MXPA97003018A - Competent progesterone antagonists to regulate female fertility as required - Google Patents

Abstract

The present invention describes the new use of progesterone antagonists competent for the preparation of a medicament for the control of female fertility according to the need (pill to be taken when required) that independently of the moment of the menstrual cycle, in a dosage unit that will be administered only once, whose dosage is below the ovulation inhibitory dosage

Description

COMPETENT PROGESTERONE ANTAGONISTS TO REGULATE FEMALE FERTILITY AS REQUIRED DESCRIPTION OF THE INVENTION The invention relates to the use of at least one progesterone antagonist competent for the preparation of a medicament for the control of female fertility according to the need ["pill to be taken when needed"], which can be used independently from the point of the menstrual cycle, in a dosage unit to be administered once, whose dosage is below the dose that inhibits ovulation. Throughout the world, the use of oral contraceptives has become a commercial factor, to which he has no objection. Especially under the aspect of rapid global growth, a continuous development of the fertility control methods hitherto used is required. The use of progesterone antagonists competent in the control of female fertility has been discussed for some years for both animal species and humans, as can be taken from the publications mentioned below, especially the use of RU 486. { 11-ß- [4-N, N- (dimethylamino) phenyl] -17-β-hydroxy-17-a-propynyl-estra-, 9, 10-dien-2-one: EP-A-0057115: Collins and cois Blocking the spontaneous gonadotropin increase in half monkeys by RU 486: An antagonist or progesterone agonist J.Cli.Metab. , 63, 1270-1276 (1986): Croxatto, H.B.M Salvatierra 1990 Cyclic use of antigestagens for the control of fertility, 3rd. International Symposium on Contraception, Heidelberg, June 19-23, 1990; Danford and cois. , Contraceptive potential of RU 486 due to the inhibition of ovulation, III. Preliminary observations with the weekly administration. Contraception 40: 195-200 (1989); Ke konen and cois. Lahteienmaki P 1990 Interference with ovulation through sequential treatment with the antiprogesterone RU 486 and synthetic progestin. Fertile Sterile 52: 4747 [1990]. Puri et al. , Responses of the gonads and the pituitary to the progesterone antagonist ZK 98 299 during the follicular phase of the menstrual cycle in capuchin monkeys. Contraception 39 (3): 227-243 [1989]; Puri et al.m Contraceptive potential of a progesterone antagonist ZK 98 734: Effects on folliculogenesis, ovulation and function of the yellow body in capuchin monkeys. In Moidgal and cois (eds) (1990). It should be mentioned here that the dosage which shows an ovulation-inhibiting effect depends strongly on the competent progesterone antagonist used.

The class of steroids substituted with llß-aryl or llß, 19-arylene differs pharmacologically according to its strong progesterone antagonist effect or glucocorticoids. Thus RU 468 can be used on the one hand for the interruption of therapeutically induced pregnancy [the human abortive dose in combination with a prostaglandin is 200-600 mg; EP-A-0 139 608], on the other hand also on its antagonistic effect on the glucurotide receptor for the therapy of Cushing's syndrome. Another possibility of the use of competent progesterone antagonists for the control of female fertility, the so-called "LH + 2" treatment, is proposed by Swahn et al. [The effect of administration of RU 486 during the early yellow phase in bleeding models, hormonal parameters and endometrium. Human reproduction 5 (4): 402-408 [1990], in which the second day after the increase of the hormone leutenisant [LH] in the menstrual cycle of the woman (this is in general on day 14, 15 or 16) a single ovulation-reducing dose of RU 486 [leukocyte contraception] is administered. This procedure has no practical meaning, since the easy and accurate temporal determination of the LH peak always represents a problem. Glasier and cois. [Mifepristone (RU 486) compared to high-dose estrogen and progesterone for post-coital emergency contraception. The New England J. of Med. 237: 1041-1044 (1992)] also describes the use of RU 486 for postcoital contraception (emergency postcoital contraception.) The method shows, in addition to a high effectiveness, a reduced extension of side effects, in a high percentage of women in this study. There was an extension of the cycle, which can be attributed to the antiovulatory effect of RU 486. Furthermore, in EP 93/23020, it is described that competent progesterone antagonists can be used in doses that are found in a dose, which is both below the abortive dose and inhibiting ovulation. Certainly here in general a repeated and regular application is required to achieve the desired effect. It also describes EP-A 0 219 447, which effect causes the daily administration of a progesterone antagonist during the follicular phase or optionally also leuteal of the female cycle in a period of up to 4 days in a dose of 10-200 mg in relation to the state of differentiation of the endometrium. The resulting variations of the endometrium are used considering the moment of nesting for in vitro fertilization. Batista and cois. [Daily administration of the progesterone antagonist RU 486 prevents implantation in cycle guinea pigs, Ara.J.Obstet.Gynecol.165: 82-86 (1991)] also describes the use of RU 486 for the control of female fertility, which by daily, precoital and full cycle, avoids the nesting with an inhibitory dose of ovulation in guinea pigs. Kawano and cois. [Effect of RU 486 on glycogen metabolism in the endoraetrium. Obstetric Act and Gynaecologica Japónica, 41: 1507-1511 (1989)] describes the influence of RU 486 on a dosage of 30 mg / kg of body weight on glycogen metabolism, in such a way that successful implantation of the egg is disrupted . The application is made on day 2 or 4 of pregnancy. It has now been found that surprisingly already by the single administration mainly according to the need for competent progesterone antagonists (at a lower dose than the ovulation inhibitor), the nest can be safely avoided and a new oral contraceptive made available. Until now the use of progesterone antagonists competent for contraception was possible only by multiple regular administration. Also the use so far in accordance with EP-A 0 210 447 is presented in contrast since here first reading should be made possible by the progesterone antagonist administration. Advantageously, according to the invention, a dissociated progesterone antagonist is used. Under a dissociated competent progesterone antagonist, a substance must be understood that its effect on the dose used does not occur through the hypothalamic-ovarian axis in the sense of inhibiting ovulation [central effect] but is limited exclusively to the endometrium, effect local (peripheral selective effect). Changes in the endometrium are observed with a certain threshold dose, while ovulation is not inhibited. The quotient between the inhibitory dose of ovulation and the inhibitory dose of the implantation [dissociation factor] can be used as a measure for dissociation. It varies depending on the species. All the competent progesterone antagonists studied show in the rats and in primates a dissociation between the central and endometrial effects. The extent of that dissociation depends on the substance. To use a dissociated competent progesterone antagonist according to the invention [determined in rats after peroral application] that dissociation factor should be approximately 30 or greater. RU 486 is an example for a substance slightly dissociated in primates. It inhibits ovulation already with lower doses and thus leads to cycle problems. Onaprisoton (llß- [4-N, N- (dimethylamino) phenyl] -17-hydroxy-17β- (3-hydroxypropyl) -13a-methyl-4,9 (10) -gonadien-3-one; EP-A 0 129 499) is an example of a dissociated progesterone antagonist compound, which at extremely high doses inhibits ovulation in primates. The endometrial effects of RU 486 and Onapriston are presented in comparable doses. This dissociation between the central and endoraetrial effect makes possible the use of a competent progesterone antagonist for the purposes of the present invention by increasing its dose and thus guaranteeing the effective inhibition of the implantation after a single administration. While the solution according to the invention meets another requirement imposed on modern drugs, which is that by means of a locally differentiated way of acting, a systematic loading of the organism by means of the single administration is avoided. From the present embodiments it is clear that a requirement-oriented fertility control was not possible until now. Especially for women, who could not be decided by the oral contraceptives until now existing of regular intake or for other reasons, for example, doctors did not have the possibility of selecting that form of fertility control, the alternative of selecting a contraceptive is now offered oral to take it when required, without subjecting your body to a hormonal control that lasts the entire menstrual cycle. The present invention also possesses the essential advantages that they are not based on the low dosage of the active substance. Thus, the female menstrual cycle is not influenced in terms of its cyclicity [as caused by the ovulation-inhibiting substances] and the organism is not loaded with unnecessarily high amounts of competent progesterone antagonists. The use of such a progesterone antagonist offers, in addition to a safe contraception, that is, the single taking of a drug of this type prevents the nesting of the blasts. Competent progesterone antagonists are used in amounts of generally a dose of 1-400 mg of Onapriston or a biologically equivalent dose of another competent progesterone antagonist. The treatment with the competent progesterone antagonists is usually carried out by means of taking an ac according to the need, this in general the pre- or psst-coital intake of a unit of daily dose depending on the point of the cycle. The precoital taking of the medicament prepared according to the invention is preferred. The time of the shot can be up to 6 hours before to 24 hours after intercourse. The taking is possible at any time when a contraceptive measure is required, add or desired. Suitable progesterone antagonists are all compounds according to the invention, which have a characteristic affinity to the progesterone receptor and have a selective effect on the endometrium. This type of progesterone antagonist shows in the dose used an inhibition of the nest without inhibiting ovulation. Thus, for example, the following progesterone antagonists are included: llß- [4-N, N- (dimethylamino) phenyl] -17a-hydroxy-17β- (3-hydroxypropyl) -l3a-methyl-4,9 (10) gonadiene -3-one (EP-A 0 129 499), llß- (4-acetylphenyl) -17β-hydroxy-17a- (3-hydroxyprop-1 (Z) -enyl) -4,9 (10) -estradien-3 -one (EP-A 0 190 759), llß, 19-. { 4- (cyanophenyl) -o-phenylene] -17β-hydroxy-17a- (3-hydroxyprop-1 (Z) -enyl) -4-androsten-3-one, llß, 190 [4- (3-pyridinyl) - o-phenylene] -17β-hydroxy-17a- (3-hydroxyprop-1 (Z) -enyl) -4-androsten-2-one (both WO-A93/23020) 17a-hydroxy-17β- (3-idroxypropyl 1) -ll- [4- (1-methylethyl) phenyl] -13-tetra-4,9-dien-3-one, llß- [4- ( 3-furanyl) phenyl] -17a-17β- (3-hydroxypropyl) -13a-estra-4,9-dien-3-one (both EP-A 0349 481), (Z) -ll- [4- (dimethyl lamino) phenyl] -17β-hydroxy-17a- (3-hydroxyprop-1-enyl) estr-4-en-3-one (EP-A 0 404 283), llß- [4- [[(acetyloxy) imino] methyl] phenyl] -17β-methoxy-17a- (methoxymethyl) estra) 4,9-dien-3-one (EP-A 0 648778, EP-A 0648 779), llß- [4- [[[[(ethoxycarbonyl) oxy] imino] methyl [phenyl [-17β-methoxy-17a- (methoxymethyl) estra-4,9-dien-3-one (EP-A 0 648 778, EP-A 0 648 779), l lß- [4 - (aceti l) f eni l] - 19, 24 -dinor- 17, 23 -epoxy-17 a-cola) 4, 9, 20-trien- 3-one, (llβ, 17a) -11- [4- (acetyl) phenyl] -17, 23-epoxy-19, 24-dinorcola-4,9, 20-trien-3-one. Competent progesterone antagonists can for example be applied locally, topically, enterally or parenterally. For the preferred oral application, tablets, dragees, capsules, pills, suspensions or solutions, which can be prepared with the additives and carrier substances customary in galenic products, are especially suitable. The dosage unit to be administered orally only once contains approximately 2 to 20 mg of Onapriston or the biologically equivalent dose (effectively equivalent amount) of another dissociated competent progesterone antagonist. An equivalent amount of effect is the dose that after the single treatment on day 22 of the cycle induces menstruation in cynomolgus monkeys, but does not inhibit ovulation when administered once before the LH peak (LH-2). Above all in the preferred oral application of the medicament prepared according to the invention, a delayed release of the active substance is desired. Thus, it must be ensured that a delayed implantation of the fertilized egg can not be achieved. A delayed release of the competent progesterone antagonist can be achieved by preparing the formulation of the dose unit to be administered orally as a matrix tablet or by providing the oral dosage unit with a retardant coating, as is known to the artisan. Also the progesterone antagonist used for the preparation of the medicament according to the invention can be prepared by derivation, for example by esterification of a free hydroxy group in an effective promoter, have a longer half-life than the previous step. This also gives a longer effect. This principle is carried out, for example, in the esters of 11- [4-N, N- (dimethylamino) phenyl] -17a-hydroxy-17β- (3-hydroxypropyl) -13a-methyl-4,9 (10) -gonadiene- 3-Ones (Onapriston) described in EP-A 0186 834, which can therefore also find use in the context of the present invention: 17β- (3-acetoxypropyl) -llβ- [4-N, N- (dimethylamino) phenyl] -17a-hydroxy-13a-methyl-4, 9 (10) -gonadien-3-one and 17β- (3-benzyloxypropyl) -ll- [4-N, N- (dimethylamino) phenyl] -17a-hydroxy -13a-methyl-4, 9 (10) -gonadiene-3one. For local or topical application, for example, vaginal ovules or transdermal systems are presented as skin patches. The dosage unit for single administration contains for such special application form such a quantity of Onapiston or a biologically equivalent dose of another progesterone antagonist, such that in a period of 4 to 72 hours 1 to 400 mg of that will be released. competent progesterone antagonist. The following examples should clarify the formulation of a competent progesterone antagonist, which in the context of the present invention is of special relevance for the application. Example 1 Composition of a tablet with 10.0 mg llß - [(4-N, N-dimethylamino) -phenyl] -17a-hydroxy-17β- (3-hydroxypropyl) -13a-methyl-4,9-merfl-4 , 9-gonadien-3-one for oral application 10.0 mg llß- [(4-N, N-dimethylamino) -phenyl] -17a-hydroxy-17B- (3-hydroxypropyl) -13a-methyl-4, 9 - methyl-4, 9-gonadien-3-one 140.5 mg lactose 69.5 mg corn starch 2.5 mg poly-N-vinylpyrrolidone 2.0 mg Aerosil 0.5 mg magnesium stearate 225.0 mg total tablet weight Example 2 Composition of a tablet with 50.0 mg llß, 19- [4- (sianylphenyl) -o-phenylene] -17β-hydroxy-17a- (3-hydroxyprop-1 (Z) -enyl) -4-androsten-3-one for oral application 50.0 mg llß, 19- [4- (cyanophenyl) -o-phenylene] -17β-hydroxy-17a- (3-hydroxyprop-l (Z) -enyl) -4- androsten-3-one 140.5 mg lactose 69.5 mg corn starch 2.5 mg poly-N-vinylpyrrolidone 2.0 mg Aerosil 0.5 ms magnesium stearate 265.0 mg total tablet weight The tablets are prepared co-opically in a tablet press and coated with a retardant cover. Pharmacological observations The suitability of competent progesterone antagonists especially dissociated for the preparation of a medicament for the control of female fertility according to need. { "pill to be used when required" which is administered in a non-inhibitory dose of the ovulation of the competent progesterone antagonist was obtained by means of the experimental animal and pharmacological observations in humans described below: Cyclic female monkeys (body weight Approximately 4-5 kg) are treated during 3 cycles in the late follicular phase of the cycle (1-2 days before ovulation) with 10 or 30 mg / kg sc or 30 mg / kg po of onapriston. During the determination of progesterone in the luteal phase, it was determined that ovulation had presented and that the course of the leukeal phase was normal.The bleeding (menstruation) was presented as expected on day 27-31 of the cycle. In treated animals, unlike control animals that only received the vehicle, a pregnancy was not determined after mating Other monkeys are treated in the early leutal phase (day 1-3 after es of ovulation) for 3 cycles once with 10 to 30 mg of Onaspriston / kg s.c. or 30 mg / kg p.o .. After mating also with this scheme of treatment with Onapriston no pregnant monkeys were determined. The test volunteers, who present a normal cycle, are treated with 100 or 400 mg of Onapriston on day 2 before ovulation [LH-2] orally. The hormonal profile (estradiol, progesterone, LH) shows that ovulation was not inhibited. An essential elongation or shortening of the cycle could not be determined. Other volunteers were treated with 100 or 400 mg of Onapriston 2 days after ovulation (LH + 2) orally. Next, an endometrial biopsy is performed on days 4 and 6 after ovulation. The histology showed clear variations in women treated in the sense of a desynchronization of the endometrium. Clinical experiences with non-fertile women show us that variations of this type of endometrium make successful implantation unlikely and thus for women in the treatment group a successful implantation can not be expected.

Claims (5)

1. CLAIMS 1. - Use of at least one progesterone antagonist competent for the preparation of a medicament for the control of female fertility as required, which can be used independent of the moment of the menstrual cycle, in a dosage unit that will be administered a only once, whose dosage is below the inhibiting dose of ovulation.
2. 2. Use according to claim 1, characterized in that the competent progesterone antagonist is selected from the group of the following compounds: llß- [4-N, N- (dimethylamino) phenyl] -17a-hydroxy-17β- (3) -hydroxypropyl) -13a-methyl-4, 9 (10) gonadien-3-one llß- (4-acetylfyl) -17β-hydroxy-17a- (3-hydroxyprop-1 (Z) -enyl) -4, 9 (10) -estradien-3-ona llß, 19-. { 4- (cyanophenyl) -ofenylene] -17β-hydroxy-17a- (3-hydroxyprop-1 (Z) -enyl) -4-androsten-3-one, llß, 190 [4- (3-pyridinyl) -o phenylene] -17β-hydroxy-17c .- (3-hydroxyprop-1 (Z) -enyl) -4-androsten-2-one 17a-hydroxy-17β- (3-idroxypropyl) -11- [4- (1 (methylethyl) f-enyl] -13a-estra-4, 9-dien-3-one, llß- [4- (3-f-uranyl) f-enyl] -17a-17β- (3-hydroxypropyl) -13a-estradiol 4, 9-dien-3-one (Z) -ll- [4- (dimethylamino) phenyl] -17β-hydroxy-17a- (3-hydroxyprop-1-enyl) estr-4-en-3-one llß- [4- [[(acetyloxy) imino] methyl] phenyl] -17β-methoxy-17a- (methoxymethyl) estra) 4,9-dien-3-one llß- [4- [[[[(ethoxycarbonyl) oxy] imino] ] methyl [phenyl [-17β-methoxy-17a- (methoxymethyl) estra-4,9-dien-3-one] -β- [4- (acetyl) phenyl] -19,24-dinor-17,23-epoxy-17a -cola04, 9, 20-trien-3-one, (llß, 17a) -ll- [4- (acetyl) phenyl] -17,23-epoxy-19,24-dinorcola- 4,9, 20-trien- 3-one.
3. 3. Use according to claim 1, characterized in that the competent progesterone antagonist is selected from the group of the following compounds: 17B- (3-acetoxypropyl) -1lβ- [4-N, N- (dimethylamino) phenyl] - 17a-hydroxy-13a-methyl-4, 9 (10) -gonadien-3-one, 17β- (3-benzoyloxypropyl) -ll- [4-N, N- (dimethylamino) phenyl] -17a-hydroxy-13a- methyl-4, 9 (10) -gonadien-3-one.
4. 4. Use according to claim 1, characterized in that the competent progesterone antagonist is prepared as a drug for application locally, topically, enterally or parenterally.
5. 5. Use according to claim 1, characterized in that the competent progesterone antagonist is contained in the dosage unit to be administered once in an amount of 1 to 400 mg or is released in an amount of 1 to 400 mg.