RU2170580C2 - Progesterone antagonists for preparing drugs used in treatment of patients with disfunctional uterine bleeding - Google Patents

Abstract

FIELD: medicine, gynecology. SUBSTANCE: invention proposes to use competitive antagonists of progesterone in treatment of patients with dysfunctional uterine bleedings. Agents effect on endometrial vessels. EFFECT: enhanced effectiveness of agents, absence of adverse effects. 8 cl, 8 ex

Description

 The invention relates to the use of at least one compound having the opposite action of progesterone / PA / for the manufacture of drugs in the treatment of dysfunctional uterine bleeding.

 Dysfunctional uterine bleeding / dysfunctional or abnormal uterine bleeding, Metrorrhagien und Metrorrhagien, Hypermenorrhea / are pathological bleeding that is not associated with organic changes in the uterus / such as endometrial carcinoma / Endometrialkarzinom /, myomas, polyps, etc. / coagulation disorders or abnormal pregnancy / for example, ectopic pregnancy, threatening abortion / / American College of Obstetricians and Gynecologists, 1982 g.

 The average blood loss during normal pregnancy is about 30 ml, and the period lasts an average of 5 days. If the menstrual blood loss exceeds 80 ml, then they are qualified as pathological / Zaradnik KP, / 1992 / Menstruation. In Kaser O. et al. (editors) Gynakologie und Geburtshilfe Bd. 1/2 Georg Thieme Verlag Stuttgart, New York, 7.31-7.51).

 Metrorrhagia is defined as bleeding that is painless or accompanied by pain, which cannot be classified as menstrual or cyclical bleeding. With a duration of more than 7 days, blood loss is often more than 80 ml.

 Menorrhagia is a painless or painful menstruation, usually every 27-28 days, which with a duration of more than 7 days causes an increased blood loss of more than 80 ml.

 Hypermenorrhea is defined as painless or painful menstruation, usually every 27 to 28 days, for 4-5 days with increased blood loss of more than 80 ml.

 Dysfunctional uterine bleeding (mainly metroragia and menorrhagia) are typical of adolescence and menopause, during which it often leads to impaired follicular maturation, anovulation and persistence of the corpus luteum and follicles. Cases of dysfunctional uterine bleeding are very common and represent the most common cause for gynecological consultations in women of reproductive age. The consultation rate for dysfunctional uterine bleeding is 33% at the reproductive age and 69% during peri- and post-menopause / Mencaglia L., Perino A., Hamon J. (1987) Hysterescopy in perimenopausal and postmenopausal women with abnormal uterine bleeding, J. Reprod. Med. 32: 577).

 The versatility of the treatment methods used for dysfunctional uterine bleeding is a direct indication that the pathogenesis of this disease is not yet clear and effective treatment still does not exist. Currently, dysfunctional uterine bleeding is treated with progestogens (for example, 10 mg of medroxyprogesterone acetate daily, 0.7-1.0 mg of norethindrone acetate daily, each time for 10-14 days), with high-dose estrogen / progestogen combinations for 10-14 days, and also non-steroidal moderators / Zyclooxygegenasehemmerh /, e.g. mefenamic acid / Mefenaminsaure /, naproxen, ibuprofen / and LHRH agonists (Cowan BD (1992) Dysfunctional uterine bleeding: Clues tu efficacious Approaches. In Alexander NJ, d'Arangues C. Steroid hormones and uterine bleeding. AAAS Press, 1922: 9-17).

 High dose estrogen / progestogen combination therapy is associated with known cardiovascular complications (mainly thromboembolic diseases). If drug therapy of dysfunctional uterine bleeding is not successful, then surgical methods are recommended (uterine curettage, hysterectomy). Dysfunctional uterine bleeding after the uterine fibroids is the second particular indication for these operations / Lee N.C., Dicker R.C., Rubin G.L., Ory H.W. (1984). Confirmation of the preoperative diagnosis for hysterektomie. Am. J. Obstet. Gynekol., 150: 283).

 It is noteworthy that the number of hysterectomies due to dysfunctional uterine bleeding, in particular in premature menopausal women, has not been able to decrease recently, although there are many drug treatment options available (Lumsden MA, (1990) Menorrhagia - the cost and scope of treatment. In Shaw RW (editor). Dysfunctional uterine bleeding. The Parthenon Publishing Group, 85-96).

 Hysterectomy contains a risk that should not be underestimated. The number of deaths after hysterectomy is 6 per 100,000 / Vingo et al., 1985 /.

 Therefore, the basis of the invention is the task of preparing a drug for the indicated indications, which stops dysfunctional bleeding and does not have undesirable effects of high-dose estrogen / progestogen preparations or has them in a small size.

 Such a new drug composition is the use of competitive progesterone antagonists / antigestagens / for the preparation of drugs for these indications.

 Antigestagens, if given in the luteal phase, can cause bleeding similar to menstruation / Nieman L.K., Healy D.L., Spitz J.M., Nisula B.S., Merriam G.R., Bardin C.W., Loriaux S.L., Chrousos G.P. (1985) Use of single doses of the antiprogesterone steroid RU 486 for induction of menstruation in normal women. In Baulieo EE; Segal SJ (editors): The antiprogestin steroid. RU 486 and human fertility control. Plenum Press. New York and London: 279-285 /.

 Experiments on examples showed that bleeding induced by antigestagens leads to the complete elimination of endometrial tissues / Chilik C. F., Hsiu J.G., Acosta A.A., van Uem JFHM, Hodgen G. D. (1986) RU 486 - induced menses in cynomolgus monkeys: uniformity of endometrial sloughing, Fertil Steril 75: 708). The exact mechanism for inducing bleeding by lowering progesterone in the normal cycle or by treatment with antigestagens has not yet been explained. It is believed that the outflow of progesterone leads to the induction of uterine prostaglandins / Prostaglandinen /, which cause bleeding / Zaradnik HP / 1992 /, loc. cit./.

 It is also known that progesterone slows down the synthesis of endothelin in the uterus and stimulates its enzymatic destruction / Casey M.L., Mac Donald P.C. (1992) Modulation of endometrial blood flow: Regulation of endothelin-1 biosynthesis and degradation in human endotherium. In Alexander NJ, d'Arcangues C. (editors), Steroid hormones and uerine bleeding. AAAS Press, 1992: 210-224 /. Endothelin is considered the most powerful vasoconstructive endogenous substance. It is believed that the increased release of endothelin at the end of the normal cycle due to a drop in progesterone leads to compression of the spiral arteries in the endometrium and thereby induces menstrual bleeding / Casey and MacDonald (1992), loc. cit./.

 It has now been found that competitive progesterone antagonists are unexpectedly able to, due to the narrowing of the vessels of the endometrial arteries, by increasing uterine contractions and the resulting effect on myometrium, in case of dysfunctional uterine bleeding lead to the cessation of bleeding. In the case of dysfunctional uterine bleeding, it is the activation of the mechanisms that lead to the narrowing of the vessels of the endometrial arteries, on the basis of an incomplete or prolonged fall of progesterone, which seems inadequate.

 Undesirable side effects that may occur during treatment with high-dose estrogen / progestogen preparations are not observed with the use of competitive progesterone antagonists. They can be considered as substances without any significant side effects.

 The treatment of dysfunctional uterine bleeding with antigestagens in the normal cycle is still unknown. Rather, the focus is on the use of progestogens for these indications / Cowan 1992, loc. cit./. The fact that it is possible to reduce the occurrence of heavy bleeding, which is learned in the treatment of low-dose, containing estrogen and progestogen contraceptives due to insufficient control of the cycle due to low dosage, is described in international patent application WO-A-93/17686. The use of progesterone antagonistic compounds alone or in combination with antiestrogens for the manufacture of drugs for conception, for termination of pregnancy or for the treatment of gynecological complications / dysmenorrhea, endometriosis / is derived from European patent EP-A-03110541.

 The medicament obtained according to the invention is suitable for treating all forms of dysfunctional uterine bleeding, such as menorrhagia, metrorrhagia and hypermenorea.

As competing PAs, we can talk about all compounds that themselves or their metabolites block the action of progesterone in its receptor; For example, the following steroids:
11 β- // 4-N, N-dimethylamino / phenyl / -17 β-hydroxy-17 α-propynyl-4.9 / 10 / -estradien-3-one / RU-38486 /,
11 β- // 4-N, N-dimethylamino / phenyl / -17 β-hydroxy-18-methyl-17 α-propynyl-4.9 / 10 / estradien-3-one and
11 β- // 4-N, N-dimethylamino / phenyl / -17a β-hydroxy-17a α-propynyl-D-homo-4.9 / 10 /, 16-estradien-3-one / all EP-A -0057115 /, in addition
11 β-p-methoxyphenyl / -17 β-hydroxy-17 α-ethinyl-4.9 / 10 / -estradien-3-one / Steroids 37/1981 / 361-382 /,
11 β- / 4-acetylphenyl / -17 β-hydroxy-17 α- / prop-1-ynyl / -4.9 / 10 / -estradien-3-one / EP-A 0190759 /.

 as well as those described in EP-A 0277676 11 β-aryl-14 β-estradienes and trienes, 19,11 β pinched are steroids that are the subject of EP-A 0283428, resulting from EP-A 0289073 11 β-aryl-6- alkyl / or 6-alkenyl or 6-alkynyl / -estradienes and pregnandienes and 11 β-aryl-7-methyl / or 7-ethyl / estradienes known from EP-A 0321010, as well as 10 β-H-steroids from EP -A 0404283, for example, / Z / -11 β- / 4- / dimethylamino / phenyl / -17 β-hydroxy-17 α- / 3-hydroxy-1-propenyl / est-4-en-3-one.

Further, as typical representatives according to the invention, competitive pregestor antagonists could be called, for example:
11 β- / 4-dimethylaminophenyl / -17 α- hydroxy-17 β- / 3-hydroxypropyl / -13 α- methyl-4,9-gonadiene-3-one / EP-A 0190759 /,
11 β, 19- / 4-acetylphenyl / -17 β-hydroxy-17 α- / 3-hydroxyprop-1- / Z / -enyl / -4.9 / 10 / -estradien-3-one / EP-A 0190759 /,
11 β-19- / 4-cyanophenyl / -17 β-hydroxy-17 α / 3-hydroxyprop-1- / Z / enyl / -4-androsten-3-one and
11 β, 19- / 4- / 3-pyridinyl / -o-phenylene / -17 β-hydroxy-17 α- / 3-hydroxyprop-1- / Z / -enyl / -4-androsten-3-one / both WO-A-93/23020 /.

 For the treatment of dysfunctional uterine bleeding with PA, it is generally sufficient, according to the invention, for short-term treatment / daily from 1 to 10 days / with a daily dosage of from 1 to 600 mg of a competitive progesterone antagonist per day. It is preferable to take according to the invention an amount of from 5 to 400 mg daily. It is particularly preferable to take from 50 to 400 mg daily of 11 β- / 4-dimethyl-aminophenyl / -17 α-hydroxy-17 β- (3-hydroxy-propyl / -13 α-methyl-4,9-gonadiene-3- he-onapriston (onapriston) or from 50 to 400 mg / Z / -11 β- / 4 / dimethylamino / phenyl / -17 β-hydroxy-17 α / 3-hydroxy-1-propenyl / -estr-4-ene 3-he.

 Already a single administration of a competitive progesterone antagonist within the indicated dosage range may be sufficient to stop bleeding, especially if the dosage is chosen within the particularly preferred dosage area of onapristone (/ Z / -11 β- / 4- / dimethylamino) phenyl / -17 β-hydroxy-17 α- / 3-hydroxy-1-propenyl / -estr-4-en-3-one. In other cases, treatment continues until the cessation of bleeding, which occurs mostly within 5 days. According to the invention, it is possible both to treat acute arising dysfunctional uterine bleeding and prophylactic exclusion of such bleeding.

 A competitive progesterone antagonist can, according to the invention, be used, for example, locally, enterally or parenterally. For a preferred enteral administration, it may be tablets, dragees, capsules, pills, suspensions or solutions which can be prepared with usual additives and carriers for galenica. For local or external use, for example, vaginal suppositories can be used.

 The following example shows the composition of a competitive progesterone antagonist for use according to the invention. Other protosterone antagonists can be formulated in exactly the same way, and the preparation may contain any amount prescribed above as suitable.

Recipe example:
11 β- // 4-N, N-Dimethylamino / phenyl / -17 α-hydroxy-17b- / 3-hydroxypropyl / -13 α-methyl-4,9-gonadiene-3-one - 100.0 mg
Lactose - 140.5 mg
Corn Starch - 69.5 mg
Polyvinylpyrrolidone - 2.5 mg
Aerosil - 2.0 mg
Magnesium Stearate - 0.5 mg
The total weight of the tablet, which is produced in the usual way on a tablet press is 315.0 mg
Example 1
Acute treatment of metroragia with a single dose of onapristone.

 Women with dysfunctional metrology are treated once with 200–400 mg of Onapriston (Onapriston) orally. Preferably, treatment in the luteal phase of the cycle. Treatment leads to a stop of bleeding within 2 to 4 days.

Example 2
Acute treatment of menorrhagia and hypermenorrhea with a single dose of onapristone.

 Women with menorrhagia and hypermenorrhea are treated orally on the 28th day of the cycle or on the first day of bleeding once with 200-400 mg of onapriston (onapriston). The treatment causes a menstrual bleeding of normal intensity (about 30 ml) and duration (about 5 days).

Example 3
Preventive treatment of metrorrhagia with a single dose of onapriston (onapriston).

 Women with dysfunctional metroragia are treated once with 200-400 mg of onapriston (onapriston) every 28 days, orally. The treatment causes menstruation-like bleeding of normal intensity (about 30 ml) and duration (about 5 days) and prevents the occurrence of metrorrhagia. Treatment continues after 3-6 cycles.

Example 4
Preventive treatment of menorrhagia and hypermenorrhea with a single dose of onapriston (onapriston).

 Women with menorrhagia and hypermenorrhea are treated orally every 28 days with 200-400 mg of onapriston (onapriston). The treatment causes a menstrual bleeding of normal intensity (approximately 30 ml) and duration (approximately 5 days) and prevents the occurrence of menorrhagia and hypermenorrhea. Treatment continues after 3 to 6 cycles.

Example 5
Acute treatment of metroragia with repeated administration of onapriston (onapriston).

 Women with dysfunctional metroragia are treated orally with 200-400 mg / day of onapriston until the bleeding stops, with a maximum of more than 10 days. The start of treatment should preferably be carried out in the luteal phase of the cycle.

Example 6
Acute treatment of menorrhagia and hypermenorrhea with repeated use of onapriston (onapriston).

 Women with menorrhagia and hypermenorrhea are treated on the 28th day of the cycle or on the first day of bleeding with 200-400 mg / day of onapriston orally until the bleeding stops, for a maximum of 10 days. The treatment causes a menstrual bleeding of normal intensity (approximately 30 ml) and duration (approximately 5 days) and, therefore, prevents increased blood loss.

Example 7
Prophylactic treatment of metroragia with repeated administration of onapriston (onapriston).

 Women with dysfunctional metroragia are treated for a maximum of 10 days with 200-400 mg / day of onapriston orally every 28 days. The treatment causes menstruation-like bleeding of normal intensity (approximately 30 ml) and duration (approximately 5 days) and prevents the occurrence of metrorrhagia. Treatment continues after 3-6 cycles.

Example 8
Preventive treatment of menorrhagia and hypermenorrhea with repeated administration of onapriston (onapriston).

 Women with menorrhagia and hypermenorrhea are treated every 28 days for a maximum of 10 days with 200-400 mg / day orally. The treatment causes menstruation-like bleeding of normal intensity (approximately 30 ml) and duration (approximately 5 days) and prevents the occurrence of menorrhagia and hypermenorrhea. Treatment continues after 3 to 6 cycles.

 In the treatment according to the invention of dysfunctional uterine bleeding using a competitive progesterone antagonist, both the usually observed duration of bleeding is reduced and the intensity is noticeably reduced, i.e. blood loss.

Claims (8)

 1. The use of a competitive progesterone antagonist as an active substance for the manufacture of medicines in the treatment of dysfunctional uterine bleeding.  2. The use of the competitive progesterone antagonist according to claim 1 for the manufacture of drugs in the treatment of metroragia.  3. The use of a competitive progesterone antagonist according to claim 1 for the manufacture of drugs in the treatment of menorrhagia.  4. The use of the competitive progesterone antagonist according to claim 1 for the manufacture of drugs in the treatment of hypermenorrhea. 5. The use of a competitive progesterone antagonist according to claim 1, which is
11β - ((4-N, N-dimethylamino) phenyl) 17β-hydroxy-17α-propynyl-4,9 / 10 / -estradien-3-one (RU 38486),
11β - ((4-N, N-dimethylamino) phenyl) 17β-hydroxy-18-methyl-17α-propinyl-4.9 (10) -estradien-3-one,
11β - ((4-N, N-dimethylamino) phenyl) 17aβ-hydroxy-7aα-propynyl-D-homo-4.9 (10), 16-estradien-3-one,
11β-p-methoxyphenyl-17β-hydroxy-17α-ethynyl-4.9 (10) -estradien-3-one,
11β- (4-acetylphenyl) -17β-hydroxy-17α- (prop-1-ynyl) -4.9 (10) -estradien-3-one,
11β- (4-dimethylaminophenyl) -17α-hydroxy-17β- (3-hydroxy-propyl) -13α-methyl-4,9-gonadiene-3-one,
(Z) -11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -estr-4-en-3-one,
11β, 19- (4-acetylphenyl) -17β-hydroxy-17α- (3-hydroxyprop-1- (Z) -enyl) -4.9 (10) -estradien-3-one,
11β, 19- (4- (cyanophenyl) -17β-hydroxy-17α- (3-hydroxyprop-1- (Z) -enyl) -4-androsten-3-one or 11β, 19- (4- (3-pyridinyl ) -o-phenylene) -17β-hydroxy-17α- (3-hydroxyprop-1- (Z) -enyl) -4-androsten-3-one.  6. The use of the competitive progesterone antagonist according to claim 1 in a daily dosage unit of 1-600 mg for the manufacture of a medicament in the treatment of dysfunctional uterine bleeding.  7. The use of a competitive progesterone antagonist according to claim 1 or 6 in an amount of 50 to 400 mg.  8. The use according to one of claims 1, 6 and 7, in which the competitive antagonist is 11β- [4-dimethylaminophenyl] -17α-hydroxy-17β- (3-hydroxy-propyl) -13α-methyl-4,9- gonadien-3-one in an amount of 50 to 400 mg or (Z) -11β- [4 (dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -estr-4-en-3- it is in an amount of 50 to 400 mg.