Antagonists of progesterone to obtain drugs in the treatment of dysfunctional uterine bleeding

 

(57) Abstract:

The invention relates to medicine. The application of the competitive progesterone antagonists in the treatment of dysfunctional uterine bleeding. Tools affect the blood vessels of the endometrium without side effects. 7 C.p. f-crystals.

The invention relates to the use of at least one compound having the action opposite to that of progesterone /PA/, to obtain 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 /as, for example, endometrial carcinoma /Endometrialkarzinom/, fibroids, polyps, etc./ system disorders of clotting or abnormal pregnancy /for example, ectopic pregnancy, threatening abortion/ /American College of Obstetricians and Gynecologists, 1982/.

The average blood loss during a normal pregnancy is about 30 ml, and the period lasts on average 5 days. If menstrual blood loss greater than 80 ml, then they qualify as pathological /Saradnik CP, /1992/ Menstruation. less or accompanied by pain, bleeding, which cannot be attributed to or cyclic menstrual bleeding. With a duration of more than 7 days, the blood loss is often more than 80 ml.

Menorrhagia is painless or accompanied by pain menstruation, usually every 27-28 days, which, with duration longer than 7 days causes increased blood loss of more than 80 ml.

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

Dysfunctional uterine bleeding /mainly metrorrhagia and menorrhagia/ are typical for adolescence and menopause, during which time it often leads to impaired maturation of follicles transfer, anovulation and persistence of yellow bodies and potentially. Cases of dysfunctional uterine bleeding is very frequent and represent the most frequent reason for gynecological consultations to women age, are capable of reproducing. Share advice about dysfunctional uterine bleeding is 33% in the age, capable of reproduction, and 69% during the peri - and post-menopause /L. Mencaglia , Perino, A., Hamon J. (1987) Hysterescopy in perimenopausal and uterine bleeding is a direct indication of the pathogenesis of this disease is not yet clear and effective treatment still does not exist. Currently dysfunctional uterine bleeding treated with progestogen (for example, 10 mg of medroxyprogesterone daily, 0.7-1.0 mg of norethindrone daily, each time for 10-14 days/, high-dose combination estrogen/progestogen for 10-14 days, and nesteroidnymi moderators /Zyclooxygegenasehemmerh/, for example, marennikova acid /Mefenaminsaure/, naproxen, ibuprofen/ and LHRH agonists (Cowan B. D. (1992) Dysfunctional uterine bleeding: Clues tu efficacious Approaches. In Alexander NJ, d Arangues C. (editor), Steroid hormones and uterine bleeding. AAAS Press, 1922: 9-17).

Therapy with high-dose combination estrogen it is thought that/gestagen associated with known cardiovascular complications /mainly thromboembolitic disease/. If medical therapy of dysfunctional uterine bleeding does not, then recommend surgical techniques /uterine scraping, hysterectomy/. Dysfunctional uterine bleeding are after uterine fibroids second particular indications for these operations /Lee N. C., Dicker, R. C., Rubin, G. L., Ory, H. W. (1984). Confirmation of the preoperative diagnsis for hysterektomie. Am. J. Obstet. Gynekol., 150:283).

It is noteworthy that the number is arousih women recently, could not decline, although there are many medical treatment options (Lumsden MA, (1990) Menorrhagia is the cost and scope of treatment. In Shaw R. W. (editor). Dysfunctional uterine bleeding. The Parthenon Publishing Group, 85-96).

Hysterectomy contains risk, which should not be underestimated. The number of deaths after hysterectomy is 6 per 100,000 /Wingo and others, 1985/.

Therefore, the basis of the invention lies task is to prepare the drug for these indications, which stops disfunctionally bleeding and does not possess unwanted effects, high-dose drugs estrogen/gestagen or is their small size.

This new drug composition is the use of competitive antagonists of the progesterone /antigestagen/ to obtain drugs for these indications.

Antigestagen, if they are given in the luteal phase, can cause bleeding similar to menstruation /Nieman L. K., Healy D. L., J. M. Spitz, Nisula, B. S., G. R. Merriam, C. W. Bardin, S. L. Loriaux, 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 hilik 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 of induction of bleeding by reducing progesterone in the normal cycle or by treatment with antigestagens have received no explanation. Believe that the outflow of progesterone leads to the induction of uterine prostaglandins /Prostaglandinen/ that cause bleeding /Zahradnik 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 the most powerful vasoconstrictive endogenous substance. Believe that increased release of endothelin at the end of a normal cycle due to the drop in progesterone causes compression of the spiral arteries in the endometrium and due to this induces menstrual bleeding /Casey and MacDonald (1992), loc. cit./.

Now it has been found that competitive antagonists of progesterone in an unexpected way be due to intra-uterine vasoconstriction of arteries, with the increase of the uterus, Obukhovo bleeding. In the case of dysfunctional uterine bleeding it is the activation of mechanisms that lead to vasoconstriction of the endometrial arteries, on the basis of incomplete or continued too long of a drop in progesterone, seems inadequate.

Unwanted side effects that may occur in the treatment of high-dose drugs estrogen/gestagen, the application of competitive antagonists of progesterone are not observed. They can be considered as substances without significant side effects.

On the treatment of dysfunctional uterine bleeding by antigestagens in the normal cycle is still unknown. Attention is usually directed to the use of gestagens for these indications /Cowan 1992, loc. cit./. That can reduce the occurrence of heavy bleeding, which pochutla in the treatment of low-dose containing estrogen and gestagen contraception, due to insufficient control of the cycle due to the low dosage, are described in international patent application WO-A-93/17686. The existing antagonistic progesterone compounds alone or in combination with antiestrogens for the manufacture of medicines for conception, for prepackage patent EP-A-03110541.

Medicine, obtained according to the invention, suitable for treatment of all forms of dysfunctional uterine bleeding, as, for example, menorrhagia, metrorrhagia and hypermenorrhea.

As a competitive PA we can talk about all the connections themselves or their metabolites block the action of progesterone to its receptor; for example, the following steroids:

11 - //4-N, N-dimethylamino-phenyl/-17 - hydroxy-17 - PROPYNYL-4,9/10/-astralian-3-one /RU-38486/,

11 - //4-N,N-dimethylamino-phenyl/-17 - hydroxy-18-methyl-17 - PROPYNYL-4,9/10/estraven-3-one and

11 - //4-N,N-dimethylamino-phenyl/-17a - hydroxy-17a - PROPYNYL-D-Homo-4,9/10/,16-astralian-3-one /all EP-A-0057115/ in addition

11-p-methoxyphenyl/-17 - hydroxy-17 - ethinyl-4,9/10/-astralian-3-he /Steroids 37 /1981/ 361-382/,

11 - /4-acetylphenyl/-17 - hydroxy-17 - /prop-1-inyl/-4,9/10/-astralian-3-he /EP-A 0190759/.

as also described in EP-A 0277676 11 - aryl-14 - estrazioni and-triene, 19,11 perejitye - steroids, which are the subject of patent EP-A 0283428 arising from EP-A 0289073 11 - aryl-6-alkyl /or 6-alkenyl or 6-quinil/-estrazioni and-pregnadien and is known from EP-A 0321010 11 - aryl-7-methyl /or 7-ethyl/-estrazioni and 10 - H-steroids from EP-A 0404283, for example, /Z/-11 - /4-/dimethylamine/phenyl/-17 - hydroxy-17 - /3-hydroxy-1-propenyl/variety-4-EN-3-one.

what you could call, for example:

11 - /4-dimethylaminophenyl/-17 - hydroxy-17 - /3-hydroxypropyl/-13 - methyl-4,9-canadian-3-he /EP-A 0190759/,

11 , 19-/4-acetylphenyl/-17 - hydroxy-17 - /3-hydroxyprop-1-/Z/-enyl/-4,9/10/-astralian-3-he /EP-A 0190759/,

11 - 19-/4-tianfeng/-17 - hydroxy-17 /3-hydroxyprop-1-/Z/-enyl/-4-androsten-3-one and

11 , 19-/4-/3-pyridinyl-o-phenylene/-17 - hydroxy-17 - /3-hydroxyprop-1-/Z/-enyl/-4-androsten-3-one /both WO-A-93/23020/.

For the treatment of dysfunctional uterine bleeding with PA in General is enough, according to the invention, the short-term treatment /daily from 1 to 10 days with a daily dosage of from 1 to 600 mg a competitive antagonist of progesterone per day. It is preferable to take according to the invention an amount of from 5 to 400 mg daily. Particularly preferably daily to take from 50 to 400 mg 11 - /4-dimethyl-AMINOPHENYL/-17 - hydroxy-17 - (3-hydroxy-propyl/-13 - methyl-4,9-canadian-3-he-onapristone (onapriston) or from 50 to 400 mg /Z/-11 - /4/dimethylamine/phenyl/-17-hydroxy-17 /3-hydroxy-1-propenyl/-variety-4-EN-3-one.

May already have just one reception competitive antagonist of progesterone within the specified range of dosing, in order to stop bleeding, especially if the dosage is selected inside especially presi-1-propenyl/-variety-4-EN-3-one. In other cases, treatment is continued until cessation of bleeding that occurs mostly within 5 days. According to the invention, it is possible as the treatment of acute emerged dysfunctional uterine bleeding, and prevention of isklucheniia such bleeding.

The competitive progesterone antagonist is possible, according to the invention, to apply, for example, locally, interline or parenteral. For the preferred enteral application we can talk about tablets, pills, capsules, pills, suspensions or solutions, which can be obtained with the usual Galenika additives and carriers. For local or topical application can be used, for example, a vaginal suppository.

The following example shows part of a competitive progesterone antagonist for use according to the invention. Other antagonists projesterone you can formulate quite similar, and the preparation can contain any prescribed above number as appropriate.

Example recipe:

11 - //4-N, N-Dimethylamino-phenyl/-17 - hydroxy-17b-/3-hydroxypropyl/-13 - methyl-4,9-canadian-3-he - 100.0 mg

Lactose - to 140.5 mg

Corn starch is 69.5 mg

Polyvine who have a regular way tabletirujut press 315,0 mg

Example 1

Acute treatment of metrorrhagia using a single dose of onapristone.

Women with dysfunctional metrorrhagia treat disposable with 200 - 400 mg of onapristone (Onapriston) orally. Preferably the treatment in the luteal phase of the cycle. The treatment leads to bleeding stop within 2 to 4 days.

Example 2

Acute treatment of menorrhagia and hypermenorrhea using a single dose of onapristone.

Women with menorrhagia and hypermenorrhea treat oral 28-day cycle or on the first day of bleeding disposable with 200-400 mg of onapristone (onapriston). The treatment causes such menstruation bleeding normal intensity /about 30 ml and the duration of /around 5 days/.

Example 3

Prophylactic treatment of metrorrhagia using a single dose of onapristone (onapriston).

Women with dysfunctional metrologiya treat disposable with 200-400 mg of onapristone (onapriston) every 28 days, orally. The treatment causes such menstruation bleeding normal intensity /about 30 ml and the duration of /around 5 days/ and prevents metrorrhagia. Treatment continues for 3-6 cycles.

Example 4

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Women with mengagumi and hipermenorrea treated orally every 28 days with 200-400 mg of onapristone (onapriston). The treatment causes such menstruation bleeding normal intensity /30 ml or/ and duration /about 5 days and prevents menergy and hypermenorrhea. The treatment lasts 3 to 6 cycles.

Example 5

Acute treatment of Metrology with repeated administration of onapristone (onapriston).

Women with dysfunctional metrologiya treated orally with 200-400 mg/day of onapristone (onapriston) to stop the bleeding, maksimum more than 10 days. Initiation of treatment should be carried out preferably in the luteal phase of the cycle.

Example 6

Acute treatment of minorai and hipermenorrea with repeated administration of onapristone (onapriston).

Women with mengagumi and hipermenorrea treated on the 28th day of the cycle or on the first day of bleeding with 200-400 mg/day of onapristone (onapriston) orally to stop bleeding, to a maximum of 10 days. The treatment causes such menstruation bleeding normal intensity /30 ml/ and length /approximately 5 days/ and thus prevents increased CROs is Riston (onapriston).

Women with dysfunctional metrologiya treated within a maximum of 10 days with 200-400 mg/day of onapristone (onapriston) orally every 28 days. The treatment causes such menstruation bleeding normal intensity /30 ml or/ and duration /about 5 days and prevents Metrology. Treatment continues for 3-6 cycles.

Example 8

Prophylactic treatment of minorai and hipermenorrea with repeated administration of onapristone (onapriston).

Women with mengagumi and hipermenorrea treated every 28 days for a maximum of 10 days with 200-400 mg/day orally. The treatment causes such menstruation bleeding normal intensity /30 ml or/ and duration /about 5 days and prevents menorrhagia and hypermenorrhea. The treatment lasts 3 to 6 cycles.

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

1. The use of a competitive antagonist of progesterone as an act of the LASS="ptx2">

2. The use of a competitive antagonist of progesterone on p. 1 to obtain drugs in the treatment of Metrorail.

3. The use of a competitive antagonist of progesterone on p. 1 to obtain drugs in the treatment of menergy.

4. The use of a competitive progesterone antagonist under item 1 for the manufacture of medicinal products in the treatment of hypermenorrhea.

5. The use of a competitive antagonist of progesterone on p. 1, representing

11-((4-N, N-dimethylamino)phenyl)17-hydroxy-17-PROPYNYL-4,9/10/-astralian-3-one (RU 38486),

11-((4-N,N-dimethylamino)phenyl)17-hydroxy-18-methyl-17-PROPYNYL-4,9(10)-astralian-3-one,

11-((4-N, N-dimethylamino)phenyl)17A-hydroxy-7a-PROPYNYL-D-Homo-4,9(10), 16-astralian-3-one,

11-p-methoxyphenyl-17-hydroxy-17-ethinyl-4,9(10)-astralian-3-one,

11-(4-acetylphenyl)-17-hydroxy-17-(prop-1-inyl)-4,9(10)-astralian-3-one,

11-(4-dimethylaminophenyl)-17-hydroxy-17-(3-hydroxy-propyl)-13-methyl-4,9-canadian-3-one,

(Z)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxy-1-propenyl)-variety-4-en-3-one,

11,19-(4-acetylphenyl)-17-hydroxy-17-(3-hydroxyprop-1-(Z)-enyl)-4,9(10)-astralian-3-one,

11,19-(4-(tianfei)-17-hydroxy-17-(3-hydroxyprop-1-(Z)-enyl)-4-androsten-3-one or 11,19-(4-(3-pyridinyl)-o-dryer is progesterone on p. 1 daily dosing unit 1 - 600 mg to obtain drugs in the treatment of dysfunctional uterine bleeding.

7. The use of a competitive progesterone antagonist under item 1 or 6 in a quantity of 50 - 400 mg

8. Use one of the PP.1, 6 and 7, in which competitive antagonist is an 11-[4-dimethylaminophenyl]-17-hydroxy-17-(3-hydroxy-propyl)-13-methyl-4,9-canadian-3-one in the amount of 50 to 400 mg, or (Z)-11-[4(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxy-1-propenyl)-variety-4-en-3-one 50 - 400 mg