CN103159835A - Lys and oligopeptide-modified curcumin derivatives, and synthesis and medical application thereof - Google Patents

Lys and oligopeptide-modified curcumin derivatives, and synthesis and medical application thereof Download PDF

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CN103159835A
CN103159835A CN2011104151539A CN201110415153A CN103159835A CN 103159835 A CN103159835 A CN 103159835A CN 2011104151539 A CN2011104151539 A CN 2011104151539A CN 201110415153 A CN201110415153 A CN 201110415153A CN 103159835 A CN103159835 A CN 103159835A
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boc
methoxy
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obzl
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CN103159835B (en
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赵明
彭师奇
吴建辉
王玉记
王枫
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Capital Medical University
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Abstract

The present invention discloses six pseudo-peptides of the general formula I, wherein R1 is H or CH3, and R2 is Lys or Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val or Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val. The present invention further discloses a preparation method and use thereof. The compounds of the present invention have excellent thrombolytic activity, antithrombotic activity, anti-inflammatory activity, and OH radical scavenging activity, and a nanostructure.

Description

The curcumin derivate that Lys and oligopeptides are modified, its synthetic application that reaches in medical science
Technical field
The present invention relates to 6 kinds of pseudo-peptides of general formula I, R in formula 1Be H or CH 3, R 2Be Lys or Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val or Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val.The invention further relates to their preparation method and purposes.Compound of the present invention is except having outstanding thrombus dissolving activity, antithrombotic acitivity, anti-inflammatory activity, OH free radical scavenging activity and nanostructure.The invention belongs to biomedicine field.
Figure BSA00000635313900011
Background technology
Curcumine is one of effective constituent of turmeric, has antithrombotic, anti-inflammatory and removes free radical activity, and be the natural product of safety and low toxicity.Inflammatory reaction promotes release and the platelet activation of thrombin, lowers simultaneously natural anticoagulant and suppresses fibrinolytic, and thrombosis attends by the process that acute inflammation transforms to unrestrained property inflammation.The inflammation of appropriateness is conducive to suffer the body of various damages to keep the stable of environment in self, is conducive to the recovery that body is safeguarded the complete and function of self structure.Yet excessively strong inflammatory reaction may aggravate the damage of body, produces the chain reaction of a sequence, causes vicious cycle.Give and anti-inflammatory drug in thromboembolism treatment, help to improve the thrombolysis rate, alleviate tissue injury.Ischemical reperfusion injury is a reason that causes tissue injury after thrombolysis, and free radical is an important factor that causes reperfusion injury.Give and free-radical scavengers in thromboembolism treatment, have provide protection for ischemical reperfusion injury.Although curcumine all shows the activity of expectation on In Vitro Anti platelet aggregation model, external free radical scavenging model, rat arteriovenous shut intubate antithrombotic model and mice ear anti-inflammatory model; and these activity all have provide protection to cerebral ischemia re-pouring injured, myocardial ischemia-reperfusion injury, lung reperfusion injury; but curcumine does not have thrombus dissolving activity, and the prerequisite that namely produces ischemia-reperfusion does not exist.The contriver recognizes, only has to introduce the thrombus dissolving oligopeptides in the curcumine and could realize its described provide protection.
P6A (Ala-Arg-Pro-Ala-Lys) is one of scleroproein β chain degradation product, has thrombus dissolving activity.The contriver has found meta-bolites PAK in the metabolism research of P6A.On rat arteriovenous shut intubate thrombus dissolving model, P6A is strong for PAK thrombus specific activity parent.According to general understanding, polypeptide all can be degraded rapidly in vivo.Tie by PAK delays vivo degradation speed and improves thrombus dissolving activity, is the important channel of oligopeptides thrombolytic agent research.
According to general understanding, contain the amphipathic molecule of polypeptide, for example the polypeptide of aliphatic alcohol chain modification, cross under suitable condition noncovalent intermolecular interactions and can form nanostructure.By nanostructure can improve in vivo conveying of polypeptide, delay polypeptide in vivo degradation rate and improve the activity in vivo of polypeptide.According to these understanding, the contriver has proposed the present invention.
Platelet membrane glycoprotein GPIIb/IIIa receptor activation is the final shared pathway of platelet aggregation, plays an important role in thrombosis.Arg-Gly-Asp (RGD)/Ala-Gly-Asp (AGD) tetrapeptide is the ligands specific of platelet surface GPIIb/IIIa acceptor, not only have antiplatelet aggregative activity, and optionally embody the antithrombotic targeting to the Activated platelet surface bonding.Utilize the antithrombotic target effect of RGD/AGD tetrapeptide can prepare the targeted drug of the treatment thrombus that contains the RGD/AGD tetrapeptide.
According to general understanding, contain the amphipathic molecule of polypeptide, for example self-assembly, can occur by noncovalent intermolecular interactions in the polypeptide of aliphatic alcohol chain modification under suitable condition, forms nanostructure.By nanostructure can improve in vivo conveying of polypeptide, delay polypeptide in vivo degradation rate and improve the activity in vivo of polypeptide.According to these understanding and discovery, the contriver has proposed the present invention.
Summary of the invention
First content of the present invention is to provide 6 kinds of pseudo-peptides of general formula I.R in formula 1Be H or CH 3, R 2Be Lys or Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val or Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val.
Figure BSA00000635313900021
Second content of the present invention is to provide the preparation method of 6 kinds of pseudo-peptides of general formula I, and the method comprises:
(1) Boc-Pro is Boc-Pro-OSu with the HOSu condensation in anhydrous THF under dicyclohexylcarbodiimide (DCC) and N-hydroxy-succinamide (HOSu) existence, at NaHCO 3Exist lower Boc-Pro-OSu and L-Ala reaction to generate Boc-Pro-Ala;
(2) Boc-Pro-Ala is Boc-Pro-Ala-Lys (Boc)-OBzl with Lys (Boc)-OBzl condensation in anhydrous THF under DCC and HOBt existence;
(3) under existing, NaOH in methyl alcohol, Boc-Pro-Ala-Lys (Boc)-OBzl is hydrolyzed to Boc-Pro-Ala-Lys (Boc);
(4) Boc-Asp (OBzl) is Boc-Asp (OBzl)-Val-OBzl with the Val-OBzl condensation in anhydrous THF under DCC and HOBt existence;
(5) Boc-Asp (OBzl)-Val-OBzl sloughs Boc and generates Asp (OBzl)-Val-OBzl in hydrogenchloride-ethyl acetate solution;
(6) Boc-Ala is Boc-Ala-Gly-OBzl with the Gly-OBzl condensation in anhydrous THF under DCC and HOBt existence;
(7) under existing, NaOH in methyl alcohol, Boc-Ala-Gly-OBzl is hydrolyzed to Boc-Ala-Gly;
(8) Boc-Ala-Gly is Boc-Ala-Gly-Asp (OBzl)-Val-OBzl with Asp (OBzl)-Val-OBzl condensation in anhydrous THF under DCC and HOBt existence;
(9) Boc-Ala-Gly-Asp (OBzl)-Val-OBzl sloughs Boc and generates Ala-Gly-Asp (OBzl)-Val-OBzl in hydrogenchloride-ethyl acetate solution;
(10) Boc-Arg is Boc-Arg-Gly-OBzl with the Gly-OBzl condensation in anhydrous THF under DCC and HOBt existence;
(11) under existing, NaOH in methyl alcohol, Boc-Arg-Gly-OBzl is hydrolyzed to Boc-Arg-Gly;
(12) Boc-Arg-Gly is Boc-Arg-Gly-Asp (OBzl)-Val-OBzl with Asp (OBzl)-Val-OBzl condensation in anhydrous THF under DCC and HOBt existence;
(13) Boc-Arg-Gly-Asp (OBzl)-Val-OBzl sloughs Boc and generates Arg-Gly-Asp (OBzl)-Val-OBzl in hydrogenchloride-ethyl acetate solution;
(14) in anhydrous K 2CO 3Under existence in anhydrous THF the reaction of Vanillin and ethyl bromoacetate generate 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde;
(15) at B 2O 3, (nBuo) 3It is 6-(3,4-, two-methoxyphenyl)-5 with the methyl ethyl diketone condensation in anhydrous ethyl acetate that there are lower Veratraldehyde in B and nBu-NH, 6-hexene-2,4-diketone;
(16) at B 2O 3, (nBuo) 3Under B and nBu-NH existed, Vanillin and methyl ethyl diketone condensation were 6-(3-methoxyl group-4-hydroxyphenyl)-5 in anhydrous ethyl acetate, 6-hexene-2,4-diketone;
(17) at B 2O 3, (nBuo) 3Under B and nBu-NH exist in anhydrous ethyl acetate 6-(3-p-methoxy-phenyl)-5,6-hexene-2,4-diketone and 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde condensation is 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3, the 5-diketone, or at B 2O 3, (nBuo) 3Under B and nBu-NH exist, 6-in anhydrous ethyl acetate (4-methyl-3-p-methoxy-phenyl)-5,6-hexene-2,4-diketone and 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde condensation is 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3, the 5-diketone;
(18) under NaOH exists in acetone with 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(3-p-methoxy-phenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone, or under NaOH exists in acetone with 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone,
(19) under DCC and HOBt exist in anhydrous THF 1-(3-p-methoxy-phenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone and Lys (Boc)-OBzl condensation is 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone, or under DCC and HOBt exist in anhydrous THF 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone and Lys (Boc)-OBzl condensation is 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone,
(20) 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1 in hydrogenchloride-ethyl acetate solution, 6-heptadiene-3, the 5-diketone is sloughed Boc and is generated 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone, or in hydrogenchloride-ethyl acetate solution 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone is sloughed Boc and is generated 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone,
(21) under NaOH exists, in methyl alcohol with 1-(3-p-methoxy-phenyl)-7-[4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl]-1, 6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone or under NaOH exists, in methyl alcohol with 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone,
(22) under DCC and HOBt exist in anhydrous THF Boc-Pro-Ala-Lys (Boc) and 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the condensation of 5-diketone is 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)-OBzl]-the 3-p-methoxy-phenyl }-1, 6-heptadiene-3, the 5-diketone, or deposit DCC and HOBt exist under in anhydrous THF Boc-Pro-Ala-Lys (Boc) and 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the condensation of 5-diketone is 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)-OBzl]-the 3-p-methoxy-phenyl }-1, 6-heptadiene-3, the 5-diketone,
(23) under NaOH exists in methyl alcohol with 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)-OBzl]-the 3-p-methoxy-phenyl-1, 6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-the 3-p-methoxy-phenyl }-1, 6-heptadiene-3, the 5-diketone, or under NaOH exists in methyl alcohol with 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys-[Boc-Pro-Ala-Lys (Boc)-OBzl]-the 3-p-methoxy-phenyl-1, 6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-the 3-p-methoxy-phenyl }-1, 6-heptadiene-3, the 5-diketone,
(24) 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc) under DCC and HOBt existence]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and Arg-Gly-Asp (OBzl)-Val-OBzl condensation is 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(25) 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc) under DCC and HOBt existence]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and Ala-Gly-Asp (OBzl)-Val-OBzl condensation is 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(26) 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc) under DCC and HOBt existence]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and Arg-Gly-Asp (OBzl)-Val-OBzl condensation is 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(27) 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc) under DCC and HOBt existence]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and Arg-Gly-Asp (OBzl)-Val-OBzl condensation is 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(28) in the methanol solution of NaOH with 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(29) in the methanol solution of NaOH with 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(30) in the methanol solution of NaOH with 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(31) in the methanol solution of NaOH with 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(32) in the ethyl acetate solution of hydrogenchloride with 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is sloughed Boc and is generated 1-(3-p-methoxy-phenyl)-7-{[4-oxygen acetyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(33) in the ethyl acetate solution of hydrogenchloride with 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is sloughed Boc and is generated 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Pro-Ala-Lys]-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(34) in the ethyl acetate solution of hydrogenchloride with 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys-[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is sloughed Boc and is generated 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Pro-Ala-Lys]-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(35) in the ethyl acetate solution of hydrogenchloride with 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is sloughed Boc and is generated 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Pro-Ala-Lys]-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone.
Described step can further describe with the synthetic route of Fig. 1.
The 3rd content of the present invention is to estimate the thrombus dissolving activity of 6 kinds of pseudo-peptides of general formula I.
The 4th content of the present invention is to estimate the antithrombotic acitivity of 6 kinds of pseudo-peptides of general formula I.
The 5th content of the present invention is to estimate the anti-inflammatory activity of 6 kinds of pseudo-peptides of general formula I.
The 6th content of the present invention is to estimate the OH free radical scavenging activity of 6 kinds of pseudo-peptides of general formula I.
The 7th content of the present invention is the nanostructure that characterizes 6 kinds of pseudo-peptides of general formula I.
Description of drawings
Fig. 1 synthetic route .3a-7a R=H, 3b-7b R=CH 3.
The transmission electron microscope photo of Fig. 2 compound 7a nano-rings.
The transmission electron microscope photo of Fig. 3 compound 7b nanotube.
The transmission electron microscope photo of Fig. 4 compound 7c nanometer ball.
The transmission electron microscope photo of Fig. 5 compound 7d nanometer rod.
Embodiment
In order further to set forth the present invention, the below provides a series of embodiment.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
Embodiment 1 preparation Boc-Pro-Ala-Lys (Boc)
1) preparation of Boc-Pro-Ala
1.075g (5.0mmol) Boc-Pro is dissolved in the anhydrous THF of 20mL, adds 0.637g (5mmol) N-hydroxy-succinamide (HOSu) under ice bath in solution, and make dissolving fully.Under ice bath, dicyclohexyl carbonyl diimine (DCC) 1.236g (6.0mmol) that is dissolved in a small amount of anhydrous THF is added in reaction solution.Stirring at room 7h, TLC (petrol ether/ethyl acetate, 3: 1) monitoring Boc-Pro disappears.Filtering dicyclohexylurea (DCU) (DCU), the concentrated THF that removes of filtrate decompression.Residue acetic acid ethyl dissolution, solution are used saturated NaHCO successively 3The aqueous solution is washed, the saturated NaCl aqueous solution is washed, and then ethyl acetate layer is evaporated to dried, residue and adds the aqueous solution that adds again 0.489g (5.5mmol) Ala after appropriate THF dissolving.Mixture NaHCO 3Solid is transferred pH 9, room temperature reaction 12h, and the reaction mixture concentrating under reduced pressure is removed THF, and residue adds the 5mL water dissolution, the saturated KHSO of the aqueous solution 4The aqueous solution is transferred pH 2, uses 30mL ethyl acetate extraction 5 times, and the ethyl acetate layer of merging is washed till neutrality, anhydrous sodium sulfate drying with the saturated NaCl aqueous solution.Filter, filtrate decompression is concentrated into dried, gets 1.35g (94%) title compound, is colorless solid.ESI-MS(m/e)：285[M-H] -.
2) preparation of Boc-Pro-Ala-Lys (Boc)-OBzl
1.202g (4.2mmol) Boc-Pro-Ala is dissolved in the anhydrous THF of 20mL, adds 0.544g (4mmol) HOBt under ice bath in solution, add 1.030g (5mmol) DCC after the dissolving fully, obtain reaction solution (I), stirred 30 minutes.2.168g (4.0mmol) Lys (Boc)-OBzl is suspended in the anhydrous THF of 20mL, then adds 1mLN-methylmorpholine (NMM), transfer pH 9, obtain reaction solution (II).After under ice bath, reaction solution (II) being added the middle 1h of stirring of reaction solution (I), stirring at room 4h, TLC (chloroform/methanol, 15: 1) show that Lys (Boc)-OBzl disappears.Filtering DCU, the concentrated THF that removes of filtrate decompression.Residue 50mL acetic acid ethyl dissolution.The solution that obtains is used saturated NaHCO successively 3The aqueous solution is washed, the saturated NaCl aqueous solution is washed, 5%KHSO 4The aqueous solution is washed with the saturated NaCl aqueous solution and is washed.The ethyl acetate layer anhydrous Na 2SO 4Drying is filtered, and filtrate decompression is concentrated into dried, obtains 1.915g (75%) title compound, is colourless powder.ESI-MS(m/e)：604[M+H] +。
3) preparation of Boc-Pro-Ala-Lys (Boc)
1.585g (3.0mmol) Boc-Pro-Ala-Lys (Boc)-OBzl is dissolved in 15mL methyl alcohol.Under ice bath, the solution that obtains is transferred pH12 and stirred 2h with NaOH (2N) aqueous solution, TLC (dichloro/methyl alcohol, 15: 1) shows that Boc-Pro-Ala-Lys (Boc)-OBzl disappears.Reaction mixture is transferred pH 2 with 2N dilute hydrochloric acid, and concentrating under reduced pressure is except methyl alcohol.Residue ethyl acetate extraction 3 times.The ethyl acetate layer that merges is washed till neutrality, anhydrous Na with the saturated NaCl aqueous solution 2SO 4Dry.Filter, filtrate decompression is concentrated into dried, gets 1.397g (85%) title compound, is colorless solid.ESI-MS(m/e)：514[M-H] -。
Embodiment 2 preparation Arg-Gly-Asp (OBzl)-Val-OBzl
1) preparation of Boc-Arg-Gly-OBzl
Press in embodiment 1 2) the preparation method by 1.600g (5.0mmol) Boc-Arg and 1.689g (5.0mmol) Gly-OBzl reaction, get 2.26g (97%) title compound, be faint yellow solid.ESI-MS(m/e)：421.7[M+H] +。
2) preparation of Boc-Arg-Gly
By in embodiment 1 3) the preparation method be hydrolyzed to get 1.236g (94%) title compound by 1.630g (3.5mmol) Boc-Arg-Gly-Obzl, be colorless solid.ESI-MS(m/e)：331.3[M-H] -。
3) preparation of Boc-Asp (OBzl)-Val-OBzl
By in embodiment 1 2) the preparation method get 2.871g (97%) title compound by 1.620g (5.0mmol) Boc-D (OBzl) and 1.607g (5.0mmol) Val-OBzl, be colorless oil.ESI-MS(m/e)：512[M+H] +。
4) preparation of Asp (OBzl)-Val-OBzl
5.12g (10mmol) Boc-Asp (OBzl)-Val-OBzl is dissolved in hydrogenchloride-ethyl acetate solution of 45mL 4N, ice bath stirs 2 hours, TLC (dichloro/methyl alcohol, 15/1) and shows that Boc-Asp (OBzl)-Val-OBzl disappears.The reaction mixture concentrating under reduced pressure is removed ethyl acetate, and residue repeatedly adds a small amount of ether and carries out concentrating under reduced pressure with except de-chlorine hydride, gets 4.27g (95%) title compound, is colorless solid.ESI-MS(m/e)：412[M+H] +。
5) preparation of Boc-Arg-Asp (OBzl)-Val-OBzl
Press in embodiment 1 2) the preparation method by 1.313g (3.5mmol) Boc-Arg-Gly and 1.747g (3.5mmol) Asp (OBzl)-Val-OBzl reaction, get 2.078g (70%) title compound through column chromatography purification, be colorless solid.ESI-MS(m/e)：725[M+H] +.
6) preparation of Arg-Asp (OBzl)-Val-OBzl
By in embodiment 2 4) the preparation method make 1.56g (95%) title compound by 1.866g (2.2mmo1) Boc-Arg-Asp (OBzl)-Val-OBzl, be faint yellow solid.ESI-MS(m/e)：625[M+H] +。
Embodiment 3 preparation Ala-Gly-Asp (OBzl)-Val-OBzl
1) preparation of Boc-Ala-Gly-OBzl
Press in embodiment 1 2) the preparation method by 1.600g (5.0mmol) Boc-Ala and 1.689g (5.0mmol) Gly-OBzl reaction, get 2.26g (97%) title compound, be faint yellow solid.ESI-MS(m/e)：337[M+H] +。
2) preparation of Boc-Ala-Gly
By in embodiment 1 3) the preparation method be hydrolyzed to get 1.236g (94%) title compound by 1.630g (3.5mmol) Boc-R-G-OBzl, be colorless solid.ESI-MS(m/e)：245[M-H] -。
3) preparation of Boc-Asp (OBzl)-Val-OBzl
By in embodiment 1 2) the preparation method get 2.871g (97%) title compound by 1.620g (5.0mmol) Boc-Asp (OBzl) and 1.607g (5.0mmol) Val-OBzl, be colorless oil.ESI-MS(m/e)：512[M+H] +。
4) preparation of Asp (OBzl)-Val-OBzl
By in embodiment 2 4) the preparation method make 4.27g (95%) title compound by 5.12g (10mmol) Boc-Asp (OBzl)-Val-Obzl, be colorless solid.ESI-MS(m/e)：412[M+H] +。
5) preparation of Boc-Ala-Gly-Asp (OBzl)-Val-OBzl
Press in embodiment 1 2) the preparation method by 1.313g (3.5mmol) Boc-Ala-Gly and 1.747g (3.5mmol) Asp (OBzl)-Val-OBzl reaction, get 2.078g (70%) title compound through column chromatography purification, be colorless solid.ESI-MS(m/e)：641[M+H] +。
6) preparation of Ala-Gly-Asp (OBzl)-Val-OBzl
By in embodiment 2 4) the preparation method make 1.56g (95%) title compound by 1.866g (2.2mmol) Boc-Ala-Gly-Asp (OBzl)-Val-OBzl, be faint yellow solid.ESI-MS(m/e)：541[M+H] +。
Embodiment 4 preparation 1-(3-methoxyl group-4-hydroxyphenyl)-7-[(4-fluoroacetic acid bases)-3-p-methoxy-phenyl]-1,6-heptadiene-3,5-diketone
1) 6-(3-methoxyl group-4-hydroxyphenyl)-5,6-hexene-2, the preparation of 4-diketone
31mL (0.3mol) methyl ethyl diketone is placed in the 250mL three-necked bottle, add 14.5g (0.21mol) boron trioxide and 70mL ethyl acetate, 70 ℃ of reactions made and become white suspension liquid in one hour, then add 29.5mL (0.11mol) tri-n-butyl borate and 15.2g (0.1mol) 3-methoxy-4-hydroxy benzaldehyde, 85 ℃ of reactions made the solution yellow suspension liquid that shoals in 0.5 hour, drip the ethyl acetate solution of 10.88mL (0.11mol) n-Butyl Amine 99 by constant pressure funnel, react and made solution become redness in 1 hour, be cooled to 50 ℃, add 200mL 1N hydrochloric acid, reacted 0.5 hour, stopped reaction.Divide water-yielding stratum, with 40mL ethyl acetate extraction three times, combined ethyl acetate, with anhydrous sodium sulfate drying, leach sodium sulfate, filtrate decompression desolventizing, residue with purification by silica gel column chromatography, obtain 8.2g (34.6%) title compound, be faint yellow solid.ESI-MS(m/e)：235[M+H] +.
2) preparation of 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde
7.6g (50mmol) Vanillin is placed in 250mL eggplant bottle dissolves with anhydrous THF, then add 9.66g (70mmol) Anhydrous potassium carbonate, reaction 30min makes mixture become white opacity liquid.Drip 5.93mL (55mmol) ethyl bromoacetate, the disappearance of reaction 48h, TLC demonstration Vanillin.Filtering insolubles, removal of solvent under reduced pressure, residue with the 200mL acetic acid ethyl dissolution, with saturated sodium bicarbonate aqueous solution wash three times, add anhydrous sodium sulfate drying.Obtain 11.316g (95.1%) title compound after desolventizing, be colorless solid.ESI-MS(m/e)：239[M+H] -。
3) 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl triethyl-3-p-methoxy-phenyl)-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 2 1) the preparation method by 1.097g (4.42mmol) 6-(3-methoxyl group-4-hydroxyphenyl)-5,6-hexene-2,4-diketone and 1.088g (4.87mmol) 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde reaction, obtain 0.435g (21.0%) title compound after purification by silica gel column chromatography, be faint yellow solid.ESI-MS(m/e)：455[M+H] +。
4) 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1,6-heptadiene-3, the preparation of 5-diketone
With 454mg (1mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3, the 5-diketone is placed in 100mL eggplant bottle, adds acetone to make dissolving, the solution yellow transparent.Then the aqueous sodium hydroxide solution, the solution that drip 1mL 4N are reddish black by red stain gradually.After 5min, there is yellow solid to separate out.After 10min, TLC shows 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3, and the 5-diketone disappears.Drip the 2N HCl aqueous solution, regulate the pH value to neutrality, acetone is removed in decompression, residue filters, with the tap water washing precipitation, obtain 424mg (96.4%) title compound, be orange powder.ESI-MS(m/e)：439[M-H] -。
Embodiment 5 preparation 1-(3-methoxyl group-4-hydroxyphenyl)-7-{[4-oxygen acetyl-Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone (7a)
1) 6-(3,4-, two-methoxyphenyl)-5,6-hexene-2, the preparation of 4-diketone
Press in embodiment 2 1) the preparation method by 16.6g (0.1mol) 3, the reaction of 4-two-methoxybenzaldehyde and 31mL (0.3mol) methyl ethyl diketone obtains 8.6g (34.6%) title compound through column chromatography purification, is faint yellow solid.ESI-MS(m/e)：235[M+H] +。
2) 1-(3,4-, two-methoxyphenyl)-7-(4-oxygen acetyl triethyl-3-p-methoxy-phenyl)-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 2 1) the preparation method by 1.097g (4.42mmol) 6-(3,4-two-methoxyphenyl)-5,6-hexene-2,4-diketone and 1.088g (4.87mmol) 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde reaction, obtain 0.435g (21.0%) title compound after purification by silica gel column chromatography, be faint yellow solid.ESI-MS(m/e)：469.6[M+H] +。
3) 1-(3,4-, two-methoxyphenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 2 4) the preparation method by 454mg (1mmol) 1-(3,4-two-methoxyphenyl)-7-(4-oxygen acetyl triethyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone are hydrolyzed to get 447mg (98%) title compound, are orange powder.ESI-MS(m/e)：454[M-H] -。
4) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{[4-oxygen acetyl-Lys (Boc)-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 2) the preparation method by 4.4g (10mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone and 5.08g (10mmol) Lys (Boc)-OBzl reaction, get 7.02g (94%) title compound, be yellow powder.ESI-MS(m/e)：745[M+H] +. 1H NMR(300MHz，CDCl 3-d1)：δ/ppm＝7.65-7.58(m，2H)，7.45(d，J＝7.2Hz，1H)，7.38-7.33(m，5H)，7.16-7.07(m，4H)，6.97-6.90(m，2H)，6.57-6.48(m，2H)，5.84(s，1H)，5.24-5.15(m，2H)，4.77-4.73(m，1H)，4.71-4.56(m，2H)，4.50(bs，0.91H)，3.97(s，3H)，3.94(s，3H)，3.06-3.04(m，2H)，1.96-1.66(m，2H)，1.45(s，11H)，1.33(m，2H)。
5) 1-(3-methoxyl group-4-hydroxyphenyl)-7-[(4-oxygen acetyl-Lys-OBzl)-3-p-methoxy-phenyl]-1,6-heptadiene-3, the preparation of 5-diketone
With 3.72g (5mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{[4-oxygen acetyl-Lys (Boc)-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone is dissolved in hydrogenchloride-ethyl acetate solution of 40mL4N, ice bath stirred 2 hours, TLC (dichloro/methyl alcohol, 15/1) show 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1,6-heptadiene-3, the 5-diketone disappears.Concentrating under reduced pressure is removed ethyl acetate, residue and is repeatedly added a small amount of ether and carry out concentrating under reduced pressure to remove hydrogen chloride gas, at last 3.32g (98%) title compound, be yellow powder.ESI-MS(m/e)：645[M+H] +。
6) 1-(3-methoxyl group-4-hydroxyphenyl)-7-[(4-oxygen acetyl-Lys)-3-p-methoxy-phenyl]-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 3) the preparation method by 2.57g (4mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-[(4-oxygen acetyl-Lys-OBzl)-3-p-methoxy-phenyl]-1,6-heptadiene-3, the 5-diketone is hydrolyzed to get 2.15g (93%) title compound, is yellow powder.ESI-MS(m/e)：555[M+H] +. 1H NMR(300MHz，DMSO-d6)：δ/ppm＝8.42-8.40(m，1H)，8.19(bs，0.7H)，7.59(s，1H)，7.54(s，1H)，7.39-7.14(m，4H)，6.97-6.76(m，4H)，6.12(s，1H)，4.64(s，2H)，4.25(m，1H)，3.86(s，3H)，3.83(s，3H)，2.73-2.71(m，2H)，1.74(m，2H)，1.54(m，2H)，1.33(m，2H)。
7) 1-(3-methoxyphenyl)-7-{[4-oxygen acetyl-Lys (Boc)-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 2) the preparation method by 4.6g (10mmol) 1-(3-methoxyphenyl)-7-[(4-fluoroacetic acid base)-the 3-p-methoxy-phenyl]-1,6-heptadiene-3,5-diketone and 5.08g (10mmol) Lys (Boc)-OBzl reaction, get 7.24g (94%) title compound, be yellow powder.ESI-MS(m/e)：759[M+H] +. 1H NMR(300MHz，CDCl 3-d1)：δ/ppm＝7.66-7.580(m，2H)，7.45(d，J＝7.2Hz，1H)，7.38-7.33(m，5H)，7.17-7.10(m，4H)，6.92-6.88(m，2H)，6.56-6.50(m，2H)，5.85(s，1H)，5.23-5.14(m，2H)，4.74-4.72(m，1H)，4.66-4.60(m，2H)，4.55(bs，1H)，3.95(s，3H)，3.94(s，3H)，3.93(s，3H)，3.03(m，2H)，1.91-1.73(m，2H)，1.46(s，11H)，1.30(m，2H)。
8) 1-(3-methoxyphenyl)-7-[(4-oxygen acetyl-Lys-OBzl)-3-p-methoxy-phenyl]-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 2 4) the preparation method by 3.81g (5mmo1) 1-(3-methoxyphenyl)-7-{[(4-oxygen acetyl-Lys (Boc)-OBzl)-3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone removes Boc and gets 3.45g (98%) title compound, is yellow powder.ESI-MS(m/e)：660[M+H] +。
9) 1-(3-methoxyphenyl)-7-[(4-oxygen acetyl-Lys)-3-p-methoxy-phenyl]-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 3) the preparation method by 261mg (0.4mmol) 1-(3-methoxyphenyl)-7-[(4-oxygen acetyl-Lys-OBzl)-3-p-methoxy-phenyl]-1,6-heptadiene-3, the 5-diketone is hydrolyzed to get 223mg (93%) title compound, is yellow powder.ESI-MS(m/e)：569[M+H] +. 1H NMR(300MHz，DMSO-d6)：δ/ppm＝8.34-8.31(m，0.4H)，7.97(bs，0.7H)，7.61(s，1H)，7.56(s，1H)，7.39-7.28(m，4H)，7.03-6.82(m，4H)，6.13(s，1H)，4.64(s，2H)，4.25(m，1H)，3.87(s，3H)，3.83(s，3H)，3.81(s，3H)，2.76-2.71(m，2H)，1.74(m，2H)，1.54(m，2H)，1.33(m，2H)。
9) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 2) the preparation method by 5.08g (10mmol) Boc-Pro-Ala-Lys (Boc) and 4.4g (10mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-[(4-oxygen acetyl-Lys-OBzl)-3-p-methoxy-phenyl]-1,6-heptadiene-3,5-two reactive ketones, get 7.02g (94%) title compound, be yellow powder.ESI-MS(m/e)：1141[M +H] +. 1H NMR(300 MHz，DMSO-d6)：δ/ppm＝7.63-7.53(m，3H)，7.35(s，5H)，7.25(bs，0.5H)，7.14-7.07(m，4H)，6.96-6.90(m，2H)，6.79(m，1H)，6.60-6.48(m，3H)，5.84(s，1H)，5.18(s，2H)，4.68-4.57(m，4H)，4.36-4.18(m，3H)，3.95(s，3H)，3.92(s，3H)，3.50-3.48(m，2H)，3.17(m，2H)，3.08(m，2H)，2.19-1.25(m，42H)。
10) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{[4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 3) the preparation method by 456mg (0.4mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)-OBzl]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is hydrolyzed to get 371mg (93%) title compound, is yellow powder.ESI-MS(m/e)：1051[M+H] +。
11) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 2) the preparation method by 5.08g (5mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{[4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-the 3-p-methoxy-phenyl-1,6-heptadiene-3,5-diketone and 2.7g (5mmol) Ala-Gly-Asp (OBzl)-Val-OBzl reaction, get title compound 7.02g (89%), be yellow powder.ESI-MS(m/e)：1573[M+H] +. 1H NMR(300MHz，DMSO-d6)：δ/ppm＝8.24-8.00(m，6H)，8.00-7.38(m，4H)，7.38-7.35(m，12H)，7.25-7.22(m，2H)，6.98-6.71(m，5H)，6.09(s，0.74H)，5.11-5.06(m，4H)，4.79(m，1H)，4.61(s，2H)，4.32-4.09(m，6H)，3.86(s，3H)，3.84(s，3H)，3.71(m，2H)，3.27(m，2H)，3.08-2.75(m，5H)，2.08-2.06(m，2H)，1.77-1.70(m，6H)，1.38-1.21(m，37H)，0.86-0.83(m，6H)。
12) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 3) the preparation method by 629mg (0.4mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp (OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is hydrolyzed to get 515.6mg (92.6%) title compound, is yellow powder.ESI-MS(m/e)：1393[M+H] +。
13) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{[4-oxygen acetyl-Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 2 4) the preparation method by 417mg (0.3mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone removes Boc and gets 348.7mg (98%) title compound, is yellow powder.ESI-MS(m/e)：1193[M+H] +. 1H NMR(300MHz，DMSO-d6)：δ/ppm＝12.48(bs，1.9H)，10.28(bs，0.49H)，9.85(s，0.59H)，8.91-8.90(d，1H)， 8.44-8.03(m，10H)，7.71-6.85(m，8H)，4.69(s，2H)，4.64(m，1H)，4.36-4.07(m，5H)，3.87(s，3H)，3.84(s，3H)，3.77-3.60(m，2H)，3.22-3.16(m，2H)，3.04-2.89(m，5H)，2.73-2.57(m，4H)，2.23(m，1H)，1.99(m，1H)，1.91(m，3H)，1.76-1.56(m，6H)，1.38-1.22(m，13H)，0.91-0.86(d，6H)。
Embodiment 6 preparation 1-(3,4-, two-methoxyphenyl)-7-{[4-oxygen acetyl-Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone (7b)
1) 1-(3,4-, two-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 2) the preparation method by 4.6g (10mmol) Boc-Pro-Ala-Lys (Boc) and 5.08g (10mmol) 1-(3,4-two-methoxyphenyl)-7-[(4-oxygen acetyl-Lys-OBzl)-3-p-methoxy-phenyl]-1,6-heptadiene-3,5-two reactive ketones, get 7.24g (94%) title compound, be yellow powder.ESI-MS(m/e)：1155[M+H] +. 1H NMR(300MHz，CDCl 3-d1)：δ/ppm＝7.66-7.52(m，3H)，7.36(m，5H)，7.17-7.10(m，4H)，6.95-6.89(m，2H)，6.74(m，1H)，6.57-6.51(m，3H)，5.87(s，1H)，5.19(m，2H)，4.68-4.56(m，3H)，4.37-4.16(m，3H)，3.96(s，3H)，3.95(s，3H)，3.93(s，3H)，3.49(m，2H)，3.17-3.07(m，4H)，2.23(m，2H)，2.08(m，2H)，1.92-1.77(m，5H)，1.48-1.35(m，30H)。
2) 1-(3,4-, two-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 3) the preparation method by 465mg (0.4mmol) 1-(3,4-two-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone is hydrolyzed to get 401mg (93%) title compound, is yellow powder.ESI-MS(m/e)：1065[M+H] +。
3) 1-(3,4-, two-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 2) the preparation method by 5.08g (5mmol) 1-(3,4-two-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and 2.7g (5mmol) Ala-Gly-Asp (OBzl)-Val-OBzl reaction, get 7.49g (94%) title compound, be yellow powder.ESI-MS(m/e)：1587[M+H] +. 1H NMR(300MHz，CDCl 3-d6)：δ/ppm＝7.67-7.57(m，4H)，7.43(m，1H)，7.35-7.26(m，10H)，7.10(m，4H)，6.92-6.90(m，4H)，6.56(s，1H)，6.50(s，1H)，5.86(s，1H)，5.19-5.08(m，4H)，4.96-4.94(m，2H)，4.60(s，2H)，4.50(s，2H)，4.24-4.23(m，4H)，3.96(s，3H)，3.95(s，3H)，3.92(s，3H)，3.51-3.49(m，4H)，3.08-2.94(m，5H)，2.27-2.22(m，2H)，2.19(m，2H)，2.06-1.85(m，7H)，1.65-1.59(m，5H)，1.49-1.21(m，37H)，0.93-0.92(m，6H)，0.88-0.86(m，6H)。
4) 1-(3,4-, two-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 3) the preparation method by 634.8mg (0.4mmol) 1-(3,4-two-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)-Ala-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone is hydrolyzed to get 513.5mg (91%) title compound, is yellow powder.ESI-MS(m/e)：1407[M+H] +。
5) 1-(3,4-, two-methoxyphenyl)-7-{[4-oxygen acetyl-Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 2 4) the preparation method by 281.4mg (0.2mmol) 1-(3,4-two-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone removes Boc and gets 235.4mg (98%) title compound, is yellow powder.ESI-MS(m/e)：1207[M+H] +. 1H NMR(300MHz，DMSO-d6)：δ/ppm＝12.48(bs，1H)，8.93-8.91(m，1H)，8.30-8.03(m，8H)，7.68-7.57(m，11H)，7.40-7.24(m，3H)，7.04-6.74(m，4H)，6.14(s，0.36H)，4.64(s，2H)，4.56-4.52(m，1H)，4.36-4.12(m，6H)，3.91(s，3H)，3.87(s，3H)，3.83(s，3H)，3.77-3.64(m，1H)，3.27-3.17(m，2H)，3.01-2.95(m，2H)，2.70-2.57(m，4H)，2.32-2.30(m，1H)，2.19(m，2H)，2.07-1.87(m，5H)，1.66-1.55(m，6H)，1.38-1.09(m，12H)，0.88-0.86(m，6H)。
Embodiment 7 preparation 1-(3-methoxyphenyl)-7-{[4-oxygen acetyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone (7c)
1) 1-(3-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp (OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 2) the preparation method by 1.06g (1mmol) 1-(3,4-two-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and 0.74g (1mmol) Arg-Gly-Asp (OBzl)-Val-OBzl reaction, get 1.45g (87%) title compound, be yellow powder.ESI-MS(m/e)：1658[M+H] +. 1H NMR(500MHz，DMSO-d6)：δ/ppm＝9.76(s，0.9H)，8.32-8.10(m，4H)，8.07-7.69(m，5H)，7.59(s，1H)，4.61(s，2H)，7.56(s，1H)，7.43-7.31(m，13H)，7.26-7.01(m，3H)，6.98-6.95(m，2H)，6.90-6.74(m，4H)，6.10(s，0.74H)，5.15-5.05(m，4H)，4.79(m，1H)，4.65(m，2H)，4.37-4.11(m，6H)，3.87(s，3H)，3.85(s，3H)，3.82(m，2H)，3.74(m，2H)，3.28(m，3H)，3.09-2.96(m，7H)，2.78(m，2H)，2.64-2.52(m，4H)，2.08(m，2H)，1.80-149(m，11H)，1.39-1.08(m，31H)，0.86-0.84(m，6H)。
2) 1-(3-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 3) the preparation method by 662.8mg (0.4mmol) 1-(3-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is hydrolyzed to get 541.2mg (92%) title compound, is yellow powder.ESI-MS(m/e)：1478[M+H] +。
3) 1-(3-methoxyphenyl)-7-{[4-oxygen acetyl-Lys (Pro-Ala-Lys (Boc)-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 2 4) the preparation method by 443.1mg (0.3mmol) 1-(3-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone removes Boc and gets 373.5mg (98%) title compound, is yellow powder.ESI-MS(m/e)：1278[M+H] +. 1H NMR(500MHz，DMSO-d6)：δ/ppm＝9.10-6.77(m，15.87H)，6.1(m，0.28)，4.79(m，1H)，4.65(m，2H)，4.29-3.96(m，6H)，3.87(s，3H)，3.85(s，3H)，3.82-2.74(m，27H)，2.16-1.15(m，23H)，0.81(s，6H)。
Embodiment 8 preparation preparation 1-(3,4-, two-methoxyphenyl)-7-{[4-oxygen acetyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone (7d)
1) 1-(3,4-, two-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 2) the preparation method by 1.1g (1mmol) 1-(3,4-two-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and 0.74g (10mmol) Arg-Gly-Asp (OBzl)-Val-OBzl reaction, get 1.24g (74.4%) title compound, be yellow powder.ESI-MS(m/e)：1672[M+H] +. 1H NMR(500MHz，DMSO-d6)：δ/ppm＝8.29-6.73(m，41H)，6.12(s，0.12H)，5.11-5.09(m，4H)，4.67-4.63(m，2H)，4.30-4.12(m，6H)，3.86(s，3H)，3.83(s，3H)，3.81(s，3H)，3.73(m，2H)，3.08-2.61(m，8H)，2.06-1.20(m，47H)，0.83(S，9H)。
2) 1-(3,4-, two-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 1 3) the preparation method by 167mg (0.1mmol) 1-(3,4-two-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone is hydrolyzed to get 138mg (93%) title compound, is yellow powder.ESI-MS(m/e)：1492[M+H] +。
3) 1-(3,4-, two-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Pro-Ala-Lys]-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the preparation of 5-diketone
Press in embodiment 2 4) the preparation method by 149mg (0.1mmol) 1-(3,4-two-methoxyphenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone removes Boc and gets 126mg (98%) title compound, is yellow powder.ESI-MS(m/e)：1292[M+H] +. 1H NMR(500MHz，DMSO-d6)：δ/ppm＝10.28(S，1H)，8.91-6.88(m，25H)，4.67(s，2H)，4.66-4.03(m，8H)，3.88(s，3H)，3.84(s，3H)，3.82(s，3H)，3.72(m，3H)，2.73-1.12(m，31H)，0.87(s，6H)。
The thrombus dissolving activity of the compound intravenous injection of embodiment 9 general formulas 1
1) evaluation method
The 200-220g male SD rat is anaesthetized with 20% urethane solution (6mL/kg, i.p.).The anesthetized rat dorsal position is fixed, and separates right common carotid artery, in proximal part folder bulldog clamp, proximal part and distal end penetrate respectively surgical thread, the surgical thread of distal end are clamped with mosquito forceps in fur, in the distal end intubate, unclamp bulldog clamp, emit approximately the 1mL arterial blood and be contained in the EP pipe of 1mL.Inject 0.1mL rat artery blood in vertical fixing Glass tubing (external diameter 5.0mm, the pipe end seals with plug for long 15mm, internal diameter 2.5mm), the thrombus standing bolt of a stainless steel material of insertion rapidly in the pipe.This thrombus fixedly spiral diameter is that the Stainless Steel Wire of 0.2mm is coiled into, and the long 12mm of spiral part contains 15 bung flanges, and the diameter of bung flange is 1.0mm, and the holder handle is connected with spiral, and long 7.0mm is question mark type.After blood coagulation 15min, open the plug of Glass tubing bottom, with the fixing fixing holder handle of spiral of thrombus of tweezers, the thrombus that taking-up is wrapped up by thrombus from Glass tubing is spiral fixedly, accurately weighs.
The bypass intubate consists of by 3 sections, and the stage casing is polyethylene rubber tube, long 60mm, internal diameter 3.5mm, two ends are identical polyethylene tube, long 100mm, internal diameter 1mm, external diameter 2mm, one end of this pipe pulls into point pipe (being used for inserting rat carotid artery or vein), external diameter 1mm, the outer cover one segment length 7mm of the other end, the polyethylene tube of external diameter 3.5mm (overstriking is used for inserting in the polyethylene rubber tube in stage casing).The equal silanization of the inwall of 3 sections pipes.With the thrombus of thrombus parcel fixedly spiral put into the stage casing polyethylene rubber tube, the two ends of sebific duct are nested with two poly butt ends that add respectively.Standby with filling with heparin-saline solution (50IU/kg) in pipe by sharp pipe end with syringe.
The left external jugular vein that separates rat, proximal part and distal end penetrate respectively surgical thread, the ligation distal end, cut carefully an angle on the left external jugular vein that exposes, the sharp pipe of the bypass duct for preparing is above inserted the proximal part of left external jugular vein opening by angle, simultaneously away from the fixing holder handle of spiral of the interior thrombus in bypass tube stage casing (containing fixedly spiral of the thrombus of accurately weighing).Push the heparin-saline (50IU/kg) of accurate amount by the sharp pipe of the other end with syringe, this moment, syringe was not withdrawn polyethylene tube, clamped flexible pipe between syringe and polyethylene tube with mosquito forceps.Proximal part in right common carotid artery stops blooding with bulldog clamp, right common carotid artery is being cut an angle carefully nearby from bulldog clamp.Extract syringe from the tip of polyethylene tube, the tip of polyethylene tube is inserted the proximal part of artery angle.The two ends of bypass duct all use 4 trumpeter's art sutures and arteriovenous to fix.
with scalp acupuncture with physiological saline, the stage casing of the normal saline solution of the normal saline solution of urokinase or different concns compound by bypass tube (containing fixedly spiral of the thrombus of accurately weighing), thrust away from the fixing nearly vein place of spiral of thrombus, open bulldog clamp, make blood flow flow to vein by bypass duct from artery, this is rat arteriovenous shut Thrombolysis Model, slowly the liquid in syringe is injected into (approximately 6min) in blood, make physiological saline, urokinase or compound of the present invention are by blood circulation, press the sequential action of vein-heart-artery to thrombus.Timing during from start injection, after 1h from bypass duct the fixing spiral of removal of thromboses, accurately weigh.Calculate fixedly of poor quality before and after the spiral administration of thrombus in every rat bypass duct, thrombolysis activity in the body of statistics and assessing compound.Thrombus loss of weight average and standard deviation
Figure BSA00000635313900181
Expression.
2) dosage
Physiological saline (blank) dosage is 3mL/kg, and urokinase (positive control) dosage is that 20000U/kg is equivalent to 1.68mg/kg, and the dosage of the compound 7a-d of general formula I is 1.0nmol/kg.
3) evaluation result sees Table 1.Result shows that the compound 7a-d of general formula I has outstanding thrombus dissolving activity.
Table 1 compound is through the thrombus dissolving activity of intravenous administration a
Figure BSA00000635313900182
A) n=10; B) with the physiological saline group than P＜0.01.
The compound 7b of embodiment 10 intravenous injection various dose general formulas 1 and the thrombus dissolving activity of 7d
1) evaluation method is with in experimental example 1 1).
2) dosage
Choose 10nmol/kg, 1nmol/kg, three dosage investigation 7b of 0.1nmol/kg, the dosage effect dependence of d.
3) the results are shown in Table 2 and table 3.Result shows that the thrombus dissolving activity of 7b and 7d and dosage present correlationship.
The dose-effect relationship of table 2 intravenous injection 7b a
Figure BSA00000635313900183
A) n=10; B) organize than p＜0.01 with 1nmol/kg; C) organize than p＜0.05 with 0.1nmol/kg; D) with the physiological saline group than p＜0.01.
The dose-effect relationship of table 3 intravenous injection 7d a
Figure BSA00000635313900192
A) n=10; B) organize than p＜0.05 with 1nmol/kg; C) organize than p＜0.01 with 0.1nmol/kg; D) with the physiological saline group than p＜0.01.
The external thrombus dissolving activity of the compound 7a-d of embodiment 11 general formulas 1
1) evaluation method
Male SD rat, 250 ± 10g weighs, abdominal injection 20% urethane anesthesia, dorsal position is fixed.Isolate the right common carotid artery of rat, in proximal part folder bulldog clamp, proximal part and distal end penetrate respectively surgical thread, the ligation distal end, right common carotid artery is being cut an angle carefully nearby from bulldog clamp, an end that inserts hexasilane pulls into the polyethylene tube of sharp pipe, unclamps bulldog clamp, emit about 5mL arterial blood at every turn and be contained in the EP pipe of hexasilane of 5mL, approximately can put 3 times.Vertically inject 0.1mL rat artery blood in fixing Glass tubing (external diameter 5.5mm, the pipe end seals with plug for long 18mm, internal diameter 4mm) with the 5mL syringe of hexasilane toward each, the thrombus standing bolt of a stainless steel material of insertion rapidly in the pipe.This thrombus fixedly spiral diameter is that the Stainless Steel Wire of 0.2mm is coiled into, and the long 20mm of spiral part, the diameter of bung flange are 1.0mm, and the holder handle is connected with spiral, and long 7.0mm is question mark type.After blood coagulation 40min, open the plug of Glass tubing bottom, with the fixing fixing holder handle of spiral of thrombus of tweezers, the thrombus that taking-up is wrapped up by thrombus from Glass tubing is spiral fixedly, hang immersion and fill in the cillin bottle of 8mL high purity water, soak 1h, remove floating blood, taking-up is dipped in dried, accurately weighs, and record.Again with thrombus fixedly spiral hang to immerse and to fill in the cillin bottle of the certain density compound solution of 8mL, 37 ℃ of shaking tables are hatched 2h, take out to dip in driedly, more accurately weigh, record.Thrombus is the thrombus loss of weight that is of poor quality of spiral front and back fixedly, thrombolysis activity in the body of statistics and assessing compound.Thrombus loss of weight average and standard deviation
Figure BSA00000635313900193
Expression.
2) medication and concentration
According to the corresponding Plasma Concentration of thrombus dissolving dosage conversion in body.Blank is physiological saline, and positive control is UK (concentration is 254 μ g/l ml), and the concentration of the compound 7a-d of through type I is 10nM.
3) evaluation result sees Table 4.Result shows that the compound of general formula I is at the outstanding thrombus dissolving activity of external demonstration.
The external thrombus dissolving activity of table 4 compound a
Figure BSA00000635313900201
A) n=6; B) with physiological saline group ratio, P＜0.01.
The antithrombotic acitivity of the compound intravenous injection of experimental example 12 general formulas 1
1) evaluation method
Intubate consists of by 3 sections, middle segment length 80mm, and internal diameter 3.5mm, two ends are identical polyethylene tube, long 100mm, internal diameter 1mm, external diameter 2mm, an end of this pipe pull into point pipe (being used for inserting rat carotid artery or vein), the equal silicon of the inwall of 3 sections pipes institute.The silk thread of the long 60mm that weighs is in advance put into stage casing polyethylene extra heavy pipe, the two ends of extra heavy pipe be nested with the not drawing-down end of two polyethylene tubules respectively (wherein one section silk thread is pushed down 0.5mm fix).Standby with filling with heparin-saline solution (50IU/kg) in pipe by sharp pipe end with syringe.
The 200-220g male SD rat is anaesthetized with 20% urethane solution (6mL/kg, i.p.).the anesthetized rat dorsal position is fixed, isolate the left external jugular vein of rat, proximal part and distal end penetrate respectively surgical thread, the ligation distal end, cut carefully an angle on the left external jugular vein that exposes, the not line ball end point pipe of the bypass duct for preparing is above inserted the proximal part of left external jugular vein opening by angle, push the heparin-saline (50IU/kg) of accurate amount by the sharp pipe of the other end with syringe, pull up syringe, again suction there is physiological saline, the syringe of the normal saline solution of the normal saline solution of urokinase or different concns compound inserts the tip of polyethylene tube, tip by polyethylene tube pushes liquid, this moment, syringe was not withdrawn polyethylene tube, separate right common carotid artery, in proximal part folder bulldog clamp, proximal part and distal end penetrate respectively surgical thread, the ligation distal end, right common carotid artery is being cut an angle carefully nearby from bulldog clamp.Extract syringe from the tip of polyethylene tube, the tip of polyethylene tube is inserted the proximal part of artery angle.The two ends of bypass duct all use 4 trumpeter's art sutures and arteriovenous to fix.Open bulldog clamp, make blood flow flow to vein by bypass duct from artery, this is the anti-bolt model of rat arteriovenous shut.From the timing of beginning circulation time, take out the silk thread that hangs with thrombus after 15min from bypass duct, accurately weigh, the wet weight of thrombus that is of poor quality before and after silk thread, anti-thrombus activity in the body of statistics and assessing compound.Wet weight of thrombus average and standard deviation Expression.
2) dosage
Physiological saline (blank) dosage is 1mL/kg, and acetylsalicylic acid (positive control) dosage is 9mg/kg, and the dosage of the compound 7a-d of general formula I is 1.0nmol/kg.
3) evaluation result sees Table 5.Result shows that the compound of general formula I can show outstanding antithrombotic acitivity through intravenous administration.
Table 5 compound is through the antithrombotic acitivity of intravenously administrable
Figure BSA00000635313900212
A) n=10; B) with physiological saline group ratio, P＜0.01
The anti-inflammatory activity of the compound oral administration of experimental example 13 general formulas 1
1) evaluation method
18-22g ICR male mice is divided into the blank group at random, positive medication group and administration group, and before mouse is used, tranquillization is 1 day, and operation room keeps 22 ℃ of room temps, 10 of every group of mouse.Difference gastric infusion during the experiment beginning, the left ear gabarit of single administration past small white mouse after 30 minutes is coated with dimethylbenzene (0.03mL), after 2 hours, the dislocation of small white mouse cervical vertebra is put to death.Left ear and the auris dextra of mouse are cut, got circular auricle with the punch tool of diameter 7mm in the same position of two ears, weigh respectively, obtain the weight difference of two circle auricles as swelling.Swelling=former weight of former of left ear weight-auris dextra.
2) dosage
Physiological saline (blank) dosage is 10mL/kg, and acetylsalicylic acid (positive control) dosage is 200mg/kg, and the dosage of the compound 7a-d of general formula I is 1.0nmol/kg.
3) evaluation result sees Table 6.Result shows that the compound oral administration administration of general formula I shows outstanding anti-inflammatory activity.
The anti-inflammatory activity of table 6 compound oral administration a
Figure BSA00000635313900213
Figure BSA00000635313900221
A) n=10; B) with the physiological saline group than P＜0.05; C) with the physiological saline group, P＜0.01.
The compound of experimental example 14 general formulas 1 is removed the activity of hydroxy radical qiao
1) evaluation method
According to the corresponding Plasma Concentration of thrombus dissolving dosage conversion in body.The compound 7a-d adding distil water of general formula I is made into the solution that concentration is 10nM, measures on EPR spectrometer.
According to standard method with FeSO 47H 2It is the solution A of 10nM that the O adding distil water is made into concentration, with 30%H 2O 2It is 1%H that adding distil water is made into concentration 2O 2Solution B, the DMPO adding distil water is made into the solution C that concentration is 1.1316mg/100mL.
The blank group adds 2.5 μ L solution A, 5 μ L solution C, 5 μ L distilled water and 2.5 μ L solution B successively, sucks quartz capillary after violent the mixing, measures the hydroxy radical qiao signal after 1min and records spectrogram.
The compound group of general formula 1 adds compound and the 2.5 μ L solution B of general formula 1 of the compound of 2.5 μ L solution A, 5 μ L solution C, 5 μ L general formulas 1 successively, sucks quartz capillary after violent the mixing, measures the hydroxy radical qiao signal after 1min and records spectrogram.
1 sample survey under 1 concentration 5 times, record each time the spectrogram peak height, calculate Scavenging action to hydroxyl free radical.Calculation formula is: clearance rate=(the compound group peak height of blank group peak height-general formula 1)/blank group peak height.
2) evaluation result sees Table 7.Result shows that the compound of general formula I is outstanding hydroxy radical scavenger.
The clearance rate of table 710nM compound to hydroxy radical qiao
Figure BSA00000635313900222
The nanostructure of the compound of experimental example 15 general formulas 1
When 1) having observed 25 ℃ and 37 ℃ on the laser light scattering particle size analyzer, the aqueous solution of the compound of general formula I and pH are the particle diameter of 7.4 phosphate buffer soln.The concentration of compound converts according to thrombus dissolving dosage in body, and the concentration of 7a-d is 10nM., the results are shown in Table 9 and 10.Data show, the compound of general formula I has suitable nanometer ball structure at water and phosphate buffer soln.
The sphere diameter of the nanometer ball that table 8 compound forms in the aqueous solution
Compound Sphere diameter (nm, 25 ℃) Sphere diameter (nm, 37 ℃)
7a 277.8 73.1
7b 281.2 178.6
7c 235.4 201.5
7d 248.6 179.3
The sphere diameter of the nanometer ball that table 9 compound forms in pH is 7.4 phosphate buffer soln
Compound Sphere diameter (nm, 25 ℃) Sphere diameter (nm, 37 ℃)
7a 268.9 168.1
7b 273.3 230.5
7c 184.1 91.0
7d 408.6 242.0
2) be 10 to 6 compound concentrations having measured general formula I under transmission electron microscope -7The transmission electron microscope photo of the aqueous solution of mg/mL.7d has also measured 10 as representative -6, 10 -7With 10 -8The transmission electron microscope photo of the aqueous solution of three concentration of mg/mL.Result shows, 6 compounds of general formula I all can be observed the different nanostructures such as nanometer ball, nanometer rod, nano-rings, nanotube under transmission electron microscope.7d can be observed different nanostructures under different concns and pH condition.The transmission electron microscope photo of 7a, 7b, 7c and 7d is seen respectively Fig. 2, Fig. 3, Fig. 4 and Fig. 5.

Claims (10)

1. 6 of general formula I kinds of pseudo-peptides, R in formula 1Be H or CH 3, R 2Be Lys or Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val or Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val.
Figure FSA00000635313800011
2. prepare the method for 6 kinds of pseudo-peptides of general formula I, the method is made of following steps:
(1) Boc-Pro is Boc-Pro-OSu with the HOSu condensation in anhydrous THF under dicyclohexylcarbodiimide (DCC) and N-hydroxy-succinamide (HOSu) existence, at NaHCO 3Exist lower Boc-Pro-OSu and L-Ala reaction to generate Boc-Pro-Ala;
(2) Boc-Pro-Ala is Boc-Pro-Ala-Lys (Boc)-OBzl with Lys (Boc)-OBzl condensation in anhydrous THF under DCC and HOBt existence;
(3) under existing, NaOH in methyl alcohol, Boc-Pro-Ala-Lys (Boc)-OBzl is hydrolyzed to Boc-Pro-Ala-Lys (Boc);
(4) Boc-Asp (OBzl) is Boc-Asp (OBzl)-Val-OBzl with the Val-OBzl condensation in anhydrous THF under DCC and HOBt existence;
(5) Boc-Asp (OBzl)-Val-OBzl sloughs Boc and generates Asp (OBzl)-Val-OBzl in hydrogenchloride-ethyl acetate solution;
(6) Boc-Ala is Boc-Ala-Gly-OBzl with the Gly-OBzl condensation in anhydrous THF under DCC and HOBt existence;
(7) under existing, NaOH in methyl alcohol, Boc-Ala-Gly-OBzl is hydrolyzed to Boc-Ala-Gly;
(8) Boc-Ala-Gly is Boc-Ala-Gly-Asp (OBzl)-Val-OBzl with Asp (OBzl)-Val-OBzl condensation in anhydrous THF under DCC and HOBt existence;
(9) Boc-Ala-Gly-Asp (OBzl)-Val-OBzl sloughs Boc and generates Ala-Gly-Asp (OBzl)-Val-OBzl in hydrogenchloride-ethyl acetate solution;
(10) Boc-Arg is Boc-Arg-Gly-OBzl with the Gly-OBzl condensation in anhydrous THF under DCC and HOBt existence;
(11) under existing, NaOH in methyl alcohol, Boc-Arg-Gly-OBzl is hydrolyzed to Boc-Arg-Gly;
(12) Boc-Arg-Gly is Boc-Arg-Gly-Asp (OBzl)-Val-OBzl with Asp (OBzl)-Val-OBzl condensation in anhydrous THF under DCC and HOBt existence;
(13) Boc-Arg-Gly-Asp (OBzl)-Val-OBzl sloughs Boc and generates Arg-Gly-Asp (OBzl)-Val-OBzl in hydrogenchloride-ethyl acetate solution;
(14) in anhydrous K 2CO 3Under existence in anhydrous THF the reaction of Vanillin and ethyl bromoacetate generate 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde;
(15) at B 2O 3, (nBuo) 3It is 6-(3,4-, two-methoxyphenyl)-5 with the methyl ethyl diketone condensation in anhydrous ethyl acetate that there are lower Veratraldehyde in B and nBu-NH, 6-hexene-2,4-diketone;
(16) at B 2O 3, (nBuo) 3Under B and nBu-NH existed, Vanillin and methyl ethyl diketone condensation were 6-(3-methoxyl group-4-hydroxyphenyl)-5 in anhydrous ethyl acetate, 6-hexene-2,4-diketone;
(17) at B 2O 3, (nBuo) 3Under B and nBu-NH exist, 6-in anhydrous ethyl acetate (3-p-methoxy-phenyl)-5,6-hexene-2,4-diketone and 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde condensation is 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3, the 5-diketone, or at B 2O 3, (nBuo) 3Under B and nBu-NH exist, 6-in anhydrous ethyl acetate (4-methyl-3-p-methoxy-phenyl)-5,6-hexene-2,4-diketone and 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde condensation is 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3, the 5-diketone;
(18) under NaOH exists in acetone with 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(3-p-methoxy-phenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone, or under NaOH exists in acetone with 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone,
(19) under DCC and HOBt exist in anhydrous THF 1-(3-p-methoxy-phenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone and Lys (Boc)-OBzl condensation is 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone, or under DCC and HOBt exist in anhydrous THF 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone and Lys (Boc)-OBzl condensation is 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone,
(20) 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1 in hydrogenchloride-ethyl acetate solution, 6-heptadiene-3, the 5-diketone is sloughed Boc and is generated 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone, or in hydrogenchloride-ethyl acetate solution 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone is sloughed Boc and is generated 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone,
(21) under NaOH exists, in methyl alcohol with 1-(3-p-methoxy-phenyl)-7-[4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl]-1, 6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone or under NaOH exists, in methyl alcohol with 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the 5-diketone,
(22) under DCC and HOBt exist in anhydrous THF Boc-Pro-Ala-Lys (Boc) and 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the condensation of 5-diketone is 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)-OBzl]-the 3-p-methoxy-phenyl }-1, 6-heptadiene-3, the 5-diketone, or under DCC and HOBt exist in anhydrous THF Boc-Pro-Ala-Lys (Boc) and 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the condensation of 5-diketone is 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)-OBzl]-the 3-p-methoxy-phenyl }-1, 6-heptadiene-3, the 5-diketone,
(23) under NaOH exists in methyl alcohol with 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)-OBzl]-the 3-p-methoxy-phenyl-1, 6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-the 3-p-methoxy-phenyl }-1, 6-heptadiene-3, the 5-diketone, or under NaOH exists in methyl alcohol with 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys-[Boc-Pro-Ala-Lys (Boc)-OBzl]-the 3-p-methoxy-phenyl-1, 6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-the 3-p-methoxy-phenyl }-1, 6-heptadiene-3, the 5-diketone,
(24) 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc) under DCC and HOBt existence]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and Arg-Gly-Asp (OBzl)-Val-OBzl condensation is 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(25) 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc) under DCC and HOBt existence]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and Ala-Gly-Asp (OBzl)-Val-OBzl condensation is 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(26) 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc) under DCC and HOBt existence]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and Arg-Gly-Asp (OBzl)-Val-OBzl condensation is 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(27) 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc) under DCC and HOBt existence]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and Arg-Gly-Asp (OBzl)-Val-OBzl condensation is 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(28) in the methanol solution of NaOH with 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(29) in the methanol solution of NaOH with 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(30) in the methanol solution of NaOH with 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(31) in the methanol solution of NaOH with 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is hydrolyzed to 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(32) in the ethyl acetate solution of hydrogenchloride with 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is sloughed Boc and is generated 1-(3-p-methoxy-phenyl)-7-{[4-oxygen acetyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(33) in the ethyl acetate solution of hydrogenchloride with 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is sloughed Boc and is generated 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Pro-Ala-Lys]-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(34) in the ethyl acetate solution of hydrogenchloride with 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys-[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is sloughed Boc and is generated 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Pro-Ala-Lys]-Arg-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone;
(35) in the ethyl acetate solution of hydrogenchloride with 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl-1,6-heptadiene-3, the 5-diketone is sloughed Boc and is generated 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys[Pro-Ala-Lys]-Ala-Gly-Asp-Val]-the 3-p-methoxy-phenyl }-1,6-heptadiene-3, the 5-diketone.
3. the thrombus dissolving activity of 6 of claim 1 kinds of pseudo-peptides.
4. the antithrombotic acitivity of 6 of claim 1 kinds of pseudo-peptides.
5. the anti-inflammatory activity of 6 of claim 1 kinds of pseudo-peptides.
6. the OH free radical scavenging activity of 6 of claim 1 kinds of pseudo-peptides.
7. 6 of claim 1 kinds of pseudo-peptides are as the application of thrombolytic agent.
8. 6 of claim 1 kinds of pseudo-peptides are as the application of thrombus dissolving and antithrombotic reagent.
9. 6 of claim 1 kinds of pseudo-peptides are as the application of thrombus dissolving, antithrombotic shape and anti-inflammatory drug.
10. 6 of claim 1 kinds of pseudo-peptides are as the application of thrombus dissolving, antithrombotic shape, anti-inflammatory and OH free radical scavenging medicine.
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