Vasopressin and vasotocin derivatives

Details Vasopressin and vasotocin derivatives Vasopressin and vasotocin derivatives

1993-12-20

1995-11-28

Warden, Jill

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Oxytocin; vasopressin; related peptides

530317, A61K 3800, C07K 716

Patent

active

054709482

DESCRIPTION:

BRIEF SUMMARY
This invention relates to new vasopressin and vasotocin derivatives of general formula I ##STR2## in which A stands for the radical Mca (=3-mercapto-3,3-cyclopentamethylene-propionyl radical) or for the radical Mpa (=3-mercaptopropionyl radical), D-Ile, D-Trp or the radical of a hydrophobic D-amino acid, and (Ile; vasotocin derivatives).
The new derivatives are distinguished from the natural hormone [Arg.sup.8 ]-vasopressin (AVP) by substitution of the amino acid radical Cys (cysteine) in 1-position by the radical Mca ##STR3## or the radical Mpa (--S--CH.sub.2 --CH.sub.2 --CO--) of the amino acid radical L-Tyr (L-tyrosine) in 2-position by the radical D-Tyr, D-Tyr(Et) [D-tyrosine-O-ethyl ether] or the radical of a hydrophobic D-amino acid, optionally of the amino acid radical phenylalanine (Phe) in 3-position by the radical isoleucine (Ile) as well as of the radical proline (Pro) in 7-position by the radical safcosine (Sar).
The derivatives of formula I have a high affinity to the oxytocin receptor and to V.sub.1 -vasopressin receptor; they have both oxytocin-antagonistic and V.sub.1 -vasopressin-antagonistic action. By introducing the Mca radical in 1-position of the vasopressin structure, this "reversal of the properties" of AVP is achieved. Preferred are ##STR4##
Compounds, which represent competitive antagonists of oxytocin, are already known.
In EP-A-0 112 809, vasotocin derivatives ##STR5## are described, in which Mpa means the 3-mercaptopropionyl radical (--S--CH.sub.2 CH.sub.2 --CO--), or D-Tyr(Et), valine (Val) as well as or citrulline (Cit).
The two vasopressin analogs ##STR6## stem from the Collection Czechoslovak Chem. Commun., Vol. 53, p. 2907, (1988).
Relative to these first-mentioned known compounds, the compounds according to the invention are distinguished by a substantially greater and longer reversible inhibition of the action of the oxytocin; the new compounds have no agonistic activity whatsoever.
The examination of (a) oxytocic and (b) oxytocin-inhibiting activity took place by continuous tonometry of the uterus of pregnant guinea pigs on d 40.+-.1 p.c.:
24 hours before the examination, a microballoon, which is filled with water, was implanted in the uterus. The balloon is connected by a catheter with a pressure sensor. An i.v. catheter simultaneously was inserted in the jugular vein. After an adaption phase of about 30 minutes to 1 hour, the oxytocin antagonist was examined for agonistic [see (a)] and antagonistic activity [see (b)]. Both oxytocin and the test substance were administered intravenously (vehicle: 0.9% common salt solution).
(a) Agonistic activity:
(b) Antagonistic activity:
Complete inhibition of the oxytocin action
1 hour after the last administration of (B), a recovery of the uterus takes place, i.e., clear contractions occur again.
When ##STR7## (E) (Compound of example 11 of EP-A-0 112 809) is administered according to the same dosage patterns, the duration and strength of the uterus contraction activity are only weakened.
Compound (B) according to the invention is comparable in the described model to compound (C) relative to the oxytocin-antagonistic action.
Because of their oxytocin-antagonistic action, the compounds according to the invention can be used to produce pharmaceutical preparations.
Oxytocin antagonists inhibit the uterus motor response by a direct action on the myometrium and indirectly by the inhibition of the uterine (decidual) prostaglandin synthesis. They are therefore suitable for treatment and prophylaxis of premature labor (premature delivery, impending miscarriage) and dysmenorrheic symptoms.
In addition to the posterior lobe of the pituitary gland, the ovary or the corpus luteum secretes oxytocin. If the latter action takes place in the uterus, the above-discussed aspects apply. In the ovary itself, oxytocin controls certain functions of the corpus luteum. The inhibition of these functions, depending on dose and phase of the cycle, can lead to an increase or inhibition of the luteal hormone production. Correspondingly, the life span of the c

REFERENCES:
patent: 4402942 (1983-09-01), Melin
patent: 4766108 (1988-08-01), Ali
F. Kaspryzkowski et al, "Synthesis, biological activity and receptor binding affinity of two [8-arginine]vasopressin analogues with inhibitory properties", Collection Czechoslovak Chem. Commun., vol. 53, pp. 2907-2913 (1988).
Z. Grzonka et al, "Synthesis and some pharmacological properties of oxytocin and vasopressin analogues with sarcosine or N-methyl-L-alanine in position 7", Journal of Medicinal Chemistry, vol. 26, pp. 555-559 (1983).
Z. Grzonka et al, "Arginine-vasopressin analogues with high antidiuretic/vasopressor selectivity. Synthesis, biological activity, and receptor binding affinity of arginine-vasopressin analogues with substitutions in positions 1,2,4,7 and 8", Journal of Medicinal Chemistry, vol. 29, pp. 96-99 (1986).
C. F. Nelson et al, "The synthesis and structure-activity studies of vasopressin antagonists modified at positions one and two", Peptides--Proceedings of the Ninth American peptide Symposium (1987), published by C. M. Deber et al., Pierce Chemical Co., (Rockford Ill., U.S.), pp. 615-618.

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