CN109810174A - 异喹啉-3-甲酰-TARGD(aa)aa, 其制备, 抗静脉血栓活性和应用 - Google Patents
异喹啉-3-甲酰-TARGD(aa)aa, 其制备, 抗静脉血栓活性和应用 Download PDFInfo
- Publication number
- CN109810174A CN109810174A CN201711161263.0A CN201711161263A CN109810174A CN 109810174 A CN109810174 A CN 109810174A CN 201711161263 A CN201711161263 A CN 201711161263A CN 109810174 A CN109810174 A CN 109810174A
- Authority
- CN
- China
- Prior art keywords
- thr
- gly
- arg
- asp
- ala
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 206010047249 Venous thrombosis Diseases 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 230000000694 effects Effects 0.000 title abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 5
- 229940079593 drug Drugs 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 10
- 210000002966 serum Anatomy 0.000 claims description 6
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 claims description 5
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 208000007536 Thrombosis Diseases 0.000 description 7
- 210000003462 vein Anatomy 0.000 description 7
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 6
- 229960005080 warfarin Drugs 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 210000000683 abdominal cavity Anatomy 0.000 description 5
- 239000002504 physiological saline solution Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 208000032843 Hemorrhage Diseases 0.000 description 3
- 210000002796 renal vein Anatomy 0.000 description 3
- 238000004252 FT/ICR mass spectrometry Methods 0.000 description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- ZSVHUITUMSDFCK-UHFFFAOYSA-N isoquinoline;quinoline Chemical compound C1=NC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 ZSVHUITUMSDFCK-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 210000001631 vena cava inferior Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了下式的异喹啉‑3‑甲酰‑Thr‑Ala‑Arg‑Gly‑Asp(aa)‑aa(式中aa为Ser,Val或Phe残基),公开了它们的制备方法,公开了它们的抗静脉血栓活性,因而本发明公开了它们在制备抗静脉血栓药物中的应用。
Description
技术领域
本发明涉及异喹啉-3-甲酰-Thr-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]-Thr-Arg-Gly-Asp(Ser)-Ser,N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰基]-Thr-Arg-Gly-Asp(Val)-Val和N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰基]-Thr-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大鼠血液中发现了异喹啉-3-甲酰-Thr-Arg-Gly-Asp(Ser)-Ser,异喹啉-3-甲酰-Thr-Arg-Gly-Asp(Val)-Val和异喹啉-3-甲酰-Thr-Arg-Gly-Asp(Phe)-Phe(见下面的转化式)。在后续研究中,发明人进一步发现异喹啉-3-甲酰-Thr-Arg-Gly-Asp(Ser)-Ser,异喹啉-3-甲酰-Thr-Arg-Gly-Asp(Val)-Val和异喹啉-3-甲酰-Thr-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
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]-Thr-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]-Thr-Ala-Arg-Gly-Asp(aa)-aa(式中aa为Ser,Val或Phe残基)在大鼠血清中脱氢定量转化为异喹啉-3-甲酰-Thr-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异喹啉-3-甲酰-Thr-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.异喹啉-3-甲酰-Thr-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]-Thr-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]-Thr-Ala-Arg-Gly-Asp(aa)-aa(式中aa为Ser,Val或Phe残基)。
实施例2制备异喹啉-3-甲酰-Thr-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]-Thr-Ala-Arg-Gly-Asp(Ser)-Ser在37℃用1mL大鼠血清溶解,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:846.33778[M-H]-.Mp 138-139℃.[α]D 25=-15.0(c=1.3,CH3OH).IR(cm-1)3670,3444,3233,2926,2360,1643,1540,1454,1392,1173,1120,1035,640,510,425.1H NMR(300MHz,DMSO)δ/ppm=10.99(s,2H),9.20(s,1H),8.55(s,1H),8.51(s,1H),8.42(d,J=8.0Hz,2H),8.14(d,J=7.5Hz,1H),8.07(s,1H),7.97(d,J=5.5Hz,1H),7.75(d,J=8Hz,1H),7.16(m,4H),4.59(m,2H),4.51(m,2H),4.45(q,J=8.0Hz,1H),4.28(m,3H),4.22(m,1H),4.12(m,8H),2.64(dd,J=6.3Hz,J=6.9Hz,1H),2.55(dd,J=6.3Hz,J=6.9Hz,1H),2.01(m,4H),1.98(m,2H),1.77(m,2H),1.55(m,2H),1.49(d,J=7.8Hz,3H),1.22(d,J=8.4Hz,3H)。
实施例3制备异喹啉-3-甲酰-Thr-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]-Thr-Ala-Arg-Gly-Asp(Val)-Val制得33mg(96%)标题化合物。ESI(+)-FT-MS:872.42941[M+H]+.Mp 162-163℃.[α]D 25=-13.1(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=11.01(s,2H),9.20(s,1H),8.53(s1H),8.51(s,1H),8.42(d,J=8.0Hz,2H),8.14(d,J=7.5Hz,1H),8.07(s,1H),7.97(d,J=5.5Hz,1H),7.75(d,J=8Hz,1H),7.16(m,4H),4.63(m,1H),4.51(m,1H),4.45(q,J=8.0Hz,1H),4.39(m,2H),4.28(m,4H),4.12(m,4H),3.11(m,2H),2.64(dd,J=6.3Hz,J=6.9Hz,1H),2.55(dd,J=6.3Hz,J=6.9Hz,1H),2.01(m,4H),1.77(m,2H),1.55(m,2H),1.49(d,J=7.8Hz,3H),1.02(d,J=8.2Hz,12H),1.22(d,J=8.2Hz,3H)。
实施例4制备异喹啉-3-甲酰-Thr-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]-Thr-Ala-Arg-Gly-Asp(Phe)-Phe制得38mg(97%)标题化合物0Mp 132-133℃.[α]D 25=-11.7(c=1.1CH3OH).IR(cm-1)3446,2931,2368,1741,1645,1516,1456,1390,1271,1027,674,508,439.1H NMR(300MHz,DMSO)δ/ppm=10.98(s,2H),9.22(s,1H),8.52(s1H),8.51(s,1H),8.42(d,J=8.0Hz,2H),8.14(d,J=7.5Hz,1H),8.07(s,1H),7.97(d,J=5.5Hz,1H),7.75(d,J=8Hz,1H),7.34-7.26(m,10H),7.16(m,4H),4.81(m,2H),4.62(m,1H),4.51(m,1H),4.45(q,J=8.0Hz,1H),4.28(m,4H),4.12(m,4H),3.15(m,4H),2.64(dd,J=6.3Hz,J=6.9Hz,1H),2.55(dd,J=6.3Hz,J=6.9Hz,1H),2.01(m,3H),1.97(m,1H),1.77(m,2H),1.55(m,2H),1.49(d,J=7.8Hz,3H),1.22(d,J=8.2Hz,3H)。
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]-Thr-Arg-Gly-Asp(Ser)-Ser,N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰基]-Thr-Arg-Gly-Asp(Val)-Val和N-[(3S)-1,2,3,4-四氢异喹啉-3-甲酰基]-Thr-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 | 13.72±3.06<sup>a</sup> |
10b | 1nmol/kg | 13.40±3.53<sup>a</sup> |
10c | 1nmol/kg | 13.76±2.88<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)
1.下式的异喹啉-3-甲酰-Thr-Ala-Arg-Gly-Asp(aa)-aa,式中aa为Ser,Val或Phe残基
2.权利要求1的异喹啉-3-甲酰-Thr-Ala-Arg-Gly-Asp(aa)-aa的制备方法,该方法步骤如下:
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]-Thr-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]-Thr-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]-Thr-Ala-Arg-Gly-Asp(Phe)-Phe;
4)在大鼠血清中将N-[(3S)-N-1,2,3,4-四氢异喹啉-3-甲酰基]-Thr-Ala-Arg-Gly-Asp(Ser)-Ser转化为异喹啉-3-甲酰-Thr-Ala-Arg-Gly-Asp(Ser)-Ser;
5)在大鼠血清中将N-[(3S)-N-1,2,3,4-四氢异喹啉-3-甲酰基]-Thr-Ala-Arg-Gly-Asp(Val)-Val转化为异喹啉-3-甲酰-Thr-Ala-Arg-Gly-Asp(Val)-Val;
6)在大鼠血清中将N-[(3S)-N-1,2,3,4-四氢异喹啉-3-甲酰基]-Thr-Ala-Arg-Gly-Asp(Phe)-Ser转化为异喹啉-3-甲酰-Thr-Ala-Arg-Gly-Asp(Phe)-Phe。
3.权利要求1的异喹啉-3-甲酰-Thr-Ala-Arg-Gly-Asp(aa)-aa在制备抗静脉血栓药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711161263.0A CN109810174B (zh) | 2017-11-21 | 2017-11-21 | 异喹啉-3-甲酰-TARGD(aa)aa,其制备,抗静脉血栓活性和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711161263.0A CN109810174B (zh) | 2017-11-21 | 2017-11-21 | 异喹啉-3-甲酰-TARGD(aa)aa,其制备,抗静脉血栓活性和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109810174A true CN109810174A (zh) | 2019-05-28 |
CN109810174B CN109810174B (zh) | 2021-01-01 |
Family
ID=66599511
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201711161263.0A Expired - Fee Related CN109810174B (zh) | 2017-11-21 | 2017-11-21 | 异喹啉-3-甲酰-TARGD(aa)aa,其制备,抗静脉血栓活性和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109810174B (zh) |
Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1431199A (zh) * | 2003-01-22 | 2003-07-23 | 浙江大学 | 1-氨基异喹啉的合成方法 |
CN1441784A (zh) * | 2000-07-12 | 2003-09-10 | 阿克佐诺贝尔公司 | 含有氨基异喹啉基团的凝血酶抑制剂 |
CN101405269A (zh) * | 2006-03-18 | 2009-04-08 | 塞诺菲-安万特股份有限公司 | 取代的1-氨基-4-苯基二氢异喹啉类、其制备方法、其作为药物的用途以及包含它们的药物 |
WO2010129816A2 (en) * | 2009-05-07 | 2010-11-11 | Intellikine, Inc. | Heterocyclic compounds and uses thereof |
CN102131784A (zh) * | 2008-06-24 | 2011-07-20 | 赛诺菲-安万特 | 作为rho激酶抑制剂的取代的异喹啉和异喹啉酮 |
US20120094997A1 (en) * | 2010-10-18 | 2012-04-19 | Millennium Pharmaceuticals, Inc. | Substituted hydroxamic acids and uses thereof |
CN103450344A (zh) * | 2012-06-01 | 2013-12-18 | 首都医科大学 | 四氢异喹啉-3-羧酸修饰的largd七肽、其合成、抗血栓活性和应用 |
CN103450343A (zh) * | 2012-06-01 | 2013-12-18 | 首都医科大学 | 四氢异喹啉-3-羧酸修饰的targd七肽、其合成、抗血栓活性和应用 |
CN103450342A (zh) * | 2012-06-01 | 2013-12-18 | 首都医科大学 | 四氢异喹啉-3-羧酸修饰的pargd七肽、其合成、抗血栓活性和应用 |
CN104211767A (zh) * | 2013-06-05 | 2014-12-17 | 首都医科大学 | 异喹啉-3-甲酰氨基酰寡肽,其制备,纳米结构,抗肿瘤活性和应用 |
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 |
-
2017
- 2017-11-21 CN CN201711161263.0A patent/CN109810174B/zh not_active Expired - Fee Related
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1441784A (zh) * | 2000-07-12 | 2003-09-10 | 阿克佐诺贝尔公司 | 含有氨基异喹啉基团的凝血酶抑制剂 |
CN1431199A (zh) * | 2003-01-22 | 2003-07-23 | 浙江大学 | 1-氨基异喹啉的合成方法 |
CN101405269A (zh) * | 2006-03-18 | 2009-04-08 | 塞诺菲-安万特股份有限公司 | 取代的1-氨基-4-苯基二氢异喹啉类、其制备方法、其作为药物的用途以及包含它们的药物 |
CN102131784A (zh) * | 2008-06-24 | 2011-07-20 | 赛诺菲-安万特 | 作为rho激酶抑制剂的取代的异喹啉和异喹啉酮 |
WO2010129816A2 (en) * | 2009-05-07 | 2010-11-11 | Intellikine, Inc. | Heterocyclic compounds and uses thereof |
US20120094997A1 (en) * | 2010-10-18 | 2012-04-19 | Millennium Pharmaceuticals, Inc. | Substituted hydroxamic acids and uses thereof |
CN103450344A (zh) * | 2012-06-01 | 2013-12-18 | 首都医科大学 | 四氢异喹啉-3-羧酸修饰的largd七肽、其合成、抗血栓活性和应用 |
CN103450343A (zh) * | 2012-06-01 | 2013-12-18 | 首都医科大学 | 四氢异喹啉-3-羧酸修饰的targd七肽、其合成、抗血栓活性和应用 |
CN103450342A (zh) * | 2012-06-01 | 2013-12-18 | 首都医科大学 | 四氢异喹啉-3-羧酸修饰的pargd七肽、其合成、抗血栓活性和应用 |
CN104211767A (zh) * | 2013-06-05 | 2014-12-17 | 首都医科大学 | 异喹啉-3-甲酰氨基酰寡肽,其制备,纳米结构,抗肿瘤活性和应用 |
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 |
Also Published As
Publication number | Publication date |
---|---|
CN109810174B (zh) | 2021-01-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Haycraft | IV. On the action of a secretion obtained from the medicinal leech on the coagulation of the blood | |
Florey et al. | The release of an inhibitory substance from mammalian brain, and its effect on peripheral synaptic transmission | |
CN101657208A (zh) | 一种中药组合物、其所含虫类药提取物及其制备方法 | |
EP2051721B1 (en) | Preparation and pharmaceutical use of euterpe oleracea (acai) extract compositions | |
CN109810170A (zh) | 二氢异喹啉-3-甲酰-PARGD(aa)aa, 其制备, 抗静脉血栓活性和应用 | |
CN109810174A (zh) | 异喹啉-3-甲酰-TARGD(aa)aa, 其制备, 抗静脉血栓活性和应用 | |
CN102727536B (zh) | 一种水杉皮提取物及其制备方法和用途 | |
CN105125601B (zh) | 一种赶黄草的提取物及其制备方法和用途 | |
CN109810173A (zh) | 二氢异喹啉-3-甲酰-TARGD(aa)aa, 其制备, 抗静脉血栓活性和应用 | |
CN109810172A (zh) | 异喹啉-3-甲酰-PARGD(aa)aa, 其制备, 抗静脉血栓活性和应用 | |
CN109810171A (zh) | 二氢异喹啉-3-甲酰-LARGD(aa)aa, 其制备, 抗静脉血栓活性和应用 | |
CN109810175A (zh) | 异喹啉-3-甲酰-LARGD(aa)aa, 其制备, 抗静脉血栓活性和应用 | |
CN105878288B (zh) | 一种美洲大蠊酶解物及其制备方法和应用 | |
CA2440333C (en) | Process for obtention of decoctions of vitis labrusca and vitis vinifera skins | |
Bowman et al. | Actions on the cardiovascular system of an inhibitory material extracted from the bovine retractor penis. | |
Orie | Direct vascular effects of plantain extract in rats | |
CN101503721A (zh) | 一种蚌肉多糖的提取方法 | |
CN107744571A (zh) | 一种改善血管内皮功能障碍的药物组合物及其制备方法和用途 | |
CN104758270B (zh) | 一种树莓多糖泡腾片及其用途 | |
CN106974862A (zh) | 一种微波辅助提取白木瓜提取液的制备方法 | |
CN105079495B (zh) | 一种缓解体力疲劳和降血脂的保健饮料及其制备方法 | |
CN108815252A (zh) | 俄色果及其提取物在制备降压药物中的用途 | |
Ravdin | Vasodepressor substances in the liver: after obstruction of the common duct | |
RU2623146C1 (ru) | Способ получения биологически активного концентрата из кожи маралов | |
Inoue et al. | Successfully Treated Massive Pulmonary Thromboembolism and Thrombus in the Right Atrium Due to Diffuse Malignant Lymphoma: A Case Report (English text) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20210101 |
|
CF01 | Termination of patent right due to non-payment of annual fee |