Process for preparing cardiodilatin fragments; highly purified c

Details Process for preparing cardiodilatin fragments; highly purified c Process for preparing cardiodilatin fragments; highly purified c

1996-12-02

1998-06-16

Saunders, David

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Synthesis of peptides

530324, 530325, 530326, 530327, 530333, 530334, 530335, A61K 3810, A61K 3812, A61K 3816

Patent

active

057672393

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP95/02050.


FIELD OF THE INVENTION

The invention relates to a process for the preparation of cardiodilatin fragments, to highly purified cardiodilatin fragments, and to appropriate intermediates for the preparation of said fragments.


BRIEF SUMMARY OF THE INVENTION

The present invention is directed to a process for the preparation of cardiodilatin fragments of formula I fragments thereof having a chain length of 0-15 amino acids, and 3! or fragments thereof having a chain length of 0-5 amino acids, fragments, and condensation of the partial fragments to give the cardiodilatin fragments of formula I is carried out between the amino acid positions Gly.sup.108 and Arg.sup.109 and the amino acid positions Gly.sup.120 and CyS.sup.121.
Cardiodilatin is a peptide of the class of natriuretic peptides. These peptides play an important role in regulating the balance of salts and water in the body. The prototype of natriuretic hormones is cardiodilatin, also referred to in literature as atrial natriuretic peptide (CDD/ANP) . The isolation of cardiodilatin and the preparation of biologically active fragments of cardiodilatin are known from U.S. Pat. No. 4,751,284 (cf., W. G. Forssmann et al., Klin. Wochenschr. 1986, 64 (Suppl. VI), 4-12). A review on isolation and characterization of cardiodilatin and fragments thereof, as well as their physiological properties has been published in Eur. J. Clin. Invest. 1986, 16; 439-451 (W. G. Forssmann). From EP 0,349,545, a specific cardiodilatin fragment having a chain length of 32 amino acids is known. Meanwhile, this fragment is also referred to in literature as urodilatin (INN: ularitide). Furthermore, U.S. Pat. No. 5,354,900 (Suntory) describes a biologically active fragment having a chain length of 28 amino acids, known as .alpha.-hANP. Further biologically active cardiodilatin fragments or derivatives thereof have been described in EP 0,180,615. Therein, in particular, cardiodilatin fragments are described which begin with the amino acid position Arg.sup.102 at the N-terminus and end with the amino acid position Arg.sup.125 or Arg.sup.126 at the C-terminus. Instead of the designation cardiodilatin, the literature frequently uses the designation "atrial natriuretic peptide" (ANP). In the numbering of the sequences of the cardiodilatin amino acids used in the following, reference is made to the nomenclature used for the ANF/CDD (1-126) peptide (=ANP) in EP 0,349,545.
A common structural feature of all hitherto known biologically active cardiodilatin fragments is the formation of a disulfide bridge between the amino acids Cys.sup.105 and Cys.sup.121, resulting in a stable ring of 17 amino acids. It is believed that the formation of this ring is substantially responsible for the biological activity of the cardiodilatin derivatives. At position Cys.sup.105, the cardiodilatin fragments are substituted by an amino acid chain R.sup.1 having a chain length of 0-15 amino acids, and at position Cys.sup.12 l by a chain R.sup.2 having a ANP(105-121) is presented in linearized form. ##STR1##
The cardiodilatin fragment ANP(95-126), with the INN designation ularitide, is a particularly stable and biologically active human peptide, having diuretic activity and a relaxing effect on the smooth vascular muscles, which is formed of 32 amino acids and has the following sequence, wherein both the cysteine amino acids at positions 11. and 27 in the peptide are forming a disulfide bridge (SEQ ID NO: 4): ##STR2##
Urodilatin is found in human urine. EP 0,349,545 describes a process for recovering urodilatin from urine using alginic acid, wherein the peptides adsorbed to alginic acid are eluted, the eluate is fractionated according to conventional purification methods, and the active fraction is recovered using a test based on the examination of the relaxing effect of urodilatin on the smooth muscles.
Furthermore, EP 0,349,545 describes a stepwise chemical synthesis of urodilatin using the Merrifield process (J. Am. Chem. Soc. 1963, 85; 2149-2156), at a solid phas

REFERENCES:
patent: 5449751 (1995-09-01), Forssmann et al.
patent: 5665861 (1997-09-01), Forsemann et al.

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