阅读说明：本技术 1S-甲基-β-四氢咔啉酰-K(RPAK)-RGDV,其合成,活性和应用 (1S-methyl-beta-tetrahydrocarbolinoyl-K (RPAK) -RGDV, and synthesis, activity and application thereof ) 是由 赵明 王玉记 冯琦琦 彭师奇 田孝纲 于 2018-06-08 设计创作，主要内容包括：本发明公开了下式的1S-甲基-1,2,3,4-四氢-β-咔啉-3S-甲酰基-Lys(Arg-Pro-Ala-Lys)-Arg-Gly-Asp-Val,公开了它的制备方法,公开了它的抗血栓活性,公开了它的溶血栓活性以及公开了它治疗中风24小时大鼠的作用,因而本发明公开了它在制备抗血栓药物,溶血栓药物以及治疗缺血性中风药物中的应用。<Image he="181" wi="700" file="DDA0001690284200000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses 1S-methyl-1, 2,3, 4-tetrahydro-beta-carboline-3S-formyl-Lys (Arg-Pro-Ala-Lys) -Arg-Gly-Asp-Val with the following formula, discloses a preparation method thereof, discloses antithrombotic activity thereof, discloses thrombolytic activity thereof and discloses the effect of the same in treating rats with 24 hours of apoplexy, so that the invention discloses the application of the same in preparing antithrombotic medicaments, thrombolytic medicaments and medicaments for treating ischemic stroke.)

1. 1S-methyl-1, 2,3, 4-tetrahydro-beta-carboline-3S-formyl-Lys (Arg-Pro-Ala-Lys) -Arg-Gly-Asp-Val of the formula,

2. The 1S-methyl-1, 2,3, 4-tetrahydro- β -carboline-3S-formyl of claim 1

A process for the preparation of-Lys (Arg-Pro-Ala-Lys) -Arg-Gly-Asp-Val, the process comprising:

(1) Preparing N-Boc-1S-methyl-1, 2,3,4 tetrahydro-beta-carboline-3S-carboxylic acid;

(2) Preparing N-Boc-1S-methyl-1, 2,3, 4-tetrahydro-beta-carboline-3S-formyl-Lys (Boc);

(3) Preparation of HCl. Arg (NO)₂)-Gly-Asp(OBzl)-Val-OBzl；

(4) Preparation of Boc-Arg (NO)₂)-Pro-Ala-Lys(Cbz)；

(5) Preparation of 1S-methyl-1, 2,3, 4-tetrahydro-beta-carboline-3S-formyl-Lys-Arg (NO)₂)-Gly-Asp(OBzl)-Val-OBzl；

(6) Preparing 1S-methyl-1, 2,3, 4-tetrahydro-beta-carboline-3S-formyl-Lys (Arg-Pro-Ala-Lys) -Arg-Gly-Asp-Val.

3. Use of the 1S-methyl-1, 2,3, 4-tetrahydro- β -carboline-3S-formyl-Lys (Arg-Pro-Ala-Lys) -Arg-Gly-Asp-Val of claim 1 for the preparation of an antithrombotic medicament.

4. Use of the 1S-methyl-1, 2,3, 4-tetrahydro- β -carboline-3S-formyl-Lys (Arg-Pro-Ala-Lys) -Arg-Gly-Asp-Val of claim 1 for the preparation of a thrombolytic drug.

5. Use of the 1S-methyl-1, 2,3, 4-tetrahydro- β -carboline-3S-formyl-Lys (Arg-Pro-Ala-Lys) -Arg-Gly-Asp-Val of claim 1 for the manufacture of a medicament for the treatment of ischemic stroke.

Technical Field

The invention discloses 1S-methyl-1, 2,3, 4-tetrahydro-beta-carboline-3S-formyl-Lys (Arg-Pro-Ala-Lys) -Arg-Gly-Asp-Val with the following formula, relates to a preparation method thereof, relates to antithrombotic activity thereof, relates to thrombolytic activity thereof and relates to the effect of treating rats with 24 hours of stroke, thus the invention relates to the application thereof in preparing antithrombotic medicaments, thrombolytic medicaments and medicaments for treating ischemic stroke. The invention belongs to the field of biological medicine.

Technical Field

Ischemic stroke is a common and serious cerebrovascular disease, and is characterized by high morbidity, high fatality rate, high disability rate and high recurrence rate. At present, the clinical treatment of ischemic stroke faces the reality that no effective medicine exists, and especially, patients with stroke for more than 4 hours are not dead or are disabled. The invention is an important clinical demand for effective medicines for patients with stroke of more than 4 h. The inventors have disclosed that imidazolines of the following formula show excellent efficacy in a rat ischemic stroke model with stroke face of 24 h. Namely imidazoline of the following formula is continuously injected into vein for 6 days, 1 time per day, the dosage is 100nmol/kg, and the imidazoline has excellent curative effect. In the formula, AA is Ser, Val or Phe. For structural reasons, imidazolines of the formula below have two inevitable disadvantages. That is, the free radical of the 1, 3-dioxoimidazoline moiety is sensitive to the reductive environment, and is difficult not only to prepare but also to store.

After 3 years of experimental research, the inventor finds that the imidazoline part is replaced by 1S-methyl-1, 2,3, 4-tetrahydro-beta-carboline-3S-formyl group, and double unexpected technical effects of stable structure and easy storage can be obtained. The inventors have made the present invention in light of this finding.

Disclosure of Invention

the first aspect of the present invention provides 1S-methyl-1, 2,3, 4-tetrahydro- β -carboline-3S-formyl-Lys (Arg-Pro-Ala-Lys) -Arg-Gly-Asp-Val of the formula.

The second aspect of the present invention is to provide 1S-methyl-1, 2,3, 4-tetrahydro-beta-carboline-3S-formyl

-Lys (Arg-Pro-Ala-Lys) -Arg-Gly-Asp-Val, comprising:

(1) Preparing N-Boc-1S-methyl-1, 2,3,4 tetrahydro-beta-carboline-3S-carboxylic acid;

(2) Preparing N-Boc-1S-methyl-1, 2,3, 4-tetrahydro-beta-carboline-3S-formyl-Lys (Boc);

(3) Preparation of HCl. Arg (NO)₂)-Gly-Asp(OBzl)-Val-OBzl；

(4) Preparation of Boc-Arg (NO)₂)-Pro-Ala-Lys(Cbz)；

(5) preparation of 1S-methyl-1, 2,3, 4-tetrahydro-beta-carboline-3S-formyl-Lys-Arg (NO)₂)-Gly-Asp(OBzl)-Val-OBzl；

(6) Preparing 1S-methyl-1, 2,3, 4-tetrahydro-beta-carboline-3S-formyl-Lys (Arg-Pro-Ala-Lys) -Arg-Gly-Asp-Val.

The third aspect of the present invention is to evaluate the antithrombotic activity, thrombolytic activity and ischemic stroke treating activity of 1S-methyl-1, 2,3, 4-tetrahydro- β -carboline-3S-formyl-Lys (Arg-Pro-Ala-Lys) -Arg-Gly-Asp-Val.

Drawings

FIG. 11 is a synthetic route for S-methyl-1, 2,3, 4-tetrahydro- β -carboline-3S-formyl-Lys (Arg-Pro-Ala-Lys) -Arg-Gly-Asp-Val. i: CH (CH)₃CHO，H₂O; ii: TEA, DMF, di-tert-butyl dicarbonate (Boc)₂O；iii：Pb/C，H₂Tetrahydrofuran; iv: n, N-Dicyclohexylcarbodiimide (DCC), N-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), tetrahydrofuran; v 2N aqueous sodium hydroxide solution, CH₃OH; vi: hydrogen chloride in ethyl acetate (4M); vii: trifluoroacetic acid (TFA), trifluoromethanesulfonic acid (TMFA).

Detailed Description

To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.