[发明专利]N‑(3S‑四氢‑β‑咔啉‑3‑羰基)‑AA‑GDV,其合成,纳米结构,抗血栓活性及应用

权利要求书

1.式5a-e所示的N-(3S-四氢-β-咔啉-3-羰基)-AA-Gly-Asp-Val五种缀合物,5a-e中的AA＝L-Ala,L-Ile,L-Leu,L-Met或Gly残基，

2.制备权利要求1的5a-e所示的N-(3S-四氢-β-咔啉-3-羰基)-AA-Gly-Asp-Val五种缀合物的方法,该法由以下步骤构成：

(1)在二环己基碳二亚胺(DCC)和N-羟基苯并三氮唑(HOBt)存在下Boc-Ala,Boc-Ile,Boc-Leu,Boc-Met,Boc-Gly在无水四氢呋喃(THF)中分别与Tos·Gly-OBzl缩合生成Boc-Ala-Gly-OBzl,Boc-Ile-Gly-OBzl,Boc-Leu-Gly-OBzl,Boc-Met-Gly-OBzl,Boc-Gly-Gly-OBzl；

(2)在NaOH存在下,在甲醇中将Boc-Ala-Gly-OBzl,Boc-Ile-Gly-OBzl,Boc-Leu-Gly-OBzl,Boc-Met-Gly-OBzl,Boc-Gly-Gly-OBzl水解为Boc-Ala-Gly,Boc-Ile-Gly,Boc-Leu-Gly,Boc-Met-Gly,Boc-Gly-Gly；

(3)在DCC存在下无水THF中Boc-Asp(OBzl)与Tos·Val-OBzl缩合为Boc-Asp(OBzl)-Val-OBzl；

(4)在氯化氢对乙酸乙酯溶液中Boc-Asp(OBzl)-Val-OBzl脱去Boc生成HCl·Asp(OBzl)-Val-OBzl；

(5)在DCC和HOBt存在下,Boc-Ala-Gly,Boc-Ile-Gly,Boc-Leu-Gly,Boc-Met-Gly,Boc-Gly-Gly在无水THF中分别与HCl·Asp(OBzl)-Val-OBzl缩合生成Boc-Ala-Gly-Asp(OBzl)-Val-OBzl,Boc-Ile-Gly-Asp(OBzl)-Val-OBzl,Boc-Leu-Gly-Asp(OBzl)-Val-OBzl,Boc-Met-Gly-Asp(OBzl)-Val-OBzl和Boc-Gly-Gly-Asp(OBzl)-Val-OBzl；

(6)在稀硫酸存在下，L-色氨酸和甲醛缩合生成3S-1,2,3,4-四氢-β-咔啉-3-羧酸,该化合物在三乙胺存在下与Boc酸酐反应，制得3S-N-Boc-1,2,3,4-四氢-β-咔啉-3-羧酸；

(7)在氯化氢的乙酸乙酯溶液中Boc-Ala-Gly-Asp(OBzl)-Val-OBzl,Boc-Ile-Gly-Asp(OBzl)-Val-OBzl,Boc-Leu-Gly-Asp(OBzl)-Val-OBzl,Boc-Met-Gly-Asp(OBzl)-Val-OBzl和Boc-Gly-Gly-Asp(OBzl)-Val-OBzl分别脱去Boc生成HCl·Ala-Gly-Asp(OBzl)-Val-OBzl,HCl·Ile-Gly-Asp(OBzl)-Val-OBzl,HCl·Leu-Gly-Asp(OBzl)-Val-OBzl,HCl·Met-Gly-Asp(OBzl)-Val-OBzl和HCl·Gly-Gly-Asp(OBzl)-Val-OBzl；

(8)在DCC和HOBt存在下3S-N-Boc-1,2,3,4-四氢-β-咔啉-3-羧酸在无水THF中与HCl·Ala-Gly-Asp(OBzl)-Val-OBzl,HCl·Ile-Gly-Asp(OBzl)-Val-OBzl,HCl·Leu-Gly-Asp(OBzl)-Val-OBzl,HCl·Met-Gly-Asp(OBzl)-Val-OBzl和HCl·Gly-Gly-Asp(OBzl)-Val-OBzl分别缩合生成N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Ala-Gly-Asp(OBzl)-Val-OBzl,N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Ile-Gly-Asp(OBzl)-Val-OBzl,N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Leu-Gly-Asp(OBzl)-Val-OBzl,N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Met-Gly-Asp(OBzl)-Val-OBzl和N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Gly-Gly-Asp(OBzl)-Val-OBzl；

(9)在钯碳(Pd/C)存在下,在甲醇中将N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Ala-Gly-Asp(OBzl)-Val-OBzl,N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Ile-Gly-Asp(OBzl)-Val-OBzl,N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Leu-Gly-Asp(OBzl)-Val-OBzl,和N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Gly-Gly-Asp(OBzl)-Val-OBzl分别氢解为N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Ala-Gly-Asp-Val,N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Ile-Gly-Asp-Val,N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Leu-Gly-Asp-Val,和N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Gly-Gly-Asp-Val；

(10)在Pd/C存在下,在甲醇中按照质量比原料:BaSO₄(100:1)加入BaSO₄,并按照体积比甲醇:甲酸(1:0.01)加入甲酸，将N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Met-Gly-Asp(OBzl)-Val-OBzl氢解为N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Met-Gly-Asp-Val；

(11)在氯化氢的乙酸乙酯溶液中分别将N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Ala-Gly-Asp-Val,N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Ile-Gly-Asp-Val,N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Leu-Gly-Asp-Val,N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Met-Gly-Asp-Val和N-[N-Boc-(3S-四氢-β-咔啉-3-羰基)]-Gly-Gly-Asp-Val脱去Boc生成HCl·N-(3S-四氢-β-咔啉-3-羰基)-Ala-Gly-Asp-Val,HCl·N-(3S-四氢-β-咔啉-3-羰基)-Ile-Gly-Asp-Val,HCl·N-(3S-四氢-β-咔啉-3-羰基)-Leu-Gly-Asp-Val,HCl·N-(3S-四氢-β-咔啉-3-羰基)-Met-Gly-Asp-Val和HCl·N-(3S-四氢-β-咔啉-3-羰基)-Gly-Gly-Asp-Val；

(12)在水溶液中，用饱和NaHCO₃调节pH至6将HCl·N-(3S-四氢-β-咔啉-3-羰基)-Ala-Gly-Asp-Val,HCl·N-(3S-四氢-β-咔啉-3-羰基)-Ile-Gly-Asp-Val,HCl·N-(3S-四氢-β-咔啉-3-羰基)-Leu-Gly-Asp-Val,HCl·N-(3S-四氢-β-咔啉-3-羰基)-Met-Gly-Asp-Val和HCl·N-(3S-四氢-β-咔啉-3-羰基)-Gly-Gly-Asp-Val并通过SephadexG-10除盐,得到N-(3S-四氢-β-咔啉-3-羰基)-Ala-Gly-Asp-Val,N-(3S-四氢-β-咔啉-3-羰基)-Ile-Gly-Asp-Val,N-(3S-四氢-β-咔啉-3-羰基)]-Leu-Gly-Asp-Val,N-(3S-四氢-β-咔啉-3-羰基)-Met-Gly-Asp-Val和N-(3S-四氢-β-咔啉-3-羰基)-Gly-Gly-Asp-Val。

3.权利要求1的5a-e所示的N-(3S-四氢-β-咔啉-3-羰基)-AA-Gly-Asp-Val五种缀合物在制备抗血栓药物中的应用。