Heptapeptide oxytocin analogues

Details Heptapeptide oxytocin analogues Heptapeptide oxytocin analogues

1999-08-02

2000-11-07

Davenport, Avis M.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

530315, 530329, 530330, A61K 3800, C07K 500, C07K 700

Patent

active

061437220

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to new heptapeptide analogues (i.e. heptapeptides in which the N-terminal residue is deaminated and the C-terminus is reduced to an alcohol) exhibiting oxytocin antagonist activity useful, inter alia, for decreasing or blocking uterus muscle contraction associated with pre-term labour and menstrual pain. The invention also relates to pharmaceutical compositions containing these peptide analogues and to their use.


BACKGROUND OF THE INVENTION

Oxytocin is a peptide hormone. It stimulates contraction of the uterine muscles. For this reason, it is believed to be involved in the etiology of pre-term labour and menstrual pain. It is further believed that oxytocin antagonists would be useful in the control of these conditions. Oxytocin antagonist peptides of adequate potency and selectivity of therapeutic use are known. They are often intended for administration in aqueous solution. The manufacture of ready-for-use doses of such antagonists requires that the solutions be stable for extended periods, which is not always true. In such cases, the medicament must be prepared immediately prior to use from, for instance, the freeze-dried peptide or its pharmaceutically acceptable salt. This sort of manipulation is inconvenient and entails the risk of contamination.


OBJECTS OF THE INVENTION

It is an object of the invention to provide new oxytocin antagonists which are heptapeptide analogues having improved stability in aqueous media while retaining adequate potency and selectivity for therapeutic efficacy.
It is a second object of the invention to provide pharmaceutical compositions containing said new heptapeptide-analogue oxytocin antagonists and having improved stability and, therefore, shelf-life.
It is a further object of the invention to provide for a method of treatment of a medical condition associated with excess or inappropriate uterine contraction, which method is the administration of a pharmaceutical composition containing said heptapeptide analogue.


SUMMARY OF THE INVENTION

The invention comprises a class of compounds which are heptapeptide analogues, pharmaceutical compositions containing such analogues, and a use for these compositions which is the treatment of uterine contractions, particularly in the context of pre-term labour and menstrual pain.
The heptapeptide analogues of the invention have an N-terminal hexapeptide moiety S and a C-terminal .beta.-aminoalcohol Z, which is considered hereinafter to be the formal equivalent of the seventh amino acid of the heptapeptide. The moiety S has the structure: ##STR1## wherein Mpa, Ile, Asn and Abu have the following meanings:


______________________________________ Mpa 3-mercaptopropionic acid residue (otherwise called desamino- cysteine) Ile isoleucine residue Asn asparagine residue Abu .alpha.-aminobutyric acid residue; ______________________________________ .alpha.-amino acid.
The aminoalcohol Z has the structure: ##STR2## wherein R is methyl or ethyl, and --C(.dbd.NH)NH.sub.2.
The compounds of the invention can form acid addition salts, and to the extent that these salts are pharmaceutically acceptable they are included within the scope of the invention.
The compounds can be incorporated into either solid or liquid formulations. Examples of such formulations include tablets, capsules, solutions and suspensions. Other components of such formulations can include, for example, diluents, dispersants, preservatives, buffering agents, flavouring agents and osmotic pressure regulating agents. Solid formulations are particularly suitable for oral administration, while solutions are most useful for injection (i.v., i.m. or s.c.) or intranasal administration. A particular merit of the compounds of the invention is that their solutions are more stable on prolonged storage than those of previously known compounds of comparable potency.
The formulated pharmaceutical is useful in the control of uterine contractions. Two indications where such control is likely to be required are pre-ter

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