TWI312680B - Use of antiprogesting for prophylaxis and treatment of hormone-dependent diseases - Google Patents

Description

1312680 IX. Description of the invention: [Technical field to which the invention belongs] The use of anti-progestogens to prevent and treat hormonal-dependent diseases. The present invention further relates to the prevention and treatment of a sputum-dependent disease, particularly breast cancer, comprising a pharmaceutical composition and a dosage form of an antiprogestin. The antiprogestin which is particularly preferred for use in the present invention is an antiprogestin β (4 乙 ^ Η 7(3_ hydroxy _17α-(1,1,2,2,2-pentafluoroethyl)-female '9-two Oral ketone or a pharmaceutically acceptable derivative thereof or the like. [Prior Art] Internal knives: Therapy represents a sputum-free, minimally toxic, palliative and palliative treatment for metastatic breast cancer. Standard palliative therapy and adjuvant therapy after initial treatment mainly use the anti-emotional hormone tamaoxifen. However, Tamosi can not cure breast cancer. Therefore, progesterone or aromatase is used: Tongshi is used for the second phase of treatment. Before menopause In female oophorectomy, the analogy between tamoxetine and LHRH (lutein hormone release hormone) achieves comparable results (Η·Τ· Mourids〇n et al. Eur. J. Cancer Clin. 〇nCo1·, 24, ΡΡ·99-105, 1988). Although ',,;, and Moses are widely used as adjuvant therapy for breast cancer, their use as a preventive training is problematic because this therapy shows intrauterine The increase in membrane tumor rate (LN. White, Carcinogenesis, 20 (7): 1153_60, 1999) Anti-progestin represents a relatively novel and promising therapeutic agent that has a significant impact on breast cancer treatment. Although antiprogestin was originally created for non-surgical pregnancy with drug 118881.doc 1312680 (European Patent No. 129 No. 499), some anti-progestogens, such as the endocrine therapy of breast cancer in the control group, the luteinizing hormone receptor (τ. Maudelonde et al.:; GM KHjn et al.

Manipulation of Cancer: Peptides, Grow Factors and New (Anti) Steroidal Agents, Raven Press, New York, 1987, pp. 55-59) is of considerable importance. This new strategy for endocrine therapy is based on the antitumor activity of antiprogestin in an in vitro xanthophynal receptor-positive human breast cancer cell line. Specifically, the anti-progestin onions (onaprist〇ne) and mesaconone (the anti-progestin) were studied in a mouse-derived hormone-dependent sedative breast tumor model and a rat DMBA- and NMU-induced breast tumor model. Ru 486) Anti-tumor mechanism (MR Schneider et al. Eur_J. Cancer. Clin. Oncol., V〇l. 25, No. 4, ρρ·691-701, 1989; H. Michna et al. Breast Cancer Research And Treatment 14: 275-288, 1989; H. Michna J. Steroid. Biochem. Vol. 34, Nos 1-6, pp. 447-453, 1989). However, due to the low activity and side effects involved in the use of ketone, this compound cannot be recommended as a single agent for the breast cancer control group (D. Perrault et al. J. Clin. Oncol. 1996 Oct, 14(10), Pp. 2709-2712). Antiprogestin compounds are suitable for the initiation of abortion and the control of pregnancy after sexual intercourse, such as contraceptives for women (WO-A 93/23020, WO-A 93/21927), and further for the treatment of hormonal irregularities, Used to initiate menstruation and start childbirth. A further value is in the field of hormone replacement therapy (WO-A 94/18983), for example, treatments associated with menstrual difficulties, and endometriosis (European Patent No. A 0 266 3 03) and uterine fibroids. £118881.doc 1312680] 7α-fluoroalkyl steroids have strong antiprogestin activity and are described in WO 98/34947. Advanced techniques or antiprogestins based on their anti-tumor activity often exhibit certain disadvantages. 2 For example, although the anti-progestin of the prior art shows that the anti-emotional hormone activity is not suitable for the hormone-dependent disease-specific oral therapy such as breast cancer, the first technical formula and the beauty service show Strong anti-glucocorticoid side effects are associated (compared to LM Kettel et al.

Fertil. SteHl. 1991 Sep, 56(3), pp. 402-407; X. Bertagna^ p-endocrinology 1997; 22 Suppl", pp η (9), which in addition shows only mild activity in clinical trials (re-limb (10) this

Clin. Oncol. 1996 Oct, 14(10), pp. 2709-2712) 〇 Regarding the side effects of other hormone-based therapies, as described above, the administration of tamaoxifene can cause

Attack on the increase in the incidence of sputum in the sputum (I N

White, Carcinogenesis, 20(7): 1 153-60, 1999) 另一 Another problem with previous techniques is the lack of bioavailability of the team. Therefore, it is generally applied at a high dose, causing an adverse side effect of the 月 丨 丨 core. In addition, oral administration is preferred based on the convenience of the patient, the medication, and the water consumption. And there is still a need for breast cancer to associate with Tamoxifen. In addition, the compounds require not only therapeutic activity but also other hormone-dependent disease-preventing activities. Preventive therapy showing that this compound is not suitable for increasing the incidence of endometrial cancer in healthy women' I can be obtained without other appropriate compounds (Compared with L, ~Catch et al. The Lancet, Vol. 356, Sept. 9, 2000; 881 ·887). U8881.doc 1312680 SUMMARY OF THE INVENTION One of the objects of the present invention is the hormone or pre-emergence of pre-cancerous cancer, which was previously taught to prevent or treat defects such as sputum-dependent diseases. What is especially needed is a method of administering a hormone-dependent disease. Second, prevention and treatment, such as breast cancer, is known to be superior to the method including the replacement of the nest.

Sexually ill, this special f is to provide surgery such as breast cancer _ 蒙 依赖 = = = = = = = ======================================================================

A method for the treatment and prevention of hormone-dependent diseases such as breast cancer. J "The further object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of breast cancer and other anti-tumor agents comprising a potent anti-tumor agent. The anti-progestin of the present invention and a medicament containing the same The composition and the form of the agent unexpectedly achieve these... In this regard, the particularly antiprogestin is the antiprogestin Up-G-ethyl phenyl)-17β-hydroxy]7α_ (^.--pentafluoroethyl) Xingtai-seven-dienyl ketone or a pharmaceutically acceptable derivative thereof or the like. Further object of the present invention is to provide, for example, an antiprogestin 丨丨Ρ_(4-ethyl benzophenone) 170-light -17 €1-(1,1,2,2,2-pentafluoroethyl)-although the antiprogestin of the pharmaceutically acceptable derivative or its analogous substance, especially the 4,9-dioxa-3-one Suitable for oral administration. The present invention is based on certain antiprogestins, in particular 11β-(4-ethylphenyl)-170-hydroxy-17〇1-(1,1,2,2,2-pentafluoroethyl) - Estradiol-4,9-dien-3one or a pharmaceutically acceptable derivative thereof or analog thereof, in DMBA (7,12-dimethyl benzo) and NMU (N-methyl nitrosourea) - Induction of breast cancer model in the view 118881.doc 1312680 Invented novel and unexpected prevention and reduced tumor growth ~ Fu Mu activity. In fact, anti-progestin Ηβ-(4-ethyl phenyl) _17β hydroxy I? (1,1,2,2,2-5) Fluoroethyl)_female-4,9-diene-3-ketone is indeed significantly more effective in preventing breast cancer growth than tamaoxifen and alpha~ nest resection. Therefore, the present invention provides treatment or prevention of breast cancer or other hormonal dependence. The method of sexually transmitted diseases for mammals in need of such treatment, especially humans, includes the administration of a pharmaceutically effective amount of an antiprogestin to a patient, in particular ^

Ethyl phenyl)-17β-hydroxy-fluoroethyl benzoquinone^bis-steel-3 steel or a pharmaceutically acceptable derivative thereof or the like. The present invention further provides a pharmaceutical composition for preventing or treating breast cancer or other hormone-dependent diseases in a sufficient amount, which comprises an antiprogestin, particularly 1113_(4_ethylphenyl)_1713_hydroxy-17〇1-(1 1,1,2,2,2-pentafluoroethyl)-hetero-4-diene-3 ketone or a pharmaceutically acceptable derivative thereof or the like. Thereafter, the preferred antiprogestin 11β_(4_acetamidophenyl), 口 _ _ 17α-(ΐ, ι, 2, 2, 2-pentafluoroethyl) _ female _ 4, 9 _ diene _ 3 ketones are called t(i) „. 柷竽 柷竽 [Embodiment] Antiprogestin (I) UP-(4_acetamidophenyl)-17β-hydroxy-17a-(lsl 2 2 2 pentafluoroethyl) -Estra-4,9-diene·3 ketone The following formula (1) represents:

118881.doc 10 • 1312680 Antiprogestin (1) (or a pharmaceutically acceptable derivative thereof or a similarly active analog thereof) is a useful agent with potent anti-pregnancy activity. Antiprogestogens (1) and more antiprogestins can be used to prevent and treat breast cancer or other hormone-dependent diseases according to this issue (4). The term "antiprogestin" as used in the present invention is intended to include all compounds which inhibit the luteinizing hormone receptor. However, it should include compounds that inhibit the biosynthesis of progestogens. The pharmaceutically acceptable derivative of the antiprogestin (1) or the like thereof in the present invention may include, for example, any of the inventive compounds disclosed in WO 98/34947. In the context of the present invention, the term "hormone-dependent disease" may include, but is not limited to, 'breast cancer' ovarian cancer, endometrial cancer, bone marrow cancer, ovarian infertility, meningitis, meaning, essentially derived from Or diseases that are affected by hormonal receptors and sputum-dependent pathways. As for the advantages of the present invention over the prior art, it is particularly advantageous, for example, to use the antiprogestin (1) according to the present invention to further elicit an endocrine side effect such as androgen, estrus hormone, or anti-glucocorticoid activity, even if it occurs, very low. Due to the high bioavailability of the antiprogestin (1), it can be administered orally, thus providing the patient in need of treatment as convenient as possible. As a further advantage, the antiprogestin (I) is quite tolerable and can be administered at relatively low doses compared to established therapies, thus reducing the effects of discomfort, such as administration of Tamoxifen endometrial cancer. Increase in rate (see

I.N_White,Carcinogenesis,20(7)··1153-60,1999·L

Bergman et al., The Lancet, %] 356, sept 9, 2, 88, 887) and the efficacy of anti-glucocorticoids administered with US-based ketones and certain toxicities U8881.doc • 11 · 1312680 ^ uD.Perr she and others; CHn 1996 machine 19), PP. 27〇9_2712; LM Kettel et al. Fexian·stedl. ph 56(3) grasping, 7; X. Bertagna's second neun) end (10) inQl〇 Gy 1997, 22 $naii; rushing. The superiority of the prior art is to provide an effective preventive method for the prevention of Hormone-dependent diseases such as breast cancer. Patients with such hormonal or refractory diseases can be treated in advance to prevent such diseases. The occurrence of the disease. The invention is directed to a method for preventing or treating breast cancer and other hormonal diseases, which comprises administering at least one antiprogestin to anti-pregnancy (I) or a pharmaceutically acceptable derivative thereof or the like. It is better to use mammals that require this prevention or treatment. In terms of the use of the antiprogestin as defined above, preferably the antiprogestogen (1) or a pharmaceutically acceptable derivative thereof for use in the manufacture of a medicament = an analogue, in particular for the prevention or treatment of breast cancer or other hormonal dependent diseases Another aspect of the present invention is directed to a pharmaceutical composition comprising at least one of the above antiprogestins, preferably an antiprogestin (1) or a pharmaceutically acceptable derivative or a straight analog thereof. The antiprogestin (1) can be combined with other pharmaceutically active agents. For example, a second antiprogestin can bind to a cytotoxic agent to attach a hormonal receptor. The manufacture of the drug can be carried out by methods known in the art. A commonly known and 1 liter adjuvant and a suitable carrier or diluent can be used. Suitable adjuvants and carriers may be those recommended in the following cosmetic and related literature: UHmann-s Encyclopedia 〇f Technical Chemistry, V〇l 4 ^ 3 Ϊ 18881.doc -12- 1312680 (1953), pp. 1-39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), p. 918ff; Hv Czetsch-Lindenwald, "Hilfsstoffe fiir Pharmazie und angreanzende Gebiete"; Pharm. Ind. 2, 1961, p. 72ff; Dr. HP Fiedler, Lexikon der Hilfsstoffe fiir Pharmazie, Kosmetik und angrenzende Gebiete, Cantor KG, Aulendorf in Wtirurttemberg, 1971.

The antiprogestin suitable for the purpose of the present invention is preferably an antiprogestin (1) or a pharmaceutically acceptable hydrazine derivative or the like thereof, which can be combined with a known method for preparing an oral or parenteral drug. It can also be implanted into tissue. The implant may comprise an inert material such as a biodegradable polymer or a synthetic oxirane such as ruthenium film. Can be used as a tablet 'pill' sugar coated ingots, capsules, granules, suppositories, implants can be a sterile aqueous solution or oil solution, suspension or lotion, ointment, = 谬 or by intravaginal (eg, vaginal ring) or intrauterine system (eg, septum, birth control ring), etc. ^ Composition with peony, suitable for the purpose of the present invention as described above (10) 1-2, water-soluble gum arabic, talc, temple powder, such as agent, hard fat heart, soil cellulose, lactose, gel acid, Surfactant, dispersant, aqueous or non-aqueous excipient, paraffin derivative 'cross-linked oil' n liquid moisturizing 'monthly agent, preservative, flavoring agent (eg, B-antiprogestin can be 八λ, & In the t-drug composition, in order to place 4 knives in the microparticle composition of the microparticles. Step-enhanced active agent·$4 t Purpose As defined above, the bioavailability of sputum is suitable for the present invention. The antiprogestin can be hydroclaved with α-, β-, or γ-cyclodextrin or a derivative thereof according to H8881.doc 1312680, as disclosed in PCT/EP95/02656. The reaction is prepared as a cyclodextrin: Parenteral administration of an antiprogestin suitable for the above objects according to the invention may be dissolved or suspended in a physiologically acceptable dilution of an oil surfactant, dispersant or emulsifier, for example with or without a co-solvent An oil that can be used as an example and not a limitation, eucalyptus oil, peanut oil Cottonseed oil, soybean oil 'castor oil, and sesame oil. The application rate (eg, pharmaceutically effective amount) varies within a wide range, and 2 is determined by the condition and mode of administration. It may include any effective treatment: 罝The "medically effective amount" is determined by the skill of the artist. ^ The unit dose can represent about ❹1 to _mg of active agent. If administered to humans, the daily dose of the active agent is about 01 to a milligram, preferably 10 to 100 mg, preferably 50 g. The pharmaceutical composition according to the present invention can be prepared by long-acting smear, implant preparation or mD (intrauterine device) according to the need for continuous delivery of the effective agent. g ^ serving is a preferred mode of administration. The anti-progestin of the present invention, particularly progestogen (I), is particularly suitable for oral administration. According to the present invention, at least h '疋 antiprogestin can also be used. (1) or a pharmaceutically acceptable derivative thereof or the like, in combination with at least one anti-emotional hormone, since many hormone-dependent diseases are breast cancers, which not only display the progesterone receptor, but also show the estrus hormone body. 、 纱 | ^ 1 / ” σ 知 know with anti-progestogen or after it, don't sputum with antiprogestin (1) or its pharmaceutically acceptable derivatives or similar substances. lJ8881.doc -/4- 1312680, And '2) Incision resection at the beginning of treatment, 3) Tamoxifen, 丨mg/m,,) anti-steroid (I), 3 oz/kg, sc·, 6 days/week. Weekly The breast tumor of the rat was tested by touch method. The tumor incidence rate (with the percentage of the tumor/group number) was determined as a preventive efficacy parameter. For further explanation and evaluation of DMb a and ^ prevention sputum type, see RG Metha : pean Journal of Cancer 36 (2000), pp. 1275-1282 ° Results:

All rats in the control group developed breast tumors within 100 weeks of the start of treatment (incidence rate 100%) and observed tumor growth in development. Tumors were completely prevented by antiprogestin (1) in 12 weeks, and tumors were found in only one rat after the U week, and at the mouth of the mouth (incidence rate of 1%). At the end of the ovarian resection at the end of the experiment, 4 G% of the rats had mature tumors. In comparison, treatment with the anti-emotional hormone tamazefide only reduced the incidence of tumors to 60°/. (See Figure ip. In the rat DMBA-induced tumor model, antiprogestin (1) completely inhibited tumorigenesis in untreated animals more than 12 weeks after the start of treatment. Figure 丨 clearly shows the activity of antiprogestin (1) in preventive treatment Better than the traditional anti-breast cancer agent Tamoxifen and even superior to standard ovarian deprivation therapy (Ovariectomy). Antiprogestin (I) is therefore superior to standard therapies established to prevent breast cancer in women at high risk of developing this disease. (Tamosifene preventive therapy). The above and the following results show that antiprogestogen (1) is superior to established standard therapy in the prevention and treatment of breast cancer. Example 2: 1] 888].doc 1312680 Rat face A_induced breast cancer model (Therapeutic experiment/dose-response study) Materials and methods: Juvenile female Shibo (1) Lida rats (49_51 days old; group) were used for this study. Oral administration of 10 mg of 7,12-dimercaptobenzophenone (_A, Serva/Heidelberg) induced breast tumors. Rats with a tumor greater than 150 square centimeters and Rimi were treated for 4 weeks in the following manner: 1) combined with ... and 2) the nest at the beginning of the treatment Resection, 3) anti-pregnancy (1) mg/kg s.c_, 4) antiprogestin (1), 2 mg/kg sc., 5) antiprogestin (I), 5 quage/eight a, gram A kg sc, 6) antiprogestin ( I), 10 mg / kg Ή 纳 斯 同, 5 mg / kg - daily. Changes in tumor area were measured weekly with a double-angled clip (relative to the size of the original tumor as a growth inhibition parameter. Statistical analysis of mean differences between the groups was performed using the Kruskal_WaUis test. Results: Observation in untreated control animals To the development of tumor growth, and the ovarian (10) surgery caused a considerable tumor reduction of 9.%. The anti-progestin (1) at a dose greater than 2 mg / kg * caused significant inhibition of tumor growth compared with the control group (see Figure 2). There is a significant dose-response relationship. Anti-pregnancy with 0.5 mg/kg. Hormone (1) did not significantly prevent tumor growth. 2 mg/kg observed a maximum of 2. 2 long inhibition. In this group of rats, tumors were completely observed. Regression. The efficacy of the anti-progestin (1) maximum dose of 0 mg/kg in this experiment was equivalent to 2 mg/kg. The efficacy of Onaps with (5 mg/kg a.) was significantly lower than the equivalent dose of antiprogestin (I). Conclusion: 118881.doc 1312680 4-AL·rU antiprogestin (I) completely inhibits tumor growth in the untreated animals in a rat DMBA-induced breast tumor model. Private owner / τ, & now 2 g / kg of antiprogestin (1) has the greatest effect on tumor growth, anti-progestin (1) is significantly better than Example 3: rat NMU-induced breast cancer model (preventive experiment) materials and METHODS: Female Spigdogley rats (purchased from Tie gamma and sin, 5〇-55 days old) were injected intravenously with a single dose of succinimide (yetidine methyl urea, 5 mg/kg). After 1G days, the following treatments were carried out: υ Solvent vs. Zhao group, 4 nest resection, 3) Tamoxifen, 3 mg/kg SC, 4) Antiprogestin (1), 3 mg/kg sc·, 5) Ray Zuoyou (―U'3 mg/kg sc, 6) leroxifene, 3 mg/kg SC·'6 days/week. Rats were examined palpation weekly. Tumor incidence (with percentage of tumor population) was determined as a prophylactic efficacy parameter. For further explanation and evaluation of the DMBA and face prevention models, see rg.仏(10) European J0Urnal of Cancer 36(2〇〇〇), 卯 i275 i2u. RESULTS: In the control group, all rats developed a breast tumor within 1 week of the start of treatment (incidence rate 100% 'see Figure 3)' and observed tumor growth in development. Prophylactic treatment with antiprogestin (1) prevented complete swelling within 12 weeks (4) and at the end of the week, only one rat observed tumors (incidence rate of 10%). Treatment with other anti-emotional hormone or aroma-enzyme inhibitors, letrozol, only reduced the incidence of tumors to 1 18881.doc -18- 1312680 2 0 - 60%. Ovary in the sinus After resection, 2〇··· rats and right mature tumors. A mouse, theory: In the rat NMU-induced 5丨&p private soil tumor model towel, antiprogestogen (I) completely pumped The effect of the preventive treatment of anti-surgical animal tumors I,, >& Ρ% anti-hormone (1) on the incidence of tumors and swelling, temples and double elements (such as Leloxime, better than the tradition of breast cancer therapy) Anti-inflammatory, ... force, He Moxifen) and aromatic enzyme inhibitors Lei Zuoyou (Rizo Zuo) and standard estrus hormone deprivation therapy (insemination resection). As in the occupational tumor model (see example), This result shows that antiprogestin (I) is effective in the occurrence of tumors in the Ρ 陆 陆 陆 礼 礼 礼The standard preventive treatment was performed as in Tamoxifen. Example 4: NMU breast cancer model of rats (treatment experiment) Materials and methods: Intravenous injection of NMU (staphthylamine methyl urea, 5 mg / mg) in a single dose Km) to female Spig-doly rats induced tumors. After 1 day, rats with a hairy tumor were treated for 4 weeks in the following manner: 1) solvent control group ' 2) _ nest resection at the beginning of treatment Surgery, 3) antiprogestin (1), 1 g / kg / day ' 4) antiprogestin (1), 〇 · 5 mg / kg / day, 5) Onaps, 5 mg / kg / day. The change in tumor area (% relative to the original tumor size) was measured weekly as a growth inhibition parameter with a double-angle clip. A statistical analysis of the mean difference between the groups was performed using the Kruskal-Wallis-test. RESULTS: In the untreated control animals, development of tumor growth was observed, while ovarian incision was observed.

118881.doc •19- S 1312680 The procedure resulted in complete tumor growth inhibition. Treatment with anti-progestin (I) at a dose of 〇·5 or 1〇mg/kg resulted in a significant tumor growth inhibition compared with the control group (see Figure 4)°Ouopus (5 mg/kg) Significantly lower than the dose of • low (0.5 mg / kg) of antiprogestin (I) is ineffective. Conclusion: In the NMU-induced breast tumor model of rats, antiprogestin (1) completely inhibited tumor growth in untreated animals. It has been found that antiprogestin (1) at a dose of 丨〇mg/kg or even 0.5 疋 only 0.5 mg/kg has a significant effect on tumor growth. Therefore, the antiprogestin (1) is superior to known antiprogestins such as Onopus. Example 5: T47D Human Transformation (Therapeutic Experiment) Materials and Methods: Female Fakai complex severe immunodeficient mice (M&B) were fed with Innovative Research of America. The T47D breast cancer cells obtained from the cell culture medium and placed in the matrigel were transplanted into the vicinity of the sputum of the s.c. Treatment begins when the tumor area is approximately 25 mm2 in size. Treatment continues until the tumor increases. The experimental population was 1) control group (vehicle), 2) knife-printing group, 3) anti-progestin (I) ' 10 mg/kg s.c. The area of the abdomen was measured with a double angle clamp. A statistical analysis of the mean difference between the groups was performed using the Kruskal-Wallis-test. Results: In the T47D breast cancer model, 'ovariectomy compared to the rapid growth of the control group' produced comparable tumor growth inhibition. Figure 5 shows 丨〇mg/kg

1>8881.d〇c 1312680 s.e, an antiprogestin (I) administration also causes tumor growth inhibition, which is almost equivalent to traditional estrus hormone deprivation therapy (ovectomy). Conclusion: Antiprogestogen (I) inhibits the efficacy of human T47D breast cancer in the sJL complex severe immunodeficiency mice, which is equivalent to the standard estrous hormone deprivation therapy (ovectomy) considered to be the most effective in this model. . Example 6:

Human MCF7 transfection (treatment experiment) Materials and Methods: Female Fakai complex severe immunodeficient mice (M&amp;B) were fed with Innovative Researcll 〇f America. MCF7 breast cancer cells derived from cell culture medium and placed in matrigel were transplanted into the vicinity of the sputum of s c. Treatment begins when the tumor area is approximately 25 mm2 in size. The treatment continues until the tumor increases. The experimental population was 丨) control group (vehicle), 2) the sputum group was removed, and 3) antiprogestin (1), 10 mg/kg s c. Tumor area was measured with a double angle clamp. Statistical analysis of mean differences between the groups was performed using the Kruskal-Wallis-test. Results: In the MCF7 breast cancer model, oophorectomy resulted in considerable tumor growth inhibition compared to the rapid growth of the control group. Figure 6 shows that progesterone (I) s.c. administration of 1 〇 mg/kg s.c. also caused tumor growth inhibition, almost equivalent to traditional estrus hormone deprivation therapy (ovectomy). Conclusion: Antiprogestogen (1) inhibits the proliferation of human MCF7 breast cancer in the f/L complex severely deficient mice in 11888].doc -1312680, which is equivalent to the standard estrous hormone considered to be the most effective in this model. Deprivation therapy (ovectomy). [Simplified illustration] Figure 1 shows the anti-progestin (1) tumor growth prevention efficacy in rat DMBA-induced breast tumors, compared with the control group 'tamoxine and oophorectomy. Figure 2 shows the anti-progestin (I) dose in the DMBA-induced breast tumor in rats, the tumor growth inhibition efficacy in the study, compared with the control group, the antiprogestin-Olympus and the nest resection . This study was performed with an antiprogestin (1) dose of 〇_5 </ 2.0 ' 5.0 ’ and 10.03⁄4 g / kg s.c•. Figure 3 shows the efficacy of antiprogestin (1) in tumor growth prevention induced by small tumors in rats, compared with the control group, antiprogestin leroxaprofen and tamoxifene, aromatase inhibitors letrozol &amp; Comparison of oophorectomy. Figure 4 shows the anti-progestin (1) dose of 0.5 and 1 mg/kg of anti-progestin (1) in rat NMU-induced tumor growth inhibition, compared with the control group, Ou Nass (5 mg / kg) and oophorectomy Comparison. Figure 5 shows the effect of antiprogestin (1) at a dose of 10.0 mg/kg sc. on tumor growth inhibition of human sputum 47 转 in combination with severely immunodeficient mice, compared with control and oophorectomy. • Figure 6 shows the comparison of anti-progestin (1) anti-progestin (1) in human MCF72 tumor growth inhibitory effect in combination with severely immunodeficient mice versus control ovariectomy. 118881.doc •22-

Claims (1)

I31_y8418 Patent Application Factory&gt; Wenshen凊 Patent Scope Replacement (April 1998) 丨·10. Application Patent Range: - A pharmaceutical composition for preventing or treating mammalian hormone-dependent diseases, which comprises an anti- Progesterone lip_(4_6醯phenyl)丨7卜hydroxy'_ 17 heart (1,1,2,2,2-pentafluoroethyl)-est-4,9-dien-3one or its medicinal Receiving a derivative or analogous substance thereof, and an anti-emotion hormone, wherein the anti-emotion hormone is a non-sterol-anti-emotion hormone, which is selected from the group consisting of tamoxifen 'nafoxidine', Lero Raloxifen and EM800; sterols - anti-emotional hormones, which are selected from non- Faslodex; 11β-fluoro·7α-{5-[Ν-methyl-N-3-(4,4,5 5 5 pentafluoropentylthio-propylamino)-pentyl]- -1,3,5(10)-tris- 3,173_-alcohol and 11β-fluoro-7α-{5-[methyl-(7,7,8,8,9,9,10,1〇, 〇〇_ 九气癸基)-Amino]-phenyl-p-Il-1,3,5(10)-triene-3,17β-diol; or an aromatic enzyme inhibitor, letrozol. 2. The pharmaceutical composition according to item 1 of the patent application' wherein the disease is breast cancer. 118881 -980429.doc