CN1450892A - Mesoprogestins (progesterone receptor modulators) for treatment and prevention of hormone dependent gynecological - Google Patents

Abstract

This present invention discloses the use of mesoprogestins, a new class of progesterone receptor modulators (PRMs), for the treatment and prevention of benign hormone dependent gynecological disorders: a) for the treatment of gynecological disorder such as endometriosis, uterine fibroids, postoperative peritoneal adhesions, dysfunctional bledding (metrorrhagia, menorrhagia) and dysmenorrhea; b) for the prevention of gynecological disorders such as postoperative, periotoneal adhesions, dysfunctional uterine bleeding (metrorrhagia, menorrhagia) and dysmenorrhea; and c) a method of treatment and prevention of the above mentioned disorders in a female, preferably in a human female, in need of treatment or prevention of one or more of these disorders, with an effective amount of a mesoprogestin.

Description

Mesoprogesterone (progesterone receptor modulator) for the treatment and prevention of hormone-dependent benign gynecological disorders

The present invention relates to the prevention and treatment of major hormone-dependent benign gynecological disorders including proliferative disorders such as endometriosis, uterine fibroids and postoperative peritoneal adhesions as well as menstrual syndromes, dysfunctional bleeding (uterine bleeding, menorrhagia) and dysmenorrhea.

Typically, these conditions are treated with moderate or high doses of progesterone. The efficacy of this treatment is sometimes variable and also produces undesired side effects including metabolic changes (increased LDL concentrations and decreased HDL concentrations), effects on mood, and significant bleeding.

Recently, the use of competitive progesterone receptor antagonists (antiprogestins) including onapristone, mifepristone (RU 486) has been proposed for the treatment of endometriosis and dysmenorrhea (EP 0 266 303B1), Uterine fibroids (Yen SSC (1993) Use of antiprogestins in the management of endometriosis andleiomyomata, In Donaldson, M:s., Dorflinger (ed.) , Clinical application ofMifepristone (RU 486) and other antiprogestins, National Academy Press, Washington, DC, pp. 189-209; Kettel L M., Murphy A.A., Morales A.J. et al. (1996), using the antiprogesterone mifepristone ( RU 486) for the treatment of endometriosis (Treatment of endometriosis with the antiprogesterone mifepristone (RU 486)), Fertil Steril65:23-28), and uterine bleeding disorders (WO 96/23503).

A potential drawback of antiprogestins is that their abuse in abortion cannot be completely banned. endometriosis

Endometriosis is a chronic disease characterized by ectopic growth of the lining of the uterus, ie, outside the uterine cavity. Although efforts have been made to estimate the frequency of endometriosis and to determine its incidence in specific clinical situations, the precise overall incidence of endometriosis is unknown (6, 8, 9, 11) . Its range is 5%-55%. The disease is characterized by histologically benign proliferation and function of endometrial glands and stroma outside the physiological site.

The ovary is the most frequent site of ectopic uterus (50-60%). Other commonly affected areas are: uterosacral ligament, blind duct, uterovesicoperitoneum, vaginal septum, and uterine ligament. Endometriotic lesions can also be found on organs such as the sigmoid colon, rectum, appendix, bladder, etc.

Endometriosis must be considered a disease of varying severity, often associated with infertility as well as marked dysfunction of pelvic pain. Clinical symptoms of endometriosis include dysmenorrhea, painful dyspareunia in females, chronic pelvic pain, dysuria, various genitourinary symptoms due to urethral obstruction and/or bladder invasion, painful defecation, rectal pressure, defecation urgency and ileus, bleeding abnormalities (including menorrhagia or uterine bleeding), infertility, primary or secondary recurrent spontaneous abortion.

The main clinical symptoms are primary or secondary dysmenorrhea, painful dyspareunia in females, and chronic pelvic pain, especially during ovulation.

The fundamental pharmacological treatment goals for endometriosis are to atrophy the endometriotic lesion and induce an acyclic hormonal milieu with GnRH-agonist/-antagonist or continuous progesterone therapy. Typically, these treatments create a hypoestrogenic environment in which the disease improves.

The most commonly used progestins in the treatment of endometriosis are danazol and gestrinone. Danazol is an isoxazole derivative of 17-ethynyltestosterone with a pronounced androgenic partial activity. Gestrinone is a derivative of 19-methyltestosterone with potent progestogenic and androgenic properties. Some advantages of danazol are less frequent dosing, better contraceptive protection, and less effect on lipid metabolism. Danazol, the most widely used progestin, is thought to act by inhibiting cyclic gonadotropin secretion, but accumulating evidence suggests that the compound has multiple mechanisms of action, including direct inhibition of ectopic uterine Intimal tissue. Treatment with danazol has significant side effects. In up to 85% of women treated with danazol, side effects (67, 68) such as: androgenic and compositional changes (acne and oily skin, thicker voice, weight gain, increased LDL concentration and HDL concentration Other side effects such as rash, hypertension due to the glucocorticoid and mineralocorticoid partial activity of danazol, and menstrual bleeding.

Pituitary suppression can be achieved with GnRH-agonists and GnRH-antagonists. Different GnRH-agonists are currently used in the treatment of endometriosis. This regimen induces a more deeply hypoestrogenic, acyclic environment without the side effects of steroids. GnRH-analogues are effective for the treatment of endometriosis. The subjective and objective effects of this treatment were comparable to or better than those of danazol (72-77). Signs and symptoms due to estrogen loss (hot flushes, psychological changes, headaches, fatigue, etc.) are the main side effects. In addition, GnRH-analogue treatment can induce osteoporosis (76, 77). The potential for accelerated bone loss during GnRH-analogue-induced ovarian suppression is another major consideration for effective treatment of endometriosis.

Meanwhile, different add back regimens have been considered to replace estrogen suppression during GnRH-treatment by selective estrogen receptor modulators (SERMs) like raloxifene (SAG: WO97/27863; Eli Lilly) effect. heavy menstrual bleeding

Menorrhagia, defined as menstrual blood greater than 80ml per cycle, is a syndrome of unknown cause and one of the most common problems in gynecology. 60% of women with heavy menstrual bleeding undergo a hysterectomy within 5 years. Current medical treatments are still unsatisfactory. During menstruation, the most commonly prescribed drugs for acute treatment in Europe are norethindrone (approximately 40%), followed by the non-steroidal anti-inflammatory drug (NSAID) mefenamic acid (approximately 30%) and the antifibrinolytic methotrexate Acid (5%) (Intercontinental Medical Statistics 1994). During bleeding, the last compound appeared to be the most effective (45% reduction in bleeding) after acute administration in women with ovarian menorrhagia. Recently, the levonorgestrel intrauterine system (Mirena) has been introduced to prevent menorrhagia. Recent studies have shown that levonorgestrel intrauterine system (Mirena) and oral norethindrone are effective in reducing menstrual blood to Aspects of the normal range are valid. However, both regimens have high rates of intermenstrual bleeding (50% in women treated with Mirena and 36% in women treated with norethindrone) (Irvine et al., 1998). Dysmenorrhea

Dysmenorrhea is caused by painful uterine contractions. Women with dysmenorrhea have higher resting and peak intrauterine pressures than normal controls. The precise mechanism of pain during dysmenorrhea remains unclear. Dysmenorrhea is most likely due to increased uterine contractions, basal tone, and spiral artery vasoconstriction during menstruation (Pickels et al., 1965; Csapo et al., 1977). Therefore, preventing both uterine contractions and uterine vasoconstriction can provide relief from menstrual pain. Dysmenorrhea can be classified as primary or secondary (Dawoo 1985; 1990). In primary dysmenorrhea, there are painful menstrual cramps but no visible pelvic pathology. But in secondary dysmenorrhea, there is visible pelvic pathology (eg, endometriosis), which causes painful menstrual cramps.

Primary dysmenorrhea is one of the most common gynecological disorders and affects up to 50% of postpubertal women (Dawood 1985; 1990). Both oral contraceptives and NSAIDs are effective in alleviating primary dysmenorrhea, and the apparent prevalence may actually be slightly lower. 10% of women with primary dysmenorrhea suffer from severe pain that immobilizes them for 1-3 days per month, which leads to significant absenteeism from work or school (Svennerud, 1959) and subsequent economic losses ( Dawood1985). Dysmenorrhea is thus an important medical and economic problem, and better (simpler, safer) treatments could reduce the burden of the disease on women and society.

Primary dysmenorrhea appears to be a single disease unit, whereas secondary dysmenorrhea may be the result of a variety of disorders, including endometriosis and uterine fibroids. Typically, primary dysmenorrhea is treated with medication, while secondary dysmenorrhea usually requires surgery for its cause (exceptions: secondary dysmenorrhea due to the presence of an IUD and endometriosis). Primary dysmenorrhea is most prevalent among women in their teens or early twenties and declines after age 30 (Widholm, 1979). Primary dysmenorrhea can be diagnosed on the basis of history and clinical features, with physical examination and transvaginal ultrasonography to rule out uterine abnormalities (Dawood, 1990).

Combining OCs and NSAIDs has been widely used to prevent or treat menstrual pain. These two drugs are about 80-90% effective in women with primary dysmenorrhea (Dawood, 1990). However, 10-20% of women with severe primary dysmenorrhea become resistant to any treatment. In Germany, ibuprofen ( ^Urern® , ^Gynofu® ) is the most popular NSAID in the treatment of dysmenorrhea. However, not all women/girls with primary dysmenorrhea are willing to take OC or can tolerate NSAID treatment. This is especially true for girls aged 13-16. An alternative medical treatment is the use of uterotonic drugs such as calcium channel blockers (Sandah et al., 1979) or betamimetics (Dawood, 1990). These drugs work by inhibiting uterine contractions, but findings on a larger scale are unacceptable to patients, gynecologists and general practitioners. The same applies to progesterone-releasing IUS. Transcutaneous electrical nerve stimulation (TENS) is effective in only 30% of women with severe dysmenorrhea (Lundberg et al., 1985).

Therefore, there is still a great need for better tolerated and/or more acceptable regimens for the treatment of the aforementioned conditions.

The invention provides the application of a novel progesterone receptor modulator (PRM) - mesoprogestin (mesoprogestin) in the treatment and prevention of hormone-dependent benign gynecological diseases.

One aspect of the present invention is the application of mesoprogesterone in the preparation of medicines for the treatment of gynecological diseases, such as endometriosis, uterine fibroids, postoperative peritoneal adhesions, dysfunctional bleeding (uterine bleeding , excessive menstrual bleeding) and dysmenorrhea.

Another aspect of the present invention is the use of mesoprogesterone in the preparation of medicaments for the prevention of gynecological diseases such as postoperative peritoneal adhesions, dysfunctional bleeding (uterine bleeding, menorrhagia) and dysmenorrhea.

Yet another aspect of the present invention is the treatment and prevention of the above-mentioned diseases in females, especially females, in need of treatment or prevention of these diseases with an effective amount of mesoprogesterone.

Another aspect of the present invention is that when treating the above-mentioned diseases, the daily dose of mesoprogesterone is 0.5-100mg; the more preferred daily dose is 5.0-50mg of mesoprogesterone; and the most preferred daily dose is 10-25mg mesoprogesterone.

Compounds such as those described in DE 43 32 283 and DE 43 32 284 are suitable mesoprogestins for the purposes of the present invention.

Mesoprogestins are preferably the following compounds: J 867, J 912, J 900, J 914 and J 956 (wherein J 867 is 4-[17β-methoxy-17α-(methoxymethyl)-3-oxo Estra-4,9-dien-11β-yl]benzaldehyde-(1E)-oxime, while J 912 is 4-[17β-hydroxyl-17α-(methoxymethyl)-3-oxoestro-4 , 9-diene-11β-yl]benzaldehyde-(1E)-oxime (see DE 43 32 283 for the above two).J 900 is 4-[17β-methoxy-17α-(methoxymethyl) -3-Oxoestro-4,9-dien-11β-yl]benzaldehyde-(1E)-[O-(ethoxy)carbonyl]oxime, J 914 is 4-[17β-methoxy-17α -(methoxymethyl)-3-oxoestro-4,9-dien-11β-yl]benzaldehyde-(1E)-(O-acetyl)oxime, and J 956 is 4-[17β- Methoxy-17α-(methoxymethyl)-3-oxoestro-4,9-dien-11β-yl]benzaldehyde-(1E)-[O-(ethylamino)carbonyl]oxime ( See DE 43 32 284 for the above substances). J 1042 is 4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestro-4,9-dien-11β-yl]benzaldehyde -(1E)-[O-(Ethylthio)carbonyl]oxime (German patent application 198 09 845.6)), which are useful in the treatment and prevention of the above-mentioned conditions and also as pharmaceutical compositions and as described below Mesoprogesterone component in combination of disorders.

J 867 is described in DE 43 32 283, and J 900 and 914 are described in DE 43 32 284 and the corresponding patent applications, they are all compounds with strong antiprogestogenic effect, and compared with RU 486 have significantly more Low antiglucocorticoid activity. In addition, these compounds are also mentioned to have (indirect) antiestrogenic properties, which are reflected in the reduction of uterine weight in guinea pigs during menstruation.

These actions allow a particularly favorable influence on pathologically altered tissues in which estrogen stimulates growth (endometriosis, uterine fibroids, etc.). None of the disclosures of these documents refer to the application of the new compounds in hormone replacement therapy. Also, these documents do not mention the progestogenic activity of the compounds which are beneficial for HRT indications. In addition, the above documents do not suggest any active doses for the treatment of the conditions described herein.

According to the invention, a mesoprogesterone is defined as a compound having both agonist and antagonist activity at the progesterone receptor (PR) in vivo. As progestins and antiprogestins, mesoprogestins show high binding affinity for PR. However, mesoprogestins have different pharmacodynamic properties than progestins or antiprogestins. The presence of progesterone agonist activity in mesoprogestins, a key property of this class of new PRMs, was measured in vivo in routinely used biological assays. However, this activity was lower than that of progesterone at the plateau of the dose-response curve. In rodents such as rats and mice, mesoprogesterone fails to maintain pregnancy in ovariectomized pregnant animals.

In the classic biological experiment, the McPhail experiment, the progestogenic and antiprogestogenic effects in rabbits were evaluated (Selye H., Textbook of Endocrinology, 1947, 345-346), progesterone produced a maximum of 4 (defined) McPhail index. However, in the absence of progesterone, treatment with mesoprogesterone produces a McPhail index higher than that of any dose of RU 486, i.e., higher than 0.5-1.0, preferably 2.0-3.0, but significantly lower than that for this indication. The plateau of the dose-response curve is an index of 4 at clinically relevant doses (eg, 0.01 mg-30 mg/rabbit).

The effect of mesoprogesterone antagonizing progesterone function was also tested in the McPhail experiment, where progesterone doses used induced a McPhail index of 3-4. Mesoprogesterone inhibited progesterone action to a significant degree, but the maximal inhibitory effect was lower than that of RU 486 or other pure antiprogestins (onapristone). Thus, mesoprogesterone stabilizes the function of PR at a moderately active level, providing the basis for a new clinical application in gynecological therapy. The corresponding function cannot be achieved with progesterone or anti-progesterone. Pharmacological results confirming the use of mesoprogesterone in said indication

In McPhail's experiment according to Selye (Textbook of Endocrinology, 1947, 345-346), the PR antagonist and agonist properties of mesoprogesterone were evaluated in estrogen-administered rabbits. (A) Evaluation of the PR agonist properties of progesterone in rabbits (Figure 1A)

J 867, J 956, J 1042 and RU 486 were evaluated in young rabbits administered estradiol after 4 days of subcutaneous (s.c.) treatment in the absence of progesterone (dose range: 0.003-100 mg/rabbit ) progesterone activity. The progestogenic effect of progesterone was observed at doses equal to or higher than 0.03 mg rabbit. At doses equal to or higher than 0.1 mg, progesterone induces endometrial transformation, with a maximal effect (McPhail index of about 4) at a dose of 1 mg/rabbit. None of the mesoprogestins tested (J 1042, J 867, J 956) reached a maximal progesterone effect. J 956 showed a biphasic response in this experiment, reaching the maximum effect at a dose of 0.3-1 mg rabbit, with a McPhail index of 1.5. (B) Evaluation of the PR antagonist properties of progesterone in rabbits (Figure 1B)

Similarly, J 867, J 956, J 1042 and RU were assessed in pups administered estradiol after 4 days of subcutaneous (s.c.) treatment in the presence of progesterone (1 mg/rabbit, s.c. 486 (dose range: 0.001-100mg/rabbit) antiprogestogen activity. The first antiprogestogenic effects of mesoprogesterone and RU 486 were observed at doses of 0.3-1 mg rabbits (McPhail index 0 = no conversion; 4 = complete conversion). Mesoprogesterone was less active than RU 486 at higher clinically relevant doses (i.e., 3-30 mg/rabbit).

In a guinea pig model that better predicts the effect of abortive activity in humans (Elger W, Beier S., Chwalisz K, Faehnrich M, Hasan SH, Henderson D, Neef G, Rohde R (1986): Progesterone antagonism Studies on the mechanism of action of progesterone antagonists (Studies on the mechanism of action of progesterone antagonists), J Steroid Biochem 25:835-845), mesoprogesterone J 867, J 912, J 956, J 1042 at doses up to 100mg/kg day A maximum 20% miscarriage rate was achieved. (C) Physiological context for the assessment of the role of abortion

Considering the guinea pig as a relevant model of human pregnancy and parturition (Elger W, Faehnrich M, Beier S, Quing SS, Chwalisz K (1987), Endometrial and myometrial effects of progesterone antagonists in pregnant guinea pigs of progesteroneantagonists in pregnant guinea pigs), Am.J Obstet.Gynecol.157:1065-1074; Elger W, Neef G, Beier S, Faehnrich M, Guendel M, Heermann J, Malmendier A, Laurent D, Puri CP, Singh MM , Hasan SH, Becker H (1992), Evaluation of antifertility activities of antigestagens in animal model, In: Puri CP and Van Look PFA (editors), Current Concepts in Fertility Regulation and Reproduction, WileyEastern Limited, New Delhi, pp. 303-328; Elger W Faehnrich M, Beier S, Qing SS, Chwalisz K (1986), Mechanism of action of progesterone antagonists in pregnant guinea pigs in pregnant guinea pigs), Contraception 6:47-62; Elger W Chwalisz K, Faehnrich M, Hasan SH, Laurent D, Beier S, Ottow E, Neef G, Garfield RE (1990), Effects of antiprogestins in animal models Studies on labor-conditioning and labor-inducing effects of antiprogesterones in animal model, In: Garfield RE (ed.), Norwell, pp. 153-175). The abortive mechanism of antiprogestins in this species is the initiation of labor and eventual conceptus rejection. During very early pregnancy, the abortive effect in rats was reflected in inhibition of implantation rather than initiation of uterine contractions. Studies in rat models lead to "overestimation" of the efficacy of antiprogestins in terminating human pregnancies. In contrast, in the guinea pig model, irrespective of the dose of antiprogesterone, there was an initial pregnancy rate similar to the human situation (Elger et al., Current Concepts in Fertility Regulation and Reproduction, same as above). In addition, antiprogestins and prostaglandins have a strong synergistic effect in inducing labor in humans and guinea pigs (see above and Elger W, Beier S (1983), Prostaglandine and antiprogestogens on termination of pregnancy (Prostaglandine und Antigestagene fuer den Schwangerschaftsabbruch), German Patent DE 3337450 12; Van Look P, Bygdeman M (1989), Antiprogestational steroids: a new starting point in human fertility regulation (Antiprogestational steroids: a new dimension in human fertility regulation), Oxford Reviews of Reproductive Medicine 11:2-60). Assessment of Labor-Inducing Activity: Figure 2

Pregnant guinea pigs were handled on days 43 and 44 of gestation and observed until 50 days of gestation. The effects of various treatments are shown in Table 1 and Figure 2. Typically for this model, conceptus exclusion occurs with a delay of several days after treatment. It can be seen that mesoprogesterone has significantly lower abortive activity than RU486. The order of abortion activity was as follows: RU 486 > J 956 > J 867, J 912 > J 1042. Differences in abortion activity appear to be quantitative. It is also not possible to overcome the low abortifacient activity of mesoprogesterone with higher doses. Table 1: Relative Binding Activity (RBA) and _ED50 Studies for Abortive Activity in Pregnant Rats and Guinea Pigs compound RBA(%)# Abortive Activity ED ₅₀ (mg/animal/day, sc) PR ¹ GR ² Rat ³ guinea pig ⁴ RU486 506 685 0.98 ^* 3.8 Onapristone twenty two 39 1.71 ^* about 3 J 867 302 78 0.65 ^* >100 J 956 345 154 0.64 ^* 20 J 912 162 16 0.36 >100 J 1042 164 42 >10 ＞＞100 #, by Kaufmann; ¹ progesterone = 100%, ² dexamethasone = 100% ³ gestation day 5-7 processing, day 9 autopsy, ⁴ pregnancy day 43-44 processing, day 50 autopsy, ^* SAS, Probabilistic testing of estrogens and mesoprogestins as administration forms for the purposes of the present invention

· Oral dose range: 0.5-100mg/day

Intramuscular: 0.1-50mg/day

Intrauterine (IUS), intravaginal (gel, sponge) formulations

Formulations are formed, for example, as described in the basic patent applications (DE 43 32 283 and DE 43 32 284) for compounds J 867, J 912, J 956.

Likewise, transdermal (gel, patch) or intravaginal (gel, suppository) administration is also possible. Combination of mesoprogesterone with other pharmacologically active compounds according to the invention for endometriosis and uterine fibroids

GnRH-agonist/-antagonist sequentially plus mesoprogesterone (2-3 months of GnRH-agonist/-antagonist, then 3-6 months of mesoprogesterone to maintain therapeutic effect)

Combination of GnRH-agonist/-antagonist for 3-6 months and mesoprogesterone (addback therapy) to reduce GnRH-induced side effects (hot flashes, osteoporosis)

GnRH-agonists/-antagonists for the above purposes selected from the group consisting of: leuprolide (US 4,005,063), cetrorelix (EP 0 299 402 B1), antide (WO-A89/01944) , Buserelin (GB 1 523 623), Remeric (EP 0 541 791 A), zoladex (US 4,100,274), 2-(4-acetylaminophenyl)-4,7-dihydro-7 -(2-methoxybenzyl)-3-(N-methyl-N-benzylaminomethyl)-4-oxothieno[2,3-b]-pyridine-5-carboxylic acid ethyl Esters (WO-A95/28405), 5-benzoyl-7-(2,6-difluorobenzyl)-4,7-dihydro-3-(N-methyl-N-benzylaminomethyl )-2-(4-propionylamidophenyl)-4-oxothieno[2,3-b]-pyridine and Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D - Cit-Leu-Lys(Mor)-Pro-D-Ala- _NH2 , (WO-A92/20711). dysfunctional bleeding

Combination with cyclooxygenase inhibitors (eg, mefenamic acid, aspirin)

Dysmenorrhea in combination with antifibrinolytics (such as tranexamic acid)

Combination with cyclooxygenase inhibitors (eg, mefenamic acid, aspirin)

Dosing regimens for different indications in combination with NO donors such as nitroglycerin Endometriosis and uterine fibroids

·See above Combinations for Dysfunctional Uterine Bleeding

Prophylaxis of dysfunctional uterine bleeding from the onset of bleeding until the cessation of bleeding

·d1 until the end of the third month (continuing 28-60 days) daily administration for dysmenorrhea

·d1 until symptoms cease to prevent dysmenorrhea

3-28 days before the onset of menstruation

Example 1. Acute treatment of dysfunctional bleeding with mesoprogesterone

Women with uterine bleeding or other dysfunctional bleeding were treated with 5-100 mg of J 867 for 1-10 days until treatment was stopped. 2. Prevention of dysfunctional bleeding with mesoprogesterone

Women with uterine bleeding or other dysfunctional bleeding were treated with 0.5-25 mg of J 867 for 21-60 days starting from the first day of bleeding. 3. Treatment of endometriosis

Women with endometriosis are treated with 5-50 mg of J 867 for 3-6 months. During the treatment period, a reduction in pelvic pain was observed. 4. Sequential treatment of endometriosis with LHRH agonist and J 867

Women with endometriosis are treated with an LHRH agonist such as Lupron for 2-3 months. After discontinuation of LHRH agonist therapy, women were subsequently treated with J 867 for 3-6 months to avoid osteoporosis caused by long-term LHRH agonist therapy. During treatment with 5-50 mg of J 867, the therapeutic effect of the LHRH agonist was maintained. Treatment with J 867 did not produce estrogen deficiency because plasma estradiol levels remained at follicular phase levels. 5. Treatment of uterine fibroids

Women with uterine fibroids were treated with 5-50 mg of J 867 for 3-6 months. During the treatment period, a reduction in pelvic pain was observed.

The entire contents of the above and following patent applications, patents and literature, and the corresponding application serial no. This is incorporated by reference.

These examples can also be repeated with similar success substituting conventional or specific reactants and/or operating conditions for those used in the above examples.

From the foregoing description, one skilled in the art can readily ascertain that the essential characteristics of this invention are susceptible to various changes and modifications to adapt it to various usages and conditions without departing from the scope of the invention.

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Claims (11)

1, the application of the middle progesterone of effective dose in the benign gynecological disorder of treatment hormonal dependent.

2, application as claimed in claim 1, wherein, described gynaecopathia is endometriosis, hysteromyoma, postoperative peritoneal adhesion, malfunction hemorrhage (metrorrhagia, menorrhagia) and dysmenorrhea.

3, the application of middle progesterone in the benign gynecological disorder of prevention of hormone dependent of effective dose.

4, application as claimed in claim 2, wherein, described gynaecopathia is postoperative peritoneal adhesion, malfunction hemorrhage (metrorrhagia, menorrhagia) and dysmenorrhea.

5, as the described application of one of claim 1-4, wherein, dosage every day of middle progesterone is 0.5-100mg.

6, application as claimed in claim 5, wherein, dosage every day of middle progesterone is 5.0-50mg.

7, application as claimed in claim 6, wherein, described every day, dosage was 10-25mg.

8, as the described application of one of claim 1-7, wherein, middle progesterone is J 867, J 912, J 856 or J 1042.

9, pharmaceutical composition, it comprises GnRH-analog or antagonist and the middle progesterone of order thereafter.

10, compositions as claimed in claim 9, it is to be used for the treatment of endometriosis and hysteromyoma.

11; as claim 9 or 10 described compositionss; wherein; GnRH-analog or antagonist are selected from following group: leuprorelin; cetrorelix; antide; buserelin; ramorelix; zoladex; 2-(4-acetyl-amino phenyl)-4; 7-dihydro-7-(2-methoxy-benzyl)-3-(N-methyl-N-benzylamino-methyl)-4-oxo thieno [2; 3-b]-pyridine-5-carboxylic acid ethyl ester; 5-benzoyl-7-(2; the 6-difluorobenzyl)-4; 7-dihydro-3-(N-methyl-N-benzylamino-methyl)-2-(4-propiono aminophenyl)-4-oxo thieno [2,3-b]-pyridine and Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Cit-Leu-Lys (Mor)-Pro-D-Ala-NH ₂, and middle progesterone is selected from J 867, J 912, J 856 and J 1042.

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