CN104997789A - Compositions and methods for suppressing endometrial proliferation - Google Patents

Abstract

The invention relates to compositions and methods for suppressing endometrial proliferation. The subject matter of the instant invention is pertinent to the field of hormone therapy. More specifically, the subject matter of the instant invention concerns methods of treating estrogen-dependent conditions such as endometrial hyperplasia and endometrial cancer in a female undergoing estrogen and/or selective estrogen receptor modulator (SERM) therapy. The instant invention is also relevant to the treatment of pain associated with endometriosis. The invention also discloses a composition including progestone receptor for implementing the method. The embodiment of the invention also discloses a novel optional progestone adjustment agent method for implementing the disclosed therapy.

Description

For suppressing compositions and the method for endometrial hyperplasia

The divisional application of the application's to be the applying date be Chinese patent application 200780039426.6 " for suppressing compositions and the method for endometrial hyperplasia " on October 24th, 2007.

Technical field

The present invention relates to compositions and the method for suppressing endometrial hyperplasia.More particularly, the present invention relates to the compositions comprising one or more progesterone antagonist for suppressing endometrial hyperplasia.

The cross reference of related application

This application claims the priority of following patent application: in the 60/862nd of submission on October 24th, 2006, No. 632 U.S. temporary patent applications and on January 17th, 2007 submit to the 60/885th, No. 348 U.S. temporary patent applications, apply for described in each being all incorporated herein by reference.

Background technology

Estrogen is the necessary one group of hormone of various physiological processes, and described physiological process comprises the growth of uterus and mammary gland, the maintenance of bone density, and the cardiovascular protective effect risen by its positivity effect for lipid conditions.Estrogenic effect is combined by its estrogen receptor in core and is mediated.According to classical model, after conjugated estrogen hormone, the estrogen receptor do not captured needs to interact with the DNA sequence in the promoter of estrogen response gene.The estrogen receptor that DNA combines just is regulating or the transcribing of these genes of negative regulator.

Known estrogen has high proliferation effect for breast and uterine cancer cell.Such as, show, use nonantagonistic (unopposed) estrogen to menopausal women and caused endometrial hyperplasia and carcinoma of endometrium.On the contrary, progesterone has resisted estrogen-dependent endometrial hyperplasia and cancer development effectively.Therefore, in order to resist the effect of unopposed estrogens, progestogen have become a part of Hormone Replacement Therapy (HRT) clinically.But recently, the large-scale clinical trials from Women ' s Health Initiative indicates conjugated estrogens and Medroxyprogesterone Acetate adds the risk developing into cardiovascular disease, apoplexy, pulmonary infarction and breast carcinoma.In addition, the experimental data in the macaque of surgical menopause shows, compared with independent estrogen, the combined therapy of estrogen and progesterone causes higher levels of mammary gland to be bred and hypertrophy.Show that administering drug combinations progesterone and discontinuity are hemorrhage relevant, this further restricts its suitability of activating agent as the estrogenic high proliferation effect of opposing.

The estrogen-dependent being known in the art a lot of compounds affect estrogen receptor activates.According to many factors, these compounds can be completely estrogenic, because they simulate estrogen, completely antiestrogenic, because they block estrogenic effect, or their certain position that can mediate.The compound showing mixed estrin and estrogen antagonist character is called selective estrogen receptor modulators (SERM).SERM applies its estrogen or estrogenic antagonist with tissue specific way.This tissue-specific mechanism it be unclear that, but may in particular to checking altogether and the raising of co-activation albumen, and the relative expression levels of these albumen can change between organization type, and the tissue specific expression of estrogen receptor isotype α and β.Estrogen receptor alpha is activator, and erss suppresses estrogen receptor alpha active by forming heterodimer with suppression estrogen receptor alpha.

The double activity of SERM provides several possibility advantage in women.The estrogenic properties of SERM can be used for the disease such as osteoporosis treating or prevent to be caused by estrogen deficiency, and simulates some undesirable effect estrogenic.On the contrary, the estrogenic antagonist of SERM can be used for prevention or disease therapy such as breast carcinoma, and wherein estrogen activity is undesirable.However, shown that endometrial hyperplasia is treated relevant with SERM, which has limited its application.

Such as, shown that SERM tamoxifen has estrogenic antagonist in mammary gland, tamoxifen blocks estrogenic proliferation function in mammary gland, and finds that there is the breast carcinoma being beneficial to some types for the treatment of afterwards.On the other hand, tamoxifen shows estrogen action for bone and uterus, and relevant with the sickness rate of the increase of endometrial hyperplasia and carcinoma of endometrium, which has limited it as antiestrogenic application.

The preliminary test carried out in primate seems to show, gestation material has endometrial antiproliferative effect.But, worry the effect due to unopposed estrogens, can endometrial hyperplasia be caused with gestation Substance treatment for a long time.The several nearest research carried out in adult female shows, during with the long-term treatment of high dose gestation material, there occurs endometrial thickness, assuming that this is the result of nonantagonistic estrogen activity, seem such endometrial thickness does not occur under low dosage.

Still need to be suitable for long term administration, resist estrogenic proliferation function, keep estrogen for the therapeutic scheme of the beneficial effect of health simultaneously.

Summary of the invention

The invention provides the method suppressing endometrial hyperplasia, described method comprises to there being the patient of these needs to use the progesterone antagonist suppressing endometrial tissue effective dose.The patient having this to need suffers from endometriotic women.Progesterone antagonist can be pure gestation material or selectivity progesterone receptor modulator (SPRM).In preferred embodiments, progesterone antagonist has low affinity for glucocorticoid receptor (GR).In another preferred embodiment, use progesterone antagonist to women and reduce progesterone level luteal phase in women.In another preferred embodiment, use progesterone antagonist to women and significantly do not reduce estrogen level in women.

In yet another aspect, the invention provides estrogen and SERM treatment in use progesterone antagonist to prevent the method for estrogen dependent conditions.More specifically, the present invention is to be enough to suppress the dosage of women's Endometrial hypertrophy to use progesterone antagonist, and described women is just standing the therapeutic scheme comprising administration estrogen or SERM.Such as, patient can be seriously by the postmenopausal women of hormone replacement therapy.In yet another aspect, the invention provides and use progesterone antagonist to prevent the method for endometrial hyperplasia and/or carcinoma of endometrium development in estrogen and SERM treatment.Progesterone antagonist can be gestation material or selectivity progesterone receptor modulator (SPRM), as long as progesterone antagonist uses effectively to suppress the amount of endometrial hyperplasia.

In yet another aspect, the invention provides the method using progesterone antagonist to treat the pain relevant with endometriosis.Progesterone antagonist may be used for the long-term treatment of the pain relevant with endometriosis.

Accompanying drawing is sketched

Fig. 1 depicts the effect of selectivity progesterone receptor modulator for rat blood serum hydrocortisone.

Fig. 2 depicts the dose-dependent effects of CDB-4124 for rat blood serum hydrocortisone.

Detailed description of the invention

Term " effective dose " refers to the amount of the compositions active component being enough to reach required effect, and required effect can be such as suppress endometrial hyperplasia or treat the pain relevant with endometriosis.

Term " selectivity progesterone receptor modulator " refers to the compound affecting progesterone receptor function with tissue specific way.Such compound (such as in uterus) in some tissue plays progesterone receptor antagonists, and in its hetero-organization, plays progesterone receptor agonist.

Term " treatment " refers to treatment and prevents or prevention property means, and wherein target is prevention or slows down (alleviating) undesirable physiological change or obstacle.For object of the present invention, clinical effectiveness that is useful or that expect includes but not limited to mitigation symptoms, the degree palliated a disease, stable (namely not worsening) morbid state, postpone or slow down progression of disease, improve or the state that palliates a disease, and to extenuate (partially or completely), can to detect or undetectable." treatment " can also refer to, and compared with the survival period desired by not accepting to treat, extends survival period.Need the individuality for the treatment of to comprise the individuality suffering from disease or disease, and have tendency to suffer from the individuality of disease or disease, or wherein wish the individuality of prevention disease or disease.

Term " progesterone agonistic " refers in conjunction with progesterone receptor, and simulates the compound of this natural hormone effect.

Term " progesterone antagonist " refers in conjunction with progesterone receptor, and suppresses the compound of progesterone effect.

The term " suppression " used when breeding about endometrial tissue herein refers to, relative to endometrial tissue untreated under similarity condition, by using progesterone antagonist, the mitosis propagation of endometrial tissue is suppressed, and has any different with the cell death via such as apoptosis.Can in uterine cell system, by such as compare with the cell of progesterone antagonist process with contrast bromodeoxyribouridine (BrdU) in (untreated) cell mix measure progesterone antagonist in uterus film mitosis breed in inhibitory action.

Refer to " significantly not reducing " about the term used during female hormone herein, during using the present composition, hormonal readiness remained in normal range.Therefore, hormonal readiness can occur to reduce to a certain degree, as long as hormonal readiness remained in normal range.

Refer to " significantly not increasing " about the term used during female hormone herein, during using the present composition, hormonal readiness remained in normal range.Therefore, hormonal readiness can occur to increase to a certain degree, as long as hormonal readiness remained in normal range.

The present invention relates to effectively to suppress the dosage of endometrial hyperplasia to use progesterone antagonist.These methods come from following unexpected discovery, and namely some progesterone antagonist show reverse dose-dependant effect for endometrial hyperplasia, and are remained in normal range by estrogen level.Specifically, have been found that, gestation material/the SPRMCDB-4124 of long term administration high dose inhibits endometrial hyperplasia, and comparatively low dosage can not suppress endometrial hyperplasia, even be tending towards promoting endometrial hyperplasia, although arrived the estrogen of similar level at high and low observed at doses.Consider following situation, this is wonderful especially: as confirmed below, gestation material/SPRM RU 486 can not suppress endometrial proliferation at high dose, and there is several report recently, the gestation material of long term administration high dose facilitates endometrial hyperplasia, assuming that this is caused by the effect due to unopposed estrogens.The present invention have also demonstrated progesterone antagonist can unexpectedly be used for the treatment of the pain relevant with endometriosis.

Described below, comprising the treatments period more than effective dosage progesterone antagonist every day 6 months periods, endometrial hyperplasia suppresses the purposes confirming such progesterone antagonist, wherein expects chronic/long term administration.In this respect, the inventive method can comprise the compositions of progesterone antagonist used and comprise and be enough to the amount suppressing endometrial hyperplasia, and the administration phase is at least 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31 day or more sky.Compositions can also interimly the administration of at least 1,2,3,4,5,6,7,8,9,10,11,12 month or more month be used.Compositions can also be used the administration at least 1,2,3,4,5,6,7,8,9,10 year or more year is interim.During the administration phase, compositions can daily, or regularly be used, and uses such as every other day, every other month etc.Compositions can also intermittently be used.Such as, then using compositions the administration of 1,2,3,4,5 month or more month is interim, is then one section of withdrawal time, is the administration phase of 1,2,3,4,5 month or more month afterwards again, etc.

" intermittence is used " refers to, the administration phase of the progesterone antagonist of administering therapeutic effective dose, is then one section of withdrawal time, is another administration phase after this withdrawal time, etc.

" withdrawal time " refers to, the time once a day, once in a week, monthly or between it stops using progesterone antagonist.The time of withdrawal time can be longer or shorter than the administration phase than the administration phase, but always long than the dosing interval during the administration phase.Such as, when the administration phase comprise once a day, weekly or mensal administration time, withdrawal time is at least 2 days, at least 8 days or at least 32 days respectively.Therefore, withdrawal time can be at least about 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32 days or more skies.

In one embodiment, intermittently use the present composition, individuality experiences menstruation during at least one withdrawal time like this.Estimate this method avoid with endometrial thickness or stagnate relevant detrimental effect, these detrimental effects can the extended treatment that carries out of adjoint progesterone antagonist, such as, play that speckle, discontinuity are hemorrhage, endometrium high hypertrophy or carcinoma of endometrium.At least one, preferably the length of each withdrawal time is enough to allow Individual Experience menstruation.More preferably, individuality experiences menstruation during each withdrawal time.In particularly preferred embodiments, using compositions once a day the administration phase of 4 months, is then withdrawal time, and individuality experiences menstruation during withdrawal time, is then another administration phase of 4 months, etc.

Optionally, gonadotropin-releasing hormone (GnRH) agonist or antagonist can be used during withdrawal time, to accelerate endometrially come off and regenerate.The limiting examples of GnRH agonist comprises naphthalene method Rayleigh, buserelin, leuprorelin, triptorelin, goserelin, [DLys ⁶] GnRH, [DAla ⁶] GnRH etc.The limiting examples of GnRH antagonist comprises histrelin, abarelix, and in U.S. patent 4,409,208,4,547,370,4,565,804,4,569,927 and 4,619, disclosed in 914 those, described full patent texts is incorporated herein by reference.

Optionally, progestogen can be used to obtain menorrhea in patients during withdrawal time.Use progestogen and preferably cause such progesterone situation, naturally increasing and decline of its simulation intermenstrual period progesterone.Such therapeutic scheme is well known to the skilled person.During withdrawal time, using progestogen can also provide except the estrogenic antagonist by using except effect that progesterone antagonist realizes, therefore can contribute to treatment estrogen dependent conditions such as endometrial thickness.The limiting examples of progestogen comprises medrogestone, medroxyprogesterone, megestrol, norethindrone, progesterone, hydroxyprogesterone, acetoxypregnenolone, allylestrenol, cyproterone, desogestrel, dimethisterone, ethisterone, oxalic acid etynodiol, gestadene, lynestrenol etc.

In one embodiment, use to suffering from endometriotic female patient the compositions comprising the progesterone antagonist suppressing endometrial hyperplasia effective dose.In the relevant embodiments, the compositions comprising progesterone antagonist is administered to the amount of effectively treating the headache relevant with endometriosis suffers from endometriotic women.Such as, use progesterone antagonist and can alleviate the pain relevant with endometrial impairment.Pain is endometriotic the most common and cause debilitating symptom, and is the medicine of this disease and the principal indication of operative treatment.Pain can show as dysmenorrhea, pelvic pain, back pain, abdominal pain, mammary gland pain, dyspareunia etc.Use the size that progesterone antagonist can also reduce endometrial impairment.Be used for the treatment of endometriotic scheme at present and comprise GnRH agonist, it induces false menolipsis state by suppressing ovarian estrogen secretion, therefore can not be used for long term administration because this can cause loss of bone density, whole health calcium loss and other osteoporosis sample side effect.The present composition can chronic administration, and significantly can not reduce estrogen level.

In another embodiment, the invention provides the method for the treatment estrogen dependent conditions relevant with current hormone therapy, described current hormone therapy adopts estrogenic compound such as estrogen or SERMS, and described method comprises the progesterone antagonist of co-administered effective dose to suppress endometrial hyperplasia. and the estrogen dependent conditions relevant with current estrogen/SERM hormone therapy includes but not limited to endometrial hyperplasia and carcinoma of endometrium..In this respect, progesterone antagonist can before estrogen or SERMS, period or afterwards, the part as associating hormone therapy scheme is used.

In another embodiment, the invention provides hormone replacement method, described method comprises progesterone antagonist and the estrogenic compound of using effective dose to menopause or postmenopausal women, and wherein the amount of progesterone antagonist can effective inhibitor estrogen dependent conditions.Estrogenic compound can be estrogen or SERM.Estrogenic compound can be used before progesterone antagonist.Use afterwards, or use with progesterone antagonist simultaneously.Estrogen dependent conditions can be but be not limited to endometrial hyperplasia, endometrium high hypertrophy or carcinoma of endometrium.

In the preferred embodiment of each method of the present invention, use progesterone antagonist to women and significantly do not reduce estrogen level in women.Therefore, the invention provides the advantage being better than being used for the treatment of endometriotic treatment at present, described current treatment often adopts gonadotropin-releasing hormone (GnRH) agonist such as (leuprorelin acetate).

In another preferred embodiment of each method of the present invention, using progesterone antagonist to women does not significantly increase progesterone level in women.More preferably, use progesterone antagonist to women and reduce progesterone level in women, particularly luteal phase progesterone level.

In another preferred embodiment of each method of the present invention, progesterone antagonist shows the affinity for glucocorticoid receptor (GR) of reduction.More preferably, progesterone antagonist is progesterone antagonist at least 1.5 times of binding affinity of glucocorticoid receptor (GR) for the binding affinity of progesterone receptor.

Any known progesterone antagonist with above-claimed cpd feature all can be used for implementing the present invention by those skilled in the art.Useful especially compound is included in U.S. patent 6,900, disclosed in 193 those, this full patent texts is incorporated herein by reference, and in U.S. patent 6,861, disclosed in 415 those, this full patent texts is incorporated herein by reference, and it is the nor-pregnane of 19-that the 21-with following general formula replaces:

Wherein:

X can be such as alkyl, alkenyl, alkynyl, hydrogen, halogen, an alkyl amino or dialkyl amido, such as N, N-dimethylamino;

R ₁it can be such as O, NOH or NO-methyl;

R ₂can be such as hydrogen or acetyl group; And

R ₃can be such as methoxyl group, formoxyl oxygen base, acetoxyl group, acyloxy, S-alkoxyl, acetyltheonyl (theonyl), glycinate (glycimate), vinyl ethers, acetoxy-methyl, methyl carbonic, halogen, methyl, hydroxyl and ethyoxyl.

The example of the nor-pregnane of 19-that 21-replaces includes but not limited to compound disclosed in following 24 kinds.

1.CDB-4247 (21-propiono Oxy-1 7 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

2.CDB-4361 (21-vinyl ethers-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

3.CDB-4059 (21-acetoxyl group-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

4.CDB-4124 (21-methoxyl group-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

5.CDB-4031 (21-bromo-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

6.CDB-3876 (21-chloro-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

7.CDB-4058 (21-fluoro-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

8.CDB-4030 (21-methyl-17-alpha-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

9.CDB-4152 (21-hydroxyl-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

10.CDB-4167 (21-ethyoxyl-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

11.CDB-4101 (21-methoxyl group sulfenyl-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

12.CDB-4110 (21-acetone solvate-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

13.CDB-4111 (21-BMD-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

14.CDB-4125 (21-(Cyp*-hydroxyl)-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

* Cyp=3-cyclopentylpropanoyl oxygen base-

15.CDB-4205 (3-hydroxyl amino-21-methoxyl group-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

16.CDB-4206 (3-hydroxyl amino-21-acetoxyl group-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

17.CDB-4226 (3-hydroxyl amino-21-ethyoxyl-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

18.CDB-4262 (3-Methoxyamino-21-ethyoxyl-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

19.CDB-4223 (21-methyl mercapto-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

20.CDB-4119 (4-benzoin-21-Acetylsulfanyl-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

21.CDB-4239 (4-benzoin-21-methoxyl group-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

22.CDB-4306 (21-glycinate-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

23.CDB-4352 (nor-pregnane-4,9-diene-3, the 20-diketone of 21-cyano group sulfenyl-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19), has following structural formula:

24.CDB-4362 (21-Methoxyacetyl-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone), has following structural formula:

11 β-mono-demethylation derivant (namely wherein X is the compound of N-methylamino) of disclosed compound 24 can be used in particular for implementing the present invention above.In this respect, confirm CDB-4453 (21-methoxyl group-17 α-acetoxyl group-11 β-(4-N-methylamino phenyl) nor-pregnane-4 of-19-, 9-diene-3,20-diketone), single demethyl derivant of CDB-4124 has the Anti-glucocorticoid Activity lower than its parent compound.The people such as Attardi, 2002, Mo1.Cell.Endocrin.188:111-123, its content is incorporated herein by reference.

Although above formula compound and single demethylation derivant thereof are preferred, any progesterone antagonist can be used for implementing the present invention, because it has antagonist action for progesterone receptor.Preferably, progesterone antagonist has one or more following features: low Anti-glucocorticoid Activity, minimum estrogen and antiestrogenic, and does not significantly increase progesterone level.

Gestation material used in the present invention includes but not limited to asoprisnil (benzaldehyde, 4-[(11 β, 17 β) female-4, the 9-diene-11-bases of-17-methoxyl group-17-(methoxy)-3-oxo]-1-(E)-oxime; J867), its metabolite J912 (4-[17 beta-hydroxyl-17 alphas-(methoxy)-3-oxo female-4,9-diene-11 beta-yl] benzaldehyde-(1E)-oxime), and other compounds described in DE 4332283 and DE 4332284; CDB-2914 (17 α-acetoxyl group-11 β-(4-N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone) and the people such as Stratton, other compounds described in 2000, Hu.Reprod.15:1092-1099; The people such as JNJ-1250132 and Allan, 2006, other compounds described in steroid 71:949-954; The people such as Zhi, 5-aryl-1,2-dihydro chromene also [3, the 4-f] quinoline described in 1998, J.Med.Chem.41:291-302; The U.S. patent 6,509,334,6,566,358 and 6,713 of the people such as Zhang, the Isosorbide-5-Nitrae-dihydro-benzo [d] [1,3] described in 478 piperazine-2-ketone; The U.S. patent 6,391 of the people such as Fensome, 1, the 3-dihydro-indol-2-one described in 907; The U.S. patent 6,417 of the people such as Ulrich, 2, the 3-dihydro-1H-indole described in 214; The U.S. patent 6,380 of the people such as Zhang, the benzimidazolone compound described in 235 and analog thereof; The U.S. patent 6,339 of the people such as Collins, 2,1-benzisothiazole 2, the 2-dioxide described in 098; The U.S. patent 6,306,851 and 6,441 of the people such as Santilli, the ring aminocaproic acid ester described in 019 and cyclic amide compounds; The U.S. patent 6,369 of the people such as Zhang, the ring urea described in 056 and Cydic amide derivatives; And the quinazolinone described in the U.S. patent 6,358,948 of the people such as Zhang and benzo oxazine derivatives.

Other gestation materials used in the present invention include but not limited to (6 α, 11 β, 17 β)-11-(4-dimethylaminophenyl)-6-methyl-4 ', 5 '-dihydro spiral shell [female-4,9-diene-17,2 ' (3 ' H)-furan]-3-ketone (ORG-31710) and U.S. patent 4,871, other compounds described in 724; (11 β, 17 α)-11-(4-acetylphenyl)-17,23-epoxy-19,24-dinorchola-4,9,20-triolefin-3-ketone (ORG-33628); (7 β, 11 β, 17 β)-11-(4-dimethylaminophenyl-7-methyl]-4 ', 5 '-dihydro spiral shell [female-4,9-diene-17,2 ' (3 ' H)-furan]-3-ketone (ORG-31806) and U.S. patent 4,921, other compounds described in 845; The people such as ZK-112993 and Michna, other compounds described in 1992, J.Steroid Biochem.Molec.Biol.41:339-348; ORG-31376; ORG-33245; ORG-31167; ORG-31343; RU-2992; RU-1479; RU-25056; RU-49295; RU-46556; RU-26819; LG1127; LG120753; LG120830; LG1447; LG121046; CGP-19984A; RTI-3021-012; RTI-3021-022; RTI-3021-020; RWJ-25333; ZK-136796; ZK-114043; ZK-230211; ZK-136798; ZK-98229; ZK-98734; And ZK-137316.

Other gestation materials used in the present invention include but not limited to mifepristone (11 β-female-4,9-diene-3-ketone of [p-(dimethylamino) phenyl]-17 beta-hydroxyl-17s-(1-propinyl); RU 486) and U.S. patent 4,386,085,4,447,424,4,519,946 and 4,634, other compounds described in 695; The people such as Jiang, 2006, phosphorous 17 β described in steroid 71:949-954-side chain mifepristone analog; Onapristone (11 β-[p-(dimethylamino) phenyl]-17 Alpha-hydroxy-17-(3-hydroxypropyl)-13 α-female-4,9-diene-3-ketone) and U.S. patent 4,780, other compounds described in 461; Lilopristone (((Z)-11 β-[(4-dimethylamino) phenyl]-17-beta-hydroxyl-17 alpha-(3-hydroxyl-1-acrylic) female-4,9-diene-3-ketone) and U.S. patent 4,609, other compounds described in 651; The people such as Belagner, the 19-norsteroid of 11 beta substitution described in 1981, steroids 37:361-382, such as 11 β-(4-methoxyphenyl)-17 beta-hydroxyl-17 alphas-acetenyl-4,9-female diene-3-ketone; U.S. patent 5,728, the 11 beta-aryl-4-estrene compounds described in 689 such as (Z)-11 β-[(4-dimethylamino) phenyl)]-17 beta-hydroxyl-17 alphas-(3-hydroxyl-1-acrylic) female-4-alkene-3-ketone; U.S. patent 5,843,933 and 5,843, the 11 beta-aromatics-female ene derivative described in 931; U.S. patent 5,693,11-benzaldoxime-female-diene derivatives such as 4-[female-4,9-diene-11 beta-yls of 17 'beta '-methoxy-17 α-(methoxy)-3-oxo] benzaldehyde-1-(the E)-oxime described in 628; U.S. patent 5,576,11-benzaldoxime-17 'beta '-methoxy-17 alpha-methoxymethyl base-female diene derivatives such as 4-[female-4,9-diene-11 beta-yls of 17 'beta '-methoxy-17 α-(methoxy)-3-oxo] benzaldehyde-1-(E)-[O-(ethylamino) carbonyl] oxime described in 310; 11 β-benzaldoxime-female-4 that the S-described in WO 99/45023 replaces, 9-diene-carbonic acid mercaptan ester is 4-[female-4,9-diene-11 beta-yls of 17 'beta '-methoxy-17 α-(methoxy)-3-oxo] benzaldehyde-1-(E)-[O-(ethylsulfanyl) carbonyl] oxime such as; Steroid ester such as (Z)-6 '-(the 4-cyano-phenyl)-9 described in DE 19652408, DE4434488, DE 4216003, DE 4216004 and WO 98/24803,11 α-dihydro-17 beta-hydroxyl-17 alpha-[4-(1-oxo-3-methylbutoxy group)-1-butylene base] 4 ' H-naphtho-[3 ', 2 ', 1 '; 10,9,11] female-4-alkene-3-ketone; Female-4, the 9-diene-3-ketone of fluoro 17 alpha-alkyl chain steroid such as 11 β-(4-acetylphenyl)-17 beta-hydroxyl-17 alphas-(1,1,2,2,2-pentafluoroethyl group) described in WO98/34947; U.S. patent 5,29, the 17-spiral shell furan-3 described in 878 ' nor--17,23-epoxy-17 α-gallbladder-4,9, the 20-triolefin-3-ketone of-subunit steroid such as 11 β-(4-acetylphenyl)-19,24-bis-; (Z)-11 β, 19-[4-(3-pyridine radicals)-o-phenylene]-17 beta-hydroxyl-17 alphas-[3-hydroxyl-1-acrylic]-4-androstene-3-ketone and U.S. patent 5,439, other compounds described in 913; U.S. patent 5,446,13-alkyl-11-beta-phenyl gonane compound such as 11 β-[4-(1-methyl ethylene) phenyl]-17 Alpha-hydroxy-17 β-(3-hydroxypropyl)-13 α-female-4, the 9-diene-3-ketone described in 036; U.S. patent 4,921,11-aryl sleroid such as 4 ', 5 '-dihydro-11 β-[4-(dimethylamino) phenyl]-6 Beta-methyl spiral shells [female-4 described in 845,9-diene-17 β, 2 ' (3 ' H)-furan]-3-ketone; U.S. patent 4,829,060,4,814,327 and 5,089, the 11-beta-aromatic-female diolefin compound described in 488; U.S. patent 5,739,125,5,407,928 and 5,273,11-beta-aromatic-4, the 9 steroid diolefin compound described in 971 and 11-beta-aromatic-13-alkyl-4,9-steroid diolefin compound; 11-beta-aromatic-6-alkyl (or alkenyl or the alkynyl) steroid described in EP 289073; U.S. patent 5,093, the 10-β described in 507,11-β-bridging steroid; U.S. patent 5,244, the 11-beta-aromatic-14-β-steroid described in 886; U.S. patent 5,095,129,5,446,178,5,478,956 and 5,232,19, the 11-β-bridging steroid described in 915; U.S. patent 5,684, the 1-aryl sulfonyl described in 151, aryl carbonyl and 1-arylphosphonyl-3-phenyl-Isosorbide-5-Nitrae, 5,6-tetrahydro pyridazine compound; U.S. patent 5,753, the 1-aryl sulfonyl described in 655, aryl carbonyl and artyl sulfo carbonyl pyridazine subbase derivant; U.S. patent 5,688,808,5,693,646,5,693,647,5,696,127,5,696,130 and 5,696,1,2-dihydro-[1, the 2-g] quinoline described in 133 and 1,2-dihydro-chromen also [3,4-f] quinoline; The people such as Kang, the oxa-steroids compound 6 derived from (8S, 13S, 14R)-7-oxa--female-4,9-diene-3,17-diketone 1 described in 2007, Bioorg.Med.Chem.Lett.15:907-910; With people such as Kang, the 7-oxa-steroids compound 4 described in 2007, Bioorg.Med.Chem.Lett.17:2531-2534.

In preferred embodiments, progesterone antagonist is gestation material/SPRMCDB-4124 (21-methoxyl group-17 α-acetoxyl group-11 β-(4N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone).Embodiment 10 confirms that using CDB-4124 with high dose (50mg/ days) inhibits endometrial hyperplasia in adult female, but does not suppress endometrial hyperplasia with comparatively low dosage (25mg/ days and 12.5mg/ days).

Progesterone antagonist compositions of the present invention can give just to experience the patient of any hormone therapy relevant with the excessive risk of endometrial hyperplasia or carcinoma of endometrium or sickness rate.These treatments can include but not limited to use estrogen or use SERM.Progesterone antagonist compositions of the present invention can also be administered to the patient just experiencing anti-estrogen therapy, because patient can benefit from the anti-proliferative effect that progesterone antagonist compound applies in the endometrial tissue in uterus.

Use SERM at present to treat multiple different syndromes, comprise breast carcinoma, osteoporosis, colon cancer, neurodegenerative disease such as parkinson disease and Alzheimer, cardiovascular disease, vaginal atrophy and obesity.But SERM treatment is relevant with endometrial hyperplasia and carcinoma of endometrium.Such as, breast carcinoma tamoxifen treatment cause in the women with intact uteri about 20% there is atypical hypertrophy sickness rate.There is the probability developing into cancer that the patient showing atypical endometrium sample has 25%.The compounds of this invention is to be enough to the dosed administration of the hypertrophy of resisting with SERM treatment.The compounds of this invention can with SERM administering drug combinations to treat any above-mentioned disease.

Estrogen is deliver medicine to as the part of hormone replacement therapy (HRT) no longer to produce estrogenic postmenopausal women at present.But for the menopausal women with intact uteri, estrin treatment is only considered to unsafe, because can with endometrial hyperplasia.Frequent administering drug combinations progestogen are with antiestrogenic high proliferative effect clinically; But, in WHI research, show to add progestogen and breast cancer related, and discontinuity can be caused hemorrhage.The compounds of this invention can with estrogen combinations administration, using the part as hormone replacement therapy.

Compound disclosed by the invention can play progesterone antagonist in uterus.The compounds of this invention can be suitable for the prolonged application needed for postmenopause of experience hormone replacement therapy to treat other indications.When considering such application, the compounds of this invention preferably has low glucocorticoid receptor binding activity, and therefore, the compounds of this invention does not significantly disturb the function of glucocorticoid receptor (GR).Use the side effect that the compounds of this invention can have minimizing, such as anxious state of mind, fatigue and lose weight, these side effect usually find when using gestation material glucocorticoid receptor (GR) to high-affinity.

In another embodiment, the invention provides the method that can be used for identifying the compound with selectivity progesterone receptor binding activities.These methods comprise bioassay in receptors bind and body, such as, after anti-McGinty, anti-Clauberg, glucocorticoid, estrogen, androgen, anti-glucocorticoid (AG), estrogen antagonist and antiandrogen active and sexual intercourse and ovulation active, wherein use the compounds of this invention as reference.

In another embodiment, present invention teaches and can also analyze potential SPRM for the active impact of people's transit cell record.When disclosed in use the present invention, SPRM is as reference, this analysis can provide the information about following aspect: (1) SPRM and acceptor interaction, (2) interaction of the receptor activated and other transcription factor, (3) activate the transcription complex on progesterone response element (PRE), and finally its for the impact of gene expression.In these experiments, under PRE-dependency promoter, the plasmid co-transfection of hPR-B will can be expressed in HeLa, HepG2 or T47D cell with any receptor well known by persons skilled in the art.Receptor can include but not limited to luciferase, beta galactosidase, green fluorescent protein, DsRed or yellow fluorescin.After transfection, a kind of SPRM process of positive control will be used as disclosed in cell test-compound or the application.After process, the reporter gene of analysis of cells is expressed.

In another embodiment, present invention teaches and in human lymphocyte system CEM-7, the ability of the cell death of induced by dexamethasone can be resisted by the SPRM of test oracle, and compare with the effect of SPRM disclosed in present specification.In these experiments, dexamethasone can add to cause the concentration of cell death.Then by cell with RU486-SPRM of the present invention or test-compound with 10 ^-6with 10 ^-8the concentration process of M.

The progesterone antagonist compound that can use according to the present invention can use synthesising chemical technology known in the art, such as U.S. patent 6,861, and technology disclosed in 415 is synthesized.Should be appreciated that at reaction conditions, some functional groups can with other reactants or Reagent evaluation mutual effect, therefore may need temporary protection.The use of protecting group is described in ' Protective Groups in OrganicSynthesis ', 2 ^ndversion, in T.W.Greene & P.G.M.Wutz, Wiley-Interscience (1991).

In one embodiment, the present composition comprises one or more progesterone antagonist or its officinal salt.According to method condition, salt compound can obtain with neutral or salt form.Salt form comprises hydrate and other solvates and crystalline polymorph.These end-products of free alkali and salt form can use according to the present invention.

Acid-addition salts can use alkaline reagent such as alkali or change into free alkali by ion exchange according to self known mode.The free alkali obtained can also form salt with organic acid or mineral acid.

When preparing acid-addition salts, preferably use the acid forming suitable officinal salt.The example of such acid is hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, aliphatic acid, alicyclic carboxylic acid or sulfonic acid, such as formic acid, acetic acid, propanoic acid, succinic acid, glycolic, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, fumaric acid, maleic acid, hydroxymaleic acid, acetone acid, aspartic acid, glutamic acid, P-hydroxybenzoic acid, flutters acid, ethyl sulfonic acid, ethylenehydrinsulfonic acid, phenylacetic acid, mandelic acid, benzenesulfonic acid (alogenbensenesulfonic acid), toluenesulfonic acid, galactobionic acid Galactonic acid, galacturonic acid or LOMAR PWA EINECS 246-676-2.All crystalline polymorphs can use according to the present invention.

Base addition salts also can use according to the present invention, and can be obtained like this: by free acid form with enough needed for alkali contact in a usual manner to generate salt.Free acid form by being contacted with acid by salt form, and can be isolated free acid to regenerate in a usual manner.Pharmaceutically acceptable base addition salts is with metal or amine, and such as alkali and alkaline earth metal ions or organic amine are formed.Example as cationic metal is sodium, potassium, calcium, magnesium etc.The example of suitable amine is aminoacid such as lysine, choline, diethanolamine, ethylenediamine, N-METHYL-ALPHA-L-GLUCOSAMINE etc.

For above-mentioned purpose, the compounds of this invention can be that activated any conventional route carrys out administration via wherein progesterone antagonist.Such as, progesterone antagonist of the present invention can be taken orally, parenteral, sublingual administration, transdermal administration, rectally, mucosal, topical, via inhalation, through cheek administration or its combination.Parenteral includes but not limited to administration and intraventricular administration in intravenous administration, intraarterial delivery, Intraperitoneal medication, subcutaneous administration, intramuscular administration, intrathecal drug delivery, intra-articular administration, pond.Form of medication can be tablet, capsule, pill, nasal spray, pilule, implant (or other depot formulations) etc.

The treatment effective dose of the compositions needed for treatment can change according to following factor: particular compound used, administering mode, the sanatory order of severity, desired activity time span etc., and finally to be decided by clinician.In all cases, the particular compound of effective dose is the dosage being enough to suppress endometrial hyperplasia.But usually, for human therapy, dosage is generally about 0.001mg/kg to about 500mg/kg/ days, such as about 1 μ g/kg was to about 1mg/kg/ days or about 1 μ g/kg to about 100 μ g/kg/ days.For the mammal that major part is large, total daily dose is about 1 to 100mg, preferably about 2 to 80mg.Can adjust dosages scheme to provide optimum therapeutic response.Required dosage can be used with single dose easily, or as multiple dosage with suitable doses at intervals, and such as every day is as 2,3,4 or more a sub-doses administration.

Illustrate, the present composition can to individual administration, to provide the progesterone antagonist of following amount to individuality: about 1 μ g/kg such as, to about 1mg/kg body weight, about 1 μ g/kg, about 25 μ g/kg, about 50 μ g/kg, about 75 μ g/kg, about 100 μ g/kg, about 125 μ g/kg, about 150 μ g/kg, about 175 μ g/kg, about 200 μ g/kg, about 225 μ g/kg, about 250 μ g/kg, about 275 μ g/kg, about 300 μ g/kg, about 325 μ g/kg, about 350 μ g/kg, about 375 μ g/kg, about 400 μ g/kg, about 425 μ g/kg, about 450 μ g/kg, about 475 μ g/kg, about 500 μ g/kg, about 525 μ g/kg, about 550 μ g/kg, about 575 μ g/kg, about 600 μ g/kg, about 625 μ g/kg, about 650 μ g/kg, about 675 μ g/kg, about 700 μ g/kg, about 725 μ g/kg, about 750 μ g/kg, about 775 μ g/kg, about 800 μ g/kg, about 825 μ g/kg, about 850 μ g/kg, about 875 μ g/kg, about 900 μ g/kg, about 925 μ g/kg, about 950 μ g/kg, about 975 μ g/kg or about 1mg/kg body weight.

The present composition can comprise the active component of about 25 to about 90% weight, more generally the active component of about 5% to 60% weight and carrier.

Solid carrier can comprise starch, lactose, dicalcium phosphate, microcrystalline Cellulose, sucrose and Kaolin, and liquid-carrier can comprise sterilized water, Polyethylene Glycol, non-ionic surface active agent, and edible oil such as Semen Maydis oil, Oleum Arachidis hypogaeae semen and Oleum sesami, be suitable according to the character of active component and required specific administration form.Correctives, coloring agent, antiseptic and antioxidant such as vitamin E and ascorbic acid can also be comprised in preparation.Under normal storage and service condition, preparation can containing antiseptic to stop microbial growth.

Can use technology well known to the skilled person, in tablet machine, the present composition is made tablet.Optionally, active component of the present invention can also be pressed into bilayer tablet separately.According to the present invention, tablet can comprise antiestrogenic, estrogen or SERM as a kind of active component.The present composition can also be mixed with oily solution.

For the patient treated with the present composition, should its serum estradiol of periodic monitoring and glucocorticoid levels.

In addition, the present invention also provides following embodiment:

1. suppress the method for endometrial hyperplasia, described method comprises to the compositions comprising progesterone antagonist having the women of these needs to use effective dose.

2. the method for embodiment 1, wherein has this women needed to suffer from endometriotic women.

3. the method for embodiment 1, wherein using compositions with as the estrogen of a part for hormone replacement therapy or selective estrogen receptor modulators simultaneously, separately or order use.

4. the method for embodiment 1, wherein said progesterone antagonist is described progesterone antagonist at least 1.5 times of binding affinity of glucocorticoid receptor (GR) for the binding affinity of progesterone receptor.

5. the method for embodiment 1, the progesterone level wherein in women does not significantly increase after compositions described in administration.

6. the method for embodiment 1, the estrogen level wherein in women does not significantly reduce after compositions described in administration.

7. the method for embodiment 1, wherein said progesterone antagonist is formula (I) compound:

Or its officinal salt, hydrate or solvate, wherein:

X represents alkyl, alkenyl, alkynyl, hydrogen, halogen, an alkyl amino or dialkyl amido;

R ₁represent O, NOH or NO-methyl;

R ₂represent hydrogen or acetyl group; And

R ₃representation methoxy, formoxyl oxygen base, acetoxyl group, acyloxy, S-alkoxyl, acetyltheonyl, glycinate, vinyl ethers, acetoxy-methyl, methyl carbonic, halogen, methyl, hydroxyl or ethyoxyl.

8. the method for embodiment 7, wherein said compound is CDB-4124.

9. the method for embodiment 8, wherein said compound uses with the dosage of 0.5mg/kg to 500mg/kg.

10. the method for embodiment 9, wherein said compound uses with the dosage of 50mg/ days.

The method of 11. embodiments 10, wherein said compound administration was at least about 1 to about 6 months.

The method of 12. embodiments 11, wherein said compound administration was at least about 4 months.

The method of the pain that 13. treatments are relevant with endometriosis, described method comprises to the compositions comprising progesterone antagonist having the women of these needs to use effective dose.

The method of 14. embodiments 13, wherein said progesterone antagonist is formula (I) compound:

Or its officinal salt, hydrate or solvate, wherein:

X represents alkyl, alkenyl, alkynyl, hydrogen, halogen, an alkyl amino or dialkyl amido;

R ₁represent O, NOH or NO-methyl;

R ₂represent hydrogen or acetyl group; And

R ₃representation methoxy, formoxyl oxygen base, acetoxyl group, acyloxy, S-alkoxyl, acetyltheonyl, glycinate, vinyl ethers, acetoxy-methyl, methyl carbonic, halogen, methyl, hydroxyl or ethyoxyl.

The method of 15. embodiments 14, wherein said compound is CDB-4124.

The method of 16. embodiments 13, the endometrial impairment size wherein in women is reduced.

The method of 17. embodiments 13, the progesterone level wherein in women does not significantly increase after compositions described in administration.

The method of 18. embodiments 13, the estrogen level wherein in women does not significantly reduce after compositions described in administration.

The method of 19. embodiments 13, wherein said progesterone antagonist is described progesterone antagonist at least 1.5 times of binding affinity of glucocorticoid receptor (GR) for the binding affinity of progesterone receptor.

The method of 20. embodiments 8, wherein said compound uses with the dosage of 0.5mg/kg to 500mg/kg.

The method of 21. embodiments 20, wherein said compound uses with the dosage of 50mg/ days.

The method of 22. embodiments 21, wherein said compound administration was at least about 1 to about 6 months.

The method of 23. embodiments 22, wherein said compound administration was at least about 4 months.

24. treat the method for estrogen dependent conditions in the women of experience hormone therapy, and described method comprises to there being the women of these needs to use progesterone antagonist.

The method of 25. embodiments 24, wherein said disease is endometrial hyperplasia or carcinoma of endometrium.

The method of 26. embodiments 24, wherein said progesterone antagonist is formula (I) compound:

Or its officinal salt, hydrate or solvate, wherein:

X represents alkyl, alkenyl, alkynyl, hydrogen, halogen, an alkyl amino or dialkyl amido;

R ₁represent O, NOH or NO-methyl;

R ₂represent hydrogen or acetyl group; And

R ₃representation methoxy, formoxyl oxygen base, acetoxyl group, acyloxy, S-alkoxyl, acetyltheonyl, glycinate, vinyl ethers, acetoxy-methyl, methyl carbonic, halogen, methyl, hydroxyl or ethyoxyl.

The method of 27. embodiments 26, wherein said compound is CDB-4124.

The method of 28. embodiments 26, wherein said hormone therapy comprises the estrogenic hormone replacement therapy of administration.

The method of 29. embodiments 26, wherein said hormone therapy comprises uses selective estrogen receptor modulators (SERM).

The method of 30. embodiments 29, wherein uses SERM and is selected from following disease with treatment: breast carcinoma, osteoporosis, colon cancer, neurodegenerative disease such as parkinson disease and Alzheimer, cardiovascular disease, vaginal atrophy and obesity.

The method of 31. embodiments 26, wherein said compound is described selectivity progesterone receptor modulator at least 1.5 times of binding affinity of glucocorticoid receptor (GR) for the binding affinity of progesterone receptor.

The method of 32. embodiments 26, the progesterone level wherein in women does not significantly increase after compositions described in administration.

The method of 33. embodiments 26, wherein said compound uses with the dosage of 0.5mg/kg to 500mg/kg.

The method of 34. embodiments 33, wherein said compound uses with the dosage of 50mg/ days.

The method of 35. embodiments 34, wherein said compound administration at least 1 month.

The method of 36. embodiments 34, wherein said compound administration at least 6 months.

The method of 37. embodiments 34, wherein said compound administration at least 1 year.

The method of 38. any one of embodiment 1,13 or 24, wherein said compositions is to described women intermittently administration, and wherein said women experiences menstruation during at least one withdrawal time.

The method of 39. embodiments 38, the wherein said administration phase is about 4 months.

Embodiment

Non-limiting example is below provided to help understand instruction of the present invention.

The most completeness that mentioned in this article so patent, patent application and publication are all allowed at law is incorporated herein by reference.

Embodiment 1. invention formulation can make tablet.

In order to obtain for implementing tablet of the present invention, can be compressed together by following component in tablet machine:

In order to obtain for implementing bilayer tablet of the present invention, can be compressed together by following component in tablet machine:

In order to obtain for implementing the tablet comprising antiestrogenic of the present invention, such as, can be compressed together by following component in tablet machine:

In order to obtain for implementing Oily preparation of the present invention, such as, following component can be mixed, and being added in ampoule:

100.0mg CDB-4124

343.4mg Oleum Ricini

608.6mg benzyl benzoate

Embodiment 2. the compounds of this invention can have only weak Antiglucocorticoid receptor-binding activity.

The ability of some gestation materials in conjunction with rabbit progesterone receptor (rbPR) and glucocorticoid receptor (GR) (rbGR) is tested in receptors bind measures.In brief, in TEGMD buffer (10mMTris, pH 7.2,1.5mM EDTA, 0.2mM sodium molybdate, 10% glycerol, 1mM DTT), preparation is respectively from the uterus of immature rabbit or the Cytoplasm containing PR or GR of thymus that give estradiol.PR is combined, by Cytoplasm and 6nM 1,2-[ ³h] progesterone (50.0Ci/mmol) cultivates together, and adds the competitor that concentration is 2-100nM.GR is combined, by Cytoplasm and 6nM 6,7-[ ³h]-dexamethasone (40Ci/mmol) cultivates together, and adds the competitor that concentration is 2-100nM.After 4 DEG C of overnight incubation, by adding the Linesless charcoal of glucosan bag quilt, and 4 DEG C with 2100 × g within centrifugal 15 minutes, come separating and combining and unconjugated [ ³h] steroid.Will containing [ ³h] supernatant of-Steroid receptors complex is decanted in the bottle containing 4ml Optifluor (Packard Instrument Co.), and vortex, balances 30 minutes in liquid scintillation counter, then counts 2 minutes.By enumeration data is inputted four parameter s igmoidal computer programs ( immunoassay Data ReductionProgram, Packard Instrument Co., Meriden, Conn.) determine the EC of each standard curve and each compound curve ₅₀(valid density).Use the RA (RBA) of following each compound of formulae discovery: the EC of reference material ₅₀the EC of/test-compound ₅₀× 100.The reference material that PR and GR measures is unlabelled progesterone and dexamethasone respectively.The result of these experiments is summed up in Table 1, represents with the ratio (rbPR/rbGR) of each compound for the RA of rbPR and rbGR receptor.This difference reflects the relative activity of compound in the cell or tissue with these two kinds of receptors and required patent cofactor.

The Relative biological activity of same compound in rabbit uterus being measured test by anti-McGinty and anti-Clauberg is given in table 1.For these experiments, use Compound C DB-2914 (listing at the last place of table) in contrast or reference compound (rabbit biological activity=1.00), because use the experimental result of CDB-2914 to be disclosed (people such as Hild-Petito, 1996; The people such as Passaro, 1997; The people such as Reel, 1998; The people such as Larner, 2000).Anti-McGinty is tested, allows jejune female rabbits accept the subcutaneous injection of 5 μ g estradiol in 10% ethanol/Oleum sesami every day, give 6 days continuously.At the 7th day, carry out aseptic abdominal operation with the sections of two of ligation 3-4cm cornua uteris to animal.By the test-compound intracavitary administration in appropriate solvent in the ligation sections of a cornua uteri, be expelled in independent carrier chamber in the ligation sections of another cornua uteri.At ensuing three days, the progesterone (267 μ g/ days) of stimulating dose is subcutaneously injected in every rabbit, with inducing endometrial hypertrophy every day.All animals were killed to take out uterus at the 10th day, wherein takes out the sections of ligation central authorities, and be fixed in 10% neutral buffered formalin, and carry out histology's process.Use the degree of the endometrial gland hypertrophy of 5 micro-cutting sheets of microscopic evaluation hematoxylin and eosin dyeing.Calculate the suppression percentage ratio of the endometrial hyperplasia of every rabbit, and record comprises the meansigma methods of the group of 5 rabbits.Anti-Clauberg is tested, allows immature rabbit accept the subcutaneous injection of 5 μ g estradiol in 10% ethanol/Oleum sesami, give 6 days continuously.At the 7th day, animal accepted progesterone (160 μ g/ days) by subcutaneous injection, and the oral or subcutaneous experimental compound be received in suitable carrier, give 5 days continuously.One group of rabbit only accepts progesterone.All animals, after 24 hours, kill to take out uterus by last administration, wash all fat and the connective tissue in uterus off, weigh closest to 0.2mg, and be placed in 10% neutral buffered formalin, to carry out histology's process subsequently.Use the degree of the endometrial gland hypertrophy of 5 micro-cutting sheets of microscopic evaluation hematoxylin and eosin dyeing.Percentage ratio is suppressed by comparing the endometrial hyperplasia obtained at the test-compound of each dosage level with the animal only by Progesterone stimulated.The data (rabbit biological activity) presented in table 1 reflect the average result being analyzed each compound relative to CDB-2914 obtained by anti-McGinty and anti-Clauberg.

The gestation material of test is carried out classification for rabbit GR to the selectivity of rabbit PR based on each Compound Phase, as outlined below in table 1.Also gestation material is carried out classification based on the biological activity in rabbit uterus.Data listed in table 1 show, main compound is at least 1.5 times of its affinity for glucocorticoid receptor (GR) for the affinity of progesterone receptor.

The result of these tests also shows, two kinds of main compound CDB-4124 and CDB-4059 have the antiprogestational action stronger than RU 486 and CDB-2914 in rabbit uterus.These two kinds of compounds all lack estrogen, androgen, see estrogen and antiandrogen active.These two kinds of compounds all have minimum Antiglucocorticoid receptor active, and this is the feature itself and RU 486 and CDB-2914 distinguished, and RU 486 and CDB-2914 has medium activity in glucocorticoid receptor (GR) combines.In these measure, what CDB-4124 showed is slightly better than CDB-4059.

The receptors bind of table 1.-SPRMS and biological activity

Embodiment 3. measures hydrocortisone.

The conclusion that several different experimental system support is such, namely RU 486 increases hydrocortisone, because RU 486 has strong Antiglucocorticoid character in people and primate.

But, as shown in Figure 1, do not show the significant difference of cortisol levels with the rat that 10mg/kg treats with RU 486.On the contrary, matched group is significantly higher than at the serum cortisol of the rat of same dose level CDB-4124 or CDB-4059 treatment.

These higher levels are in the scope of 3-4ug/dl (30-40ng/ml).These effects are dose dependents, because the dosage increase of CDB-4124 causes hydrocortisone to increase (Fig. 2).

RU 486 can explain this species diversity of the impact of cortisol levels like this relative to CDB-4124 or CDB-4059, assuming that long term administration is after 21 days, with two kinds of CDB Compound Phase ratios, rat liver can metabolism RU 486 better.

Embodiment 4. measures corticosterone.

Corticosterone is the glucocorticoid that in rat, content is maximum.The SPRM shown in Fig. 1 and 2 can be secondary to the strong impact on corticosterone for the impact of hydrocortisone.In order to explore this phenomenon better, chart reveals the group of the maximum change of cortisol levels, such as, in the group for the treatment of with 20mg/kg or 10mg/kg with the CDB-4124 level of corticosterone.In order to compare, also analyze following group: accept the group that 20mg/kg CDB-4124 adds 10mg/kg progesterone, accept the group that 10mg/kgCDB-4124 adds 10mg/kg progesterone, accept the group of 10mg/kg RU 486, only accept the group of 10mg/kg progesterone, matched group.The level of corticosterone than hydrocortisone level height 10-40 doubly.But, between each group, almost do not observe any difference of average Corticosterone Level.(p=0.43 before the treatment, Kruskal-Wallis check), treatment 21 days after (p=0.57, Kruskal-Wallis checks) or treat (p=0.061, Kruskal-Wallis check) after 28 days and when killing, do not observe difference in group yet.

In order to measure the impact of external progesterone on serum corticosterone, Corticosterone Level is compared in 3 paired group, described 3 differences organized in pairs are they whether to accept external progesterone, and (such as comparative control group is relative to progesterone, or CDB-4124,20mg/kg adds progesterone relative to CDB-4124,20mg/kg, or CDB-4124,10mg/kg adds progesterone relative to CDB-4124,10mg/kg).Detect statistically-significant difference: with in the animal of progesterone treatment, treat after 21 days, the level of corticosterone reduces (p=0.029, Mann-Whitney Wilcoxon checks, two tail).This acts in the serum taken out when killing and does not confirm this effect.Between progesterone group and CDB-4124 group, between progesterone group and RU-486 group, or between RU-486 group and CDB-4124 group, do not find the difference of serum corticosterone.

Also measured were the relation between hydrocortisone and corticosterone in each group.For CDB-4124,20mg/kg (r ²=0.78), CDB-4124,10mg/kg (r ²=0.82) and RU 486 (r ²=0.85), between hydrocortisone and corticosterone, strong positive linear relationships is had.Add in the first two CDB-4124 group progesterone make the intensity of this relation greatly reduce (for the 10th group, r ²=0.34, for the 11st group, r ²=0.3).Progesterone self does not show such positive relationship (r ²=-1.0).Matched group does not show relation (r between these two kinds of glucocorticoids ²=0.064).Therefore, in the group accepting CDB-4124, improve cortisol levels relevant with Corticosterone Level, perhaps this be improve owing to obtaining some from the conversion of corticosterone.This is consistent with the impact of the CDB-4124 seen above: on the impact of the metabolic enzyme of responsible progesterone and cortisol levels.

Although do not find the strong impact of CDB-4124 for the initial glucocorticoid of rat, but for security reasons, for the patient giving CDB-4124 or CDB-4059 in I clinical trial phase, possible Antiglucocorticoid effect should be monitored, comprise may increasing of serum cortisol, corticosterone or ACTH.

Embodiment 5. measures the antiproliferative effect of SPRM in uterine cell

Any uterine cell system can be used.Propagation is measured in the microtitration plate of 96-hole.5 × 10 are added in each hole ³individual cell.With Perkin Elmer Cetus PRO/PETTE, culture medium and drug solution are added in hole.Culture medium is the IMEM being supplemented with 5% hyclone.To measure 8 drug level of 0.078uM to 10uM in duplicate.Sample comprises independent tamoxifen, and each compound disclosed by the invention of combining with tamoxifen.

Cultivate after 4 days, the fresh culture of culture medium containing medicine is replaced, altogether after 7 days, cell monolayer trichloroacetic acid is fixed, and use sulforhodamine dyeing.The trap (492nm) of the dye solution extracted is measured with Titertek Multiscan plate reader.Build dose-effect curve (percentage ratio of contrast trap vs. drug level) to estimate IC ₅₀value, IC ₅₀value is defined as the drug level of Proliferation Ability 50% (micromole).IC ₅₀value is relevant to the effect of test-compound antiproliferative effect, because herein is provided the information that qualification is suitable for preventing needed for the compound of uterine cell high proliferation.

Embodiment 6.CDB-4124 reduces progesterone luteal phase in macaque

By macaque (Macaca fascicularis) (n=14) with CDB-4124 or RU-486 with 1.0mg/kg/ days or with placebo (contrast) oral medication 36 weeks.Another group (n=14) monthly accepts once iM.Last moon (33-36 week) of (14-17 week) and test between the interphase of test, measure the uterus progesterone level 1 month of every animal.Result is as follows:

Embodiment 7.CDB-4124 does not reduce follicular phase (Follicular Phase) estrogen of macaque

Last moon (33-36 week) of (14-17 week) and test between the interphase of test, the uterus estrogen level of every animal of mensuration embodiment 61 month.Follicular phase, result was based on 35 benchmark ovulatory cycles.Result is as follows:

Embodiment 8.CDB-4124 and suppress macaque endometrial epithelial cell propagation, but RU 486 does not suppress.

At the 36th week, in execution 24 hours, to 3 animals injection thimidine analogue bromodeoxyribouridine (BrdU) in the often group of embodiment 6, this is a kind of labelling of proliferative cell and filial generation thereof, to assess hyperblastosis.The uterus sections of full-thickness is dyeed, and breeds evidence with microscopy, represent with % BrdU being mixed to the cell be positive:

Embodiment 9.CDB-4124 and RU 486 increases the apoptosis of macaque endometrial epithelial cell, and do not increase described death.

DUTP-biotin nick end labelling (TUNEL) technology mediated by terminal deoxynucleotidyl transferase assesses the apoptosis derived from the tissue of same animals on microscope slide.The percentage ratio of the cell of apoptosis is as follows:

Embodiment 10.CDB-4124 suppresses people's endometrial epithelial cell propagation with dosage-dependent manner

Diagnosis suffers from endometriotic 39 premenopausal adult women as the Proellex in endometriosis treatment ^tM(CDB-4124) experimenter of experiment in six months.This experiment comprises CDB-4124 and the positive control arm of 3 dosage levels.Positive control is a kind of GnRH agonist, is usually used in treatment endometriosis and (is also called ).By CDB-4124 using double-blind fashion as day oral capsule with the dosed administration of 12.5mg/ days (n=2), 25mg/ days (n=3) and 50mg/ days (n=3). another group (n=4) is monthly injected once slow releasing preparation using as positive control.

All dosage of CDB-4124 and 6 months periods that dosage is being exposed to medicine on average alleviate the discomfort relevant with pain, and compared with 12.5mg or 25mg dosage, 50mgCDB-4124 dosage more effectively reduces persistent period and the intensity of pain, and with compare, reduce in pain natural law at experimental session and want significantly better.With active control compare, pain relief also occurs quickly.In this experiment, the reaction of pain for treatment is analyzed in two ways.In this experiment, patient keeps day pain diary to record Pain severity and frequency.In addition, when hospital admission each time, patient fills in the endometriosis investigation comprising application form, and this application form is with the pain intensity of the level evaluation of 0-10 in bad sky, and wherein 10 is maximum intensity.Day pain diary shows, at first trimester, accepts women's average time pain of 19.4 days.At first trimester, the Women report accepting 50mg CDB-4124 goes out to be less than the pain of 1 day.With accept maximum dose level CDB-4124 or the pain natural law that records of women compare, the Women report accepting 25mg and 12.5mg CDB-4124 goes out more pain natural law.This is seemingly for the dose-dependent effects of pain relief.At the treatments period of 180 days, pain diary showed, the women accepting 50mg CDB-4124 dosage has 170 or 96% without pain natural law (standard deviation=8.86 day).The minimizing of this durante dolors is better than (p=0.0012) statistically and accepts reached without pain natural law 117.8 (74%; Standard deviation 51.4 days).Without in pain natural law, the CDB-4124 of 50mg dosage is also better than 25mg and 12.5mg dosage statistically.The patient accepting CDB-412412.5mg and 25mg dosage has 115.9 (66% respectively; Standard deviation 69.2 days) and 133.6 (75%; Standard deviation 27.4 days) without pain natural law.These results clearly support the dose response of CDB-4124.The CDB-4124 of 25mg and 12.5mg dosage with there is no difference statistically.At the end of the first month for the treatment of, compared with benchmark, the pain natural law in 50mgProellex group (p=0.031) with statistically significant reduces, but does not then have in other 3 treatment groups.By following problem assessment pain intensity: " in 1-10 level, 0 is do not have pain, and 10 is extreme pain, how strong your pain has in bad sky? " the average mark of benchmark pain intensity is 6.3 for CDB-4124 group, for group is 6.1.In 25mg and 50mg Proellex group, the pain relief of statistically significant is obvious at the end of first month.At 3rd month, compared with benchmark, all four active treatment groups all have the pain relief of statistically significant, there is following mark: be 3.7 (p=0.03) for 12.5mg CDB-4124,3.2 (p=0.03) for 25mg CDB-4124,1.6 (p=0.015) for 50mg CDB-4124, and for 1.5 (p=0.016).These dosage custom alleviates and continues until 6th month, and at this moment pain intensity value is 2.0 (p=0.008), 2.8 (p=0.023), 0.6 (p=0.004) and 0.7 (p=0.016) respectively.Stop latter 2 months for the treatment of, recurrent pain, and in all four treatment groups, there is similar strength.

In this experiment, at the end of 3rd month, accept women's mean apparent go out estrogen and be down to post menopausal levels (< 20pg/ml), and to keep until 6th month for the treatment of.It is relevant that this result and the statistically significant of the biomarker at 3rd month bone resorption compared with benchmark increase (p=0.023), because this increasing the danger of bone lesion.At 6th month and when paying a return visit (follow up visit) in mensal tracking, with still the increase of bone resorption labelling is there is in the women for the treatment of.The CDB-4124 of all dosage keeps being significantly higher than use that observed and the estrogen concentrations (meansigma methods > 40pg/ml) remained in low normal range.Importantly, when treatment 3 months and 6 months, in any dosage arm of CDB-4124, the biomarker of bone resorption was without any remarkable change.The women having shown to have postmenopausal estrogen level is in the danger of larger bone lesion and other diseases.Therefore, be not used to the treatment of lasting more than 6 months.

The side effect of CDB-4124 is generally very light, is systematically affected without any individual tract.Although this is small test, and do not obtain any formal conclusion from data of safety, do not observe any single signal.

In this experiment, the change of womb internal membranous structure is closely monitored.Derive from these data checked to show, 3rd month period, CDB-4124 had anti-dose-dependent effects for endometrium thickness.Relatively two benchmark and an observation endometrium thickness ultrasonic measurement.Treat after 3 months, the women accepting the CDB-4124 (n=3) of 50mg dosage does not show endometrial thickness, and compared with benchmark, in fact shows the trend that endometrium thickness reduces.2 Women report of 1 women accepting the CDB-4124 (n=4) of 25mg dosage and the CDB-4124 (n=4) accepting 12.5mg dosage go out endometrial thickness.Accept 5 women there is no endometrial thickness, this is because caused by low estrogen state.Result is as follows:

Having in the patient of excessive uterine intimal thickening in 12.5mg and 25mg CDB-4124 group has been observed in speckle and hemorrhage two cases, carries out dilation and curettage (D & C) operation hemorrhage to stop.At treatments period, do not observe similar incidents at 50mg dosage.After treatment stops, there occurs in two patients of 50mg CDB-4124 group and be greater than hemorrhage normally, in a patient, carry out D & C operate, another patient is successfully controlled with conservative approach.

Claims (10)

1. the compositions comprising progesterone antagonist for the preparation of intermittent administration to treat the application in the medicine of women's pain relevant with endometriosis, described progesterone antagonist is selected from 21-methoxyl group-17 α-acetoxyl group-11 β-(4-N, N-dimethylaminophenyl) the nor-pregnane-4 of-19-, 9-diene-3, 20-diketone (CDB-4124) and 17 α-acetoxyl group-11 β-(4-N, N-dimethylaminophenyl) the nor-pregnane-4 of-19-, 9-diene-3, 20-diketone, described intermittent administration is included in the described compositions of administration phase drug treatment effective dose, wherein during the administration phase, continuous every day or every other day compositions described in administration are during 1 month to 6 months, then during withdrawal time, described administration is stopped, the length of withdrawal time is enough to allow women experience menstruation, time of described withdrawal time is shorter and longer than the dosing interval during the administration phase than the natural law of administration composition before, then the continuous described compositions of every day or every other day drug treatment effective dose during 1 month to 6 months, stop described administration afterwards, the length of withdrawal time is enough to allow women experience menstruation, time of described withdrawal time is shorter and longer than the dosing interval during the administration phase than the natural law of administration composition before, repeat the pattern of this administration and stopping administration.

2. the application of claim 1, wherein during the administration phase, comprises the compositions of progesterone antagonist with administration once a day.

3. the application of claim 1, wherein during withdrawal time, the administration comprising the compositions of progesterone antagonist stopped at least 2 weeks.

4. the application of claim 1, wherein during withdrawal time, uses effective dose progestogen to induce menstruation to described women.

5. the application of claim 4, uses wherein to described women and is selected from following progestogen: medroxyprogesterone, hydroxyprogesterone and progesterone.

6. the application of claim 1, wherein said compound is 21-methoxyl group-17 α-acetoxyl group-11 β-(4-N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone.

7. the application of claim 6, wherein said medicine uses with the dosage of 2mg/ days to 80mg/ days.

8. the application of claim 7, wherein said medicine uses with the dosage of 50mg/ days.

9. the application of claim 1, wherein said medicine be for during 4 months daily.

10. the application of claim 1, wherein said progesterone antagonist is 17 α-acetoxyl group-11 β-(4-N, N-dimethylaminophenyl)-19-nor-pregnane-4,9-diene-3,20-diketone.