WO2019141009A1 - 一种化合物及其在药学上的应用 - Google Patents

一种化合物及其在药学上的应用 Download PDF

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WO2019141009A1
WO2019141009A1 PCT/CN2018/119300 CN2018119300W WO2019141009A1 WO 2019141009 A1 WO2019141009 A1 WO 2019141009A1 CN 2018119300 W CN2018119300 W CN 2018119300W WO 2019141009 A1 WO2019141009 A1 WO 2019141009A1
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compound
pharmaceutically acceptable
acceptable salt
uhrf1
hyperplasia
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PCT/CN2018/119300
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李雄
谢国建
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长沙霍滋生物科技有限公司
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Priority to US16/962,262 priority Critical patent/US11479534B2/en
Priority to JP2020540380A priority patent/JP7018514B2/ja
Priority to EP18901791.6A priority patent/EP3741748B1/en
Priority to AU2018403404A priority patent/AU2018403404B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms

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  • the present invention relates to a compound and its pharmaceutically useful application, and in particular to a chemical small molecule by dual targeting of UHRF1 and HDAC1 and its pharmaceutical use.
  • the HDAC family of molecules and DNMT1 are important regulatory molecules of epigenetics. Although they are highly expressed in several tumor tissues, they are expressed in different normal tissues and organs to varying degrees.
  • the HDAC inhibitor vorinostat or citabin has clinically shown good therapeutic effects on cutaneous T-cell lymphoma, DNMT1 inhibitors such as 5-cytidine and decitabine. However, they show varying degrees of toxic side effects and are therefore of limited use in solid tumors.
  • UHRF1 is an important gene in epigenetic regulation of DNA methylation, and is also involved in the regulation of DNA replication and DNA damage repair.
  • UHRF1 is also an oncogene with low expression in normal tissues (5 to 70 times lower than HDAC1 and DNMT1) but is highly expressed in a variety of hematological and solid cancer tissues and is therefore an ideal anticancer drug target. .
  • Application of RNAi interference knockdown UHRF1 significantly reduced cell proliferation and promoted cell sensitivity to chemoradiotherapy.
  • UHRF1 and HDAC1 can be used alone or in combination with other methods to treat proliferative disorders and disorders, including but not limited to myelodysplastic syndrome, psoriasis, scar hyperplasia, prostate or breast hyperplasia Equal proliferative diseases, benign tumors, hematological tumors, and solid cancers, including types of cancers that are neuroendocrinely transformed.
  • the technical problem solved by the present invention is to treat the above diseases by using a chemical small molecule which double targets UHRF1 and HDAC1 or a pharmaceutically acceptable salt thereof as a corresponding inhibitor or a drug for treating diseases, for use alone or in combination with other methods, It is used to improve the efficacy of related drugs.
  • the technical solution of the present invention is to provide a compound and a pharmaceutically acceptable salt thereof, the chemical formula of which is:
  • n is selected from a positive integer of 1 to 7
  • R is selected from one of the following substituents: -H, -F, -Cl, -Br, -I, -NH 2 , -OH, -CN, -SH , -CF 3 , -CH 3 , -CH 2 CH 3 ,
  • the change in the R group can affect the solubility and crystallization properties of the compound.
  • the chemical formula of the compound is:
  • the pharmaceutically acceptable salt is: chloride, bromide, iodide, phosphate, sulfate, carbonate, hydrogencarbonate, formate, acetate, propionate, benzene Formate, picoformate, fumarate, maleate, malate, succinate, methanesulfonate, tosylate, triflate, tetrafluoroborate or Hexafluorosulfate.
  • the present invention also provides the above compound and a pharmaceutically acceptable salt thereof in the preparation of the treatment (alone or in combination with other methods) for the treatment of myeloid heterogeneous syndrome, psoriasis, scar hyperplasia, benign prostatic hyperplasia, breast hyperplasia, hematological tumors and tumors ( Mainly refers to the application of solid cancer).
  • the invention also provides the use of the above compounds and their pharmaceutically acceptable salts in the preparation of UHRF1 and/or HDAC1 inhibitors.
  • Target compound For example, the synthetic route is:
  • the beneficial effects of the present invention are that the compound of the present invention and a pharmaceutically acceptable salt thereof can simultaneously target UHRF1 and/or HDAC1 for preparation of corresponding drugs, which can treat proliferative abnormalities alone or in combination with other methods.
  • Diseases and disorders including but not limited to myelodysplastic syndrome, psoriasis, scar hyperplasia, benign prostatic hyperplasia, breast hyperplasia and other proliferative diseases, benign tumors, hematological tumors and solid cancers, and the treatment effect is very good.
  • Figure 1 shows the administration of different doses of the control drug compound M1 (a small molecule inhibitor of UHRF1, NSC232003 (2016, European Journal of Medicinal Chemistry, 114: 390-396), and the compound M3 prepared in Example 1 Targeted experimental results.
  • M1 a small molecule inhibitor of UHRF1, NSC232003 (2016, European Journal of Medicinal Chemistry, 114: 390-396)
  • M3 prepared in Example 1 Targeted experimental results.
  • Figures 2a, 2b, 2c, and 2d show IC50 values for selective killing of different cancer cells by the compounds of the present invention, respectively.
  • Figure 2a shows RWPE1 cells
  • Figure 2b shows HPrEC cells
  • Figure 2c shows PC3 cells
  • Figure 2d shows DU145 cells.
  • Figure 3a and Figure 3b show the growth inhibition effects of different compounds M1 and M3 and different doses of compound M3 on prostate cancer xenografts in nude mice, respectively.
  • Figure 4 shows the chemical structural formula of the compound M3 of the present application.
  • Figures 5a, 5b, 5c, and 5d show the effects of compound M3 on body weight, heart, liver, and kidney function in nude mice, respectively.
  • the synthetic route is as follows:
  • suberic anhydride suberic acid (5.0 g, 28.7 mmol) was added to 10 mL of acetic anhydride and stirred under reflux for 1 h, then cooled to room temperature. 4.3 g of solid (yield 96%).
  • the same number of prostate cancer cell line DU145 was planted in a 6-well culture dish. After the cells were attached for 24 hours, different doses of the compound M3 (50, 100 and 150 uM) were used to treat prostate cancer cell line DU145. Compound M1 was used as a control. drug. After 24 hours, the cells were harvested for Western blot to detect the protein levels of UHRF1 and histone H3 and acetylated H3. The results showed that the compound M3 of the present invention specifically reduced the protein level of the oncogene UHRF1 in prostate cancer cells in a dose-dependent manner, while causing an increase in the level of acetylation of histone H3, but the level of total histone H3 was not affected. Due to the dual targeting of UHRF1 and HDAC by drugs, the protein expression of the common downstream gene DNMT1 was significantly reduced (Fig. 1). The results of the experiments in this experiment demonstrate that the compounds of the invention specifically target both UHRF1 and HDAC molecules.
  • the present compound M3 kills prostate cancer cells in a dose-dependent manner, but is less toxic to normal cells.
  • Prostate cancer cells PC3 and DU145 cells, as well as non-cancerous normal cells were planted in 96-well cell culture dishes. Different doses of this compound M3 were used to treat prostate cancer cells PC3 and DU145 cells, and prostate cancer was normal. Cells RWPE1 and HPrEC. After 72 hours of drug treatment, the survival rate of the cells was measured using the MTS method, and the IC50 value of the compound M3 of the present invention in different cells was calculated using software.
  • the present compound M3 has a significant inhibitory effect on the growth of prostate cancer xenografts in nude mice.
  • the compound M3 (200 mg/kg/day) was intragastrically administered once a day, 5 days a week, and rested for 2 days, for a total of 4 weeks of continuous treatment, and the solvent DMSO was used as a control.
  • the body weight of the mice was measured every 3 days before and after treatment.
  • blood was taken, serum was separated, and changes in biochemical parameters were examined, including: liver function alanine aminotransferase (AST) and aspartate aminotransferase (ALT), renal function urea nitrogen (BUN) and creatinine (CREA), and cardiac function.
  • AST liver function alanine aminotransferase
  • ALT aspartate aminotransferase
  • BUN renal function urea nitrogen
  • CREA creatinine
  • cardiac function Heart function creatine kinase
  • CK lactate dehydrogenase
  • LDH-L lactate dehydrogenase

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Abstract

本发明公开了一种化合物及其在药学上可接受的盐，其可通过双靶向UHRF1和HDAC1的化学小分子或其药学上可以接受的盐作为相应的抑制剂或治疗疾病的药物，以用于单独或者联合其他方法治疗骨髓异样增殖综合征，银屑病，瘢痕增生，前列腺或乳腺增生，血液肿瘤和实体癌症，且治疗效果很好。

Description

一种化合物及其在药学上的应用 技术领域
本发明涉及一种化合物及其在药学上的应用，特别涉及通过双靶向UHRF1和HDAC1的化学小分子及其药学上的应用。
背景技术
HDAC家族分子和DNMT1是表观遗传重要的调节分子，虽然在几个肿瘤组织中表达较高，但是也不同程度表达在不同的正常组织和器官。HDAC抑制剂伏立诺他或西达苯胺在临床上对皮肤T细胞淋巴瘤，DNMT1抑制剂如5-扎胞苷和地西他滨对骨髓增殖异常综合征显示出了较好的治疗效果，但是他们显示出了不同程度的毒副作用，因而在实体肿瘤中应用有限。UHRF1是一个表观遗传中调节DNA甲基化的重要基因，同时也参与了DNA复制和DNA损伤修复的调控。UHRF1也是一个癌基因，在正常组织中表达低(与HDAC1和DNMT1比较低5到70倍)，但在多种血液肿瘤和实体癌症组织中表达高，因而是一个非常理想的抗癌药物靶点。应用RNAi干扰敲降UHRF1显著地减低了细胞增殖，促进了细胞对放化疗的敏感性。因此，发展有效的化学小分子靶向UHRF1和HDAC1，可用于单独或者联合其他方法治疗增殖性异常疾病和疾患，包括但不限于骨髓异样增殖综合征，银屑病，瘢痕增生，前列腺或乳腺增生等增生性疾病，良性肿瘤、血液肿瘤和实体癌症，包括神经内分泌转化的癌症类型。
发明内容
本发明解决的技术问题是，通过双靶向UHRF1和HDAC1的化学小分子或其药学上可以接受的盐作为相应的抑制剂或治疗疾病的药物，以用于单独或者联合其他方法治疗上述疾病，用于提高相关药物的药效。
本发明的技术方案是，提供一种化合物及其在药学上可接受的盐，该化合物的化学式为：
Figure PCTCN2018119300-appb-000001
其中，n选自1～7的正整数，R选自以下取代基中的一种：-H、-F、-Cl、-Br、-I、-NH 2、-OH、-CN、-SH、-CF 3、-CH 3、-CH 2CH 3、
Figure PCTCN2018119300-appb-000002
上述通式中，R基团的变化可以影响化合物的溶解度和结晶性能。
优选地，所述化合物的化学式为：
Figure PCTCN2018119300-appb-000003
优选地，所述在药学上可接受的盐为：氯化物、溴化物、碘化物、磷酸盐、硫酸盐、碳酸盐、碳酸氢盐、甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、吡啶甲酸盐、富马酸盐、马来酸盐、苹果酸盐、琥珀酸盐、甲磺酸盐、甲苯磺酸盐、三氟甲磺酸盐、四氟硼酸盐或六氟硫酸盐。
本发明还提供上述化合物及其在药学上可接受的盐在制备治疗(单独或者联合其他方法治疗)骨髓异样增殖综合征、银屑病、瘢痕增生、前列腺增生、乳腺增生、血液肿瘤及肿瘤(主要指实体癌症)的应用。
本发明还提供上述化合物及其在药学上可接受的盐在制备UHRF1和/或HDAC1抑制剂中的应用。
上述化合物的合成路线是相同的，其中，n的取值和取代基R的变化不会影响上述合成
路线。以目标化合物
Figure PCTCN2018119300-appb-000004
为例，其合成路线为：
Figure PCTCN2018119300-appb-000005
本发明的有益效果是，本发明的化合物及其药学上可接受盐类可以同时以UHRF1和/或HDAC1为靶点，用于制备相应的药物，这些药物可单独或者联合其他方法治疗增殖性异常疾病和疾患，包括但不限于骨髓异样增殖综合征，银屑病，瘢痕增生，前列腺增生、乳腺增生等增殖性疾病，良性肿瘤、血液肿瘤和实体癌症，且治疗效果很好。
附图说明
图1表示应用不同剂量的对照药物化合物M1(一个已经公开发表的UHRF1的小分子抑制剂NSC232003(2016，European Journal of Medicinal Chemistry,114:390-396)、实施例1制备的化合物M3的分子的靶向性实验结果。
图2a、图2b、图2c、图2d分别表示本发明化合物选择性杀伤不同癌细胞的IC50值。图2a为RWPE1细胞、图2b为HPrEC细胞、图2c为PC3细胞、图2d为DU145细胞。
图3a和图3b分别表示不同化合物M1与M3、不同剂量化合物M3对前列腺癌裸鼠移植瘤生长抑制效果趋势图。
图4表示本申请的化合物M3的化学结构式。
图5a、图5b、图5c、图5d分别表示表示化合物M3对裸鼠的体重、心、肝、肾功能的影响。
具体实施方式
下面结合实施例对本发明作进一步说明。
实施例1：化合物M3的合成
合成路线如下：
Figure PCTCN2018119300-appb-000006
1、辛二酸酐的合成：辛二酸(5.0g，28.7mmol)加入到10mL醋酸酐中加热搅拌回流1h，然后冷却到室温，减压蒸除溶剂，得到黄色固体用乙腈重结晶，得白色固体4.3g(产率96％)。 1HNMR(400MHz，CDCl 3)：δ2.41(m,4H),1.62(m,4H),1.34(m,4H).
2、8-((2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)amino)-8-oxooctanoic acid(8-羰基(5-氨基尿嘧啶)辛酸)的合成：辛二酸酐(1.6g，10.0mmol)用20mL THF溶解，冰浴下搅拌并加入氨基尿嘧啶(1.3g，10.0mmol)，然后室温搅拌30min，混合物用水稀释，析出白色固体，过滤并收集固体，水重结晶得白色固体2.7g(产率96％)。 1HNMR(400MHz，DMSO)：δ12.05(br,1H),11.47(br,1H),10.66(s,1H),9.07(s,1H),8.09(s,1H),8.06(s,1H),2.32-2.35(m,2H),1.94-1.96(m,2H),1.47-1.52(m,4H),1.26-1.29(m,4H).
3、N1-(羰基-5-氨基尿嘧啶)-N8-辛羟基酰胺的合成：将8-((2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)amino)-8-oxooctanoic acid(8-羰基(5-氨基尿嘧啶)辛酸)(1.4g，5.0mmol)溶解在20mL无水THF中，温度控制在0℃，加入氯甲酸乙酯(600mg，6.0mmol)和三乙胺(0.7mL)，然后混合物搅拌10min，然后过滤除掉生成的固体，滤液加入新制取的羟胺的甲醇溶液(170mg in 2mL，5.0mmol)，然后反应液室温搅拌15min，然后蒸除溶剂，残留物用乙腈重结晶的白色固体890mg(产率60％)。ESI-MS:[M+H] +＝299.10； 1HNMR(400MHz，DMSO)：δ11.41(br,1H),10.65(br,1H),10.37(s,1H),9.06(s,1H),8.68(s,1H),8.06(s,1H),2.33-2.35(m,2H),1.94(t,J＝8.0Hz,2H),1.46-1.52(m,4H),1.22-1.52(m,4H).
实施例2：生物学活性检测：
实验条件：
我们分别利用前列腺癌细胞，和前列腺癌细胞诱导的肿瘤移植瘤模型，检测了本发明化合物M3对UHRF1和HDAC1的分子靶向作用，不同浓度的本发明化合物M3对前列腺癌细胞以及对照正常细胞增殖的影响，以评价其体外抗癌活性，预测其安全性，评价本发明化合物M3口服对裸鼠前列腺癌移植瘤生长的影响。为了更好地评价本发明化合物M3药效和安全性，我们应用了一个已经公开发表的UHRF1的小分子抑制剂NSC232003(2016，European Journal of Medicinal Chemistry,114:390-396)作为对照，在下面的数据和图标中标注为M1。
实验结果：
(1)本化合物M3对于UHRF1和HDAC1分子的靶向性。
将同等数量的前列腺癌细胞系DU145种植在6-孔培养皿中，24小时待细胞贴壁后，应用不同剂量的本化合物M3(50，100和150uM)治疗前列腺癌细胞DU145，化合物M1作为对照药物。24小时后，收获细胞进行Western blot，检测UHRF1以及组蛋白H3和乙酰化的H3的蛋白水平。结果显示，本发明化合物M3以剂量依赖的方式特异性降低前列腺癌细胞中癌基因UHRF1的蛋白质水平，同时引起组蛋白H3的乙酰化水平增高，但是总的组蛋白H3的水平没有影响。由于药物对UHRF1和HDAC具有双重靶向作用，其共同的下游基因DNMT1的蛋白表达显著降低(图1)。本实验的研究结果证实本发明化合物特异性双重靶向UHRF1和HDAC分子。
(2)本化合物M3以剂量依赖的方式杀伤前列腺癌细胞，但对正常细胞的毒性较低。
前列腺癌细胞PC3和DU145细胞，以及非癌性的正常细胞(5000细胞/孔)种植在96孔细胞培养皿中，应用不同剂量的本化合物M3治疗前列腺癌细胞PC3和DU145细胞，以及前列腺癌正常细胞RWPE1和HPrEC。药物治疗72小时后，应用MTS方法检测细胞的存活率，应用软件计算本发明化合物M3在不同细胞中的IC50值。
结果显示：本发明化合物对前列腺癌细胞PC3和DU145具有明显的细胞毒性，其半致死剂量(IC50)均小于50uM，但是对正常前列腺癌上皮细胞RWPE1和HPrEC的半致死剂量(IC50)显著增高，均大于300uM。通过比较发现，本发明化合物M3对前列腺癌细胞的杀伤具有很好的选择性。(图2a-图2d)
(3)本化合物M3对于前列腺癌裸鼠移植瘤的生长具有明显的抑制作用。
应用前列腺癌DU145细胞(1×10 6)通过皮下注射在免疫缺陷小鼠中建立皮下移植瘤模型。大概2-3周，待移植瘤的体积达到250mm 3左右时，应用本化合物(100mg/kg/day)灌胃，每天1次，每周5天，中间休息2天，一共连续治疗4周。化合物M1和溶剂DMSO作为对照。在治疗前和治疗后每3天测量一次肿瘤大小。肿瘤的大小根据公式V＝长×宽 2/2进行计算。
结果显示：在前列腺癌细胞DU145建立的移植瘤模型中，本发明实施例1的化合物M3与对照药物M1相比，显著地减少了肿瘤生长。(图3a和图3b)本发明化合物显示出了非常显著的抗肿瘤活性。
实验结论：体外细胞实验和动物实验证实，本发明化合物M3对于UHRF1和HDAC1分子具有很好的靶向作用；对于前列腺癌细胞具有非常特异的杀伤作用；明显地抑制前列腺癌裸鼠移植瘤的生长。
(4)本化合物M3具有显著的安全性。
在免疫缺陷裸鼠中，应用本化合物M3(200mg/kg/day)灌胃，每天1次，每周5天，中间休息2天，一共连续治疗4周，溶剂DMSO作为对照。在治疗前和治疗后每3天测量一次老鼠体重。在实验结束时，取血，分离血清，检测生化指标的变化，具体包括：肝功能谷丙转氨酶(AST)和谷草转氨酶(ALT)，肾功能尿素氮(BUN)和肌酐(CREA)和心功能心功能肌酸激酶(CK)和乳酸脱氢酶(LDH-L)，评价化合物M3对心、肝、肾功能的影响。
结果显示：本发明实施例1的化合物M3(剂量200mg/kg/day)没有显著地减轻裸鼠的体重(图5a)。对肝、肾和心功能没有明显影响(图5b,5c和5d)。
实验结论：体外细胞实验和动物实验证实，本发明化合物M3具有显著的安全性。
另外，根据实施例相同的制备方法制备得到结构相似的衍生物
Figure PCTCN2018119300-appb-000007
Figure PCTCN2018119300-appb-000008
这些衍生物与化合物M3的区别在于侧链的长度不同，但是根据初步的实验发现，这些衍生物的药物活性在相同的模型中均不理想，说明侧链长度对药物活性存在较大的影响。

Claims (5)

  1. 一种化合物及其在药学上可接受的盐，其特征在于，该化合物的化学式为：
    Figure PCTCN2018119300-appb-100001
    其中，n选自1～7的整数，R选自以下取代基中的一种：-H、-F、-Cl、-Br、-I、-NH 2、-OH、-CN、-SH、-CF 3、-CH 3、-CH 2CH 3、
    Figure PCTCN2018119300-appb-100002
  2. 如权利要求1所述的化合物及其在药学上可接受的盐，其特征在于，所述化合物的化学式为：
    Figure PCTCN2018119300-appb-100003
  3. 如权利要求1或2所述的化合物，其特征在于，所述在药学上可接受的盐为：氯化物、 溴化物、碘化物、磷酸盐、硫酸盐、碳酸盐、碳酸氢盐、甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、吡啶甲酸盐、富马酸盐、马来酸盐、苹果酸盐、琥珀酸盐、甲磺酸盐、甲苯磺酸盐、三氟甲磺酸盐、四氟硼酸盐或六氟硫酸盐。
  4. 权利要求1-3中任一项所述的化合物及其在药学上可接受的盐在制备治疗骨髓异样增殖综合征、银屑病、瘢痕增生、前列腺增生、乳腺增生、血液肿瘤和实体癌症的药物中的治疗方法的应用。
  5. 权利要求1-3中任一项所述的化合物及其在药学上可接受的盐在制备UHRF1和/或HDAC1抑制剂中的应用。
PCT/CN2018/119300 2018-01-16 2018-12-05 一种化合物及其在药学上的应用 WO2019141009A1 (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007095584A2 (en) * 2006-02-14 2007-08-23 The President And Fellows Of Harvard College Histone Deacetylase Inhibitors
CN103159646A (zh) * 2013-03-19 2013-06-19 广东药学院 一种异羟肟酸类化合物及其制备方法和应用
CN106883217A (zh) * 2017-04-01 2017-06-23 清华大学深圳研究生院 一种核苷碱基异羟肟酸衍生化合物及其制备方法与应用
CN107011270A (zh) * 2010-11-16 2017-08-04 阿塞蒂隆制药公司 作为蛋白质去乙酰化酶抑制剂的嘧啶羟基酰胺化合物和其使用方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2750413C (en) * 2009-01-23 2016-06-21 Northlake Biosciences Llc Hydroxamic acid derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007095584A2 (en) * 2006-02-14 2007-08-23 The President And Fellows Of Harvard College Histone Deacetylase Inhibitors
CN107011270A (zh) * 2010-11-16 2017-08-04 阿塞蒂隆制药公司 作为蛋白质去乙酰化酶抑制剂的嘧啶羟基酰胺化合物和其使用方法
CN103159646A (zh) * 2013-03-19 2013-06-19 广东药学院 一种异羟肟酸类化合物及其制备方法和应用
CN106883217A (zh) * 2017-04-01 2017-06-23 清华大学深圳研究生院 一种核苷碱基异羟肟酸衍生化合物及其制备方法与应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 114, 2016, pages 390 - 396
See also references of EP3741748A4
YI-MIN LIU ET AL.: "Pyrimidinedione-mediated selective histone deacetylase 6 inhibitors with antitumor activity in colorectal cancer HCT116 cells", ORGANIC&BIOMOLECULAR CHEMISTRY, 17 August 2015 (2015-08-17), XP055628073 *

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