CN117285566A - 一种膦酸酯类化合物及其医药用途 - Google Patents
一种膦酸酯类化合物及其医药用途 Download PDFInfo
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- 125000006239 protecting group Chemical group 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
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- 238000005057 refrigeration Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- GYEMIEGAEOIJQR-UHFFFAOYSA-M silver;2-methylpropanoate Chemical compound [Ag+].CC(C)C([O-])=O GYEMIEGAEOIJQR-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- DFVFTMTWCUHJBL-BQBZGAKWSA-N statine Chemical compound CC(C)C[C@H](N)[C@@H](O)CC(O)=O DFVFTMTWCUHJBL-BQBZGAKWSA-N 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
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- NPDBDJFLKKQMCM-UHFFFAOYSA-N tert-butylglycine Chemical compound CC(C)(C)C(N)C(O)=O NPDBDJFLKKQMCM-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- BJBUEDPLEOHJGE-IMJSIDKUSA-N trans-3-hydroxy-L-proline Chemical compound O[C@H]1CC[NH2+][C@@H]1C([O-])=O BJBUEDPLEOHJGE-IMJSIDKUSA-N 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
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Abstract
一种膦酸酯类化合物,或其药学上可接受的盐或酯,在制备用于治疗、抑制或预防病毒感染或细胞增殖所引发疾病的药物中的用途,尤其可用于治疗、抑制或预防包括人类在内的哺乳动物所受的猴痘病毒感染或由猴痘病毒感染引起的疾病。
Description
技术领域
本发明涉及一种膦酸酯类化合物或其药学上可接受的盐或酯,及其在制备用于治疗、抑制或预防病毒感染疾病或细胞增殖疾病的药物中的用途。
背景技术
西多福韦是一种无环核苷膦酸酯(ANP)类似物,实质上是核苷单磷酸类似物,具有代谢稳定的优势。目前的研究已经证明,西多福韦具有对抗所有DNA病毒的广谱活性,包括腺病毒、多瘤病毒、乳头瘤病毒和痘病毒。在痘病毒中,牛痘苗、天花、牛痘、猴痘、骆驼痘、传染性软疣和羊痘病毒(orf)[De Clercq,Antiviral Research 2002,55,2002,113]。
猴痘是一种病毒性人畜共患病,人类感染后出现的症状与过去在天花患者身上所看到的症状相似。但是自1980年世界上消灭天花以后,天花已不复存在,而猴痘仍然在非洲部分地区散发。猴痘发生于非洲中西部雨林中的猴类,也可感染其他动物,偶可使人类受感染。临床表现类似天花,但病情较轻。这种疾病由猴痘病毒造成,这种病毒可以通过直接密切接触由动物传染给人,也可以在人与人之间传播。2022年猴痘疫情最先被英国在当地时间2022年5月7日发现。当地时间5月20日,随着欧洲确诊和疑似猴痘病例超过100例。
由于西多福韦的膦酸酯部分在生理PH下带负电,因此西多福韦无法穿过富含脂质的细胞膜,这阻碍了其抗病毒活性和生物利用度[De Clercq,Antiviral Research 2002,55,2002,113]。西多福韦还会导致肾功能不全[De Clercq&Holy,Nat.Rev.DrugDiscov.2005,4,928-940]。为了降低西多福韦的肾毒性,研发人员合成了环状西多福韦(cHPMPC)[Bischofberger等人.Antimicrob.Agents Chemother.1994,38,2387-2391]。不幸的是,由于剩余的膦酸酯在生理pH下带负电的问题,cHPMPC的生物利用度依旧很低。在西多福韦的基础上,研究人员已经设计出了一批类似物或前药,例如布林西多福韦(Brincidofovir,简称BCV,US8962829),然而如何设计出一款具有更好的ADMET(药物的吸收,分配,代谢,排泄和毒性)的西多福韦前药,仍是需要解决的问题。
发明内容
本申请主要解决的技术问题是提供一种膦酸酯类的前药,该前药能够具有至少以下效果中的一种或多种:
1)改变体内的药代动力学性质,调整药物在体内的吸收和分布;
2)改善药物的稳定性和溶解性;
3)减低毒性和不良反应;
4)提高向特定部位的转运和分布;以及
5)提高缓释效果,延长作用时间。
一方面,本发明提供一种式(I)所示的膦酸酯类化合物或其药学上可接受的盐或酯:
其中,X选自-OR6,或者X与R3组合成一个化学键;
R1选自H或C4-C30羰基,所述C4-C30羰基包括取代或未取代的烃基羰基、取代或未取代的芳基羰基或杂环羰基以及取代或未取代的烃氧基羰基,且所述C4-C30羰基的碳数为4~30,可以是4~10、10~30或20~30,具体地可以是10、12、14、16、18、20、22、24、26、28、30;
R2、R6独立地选自H、其中R7选自取代或未取代的C15-C30烃基,具体地可以是C16、C17、C 18、C19、C20烷基,且所述烃基可以是直链烃基或支链烃基,尤其是直链烃基;
R3选自:H、甲酰基、C4-C30羰基,其中所述C4-C30羰基包括取代或未取代的烃基羰基、取代或未取代的芳基羰基或杂环羰基,以及取代或未取代的烃氧基羰基,且所述羰基的碳数不大于30,或氨基酸残基;
R4、R5独立地选自氢(H)或氘(D);
作为限制的,当X为-OR6时,所述R1、R2、R3、R6不同时为H,且所述化合物不是布林西多福韦;当X与R3组合成一个化学键时,所述R1、R2不同时为H。
进一步地,上述化合物为式(II)所示的化合物:
在一些优选的实施方式中,式II中,R1选自取代或未取代的芳基羰基,尤其是取代或未取代的苯基羰基;C1-C6烷基羰基,尤其是C1-C4烷基羰基;并且
R2为其中R7选自取代或未取代的C15-C20,尤其是C16-C20直链烃基。
进一步地,上述化合物为式(III)所示的化合物:
作为限制的,当X为-OR6时,所述R1、R3、R6不同时为H;当X与R3组合成一个化学键时,所述R1不为H。
在一些实施方式中,式III中,R1选自H;取代或未取代的芳基羰基,尤其是取代或未取代的苯基羰基;CH3OCH2CH2O羰基;C1-C5烷基氧羰基;CH3OCH2CH2OCH2CH2OCH2CH2O羰基;CH3CH2CH2COOCH(CH3)O羰基;取代或未取代的杂芳基烷基氧羰基,尤其是取代或未取代的五元环碳酸酯基C1-C2烷氧基羰基,诸如取代或未取代的杂芳基烷基氧羰基、(CH3)2CHCOOCH(CH3)O羰基、CH3COOCH(CH3)O羰基
R3选自H;甲酰基、取代或未取代的芳基羰基,尤其是取代或未取代的苯基羰基;C1-C5烷基氧羰基;CH3OCH2CH2OCH2CH2OCH2CH2O羰基;C1-C8烷基羰基;(CH3)2CHCOOCH(CH3)O羰基;取代或未取代的杂芳基烷基氧羰基,尤其是取代或未取代的五元环碳酸酯基C1-C2烷氧基羰基,诸如(CH3)2CHCOOCH(CH3)O羰基;以及
X为羟基。
在一些实施方式中,上述化合物为(IIIa)或(IIIb)所示的化合物:
其中所涉及的X、R1或R3如上文所限定。
优选地,式(IIIa)中,R3为H;
一些实施例中,R3为
一些实施例中,上述化合物为式(IV)所示的化合物:
作为限制的,当X为-OR6时,所述R1、R3、R6不同时为H;当X与R3组合成一个化学键时,所述R1不为H。
在一些实施方式中,上述化合物为(IVa)或(IVb)所示的化合物:
其中所涉及的X、R1或R3如上文所限定。
进一步地,在上述所有通式中,R1选自取代或未取代的烃基羰基,具体地,包括以下所示的基团:
进一步地,上述R1选自取代或未取代的芳基羰基或杂环羰基,具体地,包括以下所示的基团:
其中,Y选自H、F、Cl、Br、Me、-OMe、-OEt、-CF3或-CN。
进一步地,上述R1选自取代或未取代的烃氧基羰基,具体地,包括以下所示的基团:
进一步地,上述R7包括以下基团:
具体地,R3包括以下基团;
一些实施例中,R3为一些实施例中,R3为/>进一步地,上述化合物包括式(Va)~式(Vd)所示的化合物:
化合物包括以下表1a、1b所示的化合物:
表1a
/>
/>
/>
/>
表1b
/>
本申请提供的化合物,可用于制备治疗、抑制或预防病毒感染或病毒感染所致疾病的药物。在一些实施方式中,病毒感染包括乙肝病毒(HBV)、新冠病毒(SARS-COV-2)、人类免疫缺陷病毒(HIV)、水痘带状疱疹病毒(VZV)、巨细胞病毒(CMV)、单纯疱疹病毒(HSV)、BK病毒、JC病毒、爱泼斯坦-巴尔病毒(EBV)、埃博拉病毒、多瘤病毒、乳头瘤病毒、正痘病毒、丙肝病毒(HCV)、呼吸道合胞体病毒(RSV)、登革热病毒、流感病毒、腺病毒、副流感病毒和/或鼻病毒引起的感染。
进一步地,上述正痘病毒包括重型和轻型天花病毒、猴痘病毒、牛痘病毒、骆驼痘病毒、传染性软疣、羊痘病毒、aractuba病毒、BeAn 58058病毒、cantagalo正痘病毒、小鼠痘病毒、象痘病毒、牛痘苗病毒(VV)、兔痘病毒、浣熊痘病毒、臭鼬痘病毒、沙鼠痘病毒和田鼠痘病毒。优选的,本申请公开的化合物可用于制备治疗、抑制或预防哺乳动物的猴痘病毒或天花病毒感染所致疾病的药物。
本申请提供的化合物,可用于制备治疗、抑制或预防病毒感染引发疾病的药物。进一步地,病毒感染引发的疾病包括DNA病毒感染所引起的疾病,具体地,疾病选自视网膜炎、肺炎、膀胱炎、蛋白质病变等。
本申请提供的化合物,还可用于制备治疗、抑制或预防细胞增殖引发疾病的药物。进一步地,细胞增殖引发疾病为肿瘤或癌症,具体地,肿瘤或癌症选自多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、套细胞淋巴瘤(MCL)、实体瘤、难治性实体瘤、非霍奇金淋巴瘤、血液瘤、神经母细胞瘤、结直肠癌、宫颈癌、肺癌、白血病、乳腺癌、胰腺癌、B-细胞恶性肿瘤、肿瘤、转移性肿瘤和结肠癌。
本申请还提供一种药物组合物,包括上述化合物中的一种或多种,以及至少一种药学上可接受的载体或赋形剂。具体地,药学上可接受的载体包括乳膏、乳剂、凝胶、脂质体和纳米颗粒中的一种或多种;药学上可接受的赋形剂包括粘合剂、填充剂、崩解剂、润滑剂和助流剂中的一种或多种。
进一步地,上述药物组合物适用于口服施用或者注射施用。
本申请还提供一种试剂盒,该试剂盒包括上述任意一种或多种化合物或药学上可接受的盐或酯或者任意一种或多种药物组合物。
本申请提供的特定化合物或其药学上可接受的盐或酯或者含有其的药物组合物,能够有效地治疗、抑制或预防哺乳动物的病毒感染和/或细胞增殖疾病,尤其是天花和猴痘,且至少具有改变体内的药代动力学性质、调整药物在体内的吸收和分布、改善药物的稳定性和溶解性、减低毒性和不良反应、提高向特定部位的转运和分布、提高缓释效果、延长作用时间等效果中的一种或多种。
具体实施方式
为了对本发明的说明书中所使用的术语提供清楚且一致的理解,在下文中提供一些定义。此外,除了特殊说明,本发明所用的全部技术和科学术语具有同本发明所属领域中普通技术人员通常所理解的相同的含义。
当在权利要求和/或说明书中与术语“包括”结合使用时,词语“一”的使用可以表示“一个/种”,但它也与“一个/种或多个/种”,“至少一个/种”和“一个/种或多于一个/种”的含义已知。类似地,词语“另一个/种”可以表示至少第二个/种或者很多个/种。
如在本说明书和权利要求中所使用的词语“包括”、“具有”以及同义词是包括性的和开放式的,并且不排除另外的未列出的要素或处理步骤。术语“约”或“大约”用于表示该值包括在确定该值中所用的仪器和方法带来的误差。
本发明所用术语“药学上可接受的”是指该术语描述的药物、药品、惰性成分等,适合用于与人和低等动物的组织相接触,而没有异常毒性、不相容性、不稳定性、刺激性、过敏反应等,与合理的利益/风险比率相称。它优选的是在药典或其它公认的药典中列出的用于动物,更特别是用于人的化合物、组合物以及制剂等。
化合物的“药学上可接受的盐”是指药学上可接受的化合物的盐。理想的化合物的盐(碱性、酸性或带电官能团)可以保留或改善如本发明所定义的母体化合物的生物活性和性质,并且不是生物学上不需要的。
术语“酯”意指衍生自本申请中各个通式化合物的酯,其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
术语“前药”或其等同表述是指在体外或体内直接或间接转化成活性形式的药剂(例如参见R.B.Silverman,1992,"The Organic Chemistry of Drug Design and DrugAction,"Academic Press,Chap.8;Bundgaard,Hans;Editor.Neth.(1985),"Design ofProdrugs".360pp.Elsevier,Amsterdam;Stella,V.;Borchardt,R.;Hageman,M.;Oliyai,R.;Maag,H.;Tilley,J.(Eds.)(2007),"Prodrugs:Challenges and Rewards,XVIII,1470p.Springer)。前药可用于改变具体药物的生物分布(例如,使药剂通常不会进入蛋白酶反应位点)或药代动力学。已经使用多种基团例如酯、醚、磷酸酯/盐等来修饰化合物以形成前药。当将前药施用至受试者时,该基团通过酶促或非酶促、还原、氧化或水解地裂解掉,或者以其它方式释放出活性化合物。如本文中所使用的,“前药”包括药学上可接受的盐,或药学上可接受的溶剂化物,以及上文的任何结晶形式。前药通常(尽管不一定)是药学上无活性的,直至其转化为活性形成。
应当理解的是本发明所用术语“取代”或“被取代”包括隐含的条件,即这种取代随着取代原子化合价和取代基的变化,取代产生稳定的化合物(例如化合物不能自发进行重排、环化、消除等过程)。如本发明所用术语“取代的”包括有机化合物所有允许的取代基。在广义上,允许的取代基包括的无环和环状,支链化和非支链化,碳环和杂环,芳香族和非芳香族的有机化合物。取代基可以是一个或多个。例如,术语“取代的”是指当上述基团与在一个或多个位置被取代时,取代基包括酰基氨基(包括氨基甲酰基和脲基)、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、烷氧基羰基、羧基、羧基、氨基羰基、单和二烷基氨基羰基、氰基、叠氮基、卤素(F、Cl、Br和I)、羟基、硝基、三氟甲基、硫基、烷硫基、芳硫基、烷硫基羰基、硫代羧酸酯、低烷基、低链烯基、低炔基、环烷基、杂环烷基、芳基、杂芳基、低烷氧基、芳氧基、芳氧基羰氧基、苄氧基、苄基、亚磺酰基、烷基亚磺酰基、磺酰基、硫酸盐、磺酸盐、磺酰胺、磷酸盐、膦酸盐、亚氨基、甲酰基等。如果允许,任何上述取代基可以进一步被取代,例如被烷基、芳基或其它基团取代。
术语“烃基羰基”、“芳基羰基”、“杂环羰基”或“烃氧基羰基”指-C(=O)Ra,Ra含有烃基、芳基、杂芳基、杂环基或烃氧基。术语“烃氧基”指-ORb,Rb为烃基。例如,表述“C4-C30羰基”是指其中Ra具有3至29个碳原子的“-C(=O)Ra”,具体地,碳原子数可以是3、9、11、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29,并且Ra可为取代或未取代的烃基、取代或未取代的芳基、取代或未取代的三元环、四元环、五元环、取代或未取代的烃氧基。
术语“C15-C30烃基”表示在烃基结构中具有15至所示30个碳原子,具体地,碳原子数可以是15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30,术语“C1-C16烃基”表示在烃基结构中具有1至所示16个碳原子,具体地,碳原子数可以是1、2、3、4、
本发明所用术语“芳基”或“芳基环”是指在共轭单环或多环体系(稠和或非稠和的)中具有“4n+2”个(π)电子,并具有6至14个环原子的芳族基团,其中n是1至3的整数。多环系统包括至少一个芳环。芳基可以直接连接或通过C1-C3烷基(也称为芳基烷基或芳烷基)连接。芳基的实例包括但不限于苯基、苄基、苯乙基、1-苯基乙基、甲苯基、萘基、联苯基、三联苯基、茚基、苯并环辛烯基、苯并环庚烯基、薁基、苊基、芴基、菲基、蒽基等。术语芳基包括未取代的芳基和取代的芳基。
本发明所用术语“杂芳基”或“杂芳基环”是指在共轭单环或多环体系(稠和或非稠和的)中具有“4n+2”个(π)电子的芳族基团,其中n是1至3的整数,并包括一个至六个杂原子(例如N、O、S、P)或者包括杂原子(例如NH、NRx(Rx是烷基、酰基、芳基、杂芳基或环烷基)、PO2、SO、SO2等)的基团。多环系统包括至少一个杂芳环。杂芳基可以直接连接或通过C1-C3烷基(也称为杂芳基烷基或杂芳烷基)连接。杂芳基可以与碳连接的或者与杂原子连接的(例如,通过氮原子)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、四唑基、呋喃基、噻吩基;异恶唑基、噻唑基、恶唑基、异噻唑基、吡咯烷基、喹啉基、异喹啉基、吲哚基、异吲哚基、色烯基、异色烯基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、吡嗪基、三嗪基、异吲哚基、喋啶基、呋喃基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噻唑基、苯并恶唑基、喹唑啉基、喹啉基、喹啉酮基、异喹啉酮基、喹喔啉基、萘啶基、呋喃并吡啶基、咔唑基、菲啶基、吖啶基、苝基、菲咯啉基、吩嗪基、吩噻嗪基、吩恶嗪基、二苯并呋喃基等。术语杂芳基包括未取代的杂芳基和取代的杂芳基。术语“C5-Cn杂芳基”,其中n是6至15的整数,表示在环结构中具有从5至所示“n”个原子的杂芳基,包括至少一个如上所定义的杂环基团或原子。
在一些实施方式中,本发明提供了一种膦酸酯类化合物,或其药学上可接受的盐或酯,在制备用于治疗、抑制或预防病毒感染疾病或细胞增殖疾病的药物中的用途,该膦酸酯化合物选自但不限于表1a和表1b所列化合物。
术语“氨基酸残基”是指氨基酸上的羧基脱羟基基团后的主要部分。
本发明所用术语“氨基酸”通常是指同时包含羧酸基团和氨基基团的有机化合物。术语“氨基酸”包括“天然”和“非天然”的氨基酸。另外,术语氨基酸包括O-烷基化或N-烷基化的氨基酸,以及具有含氮、硫或氧的侧链(例如Lys,Cys或Ser)的氨基酸,其中氮、硫或氧原子可以被或不被酰基化或烷基化。氨基酸可以是L-氨基酸,D-氨基酸或L-和D-混合的氨基酸,包括(但不限于)外消旋混合物。
本发明所用术语“天然氨基酸”和等同表达是指通常在天然存在的蛋白质中发现的L-氨基酸。天然氨基酸的实例包括但不限于丙氨酸(Ala),半胱氨酸(Cys),天冬氨酸(Asp),谷氨酸(Glu),苯丙氨酸(Phe),甘氨酸(Gly),组氨酸(His),异亮氨酸(Ile),赖氨酸(Lys),亮氨酸(Leu),甲硫氨酸(Met),天冬酰胺(Asn),脯氨酸(Pro),谷氨酰胺(Gln),精氨酸(Arg),丝氨酸(Ser),苏氨酸(Thr),色氨酸(Trp),酪氨酸(Tyr),β-丙氨酸(β-Ala)和γ-氨基丁酸(GABA)等。
本发明所用术语“非天然氨基酸”是指天然氨基酸的任何衍生物,包括D-型氨基酸及其衍生物,以及α-和β-氨基酸衍生物。应注意的是,在本发明中某些非天然氨基酸的(例如羟脯氨酸)可在自然界中存在于某些生物组织或特定蛋白质中。具有许多不同保护基团、适于固相肽合成中直接应用的氨基酸是可以通过购买得到的。除了二十个最常见的天然氨基酸,可以根据本发明使用如下实例的非天然氨基酸和氨基酸衍生物(括号中为常见的缩写):2-氨基己二酸(Aad),3-氨基己二酸(β-Aad),2-氨基丁酸(2-Abu),α,β-脱氢-2-氨基丁酸(8-AU),1-氨基环丙烷-1-羧酸(ACPC),氨基异丁酸(Aib),3-氨基异丁酸(β-Aib),2-氨基-噻唑啉-4-羧酸,5-氨基戊酸(5-Ava),6-氨基己酸(6-Ahx),2-氨基庚酸(Ahe),8-氨基辛酸(8-Aoc),11-氨基十一烷酸(11-Aun),12-氨基十二烷酸(12-Ado),2-氨基苯甲酸(2-Abz),3-氨基苯甲酸(3-Abz),4-氨基苯甲酸(4-Abz),4-氨基-3-羟基-6-甲基庚酸(Statine,Sta),氨基氧基乙酸(Aoa),2-氨基四氢化萘-2-羧酸(ATC),4-氨基-5-环己基-3-羟基戊酸(ACHPA),对氨基苯丙氨酸(4-NH2-Phe),2-氨基庚二酸(Apm),联苯基丙氨酸(Bip),对溴苯丙氨酸(4-Br-Phe),邻氯苯丙氨酸(2-Cl-Phe),间氯苯丙氨酸(3-Cl-Phe),对氯苯丙氨酸(3-Cl-Phe),间-氯酪氨酸(3-Cl-Tyr),对苯甲酰基苯丙氨酸(Bpa),叔丁基甘氨酸(TLG),环己基丙氨酸(Cha),环己基甘氨酸(Chg),锁链素(Des),2,2-二氨基庚二酸(Dpm),2,3-二氨基丙酸(Dpr),2,4-二氨基丁酸(Dbu),3,4-二氯苯丙氨酸(3,4-Cl2-Phe),3,4-二氟苯丙氨酸(3,4-F2-Phe),3,5-二碘酪氨酸(3,5-I2-Tyr),N-乙基甘氨酸(EtGly),N-乙基天冬酰胺(EtAsn),邻氟苯丙氨酸(2-F-Phe),间氟苯丙氨酸(3-F-Phe),对氟苯丙氨酸(4-F-Phe),间-氟酪氨酸(3-F-Tyr),高丝氨酸(Hse),高苯丙氨酸(Hfe),高酪氨酸羟基赖氨酸(Hyl),异羟基赖氨酸(aHyl),5-羟色氨酸(5-OH-Trp),3-或4-羟基脯氨酸(3-或4-Hyp),对碘苯丙氨酸-异酪氨酸(3-I-Tyr),二氢吲哚-2-羧酸(Idc),异艾杜霉素(Ide),异亮氨酸(α-Ile),异哌啶酸(Inp),N-甲基异亮氨酸(MeLys),间甲基酪氨酸(3-Me-Tyr),N-甲基缬氨酸(MeVal),1-萘基丙氨酸(1-Nal),2-萘基丙氨酸(2-Nal),对硝基苯丙氨酸(4-NO2-Phe),3-硝基酪氨酸(3-NO2-Tyr),正亮氨酸(Nle),正缬氨酸(Nva),鸟氨酸(Orn),邻磷酸酪氨酸(H2PO3-Tyr),八氢吲哚-2-羧酸(Penicillamine),五氟苯丙氨酸(F5-Phe),苯基甘氨酸(Phg),哌啶酸(Pip),炔丙基甘氨酸(Pra),焦谷氨酸(PGLU),肌氨酸(Sar),四氢异喹啉-3-羧酸(Tic),噻唑烷-4-羧酸(硫代脯氨酸,Th)。
本发明提供了治疗病毒感染、不适当的细胞增殖等有关的哺乳动物疾病的方法。这些方法具体包括给予需要治疗的人或其它哺乳动物治疗学有效量的本发明的化合物。
在一些实施方式中,本申请提供的化合物可用于制备一种药物,该药物可用于治疗、抑制或预防病毒感染或病毒感染引发疾病。在一些实施方式中,本申请提供的化合物及其药学上可接受的盐或酯用于制备治疗天花病毒感染或由天花病毒引发疾病的药物。在一些实施方式中,本申请提供的化合物及其药学上可接受的盐或酯用于制备治疗猴痘病毒感染或由猴痘病毒引发疾病的药物。
本申请提供的化合物,在治疗、抑制或预防病毒感染以及病毒感染所致疾病上具有很好的效果。同时,申请人发现本申请提供的化合物在治疗癌症或肿瘤上也有很好的效果。在一些实施方式中,本申请提供的化合物及其药学上可接受的盐或酯可用于制备药物,该药物可用于治疗、抑制或预防细胞增殖引发的肿瘤或癌症。
在一些实施方式中,本申请提供的药物还包括至少一种可药用的载体或稀释剂。在一些实施方式中,可药用的载体或稀释剂选自乳膏、乳剂、凝胶、脂质体或纳米颗粒。
本发明提供的化合物或药物可以以本领域已知的任何适当方式施用于受试者。合适的给药途径包括但不限于口服;肠胃外,例如肌内、静脉内、皮下(例如注射或植入)、腹腔内、脑池内、关节内、脑内(脑实质内和脑室内;鼻腔;阴道;舌下;眼内;直肠;局部(例如透皮);口腔和吸入。一般通过皮下或肌肉内给药的积存注射法也可用于在限定的时间段内释放本申请公开的化合物或药物。在一些实施方式中,药物是可注射的制剂。在其它实施方式中,药物被配制为用于口服施用至受试者。
本发明还提供了包含抗病毒感染化合物或药物的试剂盒。试剂盒通常为容纳各种组分的物理结构的形式,并且可用于例如实施本文提供的方法。例如,试剂盒可以包括本发明公开的一种或多种化合物或药物(例如提供在无菌容器中),其可为适合施用至受试者的药物组合物的形式。化合物可以以即用型(例如片剂或胶囊)形式或以需要例如在施用前重构或稀释(例如粉末)的形式提供。当化合物为需要使用者被重构或稀释的形式时,该试剂盒还可包括与化合物一起包装或者分别包装的稀释剂(例如无菌水)、缓冲液、药学上可接受的赋形剂等。当采用组合疗法时,试剂盒可独立地含有几种治疗剂,或者它们可已经在试剂盒中组合。试剂盒的每个组分可以被封装在单独的容器内,并且所有的各种容器可以在单个包装内。本发明的试剂盒可被设计用于适当地保持容纳在其中的组分所需的条件(例如,冷藏或冷冻)。
本文描述的药物或药物组合物可以通过药理学领域中已知的任何方法来制备。通常,此类准备的方法包括以下步骤:使在此描述的一种化合物(“活性成分”)与一种载体和/或一种或多种其他辅助成分结合,并且然后如果必要和/或希望,使产品成形和/或包装成希望的单剂量单位或多剂量单位。
其中药物或药物组合物可以呈一个单一单位剂量和/或呈多个单一单位剂量进行制备、包装和/或批量出售。如在此所使用,“单位剂量”是包含预定量的活性成分的药物组合物的离散量。该活性成分的量通常等于将要向受试者给予的该活性成分的剂量和/或这样一种剂量的一个合宜部分,例如像这样一种剂量的一半或三分之一。
为了更好地理解本发明并更清楚地展示出如何实现本发明,现通过示例的方式,并阐述了根据本发明的实施方式的特征。
实施例
通过参考以下实施例将更容易理解本发明,所述实施例用于说明本发明,而不应被解释为以任何方式限制本发明的范围。
本发明提供的化合物可以通过以下通式进行合成,其中,用于制备本发明的化合物的所有试剂都是市售的或根据文献中已经公开的制备方法进行制备。
中间体的合成:
步骤A:反应瓶中加入氢化钠(4.91g,122.82mmol,1.5eq.)和DMF(150mL)。冰水浴搅拌条件下,缓慢滴加1,3-丙二醇的DMF溶液(28.04g,368.45mmol,26.63mL,4.5eq.;溶于150mL DMF)。滴加完毕后,室温搅拌10分钟。将1-溴十六烷(25g,81.88mmol,1.0eq.)缓慢滴加入反应体系。滴加完毕后,95℃搅拌反应5小时。降温至室温,加入乙酸乙酯(400mL),水(300mL)萃洗分层,有机层浓盐水洗三次(300mL*3),有机层无水硫酸钠干燥浓缩后,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯=100:0-80:20),得产物b(12.5g,收率50.80%)
步骤B:反应瓶中加入[rac-(1S)-1-[(4-氨基-2-氧代嘧啶-1-基)甲基]-2-羟基乙氧基]甲基膦酸(1.5g,5.37mmol,1eq.)、DMF(25mL)和DIPEA(10mL)。45℃反应搅拌反应2小时。浓缩除去溶剂得白色固体残留物,加入DMF(25mL)、b(2.4g,8.06mmol,1.5eq.)、DIPEA(4.17g,32.24mmol,5.61mL,6.0eq.)和pyBOP(8.39g,16.12mmol,3.0eq.)。45℃搅拌反应16小时,浓缩除去反应溶剂,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-90:10),得中间体1(2g,收率68.47%)。
步骤C:反应瓶中加入中间体1(100mg,0.18mmol,1eq.)和氢氧化钠水溶液(0.5M,3.68mmol,10eq.)。室温条件下,搅拌反应4小时。反应体系变澄清。冰水浴下,缓慢滴加1NHCl溶液,调节pH至1左右,大量固体析出,过滤,真空干燥得中间体2(50mg,收率47.09%)。1H NMR(500MHz,CD3Cl3)δppm:0.84(t,J=6.6Hz,3H),1.21(s,26H),1.49(s,2H),1.74-1.91(m,2H),3.28-3.86(m,10H),3.93(d,J=6.4Hz,2H),4.22(d,J=13.9Hz,1H),6.11(s,1H),7.70(d,J=7.2Hz,1H);m/z(ESI+):562.6(M+H)。
化合物的合成
实施例1:化合物1b的合成
步骤A:反应瓶中加入中间体1(100mg,183.93μmol,1eq.)、DCM(15mL)、和苯甲酰氯(33.61mg,239.11μmol,27.76μL,1.3eq.)。0℃反应搅拌下,滴加三乙胺(55.84mg,551.80μmol,76.70μL,3.0eq)。室温下反应16小时,浓缩除去反应溶剂,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-97:3),得化合物1a(60mg,收率49.61%)。1H NMR(500MHz,CDCl3)δppm:0.87(t,J=6.8Hz,3H),1.26(d,J=15.6Hz,26H),1.54(s,2H),1.85-2.04(m,2H),3.39(dd,J=12.0,6.3Hz,2H),3.49(dt,J=18.5,5.9Hz,2H),3.62(dd,J=14.1,7.9Hz,1H),3.87(dd,J=27.5,14.4Hz,1H),4.10-4.48(m,7H),7.53(t,J=7.5Hz,3H),7.64(dd,J=15.7,7.1Hz,2H),7.89(d,J=6.7Hz,2H);31P NMR(203MHz,CDCl3)δppm:10.01,11.97;m/z(ESI+):648.6(M+H).
实施例2:化合物2b的合成
步骤A:反应瓶中加入中间体2(600mg,1.07mmol,1.0eq.)、DMF(10mL)和三乙胺(5mL),室温搅拌半小时,浓缩除去溶剂,加入DMF(10mL)、1-[氯-(4-甲氧基苯基)-苯基甲基]-4-甲氧基苯(545mg,1.6mmol,1.5eq.)和三乙胺(325mg,3.2mmol,3.0eq.)。室温搅拌反应一小时,浓缩除去溶剂。残留物加入DMF(20mL),配制成中间体2-1反应试剂(46mg/mL)备用。
步骤B:反应瓶中加入中间体2-1反应试剂(300mg,46mg/mL,7mL,1.0eq.)、DMF(2mL)和DIPEA(225mg,1.74mmol,3.0eq.)。冰水浴下,缓慢滴加苯甲酰氯(98mg,0.7mmol,
2.0eq.)。室温搅拌反应16小时。浓缩除去反应溶剂,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-92:8),得粗产物2-2(200mg,收率59.5%)。
步骤C:反应瓶中加入粗产品2-2(200mg,0.2mmol,1.0eq.)、乙腈(2mL)和乙酸(4mL)。室温搅拌反应16小时。反应液直接注射入反相C-18硅胶柱分离纯化(水:乙腈=100:0-35:65),冻干得粗产物。粗产物加入水(2mL),随即缓慢滴加碳酸氢钠水溶液调节pH至7-8,再滴加乙腈直至体系澄清。澄清体系经制备柱(水:乙腈=100:0-20:80)制备得化合物2b。1H NMR(500MHz,CDCl3)δppm:0.87(t,J=6.7Hz,3H),1.10-1.32(m,26H),1.36(s,2H),1.66(s,2H),3.20-3.28(m,6H),3.40-4.29(m,8H),6.11(s,1H),7.38(t,J=7.4Hz,2H),7.49(dd,J=18.4,10.7Hz,2H),7.89(dd,J=51.9,6.8Hz,3H),10.28(s,1H);31P NMR(203MHz,CDCl3)δppm:16.29;m/z(ESI+):666.6(M+H).
实施例3:化合物3b的合成
步骤B:反应瓶中加入中间体1(110mg,202.33μmol,1eq.)、DIPEA(78.45mg,606.98μmol,3eq.)、2-甲氧基乙基(4-硝基苯基)碳酸酯(97.6mg,404.65μmol,2eq.)和DMF(2mL)。50℃搅拌反应16小时。TLC柱层析检测反应原料消耗完毕。反应体系恢复至室温,加入水(40mL),乙酸乙酯萃洗(20mL*2),有机层饱和食盐水洗一次(40mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-94:6)得产物3-1(80mg,收率61.23%)。
步骤C:反应瓶中加入3-1(80mg,123.89μmol,1eq.)和THF(4mL),加入氢氧化钠水溶液(0.5mol/L,743.31μL,3eq.),室温搅拌反应一小时。LC-MS监测反应原料消耗完毕,冰水浴条件下用1mol/L的盐酸水溶液调至反应体系pH为2,再浓缩除去大部分溶剂。然后粗品产物直接用C-18反相柱分离纯化(水:乙腈=100:0-60:40),冻干得化合物3b(53.1mg,收率64.60%)。1H NMR(500MHz,MeOD)δ0.93(t,J=6.7Hz,3H),1.32(s,26H),1.54–1.62(m,2H),1.86–1.94(m,2H),3.41(s,3H),3.45(t,J=6.6Hz,2H),3.53(t,J=6.1Hz,2H),3.63(dd,J=12.2,3.8Hz,1H),3.66–3.71(m,2H),3.73–3.86(m,3H),3.93(ddd,J=21.8,13.6,8.6Hz,2H),4.07(q,J=6.5Hz,2H),4.29(d,J=11.4Hz,1H),4.34–4.40(m,2H),7.22(d,J=7.3Hz,1H),8.03(d,J=7.3Hz,1H);m/z(ESI+):664.5(M+H).
实施例4:化合物4b的合成
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步骤B:反应瓶中加入中间体1(102mg,187.61μmol,1eq.)、DIPEA(72.74mg,562.84μmol,3eq.)和DMF(2mL)。反应体系搅拌状态下滴加氯甲酸正戊酯(56.51mg,375.22μmol,2eq.)的DMF(0.5mL)溶液,50℃搅拌反应16小时。TLC柱层析检测反应原料消耗完毕。反应体系恢复至室温,加入水(40mL),乙酸乙酯萃洗(20mL*2),有机层饱和食盐水洗一次(40mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-94:6)得产物4-1(64mg,收率51.86%)。
步骤C:反应瓶中加入4-1(64mg,97.29μmol,1eq.)和THF(3mL),加入氢氧化钠水溶液(0.5mol/L,486.46μL,2.5eq.),室温搅拌反应一小时。LC-MS监测反应原料消耗完毕,冰水浴条件下用1mol/L的盐酸水溶液调至反应体系pH为2,再浓缩除去大部分溶剂。然后粗品产物直接用C-18反相柱分离纯化(水:乙腈=100:0-50:50),冻干得化合物4b(17.7mg,收率27.23%)。1H NMR(500MHz,MeOD)δ0.93(t,J=6.8Hz,3H),0.97(t,J=6.7Hz,3H),1.30–1.36(m,26H),1.40–1.47(m,4H),1.55–1.61(m,2H),1.69–1.79(m,2H),1.85–1.92(m,2H),3.44(t,J=6.6Hz,2H),3.52(t,J=6.2Hz,2H),3.57–3.63(m,1H),3.70(dd,J=13.2,9.5Hz,1H),3.80(d,J=10.0Hz,2H),3.90(td,J=13.9,8.4Hz,2H),4.03(q,J=6.2Hz,2H),4.22(t,J=6.6Hz,2H),4.27(d,J=14.2Hz,1H),7.25(d,J=7.3Hz,1H),8.05(d,J=7.3Hz,1H);m/z(ESI+):676.6(M+H).
实施例5:化合物5b的合成
步骤A:反应瓶中加入对氯苯甲酸(0.5g,3.19mmol,1.0eq.)、二氯甲烷(15mL)、对硝基苯酚(533mg,3.83mmol,1.2eq.)和DCC(0.79g,3.83mmol,1.2eq.)。室温搅拌过夜,过滤除去固体,母液浓缩后,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯=100:0-75:25),得产物4-硝基苯基-4-氯苯甲酸酯(0.8g,收率92%)
步骤B:反应瓶中加入中间体1(0.15g,0.275mmol,1eq.)、4-硝基苯基-4-氯苯甲酸酯(0.191g,0.689mmol,2.5eq.)、DMF(5mL)和DIPEA(0.11g,0.827mmol,3.0eq.)。50℃搅拌反应8小时,加入乙酸乙酯(30mL),水(15mL),萃洗分层,有机层浓盐水洗3次。浓缩除去溶剂,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-95:5),得产物5-1(130mg,收率69.1%)。
步骤C:反应瓶中加入5-1(80mg,0.12mmol,1eq.)、四氢呋喃(5mL)和氢氧化钠水溶液(0.5M,469ul,2.0eq.)。室温条件下,搅拌反应1.5小时。反应体系变澄清。冰水浴下,缓慢滴加1N HCl溶液,调节pH至1左右,加水冻干后,粗产品反相C-18硅胶柱分离纯化(水:乙腈=100:0-30:70),冻干得化合物5b(45mg,收率54.1%)。1H NMR(500MHz,CD3OD)δppm:0.89(t,J=6.7Hz,3H),1.26(d,J=10.9Hz,26H),1.48(s,2H),1.76-1.89(m,2H),3.36(t,J=6.5Hz,2H),3.47(t,J=6.2Hz,2H),3.54-3.70(m,2H),3.75-4.05(m,6H),4.28(d,J=13.6Hz,1H),7.55(t,J=8.8Hz,3H),7.98(d,J=8.4Hz,2H),8.10(d,J=7.0Hz,1H);m/z(ESI+):700.5(M+H).
实施例6:化合物6b的合成
除了使用间氯苯甲酸之外,合成步骤同实施例5,得产物化合物6b(35mg,收率38.02%)。1H NMR(500MHz,MeOD)δ0.93(t,J=6.8Hz,3H),1.30(d,J=7.0Hz,26H),1.50–1.55(m,2H),1.87–1.93(m,2H),3.41(t,J=6.6Hz,2H),3.51(t,J=6.1Hz,2H),3.65(dd,J=12.0,3.4Hz,1H),3.75(dd,J=13.4,9.7Hz,1H),3.80–3.90(m,2H),3.91–3.99(m,2H),4.06(q,J=6.4Hz,2H),4.34(d,J=11.7Hz,1H),7.54–7.62(m,2H),7.70(d,J=7.8Hz,1H),7.96(d,J=7.7Hz,1H),8.04(s,1H),8.13(d,J=7.2Hz,1H);m/z(ESI+):700.5(M+H).
实施例7:化合物7b的合成
步骤A:反应瓶中加入化合物5b(84mg,0.12mmol,1.0eq.)DMF(4mL)和NaH(47.98mg,1.20mmol,60%purity,10.0eq.)。室温搅拌20分钟。4-硝基苯基-4-氯苯甲酸酯(66.7mg,0.239mmol,2.1eq.)DMF(0.5mL)溶液滴加入反应。室温搅拌反应3小时,加入乙酸乙酯(25mL)稀释,低温环境,滴加1N HCl淬灭反应,确保水相pH为1-2。有机层浓盐水洗2次,干燥浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-80:20),得化合物7b(35mg,收率33.32%)。1H NMR(500MHz,CDCl3)δppm:0.84(t,J=6.8Hz,3H),1.19(d,J=17.3Hz,25H),1.42(s,2H),1.75(s,2H),3.25(s,2H),3.37(s,2H),3.84(t,J=51.6Hz,5H),4.28(s,2H),4.44(s,1H),4.53(s,1H),7.39(t,J=13.0Hz,4H),7.53(s,1H),7.80(s,1H),7.85-8.07(m,4H);m/z(ESI+):838.5(M+H).
实施例8:化合物8b的合成
步骤B:反应瓶中加入正戊醇(0.5g,3.32mmol,1eq.)和DCM(20mL),加入吡啶(0.31g,3.98mmol,1.2eq.),冰浴条件下滴加4-硝基苯基碳酰氯(0.46g,3.32mmol,1eq.)的DCM(15mL)溶液,滴毕室温下搅拌反应2小时。TLC监测反应原料消耗完毕,加入水(30mL),二氯甲烷萃洗(30mL*2),有机层饱和食盐水洗一次(60mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯=100:0-75:25)得产物(4-硝基苯基)碳酸戊基酯(0.8g,收率95.15%)。
反应瓶中加入中间体2(175mg,258.94μmol,1eq.)和THF(6mL),0℃下缓慢加入LiHMDS(1M,1.04mL,4eq.)。十分钟后,(4-硝基苯基)碳酸戊基酯(196.73mg,776.82μmol,3eq.)溶于THF(0.3mL)并加入上述反应中室温反应3小时。TLC检测反应完全,然后用1M盐酸淬灭反应。有机相用二氯甲烷萃取,经过过滤并且除去溶剂。剩余物经过柱层析(二氯甲烷/甲醇=100:0-80:20)和制备板制备得化合物8b(97mg,收率47.42%)。1H NMR(500MHz,CDCl3and MeOD)δppm:0.78-0.82(d,9H),1.16-1.21(d,34H),1.44(s,2H),1.58(s,4H),1.73(s,2H),3.28(s,2H),3.37(s,2H),3.52(m,3H),3.78(s,3H),4.07(m,6H),4.28(s,1H),7.11(s,1H),7.72(s,1H);m/z(ESI+):790.7(M+H).
实施例9:化合物9b的合成
步骤B:反应瓶中加入中间体1(150mg,275.90μmol,1eq.)、二氯甲烷(6mL)、DIPEA(106.97mg,827.70μmol,144.17μL,3eq.)、DMAP(16.85mg,137.95μmol,0.5eq.)和CbzCl(141.20mg,827.70μmol,116.50μL,3eq.)。室温搅拌反应16小时。反应体系加入二氯甲烷(20ml)稀释后,用0.1M稀盐酸洗一次(10mL),浓盐水洗,有机相干燥浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-95:5)得产物9-1(148mg,收率79.14%)
步骤C:反应瓶中加入9-1(30mg,44.26μmol,1eq.)、四氢呋喃(2mL)和0.5M NaOH水溶液(0.5M,,619.65μL,7eq.)。室温搅拌1小时,直接浓缩得产物9-2(30.7mg,收率99.94%)。
步骤D:反应瓶中加入2-(2-(2-甲氧基甲氧基)乙氧基)乙醇-1-醇(2.0g,12.18mmol,1eq.)和DCM(20mL),加入三乙胺(1.85g,18.27mmol,1.5eq.),冰浴条件下滴加4-硝基苯基碳酰氯(2.46g,12.18mmol,1eq.)的DCM(15mL)溶液,滴毕室温下搅拌反应16小时。TLC监测反应原料消耗完毕,加入水(100mL),二氯甲烷萃洗(30mL*2),有机层饱和食盐水洗一次(60mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯=100:0-60:40)得产物2-(2-(2-甲氧基甲氧基)乙氧基)乙基(4-硝基苯基)碳酸酯(2.1g,收率52.36%)。反应瓶中加入9-2(400mg,574.86μmol,1eq.)和DMF(5mL),冰浴下加入NaH(183.96mg,4.60mmol,60%purity,8eq.),0℃下搅拌反应20min,然后滴加2-(2-(2-甲氧基甲氧基)乙氧基)乙基(4-硝基苯基)碳酸酯(378.61mg,1.15mmol,2eq.)的DMF(1mL)溶液,滴毕室温下搅拌反应16小时。TLC监测反应大部分原料消耗完毕,冰水浴条件下用1mol/L的盐酸水溶液调至反应体系pH为2,加入水(50mL),乙酸乙酯萃洗(20mL*4),有机层饱和食盐水洗一次(60mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用制备板分离纯化(二氯甲烷:甲醇=10:1)得9-3(180mg,收率35.34%)。
步骤E:反应瓶中加入9-3(155mg,174.94μmol,1eq.)、四氢呋喃/甲醇(V/V=5:1,15mL)和钯碳(25mg,10%碳吸附量,含55%水)。氢气环境下,室温搅拌反应过夜。LC-MS监测反应大部分原料消耗完毕,过滤,滤饼用甲醇洗(50mL)。母液浓缩得粗品,粗品经反相制备柱(乙腈,水,醋酸铵体系)分离纯化,冻干得化合物9b(50mg,收率35.61%)。1H NMR(500MHz,MeOD)δ0.93(t,J=6.6Hz,3H),1.32(s,26H),1.55–1.60(m,2H),1.84–1.91(m,2H),3.38(s,3H),3.45(t,J=6.4Hz,2H),3.52–3.61(m,5H),3.64–3.69(m,6H),3.72–3.76(m,2H),3.88(dd,J=12.6,8.9Hz,1H),3.95–4.00(m,4H),4.18–4.34(m,4H),4.43(d,J=11.7Hz,1H),6.01(d,J=7.4Hz,1H),7.99(d,J=7.3Hz,1H);m/z(ESI+):752.7(M+H).
实施例10:化合物10b的合成
步骤A:反应瓶中加入4-(硝基)苯酚(2.51g,18.01mmol,1.1eq.)、二氯甲烷(80mL)、苯甲酸(2g,16.38mmol,1.0eq.)和DCC(4.05g,19.65mmol,1.2eq.)。搅拌条件下,室温反应16小时。过滤除去固体,母液浓缩除去二氯甲烷,残留物加入乙酸乙酯(100mL)和水(70mL),萃洗分层,有机层浓盐水洗(70mL)。有机相浓缩除去溶剂,浓缩后过硅胶柱(石油醚:乙酸乙酯=100:0-75:25)得产物(4-硝基苯基)苯甲酸酯(2.1g,收率:46.18%)。
步骤B:反应瓶中加入9-2(0.2g,0.287mmol,1eq.)和四氢呋喃(5mL)。冰水浴条件下滴加LiHMDs(1M,1.15mL,4eq.),滴加完毕,搅拌20分钟。将(4-硝基苯基)苯甲酸酯的四氢呋喃溶液(0.21g,0.862mmol,3.0eq.溶于1mL四氢呋喃)滴加入反应体系。搅拌条件下,室温反应4小时。加入乙酸乙酯(30mL),随后滴加1N盐酸淬灭反应,确保水相pH为1-2左右,有机层饱和食盐水洗(30mL)。有机层浓缩后过硅胶柱(二氯甲烷:甲醇=100:0-85:15)得产物10-1(0.11g,收率:47.84%)
步骤C:反应瓶中加入10-1(140mg,0.175mmol,1eq.)、四氢呋喃(20mL)、甲醇(5mL)和Pd/C(25mg)。氢气环境下室温反应16小时,过滤除去钯碳,母液浓缩后经制备柱分离纯化得化合物10b(23mg,收率19.55%)。1H NMR(500MHz,CD3OD)δppm:0.89(t,J=6.8Hz,3H),1.26(s,26H),1.48(d,J=6.4Hz,2H),1.73-1.82(m,2H),3.34(t,J=6.6Hz,2H),3.44(t,J=6.4Hz,2H),3.58-3.72(m,1H),3.92(dd,J=11.9,8.4Hz,3H),3.98(dd,J=14.1,7.1Hz,1H),4.07(s,1H),4.26(d,J=14.1Hz,1H),4.37(dd,J=12.0,3.9Hz,1H),4.55(dd,J=11.8,4.3Hz,1H),5.97(d,J=7.5Hz,1H),7.47(t,J=7.6Hz,2H),7.60(t,J=7.4Hz,1H),8.01(dd,J=21.9,7.7Hz,3H);m/z(ESI+):666.5(M+H).
实施例11:化合物11b的合成
前序合成步骤同实施例9。
步骤D:反应瓶中加入壬酸(1.0g,6.32mmol,1eq.),4-硝基苯酚(879.11mg,6.32mmol,1eq.)和DCM(30mL),加入N,N'-二环己基碳二亚胺(1.56g,7.58mmol,1.2eq.),室温下搅拌反应6小时。TLC监测绝大部分反应原料消耗完毕,加入水(60mL),二氯甲烷萃洗(30mL*2),有机层饱和食盐水洗一次(60mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯=100:0-80:20)得产物4-硝基苯基壬酸酯(670mg,收率37.95%)。反应瓶中加入9-2(175mg,251.50μmol,1eq.)和THF(2mL),冰浴下滴加LiHMDS(1M,1.01mL,4eq.),0℃下搅拌反应20min,然后滴加4-硝基苯基壬酸酯(210.76mg,754.50μmol,3eq.)的THF(0.5mL)溶液,滴毕室温下搅拌反应3小时。TLC监测反应大部分原料消耗完毕,冰水浴条件下用1mol/L的盐酸水溶液调至反应体系PH为2,加入水(50mL),乙酸乙酯萃洗(20mL*4),有机层饱和食盐水洗一次(60mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-85:15)得产物11-1(120mg,收率57.07%)。
步骤E:反应瓶中加入11-1(100mg,119.61μmol,1eq.)、四氢呋喃/甲醇(V/V=5:1,15mL)和钯碳(20mg,10%碳吸附量,含55%水)。氢气环境下,室温搅拌反应过夜。LC-MS监测反应原料消耗完毕,过滤,滤饼用甲醇洗(50mL)。母液浓缩得粗品,粗品经反相制备柱(乙腈,水,醋酸铵体系)分离纯化,冻干得化合物11b(15mg,收率17.72%)。1H NMR(500MHz,CDCl3)δ0.86(t,J=6.0Hz,6H),1.24(s,36H),1.52(s,2H),1.61(s,2H),1.85(s,2H),2.34(s,2H),3.34–3.68(m,6H),3.90–3.94(m,4H),4.07–4.39(m,3H),5.46–6.25(m,1H),7.56(d,J=145.0Hz,1H);m/z(ESI+):702.6(M+H).
实施例12:化合物12b的合成
步骤B:反应瓶中加入2-(2-(2-甲氧基甲氧基)乙氧基)乙醇-1-醇(2.0g,12.18mmol,1eq.)和DCM(20mL),加入三乙胺(1.85g,18.27mmol,1.5eq.),冰浴条件下滴加4-硝基苯基碳酰氯(2.46g,12.18mmol,1eq.)的DCM(15mL)溶液,滴毕室温下搅拌反应16小时。TLC监测反应原料消耗完毕,加入水(100mL),二氯甲烷萃洗(30mL*2),有机层饱和食盐水洗一次(60mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯=100:0-60:40)得产物2-(2-(2-甲氧基甲氧基)乙氧基)乙基(4-硝基苯基)碳酸酯(2.1g,收率52.36%)。反应瓶中加入中间体1(130mg,239.11μmol,1eq.)、DIPEA(92.71mg,717.34μmol,3eq.)和DMF(2mL)。搅拌状态下向反应体系中加入2-(2-(2-甲氧基甲氧基)乙氧基)乙基(4-硝基苯基)碳酸酯(157.48mg,478.23μmol,2eq.)的DMF(1mL)溶液,50℃搅拌反应16小时。TLC柱层析检测反应原料消耗完毕。反应体系恢复至室温,加入水(40mL),乙酸乙酯萃洗(20mL*2),有机层饱和食盐水洗一次(40mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-96:4)得12-1(110mg,收率62.69%)。
步骤C:反应瓶中加入12-1(110mg,149.89μmol,1eq.)和THF(5mL),加入氢氧化钠水溶液(0.5mol/L,749.45μL,2.5eq.),室温搅拌反应一小时。LC-MS监测反应原料消耗完毕,冰水浴条件下用1mol/L的盐酸水溶液调至反应体系PH为2,再浓缩除去大部分溶剂。然后粗品产物直接用C-18反相柱分离纯化(水:乙腈=100:0-55:45),冻干得12-2(50mg,收率45.12%)。1H NMR(500MHz,MeOD)δ0.93(t,J=6.7Hz,3H),1.32(s,26H),1.55–1.60(m,2H),1.87–1.94(m,2H),3.38(s,3H),3.45(t,J=6.5Hz,2H),3.51–3.58(m,4H),3.61–3.70(m,7H),3.74–3.87(m,5H),3.88–4.00(m,2H),4.03–4.12(m,2H),4.28(d,J=12.1Hz,1H),4.37(d,J=2.4Hz,2H),7.22(d,J=7.2Hz,1H),8.04(d,J=7.2Hz,1H);m/z(ESI+):752.7(M+H).
步骤D:反应瓶中加入12-2(235mg,312.55μmol,1eq.)和DMF(4mL),冰浴下加入NaH(100.02mg,2.50mmol,60%纯度,8eq.),0℃下搅拌反应20min,然后滴加2-(2-(2-甲氧基甲氧基)乙氧基)乙基(4-硝基苯基)碳酸酯(205.85mg,625.10μmol,2eq.)的DMF(1mL)溶液,滴毕在50℃下搅拌反应2小时。TLC监测反应大部分原料消耗完毕,冰水浴条件下用1mol/L的盐酸水溶液调至反应体系PH为2,加入水(50mL),乙酸乙酯萃洗(20mL*4),有机层饱和食盐水洗一次(60mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-85:15)得化合物12b(50mg,收率15.90%)。1H NMR(500MHz,CDCl3)δ0.79(t,J=6.2Hz,3H),1.17(s,26H),1.44(s,2H),1.70–1.74(m,2H),3.30(s,4H),3.34–3.38(m,2H),3.48(s,4H),3.52–3.60(m,17H),3.63–3.69(m,5H),3.74(s,2H),3.86–4.08(m,3H),4.15–4.60(m,6H),7.16(d,J=5.1Hz,1H),7.71(d,J=6.9Hz,1H);m/z(ESI+):942.99(M+H).
实施例13:化合物13b的合成
步骤A:反应瓶中加入甲醇(0.5g,315.6mmol,1.0eq.)、二氯甲烷(40mL)、(4-硝基苯基)羰基氯(3.15g,15.6mmol,1.0eq.)和DIPEA(3.03g,23.41mmol,1.5eq.)。搅拌条件下,室温反应4小时。浓缩除去溶剂,加入乙酸乙酯(30mL)、水(20mL)萃洗分层,有机层饱和食盐水洗(30mL)。有机层浓缩后过硅胶柱(石油醚:乙酸乙酯=100:0-75:50)得产物(4-硝基苯基)碳酸甲酯(1.6g,收率52.01%)。
步骤B:反应瓶中加入中间体1(0.15g,0.275mmol,1eq.)、(4-硝基苯基)碳酸甲酯(0.108g,0.551mmol,2.0eq.)、DMF(5mL)和DIPEA(0.11g,0.827mmol,3.0eq.)。50℃搅拌反应16小时,加入乙酸乙酯(30mL),水(15mL),萃洗分层,有机层浓盐水洗3次。浓缩除去溶剂,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-95:5),得13-1(108mg,收率65.06%)。
步骤C:13-1(110mg,0.182mmol,1eq.)、四氢呋喃(7mL)和氢氧化钠水溶液(0.5M,731ul,2.0eq.)。室温条件下,搅拌反应1小时。反应体系变澄清。冰水浴下,缓慢滴加1NHCl溶液,调节pH至1左右,加水冻干后,粗产品反相C-18硅胶柱分离纯化(水:乙腈=70:30-30:70),冻干得化合物13b(53mg,收率47.89%)。1H NMR(500MHz,CD3OD)δppm:0.89(t,J=6.8Hz,3H),1.26(d,J=17.7Hz,26H),1.53(d,J=6.8Hz,2H),1.79-1.90(m,2H),3.41(t,J=6.6Hz,2H),3.49(t,J=6.2Hz,2H),3.57(d,J=8.3Hz,1H),3.69(dd,J=13.4,9.5Hz,1H),3.73-3.82(m,5H),3.88(dt,J=14.8,7.6Hz,2H),4.01(q,J=6.5Hz,2H),4.24(d,J=13.7Hz,1H),7.20(d,J=7.3Hz,1H),8.00(d,J=7.3Hz,1H);m/z(ESI+):620.7(M+H).
实施例14:化合物14b的合成
前序合成步骤同实施例9。
步骤D:反应瓶中加入9-2(150mg,215.57μmol,1eq.)和THF(2mL),冰浴下滴加LiHMDS(1M,862.29μL,4eq.),0℃下搅拌反应20min,然后滴加4-硝基苯基戊基碳酸酯(163.78mg,646.72μmol,3eq.)的THF(0.5mL)溶液,滴毕室温下搅拌反应16小时。LC-MS监测大部分反应原料消耗完毕,冰水浴条件下用1mol/L的盐酸水溶液调至反应体系PH为2,加入水(50mL),乙酸乙酯萃洗(20mL*4),有机层饱和食盐水洗一次(60mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-85:15)得14-1(100mg,收率57.27%)。
步骤E:反应瓶中加入14-1(100mg,123.46μmol,1eq.)、四氢呋喃/甲醇(V/V=5:1,10mL)和钯碳(20mg,10%碳吸附量,含55%水)。氢气环境下,室温搅拌反应过夜。LC-MS监测大部分反应原料消耗完毕,过滤,滤饼用甲醇洗(50mL)。母液浓缩得粗品,粗品经反相制备柱(乙腈,水,醋酸铵体系)分离纯化,冻干得化合物14b(30mg,收率44.45%)。1H NMR(500MHz,CDCl3)δ0.84–0.89(m,6H),1.22(s,28H),1.32(s,4H),1.50(s,2H),1.64(s,2H),1.82(s,2H),3.34(s,2H),3.43(s,2H),3.48–3.61(m,2H),3.83(s,1H),3.90(s,2H),4.11(s,3H),4.17–4.30(m,2H),4.44(d,J=9.8Hz,1H),6.09(s,1H),7.65(s,1H);m/z(ESI+):676.6(M+H).
实施例15:化合物15b的合成
步骤A:反应瓶中加入中间体2(100mg,0.053mmol,1eq.)和甲酸(2.5mL)。60℃搅拌反应16小时,浓缩除去甲酸,残留粗产品反相C-18硅胶柱分离纯化(水:乙腈=70:30-30:70),冻干得化合物15b(20mg,收率17.77%)。1H NMR(500MHz,CD3OD)δppm:0.89(t,J=6.8Hz,3H),1.28(s,26H),1.54(s,2H),1.77-1.90(m,2H),3.41(t,J=6.5Hz,2H),3.50(t,J=6.4Hz,2H),3.54-3.62(m,1H),3.84(dd,J=21.9,14.1Hz,2H),3.92(d,J=6.0Hz,2H),3.98(s,1H),4.17(d,J=12.5Hz,2H),4.40(d,J=7.7Hz,1H),5.96(d,J=7.4Hz,1H),7.89(d,J=7.1Hz,1H),8.13(s,1H);m/z(ESI+):590.5(M+H).
实施例16:化合物16b的合成
步骤C:反应瓶中加入4-硝基苯酚(2.0g,14.38mmol,1eq.)和Py(4mL),冰浴条件下滴加乙酸酐(2.20g,21.57mmol,1.5eq.),滴毕室温下搅拌反应16小时。TLC监测反应原料消耗完毕,冰水浴条件下用1mol/L的盐酸水溶液调至反应体系为弱酸性,加入水(80mL)二氯甲烷萃洗(30mL*2),有机层饱和食盐水洗一次(60mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用硅胶柱分离纯化(二氯甲烷)得产物4-硝基苯基乙酸酯(2.2g,收率84.47%)。
反应瓶中加入中间体2(90mg,160.23μmol,1eq.)和DMF(2mL),冰浴下加入NaH(51.27mg,1.28mmol,60%purity,8eq.),0℃下搅拌反应20min,然后滴加4-硝基苯基乙酸酯(116.10mg,640.92μmol,4eq.)的DMF(0.5mL)溶液,滴毕50℃下搅拌反应2小时。LC-MS监测反应原料消耗完毕,冰水浴条件下用1mol/L的盐酸水溶液调至反应体系PH为2,加入水(50mL),乙酸乙酯萃洗(20mL*4),有机层饱和食盐水洗一次(60mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用制备板分离纯化得化合物16b(16.6mg,收率15.56%)。1HNMR(500MHz,CDCl3)δ0.87(s,3H),1.24(s,26H),1.49(s,2H),1.72(s,2H),2.06(s,3H),2.20(s,3H),3.03–3.38(m,4H),3.60–3.78(m,4H),4.02–4.08(m,3H),4.30(s,2H),7.48(s,1H),7.56(s,1H),11.55(s,1H);m/z(ESI+):646.5(M+H).
实施例17:化合物17b的合成
步骤A:反应瓶中加入中间体2(120mg,0.213mmol,1eq.)、DMF(5mL)、1-(4-硝基苯氧基)羰基氧基丁酸乙酯(95.26mg,0.32mmol,1.5eq.)和DIPEA(110.44mg,0.85mmol,1eq.)。80℃搅拌反应1小时。加入乙酸乙酯(50mL)稀释,低温环境,滴加1N HCl淬灭反应,确保水相pH为1-2。有机层浓盐水洗2次,干燥浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-75:25),得粗产物,粗产物制备纯化冻干得化合物17b(15mg,收率11.32%)。1HNMR(500MHz,CD3OD)δppm:0.89(t,J=6.7Hz,3H),0.95(dd,J=9.8,4.7Hz,6H),1.28(s,26H),1.47(d,J=5.2Hz,3H),1.52(t,J=7.2Hz,5H),1.58-1.70(m,4H),1.81(s,2H),2.32(t,J=7.2Hz,4H),3.40(t,J=6.4Hz,2H),3.48(t,J=6.2Hz,2H),3.57(s,1H),3.81(d,J=8.8Hz,1H),3.88-4.02(m,4H),4.13-4.29(m,2H),4.41(dd,J=37.2,9.9Hz,1H),6.71(d,J=5.0Hz,1H),6.86(d,J=5.4Hz,1H),7.21(d,J=7.2Hz,1H),8.10(t,J=6.9Hz,1H);m/z(ESI+):878.5(M+H).
实施例18:化合物18b的合成
步骤A:反应瓶中加入中间体1(200mg,367.87μmol,1eq.)、DCM(15mL)、和正丁酰氯(50.96mg,478.23μmol,49.66μL,1.3eq.)。0℃反应搅拌下,滴加三乙胺(111.67mg,1.10mmol,153.40μL,3.0eq)。室温反应16小时,浓缩除去反应溶剂,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-97:3),得化合物18b(125mg,收率54.39%)。1H NMR(500MHz,CDCl3)δppm:0.88(t,J=6.9Hz,3H),0.99(t,J=7.4Hz,3H),1.27(d,J=14.9Hz,26H),1.50-1.60(m,2H),1.73(d,J=7.3Hz,2H),1.87-2.07(m,2H),2.42(s,2H),3.39(q,J=6.8Hz,2H),3.49(dt,J=18.3,5.9Hz,2H),3.54-3.68(m,1H),3.86(dd,J=32.2,14.5Hz,1H),4.05-4.48(m,7H),7.41(d,J=7.3Hz,1H),7.62(s,1H);m/z(ESI+):614.6(M+H).
实施例19:化合物19b的合成
具体合成步骤见实施例12的合成,得到化合物19b(50mg,收率45.12%)。1H NMR(500MHz,MeOD)δ0.93(t,J=6.7Hz,3H),1.32(s,26H),1.55–1.60(m,2H),1.87–1.94(m,2H),3.38(s,3H),3.45(t,J=6.5Hz,2H),3.51–3.58(m,4H),3.61–3.70(m,7H),3.74–3.87(m,5H),3.88–4.00(m,2H),4.03–4.12(m,2H),4.28(d,J=12.1Hz,1H),4.37(d,J=2.4Hz,2H),7.22(d,J=7.2Hz,1H),8.04(d,J=7.2Hz,1H);m/z(ESI+):752.7(M+H).
实施例20:化合物20b的合成
步骤B:反应瓶中加入烟酸(500mg,4.06mmol,1eq.),4-硝基苯酚(677.98mg,4.87mmol,1.2eq.)和DCM(30mL),加入N,N'-二环己基碳二亚胺(1.01g,4.87mmol,1.2eq.),室温下搅拌反应16小时。TLC监测反应原料消耗完毕,加入水(70mL),二氯甲烷萃洗(30mL*2),有机层饱和食盐水洗一次(60mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:乙酸乙酯=100:0-99:1)得产物4-硝基苯基烟酸酯(400mg,收率40.33%)。反应瓶中加入中间体1(170mg,312.69μmol,1eq.)、DIPEA(121.24mg,938.07μmol,3eq.)和DMF(2mL)。向反应体系中加入4-硝基苯基烟酸盐(152.72mg,625.38μmol,2eq.)的DMF(1mL)溶液,50℃搅拌反应16小时。TLC柱层析检测反应原料消耗完毕。反应体系恢复至室温,加入水(50mL),乙酸乙酯萃洗(25mL*2),有机层饱和食盐水洗一次(50mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-95:5)得产物20-1(120mg,收率59.15%)。
步骤C:反应瓶中加入20-1(120mg,184.97μmol,1eq.)和THF(5mL),加入氢氧化钠水溶液(0.5mol/L,739.86μL,2eq.),室温搅拌反应一小时。LC-MS监测反应原料消耗完毕,冰水浴条件下用1mol/L的盐酸水溶液调至反应体系PH为2,再浓缩除去大部分溶剂。然后粗品产物直接用C-18反相柱分离纯化(水:乙腈=100:0-60:40),冻干得化合物20b(20mg,收率16.67%)。1H NMR(500MHz,CDCl3)δ0.91(t,J=6.5Hz,3H),1.28(s,26H),1.55–1.59(m,2H),1.90–1.97(m,2H),3.39–3.45(m,2H),3.53(t,J=5.7Hz,2H),3.62(d,J=12.0Hz,1H),3.73–3.93(m,4H),3.99(dd,J=13.3,7.2Hz,1H),4.10–4.15(m,2H),4.29(d,J=13.5Hz,1H),7.49(d,J=6.4Hz,1H),7.61(s,1H),7.96(d,J=7.1Hz,1H),8.48(d,J=6.9Hz,1H),8.85(s,1H),9.30(s,1H);m/z(ESI+):667.5(M+H).
实施例21:化合物21b的合成
步骤A:反应瓶中加入化合物5b(87mg,0.124mmol,1.0eq.)DMF(3mL)和NaH(50mg,1.24mmol,60%purity,10.0eq.)。室温搅拌20分钟。4-硝基苯基-4-丁酸酯(52mg,0.248mmol,2.0eq.)DMF(0.5mL)溶液滴加入反应。室温搅拌反应3小时,加入乙酸乙酯(25mL)稀释,低温环境,滴加1N HCl淬灭反应,确保水相pH为1-2。有机层浓盐水洗2次,干燥浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-85:15),得化合物21b(30mg,收率29.43%)。1H NMR(500MHz,CDCl3)δppm:0.78(t,J=6.8Hz,3H),0.86(t,J=7.4Hz,3H),1.15(d,J=5.5Hz,26H),1.39(s,2H),1.55(dt,J=14.8,7.5Hz,2H),1.62-1.75(m,2H),2.23(t,J=7.4Hz,2H),3.23(t,J=6.6Hz,2H),3.33(t,J=5.9Hz,2H),3.55(d,J=7.3Hz,1H),3.70(d,J=14.1Hz,1H),3.77(d,J=6.3Hz,3H),3.98(d,J=11.2Hz,1H),4.13(s,2H),4.25(d,J=9.3Hz,1H),7.39(d,J=8.2Hz,2H),7.47(s,1H),7.79(d,J=6.9Hz,1H),7.87(d,J=8.1Hz,2H);m/z(ESI+):770.5(M+H).
实施例22:化合物22b的合成
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步骤A:反应瓶中加入4-(羟甲基)苯酚(2.82g,22.70mmol,1eq.)、二氯甲烷(100mL)、正丁酸(2g,22.70mmol,1.0eq.)、EDCI(5.22g,27.24mmol,1.2eq.)和DMAP(277.33mg,2.27mmol,0.1eq.)。搅拌条件下,室温反应16小时。浓缩除去溶剂,浓缩后过硅胶柱(石油醚:乙酸乙酯=100:0-66:34)得产物[4-(羟甲基)苯基]正丁酸盐(2g,收率:45.36%)。
步骤B:反应瓶中加入[4-(羟甲基)苯基]正丁酸盐(2g,10.30mmol,1eq.)、二氯甲烷(30mL)、(4-硝基苯基)羰基氯(2.08g,10.3mmol,1.1eq.)和DIPEA(2g,15.45mmol,1.5eq.)。搅拌条件下,室温反应4小时。浓缩除去溶剂,加入乙酸乙酯(30mL)、水(20mL)萃洗分层,有机层饱和食盐水洗(30mL)。有机层浓缩后过硅胶柱(石油醚:乙酸乙酯=100:0-50:50)得产物[4-[(4-硝基苯氧基)羰基甲基]苯基]正丁酸盐(1.7g,收率:45.94%)
步骤C:反应瓶中加入中间体2(30mg,0.053mmol,1eq.)、DMF(3mL)、[4-[(4-硝基苯氧基)羰基甲基]苯基]正丁酸盐(28.79mg,0.080mmol,1.5eq.)和DIPEA(27.61mg,0.21mmol,1eq.)。80℃搅拌反应16小时。加入乙酸乙酯(25mL)稀释,低温环境,滴加1N HCl淬灭反应,确保水相pH为1-2。有机层浓盐水洗2次,干燥浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-75:25),得化合物22b(15mg,收率33.78%)。1H NMR(500MHz,CD3OD)δppm:0.89(t,J=6.8Hz,3H),1.03(t,J=7.4Hz,3H),1.28(d,J=9.8Hz,26H),1.50(d,J=6.5Hz,2H),1.68-1.79(m,4H),2.55(t,J=7.3Hz,2H),3.36(d,J=6.7Hz,2H),3.42(t,J=6.2Hz,2H),3.58(t,J=12.0Hz,2H),3.69-4.2(m,6H),4.61(s,1H),5.23(s,2H),7.10(d,J=8.4Hz,3H),7.46(d,J=8.3Hz,2H),8.03(d,J=7.2Hz,1H);m/z(ESI+):782.6(M+H).
实施例23:化合物23b的合成
步骤B:反应瓶中加入乙醇(457.11mg,9.92mmol,2eq.)和DCM(10mL),加入三乙胺(753.04mg,7.44mmol,1.5eq.),冰浴条件下滴加4-硝基苯基碳酰氯(1.0g,4.96mmol,1eq.)的DCM(10mL)溶液,滴毕室温下搅拌反应16小时。TLC监测反应原料消耗完毕,加入水(50mL),二氯甲烷萃洗(25mL*2),有机层饱和食盐水洗一次(50mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯=100:0-85:15)得产物(4-硝基苯基)碳酸乙酯(750mg,收率71.59%)。
反应瓶中加入中间体1(130mg,203.25μmol,85%纯度,1eq.)、DIPEA(78.80mg,609.74μmol,3eq.)和DMF(2mL)。搅拌状态下向反应体系中加入(4-硝基苯基)碳酸乙酯(85.84mg,406.49μmol,2eq.)的DMF(0.5mL)溶液,50℃搅拌反应16小时。TLC柱层析检测反应原料消耗完毕。反应体系恢复至室温,加入水(40mL),乙酸乙酯萃洗(20mL*2),有机层饱和食盐水洗一次(40mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-95:5)得产物23-1(75mg,收率59.93%)。
步骤C:反应瓶中加入23-1(75mg,121.81μmol,1eq.)和THF(4mL),加入氢氧化钠水溶液(0.5mol/L,609.03μL,2.5eq.),室温搅拌反应一小时。LC-MS监测反应原料消耗完毕,冰水浴条件下用1mol/L的盐酸水溶液调至反应体系PH为2,再浓缩除去大部分溶剂。然后粗品产物经反相制备柱(乙腈,水,醋酸铵体系)分离纯化,冻干得化合物23b(39.1mg,收率50.53%)。1H NMR(500MHz,CDCl3)δ0.88(t,J=6.7Hz,3H),1.25(s,26H),1.32(t,J=7.1Hz,3H),1.50–1.54(m,2H),1.76–1.85(m,2H),3.36(t,J=6.8Hz,2H),3.44(t,J=6.1Hz,2H),3.53–3.62(m,2H),3.69–3.78(m,3H),3.83–3.89(m,2H),3.95–4.02(m,1H),4.05–4.12(m,1H),4.22(q,J=6.9Hz,2H),7.23(d,J=7.2Hz,1H),7.86(d,J=7.2Hz,1H);m/z(ESI+):634.6(M+H).
实施例24:化合物24b的合成
步骤C:反应瓶中加入中间体2(100mg,0.053mmol,1eq.)、DMF(3mL)、(5-甲基-2-氧代-1,3-二氧代-4-基)甲基(4-硝基苯基)碳酸酯(105.11mg,0.356mmol,2.0eq.)和DIPEA(92.04mg,0.712mmol,4eq.)。80℃搅拌反应7小时,后50℃搅拌反应16小时。加入乙酸乙酯(25mL)稀释,低温环境,滴加1N HCl淬灭反应,确保水相pH为1-2。有机层浓盐水洗2次,干燥浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-75:25),得产物粗产物,粗产物制备分离得化合物24b(20mg,收率15.51%)。1H NMR(500MHz,CD3OD)δppm:0.89(t,J=6.8Hz,3H),1.27(s,26H),1.52(d,J=6.8Hz,2H),1.82(dd,J=12.8,6.5Hz,2H),2.19(d,J=11.5Hz,6H),3.39(t,J=6.6Hz,2H),3.47(t,J=6.3Hz,2H),3.55-3.62(m,1H),3.79-4.03(m,5H),4.22(dd,J=15.0,9.5Hz,2H),4.44(d,J=11.7Hz,1H),4.96(s,2H),5.03(s,2H),7.22(d,J=7.3Hz,1H),8.09(d,J=7.2Hz,1H);m/z(ESI+):874.7(M+H).
实施例25:化合物25b的合成
步骤A:反应瓶中加入1-丁酸(600mg,6.81mmol,1eq.),水(20mL)和氢氧化钠(272mg,6.81mmol,1eq.)。室温搅拌反应10分钟,体系澄清。加入硝酸银(1.16g,6.81mmol,1eq.)后室温搅拌30分钟,大量固体生成,过滤真空干燥得产物1-丁酸银(1.1g,82.85%)。
步骤B:反应瓶中加入1-丁酸银(500mg,895.93umol,1eq.),甲苯(20mL)和1-碘乙基(4-硝基苯基)碳酸酯(1.04g,3.08mmol,1eq.)。50度搅拌反应5小时,浓缩过硅胶柱(石油醚:乙酸乙酯=100:0-95:5)得产物1-(4-硝基苯氧基)羰基氧基丁酸乙酯(450mg,59.03%)。步骤C:反应瓶中加入中间体2(120mg,0.213mmol,1eq.)、DMF(5mL)、1-(4-硝基苯氧基)羰基氧基丁酸乙酯(95.26mg,0.32mmol,1.5eq.)和DIPEA(110.44mg,0.85mmol,1eq.)。80℃搅拌反应1小时。加入乙酸乙酯(50mL)稀释,低温环境,滴加1N HCl淬灭反应,确保水相pH为1-2。有机层浓盐水洗2次,干燥浓缩后,残留物用硅胶柱分离纯化(二氯甲烷:甲醇=100:0-75:25),得化合物25b(40mg,收率26.1%)。1H NMR(500MHz,CD3OD)δppm:0.89(t,J=6.7Hz,3H),0.95(t,J=7.4Hz,3H),1.28(s,26H),1.52(d,J=5.4Hz,5H),1.63(dd,J=14.7,7.3Hz,2H),1.74-1.82(m,2H),2.32(t,J=7.3Hz,2H),3.39(t,J=6.5Hz,2H),3.46(t,J=5.9Hz,2H),3.61(dd,J=26.6,10.7Hz,2H),3.71-3.82(m,2H),3.88(dd,J=14.1,7.6Hz,3H),4.08(s,1H),4.17(d,J=11.4Hz,1H),6.88(d,J=5.3Hz,1H),7.09(s,1H),8.06(d,J=7.0Hz,1H);m/z(ESI+):720.5(M+H).
实施例26:化合物26b和化合物27b的合成
步骤C:反应瓶中加入异丁酸(1.0g,11.35mmol,1eq.)和H2O(10mL),冰浴条件下滴加NaOH(454.0mg,11.35mmol,1eq.)的水溶液(10mL),滴毕室温下搅拌反应半小时。然后滴加AgNO3(1.93g,11.35mmol,1eq.)的水溶液(10mL),滴毕室温下再搅拌反应一小时。反应液直接过滤,滤饼用少量的水洗,干燥得产物(异丁酰氧基)银(1.2g,收率54.23%)。
步骤D:反应瓶中加入1-碘乙基(4-硝基苯基)碳酸酯(1.3g,3.86mmol,1eq.),(异丁酰氧基)银(902.33mg,4.63mmol,1.2eq.)和甲苯(50mL),反应液50℃下搅拌反应16小时。TLC监测大部分反应原料消耗完毕,反应液冷却过滤,滤液浓缩,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯=100:0 -95:5)得产物1-(((4-硝基苯氧基)羰基)氧基)异丁酸乙酯(690mg,收率60.18%)。
步骤E:反应瓶中加入中间体2(110mg,195.84μmol,1eq.),DIPEA(101.24mg,783.35μmol,4eq.)和DMF(3mL),然后滴加1-(((4-硝基苯氧基)羰基)氧基)异丁酸乙酯(87.33mg,293.76μmol,1.5eq.)的DMF(0.5mL)溶液,滴毕80℃下搅拌反应1小时。LC-MS监测反应原料消耗完毕,冰水浴条件下用1mol/L的盐酸水溶液调至反应体系PH为2,加入水(50mL),乙酸乙酯萃洗(20mL*4),有机层饱和食盐水洗一次(60mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,粗品经反相制备柱(乙腈,水,醋酸铵体系)分离纯化,冻干得化合物26b(45.5mg,收率32.28%)1H NMR(500MHz,MeOD)δ0.91–0.95(m,3H),1.16–1.21(m,6H),1.31(s,26H),1.56(s,5H),1.85(s,2H),2.57–2.63(m,1H),3.42–3.46(m,2H),3.50–3.60(m,4H),3.70–3.75(m,2H),3.82(d,J=11.1Hz,1H),3.94(s,3H),4.24(d,J=12.8Hz,1H),6.89(s,1H),7.22–7.26(m,1H),8.09(d,J=6.1Hz,1H);m/z(ESI+):720.6(M+H);以及化合物27b(18mg,收率12.77%)。1H NMR(500MHz,MeOD)δ0.93(t,J=6.7Hz,3H),1.16–1.22(m,12H),1.32(s,26H),1.51(d,J=5.2Hz,3H),1.53–1.60(m,5H),1.84–1.88(m,2H),2.60(dt,J=13.6,6.6Hz,2H),3.44(t,J=6.5Hz,2H),3.52(t,J=5.9Hz,2H),3.56–3.66(m,1H),3.84–3.92(m,1H),3.93–4.03(m,4H),4.18–4.30(m,2H),4.46(dd,J=40.6,10.5Hz,1H),6.71–6.76(m,1H),6.86–6.92(m,1H),7.25(d,J=7.2Hz,1H),8.14(t,J=7.0Hz,1H);m/z(ESI+):878.7(M+H).
实施例27:化合物28b的合成
步骤E:反应瓶中加入中间体2(120mg,213.64μmol,1eq.),DIPEA(110.44mg,854.56μmol,4eq.)和DMF(3mL),然后滴加1-(((4-硝基苯氧基)羰基)氧基)乙酸乙酯(86.27mg,320.46μmol,1.5eq.)的DMF(1mL)溶液,滴毕80℃下搅拌反应1小时。LC-MS监测反应原料消耗完毕,冰水浴条件下用1mol/L的盐酸水溶液调至反应体系PH为2,加入水(50mL),乙酸乙酯萃洗(20mL*4),有机层饱和食盐水洗一次(60mL),分出有机层,无水硫酸钠干燥过滤,经浓缩后,粗品经反相制备柱(乙腈,水,醋酸铵体系)分离纯化,冻干得化合物28b(42mg,收率26.18%)。1H NMR(500MHz,MeOD)δ0.93(t,J=6.6Hz,3H),1.32(s,26H),1.53–1.59(m,5H),1.85(t,J=6.0Hz,2H),2.10(s,3H),3.44(t,J=6.3Hz,2H),3.51–3.61(m,4H),3.70–3.76(m,2H),3.82(dd,J=12.3,3.0Hz,1H),3.91–3.98(m,3H),4.25(dd,J=13.6,2.4Hz,1H),6.89(d,J=5.3Hz,1H),7.24(d,J=7.2Hz,1H),8.10(d,J=7.2Hz,1H);m/z(ESI+):692.5(M+H).
除非另有定义或上下文另有明确规定,本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。应当理解,与本文所述类似或等同的任何方法和材料可用于本发明的实践或测试。
生物学测定
药代动力学研究的一般方法:
将待测化合物溶解在PBS(pH=8)中,其浓度由化合物所施用的特定动物的期望剂量和给药体积确定。向动物以口服给药的方式施用经计量的给药溶液体积。给予待测化合物之后,在特定时间点(例如0.5、1、2、4、8、24、32和48小时)收集血液样品。使用标准技术将血液样品转化为血浆样品。LC-MS/MS分析后以获得待测化合物以及Brincidofovir(BCV,对比化合物)在血浆中的浓度。
1小鼠中本发明化合物的药代动力学研究
在将各化合物与对比化合物分别单次静脉注射(iv)/口服施用(po)至禁食的ICR雄性小鼠后,在施用后的0.083h(IV)、0.25h(IV)、0.5h、1h、2h、4h、8h、24h、32h和48h时收集血液样品。通过离心(3200rpm,10min,4℃)来分离血浆,并且将其冷冻(-80℃)直至用于分析。通过UPLC-MS/MS来确定小鼠血浆中化合物的浓度。将血浆分配至含内标和沉淀剂的适当的管中,使管剧烈震荡1分钟,以实现脱蛋白,随后以12000rmp离心5分钟。取上清液转移至96孔板中进行稀释后,震荡混匀再次离心(4100rpm,5min,4℃)后,用LC-MS/MS进行定量分析。利用DAS 3.2.8软件来计算药代动力学参数,如AUC0-t,AUC0-∞,Cmax,tmax,t1/2,MRT,CL和Vd。如下计算绝对生物利用度:F=[AUC(i.g.)×剂量(i.v.)]/[AUC(i.v.)×剂量(i.g.)]×100%。
化合物2b和对比化合物分别以等摩尔量20mg/kg口服施用至ICR雄性小鼠中,实验方法如上所述,所得药代动力学参数见表2。
表2
其余化合物和对比例分别以等摩尔量40mg/kg口服施用至ICR雄性小鼠中,实验方法如上所述,所得药代动力学参数见表3。
表3
尽管参照本发明的实施例详细描述了本发明,但提供这些实施例是为了说明而不是限制本发明。根据本发明原理能够得到的其它实施例均属于本发明权利要求所界定的范畴。
Claims (20)
1.一种式(I)所示的化合物或其药学上可接受的盐或酯:
其中,X选自-OR6,或者X与R3组合成一个化学键;
R1选自H或C4-C30羰基,所述C4-C30羰基包括取代或未取代的烃基羰基、取代或未取代的芳基羰基或杂环羰基、以及取代或未取代的烃氧基羰基,且所述羰基的碳数不大于30;
R2、R6独立地选自H、其中R7选自取代或未取代的C15-C30烃基,且所述烃基可以是直链烃基或支链烃基;
R3选自:H、甲酰基、C4-C30羰基,其中所述C4-C30羰基包括取代或未取代的烃基羰基、取代或未取代的芳基羰基或杂环羰基,以及取代或未取代的烃氧基羰基,且所述羰基的碳数不大于30;或氨基酸残基;
R4、R5独立地选自氢(H)或氘(D);
作为限制,当X为-OR6时,R1、R2、R3、R6不同时为H,且所述化合物不是布林西多福韦;当X与R3组合成一个化学键时,所述R1、R2不同时为H。
2.根据权利要求1所述的化合物,其中,所述化合物为式(II)所示的化合物:
其中,R1、R2不同时为H。
3.根据权利要求1所述的化合物,其中,所述化合物为式(III)所示的化合物:
作为限制,当X为-OR6时,所述R1、R3、R6不同时为H;当X与R3组合成一个化学键时,所述R1不为H。
4.根据权利要求2所述的化合物,其中,所述化合物为式(IIIa)所示的化合物:
5.根据权利要求1至权利要求4中任一项所述的化合物,其中,所述R1为取代或未取代的烃基羰基,所述取代或未取代的烃基羰基包括以下所示的基团:
6.根据权利要求1至权利要求4中任一项所述的化合物,其中,所述R1为取代或未取代的芳基羰基或杂环羰基,所述取代或未取代的芳基羰基或杂环羰基包括以下所示的基团:
其中,Y选自H、F、Cl、Br、Me、-OMe、-OEt、-CF3或-CN。
7.根据权利要求1至权利要求4中任一项所述的化合物,其中,所述R1为取代或未取代的烃氧基羰基,所述取代或未取代的烃氧基羰基包括以下所示的基团:
8.根据权利要求1至权利要求4中任一项所述的化合物,其中,所述R7包括以下基团:
9.根据权利要求1至权利要求4中任一项所述的化合物,其中,所述R3包括以下基团:
优选地,R3选自/>
10.选自以下的化合物及其药学上可接受的盐:
。
11.一种药物组合物,其特征在于,包括至少一种根据权利要求1至10中任一项所述的化合物,以及至少一种药学上可接受的载体或赋形剂。
12.根据权利要求11所述的药物组合物,其中,所述药学上可接受的载体包括乳膏、乳剂、凝胶、脂质体和纳米颗粒中的一种或多种;所述药学上可接受的赋形剂包括粘合剂、填充剂、崩解剂、润滑剂和助流剂中的一种或多种。
13.根据权利要求11或12所述的药物组合物,其中,所述药物组合物适用于口服施用或者注射施用。
14.权利要求1至权利要求10中任一项所述的化合物或根据权利要求11至13中任一项所述的药物组合物在制备用于治疗、抑制或预防病毒感染或病毒感染所致疾病的药物中的用途。
15.根据权利要求14所述的用途,其中,所述病毒感染包括乙肝病毒(HBV)、新冠病毒(SARS-COV-2)、人类免疫缺陷病毒(HIV)、水痘带状疱疹病毒(VZV)、巨细胞病毒(CMV)、单纯疱疹病毒(HSV)、BK病毒、JC病毒、爱泼斯坦-巴尔病毒(EBV)、埃博拉病毒、多瘤病毒、乳头瘤病毒、正痘病毒、丙肝病毒(HCV)、呼吸道合胞体病毒(RSV)、登革热病毒、流感病毒、腺病毒、副流感病毒和/或鼻病毒引起的感染。
16.根据权利要求15所述的用途,其中,所述正痘病毒包括重型和轻型天花病毒、猴痘病毒、牛痘病毒、骆驼痘病毒、传染性软疣、羊痘病毒、aractuba病毒、BeAn 58058病毒、cantagalo正痘病毒、小鼠痘病毒、象痘病毒、牛痘苗病毒(VV)、兔痘病毒、浣熊痘病毒、臭鼬痘病毒、沙鼠痘病毒和田鼠痘病毒。
17.根据权利要求16所述的用途,其中,所述病毒感染包括由天花病毒、猴痘病毒引起的感染。
18.权利要求1至10中任一项所述的化合物或根据权利要求11至13中任一项所述的药物组合物在制备用于治疗、抑制或预防细胞增殖引发疾病的药物上的用途。
19.根据权利要求18所述的用途,其中,所述细胞增殖引发疾病包括肿瘤、癌症或其他病毒感染疾病,所述肿瘤或癌症选自多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、套细胞淋巴瘤(MCL)、实体瘤、难治性实体瘤、非霍奇金淋巴瘤、血液瘤、神经母细胞瘤、结直肠癌、宫颈癌、肺癌、白血病、乳腺癌、胰腺癌、B-细胞恶性肿瘤、肿瘤、转移性肿瘤、结肠癌;所述病毒感染引起的疾病选自DNA病毒感染所引起的疾病,其中包括视网膜炎、肺炎、膀胱炎、蛋白质病变等。
20.一种试剂盒,所述试剂盒包括根据权利要求1至10中任一项所限定的化合物或药学上可接受的盐或酯或者根据权利要求11至13中任一项所限定的药物组合物。
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