WO2022000946A1 - 含有酞嗪-1(2h)-酮结构的parp抑制剂、其制法及医药用途 - Google Patents

含有酞嗪-1(2h)-酮结构的parp抑制剂、其制法及医药用途 Download PDF

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WO2022000946A1
WO2022000946A1 PCT/CN2020/130061 CN2020130061W WO2022000946A1 WO 2022000946 A1 WO2022000946 A1 WO 2022000946A1 CN 2020130061 W CN2020130061 W CN 2020130061W WO 2022000946 A1 WO2022000946 A1 WO 2022000946A1
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acid
compound
pharmaceutically acceptable
acceptable salt
general formula
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PCT/CN2020/130061
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French (fr)
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朱启华
张广霞
吴尧尧
孙进进
张宏波
徐云根
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中国药科大学
江苏天士力帝益药业有限公司
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Priority claimed from CN202010604958.7A external-priority patent/CN112375070B/zh
Application filed by 中国药科大学, 江苏天士力帝益药业有限公司 filed Critical 中国药科大学
Publication of WO2022000946A1 publication Critical patent/WO2022000946A1/zh

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    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular to a PARP inhibitor containing a phthalazin-1(2H)-one structure, a preparation method and medical use thereof.
  • PARP Poly(ADP-ribose) polymerase
  • PARP-1 is a class of protein post-translational modification enzymes widely present in most eukaryotic cells.
  • Current research has found that there are at least 18 subtypes of the PARP family, which can be divided into 3 groups according to the degree of homology: PARP-1 group (including PARP-1 ⁇ PARP-4, PARP-6, PARP-8, PARP-16 ), Tankyrase group (including PARP-5a ⁇ PARP-5c) and III group (including PARP-7, PARP-9 ⁇ PARP-15).
  • PARP-1 accounts for the largest proportion.
  • PARP-1 plays an important role in DNA damage recognition and repair, regulation of chromatin structure, transcriptional regulation, regulation of cell death pathways, insulator function, and regulation of cell mitosis. Due to their significant antitumor activity, PARP-1 inhibitors can not only be used for tumor treatment alone, but also can be used as sensitizers in combination with other radiotherapy or chemotherapy drugs to enhance the efficacy.
  • Olaparib was the first PARP inhibitor approved for marketing.
  • research on PARP-1 inhibitors has also made great progress, especially in the treatment of intractable tumors such as advanced ovarian cancer and triple-negative breast cancer.
  • a large number of experiments have shown that most PARP-1 inhibitors lack a certain specificity to the target, and are prone to drug resistance, which results in the fact that the current clinical compounds fail to show a good chemosensitization effect.
  • PARP-1 inhibitor has non-negligible cytotoxicity, because it inhibits DNA damage repair, it is more likely to make normal cells cancerous.
  • the invention discloses a class of compounds containing 4-(3-(piperazine-1-carbonyl)-4-fluorobenzyl)phthalazine-1(2H)-one structure.
  • the compound or a pharmaceutically acceptable salt thereof can be used as a monotherapeutic agent for tumors.
  • R 1 and R 2 represent H, C1-4 alkyl, C1-2 alkoxy, CF 3 respectively ;
  • R 3 represents wherein R 4 , R 5 , R 6 and R 7 respectively represent H, F, Cl, CH 3 , OH, OCH 3 or CN, which may be monosubstituted or disubstituted; X and Y respectively represent O, S or NH; and when R 3 is , R 1 and R 2 cannot be H at the same time.
  • R 1 is selected from H or CH 3 .
  • R 2 is selected from CH 3 .
  • R 3 is selected from
  • the preferred partial compounds of the present invention are as follows:
  • the compounds of general formula (I) of the present invention can be prepared by the following methods:
  • R 1 , R 2 and R 3 are as defined above
  • Compound II was prepared with Boc 2 O to compound III, the solvent is selected from ethyl acetate, dichloromethane, methanol, tetrahydrofuran, acetonitrile, preferably dichloromethane.
  • the reaction temperature is 10°C to 50°C, preferably 20°C to 30°C.
  • Compound IV is prepared from compound III, and the alkali acid binding agent used is selected from triethylamine, N,N-diisopropylethylamine (DIEA), 4-dimethylaminopyridine (DMAP), pyridine, sodium acetate, sodium carbonate or potassium carbonate, preferably triethylamine.
  • the solvent used is selected from ethyl acetate, dichloromethane, methanol, tetrahydrofuran, acetonitrile, preferably dichloromethane.
  • the reaction temperature is -20°C to 50°C, preferably 0°C to 5°C.
  • Compound V is prepared from compound IV, and the solvent used is selected from 1-10 mol/L hydrogen chloride in EA solution, trifluoroacetic acid and acetic acid, preferably 2.8 mol/L hydrogen chloride in EA solution.
  • Compound I is prepared by reacting compound V with VI, and the used condensing agent is selected from hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidinophosphorus (PyBOP), 1-hydroxybenzotriazole (HOBT)/ 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC) or N,N-carbonyldiimidazole (CDI), preferred PyBOP; the acid binding agent is selected from triethylamine, N,N-diisopropylethylamine (DIEA), 4-dimethylaminopyridine (DMAP), pyridine, sodium acetate, sodium carbonate or potassium carbonate, preferably DIEA.
  • the used condensing agent is selected from hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidinophosphorus (P
  • the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably N,N-dimethylformamide; the reaction temperature is 10°C to 50°C, preferably 20°C ⁇ 30°C.
  • R 1 , R 2 and R 3 are as defined above
  • Compound VII is prepared by reacting compound III with VI, and the used condensing agent is selected from benzotriazol-1-yl-oxytripyrrolidinohexafluorophosphate (PyBOP), 1-hydroxybenzotriazole (HOBT)/ 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC) or N,N-carbonyldiimidazole (CDI), preferred PyBOP; the acid binding agent is selected from triethylamine, N,N-diisopropylethylamine (DIEA), 4-dimethylaminopyridine (DMAP), pyridine, sodium acetate, sodium carbonate or potassium carbonate, preferably DIEA.
  • PyBOP benzotriazol-1-yl-oxytripyrrolidinohexafluorophosphate
  • HOBT 1-hydroxybenzotriazole
  • the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably N,N-dimethylformamide; the reaction temperature is 10°C to 50°C, preferably 20°C ⁇ 30°C.
  • Compound VIII is prepared from compound VII, and the solvent used is selected from 1-10 mol/L hydrogen chloride in EA solution, trifluoroacetic acid, preferably 2.8 mol/L hydrogen chloride in EA solution.
  • Compound I is prepared from compound VIII, and the base acid binding agent used is selected from triethylamine, N,N-diisopropylethylamine (DIEA), 4-dimethylaminopyridine (DMAP), pyridine, sodium acetate, sodium carbonate or potassium carbonate, preferably triethylamine.
  • the solvent used is selected from ethyl acetate, dichloromethane, methanol, tetrahydrofuran, acetonitrile, preferably dichloromethane, acetonitrile.
  • the reaction temperature is -0°C to 100°C, preferably 25°C to 50°C.
  • the present invention also discloses a pharmaceutical composition, which comprises a pharmaceutically effective dose of compound (I) or a salt thereof of the present invention and a pharmaceutically acceptable carrier.
  • the compounds of the present invention can be added with pharmaceutically acceptable carriers to prepare common pharmaceutical preparations, such as tablets, capsules, powders, syrups, liquids, suspensions, freeze-dried powder injections, and injections.
  • common pharmaceutical preparations such as tablets, capsules, powders, syrups, liquids, suspensions, freeze-dried powder injections, and injections.
  • Commonly used pharmaceutical excipients such as flavors, liquid or solid fillers or diluents.
  • the clinical administration of the compounds of the present invention can be oral administration, injection, or the like.
  • the dosage for human use is in the range of 1 mg to 1000 mg/day. Dosages outside this range may also be employed, depending on the dosage form and the severity of the disease.
  • the present invention provides some new PARP inhibitors containing phthalazine-1(2H)-one structure, which can be used as a single therapeutic agent for tumors, or used in combination with other anti-tumor drugs, so as to improve the existing anti-tumor drugs.
  • the reaction of the raw materials was monitored by TLC, the reaction solution was poured into 80 mL of water, the organic phase was separated, the aqueous phase was extracted with DCM (3 ⁇ 50 mL), the organic phases were combined, the organic phase was washed with saturated brine (3 ⁇ 100 mL), anhydrous sulfuric acid Dry over sodium, filter, and concentrate the filtrate to give 340 mg of a pale yellow oil.
  • reaction solution was poured into 50 mL of saturated NH 4 Cl solution, extracted with EA (3 ⁇ 15 mL), the organic phases were combined, washed with saturated brine (3 ⁇ 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 320mg yellow oil.
  • VIII-1 was dissolved in 5 mL of DCM, adjusted to pH 8, then (125 mg, 0.9 mmol) K 2 CO 3 was added, and 5 mL of DCM dissolved (32 mg, 0.3 mmol) cyclopropylcarbonyl chloride was slowly added dropwise under ice bath, After the dropwise addition, the reaction was continued to be stirred under an ice bath for 3 h.
  • the compound samples were dissolved in DMSO to prepare a 10mM stock solution, and then the compounds were added to the screening system.
  • the compound detection concentration ranged from 0.1nM to 10 ⁇ M, and the dilution was carried out according to a 3-fold gradient, and two duplicate wells were made for each concentration.
  • the experimental results were converted into the percentage of activity, the drug concentration was taken as the abscissa, the percentage of enzyme activity corresponding to each concentration was taken as the ordinate, the dose-response curve was drawn, and the GRAPHPAD PRISM 5 was used for nonlinear regression to calculate the inhibition of PARP-1 enzyme by the test compound. the IC 50 values.
  • the specific operation steps are as follows:
  • the inhibitory activity of target compounds on PARP-1 enzyme was tested in 96-well plates. Wells were precoated with histones (20 ⁇ g/mL) diluted in 100 ⁇ L of PBS buffer (10 mM sodium dihydrogen phosphate, 10 mM disodium hydrogen phosphate, 150 mM sodium chloride, pH 7.4) and incubated overnight at 4°C. After that, 100 ⁇ M NAD+ , 25 ⁇ M biotinylated NAD + and 200 nM slDNA diluted in 30 ⁇ L buffer (50 mM Tris, 2 mM MgCl, pH 8.0) were added to each well, followed by 5 ⁇ L of test compound or solvent control at various concentrations .
  • PBS buffer 10 mM sodium dihydrogen phosphate, 10 mM disodium hydrogen phosphate, 150 mM sodium chloride, pH 7.4
  • Percentage of enzyme activity (OD value of drug administration hole - OD value background ) / (OD value control hole - OD value background ) ⁇ 100%

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Abstract

本发明公开了含有酞嗪-1(2H)-酮结构的PARP抑制剂、其制法及医药用途。通式(I)的化合物或其药学上可接受的盐：本发明提供了一些新的含有酞嗪-1(2H)-酮结构的PARP抑制剂，可作为肿瘤的单一治疗剂，或者与其它抗肿瘤药物联用，从而达到提高现有抗肿瘤药物疗效并降低剂量和毒性的作用。

Description

含有酞嗪-1(2H)-酮结构的PARP抑制剂、其制法及医药用途 技术领域
本发明涉及药物化学领域，具体涉及含有酞嗪-1(2H)-酮结构的PARP抑制剂、其制法及医药用途。
背景技术
聚腺苷二磷酸核糖聚合酶(PARP)，是一类广泛存在于多数真核细胞中的蛋白质翻译后修饰酶。目前研究发现PARP家族至少有18种亚型，根据同源性程度的不同可分为3组：PARP-1组(包括PARP-1～PARP-4,PARP-6,PARP-8,PARP-16)，Tankyrase组(包括PARP-5a～PARP-5c)和III组(包括PARP-7,PARP-9～PARP-15)。其中PARP-1所占比例最大，其能识别并结合到DNA发生损伤的缺口部位，并迅速催化NAD +分解成尼克酰胺和ADP-核糖，再以ADP-核糖为底物，使核受体蛋白与ADP-核糖形成多聚物从而启动DNA的损伤修复。PARP-1在参与DNA损伤识别与修复、调节染色质结构、转录调控、细胞死亡途径的调节、绝缘子功能以及细胞有丝分裂的调控等方面均发挥重要作用。PARP-1抑制剂因其显著的抗肿瘤活性，既可以单独用于肿瘤的治疗，也可作为增敏剂与其他放疗或化疗药物联用以增强疗效。奥拉帕尼是第一个被批准上市的PARP抑制剂。目前针对PARP-1抑制剂的研究也已取得了巨大进展，特别是在晚期卵巢癌和三阴性乳腺癌等顽固性肿瘤的治疗方面。但同时大量实验表明，大部分的PARP-1抑制剂对靶点缺乏一定的特异性，易产生耐药性，也就造成了目前临床中的化合物未能体现出较好的化疗增敏效果。另外，PARP-1抑制剂具有不可忽视的细胞毒性，由于其抑制了DNA损伤修复，更易使正常细胞发生癌变。因此，未来对PARP-1抑制剂的研究应努力增强特异性、改善细胞的耐药情况，重点发掘其单药治疗DNA修复缺陷患者的潜力。相信随着研究的不断深入，更多安全有效的PARP-1抑制剂将被开发出来并得到应用。
发明内容
本发明公开了一类含有4-(3-(哌嗪-1-羰基)-4-氟苄基)酞嗪-1(2H)-酮结构的化合物，药效学试验结果显示，本发明的化合物或其药学上可接受的盐可作为肿瘤的单一治疗剂。
Figure PCTCN2020130061-appb-000001
其中：R 1、R 2分别代表H、C1-4的烷基、C1-2的烷氧基、CF 3；
R 3代表
Figure PCTCN2020130061-appb-000002
其中R 4、R 5、R 6、R 7分别代表H、F、Cl、CH 3、OH、OCH 3或CN，可以单取代或双取代；X、Y分别代表O、S或NH；且当R 3为
Figure PCTCN2020130061-appb-000003
时，R 1、R 2不能同时为H。
在本发明的一些实施例中，R 1选自H或CH 3。
在本发明的一些实施例中，R 2选自CH 3。
在本发明的一些实施例中，R 3选自
Figure PCTCN2020130061-appb-000004
本发明优选的部分化合物如下：
Figure PCTCN2020130061-appb-000005
Figure PCTCN2020130061-appb-000006
本发明通式(I)化合物可用下列方法制备：
包括方法一：
Figure PCTCN2020130061-appb-000007
其中：R 1，R 2和R 3的定义同前
由化合物II与Boc 2O制备化合物III，所用溶剂选自乙酸乙酯、二氯甲烷、甲醇、四氢呋喃、乙腈，优选二氯甲烷。反应温度为10℃～50℃，优选20℃～30℃。
由化合物III制备化合物IV，所用的碱缚酸剂选自三乙胺、N,N-二异丙基乙胺(DIEA)、4-二甲氨基吡啶(DMAP)、吡啶、醋酸钠、碳酸钠或碳酸钾，优选三乙胺。所用溶剂选自乙酸乙酯、二氯甲烷、甲醇、四氢呋喃、乙腈，优选二氯甲烷。反应温度为-20℃～50℃，优选0℃～5℃。
由化合物IV制备化合物Ⅴ，所用的溶剂选自1～10mol/L氯化氢的EA溶液、三氟乙酸乙酸，优选2.8mol/L氯化氢的EA溶液。
由化合物V与Ⅵ反应制备化合物Ⅰ，所用的缩合剂选自六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(PyBOP)、1-羟基苯并三唑(HOBT)/1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、二环己基碳二亚胺(DCC)或N,N-羰基二咪唑(CDI)，优先PyBOP；缚酸剂选自三乙胺、N,N-二异丙基乙胺(DIEA)、4-二甲氨基吡啶(DMAP)、吡啶、醋酸钠、碳酸钠或碳酸钾，优选DIEA。反应溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲亚砜，优选N,N-二甲基甲酰胺；反应温度为10℃～50℃，优选20℃～30℃。
方法二：
Figure PCTCN2020130061-appb-000008
其中：R 1，R 2和R 3的定义同前
由化合物III与Ⅵ反应制备化合物VII，所用的缩合剂选自六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(PyBOP)、1-羟基苯并三唑(HOBT)/1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、二环己基碳二亚胺(DCC)或N,N-羰基二咪唑(CDI)，优先PyBOP；缚酸剂选自三乙胺、N,N-二异丙基乙胺(DIEA)、4-二甲氨基吡啶(DMAP)、吡啶、醋酸钠、碳酸钠或碳酸钾，优选DIEA。反应溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲亚砜，优选N,N-二甲基甲酰胺；反应温度为10℃～50℃，优选20℃～30℃。
由化合物VII制备化合物VIII，所用的溶剂选自1～10mol/L氯化氢的EA溶液、三氟乙酸，优选2.8mol/L氯化氢的EA溶液。
由化合物VIII制备化合物I，所用的碱缚酸剂选自三乙胺、N,N-二异丙基乙胺(DIEA)、4-二甲氨基吡啶(DMAP)、吡啶、醋酸钠、碳酸钠或碳酸钾，优选三乙胺。所用溶剂选自乙酸乙酯、二氯甲烷、甲醇、四氢呋喃、乙腈，优选二氯甲烷，乙腈。反应温度为-0℃～100℃，优选25℃～50℃。
本发明还公开了一种药物组合物，其包括药物有效剂量的本发明的化合物(I)或其盐和药学上可接受的载体。
本发明所述的化合物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、冻干粉针、针剂，可以加入香料、甜味剂、液体或固体填料或稀 释剂等常用药用辅料。
本发明所述的化合物在临床上的给药方式可以采用口服、注射等方式。
一般地，本发明的化合物用于治疗时，人用剂量范围为1mg～1000mg/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。
有益效果：本发明提供了一些新的含有酞嗪-1(2H)-酮结构的PARP抑制剂，可作为肿瘤的单一治疗剂，或者与其它抗肿瘤药物联用，从而达到提高现有抗肿瘤药物疗效并降低剂量和毒性的作用。
具体实施方式
实施例1
4-(3-(4-(环丙基羰基)-3-甲基哌嗪-1-羰基)-4-氟苄基)酞嗪-1(2H)-酮(I-1)的合成
3-甲基哌嗪-1-甲酸叔丁酯(Ⅲ-1)
将(1.0g,9.8mmol)2-甲基哌嗪(Ⅱ-1)溶于20mL二氯甲烷(DCM)中，滴加DCM溶解的(2.2g,10.0mmol)Boc 2O，室温搅拌反应5h。TLC监测原料反应完全，减压旋出溶剂，加入40mL水，用EA萃取(3×20mL)，合并有机相，有机相用饱和食盐水洗涤(3×50mL)，无水硫酸钠干燥，过滤，滤液浓缩得1.7g无色油状物。粗品经柱层析纯化(洗脱剂，DCM:EA＝1:1)制得1.2g无色油状物。收率60.0％。 1H-NMR(300MHz,CDCl 3)δ(ppm):3.95(brs,2H,-NC H 2CH-,-C HCH 3),2.96(d,J＝7.9Hz,1H,-NC H 2CH-),2.77(d,J＝8.3Hz,2H,-NC H 2CH 2-),2.74–2.66(m,1H,-NHC H 2-),2.40(brs,1H,-NHC H 2-),1.80(s,1H,-NH),1.46(s,9H,-C(C H 3 ) 3 ),1.06(d,J＝6.3Hz,3H,-CHC H 3 ).
4-(环丙基羰基)-3-甲基哌嗪-1-甲酸叔丁酯(Ⅳ-1)
将(250mg,1.2mmol)3-甲基哌嗪-1-甲酸叔丁酯(Ⅲ-1)溶于10mL DCM中，加入(253mg,2.5mmol)三乙胺(Et 3N)，于冰浴中氮气保护下滴加10mL DCM溶解的(130mg,1.2mmol)环丙基甲酰氯，滴加完毕后冰浴下继续搅拌反应3h。TLC监测原料反应完全，将反应液倒入80mL水中，分出有机相，水相用DCM萃取(3×50mL)，合并有机相，有机相用饱和食盐水洗涤(3×100mL)，无水硫酸钠干燥，过滤，滤液浓缩得340mg淡黄色油状物。粗品经柱层析纯化(洗脱剂，PE:EA＝7:3)得206mg无色油状物。收率为61.5％。 1H-NMR(300MHz,CDCl 3)δ(ppm):4.85–3.72(m,4H,-NC HC H 2-,-C H 2 CH 2NCOO-),3.53–2.67(m,3H,-NCHC H 2-,-CH 2C H 2 NCOO-),1.84–1.54(m,1H,-CH 2C HCH 2-),1.47(s,9H,-C(C H 3) 3 ),1.29–1.10 (m,3H,-CHC H 3 ),1.04–0.94(m,2H,-C H 2CHC H 2-),0.78(dd,J 1＝7.8,J 2＝2.9Hz,2H,-C H 2CHC H 2-).
4-(3-(4-(环丙基羰基)-3-甲基哌嗪-1-羰基)-4-氟苄基)酞嗪-1(2H)-酮(I-1)
将(140mg,0.5mmol)4-(环丙基羰基)-3-甲基哌嗪-1-甲酸叔丁酯(Ⅳ-1)加入至25mL单颈瓶中，加入3.2mL 2.8mol/L氯化氢的EA溶液，室温搅拌反应4h。TLC监测原料反应完全。减压旋出溶剂得到中间体V-1，不经提纯直接用于下一步反应。
将V-1溶于10mL无水DMF中，用三乙胺调pH至8，再依次加入(148mg,0.5mmol)2-氟-5-((4-氧代-3,4-二氢酞嗪基)甲基)苯甲酸(Ⅵ)和(311mg,0.6mmol)PyBOP，室温搅拌反应12h。TLC监测原料反应完全，将反应液倒入50mL饱和NH 4Cl溶液，用EA萃取(3×15mL)，合并有机相，有机相用饱和食盐水洗涤(3×25mL)，无水硫酸钠干燥，抽滤，滤液浓缩得350mg黄色油状物。粗品经柱层析纯化(洗脱剂，DCM:EA＝1:1)制得146mg乳白色固体。收率65.6％。m.p.176.3～177.9℃。 1H-NMR(300MHz,DMSO-d 6)δ(ppm):12.62(s,1H,-N HCO-),8.27(d,J＝6.8Hz,1H,Ar H),8.10–7.74(m,3H,Ar H),7.57–7.16(m,3H,Ar H),4.68(brs,1H,-C HCH 3),4.44–3.97(m,5H,-ArC H 2 -,-NC H 2CH-,-NC H 2CH 2-,-NCH 2C H 2-),3.21–2.67(m,3H,-NC H 2CH-,-NC H 2CH 2-,-NCH 2C H 2-),1.90(s,1H,-CH 2C HCH 2-),1.32–0.83(m,3H,-CHC H 3 ),0.73(s,4H,-C H 2 CHC H 2 -). 13C-NMR(75MHz,DMSO-d 6)δ(ppm):171.37,164.66(d,J＝10.5Hz),159.35,156.30(d,J＝244.1Hz),144.87,134.83,133.45,131.68,131.52,129.01(d,J＝5.6Hz),128.88,127.84,126.02,125.43,123.56(d,J＝18.7Hz),115.88(d,J＝21.6Hz),50.12,47.83,45.44,44.32,36.42,15.83,10.49,7.13.HRMS(ESI):m/z[M+H] +.Calcd for C 25H 26FN 4O 3:449.1983；Found:449.1990.
实施例2
4-(4-氟-3-(3-甲基-4-(2-氧代-2-苯基乙基)哌嗪-1-羰基)苄基)酞嗪-1(2H)-酮(I-2)的合成
3-甲基-4-(2-氧代-2-苯乙基)哌嗪-1-甲酸叔丁酯(Ⅳ-2)
将(250mg,1.2mmol)3-甲基哌嗪-1-甲酸叔丁酯(Ⅲ-1)溶于10mL乙腈中，再分别加入(248mg,1.2mmol)2-溴苯乙酮和(862mg,6.2mmol)K 2CO 3，升温至80℃，搅拌反应5h。TLC监测原料反应完全，冷却至室温，过滤，用EA洗涤滤饼，滤液浓缩得400mg油状物。粗品经柱层析纯化(洗脱剂，PE:EA＝9:1)制得250mg无色油状物。收率为63.0％。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.03(d,J＝7.4Hz,2H,Ar H),7.61(t,J＝7.3Hz,1H,Ar H), 7.49(t,J＝7.5Hz,2H,Ar H),4.18(d,J＝16.3Hz,1H,-NC H 2CHN-),3.97–3.60(m,3H,-COC H 2 N-,-NC H 2CHN-),3.28–3.08(m,1H,-C HCH 3),2.88(t,J＝6.7Hz,1H,-CONC H 2CH 2-),2.84(t,J＝6.8Hz,1H,-CONC H 2CH 2-),2.74(brs,1H,-CONCH 2C H 2-),2.53(s,1H,-CONCH 2C H 2-),1.49(s,9H,-C(C H 3) 3 ),1.12(d,J＝6.2Hz,3H,-CHC H 3 ).
4-(4-氟-3-(3-甲基-4-(2-氧代-2-苯基乙基)哌嗪-1-羰基)苄基)酞嗪-1(2H)-酮(I-2)
以(250mg,0.8mmol)3-甲基-4-(2-氧代-2-苯乙基)哌嗪-1-甲酸叔丁酯(Ⅳ-2)和为原料，操作同I-1，制得140mg白色粉末状固体。收率35.8％。m.p.73.5～75.5℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):10.90(s,1H,-N HCO-),8.52–8.41(m,1H,Ar H),8.11(d,J＝7.3Hz,1H,Ar H),7.98(d,J＝7.5Hz,2H,Ar H),7.84–7.67(m,3H,Ar H),7.58(t,J＝7.3Hz,1H,Ar H),7.46(t,J＝7.6Hz,2H,Ar H),7.34(d,J＝6.3Hz,1H,Ar H),7.09–6.94(m,1H,Ar H),4.29(s,2H,ArC H 2 -),3.90–3.71(m,1H,-C HCH 3),3.33(s,2H,-C H 2 CO-),3.11–2.88(m,2H,-NC H 2 CH-),2.90–2.56(m,3H,-CONC H 2 CH 2-,-CONCH 2C H 2-),2.56–2.39(m,1H,-CONCH 2C H 2-),1.17(d,J＝6.2Hz,1.5H,-CHC H 3 ),0.93(d,J＝6.2Hz,1.5H,-CHC H 3 ). 13C-NMR(75MHz,CDCl 3)δ(ppm):196.71,164.37,160.53,156.52(d,J＝248.2Hz),145.36,135.35,133.26,132.94,132.41,131.13,130.87,129.47,129.05,128.65,128.15,127.80,127.55,126.61,124.61,115.66(d,J＝17.2Hz),59.14,52.73,47.66,46.63,41.49,37.23,14.72.HRMS(ESI):m/z[M+H] +.Calcd for C 29H 28FN 4O 3:499.2140；Found:449.2133.
实施例3
4-(3-(4-(2-(苯并呋喃-3-基)-2-氧代乙基)-3-甲基哌嗪-1-羰基)-4-氟苄基)酞嗪-1(2H)-酮(I-3)的合成
4-(2-(苯并呋喃-3-基)-2-氧代乙基)-3-甲基哌嗪-1-甲酸叔丁酯(Ⅳ-3)
将(200mg,1.0mmol)3-甲基哌嗪-1-甲酸叔丁酯(Ⅲ-1)溶于10mL DMF中，再分别加入(239mg,1.0mmol)1-(苯并呋喃-3-基)-2-溴乙酮和(303mg,3.0mmol)Et 3N，室温搅拌反应12h，TLC监测原料反应完全。将反应液倒入50mL饱和NH 4Cl溶液中，用EA萃取(3×15mL)，合并有机相，有机相用饱和食盐水洗涤(3×30mL)，无水硫酸钠干燥，过滤，滤液浓缩得320mg黄色油状物。粗品经柱层析纯化(洗脱剂，PE:EA＝9:1)制得200mg淡黄色油状物。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.81(s,1H,-C H＝C-),8.26(dd,J 1＝6.1Hz,J 2＝2.7Hz,1H,Ar H),7.54(dd,J 1＝6.0Hz,J 2＝3.0Hz,1H,Ar H),7.44–7.32(m,2H,Ar H),3.99(d,J＝15.2Hz,1H,-NC H 2CHN-),3.78(d,J＝13.4Hz,2H,-COC H 2 N-),3.47(d,J＝15.2Hz,1H,-NC H 2CHN-),3.24–3.08(m,1H,-C HCH 3),2.99–2.75(m,2H,-CONC H 2 CH 2-),2.64(brs,1H,-CONCH 2C H 2-),2.48(brs,1H,-CONCH 2C H 2-),1.47(s,9H,-C(C H 3) 3 ),1.14(d,J＝6.3Hz,3H,-CHC H 3 ).
4-(3-(4-(2-(苯并呋喃-3-基)-2-氧代乙基)-3-甲基哌嗪-1-羰基)-4-氟苄基)酞嗪-1(2H)-酮(I-3)
以(200mg,0.5mmol)4-(2-(苯并呋喃-3-基)-2-氧代乙基)-3-甲基哌嗪-1-甲酸叔丁酯(Ⅳ-3)为原料，操作同I-1，制得110mg白色粉末状固体。收率36.7％。m.p.183.8～185.2℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):10.74(s,1H,-N HCO-),8.71(s,1H,-C H＝C-),8.53–8.39(m,1H,Ar H),8.29–8.17(m,1H,Ar H),7.87–7.62(m,3H,Ar H),7.58–7.48(m,1H,Ar H),7.46–7.27(m,4H,Ar H),7.10–6.95(m,1H,Ar H),4.42–4.31(m,1H,-NCHC H 2-),4.29(s,2H,ArC H 2 -),3.98(t,J＝15.2Hz,1H,-NCHC H 2-),3.68–3.45(m,1H,-C HCH 3),3.35(s,2H,-COC H 2 N-),3.20–2.88(m,2H,-CONC H 2 CH 2N-),2.89–2.73(m,1H,-CONCH 2C H 2N-),2.73–2.38(m,1H,-CONCH 2C H 2N-),1.21(d,J＝6.3Hz,1.5H,-CHC H 3 ),0.98(d,J＝6.2Hz,1.5H,-CHC H 3 ).
13C-NMR(75MHz,CDCl 3)δ(ppm):193.49,164.39,160.34,156.51(d,J＝247.6Hz),154.56,151.28,145.18,133.75,133.19,131.10,130.95,130.85,129.05,128.67,127.73,126.64,125.23,124.58,124.15,123.89,122.40,119.93,115.63(d,J＝21.9Hz),110.97,62.21,55.03,52.73,47.67,41.51,37.22,15.04.
HRMS(ESI):m/z[M+H] +.Calcd for C 31H 28FN 4O 4:539.2089；Found:539.2082.
实施例4
4-(3-(4-(环丙基羰基)-反式-2,5-二甲基哌嗪-1-羰基)-4-氟苄基)酞嗪-1(2H)-酮(I-4)的合成
4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)-反式-2,5-二甲基哌嗪-1-甲酸叔丁酯(VII-1)
将(1.6g,7.5mmol)反式-2,5-二甲基哌嗪-1-甲酸叔丁酯(III-4)溶于20mL无水DMF 中，再分别加入(2.2g,7.5mmol)2-氟-5-((4-氧代-3,4-二氢酞嗪基)甲基)苯甲酸(Ⅵ)，(1.9g,15.0mmol)DIPEA和(4.6g,9.0mmol)PyBOP，室温搅拌反应过夜。TLC监测原料反应完全，将反应液倒入100mL饱和NH 4Cl溶液，用EA萃取(3×30mL)，合并有机相，有机相用饱和食盐水洗涤(3×70mL)，无水硫酸钠干燥，抽滤，滤液浓缩得7.0g酒红色油状物。粗品经柱层析纯化(洗脱剂，DCM:EA＝1:1)制得3.0g乳白色固体。收率81.3％。
m.p.171.3～173.3℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):10.90(s,1H,-CON H-),8.47(s,1H,Ar H),7.87–7.62(m,3H,Ar H),7.30(s,2H,Ar H),7.14–6.92(m,1H,Ar H),4.91(s,1/2H,-C HCH 3),4.54(s,1/2H,-C HCH 3),4.31(s,1H,-C HCH 3),4.29(d,J＝4.4Hz,2H,ArC H 2-),3.89–3.41(m,2H,-CHC H 2 -),3.37–2.90(m,2H,-CHC H 2 -),1.56–1.36(m,9H,-C(C H 3) 3 ),1.25–1.14(m,3H,-CHC H 3 ),1.13–0.80(m,3H,-CHC H 3 ).
4-(3-(4-(环丙基羰基)-反式-2,5-二甲基哌嗪-1-羰基)-4-氟苄基)酞嗪-1(2H)-酮(I-4)
将(150mg,0.3mmol)4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)-反式-2,5-二甲基哌嗪-1-甲酸叔丁酯(VII-1)加入25mL单颈瓶中，加入3mL 2.8mol/L氯化氢的EA溶液，室温搅拌反应4h，TLC监测原料反应完全。减压旋出溶剂得VIII-1，该产物不经提纯，直接用于下一步。
将VIII-1溶于5mL DCM中，调节pH至8，再加入(125mg,0.9mmol)K 2CO 3，冰浴下缓慢滴加5mL DCM溶解的(32mg,0.3mmol)环丙基甲酰氯，滴加完毕后继续在冰浴下搅拌反应3h。TLC监测原料反应完全，将反应液倒入50mL水中，用DCM萃取(3×15mL)，合并有机相，有机相用饱和食盐水洗涤(3×25mL)，无水硫酸钠干燥，抽滤，滤液浓缩得185mg黄色固体。粗品经柱层析纯化(洗脱剂，DCM:EA＝4:6)制得110mg乳白色固体。收率78.9％。m.p.145.3～147.0℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):10.70(s,1H,-CON H-),8.49(s,1H,Ar H),7.91–7.64(m,3H,Ar H),7.34(s,2H,Ar H),7.08(q,J＝9.2Hz,1H,Ar H),5.03(s,1/2H,-C HCH 3),4.75(s,1/2H,-C HCH 3),4.65–4.41(m,1H,-C HCH 3),4.32(s,2H,ArC H 2 -),3.97–3.70(m,1H,-CHC H 2N-),3.70–3.39(m,1H,-CHC H 2N-),3.36–2.93(m,2H,-CHC H 2N-),1.81(brs,1H,-CH 2C HCH 2-),1.43–1.21(m,6H,-CHC H 3 ),1.02(brs,4H,-C H 2CHC H 2-). 13C-NMR(75MHz,DMSO-d 6)δ(ppm):171.68,164.78(d,J＝8.2Hz),159.34,156.20(d,J＝245.2Hz),144.93,134.93,133.46,131.53,131.47,129.01(d,J＝2.4Hz),128.49,127.83,126.03,125.43,123.95(d,J＝18.5Hz),115.95(d, J＝21.8Hz),49.90,47.17,43.77,43.23,36.38,15.46,14.87,10.46,7.06.HRMS(ESI):m/z[M+H] +.Calcd for C 26H 28FN 4O 3:463.2140；Found:463.2138.
实施例5
4-(3-(反式-2,5-二甲基-4-(2-氧代-2-苯乙基)哌嗪-1-羰基)-4-氟苄基)酞嗪-1(2H)-酮(I-5)的合成
以(300mg,0.6mmol)4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)-反式-2,5-二甲基哌嗪-1-甲酸叔丁酯VII-1)和(115mg,0.6mmol)2-溴苯乙酮为原料，操作同I-4，经柱层析纯化(洗脱剂，DCM:EA＝1:1)制得120mg白色粉末状固体。m.p.110.9～111.5℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):11.01(s,1H,-CON H-),8.53–8.38(m,1H,Ar H),8.02–7.84(m,2H,Ar H),7.83–7.60(m,4H,Ar H),7.59–7.41(m,2H,Ar H),7.41–7.27(m,2H,Ar H),7.15–6.94(m,1H,Ar H),5.16(brs,1/2H,-CONC HCH 2-),4.94(s,1H,-CONC H 2CH-),4.77(s,1/2H,-CONC HCH 2-),4.52(d,J＝14.5Hz,1/2H,-CONC H 2CH-),4.39(d,J＝13.9Hz,1/2H,-CONC H 2CH-),4.28(s,2H,ArC H 2 -),3.86(s,1H,-CONCH 2C H-),3.64(s,2H,-COC H 2 N-),3.38–2.99(m,2H,-CONCHC H 2 -),1.47–1.29(m,3H,-CHC H 3 ),1.29–1.19(m,3H,-CHC H 3 ).HRMS(ESI):m/z[M+H] +.Calcd for C 30H 30FN 4O 3:513.2296；Found:513.2292.
实施例6
4-(3-(4-(2-(苯并呋喃-3-基)-2-氧代乙基)-反式-2,5-二甲基哌嗪-1-羰基)-4-氟苄基)酞嗪-1(2H)-酮(I-6)的合成
以(200mg,0.4mmol)4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)-反式-2,5-二甲基哌嗪-1-甲酸叔丁酯(VII-1)和(83mg,0.4mmol)1-(苯并呋喃-3-基)-2-溴乙酮为原料，操作同I-4，经柱层析纯化(洗脱剂，DCM:EA＝3:2)制得90mg乳白色固体。收率39.0％。m.p.197.2～198.9℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):10.70(s,1H,-N HCO-),8.69(s,1H,-C H＝C-),8.52–8.39(m,1H,Ar H),8.28–8.15(m,1H,Ar H),7.82–7.62(m,3H,Ar H),7.59–7.48(m,1H,Ar H),7.45–7.33(m,2H,Ar H),7.33–7.26(m,2H,Ar H),7.03(s,1H,Ar H),4.91(brs,1/2H,-CONC HCH 2-),4.40(d,J＝12.1Hz,1/2H,-CONC H 2CH-),4.28(s,2H,ArC H 2 -),3.78–3.45(m,3H,-COC H 2 N-,-CONCH 2C H-),3.36(d, J＝12.6Hz,1/2H,-CONC H 2CH-),3.23(brs,1/2H,-CONC HCH 2-),3.12–2.78(m,2H,-CONCHC H 2-,-CONC H 2CH-),2.50(d,J＝11.1Hz,1/2H,-CONCHC H 2-),2.31(d,J＝11.6Hz,1/2H,-CONCHC H 2-),1.38(brs,3H,-CHC H 3 ),1.11(brs,3H,-CHC H 3 ). 13C-NMR(75MHz,DMSO-d 6)δ(ppm):193.88,164.64,159.34,156.15(d,J＝245.6Hz),154.41,153.88,144.93,134.87,133.42,131.51,131.19,131.10,129.00,128.34,127.84,126.02,125.49(d,J＝5.4Hz),124.51,124.21,124.13,122.04,119.34,115.89(d,J＝20.5Hz),111.65,62.58,51.92,50.11,49.19,44.29,36.69,16.69,15.91.HRMS(ESI):m/z[M+H] +.Calcd for C 32H 30FN 4O 4:553.2246；Found:553.2240.
实施例7
本发明部分化合物的药理学实验及结果如下：
检测化合物在酶水平抑制PARP-1的IC 50值
实验方法
将化合物样品用DMSO溶解，配制10mM母液，然后把化合物加到筛选体系中，化合物检测浓度范围是0.1nM～10μM，按照3倍梯度进行稀释，每个浓度做两个复孔。实验结果换算成活性百分率，将药物浓度作为横坐标，各浓度对应的酶活性百分率作为纵坐标，描绘量效曲线，使用GRAPHPAD PRISM 5做非线性回归，计算得到受试化合物对PARP-1酶抑制的IC 50值。具体操作步骤如下：
在96孔板中测试目标化合物对PARP-1酶的抑制活性。各孔预涂稀释在100μL PBS缓冲液(10mM磷酸二氢钠，10mM磷酸氢二钠，150mM氯化钠，pH 7.4)中的组蛋白(20μg/mL)，4℃下培养过夜。之后，每孔加入稀释在30μL缓冲液(50mM Tris，2mM氯化镁，pH 8.0)中的100μM的NAD +，25μM生物素化的NAD +和200nM slDNA，然后加入不同浓度的5μL受试化合物或溶剂对照。30℃下每孔加入20μL(5ng)PARP-1，1h后加入50μL HRP，培养30min后再加100μL缓冲液(0.1M H 2O 2柠檬酸盐缓冲液，pH 5.4)终止反应，在SpectraMax M5仪器上检测化学发光值。按下列公式计算酶活性百分率：
酶活性百分率(％)＝(OD值 给药孔－OD值 本底)/(OD值 对照孔－OD值 本底)×100％
实验结果见表1
表1.部分受试化合物化合物在酶水平对PARP-1 IC 50值
Figure PCTCN2020130061-appb-000009

Claims (10)

  1. 通式(I)的化合物或其药学上可接受的盐：
    Figure PCTCN2020130061-appb-100001
    其中：R 1、R 2分别代表H、C1-4的烷基、C1-2的烷氧基、CF 3；
    R 3代表
    Figure PCTCN2020130061-appb-100002
    其中R 4、R 5、R 6、R 7分别代表H、F、Cl、CH 3、OH、OCH 3或CN，可以单取代或双取代；X、Y分别代表O、S或NH；且当R 3为
    Figure PCTCN2020130061-appb-100003
    时，R 1、R 2不能同时为H。
  2. 根据权利要求1所述的通式(I)的化合物或其药学上可接受的盐，其特征在于R 1选自H或CH 3。
  3. 根据权利要求1所述的通式(I)的化合物或其药学上可接受的盐，其特征在于R 2选自CH 3。
  4. 根据权利要求1所述的通式(I)的化合物或其药学上可接受的盐，其特征在于R 3选自
    Figure PCTCN2020130061-appb-100004
  5. 根据权利要求1所述的通式(I)的化合物或其药学上可接受的盐，其特征在于选自以下任意一种化合物：
    Figure PCTCN2020130061-appb-100005
    Figure PCTCN2020130061-appb-100006
  6. 根据权利要求1～5中任一项所述的通式(I)的化合物或其药学上可接受的盐，其特征在于药学上可接受的盐为所述的通式(I)化合物与酸形成的酸加成盐，所述的酸选自：氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
  7. 一种药物组合物，其中含有权利要求1～5中任一项所述的通式(I)化合物或其药学上可接受的盐及药学上可接受的载体。
  8. 根据权利要求7所述的药物组合物，其特征在于所述的药物组合物被制备成片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、冻干粉针或针剂中的任意一种剂型。
  9. 权利要求1所述的通式(I)的化合物的制备方法，其特征在于反应路线选自以下任意一种：
    方法一：
    Figure PCTCN2020130061-appb-100007
    方法二：
    Figure PCTCN2020130061-appb-100008
  10. 权利要求1的化合物或其药学上可接受的盐、权利要求7或8所述的药物组合物在制备抗肿瘤药物中的用途。
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