CN112996565A - 取代的1,2,4-噁二唑、其应用和包含它的药物制剂 - Google Patents
取代的1,2,4-噁二唑、其应用和包含它的药物制剂 Download PDFInfo
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- CN112996565A CN112996565A CN201980073852.4A CN201980073852A CN112996565A CN 112996565 A CN112996565 A CN 112996565A CN 201980073852 A CN201980073852 A CN 201980073852A CN 112996565 A CN112996565 A CN 112996565A
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- Prior art keywords
- substituted
- oxadiazole
- general formula
- phenyl
- oxadiazoles
- Prior art date
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- 150000005071 1,2,4-oxadiazoles Chemical class 0.000 title claims abstract description 13
- 239000000825 pharmaceutical preparation Substances 0.000 title description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims description 18
- 201000008827 tuberculosis Diseases 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims 2
- ZBZJXHCVGLJWFG-UHFFFAOYSA-N trichloromethyl(.) Chemical compound Cl[C](Cl)Cl ZBZJXHCVGLJWFG-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 22
- 239000013543 active substance Substances 0.000 abstract description 14
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- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 239000000203 mixture Substances 0.000 abstract description 7
- 229940124976 antitubercular drug Drugs 0.000 abstract description 6
- 239000000814 tuberculostatic agent Substances 0.000 abstract description 6
- 238000009472 formulation Methods 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 150000004866 oxadiazoles Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 44
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- RTQOYSSNAMTQMS-UHFFFAOYSA-N 3-(3,5-dinitrophenyl)prop-2-enoic acid Chemical compound OC(=O)C=CC1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 RTQOYSSNAMTQMS-UHFFFAOYSA-N 0.000 description 8
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- LZVJAPUKTCDCQT-UHFFFAOYSA-N 5-[(3,5-dinitrophenyl)methylsulfanyl]-3-(4-methylphenyl)-1,2,4-oxadiazole Chemical compound C1=C(C=C(C=C1CSC1=NC(C2=CC=C(C)C=C2)=NO1)N(=O)=O)N(=O)=O LZVJAPUKTCDCQT-UHFFFAOYSA-N 0.000 description 6
- IHDULOLGBBYTAZ-UHFFFAOYSA-N 5-[(3,5-dinitrophenyl)methylsulfanyl]-3-phenyl-1,2,4-oxadiazole Chemical compound C1=C(C=C(C=C1CSC1=NC(=NO1)C1=CC=CC=C1)N(=O)=O)N(=O)=O IHDULOLGBBYTAZ-UHFFFAOYSA-N 0.000 description 6
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- SMJODKZAFKWUJG-UHFFFAOYSA-N 1-(chloromethyl)-3,5-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC(CCl)=CC([N+]([O-])=O)=C1 SMJODKZAFKWUJG-UHFFFAOYSA-N 0.000 description 3
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Abstract
有效对抗结核病的基于通式I的取代的1,2,4‑噁二唑的物质,其中Y=S或CH2并且R=苯基或2、3、4和5位被一个或几个电子受体基团或电子供体基团取代的苯基。这些化合物可通过容易的合成来制备,并且特征在于低毒性和对分枝杆菌(包括其多耐药性菌株)的高功效。本发明还公开了包含式I的取代的1,2,4‑噁二唑作为活性物质的药物制剂,以及该取代的1,2,4‑噁二唑作为抗结核药物的用途。
Description
技术领域
本发明涉及有效对抗敏感的以及多耐药性分枝杆菌菌株的基于硝基取代的1,2,4-噁二唑化合物的新型抗结核药物。
背景技术
结核病(TB)是尤其由结核分枝杆菌(Mycobacterium tuberculosis(M.tb.))引起的感染性疾病,其容易从具有肺结核病形式的人通过液滴感染传播。全世界约1/4的人群被TB的潜在形式感染,其中5–15%的人群具有发展活动型TB的风险。2016年,约1040万人感染该疾病,并且在170万人中,TB是死因(世卫组织–2017年全球结核病报告)。这些数字将TB列为十种最常见的死因之一,并且在AIDS患者中,这是有史以来最常见的原因。TB的治疗包括在6到9个月期间同时施用若干种有效对抗结核病的药物,其中加剧了药物副作用、部分患者依从性差、最后但并非最不重要的治疗的昂贵。普通TB的标准治疗包括在强化治疗期的2个月期间同时施用异烟肼、利福平、吡嗪酰胺和乙胺丁醇,然后以利福平和异烟肼联合治疗4至6个月。最近,耐一线药品(即MDR-TB)的TB形式的发病率日益常见。MDR形式的TB需要特殊治疗,包括二线药物例如氟喹诺酮、阿米卡星、卡那霉素、链霉素、环孢菌素、乙硫酰胺、对氨基水杨酸等的混合物。标准疗法包括具有不同的抗结核作用机制的五种药物,其持续时间通常为20个月。长期施用此类药物组合可能导致发生严重的不良事件,并普遍降低患者的依从性。
由于上述原因,仍然需要寻找将减少目前使用的TB疗法、有效对抗MDR-TB菌株以及TB的潜在形式并且能够使治疗更加有效的物质。这需要具有不同于目前使用药物的作用机制的物质。就结构而言,处于临床前和临床发展阶段的新分子通常包含硝基。硝基对于其抗分枝杆菌活性似乎至关重要。然而,此类硝基物质具有不同的作用机制。尤其是,目前关注处于其III期临床研究的迪拉马尼((2R)-2-甲基-6-硝基-2-[(4-{4-[4-(三氟甲氧基)苯氧基]-1-哌啶基}苯氧基)甲基]-2,3-二氢咪唑并[2,1-b][1,3]噁唑)和普托马尼((6S)-2-硝基-6-{[4-(三氟甲氧基)苄基]氧基}-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪)硝基咪唑。迪拉马尼甚至被批准用于治疗耐药性TB,并已被世界卫生组织包括入推荐药物中(Stover,C.K.;Warrener,P.;VanDevanter,D.R.;Sherman,D.R.;Arain,T.M.;Langhorne,M.H.;Anderson,S.W.;Towell,J.A.;Yuan,Y.;McMurray,D.N.;Kreiswirth,B.N.;Barry,C.E;Baker W.R.A small-molecule nitrimidazopyran drug candidate for thetreatment of tuberculosis.Nature 2000,405,962–966;Matsumoto,M.;Hashizume,H.;Tomishige,T.;Kawasaki,M.;Tsubouchi,H.;Sasaki,H.;Shimokawa,Y.;Komatsu,M.OPC-67683,a nitro-dihydro-imidazooxazole derivative with promising action againsttuberculosis in vitro and in mice.PLOSMedicine 2006,3,2131–2143;Gler,M.T.etal.,N.Engl.J.Med.2012,366,23)。
具有与存在硝基相关的作用的另一种重要的抗结核药物是苯并噻嗪酮,特别是II期研究中发现的PBTZ169(2-[4-(环己基甲基)-1-哌嗪基]-8-硝基-6-(三氟甲基)-4H-1,3-苯并噻嗪-4-酮)(Makarov,V.;Manina,G.;Mikusova,K.;U.;Ryabova,O.;Saint-Joanis,B.;Dhar,N.;Pasca,M.R.;Buroni,S.;Lucarelli,A.P.;Milano,A.;DeRossi,E.;Belanova,M.;Bobovska,A.;Dianiskova,P.;Kordulakova,J.;Sala,C.;Fullnm,E.;Schneder,P.;McKinney,J.D.;Brodin,P.;Christophe,T.;Waddell,S.;Butcher,P.;Albrethesen,J.;Rosenkrands,I.;Brosch,R.;Nandi,V.;Bharath,S.;Gaonkar,S.;Shandil,R.K.;Balasubramanian,V.;Balganesh,T.;Tyagi,S.;Grosset,J.;Riccardi,G.;Cole,S.T.Benzothiazinones kill Mycobacterium tuberculosis by blockingarabinan synthesis.Science 2009,324,801–804)。
在其他硝基化合物中,例如提及二硝基苯甲酰胺DNB1(N-(2-(4-甲氧基苯氧基)乙基)-3,5-二硝基苯甲酰胺)和DNB2(N-(2-(苄氧基)乙基)-3,5-二硝基苯甲酰胺)(Christophe,T.;Jackson,M.;Jeon,H.K.;Fenistein,D.;Contreras-Dominguez,M.;Kim,J.;Genovesio,A.;Carralot,J.P.;Ewann,F.;Kim,E.H.;Lee,S.Y.;Kang,S.;Seo,M.S.;Park,E.J.;H.;Pham,H.;Riccardi,G.;Nam,J.Y.;Marsollier,L.;Kempf,M.;Joly-Guillou,M.L.;Oh,T.;Shin,W.K.;No,Z.;Nehrbass,U.;Brosch,R.;Cole,S.T.;Brodin,P.High content screening identifies decaprenyl-phosphoribose 2′epimerase as a target for intracellular antimycobacterial inhibitors.PLOSPathog 2009,5,1-10)或硝基呋喃衍生物–例如化合物Lee878(5-(4-(4-苄基哌嗪-1-基)苯基)-3-(5-硝基呋喃-2-基)-4,5-二氢异噁唑)(Hurdle J.G.et al.,J.Antimicrob.Chemother.2008,62,1037)。
出版物FLIPO,Marion,et al.Ethionamide boosters.2.Combiningbioisosteric replacement and structure-based drug design to solvepharmacokinetic issues in a series of potent 1,2,4-oxadiazole EthRinhibitors.Journal of medicinal chemistry,2011,55.1:68–83公开了对抗分枝杆菌/抗结核剂有效和无效的化合物。该出版物涉及化合物的结构与其作用之间的关系。显然,不同的结构衍生物显示出不同或不同有效的生物学效应。像许多其他出版物一样,该出版物证明无法预测分子的生物学活性。取代基替换或重新定位或甚至构象变化导致完全不同的分子作用。
最接近的现有技术是WO 2014161516文献,其公开了1,3,4-噁二唑和1,3,4-噻二唑的衍生物及其对抗结结核分枝杆菌的耐药菌株的作用。与本发明相比,该文献是分子的生物学活性绝对不可预先估量的另一证明。
发明内容
新化合物对抗结核分枝杆菌以及非典型菌株(包括分离自患病患者的致病性和多耐药性菌株)的显著活性。即,它们涉及通式I的1,2,4-噁二唑:
其中Y=S、CH2;
R=苯基或2、3、4和5位被一个或几个电子受体基团和/或一个或几个电子供体基团取代的苯基。
电子供体基团是指增加R苯基取代基上的电子密度的取代基。
它们尤其涉及:-NH2、-NHAl、-NAl2、-OH、-OAl、-OAr、-NHCOCH3、-NHCOAl、-NHCOAr、-Al、-Ar,其中Alk=烷基,特别是具有1-4个碳原子的烷基,Ar=芳基,其中芳基=苯基或2、3、4和5位被一个或几个电子受体基团和/或一个或几个电子供体基团取代的苯基、萘基或吡啶基。
电子受体基团是指降低R苯基取代基上的电子密度的取代基。它们尤其涉及:-NO2、-N+Alk3、-CF3、CCl3、-CN、-COOH、-COOAlk、-COOAr、-CHO、-COAlk、-COAr、-F、-Cl、-Br、-I,其中Alk=烷基,特别是具有1-4个碳原子的烷基,Ar=芳基,其中芳基=苯基或2、3、4和5位被一个或几个电子受体基团和/或一个或几个电子供体基团取代的苯基、萘基或吡啶基。
(来源:a)John McMurry:Organic Chemistry,Sixth edition,2004,Brooks/Cole,and Thomson Learning Company;b)L.G.Wade,Jr.:Organic Chemistry,Sixthedition,2006,Pearson Prentice Hall Inc.;c)J.Clayden,N.Greeves,S.Warren,P.Wothers:Organic Chemistry,2001,Oxford University Press)
本发明的另一主题是上述根据本发明的具有通式I的取代的1,2,4-噁二唑用作抗结核药物的用途。
本发明的另一方面是药物制剂,其包含具有式I的1,2,4-噁二唑形式的活性物质。
具有通式I的化合物可以通过有机化学中已知的通常可得的方法获得。在合成具有通式I(其中Y=S)的化合物所需的前体1,2,4-噁二唑-5-硫醇的合成期间,采用以下出版物中使用的已知合成方法:a)Xia,G.;You,X.;Liu,L.;Liu,H.;Wang,J.;Shi,Y.;Li,P.;Xiong,B.;Liu,X.;Shen,J.,Design,synthesis and SAR of piperidyl-oxadiazoles as11beta-hydroxysteroid dehydrogenase 1inhibitors.European Journal of MedicinalChemistry 2013,62,1-10;b)Burns,A.R.;Kerr,J.H.;Kerr,W.J.;Passmore,J.;Paterson,L.C.;Watson,A.J.B.,Tuned methods for conjugate addition to a vinyloxadiazole;Synthesis of pharmaceutically important motifs.Organic andBiomolecular Chemistry 2010,8(12),2777-2783;c)Charton,J.;Cousaert,N.;Bochu,C.;Willand,N.;Deprez,B.;Deprez-Poulain,R.Tetrahedron Letters,2007,vol.48,No.8,p.1479-1483;d)Astellas Pharma Inc.-EP2511265,2012,A1.(方案1)。
方案1.合成前体1,2,4-噁二唑-5-硫醇
(DIPEA:N,N-二异丙基乙胺;DBU:1,8-二氮杂双环[5.4.0]十一碳-7-烯)
然后,通过Williamson合成法,通过与可商购的3,5-二硝基苄基氯反应,由相关的1,2,4-噁二唑-5-硫醇获得通式I(其中Y=S)的最终产物(方案2)。它们的制备在合成方面没有要求,并且制备它们所需的原料容易获得且廉价。
方案2.合成具有通式I的最终产物,其中Y=S
通过以下参考文献中所述的方法制备具有通式I的最终产品,其中Y=CH2:a)Xia,G.;You,X.;Liu,L.;Liu,H.;Wang,J.;Shi,Y.;Li,P.;Xiong,B.;Liu,X.;Shen,J.,Design,synthesis and SAR of piperidyl-oxadiazoles as 11beta-hydroxysteroiddehydrogenase 1inhibitors.European Journal of Medicinal Chemistry 2013,62,1-10;b)Burns,A.R.;Kerr,J.H.;Kerr,W.J.;Passmore,J.;Paterson,L.C.;Watson,A.J.B.,Tuned methods for conjugate addition to a vinyl oxadiazole;Synthesis ofpharmaceutically important motifs.Organic and Biomolecular Chemistry 2010,8(12),2777–2783。
使用水溶性碳二亚胺根据肽化学中已知的标准程序将3-(3,5-二硝基苯基)丙酸与N'-羟基-脒缩合(El-Faham,A.;Albericio,F.Chem.Rev.,2011,111(11),pp 6557–6602)。然后,通过在环境温度下与四氢呋喃中的甲醇钠反应,将反应(B)的副产物转化为具有通式I的最终产物(方案3)。
方案3.合成具有通式I的最终产物,其中Y=CH2。(DIPEA:N,N-二异丙基乙胺;WSC:1-乙基-3-(3-二甲基氨基丙基)碳二亚胺;HOBT:1-羟基苯并三唑)
由斯特拉瓦公共卫生研究所(Department of Bacteriology and Mycology,Laboratory for Diagnostics of Mycobacteria,Partyzánskénáměstí7,702 00Ostrava)在液态Sula培养基中在体外条件下测试了所制备的具有通式I的化合物,并测定了它们的最低抑制浓度(MIC),因为不能预测分子的生物学效应。在收集菌株结核分枝杆菌CNCTC My331/88、非典型收集菌株鸟分枝杆菌(M.avium)CNCTC My 330/88和堪萨斯分枝杆菌(M.kansasii)CNCTC My 235/80上测试了所制备化合物的抗分枝杆菌活性。将它们的活性与常用药物异烟肼(INH)的作用比较。测试结果总结于表3中。
将具有通式I的最有效化合物在命名为Praha 1、Praha 4、Praha 131、9449/2007、234/2005、7357/1998和8666/2010的分枝杆菌的多耐药性菌株(MDR菌株)上进一步测试,所述菌株临床分离自患者并且保藏于斯特拉瓦公共卫生研究所(DepartmentofBacteriology and Mycology,Laboratory for Diagnostics of Mycobacteria,Partyzánskénáměstí7,702 00Ostrava)。这些临床分离的菌株对通常可得的抗结核药物的敏感性值总结于表4中。具有通式I的物质对这些多药耐性菌株的抗分枝杆菌活性总结于表5中。
已经发现上述物质显示出高度选择性的抗分枝杆菌作用,因为它们不影响其他类型细胞的生存力。对于所有化合物,均在体外对哺乳动物细胞系(COS-1、HepG2、CHO-K1细胞系)评估了它们的细胞毒性。浓度高达50μM时,相应的物质均不影响哺乳动物细胞的生存力。此外,浓度高达250μM时,相应的物质均不影响标准G+和G-细菌菌株或真菌菌株的生存力。
具体实施方式
下文将公开具有通式I的取代的1,2,4-噁二唑:
其中Y、R符号具有上文解释的含义。
实施例1:5-((3,5-二硝基苄基)硫烷基)-3-苯基-1,2,4-噁二唑(1)
根据方案2通过在乙腈(30ml)中在环境温度下使3-苯基-1,2,4-噁二唑-5-硫醇(0.42g,2.34mmol)与可商购3,5-二硝基苄基氯(97%纯度,0.47g,2.1mmol)和可商购三乙胺(0.35ml,2.51mmol)反应12小时来制备化合物5-((3,5-二硝基苄基)硫烷基)-3-苯基-1,2,4-噁二唑1。反应完成后,蒸出乙腈,将蒸发残余物与饱和NaHCO3水溶液(15ml)混合,并滤出固体级分。将获得的固体物质重悬浮于乙醚/乙酸乙酯2:1(15ml)的混合物中,滤出,并将获得的晶体5-((3,5-二硝基苄基)硫烷基)-3-苯基-1,2,4-噁二唑1在干燥器中脱水。可以使用流动相己烷/乙酸乙酯5:1通过柱色谱再纯化产物。
通过已知方法(Charton,J.;Cousaert,N.;Bochu,C.;Willand,N.;Deprez,B.;Deprez-Poulain,R.Tetrahedron Letters,2007,vol.48,No.8,p.1479–1483)根据方案1制备前体3-苯基-1,2,4-噁二唑-5-硫醇。其他物质通常可商购获得。
实施例2:5-((3,5-二硝基苄基)硫烷基)-3-(对甲苯基)-1,2,4-噁二唑(2)
根据方案2通过在乙腈(30ml)中在环境温度下使3-(4-甲基苯基)-1,2,4-噁二唑-5-硫醇(0.45g,2.34mmol)与可商购3,5-二硝基苄基氯(97%纯度,0.47g,2.1mmol)和可商购三乙胺(0.35ml,2.51mmol)反应12小时来制备化合物5-((3,5-二硝基苄基)硫烷基)-3-(对甲苯基)-1,2,4-噁二唑2。反应完成后,蒸出乙腈,将蒸发残余物与饱和NaHCO3水溶液(15ml)混合,并滤出固体级分。将获得的固体物质重悬浮于乙醚/乙酸乙酯2:1(15ml)的混合物中,滤出,并将获得的晶体5-((3,5-二硝基苄基)硫烷基)-3-(对甲苯基)-1,2,4-噁二唑2在干燥器中脱水。可以使用流动相己烷/乙酸乙酯5:1通过柱色谱再纯化产物。
根据方案1通过在四氢呋喃(20ml)中在氩气气氛下使可商购1,8-二氮杂双环[5.4.0]十一碳-7-烯(2ml,2.03g,0.0133mol)与N'-羟基-4-甲基苯甲脒(0.5g,0.0033mol)和可商购1.1'-硫代羰基-二咪唑(0.89g,0.005mol)反应12小时来制备前体3-(4-甲基苯基)-1,2,4-噁二唑-5-硫醇。然后蒸出溶剂,将粗产物溶于水(30ml)并用乙醚(1×30ml)洗涤。用盐酸将水层酸化至pH=2,并将产物滤出并用水洗涤。将获得的3-(4-甲基苯基)-1,2,4-噁二唑-5-硫醇从乙醇水溶液中重结晶。
前体N'-羟基-4-甲基苯甲脒通过由Murarka,Sandip;Martín-Gago,Pablo;Schultz-Fademrecht,Carsten;Al Saabi,Alaa;Baumann,Matthias;Fansa,Eyad K.;Ismail,Shehab;Nussbaumer,Peter;Wittinghofer,Alfred;Waldmann,Herbert–Chemistry–A European Journal,2017,vol.23,#25,p.6083–6093发明的方法制备。其他物质通常可商购获得。
使用上述合成方法,可以合成许多其他具有通式I的化合物(化合物3-10)。
表1.具有通式I的物质的实例(化合物1-10)
实施例3:5-(3,5-二硝基苯乙基)-3-苯基-1,2,4-噁二唑(11)
根据方案3通过在30ml四氢呋喃中在沸腾温度下使3-(3,5-二硝基苯基)丙酸(0.3g,1.25mmol)、可商购1-羟基苯并三唑水合物(0.71g,4.62mmol)、可商购二异丙基乙胺(0.65ml,0.48g,3.75mmol)、可商购N-(3-二甲基氨基丙基)-N`-乙基碳二亚胺(0.44ml,0.39g,2.5mmol)和N'-羟基苯甲脒(0.19g,1.38mmol)反应8小时来制备化合物5-(3,5-二硝基苯乙基)-3-苯基-1,2,4-噁二唑11。反应完成后,蒸出溶剂,将蒸发残余物溶于乙酸乙酯(30ml)中,并用NaHCO3饱和溶液(1×15ml)和水(1×30ml)洗涤。将有机层用无水Na2SO4脱水,蒸发,并通过柱色谱分离产物5-(3,5-二硝基苯乙基)-3-苯基-1,2,4-噁二唑11(流动相:己烷/乙酸乙酯5:1)。副产物N'-((3-(3,5-二硝基苯基)丙酰基)氧基)苯甲脒也通过柱色谱法分离,并且可通过与1.5摩尔当量的四氢呋喃中的甲醇钠反应而转化为最终产物11。
通过上述方法(Strawn,L.M.;Martell,R.E.;Simpson,R.U.;Leach,K.L.;Counsell R.E.Iodoaryl Analogues of Dioctanoylglycerol and 1-Oleoyl-2-acetylglycerol as Probes for Protein Kinase C,J.Med.Chem.1989,32,2104–2110)将3,5-二硝基肉桂酸还原而制备前体3-(3,5-二硝基苯基)丙酸。在10℃下将硫酸羟铵(0.96g,5.85mmol)和羟胺邻磺酸(2.33g,20.6mmol)添加到3,5-二硝基肉桂酸(0.7g,2.94mmol)于30ml水的悬浮液中。用NaOH溶液将pH值调至6-7。然后将反应混合物在10℃的温度下搅拌5小时,然后在环境温度下搅拌12小时。在上述时间之后,通过NaOH溶液将pH调至8的值,将溶液滤出并使用浓HCl酸化至pH=2。然后将水溶液用乙酸乙酯(2×70ml)提取,将有机提取物用水(2×40ml)洗涤并蒸发。将3-(3,5-二硝基苯基)丙酸通过柱色谱(流动相:己烷/EtOAc/CH3COOH,50:10:1)再纯化。
根据以下方法由可商购3,5-二硝基苯甲醛制备3,5-二硝基肉桂酸:将丙二酸(0.8g,7.67mmol)和0.1ml哌啶加入3,5-二硝基苯甲醛(1g,5.1mmol)在10ml吡啶的溶液中。将反应混合物加热至溶剂的沸腾温度6小时。然后将反应混合物倒入100ml的2M HCl溶液中。将所得沉淀物滤出并溶于70ml乙酸乙酯中。将有机溶液用水(2×40ml)洗涤,用Na2SO4干燥并蒸发。将3,5-二硝基肉桂酸通过柱色谱(流动相:己烷/EtOAc/CH3COOH,40:10:1)再纯化。
前体N'-羟基苯甲脒通过已知方法制备(Burns,A.R.;Kerr,J.H.;Kerr,W.J.;Passmore,J.;Paterson,L.C.;Watson,A.J.B.,Tuned methods for conjugate additionto a vinyl oxadiazole;Synthesis of pharmaceutically important motifs.Organicand Biomolecular Chemistry 2010,8(12),2777–2783.)。
实施例4:5-(3,5-二硝基苯乙基)-3-(对甲苯基)-1,2,4-噁二唑(12)
根据方案3通过在30ml四氢呋喃中在沸腾温度下使3-(3,5-二硝基苯基)丙酸(0.3g,1.25mmol)、可商购1-羟基苯并三唑水合物(0.71g,4.62mmol)、可商购二异丙基乙胺(0.65ml,0.48g,3.75mmol)、可商购N-(3-二甲基氨基丙基)-N`-乙基碳二亚胺(0.44ml,0.39g,2.5mmol)和N'-羟基-4-甲基苯甲脒(0.206g,1.38mmol)反应8小时来制备化合物5-(3,5-二硝基苯乙基)-3-(对甲苯基)-1,2,4-噁二唑12。反应完成后,蒸出溶剂,将蒸发残余物溶于乙酸乙酯(30ml)中,并用NaHCO3饱和溶液(1×15ml)和水(1×30ml)洗涤。将有机层用无水Na2SO4脱水,蒸发,并通过柱色谱分离产物5-(3,5-二硝基苯乙基)-3-(对甲苯基)-1,2,4-噁二唑12(流动相:己烷/乙酸乙酯5:1)。副产物N'-((3-(3,5-二硝基苯基)丙酰基)氧基)-4-甲基苯甲脒也通过柱色谱法分离,并且可通过与1.5摩尔当量的四氢呋喃中的甲醇钠反应而转化为最终产物12。
通过上述方法(Strawn,L.M.;Martell,R.E.;Simpson,R.U.;Leach,K.L.;Counsell R.E.Iodoaryl Analogues of Dioctanoylglycerol and 1-Oleoyl-2-acetylglycerol as Probes for Protein Kinase C,J.Med.Chem.1989,32,2104–2110.)将3,5-二硝基肉桂酸还原而制备前体3-(3,5-二硝基苯基)丙酸。在10℃下将硫酸羟铵(0.96g,5.85mmol)和羟胺邻磺酸(2.33g,20.6mmol)添加到3,5-二硝基肉桂酸(0.7g,2.94mmol)于30ml水的悬浮液中。用NaOH溶液将pH值调至6-7。然后将反应混合物在10℃的温度下搅拌5小时,然后在环境温度下搅拌12小时。在上述时间之后,通过NaOH溶液将pH调至8的值,将溶液滤出并使用浓HCl酸化至pH=2。然后将水溶液用乙酸乙酯(2×70ml)提取,将有机提取物用水(2×40ml)洗涤并蒸发。将3-(3,5-二硝基苯基)丙酸通过柱色谱(流动相:己烷/EtOAc/CH3COOH,50:10:1)再纯化。
根据以下方法由可商购3,5-二硝基苯甲醛制备3,5-二硝基肉桂酸:将丙二酸(0.8g,7.67mmol)和0.1ml哌啶加入3,5-二硝基苯甲醛(1g,5.1mmol)在10ml吡啶的溶液中。将反应混合物加热至溶剂的沸腾温度6小时。然后将反应混合物倒入100ml的2M HCl溶液中。将所得沉淀物滤出并溶于70ml乙酸乙酯中。将有机溶液用水(2×40ml)洗涤,用Na2SO4干燥并蒸发。将3,5-二硝基肉桂酸通过柱色谱(流动相:己烷/EtOAc/CH3COOH,40:10:1)再纯化。
前体N'-羟基-4-甲基苯甲脒通过基于以下出版物的已知方法制备:Murarka,Sandip;Martín-Gago,Pablo;Schultz-Fademrecht,Carsten;Al Saabi,Alaa;Baumann,Matthias;Fansa,Eyad K.;Ismail,Shehab;Nussbaumer,Peter;Wittinghofer,Alfred;Waldmann,Herbert–Chemistry–A European Journal,2017,vol.23,#25,p.6083–6093。
使用上述合成方法,可以合成许多其他具有通式I的化合物(化合物13-16)。
表2.具有通式I的物质的实例(化合物11-16)
表3.具有通式I的物质的体外最小抑菌浓度(μmol.l-1)–用于测定孵育14和21天后的结核分枝杆菌和鸟分枝杆菌以及孵育7、14和21天后的堪萨斯分枝杆菌的塑料P板中Sula培养基中药物的最小抑菌浓度的微方法。
结核分枝杆菌 | 鸟分枝杆菌 | 堪萨斯分枝杆菌 | |
My 331/88 | My 330/88 | My 235/80 | |
1 | 0.5/1 | 250/250 | 0.5/1/1 |
2 | 0.5/1 | 250/250 | 0.5/1/2 |
3 | 0.5/0.5 | 250/250 | 0.5/1/2 |
4 | 0.5/1 | 250/250 | 1/2/4 |
5 | 0.5/1 | 250/250 | 2/2/4 |
6 | 0.5/1 | 125/125 | 8/16/32 |
7 | 1/1 | 250/250 | 1/1/2 |
8 | 0.25/0.5 | 250/250 | 0.5/1/2 |
9 | 1/1 | 125/125 | 1/1/2 |
10 | 0.5/1 | 250/250 | 2/2/4 |
11 | 4/4 | 250/250 | 2/4/8 |
12 | 2/4 | 250/250 | 2/4/4 |
13 | 0.5/1 | 250/250 | 0.5/1/2 |
14 | >32/>32 | 250/250 | >32/>32/>32 |
15 | >32/>32 | 250/250 | 32/>32/>32 |
16 | >32/>32 | 250/250 | >32/>32/>32 |
表4.常用抗生素和抗结核药物的体外最小抑菌浓度(μmol.1-1)-用于测定多耐药性菌株结核分枝杆菌的塑料P板中Sula培养基中药物的最小抑菌浓度的微方法。
R-耐给定的抗结核药物的菌株
C-对给定的抗结核药物敏感的菌株
表5.具有通式I的物质的体外最小抑菌浓度(μmol.l-1)-用于测定孵育14天后的多耐药性菌株结核分枝杆菌的塑料P板中Sula培养基中药物的最小抑菌浓度的微方法。
表6.具有通式I的物质的熔点和NMR光谱
表9.具有通式I的物质的元素分析
药物产品实施例–片剂
在药物形式的生产中,本领域技术人员已知选择该领域通常采用的技术,即干法或湿法制粒。使用提供具有所需物理性质的药物形式的常用且经充分证实的赋形剂和合适的制剂。
干法制粒的实施例
实施例1(活性物质含量100mg)
实施例2(活性物质含量200mg)
实施例3(活性物质含量300mg)
实施例4(活性物质含量400mg)
实施例5(活性物质含量500mg)
将活性物质与片剂材料的各成分混合,并将混合物在制片机中以常规方法转化成片剂。
湿法制粒的实施例
实施例6(活性物质含量100mg)
实施例7(活性物质含量200mg)
实施例8(活性物质含量300mg)
实施例9(活性物质含量400mg)
实施例10(活性物质含量500mg)
将活性物质与乳糖、马铃薯淀粉逐渐混合,将混合物通过聚乙烯吡咯烷酮制粒,将干燥的颗粒与羟乙酸淀粉钠、硬脂酸镁和滑石混合,并将所得混合物在制片机中以常规方法制成片剂。
工业实用性
基于硝基取代的1,2,4-噁二唑化合物的新型抗结核药物有效对抗敏感和多耐药性分枝杆菌菌株。
Claims (5)
2.根据权利要求1所述的通式I的取代的1,2,4-噁二唑:其中Y是S。
3.根据权利要求1所述的通式I的取代的1,2,4-噁二唑:其中Y是CH2。
4.根据权利要求1-3任一项所述的通式I的取代的1,2,4-噁二唑在制备用于治疗结核病的药物的用途。
5.根据权利要求1-3任一项所述的通式I的取代的1,2,4-噁二唑,其作为药物组合物的一部分。
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WO (1) | WO2020128675A1 (zh) |
ZA (1) | ZA202103380B (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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RU2415845C1 (ru) * | 2009-10-14 | 2011-04-10 | Государственное образовательное учреждение высшего профессионального образования "Астраханский государственный университет" (АГУ) | Сульфонные производные 2-нитро-2-(3-арил-1,2,4-оксадиазол-5-ил)этана, обладающие противолепрозной и противотуберкулезной активностью |
WO2014049107A1 (fr) * | 2012-09-27 | 2014-04-03 | Universite De Droit Et De La Sante De Lille 2 | Composes utilisables dans le traitement des infections mycobacteriennes |
WO2014161516A1 (en) * | 2013-04-04 | 2014-10-09 | Univerzita Karlova V Praze Farmaceuticka Fakulta V Hradci Kralove | Oxa- and thia-diazoles useful in the treatment of tuberculosis |
Family Cites Families (1)
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CA2783537A1 (en) | 2009-12-11 | 2011-06-16 | Astellas Pharma Inc. | Benzamide compound |
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2019
- 2019-11-19 EA EA202190959A patent/EA202190959A1/ru unknown
- 2019-11-19 US US17/293,446 patent/US20210403443A1/en active Pending
- 2019-11-19 WO PCT/IB2019/059934 patent/WO2020128675A1/en active Application Filing
- 2019-11-19 CN CN201980073852.4A patent/CN112996565A/zh active Pending
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2021
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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RU2415845C1 (ru) * | 2009-10-14 | 2011-04-10 | Государственное образовательное учреждение высшего профессионального образования "Астраханский государственный университет" (АГУ) | Сульфонные производные 2-нитро-2-(3-арил-1,2,4-оксадиазол-5-ил)этана, обладающие противолепрозной и противотуберкулезной активностью |
WO2014049107A1 (fr) * | 2012-09-27 | 2014-04-03 | Universite De Droit Et De La Sante De Lille 2 | Composes utilisables dans le traitement des infections mycobacteriennes |
WO2014161516A1 (en) * | 2013-04-04 | 2014-10-09 | Univerzita Karlova V Praze Farmaceuticka Fakulta V Hradci Kralove | Oxa- and thia-diazoles useful in the treatment of tuberculosis |
Also Published As
Publication number | Publication date |
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EA202190959A1 (ru) | 2021-10-11 |
CZ2018664A3 (cs) | 2020-06-10 |
ZA202103380B (en) | 2022-07-27 |
CZ308557B6 (cs) | 2020-11-25 |
WO2020128675A1 (en) | 2020-06-25 |
US20210403443A1 (en) | 2021-12-30 |
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