CN1172675C - Progesterone antagonists useful for preparing medicaments for treating dysfunctional uterine bleeding - Google Patents
Progesterone antagonists useful for preparing medicaments for treating dysfunctional uterine bleeding Download PDFInfo
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- CN1172675C CN1172675C CNB951914561A CN95191456A CN1172675C CN 1172675 C CN1172675 C CN 1172675C CN B951914561 A CNB951914561 A CN B951914561A CN 95191456 A CN95191456 A CN 95191456A CN 1172675 C CN1172675 C CN 1172675C
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Abstract
The present invention relates to competitive progesterone antagonist (anti-gestagen) which is suitable for preparing medicine for curing dysfunctional uterine bleeding (metrorrhagia, menorrhagia, hypermenorrhea).
Description
Dysfunctional uterine bleeding (malfunction or undesired metrorrhagia, metrorrhagia and through excessive many, menorrhagia) be that pathologic is hemorrhage, organic variation in it and the uterus is (as intrauterine dysfunctional uterine bleeding (malfunction or undesired metrorrhagia, metrorrhagia and menorrhagia, menorrhagia) be that pathologic is hemorrhage, organic variation in it and the uterus is (as carcinoma of endometrium, muscular tumor, polyp etc.), with systematic blood coagulation disorders or pathologic gestation (as ectopic pregnancy, dangerous miscarriage) irrelevant (American College of Obstetricians andGynecologists, 1982).
Normal on average losing blood of menstruation is 30 milliliters, persistent period average out to 5 days.If menstrual blood loss is above 80 milliliters, then belong in hemorrhage (the Zahradnik HP of pathologic, (1992) Menstruation.In Kaser O et al. (editors) Gynakologie und Geburtshilfe.Band 1/2.Georg Thieme Verlag Strttgart, New York:7.31-7.51).
Metrorrhagia is defined as painless hemorrhage or pain is hemorrhage, and its menstruation and cycle are impossible orderly.In the persistent period amount of bleeding more than 7 days usually above 80 milliliters.
Menorrhagia is a kind of painless or pain menstruation, and the general cycle is 27～28 days, in the persistent period more than 7 days, occur surpassing thereupon 80 milliliters increase lose blood.
Menorrhagia is defined to be done painless or the pain menstruation, and the general cycle is 27-28 days, in 4-5 days, have surpass 80 milliliters increase lose blood.
Dysfunctional uterine bleeding (mainly being metrorrhagia and menorrhagia) is common for young women and climacteric women, and it is remaining usually to occur ovarian follicle dysmaturity, anovulation, corpus luteum remaining (Gelbk rperpersistenz) and follicle in these women.Modal reason in the incidence rate height of dysfunctional uterine bleeding and the formation women of child-bearing age's the gynecological's consulting.The diagnosis and treatment rate of dysfunctional uterine bleeding is 33% in the women of child-bearing age, in menopause edge phase (Perimenopause) and postmenopause women 69% (Mencaglia L., Perino A., Hamon J. (1987) Hysterescopy in perimenopausal and postmenopau sal women withabnormal uterine bleeding.J.Reprod.Med.32:577).
Multiformity to the applied treatment of dysfunctional uterine bleeding shows indirectly, the pathogeny of this disease it be unclear that and also not have effective therapeutic scheme so far, use at present gestagen (for example every day 10mg medroxyprogesterone acetate, every day 0.7-1.0mg norethindrone acetate, took respectively 10-14 days), high dose estrogen/gestagen compositions was through administration in 10-14 days, but also use nonsteroidal Zyklooxygegenasehemmern (for example: mefenamic acid, naproxen, ibuprofen) and the LHRH-synergist treat (Cowan BD (1992) Dysfunctional uterine bleeding:Clues to efficacious Approaches.InAlexander NJ, d ' Arangues C (editors), Steroid hormones and uterinebleeding.AAAS Press, 1922:9-17).
With the treatment of the estrogen/gestagen compositions of high dose with known cardiovascular danger (mainly being the thromboembolism disease).If the drug treatment curative effect of dysfunctional uterine bleeding is bad, then recommend to use surgical method (uterus K ü rretage, hysterectomy).Dysfunctional uterine bleeding becomes the second common indication (LeeNC of stepchild palace muscular tumor this operation afterwards, Dicker RC, Rubin GL, Ory HW (1984) Confirmation of the preoperat-ive diagnosis for hysterctomie.Am.J.Obstet.Gynecol., 150:283).It should be noted that, although there is multiple Drug therapy possibility approach, the number of carrying out uterectomy because of dysfunctional uterine bleeding (especially premenopause women in) descend in recent years (Lumsden MA, (1990) Menorrhagia-the cost and scope of treatment.InShaw RW. (editor) Dysfunctional uterine bleeding.The ParthenonPublishing Group:85-96).Hysterectomy is with immeasurable danger.Mortality rate behind the hysterectomy count per 100,000 philtrums have 6 (Wingo etc., 1985).
Task of the present invention is, a kind of medicine that is used for described indication is provided, the undesirable side effects that it can make the malfunction stopped bleeding and not have or occur during only with seldom use high dose estrogen/gestagen preparation.
The medicine that uses progesterohe antagonists (antigestagens) preparation of competing to be used for above-mentioned indication has made a kind of so new pharmaceutical formulation.
Antigestagens, when in the luteal phase administration, can bring out hemorrhage (the Nieman LK that is similar to menstruation, Healy DL, Spitz IM, Nisula BC, Merriam GR, BardinCW, Loriaux DL, Chrousos GP (1985) Use of single doses of theantiprogesterone steroid RU 486 for induction of menstruation innormal women.In Baulieu EE; Segal SJ (editors): The antiprogestinsteroid RU 486 and human fertility control.Plenum Press, New York andLondon:279-285).Experiment to primates shows, hemorrhage (the Chilik CF of eliminating fully that causes endometrial tissue that antigestagens brings out, Hsiu JG, Acosta AA, van UemJFHM, Hodgen GD (1986) RU 486-induced Menses in cynomolgusmonkeys:uniformity of endometrial sloughing.Fertil Steril 45:708).Decline by Progesterone in a normal cycle or to bring out hemorrhage accurate mechanism by the treatment of antigestagens not clear.The cancellation that is assumed to Progesterone causes inducing of uterus prostaglandin, and this has brought out hemorrhage (Zahradnik HP, (1992) loc.cit.).
Also known Progesterone is suppressed at the synthetic of Endothelin in the uterus and stimulates its enzyme to decompose (Casey ML, MacDonald PC (1992) Modulation of endometrial bloodflow:Regulation of endothelin-1 biosynthesis and degradation in humanendometrium.In Alexander NJ, d ' Arcangues C (editors), Steroidhormones and uerine bleeding.AAAS Press, 1992:210-224).Endothelin is considered to pressor endogenous substance having great ability.The release that is assumed to the Endothelin that increases that causes because Progesterone descends when normal cycle finishes has caused the contraction of endometrium spiral artery and has therefore brought out menses (Casey and Mac Donald (1992) loc.cit.).
Find now that based on by uterotonic reinforcement with rely the vasoconstriction to the caused endometrium tremulous pulse of myometrial effect in this, it is hemorrhage that the progesterohe antagonists of competition unexpectedly can make dysfunctional uterine bleeding stop.Under the situation of dysfunctional uterine bleeding, because the decline of incomplete or lasting oversize Progesterone causes the activation of the vasoconstrictive mechanism of endometrium tremulous pulse to seem improper.
Occur when when using the progesterohe antagonists of competition, not observing with high dose estrogen/gestagen preparation, undesirable side effects.This can be regarded as the material that has only insignificant side effect.
It is unknown so far with antigestagens dysfunctional uterine bleeding being treated in normal cycle.To this indication usually attention is placed in the application of gestagen (Cowan1992, loc.cit.).With low dosage contain the oral contraceptive of estrogen and gestagen the time the insufficient menstrual cycle control that causes based on the low dosage state and BB (Durch-bruch blutungen) phenomenon that occurs has reduced, this is described among International Patent Application WO-A-93/17686.The active compound of Progesterone antagonism combine the medicament that is used for that preparation is used for induced labor, gestation is interrupted and treats gynecological's obstacle (dysmenorrhea, endometriosis) separately or with the estrogen antagonist active compound have been described in EP-A-03110541.
The medicament of the present invention's preparation is suitable for treating the dysfunctional uterine bleeding of form of ownership, as metrorrhagia, menorrhagia and menorrhagia.
PA as competition considers the chemical compound that all are such, and these chemical compounds self or its metabolite are blocked the effect of Progesterone to its receptor, for example following steroid:
11 β-((4-N, N-dimethylamino)-phenyl)-17 beta-hydroxyl-17 alphas-propinyl-4,9 (10)-female diene-3-ketone (RU-38486),
11 β-((4-N, N-dimethylamino)-phenyl)-17 beta-hydroxies-18-methyl-17 alpha-propynyl-4,9 (10)-female diene-3-ketone and
11 β-((4-N, N-dimethylamino)-phenyl)-17a beta-hydroxyl-17 a alpha-propynyl-D-is with-4,9 (10), 16-estratriene-3-ketone (all in EP-A-0057115),
In addition
11 β-P-anisyl-17 beta-hydroxyl-17 alphas-acetenyl-4,9 (10)-female diene-3-ketone (Steroids 37 (1981), 361-382),
11 β-(4-acetylphenyl)-17 beta-hydroxyl-17 alphas-(third-1-alkynyl)-4; 9 (10)-female diene-3-ketone (EP-A0190759); and 11 beta-aromatics-14 β-female diene and triolefin of in EP-A0277676, describing; 19; the steroid of 11 β-bridge joint; it is the theme of EP-A-0283428; 11 beta-aromatics that in EP-A-0289073, propose-6-alkyl (or 6-alkenyl or 6-alkynyl)-female diene and-pregnant diene and EP-A-0321010 in 10 β-H-steroid of known 11 beta-aromatics-7-methyl (or 7-ethyl)-female diene and EP-A-0404283, for example (Z)-11 β-(4-(dimethylamino) phenyl)-17 beta-hydroxyl-17 alphas-(3-hydroxyl-1-acrylic)-female-4-alkene-3-ketone.
In addition, the typical typical example of the progesterohe antagonists of the used competition of the present invention is as also having:
11 β-(4-dimethylamino phenyl)-17 Alpha-hydroxy-17 β-(3-hydroxyl-propyl group)-13 Alpha-Methyls-4,9-diene (gonadien)-3-ketone (EP-A-0190759);
11 β, 19-(4-acetylphenyl)-17 beta-hydroxyl-17 alphas-(3-hydroxyl third-1-(Z)-thiazolinyl)-4,9 (10)-female diene-3-ketone (EP-A-0190759);
11 β, 19-(4-(cyano-phenyl)-17 beta-hydroxyl-17 alpha-(3-hydroxyl third-1-(Z)-thiazolinyl)-4-androstene-3-ketone and
11 β, 19-(4-(3-pyridine radicals)-neighbour-phenylene)-17 beta-hydroxyl-17 alphas-(3-hydroxyl third-1-(Z)-thiazolinyl)-4-androstene-3-ketone (both is in WO-A-93/23020).
By the present invention with PA to the treatment of dysfunctional uterine bleeding-as to carry out the treatment (1 day to maximum 10 days) of short time with the daily dose of the progesterohe antagonists of 1-600mg competition every day just enough.
The preferred daily dose of the present invention is 5-400mg.Especially preferred administration every day 50-400mg11 β-(4-dimethylamino phenyl)-17 Alpha-hydroxy-17 β-(3-hydroxyl-propyl group)-13 Alpha-Methyls-4,9-diene-3-ketone (onapristone) or 50-400mg (Z)-11 β-(4-(dimethylamino) phenyl)-17 beta-hydroxyl-17 alphas-(3-hydroxyl-1-acrylic)-female-4-alkene-3-ketone.
For making stopped bleeding, the single administration of the progesterohe antagonists of competing in described dosage range is just enough, particularly the onapristone in selecting especially preferred daily dose scope for use or (Z)-11 during β-(4-(dimethylamino) phenyl)-17 beta-hydroxyl-17 alphas-(3-hydroxyl-1-acrylic)-female-4-alkene-3-ketone.Otherwise just continue treatment until stopped bleeding, this has just occurred at 5 days the latest as a rule.Both can carry out acute treatment by the present invention and also can hemorrhagely carry out preventative control these to dysfunctional uterine bleeding.
By the present invention, the progesterohe antagonists of competition for example can be local, the intestines and stomach or parenteral administration.Especially consider tablet, dragee, capsule, pill, suspending agent or solution for preferred the intestines and stomach administration, they are to use with usual way to cover additive commonly used in the Lun Shi preparation and carrier mass preparation.Then consider for example vaginal suppository for local application.
Following embodiment has illustrated the preparation of the progesterohe antagonists of the competition that is used for purposes of the present invention with way of example.Other progesterohe antagonists is preparation fully in a similar manner, wherein, respectively contains the aforementioned amount that sees fit in preparation.
Example of formulations:
100.0mg 11 β-((4-N, N-dimethylamino)-phenyl)-17 Alpha-hydroxies-17b-(3-hydroxyl
The base propyl group)-13 Beta-methyls-4,9-diene-3-ketone
140.5mg lactose
69.5mg corn starch
2.5mg polyvinylpyrrolidone
2.0mg the silica gel of high degree of dispersion
0.5mgMagnesium stearate
315.0mg the gross weight of the tablet that in tablet machine, prepares in due form.
Embodiment 1
By the acute treatment of disposable onapristone administration to metrorrhagia
Women to the dysfunctional uterine irregular bleeding uses the disposable oral medication of 200-400mg onapristone.Preferably in the treatment luteal phase of menstrual cycle.This treatment can make stopped bleeding in 2-4 days.
Embodiment 2
By disposable onapristone administration to menorrhagia and menorrheal acute treatment.
To menorrhagia and menorrheal women the 28th day of menstrual cycle or at hemorrhage first day disposable oral 200-400mg onapristone.What this treatment caused normal intensity (about 30 milliliters) and persistent period (about 5 days) is similar to the hemorrhage of menstruation.
Embodiment 3
By the prophylactic treatment of disposable onapristone administration to metrorrhagia
To the women of dysfunctional uterine irregular bleeding every 28 days with 200-400mg onapristone oral medication.This treatment causes (about 30 milliliters) and the appearance that is similar to the hemorrhage of menstruation and has stoped metrorrhagia of persistent period (about 5 days) of normal intensity, and this treatment will continue 3-6 menstrual cycle.
Embodiment 4
By disposable onapristone administration prophylactic treatment menorrhagia and menorrhagia.
To menorrhagia and menorrheal women every 28 days with 200-400mg onapristone oral medication.This treatment causes being similar to the hemorrhage of menstruation and having stoped menorrhagia and menorrheal appearance of normal intensity (about 30 milliliters) and persistent period (about 5 days).This treatment continues 3-6 menstrual cycle.
Embodiment 5
By onapristone administration repeatedly to the acute treatment of metrorrhagia
Women to the dysfunctional uterine irregular bleeding uses 200-400mg/ days onapristone oral medications until stopped bleeding, and administrations are ten days at most.Preferably at the begin treatment luteal phase of menstrual cycle.
Embodiment 6
By onapristone administration repeatedly menorrhagia and menorrhagia are carried out acute treatment
To menorrhagia and menorrheal women the 28th day of menstrual cycle or hemorrhage first day with 200-400mg/ days onapristone oral administrations until stopped bleeding, administrations are 10 days at most.This treatment causes being similar to the hemorrhage of menstruation and having stoped losing blood of increasing of normal intensity (about 30 milliliters) and persistent period (about 5 days).
Embodiment 7
By onapristone administration prophylactic treatment metrorrhagia repeatedly
Women to the dysfunctional uterine irregular bleeding used the longest 10 day time of 200-400mg/ days onapristone oral medications in per 28 days.What this treatment caused normal intensity (about 30 milliliters) and persistent period (about 5 days) is similar to the hemorrhage of menstruation.This treatment continues 3-6 menstrual cycle.
Embodiment 8
Multiple dosing by onapristone is to menorrhagia and menorrheal prophylactic treatment
Menorrhagia and menorrheal women are used 200-400mg/ days onapristone the longest 10 day time of oral medication in per 28 days.This treatment causes being similar to the hemorrhage of menstruation and having stoped menorrhagia and menorrheal appearance of normal intensity (about 30 milliliters) and persistent period (about 5 days).This treatment continues 3-6 menstrual cycle.
With the progesterohe antagonists of competition when by the present invention the dysfunctional uterine irregular bleeding being treated, the not only observed hemorrhage persistent period has shortened, and intensity is promptly lost blood and also significantly reduced.
Claims (5)
1. the application of Jing Zheng progesterohe antagonists is used to prepare the medicine for the treatment of dysfunctional uterine bleeding, and it is excessive that described dysfunctional uterine bleeding is selected from metrorrhagia, menorrhagia and menstruation.
2. according to the application of the progesterohe antagonists of the competition of claim 1, the progesterohe antagonists of wherein said competition is
11 β-((4-N, N-dimethylamino)-phenyl)-17 beta-hydroxyl-17 alphas-propinyl-4,9 (10)-female diene-3-ketone,
11 β-((4-N, N-dimethylamino)-phenyl)-17 beta-hydroxies-18-methyl-17 alpha-propynyl-4,9 (10)-female diene-3-ketone,
11 β-((4-N, N-dimethylamino)-phenyl)-17a beta-hydroxyl-17 a alpha-propynyl-D-is with-4,9 (10), 16-estratriene-3-ketone,
11 β-right-anisyl-17 beta-hydroxyl-17 alphas-acetenyl-4,9 (10)-female diene-3-ketone,
11 β-(4-acetylphenyl)-17 beta-hydroxyl-17 alphas-(third-1-alkynyl)-4,9 (10)-female diene-3-ketone,
11 β-(4-dimethylamino phenyl)-17 Alpha-hydroxy-17 β-(3-hydroxyl-propyl group)-13 Alpha-Methyls-4,9-diene 3-ketone,
(Z)-11 β-(4-(dimethylamino) phenyl)-17 beta-hydroxyl-17 alphas-(3-hydroxyl-1-acrylic)-female-4-alkene-3-ketone,
11 β, 19-(4-acetylphenyl)-17 beta-hydroxyl-17 alphas-(3-hydroxyl third-1-(Z)-thiazolinyl)-4,9 (10)-female diene-3-ketone,
11 β, 19-(4-(cyano-phenyl)-17 beta-hydroxyl-17 alpha-(3-hydroxyl third-1-(Z)-thiazolinyl)-4-androstene-3-ketone or
11 β, 19-(4-(3-pyridine radicals)-neighbour-phenylene)-17 beta-hydroxyl-17 alphas-(3-hydroxyl third-1-(Z)-thiazolinyl)-4-androstene-3-ketone.
3. according to the application of the progesterohe antagonists of the competition of claim 1, wherein be used to prepare described medicine with the amount that every day, dosage device comprised the progesterohe antagonists of 1-600mg competition.
4. according to the application of claim 3, wherein every day, dosage device comprised the progesterohe antagonists that 50-400mg competes.
5. according to the application of claim 3, intact 50-400mg 11 β-(4-dimethylamino phenyl)-17 Alpha-hydroxy-17 β-(3-hydroxyl-propyl group)-13 Alpha-Methyls-4,9-diene-3-ketone or 50-400mg (Z)-11 β-(4-(dimethylamino) phenyl)-17 beta-hydroxyl-17 alphas-(3-hydroxyl-1-acrylic)-female-4-alkene-3-ketone of comprising of dosage list every day wherein.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB951914561A CN1172675C (en) | 1995-02-02 | 1995-02-02 | Progesterone antagonists useful for preparing medicaments for treating dysfunctional uterine bleeding |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB951914561A CN1172675C (en) | 1995-02-02 | 1995-02-02 | Progesterone antagonists useful for preparing medicaments for treating dysfunctional uterine bleeding |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1140993A CN1140993A (en) | 1997-01-22 |
| CN1172675C true CN1172675C (en) | 2004-10-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB951914561A Expired - Lifetime CN1172675C (en) | 1995-02-02 | 1995-02-02 | Progesterone antagonists useful for preparing medicaments for treating dysfunctional uterine bleeding |
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| Country | Link |
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| CN (1) | CN1172675C (en) |
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1995
- 1995-02-02 CN CNB951914561A patent/CN1172675C/en not_active Expired - Lifetime
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| Publication number | Publication date |
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| CN1140993A (en) | 1997-01-22 |
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