CN109810171B - 二氢异喹啉-3-甲酰-LARGD(aa)aa,其制备,抗静脉血栓活性和应用 - Google Patents
二氢异喹啉-3-甲酰-LARGD(aa)aa,其制备,抗静脉血栓活性和应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及1,2-二氢异喹啉-3-甲酰-Leu-Ala-Arg-Gly-Asp(aa)-aa,涉及它们的制备方法,涉及它们的抗静脉血栓活性,因而本发明涉及它们在制备抗静脉血栓药物中的应用。本发明属于生物医药领域。
背景技术
血栓症已成为发病率高和死亡率高的疾病。静脉血栓症患者数,包括深静脉血栓和肺栓塞的患者数超过了心肌梗塞和中风发病总人数,比乳腺癌和艾滋病引起死亡的总人数高。血栓症的发病率随年龄增长呈指数态增加,对我国这样的老龄化国家的人民健康的威胁尤其严重。如计入人口基数,静脉血栓症对我国国计民生的负面影响尤其严重。静脉血栓症的预防及治疗一直是医药领域关注的重点之一。虽然华法林1941年就用于临床,但是它的安全窗口窄。剂量低会导致肺栓塞,剂量高会导致致命性出血。50多年来虽然为发明安全的抗静脉血栓药物付出了大量心血,但是成效甚微。在抗血栓药物研究中,发明人曾经公开在10nmol/kg剂量下静脉注射N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Arg-Gly-Asp(Ser)-Ser,N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Arg-Gly-Asp(Val)-Val和N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Arg-Gly-Asp(Phe)-Phe可有效抑制大鼠动脉血栓,对静脉血栓无治疗作用。发明人在它们治疗的小鼠血液中发现了1,2-二氢异喹啉-3-甲酰-Leu-Arg-Gly-Asp(Ser)-Ser,1,2-二氢异喹啉-3-甲酰-Leu-Arg-Gly-Asp(Val)-Val和1,2-二氢异喹啉-3-甲酰-Leu-Arg-Gly-Asp(Phe)-Phe(见下面的转化式)。在后续研究中,发明人进一步发现1,2-二氢异喹啉-3-甲酰-Leu-Arg-Gly-Asp(Ser)-Ser,1,2-二氢异喹啉-3-甲酰-Leu-Arg-Gly-Asp(Val)-Val和1,2-二氢异喹啉-3-甲酰-Leu-Arg-Gly-Asp(Phe)-Phe具有优秀的抗静脉血栓活性。于是,发明人提出本发明。
发明内容
本发明的第一个内容是按照已知方法制备N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰
基]-Leu-Ala-Arg-Gly-Asp(aa)-aa(式中aa为Ser,Val或Phe残基)。
本发明的第二个内容是将N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Ala-Arg-Gly-Asp(aa)-aa(式中aa为Ser,Val或Phe残基)在小鼠血清中脱氢定量转化为1,2-二氢异喹啉-3-甲酰-Pro-Ala-Arg-Gly-Asp(aa)-aa(式中aa为Ser,Val或Phe残基)。
本发明的第三个内容是评价1,2-二氢异喹啉-3-甲酰-Leu-Ala-Arg-Gly-Asp(aa)-aa(式中aa为Ser,Val或Phe残基)的抗静脉血栓活性并观察出血副作用。
附图说明
图1. 1,2-二氢异喹啉-3-甲酰-Leu-Ala-Arg-Gly-Asp(aa)-aa(式中aa为Ser,Val或Phe残基)的合成路线。
实施方式
为了进一步阐明本发明下面给出一系列实施例。必须指出,这些实施例完全是例证性的。给出这些实施例的目的是为了充分明示本发明的意义和内容,决不对本发明造成任何形式的限制。
实施例1制备N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Ala-Arg-Gly-Asp(aa)-aa
按照已经公开的方法制备N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Ala-Arg-Gly-Asp(aa)-aa(式中aa为Ser,Val或Phe残基)。
实施例2制备1,2-二氢异喹啉-3-甲酰-Leu-Ala-Arg-Gly-Asp-(Ser)-Ser(10a)
将50mg(0.04mmol)N-[(3S)-N-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Ala-Arg-Gly-Asp(Ser)-Ser在37℃用1mL小鼠血清溶解,得到的溶液在在37℃恒温震荡4小时,TLC监测原料消失。向血清液中加入2mL甲醇37℃恒温震荡10分钟,得到的混合溶液于3000转/分离心10分钟。离心得到的残留物用超纯水充分萃取,分出萃取液并离心。离心得到的上清液于37℃减压浓缩,残留物用超纯水充分萃取,分出萃取液。合并的萃取液冷冻干燥,得到33mg(96%)标题化合物。ESI(+)-FT-MS:862.50597[M+H]+.Mp 134-135℃.[α]D 25=-19.1(c=1.3,CH3OH).IR(cm-1)3674,3446,3235,2927,2362,1645,1543,1455,1390,1174,1124,1036,644,515,426.1H NMR(300MHz,DMSO)δ/ppm=10.99(s,2H),8.57(s,1H),8.56(s,1H),8.04(m,7H),7.29(m,1H),7.22(m,2H),7.19(m,1H),6.66(s,1H),4.38-4.27(m,4H),4.18(m,3H),3.99(s,1H),3.78-3.71(m,3H),3.32(d J=5.1Hz,1H),3.26(d,J=4.8Hz,1H),3.15-3.03(m,2H),2.80(m,1H),1.63-1.56(m,5H),1.32(d J=7.2Hz,3H),0.87(d,J=5.4Hz,3H),0.84(d,J=5.7Hz,3H)。
实施例3制备1,2-二氢异喹啉-3-甲酰-Leu-Ala-Arg-Gly-Asp(Val)-Val(10b)
按照实施例1的方法由50mg(0.04mmol)N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Ala-Arg-Gly-Asp(Val)-Val制得33mg(96%)标题化合物。ESI(-)-FT-MS:884.47145[M-H]-.Mp 162-163℃.[α]D 25=-14.2(c=1.6,CH3OH).IR(cm-1)3448,3250,2965,2383,1656,1544,1458,1392,1250,1170,1027,765,643,514,439.1H NMR(300MHz,DMSO)δ/ppm=11.02(s,2H),8.56(s,1H),8.55(s,1H),8.04(m,7H),7.50(d,J=7.5Hz,1H),7.24(m,J=5.5Hz,2H),7.15(d,J=8Hz,1H),6.66(s,1H),4.38(d,J=3.9Hz,1H),4.37-4.26(m,3H),3.21-3.11(m,2H),2.80(d,J=4.8Hz,1H),2.14-2.03(m,2H),1.92-1.77(m,3H),1.67-1.53(m,5H),1.35(d,J=2.1Hz,3H),0.91-0.76(m,18H)。
实施例4制备1,2-二氢异喹啉-3-甲酰-Leu-Ala-Arg-Gly-Asp(Phe)-Phe(10c)
按照实施例1的方法由50mg(0.04mmol)N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Ala-Arg-Gly-Asp(Phe)-Phe制得38mg(97%)标题化合物。ESI(-)-FT-MS:980.47343[M-H]-.Mp 128-129℃.[α]D 25=-14.2(c=1.1CH3OH).IR(cm-1)3440,2935,2366,1743,1642,1518,1454,1392,1274,1028,672,506,437.1H NMR(300MHz,DMSO)δ/ppm=11.10(s,2H),8.56(s,1H),8.55(s,1H),8.06(m,7H),7.30(m,1H),8.22(m,2H),7.17(m,1H),7.35-7.42(m,10H),6.67(s,1H),4.43(d,J=4.5Hz,3H),4.27(m,3H),4.08(m,1H),3.70(m,1H),3.45(d,J=5.4Hz,4H),3.20-3.05(m,6H),2.94(m,3H),2.02(d,J=1.8Hz,1H),1.61(m,3H),1.59(m,3H),1.34(d,J=7.2Hz,3H),0.88(dd,J=5.7Hz,J=5.7Hz,7H)。
实施例5评价10a-c的抗静脉血栓活性
雄性SD大鼠(250±20g)适应环境并禁食一天,手术前2min用20%乌拉坦溶液腹腔给药麻醉,固定于板上。从颈动脉取2mL血,用于血液相关指标的测定。将大鼠腹部备皮,消毒,沿腹白线打开腹腔(下至凝固腺,上至露出肝脏一角)。移开腹腔内小肠等器官并用浸润过生理盐水的纱布包裹。钝性分离血管周围结缔组织,暴露下腔静脉及其分支。在肾静脉下方将腹主动脉和下腔静脉剥离,然后用生理盐水浸湿的缝合线在下腔静脉与左肾静脉交汇处将下腔静脉结扎。按解剖位置将肠等器官移回腹腔,用缝合线逐层缝合腹腔。从尾静脉注射10a-c的生理盐水溶液,剂量为1nmol/kg,阳性对照华法林的剂量为4.87μmol/kg,阴性对照为生理盐水。于25-28℃环境中循环4小时之后打开大鼠腹腔,逐个将其分支结扎,从下腔静脉与左肾静脉的交汇处的结扎处开始取出2cm下腔静脉,从中取出血栓。血栓称重,用t检验统计结果。手术以每组两只交替进行,每组12只。血栓称重见表1。结果表明,在1nmol/kg剂量下10a-c可有效地抑制静脉血栓,与在10nmol/kg剂量下对静脉血栓无治疗作用的N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Arg-Gly-Asp(Ser)-Ser,N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Arg-Gly-Asp(Val)-Val和N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Arg-Gly-Asp(Phe)-Phe相比本发明有意想不到的技术效果。此外,10a-c的有效剂量为华法林的1/4870却没有华法林的出血副作用。本发明有意想不到的技术效果。
表1 10a-c的抗静脉血栓活性
化合物 | 剂量 | 血栓湿重(均值±SD mg) |
生理盐水 | 3ml/kg | 25.35±1.41 |
华法林 | 4.87μmol/kg | 13.13±3.71 |
10a | 1nmol/kg | 13.01±3.00<sup>a</sup> |
10b | 1nmol/kg | 12.73±2.43<sup>a</sup> |
10c | 1nmol/kg | 13.22±2.80<sup>a</sup> |
a)与生理盐水比p<0.01,与华法林比p>0.05;n=12。
Claims (3)
2.权利要求1的1,2-二氢异喹啉-3-甲酰-Leu-Ala-Arg-Gly-Asp(aa)-aa的制备方法,该方法包括以下步骤:
1)按照已经公开的方法制备N-[(3S)-N-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Ala-Arg-Gly-Asp(Ser)-Ser;
2)按照已经公开的方法制备N-[(3S)-N-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Ala-Arg-Gly-Asp(Val)-Val;
3)按照已经公开的方法制备N-[(3S)-N-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Ala-Arg-Gly-Asp(Phe)-Phe;
4)在小鼠血清中将N-[(3S)-N-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Ala-Arg-Gly-Asp(Ser)-Ser转化为1,2-二氢异喹啉-3-甲酰-Leu-Ala-Arg-Gly-Asp(Ser)-Ser;
5)在小鼠血清中将N-[(3S)-N-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Ala-Arg-Gly-Asp(Val)-Val转化为1,2-二氢异喹啉-3-甲酰-Leu-Ala-Arg-Gly-Asp(Val)-Val;
6)在小鼠血清中将N-[(3S)-N-1,2,3,4-四氢异喹啉-3-甲酰基]-Leu-Ala-Arg-Gly-Asp(Phe)-Phe转化为1,2-二氢异喹啉-3-甲酰-Leu-Ala-Arg-Gly-Asp(Phe)-Phe。
3.权利要求1的1,2-二氢异喹啉-3-甲酰-Leu-Ala-Arg-Gly-Asp(aa)-aa在制备抗静脉血栓药物中的应用。
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CN105218629A (zh) * | 2014-06-10 | 2016-01-06 | 首都医科大学 | 异喹啉-3-甲酰-RC-OBzl,其制备,纳米结构,活性和应用 |
CN105315334A (zh) * | 2014-06-10 | 2016-02-10 | 首都医科大学 | 异喹啉-3-甲酰-RF-OBzl,其制备,纳米结构,活性和应用 |
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