TW201002736A - Compositions and methods for treating progesterone-dependent conditions - Google Patents

Abstract

The subject matter of the instant invention is pertinent to field of treatment of progesterone-dependent conditions. Compositions for practicing the methods, comprising one or more 19-norsteroid progesterone receptor modulators having a monomethylamine-substituted phenyl ring at the 11 β -position of carbon 11 and exhibiting low antiglucocorticoid activity, are also disclosed. Embodiments of the instant invention disclose methods for treating endometriosis, dysmenorrhea, breast cancer, uterine fibroids and endometrial hyperproliferation.

Description

201002736 VI. Description of the invention: [Reciprocal reference to the relevant application] This application claims the benefit of U.S. Provisional Application No. 61/048,459, filed on Apr. 28, 2008, the content of which is hereby incorporated by reference. FIELD OF THE INVENTION The present invention relates to compositions and methods for treating various progesterone-dependent symptoms. More specifically, the present invention relates to a composition comprising one or more 19-nor-steroid steroid progesterone receptor modulators, preferably derived from 19-defluorenone or 19-norgestrel. The carbon 11-11-position includes a monodecylamine-substituted benzene ring with low anti-glucocorticoid activity to treat progesterone-dependent symptoms. BACKGROUND OF THE INVENTION The effects of the steroid hormone progesterone on the reproductive system have been fully demonstrated. For example, pregnancy is essential for establishing and maintaining pregnancy and for the various tissues of the reproductive system. The role of progesterone in tissues other than the reproductive system has been reported 'but not fully characterized. Antiprogestin (a compound that acts as a progesterone, has considerable potential for infertility and pharmacological regulation of various symptoms and diseases such as breast cancer and endometriosis. Antiprogestin _ mifepristone η^Ρηδη>η6)(κυ486) 'is a member of the 19_normethonone derivative having strong affinity for both progesterone and glucocorticoid receptors, and has 201002736 anti-pregnancy And anti-glucocorticoids of the anti-glucocorticoid main chain; anti-glucocorticoid activity. active. Also synthesized * based on 19-norgestrine, however, many of these 4b VIII 7 ^ ~ knives also exhibit significant anti-pregnancy resistance that is not suitable for long-adrenal corticosteroids with very low anti-glucose-dependent symptoms The anti-glucocorticoid active phase of progesterone is administered in particular because it increases the circulating concentrations of corticosteroids and adrenal androgens. Therefore, there is still a need for long-term administration of hormonal activity to treat pregnancy hormones. SUMMARY OF THE INVENTION The present invention relates to the use of 19-nor- ketone ketone or 19-norgestrel-derived antiprogestin (which includes a monomethylamine-substituted benzene ring at the " location of the charcoal u), To treat various progesterone-dependent symptoms. The anti-pregnancy may be a pure antiprogestin or a selective pregnancy receptor modulator (seiectiye)

Progesterone receptor modulator (SPRM)' As long as the antiprogestin has low affinity for the glucoside hormone steroid, it is administered in an amount effective to treat progesterone-dependent symptoms. Hormone-dependent symptoms that can be treated by the compositions of the invention include, but are not limited to, endometriosis, dysmenorrhea, endocrine hormone dependent tumors, uterine fibroids, and endometrial hyperproliferation. Compositions of the invention may also be used to induce menstruation, induce labor, and contraception. The invention also relates to methods of improving the operational characteristics of 19-nor-steroid-derived antiprogestins. 201002736 [detailed description of the invention] The term "political dose" means the specific symptom of the amount of the active component of the composition. The term s-therapeutic progesterone receptor modulator, the term means the tissue-specific influence of progesterone A compound that functions as a receptor. The compound acts as a progesterone receptor antagonist in certain tissues (eg, in atrial tissue) and a progesterone receptor agonist in other tissues in the uterus. The term "use,", "treat," or "treat," as used herein, refers to any treatment that depends on a condition or disease, and includes, but is not limited to, inhibiting the progression of a 2: disease n condition or disease; A disease, for example, a dissipating of a disease or a disease; or a symptom of a disease or a condition that is caused by a disease or a disease. A positive symptom or disease, 'prevention, or, prevention, A qi, - not yet appearing, means preventing the onset of a disease or disease, or if a condition or disease is present, preventing the development of a further condition or disease. For example, a composition of the invention can be used to prevent swelling Recurrence. The residual microscopy or nest of cells can then be expanded to be clinically detectable = and the recurrence of the tumor occurs. "Progesterone agonist," means the combination with the progesterone receptor. compound of. ",, progesterone antagonist, 'the term means a compound that is affected by the progesterone receptor knot. And inhibits progesterone when it is mentioned in the article that the hormone level in the female is not lowered" - word, meaning It means that during the administration of the composition of the present invention, the level of 201002736 is still maintained within the normal range. Therefore, as long as the hormone levels are maintained within the normal range, it is considered that there may be some decrease in hormone levels. When the term "hormone in a female is mentioned herein, the term "substantially no increase" is used, it means that during the administration of the composition of the present invention, the hormone level is maintained within the normal range. Therefore, as long as the hormone The level is maintained within the normal range' and it is believed that there may be some increase in hormone levels. The present invention relates to the administration of anti-pregnancy by including one or more 19-nor-ketone- or 19-norgestrel-derived A method for treating progesterone-dependent symptoms of a hormone (which includes a monodecylamine-substituted benzene ring at the position of carbon n). It is expected to have a position at 11 /5 - of carbon 11 The 19-desanone- or 19-norgestrel-derived antiprogestin substituted by the monomethylamine-substituted ring may not exhibit a phenyl ring substituted with a dimercaptoamine-substituted at the same position. The same compound has lower antiglucocorticoid activity while still retaining at least a substantial portion of the antiprogestin activity. The antiprogestin may be a pure antiprogestin or may be a specific progesterone receptor modulator (spRM) As long as the antiprogestin has a low-glucose negative hormone activity Preferably, the antiprogestin has low estrogen/antiestrogenic activity to substantially maintain serum estrogen levels in the patient after administration of the antiprogestin. "In an aspect of the invention The composition of the present invention is administered to a patient having breast cancer to treat breast cancer. In a related aspect of the invention, the composition of the present invention is administered to a breast cancer patient having one or more tumors resistant to estrogen therapy to treat breast cancer. For example, the compounds of the invention may be particularly useful for treating breast cancer with anti-tamoxifen in a patient towel. 201002736 In another aspect of the invention, the composition of the invention is administered to a female estrogen-treated female to prevent the development of breast cancer in the female. In still another aspect of the invention, the composition of the invention is administered to a female patient in need thereof to suppress proliferation of the endometrium. In a related aspect of the invention, the composition of the invention is administered to a female patient in need thereof for the treatment of endometriosis. In another aspect of the present invention, the composition of the present invention is administered to a female in need thereof for the treatment of dysmenorrhea. In another aspect of the present month, the composition of the present invention is administered to a female in need thereof for the treatment of uterine fibroids. In a further aspect of the invention, the composition of the invention is administered to a female in need thereof to induce menstruation in the female. In another aspect of the diarrhea, the composition of the present invention is administered to a female in need thereof to induce labor. In another aspect of the invention, the composition of the invention is administered to a female in need thereof as a contraceptive. The compound of this month is suitable for long-term administration because the compound has only low glycoside g-body binding activity, and therefore the compound does not interfere with the glucocorticoid receptor @ m , - force b ° thus the application of the compound There may be a reduced field effect, such as blood stroke from m ^ 1 also using the high affinity for the glucocorticoid receptor, anti-progestin, and the emotional swing, fatigue and weight loss. Preferably, the compound of the present month also has low, or substantially no estrogenic, anti-estrogen and anti-androgenic activity. The package of the present invention, γ t , 70,000 can include the composition of the present invention, continuing 201002736 at least ι, 2, 3, 4, $, & 15, 16, 17, 18, 〖9, 2 〇, 7: 8, 9, 9, 1 , U, 12, 13, 14, 28, 29, 30, 31 or more days, 23, 24, 25, 26, 27, lasting at least 1, 2 L 4 eve $, during the administration period. The composition may also be administered for a plurality of months of administration period door 9(7) '11, 1] or 4, 5, 6, or 7 8 days, the composition may be administered for at least 1, 2, 3, or within Set: Two or more years of administration. During the administration, a slave and the composition, such as every other day, every other month, and the class goes to + the mother knows one. The composition may also be administered intermittently. Is the composition continued for 1,? 7 1 c 4 J If the loss is I 2, 3, 4, 5 or more months, then the withdrawal period, followed by the 2, 3, 4: period, period, and so on. Sub-more months of administration can be accomplished by any of the known 19.pregnant steels or 19-nor- fluorenone derivatives (which include monomethylamine-substituted at the position of carbon U). The benzene ring, which has the characteristics of the above compounds, is used to carry out the invention. In a specific case, the compounds of the present invention can be synthesized by the single demethylation of the compounds disclosed in U.S. Patent Nos. 6,861,415 and 6,900,193, each of which is incorporated herein by reference in its entirety.丨/, π "Μ-type 21-substituted 19-norpregnane:

9 201002736 wherein: X is N,N-dimethylamino;

Ri may be, for example, hydrazine, NOH or NO-methyl; R2 may be, for example, hydrogen or acetamidine; and R.sup.3 may be, for example, methoxy, decyloxy, ethoxylated, decyloxy. , S-alkoxy, acetylthe 〇nyl, glycerate, vinyl, ethoxymethyl, cesium carbonate, dentate, methyl, thiophene and Oxygen. For example, 21-substituted 19-desopregnanes which may be mono-demethylated to form the compounds useful in the present invention include, but are not limited to, the following 24 compounds disclosed below. l.CDB-4247(21-propenyloxy_17α_acetoxy_n dot_(4n,n-diaminoaminophenyl)-19-norpregna- _4,9-diene-3, 2〇-dione), having the following structural formula: 〇

When S is demethylated, it becomes 21-propenyloxy _17 〇: _ ethoxylated -11/5-(4-indole-ylaminophenyl) _19_nor-pregnant _4, 9 diene _3, 2 fluorenone. 10 201002736 2.CDB-43 61(21-(1'-vinyloxy)-17〇:-ethyloxy-11- (4N,N-diaminoaminophenyl)-19-depregnancy -4,9-diene-3,20-dione) having the following structural formula: ο c——NC 3 Η

Ac, when it is mono-demethylated, becomes 21-vinyl ether-17α; -ethyloxy-11/3-(4-indole-methylaminophenyl)-19-norpregna-4. 9-diene-3,20-dione. 3. CDB-405 9(21-Ethyloxy-17α-ethoxycarbonyl-11-(4Ν, Ν-diamidinophenyl)-19-depregna-4,9-diene- 3,20-dione), having the following structural formula:

When it is mono-demethylated, it becomes 21-ethoxyl-17-ethoxycarbonyl-11 yS-(4-indole-methylphenyl)-19-depretated-4,9- Diene-3,20-dione. 4. CDB-4124 (21-methoxy-17α-ethyloxy-ll/3-(4N,N-di 11 201002736 amidinophenyl)-19-depretated-4,9-diene -3,20-dione), having the following structural formula: C 3 Η

When it is mono-demethylated, it becomes 21-methoxy-17α-acetoxy-11 cold-(4-Ν-decylaminophenyl)-19-depretated-4,9- Diene-3,20-dione (CDB-4453). 5. 〇 6-4031 (21-bromo-17 〇:-acetoxy-11/3-(4 team: ^diamidophenyl)-19-norpregna-4,9-diene -3,20-dione), having the following structural formula:

When it is mono-demethylated, it becomes 21-bromo-17 α -ethyloxy-1 1 /3 -(4-N-nonylaminophenyl)-19-norpregna-4,9- Diene-3,20-dione. 6丄08-3876(2 Bu -17 〇:-Ethyloxy-11) 5-(4 ^^diamidophenyl)-19-depregnant-4,9-diene-3, 20-diketone), having the following structural formula: 12 201002736

When it is mono-demethylated, it becomes 21-chloro-17α-acetoxy-11/3-(4-anthracene-methylphenyl)-19-depregna-4,9-diene -3,20-dione. 7. CDB-4058 (21-fluoro-17α; -ethyloxy-ll/3-(4N,N-dialylaminophenyl)-19-norpregna-4,9-diene-3, 20-diketone), having the following structural formula: c - N 〇 C 3 Η

When it is mono-demethylated, it becomes 21-fluoro-17α-ethoxylated -11/5-(4-indole-methylphenyl)-19-depretated-4,9-di Alkene-3,20-dione. 8. CDB-403 0(21-fluorenyl-17α-acetoxy-11/5-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3 , 20-diketone), having the following structural formula: 13 201002736

V° I 丄,, OAc, when it is mono-demethylated, it becomes 21-methyl-17a-acetoxy-11 /5-(4-yimidylphenyl)-19-norpregnant -4,9-diene-3,20-dione. 9. €03-415 2(21-hydroxy-17«-acetoxy-11/5-(4 team: ^diamidophenyl)-19-depregated-4,9-diene- 3,20-dione), having the following structural formula:

When it is mono-demethylated, it becomes 2 1 -hydroxy-1 7 α -ethyloxy-1 1 /3 -(4-indole-methylphenyl)-19-depregna-4. 9-diene-3,20-dione. 10. CDB-4167 (21-ethoxy-17α-ethyloxy-11/3-(4N,N-didecylaminophenyl)-19-depregna-4,9-diene-3 , 20-diketone), having the following structural formula · 14 201002736

CH

When it is mono-demethylated, it becomes 21-ethoxy-17α-acetoxy-110,000-(4-anthracene-methylphenyl)-19-norpregna-4,9-di Alkene-3,20-dione. ll.CDB-4101(21-methoxysulfanyl-17-ethenyloxy-11 /3-(4-yiyidimethylaminophenyl)-19-norpregna-4,9-diene-3 , 20-diketone), having the following structural formula··

CH, h3ct

When it is mono-demethylated, it becomes 21-methoxysulfo-17α-acetoxy-11-(4-indole-methylphenyl)-19-depretated-4,9- Diene-3,20-dione. 12. CDB-4110 (21-acetone compound (acetonide)-17 a-acetoxy-11/3 -(4N,N-didecylaminophenyl)-19-depregnant-4,9-two Alkene-3,20-dione) having the following structural formula: 15 201002736

c 3 H

When it is mono-demethylated, it becomes 21-acetone compound-1 7 α -ethoxymethoxy-11/5-(4-^methylaminophenyl)-19-norpregna-4,9- Diene-3,20-dione. 13. CDB-4111 (21-BMD-17 α-acetoxy-1 1 /5 -(4Ν,Ν-dimethylaminophenyl)-19-norpregna-4,9-diene-3 , 20-diketone), having the following structural formula··

c——N c 3 H

AcoOA when it is mono-demethylated, becomes 21-BMD-17 α-acetoxy-11 /3 -(4-Ν-methylaminophenyl)-19-norpregna-4,9- Diene-3,20-dione. 14.CDB-4125(21-(Cyp*-hydroxy)-17α-acetoxy-11/S-(4Ν,Ν-dimethylaminophenyl)-19-norpregna-4,9-di The ene-3,20-dione)' has the following structural formula: 16 201002736

c 3 H

Η c——N

〇: Cyp = 3-cyclopentylpropenyloxy group, when it is mono-demethylated, it becomes 21-(Cyp*-hydroxy)-17α-acetoxy-1/5-(4-yiguanamine Phenylphenyl)-19-norpregna-4,9-diene-3,20-dione. 15. CDB-4205 (3-hydroxylamino-21-decyloxy-17α-acetoxy-11 /5 -(4Ν,Ν-dimethylaminophenyl)-19-depregnant-4,9 -diene-3,20-dione), having the following structural formula:

When it is mono-demethylated, it becomes 3-hydroxyamino-21-methoxy-17α-ethyloxy-11 yS-(4-indole-ylaminophenyl)-19-dean Pregnancy-4,9-diene-3,20-dione. 16.〇08-4206(3-Hydroxyamino-21-ethoxymethoxy-17〇:-ethoxycarbonyl 17 201002736 -1 1 /3 -(4N,N-diaminoaminophenyl)-19- Go to the progesterone-4,9-diene-3,20-dione) with the following structural formula:

When it is mono-demethylated, it becomes 3-hydroxyamino-21-acetoxy-17α-ethoxycarbonyl-11/5-(4-N-nonylaminophenyl)-19- Megestrol-4,9-diene-3,20-dione. 17. CDB-4226 (3-hydroxylamino-21-ethoxy-17α-ethoxycarbonyl-11 /3 -(4Ν,Ν-didecylaminophenyl)-19-norpregna-4,9 -diene-3,20-dione), having the following structural formula:

HON 乂 / When it is mono-demethylated, it becomes 3-hydroxyamino-21-ethoxy-17 α -ethyloxy-1 1 /3 -(4-indole-ylaminophenyl)- 19-Deprecipitated-4,9-diene-3,20-dione. 18 201002736 18.CDB-4262(3-methoxyamino-21-ethoxy-17α-ethyloxy-11 /3 -(4Ν,Ν-dimethylaminophenyl)-19-norpregnancy -4,9-diene-3,20-dione) having the following structural formula: CH.

When it is mono-demethylated, it becomes 3-methoxyamino-21-ethoxy-17α-ethyloxy-1 1 /3 -(4-N-methylaminophenyl)-19 - Norgestimate-4,9-diene-3,20-dione. 19.CDB-4223(21-Methylthio-17α-ethyloxy-1 1 /5 -(4N,N-diaminoaminophenyl)-19-depregna-4,9-diene -3,20-dione), having the following structural formula

When it is mono-demethylated, it becomes 21-methylthio-17α-acetoxy 19 201002736 -11 yS -(4-N-nonylaminophenyl)-19-depregnant-4,9 -diene-3,20-dione. 20. CDB-4119 (4-benzoin-2 ethane thiol-17 cc - ethoxylated-11 泠-(4N,N-didecylaminophenyl)-19-norpregnant-4,9 -diene-3,20-dione) having the following structural formula: οι

When it is mono-demethylated, it becomes 4-benzoin-2 1 -acetylsulfonyl-1 7 α -ethoxycarbonyl-11 cold-(4-N-decylaminophenyl)-19- Pregnancy-4,9-diene-3,20-dione. 21丄08-423 9(4-benzoin-21-decyloxy-17〇:-acetoxy-11 /3 -(4N,N-dimethylamino stupyl)-19-depregnant-4 , 9-diene-3,20-dione), having the following structural formula: 20 201002736

When it is mono-demethylated, it becomes 4-benzoin-21-methoxy-17α-ethyloxy-11 /3-(4-indole-aminophenyl)-19-depregated -4,9-diene-3,20-dione. 22. CDB-4306 (21-glycinate-17α-acetoxy-11 cold-(4 team 1 dimethylaminophenyl)-19-depregna-4,9-diene-3 , 20-diketone), having the following structural formula:

When it is mono-demethylated, it becomes 21-glycinate-17α-acetoxy-11 /9-(4-indole-ylaminophenyl)-19-norpregna-4. 9-diene-3,20-dione. 21 201002736 23.CDB-43 5 2(21-cyanothio-17α-acetoxy-11/3-(4N,N-diguanylaminophenyl)-19-depregnant-4,9- Diene-3,20-dione), having the following structural formula

S-CN

When it is mono-demethylated, it becomes 2 1 -cyanothio-1 7 a-acetoxy-1 1 /3 -(4-N-nonylaminophenyl)-19-norpregnancy- 4,9-diene-3,20-dione. 24. CDB-4362 (21-oxoethoxyethyl-7 α-acetoxy-11 /3 - (4:^-dimethylaminophenyl)-19-norpregnant-4,9- Diene-3,20-dione), having the following structural formula··

When it is mono-demethylated, it becomes 21-methoxyethenyl-17α-acetoxy-1 1 /5 -(4-indole-methylphenyl)-19-depregnant-4 , 9-diene-3,20-di 22 201002736 CDB-4453 (21-decyloxy-17α-ethoxylated _up-(4-N-methylaminophenyl)_i9-norpregnancy has been confirmed -4,9-diene-3,20-dioxime), the mono-demethylated derivative of CDB-4 1 24 has lower anti-glucocorticoid activity than its parent. Attardi et al., 2002, Mol. Cell. Endocrin 1 88:1 1 1-123, the contents of which are incorporated herein by reference. Any 19-demethylketone- or 19-norgestrel-derived antiprogestin (which has a dip in the annihilation of carbon π) can occur by any method known in the art. Monodemethylation of a amide-substituted benzene ring, as described in Example 46 of U.S. Patent No. 6,900,193, for the synthesis of N-demethylation procedures from dimethylaminophenyl precursors 17α-Ethyloxy-π/5-[4-(Ν-methylamino)phenyl]-21-methoxy-17-norgestrel-4,9-diene-3,2 0 -2 Hey. Other compounds which may be mono-demethylated to form compounds useful in the present invention include, but are not limited to, the following: Mifepristone (RU-486, 11 no-[4Ν, Ν-dimethyl Amino-based]-17/S-hydroxy-17-(p-propynyl)-est-4,9-dien-3-one) which becomes 11 /9 -[4 after mono-demethylation -Ν-Aminophenyl]-17/5-hydroxy-17-(1-propynyl)·est-4,9-dien-3-one having the following structure: 23 201002736

11 /3 -[4-N-methylaminophenyl]-17 /3 -hydroxy-l7 (1, C;, u* _4,9-dien-3-one is particularly useful in the present invention Anti-pregnancy to Habitat "Onapristone (l 1 point - (4N, N-dadalamylphenyl)-17 (2-海基-17-(3-Zhepropyl)-13 〇:-Although -4,9-di-salt - 56, then, after monomethylation, it becomes (1 1 call-(4-N-decylaminophenyl)-17 α _ 抱 基 - 1 7-(3-Light propyl)-13〇:-Estra-4,9-diene-3-8), having the following structure: 9H3

OH lysine (Lil〇pristone) (n call _(4N,N•dimethylaminophenyl)_17 /5-hydroxy-17-((2)-3-hydroxypropenyl) female _4,9 -diene-3-ketone) which, after mono-demethylation, becomes (11-[4_N_methylaminophenyl)-170,000-hydroxy-1 7-((Z)-3-hydroxypropenyl) Female _4,9-diene _3 ketone) having the following structure: 24 201002736

〇H 〇h -> Lilosterone ORG-3 1710 ((6 α , 11 cold, 17 /5 )-ll-(4N,N-dimethylaminophenyl)-6-methyl-4' , 5'-dihydrospiro[estra-4,9-diene-17,2'(3'Η)-furan]-3-one), which becomes (6α, after mono-demethylation 11 /3 ,17 y? )-;11_(4->4-Methylaminophenyl)-6-methyl-4',5'-di-argon spiro[Estra-4,9-diene- 17,2'(3'HVfuran]-3-one, having the following structure:

\

ORG-3 18 06((7 /3,1 1 /5 ,17 cold)-1 1-(4N,N-diaminoaminophenyl)-7-methyl-4',5'-dihydrospiro Ring [est-4,9-diene-17,2'(3'H)-furan]-3-one) which becomes mono-demethylated ((7 no, 110,000, 17 cold) - 11_(4-Ν-曱aminophenyl)-7-mercapto-4',5'-dihydrospiro[est-4,9-diene-17,2'(3'H)-furan] -3-ketone), having the following structure: 25 201002736 9H3

ORG-31806 9h3

0110-33245((1 1 stone, 17 6〇-17,23-epoxy-11-[(4>^:^-diamido)phenyl]-19,24-didebend-4, 9,20-Trien-3-one) which becomes (11 /3 ,17 a )-17,23-epoxy-11-[(4-anthracene-methyl)benzene after monodemethylation Base]-19,24-dinormethylene-4,9,20-trien-3-one, having the following structure: 9h3 9h3

Further contemplated for use in the present invention is monomethylaminophenyl-substituted 11/3-aryl-derived by mono-demethylation of a compound of formula I of U.S. Patent No. 4,82,060 Female diene is incorporated herein by reference in its entirety. Further contemplated for use in the present invention is a monoammonium-based surface group produced by mono-demethylation of a compound of the formula disclosed in U.S. Patent No. 26, 2010,027,036, 4,386,085, 4,447,424, 4,519,946, 4, 634, 695. - Substituted 19-nor steroids and 19-nor-D sterols, all incorporated herein by reference, wherein Ri is dimethylaminophenyl. Further contemplated for use in the present invention is monomethylaminophenyl-substituted by mono-demethylation of a compound of formula I as disclosed in U.S. Patent No. 4,359,401. 11 _ aryl estradiol, the entire contents of which are incorporated herein by reference, wherein Ri is dimethylamino. Further contemplated for use in the present invention is monomethylaminophenyl-substituted by mono-demethylation of a compound of formula I as disclosed in U.S. Patent No. 4,780,46. 13α-Alkyl-retentane (g〇nane), the entire contents of which are incorporated herein by reference. Further contemplated for use in the present invention is 11 cold aryl aryl diene having the general formula I of U.S. Patent No. 4,609,651, the disclosure of which is incorporated herein in its entirety . Further intending to be used in the present invention is 11 /5-aryl-4-estrene of the formula I of U.S. Patent No. 5,728,689, the disclosure of which is incorporated herein in its entirety by reference in its entirety in its entirety. Further contemplated for use in the present invention are the 11/3 _ aryl-4 estrene derivatives of Formula I of U.S. Patent Nos. 5,843,933 and 5,843,93, each incorporated herein by reference herein It is a monoamine group. Further in the present invention is the 11-aryl steroid disclosed in U.S. Patent No. 4,921,845, the disclosure of which is incorporated herein in 27 201002736 Further steps are intended to be used in the present invention. The lly9-aryl-residue (g〇na) _4,9-diene_3-one of the formula I of U.S. Patent No. 5,739, i25 is incorporated herein by reference. Incorporated herein by reference, wherein R2 is a monomethylamino group. Further step-by-step is intended to be used in the present invention. 11/5-aryl-甾·4,9-diene of the formula I of U.S. Patent No. 5,4,7,928, the entire contents of which is incorporated herein by reference. Wherein R2 is a monomethylamino group. Further intends to be used in the present invention is by Kan et al.

Biomono. Med. Chem. Lett. 17(4): 907-910 (2007) by mono-demethylation of a monoammonium phenyl-substituted oxa-steroid 6 produced by the compound, all cited The way is included in this article. Importantly, the monomethylamine group can be in the para, ortho or meta position of the phenyl group, but is preferably in the para position. In other specific instances, the present invention provides methods for improving the operational characteristics of 19-nor-sterols. Many of the 19-nor-steroidal anti-progestogens (including those disclosed in International Publication No. W097/41 145, incorporated herein by reference) are very difficult to operate amorphous solids. For example, these compounds are often difficult to separate and characterize and separate the purity of hydrazine. It has been unexpectedly discovered that certain 19-nor-sterol-derived anti-pregniniins having a dimonomethylamine-substituted benzene ring at the --position of carbon u crystallize in the form of a free base. Conversely, the free base form of the 19-steroid-derived anti-pregnancy with a dimethylamine-substituted benzene ring at the annihilation-position of the carbonium is an amorphous solid. Unintentionally combined with theory, an antiprogestin with a monodecylamine-substituted benzene ring at the Π/3-position of carbon 11 may be based on a higher charge relative to the dimethylamine-substituted compound 28 201002736 Density shows crystallization characteristics. In the carbon " η α methylamine-substituted benzene ring set /, there is an early 19-steroid _ derived anti-pregnancy & improved salt - formed special micro-jing Fang Xunming P 1 Sign. The anti-pregnancy of the i9-steroid derived from the monomethylamine-substituted stupid ring of 10 i /, 令,土土 f at the 1M-position of carbon 11 provides operation and purification advantage. In the other eight facts, the present invention teaches a method for identifying a compound having a selective progesterone receptor binding activity. These methods include binding and in vivo. The creatures, the eyes, the cockroaches, the cockroaches and the cockroaches, such as anti-McGinty, anti-Claube glucocorticoids, estrogen, mask, 5', A hormone, anti-glucocorticoid (ag , anti-carving hormone and anti-androgenic methods, and after sexual intercourse and anti-ovulation activity, wherein the lead compound of the present invention is used as a reference. ^ In another specific fact, the teachings of the present invention may also be directed thereto. Transcriptional activity in human cells' analysis of possible antiprogestins. At this time use in this # Θ t progesterone as a reference 'this analysis can supply about (1) candidate interaction with the pregnancy, (7) activated progesterone The interaction of the receptor plate with his transcription factor, and (3) the activation of the transcription complex at the Pwgester〇ne response elemem (PRE). Under this -experimental 纟PRE-dependent promoter gene, the human PR-B isoform (hPR_B) if body will be reported to anyone known to those skilled in the art. The cells are co-transfected into HeLa, HepG2 or T47D cells. Reporters may include, but are not limited to, luciferase, galactosidase, green fluorescent white fluorescent protein or yellow fluorescent protein. After transfection, the cells were treated with a candidate compound or one of the antiprogestins disclosed in the present application, which served as a positive control. After treatment, cells were assayed for the performance of the reporter. 29 201002736 In another specific aspect, the present teachings are directed to its ability to combat dexamethasone-induced cell death in cell line CEM-7 of human lymphocytes, and to anti-pregnancy disclosed in the present specification Compare the effects of hormones and test promising antiprogestins. In these experiments, dexamethasone can be added to the concentration that causes cell death. Then, RU486 (between 10 and 6 to 1〇-8Μ) is produced. The anti-progestin of the invention - or the test compound is used to treat the cells. Synthetic chemistry techniques known in the art can be used, such as those disclosed in U.S. Patent No. 6,86 1,415, which can be synthesized according to the present invention. Antiprogestin compounds are used. Under certain reaction conditions, certain functional groups may be interfered with by other reagents or reagents, and thus may require temporary protection. Protective groups in 'organic synthesis' (Protective Gr 〇ups m 〇rganic Synthesis),, 2nd edition, Tw heart (10) & pGM

The use of protecting groups is described in Wiley-InterSCience (l991). In a specific fact, the composition of the present invention comprises _ or a plurality of (four) receptor modulators (which include a monomethylamine-substituted benzene ring at the 11/3-position of carbon 11), or Acceptable salts. The salt compound can be obtained in a neutral or salt form depending on the processing conditions. Salt forms include hydrates and other conjugates, as well as crystalline polymorphs. Both free tests and salts of these end products can be used in accordance with the present invention. Acid addition salts may in some sense be originally known to use an alkaline agent (such as a metal test) or to be converted into a free test by ion exchange. It is also possible to use an organic or inorganic acid to form a salt which is obtained as a free base. In the preparation of acid addition salts, it is preferred to use such acids which are suitably formed in the salts acceptable for use in Pharmacy 30 201002736. Examples of such acids are hydrogen acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic acids, alicyclic carboxylic acids or sulfonic acids, such as formic acid, acetic acid, propionic acid, spearic acid, glycolic acid, lactic acid, malic acid, tartaric acid, Citric acid, ascorbic acid, uric acid, fumaric acid, maleic acid, hydroxy maleic acid, pyruvic acid, aspartic acid, glutamic acid, p-hydroxybenzoic acid, pamoic acid Ethanesulfonic acid, hydroxyethanesulfonic acid, stupid acetic acid, mandelic acid, dentate benzenesulfonic acid, toluenesulfonic acid, galactonic acid, galacturonic acid or naphthalenesulfonic acid. All crystalline form polymorphs can be used in accordance with the present invention.

Base addition salts can also be used in accordance with the present invention and can be prepared in a conventional manner by contacting the free acid form with a sufficient amount of the desired base. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The use of metals or amines, such as metal and soil metals or organic amines, forms pharmaceutically acceptable test addition salts. Examples of metals used as cations are sodium, potassium, calcium, magnesium and the like. Examples of suitable amines are amino acids such as lysine, bilirubin, triethanolamine, diamine, N-methylglucamine and the like. The composition of the present invention can be prepared into an oral, parenteral, transdermal, or a direct administration, or a suitable dosage. The parenteral administration includes, but is not limited to, intravenous: Subcutaneous, intramuscular, intrathecal, and intra-articular., peritoneal cavity, herein, orally administered, or "a therapeutic agent of a palatable individual or its composition k" includes delivery to a subject placed in the mouth of the individual,八f The preparation or group ',,, whether or not the preparation or composition 201002736. Therefore, the drug is administered. Oral administration "including buccal and sublingual and esophagus (for example, in the case of absorption, the composition of the present invention is formulated into a rectal examination containing a suppository base] including but not limited to cocoa butter or glycerin vinegar. The composition of the present invention may be in the form of, but not limited to, a solution, a suspension or an emulsion, and may be administered as a sol in the form of a propellant (e.g., a two-gas or three-gas fluorocarbon). For delivery via the skin, compositions of the invention are formulated, such as creams, ointments, lotions, pastes, gels, drapes, patches or films. Such electroforms may include any suitable excipients, for example Penetration enhancers and the like can also be formulated for parenteral administration (including but not limited to by injection or continuous infusion). The formulation for injection can be suspended in an oily or aqueous vehicle. In the form of a liquid, solution or emulsion. Such compositions may also be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile, pyrogen-free water, WFI and the like. The composition of the composition is formulated into a reservoir preparation which can be administered by implantation or by intramuscular injection. Appropriate polymeric or hydrophobic materials (such as 'emulsions in acceptable oils'), ion exchange resins can be utilized. Formulating such compositions, or formulating them as sparingly soluble derivatives (such as, for example, sparingly soluble salts). The compositions of the invention may also be formulated as liposomal formulations. Liposomal formulations may include cells or stratum corneum throughout the fungus. 'Liposomes fused to the cell membrane, as a result, the contents of the liposome are delivered to the cells. For example, U.S. Patent No. 5, 〇77, 211, Redziniak 32 201002736, to Yarosh, U.S. Patent 4, The liposomes described in U.S. Patent No. 4,508,703, the entire disclosure of which is incorporated herein by reference. Ingots, chewable ingots, foaming ingots, double-layer ingots, etc.), capsules (caplets), capsules (such as soft or hard gelatin capsules), powders (eg, packaged powders, dispersible) Foaming agents or powder), tablets, kits (sachets), bean shape capsule Qin "" ⑷, lozenges, pellets, granules,

Microparticles, encapsulated microparticles, powder aerosol formulations, or any other solid dosage form that is modestly modified for administration. Tablets can be prepared according to any of a number of related and well known pharmaceutical techniques. In a specific fact, lozenges or other solid dosage forms can be prepared by using processes including, but not limited to, one or a combination of the following methods: (1) dry core, (2) direct compression, (3) grinding (4) Dry or non-aqueous granulation, (7) wet granulation, or (6) fusion. In the individual steps of the wet granulation process for the preparation of the key preparation, the blood type is ground and sieved, dry powder mixed, wet lumped (massi: g), into: - < Dry granulation involves pressing on a heavy-duty rotary tablet press, :::::: compacted into a thick lozenge or strip, then by grinding operation, something else: ¥ by vibrating granulator, strip The block breaks into granular particles. The steps include... mixing powder, compacting (dry pressing or granulation). Blood type 妯 ^ 7 Μ唧 ( 条 条 条 条 条 条 条 条 条 条 条 条 ( ( 条 条 ( 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在A pre-prescription blend on a beetle to prepare a solid dosage form of 33 201002736. Then processed (eg, compacted, type. °, knife, such as a blend, and further encapsulated H dispersion, etc.) To become any desired agent, it is possible to prepare a tablet by squeezing the invention with the invention of the invention, the addition of the powder, or the granulation composition." The syllabary generally means that it is suitable for the original taste of the P # serving, The uncoated tablet 'It's simple to replace the ten, station # 》 the second borrower taps before extrusion, and then the final compression to prepare. Can be coated with the red moon, or mixed separately To provide a dosage form with the advantages of improved handling or storage testing. In a specific case, any such coating will be selected so as not to substantially delay the onset of the therapeutic effect of the compositions of the invention after administration to an individual. When used in this article, "hanging ingots" - By means of a compacted tablet, it will decompose rapidly after it is placed in water. Suitable liquid dosage forms for the compositions of the invention include solutions, aqueous or oil: core floats, elixirs, syrups, emulsions, liquid aerosols Formulations, gels, <ointments, etc. 4. Such compositions may also be formulated as dry products, which may be reconstituted with water or other suitable vehicle when used. In the specific case, 'in the liquid or half _ The solid composition is stored in a closed valley, maintained at room temperature, refrigerated (eg, at a temperature of about 5_1 (rc) or a frozen shirt' for about i'2'3, 4, 5, 6, 7, 8, 9, 10, After 11 or 12 months, at least about 9%, at least about, at least about 95%, or at least about 975% of the original antiprogestin compound provided herein is shown. Right hope that the composition of the invention may comprise one or more A pharmaceutically acceptable excipient. As used herein, the term excipient, means any substance that is not itself a therapeutic agent for the treatment of 34 201002736, and is used as a delivery therapeutic agent to a second drug composition. Improve its handling or storage characteristics = two: :) thin: the bit Forming amount of agents include (without also illustrates Shu, typically only read • * 1 by Shu agents, wetting agents, lubricants, '... movable modifiers agents or surfactants, perfumes, county floating agent,

Emulsifier, non-aqueous agent, preservative, antioxidant 1 agent, system for whole pH and osmotic pressure _ such as buffer), (iv) agent, thickener, sweetener, flavoring agent, taste masking agent 1 A toner or dye, a penetration enhancer, and a substance added to improve the appearance of the composition. The dosage agent to be used in the composition of the present invention may be a solid, a semi-solid, a liquid or a combination thereof as needed. The composition of the present invention containing an excipient can be prepared by any known pharmaceutical technique, including mixing an excipient with a drug or a therapeutic agent. The compositions of the present invention may optionally comprise one or more pharmaceutically acceptable diluents as excipients. Suitable diluents include, for example, individual or mixed lactose, including anhydrous lactose and lactose monohydrate; starch, including directly compressible starch and hydrolyzed starch (eg, CelutabTM and EmdeXTM); mannitol; sorbose Alcohol; xylitol; dextrose (such as CereloseTM 2000) and dextrose monohydrate; calcium hydrogen phosphate dihydrate; thinner for sucrose; fine texture broken sugar (confectioner, sugar); Dicalcium calcium monohydrate; calcium sulfate dihydrate; granular lactic acid trihydrate. glucose binder (dextrates); inositol; hydrolyzed anthraquinone solid; direct bond starch; cellulose 'including microcrystalline cellulose , food grade source of alpha _ and amorphous cellulose (eg, RexcelTM) and powdered cellulose; calcium carbonate; glycine oxime. 35 201002736 bentonite, polyvinylpyrrolidone; and the like. Such diluents, if any, constitute from about 5% to about 99%, from about 10% to about 85%, or from about 2% to about 8%, based on the total weight of the composition. It is preferred to select any diluent or diluent to exhibit proper flow characteristics and to exhibit compressibility where the tablet is desired. *τ uses the use of superparticulate microcrystalline cellulose (i.e., the addition of microcrystalline cellulose to the wet granulated composition after the dehydration step) to improve hardness (for tablets) and/or disintegration time. The compositions of the present invention may optionally comprise one or more pharmaceutically acceptable disintegrants as excipients, particularly for lozenges, capsules or other solid formulations. Suitable disintegrants include individual or mixed starches, including glycolic acid 'sodium powder (such as Pen West's Exp lotabTM) and pregelatinized corn starch

Powder (eg Nati〇naiTM i55i 'Nati〇naiTM ι 550 and c〇iocornTM uoo), clay (eg VeegumTM HV), cellulose, such as purified cellulose, microcrystalline cellulose, methyl cellulose, carboxymethyl Cellulose and sodium carboxymethylcellulose, croscarmellose sodium (eg Ac-Di_SolTM from FMC), alginate, cropodone (crosp〇vid〇ne) and gum Such as agar, guar, xanthan, locust bean, karaya, pectin and tragacanth. The disintegrant can be added at any suitable step during the preparation of the composition, particularly prior to the granulation step' or during the lubrication step prior to compaction. Such penetrants', if any, constitute a total of from about 0.2% to about 30%, from about 0.2% to about 10%, or from about 0.2% to about 5%, by total weight of the composition. The compositions of the present invention may optionally comprise one or more pharmaceutically acceptable adhesives or adhesives as excipients, particularly for lozenge formulations. This type of adhesive and adhesive IJ|J, preferably {giving 9 a sufficient amount of coagulant to make the bulking force to allow normal lifting operations, such as screening size, lubrication, compaction and packaging' but still allow The rotatory agent disintegrates and absorbs the composition after ingestion. Suitable binders and adhesives include, individual or mixed Allah

Berber gum; tragacanth, sucrose; gelatin; glucose: starch, such as but not limited to pre-gelatinized starch (eg NationalTM 1511 and Nati〇naiTM 1500); cellulose, such as but not limited to methylcellulose and carboxyl Carmellose sodium (eg Tyl0seTM); salts of alginic acid and alginic acid; magnesium aluminum citrate; PEG; guar gum; polysaccharide acid; bentonite; povidone (p〇vid〇ne), eg poly Vesone K-15, K-30 and K-29/32; polymethacrylate; HPMC; hydroxypropyl cellulose (eg KlucelTM); and ethyl cellulose (eg EthocelTM). Such binders and/or adhesives, if any, constitute a total of about 5% to about 25%, about 7575% to about 15%, or about 1% to about 〖the total weight of the composition. 〇〇/〇. The compositions of the present invention may optionally include one or more pharmaceutically acceptable humectants as excipients. Non-limiting examples of surfactants useful as wetting agents in the compositions of the present invention include quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, and spirulina. CetylpyHdinium chloride, dioctyl sulfosuccinate, polyoxyethylene alkyl phenyl ether such as nonoXyn〇l 9, nonyl phenolphthalein 1 and octyl benzene (〇ctoxyn) 〇l)9, poloxamer (p〇l〇xamers) (polyoxyethylene and polyoxypropylene block copolymer), polyoxyethylene fatty acid glycerides and oils, such as polyoxyethylene 37 201002736 dilute (8) octanoic acid / Hydrogenation of the oil by mono- and diglycerides of decanoic acid (such as Labrasc^ of Gattef〇sse), polyoxyethylene (35) t sesame oil and polyoxyethylene (10); polyoxyethylene hydrazines, such as polyoxyethylene ( 2 ()) _ hard @ 醯 醯 base, polyoxyethylene fatty acid esters, such as polyoxyethylene (4 〇) stearate, polyoxyethylene sorbitan ester, such as polysorbate 2 〇 and Polysorbate 80 (eg TweenTM 80 from ICI), propylene glycol fatty acid esters such as propylene glycol laurate (eg Catt) EuroglycolTM of efosse, sodium lauryl sulfate, fatty acids and their salts, such as oleic acid, sodium oleate and triethanolammonium oleate, glycerol fatty acids such as glyceryl monostearate, sorbitan, For example, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof. Such humectants, if any, collectively comprise from about 0.25% to about 5%, from about 0.4% to about 10%, or about 0.5, of the total weight of the composition. /. To about 5%. The compositions of the present invention may optionally comprise one or more pharmaceutically acceptable lubricants (including anti-adherents and/or slip agents) as excipients. Suitable lubricants include 'individually or in combination with glyceryl behenate (eg CompritolTM 888); stearic acid and its salts, including magnesium stearate (magnesium stearate), calcium and sodium; hydrogenated vegetable oils (eg Sterotex) TM); colloidal silica dioxide eve; talc; wax; boric acid; sodium alginate; sodium acetate; sodium fumarate; gas 4 匕 DL 'DL-free amine mann; PEG ({ column such as CarbowaxTM 4000 CarbowaxTM 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if any, constitute a total of from about 0.1% to about 10%, from about 0.2% to about 8%, or from about 38% to about 5% of the total weight of the composition. Suitable anti-adhesive agents include talc, corn starch, DL-leucine, sodium lauryl sulfate, and metal stearates. Talc is an anti-adhesive or slip agent that, for example, reduces the adhesion of the formulation to the surface of the device and also reduces static in the exchange. One or more anti-adhesive agents, if any, constitute from about 〇_1% to about 10%, from about 0.25% to about 5%, or from about 0.5% to about 2% of the total weight of the composition. A slip agent can be used to promote the flow of the solid formulation. Suitable slip agents include colloidal silica dioxide, starch, talc, tri-phosphate, powdered cellulose, and magnesium tricaprate. Colloidal cerium oxide is particularly preferred. The compositions of the present invention may include one or more antifoaming agents. Simethicone is an exemplary defoamer. The antifoaming agent, if any, constitutes from about 0.001% to about 5%, from about 〇q 〇 1%' to about 2%, or from about 0.001«% to about 1 〇/〇 of the total weight of the composition. Antioxidants exemplified in the present invention include, but are not limited to, #butylated hydroxytoluene, butylated hydroxyanisole, potassium metabisulfite', and the like. One or more antioxidants, if desired, are typically from about 0.01% to about 2.5% by weight, such as about 0.01%, about 0.05%, about 0.1%, about 5%, about 5%, about 5%, about ??? An amount of 5%, about 1-75%, about 2%, about 2.25% or about 2.5% is present in the compositions of the present invention. In various specific facts, the compositions of the present invention may include a preservative. Suitable preservatives include, but are not limited to, benzalkonium chloride, methylparaben, ethyl ester, propyl or butyl ester, phenylhydrin, phenylethyl alcohol, benzethonium chloride, _ 39 201002736 hydroxybenzoic acid The ester or propyl ester and sorbet are preservatives in an amount of from about two: 0.01% to about 2.5 by weight. /. The amount exists. Typically, the 0.5% or about in a particular fact, the compositions of the present invention may optionally include a buffer. Buffers include formulations that reduce pH changes. Illustrative classes of buffering agents useful in the various specific aspects of the invention include salts of Group A metals, including, for example, cerium carbonate salts of Group IA metals, carbonates of Group VIII metals, alkali metal or soil-measuring metal buffers. , buffer, granules, nano buffer or lock buffer. Suitable buffering agents include any of the foregoing carbonates, discates, hydrogen sulphates, citrates, terephthalates, acetates, phthalates, tartrates, succinates, such as phosphoric acid, Citric acid, ceradic acid, acetic acid, hydrogen carbonate and sodium or potassium carbonate. Non-limiting examples of suitable buffers include aluminum, magnesium hydroxide, calcium glycinate, calcium carbonate, hydrogen carbonate, boric acid, calcium carbonate, citric acid dance, glucose i*·about, glycerol acid, hydrogen. Oxidative feeding, lactating mother, calcium phthalate, calcium phosphate 'calcium succinate, calcium tartrate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, dipotassium phosphate 'disodium hydrogen phosphate, disodium succinate' anhydrous aluminum hydroxide Swirling gel, magnesium acetate, magnesium aluminate, magnesium borate, magnesium hydrogencarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium phthalate, magnesium oxide, magnesium phthalate, Magnesium phosphate, magnesium citrate, magnesium succinate, magnesium tartrate, potassium acetate, potassium carbonate, potassium hydrogencarbonate, potassium borate, potassium citrate, potassium potassiumate, potassium phthalate, potassium potassiumate, potassium polyphosphate, Coke potassiumate, succinic acid clock, potassium tartrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium hydroxide, lactic acid 40 201002736 sodium, o-benzene Sodium citrate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, Sodium half carbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, synthetic smithite, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, trisodium phosphate and trishydroxyl amide (trometamol) (- based in part on the list provided in The Marck Index, Merck & Co. Rahway, NJ (2001)). Furthermore, any combination or mixture of two or more of the above mentioned buffering agents can be used in the pharmaceutical compositions described herein. One or more buffers, if desired, are present in the compositions of the present invention in an amount of from about 0.01% to about 5% by weight or from about 0.01% to about 3% by weight. In various specific instances, the compositions of the present invention may include one or more formulations that increase viscosity. Exemplary viscous formulations include, but are not limited to, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, carrageenan, carbopol & / or combinations thereof. Typically, one or more tackifiers, if desired, are present in the compositions of the present invention in an amount of from about 1% to about 1% by weight or from about 0.1% to about 5% by weight.

V. In various specific facts, the compositions of the present invention include, an "organoleptic agent" to improve the functional properties of the composition. As used herein, "functional agent" means any composition that improves the composition of the present invention. The taste or odor of the article' or an excipient that assists in masking its unpleasant taste or odor. Such formulations include sweeteners, flavoring agents and/or taste masking agents. Suitable sweeteners and/or flavoring agents include A sweetening or flavoring agent for a pharmaceutical composition. Any functional agent typically ranges from about 1 mg/ml to about g/ml, from about 0.5 mg/ml to 5 mg/ml, or about/ml. Amounts are present in the compositions of the invention. Brother 41 201002736 Exemplary sweeteners or flavorings include, but are not limited to, arabinose, anethole, anise 〇il, aromatic hydrazine, benzaldehyde , benzofurald oxime, cyclodextrin, caraway, coriander oil, cardamom oil, alfalfa seeds, alfalfa alcohol, stalks, cherry juice, cherry syrup, cinnamon (cinnam〇n ), cinnamon oil, Guishui, citric acid, citric acid syrup, clove oil (Cl0ve 〇il), cocoa, cocoa syrup, coriander oil, dextrose, eri〇dicty〇n, hairy grass FluidXtract, hairy grass syrup, fragrance, ethyl acetate, ethyl vanillin, fennel oil (fennel 〇u), ginger ginger dip, ginger resin oil, right Sugar, glucose, sugar, maltodextrin, glycerin, licorice (glycyrrlnza), licorice, licorice extract, licorice pure extract, licorice "•I· / paste licorice syrup, honey, etc. - alcohol touch ( Iso-alcoholic elixir), lavender oil, lemon oil, lemon tart, mannitol, nutmeg oil, orange bitter, bitter oil 'Lianhua oil, orange blossom water, oil, orange peel, sweet skin, orange alcohol, orange syrup, peppermint, peppermint oil, mint alcohol 'mint water, phenylethyl alcohol, raspberry juice, € bowl of sugar, rosemary oil, rose oil, concentrated rose water, saccharin Calcium saccharin, sodium saccharin 'sarsaparilla syrup, salsa, sorbitol solution' spearmint, spearmint oil, sucrose, sucral〇se, syrup, rucola oil ( Thyme 011), t〇lu baisam, toluoli gum t, vanilla (vaniUa)' vanilla, vanillin, wild cherry syrup or a combination thereof. Illustrative taste masking agents include, but are not limited to, cyclodextrins, cyclodextrin emulsions, cyclodextrin particles, cyclodextrin complexes, or combinations thereof. , 42 201002736 The suspension of the certificate includes, but is not limited to, sorbitol trans, A, "glycemic sugar syrup, gelatin, lycopene, cellulose, stearic acid gel And hydrogenated edible fat. Exemplary emulsifiers include, but are not limited to, phospholipid monooleate and arabic eight oil, apricot, and 1 vehicle including 'but not limited to food /, coconut oil, oily ester , propylene glycol and ethanol. Previously used excipients may have multiple roles, as in the technical field. For example, 'house powder can be used as a filler and disintegrant. It should not be interpreted in any way: the above excipient classification is interpreted as a limitation. < Service = any means for administering the compositions of the present invention, including but not limited to oral inhalation, second intestine, sublingual, transdermal, transrectal transmucosal, topical, transluminal, buccal administration or combination. Non-menstrual :: static:: inside: intrapulmonary, abdominal cavity " lower, intramuscular 1 2 p η in the pool and intraventricular. The therapeutically effective amount of the composition required for use in therapy can be determined by the attending physician depending on the length of active time desired, the age and condition of the patient to be treated. However, usually for humans = the agent 'typically ranges from about 1 mg/kg to about 5 g/kg per day, for example about i micrograms/kg to about gram per kilogram per day or About 1 microgram/kg to about 100 micrograms/kg per day. For most large mammals, the total daily dose is from about 1 to 1 gram per gram: preferably from about 2 to 80 mg. The dosage regimen can be adjusted to best suit the response. The desired θ ϊ can be conveniently administered in a single dose, or administered in multiple doses at appropriate intervals, for example, two, 43 201002736 three, four or more subdose per day. For example, a composition of the invention can be administered to an individual to provide an antiprogestin in an amount of from about 1 microgram/kg to about 1 milligram per kilogram of body weight of the individual, such as about 1 microgram/kg, about 25 micrograms per second. Kilograms, approximately 50 μg/kg, approximately 75 μg/kg, approximately 1 μg/kg, approximately 125 μg/kg, approximately 150 μg/kg, approximately 175 μg/kg, approximately 200 μg/kg, approximately 225 μg /kg, approximately 250 μg/kg, approximately 275 μg/kg, approximately 300 μg/kg, approximately 325 μg/kg, approximately 350 μg/kg, approximately 375 μg/kg, approximately 4 μg/kg, approximately 425 μg /kg, approximately 45 μg/kg, approximately 475 μg/kg, approximately 500 μg/kg, approximately 525 μg/kg, approximately 550 μg/kg 'About 575 μg/kg, approximately 6 μg/kg, approximately 625 Micrograms/kg, approximately 650 μg/kg, approximately 675 μg/kg, approximately 700 μg/kg, approximately 725 μg/kg, approximately 750 μg/kg, approximately 775 μg/kg, approximately 8 μg/g/ Kilograms, approximately 825 μg/kg, approximately 85 μg/kg, approximately 875 μg/kg, approximately 900 μg/kg, approximately 925 μg/kg, approximately 950 μg/kg 'approx. 975 μg/kg or approximately i mg/kg body weight. Patients receiving treatment with the compositions of the invention should routinely monitor their serum estrogen and glucocorticoid levels. The following non-limiting examples are provided to assist in understanding the teachings of the present invention. Example 1. Preparation of a formulation of the present invention into a tablet. To obtain a tablet of the present invention, the following ingredients 44 201002736 can be pressed together in a tablet press: 1 〇·〇mgη泠-[4 -N-methylaminophenyl] 17 (λ 7 /3 - thiol 140.5 mg, 69.5 mg, 2.5 mg, 2.0 mg, 0.5 mg, to obtain -7-(indolyl)- _4,9-dilactose鲷 搬 搬 搬 乙 乙 „ „ 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比Medium: j component of this 1〇〇_〇mg n/5_[4-N-methylaminophenyl μ ρ _ hydroxy alley ^ - (- propyl block) - female-4,9-diene 343.4 mg castor oil 608.6 mg benzyl benzoate Example 2. Measurement of in-tube binding affinity soils comprising a 19-nor steroid of a phenyl ring substituted with a monodecylamine at the "stone-position" of carbon" using a cell-soluble negative preparation for competition Binding assay.

To measure binding to the progesterone receptor (PR) and glucocorticoid receptor (GR) in rabbits, cells/strain were prepared from the uterus or thymus of premature rabbits that previously provided estradiol. For binding to rabbit uterus PR, cytosol containing rabbit uterus PR was prepared in TEGMD buffer solution (10 mM Tris, pH 7.2, 1.5 mM EDTA, 0.2 mM sodium molybdate, 10% glycerol, ImMDTT), and with 6 nM 1 2-[3H]progesterone (NEN Life Science Products; 45 201002736 52 Curie/mole) was cultured together; the test compound was added at a concentration from 2 to ΙΟΟηΜ. For binding to rabbit thymus GR, cytosol was prepared in TEGMD buffer solution and incubated with 6nM 6,7_[3H]dex (dexamethasone) (NEN; 35 or 40 Curie/mole); The test compound was added to a concentration of 100 nM. To measure binding to human progesterone receptor _A (rhPR-A) or progesterone receptor-B (rhPR-B), prepared from Sf9 insect cells infected with recombinant baculovirus expressing hpR_A or hPR-B Cell solute extract. Sf9 cytosol (prepared in TEGMD buffer solution containing the following protease inhibitors: 100 μg/ml bacitracin, 2 μg/ml aprotinin, 94 gram/home luciferin ( Eupeptin), 2 μg/ml pepsin A) and 6_8 nM 1,2,6,7,16,17-[311] progesterone (NEN, M3 Curie/mole); The test compound was added from a hydrazine to a concentration of 1 〇〇 nM. After overnight incubation at 4 ° C, the bound and unsuper-conjugated [3h]-steroids were separated by adding live heptasaccharide of coated dextran and centrifugation at 2100 xg for 15 minutes at 4 °C. Pour out the supernatant from the GR measurement, and name

Count in the BeCkman LS-1800 liquid scintillation counter. The supernatant containing pR was pipetted into a 24-well microplate, a Μ and counted in a Packard TopCount Concentration Scintillation Counter. The count of each parent knife (cpm) is recorded in Packard, RIASmartTM, and the ECw dry > 5G value is calculated. The relative binding affinities of each test compound were calculated as follows: (Ec & ECM of the standard) x100. The standard for the PR binding assay was P4, and the standard for the GR binding assay was dex ° 46 201002736 κ Example 3. Measurement of antiglucocorticoid activity and progesterone antagonist activity in vivo, in order to measure the activity of the test compound in the living body, in the presence of appropriate hormone sensitivity reporter genoplasts (eg PRE2-tk-LUC, which contains two copies of the progesterone/glucocorticoid/, renin response element and the firefly luciferase (LUc) reporter gene upstream of the thymocyte nuclear bud kinase (tk) promoter gene Transfection was grown on monolayer cultures in phenol red-free DMEM supplemented with 1% fetal bovine blood e (FBS), 1 〇 unit/ml penicillin G, and 1 〇 microgram/ml streptomycin sulfate. T47D_c〇 human breast cancer cells. Transfected t47d_c〇 cells are cultured with a (predetermined) maximum stimulatory concentration of progesterone (eg P4) with or without various concentrations of test compound ^ using Promega's Insect luciferase assay system for measuring LU C activity, and determine the IC5〇 of the test compound. In order to measure the activity of glucocorticoid antagonist in vivo, the appropriate hormone sensitivity reporter gene plastid (such as PRE^tk-LUC) and GR expression vector /, HepG2 human hepatic blastoma cells grown on a monolayer culture (with i〇% FBS and penicillin/streptomycin supplemented) in the absence of discretionary red ΜΕΜα, with or without various concentrations of the test. Under the compound, the transfected HePG2 cells were cultured for 2 hrs with the (predetermined) maximum stimulating concentration of dexamethasone. By measuring the LUC activity, the IC5 受 of the test compound was determined. Benzene and norxylamine antiprogestin substituted with monomethylamine will show higher IC5 比 than the same compound including benzene ring substituted with monomethylamine at the same position (thus there are still more 47,070,027,36 lower) Glucocorticoid activity, so it is suitable for long-term administration. [Simplified description] No [Main component symbol description] No 48

Claims (1)

201002736 VII. Scope of application for patents: 1. A method for treating sympathetic stagnation of human pregnancy                                     The base amine = substituted =) = the antiprogestin has a lower anti-progesterone than the same compound as the antiprogestin except for the "methylamine-substituted benzene ring" at the carbon "stone position The method of claim 2, wherein the antiprogestin has a benzene ring as described above with the antiprogestin except at the position of carbon n. The anti-progestin activity of the same compound. The method of claim 1, wherein the antiprogestin comprises dimethylamine by addition to the antiprogestin at a u/s-position of carbon η. - a method of monomethylation of the same compound of a substituted benzene ring. The method of the first aspect of the patent of the patent of the patent of the present invention, wherein the progesterone-dependent symptom is selected as follows: endometriosis, Dysmenorrhea k (dySmen〇rrhea), breast cancer, uterine fibroids Uterine version 〇 1 call and Intrauterine film group consisting of hyperproliferation. 5. The method of claim 4, wherein the antiprogestin is 11-[4-N-methylaminophenyl]-17-dozenyl- 17-propenyl)- Dien-3-one. The method of claim 4, wherein the anti-pregnancy is a compound of the following formula: , 49 201002736 D X is N-methylamino; Ri represents hydrazine, NOH or NO-fluorenyl; R. 2 represents hydrogen or acetyl group; and R3 represents methoxy, decyloxy, ethoxylated, decyloxy, 8 - alkoxy, aCetylthe 〇nyl, glycinate, vinyl ether, ethoxymethyl, methyl carbonate, ketone, methyl, hydroxy or ethoxy. 7. The method of claim 5, 5 or 6, wherein the antiprogestin is administered at a dose of from 0.5 mg/kg to 500 mg/kg. 8. A method for improving 1-9-nor-type solid-state _ hopper + >& mysterious cheeks to know the operational characteristics of anti-progestin, including (a) providing 19-depreservative ketone 19 Feng H, slave ninety (four) times 19-normethanone-derived antiprogestin, (b) chemically modified stepping shovel, & 1 antiprogestin, so that in the anti-progestin carbon The benzene ring at the 11/3 position, and (4) the chemically 7 methylamine _ substituted cyclin may be used to produce the antiprogestin of step (4). 抗 ^ (8) anti-pregnancy 9 · as claimed The 1Μ-position of the 8th item carries the 19-nor-methyl group of the benzene ring by monomethylation of the anti-progestin derived from carbon 11 alcohol by dimethylamine_substitution 1〇·If you order the anti-progestin of step (b) of the patent scope item 8 , 4 , wherein the anti-pregnancy 50 201002736 of step (a) is CDB-4124. 8. Pattern: No 51