CN117946025A - 1-氧-2,8-二氮杂环葵酮衍生物及其合成方法和应用 - Google Patents
1-氧-2,8-二氮杂环葵酮衍生物及其合成方法和应用 Download PDFInfo
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- CN117946025A CN117946025A CN202410099899.0A CN202410099899A CN117946025A CN 117946025 A CN117946025 A CN 117946025A CN 202410099899 A CN202410099899 A CN 202410099899A CN 117946025 A CN117946025 A CN 117946025A
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Abstract
本发明公开了一系列1‑氧‑2,8‑二氮杂环葵酮衍生物及其合成方法和应用,属于医药技术领域。申请人的试验结果表明,本发明所述衍生物对脂多糖诱导的小鼠巨噬细胞RAW 264.7释放NO具有良好的抑制作用,显示出较好的抗炎活性,可用于制备治疗炎症的药物。
Description
技术领域
本发明涉及1-氧-2,8-二氮杂环葵酮衍生物及其合成方法和应用,属于医药技术领域。
背景技术
中型(8~12)氮杂环是一类极其重要的化合物,它存在于一系列天然和非天然产物中,这些化合物在药物发现中也展现了巨大的潜力,其中含氮杂十元环的骨架存在于许多不同的天然产物和具有生物学意义的化合物分子中,例如muramine、protopine和dysazecine是发现于紫堇属植物中的一类生物碱,其具有苯并喹嗪结构骨架。目前,已有大量文献研究报道此类化合物的药理活性,如可用于抑制神经元兴奋性(Phytochemistry2018,150,85-92),同时对胃酸分泌物有一定的抑制作用,具有抗菌、抗病毒、抗炎等活性(Chin.J.Vet.Sci.2008,12,1098–1101&Journal of Animal Science and VeterinaryMedicine,2013,32,3-5.)。Picraphylline是萝芙木植物中的一类生物碱,具有很好的药理活性,例如可用来抗疟疾,抗炎,抗细胞毒性,抗氧化剂,抗溃疡等药理学作用(AsianPac.J.Trop.Med.2014,7,1-8)。然而,由于中环化合物存在不利的环间相互作用和熵效应等原因,有效构建此类骨架仍然是一个巨大的挑战。因此,发展新的策略来构建含氮杂十元环化合物具有非常重要的意义。
发明内容
本发明要解决的技术问题是提供一系列结构新颖且具有较好抗炎活性的1-氧-2,8-二氮杂环葵酮衍生物及其合成方法和应用。
为解决上述技术问题,本发明采用以下技术方案:
本发明所述的1-氧-2,8-二氮杂环葵酮衍生物为具有下述式(I)所示结构的化合物或其药学上可接受的盐:
其中:
R1表示未取代或单取代的苯基,或者是未取代的噻吩基;其中,取代基为C1~6的烷基、烷氧基或卤原子;
R2表示氢原子,或者是未取代或单取代的苯基,或者是未取代或单取代的苯乙烯基;其中,取代基为C1~6的烷基、烷氧基或卤原子;
R3表示氢原子、甲基、乙基、正丁基或卤原子,或者是取代的C1~6的烷基;
R4表示氢原子或苯基,或者是未取代或单取代的C1~4的烷基,或者是未取代或单取代的C1~4的烷氧基;
R5表示氢原子;
R6表示甲基、乙基或苯基;
R7表示氢原子或甲基;
R8表示甲基、烯丙基或苯基炔丙基,或者是未取代或单取代的苄基。
进一步的,本发明所述的1-氧-2,8-二氮杂环葵酮衍生物具体可以是以下化合物3aa~3al中的任意一个:
3aa:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ba:R1=4-OMe-Ph,R2=CH2-CH2-4-OMe-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ca:R1=4-Me-Ph,R2=CH2-CH2-4-Me-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3da:R1=4-Cl-Ph,R2=CH2-CH2-4-Cl-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ea:R1=4-CF3-Ph,R2=CH2-CH2-4-CF3-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3fa:R1=3-Br-Ph,R2=CH2-CH2-3-Br-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ga:R1=2-Br-Ph,R2=CH2-CH2-2-Br-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ha:R1=Ph,R2=Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ia:R1=Ph,R2=4-OMe-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ja:R1=Ph,R2=4-F-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ka:R1=Ph,R2=2-Br-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3la:R1=4-Br-Ph,R2=Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ma:R1=4-CF3-Ph,R2=Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3na:R1=2-thienyl,R2=Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3oa:R1=Ph,R2=H,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3pa:R1=Ph,R2=CH2-CH2-Ph,R3=H,R4=n-Bu,R5=H,R6=Me,R7=Me,R8=Bn;
3qa:R1=Ph,R2=CH2-CH2-Ph,R3=Ph,R4=Et,R5=H,R6=Me,R7=Me,R8=Bn;
3ra:R1=Ph,R2=CH2-CH2-Ph,R3=Ph,R4=H,R5=H,R6=Me,R7=Me,R8=Bn;
3sa:R1=Ph,R2=CH2-CH2-Ph,R3=H,R4=(CH2)4Cl,R5=H,R6=Me,R7=Me,R8=Bn;
3ta:R1=Ph,R2=CH2-CH2-Ph,R3=H,R4=(CH2)3CO2Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ua:R1=Ph,R2=CH2-CH2-Ph,R3+R4=Cyclopentane,R5=H,R6=Me,R7=Me,R8=Bn;
3va:R1=Ph,R2=CH2-CH2-Ph,R3+R4=Cyclohexane,R5=H,R6=Me,R7=Me,R8=Bn;
3wa:R1=Ph,R2=CH2-CH2-Ph,R3+R4=Cycloheptane,R5=H,R6=Me,R7=Me,R8=Bn;
3xa:R1=Ph,R2=CH2-CH2-Ph,R3+R4=pyran,R5=H,R6=Me,R7=Me,R8=Bn;
3ya:R1=Ph,R2=CH2-CH2-Ph,R3+R4=spirocyclic,R5=H,R6=Me,R7=Me,R8=Bn;
3ab:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=CH2-4-OMe-Ph;
3ac:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=CH2-4-Br-Ph;
3ad:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=CH2-4-CF3-Ph;
3ae:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=CH2-3-Me-Ph;
3af:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=CH2-2-Me-Ph;
3ag:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Me;
3ah:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=allyl;
3ai:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Phenylpropargyl;
3aj:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=H,R8=Bn;
3ak:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Et,R7=H,R8=Bn;
3al:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Ph,R7=H,R8=Bn。
本发明所述1-氧-2,8-二氮杂环葵酮衍生物的合成方法,主要包括以下步骤:取如下式(II)所示化合物和式(III)所示化合物置于有机溶剂中,加入碱性物质和催化剂,于加热或不加热条件下进行反应,制得目标化合物粗品;
其中:
R1表示未取代或单取代的苯基,或者是未取代的噻吩基;其中,取代基为C1~6的烷基、烷氧基或卤原子;
R2表示氢原子,或者是未取代或单取代的苯基,或者是未取代或单取代的苯乙烯基;其中,取代基为C1~6的烷基、烷氧基或卤原子;
R3表示氢原子、甲基、乙基、正丁基或卤原子,或者是取代的C1~6的烷基;
R4表示氢原子或苯基,或者是未取代或单取代的C1~4的烷基,或者是未取代或单取代的C1~4的烷氧基;
R5表示氢原子;
R6表示甲基、乙基或苯基;
R7表示氢原子或甲基;
R8表示甲基、烯丙基或苯基炔丙基,或者是未取代或单取代的苄基;
X表示溴原子或氯原子。
为了进一步提高目标化合物的产率,优选反应在惰性气氛(如氮气、氩气或氦气等)保护下进行。
上述合成方法中,反应优选是在低于100℃的条件下进行,进一步优选是在常温至80℃的条件下进行。反应通过TLC跟踪检测直至反应完全。根据申请人的经验,当反应在常温或室温下进行时,反应时间控制在10~20h较为适宜。
上述合成方法中,所述的有机溶剂具体可以是选自苯、甲苯、环己烷、石油醚、四氯化碳、四氢呋喃、乙酸乙酯、乙腈、***、二氯甲烷、丙酮、三氯甲烷、正己烷和二氧六环中一种或两种以上的组合;优选采用乙腈、甲苯或四氢呋喃。所述有机溶剂的用量可以根据需要进行确定,通常以能够充分溶解所要参加反应的原料为宜,具体地,以0.1mmol的式(II)所示化合物为基准计算,全部原料所用有机溶剂的总用量通常为1~5mL。
上述合成方法中,所述的碱性物质可以是现有技术的常规选择,优选为选自磷酸三钾、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化铯、碳酸铯,碳酸钾、叔丁醇钾、叔丁醇钠、氟化钾、吡啶、三乙胺和N,N-二异丙基乙基胺中的一种或两种以上的组合;进一步优选为碳酸钾或碳酸铯。所述催化剂的用量优选为式(II)所示化合物物质的量的0.1~2.0倍。
上述合成方法中,所述的催化剂可以是选自铜盐、镱盐和钪盐中的一种或两种以上的组合。其中,铜盐优选为选自溴化铜、碘化铜、氯化铜、硫酸铜、醋酸酮、三氟甲磺酸铜、溴化亚铜、碘化亚铜和氯化亚铜中的一种或两种以上的组合;镱盐优选为三氟甲磺酸镱;钪盐优选为三氟甲磺酸钪。所述催化剂的用量优选为式(II)所示化合物物质的量的0.1~0.2倍。
本发明所述合成方法中,涉及的原料式(II)所示化合物为N-烯基α,β-不饱和硝酮衍生物,其可参考现有文献(D.Kontokosta,D.S.Muller,D.L.Mo,W.H.Pace,R.A.Simpon,L.L.Anderson,Beilstein J.Org,Chem.2015,11,2097)进行合成,也可自选设计合成路线进行合成,在此不再详述。涉及的原料式(III)所示化合物为ɑ-卤代酰胺试剂,其可以直接从市场上购买得到(如2-溴-2-甲基-N-苄基丙酰胺、2-溴-2-甲基-N-苄基乙酰胺、2-溴-2-甲基-N-甲氧基丙酰胺等),也可以参考现有文献(Chin.J.Org.Chem.2019,39,1970-1975)进行合成。
本发明所述的合成方法中,各原料的用量配比为化学计量比。
由上述方法制得的是式(I)化合物的粗品,还包括对制得的目标化合物粗品进行纯化的步骤。具体的,可采用现有常规的纯化方法对其进行纯化以提高式(I)化合物的纯度,如采用硅胶薄层色谱或硅胶柱层析,或者是重结晶的方式对精品进行纯化。在层析时用的洗脱剂和重结晶时用的溶剂相同,可以是由石油醚和乙酸乙酯按20:1~10:1的体积比组成的混合溶剂,也可以是由正己烷和乙酸乙酯按20:1~10:1的体积比组成的混合溶剂。
申请人通过实验发现,本发明所述1-氧-2,8-二氮杂环葵酮衍生物具有良好的抗炎活性,基于此,本发明还提供上述1-氧-2,8-二氮杂环葵酮衍生物或其药学上可接受的盐在制备治疗炎症的药物中的应用,进一步是在制备治疗由脂多糖引起的炎症的药物中的应用。
进一步的,本发明还包括一种药物组合物,其包括作为活性成分的治疗上有效剂量的上述1-氧-2,8-二氮杂环葵酮衍生物或其药学上可接受的盐,以及至少一种药学上可接受的载体。
与现有技术相比,本发明提供了一系列结构新颖的1-氧-2,8-二氮杂环葵酮衍生物及其合成方法。申请人的试验结果表明,本发明部分目标化合物对脂多糖诱导的小鼠巨噬细胞RAW 264.7内NO的释放具有良好的抑制作用,可用于制备治疗炎症的药物。
具体实施方式
为了更好的解释本发明的技术方案,下面结合实施例对本发明作进一步详细的描述,但本发明的实施方式不限于此。
以下各实施例中涉及的N-烯基α,β-不饱和硝酮衍生物(即式(II)所示化合物)参照下述合成路线进行合成:
其中,
R1表示未取代或单取代的苯基,或者是未取代的噻吩基;其中,取代基为C1~6的烷基、烷氧基或卤原子;
R2表示氢原子,或者是未取代或单取代的苯基,或者是未取代或单取代的苯乙烯基;其中,取代基为C1~6的烷基、烷氧基或卤原子;
R3表示氢原子、甲基、乙基、正丁基或卤原子,或者是取代的C1~6的烷基;
R4表示氢原子或苯基,或者是未取代或单取代的C1~4的烷基,或者是未取代或单取代的C1~4的烷氧基;
R5表示氢原子。
具体的合成方法为:将Cu(OAc)2(0.3mmol,54mg)、α,β-不饱和肟底物S1(0.3mmol)和烯基硼酸S2(0.9mmol)置于反应管中,加入3mL 1,2-二氯乙烷,然后加入吡啶(3mmol,0.24mL),在25℃下搅拌12~24h,在所得反应物中加水(10mL),用二氯甲烷萃取(2×10mL),合并有机相,用无水硫酸钠干燥后过滤,减压除去溶剂,残渣上硅胶柱层析分离(石油醚/乙酸乙酯=10:1~1:1,体积比),得到产物1(即式(II)所示化合物N-烯基α,β-不饱和硝酮)。
以下各实施例中涉及的ɑ-卤代酰胺试剂(即式(III)所示化合物)按下述合成路线合成:
其中,R6表示甲基、乙基或苯基;R7表示氢原子或甲基;R8表示甲基、烯丙基或苯基炔丙基,或者是未取代或单取代的苄基;X表示溴原子。
具体的合成方法为:在100mL圆底烧瓶中加入苄氧基羟胺盐酸盐S4(2.0g,12.5mmol,1.0eq)、二氯甲烷(50mL)和三乙胺(1.75ml,12.5mmol,1.0eq),然后将反应混合物在冰水浴中冷却至0℃。接着,取ɑ-卤代酰溴化合物S3(12.5mmol,1.0eq)逐滴添加到该反应混合物中,继续在0℃下搅拌反应4h,然后将混合物移至室温下搅拌5min;之后用水淬灭反应。所得混合物用二氯甲烷萃取三次,然后用饱和氯化钠溶液萃取一次,过滤并在真空下浓缩。所得残渣上硅胶柱层析分离(石油醚/乙酸乙酯=4:1~1:1,体积比),得到产物2(即式(III)所示化合物ɑ-卤代酰胺试剂)。
实施例1
按下述合成路线合成本发明所述的1-氧-2,8-二氮杂环葵酮衍生物。
3aa:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ba:R1=4-OMe-Ph,R2=CH2-CH2-4-OMe-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ca:R1=4-Me-Ph,R2=CH2-CH2-4-Me-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3da:R1=4-Cl-Ph,R2=CH2-CH2-4-Cl-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ea:R1=4-CF3-Ph,R2=CH2-CH2-4-CF3-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3fa:R1=3-Br-Ph,R2=CH2-CH2-3-Br-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ga:R1=2-Br-Ph,R2=CH2-CH2-2-Br-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ha:R1=Ph,R2=Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ia:R1=Ph,R2=4-OMe-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ja:R1=Ph,R2=4-F-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ka:R1=Ph,R2=2-Br-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3la:R1=4-Br-Ph,R2=Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ma:R1=4-CF3-Ph,R2=Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3na:R1=2-thienyl,R2=Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3oa:R1=Ph,R2=H,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3pa:R1=Ph,R2=CH2-CH2-Ph,R3=H,R4=n-Bu,R5=H,R6=Me,R7=Me,R8=Bn;
3qa:R1=Ph,R2=CH2-CH2-Ph,R3=Ph,R4=Et,R5=H,R6=Me,R7=Me,R8=Bn;
3ra:R1=Ph,R2=CH2-CH2-Ph,R3=Ph,R4=H,R5=H,R6=Me,R7=Me,R8=Bn;
3sa:R1=Ph,R2=CH2-CH2-Ph,R3=H,R4=(CH2)4Cl,R5=H,R6=Me,R7=Me,R8=Bn;
3ta:R1=Ph,R2=CH2-CH2-Ph,R3=H,R4=(CH2)3CO2Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ua:R1=Ph,R2=CH2-CH2-Ph,R3+R4=Cyclopentane,R5=H,R6=Me,R7=Me,R8=Bn;
3va:R1=Ph,R2=CH2-CH2-Ph,R3+R4=Cyclohexane,R5=H,R6=Me,R7=Me,R8=Bn;
3wa:R1=Ph,R2=CH2-CH2-Ph,R3+R4=Cycloheptane,R5=H,R6=Me,R7=Me,R8=Bn;
3xa:R1=Ph,R2=CH2-CH2-Ph,R3+R4=pyran,R5=H,R6=Me,R7=Me,R8=Bn;
3ya:R1=Ph,R2=CH2-CH2-Ph,R3+R4=spirocyclic,R5=H,R6=Me,R7=Me,R8=Bn;
3ab:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=CH2-4-OMe-Ph;
3ac:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=CH2-4-Br-Ph;
3ad:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=CH2-4-CF3-Ph;
3ae:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=CH2-3-Me-Ph;
3af:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=CH2-2-Me-Ph;
3ag:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Me;
3ah:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=allyl;
3ai:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Phenylpropargyl;
3aj:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=H,R8=Bn;
3ak:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Et,R7=H,R8=Bn;
3al:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Ph,R7=H,R8=Bn。
具体的合成方法:在氩气氛围下,取N-烯基α,β-不饱和硝酮底物1(0.2mmol)、ɑ-卤代酰胺试剂2(0.4mmol,该原料结构式中X表示溴原子)、三氟甲磺酸铜(0.04mmol)和碳酸钾(0.4mmol)置于反应管中,加入乙腈(2mL),在室温下搅拌反应10~20h(TLC监测反应至完全),所得反应物减压除去溶剂,残渣上硅胶柱层析分离(石油醚/乙酸乙酯=20:1~10:1,体积比),得到目标产物3(即式(I)所示化合物1-氧-2,8-二氮杂环葵酮衍生物)。不同的目标产物及其表征如下:
3aa:固体,66mg,67%yield;Mp:131–132℃;1H NMR(400MHz,CDCl3):δ7.46-7.40(m,4H),7.35-7.24(m,8H),7.19-7.13(m,3H),6.72(d,J=16.4Hz,1H),6.65(d,J=16.0Hz,1H),5.78(d,J=10.8Hz,1H),4.78(s,2H),3.55-3.49(m,1H),3.42-3.36(m,1H),1.77(s,3H),1.76(s,3H),1.59(s,3H),0.78(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ173.2,159.8,140.0,136.9,135.1,134.7,133.8,131.9,129.4,129.0,128.6,128.2,128.0,127.8,127.7,127.2,126.6,120.3,84.8,74.7,48.7,39.4,28.7,24.6,17.3,14.5;IR(thinfilm)3441,2976,1660,1370,964,695cm-1;HRMS(ESI)m/z calcd for C32H35N2O3(M+H)+495.2642,found 495.2655.其结构式如下:
3ba:油状,40mg,36%yield.1H NMR(400MHz,CDCl3):δ7.40-7.38(m,2H),7.31-7.30(m,2H),7.21-7.18(m,5H),6.96-6.94(m,2H),6.89-6.87(m,2H),6.65(d,J=16.0Hz,1H),6.50(d,J=16.4Hz,1H),5.72(d,J=10.8Hz,1H),4.77(s,2H),3.85(s,3H),3.82(s,3H),3.49-3.41(m,1H),3.38-3.32(m,1H),1.76(s,3H),1.58(s,6H),0.78(d,J=7.2Hz,3H);13C NMR(150MHz,CDCl3):δ173.3,160.0,159.4,158.6,135.2,134.0,133.7,132.1,131.3,129.7,129.5,128.7,128.3,128.0,127.8,118.3,114.4,114.1,84.7,74.5,55.3,47.8,39.6,28.7,24.6,17.4,14.5;IR(thin film)3465,2935,1645,1250,923,639cm-1;HRMS(ESI)m/z calcd for C34H39N2O5(M+H)+555.2853,found 555.2839.其结构式如下:
3ca:固体,68mg,65%yield.Mp:71-72℃;1H NMR(400MHz,CDCl3):δ7.36(d,J=8.0Hz,2H),7.31(d,J=6.8Hz,2H),7.24-7.13(m,9H),6.68-6.56(m,2H),5.78(d,J=10.8Hz,1H),4.76(s,2H),3.51-3.46(m,1H),3.40-3.35(m,1H),2.39(s,3H),2.34(s,3H),1.76(s,3H),1.75(s,3H),1.58(s,3H),0.78(d,J=6.4Hz,3H);13C NMR(100MHz,CDCl3):δ173.3,160.0,137.8,137.1,136.8,135.2,134.4,134.2,133.7,131.8,129.7,129.4,129.3,128.2,128.0,127.7,126.5,119.4,84.7,74.5,48.3,39.5,28.7,24.6,21.2,21.2,17.3,14.5;IR(thin film)3273,2931,1650,1372,965,639cm-1;HRMS(ESI)m/z calcd forC34H39N2O3(M+H)+523.2955,found 523.2968.其结构式如下:
3da:固体,62mg,55%yield.Mp:152-153℃;1H NMR(400MHz,CDCl3):δ7.41-7.36(m,4H),7.31-7.26(m,4H),7.22-7.12(m,5H),6.64(d,J=16.4Hz,1H),6.57(d,J=16.0Hz,1H),5.66(d,J=10.8Hz,1H),4.79(s,2H),3.49-3.41(m,1H),3.36-3.30(m,1H),1.75(s,3H),1.73(s,3H),1.57(s,3H),0.78(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ173.3,159.4,138.5,135.3,135.1,134.4,134.0,133.5,133.0,130.7,129.5,129.2,129.1,128.9,128.4,128.0,127.7,120.6,84.9,74.8,48.1,39.3,28.8,24.5,17.3,14.4;IR(thinfilm)3444,2981,1656,1264,965,694cm-1;HRMS(ESI)m/z calcd for C32H33Cl2N2O3(M+H)+563.1863,found 563.1846.其结构式如下:
3ea:固体,79mg,63%yield.Mp:147-148℃;1H NMR(400MHz,CDCl3):δ7.71(d,J=8.0Hz,2H),7.60(d,J=8.4Hz,2H),7.55(d,J=8.0Hz,2H),7.42(d,J=7.6Hz,2H),7.29-7.26(m,2H),7.18-7.08(m,3H),6.74-6.65(m,2H),5.70(d,J=10.8Hz,1H),4.80(s,2H),3.55-3.51(m,1H),3.49-3.39(m,1H),1.77(s,3H),1.75(s,3H),1.60(s,3H),0.80(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ173.3,159.1,144.0,140.2,135.0,134.8,134.3,130.7,129.6,128.4,128.2,128.0,126.7,126.1(q,J=37.9Hz),125.5(q,J=270.5Hz),122.3,85.0,75.0,48.6,39.1,28.8,24.4,17.3,14.4;IR(thin film)3469,2942,1661,1327,967,696cm-1;HRMS(ESI)m/z calcd for C34H33 F6N2O3(M+H)+631.2390,found631.2401.其结构式如下:
3fa:固体,39mg,30%yield.Mp:100-101℃;1H NMR(400MHz,CDCl3):δ7.59(s,1H),7.48(d,J=8.0Hz,1H),7.41(s,1H),7.38-7.32(m,3H),7.30-7.26(m,3H),7.22-7.16(m,4H),6.61-6.52(m,2H),5.62(d,J=11.2Hz,1H),4.80(s,1H),3.49-3.43(m,1H),3.41-3.27(m,1H),1.75(s,3H),1.73(s,3H),1.59(s,3H),0.80(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ173.3,159.2,142.2,139.0,135.1,134.6,134.1,131.0,130.7,130.6,130.5,130.4,130.2,129.6,129.0,128.4,128.0,126.3,125.5,123.0,122.9,121.3,84.9,75.0,48.3,39.1,28.8,24.4,17.2,14.4;IR(thin film)3456,2966,1641,1460,968,692cm-1;HRMS(ESI)m/z calcd for C32H33Br2N2O3(M+H)+651.0852,found 651.0882.其结构式如下:
3ga:固体,70mg,54%yield.Mp:170-171℃;1H NMR(400MHz,CDCl3):δ7.64(d,J=7.6Hz,1H),7.57-7.54(m,2H),7.43-7.39(m,1H),7.35-7.28(m,4H),7.20-7.11(m,5H),7.09-7.05(m,1H),6.60(d,J=16.0Hz,1H),5.50(d,J=10.4Hz,1H),4.83(s,2H),4.17-4.11(m,1H),3.54(s,1H),1.81(s,3H),1.79(s,3H),1.61(s,3H),0.81(d,J=6.8Hz,3H);13CNMR(100MHz,CDCl3):δ173.1,159.4,139.3,137.0,135.3,134.8,133.6,133.2,132.0,129.5,129.0,128.4,128.3,128.1,127.9,127.5,126.9,126.7,125.8,124.1,123.8,84.9,75.0,46.4,39.1,28.6,24.7,17.3,13.7;IR(thin film)3478,2963,1663,1262,804,698cm-1;HRMS(ESI)m/z calcd for C32H33Br2N2O3(M+H)+651.0852,found 651.0880.其结构式如下:
3ha:固体,76mg,81%yield.Mp:123-124℃;1H NMR(400MHz,CDCl3):δ7.43-7.36(m,5H),7.33-7.27(m,6H),7.11-7.06(m,4H),5.86(d,J=10.8Hz,1H),4.75(d,J=10.4Hz,1H),4.68(d,J=10.8Hz,1H),3.50-3.45(m,1H),3.42-3.37(m,1H),1.90(s,3H),1.65(s,3H),1.13(s,3H),0.57(d,J=5.6Hz,3H);13C NMR(100MHz,CDCl3):δ172.9,160.4,139.9,136.2,135.0,133.8,130.9,129.8,129.2,129.0,128.1,128.0,127.8,127.6,127.0,84.3,74.6,48.5,39.0,28.6,25.0,16.0,14.1;IR(thin film)3482,2916,1662,1371,917,704cm-1;HRMS(ESI)m/z calcd for C30H33N2O3(M+H)+469.2486,found 469.2486.其结构式如下:
3ia:固体,59mg,59%yield.Mp:113-114℃;1H NMR(400MHz,CDCl3):δ7.44-7.40(m,2H),7.33-7.24(m,5H),7.12-7.09(m,5H),6.93(d,J=8.4Hz,2H),5.78(d,J=11.2Hz,1H),4.74(d,J=10.4Hz,1H),4.67(d,J=10.4Hz,1H),3.83(s,3H),3.51-3.46(m,1H),3.41-3.35(m,1H),1.88(s,3H),1.64(s,3H),1.19(s,3H),0.59(d,J=6.4Hz,3H);13C NMR(100MHz,CDCl3):δ173.0,160.6,159.3,140.2,135.9,135.1,131.1,129.8,129.3,129.0,128.1,127.9,127.7,127.0,126.3,113.6,84.4,74.6,55.2,48.6,39.2,28.7,25.1,16.3,14.2;IR(thin film)3499,2971,1647,1372,910,699cm-1;HRMS(ESI)m/z calcd forC31H35N2O4(M+H)+499.2591,found 499.2603.其结构式如下:
3ja:固体,83mg,85%yield.Mp:77-78℃;1H NMR(500MHz,CDCl3):δ7.44-7.41(m,2H),7.35-7.32(m,1H),7.30-7.28(m,2H),7.27-7.25(m,3H),7.13(s,1H),7.12-7.11(m,2H),7.10-7.07(m,3H),5.85(d,J=11.0Hz,1H),4.73(d,J=10.0Hz,1H),4.68(d,J=10.5Hz,1H),3.50-3.45(m,1H),3.33-3.28(m,1H),1.88(s,3H),1.65(s,3H),1.19(s,3H),0.60(d,J=7.0Hz,3H);13CNMR(125MHz,CDCl3):δ173.0,163.4(d,J=246.9Hz),160.5,139.8,135.4,135.0,131.7(d,J=8.3Hz),130.9,130.1,130.0,129.4,129.1,128.3,128.0,127.7,127.2,115.4(d,J=21.9Hz),84.5,74.8,48.7,39.2,28.7,25.1,16.3,14.2;19FNMR(470MHz,CDCl3)δ-112.8;IR(thin film)3658,2964,1651,1371,911,697cm-1;HRMS(ESI)m/z calcd for C30H32FN2O3(M+H)+487.2391,found 487.2400.其结构式如下:
3ka:固体,105mg,96%yield.Mp:60-61℃;1H NMR(400MHz,CDCl3):δ7.64-7.62(m,1H),7.45(d,J=7.6Hz,1H),7.39-7.34(m,4H),7.32-7.30(m,2H),7.25(s,2H),7.21-7.20(m,3H),7.16-7.11(m,1H),6.27(d,J=11.6Hz,1H),4.85(d,J=9.6Hz,1H),4.75(d,J=9.6Hz,1H),3.49-3.41(m,1H),3.07-3.01(m,1H),1.90(s,3H),1.66(s,3H),1.28(s,3H),0.58(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ172.6,160.6,139.5,134.7,133.9,133.2,133.1,132.9,131.9,129.6,129.4,128.6,128.5,128.3,128.0,127.4,127.0,124.4,84.7,74.8,49.7,39.9,28.8,25.1,16.9,14.3;IR(thin film)3468,2130,1640,1383,909,694cm-1;HRMS(ESI)m/z calcd for C30H32BrN2O3(M+H)+547.1591,found547.1605.其结构式如下
3la:固体,0.069mg,63%yield.Mp:60-61℃;1H NMR(500MHz,CDCl3):δ7.48-7.46(m,1H),7.41-7.38(m,3H),7.33(d,J=8.0Hz,1H),7.30-7.26(m,3H),7.21(d,J=7.5Hz,1H),7.15-7.09(m,5H),5.70(d,J=11.5Hz,1H),4.78(d,J=10.5Hz,1H),4.70(d,J=11.0Hz,1H),3.45-3.41(m,1H),3.35-3.31(m,1H),1.89(s,3H),1.66(s,3H),1.12(s,3H),0.59(d,J=6.5Hz,3H);13C NMR(125MHz,CDCl3):δ173.0,160.0,142.6,137.0,135.2,133.7,130.8,130.6,130.2,130.0,129.8,129.5,128.3,128.2,127.9,126.3,123.0,84.6,75.0,48.3,39.0,28.8,25.1,16.1,14.1;IR(thin film)3488,2967,1649,1325,911,693cm-1;HRMS(ESI)m/z calcd for C30H32BrN2O3(M+H)+547.1591,found 547.1591.其结构式如下:
3ma:固体,78mg,73%yield.Mp:70-71℃;1H NMR(500MHz,CDCl3):δ7.70-7.68(m,2H),7.42-7.39(m,4H),7.35-7.32(m,1H),7.30-7.26(m,3H),7.13-7.10(m,4H),5.73(d,J=10.5Hz,1H),4.76(d,J=10.5Hz,1H),4.68(d,J=10.5Hz,1H),3.49-3.44(m,2H),1.89(s,3H),1.65(s,3H),1.14(s,3H),0.59(d,J=6.5Hz,3H);13C NMR(125MHz,CDCl3):δ173.0,160.0,144.4,137.2,135.2,133.7,129.9,129.7,129.5,129.4,128.4,128.3,128.2,128.1,127.9,126.0,125.9,84.7,75.0,48.6,39.0,28.8,25.1,16.2,14.2;19F NMR(470MHz,CDCl3)δ-62.4;IR(thin film)3645,2962,1654,1325,805,699cm-1;HRMS(ESI)m/zcalcd for C31H32F3N2O3(M+H)+537.2360,found 537.2368.其结构式如下:
3na:固体,42mg,44%yield.Mp:53-54℃;1H NMR(400MHz,CDCl3):δ7.40-7.37(m,2H),7.33-7.26(m,4H),7.19-7.15(m,5H),7.05-7.03(m,1H),6.94(d,J=2.8Hz,1H),5.81(d,J=11.2Hz,1H),4.78(d,J=10.4Hz,1H),4.70(d,J=10.8Hz,1H),3.77-3.72(m,1H),3.39-3.35(m,1H),1.87(s,3H),1.61(s,3H),1.12(s,3H),0.70(d,J=7.2Hz,3H);13C NMR(100MHz,CDCl3):δ173.1,160.2,143.5,136.5,135.1,133.7,130.5,129.8,129.5,128.4,128.3,128.2,128.0,127.0,124.8,124.1,84.6,74.8,44.2,40.5,28.7,25.1,16.2,14.2;IR(thin film)3664,2968,1654,1369,910,698cm-1;HRMS(ESI)m/z calcd for C28H31N2O3S(M+H)+475.2050,found 475.2064.其结构式如下:
3oa:固体,30mg,38%yield.1H NMR(400MHz,CDCl3):δ7.37-7.30(m,4H),7.24-7.22(m,2H),7.20-7.19(m,1H),7.04-7.01(m,4H),5.79(d,J=10.8Hz,1H),4.68(d,J=10.0Hz,1H),4.61(d,J=10.4Hz,1H),3.43-3.30(m,2H),1.82(s,3H),1.58(s,3H),1.06(s,3H),0.52(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ173.0,160.6,140.0,136.3,135.1,133.9,131.0,129.9,129.4,129.0,128.3,128.2,127.9,127.7,127.1,84.5,74.7,48.6,39.2,28.7,25.1,16.2,14.1;IR(thin film)3465,2971,1743,1263,905,697cm-1;HRMS(ESI)m/z calcd for C24H29N2O3(M+H)+393.2173,found 393.2162.其结构式如下:
3pa:固体,53mg,51%yield.Mp:149-150℃;1H NMR(500MHz,CDCl3):δ7.46(d,J=7.5Hz,2H),7.41(d,J=7.5Hz,2H),7.35-7.32(m,3H),7.30-7.24(m,5H),7.18-7.11(m,3H),6.68(s,2H),6.56(d,J=7.0Hz,1H),5.74(d,J=11.0Hz,1H),4.79(s,2H),3.45-3.41(m,1H),3.23-3.18(m,1H),1.75(s,3H),1.61(s,3H),1.26-1.18(m,4H),1.12-1.07(m,2H),0.77-0.74(m,3H);13C NMR(125MHz,CDCl3):δ173.2,154.0,140.0,137.0,135.5,135.2,133.9,131.8,129.5,129.0,128.6,128.3,128.0,127.9,127.7,127.2,126.8,121.0,85.6,74.7,48.3,44.3,30.4,30.1,28.8,24.3,22.4,13.8;IR(thin film)3028,2938,1633,1454,958,693cm-1;HRMS(ESI)m/z calcd for C34H39N2O3(M+H)+523.2955,found 523.2965.其结构式如下:
3qa:固体,69mg,61%yield.Mp:87-88℃;1H NMR(500MHz,CDCl3):δ7.54(s,2H),7.44(d,J=6.5Hz,2H),7.37(d,J=7.5Hz,1H),7.34(d,J=7.0Hz,1H),7.30(d,J=7.0Hz,2H),7.24-7.19(m,4H),7.17(s,1H),7.16(d,J=3.5Hz,1H),7.15-7.12(m,3H),6.95(s,1H),6.56(d,J=15.0Hz,1H),6.45(d,J=13.5Hz,1H),5.88(d,J=10.0Hz,1H),4.83-4.78(m,2H),4.09-4.04(m,1H),3.63(s,1H),1.84(s,3H),1.68(s,3H),1.42-1.26(m,2H),0.46(s,3H);13C NMR(125MHz,CDCl3):δ173.0,160.0,140.5,136.7,135.3,135.2,135.0,134.2,132.0,129.5,129.1,128.7,128.5,128.3,128.1,128.0,127.8,127.6,127.5,127.2,126.7,121.7,85.8,74.7,49.1,47.1,28.7,24.4,21.6,12.5;IR(thin film)3655,2904,1651,1451,966,696cm-1;HRMS(ESI)m/z calcd for C38H39N2O3(M+H)+571.2955,found571.2969.其结构式如下:
3ra:固体,71mg,66%yield.Mp:87-88℃;1H NMR(500MHz,CDCl3):δ7.63(d,J=7.5Hz,2H),7.45-7.42(m,2H),7.36-7.33(m,5H),7.28-7.20(m,5H),7.16-7.13(m,4H),6.93(d,J=6.0Hz,2H),6.67(d,J=15.5Hz,1H),6.41(d,J=16.0Hz,1H),5.82(d,J=11.0Hz,1H),4.87(s,2H),4.00-3.94(m,1H),3.49-3.45(m,1H),2.96-2.93(m,1H),1.84(s,3H),1.64(s,3H);13C NMR(125MHz,CDCl3):δ173.4,155.2,141.2,136.8,135.5,135.4,135.0,134.8,131.2,129.5,129.4,129.0,128.6,128.4,128.3,128.2,127.6,127.3,127.1,126.8,126.1,121.4,86.2,74.9,42.2,33.8,29.0,24.5;IR(thin film)3489,2930,1655,1450,958,693cm-1;HRMS(ESI)m/z calcd for C36H35N2O3(M+K)+543.2642,found543.2662.其结构式如下:
3sa:固体,33mg,30%yield.Mp:136-137℃;1H NMR(400MHz,CDCl3):δ7.46-7.40(m,4H),7.35-7.32(m,3H),7.30-7.26(m,5H),7.18-7.12(m,3H),6.72-6.64(m,2H),6.57(d,J=6.8Hz,1H),5.73(d,J=11.2Hz,1H),4.79(s,2H),3.47-3.36(m,3H),3.22(s,1H),1.75(s,3H),1.71-1.66(m,1H),1.62(s,3H),1.45-1.39(m,1H),1.29-1.21(m,3H);13C NMR(100MHz,CDCl3):δ173.1,153.5,139.7,136.9,135.1,134.0,132.0,129.5,129.1,128.6,128.3,128.0,127.9,127.7,127.4,126.8,120.8,85.7,74.8,48.2,44.5,44.2,32.1,30.0,28.7,25.2,24.3;IR(thin film)3448,2940,1642,1453,967,694cm-1;HRMS(ESI)m/z calcdfor C34H38ClN2O3(M+H)+557.2565,found 557.2573.其结构式如下:
3ta:固体,35mg,31%yield.Mp:130-131℃;1H NMR(400MHz,CDCl3):δ7.38-7.32(m,4H),7.28-7.24(m,3H),7.22-7.17(m,5H),7.10-7.02(m,3H),6.64(d,J=16.4Hz,1H),6.60(d,J=16.4Hz,1H),6.51(d,J=6.8Hz,1H),5.64(d,J=11.2Hz,1H),4.71(s,2H),3.49(s,3H),3.3-3.33(m,1H),3.17-3.12(m,1H),2.14-1.99(m,2H),1.67(s,3H),1.53(s,3H),1.34-1.09(m,4H);13C NMR(100MHz,CDCl3):δ173.3,173.1,153.3,139.6,136.8,135.1,135.0,134.0,131.9,129.4,129.1,128.6,128.3,128.0,127.9,127.6,127.3,126.7,120.7,85.6,74.7,51.4,48.1,44.0,33.5,30.0,28.7,24.2,23.2;IR(thin film)3475,2934,1650,1352,969,694cm-1;HRMS(ESI)m/z calcd for C35H39Cl2N2O5(M+H)+567.2853,found 567.2831.其结构式如下:
3ua:固体81mg,80%yield.Mp:136-137℃;1H NMR(400MHz,CDCl3):δ7.46-7.40(m,5H),7.36-7.30(m,6H),7.27-7.23(m,1H),7.20-7.14(m,3H),6.75-6.67(m,2H),5.83(d,J=10.8Hz,1H),4.80(s,2H),3.63-3.57(m,1H),3.41-3.38(m,1H),2.46-2.40(m,1H),2.32-2.23(m,1H),1.91-1.79(m,3H),1.75(s,3H),1.68-1.66(m,1H),1.61(s,3H);13C NMR(100MHz,CDCl3):δ173.1,167.2,140.8,136.9,135.1,134.8,133.3,131.7,129.4,129.0,128.7,128.3,128.0,127.9,127.8,127.2,126.5,120.1,85.0,74.8,47.3,46.6,30.4,29.6,29.0,24.5,22.1;IR(thin film)3459,2938,1754,1376,966,709cm-1;HRMS(ESI)m/zcalcd for C33H35N2O3(M+H)+507.2642,found 507.2639.其结构式如下:
3va:固体,73mg,70%yield.Mp:70-71℃;1H NMR(500MHz,CDCl3):δ7.46-7.41(m,4H),7.36-7.33(m,3H),7.29-7.28(m,4H),7.25(d,J=5.5Hz,1H),7.18-7.12(m,3H),6.70-6.63(m,2H),5.78(d,J=11.0Hz,1H),4.80-4.75(m,2H),3.78-3.74(m,1H),3.55-3.52(m,1H),2.30(d,J=15.5Hz,1H),2.21-2.16(m,1H),1.77(s,3H),1.57(s,3H),1.45-1.41(m,2H),1.39-1.34(m,2H),1.32-1.26(m,2H);13C NMR(125MHz,CDCl3):δ173.7,160.0,140.0,136.9,135.3,135.2,134.0,132.1,129.5,129.1,128.7,128.3,128.0,127.9,127.8,127.2,126.7,120.5,84.8,74.6,45.4,40.8,29.2,29.0,25.5,24.8,24.4,21.0;IR(thinfilm)3482,2936,1647,1370,967,696cm-1;HRMS(ESI)m/z calcd for C34H37N2O3(M+K)+521.2799,found 521.2817.其结构式如下:
3wa:固体,99mg,93%yield.Mp:64-65℃;1H NMR(400MHz,CDCl3):δ7.45-7.39(m,4H),7.36-7.23(m,8H),7.19-7.13(m,3H),6.70-6.59(m,2H),5.77(q,J=10.0Hz,1H),4.77(s,1H),3.44-3.37(m,1H),2.30-2.25(m,1H),2.19-2.13(m,1H),1.84(d,J=5.2Hz,1H),1.77(s,3H),1.61(s,3H),1.59(s,3H),1.29-1.21(m,4H);13C NMR(100MHz,CDCl3):δ173.3,164.1,140.4,137.1,135.2,135.0,133.4,131.5,129.5,129.0,128.7,128.3,128.0,127.8,127.7,127.1,126.6,120.4,84.8,82.9,74.7,49.0,46.3,32.0,30.9,30.1,29.6,28.7,26.8,24.6;IR(thin film)3455,2967,1639,1374,814,693cm-1;HRMS(ESI)m/z calcdfor C35H39N2O3(M+H)+535.2955,found 535.2951.其结构式如下:
3xa:固体,79mg,76%yield.Mp:53-54℃;1H NMR(400MHz,CDCl3):δ7.48-7.42(m,4H),7.37-7.27(m,8H),7.20-7.14(m,3H),6.76-6.65(m,2H),5.81(d,J=11.2Hz,1H),4.82-4.76(m,2H),4.07-3.97(m,2H),3.56(d,J=12.4Hz,1H),3.42-3.24(m,3H),2.61-2.53(m,1H),2.24(d,J=15.6Hz,1H),1.78(s,3H),1.59(s,3H);13C NMR(100MHz,CDCl3):δ173.3,155.5,139.0,136.6,135.1,134.3,134.2,132.4,129.5,129.2,128.7,128.3,128.0,127.9,127.5,126.7,120.1,85.1,74.7,67.4,66.5,44.3,42.7,29.3,28.9,24.4;IR(thin film)3477,2964,1648,1370,909,696cm-1;HRMS(ESI)m/z calcd for C33H35N2O4(M+H)+523.2591,found 523.2604.其结构式如下:
3ya:固体,52mg,45%yield.Mp:187-188℃;1H NMR(400MHz,CDCl3):δ7.48-7.47(m,2H),7.44-7.40(m,2H),7.37-7.24(m,9H),7.18-7.11(m,2H),6.79(d,J=16.0Hz,1H),6.67(d,J=16.0Hz,1H),5.73(d,J=11.2Hz,1H),4.77(s,2H),4.15-4.09(m,1H),4.03-4.02(m,1H),3.84-3.78(m,3H),3.69-3.66(m,1H),2.67-2.50(m,2H),2.34-2.31(m,1H),2.03-2.00(m,1H),1.77(s,3H),1.72-1.64(m,1H),1.61(s,1H),1.59(s,3H);13C NMR(100MHz,CDCl3):δ173.4,158.2,140.2,137.9,136.9,135.8,135.2,134.1,131.7,129.4,129.3,129.0,128.8,128.7,128.6,128.3,128.2,128.0,127.8,127.1,126.7,120.3,108.3,85.0,78.1,74.7,64.8,64.1,46.1,40.4,33.7,32.4,28.9,27.3,24.4,18.4;IR(thin film)3468,2962,1740,1262,981,694cm-1;HRMS(ESI)m/z calcd for C36H39N2O5(M+H)+579.2853,found 579.2845.其结构式如下:
3ab:固体,68mg,65%yield.Mp:130-131℃;1H NMR(400MHz,CDCl3):δ7.46-7.40(m,4H),7.36-7.26(m,6H),7.25-7.22(m,4H),6.72-6.63(m,4H),5.79(d,J=10.8Hz,1H),4.75-4.69(m,2H),3.68(s,3H),3.52-3.48(m,1H),3.42-3.36(m,1H),1.77(s,3H),1.76(s,3H),1,61(s,3H),0.78(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ173.2,159.8,159.7,140.1,136.9,134.4,134.0,131.9,131.0,129.0,128.7,127.8,127.7,127.3,127.2,126.6,120.4,113.4,84.8,74.3,55.1,48.8,39.6,28.8,24.6,17.3,14.5;IR(thin film)3465,2934,1650,1252,965,694cm-1;HRMS(ESI)m/z calcd for C33H37N2O4(M+H)+525.2748,found 525.2756.其结构式如下:
3ac.固体,62mg,54%yield.Mp:139-140℃;1H NMR(400MHz,CDCl3):δ7.46-7.41(m,4H),7.36-7.26(m,8H),7.19-7.17(m,2H),6.70(d,J=16.0Hz,1H),6.64(d,J=15.6Hz,1H),5.84(d,J=11.2Hz,1H),4.75-4.69(m,2H),3.56-3.50(m,1H),3.43-3.38(m,1H),1.77(s,6H),1.60(s,3H),0.79(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ173.4,159.9,139.9,136.8,134.7,134.2,133.8.132.1,131.2,131.0,129.1,128.7,128.0,127.7,127.3,126.6,122.4,120.2,84.8,73.8,48.8,39.5,28.8,24.6,17.3,14.5;IR(thin film)3491,2972,1949,1374,966,690cm-1;HRMS(ESI)m/z calcd for C32H34BrN2O3(M+H)+573.1747,found 573.1756.其结构式如下:
3ad:固体,68mg,61%yield.Mp:64-65℃;1H NMR(400MHz,CDCl3):7.48-7.40(m,8H),7.37-7.33(m,3H),7.31(d,J=8.0Hz,2H),7.26(s,1H),6.72-6.61(m,2H),5.87(d,J=10.8Hz,1H),4.86-4.79(m,2H),3.54-3.50(m,1H),3.44-3.39(m,1H),1.77(s,6H),1.59(s,3H),0.79(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ173.6,159.9,139.9,139.3,136.8,134.8,133.9,132.2,130.5,130.1,129.3,129.1,128.7,128.0,127.7,127.3,126.6,125.1,120.2,84.8,73.8,48.8,39.5,28.7,24.6,17.3,14.5;IR(thin film)3459,2090,1639,1383,950,694cm-1;19F NMR(376MHz,CDCl3)δ-62.6;HRMS(ESI)m/z calcd forC33H34F3N2O3(M+H)+563.2516,found 563.2533.其结构式如下:
3ae:固体,62mg,61%yield.Mp:170-171℃;1H NMR(400MHz,CDCl3):δ7.46-7.44(m,2H),7.42-7.40(m,2H),7.36-7.31(m,2H),7.29-7.23(m,4H),7.11-7.05(m,3H),6.94-6.93(m,1H),6.71(d,J=16.4Hz,1H),6.63(d,J=15.6Hz,1H),5.72(d,J=10.8Hz,1H),4.78-4.73(m,2H),3.54-3.46(m,1H),3.40-3.35(m,1H),2.16(s,3H),1.77(s,3H),1.76(s,3H),1.60(s,3H),0.78(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ173.2,159.8,140.1,137.6,136.9,135.0,134.6,133.9,131.8,130.4,129.0,128.7,127.9,127.8,127.7,127.2,126.6,126.5,120.4,84.8,74.7,48.7,39.5,28.8,24.6,21.1,17.3,14.5;IR(thinfilm)3467,2914,1650,1252,975,695cm-1;HRMS(ESI)m/z calcd for C33H37N2O3(M+H)+509.2799,found 509.2802.其结构式如下:
3af:固体,69mg,68%yield.Mp:180-181℃;1H NMR(400MHz,CDCl3):δ7.45-7.40(m,3H),7.36-7.32(m,3H),7.28-7.25(m,4H),7.20-7.18(m,1H),7.00-6.99(m,2H),6.93-6.92(m,1H),6.71(d,J=16.0Hz,1H),6.61(d,J=16.0Hz,1H),5.69(d,J=10.8Hz,1H),4.83(s,2H),3.53-3.48(m,1H),3.39-3.33(m,1H),2.28(s,3H),1.77(s,3H),1.76(s,3H),1.65(s,3H),0.78(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ173.1,159.8,140.1,138.5,137.0,134.3,133.9,133.0.131.8,131.0,129.9,129.0,128.7,128.6,127.8,127.2,126.5,125.4,120.4,84.8,73.0,48.7,39.4,28.8,24.6,18.9,17.4,14.5;IR(thin film)3665,2964,1660,1272,975,708cm-1;HRMS(ESI)m/z calcd for C33H37N2O3(M+H)+509.2799,found 509.2778.其结构式如下:
3ag:固体,61mg,73%yield.Mp:168-169℃;1H NMR(400MHz,CDCl3):δ7.47-7.44(m,2H),7.42-7.40(m,2H),7.35-7.30(m,5H),7.27-7.23(m,1H),6.69-6.61(m,2H),5.99(d,J=10.4Hz,1H),3.60-3.55(m,4H),3.48-3.42(m,1H),1.80(s,3H),1.78(s,3H),1.72(s,3H),0.80(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ172.9,159.8,140.1,136.7,134.5,133.3,132.0,129.1,128.7,127.9,127.8,127.2,126.5,120.1,84.7,60.1,48.8,39.5,28.7,24.6,17.4,14.5;IR(thin film)3454,2921,1644,1265,965,740cm-1;HRMS(ESI)m/z calcd for C26H31N2O3(M+H)+419.2329,found 419.2317.其结构式如下:
3ah:固体,45mg,51%yield.Mp:190-191℃;1H NMR(400MHz,CDCl3):δ7.47-7.44(m,2H),7.42-7.40(m,2H),7.36-7.30(m,5H),7.27-7.23(m,1H),6.70(d,J=15.6Hz,1H),6.65(d,J=16.0Hz,1H),6.00-5.97(m,1H),5.94-5.86(m,1H),5.22-5.14(m,2H),4.27-4.25(m,2H),3.57-3.53(m,1H),3.47-3.41(m,1H),1.79(s,3H),1.77(s,3H),1.70(s,3H),0.79(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ173.5,159.8,140.2,136.9,134.6,133.9,132.6,132.0,129.1,128.7,127.9,127.8,127.2,126.6,120.3,119.6,84.8,73.7,48.8,39.5,29.0,24.6,17.3,14.5;IR(thin film)3479,2935,1745,1350,952,694cm-1;HRMS(ESI)m/z calcd for C28H33N2O3(M+H)+445.2486,found 445.2475.其结构式如下:
3ai:固体,43mg,41%yield.Mp:160-161℃;1H NMR(400MHz,CDCl3):δ7.48-7.46(m,2H),7.40-7.31(m,9H),7.24-7.23(m,1H),7.17-7.13(m,3H),6.71-6.62(m,2H),6.21(d,J=10.8Hz,1H),4.76(d,J=15.6Hz,1H),4.64(d,J=15.6Hz,1H),3.60-3.52(m,1H),3.48-3.42(m,1H),1.80(s,3H),1.78(s,3H),1.72(s,3H),0.79(d,J=6.8Hz,3H);13C NMR(150MHz,CDCl3):δ173.9,160.0,140.1,136.8,134.8,134.7,131.9,131.5,129.1,128.7,128.2,128.1,127.8,127.2,126.6,122.3,120.4,87.1,84.9,83.6,61.2,48.8,39.4,29.1,24.4,17.4,14.5;IR(thin film)3665,2974,1656,1262,998,680cm-1;HRMS(ESI)m/z calcdfor C34H35N2O3(M+H)+519.2642,found 519.2632.其结构式如下:
3aj:固体,49mg,51%yield.Mp:147-148℃;1H NMR(400MHz,CDCl3):δ7.46-7.40(m,4H),7.34-7.25(m,8H),7.19-7.13(m,3H),6.76(d,J=16.0Hz,1H),6.68(d,J=16.0Hz,1H),5.77(d,J=11.2Hz,1H),5.02-4.97(m,1H),4.85-4.79(m,2H),3.53-3.47(m,1H),3.43-3.38(m,1H),1.77(s,3H),1.61(d,J=7.2Hz,3H),0.78(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ170.8,160.8,139.7,136.7,135.6,135.0,132.8,132.0,129.4,129.3,129.0,128.6,128.3,128.0,127.9,127.8,127.2,126.6,119.8,80.7,74.9,48.5,39.5,19.8,16.9,14.5;IR(thin film)3453,2971,1661,1369,967,696cm-1;HRMS(ESI)m/z calcdfor C31H33N2O3(M+H)+481.2486,found 481.2475.其结构式如下:
3ak:固体,60mg,61%yield.Mp:165-166℃;1H NMR(400MHz,CDCl3):δ7.46-7.40(m,4H),7.35-7.32(m,3H),7.29-7.23(m,5H),7.18-7.12(m,3H),6.75(d,J=16.0Hz,1H),6.68(d,J=16.0Hz,1H),5.80(d,J=11.2Hz,1H),4.90-4.87(m,1H),4.84-4.78(m,2H),3.55-3.49(m,1H),3.43-3.38(m,1H),2.10-2.02(m,2H),1.78(s,3H),1.04(t,J=7.2Hz,3H),0.78(d,J=6.4Hz,3H);13C NMR(100MHz,CDCl3):δ170.0,160.6,139.7,136.8,135.6,135.1,132.7,131.9,129.4,129.0,128.6,128.3,128.0,127.9,127.8,127.2,126.6,119.9,85.2,74.9,48.5,39.5,27.1,16.9,14.5,10.0;IR(thin film)3443,2932,1669,1252,975,697cm-1;HRMS(ESI)m/z calcd for C32H35N2O3(M+H)+495.2642,found 495.2623.其结构式如下:
3al:固体,72mg,66%yield.Mp:187-188℃;1H NMR(400MHz,CDCl3):δ7.50-7.48(m,2H),7.44-7.40(m,2H),7.37-7.34(m,7H),7.29-7.25(m,6H),7.17-7.09(m,3H),6.84(d,J=15.6Hz,1H),6.74(d,J=16.0Hz,1H),5.98(d,J=10.0Hz,1H),4.85(d,J=10.8Hz,1H),4.81(d,J=11.2Hz,1H),4.69(s,1H),3.50-3.43(m,2H),1.81(s,3H),0.74(d,J=5.6Hz,3H);13C NMR(100MHz,CDCl3):δ169.0,161.3,141.1,139.5,137.9,136.7,135.9,135.2,132.9,132.3,129.5,129.1,128.7,128.5,128.4,128.3,128.1,128.0,127.8,127.6,127.3,127.0,126.7,119.9,86.8,74.6,65.3,48.6,39.7,16.9,14.5;IR(thinfilm)3465,2943,1665,1355,931,694cm-1;HRMS(ESI)m/z calcd for C36H35N2O3(M+H)+543.2642,found 543.2623.其结构式如下:
实施例2:化合物3aa、3ba、3ta、3ya、3ab的制备
化合物3aa:重复实施例1,不同的是,用二氯甲烷代替乙腈,用碘化铜代替三氟甲磺酸铜,用吡啶代替碳酸钾,在50℃条件下进行反应直至完全。所得残留物用经硅胶柱层析纯化(正己烷/乙酸乙酯=20:1~10:1,体积比),得到黄色固体,产率为75%。经核磁氢谱、碳谱及高分辨质谱表征,确定为化合物3aa。
化合物3ba:重复实施例1,不同的是,用四氢呋喃代替乙腈,用三氟甲磺酸镱代替三氟甲磺酸铜,用氢氧化钠代替碳酸钾,在80℃条件下进行反应直至完全。得到无色油状,产率为36%。经核磁氢谱、碳谱及高分辨质谱表征,确定为化合物3ba。
化合物3ta:重复实施例1,不同的是,用苯代替乙腈,用三氟甲磺酸钪代替三氟甲磺酸铜,用三乙胺代替碳酸钾,在室温下反应至完全。得到白色固体,产率为31%。经核磁氢谱、碳谱及高分辨质谱表征,确定为化合物3ta。
化合物3ya:重复实施例1,不同的是,反应不在氩气保护条件下进行,而是在空气中进行。得到白色固体,产率为45%。经核磁氢谱、碳谱及高分辨质谱表征,确定为化合物3ya。
化合物3ab:重复实施例1,不同的是,用由丙酮和正己烷按1:1的体积比组成的混合溶剂代替乙腈,用氯化亚铜代替三氟甲磺酸铜,用叔丁醇钠代替碳酸钾,在室温下反应至完全。得到白色固体,产率为65%。经核磁氢谱、碳谱及高分辨质谱表征,确定为化合物3ab。
实验例1:本发明所述1-氧-2,8-二氮杂环葵酮衍生物的体外抗炎活性实验
一、采用MTT法测定化合物及对照药吲哚美辛在浓度为100μM时对RAW264.7细胞(小鼠单核巨噬细胞白血病细胞)活力的测试
1.受试细胞的消化及接种:培养受试细胞RAW 264.7至对数期,用0.25%胰蛋白酶进行消化,加入含10%胎牛血清的培养基,无菌塑料吸管吹匀成单细胞悬液,接种到96孔板,每孔加180μL.96孔板四周加200μL PBS缓冲基以减少培养基蒸发。
2.对细胞株加药:待孔内细胞生长到占整个孔面积约70%时,每孔加药20μL,则药物稀释浓度至100μM,用手轻拍,设5个复孔(平行实验),每块96孔板设置空白孔(不加入药物)和调零孔(含10%胎牛血清的培养基),继续放入培养箱,显微镜下观察细胞的生存情况。
3.测板:加药继续培养48h后,每孔加入10μL的MTT进行染色,用手轻拍,继续培养4~6h,然后弃去孔内的培养基,每孔加入100μL的DMSO,置微型震荡器上震荡10min,使生成的甲臜充分溶解,移至酶联免疫检测仪中检测各孔的吸光值,再用PASW软件处理数据。实验结果见表1。
表1.MTT法检测化合物对RAW264.7细胞活力的影响
申请人利用MTT法探究部分目标化合物对RAW 264.7细胞的存活率的影响,从测试结果可以看出,在化合物浓度为100μM时,其中含有氯、溴和肉桂基取代的化合物对于细胞的存活有一定的抑制作用。因此,我们进一步探究了部分毒性较低的目标化合物对有脂多糖诱导的细胞的NO释放量的影响。
二、Griess法测定部分低毒性目标化合物对脂多糖(lipopolysaccharides,LPS)诱导的小鼠巨噬细胞RAW 264.7释放NO的抑制作用
化合物3aa、3ba、3ha、3ta、3ya、3ab、3al对RAW 264.7细胞显示了很低的毒性,因此本申请人进一步测试了这些化合物抑制LPS诱导的RAW 264.7细胞释放NO的作用。
实验方法及实验结果:
1.细胞的接种及预处理:将长至对数生长期的RAW 264.7细胞接种于24孔培养板中,每孔400μL,设对照组、LPS应激模型组(1μg/mL LPS)、不同浓度药物实验组(6.25、12.5、25、50μg/m L),对照组和LPS应激模型组添加终浓度为0.1%DMSO的培养基,实验组先用不同浓度药物溶液预处理1h后再添加1μg/mL的LPS共同处理24h,收集细胞上清液。
2.Griess法测定NO释放量:取稀释的系列浓度梯度标准试剂和待测细胞培养上清液至96孔板中,每孔0.05mL,遵照试剂盒说明书进行操作,具体步骤如下:
(1)加入室温状态下的Griess Regent 1试剂,每孔0.05mL,静置10min。
(2)加入室温状态下的Griess Regent 2试剂,每孔0.05mL,静置10min。
(3)于540nm处测定吸光值,得出标准曲线,确定待测样品中NO浓度。
采用Griess法检测了化合物3aa、3ba、3ha、3ta、3ya、3ab、3al在浓度为6.25μM下抑制LPS诱导的小鼠巨噬细胞NO释放的能力。测试结果见表2。
表2.不同化合物在同一浓度(6.25μM)下对RAW264.7细胞NO释放的影响
从测试结果可以看出,大部分目标化合物对于细胞内NO的抑制作用与抗炎药物吲哚美辛的作用相当。以上结果进一步表明本发明所述1-氧-2,8-二氮杂环葵酮衍生物具有潜在的抗炎活性。
Claims (9)
1.下述式(I)所示结构的1-氧-2,8-二氮杂环葵酮衍生物或其药学上可接受的盐:
其中:
R1表示未取代或单取代的苯基,或者是未取代的噻吩基;其中,取代基为C1~6的烷基、烷氧基或卤原子;
R2表示氢原子,或者是未取代或单取代的苯基,或者是未取代或单取代的苯乙烯基;其中,取代基为C1~6的烷基、烷氧基或卤原子;
R3表示氢原子、甲基、乙基、正丁基或卤原子,或者是取代的C1~6的烷基;
R4表示氢原子或苯基,或者是未取代或单取代的C1~4的烷基,或者是未取代或单取代的C1~4的烷氧基;
R5表示氢原子;
R6表示甲基、乙基或苯基;
R7表示氢原子或甲基;
R8表示甲基、烯丙基或苯基炔丙基,或者是未取代或单取代的苄基。
2.根据权利要求1所述的1-氧-2,8-二氮杂环葵酮衍生物,其特征是,其特征是,具体为下述化合物3aa~3al中的任意一个:
3aa:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ba:R1=4-OMe-Ph,R2=CH2-CH2-4-OMe-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ca:R1=4-Me-Ph,R2=CH2-CH2-4-Me-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3da:R1=4-Cl-Ph,R2=CH2-CH2-4-Cl-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ea:R1=4-CF3-Ph,R2=CH2-CH2-4-CF3-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3fa:R1=3-Br-Ph,R2=CH2-CH2-3-Br-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ga:R1=2-Br-Ph,R2=CH2-CH2-2-Br-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ha:R1=Ph,R2=Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ia:R1=Ph,R2=4-OMe-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ja:R1=Ph,R2=4-F-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ka:R1=Ph,R2=2-Br-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3la:R1=4-Br-Ph,R2=Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ma:R1=4-CF3-Ph,R2=Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3na:R1=2-thienyl,R2=Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3oa:R1=Ph,R2=H,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Bn;
3pa:R1=Ph,R2=CH2-CH2-Ph,R3=H,R4=n-Bu,R5=H,R6=Me,R7=Me,R8=Bn;
3qa:R1=Ph,R2=CH2-CH2-Ph,R3=Ph,R4=Et,R5=H,R6=Me,R7=Me,R8=Bn;
3ra:R1=Ph,R2=CH2-CH2-Ph,R3=Ph,R4=H,R5=H,R6=Me,R7=Me,R8=Bn;
3sa:R1=Ph,R2=CH2-CH2-Ph,R3=H,R4=(CH2)4Cl,R5=H,R6=Me,R7=Me,R8=Bn;
3ta:R1=Ph,R2=CH2-CH2-Ph,R3=H,R4=(CH2)3CO2Me,R5=H,R6=Me,R7=Me,R8=Bn;
3ua:R1=Ph,R2=CH2-CH2-Ph,R3+R4=Cyclopentane,R5=H,R6=Me,R7=Me,R8=Bn;
3va:R1=Ph,R2=CH2-CH2-Ph,R3+R4=Cyclohexane,R5=H,R6=Me,R7=Me,R8=Bn;
3wa:R1=Ph,R2=CH2-CH2-Ph,R3+R4=Cycloheptane,R5=H,R6=Me,R7=Me,R8=Bn;
3xa:R1=Ph,R2=CH2-CH2-Ph,R3+R4=pyran,R5=H,R6=Me,R7=Me,R8=Bn;
3ya:R1=Ph,R2=CH2-CH2-Ph,R3+R4=spirocyclic,R5=H,R6=Me,R7=Me,R8=Bn;
3ab:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=CH2-4-OMe-Ph;
3ac:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=CH2-4-Br-Ph;
3ad:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=CH2-4-CF3-Ph;
3ae:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=CH2-3-Me-Ph;
3af:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=CH2-2-Me-Ph;
3ag:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Me;
3ah:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=allyl;
3ai:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=Me,R8=Phenylpropargyl;
3aj:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Me,R7=H,R8=Bn;
3ak:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Et,R7=H,R8=Bn;
3al:R1=Ph,R2=CH2-CH2-Ph,R3=Me,R4=Me,R5=H,R6=Ph,R7=H,R8=Bn。
3.权利要求1所述1-氧-2,8-二氮杂环葵酮衍生物的合成方法,其特征是,取如下式(II)所示化合物和式(III)所示化合物置于有机溶剂中,加入碱性物质和催化剂,于加热或不加热条件下进行反应,制得目标化合物粗品;
其中:
R1表示未取代或单取代的苯基,或者是未取代的噻吩基;其中,取代基为C1~6的烷基、烷氧基或卤原子;
R2表示氢原子,或者是未取代或单取代的苯基,或者是未取代或单取代的苯乙烯基;其中,取代基为C1~6的烷基、烷氧基或卤原子;
R3表示氢原子、甲基、乙基、正丁基或卤原子,或者是取代的C1~6的烷基;
R4表示氢原子或苯基,或者是未取代或单取代的C1~4的烷基,或者是未取代或单取代的C1~4的烷氧基;
R5表示氢原子;
R6表示甲基、乙基或苯基;
R7表示氢原子或甲基;
R8表示甲基、烯丙基或苯基炔丙基,或者是未取代或单取代的苄基;
X表示溴原子或氯原子。
4.根据权利要求3所述的合成方法,其特征是,反应在惰性气氛保护下进行。
5.根据权利要求3或4所述的合成方法,其特征是,反应在低于100℃的条件下进行。
6.根据权利要求3或4所述的合成方法,其特征是,
所述的有机溶剂为选自苯、甲苯、环己烷、石油醚、四氯化碳、四氢呋喃、乙酸乙酯、乙腈、***、二氯甲烷、丙酮、三氯甲烷、正己烷和二氧六环中一种或两种以上的组合;
所述的碱性物质为选自磷酸三钾、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化铯、碳酸铯,碳酸钾、叔丁醇钾、叔丁醇钠、氟化钾、吡啶、三乙胺和N,N-二异丙基乙基胺中的一种或两种以上的组合;
所述的催化剂为选自铜盐、镱盐和钪盐中的一种或两种以上的组合。
7.根据权利要求3或4所述的合成方法,其特征是,还包括对制得的目标化合物粗品进行纯化的步骤。
8.权利要求1所述的1-氧-2,8-二氮杂环葵酮衍生物或其药学上可接受的盐在制备治疗炎症的药物中的应用。
9.一种药物组合物,其包括作为活性成分的治疗上有效剂量的权利要求1所述1-氧-2,8-二氮杂环葵酮衍生物或其药学上可接受的盐,以及药学上可接受的载体。
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