CN116903622A - 选择性抑制paf的氨基酸修饰的四环化合物及其制备和应用 - Google Patents
选择性抑制paf的氨基酸修饰的四环化合物及其制备和应用 Download PDFInfo
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Abstract
本发明公开了一种选择性抑制PAF的氨基酸修饰的四环化合物及其制备方法和应用。所述的氨基酸修饰的四环化合物的结构如通式Ⅰ所示。式中AA为L‑Val残基,L‑Thr残基,L‑Asp残基及L‑Phe残基。本发明还公开了上述化合物的制备方法,以及所述化合物在治疗动脉血栓性疾病中的应用。
Description
技术领域
本发明涉及一种选择性抑制小板活化因子(PAF)的四种氨基酸修饰的四环化合物,涉及它的制备方法以及在治疗动脉血栓性疾病中的应用。实验证明,本发明的PAF选择性抑制剂有良好的抗动脉血栓作用。本发明属于生物医药领域。
背景技术
动脉栓塞已成为目前发病率高和死亡率高的疾病之一。动脉血栓形成对暂时性脑缺血发作,急性冠状动脉综合症,心肌梗塞和心房颤动负责。在房颤中有18%-47%病人患有冠状动脉疾病,在伴随冠状动脉疾病的房颤患者中有大约20%接受经皮冠状动脉介入治疗。动脉血栓形成还对人工心脏瓣膜,动静脉瘘和其他手术后的动脉血栓及不稳定型心绞痛负责。例如肝移植手术之后,患者面临肝脏动脉血栓风险。此外,抗磷脂综合症患者也面临动脉血栓风险。动脉血栓形成与血小板聚集关联。通常诱发血小板聚集的诱导剂,包括血小板活化因子(PAF),腺苷二磷酸(ADP),凝血酶(TH)及花生四烯酸(AA)。发现血小板活化因子,腺苷二磷酸,凝血酶及花生四烯酸的选择性抑制剂是抗动脉血栓药物研究的重要方向。发明人在研究中发现一种新型的氨基酸修饰的四环化合物,实验发现,该类化合物具有优秀的选择性抑制PAF诱发的血小板聚集的作用。
发明人通过在大鼠丝线法动脉血栓模型上发现,该类四环化合物也显示了优秀的抗动脉血栓活性。根据这些发现,发明人提出了本发明。
发明内容
本发明要解决的技术问题是提供选择性抑制PAF的四种氨基酸修饰的四环化合物,
实验证明,由本发明制备的氨基酸修饰的四环化合物具有选择性抑制小板活化因子(PAF)的作用,和优秀的抗动脉血栓作用。为了达到所述目的,本发明采用了以下技术手段。
第一个技术手段是提出了具有通式Ⅰ结构的四种氨基酸修饰的四环化合物
式中AA代表的氨基酸分别为L-Val残基,L-Thr残基,L-Asp残基或L-Phe残基。
第二个技术手段是提出了制备所述氨基酸修饰的四环化合物方法,该方法包括以下步骤:
1)制备3S-四氢-β-咔啉-3-羧酸;
2)制备3S-四氢-β-咔啉-3-羧酸甲酯;
3)制备3S-2-Boc-Asp(OMe)-四氢-β-咔啉-3-羧酸甲酯;
4)制备3S-2-Asp(OMe)-四氢-β-咔啉-3-羧酸甲酯;
5)制备乙酰甲酯基取代的四环化合物;
6)制备乙酸基取代的四环化合物;
7)制备乙酰-Val-OBzl,乙酰-Thr-OBzl,乙酰-Asp-OBzl及乙酰-Phe-OBzl取代的四环化合物;
8)制备乙酰-Val,乙酰-Thr,乙酰-Asp及乙酰-Phe取代的四环化合物。
本发明提供了上述结构的四种氨基酸取代的四环化合物在制备对PAF诱发的血小板聚集的选择性抑制中的作用。
本发明还提供了所述的四种氨基酸取代的四环化合物在制备抑制动脉血栓药物中作用。
相较于现有技术,本发明的有益效果是:
本发明制备得到了具有通式I结构的四种氨基酸修饰的四环化合物,通过实验发现,该类化合物表现出了良好的抑制PAF诱发的血小板聚集的活性,具有有效抑制大鼠患动脉血栓症的作用。本发明的提出为动脉血栓症的治疗提供了新的治疗药物,丰富了人们对于治疗血栓症的药物选择。
附图说明
图1为选择性抑制PAF的氨基酸修饰的四环化合物的合成路线图:i)CH2O,H2SO4;ii)SOCl2,CH3OH;iii)DCC,HOBt,N-甲基吗啉,Boc-Asp(OMe);iv)氯化氢的乙酸乙酯溶液4N;v)CH3OH,N-甲基吗啉;vi)2N NaOH,CH3OH;vii)H2,钯碳。
具体实施方式
为了进一步阐述本发明,下面给出一系列实施例。这些实施例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。
实施例1制备3S-四氢-β-咔啉-3-羧酸(1)
往400mL水中缓慢加入0.2mL浓硫酸。往得到的稀硫酸水溶液中加入5.0g(24.5mmol)L-Trp,超声振荡至L-Trp完全溶解。往得到的溶液中加入10mL浓度为35%的甲醛水溶液。反应混合物室温搅拌6小时,薄层层析(乙酸乙酯/乙醚,20/1)监测到L-Trp消失,终止反应。反应液中缓慢滴加浓氨水,调节至pH6,静置30分钟。滤出生成的沉淀并用水洗,滤出的无色固体平铺于培养皿,于空气中干燥,得到5.05g(95%)标题化合物,为无色固体。ESI(m/e):217[M+H]+。
实施例2制备3S-四氢-β-咔啉-3-羧酸甲酯(2)
0℃下往3.3g(15mmol)3S-四氢-β-咔啉-3-羧酸的甲醇溶液中缓慢加入SOCl2。反应混合物0℃搅拌6小时,反应混合物不再有HCl气释放及有固体缓慢析出,薄层层析(乙酸乙酯/乙醚,20/1)监测到3S-四氢-β-咔啉-3-羧酸消失,终止反应。反应液减压浓缩至干。残留物用饱和氯化钠水溶液反复洗,过滤,得到3.2g(92%)标题化合,为无色粉末。ESI(m/e)231[M+H]+。
1)实施例3制备3S-[2-Boc-Asp(OCH3)]-四氢-β-咔啉-3-羧酸甲酯(3)制备3S-2-Boc-Asp(OMe)-四氢-β-咔啉-3-羧酸甲酯;
0℃下往3.2g(13.9mmol)3S-四氢-β-咔啉-3-羧酸甲酯与3.4g(13.9mmol)Boc-Asp(OCH3)及150mL无水四氢呋喃的溶液中加2.0g(14.8mmol)N-羟基苯并三唑(HOBt),3.1g(14.8mmol)二环己基羰二亚胺(DCC)。反应混合物0℃搅拌30分钟。然后用N-甲基吗啉(NMM)调pH8。反应混合物0℃搅拌6小时,薄层层析(乙酸乙酯/甲醇,20/1)监测到3S-四氢-β-咔啉-3-羧酸甲酯消失,终止反应。反应混合物过滤,滤液减压浓缩至干,残留物用200mL乙酸乙酯溶解。得到的溶液依次用5%碳酸氢钠水溶液洗(30mL×3),饱和氯化钠水溶液洗(30mL×3),5%盐酸水溶液洗(30mL×3),饱和氯化钠水溶液洗(30mL×3)。分离乙酸乙酯层,用无水硫酸钠干燥12小时,过滤,滤液减压浓缩至干,得到5.9g(93%)标题化合,为无色粉末。ESI(m/e)460[M+H]+。
2)制备3S-2-Asp(OMe)-四氢-β-咔啉-3-羧酸甲酯;
实施例4制备3S-[2-Asp(OCH3)]-四氢-β-咔啉-3-羧酸甲酯(4)
将5.9g(12.9mmol)3S-[2-Boc-Asp(OCH3)]-四氢-β-咔啉-3-羧酸甲酯溶于50mL氯化氢的乙酸乙酯溶液(4N),反应混合物室温搅拌60分钟。薄层层析(乙酸乙酯/甲醇,20/1)监测到3S-[2-Boc-Asp(OCH3)]-四氢-β-咔啉-3-羧酸甲酯消失,终止反应。反应混合物减压浓缩,残留物溶于50mL乙酸乙酯,再减压浓缩。该操作重复5次,得到5.8g(98%)标题化合物,为无色粉末。ESI(m/e)460[M+H]+。
实施例5制备(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酸甲酯(5)
将4.10g(8.9mmol)3S-[2-Asp(OCH3)]-四氢-β-咔啉-3-羧酸甲酯与30mL乙酸乙酯的溶液在30℃搅拌60分钟,完成环合反应。得到1.9g(70%)标题化合物,为无色粉末。ESI(m/e)327[M+Na]+
实施例6制备(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酸(6)
0℃下将1.1g(3.6mml)(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酸甲酯用20mL甲醇溶解,向溶液中滴加2N氢氧化钠水溶液将反应液pH调节到12,反应液再持续搅拌3小时,薄层层析(乙酸乙酯/甲醇,20/1)监测到(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酸甲酯消失,终止反应。反应液先用稀盐酸调pH值到2,再减压浓缩。往残留物中加入50mL蒸馏水,得到的混合物用乙酸乙酯萃取(30mL×3)。合并乙酸乙酯萃取液,用饱和氯化钠水溶液洗(30mL×3)。乙酸乙酯萃取液用无水硫酸钠干燥12小时,过滤,滤液减压浓缩,得0.91g(87%)标题化合物,为无色粉末。Rf=0.35(二氯甲烷/甲醇,5/1)。Mp:228-232℃。[ɑ]2 D 5=-86(c=0.5,甲醇)。ESI(m/e)313[M-H]-。1H NMR(300MHz,DMSO-d6):δ/ppm=11.04(s,1H),8.23(s,1H),7.44(d,J=7.5Hz,1H),7.33(t,J=7.5Hz,1H),7.06(t,J=7.5Hz,1H),6.95(t,J=7.5Hz,1H),5.38(d,J=17.1Hz,1H),4.25(dd,J=3.9Hz,J=11.4Hz,1H),4.20(d,J=17.1Hz,1H),4.16(d,J=15.0Hz,1H),3.18(dd,J=3.3Hz,J=14.7Hz,1H),2.97(t,J=13.5Hz,1H),2.51(d,J=10.5Hz,2H)。13C NMR(75MHz,DMSO-d6):δ/ppm=172.44,165.97,165.05,135.96,129.84,126.35,120.86,118.55,117.53,111.03,105.70,55.61,52.35,40.64,26.43。
实施例7制备(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酰-Val-OBzl(7a)
采用实施例2的反应条件及操作由570mg(1.82mmol)(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酸(6)及800mg(1.82mmol)Val-OBzl得787mg(85%)标题化合物,为无色固体。ESI(m/e)525[M+Na]+。
实施例8制备(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酰-Thr-OBzl(7b)
采用实施例2的反应条件及操作由570mg(1.82mmol)(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酸(6)及806mg(1.82mmol)Thr-OBzl制得448mg(53%)标题合物,为无色固体。ESI(m/e)589[M+Na]+。
实施例9制备(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酰-Asp-OBzl(7c)
采用实施例2的反应条件及操作由570mg(1.82mmol)(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酸(6)及519mg(1.82mmol)Asp-OBzl得530mg(93%)标题化合物,为无色固体。ESI(m/e)631[M+Na]+。
实施例10制备(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酰-Phe-OBzl(7d)
采用实施例2的反应条件及操作由570mg(1.82mmol)(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酸(6)及777mg(1.82mmol)Phe-OBzl得916mg(91%)标题化合物,为无色固体。ESI(m/e)573[M+Na]+。
实施例11制备(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酰-Val(8a)
将130mg(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酰-Val-OBzl(7a)溶于15mL甲醇,并加入30mg钯碳,持续通入氢气,反应2小时,TLC检测7a消失,过滤,甲醇反复冲洗滤饼,滤液减压浓缩,用乙醚带干至无色粉末,得87mg(82%)标题化合物,为无色固体。Rf=0.34(二氯甲烷/甲醇,5/1),Mp:179-193℃。[ɑ]2 D 5=-27(c=0.5,甲醇)。ESI(m/e):411.1663[M-H]-。IR(KBr):3319,3221,2929,1647,1456,1330cm-1。1HNMR(DMSO-d6,300MHz):δ/ppm=10.936(s,1H),8.185(s,1H),8.098(d,J=8.1Hz,1H),7.446(d,J=7.5Hz,1H),7.333(d,J=7.8Hz,1H),7.121(t,J=7.8Hz,1H),6.988(t,J=7.2Hz,1H),5.387(d,J=16.5Hz,1H),4.245(m,2H),4.169(d,J=16.8Hz,1H),4.056(m,1H),3.164(m,1H),3.033(m,1H),2.748(m,2H),0.985(m,1H),0.796(t,J=6.0Hz,6H)。13CNMR(75MHz,DMSO-d6):δ/ppm=173.31,169.36,166.57,165.05,136.41,130.11,126.82,121.48,119.17,118.11,111.51,106.30,57.46,56.22,33.77,30.26,19.34,18.51。
实施例12制备(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酰-Thr(8b)
采用实施例11的反应条件及操作由100mg(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酰-Thr-OBzl制得60mg(71%)标题化合物,为无色固体。Rf=0.25(二氯甲烷/甲醇,5/1),Mp:192-194℃。[ɑ]2 D 5=-14(c=0.5,甲醇)。ESI(m/e)413.145561[M-H]-。IR(KBr):3307,2922,1643,1516,1332,1126cm-1。1HNMR(DMSO-d6,300MHz):δ/ppm=10.971(s,1H),8.213(m,1H),7.450(d,J=8.0Hz,1H),7.340(d,J=8.0Hz,1H),7.076(t,J=7.5Hz,1H),6.998(t,J=7.5Hz,1H),6.934(d,J=9.0Hz,2H),6.611(d,J=9.0Hz,2H),5.387(d,J=16.5Hz,1H),4.270(m,3H),4.175(d,J=16.5Hz,1H),3.185(m,1H),3.023(m,1H),2.852(dd,J=5.5Hz,J=13.5Hz,1H),2.734(dd,J=8.0Hz,J=14.0Hz,1H),2.654(m,2H)。13CNMR(75MHz,DMSO-d6):δ/ppm=173.33,169.43,166.71,165.03,156.53,143.97,136.16,130.56,121.49,119.18,118.10,115.36,111.54,106.29,72.70,65.53,56.26,36.55,26.50。
实施例13制备(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酰-Asp(8c)
采用实施例11的反应条件及操作由200mg(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酰-Asp-OBzl制得140mg标题化合物,为无色固体。Rf=0.33(二氯甲烷/甲醇,5/1),Mp:191℃。[ɑ]2 D 5=-44(c=0.5,甲醇)。ESI(m/e)427.1248[M-H]-。IR(KBr):3315,2848,1647,1463,1192,748cm-1。1HNMR(DMSO-d6,300MHz):δ/ppm=10.953(s,1H),8.321(d,J=7.8Hz,1H),8.228(s,1H),7.444(d,J=7.5Hz,,1H),7.336(d,J=7.8Hz,1H),7.069(t,J=7.2,1H),6.988(t,J=7.2Hz,1H),5.387(d,J=16.8Hz,1H),4.477(dd,J=6.0Hz,J=13.8Hz,1H),4.247(m,2H),4.174(d,J=16.8Hz,1H),3.150(m,1H),3.020(m,1H),2.673(m,2H),2.585(m,2H)。13C NMR(75MHz,DMSO-d6):δ/ppm=172.83,172,21,169.07,166.60,165.07,136.41,130.28,126.84,121.47,119.17,118.10,111.58,106.30,60.23,56.21,52.13,49.06,31.89,26.67,21.24。
实施例14制备(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酰-Phe(8d)
采用实施例11的反应条件及操作由120mg(3S,12aS)-2,3,6,7,12,12a-六氢吡嗪并[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮-3-乙酰-Phe-OBzl制得96mg标题化合物,为无色固体。Rf=0.32(二氯甲烷/甲醇,5/1),Mp:175-178℃。[ɑ]2 D 5=-43(c=0.5,甲醇)。ESI(m/e)460[M-H]-。IR(KBr):3302,2854,1616,1330,1224,1004,744cm-1。1HNMR(DMSO-d6,300MHz):δ/ppm=10.928(S,1H),8.223(d,J=7.8Hz,1H),8.115(S,1H),7.447(d,J=7.5Hz,1H),7.337(d,J=7.8Hz,1H),7.187(m,5H),7.072(t,J=7.2Hz,1H),6.992(t,J=7.5Hz,1H),5.383(d,J=16.5Hz,1H),4.380(m,1H),4.270(m,2H),4.171(d,J=16.8Hz,1H),3.209(m,1H),2.956(m,2H),2.845(dd,J=8.1Hz,J=13.8Hz,1H),2.655(d,J=4.8Hz,2H)。13CNMR(75MHz,DMSO-d6):δ/ppm=173.24,169.14,166.57,165.02,137.91,136.45,130.29,129.62,128.57,126.88,126.79,121.46,119.15,118.09,111.57,106.34,56.27,54.10,37.40,26.68,25.59。
实施例15评价抗血小板聚集活性
将新鲜的猪颈动脉血用3.8%枸橼酸钠(按体积比1/9)抗凝。1000g离心10分钟得富血小板血浆(PRP),3000g离心10分钟得贫血小板血浆(PPP)。用贫血小板血浆调节富血小板血浆,使富血小板血浆中的血小板数适合测定抗血小板聚集活性。8a-d用生理盐水溶解。往比浊管中加0.24mL调节过的富血小板血浆,再加5μL生理盐水溶液或8a-d的生理盐水溶液(5μL,浓度为0.1μM,10μM,15μM,20μM)。调好吸光度的基线,加入5μL四种诱导因子的生理盐水溶液观察血小板在5分钟内的最大聚集率(Am)。四种诱导剂分别是血小板活化因子(PAF,终浓度为50μM),腺苷二磷酸(ADP,终浓度为500μM),凝血酶(TH,终浓度为50IU/L)及花生四烯酸(AA,终浓度为7.5mg/mL)。最大聚集率是对应于聚集曲线波峰的值。每个浓度平行测定6次,形成血小板聚集曲线。根据血小板聚集曲线确定,8a-d抑制血小板活化因子,腺苷二磷酸,凝血酶及花生四烯酸诱发的血小板聚集的IC50(见表1)。
表1 8a-d抑制4种诱导剂诱发的血小板聚集的IC50(均值±SD,μM)
化合物 | ADP | PAF | TH | AA |
8a | 25.24±0.32 | 2.30±0.08 | 16.50±0.22 | 26.58±0.30 |
8b | 26.96±0.32 | 2.41±0.09 | 18.36±0.25 | 20.38±0.28 |
8c | 24.13±0.31 | 2.22±0.07 | 14.42±0.20 | 24.32±0.29 |
8d | 21.31±0.24 | 2.34±0.08 | 15.40±0.21 | 24.48±0.31 |
n=6
表1的数据表明,8a-d代表的四种化合物抑制PAF诱发的血小板聚集的IC50值最小,8a-d是PAF的选择性抑制剂。
实施例16评价抗动脉血栓活性
1)将聚乙烯管拉成一端为斜口的细管,定长为10.0cm,分别为右颈静脉(管径较粗)及左颈动脉(管径较细)插管;中段聚乙烯管定长为8.0cm,血栓线压在颈动脉插管方向,插管前需在管中充满肝素。
2)将体重为200±20g的雄性SD大鼠在手术前适应环境并禁食一天。随机分为生理盐水组(空白对照,口服剂量为0.3mL/100g,10只大鼠),阿司匹林组(阳性对照,口服剂量为167μmol/kg,10只大鼠),8a-d的生理盐水溶液组(口服剂量为1nmol/kg,10只大鼠)。口服30分钟后,大鼠腹腔注射20%乌拉坦溶液麻醉(7mL/kg),2分钟之后开始手术。手术中将大鼠仰卧位于固定板上,剪开颈部皮肤,分离右颈总动脉及左颈静脉,血管下压一根精确称重的丝线,结扎远心端,在静脉的远心端处剪一小口,将插管插入静脉端,注射肝素,而后取下注射肝素的注射器,系线固定,再用动脉夹夹住动脉近心端,在动脉的远心端剪一小口,将动脉端结扎,系线固定后松开动脉夹,建立体外循环旁路。循环15分钟后先剪断静脉观察血液循环是否正常,若血液循正常从动脉端取出附有血栓的丝线,用滤纸吸干未凝固血液,精确称附有血栓的丝线重,将附有血栓的丝线的重量减丝线的重量得到血栓的重量,数据列入表2。表2 8a-d对大鼠动脉血栓的影响
a)与生理盐水比p<0.01;b)与生理盐水比p>0.05;n=10.表2中的血栓重量表明,在1nmol/kg口服剂量下8a-d代表的四种化合物,可以有效的抑制大鼠患动脉血栓症(与生理盐水比p<0.01)。由此可见,本发明有显著的技术效果。
需要声明的是,上述发明内容及具体实施方式意在证明本发明所提供技术方案的实际应用,不应解释为对本发明保护范围的限定。本领域技术人员在本发明的精神和原理内,当可作各种修改、等同替换、或改进。
Claims (5)
1.选择性抑制PAF的四种氨基酸修饰的四环化合物,其特征在于,所述的四环化合物结构式如下:
式中AA代表的氨基酸选自L-Val,L-Thr,L-Asp或L-Phe。
2.权利要求1所述的选择性抑制PAF的四种氨基酸修饰的四环化合物,其特征在于,所述化合物的制备方法包括以下步骤:
1)制备3S-四氢-β-咔啉-3-羧酸;
2)制备3S-四氢-β-咔啉-3-羧酸甲酯;
3)制备3S-2-Boc-Asp(OMe)-四氢-β-咔啉-3-羧酸甲酯;
4)制备3S-2-Asp(OMe)-四氢-β-咔啉-3-羧酸甲酯;
5)制备乙酰甲酯基取代的四环化合物;
6)制备乙酸基取代的四环化合物;
7)制备乙酰-Val-OBzl,乙酰-Thr-OBzl,乙酰-Asp-OBzl及乙酰-Phe-OBzl取代的四环化合物;
8)制备乙酰-Val,乙酰-Thr,乙酰-Asp及乙酰-Phe取代的四环化合物。
3.权利要求1或2所述的四环化合物,其特征在于,所述化合物在制备选择性抑制PAF药物中的应用。
4.权利要求3所述的四环化合物,其特征在于,所述化合物在制备选择性抑制血小板活化因子诱发的血小板聚集药物中的应用。
5.权利要求1或2所述的四环化合物,其特征在于,所述化合物在制备抗动脉血栓药用中的应用。
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