CN1506359A - 新的香豆素酰胺衍生物及其制法和其药物组合物与用途 - Google Patents
新的香豆素酰胺衍生物及其制法和其药物组合物与用途 Download PDFInfo
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- CN1506359A CN1506359A CNA021555257A CN02155525A CN1506359A CN 1506359 A CN1506359 A CN 1506359A CN A021555257 A CNA021555257 A CN A021555257A CN 02155525 A CN02155525 A CN 02155525A CN 1506359 A CN1506359 A CN 1506359A
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- C07—ORGANIC CHEMISTRY
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract
本发明涉及新的香豆素和其酰胺类衍生物,其制备方法,含有他们的药物组合物,及其作为药物,尤其作为肾保护,治疗高血压、心脑血管疾患、II型糖尿病、肿瘤、癌前病变以及水肿药物的应用。
Description
本发明涉及新的香豆素和其酰胺类衍生物,其制备方法,含有他们的药物组合物,及其作为药物,尤其作为肾保护,治疗高血压、心脑血管疾患、II型糖尿病、肿瘤、癌前病变以及水肿药物的应用。
1990年,联邦德国医药研究所在Meliloti Herba上发表专论称一些中草药中的香豆素类化合物治疗水肿血栓性静脉炎,淋巴淤滞等疾患。Scheel等(MicrobiolToxins 847-66,1972)报道香豆素能抗菌、抗病毒、抗肿瘤作用。Kovach等(Arzneim-Forsch/Drug Res 20 1630-33,1970)证明香豆素增加血流量,改善心肌缺血。Casley-Smith,(Vasomed 6 232-4,1994),Gaaffney,(J Pathol 133:229-42,1981),Piller,(Br J Exp Pathol 59:319-26,1978)和Knight,(Clin Sci 77:69-76,1989)证明香豆素有内皮保护和促进淋巴循环等作用。Nair等,(Carcinogenesis 12(1):65-69,1991)证明香豆素类化合物的抗癌作用。Ishizuka等,(美国专利No.5,096,924,证明取代的香豆素有抗癌作用。Marshall等,(L.Biol.Resp.Mod.8:62,1989),报道香豆素的增强免疫功能。如使癌症患者的单核细胞显著增加,因而增加抗癌能力。Preuss-Ueberschar等,(Drug Res.34:1305,1313,1984),证明香豆素是不致畸的。Takagaki,Hidetsugu等证明3-,4-,7-羟基或烷氧基取代香豆素治疗心脏病的作用(EP 0796854 A1,1997)。Markal等证明取代的4-芳基香豆素治疗病毒感染,特别是带状疱疹,单纯疱疹等有较好效果(WO 98/25608,1998)。Trkovnik等报告7-羟基4-甲基香豆素等能治疗或预防肾硬变、胰腺炎、膀胱和消化道疾病(WO 99/21550,1999)。Takagaki,Hideji等报道了香豆素衍生物对streptozotocin诱发的大鼠糖尿病有抑制作用(Jpn.Kokai Tokkyo Koho JP 07277972,1995)。Scott等报道了3-酰胺4-羟基香豆素类化合物对II型糖尿病模型有效(US 005723476A,1998)。韩兴梅等报道了6,7-二甲氧基香豆素对内毒素诱发的急性肾衰有效(中国药理学通报,1999,15,4:332-5)。len报道,TGF-β的对抗物质,可以用来防治慢性肾炎等疾患(PCT Int.Appl.WO 2001019396A1)
我们在研究工作中合成了一系列香豆素衍生物,并研究了有关生物活性;如,黄晓龙等研究证明,3-乙酰基和3-酮醛基取代香豆素有较好的抗致突作用(药学学报,1996,31,6:431-436;药学学报,1996,31,7:509-516)。徐世平等研究的维甲酰香豆素类化合物具有较强的诱导分化,抗致突和抗致癌等作用(中国专利,申请号:97116602.1,公开号:CN1207392-15卷,6期,1999)。徐嵩等研究的6-或7-取代苯乙烯基、4-苯乙烯基和4-,6-或7-取代苯亚胺次甲基香豆素类化合物,有抗癌活性(药学学报,2000,35,2:103-107;药学学报,2001,36,4:269-273;药学学报,2002,37,2:113-116)。
在继续对香豆素类化合物的研究中合成了一系列新的香豆素及其酰胺类化合物,发现,这类香豆素酰胺化合物对转化生长因子-β1(TGF-β1)有较好的抑制作用,香豆素对TGF-β的抑制,至今尚未见有其他文献报道。抑制TGF-β的物质是治疗慢性肾功能障碍,糖尿病性肾功能障碍等有关的物质。同时也能非常显著地降低血管紧张素II(AII),所以本发明的药物,对慢性肾衰、肾炎、高血压、甚至肝硬变以及肺纤维化的药物研究都是相关的。如len报道,TGF-β的对抗物质,可以用来防治慢性肾炎等疾患(PCT Int.Appl.WO 2001019396A1)
肾功能不全,尤其是慢性肾功能不全,均是由各种病因引起肾脏损害及进行性恶化的结果。在原发性肾脏病中,常见为慢性肾小球肾炎,其次为小管间质性肾炎。在继发性肾病中,常见为糖尿病肾病等。目前慢性肾功能不全病因中,糖尿病肾病占第一位,为27%,而且还在日益增多,高血压病占22.7%,而肾小球肾炎已由以前的第一位降为第三位,占21.2%,其它病因共占26.6%。肾脏疾病是常见病,不论何种病因,也不论是免疫机制或非免疫机制,如果得不到有效治疗,都将造成慢性肾功能不全和不可逆转的损伤。
研究表明,转化生长因子-β1(transforming growth factor β1,TGF-β1)和肾素血管紧张素系统与多种原因引起的肾功能不全关系密切。大鼠肾脏部分切除后4小时,TGF-β1开始升高,进而影响肾素血管紧张素系统,TGF-β1的持续增高和过度表达,抑制基质降解,促进基质的整合作用,并且与肾功能不全的蛋白尿及基质纤维化成正比。因此肾小球硬化、间质纤维化与TGF-β1直接相关。所以肾素血管紧张素系统和TGF-β1是与肾功能不全有关的两个最重要因素,并且前者的抑制与TGF-β1产生的减少有密切关系,提示TGF-β1增高可能是肾脏损伤发展成为晚期肾功能不全的重要原因,是寻找理想的抗肾衰新药的靶点。
香豆素有着广泛的生物活性,但在治疗慢性肾衰方面尚未见有其它报道,本发明的化合物是一类新型的,有非常明显的抑制TGF-β1的作用,TGF-β1增高是肾损伤发展成晚期肾衰的重要原因。经验证,本发明的化合物有较好的治疗肾功能不全的作用。肾功能不全,尤其是慢性肾功能不全,是一种难以治疗的慢性病,随着糖尿病、高血压等疾患的不断增加,其发病率越来越高,而且至今尚无非常有效的药物及其他较好的防治方法。本发明的目的就是研制治疗肾功能不全的新型药物。
为了克服现有技术的不足,本发明的目的在于提供一种新的香豆素,特别是其酰胺类衍生物。
本发明的另一目的在于提供一种香豆素酰胺类衍生物的制备方法。
本发明一方面涉及药物组合物,其中包括作为活性成份的通式(I)的化合物,其异构体及制药领域中常用的载体。
本发明的另一目的在于提供一种新的香豆素酰胺类衍生物及其组合物作为转化生长因子-β1抑制剂,血管紧张素II抑制剂的应用。
本发明的另一目的在于提供一种新的香豆素酰胺类衍生物及其组合物在制备治疗肾脏疾患(如各类慢性肾炎、糖尿病肾病及高血压性肾损害)、II型糖尿病、心脑血管、高血压的药物中的应用。
具体讲,本发明一方面涉及如通式(I)所示的化合物
其中:
R3选自H,羧基,酯基,5’-(苯基噁二唑基-2’),5’-(吡啶基-4”-噁二唑基-2’),
CONHR9,
其中R9选自C2-C8脂肪酸,苯甲酰氨基,异烟酰氨基,未取代、单取代或多取代的苯基,苯环上的取代基可以为OH,C1-C8烷氧基,CF3,羧基,酯基,OCH2CO2H,NO2,卤素,SO3H,SO2NHR11,
其中R11选自脒基,2”-噻唑基,3”-(5”-甲基异噁唑基),2”-嘧啶基,2”-(4”,6”-二甲基嘧啶基),4”-(5”,6”-二甲氧基嘧啶基);
R4选自H,CONHR10,R10选自C2-C8脂肪酸,苯甲酰氨基,异烟酰氨基,未取代、单取代或多取代的苯基,苯环上的取代基可以为OH,C1-C8烷氧基,CF3,羧基,酯基,OCH2CO2H,NO2,卤素,SO3H,SO2NHR12,其中R12为脒基,2”-噻唑基,3”-(5”-甲基异噁唑基),2”-嘧啶基,2”-(4”,6”-二甲基嘧啶基),4”-(5”,6”-二甲氧基嘧啶基);
R5选自H,C1-C4的烷基;
R6选自H,C1-C12的烷基,卤素,NO2,CONHR13,其中R13选自取代苯基;
R7选自H,OH,C1-C4烷基,烷氧基,烷氧基酸,OCH2CONHR14,其中R14选自未取代、单取代、多取代苯基,苯环上的取代基可以是OH,OCH3,CF3,CO2H,CO2C2H5,NO2;
R8选自H,C1-C4烷基,烷氧基,NO2;
为完成本发明的目的,优选的化合物包括但不限定于:R3选自H,COOH,CO2C2H5,5’-(苯基噁二唑基-2’),5’-(吡啶基-4”-噁二唑基-2’),CONHR,其中R为n-丁酸基,o-,m-,p-苯酚基,o-,m-,p-苯甲酸基,o-,m-,p-苯甲酸酯基,甲氧苯基,m-羧基亚甲氧苯基3’-水杨酸基,4’-水杨酸基,m-CF3-苯基,3’-CF3-4’-NO2-苯基,2’-COOH-4’-I苯基,异烟酰氨基,苯甲酰氨基,4-氨磺酰苯基,4-胍磺酰苯基,4-(2’-噻唑氨磺酰)苯基,4-(5’-甲基异噁唑-3’-氨磺酰)苯基,4-嘧啶氨磺酰苯基,4-二甲基嘧啶氨磺酰苯基,4-(5”,6”-二甲氧基嘧啶)氨磺酰苯基等;
R4选自H,CONHR10,R10选自H,4-COOH-苯基,4-CO2C2H5-苯基,3-CF3-苯基;R5选自H,CH3;
R6选自H,C2H5,n-C6H13,NO2,NH2,Cl,Br,CONHR13,其中R13选自羧基和酯基取代的苯基;
R7选自H,OH,CH3,OCH3,OCH2CONHR14,,其中R14为苯基,o-,m-,p-羟基苯基,o-,m-,p-羧基苯基,4’-乙氧羰基苯基,3’-乙氧羰基苯基,3’-三氟甲基苯基,3’-三氟甲基4-硝基苯基,4’-甲氧苯基,4’-水杨酸基,3’-水杨酸基;
R8选自H,CH3,OCH3,NO2;
为完成本发明的目的,优选的化合物包括但不限定于如通式(Ia)所示的化合物:
其中R4、R5、R6、R7、R8所代表的与通式I的各种情况下所代表的相同;
为完成本发明的目的,优选的化合物包括但不限定于如通式(Ib)所示的化合物:
其中R4、R5、R6、R7、R8所代表的与通式I的各种情况下所代表的相同;
R’2选自H,OH,COOH等;
R’3选自H,OH,COOH,CF3,OCH2COOH等;
R’4选自H,OH,COOH,COOEt,I,NO2,OCH3,SO3H,SO2NH2,
SONH(C=NH)NH2,
等
R’5,R’6为H
为完成本发明的目的,优选的化合物包括但不限定于如通式下列表中所示的化合物:其中R-R8基团,除标出者外,其它均为H;表中R’2-R’6基团,除标出者外,其它均为H。
在本发明中,术语“卤素″是指氟、氯、溴、碘。术语“低级烷基”“低级烷”是1-6碳原子的直链或支链的烷基。
根据本发明,本发明化合物可以异构体的形式存在,而且通常所述的“本发明化合物”包括该化合物的异构体。
本发明化合物可存在双键的顺反异构体,不对称中心具有S构型或R构型,本发明包括所有可能的立体异构体以及两种或多种异构体的混合物。如果存在顺/反异构体,本发明涉及顺式形式和反式形式以及这些形式的混合物,如果需要单一异物体可根据常规方法分离或通过立体选择合成制备。
根据本发明的实施方案,所述的本发明化合物还包括其药效学上可接受的盐、盐的水合物、酯或前体药物。
根据本发明还涉及制备本发明化合物的方法,用各种取代的3-酯基或羧酸香豆素类化合物进行硝化或双硝化,得部分本发明的化合物,也是部分本发明化合物的中间体。以这些中间体的酸、3-羧基的各种取代香豆素、4-羧基的各种取代香豆素、6-羧基的各种取代香豆素或7-羧基烷氧基的各种取代香豆素与相应的各种取代氨类化合物反应制备。酰氨化反应是在合适的反应剂、催化剂及合适的溶剂条件下进行的。这些反应剂包括三氯化磷、三氯氧磷、五氯化磷、二氯亚砜、1,3-二环己基亚胺(DCC)、二吡啶碳酸酯(2-DPC)、1,3-二异丙基碳酰亚胺(DIPC)、1-(3-二甲胺丙基)-3-乙基碳酰亚胺(EDCI)等。其中优选的反应剂为五氯化磷、三氯化磷和二氯亚砜,更优选五氯化磷、二氯亚砜。制备本发明化合物所使用的催化剂包括三级胺、吡啶、4-二甲氨基吡啶和4-吡咯烷基吡啶等。其中优选为三级胺和吡啶。更优选为吡啶。反应在适宜的溶剂中或上述缩合剂中进行,如无水非质子溶剂,二甲基亚砜(DMSO)、甲苯、二氯甲烷、1,2-二氯乙烷、乙二醇二甲醚、四氢呋喃和N,N-二甲基甲酰胺(DMF)等。其中优选为甲苯、DMSO和DMF,更优选甲苯和DMF。反应温度为10-110℃,优选为20-90℃,更优选为30-80℃,特别优选为50-70℃。
下列反应方程式IIa、IIb、IIc、IId、Iie、Iif具体说明
本发明因此还涉及含有作为活性成份的本发明化合物和常规药物赋形剂或辅剂的药物组合物。通常本发明药物组合物含有0.1-95重量%的本发明化合物。
本发明化合物的药物组合物可根据本领域公知的方法制备。用于此目的时,如果需要,可将本发明化合物与一种或多种固体或液体药物赋形剂和/或辅剂结合,制成可作为人药或兽药使用的适当的施用形式或剂量形式。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等。
本发明化合物或含有它的药物组合物的给药途径可为注射给药。注射包括静脉注射、肌肉注射、皮下注射、皮内注射和穴位注射等。
给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明化合物可以制成普通制剂、也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将单位给药剂型制成片剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等;湿润剂与粘合剂,如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等;崩解剂,例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等;崩解抑制剂,例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等;吸收促进剂,例如季铵盐、十二烷基硫酸钠等;润滑剂,例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
例如为了将给药单元制成丸剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等;粘合剂,如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等;崩解剂,如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
例如为了将给药单元制成胶囊,将有效成分本发明化合物与上述的各种载体混合,并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分本发明化合物制成微囊剂,混悬于水性介质中形成混悬剂,亦可装入硬胶囊中或制成注射剂应用。
例如,将本发明化合物制成注射用制剂,如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂,这种制剂可以是含水或非水的,可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外,为了制备等渗注射液,可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油,此外,还可以添加常规的助溶剂、缓冲剂、pH调节剂等。这些辅料是本领域常用的
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量取决于许多因素,例如所要预防或治疗疾病的性质和严重程度,患者或动物的性别、年龄、体重、性格及个体反应,给药途径、给药次数、治疗目的,因此本发明的治疗剂量可以有大范围的变化。一般来讲,本发明中药学成分的使用剂量是本领域技术人员公知的。可以根据本发明化合物组合物中最后的制剂中所含有的实际药物数量,加以适当的调整,以达到其治疗有效量的要求,完成本发明的预防或治疗目的。本发明化合物的每天的合适剂量范围本发明的化合物的用量为0.001-150mg/Kg体重,优选为0.1-100mg/Kg体重,更优选为1-60mg/Kg体重,最优选为2-30mg/Kg体重。。上述剂量可以单一剂量形式或分成几个,例如二、三或四个剂量形式给药这受限于给药医生的临床经验以及包括运用其它治疗手段的给药方案。
每一种治疗所需总剂量可分成多次或按一次剂量给药。本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用并调整剂量。
用已知体内外试验方法测定本发明化合物和/或组合物的活性和效果,如对TGF-β1的拮抗试验,治疗肾功能不全等,这些方法都是公知的。近年研究证实,TGF-β1是导致进展期肾衰肾小球硬化和间质纤维化的最关键因子之一。药理实验表明本发明化合物具有阻断转化生长因子-β1与受体结合和抑制转化生长因子-β1产生的作用。在10μg/ml剂量下受试的33个化合物中,活性超过50%的化合物有11个,超过60%的化合物有8个,超过70%的化合物有7个,超过80%的化合物有5个,超过90%的化合物有4个。对TGF-β1诱发的水貂肺上皮细胞的生长抑制,在受试的5个化合物中有三个化合物的活性超过60%,两个化合物超过70%,一个化合物超过90%。因此本发明化合物能用于治疗慢性肾脏疾患,包括:①原发性肾脏病,常见的有慢性肾小球肾炎、间质性肾炎、慢性肾盂肾炎等;②继发性肾病,常见的有糖尿病肾病、高血压肾病、狼疮性肾病等;③先天性及梗阻性疾病,如多囊肾、后尿道瓣膜病、神经源性膀胱增生症、前列腺增生症、尿路结石等。
进一步的试验表明具有非常明显的抑制血管紧张素II(AII,P<O.01)的作用。转化生长因子-β1和肾素血管紧张素系统与上述提到的多种原因引起的肾功能不全密切相关,是肾病进行性恶化的两个最重要因素,并且血管紧张素II的抑制与转化生长因子-βl产生的减少有密切关系。血管紧张素II在各种高血压的产生过程中起到了重要作用。所以本发明的化合物可以治疗由各种因素引起的肾性高血压、糖尿病性高血压及外周血管疾病性高血压,以及由上述原因所引起的心脑血管疾病。
体内试验表明,对大鼠5/6肾切除致慢性肾衰的作用,与阳性对照药Benazepril和Losartan比较,证明本发明化合物在降低血清尿素氮(BUN)、肌酐(Cre),抑制转化生长因子-βl(TGF-β1)和血管紧张素II(AII)方面均好于Benazepril,而与Losartan相当(略好)。
对大鼠单侧输尿管结扎所致肾间质纤维化的作用表明,受试化合物149在各项生化指标中均好于Losartan,而与Benazepril相当(略好),但病理结果表明,本发明的化合物好于Benazepril而与Losartan相当。
受试化合物毒性很小,在剂量5g/Kg和10g/Kg时,连续观察二周,未见动物死亡,也未见小鼠有其它异常表现,说明其毒性小,安全系数较大。另外,受试化合物149的微生物回复突变试验结果均为阴性,表明没有致突变作用。
下面的实施例用来进一步说明本发明,但是这并不意味着对本发明的任何限制。
实施例1 3-乙氧羰基-6-氯-7-羟基-8-硝基香豆素(241)的合成
将2.75g(10.2mmol)3-乙氧羰基-6-氯-7-甲氧基香豆素,加入10ml浓硫酸中,在冰盐浴冷却下分批加入浓硝酸1.74g(20.4mmol)薄层析跟踪至反应完全后,加入冰终止反应,过虑,以水洗涤,干燥得产品1.52g标题化合物(241)。
H-NMR 300MHz(DMSO):1.266(t,3H,CH3);4.232(q,2H,CH2);8.017(s,1H,5-H);8.593(s,1H,4-H)
表2中化合物229-246,都可按此法制备
实施例2 3-乙氧羰基-6-乙基-7-羟基-8-硝基香豆素(233)的合成
根据实施例化合物241的制备方法,化合物233的制备,不同点在于以3-乙氧羰基-6-乙基-7-甲氧基香豆素进行硝化反应,得化合物233
H-NMR 300MHz(DMSO):1.262(t,3H,6-乙基-CH3),1.401(t,3H,酯基-CH3),2.753(q,2H,6-乙基-CH2),3.988(s,3H,7-OCH3),4.408(q,2H,酯基-CH2),7.527(s,1H,5-H),8.479(s,1H,4-H)
实施例3 3-乙氧羰基-6-硝基-7,8-二甲氧基香豆素(227)的合成
根据实施例化合物241的制备方法,化合物229的制备,不同点在于以3-乙氧羰基-7,8-二甲氧基香豆素进行硝化反应,得化合物229
H-NMR 300MHz(DMSO):1.397(t,3H,酯基-CH3),4.063-4.118(d,6H,7,8-OCH3),4.423(q,2H,酯基-CH2),7.757(s,1H,5-H),9.252(s,1H,4-H)
实施例4 3-乙氧羰基-6,8-二硝基-7-甲氧基香豆素(239)的合成
根据实施例化合物241的制备方法,化合物239的制备,不同点在于以3-乙氧羰基-7-甲氧基香豆素进行双硝化反应,得化合物239
H-NMR 300MHz(DMSO):1.290(t,3H,酯-CH3),4.011(s,3H,7-OCH3),4.292(q,2H,酯-CH2),8.873(s,1H,4-H),8.955(s,1H,5-H)
实施例5 3-乙氧羰基-6,8-二硝基-7-羟基香豆素(237)的合成
根据实施例化合物241的制备方法,化合物237的制备,不同点在于以3-乙氧羰基-7-羟基香豆素进行双硝化反应,得化合物237
H-NMR 300MHz(DMSO):1.237(t,3H,酯-CH3),4.196(q,2H,酯-CH2),8.399(s,1H,4-H),8.636(s,1H,5-H)
实施例6 3-(3’-羟基-4’-羧基苯胺羰基)-6-乙基-7-甲氧基香豆素(26)的合成
将248mg(1mol)3-羧基-6-乙基-7-甲氧基香豆素和2ml SOCl2加热使反应完全后,去除SOCl2,加入153mg(1mol)4-氨基水杨酸及2ml吡啶,加热使反应完全,所得产物以DMSO精制,得产品140mg标题化合物(26)。
H-NMR 300MHz(DMSO):1.142(t,3H,CH3),2.569(q,2H,CH2),3.906(s,3H,7-OCH3);7.069(d,1H,6’-H),7.098(s,1H,8-H),7.509(s,1H,2’-H),7.758(d,1H,5-H),8.856(s,1H,4-H),10.848(s,1H,CONH),11.399(s,1H,OH)
表1中1-109号化合物,204-206,208,209,213,214,217,218,220,222-228表2中247-249号化合物,均按以上操作步骤进行制备。
实施例7 3-(3’-羧基-4’羟基苯胺羰基)-6-乙基-7-甲氧基香豆素(27)的合成
根据实施例化合物26的制备方法,化合物27的制备,不同点在于以5-氨基水杨酸代替4-氨基水杨酸进行反应,得化合物27
H-NMR500MHz(DMSO):1.162(t,3H,乙基-CH3),2.602(q,2H,乙基-CH2),3.937(s,3H,7-OCH3),6.786(d,1H,5’-H),7.178(s,1H,6-H),7.746(d,1H,6’-H),7.770(s,1H,5-H),8.239(s,1H,2’-H),8.834(s,1H,4-H),10.583(s,1H,CONH)
元素分析:C20H17NO7
计算值:C62.66,H4.47,N3.65
测定值:C62.87,H4.49,N3.71
实施例8 3-(m-羧基苯胺羰基)-7-甲氧基香豆素(2)的合成
根据实施例化合物26的制备方法,化合物2的制备,不同点在于以3-羧基7-甲氧基香豆素与m-氨基苯甲酸进行反应,得化合物2
元素分析:C18H13NO6·1/2H2O
计算值:C62.07,H4.05,N4.02
测定值:C62.72,H3.74,N4.55
实施例9 3-(3’-羟基-4’-羧基苯胺羰基)-7-甲氧基香豆素(7)的合成
根据实施例化合物26的制备方法,化合物7的制备,不同点在于以3-羧基-7-甲氧基香豆素与4-氨基水杨酸进行反应,得化合物7
H-NMR 300MHz(DMSO):3.91(s,3H,7-OCH3),7.08(d,1H,6-H),7.11(s,1H,6’-H),7.53(s,1H,2’-H),7.77(d,1H,5-H),7.95(d,1H,5’-H),8.91(s,1H,4-H),10.83(s,1H,CONH),11.40(br,1H,OH)
元素分析:C18H13NO7
计算值:C60.85,H3.69,N3.94
测定值:C60.52,H3.59,N4.10
实施例10 3-(3’-羧基-4’-羟基苯胺羰基)-7-甲氧基香豆素(8)的合成
根据实施例化合物26的制备方法,化合物8的制备,不同点在于以3-羧基-7-甲氧基香豆素和5-氨基水杨酸进行反应。得化合物8
H-NMR 300MHz(DMSO):3.906(s,3H,7-OCH3),6.964(d,1H,5’-H),7.037(d,1H,6-H),7.083(s,1H,8-H),7.745(d,1H,6’-H),8.001(d,1H,5-H),8.234(s,1H,2’-H),8.877(s,1H,4-H),10.547(s,1H,CONH),11.103(br,OH)
元素分析:C18H13NO7
计算值:C60.85,H3.69,N3.94
测定值:C60.50,H3.62,N3.64
实施例11 3-[4’-(5”-甲基异噁唑-3”)-氨磺酰基-苯胺羰基]-7-甲氧基香豆素(19)的合成
根据实施例化合物26的制备方法,化合物19的制备,不同点在于以3-羧基-7-甲氧基香豆素和磺氨甲基异噁唑(SMZ)进行反应。得化合物19
元素分析:C21H17N3O7S·1/2H2O
计算值:C54.31,H3.91,N9.05
测定值:C54.56,H3.49,N8.90
实施例12 3-(3’-羧基丙氨羰基)-7-甲氧基香豆素(203)的合成
根据实施例化合物26的制备方法,化合物203的制备,不同点在于以3-羧基-7-甲氧基香豆素和γ-氨基丁酸进行反应。得化合物203
H-NMR 300MHz(DMSO):1.719(t,2H,3’-H),2.235(t,2H,2’-H),3.311(t,2H,4’-H),3.861(s,3H,7-OCH3),7.001(d,1H,6-H),7.074(s,1H,8-H),7.861(d,1H,5-H),8.771(s,1H,4-H)
元素分析:C15H15NO6
计算值:C59.01, H4.95,N4.59
测定值:C59.05, H4.60,N4.73
实施例13 3-[4’-(5”-甲基异噁唑-3”)-氨磺酰基苯胺羰基]-7-甲氧基-8-甲基香豆素(55)
根据实施例化合物26的制备方法,化合物55的制备,不同点在于以3-羧基-7-甲氧-8-甲基香豆素和磺氨甲基异噁唑(SMZ)进行反应。得化合物55
元素分析:C22H19N3O7S
计算值:C56.28,H4.08,N8.95
测定值:C56.61,H4.06,N9.01
实施例14 3-(m-羧基亚甲氧基苯胺羰基)-7,8-二甲氧基香豆素(64)的合成
根据实施例化合物26的制备方法,化合物64的制备,不同点在于以3-羧基-7,8-二甲氧基香豆素和m-羧基亚甲氧基苯氨进行反应得化合物64
H-NMR 300MHz(DMSO):3.852(s,3H,8-OCH3),3.951(s,3H,7-OCH3),4.641((s,2H,OCH2),6.676(q,1H,5’-H),7.198-7.420(m,3H,4’,6’,6-H),7.502(s,1H,2’-H),7.751(d,1H5-H),8.853(s,1H,4-H),10.584(s,1H,CONH)
元素分析:C20H17NO8
计算值:C60.15,H4.29,N3.51
测定值:C60.41,H4.65,N3.75
实施例15 3-(4’-胍基磺酰基苯胺羰基)-7,8-二甲氧基香豆素(66)
根据实施例化合物26的制备方法,化合物66的制备,不同点在于以3-羧基-7,8-二甲氧基香豆素和磺氨胍(SG)进行反应得化合物66
元素分析:C19H18N4O7S·2H2O
计算值:C47.30,H4.56,N11.61
测定值:C47.34,H4.08,N11.00
实施例16 3-(3’-羧基-4’-羟基苯胺羰基)-7,8-二甲氧基香豆素(60)的合成
根据实施例化合物26的制备方法,化合物60的制备,不同点在于以3-羧基-7,8-二甲氧基香豆素和5-氨基水杨酸进行反应得化合物60
H-NMR 300MHz(DMSO):3.849-3.947(d,6H,7,8-bis-OCH3),6.962(d,1H,5’-H),7.233(d,1H,6-H),7.727-7.755(d,2H,5,6’-H),8.210(s,1H2’-H),8.813(s,1H,4-H),10.495(s,1H,CONH)
元素分析:C19H15NO8·1/4H2O
计算值:C58.61,H4.01,N3.59
测定值:C58.27,H3.86,N3.92
实施例17 3-(苯甲酰肼羰基)-5-甲基-7-甲氧基香豆素(210)的合成
根据实施例化合物26的制备方法,化合物210的制备,不同点在于以3-羧基-5-甲基-7-甲氧基香豆素和苯甲酰肼进行反应得化合物210
H-NMR 300MHz(DMSO):2.482(s,3H,5-CH3),3.888(s,3H,7-OCH3),6.979(d,2H,6,8-H),7.477-7.583(q,2H,3’,5’-H),7.500(t,1H,5’-H),7.889(d,2H,2’,6’-H),8.792(s,1H,4-H),10.24(s,1H,CONH),10.868(s,1H,CONH)
实施例18 3-(异烟肼基羰基)-5-甲基-7-甲氧基香豆素(213)的合成
根据实施例化合物26的制备方法,化合物213的制备,不同点在于以3-羧基-5-甲基-7-甲氧基香豆素和异烟肼进行反应得化合物213
H-NMR 300MHz(DMSO):2.553(s,3H,5-CH3),3.878(s,3H,7OCH3),6.979(d,2H,6,8-H),7.935(d,2H,3’,5’-H),8.781(s,1H,4-H),10.545(s,1H,CONH),11.362(s,1H,CONH)
实施例19 3-(3’-羧基-4’-羟基苯胺羰基)-5-甲基-7-甲氧基香豆素(74)的合成
根据实施例化合物26的制备方法,化合物74的制备,不同点在于以3-羧基-5-甲基-7-甲氧基香豆素和5-氨基水杨酸进行反应得化合物74
元素分析:C19H15NO7
计算值:C61.79,H4.09,N3.79
测定值:C61.57,H4.07,N3.81
实施例20 3-(3’-羟基-4’-羧基苯胺羰基)-6-Cl-7-甲氧基香豆素(87)的合成
根据实施例化合物26的制备方法,化合物87的制备,不同点在于以3-羧基-6-Cl-7-甲氧基香豆素和4-氨基水杨酸进行反应得化合物87
H-NMR 300MHz(DMSO):3.996(s,3H7-OCH3),7.114(d,1H,6’-H),7.376(s,1H,8-H),7.485(s,1H,2’-H),7.768(d,1H,5’-H),8.146(s,1H,5-H),8.839(s,1H,4-H),10.721(s,1H,CONH)
元素分析:C18H12ClNO7
计算值:C55.47,H3.11,N3.59
测定值:C55.97,H3.13,N4.48
实施例21 3-(3’-羧基-4’-羟基苯胺羰基)-6-Cl-7-甲氧基香豆素(88)的合成
根据实施例化合物26的制备方法,化合物88的制备,不同点在于以3-羧基-6-Cl-7-甲氧基香豆素和5-氨基水杨酸进行反应得化合物88
H-NMR 300MHz(DMSO):4.010(s,3H,7-OCH3),6.968(d,1H,5’-H),7.380(s,1H,8-H),7.752(d,1H,6’-H),8.153(s,1H,5-H),8.211(s,1H,2’-H),8.817(s,1H,4-H),10.475(s,1H,CONH)
元素分析:C18H12ClNO7
计算值:C55.47,H3.11,N3.59
测定值:C55.60,H3.18,N4.1
实施例22 3-(3’-羟基-4’-羧基苯胺羰基)-6-Br-7-甲氧基香豆素(96)的合成
根据实施例化合物26的制备方法,化合物96的制备,不同点在于以3-羧基-6-Br-7-甲氧基香豆素和4-氨基水杨酸进行反应得化合物96
H-NMR 300MHz(DMSO):3.996(s,3H,7-OCH3),7.118(d,1H,6 ’-H),7.343(s,1H,8-H),7.496(s,1H,2’-H),7.774(d,1H,5’-H),8.306(s,1H,5-H),8.846(s,1H,4-H),10.722H(s,1H,CONH)
实施例23 3-(4’-胍基磺酰基苯胺羰基)-6-乙基-7-甲氧基香豆素(32)的合成
根据实施例化合物26的制备方法,化合物32的制备,不同点在于以3-羧基-6-乙基-7-甲氧基香豆素和磺氨胍(SG)进行反应得化合物32
H-NMR 300MHz(DMSO):1.148(t,3H,乙基-CH3),2.572(q,2H,乙基-CH2),3.896(s,3H,OCH3),6.690(br,4H,胍基-H),7.125(s,1H,8-H),7.709(s,1H5-H),7.739(q,4H,Ar-H),8.827(s,1H,4-H),10.841(s,1H,CONH)
元素分析:C20H20N4O6S·1/4H2O
计算值:C53.55,H4.60,N12.48
测定值:C53.49,H4.63,N12.40
实施例24 3-(4’-胍基磺酰基苯胺羰基)-6-Cl-7-甲氧基香豆素(92)
根据实施例化合物26的制备方法,化合物92的制备,不同点在于以3-羧基-6-Cl-7-甲氧基香豆素和磺氨胍(SG)进行反应得化合物92
H-NMR 300MHz(DMSO):3.999(s,3H,7-OCH3),7.407(s,1H,8-H),7.776(q,4H,Ar-H),8.172(s,1H,5-H),8.860(s,1H,4-H),10.787(s,1H,CONH)
元素分析:C18H15ClN4O6S
计算值:C47.95,H3.35,N12.43
测定值:C47.54,H3.45,N12.15
实施例25 3-(3’-羟基-4’-羧基苯胺羰基)-7-甲氧基-8-甲基香豆素(43)的合成
根据实施例化合物26的制备方法,化合物43的制备,不同点在于以3-羧基-7-甲氧基-8-甲基香豆素和4-氨基水杨酸进行反应得化合物43
H-NMR 300MHz(DMSO):2.215(s,3H,8-CH3),3.912(s,3H,7-OCH3),7.081(d,1H,6’-H),7.182(d,1H,6-H),7.612(s,1H,2’-H),7.747(d,1H,5-H),7.872(d,1H,5’-H),8.834(s,1H,4-H),10.813(s,1H,CONH)
元素分析:C19H15NO7·1/2H2O
计算值:C60.32,H4.26,N3.70
测定值:C60.26,H4.03,N4.14
实施例26 3-(3’-羧基-4’-羟基苯胺羰基)-7-甲氧基-8-甲基香豆素(44)的合成
根据实施例化合物26的制备方法,化合物44的制备,不同点在于以3-羧基-7-甲氧基-8-甲基香豆素和5-氨基水杨酸进行反应得化合物44
H-NMR 300MHz(DMSO):2.209(s,3H,8-CH3),3.753(s,3H,7-OCH3),6.959(d,1H,5’-H),7.168(d,1H,6-H),7.723(d,1H,6’-H),7.848(d,1H,5-H),8.197(s,1H,2’-H),8.794(s,1H,4-H),10.504(s,1H,CONH)
元素分析:C19H15NO7·1/2H2O
计算值:C60.32,H4.26,N3.70
测定值:C59.66,H3.92,N3.81
实施例27 3-(4’-甲氧苯胺羰基)-6-硝基-7-羟基-8-甲基香豆素(146)
将160mg(0.604mmol)3-羧基-6-硝基-7-羟基-8-甲基香豆素和2ml二氯亚砜,加热使反应完全,除去多余的二氯亚砜,加入74.3mg(0.604mmol)p-氨基苯甲醚及1ml吡啶和1mlDMF,加热使反应完全,过滤,以水、稀盐酸、水和乙醇洗涤,干燥,冰醋酸精制,得产品(146)170mg
H-NMR 300MHz(DMSO):2.280(s,3H,Ar-CH3);3.740(s,3H,OCH3);6.941(d,2H,3’,5’-H);7.621(d,2H,2’,6’-H);8.673(s,1H,5-H);8.897(s,1H.4-H);10.374(s,1H,CONH)
表1中110-203,225-228号化合物按以上操作步骤制备。
实施例28 3-(4’-胍基磺酰基苯胺羰基)-6-硝基-7-甲氧基-8-甲基香豆素(169)
根据实施例化合物146的制备方法,化合物169的制备,不同点在于以磺氨胍(SG)和3-羧基-6-硝基-7-甲氧基-8-甲基香豆素进行反应,以DMF精制。得化合物169H-NMR 300MHz(DMSO):2.382(s,3H,8-CH3),3.940(s,3H,7-OCH3),6.677(br,4H,胍基-H),7.790(q,4H,Ar-H),8.593(s,1H,5-H),8.903(s,1H,4-H),10.707(s,1H,CONH)
元素分析:C19H17N5O8S·1/2H2O
计算值:C47.10,H3.75,N14.46
测定值:C47.27,H3.73,N14.58
实施例29 3-(4’-羧基苯胺羰基)-6-硝基-7,8-二甲氧基香豆素(110)
根据实施例化合物146的制备方法,化合物110的制备,不同点在于以p-氨基苯甲酸和3-羧基-6-硝基-7,8-二甲氧基香豆素进行反应。得化合物110
H-NMR 300MHz(DMSO):3.99-4.06(q,6H,7,8-bis-OCH3),7.82(d,2H,J=8.7,Ar-H),7.9(d,2H,J=8.7,Ar-H),8.15(s,1H,5-H),9.09(s,4-H)10.91(s,1H,CONH)
实施例30 3-(3’-羧基苯胺羰基)-6-硝基-7,8-二甲氧基香豆素(111)
根据实施例化合物146的制备方法,化合物111的制备,不同点在于,以m-氨基苯甲酸和3-羧基-6-硝基-7,8-二甲氧基香豆素进行反应。得化合物111
H-NMR 300MHz(DMSO):3.97-4.05(q,6H,7,8-bis-OCH3),7.49(t,1H,5’-H),7.67(d,1H,6’-H),7.76(d,1H,4’H),7.93(s,1H,2’-H),8.32(s,1H,5-H),9.08(s,1H,4-H),10.66(s,1H,CONH)
实施例31 3-[4’-(5”,6”-二甲氧基嘧啶-4”)-胺磺酰基苯胺羰基]-6-硝基-7,8-二甲氧基香豆素(123)
根据实施例化合物146的制备方法,化合物111的制备,不同点在于,以磺氨5,6-二甲氧基嘧啶(SDM’)和3-羧基-6-硝基-7,8-二甲氧基香豆素进行反应。得化合物123
H-NMR 300MHz(DMSO):3.694(s,3H,嘧啶-OCH3),3.894(s,3H,8-OCH3),4.064(s,3H,7-OCH3),7.886-7.996(q,4H,Ar-H),7.974(s,1H,2”-H),8.109(s,1H,5-H),9.092(s,1H,4-H),10.791(s,1H,CONH),10.947(br,1H,SO2NH)
实施例32 3-(3’-羟基-4’-羧基苯胺羰基)-6-硝基-7-羟基-8-甲基香豆素(148)
根据实施例化合物146的制备方法,化合物148的制备,不同点在于以4-氨基水杨酸和3-羧基-6-硝基-7-羟基-8-甲基香豆素进行反应,
得化合物148
H-NMR 300MHz(DMSO):2.27(s,3H,Ar-CH3),7.11(dd,1H,J=7.8Hz,1.8Hz,6’-H),7.498(d,1H,J=1.8Hz,2’-H),7.775(d,1H,J=7.8,5’-H),8.65(s,1H,5-H),8.892(s,1H,4-H),10.69(s,1H,CONH)
实施例33 3-(3’-羧基-4’-羟基苯胺羰基)-6-硝基-7-羟基-8-甲基香豆素(149)
根据实施例化合物146的制备方法,化合物149的制备,不同点在于以5-氨基水杨酸和3-羧基-6-硝基-7-羟基-8-甲基香豆素进行反应,得化合物149
H-NMR 300MHz(DMSO):2.268(s,3H,Ar-H),6.971(d,1H,J=8.7Hz,5’-H),7.747(dd,1H,J=8.7Hz,2.7Hz,6’-H),8.208(d,1H,J=2.7Hz,2’-H),8.658(s,1H,5-H),8.867(s,1H,4-H),10.403(s,1H,CONH)
实施例34 3-[4’-(2”-嘧啶氨磺酰基)苯胺羰基]-5甲基-6,8-二硝基-7-羟基香豆素(200)
根据实施例化合物146的制备方法,化合物200的制备,不同点在于以磺氨嘧啶(SD)和3-羧基-5甲基-6,8-二硝基-7-羟基香豆素进行反应,得化合物200
H-NMR 300MHz(DMSO):2.291(s,3H,5-CH3),7.025(t,1H,5”-H),7.884(q,4H,Ar-H),8.483(d,2H,4”,6”-H),8.640(s,1H,4-H),10.705(s,1H,CONH)
实施例35 3-(4’-氨磺酰基苯胺羰基)-5甲基-6,8-二硝基-7-羟基香豆素(198)
根据实施例化合物146的制备方法,化合物198的制备,不同点在于以氨基苯磺酰氨和3-羧基-5甲基-6,8-二硝基-7-羟基香豆素进行反应,得化合物198
H-NMR 300MHz(DMSO):2.254(s,3H,5-CH3),7.240(br,2H,NH2),7.788(q,4H,Ar-H),8.666(s,1H,4-H),10.676(s,1H,CONH)
实施例36 3-(2”-噻唑氨磺酰基苯胺羰基)-5甲基-6,8-二硝基-7-羟基香豆素(201)
根据实施例化合物146的制备方法,化合物201的制备,不同点在于以磺氨噻唑(ST)和3-羧基-5甲基-6,8-二硝基-7-羟基香豆素进行反应,得化合物201
H-NMR 300MHz(DMSO):2.291(s,3H,5-CH3),6.802(d,1H,噻唑-H),7.225(d,1H,噻唑-H),7.737(q,4H,Ar-H),8.651(s,1H,4-H),10.667(s,1H,CONH)
实施例37 3-(4’-胍基磺酰基苯胺羰基)-5甲基-6,8-二硝基-7-羟基香豆素(199)
根据实施例化合物146的制备方法,化合物199的制备,不同点在于以磺氨胍(SG)和3-羧基-5甲基-6,8-二硝基-7-羟基香豆素进行反应,得化合物199
H-NMR 300MHz(DMSO):2.293(s,3H,5-CH3),6.685(br,4H,胍基-H),7.746(q,4H,Ar-H),8.657(s,1H,4-H),10.647(s,1H,CONH)
实施例38 3-(2’-苯基-1’,3’,4’-噁二唑-5’)-7-甲氧基-8-甲基香豆素(216)
将295mg(0.84mmol)3-(苯甲酰肼基羰基)-7-甲氧基-8-甲基香豆素和4.6ml三氯氧磷,在100℃反应5小时,逐渐冷却后,倾入冰水中,过滤,以水洗涤,干后得290mg,以DMF精制后,得160mg,
H-NMR 300MHz(DMSO):2.252(s,3H,8-CH3);3.968(s,3H,7-OCH3);7.174(d,1H,6-H);7.634(m,3H,Ar’-H);7.812(d,1H,5-H);8.088(m,2H,Ar’-H);8.874(s,1H,4-H)
表2中207,210-212,215,216,219,221号化合物都按以上操作步骤制备。
实施例39 3-(2’-苯基-1’,3’,4’-噁二唑-5’基)-7-甲氧基香豆素(206)
根据实施例化合物216的制备方法,化合物206的制备,不同点在于以3-(苯甲-酰肼基羰基)-7-甲氧基香豆素代替3-(苯甲酰肼基羰基)-7-甲氧基-8-甲基香豆素进行反应得化合物206
H-NMR 300MHz(DMSO):3.929(s,3H,7-OCH3),7.021(d,1H,6-H),7.085(s,1H,8-H),7.599-7.668(m,3H,Ar-H),7.871(d,1H,5-H),8.095(m,2H,Ar-H),8.898(s,1H,4-H)
元素分析:C18H12N2O4
计算值:C67.49,H3.78,N8.75
测定值:C67.57,H3.98,N8.41
实施例40 3-[2’-(吡啶基-4”)-1’,3’,4’-噁二唑-5’]-6-己基-7-甲氧基香豆素(221)
根据实施例化合物216的制备方法,化合物221的制备,不同点在于以3-(异烟肼基羰基)-6己基-7-甲氧基香豆素代替3-(苯甲酰肼基羰基)-7-甲氧基-8-甲基香豆素进行反应得化合物221
H-NMR 300MHz(DMSO):0.869(t,3H,己基-CH3),1.240(br,6H,己基-CH2),1.574(t,2H,己基-CH2),2.734(t,2H,己基-CH2),3.959(s,3H,7-OCH3),7.116(s,1H,8-H),7.699(s,1H,5-H),8.070(br,2H,吡啶-H),8.920(br,2H,吡啶-H),8.921(s,1H,4-H)
元素分析:C23H23N3O4·3H2O
计算值:C60.12,H6.36,N9.15
测定值:C59.51,H5.51,N8.96
实施例41 4-甲基-7-(4’-乙氧羰基苯胺羰基亚甲氧基)香豆素(255)
将4-甲基-7-羧基亚甲氧基香豆素60mg(0.256mmol)与2ml二氯亚砜加热使反应完全后除去多余的二氯亚砜,残余物溶于5ml二氯甲烷,加入对-氨基苯甲酸乙酯44mg(0.267mmol)在5ml二氯甲烷的溶液和吡啶3ml,搅拌半小时析出固体,再继续搅拌1小时,过滤,以二氯甲烷洗涤干燥80mg,
H-NMR 300MHz(DMSO):1.293(t,3H,酯甲基);2.389(s,3H,4-甲基);4.269(q,2H,酯-CH2);4.881(s,2H,OCH2);6.219(s,1H,3-H);7.018(d,1H,8-H);7.056(d,1H,6-H);7.712(d,1H,5-H);7.760(d,2H,2’,6’-H);7.919(d,2H,3’,5’-H);10.479(s,1H,CONH)
元素分析:C21H19NO6
计算值:C66.13,H5.02,N3.67
测定值:C66.26,H4.91,N3.81
表2中250-264号化合物按以上步骤进行制备。
实施例42 4-甲基-7-苯胺羰基亚甲氧基香豆素(248)
根据实施例化合物255的制备方法,化合物248的制备,不同点在于以苯氨代替p-氨基苯甲酸乙酯进行反应,得化合物248
H-NMR 300MHz(DMSO):2.377(s,3H,4-CH3),4.825(s,2H,7OCH2),6.208(s,1H,3-H),6.997(m,3H,4’,6,8-H),7.306(t,2H,3’,5’-H),7.593(d,2H,2’,6’-H),7.711(d,1H,5-H),10,144(s,CONH)
元素分析:C18H15NO4
计算值:C69.89,H4.89,N4.53
测定值:C69.61,H4.891,N4.58
实施例43 4-甲基-7-(4’-羧基苯胺羰基亚甲氧基)-香豆素(252)
根据实施例化合物255的制备方法,化合物252的制备,不同点在于以p-氨基苯甲酸代替p-氨基苯甲酸乙酯进行反应,得化合物252
H-NMR 300MHz(DMSO):2.404(s,3H,4-CH3),4.899(s,2H,7-OCH2),6.235(s,1H,3-H),7.036(s,1H8-H), 7.073(d,1H,6-H),7.713(d,1H,5-H),7.739-7.924(q,4H,Ar-H),10.491(s,1H,CONH)
元素分析:C19H15NO6·1/4H2O
计算值:C63.77,H4.37,N3.92
测定值:C63.76,H4.28,N4.24
实施例44 4-甲基-7-(4’-羟基苯胺羰基亚甲氧基)香豆素(249)
根据实施例化合物255的制备方法,化合物249的制备,不同点在于以p-氨基苯酚代替p-氨基苯甲酸乙酯进行反应,得化合物249
H-NMR 300MHz(DMSO):2.084(s,3H,4-CH3),4.781(s,2H,7-OCH2),6.230(s,1H,3-H),6.705-7.390(q,4H,Ar-H),7.014(s,1H,8-H),7.060(d,1H,6-H),7.723(d,1H,5-H),9.905(s,1H,CONH)
元素分析:C18H15NO5
计算值:C66.45,H4.65,N4.31
测定值:C66.14,H4.62,N4.32
实施例45 4-甲基-7-(3’-羧基-4’-羟基苯胺羰基亚甲氧基)-香豆素(261)
根据实施例化合物255的制备方法,化合物261的制备,不同点在于以5-氨基水杨酸代替p-氨基苯甲酸乙酯进行反应,得化合物261
H-NMR 300MHz(DMSO):2.495(s,3H,4-CH3),4.818(s,2H,7-OCH2),6.233(s,1H,3-H),6.940(d,1H,6-H),7.052(s,1H,8-H),7.077(d,1H,5’-H),7.705(d,1H,6’-H),7.739(d,1H,5-H),8.138(s,1H,2’-H)
元素分析:C19H15NO7
计算值:C61.79,H4.09,N3.79
测定值:C61.49,H3.96,N3.86
实施例46 4-甲基-7-(3’-三氟甲基苯胺羰基亚甲氧基)-香豆素(257)
根据实施例化合物255的制备方法,化合物257的制备,不同点在于以3-三氟甲基苯氨代替p-氨基苯甲酸乙酯进行反应,得化合物257
H-NMR 300MHz(DMSO):2.389(s,3H,4-CH3),4.872(s,2H,7-OCH2),6.220(s,1H,3-H),7.027-7.075(m,2H,6,8-H),7.429(d,1H,6’-H),7.567(t,1H,5’-H),7.719(d,1H,5-H),7.857(d,1H,4’-H),8.096(s,1H,2’-H),10.446(s,1H,CONH)
元素分析:C19H14F3NO4
计算值:C60.48,H3.74,N3.71
测定值:C60.17,H3.45,N3.79
实施例47 4-甲基-7-(3’-三氟甲基-4’-硝基苯胺羰基亚甲氧基)-香豆素(258)
根据实施例化合物255的制备方法,化合物258的制备,不同点在于以3-三氟甲基-4-硝基苯氨代替p-氨基苯甲酸乙酯进行反应,得化合物258
H-NMR 300MHz(DMSO):2.409(s,3H,4-CH3),4.955(s,2H,7-OCH2),6.243(s,1H,3-H),7.061(s,1H,8-H),7.086(d,1H,6-H),7.734(d,1H,5’-H),8.127(d,1H,6’-H),8.215(d,1H,5-H),8.331(s,1H,2’-H),10.945(s,1H,CONH)
元素分析:C19H13F3N2O6·1/2H2O
计算值:C52.91,H3.27,N6.50
测定值:C53.19,H3.05,N6.76
实施例48 4,8-二甲基-7-(3’-三氟甲基苯胺羰基亚甲氧基)香豆素(262)
根据实施例化合物255的制备方法,化合物262的制备,不同点在于以3-三氟甲基苯氨和4-甲基-7-羧基亚甲氧基-8-甲基香豆素进行反应,得化合物262
H-NMR 300MHz(DMSO):2.291(s,3H,8-CH3),2.392(s,3H,4-CH3),4.934(s,2H,7-OCH2),6.237(s,1H,3-H),7.002(d,1H,6-H),7.440(d,1H,6’-H),7.564(d,1H,5’-H),7.603(d,1H,5-H),7.816(d,1H,4’-H),8.103(s,1H,2’-H),10.503(s,1H,CONH)
元素分析:C20H16F3NO4
计算值:C61.38,H4.12,N3.58
测定值:C61.16,H4.03,N3.67
实施例49 4,8-二甲基-7-(3’-羟基-4’-羧基苯胺羰基亚甲氧基)香豆素(264)
根据实施例化合物255的制备方法,化合物264的制备,不同点在于以4-氨基水杨酸和4-甲基-7-羧基亚甲氧基-8-甲基香豆素进行反应,得化合物264
H-NMR 300MHz(DMSO):2.270(s,3H,8-CH3),2.371(s,3H,4-CH3),4.931(s,2H,7-OCH2),6.215(s,1H,3-H),6.958(d,1H,6-H),7.087(d,1H,6’-H),7.337(s,1H,2’-H),7.546(d,1H,5’-H),7.717(d,1H,5-H),10.455(s,1H,CONH)
元素分析:C20H17NO7
计算值:C62.66,H4.47,N3.65
测定值:C62.43,H4.43,N3.88
实施例50 6-(4’-乙氧羰基苯胺羰基)香豆素(265)
将6-羧基香豆素95mg(0.5mmol)和五氯化磷210mg(1mmol),在50ml甲苯回流1小时,浓缩后,加入83mg(0.5mol)p-氨基苯甲酸乙酯和1ml吡啶继续回流10分钟,冷后以盐酸酸化得固体,以乙醇精制得100mg产物(265)。
H-NMR 300MHz(DMSO):1.31(t,3H,酯基-CH3),4.28(q,2H,酯基-CH2),6.59(d,1H,3-H),7.55(d,1H,8-H),7.92(d,2H,Ar’-H),7.96(d,2H,Ar’-H),8.16(m,2H,4,7-H),8.34(d,1H,5-H),10.68(s,1H,CONH)
元素分析:C19H15NO5·1/2H2O
计算值:C65.80,H4.65,N4.04
测定值:C66.07,H4.59,N4.06
化合物266按本法制备。
药理实验
实验例1 本发明的化合物对TGF-β诱导的水貂肺上皮细胞增殖的抑制作用
将水貂肺上皮细胞接种到24孔板,密度为3×104个细胞/孔,培养条件为37℃,5%CO2,MEM培养基(含10%胎牛血清)。次日将培养基更换成含0.2%胎牛血清的MEM。24小时后,弃去培养基,加入含有10pmol/L的TGF-β1及受试化合物的新鲜培养基,温孵24小时。在温孵结束前2小时加入[3H]胸腺嘧啶。弃去培养基并用PBS洗涤细胞。用0.5mol/L NaOH溶液溶解细胞,测定其放射性。受试化合物对[3H]胸腺嘧啶掺入的抑制作用可反映其对细胞增殖的抑制作用。(结果列于表3)
表3受试化合物对TGF-β诱导的水貂肺上皮细胞增殖的抑制作用
实施例化合物编号(10μg/ml) 26 92 73 7 2
对水貂肺上皮细胞增殖的抑制百分率(%) 70.7 95.0 15.1 67.1 27.1
实验例2 本发明的化合物对TGF-β1受体结合试验的拮抗作用
将Balb/c 3T3细胞接种到24孔板,培养条件为37℃,5%CO2,DMEM培养基(含10%胎牛血清)。培养2-4天后,在细胞接近融合时,将培养液换成结合缓冲液(50mmol/L HEPES中含有NaCl,KCl,MgSO4和CaCl2),加入50pmol/L[125I]TGF-β1激发试验,同时加入受试化合物。细胞培养210-240分钟后,弃去培养基,用冰冷的结合缓冲液洗涤细胞。测定10nmol/LTGF-β1的非特异性结合。细胞溶解在Triton X-100缓冲液中,测定放射性。(结果见表4)
表4.本发明化合物对TGF-β1受体结合的拮抗作用
实施例化合物 抑制作用 IC50 实施例化合物 抑制作用 IC50
(10μg/ml) (%) (μg/ml) (10μg/ml) (%) (μg/ml)
1 32.2 42 4.1
2 74.1 13.8 49 15.5
3 11.7 55 52.3
6 -6.0 66 52.3
7 94.2 7.8 67 16.2
9 11.4 73 60.0
12 5.1 79 16.2
14 35.9 83 21.2
21 10.1 87 91.1
22 37.4 88 111.2 5.3
25 11.6 91 34.7
26 95.4 8.5 92 106.4
27 77.2 93 29.7
31 29.2 96 82.3
33 32.1 104 42.8
34 36.4 206 -0.7
37 41.4
实验例3 本发明化合物对5/6大鼠肾切除致慢性肾衰的保护作用
参照《新药临床前研究指导原则》建立大鼠部分肾脏切除引起的慢性肾衰模型。
取体重200g左右的雄性Wistar大鼠,腹腔注射戊巴比妥钠35mg/kg,待麻醉后,手术摘除右肾,切除左肾上下极肾实质,止血,关闭腹腔,缝合。手术4周后检测大鼠血清尿素氮、肌酐、尿蛋白,放免法测定血管紧张素II(AII)水平,ELISA法测定TGF-β1水平。随机分组并开始给药。每组30只鼠,设假手术组、模型对照组、Benazepril(4mg/kg)和Losartan(10mg/kg)阳性对照药组、受试药(实施例149)7.5mg/kg、15mg/kg和30m/kg三个剂量组。均为灌胃给药,每日一次,每周6次,持续到手术后16周。每周称体重,观察大鼠生长状况;于术后8周(给药4周)、术后12周(给药8周)、术后16周(给药12周),各组分别测定上述指标,并处死部分动物,取肾脏做病理。
大鼠慢性肾衰模型肾脏病理损伤主要为肾小球硬化和间质纤维化,肾小球硬化按程度分为五级(0-IV),0级为肾小球无任何变化,IV级为肾小球完全硬化,玻璃样变性。各组每例动物切片连续观察50个肾小球,分别按五个等级归类计算出每组动物各级肾小球病变百分比。
模型建立4周后血清BUN升高111.21%(p<0.01),尿蛋白升高86.13%(p<0.01),TGF-β1水平增高70.48%(p<0,02),表明模型建立成功。
模型建立12周(给药8周)病理结果表明,实施例149化合物30mg/kg剂量组和Losartan组残肾保留0级以上肾小球多于模型组,有显著差异,(p<0.05),肾小球病变积分明显低于模型组。Benazpril组部分动物炎性细胞浸润比较严重,小管扩张严重多数有蛋白样物质沉淀。
模型建立16周(给药12周)病理结果表明,受试化合物(149)30mg/kg剂量组,III级病变小球明显少于模型组(p<0.01),阳性药Losartan也小于对照组(p<0.05)。阳性药Benazepril组小球病变积分最高,肾间质炎性细胞浸润为中度偏重,纤维组织增生,小管扩张严重多数有蛋白样物质沉淀。
试验结果主要数据列于表5A-E。
表5.本发明化合物对5/6大鼠肾切除致慢性肾衰的保护作用
A.给药8周(术后12周)血清肌酐(Scr.)及尿素氮(BUN)变化
剂量
组别 (mg/k Scr.(mg/dL) 变化率(%) BUN(mg/dL) 变化率(%)
g)
对照组 - 2.08±0.742 13.00±2.328
模型组 - 3.06±0.768 47.93↑ 29.37±3.079# 125.90↑
Benazepril 4 3.54±1.140 15.36↑ 37.66±8.895 12.68↑
Losartan 10 2.34±0.268* 23.46↓ 25.64±5.116 28.23↓
化合物 22.35 ±
7.5 2.14±0.500* 30.26↓ 23.89↓
149 3.120*
化合物
15 1.80±0.550* 41.34↓ 26.04±4.234 11.33↓
149
化合物
30 1.89±0.184 38.20↓ 30.54 ± 3.98↑
149 11.697
*:P<0.05,与模型组相比较;#:P<0.05,与对照组相比较;↑:表示增加;↓:表示降低
B.给药8周(术后12周)血清TGF-β1、血管紧张素II(AII)及尿蛋白(UP)变化
剂量 TGF-β1(ng/ml) AII(pg/ml) UP(mg/day)
组别 (mg/ 变化率(%) 变化率(%) 变化率(%)
kg)
对照组 - 20.1±6.2 154.5±22.7 18.3±2.5
122.5
模型组 - 25.6±12.1 27.4↑ 94.5±7.4 40.7±14.2#
Benazepri ↑
4 40.9±26.6 59.8↑ 74.3±13.2* 21.4↓ 51.1±23.6 25.8↑
l
Losartan 10 18.7±9.2 26.8↓ 96.7±32.1 2.2↑ 32.7±10.3 19.6↓
化合物
7.5 20.0±6.7 21.8↓ 63.9±13.2* 32.4↓ 30.1±16.6 26.0↓
149
化合物
15 18.6±12.2 27.6↓ 49.9±21.3* 47.2↓ 30.4±16.2 25.3↓
149
化合物
30 18.9±10.1 26.1↓ 41.0±12.5* 56.6↓ 34.3±12.1 15.7↓
149
*:P<0.05,与模型组相比较;#:P<0.05,与对照组相比较;
↑:表示增加;↓:表示降低。
C.给药12周(术后16周)血清肌酐(Scr.)及尿素氮(BUN)变化
剂量 Scr.(mg/dL) BUN(mg/dL)
组别
(mg/kg) 变化率(%) 变化率(%)
对照组 - 2.25±0.39 21.24±3.354
38.93 ±
模型组 - 2.71±0.49# 20.7↑ 83.32↑
8.755#
Benazepril 4 2.28±0.70 19.01↓ 39.48±7.109 1.41↑
Losartan 10 2.21±0.48* 22.73↓ 37.84±5.672 2.80↓
化合物
7.5 2.73±0.78 0.75↑ 39.42±4.686 1.25↑
149
化合物
15 2.63±0.38 2.87↓ 37.32±5.467 4.14↓
149
化合物
30 2.10±0.71* 28.82↓ 36.60±5.422 5.99↓
149
*:P<0.05,与模型组相比较;#:P<0.05,与对照组相比较;↑:表示增加;↓:表示降低
D.给药12周(术后16周)血清TGF-β1、血管紧张素II(AII)及尿蛋白(UP)变化
剂量 TGF-β1(ng/ml) AII(pg/ml) UP(mg/day)
组别 (mg/kg 变化率(%) 变化率(%) 变化率(%)
)
16.5 ±
对照组 - 18.2±8.9 130.0±37.6
17.3
54.2 ± 228.5
模型组 - 12.8±7.9 61.7±24.3
26.1# ↑
Benazepri 4 12.8 ± 0.57↑ 47.8±12.0 22.6↓ 66.3 ± 22.3↑
l 14.8 31.9
11.8 ± 39.3 ±
Losartan 10 7.48↓ 38.9±17.4*37.2↓ 18.4↓
12.6 14.2
化合物 66.7 ±
7.5 13.6±7.1 6.28↑ 48.3±48.5 21.6↓ 23.1↑
149 38.8
化合物 52.3 ±
15 12.3±7.7 3.91↓ 41.3±28.4 33.0↓ 0.06↓
149 34.4
化合物 48.2 ±
30 11.6±6.7 9.38↓ 19.2±9.19*68.6↓ 11.1↓
149 31.6
*:P<0.05,与模型组相比较;#:P<0.05,与对照组相比较;↑:表示增加;↓:表示降低
E.病理结果
给药 肾小球硬化分级
后 组别 0级 I级 II级 III级 IV级 总分
周数
8周 模型组 10.0±17.3 38.7±21.2 31.5±17.3 13.6±18.3 1.8±3.3 4.9±1.5
Benazepril 12.2±19.0 29.6±23.9 28.1±18.1 19.6±24.4 5.9±11.2 5.5±2.6
Losartan 54.4±29.2* 31.9±20.0 13.7±14.0 1.1±3.3** 0 2.8±1.0**
*
化合物(149) 28.3±20.8 34.2±23.0 7.5±8.8* 17.5±30.7 6.7±13.4 4.9±3.5
7.5mg/kg组
化合物149 37.5±29.3* 27.5±16.3 18.8±9.9 13.3±20.7 2.9±8.2 3.9±1.7*
15mg/kg组
化合物149 15.7±19.0 24.0±21.1 30.0±20.8 23.3±28.5 8.0±13.0 5.7±2.9
30mg/kg组
0 3.3±6.4 29.0±23.4 50.5±18.7 17.6=14. 8.5±1.3
12周 模型组 1
0 0 19.1±27.1 46.2±15.6 34.8=29. 9.8±1.4
Benazepril 9
Losartan 0 10.0±2.9 45.7±17.7 41.9±25.6 2.8=4.8 7.2±1.3*
化合物149 0 2.0±4.5 71.3±11.5*26.7±7.8** 0 6.7±0.2**
7.5mg/kg组 *
化合物149 0 8.1±14.1 38.1±27.4 46.2±26.1 9.1±12.6 7.7±1.7
15mg/kg组
化合物149 0 2.3±6.3 37.1±16.0 51.4±8.6 13.8=20. 8.6±1.9
30mg/kg组 6
*:P<0.05,与模型组相比较
以上结果表明,受试化合物(149)在各项生化指标中,均好于Benazepril,而与Losartan相当(略好)。此外,病理结果显示受试化合物在给药三个月后,各剂量组对主要脏器如心、肝、脾和肺均无明显影响。
实验例4 本发明化合物对大鼠单侧输尿管结扎所致肾间质纤维化的抑制作用
取雄性Wistar大鼠,180-230g,腹腔注射戊巴比妥钠35mg/kg,待麻醉后在下腹正中略偏左侧切口,近膀胱端行左侧输尿管结扎术。设假手术组、模型对照组、Benazepril(4mg/kg)和Losartan(10mg/kg)阳性对照药组、受试药(实施例149)5mg/kg、10mg/kg和20m/kg三个剂量组。于手术前2天开始灌胃给药,每日一次,每周6次,持续给药至术后2周。于手术后14天(给药后16天)测定肌酐和尿素氮等,结果列于表6。模型组手术9天血清尿素氮(BUN)增加78.70%(p<0.01),肌酐(Scr.)增加20.73%(p<0.05),说明模型建立成功。
表6本发明化合物对大鼠单侧输尿管结扎所致肾间质纤维化的抑制作用
剂量
组别 (mg/k Scr.(mg/dL) 变化率(%) BUN(mg/dL) 变化率(%)
g)
对照组 - 1.45±0.44 16.23±2.70
模型组 - 2.20±0.14# 51.58↑ 27.54±3.32# 69.73↑
20.99 ±
Benazepril 4 1.92±0.29 12.50↓ 23.78↓
1.58*
Losartan 10 2.15±0.51 2.31↓ 23.88±2.94 13.30↓
化合物149 7.5 1.58±0.49* 28.24↓ 23.71±4.17 13.92↓
20.76 ±
化合物149 15 1.61±0.36* 26.50↓ 24.61↓
1.56*
20.77 ±
化合物149 30 1.60±0.14* 27.27↓ 24.58↓
2.04*
*:P<0.05,与模型组相比较;#:P<0.05,与对照组相比较;↑:表示增加:↓:表示降低
本试验中,受试化合物149在各项生化指标中,均好于Losartan,而与Benazepril相当(略好)。但病理结果有所不同,Benazepril组炎性细胞浸润更明显,4/7动物肾髓质小脓肿形成,大量的坏死细胞,炎性细胞和脓细胞堆积。Losartan组间质炎性细胞浸润和纤维增生明显减轻,小球囊增厚不明显。给药组,特别是大剂量组动物间质炎性细胞浸润和纤维增生明显减轻,小球病变比较轻。因此在病理方面,好于Benazepril,与Losartan相当。
实验例5 本发明化合物对小鼠的初步急性毒性试验
灌胃给予小鼠受试化合物(149)5g/kg和10g/kg两个剂量,未见小鼠异常,给药后48小时称体重,给5g/kg、10g/kg小鼠体重无变化,给药后14天,5g/kg的小鼠平均体重增加7g;10g/kg的小鼠体重增加5g,其余未见异常,未出现动物死亡。
实验例6 本发明化合物的微生物回复突变试验(Ames试验)
采用组氨酸缺陷型鼠伤寒沙门氏菌TA97,TA98,TA100,TA102菌株。药物浓度为0.5,5,50,500,5000μg/皿。S9系苯巴比妥诱导的体重200g的大鼠肝匀浆微粒体组分。受试化合物(149)在加或不加S9平行条件下进行测试。
参照Ames(1983)修订的鼠伤寒沙门氏菌哺乳动物微粒体酶致突变试验方法,对受试化合物(149)进行代谢活化和非代谢活化的平板掺入检测。将鉴定合格的液氮保存菌液接种到培养基中,37℃震荡培养15小时。取上述菌液0.1ml,加入不同浓度的受试药液100μl再加入S9混合液或磷酸缓冲液0.5ml,37℃水浴培养20分钟。然后加入顶层琼脂2ml混匀倒入铺有底层琼脂的平皿中,37℃培养48小时后,计数每皿菌落数。
本试验剂量下受试化合物(149)对各菌株的回复突变菌落数均未诱发升高,说明受试化合物的Ames试验结果为阴性,无致突变作用。
Claims (17)
1、一种如通式(I)所示的化合物
其特征在于,
R3选自H,羧基,酯基,5’-(苯基噁二唑基-2’),5’-(吡啶基-4”-噁二唑基-2’),
CONHR9,
其中R9选自C2-C8脂肪酸,苯甲酰氨基,异烟酰氨基,未取代、单取代或多取代的苯基,苯环上的取代基可以为OH,C1-C8烷氧基,CF3,羧基,酯基,OCH2CO2H,NO2,卤素,SO3H,SO2NHR11,
其中R11选自脒基,2”-噻唑基,3”-(5”-甲基异噁唑基),2”-嘧啶基,2”-(4”,6”-二甲基嘧啶基),4”-(5”,6”-二甲氧基嘧啶基);
R4选自H,CONHR10,R10选自C2-C8脂肪酸,苯甲酰氨基,异烟酰氨基,未取代、单取代或多取代的苯基,苯环上的取代基可以为OH,C1-C8烷氧基,CF3,羧基,酯基,OCH2CO2H,NO2,卤素,SO3H,SO2NHR12,其中R12为脒基,2”-噻唑基,3”-(5”-甲基异噁唑基),2”-嘧啶基,2”-(4”,6”-二甲基嘧啶基),4”-(5”,6”-二甲氧基嘧啶基);
R5选自H,C1-C4的烷基;
R6选自H,C1-C12的烷基,卤素,NO2,CONHR13,其中R13选自取代苯基;
R7选自H,OH,C1-C4烷基,烷氧基,烷氧基酸,OCH2CONHR14其中R14为未取代、单取代、多取代苯基,苯环上的取代基可以是OH.OCH3,CF3,CO2H,CO2C2H5,NO2;
R8选自H,C1-C4烷基,C1-C4烷氧基,NO2;
2、根据权利要求1所述的化合物,其特征在于,
R3选自H,COOH,CO2C2H5,5’-(苯基噁二唑基-2’),5’-(吡啶基-4”-噁二唑基-2’),CONHR9,其中R9为n-丁酸基,o-,m-,p-苯酚基,o-,m-,p-苯甲酸基,o-,m-,p-苯甲酸酯基,甲氧苯基,3’-水杨酸基,4’-水杨酸基,m-CF3-苯基,3’-CF3-4’-NO2-苯基,2’-COOH-4’-I苯基,异烟酰氨基,苯甲酰氨基,3’-羧基亚甲氧基苯基,4-氨磺酰苯基,4-胍磺酰苯基,4-(2’-噻唑氨磺酰)苯基,4-(5’-甲基异噁唑-3’-氨磺酰)苯基,4-嘧啶氨磺酰苯基,4-二甲基嘧啶氨磺酰苯基,4-(5”,6”-二甲氧基嘧啶)氨磺酰苯基;
R4选自H,CONHR10,R10为H,4-COOH-苯基,4-CO2C2H5-苯基,3-CF3-苯基;R5选自H,CH3;
R6选自H,C2H5,n-C6H13,NO2,NH2,Cl,Br,CONHR13,其中R13为4-苯甲酸和4-苯甲酸乙酯;
R7选自H,OH,CH3,OCH3,OCH2CONHR14,,其中R14为苯基,o-,m-,p-羟基苯基,o-,m-,p-羧基苯基,4’-乙氧羰基苯基,3’-乙氧羰基苯基,3’-三氟甲基苯基,3’-三氟甲基苯基,4’-甲氧苯基,4’-水杨酸基,3’-水杨酸基;R8选自H,CH3,OCH3,NO2;
5、如权利要求2所述的化合物,其特征在于所述的化合物,选自以下化合物的群组之一,其中,
R3=p-COOH-苯胺羰基,R4=R5=R6=R8=H,R7=OCH3;
R3=m-COOH-苯胺羰基,R4=R5=R6=R8=H,R7=OCH3;
R3=o-COOH-苯胺羰基,R4=R5=R6=R8=H,R7=OCH3;
R3=o-OH-苯胺羰基,R4=R5=R6=R8=H,R7=OCH3;
R3=m-OH-苯胺羰基,R4=R5=R6=R8=H,R7=OCH3;
R3=p-OH-苯胺羰基, R4=R5=R6=R8=H,R7=OCH3;
R3=m-OH-p-COOH-苯胺羰基,R4=R5=R6=R8=H,,R7=OCH3;
R3=m-COOH-p-OH-苯胺羰基,R4=R5=R6=R8=H,,R7=OCH3;
R3=o-COOH-p-I-苯胺羰基,R4=R5=R6=R8=H,R7=OCH3;
R3=4-乙氧羰基苯胺羰基,R4=R5=R6=R8=H,R7=OCH3;
R3=m-CF3-苯胺羰基,R4=R5=R6=R8=H,,R7=OCH3;
R3=m-CF3-4-NO2-苯胺羰基,R4=R5=R6=R8=H,,R7=OCH3;
R3=4-氨磺酰基苯胺羰基,R4=R5=R6=R8=H,,R7=OCH3;
R3=4-胍磺酰基苯胺羰基,R4=R5=R6=R8=H,,R7=OCH3;
R3=4-(2’-噻唑)胺磺酰基苯胺羰基,R4=R5=R6=R8=H,,R7=OCH3;
R3=4-(2’-嘧啶)胺磺酰基苯胺羰基,R4=R5=R6=R8=H,,R7=OCH3;
R3=4-(4’,6’-二甲基嘧啶-2’)胺磺酰基苯胺羰基,R4=R5=R6=R8=H,R7=OCH3;
R3=4-(5’,6’-二甲氧基嘧啶-4’)胺磺酰基苯胺羰基,R4=R5=R6=R8=H,R7=OCH3;
R3=4-(5’-CH3-异噁唑-3’)胺磺酰基苯胺羰基,R4=R5=R6=H,R7=OCH3;
R3=p-OCH3-苯胺羰基,R4=R5=R6=R8=H,R7=OCH3;
R3=p-磺酸基苯胺羰基,R4=R5=R6=R8=H,R7=OCH3;
R3=p-COOH-苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=m-COOH-苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=o-COOH-苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=p-OH-苯胺羰基, R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=m-OH-p-CO2H苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=m-CO2H-p-OH-苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=4-乙氧羰基苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=m-CF3-苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=m-CF3-4-NO2-苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=4-胺磺酰基苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=4-胍磺酰基苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=4-(2’-噻唑)胺磺酰基苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=4-(2-嘧啶)胺磺酰基苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=4-(4’,6’-二甲基嘧啶-2’)胺磺酰基苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=4-(5’,6’-二甲氧基嘧啶-4’)胺磺酰基苯胺羰基,R4=R5=R8=H,R6=C2H5,
R7=OCH3;
R3=(5’-CH3-异噁唑-3’)-4-胺磺酰基苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=p-OCH3-苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=p-磺酸基苯胺羰基,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R3=p-COOH-苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=CH3;
R3=m-COOH-苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=CH3;
R3=o-COOH-苯胺羰基,R4=R5=R6=H,R7=OCH3.R8=CH3;
R3=m-OH-p-COOH-苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=CH3;
R3=m-COOH-p-OH-苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=CH3;
R3=o-COOH-p-I-苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=CH3;
R3=p-乙氧羰基苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=CH3;
R3=m-CF3-苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=CH3;
R3=m-CF3-4-NO2-苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=CH3;
R3=4-胺磺酰基苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=CH3;
R3=4-胍磺酰基苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=CH3;
R3=4-(2’-噻唑)胺磺酰基苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=CH3;
R3=4-(2’-嘧啶)胺磺酰基苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=CH3;
R3=4-(4’,6’-二甲基嘧啶-2’)胺磺酰基苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=CH3;
R3=4-(5’,6’-二甲氧基嘧啶-4’)胺磺酰基苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=
CH3;
R3=(5’-CH3-异噁唑-3’)-4-氨磺酰基苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=CH3;
R3=p-OCH3-苯胺羰基,R4=R5=R6=H,R7=OCH3,R8=CH3;
R3=p-磺酸基苯胺羰基,R4=R5=R6=H,R7=OCH3 R8=CH3;
R3=p-COOH-苯胺羰基,R4=R5=R6=H,R7=R8=OCH3;
R3=m-OH-p-COOH-苯胺羰基,R4=R5=R6=H,R7=R8=OCH3;
R3=m-COOH-p-OH-苯胺羰基,R4=R5=R6=H,R7=R8=OCH3;
R3=p-乙氧羰基苯胺羰基,R4=R5=R6=H,R7=R8=OCH3;
R3=m-CF3-苯胺羰基,R4=R5=R6=H,R7=R8=OCH3;
R3=m-CF3-p-NO2-苯胺羰基,R4=R5=R6=H,R7=R8=OCH3;
R3=m-羧基亚甲氧基苯胺羰基,R4=R5=R6=H,R7=R8=OCH3;
R3=4-胺磺酰基苯胺羰基,R4=R5=R6=H,R7=R8=OCH3;
R3=4-胍磺酰基苯胺羰基,R4=R5=R6=H,R7=R8=OCH3;
R3=p-COOH-苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3;
R3=m-COOH-苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3;
R3=o-COOH-苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3;
R3=o-OH-苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3;
R3=m-OH-苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3;
R3=p-OH-苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3;
R3=m-OH-p-COOH-苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3;
R3=m-COOH-p-OH-苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3;
R3=p-乙氧羰基苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3;
R3=m-CF3-苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3;
R3=m-CF3-p-NO2-苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3;
R3=4-胺磺酰基苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3;
R3=4-胍磺酰基苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3;
R3=4-(2’-噻唑)胺磺酰基苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3;
R3=4-(2’-嘧啶)胺磺酰基苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3;
R3=4-(4’,6’-二甲基嘧啶-2’)胺磺酰基苯胺羰基,R4=R5=R8=H,R5=CH3,R7=OCH3;
R3=4-(5’,6’-二甲氧基嘧啶-4’)胺磺酰基苯胺羰基,R4=R6=R8=H,
R5=CH3,R7=OCH3;
R3=4-(5’-CH3-异噁唑-3’)氨磺酰基苯胺羰基,R4=R6=R8=H,
R5=CH3,R7=OCH3;
R3=p-OCH3-苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3,;
R3=p-COOH-苯胺羰基,R4=R5=R8=H,R6=Cl,R7=OCH3;
R3=m-OH-p-COOH-苯胺羰基,R4=R5=R8=H,R6=Cl,R7=OCH3;
R3=m-COOH-p-OH-苯胺羰基,R4=R5=R8=H,R6=Cl,R7=OCH3;
R3=p-乙氧羰基苯胺羰基,R4=R5=R8=H,R6=Cl,R7=OCH3;
R3=m-CF3-苯胺羰基,R4=R5=R8=H,R6=Cl,R7=OCH3;
R3=4-胺磺酰基苯胺羰基,R4=R5=R8=H,R6=Cl,R7=OCH3;
R3=4-胍磺酰基苯胺羰基,R4=R5=R8=H,R6=Cl,R7=OCH3;
R3=4-(5’,6’-二甲氧基嘧啶-4’)胺磺酰基苯胺羰基,R4=R5=R8=H,
R6=Cl,R7=OCH3;
R3=p-COOH-苯胺羰基,R4=R5=R8=H,R6=Br,R7=OCH3;
R3=o-COOH-苯胺羰基,R4=R5=R8=H,R6=Br,R7=OCH3;
R3=m-OH-p-COOH-苯胺羰基,R4=R5=R8=H,R=Br,R7=OCH3;
R3=o-COOH-p-I苯胺羰基,R4=R5=R8=H,R6=Br,R7=OCH3;
R3=p-乙氧羰基苯胺羰基,R4=R5=R8=H,R6=Br,R7=OCH3;
R3=m-CF3-苯胺羰基,R4=R5=R8=H,R6=Br,R7=OCH3;
R3=4-胺磺酰基苯胺羰基,R4=R5=R8=H,R6=Br,R7=OCH3;
R3=p-OCH3-苯胺羰基,R4=R6=R8=H,R5=CH3,R7=OCH3,;
R3=p-COOH-苯胺羰基,R4=R5=R8=H,R6=n-Hex,R7=OCH3;
R3=o-COOH-苯氨羰基,R4=R5=R8=H,R6=n-Hex,R7=OCH3;
R3=m-OH-p-COOH-苯胺羰基,R4=R5=R8=H,R=Hex,R7=OCH3;
R3=o-COOH-p-I-苯胺羰基,R4=R5=R8=H,R6=n-Hex,R7=OCH3;
R3=p-乙氧羰基苯胺羰基,R4=R5=R8=H,R6=Hex,R7=OCH3;
R3=m-CF3-苯胺羰基,R4=R5=R8=H,R6=Hex,R7=OCH3;
R3=4-胺磺酰基苯胺羰基,R4=R5=R8=H,R6=Hex,R7=OCH3;
R3=p-OCH3-苯胺羰基,R4=R5=R8=H,R6=Hex,R7=OCH3;
R3=p-COOH-苯胺羰基,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=m-COOH-苯胺羰基,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=p-OCH3-苯胺羰基,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=m-OH-苯胺羰基,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=o-OH-苯胺羰基,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=p-乙氧羰基苯胺羰基,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=m-OH-p-COOH-苯胺羰基,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=m-COOH-p-OH苯胺羰基,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=m-CF3-苯胺羰基,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=m-CF3-p-NO2-苯胺羰基,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=4-胺磺酰基苯胺羰基,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=4-胍基磺酰基苯胺羰基,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=4-(2’-嘧啶)胺磺酰基苯胺羰基,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=4-(5’,6’-二甲氧基嘧啶-4’)胺磺酰基苯胺羰基,R4=R5=H,
R6=NO2,R7=R8=OCH3;
R3=4-(2’-噻唑)胺磺酰基苯胺羰基,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=p-COOH-苯胺羰基,R4=R5=H,R6=C2H5,R7=OH,R8=NO2;
R3=p-OCH3-苯胺羰基,R4=R5=H,R6=C2H5,R7=OH,R8=NO2;
R3=m-OH-苯胺羰基,R4=R5=H,R6=C2H5,R7=OH,R8=NO2;
R3=o-OH-苯胺羰基,R4=R5=H,R6=C2H5,R7=OH,R8=NO2;
R3=p-乙氧羰基苯胺羰基,R4=R5=H,R6=C2H5,R7=OH,R8=NO2;
R3=m-OH-p-COOH-苯胺羰基,R4=R5=H,R6=C2H5,R7=OH,R8=NO2;
R3=m-COOH-p-OH-苯胺羰基,R4=R5=H,R6=C2H5,R7=OH,R8=NO2;
R3=m-CF3-苯胺羰基,R4=R5=H,R6=C2H5,R7=OH,R8=NO2;
R3=4-胺磺酰基-苯胺羰基,R4=R5=H,R6=C2H5,R7=OH,R8=NO2;
R3=4-胍磺酰基-苯胺羰基,R4=R5=H,R6=C2H5,R7=OH,R8=NO2;
R3=4-(2’-噻唑)胺磺酰基-苯胺羰基,R4=R5=H,R6=C2H5,R7=OH,R8=NO2;
R3=p-COOH-苯胺羰基,R4=R5=H,R6=C2H5,R7=OCH3,R8=NO2;
R3=p-OH-苯胺羰基,R4=R5=H,R6=C2H5,R7=OCH3,R8=NO2;
R3=p-OCH3-苯胺羰基,R4=R5=H,R6=C2H5,R7=OCH3,R8=NO2;
R3=p-乙氧羰基苯胺羰基,R4=R5=H,R6=C2H5,R7=OH,R8=NO2;
R3=4-胍磺酰基-苯胺羰基,R4=R5=H,R6=C2H5,R7=OCH3,R8=NO2;
R3=p-COOH-苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3;
R3=o-COOH-苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3;
R3=p-OH-苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3;
R3=m-OH-苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3;
R3=o-OH-苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3;
R3=p-OCH3-苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3;
R3=p-乙氧羰基苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3;
R3=m-OH-p-COOH-苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3;
R3=m-COOH-p-OH-苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3
R3=m-CF3-苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3
R3=m-CF3-p-NO2-苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3
R3=4-胺磺酰基-苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3;
R3=4-胍基磺酰基-苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3;
R3=4-(2’-嘧啶)胺磺酰基-苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3;
R3=4-(5’,6’-二甲氧基嘧啶-4’)胺磺酰基苯胺羰基,R4=R5=H,R6=NO2,R7=OH,
R8=CH3;
R3=4-(2’-噻唑)胺磺酰基-苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3;
R3=o-OH-p-I-苯胺羰基,R4=R5=H,R6=NO2,R7=OH,R8=CH3;
R3=p-COOH-苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,R8=CH3;
R3=m-COOH-苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,R8=CH3;
R3=o-COOH-苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,R8=CH3;
R3=p-OH-苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,R8=CH3;
R3=m-OH-苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,R8=CH3;
R3=o-OH-苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,R8=CH3;
R3=p-OCH3-苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,R8=CH3;
R3=p-乙氧羰基苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,R8=CH3;
R3=m-OH,p-COOH-苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,R8=CH3;
R3=m-CF3-苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,R8=CH3;
R3=m-CF3-p-I-苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,R8=CH3;
R3=4-胍基磺酰基-苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,R8=CH3;
R3=4-胺磺酰基-苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,R8=CH3;
R3=4-(5’,6’-二甲氧基嘧啶-4’)胺磺酰基苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,
R8=CH3;
R3=4-(2’-噻唑)胺磺酰基-苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,R8=CH3;
R3=4-(2’-嘧啶)胺磺酰基-苯胺羰基,R4=R5=H,R6=NO2,R7=OCH3,
R8=CH3;
R3=p-COOH-苯胺羰基,R4=R5=H,R6=R8=NO2,R7=OH;
R3=p-OH-苯胺羰基,R4=R5=H,R6=R8=NO2,R7=OH;
R3=m-OH-苯羰基,R4=R5=H,R6=R8=NO2,R7=OH;
R3=o-OH-苯胺羰基,R4=R5=H,R6=R8=NO2,R7=OH;
R3=p-OCH3-苯胺羰基,R4=R5=H,R6=R8=NO2,R7=OH;
R3=乙氧羰基苯胺羰基,R4=R5=H,R6=R8=NO2,R7=OH;
R3=CF3-苯胺羰基,R4=R5=H,R6=R8=NO2,R7=OH;
R3=4-胺磺酰基苯胺羰基,R4=R5=H,R6=R8=NO2,R7=OH;
R3=4-胍磺酰基苯胺羰基,R4=R5=H,R6=R8=NO2,R7=OH;
R3=4-(2’-嘧啶)胺磺酰基苯胺羰基,R4=R5=H,R6=R8=NO2,R7=OH;
R3=4-(5’,6’-二甲氧基嘧啶-4’)胺磺酰基苯胺羰基,R4=R5=H,R6=R8=NO2,R7=OH;
R3=4-(2’-噻唑)胺磺酰基苯胺羰基,R4=R5=H,R6=R8=NO2,R7=OH;
R3=o-COOH-苯胺羰基,R4=R5=H,R6=R8=NO2,R7=OH;
R3=p-OH-苯胺羰基,R4=R5=H,R6=R8=NO2,R7=OCH3;
R3=乙氧羰基苯胺羰基,R4=R5=H,R6=R8=NO2,R7=OCH3;
R3=p-OCH3-苯胺羰基,R4=R5=H,R6=R8=NO2,R7=OCH3;
R3=p-OCH3-苯胺羰基,R4=R5=H,R6=Cl,R7=OH,R8=NO2;
R3=4-胍磺酰基苯胺羰基,R4=R5=H,R6=Cl,R7=OH,R8=NO2;
R3=m-OH-pCOOH-苯胺羰基,R4=H,R5=CH3,R7=OH,R6=R8=NO2;
R3=p-COOH-苯胺羰基,R4=H,R5=CH3,R7=OH,R6=R8=NO2;
R3=m-COOH-苯胺羰基,R4=H,R5=CH3,R7=OH,R6=R8=NO2;
R3=o-COOH-苯胺羰基,R4=H,R5=CH3,R7=OH,R6=R8=NO2;
R3=p-OCH3-苯胺羰基,R4=H,R5=CH3,R7=OH,R6=R8=NO2;
R3=p-乙氧羰基苯胺羰基,R4=H,R5=CH3,R7=OH,R6=R8=NO2;
R3=p-胺磺酰基苯胺羰基,R4=H,R5=CH3,R7=OH,R6=R8=NO2;
R3=p-胍磺酰基苯胺羰基,R4=H,R5=CH3,R7=OH,R6=R8=NO2;
R3=4-(2’-嘧啶)胺磺酰基苯胺羰基,R4=H,R5=CH3,R7=OH,R6=R8=NO2;
R3=4-(2’-噻唑)胺磺酰基苯胺羰基,R4=H,R5=CH3,R7=OH,R6=R8=NO2;
R3=4-(4’,6’-二甲基嘧啶-2’)磺酰基苯胺羰基,R4=H,R5=CH3,R7=OH.
R3=CONH(CH)3COOH,R4=R5=R6=R8=H,R7=OCH3;
R4=R5=R6=R8=H,R7=OCH3;
R3=CONH(CH)3COOH,R4=R5=R8=H,R6=C2H5,R7=OCH3;
R4=R5=R8=H,R6=C2H5,R7=OCH3;
R4=R5=R6=H,R7=OCH3,R8=CH3;
R4=R5=R6=H,R7=OCH3,R8=CH3;
R4=R5=R8=H,,R6=Br,R7=OCH3;
R4=R5=R8=H,,R6=Hex,R7=OCH3;
R4=R5=R8=H,,R6=Hex,R7=OCH3;
R3=CO2C2H5,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=CO2H,R4=R5=H,R6=NO2,R7=R8=OCH3;
R3=CO2C2H5,R4=R5=H,R6=NO2,R7=OH,R8=CH3;
R3=CO2H,R4=R5=H,R6=NO2,R7=OH,R8=CH3;
R3=CO2C2H5,R4=R5=H,R6=NH2,R7=OH,R8=CH3;
R3=CO2H,R4=R5=H,R6=NO2,R7=OCH3,R8=CH3;
R3=CO2C2H5,R4=R5=H,R6=C2H5,R7=OH,R8=NO2;
R3=CO2H,R4=R5=H,R6=C2H5,R7=OH,R8=NO2;
R3=CO2C2H5,R4=R5=H,R6=C2H5,R7=OCH3,R8=NO2;
R3=CO2H,R4=R5=H,R6=C2H5,R7=OCH3,R8=NO2;
R3=CO2C2H5,R4=R5=H,R6=R8=NO2,R7=OH;
R3=CO2H,R4=R5=H,R6=R8=NO2,R7=OCH3;
R3=CO2C2H5,R4=R5=H,R6=R8=NO2,R7=OCH3;
R3=CO2H,R4=R5=H,R6=R8=NO2,R7=OCH3;
R3=CO2C2H5,R4=R5=H,R6=Cl,R7=OH,R8=NO2;
R3=CO2H,R4=R5=H,R6=Cl,R7=OH,R8=NO2;
R3=CO2H,R4=H,R5=CH3,R6=R8=NO2,R7=OH;
R3=CO2C2H5,R4=H,R5=CH3,R6=R8=NO2,R7=OH;
R3=R5=R6=R8=H,R7=CH3;
R3=R5=R6=R8=H,R7=CH3;
R3=R5=R6=R8=H,R4=CH3,
R3=R5=R6=R8=H,R4=CH3,
R3=R5=R6=R8=H,R4=CH3,
R3=R5=R6=R8=H,R4=CH3,
R3=R5=R6=R8=H,R4=CH3,
R3=R5=R6=R8=H,R4=CH3,
R3=R5=R6=R8=H,R4=CH3,
R3=R5=R6=R8=H,R4=CH3,
R3=R5=R6=H,R4=R8=CH3,
R3=R5=R6=H,R4=R8=CH3,
6、根据权利要求1所述的化合物,其特征在于,该化合物还包括其药用盐、盐的水合物、酯或前体药物。
7、制备如权利要求1所述的化合物的方法,其特征在于,用取代的3-羧基香豆素、取代的4-羧基的香豆素,取代的6-羧基香豆素或者取代的7-羧基香豆素与相应的取代胺类或肼类化合物缩合。
8、制备如权利要求1所述的化合物的方法,其特征在于,用取代的3-羧基香豆素、取代的4-羧基的香豆素,取代的6-羧基香豆素或者取代的7-羧基香豆素与相应的取代肼类化合物缩合后,形成的酰肼经一步环和形成杂环衍生物。
9、根据权利要求7和8中任一制备方法,其特征在于,所述的酰氨化反应所用的反应试剂包括三氯化磷、三氯氧磷、五氯化磷、二氯亚砜、1,3-二环己基亚胺(DCC)、二吡啶碳酸酯(2-DPC)、1,3-二异丙基碳酰亚胺(DIPC)、1-(3-二甲胺丙基)-3-乙基碳酰亚胺(EDCI);所用的催化剂包括三级胺、吡啶、4-二甲氨基吡啶和4-吡咯烷基吡啶;所用的有机溶剂包括二甲基亚砜(DMSO)、甲苯、二氯甲烷、乙二醇二甲醚,1,2-二氯乙烷、四氢呋喃和N,N-二甲基甲酰胺(DMF)。
10、一种药物组合物,其特征在于,含有药物有效剂量的如权利要求1-6所述的任一化合物,及药用载体。
11、根据权利要求9的药物组合物,其特征在于,所述的药物组合物可以是片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂及各种微粒给药系统。
12、如权利要求1-6任一化合物作为制备转化生长因子-β1(TGF-β1)抑制剂中的应用。
13、如权利要求1-6任一化合物作为制备转化血管紧张素II(AII)抑制剂中的应用。
14、如权利要求1-6任一化合物在制备治疗肾脏疾患的药物中的应用。
15、如权利要求1-6任一化合物在制备治疗心脑血管疾患的药物中的应用。
16、如权利要求1-6任一化合物在制备治疗II型糖尿病的药物中的应用。
17、根据权利要求14的应用,其特征在于,所述的心脑血管疾患是高血压、心栓、心肌梗塞、脑中风。
Priority Applications (15)
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CNA021555257A CN1506359A (zh) | 2002-12-05 | 2002-12-05 | 新的香豆素酰胺衍生物及其制法和其药物组合物与用途 |
BR0316595-7A BR0316595A (pt) | 2002-12-05 | 2003-12-05 | Composto, método para a preparação de compostos, composição farmacêutica e usos do composto |
AU2003289641A AU2003289641A1 (en) | 2002-12-05 | 2003-12-05 | The novel coumarin-amide derivatives and its preparation, said drug composition and its use |
BRPI0316595A BRPI0316595B1 (pt) | 2002-12-05 | 2003-12-05 | composto, método para a preparação de compostos, composição farmacêutica e usos de um composto |
EP10190730.1A EP2295053B8 (en) | 2002-12-05 | 2003-12-05 | Novel 2H-chromen-2-one-3-carboxamides for medical uses |
US10/537,711 US8338401B2 (en) | 2002-12-05 | 2003-12-05 | Coumarin-amide derivatives and its preparation, said drug composition and its use |
CA2508573A CA2508573C (en) | 2002-12-05 | 2003-12-05 | Novel coumarins, their carboxamide derivatives, preparation methods, compositions, and uses |
KR1020107013277A KR20100087748A (ko) | 2002-12-05 | 2003-12-05 | 신규한 쿠마린 아미드 유도체와 그 제조방법, 약제학적 조성물과 용도 |
KR1020057010241A KR101000395B1 (ko) | 2002-12-05 | 2003-12-05 | 신규한 쿠마린 아미드 유도체와 그 제조방법, 약제학적조성물과 용도 |
PCT/CN2003/001046 WO2004050082A1 (fr) | 2002-12-05 | 2003-12-05 | Nouveaux derives coumarine-amide et leur preparation, composition medicamenteuse associee et son utilisation |
CNB200380109516XA CN100488504C (zh) | 2002-12-05 | 2003-12-05 | 新的香豆素酰胺衍生物及其制法和其药物组合物与用途 |
JP2004555972A JP4722487B2 (ja) | 2002-12-05 | 2003-12-05 | 新規なクマリン、それらのカルボキサミド誘導体、調製法、組成物、および使用 |
EP03776786A EP1570846A4 (en) | 2002-12-05 | 2003-12-05 | NOVEL CUMARINAMIDE DERIVATIVES AND THEIR PREPARATION, THE MEDICAMENTAL COMPOSITION AND THEIR USE |
RU2005121137/04A RU2361870C2 (ru) | 2002-12-05 | 2003-12-05 | Новые кумарины, их карбоксамидные производные, способы получения, композиции и применение |
IL168959A IL168959A (en) | 2002-12-05 | 2005-06-02 | History of Qumrin-Amid and their preparation, pharmaceutical preparations containing these histories and their uses |
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JP4722487B2 (ja) | 2011-07-13 |
JP2006512328A (ja) | 2006-04-13 |
US20060148834A1 (en) | 2006-07-06 |
IL168959A (en) | 2013-08-29 |
BR0316595A (pt) | 2005-10-04 |
CN100488504C (zh) | 2009-05-20 |
US8338401B2 (en) | 2012-12-25 |
EP2295053B8 (en) | 2018-03-28 |
CN1829506A (zh) | 2006-09-06 |
KR20100087748A (ko) | 2010-08-05 |
WO2004050082A1 (fr) | 2004-06-17 |
EP2295053A1 (en) | 2011-03-16 |
RU2361870C2 (ru) | 2009-07-20 |
RU2005121137A (ru) | 2006-01-20 |
EP1570846A4 (en) | 2008-02-20 |
BRPI0316595B1 (pt) | 2018-12-26 |
EP2295053B1 (en) | 2016-10-19 |
CA2508573C (en) | 2012-09-11 |
KR101000395B1 (ko) | 2010-12-13 |
AU2003289641A1 (en) | 2004-06-23 |
EP1570846A1 (en) | 2005-09-07 |
KR20050084184A (ko) | 2005-08-26 |
CA2508573A1 (en) | 2004-06-17 |
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