 CH 3 and -CH 2 CH(C 2 H 5 ) 2 .
  • the preparation method of the pyrazolopyrimidine ester compound adopts the following steps:
  • the preparation method of the pyrazolopyrimidine ester compound can also adopt the following steps:
  • the amount of base added is 6.0 ⁇ 0.5eq.
  • the amount of chloroformate added is 2.0 ⁇ 0.5eq.
  • the chloroformate is dissolved in a solvent and added to react at 0-10°C.
  • the pyrazolopyrimidine ester compound is obtained by separating and purifying after the reaction.
  • the third aspect of the present invention provides the application of the pyrazolopyrimidine ester compound for the preparation of drugs for the treatment of blood diseases such as lymphoma and lymphocytic leukemia.
  • the first-pass effect of the pyrazolopyrimidine ester compounds of the present invention is small, and after oral absorption, it quickly enters the plasma and is hydrolyzed into the active metabolite 1-[(3R)-3-[4-amino-3-(4- Phenoxyphenyl)-1H-pyrazolo[3,4-D]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one, which is hydrolyzed to the 4-amino active metabolite (4-AAM) exerts a drug effect, and the 4-amino active metabolite is an active substance generally recognized in clinical practice.
  • the compound of the present invention Compared with the 4-amino active metabolite, the compound of the present invention has a smaller peak blood concentration and a larger AUC due to different absorption and metabolism behaviors, and its pharmacokinetic properties are more suitable for clinical needs than existing BTK inhibitors .
  • compound 3 had the highest hydrolysis rate in plasma, and the AUC of 4-amino active metabolite was the highest, which was much higher than that of compound 3 itself.
  • the AUC of the pyrazolopyrimidine ester compound of the present invention is equivalent to 77%-180% of the amount of the same substance administered as the 4-amino active metabolite, and the peak time is up to 2h, and the average residence time is 2.5 -4.3h, which has obvious advantages over 4-amino active metabolites.
  • compound 3 has the highest hydrolysis rate, and the AUC and blood drug concentration of the 4-amino active metabolite are higher than that of compound 3 itself, and the AUC is equivalent to 180% of the direct administration of the same substance of the 4-amino active metabolite,
  • the peak time is 2h, and the average residence time is 2.9h;
  • the AUC of compound 1 is equivalent to 137% of the amount of the same substance administered as the 4-amino active metabolite, the peak time is 1h, and the average residence time is 2.8h;
  • the AUC of compound 4 It is equivalent to 127% of the amount of the same substance of the 4-amino active metabolite administered, the peak time is 2h, and the average residence time is 2.5h;
  • the AUC of compound 2 is equivalent to the amount of the same substance of the 4-amino active metabolite administered 88% of the drug, peak time 2h, average residence time 4.3h.
  • the pyrazolopyrimidine ester compounds of the present invention can provide higher bioavailability, more stable blood drug concentration and longer duration of action.
  • Figure 1 shows the drug-time curve of the 4-amino active metabolite after intragastric administration to rats
  • Figure 2 shows the drug-time curve of Compound 1 after intragastric administration to rats
  • Figure 3 shows the drug-time curve of Compound 2 after intragastric administration to rats
  • Figure 4 shows the drug-time curve of Compound 3 after intragastric administration to rats
  • Figure 5 shows the drug-time curve of compound 4 after intragastric administration to rats
  • Figure 6 shows the drug-time curve of Compound 5 after intragastric administration to rats.
  • Blood drug concentration refers to the total concentration of a drug in plasma after absorption, including the drug bound to plasma protein or free in plasma, and sometimes generally refers to the concentration of a 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 of the drug is the highest, which is used to analyze the reasonable time of taking the drug.
  • 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.
  • Elimination half-life refers to the time required for the blood drug concentration to decrease by 50% after the drug reaches distribution equilibrium.
  • First-pass effect Refers to the phenomenon that an oral drug is administered through the gastrointestinal tract, and before it is absorbed into the blood circulation, it is metabolized in the intestinal mucosa and liver, thereby reducing the amount of the original drug entering the blood circulation.
  • the preparation steps are the same as in Example 1, the difference is that 5eq. n-undecyl alcohol and 7.5eq. triethylamine and 2.5eq. triphosgene are used to prepare the n-undecyl chloroformate crude product, which directly replaces the chlorine Isopropyl formate, after the reaction, column chromatography obtained 1.38 g of the target compound, with a yield of 19.1%.
  • Example 2 The preparation steps are the same as in Example 1, except that 5eq.2,4-dimethyl-3-pentanol and 7.5eq.triethylamine and 2.5eq.triphosgene are used to prepare chloroformic acid-2,4-dimethyl-3 -Crude amyl alcohol ester, the crude product directly replaces the isopropyl chloroformate in Example 1, and after the reaction, column chromatography obtains 1.07 g of the target compound with a yield of 16.3%.
  • 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 0.57 g of the target compound with a yield of 8.4%.
  • the raw material is selected as butyl chloroformate, the main difference is that the order of addition of embodiment 3 is that the substrate and butyl chloroformate are first dissolved in the solvent, and then alkali is added dropwise to react, while the order of addition of the present embodiment After substrate and alkali are dissolved in solvent, butyl chloroformate is added dropwise to react.
  • the preparation steps of this comparative example are as follows:
  • reaction product included 0.97% of the residue of the raw material substrate and 1.31% of the double-substituted product, i.e. the product of the structure shown in formula (II), and the remainder was the target product compound 3.
  • the raw material is also selected as butyl chloroformate, and the order of addition is that after the substrate and alkali are dissolved in the solvent, butyl chloroformate is added dropwise to react.
  • the preparation steps of this comparative example are as follows:
  • the raw material is also selected as butyl chloroformate, and the order of addition is that after the substrate and alkali are first dissolved in the solvent, butyl chloroformate is added dropwise to react.
  • the preparation steps of this comparative example are as follows:
  • Raw material is selected as butyl chloroformate equally, and order of addition is after substrate and alkali are dissolved in solvent earlier, drips butyl chloroformate and reacts, and the preparation steps of this comparative example are specifically as follows:
  • reaction products included 53% of the target compound 3 and 32% of the disubstituted product, ie the product with the structure shown in formula (II).
  • the raw material is also selected as butyl chloroformate, and the order of addition is that after the substrate and alkali are first dissolved in the solvent, butyl chloroformate is added dropwise to react.
  • the preparation steps of this comparative example are as follows:
  • reaction products included 74.4% of the target compound 3 and 18.6% of the disubstituted product, ie the product with the structure shown in formula (II).
  • reaction conditions must be strictly controlled, including the addition ratio of base,
  • the addition ratio of chloroformate and the addition temperature of chloroformate when controlling the reaction with the conditions of Example 12, are conducive to generating the 4-amino monosubstituted target product; otherwise, it is easy to react to obtain 4-amino disubstituted impurities or cause The reaction of raw materials is not complete, and the target product of 4-amino monosubstituted cannot be obtained.
  • Embodiment 13 compound pharmacokinetic detection
  • Mass spectrometry conditions positive ion multiple reaction monitoring (MRM) mode, Curtain Gas, Gas1, Gas2 are set to 45psi, ion source temperature is 500°C, ion source voltage is 5000V.
  • MRM positive ion multiple reaction monitoring
  • mice Male SD rats, weighing 200-240 grams, fasted overnight before the experiment.
  • Drug preparation accurately weigh the 4-amino active metabolite and each test compound (compound 1 ⁇ 5), the dosage is 30.0mg/kg, disperse in 0.5% CMC-Na solution and prepare into suspension, give The drug volume is 2ml/200g, and it is prepared before administration.
  • Animal administration and blood collection intragastric administration of rats, before administration and after administration 10min, 20min, 40min, 1h, 1.5h, 4.5h, 7h, 9h, 10h, 22h, 24h to take blood 100ul, put on ice On the bath, centrifuge to prepare plasma, and freeze it.
  • 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.
  • Fig. 1-Fig. 6 respectively shows the blood drug concentration and time relationship diagram of 4-amino active metabolite and compound 1-5 test group, compound 1-5 enters plasma rapidly after absorbing and hydrolyzes to described 4-amino active metabolite
  • the drug (4-AAM) exerts its medicinal effect.
  • Table 4 shows the results of the pharmacokinetic test.
  • the compound of the present invention has a small first-pass effect, and exerts its drug effect in plasma after oral absorption, and compounds 1, 3, and 4 are administered in the same amount
  • the AUC of the compound is significantly higher than that of the 4-amino active metabolite, and the peak blood concentration of the compound of the present invention becomes smaller, the peak time is delayed, the average residence time is longer, and the pharmacokinetic properties are more suitable for clinical needs.
  • the hydrolysis rate of compound 3 is the highest, and the AUC and blood concentration of the 4-amino active metabolite are higher than that of compound 3 itself, and the AUC is equivalent to 180% of the direct administration of the same substance amount of the 4-amino active metabolite , peak time 2h, average residence time 2.9h;
  • the AUC of compound 1 is equivalent to 137% of the administration of the same substance of 4-amino active metabolite, the peak time is 1h, and the average residence time is 2.8h;
  • the AUC of compound 4 is equivalent to the administration of the same substance of 4-amino active metabolite. 127% of the drug, the peak time is 2 hours, and the average residence time is 2.5 hours;
  • the AUC of compound 2 is equivalent to 88% of the amount of 4-amino active metabolites administered, the peak time is 2 hours, and the average residence time is 4.3 hours.
  • the compound of the present invention can provide higher bioavailability, more stable blood drug concentration and longer duration of action, which are significantly improved compared with existing drugs.

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Abstract

本发明提供了一种吡唑并嘧啶酯类化合物，其结构如通式所示。本发明还提供了所述吡唑并嘧啶酯类化合物的制备方法及其用于制备治疗淋巴瘤和淋巴细胞白血病等血液疾病的药物的应用。本发明的吡唑并嘧啶酯类化合物的首过效应较小，口服吸收后迅速进入血浆并发挥药效，血药浓度峰值较平坦但AUC较大，可提供高的生物利用度、平稳的血药浓度和持久的作用时长，较现有的BTK抑制剂更适合临床需求。

Description

一种吡唑并嘧啶酯类化合物 技术领域
本发明属于医药技术领域，具体地说，是关于一种吡唑并嘧啶酯类化合物。
背景技术
淋巴瘤是从淋巴细胞发展而来的血液癌症，淋巴细胞是在骨髓中产生并在血液及淋巴组织中发现的一种亚型血液细胞。淋巴瘤的两种主要类型是霍奇金淋巴瘤(HL)及非霍奇金淋巴瘤(NHL)，其中后者占80％～90％。NHL包括由淋巴组织引起的一组异质性恶性肿瘤，在中国最常见的亚型为DLBCL(弥漫性大B细胞淋巴瘤)、CLL/SLL(慢性淋巴细胞白血病/小淋巴细胞性淋巴瘤)、FL(滤泡性淋巴瘤)、MZL(淋巴结边缘区B细胞淋巴瘤)及MCL(套细胞淋巴瘤)，其中根据不同的淋巴细胞起源，约85％为B细胞淋巴瘤。
BTK(布鲁顿酪氨酸激酶，Bruton's tyrosine kinase)是Tec家族中一种非受体类、细胞质中的酪氨酸蛋白激酶，参与TLR、BAFF-R、BCR以及CXCR4/5信号的转导，参与调控B细胞的增殖、分化、凋亡及迁移。BTK在恶性B细胞淋巴瘤的发病过程中具有重要作用，BTK抑制剂是B细胞淋巴瘤治疗的重要药物。
目前多种BTK抑制剂在临床试验中明确证实了其对于发病率最高的淋巴瘤——恶性B细胞淋巴瘤具有超越传统化疗的疗效。目前已上市的BTK抑制剂包括伊布替尼(Ibrutinib)、阿卡替尼(Acalabrutinib)、泽布替尼(Zanubrutinib)、替拉鲁替尼(Tirabrutinib)和奥布替尼(Orelabrutinib)等，其结构式分别如下所示：
Figure PCTCN2022097873-appb-000001
Figure PCTCN2022097873-appb-000002
其中伊布替尼是全球第一个上市的BTK抑制剂，它改变了CLL和MCL的治疗模式，可以口服进行治疗，并获得相对持久的缓解。
BTK抑制剂的长期疗效已得到证实，但仍存在一些不足。如口服吸收后首过效应明显，导致绝对生物利用度低；体内血药达峰时间和消除半衰期均较短，导致血药浓度波动大。
使用BTK抑制剂一旦出现出血、骨髓抑制等不良反应，必须调整剂量甚至终止治疗。由于其吸收、消除速度快，血药浓度波动大，其较高的血药浓度峰值成为使用剂量的限制因素，直接影响药物疗效。
发明内容
基于BTK抑制剂在实际使用中所存在的上述缺点和不足，本案发明人对现有BTK抑制剂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吡唑并嘧啶酯类化合物。
因此，本发明的第一个方面，提供了一种吡唑并嘧啶酯类化合物，其结构如通式(Ⅰ)所示：
Figure PCTCN2022097873-appb-000003
其中，R选自-C 2H 5，-CH(CH 3) 2，-(CH 2) 2CH 3，-(CH 2) 3CH 3，-CH 2CH(CH 3) 2，-(CH 2) 5CH 3，-Bn，-(CH 2) 10CH 3，-(CH 2) 13CH 3，-CH(C 2H 5) 2，-CH(CH(CH 3) 2) 2，-(CH 2) 7CH 3以及-CH 2CH(C 2H 5) 2。
本发明的第二个方面，提供了所述吡唑并嘧啶酯类化合物的制备方法：
以市售的1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮为原料，与相应的氯甲酸酯反应得到目标化合物：
Figure PCTCN2022097873-appb-000004
其中，R选自-C 2H 5，-CH(CH 3) 2，-(CH 2) 2CH 3，-(CH 2) 3CH 3，-CH 2CH(CH 3) 2，-(CH 2) 5CH 3，-Bn，-(CH 2) 10CH 3，-(CH 2) 13CH 3，-CH(C 2H 5) 2，-CH(CH(CH 3) 2) 2，-(CH 2) 7CH 3以及-CH 2CH(C 2H 5) 2。
进一步的，所述吡唑并嘧啶酯类化合物的制备方法采用如下步骤：
在反应器中加入原料1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮、氯甲酸酯和溶剂，原料和氯甲酸酯溶于溶剂后加入碱发生反应。
进一步的，所述吡唑并嘧啶酯类化合物的制备方法还可采用如下步骤：
在反应器中加入原料1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮、溶剂和碱，原料和碱溶于溶剂后加入氯甲酸酯发生反应；
其中，以原料为基准，碱的加入量为6.0±0.5eq.，氯甲酸酯的加入量为2.0±0.5eq.，氯甲酸酯溶于溶剂后于0-10℃加入反应。
进一步的，反应结束后通过后处理分离提纯，得到所述吡唑并嘧啶酯类化合物。
本发明的第三个方面，提供了所述吡唑并嘧啶酯类化合物用于制备治疗淋巴瘤和 淋巴细胞白血病等血液疾病的药物的应用。
本发明具有以下有益效果：
1、本发明的吡唑并嘧啶酯类化合物的首过效应较小，口服吸收后迅速进入血浆并水解为活性代谢物1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮，即水解为4-氨基活性代谢物(4-AAM)发挥药效，所述4-氨基活性代谢物是目前临床中普遍认可的活性物质。
与所述4-氨基活性代谢物相比，本发明所述化合物由于吸收代谢行为不同，血药浓度峰值变小且AUC更大，药代动力学特性较现有的BTK抑制剂更适合临床需求。其中化合物3在血浆中水解速率最高，4-氨基活性代谢物AUC最高，且远高于化合物3本身。
2、本发明的吡唑并嘧啶酯类化合物的AUC相当于所述4-氨基活性代谢物同物质的量给药的77％-180％，且达峰时间最高达2h，平均滞留时间达2.5-4.3h，较4-氨基活性代谢物均有明显的优势。
其中，化合物3水解速率最高，4-氨基活性代谢物的AUC和血药浓度均高于化合物3本身，且AUC相当于所述4-氨基活性代谢物同物质的量直接给药的180％，达峰时间2h，平均滞留时间2.9h；化合物1的AUC相当于所述4-氨基活性代谢物同物质的量给药的137％，达峰时间1h，平均滞留时间2.8h；化合物4的AUC相当于所述4-氨基活性代谢物同物质的量给药的127％，达峰时间2h，平均滞留时间2.5h；化合物2的AUC相当于所述4-氨基活性代谢物同物质的量给药的88％，达峰时间2h，平均滞留时间4.3h。
3、本发明的吡唑并嘧啶酯类化合物可提供更高的生物利用度、更平稳的血药浓度和更持久的作用时长。
附图说明
图1显示了4-氨基活性代谢物大鼠灌胃给药后的药时曲线；
图2显示了化合物1大鼠灌胃给药后的药时曲线；
图3显示了化合物2大鼠灌胃给药后的药时曲线；
图4显示了化合物3大鼠灌胃给药后的药时曲线；
图5显示了化合物4大鼠灌胃给药后的药时曲线；
图6显示了化合物5大鼠灌胃给药后的药时曲线。
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：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。
消除半衰期：指药物达到分布平衡后的血药浓度减少50％所需的时间。
首过效应：指内服药物经胃肠道给药，在尚未吸收进入血循环之前，在肠粘膜和肝脏被代谢，而使进入血循环的原形药量减少的现象。
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基的对应关系如表1所示：
表1
化合物编号 R基
1 -CH(CH 3) 2
2 -(CH 2) 2CH 3
3 -(CH 2) 3CH 3
4 -CH 2CH(CH 3) 2
5 -(CH 2) 5CH 3
6 -Bn
7 -(CH 2) 10CH 3
8 -(CH 2) 13CH 3
9 -CH(C 2H 5) 2
10 -CH(CH(CH 3) 2) 2
11 -(CH 2) 7CH 3
12 -C 2H 5
13 -CH 2CH(C 2H 5) 2
实施例1 化合物1的制备
在氮气保护下的500ml三口瓶中，加入底物(1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮)10g、溶剂(二氯甲烷)200g和氯甲酸异丙酯10g，底物和氯甲酸异丙酯溶于溶剂后，降温至10度，滴加碱(吡啶)6.45g，10-20分钟滴完，保温反应3-4小时，TLC监控至几乎无原料点时停止反应。
加入冰水100g，分液，水相通过50g二氯甲烷萃取，合并分液和萃取后的有机相，水洗，浓缩过柱得产品5.0g，收率41.9％。
1H NMR(400MHz,CDCl 3)δ8.78(s,1H),8.33(s,1H),7.76(d,J＝5.6Hz,2H),7.37–7.40(t,J＝5.2Hz,2H),7.15-7.18(m,3H),7.07-7.09(m,2H),6.54-6.65(m,1H),6.27-6.33(t,J＝12Hz,1H),5.66–5.74(dd,J＝25.2,6.8Hz,1H),4.82-4.86(m,1H),4.01-4.61(m,1H),3.19-3.82(m,1H),2.38-2.46(m,1H),2,27-2.29(m,1H),2.00-2.04(m,2H),1.74-1.76(m,1H),1.20-1.34(m,8H).
13C NMR(400MHz,CDCl 3)δ171.19,165.77,158.51,156.46,155.13,153.04,150.88,144.12,129.94(2C),129.70(2C),128.19,127.81,127.56,123.98,119.43(2C),119.03(2C),102.16,70.41,53.77,52.75,49.98,46.01,30.13(2C),25.31。
质谱测得[M+H] +＝527.3，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5.5g，收率46.1％。
1H NMR(400MHz,CDCl 3)δ8.77(s,1H),8.26(s,1H),7.60-7.67(m,2H),7.37–7.40(t,J＝5.2Hz,2H),7.15-7.19(m,3H),7.07-7.10(m,2H),6.54-6.65(m,1H),6.27-6.33(t,J＝12Hz,1H),5.66–5.74(dd,J＝26.4,6.8Hz,1H),4.89-4.91(m,1H),4.04-4.61(m,1H),3.20-3.82(m,1H),2.38-2.45(m,1H),2,27-2.29(m,1H),2.02-2.04(m,2H),1.74-1.76(m,1H),1.52-1.64(m,3H),1.26-1.46(m,1H),0.79-1.04(m,4H).
13C NMR(400MHz,CDCl 3)δ165.78,158.58,156.45 155.22,154.74,152.79,151.25, 143.97,129.95(2C),129.78(2C),128.21,127.55,124.01,119.42(2C),119.14,119.09(2C),102.01,53.79,52.79,49.99,45.92,42.20,25.30,23.88,14.20。
质谱测得[M+H] +＝527.3，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5.8g，收率47.3％。
1H NMR(400MHz,CDCl 3)δ8.77(s,1H),8.40(s,1H),7.64-7.66(m,2H),7.38–7.44(t,J＝5.2Hz,2H),7.16-7.19(m,3H),7.08-7.09(m,2H),6.54-6.65(m,1H),6.27-6.33(t,J＝12Hz,1H),5.66–5.74(dd,J＝26.0,6.4Hz,1H),4.89-4.90(m,1H),4.06-4.61(m,1H),3.19-3.81(m,1H),2.35-2.45(m,1H),2,27-2.29(m,1H),2.01-2.09(m,2H),1.74-1.76(m,1H),1.52-1.60(m,3H),1.14-1.38(m,3H),0.81-0.95(m,4H).
13C NMR(400MHz,CDCl 3)δ165.77,158.64,156.42,155.29,154.74,152.81,151.13,143.84,129.95(2C),129.81(2C),128.19,127.56,124.02,119.56,119.44(2C),119.12(2C),106.47,66.20,53.80,52.79,49.98,45.91,42.19,29.99,25.29,23.88。
质谱测得[M+H] +＝541.3，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，差别在于以氯甲酸异丁酯替代氯甲酸异丙酯，得目标化合物5.2g，收率42.4％。
1H NMR(400MHz,CDCl 3)δ8.78(s,1H),8.06(s,1H),7.76-7.77(d,J＝4.4Hz,2H),7.37–7.40(t,J＝5.2Hz,2H),7.15-7.18(m,3H),7.07-7.09(m,2H),6.54-6.65(m,1H),6.27-6.33(t,J＝12.6Hz,1H),5.66–5.74(dd,J＝26.0,6.4Hz,1H),4.89-4.91(m,1H),4.04-4.61(m,1H),3.20-3.80(m,1H),2.38-2.45(m,2H),2,27-2.29(m,1H),2.01-2.04(m,2H),1.88-1.92(m,2H),0.76-1.02(m,8H).
13C NMR(400MHz,CDCl 3)δ165.78,158.63,156.37,155.32,154.75,152.77,151.07,143.77,129.96(2C),129.85(2C),129.73,128.21,127.54,124.06,119.40(2C),119.06(2C),101.72,72.23,53.80,52.79,49.98,46.09,29.99(2C),25.29,23.87。
质谱测得[M+H] +＝541.3，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，差别在于以氯甲酸己酯替代氯甲酸异丙酯，得目标化合物4.8g，收率37.3％。
1H NMR(400MHz,CDCl 3)δ8.77(s,1H),8.11-8.13(d,J＝8.4Hz,1H),7.64-7.67(m,2H),7.37–7.40(t,J＝5.2Hz,2H),7.15-7.18(m,3H),7.07-7.09(m,2H),6.54-6.63(m,1H),6.27-6.33(t,J＝12.8Hz,1H),5.66–5.74(dd,J＝26.0,6.8Hz,1H),4.89-4.91(m,1H),4.01-4.61(m,1H),3.19-3.81(m,1H),2.35-2.45(m,1H),2,27-2.29(m,1H),2.01-2.03(m,2H),1.74-1.76(m,1H),1.50-1.59(m,3H),1.24-1.37(m,7H),0.84-0.90(m,4H).
13C NMR(400MHz,CDCl 3)δ165.79,158.56,156.47,155.27,154.75,152.79,151.19,143.78,129.94(2C),129.80(2C),128.21,127.54,124.00,119.56,119.37(2C),119.14(2C),101.93,66.51,53.80,52.79,49.98,45.92,42.20,32.77,30.26,29.98,23.88,14.20。
质谱测得[M+H] +＝569.3与分子式相符。
实施例6 化合物6的制备
制备步骤与实施例1相同，差别在于以氯甲酸苄酯替代氯甲酸异丙酯，得目标化合物6.5g，收率49.9％。
1H NMR(400MHz,CDCl 3)δ8.77(s,1H),7.85(s,1H),7.63-7.65(m,2H),7.34–7.38(m,7H),7.13-7.18(m,3H),7.06-7.07(d,J＝5.6Hz,2H),6.53-6.65(m,1H),6.27-6.33(t,J＝9.2Hz,1H),5.65–5.74(dd,J＝26.8,6.0Hz,1H),5.10(s,2H),4.88-4.90(m,1H),4.04-4.60(m,1H),3.19-3.80(m,1H),2.36-2.42(m,1H),2,26-2.28(m,1H),2.01-2.03(m,1H),1.70-1.75(m,3H).
13C NMR(400MHz,CDCl 3)δ165.77,158.69,156.35,154.72,152.54,150.72,143.62,135.14,129.99(2C),129.88(2C),128.75,128.65(2C),128.58,128.42(2C),128.22,127.54,124.09,124.06,119.50(2C),119.14(2C),101.75,67.87,53.82,45.84,42.19,30.28,25.29。
质谱测得[M+H] +＝575.3，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，所述粗品直接替代实施例1中的氯甲酸异丙酯，反应后柱层析得到目标化合物1.38g，收率19.1％。
1H NMR(400MHz,DMSO-d 6)δ11.48(s,1H),8.84(d,J＝10.4Hz,1H),7.82(d,J＝8.3Hz,2H),7.42–7.37(m,2H),7.15(t,J＝7.4Hz,1H),7.10(d,J＝8.7Hz,2H),7.07– 7.03(m,2H),6.76(ddd,J＝39.6,16.3,10.5Hz,1H),6.07(t,J＝15.7Hz,1H),5.63(dd,J＝32.5,10.3Hz,1H),4.45–4.01(m,5H),2.13–1.98(m,2H),1.86(d,J＝11.1Hz,1H),1.58(dd,J＝13.6,6.6Hz,2H),1.43(s,1H),1.24(dd,J＝24.6,8.0Hz,18H),0.81(dd,J＝9.0,4.6Hz,3H).
质谱测得[M+H] +＝639.39，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.正十四醇和7.5eq.三乙胺及2.5eq.三光气制备氯甲酸正十四醇酯粗品，粗品直接替代实施例1中的氯甲酸异丙酯，反应后柱层析得到目标化合物1.35g，收率17.5％。
1H NMR(600MHz,DMSO-d 6)δ11.47(s,1H),8.88–8.77(m,1H),7.81(d,J＝7.8Hz,2H),7.40–7.36(m,2H),7.14(t,J＝7.4Hz,1H),7.11–7.05(m,2H),7.05–7.01(m,2H),6.82–6.67(m,1H),6.05(dd,J＝23.3,17.2Hz,1H),5.61(dd,J＝49.7,10.5Hz,1H),4.44,4.00(d,J＝10.7Hz,1H),4.30(d,J＝10.5Hz,1H),4.19–4.05(m,3H),3.50,2.90(t,J＝11.0Hz,1H),3.12–3.05(m,1H),2.02–1.95(m,1H),1.85(d,J＝12.7Hz,1H),1.60–1.53(m,2H),1.28–1.16(m,24H),0.79(t,J＝6.9Hz,3H).
质谱测得[M+H] +＝681.23，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.3-戊醇和7.5eq.三乙胺及2.5eq.三光气制备氯甲酸3-戊醇酯粗品，粗品直接替代实施例1中的氯甲酸异丙酯，反应后柱层析得到目标化合物1.11g，收率17.1％。
1H NMR(600MHz,DMSO-d 6)δ11.44(s,1H),8.86–8.47(m,1H),7.82–7.32(m,5H),7.25–6.89(m,6H),6.74(ddd,J＝25.8,16.0,10.2Hz,1H),6.05(dd,J＝23.7,17.5Hz,1H),5.61(dd,J＝55.1,10.5Hz,1H),5.02–3.74(m,6H),1.79–1.29(m,8H),0.81(dt,J＝27.6,7.4Hz,6H).
质谱测得[M+H] +＝555.19，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.2,4-二甲基-3-戊醇和7.5eq.三乙胺及 2.5eq.三光气制备氯甲酸-2,4-二甲基-3-戊醇酯粗品，粗品直接替代实施例1中的氯甲酸异丙酯，反应后柱层析得到目标化合物1.07g，收率16.3％。
1H NMR(400MHz,DMSO-d 6)δ11.43(s,1H),8.88(d,J＝12.4Hz,1H),7.82(d,J＝8.3Hz,2H),7.42–7.37(m,2H),7.17–7.04(m,5H),6.86–6.68(m,1H),6.07(t,J＝15.8Hz,1H),5.69–5.54(m,1H),4.46(d,J＝5.3Hz,1H),4.37–4.30(m,1H),4.12(d,J＝14.2Hz,1H),3.99(dd,J＝14.2,7.1Hz,1H),2.07(dd,J＝13.2,10.0Hz,2H),1.96–1.82(m,4H),1.44(s,1H),1.26–1.12(m,1H),0.85(d,J＝6.4Hz,12H).
质谱测得[M+H] +＝583.32，与分子式相符。
实施例11 化合物11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，反应后柱层析得到目标化合物0.57g，收率8.4％。
1H NMR(600MHz,DMSO-d 6)δ11.49(s,1H),8.84(d,J＝17.2Hz,1H),7.83(d,J＝7.6Hz,2H),7.40(dd,J＝8.2,7.7Hz,2H),7.16(t,J＝7.4Hz,1H),7.11(t,J＝9.6Hz,2H),7.05(t,J＝6.6Hz,2H),6.84–6.69(m,1H),6.08(dt,J＝22.5,11.3Hz,1H),5.64(dd,J＝49.0,10.3Hz,1H),4.38(d,J＝85.6Hz,1H),4.21–3.95(m,4H),3.52,2.92(t,J＝11.2Hz,1H),3.11(dd,J＝22.3,11.0Hz,1H),2.10–1.85(m,4H),1.65–1.56(m,2H),1.27–1.20(m,10H),0.83(t,J＝6.8Hz,3H).
质谱测得[M+H] +＝597.35，[M+Na] +＝619.33，与分子式相符。
实施例12 化合物3的制备
与实施例3相同，原料选取为氯甲酸丁酯，主要区别在于实施例3的加料顺序为底物和氯甲酸丁酯先溶于溶剂后，滴加碱发生反应，而本实施例的加料顺序为底物和碱溶于溶剂后，滴加氯甲酸丁酯发生反应，本对比例的制备步骤具体如下：
在反应瓶中加入底物(1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮)0.5g、溶剂(二氯甲烷)7.5mL和6.0eq碱(吡啶)，底物和碱溶于溶剂后，将2.0eq氯甲酸丁酯溶于溶剂(二氯甲烷)1mL中于0-10℃缓慢滴加至反应瓶中，升温至10-20℃搅拌后取样检测。
通过HPLC分析显示反应产物中包括0.97％的原料底物的剩余和1.31％的双取代 产物，即结构如式(Ⅱ)所示的产物，剩余部分为目标产物化合物3。
Figure PCTCN2022097873-appb-000005
对比例1
原料同样选取为氯甲酸丁酯，加料顺序为底物和碱溶于溶剂后，滴加氯甲酸丁酯发生反应，本对比例的制备步骤具体如下：
在氮气保护下的500ml三口瓶中，加入底物(1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮)10g、溶剂(二氯甲烷)200g和3.6eq碱(吡啶)，即吡啶6.45g，底物和碱溶于溶剂后，于25℃滴加3.2eq氯甲酸丁酯，即氯甲酸丁酯10g，滴完后于室温反应3-4小时。
通过TLC监控显示反应3-4小时后的主要产物为双取代产物，即结构如式(Ⅱ)所示的产物，且部分起始物料未反应完。
对比例2
原料同样选取为氯甲酸丁酯，加料顺序为底物和碱先溶于溶剂后，滴加氯甲酸丁酯发生反应，本对比例的制备步骤具体如下：
在反应瓶中加入底物(1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮)0.5g、溶剂(二氯甲烷)5mL和2.0eq碱(三乙胺)，于0-10℃缓慢滴加2.0eq氯甲酸丁酯，搅拌2h后取样检测。
通过HPLC分析显示仍有大量原料剩余。
对比例3
原料同样选取为氯甲酸丁酯，加料顺序为底物和碱先溶于溶剂后，滴加氯甲酸丁 酯发生反应，本对比例的制备步骤具体如下：
在反应瓶中加入底物(1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮)0.5g、溶剂(四氢呋喃)7.5mL和5.0eq碱(吡啶)，将6.0eq氯甲酸丁酯溶于溶剂(四氢呋喃)1mL中并于0-10℃缓慢滴加至反应瓶中，升温至10-20℃搅拌后取样检测。
通过HPLC分析显示反应产物中，包括53％目标产物化合物3，和32％双取代产物，即结构如式(Ⅱ)所示的产物。
对比例4
原料同样选取为氯甲酸丁酯，加料顺序为底物和碱先溶于溶剂后，滴加氯甲酸丁酯发生反应，本对比例的制备步骤具体如下：
在反应瓶中加入底物(1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮)0.5g、溶剂(二氯甲烷)7.5mL和6.0eq碱(吡啶)，将3.0eq氯甲酸丁酯溶于溶剂(二氯甲烷)1mL中并于0-10℃缓慢滴加至反应瓶中，升温至10-20℃搅拌后取样检测。
通过HPLC分析显示反应产物中，包括74.4％目标产物化合物3，和18.6％双取代产物，即结构如式(Ⅱ)所示的产物。
根据上述实施例12和对比例1-4分析可得，采用底物和碱先溶于溶剂后，再滴加氯甲酸丁酯的加料方式时，须严格控制反应条件，包括碱的加入比例、氯甲酸酯的加入比例和氯甲酸酯的加入温度，以实施例12条件控制反应时，有利于生成4-氨基单取代的目标产物；否则易反应得到4-氨基双取代的杂质或导致原料反应不完全，无法得到4-氨基单取代的目标产物。
根据对比例1结果，对所述碱和氯甲酸酯的加入比例、氯甲酸酯的加入温度控制不当时，无法生成单取代目标产物；
根据对比例2结果，对所述碱的加入比例控制不当时，导致取代反应难以发生；
根据对比例3、4结果，对所述碱和氯甲酸酯的加入比例控制不当时，极易生成相当比例的双取代杂质，使得单取代的目标产物的含量大大降低。
实施例13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Waters BEH C18 2.1x 50mm，1.7μm，柱温45℃。流动相由0.1％甲酸水溶液(A)和乙腈构成，梯度见表2所示：
表2
Gradient Table      
Time Flow Rate ％A ％B
initial 0.400 70.0 30.0
3.00 0.400 0.0 100.0
3.50 0.400 0.0 100.0
4.00 0.400 0.0 100.0
4.10 0.400 70.0 30.0
5.10 0.400 70.0 30.0
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。
各化合物的母离子(Q1)、子离子(Q3)及碰撞能量(CE)见表3：
表3
  ID Q1 Mass(Da) Q3 Mass(Da) Time(msec) CE(volts)
1 4-AAM 441.200 304.100 100.0 40.000
2 1 527.200 441.200 100.0 35.000
3 2 527.200 441.200 100.0 35.000
4 3 541.300 441.200 100.0 40.000
5 4 541.300 441.200 100.0 40.000
6 5 569.300 441.200 100.0 40.000
7 IS 570.300 138.100 100.0 35.000
实验动物：雄性SD大鼠，体重200-240克，实验前禁食过夜。
药物配制：精确称量所述4-氨基活性代谢物及各供试化合物(化合物1～5)，给药剂量30.0mg/kg，分散于0.5％CMC-Na溶液中制备成混悬液，给药体积2ml/200g，给药前配制。
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，4.5h，7h，9h，10h、22h、24h取血100ul，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-图6分别显示了4-氨基活性代谢物以及化合物1-5测试组的血药浓度与时间的关系图，化合物1-5吸收后迅速进入血浆并水解为所述4-氨基活性代谢物(4-AAM)发挥药效。表4显示了药代动力学的试验结果。
表4
参数 单位 4-AAM 化合物1 化合物2 化合物3 化合物4 化合物5
AUC(0-t) ug/L*h 757.5 1038.6 663.0 1366.7 964.1 584.0
AUC(0-∞) ug/L*h 822.2 1059.6 706.3 1375.6 976.4 587.1
AUMC(0-t)   1316.6 2950.4 2844.3 3939.9 2405.5 1659.5
AUMC(0-∞)   2805.6 3200.9 3495.04 4052.0 2586.7 1696.7
MRT(0-t) h 1.7 2.8 4.29 2.9 2.5 2.8
MRT(0-∞) h 3.4 3.0 4.9 2.9 2.6 2.9
VRT(0-t) h^2 2.0 4.6 7.2 3.3 2.9 3.0
VRT(0-∞) h^2 47.6 6.3 13.5 3.8 4.8 3.5
t1/2z h 8.9 1.7 2.338 1.3 2.5 1.3
Tmax h 1.5 1.0 2.0 2.0 2.0 2.0
CLz/F L/h/kg 36.5 28.3 42.5 21.8 30.7 51.1
Vz/F L/kg 470.6 71.3 143.3 42.0 109.1 92.6
Cmax ug/L 312.0 257.2 111.0 304.4 256.7 143.9
由图1-6以及表4的药代动力学试验结果可知，本发明所述的化合物首过效应小，口服吸收后在血浆中发挥药效，化合物1、3、4同物质的量给药的AUC显著高于4-氨基活性代谢物，且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。
其中，化合物3的水解速率最高，4-氨基活性代谢物的AUC和血药浓度均高于化合物3本身，且AUC相当于所述4-氨基活性代谢物同物质的量直接给药的180％，达峰时间2h，平均滞留时间2.9h；
化合物1的AUC相当于4-氨基活性代谢物同物质的量给药的137％，达峰时间1h，平均滞留时间2.8h；化合物4的AUC相当于4-氨基活性代谢物同物质的量给药 的127％，达峰时间2h，平均滞留时间2.5h；化合物2的AUC相当于4-氨基活性代谢物同物质的量给药的88％，达峰时间2h，平均滞留时间4.3h。
本发明所述化合物可提供更高的生物利用度、更平稳的血药浓度和更持久的作用时长，较现有药物均有明显的改善。

Claims (9)

  1. 一种吡唑并嘧啶酯类化合物，其特征在于，所述化合物的结构通式如下：
    Figure PCTCN2022097873-appb-100001
    其中，R选自-C 2H 5，-CH(CH 3) 2，-(CH 2) 2CH 3，-(CH 2) 3CH 3，-CH 2CH(CH 3) 2，-(CH 2) 5CH 3，-Bn，-(CH 2) 10CH 3，-(CH 2) 13CH 3，-CH(C 2H 5) 2，-CH(CH(CH 3) 2) 2，-(CH 2) 7CH 3以及-CH 2CH(C 2H 5) 2。
  2. 根据权利要求1所述的吡唑并嘧啶酯类化合物，其特征在于，所述R选自：-CH(CH 3) 2，-(CH 2) 2CH 3，-(CH 2) 3CH 3，-CH 2CH(CH 3) 2以及-(CH 2) 5CH 3。
  3. 根据权利要求2所述的吡唑并嘧啶酯类化合物，其特征在于，所述R选自：-(CH 2) 3CH 3。
  4. 根据权利要求2所述的吡唑并嘧啶酯类化合物，其特征在于，所述R选自：-(CH 2) 2CH 3。
  5. 根据权利要求2所述的吡唑并嘧啶酯类化合物，其特征在于，所述R选自：-CH(CH 3) 2和-CH 2CH(CH 3) 2。
  6. 权利要求1-5中任一项所述的吡唑并嘧啶酯类化合物的制备方法，其特征在于，所述方法以1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮为原料，与相应的氯甲酸酯反应得到目标化合物，反应式如下：
    Figure PCTCN2022097873-appb-100002
    其中，R选自-C 2H 5，-CH(CH 3) 2，-(CH 2) 2CH 3，-(CH 2) 3CH 3，-CH 2CH(CH 3) 2，-(CH 2) 5CH 3，-Bn，-(CH 2) 10CH 3，-(CH 2) 13CH 3，-CH(C 2H 5) 2，-CH(CH(CH 3) 2) 2，-(CH 2) 7CH 3以及-CH 2CH(C 2H 5) 2。
  7. 根据权利要求6所述的制备方法，其特征在于，所述制备方法包括如下步骤：
    在反应器中加入原料1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮、氯甲酸酯和溶剂，原料和氯甲酸酯溶于溶剂后加入碱发生反应。
  8. 根据权利要求6所述的制备方法，其特征在于，所述制备方法包括如下步骤：
    在反应器中加入原料1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮、溶剂和碱，原料和碱溶于溶剂后加入氯甲酸酯发生反应；
    其中，以原料为基准，碱的加入量为6.0±0.5eq.，氯甲酸酯的加入量为2.0±0.5eq.，氯甲酸酯溶于溶剂后于0-10℃加入反应。
  9. 权利要求1-5中任一项所述的吡唑并嘧啶酯类化合物的应用，其特征在于，用于制备治疗淋巴瘤和淋巴细胞白血病的药物。
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