Endothelin antagonist peptides

Details Endothelin antagonist peptides Endothelin antagonist peptides

1996-10-28

1999-07-20

Tsang, Cecilia J.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

4 to 5 amino acid residues in defined sequence

530331, 514 16, 514 17, 514 18, A61K 3807

Patent

active

059257318

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
This invention relates to a novel peptide derivative, exhibiting endothelin receptor antagonistic action, which is pharmaceutically useful as, for example, a therapeutic or prophylactic agent of cardio- or cerebro-circulatory disease, hepatic disease and/or renal disease, a method of producing it, and a pharmaceutical composition containing the compound.
2. Description of Related Art
Endothelin (ET) is a vasoconstricting peptide consisting of 21 amino acids, which was isolated from the supernatant of swine arterial endothelial al.: Nature, Vol. 332, pp.411-415 (1988)!. Endothelin was later found to exhibit a variety of actions, and endothelin antibodies as endothelin antagonists have proven effective in the treatment of myocardial infarction, renal failure and other diseases. Since endothelin is present in living bodies and exhibits vasoconstricting action, it is be an endogenous factor involved in the regulation of the circulatory system and has an association with hypertension, cardio- or cerebro-vascular diseases, e.g. myocardial infarction: and renal diseases, e.g. acute renal failure: and hepatic diseases, e.g. hepatargia. Since it also exhibits bronchial smooth muscle constricting action, it has an association with asthma.
While, as endothelin antagonists, there have recently been disclosed peptides exhibiting endothelin antagonistic action in JP-A 107680/1994 and Bioorganic & Medicinal Chemistry Letters, Vol. 5, pp.1483 (1995), those exhibiting actions are not sufficient.


SUMMARY OF THE INVENTION

Circumstances being such as above, the present inventors have studied intensively. As a result, the inventors found that a peptide derivative whose C-terminal is an amino acid reside which is amidated with an optionally substituted heterocyclic group and is substituted with a carboxyl group or an heterocyclic group capable of releasing proton, or a salt thereof, exhibits excellent endothelin receptor antagonistic action.
Namely, the present invention relates to: is amidated with an optionally substituted heterocyclic group, and is substituted with a carboxyl group or a heterocyclic group capable of releasing proton, or a salt thereof, residue at C-terminal is amidated with an optionally substituted heterocyclic group, and the hydrogen atom on a carbon atom in the amino acid residue at C-terminal is substituted with a carboxyl group or a heterocyclic group capable of releasing proton, or a salt thereof, N-terminal is acylated, derivative is acylated by an acyl group represented by the formula R.sup.1 --CO--, wherein R.sup.1 is an optionally substituted hydrocarbon residue or an optionally substituted hydrocarbonoxy group, or a group represented by the formula R.sup.2 R.sup.3 N--CO--, wherein R.sup.2 is an optionally substituted hydrocarbon residue or a heterocyclic group, R.sup.3 is a hydrogen atom or an optionally substituted hydrocarbon residue, or R.sup.2 and R.sup.3 are combined with each other to form, taken together with the adjacent nitrogen atom, an N-containing saturated heterocyclic ring, 3 to 6 amino acid residues, heterocyclic group capable of releasing proton is a 4- to 6-membered heterocyclic group having 1 to 4 nitrogen atom, oxygen atom or/and sulfur atom, and optionally having a hydroxy or oxo group as the substituent, or the heterocyclic-group which is condensed with a benzene-ring, substituent of the optionally substituted heterocyclic group is a C.sub.1-6 alkyl group, an optionally substituted C.sub.6-14 aryl group, a N-containing 5- to 6-membered heterocyclic group, a halogen atom, nitro, cyano, hydroxy, a C.sub.1-6 alkoxy group, amino, oxo, amidino, imino, mercapto, sulfo, a mono- or di-C.sub.1-6 alkylamino, formylamino, a C.sub.1-6 alkylsulfonylamino group, a C.sub.1-6 alkoxycarbonyl group, carboxyl, formyl, a C.sub.1-6 alkylcarbonyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.3-9 cycloalkyl group, a C.sub.5-7 cycloalkenyl group, a C.sub.7-13 aralkyl group, a C.sub.1-6 alkylthio group, a C.sub.1-6 alkyls

REFERENCES:
patent: 5268360 (1993-12-01), Yoshikawa
patent: 5688913 (1997-11-01), Arrhenius
T. Fukami et al., Bioorganic & Medicinal Chemistry Letters, 5(14), 1483-1488 (1995).

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