Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1998-01-14
1999-10-05
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 9, 530311, 530317, C07K 14655, A61K 3831
Patent
active
059624094
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to cyclic peptides which are homologues of somatostatin and have inhibitory activity on growth hormone.
BACKGROUND OF THE INVENTION
Somatostatin, or somatotropin-release inhibition factor, is a neuropeptide inhibiting the release of the growth hormone (somatotropin).
A number of somatostatin synthetic analogues are known, which are used in human and animal therapies.
In particular, octreotide has been known for some time, which is a somatostatin synthetic analogue used in therapy for the treatment of syndromes due to gastroenteral-pancreatic endocrine tumours, acromegaly as well as in the post-surgery treatment after pancreas surgery. Octreotide is also indicated as an agent inhibiting gastric secretion. This compound is described in U.S. Pat. No. 4,395,403 (Sandoz) and has the formula: ##STR2##
The octapeptide described above lies within a general formula of monocyclic polypeptides, comprising an hexapeptide residue containing a phenylalanine residue, optionally substituted at the 1-position of the aromatic ring, a cysteine residue at the 2-position, a D-trypthophan residue optionally substituted at the 4-position of the indole ring, a lysine residue at the 5-position, optionally N-alkylated at the position .epsilon., an amino acid residue at the 6-position and a cysteine residue at the 7-position, the two sulfur atoms of the 2 and 7 cysteine residues are linked together and an amino acid residue at the 8-position.
Another somatostatin synthetic analogue, known under the name of Lanreotide, has been recently used in therapy. This compound has formula: ##STR3##
SUMMARY OF THE INVENTION
Now it has been found that compounds of formula (I) ##STR4## wherein A is D-2AlkTrp, D-.beta.Nal, D-Phe; R is not ThrNH.sub.2 and the pharmaceutically acceptable salts of these peptides have activity inhibiting the release of the growth hormone and therefore are useful as active principles in human and animal medicine.
The present invention is based on the most surprising finding that the change of some structural characteristics, which had been defined essential in U.S. Pat. No. 4,395,403, not only keeps the somatostatin-like activity, but also shows further advantages in terms of specificity (see for example the expression of receptor sub-types in pituitary adenomas (G. M. Miller et al. J.C.E.M. 80, 1386, 1995) and in bronchial carcinoid tumors (H. Lefabre et al. J.C.E.M. 80, 1423, 1995).
DETAILED DISCLOSURE OF THE INVENTION
The abbreviations for the residues of amino acids therein used are in agreement with the standard nomenclature for the peptides, therefore, in the formula (I) reported above:
According to the present invention, for alkyl at position 2- of the tryptophan residue it is intended that lower alkyl, comprising from 1 to 3 carbon atoms, be used. Examples of lower alkyl are methyl, ethyl, propyl, isopropyl. Among them, the methyl group is most preferred, and the abbreviation MeTrp is used to indicate 2-methyltryptophan.
All the three letter-abbreviations of the amino acids preceded by a "D" indicate the D-configuration of the amino acidic residue.
Preferred compounds according to the present invention are: ##STR5## wherein MeTrp is 2-methyltryptophan.
The compound:
The polypeptide compounds according to the present invention can be synthesized according to the usual methods of peptide chemistry, both solid-phase and solution, or by means of the classical methods known in the art. The solid-phase synthesis starts from C-terminal end of peptide. A suitable starting material can be prepared, for example attaching the required protected alpha-amino acid to a chloromethylated resin, a hydroxymethylated resin, a benzhydrylamine resin (BHA), or to a para-methylbenzhydrylamine resin (p-Me-BHA). As example, a chloromethylated resin is sold with the Trade Mark BIOBEADS.RTM. SX 1 by BioRad Laboratories, Richmond, Calif. The preparation of the hydroxymethyl resin is described by Bodansky et al., Chem. Ind. (London) 38, 15997, (1966). The BHA resin is described by Pie
REFERENCES:
patent: 4904642 (1990-02-01), Coy et al.
patent: 5480870 (1996-01-01), Keri et al.
R.Z. Cai et al.. "Superactive Octapeptide Somatostatin Analogs Containing Tryptophan at Position 1"; Proceedings of the National Academy of Sciences of USA, vol. 84, Apr. 1987, Washington, US.; pp. 2502-2506.
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