TW404834B - Pharmaceutical compositions for inhibiting endometrial cancer - Google Patents

Abstract

A pharmaceutical composition of inhibiting endometrial cancer comprising an effective amount of a compound having the formula (I) wherein R1 and R3 are independently hydrogen, -CH3, O=-C-(C1-C6 alkyl), or O=-C-Ar, wherein Ar is optionally substituted phenyl; R2 is selected from the group consisting of pyrrolidine, hexamethyleneamino, and piperidino; or a pharmaceutically acceptable salt of solvate thereof.

Description

Produced by Shellfish Consumer Cooperation of the Central Standards Bureau of the Ministry of Economic Affairs, printed by Du 404834 V. Description of the Invention (彳) The lining of the uterus (endometrium) is made of tissues, blood vessels and glands, and grows when stimulated by estrogen. In women with normal menstrual cycles, monthly hormone fluctuations cause endometrial growth and shedding. If pregnancy occurs, the endometrium nourishes the developing embryo. Most cases of endometrial cancer are related to a previous disease called " endometrial proliferation. The classification of Zi Lu endometrial growth is based on the presence or absence of heterotypic cells, the development of heterogeneous growth and structural complexity. The most commonly used predictive criterion for the likely progression of atypical cell line cancer. In-simple or cystic growth with atypical cells, about 8% chance of progressing to cancer. Complex or adenoma hyperplasia with thriving cells, about 29% chance. When no atypical cells are present, the rate of simple hyperplasia is 1% and the rate of complex hyperplasia is 3%. Continue to increase the estrogen content, the endometrium always stays in its growing period, some * cyan may cause excessive endometrial tissue or endometrial hyperplasia. Endometrial overgrowth is usually a good condition, but it can also be a precursor to endometrial cancer. Because of this danger, doctors urge women to avoid long-term non-opposing estrogen therapy, if the lining does not continue to fall off, it can cause endometrial overgrowth and seek immediate treatment for the disease that causes excessive estrogen production. (Pregnancy ketones are used in hormone replacement therapy to cause blood collapse and established endometrial shedding. Doctors' decisions are based on several factors. First, the doctor examines cells obtained from a living body or cervical dilation and curettage (D & C). The cells are normal but simple in excess, and the cancer progresses less than atypical cells showing enlarged nuclei and other abnormal signs. In some cases, D & C may indicate that the cancer has developed. Endometrial cancer is the most common gynecological lesion , Followed by breast cancer, colorectal cancer -4-------------% — (Please read the precautions on the back before filling this page) Order

r C * Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 404834 B7 V. Description of Invention (2) ~ and the fourth most common malignant disease in women after lung cancer. Approximately 30,000 to 40,000 new cases of endometrial cancer are diagnosed each year. Most patients have the most common disease in the early stages. Endometrial cancer mainly affects postmenopausal women. The mean age at diagnosis is 58 years, and less than 5% of cases are older than 40 years. The incidence of endometrial cancer is higher among women with a history of breast, endometrial, or indo-malignant disease and among women of high socioeconomic status. The most significant risk factor for endometrial cancer is obesity and the presence of estrogen that is not resistant to pregnancy. Inaccuracy in the clinical stage of endometrial cancer hinders analysis of the best therapies and results. Unless metastasis or systemic disease is identified, the current initial medically appropriate approach for all patients is total hysterectomy (TAH) / bilateral salpingectomy (BSO). Plan for adjuvant therapy as needed based on the surgical lesion determination indicator for intrauterine or extrauterine disease as needed. The patient can receive external radiation to the pelvis (if the pelvic nodules are positive) and external radiation to the sub-aortic area (if these nodules are positive). Patients with other parts of extrauterine disease may require whole abdominal irradiation. Depending on the spreading site, some patients may require systemic therapy in addition to radiotherapy. 0:} J · Patients with stage Π are at higher risk of extrauterine disease and recurrence. If the cervix is normal in size and generally normal, the method is to use a complete surgical stage with external fascia TAH / BSO followed by irradiation. If there is generally cervical involvement, there are two options. The first type is total pelvic irradiation followed by a lumen implantation, and then TAH / BSO and accessory aortic lymph nodes are sampled. Ν The second selective radiation is ΊΪ-ΊΪ-1 I nn In I. n I n I ΪΓ m. Ir ( Please read the notes on the back before filling this page]

404834 V. Description of the invention (3) Hysterectomy. BSO was modified as required for surgical findings, and pelvic and paraaortic lymphadenectomy was performed. For surgical stage III disease, try TAH / BSO and preliminary surgery to remove the tumor. The location and extent of extrapelvic disease can be extended field irradiation, systemic chemotherapy or hormone therapy. Patients at stage 〖〗 are actually extensions of connective tissue in the vagina or uterus, which must be investigated for metastasis and then irradiated. Most patients with stage IV disease are best treated with systemic therapies, which include hormones or chemotherapy. Keep pelvic irradiation or hysterectomy for control purposes. Patients with recurrence of endometrial cancer in the pelvis can be treated with radiation therapy. Unfortunately, most of these patients also have long-distance metastases. The pelvis has been separated after irradiation. The central recurrence is very rare. However, if this happens, the patient can be selected for pelvic visceral enucleation. Most patients with relapsed disease are treated with hormone il chemotherapy. Regestive endometrial cancer has been treated with progestins for the past decade. The lower response rate was confirmed to be 15 to 20%, but the overall response to the corpus luteum preparation was about 25%. Although patients with endometrial cancer, progesterone-positive and estrogen-positive receptors have recently been tested, they have responded better to endocrine therapy. Most patients who have positive receptors for the corpus luteum 丨 »!! React only 5% of the negative i receptors. 6 α -methyl 17ατ -acetic acid progesterone || (Μβ (ΐΓ〇χγρΓ〇§68Ϊ6Γ〇η6 'acetate (Provera) and Megacete acetate are the most commonly used agents. Tamoxifen (Nolvadex) is also used in the treatment Patients with recurrent endometrial cancer are more likely to respond to patients who have previously responded to luteal preparations. Several cytotoxic agents have endometrial activity, but the response is shorter and -6- This paper applies to Chinese nationalities · Standard (CNS) A4 size (210x297) (Please read the notes on the back before filling out this page) 袈.-'Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Light Economy M.4 & 34 A7 B7 V. Description of the invention (4. Further treatment and recovery of disease considerations are temporarily slowed. Station also 丨, ·. The two most active single single agents are doxorubicin and cisplatin. Ρ κι Λ] Many combinations of cytotoxic swords are known, but the results of multiple agent chemotherapy Not ^ ^ · ±. ^ ^ ^ 'Is significantly less effective than single-agent chemotherapy. The present invention provides methods for inhibiting endometrial cancer, and humans include those who need to administer an effective amount of a compound of formula I to a person in need.

〇ch2ch2-R2 (I) (Please read the notes on the back before filling in this page). • Ordered by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 〇 Among them, R1 and R3 are hydrogen, _CH3, and i (Ci_C6 alkane respectively). Group), or OII-C-Ar, wherein Ar is an optionally substituted phenyl group; R2 is selected from N-pyrrolidinyl, hexamethyleneimino, and ^ N-hexapyridyl ::, and A pharmaceutically acceptable salt or solvate. In the present invention, it is found that the selective group of 2-benzyl-3.arylarylphenylpyrimidine in the phenanthrenes of formula I can inhibit endometrial cancer. The therapeutic and prophylactic treatments of the present invention are performed by administering a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof effective to inhibit endometrial cancer to a person in need thereof. This paper size applies to China National Standard (CNS) 8-4 specifications (21〇 > < 297 mm), printed by employee consumer cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, 404834, 5 'Invention Description (5) Terminology " Inhibition "and general acceptance The definition includes banning, preventing, suppressing, slowing, discontinuing or reversing symptoms of progression, severity or gain. The method of the invention includes medical treatment and / or prophylactic administration as needed. Raloxifene is a preferred compound of the invention and It is the hydrochloride salt of the formula ^, wherein R1 and R3 are hydrogen and R2 is 1. hexahydropyridyl. Generally, at least one compound of formula I is formulated with commonly used excipients, diluents or carriers and Extruded into tablets, or formulated into elixirs or solutions to facilitate oral, intramuscular or intravenous administration. The compound can be administered transdermally and can be formulated into a 1 release dosage form, etc. According to established procedures such as US Patent 4, 133,814,4,418,068 and 4,380,635 and other patents (incorporated herein by reference) can be used to make the compounds used in the method of the present invention. Generally, the method is based on benzene having 6-amino groups and 2- (4-hydroxyphenyl) [b] Pyridine initiation. The starting compound is protected, acidified and deprotected to form a compound of formula I. Examples of the preparation of this compound are U.S. patents discussed above. The term "any substituted phenyl" includes phenyl and a Or a phenyl group substituted with (^-(: 6 alkyl, C ^ -C: 4 alkoxy, hydroxyl, nitro, gas, fluorine or tris (gas or fluoro) methyl). Compounds used in the method of the present invention A wide range of organic and non-stick acids are used to form pharmaceutically acceptable acid and base addition salts and include the physiologically acceptable salts commonly used in medicine. Acceptable salts. This salt is also part of the present invention. Used to form this Typical inorganic acids of salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, scale acid, low phosphoric acid, etc. Organic acids such as aliphatic mono and dicarboxylic acids, and phenyl-substituted alkanes can also be used. Salts derived from acids, hydroxyalkanoic acids and hydroxyalkane diacids, aromatic acids, fats, and aromatic sulfonic acids. This pharmaceutically acceptable salt includes acetate-8. This paper is in accordance with Chinese national standards ( CNS) A4% grid (210X297 mm) (Please read the notes on the back before filling this page)

* 1T A7 B7.404834 U ύ U u 5. Description of the Invention (6), phenylacetate, triacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoic acid Salt, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-ethoxybenzoate, tea-2-benzoate, bromide, isobutyrate, Phenylbutyrate, Luthyl Butyrate, Butyl-1,4-Di-Acid, Hexagonal " * 1,4-Di-Acid, Decanoate, Caprylate, Gas, Cinnamate Salt, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonic acid Salt, bitter almond, mesylate, nicotinate, isonicotinate, nitrate, oxalate 'phthalate, terephthalate, phosphate, monohydrogen Phosphonium, dihydrogen phosphate, metaphosphate, pyrophosphate, propionate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberic acid Salt, sulfate, hydrogen sulfate , Pyrosulfate, sulfite, nitrite ', sulfonate, benzenesulfonate, p-bromophenylsulfonate, gas benzoate, ethanesulfonate, 2-hydroxyethanesulfonic acid Salt, mesylate, benzoate, benzene-2-sulfonate, p-toluenesulfonate, xylenesulfonic acid, tartrate, etc. The preferred salt is the hydrochloride. A pharmaceutically acceptable acid addition salt is typically formed by the reaction of a compound of formula I with an isomolar or / excess acid. Reactants are typically bound to solvents such as acetone or benzene. The salt is generally precipitated from the solution from 1 hour to 10 days and can be separated by filtration or the solvent can be stripped in a conventional manner. Bases commonly used to form salts include ammonium hydroxide, hydroxides of alkali metals and alkaline earth metals, carbonates, and aliphatic amines, primary amines, secondary amines, tertiary amines, and aliphatic diamines. The best bases used for the preparation of addition salts include hydroxide-9. This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm) (please read the precautions on the back before filling this page) ^ / T-- 6 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs with general availability capsules, suspensions J0834 V. Description of the invention (ammonium, potassium carbonate, methylamine, diethylamine, ethylenediamine, and cyclohexyl and their derivatives In contrast, pharmaceutically acceptable salts have solubility characteristics and are often formulated as liquids or emulsions. Pharmaceutical compositions can be prepared by known techniques. For example, excipients, diluents, or carriers can be compounded to form tablets. Flotation agents, powders, etc. Examples of excipients and diluents suitable for this composition include the following: fillers and fillers such as starch, sugar, mannitol, and silicic acid derivatives; binders such as carboxymethyl fiber And other cellulose derivatives, sea salt, gelatin and polyvinylpyrrolidone; wetting agents such as glycerol; disintegrating agents such as calcium carbonate and sodium argon carbonate, slowing down dissolving agents such as paraffins; and promoting absorption agents such as four Grade ammonium compound Surfactants such as cetyl alcohol, glyceryl monostearate; absorbent carriers such as kaolin and pulp, and lubricants such as talc, calcium stearate and magnesium, and solid polyethylene glycols. Formulated into a tincture or solution to facilitate oral or parenteral administration (such as intramuscular, subcutaneous or intravenous routes). In addition, the compound is suitably formulated into a sustained release dosage form, etc. Therefore, the composition can be constituted over a period of time The active ingredient is released only or preferably in a specific part of the intestine. For example, coatings, coatings and protective matrices can be made from polymeric substances or waxes. According to the invention, the known dose of a compound of formula I in endometrial cancer is The caregiver depends on the severity of the condition, the route of administration, and related factors. Generally, the accepted and effective daily dose is from about 0.1 to about 1000 mg / day, and more typically from about 50 to about 200 mg / day. This dose can be Administer the subject to be treated once to about 3 times a day, or to effectively suppress the disease or symptoms as many times as necessary, and to effectively treat or prevent endometrial cancer. -10- This paper standard applies to the country of China Mark (CNS) A4 size (210X297 mm) Shiyi-(Please read the precautions on the back before filling this page) Order printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, printed A7, A7, B7 ingredients, active ingredient starch, NF starch Flowable powder siloxane solution 3 50% history 404U4r V. Description of the invention (8) It is usually better to administer the compound of formula i as an acid addition salt, and generally administer drugs with a test group such as N-hexahydro The pidolide ring is available for this purpose. The following oral Liu type is available for this purpose. Compositions In the following compositions, "active ingredient means a compound of formula I. Composition 1: Ming capsules Use the following to prepare hard shell Ming capsules:-amount (Mg / capsule) 0.1-1000 0-650 0-650 0- 15 Examples of specific capsule compositions mixed with present ingredients, passed through a No. 45 mesh US sieve, and filled with raloxifene, a hard-shelled capsule, have been manufactured and Including the following: Composition 2: Rosifen capsules in-(Please read the precautions on the back before filling this page)

、 1T Ministry of Economic Affairs, Central Bureau of Standards, Work and Consumption Cooperation, Du Yin, made Rosifen Starch, NF Starch Flowable Powder Siloxane 3 50% (mg / capsule) 1 112 225.3 1.7 -11 404834 A7 B7 Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China. 5. Description of the invention (9) Composition 3: Rosifen capsule content (mg / capsule) Rosifen 5 starch, NF 108 starch flowable powder 225.3 Siloxane liquid 3 5 0% 1.7 Composition 4: Rosifen Capsules-Ingredient Amount (mg / capsule) Rosifen 10 • Dried Dried, NF 103 Starch Flowable Powder 225.3 Siloxane Liquid 3 50 Cent History 1.7 Composition 5: Rosifen Capsules * Ingredient 4 I > Amount (mg / capsule) Rosifen 50 Starch, NF 150 Starch Flowable Powder 397 Silicone Liquid 3 50 Cents 3.0 3.0 -12- (Please read the precautions on the back before filling out this page) This paper size applies to Chinese national standards (CNS) A4 specification (210X297 mm). Order 4048St V. Description of the invention (A7 B7 The specific composition listed above can be changed according to the reasonable changes provided and prepared with the following ingredients Agent composition: Composition 6: Bonding ingredient Active ingredient Microcrystalline cellulose Fuming amount of stearic acid dioxide (mg / tablet) 0.1-1000 0-650 0-650 0- 15 Mix the ingredients and press Extruded into tablets. In addition, each bond containing 0,1-1000 mg of active ingredient is prepared as follows: Composition 7-Tablets--C--Γ 11 ^ 1 m ^ l ^ ϋ * β ^^^^ 1 I ^ nv nn —HI— ii ^. ^ T * (Please read the notes on the back before filling out this page} Ingredients (mg / ingot 剤) Active ingredient starch microcrystalline fiber printed by Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs Polyvinylidene ratio (such as 10% solution in water) Carboxymethylcellulose sodium stearate talc. 1-1000 45 35 4 4.5 0.5

This paper size is applicable to China National Standard (CNS) A4 (210 > < 297 mm) Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs _404834 _ ^ __ 5. Description of the invention (n). The obtained powder was mixed with a solution of polyvinylpyrrolidone and passed through a No. 4 mesh US sieve. The granulating agent was at 50 ° -60. O Dried and passed through a No. 18 mesh U.S. sieve. First, sodium carboxymethylcellulose, magnesium stearate and talc were passed through a No. 60 US sieve, and then granules were added. After mixing, the tablets were squeezed in a tablet machine to produce tablets. The following composition 8 is prepared in a 5 ml dose containing each suspension of pharmacological drug of 0.005 mg: the suspension is the master batch (mg / 5 ml) active ingredient 0.1-1000 mg sodium carboxymethyl cellulose 50 mg syrup 1.25 milligrams of phenylarsinic acid solution, 0.10 milliliter of flavoring agent, pure amount of water, and 5 milliliters of medicine were passed through a 45 mesh US sieve and mixed with carboxymethyl oryzanol sodium and syrup to form a smooth paste. Add some water to the benzoic acid solution, flavor, and agent: Dilute and stir. Then add enough water to make the desired g product. ’Test Test 1 Maintain continuous culture in culture that reflects the transformed cells of endometrial cancer. Assess the proliferation of estrogen receptor-containing cells (such as the Ishikawa line) in response to estrogen and compounds of formula I. By monitoring the known estrogen / anti-estrogen regulatory gene -14- Zhang scale is applicable to Chinese national standards (CNS> A4 specification (210X297 mm)-:----------- / — _ (Please (Read the notes on the back before filling out this page)

'1T Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Consumer Cooperatives 404834 V. Evaluation of the greening effect of the invention description (12) (such as progesterone receptor, PS2 and others). Test 2 Induced animal model-Injecting estrogen (such as 17-meta-progesterone or DES) during the development of a newborn child induces endometrial cancer. The presence of cancer in adult animals is confirmed by the biopsy of the affected animal's biopsies and / or slaughter and biopsies. After damage assessment, affected animals are treated with estrogen, a compound of formula I or a luteal preparation for 1 to 8 weeks. After treatment ′ Examine the progress, degeneration or stagnation of damage in surviving animals ^ Test 3 5 to 50 women were selected for clinical study. These women suffer from endometrial cancer. The study had a placebo-controlled group where women were divided into two groups, one group receiving a compound of formula I as an active agent and the other group receiving standard treatment for endometrial cancer. Women in the test group took 50 to 200 mg of the drug daily by mouth. He continued this treatment for 3 to 12 months. Correctly remember the symptoms of the two groups of green and the state of the cancer and compare the results at the end of the study. This result is a comparison of the members of each group and the results of each patient are compared to the status reported by each patient before the study began. Trial 4 ». A total of 2 51 healthy, postmenopausal women were recruited. Every woman, the last menstrual period: more than 6 months but less than 6 years before the start of the study period. Before treatment, the postmenopausal status of each woman was confirmed with serum progesterone &lt; 120 pmol / L and FSH &gt; 30 IU / L. Each woman had not been treated with estrogen for at least 3 months and had not been treated with fluoride, calcitonin, or bisulfate before the study. Women are in good health and are 46 to 60 years old. -15- This paper size applies to China National Standard (CNS) A4 (210X297mm),--: — ^ — nn ml L — ^ n — ^ 1 · ml-^ (Please read the precautions on the back first (Fill in this page again) 404834 13 V. Description of the Invention (This study is a multi-center, randomized, controlled, double-blind study. The eligible women agreed to be randomly inserted into any of the four treatment groups: placebo group, daily 200. Mg of a compound of formula I, 600 mg of a compound of formula I per day, or 0625 mg of estrogen per day. All women also take calcium carbonate additives (52 mg / day elemental calcium) orally daily. All drugs and additives are daily during the 8-week treatment period. Take in the morning. Once treatment is complete (Visit 5), each woman receives Prova <85 mg / day for 12 days. After 8 weeks of treatment, use a pipelle catheter to perform a hysterectomy at the bottom line The biopsy method is performed in a conventional manner and the tissue specimen is placed in 10% buffered formalin. The specimen is poured into tissue filter paper to retrieve the specimen and then roughly inspected and classified for its appearance (color, group, And-consistent) and volume. The standard tissue treatment method that turned into paraffin blocks and the serial sections were organized into the smallest two pieces, which resulted in continuous strips of 6 to 20 sections. Women were excluded from the study because of clinically significant endometrial abnormalities or If they develop abnormalities that make the study unsustainable, immediately evaluate the biopsy for descriptive diagnosis. This is performed by one of two pathologists and reported immediately to the clinician. The original purpose of the biopsy was identified Study the extent of estrogen action on the morphology. Two pathologists interpreted the biopsy test using a series of Pipresson-tissue tests with a contempt study of the external representative / all models of endometrial morphology. A system of hormonal hyperplasia is designed to quantify this estrogen effect and include more subtle changes that may be faced. Each pathologist then uses this system to calculate 10 external cases and review these cases together to ensure that System—Identify and use benchmarks. Each pathologist calculates from the basis line students in the study by the criteria alone. Rubbing CNS) Α4ϋ⑴ 404,834 that the five well-described (14) of the first invention, the body tissue twenty test cases, to examine the scoring confirm proper use of the system. Pathologists assess the specimens of a biopsy for the following elements: 1) the validity of the specimen, 2) the shape of the gland, 3) the shape of the matrix, and 4) the opinion of the tissue. Additional findings added as organizational opinions. Based on gland and matrix type characteristics, points were scored and totaled and graded into 4 points of estrogen production level, where level 0 is the typical endometrium after menopause and level 2 is a marker of estrogen action. The average two pathologists totaled the points and then assigned a final grade of 0 to 3. Points have been scored immediately after the initial immediate diagnosis and often between 10 and 20 cases. The endometrial system of the tortoise is typically inactive after typical menopause and includes very shallow (5-mm or less) tissue lining and the Pipley biopsy is a restricted blind biopsy, so it is expected The ratio of rare tissues in the preliminary biopsy is quite high. Because endometrial glands must be scored for the characteristics of glands and stromal types, the final biopsy test should have glands before an individual makes a decision. The appropriateness of a specimen is defined as follows: If no endometrial-derived or disputed tissue exists, the specimen is considered inappropriate and not included in the assessment. If multiple fragments of the endometrial epidermis are obtained, the specimen cannot be scored. However, the biopsy test is deemed appropriate and there are no indications. 4 points of the effect of 丨 _ printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Order number The grade is designated as 0. &gt; u If a ruptured endometrium with glands is obtained, a biopsy test is appropriate and scores the characteristics of the glands and the stroma. If complete endometrial tissue is obtained, a biopsy test is appropriate and scores for glandular and stromal changes. In addition, consider the volume of the tissue as an indicator of estrogen action. -17-

404834 A7 _B7 V. Description of the Invention (15) The gland type is the first scoring factor for appropriate biopsy specimens. Matrix type is the second scoring factor for appropriate biopsy specimens. Tables 1 and 2 show the characteristics used to calculate samples with glands and / or stroma. Glands are distinguished by four characteristics: morphology, nucleus-to-cytoplasmic section area, nucleus pseudostratification, and mitotic activity. Table 1. Gland characteristics: Scores of estrogen production Estrogen action / points 値 Gland characteristics No estrogen production (0 points) Restricted estrogen production (1 point) High estrogen production-(2 points) Small, open, straight, straight, sac-like tubular curved straight nucleus to cytoplasm with a very high, moderate, and low ratio (&gt; 75%) (75% to 50%) (&lt; 50%) Limit the distribution of mitosis without sparse dispersion to many (please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 4 consecutive sections). In more rare specimens, at least the company should be examined before judging that there is no mitosis; there are 20 glandular contours in the performance section. In Table 2, the radicals f and "chita" properties 1 i i 'are listed. Four characteristics are also used to distinguish matrix · density, mitosis, epidermal tissue deformation, and tissue volume. -18- This paper size applies the Chinese National Standard (CNS) grid (210X297 mm) 404834 V. Description of the invention (16 / Table 2. Matrix properties: estrogen-produced fractionin production effect / point 値 A7 matrix properties mitotic tissue Change & Tissue Volume 15 No estrogen production with limited hormonal production High estrogen production-(0 points) (1 point) (2 points) Densely recognizable shape ~ Hidden cell shape-WmE No scarcity / Many non-rarely scattered, scattered ruptures, or some complete, appropriate, more complete, full, full, and adequate full-printed prints. Organizational changes include glands, eosinophilia, and squamous shapes. B The glands can show some estrogen Effect (1 or 2 points). Type characteristics indicate a lack of estrogen production as 0 points and the characteristics indicate that eye or significant estrogen effects produce 1 to 2 points respectively. Using this method, a biopsy test can be obtained 0 to 16. In addition to glandular and stromal patterns, other important pattern characteristics include luteinizing hormone action, inflammatory processes, disintegrating bleeding, polyploid growth, or other pathological findings. The score of the proliferative effect of the original non-proliferative nature is 0. Total 4 points of estrogen production grades due to glandular and matrix type characteristics. Scoring, in which each specimen is designated as follows: V i \, 〖; Number 0 = 0 to 3 points Typical endometrial levels after menopause with or without estrogen 1 = 4 to 6 points Level 2 = 7 to 1 0 points 3 = &gt; 10 points positive but limited Estrogen action Medium estrogen action has been calibrated for estrogen action-19 This paper size is applicable to China National Standard (CNS) A4 specification (210X2.97 mm) (Please read the precautions on the back first and fill in this page) tr 404834 A7 B7 V. Description of the invention (17) As previously noted, if the biopsy specimen contains multiple fragments of endometrial epidermis, these specimens are designated as Grade 0. For each biopsy test, there are 8 points: 4 are used to evaluate the gland type, 2 are used to evaluate the matrix type (combined density and mitosis, combined with tissue changes, and histone volume for statistical analysis). The total number and classification of the six scores are as defined above. Calculate similar correction coefficients To assess two readers' answers Consistency of the total number of scores. (Fleiss, JL (1981) Statistical Methods for Rates and Proportions. New York: John Wiley and Sons, p. 218.]. Cochran-Mantel- Haenazel's green meter technique was used to analyze the baseline, change from baseline to the 8th week, and the difference between treatment and supply at the 8th week [Landis, RJ Heyman, ER and Koch, GG (1978). &quot; Average Partial Association in Three-Way Contingency Tables: A Review and Discussion of Alternative Tests &quot; 0 International Statistical Review 46: 237-254 ·] 0 The chi-square test was used to evaluate the The incidence of endometrial glands in body tissues is used for treatment differences. Β: If the entire treatment difference system is significant, then compare the paired treatments between each living agent treatment and placebo. Judging that the statistically significant department is bilaterally 0.05-significant. Α1 SAS System for Statistical Analysis [SAS Institute Inc. (1989), SAS / STAT User's Guide, 6th Edition, 4th Series, Volumes 1 and 2, Cary, NC: SAS Institute Inc.] The positive results are glands The score of mitosis is reduced, and the paper size of the paper is applicable to the Chinese National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page) .. r Printed by the Industrial and Commercial Cooperatives 4 3 8 4o 4 V. Description of the invention (18) For placebo reduced cell replication. Table 3 describes the important results of the study. Table 3 Mean gland characteristics (± SEM) score variables at the end point Placebo (n = 53) Rosifen 200 mg (n-54) Rosifen 600 mg (n = 54) Estrogen 0.625 mg (n = 47) Type 0.44 soil 0.08 0.58 people 0.07 0.51 people 0.06 1.37 soil 0.06 # false layering 0_64 soil 0.10 0.57 soil 0.06 0.56 soil 0.06 1.68 soil 0.07 # green split 0.19 ± 0.05 0.05 soil 0.021 &quot; 0.07 soil 0.03 / 0.98 ± 0.08 # cell nucleus · · Cytoplasm 0_48 ± 0.09 0.58 ± 0_06 0.58 ± 0.05 1.56 ± 0.08 * Statistically significant difference from the placebo double-row test (p &lt; .050) / Significant difference from the edge of the double-row placebo test (p = .053) In at least one of the above tests, the use of a compound of formula I is described with a positive effect. (Please read the notes on the back of t *. Before filling this page) i- ΐτ1- Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -21-This paper size applies to China National Standard (CNS) A4 (210X297 mm)

Claims (1)

Patent Application No. 84108700 Chinese Patent Application Amendment (March 87) AJ B; C! Di Application Patent 404834 A pharmaceutical composition suitable for inhibiting endometrial cancer, including a compound containing rosifen as an active ingredient (Please read the note on the back before filling this page). Among them, R1 and R3 are hydrogen respectively; R2 is N_hexahydropyridyl; or a pharmaceutically acceptable salt or solvent thereof. The pharmaceutical composition according to item 丨, wherein the compound is its hydrochloride. 3. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the compound is Yin Chang, a shelling consumer cooperative of the Central Bureau of the Ministry of Economic Affairs ------- π V ----- * Loading ---- u ---- line ---------- £ __U_ This paper size applies to China National Standard (CNS) Α4 specifications (210X297 mm) No. 84108700 Patent Application Chinese Patent Application Amendment (March 87) AJ B; C! Di Application Patent Scope 404834 A pharmaceutical composition suitable for inhibiting endometrial cancer, including compounds containing rosifen As active ingredient (Please read the note on the back before filling this page). Among them, R1 and R3 are hydrogen respectively; R2 is N_hexahydropyridyl; or a pharmaceutically acceptable salt or solvent thereof. The pharmaceutical composition according to item 丨, wherein the compound is its hydrochloride. 3. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the compound is Yin Chang, a shelling consumer cooperative of the Central Bureau of the Ministry of Economic Affairs ------- π V ----- * Loading ---- u ---- line ---------- £ __U_ This paper size applies to China National Standard (CNS) Α4 specifications (210X297 mm)