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

Middle progesterone (progesterone receptor modulator) is used for the treatment of and the prevention of hormone dependent benign gynecological disorder

The present invention relates to the prevention and the treatment of main hormonal dependent benign gynecological disorder, described disease comprises proliferative disorders, as endometriosis, hysteromyoma and postoperative peritoneal adhesion and menstruation syndrome, malfunction hemorrhage (metrorrhagia, menorrhagia) and dysmenorrhea.

Generally, these diseases are to treat with the progesterone of medium or high dose.The effectiveness of this treatment is variable sometimes, but also produces unwished-for side effect, comprises metabolic alterations (LDL concentration increases, and HDL concentration reduces), to the influence of emotion and significantly hemorrhage.

Recently, existing people proposes to use competitive progesterone receptor antagonists (progesterone antagonist) (to comprise onapristone, mifepristone (RU 486)) treatment endometriosis and dysmenorrhea (EP 0 266 303B1), hysteromyoma (the application (Use of antiprogestins in the management of endometriosis andleiomyomata) of Yen SSC (1993) progesterone antagonist in treatment endometriosis and leiomyoma, In Donaldson, M:s., Dorflinger (editor), Clinical application ofMifepristone (RU 486) and other antiprogestins, National Academy Press, Washington, DC, the 189-209 page or leaf; Kettel L M., Murphy A.A., people (1996) such as Morales A.J., with progesterone antagonist mifepristone (RU 486) treatment endometriosis (Treatment ofendometriosis with the antiprogesterone mifepristone (RU 486)), Fertil Steril65:23-28) and metrorrhagia disease (WO 96/23503).

The latent defect of progesterone antagonist is can not the abuse of total ban in induced abortion. Endometriosis

Endometriosis is a kind of chronic disease, it is characterized in that the growth of endometrial dystopy, promptly, in the cavity of uterus outside.Although paidly go out to make great efforts to estimate endometriotic occurrence frequency and determine sickness rate under special clinical setting that endometriotic accurate total incidence rate is still unknown (6,8,9,11).Its scope is at 5%-55%.The feature of this disease is outer endometrial gland and substrate benign propagation and function on the histology of physiological location.

Ovary is the position (50-60%) of the most frequent generation metrecotpia.Other common affected zones are: behind jarjavay's ligaments, blind pipe, uterus bladder peritoneum, the vagina every and uterine ligaments.Also can on such as organs such as sigmoid colon, rectum, vermiform appendix, bladders, find the endometriosis damage.

Endometriosis must be considered to a kind of disease with different orders of severity, and it is relevant with the remarkable malfunction of sterile and pelvic pain usually.Endometriotic clinical symptoms comprises that various Genito-urinary symptoms that dysmenorrhea, women pain sexual intercourse coition difficulty, chronic pelvic pain, dysurea, urethral obstruction and/or bladder infringement cause, the defecation of pain property, rectal pressure, defecation are promptly and intestinal obstruction, hemorrhage (comprising menorrhagia or metrorrhagia) unusually, sterile, constitutional or insecondary repeatability spontaneous abortion.

The main clinical symptom is constitutional or secondary dysmenorrhea, women's pain sexual intercourse coition difficulty and chronic pelvic pain, particularly between the onset of ovulation.

Endometriotic essential drugs therapeutic goal be to use the GnRH-agonist/-treatment of antagonist or successive progesterone makes endometriosis damage atrophy, and induces acyclic hormone environment.Generally, these Therapeutic Method produce the low estrogen environment, and disease is improved.

In the endometriotic treatment the progesterone of normal use be danazol and gestrinone.Danazol is the Isoxazole derivative of 17-pregnine, and it is active to have significant androgen part.Gestrinone is the derivant that 19-gets methyltestosterone, has potent progestogen and androgen character.Some advantages of danazol are low, the better protective effects and little to the influence of lipid metabolism of practising contraception of administration frequency.As the most widely used progesterone, danazol is thought that by everybody the cycle gonadotrophin secretion works by suppressing, but more and more evidences shows that this chemical compound has a plurality of mechanism of action, comprises direct inhibition dystopy endometrial tissue.The treatment of carrying out with danazol has pronounced side effects.In the women of danazol treatment, as many as 85% all has side effects (67,68), as: androgen and anabolism change (acne and oily skin, sound chap, weight increase, LDL concentration increase and HDL concentration reduces, other side effect such as rash, by the glucocorticoid of danazol and the active hypertension that causes of mineralocorticoid part and through during hemorrhage.

Can realize the hypophysis inhibitory action with GnRH-agonist and GnRH-antagonist.When the treatment endometriosis, use different GnRH-agonist at present.This therapeutic scheme is induced darker low estrogen, acyclic environment, the side effect that does not produce steroidal.The GnRH-analog is effective for the treatment endometriosis.The subjectivity of this treatment and objective action can with the comparing favourably or better (72-77) of danazol.Because sign that the estrogen forfeiture is produced and symptom (hot flush (hot flushes), mental change, headache, fatigue or the like) are main side effect.In addition, but GnRH-analogue treatment induced osteoporosis disease (76,77).During the ovary inhibitory action that the GnRH-analog brings out, the probability that bone loss quickens is effectively another major consideration of treatment of endometriosis.

Simultaneously, considered that different add-backs (add back) scheme is to pass through as raloxifene (SAG:WO97/27863; Eli Lilly) selective estrogen receptor modulators (SERM) substitutes the estrogen inhibitory action during the GnRH-treatment. Menorrhagia

Menorrhagia is defined as each cycle menses greater than 80ml, and it is a kind of syndrome of reason unknown, and is one of modal problem of gynecological.Suffering among the women of menorrhagia has 60% to be with the interior uterectomy that experienced in 5 years.Present medical treatment still can not be satisfactory.At intermenstrual period, be norethindrone (about 40%), be non-steroidal anti-inflammatory medicine (NSAID) mefenamic acid (about 30%) and anti-fibrinolytic medicine tranexamic acid (5%) (Intercontinental Medical Statistics 1994) then for the modal prescription drugs of acute treatment in Europe.During hemorrhage, last chemical compound seemingly after acute administration for the women who suffers from the ovary menorrhagia the most effective (hemorrhage reduction by 45%).Recently, levonorgestrel in utero system (Mirena) be used to prevent menorrhagia to be introduced into.Nearest studies show that, is administered three times every day according to the dosage of 5mg, and each cycle is 5-26 days, totally three cycles, levonorgestrel in utero system (Mirena) and oral norethindrone menses are reduced to normal range aspect all be effective.Yet these two therapeutic schemes all have hemorrhage rate during the very high warp (have 50% among the women with the Mirena treatment, have 36% among the women with the norethindrone treatment) people such as (, 1998) Irvine. Dysmenorrhea

Dysmenorrhea is that the painful uterine contraction causes.The women who suffers from dysmenorrhea compares with normal contrast has the static and surge pressure of higher intrauterine.Accurate pain mechanism is not still removed during dysmenorrhea.Dysmenorrhea most possibly is (people such as Pickels, 1965 because intermenstrual period uterine contraction, keynote (basal tone) and the vasoconstrictive increase of spiral artery; People such as Csapo, 1977).Therefore, preventing that uterine contraction and uterine vascular from shrinking can alleviate pain in menstrual period.Dysmenorrhea can be divided into constitutional or secondary dysmenorrhea, and (Dawoo 1985; 1990).In primary dysmenorrhea, the painful menstruation spasm is arranged, but do not have visible pelvis pathology.But in secondary dysmenorrhea, visible pelvis pathology (as endometriosis) is arranged, this causes the painful menstruation spasm.

Primary dysmenorrhea is one of modal gynaecopathia, and after affecting nearly 50% adolescence the women (Dawood 1985; 1990).Oral contraceptive and NSAID can be alleviated primary dysmenorrhea effectively, and apparent prevalence rate in fact might be lower slightly.Suffering among the women of primary dysmenorrhea has 10% to suffer from serious pain, make they have every month 1-3 days inactive, this causes significantly staying away from work without leave or cut classes (Svennerud, 1959), and causes economic loss (Dawood1985) subsequently.Therefore, dysmenorrhea is an important medical treatment and economic problems, and the treatment of better (simpler, safer) can reduce women and social burden to this disease.

The seemingly single disease unit of primary dysmenorrhea causes and secondary dysmenorrhea might be a various diseases, and described disease comprises endometriosis and hysteromyoma.Generally, primary dysmenorrhea is to heal with medicine, and secondary dysmenorrhea usually need be at the treatment (exception: because the secondary dysmenorrhea that exists IUD and endometriosis to be caused) that undergos surgery of its cause of disease.Primary dysmenorrhea is the most general in the women of tens years old or 20 annual expenditure heads, and (Widholm, 1979) then descended after 30 years old.Primary dysmenorrhea can be diagnosed according to medical history and Clinical symptoms, and physical examination and transvaginal sonography scanning can be got rid of abnormal uterine (Dawood, 1990).

Pain during combination OC and NSAID have been widely used in prevention or have treated warp.These two kinds of medicines effective percentage in suffering from the women of primary dysmenorrhea is about 80-90% (Dawood, 1990).But the women that 10-20% suffers from serious primary dysmenorrhea develops immunity to drugs to any treatment.In Germany, ibuprofen (Urern ^, Gynofu ^) be most popular NSAID in the dysmenorrhea treatment.Yet not all women/girl who suffers from primary dysmenorrhea is ready to take OC or can stands the NSAID treatment.This girl for 13-16 year is particularly like this.Interchangeable Drug therapy is to use uterine contraction class medicine such as calcium channel blocker (people such as Sandah, 1979) or betamimetics (Dawood, 1990).These medicines are to play a role by suppressing uterine contraction, but find but to be difficult to accept for patient, gynecologist and gengral practitioner on bigger scale.This is equally applicable to discharge the IUS of progesterone.Transcutaneous electrical neural stimulation (TENS) only has 30% to be effectively people such as (, 1985) Lundberg in the women who suffers from serious dysmenorrhea.

Therefore, still be starved of for the above-mentioned disease of treatment and have better toleration and/or more can received scheme.

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

To be middle progesterone be used for the treatment of application in the medicine of gynaecopathia in preparation to one aspect of the present invention, and described gynaecopathia for example is endometriosis, hysteromyoma, postoperative peritoneal adhesion, malfunction hemorrhage (metrorrhagia, menorrhagia) and dysmenorrhea.

To be middle progesterone be used for the application of the medicine of prophylaxis of gynaecological disorders in preparation in another aspect of the present invention, and described gynaecopathia for example is postoperative peritoneal adhesion, malfunction hemorrhage (metrorrhagia, menorrhagia) and dysmenorrhea.

Another aspect of the present invention is to need treatment or prevent female, these diseases among the women particularly of above-mentioned disease with the middle progesterone treatment of effective dose and prevention.

Another aspect of the present invention is that when the above-mentioned disease of treatment, dosage every day of middle progesterone is 0.5-100mg; Preferred daily dose is the middle progesterone of 5.0-50mg; And most preferred daily dose is the middle progesterone of l0-25mg.

As the chemical compound of describing among DE 43 32 283 and the DE 43 32 284, be the middle progesterone that is suitable for the object of the invention.

The middle preferably following chemical compound of progesterone: (wherein J 867 is 4-[17 'beta '-methoxy-17 α-(methoxy)-3-oxos female-4 for J 867, J 912, J 900, J 914 and J 956,9-diene-11 beta-yl] benzaldehyde-(1E)-oxime, and J 912 to be 4-[17 beta-hydroxyl-17 alpha-(methoxy)-3-oxos female-4,9-diene-11 beta-yl] benzaldehyde-(1E)-oxime (above two referring to DE 43 32 283).J 900 is 4-[17 'beta '-methoxy-17 α-(methoxy)-3-oxos female-4; 9-diene-11 beta-yl] oxime of benzaldehyde-(1E)-[O-(ethyoxyl) carbonyl]; J 914 is 4-[17 'beta '-methoxy-17 α-(methoxy)-3-oxos female-4; 9-diene-11 beta-yl] oxime of benzaldehyde-(1E)-(O-acetyl group); with J 956 be that 4-[17 'beta '-methoxy-17 α-(methoxy)-3-oxo is female-4,9-diene-11 beta-yl] oxime (above material is referring to DE 43 32 284) of benzaldehyde-(1E)-[O-(ethylamino) carbonyl].J 1042 is 4-[17 'beta '-methoxy-17 α-(methoxy)-3-oxos female-4,9-diene-11 beta-yl] oxime (German patent application 198 09 845.6) of benzaldehyde-(1E)-[O-(ethylmercapto group) carbonyl]), they can be used for treating and prevent above-mentioned disease and as pharmaceutical composition with as described belowly also can be used for treating and prevent middle progesterone component in the combination of above-mentioned disease.

J 867 is described among the DE 43 32 283, and J 900 and 914 is described in DE 43 32 284 and the corresponding patent application, they all are the chemical compounds with strong gestation effect, and compare with RU 486 and to have significantly lower Antiglucocorticoid activity.In addition, also mention these chemical compounds and have (indirectly) estrogen antagonist character, this is reflected in the uterus weight that can reduce through interim Cavia porcellus.

These effects allow the pathological change tissue of estrogen stimulating growth (endometriosis, hysteromyoma etc.) is wherein produced particularly advantageous influence.The disclosure of these documents does not all relate to the application of noval chemical compound in Hormone Replacement Therapy.And these documents are not mentioned the progestin for the favourable chemical compound of HRT indication yet.In addition, above-mentioned document is not pointed out any active dose of the said disease of treatment.

According to the present invention, middle progesterone is defined as the chemical compound that antagonist activities is arranged again for the existing agonist of progesterone receptor (PR) in vivo.As progesterone and progesterone antagonist, middle progesterone demonstrates high binding affinity for PR.Yet middle progesterone is compared with progesterone or progesterone antagonist has different pharmacodynamic properties.In the biotic experiment that routine is used in in-vivo measurement in middle progesterone, there being the progesterone agonist activity, it is the key property of this type of new PRM.But this activity is lower than the activity of progesterone when the plateau of dosage-response curve.In the rodent such as rat and mice, middle progesterone can not be kept pregnancy in OO pregnant animal.

In biotic experiment at classics---the McPhail experiment, assessed progestogen in rabbit and gestation effect (Selye H., Textbook of Endocrinology, 1947,345-346), progesterone is produced as the maximum McPhail index of 4 (definition).But, when not having progesterone, index when the McPhail index that is produced with the treatment of middle progesterone is higher than the RU 486 of any dosage, promptly, be higher than 0.5-1.0, preferred 2.0-3.0, but when significantly being lower than the clinical relevant dose (for example 0.01mg-30mg/ rabbit) of this indication the plateau of dosage-response curve be 4 index.

Also tested the effect of middle progesterone antagonism progesterone function in the McPhail experiment, use therein progesterone dosage can be induced the McPhail index of 3-4.In progesterone effect has the inhibition of significance degree to progesterone, but maximum inhibitory action is lower than the effect of RU 486 or other pure progesterone antagonists (onapristone).Therefore, middle progesterone is with the function of medium activity horizontal stable PR, for the new clinical practice in gyniatrics provides the foundation.Can not realize function corresponding with progesterone or progesterone antagonist. The pharmacology result of the application of progesterone in described indication in the confirmation

According to Selye (Textbook of Endocrinology, 1947, in 345-346) the McPhail experiment, in the estrogenic rabbit of administration, assessed the PR antagonist and the agonist character of middle progesterone.(A) assessment (Figure 1A) of the PR agonist character of progesterone in rabbit in

Do not having under the situation of progesterone, through 4 days subcutaneous (s.c.) treatment back assessment J 867, J 956, J 1042 and RU 486 (dosage range: the progestin 0.003-100mg/ rabbit) in the young rabbit of administration estradiol.The progestogen action of progesterone in the dosage that equals or be higher than the 0.03mg rabbit is observed.Equaling or be higher than under the dosage of 0.1mg, progesterone brings out endometrium and transforms, and is issued to the effect (about 4 McPhail indexes) of maximum at the dosage of 1mg/ rabbit.The middle progesterone of being tested (J 1042, J 867, J 956) neither one reaches maximum progesterone effect.J 956 shows two-phase and replys in this experiment, reach maximum effect when the dosage of 0.3-1mg rabbit, and the McPhail index is 1.5.(B) assessment (Figure 1B) of the PR antagonist properties of progesterone in rabbit in

Similarly, progesterone (1mg/ rabbit is being arranged, s.c.) under the situation, through 4 days subcutaneous (s.c.) treatment back assessment J 867, J 956, J 1042 and RU 486 (dosage range: the antiprogestational action 0.001-100mg/ rabbit) in the young rabbit of administration estradiol.(McPhail index 0=does not have conversion in the effect of gestation first of progesterone and RU 486 in observing when the dosage of 0.3-1mg rabbit; 4=transforms fully).The middle antiprogestational action of progesterone when higher clinical relevant dose (3-30mg/ rabbit promptly) is lower than RU's 486.

(ElgerW in guinea pig model (it can predict the induced abortion active function in the people better), Beier S., Chwalisz K, Faehnrich M, Hasan SH, Henderson D, Neef G, Rohde R (1986): the research of the progesterone antagonist mechanism of action (Studies on the mechanismof action of progesterone antagonists), J Steroid Biochem 25:835-845), middle progesterone J 867, J 912, J 956, J 1042 reach maximum 20% abortion ratio during to 100mg/kg days dosage at height.(C) the assessment physiology background of induced abortion effect

Consider correlation model (the Elger W of Cavia porcellus as people's gestation and childbirth, Faehnrich M, BeierS, Quing SS, Chwalisz K (1987), endometrium and the myometrium effect (Endometrial and myometrial effects of progesteroneantagonists in pregnant guinea pigs) of progesterone antagonist in conceived Cavia porcellus, 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), the gestation active assessment of antifertility power in animal model (Evaluation of antifertilityactivities of antigestagens in animal model), In:Puri CP and Van Look PFA (editor), Current Concepts in Fertility Regulation and Reproduction, WileyEastern Limited, New Delhi, 303-328 page or leaf; Elger W Faehnrich M, Beier S, Qing SS, Chwalisz K (1986), the mechanism of action (Mechanism of action of progesterone antagonists in pregnant guinea pigs) of progesterone antagonist in conceived Cavia porcellus, Contraception 6:47-62; Elger W Chwalisz K, Faehnrich M, Hasan SH, Laurent D, Beier S, Ottow E, Neef G, Garfield RE (1990), the childbirth adjusting of progesterone antagonist in animal model and the research (Studies on labor-conditioningand labor-inducing effects of antiprogesterones in animal model) of childbirth inducing action, In:GarfieldRE (editor), Norwell, 153-175 page or leaf).The mechanism of abortion of progesterone antagonist in these species is to cause childbirth and finally cause conceptus to be got rid of.At phenolics very early, the induced abortion effect in rat is reflected in the inhibitory action to implantation, rather than causes uterine contraction.Research in the rat model causes " the excessively estimation " to the effectiveness of progesterone antagonist termination people's pregnancy.On the contrary, in guinea pig model, the dosage of progesterone antagonist no matter all has the beginning pregnancy rate (people such as Elger, Current Concepts in Fertility Regulation and Reproduction, same as described above) of the situation that is similar to the people.In addition, in people and Cavia porcellus, progesterone antagonist and prostate have strong synergism and (see above-mentioned article and Elger W aspect induced parturition, Beier S (1983), prostaglandin and gestation are to the termination (Prostaglandine und Antigestagene fuer denSchwangerschaftsabbruch) of pregnancy, German patent DE 3,337,450 12; Van Look P, Bygdeman M (1989), the gestation sex steroid: the people gives birth to the ground zero (Antiprogestational steroids:a new dimension in human fertility regulation) of adjusting aspect, Oxford Reviews of Reproductive Medicine 11:2-60).The assessment of childbirth induced activity: Fig. 2

Handle conceived Cavia porcellus the 43rd and 44 day of pregnancy, and observe to gestation 50 days.The effect of various processing sees Table 1 and Fig. 2.Be typically for this model, after processing, postpone several days generation conceptus and get rid of.As can be seen, middle progesterone has significantly lower induced abortion activity than RU486.The active order of having an abortion is as follows: RU 486＞J 956＞J 867, J 912＞J 1042.Difference on the induced abortion activity is seemingly quantitative.Use higher dosage also can not overcome the low induced abortion activity of middle progesterone.Table 1: relative to active (RBA) and the active ED that has an abortion in conceived rat and Cavia porcellus ₅₀Research

Chemical compound	????RBA(％)#		Active ED has an abortion 50(mg/ animal/sky, s.c.)
					????PR 1	???GR 2	????Rat 3	Cavia porcellus 4
	????RU486	????506	???685	????0.98 *					????3.8
Onapristone					????22	???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

# is by Kaufmann; ¹Progesterone=100%, ²Dexamethasone=100% ³Handled in conceived 5-7 days, the 9th day obduction, ⁴Handled in conceived 43-44 days, the 50th day obduction, ^*SAS, probability inspection Estrogen and middle progesterone are the administration form of the object of the invention

Oral dose scope: 0.5-100mg/ days

Intramuscular: 0.1-50mg/ days

Intrauterine (IUS), intravaginal (gel, sponge) Dosage form

For example, form dosage form according to described in the basic patent application (DE 43 32 283 and DE 43 32 284) of chemical compound J 867, J 912, J 956.

Equally, but also transdermal (gel, plaster) or intravaginal (gel, suppository) administration. Combination according to progesterone in of the present invention and other pharmaceutically active compoundsEndometriosis and hysteromyoma

The GnRH-agonist/-antagonist sequentially add middle progesterone (2-3 month GnRH-agonist/-antagonist, 3-6 month middle progesterone then is to keep therapeutic effect)

Be used in combination the GnRH-agonist/-antagonist 3-6 month and middle progesterone (add-back (addback) treatment), the side effect of bringing out with reduction GnRH (hot flush, osteoporosis)

Be used for the GnRH-agonist of above-mentioned purpose/-antagonist is selected from following group: (US 4 for leuprorelin; 005; 063); cetrorelix (EP 0 299 402 B1); antide (WO-A89/01944); buserelin (GB 1 523 623); ramorelix (EP 0 541 791 A); (US 4 for zoladex; 100; 274); 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 (WO-A95/28405); 5-benzoyl-7-(2; the 6-difluorobenzyl)-4; 7-dihydro-3-(N-methyl-N-benzylamino-methyl)-2-(4-propiono amido phenyl)-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, (WO-A92/20711).Malfunction is hemorrhage

Make up with cyclooxygenase-2 inhibitor (as mefenamic acid, aspirin)

With anti-fibrinolytic medicine (as tranexamic acid) combination dysmenorrhea

Make up with cyclooxygenase-2 inhibitor (as mefenamic acid, aspirin)

Make up with NO donor (as nitroglycerin) Dosage regimen for different indicationsEndometriosis and hysteromyoma

See that above combined therapy malfunction temper palace is hemorrhage

Prevent dysfunctional uterine bleeding by hemorrhage beginning until stopped bleeding

D1 finished (continuing 28-60 days) drug treatment dysmenorrhea every day until three month

D1 stops to prevent dysmenorrhea until symptom

Before menstruation begins 3-28 days

Embodiment1, progesterone acute treatment malfunction is hemorrhage in the usefulness

Suffer from the hemorrhage women of metrorrhagia or other malfunctions and use the J 867 of 5-100mg to treat 1-10 days, stop until treatment.2, progesterone prevention malfunction is hemorrhage in the usefulness

By beginning in hemorrhage the 1st day, treat with the J 867 of 0.5-25mg and to suffer from metrorrhagia or other malfunctions hemorrhage women 21-60 days.3, treatment endometriosis

J 867 treatments with 5-50mg suffer from endometriotic women 3-6 month.During treating, observe pelvic pain and alleviate.4, sequentially treat endometriosis with LHRH agonist and J 867

Suffer from endometriotic women 2-3 month with LHRH agonist such as Lupron treatment.After stopping the LHRH agonist treatment, next treated women 3-6 months, with the osteoporosis of avoiding being caused with the LHRH agonist treatment for a long time with J 867.During J 867 treatments, still keep the therapeutic effect of LHRH agonist with 5-50mg.Treatment with J 867 does not produce estrogen deficiency, and this is because the plasma estradiol level still is in level follicular phase.5, treatment hysteromyoma

J 867 with 5-50mg treated women 3-6 month that suffers from hysteromyoma.During treating, observe pelvic pain and alleviate.

The whole contents of above-mentioned and following patent application, patent and document, and the whole contents of the 09/386th, No. 140 the corresponding application (having changed provisional application on August 29th, 2000 into) of application on August 31st, 1999 are incorporated herein by reference at this.

With used in conventional or concrete reactant and/or operating condition replacement the foregoing description, also can similarly successfully repeat these embodiment.

For foregoing description, those skilled in the art can confirm easily that basic feature of the present invention also can carry out various changes and modifications under the situation that does not depart from the scope of the invention, so that it adapts to various application and condition.

List of references

Preston JT, Cameron IT, Adams EJ, Smith SK (1995) tranexamic acid and norethindrone comparative research (Comparative study of tranexamic acidand norethisterone in the treatment of ovulatory menorrhagia) the .Br.J ObstetGynewl 102:401-406 in treatment ovulation pain warp

Bonnar J, Sheppard BI (1996) intermenstrual period TREATMENT OF DYSMENORRHOEA: the random controlled test of etamsylate, mefenamic acid and tranexamic acid (Treatment of menorrhagia duringmenstruation:randomised controlled trial of ethamsylate, mefenamic acidand tranexamic acid) .BMJ 313:579-582

Intercontinental medical statistics company limited (London) (Intercontinental Medical Statistics Ltd.London): IMS, 1994

Chwalisz K., Buhimschi I., Garfield R.E. (1996) nitrogen oxide effect (Role of nitric oxide in obstetrics) the .Prenat Neonat Med 1 in obstetrics: 292-329.

Dawood MY (1984) ibuprofen and dysmenorrhea (Ibuprofen and dysmenorrhea) .Am J Med 77:87

The etiology of Dawood MY (1985) dysmenorrhea and treatment (Etiology and treatment ofdysmenorrhoea) .Semin Reprod Endocrinol 3:283

Dawood MY (1990) dysmenorrhea (Dysmenorrhoea) .Clin Obstet Gynaecol 33:168

The method summary (Overall approach tomanaging dysmenorrhoea) of Dawood MY (1985) treatment dysmenorrhea. at Dawood MY, McGuire JL, .Baltimore:Urban Schwarzenberg among " premenstrual syndrome and dysmenorrhea (the Premenstrual syndrome and dysmenorrhoea) " that Demers LM edits, pp:177

Lundberg T, Bondesson L, the subcutaneous electrical nerve stimulation of Lundstrom V (1985) is to alleviation (Relief of primary dysmenorrhoea by transcutaneouselectrical nerves stimulation) the .Acta Obstet Gynaecol Scand 64:491 of primary dysmenorrhea

Pittrof R, Lees C, Thompson C, Martin JF, Campbell S (1996) nitroglycerin plaster reduces pain (Glyceryl trinitrate patches reducepain in women with severe dysmenorrhoea) the .Brit.Med J 312:884 among the women who suffers from dysmenorrhea

6.Williams, T, Pratt, the endometriosis during J cuts open the belly for H:1000 time continuously: medicine and treatment (Endometriosis in 1000 consecutive celiotomies:medicine andmanagement) .Am J Obstet Gynecol 129:245 (1977)

8.Redwine D B: endometriotic distribution and fertility in the age group pelvis (Thedistribution of endometriosis in the pelvis by age groups and fertility) .FertilSteril 47:173 (1987)

9.Houston D E: age, race and socioeconomics are to evidence (Evidence for the risk of pelvic endometriosis by age, race andsocioeconomic status) the .Epidemiol Rev 6:167 (1984) of pelvis endometriosis risk

11.Chartman, D L, M D: modern diagnosis method (Modem diagnosis of endometriosis state of the art) the .J Reproduct Med 33 of existing endometriosis state, 11:861 (1988)

67.Dmowskd, W P: the endocrine character of danazol and clinical practice (Endocrineproperties and clinical application of danazol) .Fertil Steril 31:237 (1979)

68.Buttram, V C, Reiter, R C, Ward, S: danazol is to endometriotic treatment: report (Treatment of endometriosis with danazol:reportof a 6-year prospective study) the .Fertil Steril 43:3 (1985) of expection research in 6 years

72.Rose, G L, Dowsett, M, Mudge, J E, White, J O, Jeffcoate, S L:266. danazol, danazol metabolite, gestrinone and testosterone external inhibitory action (The inhibitory effects of danazol, danazol metabolites to the endometrial cell growth, gestrinoneand testosterone on the growth of human endometrial cells in vitro, item)

73.Schriock, E, Monroe, S E, Henzl, M, Jaffe, R B: the potent agonist (nafarelin) of chorionic gonadotropin releasing hormone is to endometriotic treatment (Treatment ofendometriosis with a potent agonist of gonadotropin-releasing hormone (nafarelin)), Fertil and Steril 44:5 (1985)

74.Lemay, A, Maheux, R, Huot, C, Blanchet J, Faure, N: intranasal or subcutaneous administration luteinizing hormone-releasing hormone agonist are renderd a service (Efficacy of intranasal or subcutaneous luteinizing hormone-releasing hormone agonist inhibition of ovarian function in the treatment ofendometriosis) .Am J Obstet Gynecol 158:233 (1988) to the inhibitory action of ovarian function when the treatment endometriosis

75.Cortes-Prieto, J, Lledo, A, Avila, C, Cortes-Garcia, L, D ' acunto, A, Luisi, M, ComaruSchally, A M, Schally, the long-acting agonist of A V:LH-RH is to treatment (Long-acting agonists of LH-RH in the treatmentof large ovarian endometriomas) the .Int J Fertil 32 of big adenoma endometrioides ovarii, 4:290 (1987)

76.Gudmundsson, J A, Ljunghall, S, Bergquist, C, Wide, L, Nillius, S J: increase (Increased bone turnover during gonadotropin releasing hormonesuperagonist-induced ovulation inhibition) the .J Clin Endocrinol Metabol 65 that bone upgrades in the ovulation inhibitory action that chorionic gonadotropin releasing hormone super agonist brings out, 1:159 (1987)

77.Steingold, K A, Cedars, M, Lu, J K H, Randle, D, Judd, H L, Meldrum D R: with long-acting chorionic gonadotropin releasing hormone agonist treatment endometriosis (Treatment of endometriosis with a long-acting gonadotropin-releasinghormone agonist) .Obstet Gynecol 69,3:49 (1987)

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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