US 2003/0191278 A1 · Cyclic pentapeptides and their preparation

Abstract

This invention relates to cyclic peptides, with the following formula (I) (SEQ ID NO: 1), cyclo(Xaa-Arg-Pro-Ala-Lys) (I) where Xaa is Ala, Gly, Glu, Gln, Asp, Asn, Arg or Lys. The cyclic peptides have thrombolytic effects. This invention also relates to cyclic peptide preparations.

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Claims26

Dependent claims

A cyclic peptide of the formula (I):

cyclo(Xaa-Arg-Pro-Ala-Lys) (I)
wherein Xaa is Ala, Gly, Glu, Gln, Asp, Asn, Arg, or Lys.

A method for preparing cyclic peptides of the formula (I) (SEQ ID NO:

1):
cyclo(Xaa-Arg-Pro-Ala-Lys) (I)
wherein Xaa is Ala, Gly, Glu, Gln, Asp, Asn, Arg, or Lys, including steps as follows:
(A) providing a peptide with N-terminal protecting groups, wherein at least one peptide is selected from the group consisting of
B-Xaa-Arg(T)-Pro-Ala-Lys(Z′)-OH (SEQ ID NO:
2),
B-Arg(T)-Pro-Ala-Lys(Z′)-Xaa-OH (SEQ ID NO:
3),
B-Pro-Ala-Lys(Z′)-Xaa-Arg(T)-OH (SEQ ID NO:
4),
B-Ala-Lys(Z′)-Xaa-Arg(T)-Pro-OH (SEQ ID NO:
5),
B-Lys(Z′)-Xaa-Arg(T)-Pro-Ala-OH (SEQ ID NO:
6);
wherein Xaa is Ala, Gly, Glu, Gln, Asp, Asn, Arg or Lys;
B is the N-terminal protecting group of the peptide chain;
Z is the side chain protecting group of Lys residue;
and T is the side chain protecting group of Arg residue;
(B) adding p-nitrophenol, organic solvents and coupling agents to activate the C-terminal group of said peptide and to form a first intermediate;
(C) deprotecting the N-terminal group of said first intermediate to form a second intermediate;
(D) dissolving said second intermediate in organic solvents to perform the intramolecular cyclization of said second intermediate to form a third intermediate;
and
(E) removing the protecting groups on the side chains of Lys and Arg residue to form a final compound.

20 more elements

A method for preparing cyclic peptides of the formula (I) (SEQ ID NO:

1):
cyclo(Xaa-Arg-Pro-Ala-Lys) (I)
wherein Xaa is Ala, Gly, Glu, Gln, Asp, Asn, Arg, or Lys, including steps as follows:
(A) providing at least one peptide with N-terminal protecting groups, wherein at least one peptide is selected from the group consisting of
8 B-Xaa-Arg(T)-Pro-Ala-Lys(Z′)-OH, (SEQ ID NO:
2) B-Arg(T)-Pro-Ala-Lys(Z′)-Xaa-OH, (SEQ ID NO:
3) B-Pro-Ala-Lys(Z′)-Xaa-Arg(T)-OH, (SEQ ID NO:
4) B-Ala-Lys(Z′)-Xaa-Arg(T)-Pro-OH, (SEQ ID NO:
5) B-Lys(Z′)-Xaa-Arg(T)-Pro-Ala-OH;
(SEQ ID NO:
6)
wherein Xaa is Ala, Gly, Glu, Gln, Asp, Asn, Arg or Lys;
B is the N-terminal protecting group of the peptide chain;
Z is the side chain protecting group of Lys residue;
and T is the side chain protecting group of Arg residue;
(B) dissolving said first intermediate in organic solvents and then adding coupling agents to perform direct coupling reactions, which provides a second intermediate;
and
(C) removing the protecting groups on the side chain of Lys and Arg residue to form a final compound.

15 more elements

Dependencies are inferred from the claim text.

Description4,065 words

Summary781 words

#1. Field of the Invention

#The present invention relates to a novel cyclic peptide and its preparation.

#2. Description of Related Art

Brief description of the drawings2 figures

#FIG. 1 shows P6A (SEQ ID NO: 25) and P6A analogue synthesis path, wherein AA represents the corresponding protected L-Ala, Gly, L-Lys, and L-Gln.

#FIG. 2 shows the Compound (5-8) (SEQ ID NO: 11-14) synthesis path, wherein AA represents the corresponding protected L-Ala, Gly, Lys, and Gln.

Detailed description3,237 words

#The present invention provides a method to converse the linear peptide 6A and its analogues into cyclic structures whose backbone conformation mobility is restricted. Thus, the degradation rate of cyclic peptide of the present invention decreases dramatically and therefore its half-life in vivo will be prolonged.

#In the present invention, peptides 6A and the analogues, respectively, are prepared by solid phase or solution phase synthesis. The corresponding cyclic pentapeptide is also prepared by the same methods. The thrombolytic effect was evaluated on a rat model of thrombolysis.

#The present invention provides a cyclic peptide of the following formula (I) (SEQ ID NO: 1):

Facts

Application

10/404,124Filed 2 Apr 2003

Priority

TW 911067083 Apr 2002

Published

9 Oct 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07K 7/64
Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof: cyclic peptides containing only normal peptide links
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/08
Drugs for disorders of the cardiovascular system: vasodilators for multiple indications

Cyclic pentapeptides and their preparation

Life of this patent

Cyclic pentapeptides and their preparation

Life of this patent

Life of this patent

Abstract

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Claims26

Description4,065 words

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Classification10 codes

Life of this patent

Description4,065 words