Multi-target compound with anticoagulation and antiplatelet activity, preparation method therefor, and use thereof

1. A multi-target compound with anticoagulation and platelet GPIIb/IIIa receptor antagonism, said compound having a structure as shown in Formula (1):

A-L-B-L′-C  Formula (1)

wherein A and B are thrombin binding sites, C is a platelet GPIIb/IIIa receptor binding site, L is a first linker, and L′ is a second linker;

wherein L′ has a structure as shown in Formula (2):

((Gly)n 1 -(Ser)n 2   Formula (2)

wherein n1 is 1, 2, 3 or 4; n2 is 0 or 1; and n3 is 0, 1, 2 or 3; or

L′ has a structure as shown in Formula (3):

(Glu-Ala-Ala-Ala-Lys)n 1   Formula (3)

wherein n1 is 0, 1, 2 or 3; or

L′ has a structure as shown in Formula (4):

(Arg-Val-Leu-Ala-Glu-Ala)n 1   Formula (4)

wherein n1 is 0, 1, 2 or 3;

wherein C has a structure as shown in Formula (7):

Cys-Har-C1-Asp-Trp-Pro-C2  Formula (7)

wherein C1 is Gly or Ser; C2 is Cys or a structure obtained by replacing —OH in Cys with —NH 2 ; and a disulfide bond is formed between two mercapto groups in the Formula (7);

wherein A-L-B is selected from one of polypeptide sequences shown in SEQ ID NO: 1 to SEQ ID NO: 3.

2. The compound according to claim 1 , wherein said compound has a structure as shown in Formula (9):

X-A-L-B-L′-C—Y  Formula (9)

wherein X is one selected from hydrogen, one or two C1-C6 alkyl, one or two C2-C10 acyl, benzyloxycarbonyl and tert-butoxycarbonyl; Y is one selected from OH, C1-C6 alkoxy, an amino, and an amino substituted with one or two C1-C4 alkyl.

3. The compound according to claim 2 , wherein said compound comprises a polypeptide sequence of polypeptide structures shown in SEQ ID NO: 4 to SEQ ID NO: 7.

4. The compound according to claim 3 , wherein said compound is selected from one of polypeptide structures shown in SEQ ID NO: 4 to SEQ ID NO: 7.

5. A salt of a compound according to claim 1 .

6. The salt of a compound according to claim 5 , wherein said salt is an acetate salt of the compound or a trifluoroacetate salt of the compound.

7. A method for preparing a compound according to claim 1 , wherein said method comprises the steps of:

(1) sequentially introducing protected amino acids or fragments starting from carboxyl terminal according to polypeptide sequence using a solid phase synthesis method, to obtain a polypeptide-Wang resin in which side chains of amino acids are all protected;

(2) subjecting the polypeptide-Wang resin in which side chains of amino acids are all protected to acid hydrolysis with an acid hydrolyzing agent to obtain a crude linear polypeptide; and

(3) cyclizing the crude linear polypeptide to form a disulfide bond and then purifying with high-pressure preparative liquid chromatography, to obtain a polypeptide sequence.

8. A pharmaceutical composition, wherein said pharmaceutical composition comprises a compound according to claim 1 as an active ingredient.

9. The pharmaceutical composition according to claim 8 , wherein the dosage form of said pharmaceutical composition is an injection, a tablet, a capsule, a pill, a powder, a granule, a suspension or an emulsion.

10. A pharmaceutical composition, wherein said pharmaceutical composition comprises a salt according to claim 5 as an active ingredient.

11. The pharmaceutical composition according to claim 10 , wherein the dosage form of said pharmaceutical composition is an injection, a tablet, a capsule, a pill, a powder, a granule, a suspension or an emulsion.

12. A method of treating the following diseases or conditions:

peripheral arterial thrombosis; arterial and venous bypass thrombosis; thrombosis formed in acute coronary syndromes, percutaneous coronary intervention, or therapy with a coronary stent in PCI; progressive ischemic stroke; acute pulmonary embolism; or thrombosis in organ and tissue transplantation;

comprising administering a subject in need thereof a compound according to claim 1 .

13. A method of treating the following diseases or conditions:

peripheral arterial thrombosis; arterial and venous bypass thrombosis; thrombosis formed in acute coronary syndromes, percutaneous coronary intervention, or therapy with a coronary stent in PCI; progressive ischemic stroke; acute pulmonary embolism; or thrombosis in organ and tissue transplantation;

comprising administering to a subject in need thereof a salt according to claim 5 .