CN101098860A - 芳基嘧啶基化合物、含有它们的药物组合物及其作为抗微生物剂的应用 - Google Patents
芳基嘧啶基化合物、含有它们的药物组合物及其作为抗微生物剂的应用 Download PDFInfo
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- CN101098860A CN101098860A CNA2005800460269A CN200580046026A CN101098860A CN 101098860 A CN101098860 A CN 101098860A CN A2005800460269 A CNA2005800460269 A CN A2005800460269A CN 200580046026 A CN200580046026 A CN 200580046026A CN 101098860 A CN101098860 A CN 101098860A
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Abstract
符合通式(I)的被取代的芳基嘧啶基化合物及其在制备用于预防和/或治疗由分支杆菌引起的病理的药物中的应用。
Description
技术领域
本发明涉及某些取代的芳基嘧啶基化合物及其合成方法。本发明还涉及含有它们的药物组合物及其作为抗微生物剂的应用,尤其是在预防或治疗与分支杆菌有关的病理中的应用。
本发明特别涉及这些分子在预防或治疗由分支杆菌引起的结核病和其他疾病中的应用。
背景技术
结核病的发病率在过去二十年间持续增长并且如今是世界上传染病中死亡率的首要因素,每年有多于两百万的人死于该病。结核杆菌(Mycobacterium tuberculosis,M.tuberculosis)是与人类有关的主要微生物因素。结核病主要通过空气中气溶胶化分泌物来传播。其致病性的特殊方面在于它可以保持静止而在数十年后变得活跃。发生结核病的最重要的危险因素之一是人类免疫缺陷病毒(HIV)感染。活动性结核病的常用治疗法包括四种药物(异烟肼、利福平、吡嗪酰胺及乙胺丁醇),用药至少六个月。很大比例的患者无法完成治疗,尤其是在发展中国家,这已导致耐药性结核杆菌(M.tuberculosis)菌株的出现。
因此需要一种可有效对抗结核杆菌(M.tuberculosis)的新的分子。
就此而言,一种核苷代谢必需的酶胸苷单磷酸激酶(TMPK)是令人感兴趣的靶点。
TMPK(E.C.2.7.4.9,ATP:TMP磷酸转移酶)属于一大类核苷单磷酸激酶(NMPK)超家族。它利用ATP作为优选的磷酰基供体催化胸苷单磷酸(TMP)磷酸化为胸苷二磷酸(TDP)。它位于胸苷三磷酸(TTP)代谢的从新(de novo)和补救路径的交叉点并且是用于其合成的最后的特异性酶。这些特点使TMPK成为设计新型抗生素药物的好靶点。
作用于结核杆菌(M.tuberculosis)的TMPK的嘌呤和嘧啶核苷类似物已经由S.Pochet等在Chem.Bio.Chem.2003,
4,742-747中公开。
然而始终需要生物活性更强、特异性更好、生物利用度提高的分子以及易于合成从而可以实现工业化规模生产的分子。
发明内容
本发明的目的是符合(responding to)通式(I)的分子及其药物学可接受的盐:
其中:
·R1选自以下组中:CH3、-CF3、卤素原子、-NH2、-COOH、-CONH2,
·R2、R3、R4相同或不同,选自以下组中:
-H、卤素原子,
-C1-C8烷基、C2-C8烯基、C2-C8炔基,其中该烷基、烯基或炔基链可以被杂原子桥间断,所述的杂原子优选自:N、S、O、Se,
--OH、-NH2、-CHO、-COOH、-SO4H、-CONH2、-CN、-COOR5、-COR5、-OR5,
-取代的C1-C8烷基、取代的C2-C8烯基、或取代的C2-C8炔基,其中该取代基选自以下组中:-OH、-NH2、-CHO、-COOH、-SO4H、-CONH2、-CN、-COOR5、-COR5、-OR5、卤素原子,其中该烷基、烯基或炔基链可以被杂原子桥间断,所述的杂原子优选自:N、S、O、Se;
·R5选自C1-C6烷基;
·R6选自:C1-C4亚烷基、C2-C4亚烯基、羰基(=C=O)、-(CF2)n-
·n为选自1、2、3的整数。
烷基为直链、支链或环状碳氢基团(hydrogeno carbon radical)。
烯基为含有至少一个双键的直链、支链或环状烃基。
炔基为含有至少一个三键的直链、支链或环状烃基。
卤素选自Cl、F、Br、I。
当烷基、烯基或炔基链被杂原子间断时,该杂原子可以为二价或三价。在后一种情况下,该杂原子可以被烷基、烯基或炔基取代,这些取代基本身可以被下列官能团之一所取代:-OH、-NH2、-CHO、-COOH、-SO4H、-CONH2、-CN、-COOR5、-COR5、-OR5或卤素原子。
优选地,符合通式(I)的分子满足以下一个或多个条件:
·R6为-CH2-;
·R1选自-CH3、-Br、-Cl;
·在R2、R3、R4中至少一个基团为H。
更优选地,R2=R3=H。
有利地,R4在苯环上处于对位。
在优选的形式中,R4选自取代的C1-C6烷基或取代的C2-C6烯基,其中所述取代基为-COOH,并可能包含杂原子桥,所述的杂原子选自:N、S、O、Se。
甚至更优选地,R4选自被一个-COOH取代的C2-C4烷基或被硫桥间断的C1-C8烷基。
有利地,R4为4-基-正丁酸。
适宜的分子如以下化学式所示:
已证实上述分子能够抑制结核杆菌TMPK,因此它们可以用于制备用于预防和/或治疗结核病的药物。必须得说,这些分子在体外具有抑制结核杆菌TMPK的能力,根据所涉及的分子不同,其Ki值不一样。然而,该抑制活性存在并允许存在在体内抑制结核杆菌TMPK的希望。优选的分子是那些其Ki低于或等于40μM的分子,甚至更优选为低于或等于30μM的分子。以上所述分子20、21、22、39、61、63和64由于其作为结核杆菌TMPK抑制剂的活性因而是优选的分子。
本发明的分子也可在体外用作结核杆菌TMPK,尤其是结核杆菌TMPK的抑制剂,例如用于生物测试。
此外,这些分子也可以用于制备用于预防或治疗由分支杆菌引起的包括麻风病(M.leprae)在内的其他病理的药物。
本发明的化合物具有对人类TMPK的亲和力比对结核杆菌TMPK的亲和力低的优势。因此,在治疗剂量下给药的基于这些化合物的药物的副作用将被限制。
本发明包括药物组合物,所述药物组合物包含在药物学可接受的载体中的至少一种通式(I)的化合物。给药途径包括口服、含服、鼻内、眼部、静脉内、肌肉内、透皮、非胃肠道和直肠途径。优选地,当所治疗的疾病是结核病时,本发明的药物组合物是通过口服或鼻内途径以片剂、丸剂、糖锭剂、胶囊、凝胶、混悬液、糖浆的形式给药。它可以分布在气雾剂中或者作为用于吸入的溶液或其他任意易于挥发从而可快速对肺给药的形式来给药。
该药物组合物的用量和剂量将根据患者的体重、年龄和症状以及分子的抑制活性而定。所含的活性成分的日剂量介于0.1至500mg/kg之间。
药物学可接受的盐包括(I)的酸官能团与有机或无机碱的盐以及(I)的胺官能团与有机或矿物酸的盐。
酸加成盐包括:乙酸盐、草酸盐、琥珀酸盐、富马酸盐、葡萄糖酸盐、苹果酸盐、抗坏血酸盐、苯甲酸盐、盐酸盐、磷酸盐、氢溴酸盐、硫酸盐、亚磺酸盐、甲酸盐、甲苯磺酸盐、甲磺酸盐、硝酸盐、苯甲酸盐、柠檬酸盐、酒石酸盐、马来酸盐、氢碘酸盐。
碱加成盐包括:钠、钾和锂盐;钙、钡和镁盐;铵、亚铁、铁、锌、锰、铝、镁盐;三甲胺、三乙胺、三正丙胺、二环己胺、三乙醇胺、精氨酸、赖氨酸、组氨酸、乙二胺、葡糖胺、甲基葡糖胺、嘌呤、哌嗪、哌啶、咖啡因、普鲁卡因盐。
药物学可接受的载体可以非限制的方式包括一种或若干种下列化合物:填充剂如糖、淀粉、明胶、树脂、纤维素衍生物(甲基纤维素、羟丙基甲基纤维素)、聚乙烯吡咯烷酮、琼脂、褐藻酸、滑石、聚乙二醇、药物学可接受的色素和染料、稳定剂、油、液体石蜡、乙醇、甘油酯。
具体实施方式
分子的制备
本发明的另一目的是通式(I)的分子的合成方法。
该方法可以由以下路线1描述:
路线1
根据本发明的方法,通式(II)的卤代芳基与通式(III)的胸腺嘧啶或胸腺嘧啶衍生物或尿嘧啶(uracyle)或尿嘧啶衍生物反应生成缩合物(IV)。在通式(II)中:X代表卤素原子,优选为Br;X2、X3、X4分别选自R2、R3、R4及其化学前体。在通式(III)和通式(IV)中,X1选自R1及其化学前体,X5选自H和苄基(Bzl)。
化学前体(X1、X2、X3和X4)是指可以通过一步或多步反应转化为所需官能团(R1、R2、R3和R4)的官能团。
例如,如果R1为H或卤素,那么X1分别为H或所述的卤素,但是如果R1为-CH2-COOH,那么X1可以为-CH2-COOBzl或-CH2-OH或-CH2-Br,从而,胸腺嘧啶环的烷基化反应可以在没有任何副反应的情况下发生。
在第二步反应中,如果必要,X1、X2、X3、X4和X5分别转化为R1、R2、R3、R4和H,从而生成通式(I)的分子。
根据本发明最适宜的变量,R2=R3=H且R6=CH2。那么对于合成通式(I)的分子的关键中间体为:
其中X1和X5具有如上所解释的相同定义。
特别是在R1为CH3的情况下,制备通式(I)的其他分子最适宜的中间体分子(V)为:
通式(V)的化合物,特别是化合物11和11bis在符合通式(I)的分子的制备中的应用是本发明的另一个目的。
上述策略在实施例和下面的路线2和3中进行阐明。
路线3
最适宜的合成路线是基于在芳基卤化物和适宜的烯烃或炔烃之间的Heck或Sonogashira C-C钯催化的偶联反应(路线4)。通常,第一步为胸腺嘧啶或尿嘧啶(N1-苯甲酰化)的烷基化。从这个关键的卤化物中间体(IV)开始,利用Heck或Sonogashira反应将各种市售的酸、酯或醇(取决于所选择的链长)进行偶联。
路线4
我们考虑在被C3链取代的N1-苄基胸腺嘧啶的制备中使芳基溴化物或碘化物与作为C3链前体的烯烃发生Heck钯催化的偶联反应(Palladium-catalyzed reactions oforganic halides with olefins,R.F.Heck等,Accounts of Chemical Research,(1979),12(4),146-151)(路线5)。从市售的4-碘-苄基溴开始,先将N3-苯甲酰基胸腺嘧啶烷基化生成23(收率88%),然后去苯甲酰化得到碘化物24(收率95%)。在Pd(OAc)2(2%)、三-邻甲苯甲酰基膦(tri-o-toluylphosphine)(4%)和三乙胺存在下,将24和丙烯酸乙酯在无水乙腈中的混合物于90℃搅拌18h。分离该反式-烯烃17,收率97%。化合物17可用于获得目标分子1和2,其还可用作合成三种其他相关衍生物(14、18、19)的前体。因此,丙烯酸乙酯17以10%Pd/C氢化得到丙酸乙酯19(收率91%)。用1N NaOH处理19得到丙酸2(收率59%),用35%的氨水处理19得到目标化合物1(收率90%)。以相同的方式,将17皂化得到丙烯酸(propenacid)衍生物18,将17进行氨解以相似的收率得到丙烯酰胺14。
路线5
在路线5中描述了对位由C4链取代的N1-苄基-胸腺嘧啶的合成。根据为引入羧酸官能团所选择的前体对两条路线进行了研究。为了通过Heck偶联反应得到化合物20,在Pd(OAc)2(2%)、三-邻甲苯甲酰基膦(4%)在乙腈和三乙胺中的溶液存在下,将24和3-丁烯酸的混合物于60℃加热。以27%的收率分离烯烃28,同时回收碘化物24。通过NMR分析确认仅分离一种立体异构体(Z-3,4)。将温度提高到90℃并未提高收率。当从碘化物23开始进行芳基化时,由于相应的得到的N1-苯甲酰化衍生物28易于分离,其偶联收率略有提高(39%)。然后用H2在10%Pd-C上对烯28进行还原得到C4酸20(收率97%)。或者,通过24和市售的炔烃进行C-C偶联(Sonogashira反应)得到了化合物20。从而,在四(三苯基膦)合钯(6%)、碘化亚铜(I)(2%)存在下将丁-3-炔-1-醇和碘化物24在CH2Cl2和Et3N的混合物中于氩气下90℃回流72h。以40%的收率分离化合物30作为主要的芳基化产物。当芳基化于60℃进行72h时,以49%收率分离30。然后用H2在10%Pd-C上将炔醇30进行还原得到醇31(收率98%)。在叔丁醇的存在下用PDC进行氧化,之后将中间体叔丁基酯进行酸水解得到C4酸20(两步收率46%)。在Dowex H+存在下将酸20在甲醇中回流,然后将得到的甲酯40a用氨在甲醇中处理得到酰胺40b(两步收率58%)。
对于尿嘧啶衍生物的合成,从4-卤代苄基-尿嘧啶开始按照相同的步骤进行。这样,碘化物25(由以4-碘苄基溴使N1-苯甲酰基尿嘧啶烷基化获得)与3-丁炔酸甲酯进行Heck偶联反应以42%的收率生成甲酯29a。将29a进行皂化得到酸29b,而29a进行催化氢化和皂化得到酸38a。或者,溴化物11与丁-3-炔-1-醇进行Sonogashira偶联以良好的收率得到炔36(64%)。催化还原成醇37,氧化成叔丁基酯,然后进行酸水解得到尿嘧啶酸衍生物38a(三步收率49%)。将38a进行溴化和氯化分别得到相应的5-Br和5-Cl衍生物21(收率70%)和39(收率49%)。酸39b通过甲酯38a转化为酰胺41,然后进行溴化或氯化分别得到5-溴或5-氯尿嘧啶氧生物42和43。
通过将芳基卤化物和适当的C5炔进行偶联,以两步生成具有以羧酸为末端的C5链的N1-苄基-胸腺嘧啶(路线6)。溴化物11和4-戊烯酸在Pd(OAc)2和三-邻甲苯甲酰基膦存在下进行Heck反应以48%的收率生成44,它是三种立体异构体的混合物:4-E-戊烯酸(44a)、3-E-戊烯酸(44b)和2-E-戊烯酸(44c),根据NMR分析其比例为5/2/1。自N3-苯甲酰基化的胸腺嘧啶溴化物11bis开始,该偶联反应稍有改进(收率63%)而产物的纯化得到提高。去苯甲酰化后,以相似的总收率得到44。将烯烃44的异构体混合物还原得到饱和的C5酸45(收率55%)。类似地,由C5链取代的N1-苄基-尿嘧啶是通过以下方法获得:将N3-苯甲酰基化的尿嘧啶碘化物25与4-戊烯酸发生Heck偶联(61%),然后烯烃46进行去苯甲酰化和催化氢化得到酸47,对其溴化和氯化分别得到5-溴和5-氯衍生物48和49。
路线6
具有C6链的N-苄基-胸腺嘧啶和5-卤代尿嘧啶是利用碘化物和适宜的以羧酸或醇为末端的C6炔之间进行钯催化的Sonogashira反应而得到。各个合成路线的实例如路线7所示。为了便于芳基化产物的纯化,我们从关键的中间体23或25(当碱为N1-苯甲酰基化物时)开始。从而,在四(三苯基膦)合钯(6%)、碘化亚铜(I)(2%)存在下,23和5-己炔酸间进行钯催化的Sonogashira反应生成50,收率为80%。将50进行去苯甲酰化得到51,接着氢化得到饱和的C6酸22(两步收率50%)。将酸51通过相应的甲酯52转化为酰胺53,接着将53进行还原得到C6间隔基酰胺54(两步收率42%)。当5-己炔-1-醇与碘化物25进行偶联时,生成化合物55,收率为70%。去苯甲酰化然后进行氢化得到C6醇56(83%)。铬氧化(chromic oxidation)56得到C6酸57,将其溴化和氯化分别得到5-溴和5-氯-尿嘧啶衍生物58和59。同样,以C6酰胺为末端的5-卤代尿嘧啶衍生物61和62是从酰胺60(从酸57得到)来进行合成。
路线7
实施例
A-化学合成
总体说明溶剂为色谱级或HPLC级。试剂是从Sigma-Aldrich或Fluka购买并未经纯化而使用。1H及13C NMR色谱是在Bruker AC-400色谱仪上记录,并分别于400.13MHz和100.62MHz操作。1H及13C化学位移是相对于残余溶剂峰以ppm(δ)给出,偶联常数(J)是以赫兹(Hertz)为单位并以正常缩写表示。薄层色谱(TLC)使用Merck硅胶板(Kieselgel 60 F254/厚度0.2mm)进行,并用UV光使各点可视化,然后喷洒硫酸-茴香醛之后加热来显色。使用Merck silica gel 60(230-400目)进行柱色谱。制备HPLC利用Perkin Elmer系统(200Pump)使用C18反相柱(Kromasil,5μ100_,150×4.5mm)进行,流速5.5ml/min,以在10mM pH7.5的三乙基乙酸铵缓冲液(B)中的CH3CN(A)为线性梯度洗脱大约20min。洗脱的产物经二极管阵列检测器显示。化合物的纯度使用分析HPLC在C18反相柱上以1ml/min流速进行检测。ESI-TOF质谱由质谱实验室(CNRS-ICSN,Gif-sur-Yvette)进行测定。
N-烷基化的通用方法(路线2和路线3)
向胸腺嘧啶(或相关碱)(100mg)在DMF(4ml)中的搅拌溶液中加入无水K2CO3(100mg)。在1h内加入芳基卤化物(1.1当量)在DMF(1ml)中的溶液,室温下维持搅拌过夜。过滤除去不溶物并用二甲苯共蒸发浓缩至干燥。将粗的残余物溶于CH2Cl2中并用水洗涤。将有机层干燥,真空浓缩并经硅胶柱色谱纯化(甲醇在二氯甲烷中的梯度洗脱)得到比例为1∶1.2-1.3的N1,N3-二烷基化和N1-烷基化胸腺嘧啶。
或者,将N3-苯甲酰基-胸腺嘧啶进行烷基化(根据在“The Benzoylation of Uraciland Thymine”,Cruickshank,K.A.;Jiricny,J.;Reese,C.B.;(1984)Tet.Letts.,25(6),681-684所述的方法从胸腺嘧啶经两步获得,收率为74%)得到唯一产物N1-烷基化N3-苯甲酰基-胸腺嘧啶,收率为84%。在碱性条件(33%的氨水在甲醇中的溶液)下脱去苯甲酰基保护基生成相应的N1-烷基化胸腺嘧啶(几乎定量地生成)。
5-甲基-1-(4-溴-苄基)-1H-嘧啶-2,4-二酮(11)
将胸腺嘧啶(300mg)、K2CO3(330mg)与4-溴-苄基溴(1.1当量)在DMF(15mL)中反应,经纯化后得到化合物11(302mg,收率43%)。1H NMR(CDCl3)δ:1.96(d,3H,CH3,J=1.2Hz),4.85(s,2H,PhCH2),6.98(d,1H,H6,J=1.2Hz),7.19(d,2H,H arom.,J=8Hz),7.51(d,2H,H arom.),9.47(bs,1H,NH)。13C NMR(CDCl3)δ:12.76(CH3),50.86(PhCH2),111.98(C5),122.94(C arom.),130.07和132.63(CH arom.),134.93(C arom.),139.88(C6),151.59(C2),164.53(C4)。MS(ESI-TOF)m/z 295.0和297.0(15%,M+H)+,317.0和319.0(20%,M+Na)+,339.0和341.0(100%,85%,M+2Na)+。
N3-苯甲酰基-5-甲基-1-(4-溴-苄基)-1H-嘧啶-2,4-二酮(11bis)
N3-苯甲酰基-胸腺嘧啶(230mg,1mmol)与4-溴-苄基溴(140mg)反应,经纯化后得到化合物11bis(336mg,收率84%)。1H NMR(DMSO-d6)δ:1.85(d,3H,CH3,J=1.1Hz),4.90(s,2H,PhCH2),7.32(d,2H,H arom.,J=8.4Hz),7.78(m,4H,Harom.和H arom.Bz),7.78(t,1H,H arom.Bz),7.93(m,2H,H arom.Bz),7.95(d,1H,H6,J=1.1Hz)。13C NMR(DMSO-d6)δ:12.73(CH3),51.14(PhCH2),110.08(C5),121.93(Carom.),130.36,130.71,131.14(CH arom.),131.98(C arom.),132.49和136.32(CHarom.),136.64(C arom.),143.04(C6),150.38(C2),163.69(C4),170.46(COBz)。MS(ESI-TOF)m/z 421.0和423.0(100%和90%,M+Na)。
1-[4-(4-羟基-丁-1-炔基)-苄基]-5-甲基-1H-嘧啶-2,4-二酮(30)
氩气下向化合物11(1.94g,6.57mmol)在无水CH2Cl2(10mL)的溶液中加入新蒸馏的Et3N(27ml)、3-丁炔-1-醇(0.46g,6.57mmol)、四(三苯基膦)合钯(0.45g,0.39mmol)和碘化亚铜(25mg,0.13mmol)。将反应混合物加热回流72h。将CH2Cl2(100ml)加入到冷却的混合物中并用5%柠檬酸水溶液洗涤(3×100ml)所得的溶液。有机层经Na2SO4干燥并在真空下浓缩。经硅胶柱色谱纯化(0-10%梯度的甲醇在二氯甲烷中的溶液)得到回收的起始原料(0.52g,27%),然后是化合物30,为白色粉末(0.44g,24%)。1H NMR(DMSO-d6)δ:1.75(d,3H,CH3,J=1.2Hz),2.54(t,2H,CH2),3.58(q,2H,CH2OH),4.83(s,2H,PhCH2),4.92(t,1H,OH),7.25(d,2H,H arom.,J=8Hz),7.37(d,2H,H arom.,J=8Hz),7.61(d,1H,H6,J=1.2Hz),11.33(bs,1H,NH)。13C NMR(DMSO-d6)δ:12.77(CH3),24.09(CH2),50.72(PhCH2),60.57(CH2),81.54(C alcyn),89.68(C alcyn),109.98(C5),123.32(C arom.),128.40(CHarom.),132.38(CH arom.),137.63(C arom.),142.14(C6),151.84(C2),165.13(C4)。HRMS(ESI-TOF)m/z计算得C16H17N2O3+Na 307.1059;实测307.1048。
1-[4-(4-羟基-丁基)-苄基]-5-甲基-1H-嘧啶-2,4-二酮(31)
向化合物30(0.34g,1.19mmol)在CH2Cl2/甲醇(1ml/10ml)混合物的溶液中加入Pd/C(100mg)。通氢气过夜然后将混合物通过硅藻土并将滤液浓缩至干燥,经硅胶柱色谱(0-10%梯度的甲醇在二氯甲烷中的溶液)纯化得到31(0.24g,收率70%)。1H NMR(DMSO-d6)δ:1.42(m,2H,CH2CH2),1.57(m,2H,CH),1.75(d,3H,CH3,J=1.2Hz),2.55(t,2H,CH2Ph),3.40(m,2H,CH2OH),4.36(t,1H,OH),4.79(s,2H,PhCH2),7.11(d,2H,H arom.,J=8.4Hz),7.20(d,2H,H arom.,J=8.4Hz),7.61(d,1H,H6,J=1.2Hz),11.30(bs,1H,NH)。13C NMR(DMSO-d6)δ:12.77(CH3),28.27(CH2),32.93(CH2),35.47(CH2),50.63(PhCH2),61.36(CH2),109.83(C5),128.29(Carom.),129.41(CH arom.),135.13(CH arom.),142.12(C6),142.67(C arom.),151.85(C2),165.09(C4)。HRMS(ESI-TOF)m/z计算得C16H20N2O3+Na 311.1372;实测311.1374。
4-[4-(5-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-丁酸(20)
向化合物31(80mg,0.28mmol)在无水CH2Cl2(3ml)的搅拌溶液中加入叔丁醇(0.54ml,5.6mmol)、乙酸酐(0.26ml,2.8mmol)及重铬酸吡啶盐(0.21g,0.56mmol)。于室温下搅拌1小时30分钟后,通过TLC判断起始原料被消耗。将粗混合物置于在乙酸乙酯中处理的(conditionned)硅胶柱色谱上15min,然后用乙酸乙酯洗脱。将含有预期的酯的部分合并并真空浓缩,然后用2N NaOH(1ml)的甲醇(5ml)溶液处理过夜。反应混合物通过加入阳离子树脂(Dowex H+)酸化直至pH3,过滤并冻干。经反相HPLC(5-30%线性梯度的乙腈在缓冲液中的溶液。Rt=14min)纯化得到化合物20(20mg,25%)。1H NMR(DMSO-d6)δ:1.75(d,3H,CH3,J=1.2Hz),1.78(m,2H,CH2),2.20(t,2H,CH2),2.57(t,2H,CH2),4.80(s,1H,H5),7.19(m,4H,H arom.),7.61(d,1H,H6,J=1.2Hz),11.30(bs,1H,NH)。13C NMR(DMSO-d6)δ:12.78(CH3),27.12(CH2),33.97(CH2),34.90(CH2),50.61(PhCH2),109.83(C5),128.37(CH arom.),129.44(CH arom.),135.37(C arom.),141.92(C arom.),142.12(C6),151.86(C2),165.08(C4),175.09(COOH)。MS(ESI-TOF)m/z 325.1(100%,M+Na)+。HRMS(ESI-TOF)m/z计算得C16H18N2O4+Na 325.1178;实测325.0357。
1-(4-溴-苄基)-1H-嘧啶-2,4-二酮(35)
将尿嘧啶(4.94g,44.0mmol)和碳酸钾(4.7g,33.9mmol)在无水DMF(60ml)中的混悬液室温搅拌1h,然后加入4-溴苄基甲基溴(8.47g,33.9mmol)。搅拌过夜后,混合物经纯化得到化合物35(3.15g,收率33%)。1H NMR(DMSO-d6)δ:4.85(s,2H,PhCH2),5.60(d,1H,H5,J=7.8Hz),7.26(d,2H,H arom.,J=8.4Hz),7.60(dt,2H,H arom.,J=8.4Hz,J=2Hz),7.76(d,1H,H6,J=7.8Hz),11.34(bs,1H,NH)。13C NMR(DMSO-d6)δ:50.60(PhCH2),102.32(C5),121.69(C arom.),130.58 CHarom.),132.39(CH arom.),137.17(CH arom.),146.38(C6),151.84(C2),164.48(C4)。MS(ESI-TOF)m/z 281.0和283.0(M+H)+,303.0和305.0(M+Na)+,325.0和327.0(M+2Na)+,335.0和337.0。
1-(4-羟基-丁-1-炔基-苄基)-1H-嘧啶-2,4-二酮(36)
于氩气下向化合物35(1.46g,5.21mmol)在无水CH2Cl2(40mL)的溶液中加入新蒸馏的Et3N(45ml)、3-丁炔-1-醇(0.44g,6.57mmol)、四(三苯基膦)合钯(0.37g,0.31mmol)和碘化亚铜(20mg,0.10mmol)。将反应混合物于80℃加热90h并经如化合物30的方法处理得到化合物36。1H NMR(DMSO-d6)δ:1.19(t,21H,CH3),2.54(t,2H,CH2),3.10(t,14H,CH2),3.57(q,2H,CH2),4.87(s,2H,PhCH2),4.89(t,1H,OH),5.60(dd,1H,H5,J=7.8Hz,J=2.1Hz),7.25(d,2H,H arom.,J=8.3Hz),7.38(dd,2H,H arom.,J=6.5Hz,J=2.7Hz),7.76(d,1H,H6),9.10(bs,2.3H,NH),11.33(bs,1H,NH)。13C NMR(DMSO-d6)δ:24.12(CH2),50.88(PhCH2),60.56(CH2),81.52(C alcyn),89.72(C alcyn),102.26(C5),123.36(C arom.),128.41(CH arom.),132.38(CH arom.),137.50(C arom.),146.38(C6),151.85(C2),164.50(C4)。MS(ESI-TOF)m/z 293.1(100%,M+Na)+,333.2(5%,M+Na+K)+。
1-[4-(4-羟基-丁基)-苄基]-1H-嘧啶-2,4-二酮(37)
如对化合物30所述,将化合物36(0.55g,2.0mmol)进行氢化并经纯化后得到化合物37(0.25g,46%)。1H NMR(DMSO-d6)δ:1.41(m,2H,CH2),1.57(m,2H,CH2),2.55(t,2H,CH2),3.39(m,2H,CH2),4.35(t,1H,OH),4.83(s,2H,PhCH2),5.58(dd,1H,H5,J=7.8Hz,J=2.3Hz),7.19(m,4H,H arom.),7.74(d,1H,H6,J=7.8Hz),11.30(bs,1H,NH)。13C NMR(DMSO-d6)δ:28.26(CH2),32.93(CH2),35.46(CH2),50.84(PhCH2),61.34(CH2OH),102.14(C5),128.40(CH arom.),129.42(CH arom.),134.95(C arom.),142.74(C arom.),146.45(C6),151.86(C2),164.50(C4)。MS(ESI-TOF)m/z 297.1(100%,M+Na)+,431.4(40%)。
4-[4-(2,4-二氧代-3,4-二氢-2H-嘧啶-1-基甲基)-苯基]-丁酸(38b)
化合物38b通过两步得到:如对化合物32所述,将化合物37(135mg,0.5mmol)经铬氧化(chromic oxidation)得到相应的叔丁基酯(125mg,70%)。该酯(105mg,0.29mmol)经皂化得到化合物38b,为白色粉末(68mg,80%)。1H NMR(DMSO-d6)δ:1.77(m,2H,CH2),2.21(t,2H,CH2),2.57(t,2H,CH2),4.83(s,2H,PhCH2),5.58(dd,1H,H5,J=2.2Hz和J=7.8Hz),7.20(m,4H,H arom.),7.74(d,1H,H6,J=8.8Hz),11.30(bs,IH,NH),12.05(bs,1H,COOH)。13C NMR(DMSO-d6)δ:27.08(CH2),33.91(CH2),34.89(CH2),50.83(PhCH2),102.15(C5),128.40(CH arom.),129.46(CH arom.),135.19(C arom.),141.97(C arom.),146.44(C6),151.86(C2),164.50(C4),175.04(COOH)。HRMS(ESI-TOF)m/z计算得C15H16N2O4+Na 311.1008;实测311.1022。
4-(5-溴-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基甲基)-丁酸(21)
向在吡啶(3ml)中的化合物38b(50mg,0.17mmol)内加入1M的溴在CCl4(0.23ml)中的溶液。搅拌1小时30分钟后反应完全,溶液真空浓缩。经硅胶柱色谱纯化(0-20%梯度的甲醇在二氯甲烷中的溶液)得到化合物21的浅黄色粉末(45mg,70%)。1H NMR(DMSO-d6)δ:1.77(m,2H,CH2),2.21(t,2H,CH2,J=7.3Hz),2.57(t,2H,CH2),4.84(s,2H,PhCH2),7.18(d,2H,H arom.,J=8.1Hz),7.25(d,2H,Harom.),8.35(d,1H,H6),11.83(bs,1H,NH),12.05(bs,1H,COOH)。13C NMR(DMSO-d6)δ:27.08(CH2),33.92(CH2),34.90(CH2),51.32(PhCH2),95.92(C5),128.51(CH arom.),129.45(CH arom.),134.84(C arom.),142.09(C arom.),146.02(C6),151.22(C2),160.44(C4),175.04(COOH)。MS(ESI-TOF)m/z 389.0(100%,M+Na)+,391.0(86%,M+Na)+。HRMS(ESI-TOF)m/z计算得C15H15N2O4 79Br+Na 389.0113和C15H15N2O4 81Br+Na 391.0092;实测389.0140(100%)和391.0136(87%)。
5-甲基-1-苄基-1H-嘧啶-2,4-二酮(3)
胸腺嘧啶与苄基溴反应经纯化后得到化合物3(57mg,收率%)。1H NMR(CDCl3)δ:1.90(d,3H,CH3,J=1.1Hz),4.92(s,2H,PhCH2),7.00(d,1H,H6,J=1.1Hz),7.31(m,2H,H arom.),7.39(m,3H,H arom.),9.14(bs,1H,NH)。MS(ESI-TOF)m/z 217.1(60%,M+H)+,239.1(100%,M+Na)+。
5-溴-1-苄基-1H-嘧啶-2,4-二酮(4)
5-溴-尿嘧啶与苄基溴反应经纯化后得到化合物4。1H NMR(CDCl3)δ:4.91(s,2H,PhCH2),7.30-7.40(m,5H,H arom.),8.37(s,1H,H6),11.84(bs,1H,NH)。
5-氟-1-苄基-1H-嘧啶-2,4-二酮(5)
5-氟-尿嘧啶与苄基溴反应经纯化后得到化合物5。1H NMR(DMSO-d6)δ:4.89(s,2H,PhCH2),7.34(m,5H,H arom.),8.37(s,1H,H6),11.84(bs,1H,NH)。MS(ESI-TOF)m/z 279(M+2Na)。
5-甲基-1-(4-氟-苄基)-1H-嘧啶-2,4-二酮(6)
胸腺嘧啶与4-氟-苄基氯反应经纯化后得到化合物6(64mg,收率35%)。1H NMR(CDCl3)δ:1.89(d,3H,CH3,J=1.1Hz),4.87(s,2H,PhCH2),6.99(d,1H,H6,J=1.1Hz),7.06(m,2H,H arom.),7.30(m,2H,H arom.),9.75(bs,1H,NH)。13C NMR(CDCl3)δ:12.75(CH3),50.76(PhCH2),111.87(C5),116.18和116.52(CH arom.),130.25和130.33(CH arom.),131.78和131.81(C arom.),139.95(C6),151.73(C2),161.84和161.30(C arom.),164.74(C4)。MS(ESI-TOF)m/z 235.1(90%,M+H)+,257.1(40%,M+Na)+,279.1(50%,M+2Na)+。
5-甲基-1-(3-氟-苄基)-1H-嘧啶-2,4-二酮(7)
胸腺嘧啶与3-氟-苄基氯反应经纯化后得到化合物7(48mg,收率26%)。1H NMR(CDCl3)δ:1.90(d,3H,CH3,J=1.1Hz),4.90(s,2H,PhCH2),7.05(m,3H,H6和Harom.),7.08(d,1H,H arom.),7.35(m,1H,H arom.),9.75(bs,1H,NH)。13C NMR(CDCl3)δ:12.75(CH3),50.86(PhCH2),111.98(C5),115.18和115.40(CH arom.),115.69和115.90(CH arom.),123.83和123.86(CH arom.),131.06和131.14(CH arom.),138.36和138.44(C arom.),140.00(C6),151.68(C2),162.19(C4),164.66和164.72(Carom.)。MS(ESI-TOF)m/z 235.1(100%,M+H)+,257.1(5%,M+Na)+,279.1(70%,M+2Na)+。
5-甲基-1-(3,4-二氟-苄基)-1H-嘧啶-2,4-二酮(8)
胸腺嘧啶与3,4-二氟-苄基溴反应经纯化后得到化合物8(60mg,收率30%)。
1H NMR(CDCl3)δ:1.89(d,3H,CH3,J=1.1Hz),4.90(s,2H,PhCH2),5.30(d,1H,=CH,J=11Hz),5.77(d,1H,=CH,J=18Hz),6.72(dd,1H,=CH,J=11Hz,J=18Hz),6.98(d,1H,H6,J=1.1Hz),7.27(m,2H,H arom.,J=8Hz),7.42(m,2H,H arom.),9.26(bs,1H,NH)。13C NMR(CDCl3)δ:12.74(CH3),50.61(PhCH2),112.15(C5),117.47和117.64(CH arom.),118.25和118.43(CH arom.),124.46,124.49,124.52和124.56(CHarom.),132.85和132.90(C arom.),139.76(C6),149.46,149.58,149.63和149.75(Carom.),151.49(C2),151.93,152.06,152.11和152.24(C arom.),164.48(C4)。MS(ESI-TOF)m/z 253.1(100%,M+H)+。
5-甲基-1-(4-氯-苄基)-1H-嘧啶-2,4-二酮(9)
胸腺嘧啶与4-氯-苄基氯(1.1当量)反应经纯化后得到化合物8(71mg,收率36%)。1H NMR(CDCl3)δ:1.89(d,3H,CH3,J=1Hz),4.86(s,2H,PhCH2),6.99(d,1H,H6),7.25(d,2H,H arom.),7.34(d,2H,H arom.),9.88(bs,1H,NH)。13C NMR(CDCl3)δ:12.75(CH3),50.80(PhCH2),111.96(C5),126.65和1 29.77(CH arom.),134.44和134.82(C arom.),139.92(C6),151.68(C2),164.66(C4)。MS(ESI-TOF)m/z 251.1(20%,M+H)+,295.0(100%,M+2Na)+。
5-甲基-1-(3-氯-苄基)-1H-嘧啶-2,4-二酮(10)
胸腺嘧啶与3-氯-苄基氯(1.1当量)反应经纯化后得到化合物(52mg,收率26%)。1H NMR(CDCl3)δ:1.92(d,3H,CH3,J=1.1Hz),4.88(s,2H,PhCH2),6.99(d,1H,H6,J=1.1Hz),7.20(m,1H,H arom.),7.28(m,1H,H arom.),7.32(m,2H,H arom.),9.45(bs,1H,NH)。13C NMR(CDCl3)δ:12.77(CH3),50.85(PhCH2),112.03(C5),126.44,128.37,129.06和130.79(CH arom.),135.36(C arom.),137.92(C6),139.92(C arom.),151.55(C2),164.52(C4)。MS(ESI-TOF)m/z 251.1(100%,M+H)+,273.0(25%,M+Na)+,295.0(35%,M+2Na)+。
5-甲基-1-(4-溴-苄基/-1H-嘧啶-2,4-二酮(11)
胸腺嘧啶(300mg)、K2CO3(330mg)与4-溴苄基溴(1.1当量)在DMF(15ml)中反应经纯化后得到化合物(302mg,收率43%)。
1H NMR(DMSO-d6)δ:1.75(d,3H,CH3,J=1.2Hz),4.81(s,2H,PhCH2),7.26(d,2H,H arom.,J=8.3Hz),7.56(d,2H,H arom.,J=8.3Hz),7.64(d,1H,H6,J=1.2Hz),11.34(bs,1H,NH)。13C NMR(DMSO-d6)δ:12.79(CH3),50.37(PhCH2),109.99(C5),121.63(C arom.),130.57和132.38(CH arom.),137.34(C arom.),142.03(C6),151.83(C2),165.07(C4)。MS(ESI-TOF)m/z 295.0和297.0(15%,M+H)+,317.0和319.0(20%,M+Na)+,339.0和341.0(100%,85%,M+2Na)+。
3-[4-(5-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基甲基)-苯基]-丙烯酸乙酯(17)
1H NMR(DMSO-d6)δ:1.26(t,3H,CH3),1.76(d,3H,CH3,J=1.1Hz),4.19(q,2H,OCH2),4.86(s,2H,PhCH2),6.62(d,1H,=CH,J=16Hz),7.32(d,2H,H arom,J=8.1Hz),7.63(d,1H,=CH),7.64(d,1H,H6,J=1.1Hz),7.71(d,2H,H arom.),11.33(bs,1H,NH)。13C NMR(CDCl3)δ:12.79(CH3),15.04(CH2CH3),50.72(PhCH2),60.97(OCH2),109.98(C5),119.13(=CH),128.75和129.49(CH arom.),134.26(C arom.),140.27(Carom.),142.27(C6),144.70(=CH),151.86(C2),165.09(C4),167.01(CO)。MS(ESI-TOF)m/z 315.1(5%,M+H)+,337.1(100%,M+Na)+,359.1(5%,M+2Na)+。
3-[4-(2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-丙烯酸(18)
将化合物17(50mg,0.16mmol)用NaOH(1.3当量)处理1h。将反应混合物通过Dowex H+用水洗脱。分离化合物18为白色粉末(27mg,收率59%)。1H NMR(DMSO-d6)δ:1.76(d,3H,CH3,J=1.2Hz),4.86(s,2H,PhCH2),6.52(d,1H,=CH,J=16Hz),7.32(d,2H arom.,J=8.2Hz),7.57(d,1H,=CH),7.64(s,1H,H6),7.68(d,2H,H arom.),11.34(bs,1H,NH),12.40(bs,1H,COOH)。13C NMR(DMSO-d6)δ:13.96(CH3),51.87(PhCH2),111.14(C5),121.37(=CH),129.93(CH arom.),130.52(CHarom.),135.65(C arom.),141.19(C arom.),143.28(C6),145.42(=CH),153.04(C2),166.26(C4),169.54(COOH)。HRMS(ESI-TOF)m/z计算得C15H13N2O4 285.0875;实测285.0891。
3-[4-(5-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基甲基)-苯基]-丙烯酰胺(14)
1H NMR(DMSO-d6)δ:1.76(d,3H,CH3,J=1.2Hz),4.82(s,2H,PhCH2),6.59(d,1H,=CH,J=16Hz),7.09(bs,1H,CONH2),7.32(d,2H,H arom.,J=8.2Hz),7.40(d,1H,=CH),7.55(bd,3H,H arom.和CONH2),7.64(s,1H,H6),11.32(bs,1H,NH)。13CNMR(DMSO-d6)δ:12.79(CH3),50.69(PhCH2),109.87(C5),123.30(=CH),127.50(CH arom.),128.23,128.68和128.80(CH arom.),135.12(C arom.),139.18(C arom.),139.48(=CH),142.12(C6),151.86(C2),165.09(C4),167.45(CONH2)。MS(ESI-TOF)m/z 285.2(75%)286.2(100%,M+H)+,307.1 308.1(40%,M+Na)+。
3-[4-(5-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基甲基)-苯基]-丙酸乙酯(19)
向在甲醇(10ml)中的化合物17(90mg,0.28mmol)中加入钯黑(9mg)。通氢气过夜,然后将混合物通过硅藻土并将滤液浓缩至干燥得到19(83mg,收率91%)。1H NMR(DMSO-d6)δ:1.14(t,3H,CH3),1.74(d,3H,CH3,J=1Hz),2.59(t,2H,CH2,J=7.5Hz),2.82(t,2H,CH2),4.03(q,2H,OCH2,J=7Hz),4.79(s,2H,PhCH2),7.20(bs,4H,H arom.),7.60(d,1H,H6,J=1.0Hz),11.29(bs,1H,NH)。13C NMR(DMSO-d6)δ:12.79(CH3),14.92(OCH2CH3),30.77(CH2),35.82(CH2),50.59(PhCH2),60.67(OCH2),109.82(C5),128.38(CH arom.),129.38(CH arom.),135.67(C arom.),140.83(C arom.),142.06(C6),151.92(C2),165.17(C4),172.97(COOEt)。MS(ESI-TOF)m/z 339.1(100%,M+Na)+。
3-[4-(5-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基甲基)-苯基]-丙酸(2)
将化合物19(90mg,0.28mmol)用0.5N NaOH(1.3当量)处理1h。将反应混合物通过Dowex H+用水洗脱。分离化合物2的白色粉末(27mg,收率59%)。
1H NMR(DMSO-d6)δ:1.75(d,3H,CH3,J=1.0Hz),2.47(t,2H,CH2),2.79(t,2H,CH2,J=7.7Hz),4.70(s,2H,PhCH2),7.15(d,4H arom.),7.65(d,1H,H6),11.30(bs,1H,NH)。13C NMR(DMSO-d6)δ:12.77(CH3),31.09(CH2),36.43(CH2),50.58(PhCH2),109.84(C5),128.34和129.37(CH arom.),135.45和141.48(C arom.),142.10(C6),151.85(C2),165.07(C4)。HRMS(ESI-TOF)m/z计算得C15H16N2O4+Na 311.1008;实测311.1029。
3-[4-(5-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基甲基)-苯基]-丙酰胺(1)
在室温下将化合物19(70mg,0.22mmol)用33%氨水(25ml)处理过夜。经硅胶柱色谱纯化(0-8%梯度的甲醇在二氯甲烷中的溶液)得到化合物1的白色粉末(57mg,90%)。1H NMR(DMSO-d6)δ:1.75(d,3H,CH3,J=1Hz),2.33(m,2H,CH2),2.79(m,2H,CH2),4.79(s,1H,H5),6.74(bs,1H,CONH2),7.20(m,4H,H arom.),7.28(bs,1H,CONH2),7.60(d,1H,H6,J=1Hz),11.29(bs,1H,NH)。13C NMR(DMSO-d6)δ:12.77(CH3),31.25(CH2),37.41(CH2),50.59(PhCH2),109.83(C5),128.33(CH arom.),129.33(CH arom.),135.37(C arom.),141.82(C arom.),142.09(C6),151.85(C2),165.07(C4),174.18(CONH2)。MS(ESI-TOF)m/z 310.1(100%,M+Na)+。HRMS(MALDI-TOF)m/z计算得C15H17N3O3+Na 310.1168;实测310.1174。
4-[5-溴-(2,4-二氧代-3,4-二氢-2H-嘧啶-1-基甲基)-苯基]丁酸(21)
向在吡啶(3ml)中的化合物38b(50mg,0.17mmol)中加入1M的溴在CCl4(0.23ml)中的溶液。搅拌1小时30分钟后反应完全,溶液真空浓缩。经硅胶柱色谱纯化(0-20%梯度的甲醇在二氯甲烷中的溶液)得到化合物21的浅黄色粉末(45mg,70%)。1H NMR(DMSO-d6)δ:1.77(m,2H,CH2),2.21(t,2H,CH2,J=7.3Hz),2.57(t,2H,CH2),4.84(s,2H,PhCH2),7.18(d,2H,H arom.,J=8.1Hz),7.25(d,2H,Harom.),8.35(d,1H,H6),11.83(bs,1H,NH),12.05(bs,1H,COOH)。13C NMR(DMSO-d6)δ:27.08(CH2),33.92(CH2),34.90(CH2),51.32(PhCH2),95.92(C5),128.51(CH arom.),129.45(CH arom.),134.84(C arom.),142.09(C arom.),146.02(C6),151.22(C2),160.44(C4),175.04(COOH)。MS(ESI-TOF)m/z 389.0(100%,M+Na)+,391.0(86%,M+Na)+。HRMS(ESI-TOF)m/z计算得C15H15N2O4 79Br+Na 389.0113和C15H15N2O4 81Br+Na 391.0092;实测389.0140(100%)和391.0136(87%)。
5-[5-氯-4-(2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-丁酸(39)
1H NMR(DMSO-d6)δ:1.77(m,2H,CH2),2.21(t,2H,CH2,J=7.4Hz),2.57(t,2H,CH2,J=7.7Hz),4.84(s,2H,PhCH2),7.15(d,2H,H arom.,J=8.1Hz),7.25(d,2H,Harom.,J=8.1Hz),8.29(s,1H,H6),11.89(bs,1H,NH)。13C NMR(DMSO-d6)δ:27.09(CH2),33.92(CH2),34.90(CH2),51.37(PhCH2),107.42(C5),128.49,128.51和129.46(CH arom.),134.78(C arom.),142.10(C arom.),143.67(C6),150.99(C2),160.28(C4),175.05(COOH)。HRMS(ESI-TOF)m/z计算得C15H15N2O4 35Cl+Na 321.0642;实测321.0638(100%)。
4-(5-溴-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基甲基)-丁酸酰胺(42)
1H NMR(DMSO-d6)δ:1.76(m,2H,CH2),2.05(t,2H,CH2,J=7.5Hz),2.54(t,2H,CH2,J=7.8Hz),4.84(s,2H,PhCH2),6.71(bs,1H,CONH2),7.18(d,2H,H arom.,J=8.1Hz),7.24(bs,1H,CONH2),7.25(d,2H,H arom.),8.36(s,1H,H6),11.83(bs,1H,NH)。13C NMR(DMSO-d6)δ:27.63(CH2),35.18(CH2),35.36(CH2),51.32(PhCH2),95.93(C5),128.49(CH arom.),129.46(CH arom.),134.76(C arom.),142.37(C arom.),146.01(C6),151.24(C2),160.47(C4),174.79(CONH2)。HRMS(ESI-TOF)m/z计算得C15H16N3O3 79Br+Na 389.0113和C15H16N3O3 81Br+Na 390.0252;实测388.0299(100%)和390.0282(83%)。
4-(5-氯-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基甲基)-丁酸酰胺(43)
1H NMR(DMSO-d6)δ:1.76(m,2H,CH2),2.05(t,2H,CH2,J=7.4Hz),2.54(t,2H,CH2,J=7.7Hz),4.84(s,2H,PhCH2),6.71(bs,1H,CONH2),7.18(d,2H,H arom.,J=8.1Hz),7.24(bs,1H,CONH2),7.25(d,2H,H arom.),8.29(s,1H,H6),11.86(bs,1H,NH)。13C NMR(DMSO-d6)δ:27.63(CH2),35.18(CH2),35.36(CH2),51.37(PhCH2),107.41(C5),128.49(CH arom.),129.46(CH arom.),134.69(C arom.),142.37(C arom.),143.67(C6),151.00(C2),160.28(C4),174.79(CONH2)。HRMS(ESI-TOF)m/z计算得C15H15N2O4 35Cl+Na 344.0778和C15H15N2O4 37Cl+Na 346.0748;实测344.0798(100%)和346.0798(4%)。
5-[4-(5-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-戊烯-2-羧酸(28)
HRMS(ESI-TOF)m/z计算得C16H16N2O4+Na 323.1008;实测232.1044。
5-[4-(5-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-戊酸(45)
1H NMR(CDCl3)δ:1.67(m,4H,2×CH2),1.90(d,3H,CH3,J=1.1Hz),2.35(t,2H,CH2,J=7.1Hz),2.65(t,2H,CH2,J=7.1Hz),4.87(s,2H,PhCH2),6.99(d,1H,H6,J=1.2Hz),7.21(m,4H,H arom.),8.74(bs,1H,NH)。13C NMR(CDCl3)δ:12.77(CH3),24.90(CH2),31.11(CH2),34.26(CH2),35.60(CH2),51.12(PhCH2),111.52(C5),128.47,128.55和129.50(CH arom.),133.26(C arom.),140.15(C arom.),142.95(C6),151.42(C2),164.31(C4),174.39(COOH)。HRMS(ESI-TOF)m/z计算得C18H22N2O4+Na353.1477;实测353.1463。
5-[4-(2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-戊酸(47)
1H NMR(DMSO-d6)δ:1.52(m,4H,2×CH2),2.22(t,2H,CH2,J=7.1Hz),2.56(t,2H,CH2,J=7.2Hz),4.83(s,2H,PhCH2),5.59(d,1H,H5,J=7.8Hz),7.20(m,4H,Harom.),7.74(d,1H,H6,J=7.8Hz),11.31(bs,1H,NH)。13C NMR(DMSO-d6)δ:24.98(CH2),31.32(CH2),34.37(CH2),35.30(CH2),50.83(PhCH2),102.15(C5),128.34,129.18和129.41(CH arom.),135.02(C arom.),142.42(C arom.),146.44(C6),151.87(C2),164.50(C4),175.28(COOH)。
5-[4-(5-溴-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-戊酸(48)
1H NMR(DMSO-d6)δ:1.52(m,4H,2×CH2),2.20(t,2H,CH2,J=7.1Hz),2.56(t,2H,CH2,J=7.2Hz),4.84(s,2H,PhCH2),7.19(d,2H,H arom.),7.23(d,2H,H arom.),8.35(s,1H,H6),11.62(bs,1H,NH)。13C NMR(DMSO-d6)δ:25.07(CH2),31.25(CH2),34.58(CH2),35.33(CH2),51.31(PhCH2),95.93(C5),128.45和129.51(CH arom.),134.68(C arom.),142.58(C arom.),146.00(C6),151.25(C2),160.48(C4),175.43(COOH)。HRMS(ESI-TOF)m/z计算得C16H17N2O4 79Br+Na 403.0269;实测403.0302。
6-[4-(5-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-己炔-5-羧酸(51)
HRMS(ESI-TOF)m/z计算得C18H18N2O4+Na 349.1164;实测349.1160。
6-[4-(5-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-己炔-5-羧酸酰胺(53)
HRMS(ESI-TOF)m/z计算得C18H19N3O3+Na 348.1324;实测348.1292。
6-[4-(5-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-己酸(22)
13C NMR(DMSO-d6)δ:12.78(CH3),25.19(CH2),29.08(CH2),31.55(CH2),34.50(CH2),35.51(CH2),50.62(PhCH2),109.81(C5),128.31(CH atom.),129.39(CH arom.),135.15(C arom.),142.13(C6),142.56(C atom.),151.84(C2),165.07(C4),175.33(COOH)。HRMS(ESI-TOF)m/z计算得C18H22N3O4+Na 353.1477;实测353.1455。
6-[4-(5-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-己酸酰胺(54)
13C NMR(DMSO-d6)δ:12.78(CH3),25.77(CH2),29.19(CH2),31.60(CH2),35.54(CH2),35.88(CH2),50.63(PhCH2),109.81(C5),128.30(CH arom.),129.39(CH arom.),135.14(C arom.),142.15(C6),142.62(C arom.),151.85(C2),165.08(C4),175.11(CONH2)。HRMS(ESI-TOF)m/z计算得C18H23N3O3+Na 352.1637;实测352.1601。
6-[4-(5-溴-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-己酸(58)
1H NMR(DMSO)δ:1.27(m,2H,CH2(c)),1.52(m,4H,2×CH2(b和d),2.19(t,2H,CH2(a),J=6.3Hz),2.53(t,2H,CH2(e),J=7.8Hz和J=7.5Hz),4.84(s,2H,PhCH2),7.18(d,2H,H arom(x),J=8.2Hz),7.24(d,2H,H arom(y),J=8.2Hz),8.35(s,1H,H6),11.83(bs,1H,NH),11.97(bs,1H,COOH)。13C NMR(DMSO-d6)δ:25.17(CH2(b)),29.06(CH2(c)),31.52(CH2(d)),34.44(CH2(a)),35.52(CH2(e)),51.33(CH2(Bz)),95.90(C-Br),128.45(2×CH(y)),129.41(2×CH(x)),134.62(Cq(e)),142.76(Cq),146.02(C6),151.22(C2),160.44(C4),175.29(COOH)。HRMS(ESI-TOF)m/z计算得C17H19N2O4 79Br+Na 417.0426;实测417.0443;计算得C17H19N2O4 81Br+Na 419.0405;实测419.0412。
6-[4-(5-氯-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-己酸(59)
1H NMR(DMSO)δ:1.28(m,2H,CH2(c)),1.52(m,4H,2×CH2(b和d),2.21(t,2H,CH2(a),J=7.3Hz),2.55(t,2H,CH2(e),J=7.8Hz和J=7.5Hz),4.83(s,2H,CH2(Bz)),7.18(d,2H,H arom(x),J=8.1Hz),7.24(d,2H,H arom(y),J=8.1Hz),8.29(s,1H,H6),11.86(s,1H,NH),12.01(bs,1H,COOH)。13C NMR(DMSO-d6)δ:25.17(CH2(b)),29.06(CH2(c)),31.53(CH2(d)),34.44(CH2(a)),35.51(CH2(e)),51.37(CH2(Bz)),107.40(C-Br),128.44(2×CH(y)),129.41(2×CH(x)),134.56(Cq(e)),142.76(Cq(Bz)),143.67(C6),150.99(C2),160.27(C4),175.29(COOH)。HRMS(ESI-TOF)m/z计算得C17H19N2O4 35Cl+Na 373.0931;实测373.0921;计算得C17H19N2O4 37Cl+Na 375.0902;实测375.0923。
6-[4-(5-溴-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-己酸酰胺(61)
1H NMR(DMSO)δ:1.25(m,2H,CH2(c)),1.51(m,4H,2×CH2(b和d),2.04(t,2H,CH2(a),J=7.4Hz),2.54(t,2H,CH2(e),J=7.8Hz和J=7.5Hz),4.84(s,2H,CH2(Bz)),6.67和7.19(d,2H,CONH2),7.18(d,2H,H arom(x),J=8.1Hz),7.23(d,2H,H arom(y),J=8.1Hz),8.35(s,1H,H6),11.82(s,1H,NH)。13C NMR(DMSO-d6)δ:25.77(CH2(b)),29.19(CH2(c)),31.59(CH2(d)),35.55(CH2(e)),35.89(CH2(a)),51.33(CH2(Bz)),95.92(C-Br),128.44(2×CH(y)),129.41(2×CH(x)),134.62(Cq(e)),142.81(Cq(Bz)),146.00(C6),151.24(C2),160.47(C4),175.09(CONH2)。HRMS(ESI-TOF)m/z计算得C17H20N3O3 79Br+Na 416.0586;实测416.0571;计算得C17H20N3O3 81Br+Na 418.0565;实测418.0555。
6-[4-(5-氯-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-己酸酰胺(62)
1H NMR(DMSO)δ:1.25(m,2H,CH2(c)),1.51(m,4H,2×CH2(b和d),2.02(t,2H,CH2(a),J=7.4Hz),2.54(t,2H,CH2(e),J=7.7Hz和J=7.5Hz),4.83(s,2H,CH2(Bz)),6.67和7.19(各为bs,2H,CONH2),7.18(d,2H,H arom.,J=8.2Hz),7.24(d,2H,Harom.,J=8.2Hz),8.29(s,1H,H6),11.86(s,1H,NH)。13C NMR(DMSO-d6)δ:25.77(CH2(b)),29.19(CH2(c)),31.59(CH2(d)),34.55(CH2(e)),35.89(CH2(a)),51.38(PhCH2),107.40(C5),128.43(2×CH),129.41(2×CH),134.54(Cq),142.81(Cq),143.67(C6),150.99(C2),160.28(C4),175.09(CONH2)。HRMS(ESI-TOF)m/z计算得C17H20N3O3 35Cl+Na 372.1091;实测372.1093;计算得C17H20N3O3 37Cl+Na 374.1061;实测374.1073。
3-[4-(5-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基甲基)-苄基硫烷基]-乙酸(63)
13C NMR(DMSO-d6)δ:12.79(CH3),23.35(CH2),33.55(CH2),50.60(PhCH2),109.89(C5),128.38和130.08(CH arom.),136.63和138.08(C arom.),142.12(C6),151.86(C2),165.10(C4),172.101(COOH)。HRMS(ESI-TOF)m/z计算得C15H16N2O4S+Na 343.0728;实测343.0728。
3-氟-4-[4-(5-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-丁醛(64)
HRMS(ESI-TOF)m/z计算得C16H17N2O3F+Na 327.1121;实测327.1098。
3-氟-4-[4-(5-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基-甲基)-苯基]-丁酸(65)
HRMS(ESI-TOF)m/z计算得C16H17N2O4F+Na 343.1070;实测343.1052。
B-生物活性
利用Blondin等记载(C.Blondin,L.Serina,L. Wiesmüller,A.-M.Gilles,O.B_rzu,Anal.Biochem.1994,220,219)的偶联分光光度法进行活性测定。
每摩尔转移磷酰基产生两摩尔NAD+并随后利用Eppendorf ECOM 6122光度计检测到在334nm处吸收减弱。反应介质(最终体积0.5ml)含有50mM Tris-HCl pH7.4、50mM KCl、2mM MgCl2、0.2mM NADH、1mM磷酸烯醇丙酮酸以及2单位乳酸脱氢酶、丙酮酸激酶和二磷酸核苷激酶。一单位的酶活性相当于在30℃以及pH7.4条件下1min生成的1μmole产物。ATP和dTMP的浓度分别保持在0.5mM和0.05mM,类似物的浓度在0.005和8mM之间变化。利用方程式2和3,将方程式1用于计算Ki值(遵循Lineweaver-Burk表示法的经典竞争性抑制模型):
其中v和vi分别为不含和含有浓度值为[I]的类似物时的反应速率;Km为dTMP的Km(对于TMPKmt为4.5μM、对于TMPKh为5μM);[S]为dTMP的浓度(50μM)。
结果如表1和表2中所示:
化合物 | TMPKmt W1002 |
Ki(μM) | |
dTMP | Km=4.5 |
dT | 27 |
1 | 110 |
2 | 68 |
3 | 75 |
4 | 44 |
5 | N.A. |
6 | 45 |
7 | 90 |
8 | 67 |
9 | 50 |
10 | 44 |
11 | 38 |
12 | 980 |
13 | 810 |
14 | 240 |
15 | N.A. |
16 | N.A. |
17 | N.A. |
18 | N.A. |
19 | 265 |
20 | 16.5 |
21 | 12.3 |
22 | 32 |
表1:分子1至22的生物活性
化合物 | Ki(μM) |
28 | 48 |
30 | 86 |
31 | 63 |
39 | 15 |
40a | 70 |
40b | 139 |
42 | 48 |
43 | 48 |
45 | 72 |
48 | 47 |
51 | 119 |
52 | N.A. |
53 | 113 |
54 | 33 |
58 | 42 |
59 | 49 |
61 | 24 |
62 | 32 |
63 | 15 |
64 | 26 |
65 | 63 |
表2:分子28、30、31、39、40a、40b、42、43、45、48、51至54、58、59、61至65的生物活性
三个化合物的IC50值已经在结核分枝杆菌(Mycobacterium tuberculosis)H37Ra培养基上进行了测定。结果总结于表3中:
化合物 | IC50(μg/ml) |
20 | 100 |
21 | 50 |
22 | 25 |
表3:分子20、21和22的生物活性(IC50)
细胞毒性:测定了分子22对VERO细胞的细胞毒性。已经确认在最高250μg/ml的化合物22浓度下未检测到生长抑制作用,因此无细胞毒性。
权利要求书(按照条约第19条的修改)
1、符合通式(I)的分子及其药物学可接受的盐:
其中:
·R1选自以下组中:CH3、-CF3、卤素原子、-NH2、-COOH、-CONH2,
·R2、R3、R4相同或不同,选自以下组中:
-H、卤素原子,
-C1-C8烷基、C2-C8烯基、C2-C8炔基,其中该烷基、烯基或炔基链可以被杂原子桥间断,
- -OH、-NH2、-CHO、-COOH、-SO4H、-CONH2、-CN、-COOR5、-COR5、-OR5,
- 取代的C1-C8烷基、取代的C2-C8烯基或取代的C2-C8炔基,其中该取代基选自以下组中:-OH、-NH2、-CHO、-COOH、-SO4H、-CONH2、-CN、-COOR5、-COR5、-OR5、卤素原子,其中该烷基、烯基或炔基链可以被杂原子桥间断;
·R5选自C1-C6烷基;
·R6选自:C1-C4亚烷基、C2-C4亚烯基、羰基(=C=O)、-(CF2)n-;
·n为选自1、2、3的整数,
以下情况除外:
R1=-CH3、R2=R3=R4=H且R6=-CH2-
R1=-CF3、R2=R3=R4=H且R6=-CH2-
R1=-CH3、R2=R3=H、R4=-OCH3(对位)且R6=-CH2-
R1=-CH3、R2=R3=CH3(邻位,对位)、R4=H且R6=-CH2-
R1=-CH3、R2=CH3(邻位)、R3=R4=H且R6=-CH2-
R1=-CH3、R2=R3=R4=H且R6=-CO-
R1=-CH3、R2=OH(间位)、R3=R4=H且R6=-CH2-
R2=R3=R4=H、R6=-CH2-且R1=Cl、I或Br。
2、如权利要求1的分子,其中满足以下一个或多个条件:
·R6为-CH2-;
·R1选自-CH3、-Br、-Cl;
·在R2、R3、R4中至少一个基团为H。
3、如前述权利要求中任意一项所述的分子,其中,R2=R3=H,R4在苯环上处于对位并且R4选自取代的C1-C6烷基或取代的C2-C6烯基,其中所述取代基为-COOH,并可能包含杂原子桥,所述的杂原子选自:N、S、O、Se。
4、如前述权利要求中任意一项所述的分子,其选自以下组中:
5、如权利要求1-4中任意一项所述的分子,其选自以下组中:
6、一种药物组合物,其包含在药物学可接受的载体中的至少一种通式(I)的化合物或其药物学可接受的盐:
其中:
·R1选自以下组中:CH3、-CF3、卤素原子、-NH2、-COOH、-CONH2,
·R2、R3、R4相同或不同,选自以下组中:
-H、卤素原子,
-C1-C8烷基、C2-C8烯基、C2-C8炔基,其中该烷基、烯基或炔基链可以被杂原子桥间断,
- -OH、-NH2、-CHO、-COOH、-SO4H、-CONH2、-CN、-COOR5、-COR5、-OR5,
-取代的C1-C8烷基、取代的C2-C8烯基、或取代的C2-C8炔基,其中该取代基选自以下组中:-OH、-NH2、-CHO、-COOH、-SO4H、-CONH2、-CN、-COOR5、-COR5、-OR5、卤素原子,其中该烷基、烯基或炔基链可以被杂原子桥间断;
·R5选自C1-C6烷基;
·R6选自:C1-C4亚烷基、C2-C4亚烯基、羰基(=C=O)、-(CF2)n-;
·n为选自1、2、3的整数。
7、一种药物组合物,其包含在药物学可接受的载体中的至少一种如权利要求2-5中任意一项所述的通式(I)的化合物。
8、通式(I)的分子或其药物学可接受的盐在制备用于预防和/或治疗由分支杆菌引起的病理的药物中的应用
其中:
·R1选自以下组中:CH3、-CF3、卤素原子、-NH2、-COOH、-CONH2,
·R2、R3、R4相同或不同,选自以下组中:
-H、卤素原子,
-C1-C8烷基、C2-C8烯基、C2-C8炔基,其中该烷基、烯基或炔基链可以被杂原子桥间断,
- -OH、-NH2、-CHO、-COOH、-SO4H、-CONH2、-CN、-COOR5、-COR5、-OR5,
-取代的C1-C8烷基、取代的C2-C8烯基、或取代的C2-C8炔基,其中该取代基选自以下组中:-OH、-NH2、-CHO、-COOH、-SO4H、-CONH2、-CN、-COOR5、-COR5、-OR5、卤素原子,其中该烷基、烯基或炔基链可以被杂原子桥间断;
·R5选自C1-C6烷基;
·R6选自:C1-C4亚烷基、C2-C4亚烯基、羰基(=C=O)、-(CF2)n-;
·n为选自1、2、3的整数。
9、如权利要求8的应用,其用于预防和/或治疗结核病。
10、如权利要求8的中应用,其用于预防和/或治疗麻疯病。
11、如前述权利要求中任意一项所述的应用,其中所包含的活性成分的每日剂量为0.1至500mg/kg。
12、如权利要求1-5中任意一项所述的通式(I)的分子在体外作为分枝杆菌TMPK的抑制剂的应用。
13、如权利要求12的应用,其在体外作为结核杆菌TMPK的抑制剂。
14、如权利要求8-13任意一项所述的应用,其中通式(I)的分子选自对应于权利要求2-5中任意一项所述的分子。
15、权利要求1-5中任意一项所述的符合通式(I)的分子的制备方法,其特征为:
-通式(II)的卤代芳基与通式(III)的胸腺嘧啶或胸腺嘧啶衍生物或尿嘧啶或尿嘧啶衍生物反应生成缩合物(IV),
其中:X代表卤素原子,优选为Br;
X2、X3、X4分别选自R2、R3、R4以及可以通过一步或多步反应转化为R2、R3和R4的官能团,
X1选自R1以及可以通过一步或多步反应转化为R1的官能团,
X5选自H和苄基(Bzl);
-在第二步反应中,如果必要,将X1、X2、X3、X4和X5分别转化为R1、R2、R3、R4和H,以生成通式(I)的分子
16、符合通式(V)的分子:
其中X1选自R1和可以通过一步或多步反应转化为R1的官能团,
R1选自以下组中:CH3、-CF3、卤素原子、-NH2、-COOH、-CONH2,且
X5选自H和苄基(Bzl)。
17、如权利要求16的分子,其特征在于其对应于式11或式11bis:
Claims (17)
1、符合通式(I)的分子及其药物学可接受的盐:
其中:
·R1选自以下组中:CH3、-CF3、卤素原子、-NH2、-COOH、-CONH2,
·R2、R3、R4相同或不同,选自以下组中:
-H、卤素原子,
-C1-C8烷基、C2-C8烯基、C2-C8炔基,其中该烷基、烯基或炔基链可以被杂原子桥间断,
- -OH、-NH2、-CHO、-COOH、-SO4H、-CONH2、-CN、-COOR5、-COR5、-OR5,
-取代的C1-C8烷基、取代的C2-C8烯基或取代的C2-C8炔基,其中该取代基选自以下组中:-OH、-NH2、-CHO、-COOH、-SO4H、-CONH2、-CN、-COOR5、-COR5、-OR5、卤素原子,其中该烷基、烯基或炔基链可以被杂原子桥间断;
·R5选自C1-C6烷基;
·R6选自:C1-C4亚烷基、C2-C4亚烯基、羰基(=C=O)、-(CF2)n-;
·n为选自1、2、3的整数,
以下情况除外:
R1=-CH3、R2=R3=R4=H且R6=-CH2-
R1=-CF3、R2=R3=R4=H且R6=-CH2-
R1=-CH3、R2=R3=H、R4=-OCH3(对位)且R6=-CH2-
R1=-CH3、R2=R3=CH3(邻位,对位)、R4=H且R6=-CH2-
R1=-CH3、R2=CH3(邻位)、R3=R4=H且R6=-CH2-
R1=-CH3、R2=R3=R4=H且R6=-CO-
R1=-CH3、R2=OH(间位)、R3=R4=H且R6=-CH2-
R2=R3=R4=H、R6=-CH2-且R1=Cl、I或Br。
2、如权利要求1的分子,其中满足以下一个或多个条件:
·R6为-CH2-;
·R1选自-CH3、-Br、-Cl;
·在R2、R3、R4中至少一个基团为H。
3、如前述权利要求中任意一项所述的分子,其中,R2=R3=H,R4在苯环上处于对位并且R4选自取代的C1-C6烷基或取代的C2-C6烯基,其中所述取代基为-COOH,并可能包含杂原子桥,所述的杂原子选自:N、S、O、Se。
6、一种药物组合物,其包含在药物学可接受的载体中的至少一种通式(I)的化合物或其药物学可接受的盐:
其中:
·R1选自以下组中:CH3、-CF3、卤素原子、-NH2、-COOH、-CONH2,
·R2、R3、R4相同或不同,选自以下组中:
-H、卤素原子,
-C1-C8烷基、C2-C8烯基、C2-C8炔基,其中该烷基、烯基或炔基链可以被杂原子桥间断,
- -OH、-NH2、-CHO、-COOH、-SO4H、-CONH2、-CN、-COOR5、-COR5、-OR5,
-取代的C1-C8烷基、取代的C2-C8烯基、或取代的C2-C8炔基,其中该取代基选自以下组中:-OH、-NH2、-CHO、-COOH、-SO4H、-CONH2、-CN、-COOR5、-COR5、-OR5、卤素原子,其中该烷基、烯基或炔基链可以被杂原子桥间断;
·R5选自C1-C6烷基;
·R6选自:C1-C4亚烷基、C2-C4亚烯基、羰基(=C=O)、-(CF2)n-;
·n为选自1、2、3的整数。
7、一种药物组合物,其包含在药物学可接受的载体中的至少一种如权利要求2-5中任意一项所述的通式(I)的化合物。
8、通式(I)的分子或其药物学可接受的盐在制备用于预防和/或治疗由分支杆菌引起的病理的药物中的应用
其中:
·R1选自以下组中:CH3、-CF3、卤素原子、-NH2、-COOH、-CONH2,
·R2、R3、R4相同或不同,选自以下组中:
-H、卤素原子,
-C1-C8烷基、C2-C8烯基、C2-C8炔基,其中该烷基、烯基或炔基链可以被杂原子桥间断,
- -OH、-NH2、-CHO、-COOH、-SO4H、-CONH2、-CN、-COOR5、-COR5、-OR5,
-取代的C1-C8烷基、取代的C2-C8烯基、或取代的C2-C8炔基,其中该取代基选自以下组中:-OH、-NH2、-CHO、-COOH、-SO4H、-CONH2、-CN、-COOR5、-COR5、-OR5、卤素原子,其中该烷基、烯基或炔基链可以被杂原子桥间断;
·R5选自C1-C6烷基;
·R6选自:C1-C4亚烷基、C2-C4亚烯基、羰基(=C=O)、-(CF2)n-;
·n为选自1、2、3的整数。
9、如权利要求8的应用,其用于预防和/或治疗结核病。
10、如权利要求8的中应用,其用于预防和/或治疗麻疯病。
11、如前述权利要求中任意一项所述的应用,其中所包含的活性成分的每日剂量为0.1至500mg/kg。
12、如权利要求1-5中任意一项所述的通式(I)的分子在体外作为分枝杆菌TMPK的抑制剂的应用。
13、如权利要求12的应用,其在体外作为结核杆菌TMPK的抑制剂。
14、如权利要求8-13任意一项所述的应用,其中通式(I)的分子选自对应于权利要求2-5中任意一项所述的分子。
17、如权利要求16的分子,其特征在于其对应于式11或式11bis:
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04292629A EP1655288A1 (en) | 2004-11-05 | 2004-11-05 | Aryl pyrimidyl compounds, pharmaceutical compositions comprising them, their use as antimicrobial agents |
EP04292629.5 | 2004-11-05 |
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CN101098860A true CN101098860A (zh) | 2008-01-02 |
Family
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CNA2005800460269A Pending CN101098860A (zh) | 2004-11-05 | 2005-11-04 | 芳基嘧啶基化合物、含有它们的药物组合物及其作为抗微生物剂的应用 |
Country Status (7)
Country | Link |
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US (1) | US20080096907A1 (zh) |
EP (2) | EP1655288A1 (zh) |
JP (1) | JP2008519001A (zh) |
CN (1) | CN101098860A (zh) |
BR (1) | BRPI0517646A (zh) |
CA (1) | CA2586073A1 (zh) |
WO (1) | WO2006048336A2 (zh) |
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CN103476411A (zh) * | 2010-11-29 | 2013-12-25 | 法玛科技顾问股份有限公司 | 标靶人类胸腺核苷酸激酶诱导恶性肿瘤中的dna修复毒性 |
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RU2475482C1 (ru) * | 2012-01-13 | 2013-02-20 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Башкирский государственный университет" | Комплексное соединение 5-гидрокси-6-метилурацила с сукцинатом натрия и способ его получения |
HUE051349T2 (hu) * | 2016-03-22 | 2021-03-01 | Glaxosmithkline Ip Dev Ltd | Tuberkulózis elleni szer |
WO2020117938A1 (en) * | 2018-12-04 | 2020-06-11 | University Of Maryland, Baltimore | Prodrugs of anti-cancer and anti-autoimmune diseases therapeutic agents, and methods of making and use thereof |
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DE1959705A1 (de) * | 1969-11-28 | 1971-06-03 | Bayer Ag | Verfahren zur Herstellung von Uracilderivaten |
JPH08325238A (ja) * | 1995-05-30 | 1996-12-10 | Asahi Glass Co Ltd | 5−トリフルオロメチルウラシル誘導体およびその製造方法 |
ES2157366T3 (es) * | 1995-06-09 | 2001-08-16 | Hoffmann La Roche | Derivados de pirimidindiona, pirimidintriona, triacindiona como antagonistas de receptores alfa-1-adrenergicos. |
KR100814269B1 (ko) * | 2000-01-25 | 2008-03-18 | 뉴로크린 바이오사이언시즈 인코퍼레이티드 | 고나도트로핀-분비 호르몬 수용체 길항제 및 이를 포함하는 약제학적 조성물 |
JP4542311B2 (ja) * | 2001-01-29 | 2010-09-15 | バイオ−ラッド ラボラトリーズ インコーポレイテッド | 核酸誘導体 |
US6977300B2 (en) * | 2001-11-09 | 2005-12-20 | Cv Therapeutics, Inc. | A2B adenosine receptor antagonists |
-
2004
- 2004-11-05 EP EP04292629A patent/EP1655288A1/en not_active Withdrawn
-
2005
- 2005-11-04 WO PCT/EP2005/012346 patent/WO2006048336A2/en active Application Filing
- 2005-11-04 BR BRPI0517646-8A patent/BRPI0517646A/pt not_active IP Right Cessation
- 2005-11-04 CN CNA2005800460269A patent/CN101098860A/zh active Pending
- 2005-11-04 US US11/718,764 patent/US20080096907A1/en not_active Abandoned
- 2005-11-04 JP JP2007539555A patent/JP2008519001A/ja not_active Withdrawn
- 2005-11-04 CA CA002586073A patent/CA2586073A1/en not_active Abandoned
- 2005-11-04 EP EP05819227A patent/EP1814867A2/en not_active Withdrawn
Cited By (1)
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CN103476411A (zh) * | 2010-11-29 | 2013-12-25 | 法玛科技顾问股份有限公司 | 标靶人类胸腺核苷酸激酶诱导恶性肿瘤中的dna修复毒性 |
Also Published As
Publication number | Publication date |
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WO2006048336A3 (en) | 2006-10-12 |
WO2006048336B1 (en) | 2006-11-09 |
EP1814867A2 (en) | 2007-08-08 |
BRPI0517646A (pt) | 2008-10-14 |
CA2586073A1 (en) | 2006-05-11 |
EP1655288A1 (en) | 2006-05-10 |
WO2006048336A2 (en) | 2006-05-11 |
JP2008519001A (ja) | 2008-06-05 |
US20080096907A1 (en) | 2008-04-24 |
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