Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-09-17
2002-01-22
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S579000, C514S843000, C546S344000, C558S412000, C558S423000
Reexamination Certificate
active
06340688
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a novel contraceptive method employing a competitive progesterone antagonist and to novel progesterone antagonists useful therein.
By inhibiting the formation of endometrial glands and epithelium growth, the implantation of a fertilized egg in the uterus is rendered impossible (inhibition of the uterine receptivity). The employment of competitive progesterone antagonists according to the invention can thus be used for contraception in the female.
RU 486 (11&bgr;-[4-N,N-(dimethylamino)phenyl]-17&bgr;-hydroxy-17&agr;-propinyl-estra-4,9(10)-dien-3-one; EP-A-0057115) and other 11&bgr;-aryl or 11&bgr;,19-arylene-substituted steroids are compounds which can displace progesterone and the glucocorticoids from their respective receptors. These substances are pharmacologically distinguished by strong progesterone- and glucocorticoid-antagonistic effects. These properties determine their previously practiced therapeutic uses. RU 486 is useful, e.g., as a progesterone antagonist for therapeutic termination of pregnancy and also as a glucocorticoid antagonist for treatment of Cushing's syndrome in the wake of a pathologically increased secretory activity of the suprarenal cortex. The abortive dose of RU 486 is 200-600 mg in the female.
It has also long been known that competitive progesterone antagonists are able to inhibit ovulation in various animal species and in the human female. (Collins et al., “Blockade of the spontaneous mid-cycle gonadotropin surge in monkeys by RU 486; A progesterone antagonist or agonist”, J. Clin. Metab., 63:1270-1276 (1986);
Croxatto, H. B., “Salvatierra 1990 Cyclic use of anti-gestagens for fertility control”, IIIrd International Symposium on Contraception, Heidelberg, Jun. 19-23, 1990;
Danford et al., “Contraceptive potential of RU 486 by ovulation inhibition. III. Preliminary observations on once weekly administration”, Contraception 40: 195-200 (1989);
Kekkonen et al., “Lähteoenmäki P 1990 Interference with ovulation by sequential treatment with the antiprogesterone RU 486 and synthetic progestin”, Fertil Steril [Fertile Sterile] 53,4747;
Puri et al., “Gonadal and pituitary responses to progesterone antagonist ZK 98 299 during the follicular phase of the menstrual cycle in bonnet monkeys”, Contraception 39, 2: 227-243 (1989);
Puri et al., “Contraceptive potential of a progesterone antagonist ZK 98 734: Effect on folliculogenesis, ovulation and corpus luteum function in bonnet monkeys”. In Moudgal et al., (eds) (1990);
U.S. Pat. No. 4,764,513 teaches that the receptivity of the endometrium for implantation (implantation window) can be shifted (delayed) by administering a competitive progesterone antagonist to a female to increase the likelihood of successful implantation of an in vitro fertilized egg.
11&bgr;,19-o-Phenylene-bridged steroids, which exhibit especially strong competitive progesterone-antagonistic effectiveness in the case of considerably reduced anti-glucocorticoid activity relative to the comparison compound
11&bgr;-
(4-dimethylaminophenyl)-17&bgr;-hydroxy-17&agr;-(propin-1-yl)-4,9(10)-estradien-3-one (RU 486; EP-A-0 057 115), are described for the first time in U.S. Pat. No. 5,095,129. The novel compounds of this invention (Compounds I and II) fall within the scope of the generic formula of U.S. Pat. No. 5,095,129, but are not disclosed therein by name or by example.
The dose of a competitive progesterone antagonist having an ovulation inhibition effect depends greatly on the species thereof employed. In the case of RU 486, it is 50-100 mg in the human female. (Croxatto et al.; loc. cit., Ledge et al. (1992) Inhibition of ovulation using very low dose mifepristone; Abstract: Second Congress of the European Society of Contraception. RU 486 shows little or no dissociation of its central and endometrial effects in humans (Ledge W. L. et al., Terra Symposium on Progesterone Antagonists, May 25-29, 1992, Mohouk, N.Y.).
An “LH+2” treatment for implantation inhibition has been proposed (Swahn et al., “The effect of RU 486 administration during the early luteal phase on bleeding pattern, hormonal parameters and endometrium,”
Human Reproduction
5, 4:402-408 (1990)): 2 days after the LH peak (LH=Luteinizing Hormone) in the menstrual cycle (occurrence of the LH peak corresponds to the time of ovulation) of the female (i.e., thus on day 14, 15 or 16), an ovulation-inhibiting dose of RU 486 is administered one time. The active compound is thus administered only after the time of ovulation in the luteal phase of the menstrual cycle (luteal contraception).
It was only recently reported that an endometrial desynchronization in the female without hormonal changes (progesterone and estradiol concentrations) can be achieved by the competitive progesterone antagonist RU 486, when the latter was administered on day 5 and day 8 after the occurrence of the LH peak in the menstrual cycle (dosage in each case 10 mg, peroral) (Kettel et al., 1992). Reliable conception without ovulation inhibition cannot be achieved if a competitive progesterone antagonist is administered only after LH peaks in the menstrual cycle is achieved.
It has now been found that in accordance with this invention, competitive progesterone antagonists are capable, at a dosage regime which does not inhibit ovulation or induce abortion, of inhibiting the formation of endometrial glands in the proliferation phase as well as the function of the glands in the luteal phase of the menstrual cycle, thereby achieving contraception, if the administration of the dose takes place at least once before and optionally also after the occurrence of the LH peak.
SUMMARY OF THE INVENTION
In a method aspect, this invention relates to a method of contraception in a female, which comprises administering thereto during the follicular phase of her menstrual cycle and optionally also in the luteal phase thereof an amount of a competitive progesterone antagonist, which is less than an ovulation-inhibiting and less than an abortion-inductive dose and which is effective to inhibit the formation of endometrial glands, which glands are a requirement for the implantation of a fertilized egg in the uterus.
In a composition aspect, this invention relates to an 11&bgr;,19-o-phenylene-17&bgr;-hydroxy-17&agr;-(3-hydroxyprop-1(Z)-enyl)-4-androsten-3-one of the formula:
wherein R is
In another composition aspect, this invention relates to a pharmaceutical composition comprising in admixture with a pharmaceutically acceptable carrier, an amount per unit dosage of a competitive progesterone antagonist which is less than an ovulation-inhibiting and less than an abortion-inductive dose and which is effective to inhibit the formation of endometrial glands and epithelium growth.
DETAILED DISCUSSION
In the proliferation phase, an estrogen-induced formation of the secretory glands in the endometrium occurs in the normal menstrual cycle, while in the luteal phase (also designated as the secretion phase), the secretory activity of the glands is induced by progesterone. The described effect of the competitive progesterone antagonists in the proliferation phase, i.e., before ovulation, thus is not inherently based on a progesterone inhibition effect, since the proliferation of the endometrial glands is estrogen-dependent. Further, the progesterone concentrations in the blood in the proliferation phase of the menstrual cycle are very low. By the use of competitive progesterone antagonists according to the invention, a selective inhibition of the uterine receptivity is achieved without adversely influencing the menstrual cycle and at doses too low to induce abortion if ovum implant has already occurred.
The ability to achieve contraception at lower than abortion-inducing doses and ovulation inhibiting doses is a very important consideration for some human females who are opposed to abortion or are concerned about the long-term medical effects of ovulation inhibition.
A decisive advantage of the use proposed here exists in the very high contraceptive r
Chwalisz Krzystof
Elger Walter
Ottow Eckhard
Schmidt-Gollwitzer Karin
Millen White Zelano & Branigan P.C.
Owens Amelia
Schering Aktiengesellschaft
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