Methods of use for 2-deoxy ecdysterone

Details Methods of use for 2-deoxy ecdysterone Methods of use for 2-deoxy ecdysterone

2002-01-16

2003-09-09

Qazi, Sabiha (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S169000, C514S170000, C514S171000, C514S181000, C514S182000

Reexamination Certificate

active

06617319

ABSTRACT:

FIELD
The present invention relates to a process for the isolation of 2-deoxy ecdysterone from Zoanthus sp useful as an oxytocic agent. The invention also relates to a method of inducing uterus contractions in mammals by administering an effective amount of 2-deoxy ecdysterone obtained from Zoanthus sp.
BACKGROUND
The animal Zoanthus sp is a marine invertebrate belonging to the Phylum Coelenterata, class Anthozoa and order Zoanthidea. Several bioactive compounds have been isolated from this source. Most important among them is the highly toxic palytoxin (LD
50
in mice=0.15 mg/Kg, Moore R E and Scheuer P J, 1971,
Science,
172:495), which is also an active cardiovascular agent. Other compounds reported from this group of animals are: homopalytoxin, bishomopalytoxin, neopalytoxin, deoxypalytoxin (Quinn R. J in
Bioorganic Marine Chemistry
, Vol 2, 1988, Edited by P J Scheuer, pp 25-27), two pyrazine derivatives: palythazine and isopalythazine, and a group of nitrogen pigments, paragracine I-VII (Bakus G J, Targett N M and Schulte B, 1986 ,
J Chem Ecol
, Vol 12:951-987), 3-norpseudozoanthoxanthin (Cimino G, De Stefano S, Fenical W, Lin G H Y, Wing R M, Radick P and Sima J J,
J Am Chem Soc,
1973, 95:4049) besides the alkaloids, zoanthamine, zoanthenamine and zoanthamide (Rao C B, Anjaneyulu A S R, Sarma N S, Venkateswarlu Y, Rosser R M, Faulkner D J, 1985.
J Org Chem,
50:3757-3760).
Ecdysones and ecdysterones are moulting hormones found in crustaceans and insects (D J Tighe-Ford, 1977. Hormonal aspects of Barnacle antifouling research. In
Marine Natural Products Chemistry
, D J Faulkner and W H Fenical (eds), Plenum Press, 383). The zoanthid
Gerardia savaglia
was found to contain large quantities of the crustacean molting hormone, ecdysterone (Sturaro A, Guerriero A, De Clauser R and Pietra F,
Experientia,
1982, 38:1184-1185). The related compounds, Palythoalones A and B (ecdysteroids) from the marine zoanthid
Palythoa australiae
have recently been isolated. (Shigemori H; Sato Y; Kagata T; Kobayashi J, 1999. Palythoalones A and B, new ecdysteroids from the marine zoanthid
Palythoa australiae. J. Nat. Prods,
62(2):373).
Agents that stimulate the pregnant uterus and are of importance in obstetrics are:
1-Oxytocics: Oxytocin and ergometrine
2-Prostaglandin E and F type compounds
Oxytocin causes regular coordinated uterine contractions each followed by relaxation. It is the drug of choice used to induce or augment labour when the uterine muscle is not functioning adequately (Rang H. P., Dale M. M; Ritter J. M., Pharmacology, third edition, pp 470, Churchill Livingstone, 1995). It is particularly used in those cases such as diabetes, isoimmunisation, hypertensive states, intrauterine growth retardation, placental insufficiency in which continuation of pregnancy is considered to be more harmful to the mother and/or foetus than the risks of delivery or pharmacological induction (Andrew J. Nichols; Robert R. Ruffolo, Jr., Uterine Pharmacology, in Principles of Pharmacology. Basic Concepts and Clinical Applications. Ed. Paul L. Munson. pp 202, 1995). Oxytocin may also be used in the treatment of postpartum hemorrhage resulting from uterine atony (Andrew J. Nichols; Robert R. Ruffolo, Jr., Uterine Pharmacology, in Principles of Pharmacology. Basic Concepts and Clinical Applications. Ed. Paul L. Munson. pp 202, 1995). Historically the ergot alkaloids were the first agents used to initiate or accelerate parturition. In modem obstetrics, oxytocin is used for this function and ergot alkaloids are most often used for treatment of postpartum hemorrhage (Cornelia R. Graves, Agents that cause contraction or relaxation of the uterus, in Goodman and Gilman's, The Pharmacological basis of therapeutics. Eds. Perry B. Molinoff and Raymond W. Ruddon, pp. 939, 1996). Specific receptors for oxytocin in human myometrium have been identified and differences in receptor density at various stages of labour also have been noted (Bossmar T; Akerlund M; Fantoni G; Szamatowicz J; Melin P; and Maggi M., Receptors for and myometrial responses to oxytocin and vasopressin in preterm and term human pregnancy: effects of the oxytocin antagonist atosiban. Am. J. Obstet. Gynecol. 1994, 171: 1634-1642, 1994). Oxytocin has dual effects on the uterus. It regulates the contractile properties of myometrial cells and elicits prostaglandin production by endometrial/decidual cells.
Prostaglandins currently used in obstetrical practice include PGE
2
, PGF
2&agr;
and the synthetic derivative 15-methyl PGF
2&agr;
. More recently, the PGE
1
analog, misoprostol, has been under clinical investigation for use as an abortifacient and cervical ripening.
The major use of PGE
2
(dinoprostone, Prostin E
2
) and 15-methyl PGF
2&agr;
(Carboprost, Hemabate) currently approved in the U.S.A is for the performance of mid-trimester abortions. 15-Methyl PGF
2&agr;
is also used as an alternative to ergonovine or oxytocin in the treatment of postpartum hemorrhage. In addition, numerous studies have supported the beneficial effect of locally applied PGE
2
as a cervical ripening agent (Buchanam D; Macer J and Yonekura M. L., Cervical Ripening with Prostaglandin E
2
Vaginal Suppositories. Obstet. Gynecol. 1984, 63:659-663).
Prostaglandins E
2
and F
2
&agr;, presently used for clinical purposes are not very stable. For example, radiolabelled PGE
2
, when injected into human volunteers, about 50% of the radioactivity is excreted in the urine within 5 hours. The corresponding value for PGF
2&agr;
is around 90% (W P Collins; E A Willman, 1978. Prostaglandins and uterine functions, In Topics in hormone chemistry, W R Butt (eds), Ellis Horwood Publishers, 183). At least 15 compounds have been identified in both the studies by mass spectrometry.
OBJECTS
The main objective of the present investigation is to provide a process for the isolation of 2-deoxy ecdysterone from Zoanthus sp.
Another objective of the investigation is to find out the unknown property of the compound, 2-deoxy ecdysterone, isolated and purified from Zoanthus sp in inducing uterus contractions.
Still another objective of the invention relates to a method of inducing uterus contractions in mammals, said method comprising administering in known manner an effective amount of 2-deoxy ecdysterone which isolated and purified from Zoanthus sp.
Yet another objective of the invention is to provide a stable bioactive compound which may be useful in obstetrics, to induce or augment labour, to control postpartum uterine atony and hemorrhage, to cause uterine contraction after cesarean section or during uterine surgery or to induce therapeutic abortion.
DETAILED DESCRIPTION
The present investigation undertaken by the inventors has led to the development and standardization of a facile method for the isolation and purification of 2-deoxy ecdysterone from a new source, Zoanthus sp using flash chromatography over silica gel and gel permeation chromatography over Sephadex LH-20. The invention further provides a novel biomedical use of this compound as a potent oxytocic agent. The invention has established that this compound is more potent than the standard oxytocin and PGF
2&agr;
at the concentration of 200 &mgr;g/ml. The compound, 2-deoxy ecdysterone is also very stable and soluble in aqueous solvents and may have wider therapeutical applications.
The compound, 2-deoxy ecdysterone also known as 2-deoxy &bgr;-ecdysone or 2-deoxy-20-hydroxy ecdysone, was found to be effective in inducing contractions in the guinea pig uterus. It was found that the percentage of active component oxytocin contained in 50 &mgr;g/ml of compound amounts to 80.8%, that at 100 &mgr;g/ml to 92.3% which further increases to 118.0% at concentration of 200 &mgr;g/ml. Uterine contractions produced by the compound were also compared with the standard contraction produced by prostaglandin (PGF
2&agr;
). It was observed that for the active compound, the percentage of active component PGF
2&agr;
contained in 50 &mgr;g/ml of compound amounts to 69.4%, that at 100 &mgr;g/ml to 82.3% which further increases

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