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WO1996005833A1 - Procedes enrayant le cancer de l'uterus - Google Patents

Procedes enrayant le cancer de l'uterus Download PDF

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Publication number
WO1996005833A1
WO1996005833A1 PCT/US1995/010651 US9510651W WO9605833A1 WO 1996005833 A1 WO1996005833 A1 WO 1996005833A1 US 9510651 W US9510651 W US 9510651W WO 9605833 A1 WO9605833 A1 WO 9605833A1
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WO
WIPO (PCT)
Prior art keywords
endometrial
endometrial cancer
compound
biopsy
formula
Prior art date
Application number
PCT/US1995/010651
Other languages
English (en)
Inventor
Susan Margaret Boss
Original Assignee
Eli Lilly And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to KR1019970701095A priority Critical patent/KR970705387A/ko
Priority to AU33700/95A priority patent/AU688112B2/en
Priority to JP8508265A priority patent/JPH10504824A/ja
Priority to EP95930243A priority patent/EP0777476A4/fr
Priority to MX9701327A priority patent/MX9701327A/es
Publication of WO1996005833A1 publication Critical patent/WO1996005833A1/fr
Priority to NO970783A priority patent/NO970783L/no
Priority to FI970717A priority patent/FI970717L/fi

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • endometrial hyperplasia The classification of endometrial hyperplasia is based on the presence or absence of cytologic atypia, the presence of dysplasia, and the degree of complexity of the architectural pattern. Cytologic atypia is the most predictive criterion for the likelihood of progression to carcinoma.
  • Endometrial cancer is the most common gynecologic pathology and the fourth most common malignancy in women, after breast, colorectal, and lung cancer.
  • Endometrial cancer affects mainly postmenopausal women, as the average age at diagnosis is 58 years, and fewer than 5% of cases occur prior to age 40.
  • the incidence of endometrial cancer is higher among women with a history of breast, endometrial, or ovarian malignancies, and also in women that belong to a high socioeconomic status.
  • cervix Patients with Stage II disease are at higher risk for having extrauterine disease and recurrence.
  • cervix is of normal size and grossly normal, one approach is an extrafascial TAH/BSO with complete surgical staging followed by postoperative irradiation. With gross cervical involvement, two options are available. The first is whole pelvic irradiation followed by one intracavitary implant, which is then followed by a TAH/BSO and para- aortic lymph node sampling. The second option is a radical hysterectomy. BSO, and pelvic and para-aortic lymphadenectomy with irradiation tailored to the surgical findings, if necessary.
  • Stage III disease In surgical Stage III disease, primary surgery with the use of a TAH/BSO with tumor debulking may be attempted. Extrapelvic disease, depending on the site and extent, may necessitate extended field irradiation, systemic chemotherapy, or hormone therapy. Patients with Stage III disease, by virtue of vaginal or parametrial extension, need a thorough metasta ic survey and then irradiation.
  • Stage IV disease Most patients with Stage IV disease are best treated with systemic therapy, which includes hormones or chemotherapy. Pelvic irradiation or hysterectomy is reserved for palliative control purposes.
  • Patients with recurrent endometrial cancer in the pelvis may be treated with radiotherapy. Unfortunately, the majority of these patients also have distant metastases as well. Isolated central recurrences in the pelvis after irradiation are rare. However, if this situation does occur, selected patients may be candidates for pelvic exenterative surgery. The majority of patients with recurrent disease are treated with hormones or chemotherapy. Progestins have been used for decades to treat recurrent endometrial cancer. The overall response to progestins is approximately 25%, although recent trials demonstrate lower response rates, in the range of 15 to 20%. Patients with endometrial carcinoma with progesterone-positive and estrogen-positive receptors have a better response to endocrine therapy.
  • R 2 is selected from the group consisting of pyrrolidino, hexamethyleneimino, and piperidino; and pharmaceutically acceptable salts and solvates thereof.
  • the current invention concerns the discovery that a select group of 2-phenyl-3-aroylbenzothiophenes
  • the therapeutic and prophylactic treatments provided by this invention are practiced by administering to a human in need thereof a dose of a compound of formula
  • inhibitor includes its generally accepted meaning which includes prohibiting, preventing, restraining, and slowing, stopping or reversing progression, severity or a resultant symptom.
  • the present method includes both medical therapeutic and/or prophylactic administration, as appropriate.
  • Raloxifene is a preferred compound of this invention and it is the hydrochloride salt of a compound of formula 1 wherein R 1 and R 3 are hydrogen and R 2 is 1- piperidinyl.
  • At least one compound of formula I is formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered by the intramuscular or intravenous routes.
  • the compounds can be administered transdermally, and may be formulated as sustained release dosage forms and the like.
  • the compounds used in the methods of the current invention can be made according to established procedures, such as those detailed in U.S. Patent Nos. 4,133,814, 4,418,068, and 4,380,635 all of which are incorporated by reference herein. In general, the process starts with a benzo[b]thiophene having a 6-hydroxyl group and a 2- (4- hydroxyphenyl) group. The starting compound is protected, acylated, and deprotected to form the formula I compounds. Examples of the preparation of such compounds are provided in the U.S. patents discussed above.
  • phenyl includes phenyl and phenyl substituted once or twice with C -C ⁇ alkyl, C 1 -C 4 alkoxy, hydroxy, nitro, chloro, fluoro, or tri(chloro or fluoro)methyl.
  • the compounds used in the methods of this invention form pharmaceutically acceptable acid and base addition salts with a wide variety of organic and inorganic acids and bases and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention.
  • Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like.
  • Salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic ⁇ and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used.
  • Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, ⁇ -hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate, monohydrogenphosphat
  • the pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or excess amount of acid.
  • the reactants are generally combined in a mutual solvent such as diethyl ether or benzene.
  • the salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means.
  • Bases commonly used for formation of salts include ammonium hydroxide and alkali and alkaline earth metal hydroxides, carbonates, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diamines.
  • Bases especially useful in the preparation of addition salts include ammonium hydroxide, potassium carbonate, methyla ine, diethylamine, ethylene diamine and cyclohexylamine.
  • the pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions.
  • compositions can be prepared by procedures known in the art.
  • the compounds can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, powders, and the like.
  • excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid
  • the compounds can also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes. Additionally, the compounds are well suited to formulation as sustained release dosage forms and the like.
  • the formulations can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time.
  • the coatings, envelopes, and protective matrices may be made, for example, from polymeric substances or waxes. -
  • the particular dosage of a compound of formula I required to inhibit endometrial cancer according to this invention will depend upon the severity of the condition, the route of administration, and related factors that will be decided by the attending physician.
  • accepted and effective daily doses will be from about 0.1 to about 1000 mg/day, and more typically from about 50 to about 200 mg/day.
  • Such dosages will be administered to a subject in need thereof from once to about three times each day, or more often as needed, and for a time to effectively treat or prevent endometrial cancer. It is usually preferred to administer a compound of formula I in the form of an acid addition salt, as is customary in the administration of pharmaceuticals bearing a basic group, such as the piperidino ring.
  • a basic group such as the piperidino ring.
  • Hard gelatin capsules are prepared using the following :
  • raloxifene examples include those shown below:
  • Silicone fluid 350 centistokes 1 .7 Formulation 3 Raloxifene capsule
  • Silicone fluid 350 centistokes 3.0
  • a tablet formulation is prepared using the ingredients below: Formulation 6: Tablets
  • the components are blended and compressed to form tablets ,
  • tablets each containing 0.1 - 1000 mg of Active ingredient are made up as follows :
  • Polyvinylpyrrolidone 4 (as 10% solution in water)
  • the Active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°-60° C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
  • Suspensions each containing 0.1 - 1000 mg of Active ingredient per 5 mL dose are made as follows:
  • the Active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
  • the benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
  • ASSAYS ASSAY 1 Continuous cultures of transformed endometrial cells reflective of endometrial carcinoma are maintained in culture.
  • Estrogen receptor containing cells such as the Ishikawa line
  • Responsiveness is assessed by monitoring transcription of known estrogen/anti-estrogen regulated genes such as progesterone receptor, PS2 and others.
  • ASSAY 2 Induced Animal Models - Endometrial carcinoma is induced by injections of estrogenic substances such as 17- ⁇ -estradiol or DES during neonatal development. The presence of carcinoma in the adult animal is confirmed by biopsy of affected animals and/or sacrifice and biopsy of syngeneic animals identically treated. After evaluation of the lesions, affected animals are treated with estrogen, compounds of formula I, or progestins for 1-8 weeks. After treatment, lesions of surviving animals are examined for progression, regression or stasis.
  • estrogenic substances such as 17- ⁇ -estradiol or DES
  • ASSAY 3 Five to fifty women are selected for the clinical study. The women suffer from endometrial cancer.
  • the study has a placebo control group, i.e., the women are divided into two groups, one of which receives a compound of formula 1 as the active agent and the other receives a standard treatment for endometrial cancer. Women in the test group receive between 50-200 mg of the drug per day by the oral route. They continue this therapy for 3-12 months.
  • Accurate records are kept as to the symptoms and status of the cancer in both groups and at the end of the study these results are compared. The results are compared both between members of each group and also the results for each patient are compared to the status reported for each patient before the study began.
  • a total of 251 healthy, postmenopausal women are recruited. Each subject has had her last menstrual period more than 6 months but less than 6 years prior to beginning the treatment phase of the study. Postmenopausal status of each subject is confirmed before beginning treatment by serum estradiol ⁇ 120 pmol/L and by FSH >30 IU/L. Subjects will not have been treated with estrogen over at least the last 3 months before the study and have never been treated with fluoride, calcitonin, or bisphosphonate. Subjects are in good health and range in age from 46 to 60 years. The study is a multi-center, randomized, controlled, double-blind study.
  • Qualified subjects who consent are randomized to one of four treatment groups: placebo, a compound of formula I 200 mg once daily, a compound of formula I 600 mg once daily, or estrogen 0.625 mg once daily. All subjects also receive daily oral calcium carbonate supplements (520 mg/day elemental calcium) . All medications and supplements are taken daily in the morning during the 8-week treatment period. Once treatment is completed (Visit 5), each suject receives Provera® 5 mg/day for 12 days.
  • a uterine biopsy is performed at baseline and after 8 weeks of treatment.
  • the biopsies are performed in a routine manner and the tissue specimens are placed in 10% buffered formalin. Specimens are retrieved by pouring them into tissue paper filters and then are grossly examined and classified as to appearance (color, texture, and consistency) and volume. Standard histologic processing into paraffin blocks is used and the tissues are serially sectioned onto a minimum of two slides which results in serial strips of 6 to 20 cross sections. Since subjects with clinically significant endometrial abnormalities are to be excluded from the study or are discontinued from the study if they develop abnormalities,' the biopsies are evaluated immediately for a descriptive diagnosis.
  • biopsies This is performed by one of two pathologists and immediately reported to the clinical physicians.
  • the primary purpose of the biopsies is to determine the degree of morphologic estrogenic effect of study treatment.
  • Two pathologists are trained to read the biopsies by reviewing a series of Pipelle biopsies obtained outside the study that represent the full spectrum of endometrial morphology.
  • a scoring system is devised to quantitate this estrogenic effect and include the more subtle changes that may be encountered. Ten of these outside cases are then scored with this system by each pathologist, and the cases are reviewed together to assure uniform understanding and use of the criteria.
  • Scoring occurs well after the initial immediate diagnosis and usually 10 to 20 cases are scored sequentially. It is expected that the rate of scant tissue is relatively high on the initial biopsy since the typical postmenopausal endometrium is inactive and consists of a very shallow (5 mm or less) tissue lining and the Pipelle biopsy is a limited, blind biopsy method. Because endometrial glands are required to score features of glandular and stromal morphology, the final biopsy must have contained glands before any conclusions can be drawn in individual subjects. Specimen adequacy is defined as follows: If no tissue or debatable tissue of endometrial origin is present, the specimen is deemed inadequate and not included in the evaluation. If multiple fragments of endometrial surface epithelium are obtained, the specimen can not be scored. However the biopsy is deemed adequate and is assigned a grade of 0 on the 4-point scale indicating no estrogen effect.
  • the biopsy is adequate and is scored for the glandular and stromal features.
  • the biopsy is adequate and is scored for the glandular and stromal changes.
  • the volume of the tissues is taken into account as an indication of estrogen effect.
  • Glandular morphology is the primary scoring factor for adequate biopsy specimens.
  • Stromal morphology is the secondary scoring factor for adequate biopsy specimens.
  • Tables 1 and 2 display the features to be used to score each specimen that have glands and/or stroma present. Four features are used to classify the glands: shape, cellular nuclear to cytoplasmic cross sectional areas, nuclear pseudostratification, and mitotic activity.-
  • At least 20 gland profiles are used to grade for mitotic activity (four serial sections of scant specimens) .
  • Metaplasia includes tubular, eosinophilic, and squamous type. b Used only if glands show some estrogenic effect (1 or 2 points) .
  • a biopsy can receive between 0 to 16 points.
  • glandular and stromal morphology/ and other important morphologic features including progestational effect inflammatory processes, breakdown bleeding, polypoid growth, or other pathologic findings are described but are not included in the scoring of proliferative effects since the other changes are primarily nonproliferative.
  • biopsy specimens contain multiple fragments of endometrial surface epithelium, those specimens are assigned a grade of 0.
  • grade 0.
  • Intraclass correlation coefficients are calculated to assess agreement between the two readers on the sum of the scores obtained at baseline and at 8 weeks (Fleiss, JL (1981) Statistical Methods for Rates and Proportions. New York: John Wiley and Sons, p. 218.]
  • a positive result in this assay is the reduction of the score for glandular mitoses indicating a decrease in cell replication relative to placebo.
  • Table 3 illustrates important results of the study. Table 3. Mean ( ⁇ SEM) Scores for Glandular Fatures At Endpoint

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Le procédé enrayant le cancer de l'utérus de la présente invention consiste à administrer à un être humain le nécessitant une dose efficace d'un composé représenté par la formule générale (I) ou de l'un de ses sels ou solvates pharmaceutiquement acceptables. Dans cette formule générale (I) R1 et R3 représentent indépendamment hydrogène, -CH¿3?, (a), ou (b), où Ar représente un phényle éventuellement substitué. R?2¿ appartient au groupe constitué de pyrrolidine, hexaméthylèneimino et pipéridino.
PCT/US1995/010651 1994-08-22 1995-08-21 Procedes enrayant le cancer de l'uterus WO1996005833A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
KR1019970701095A KR970705387A (ko) 1994-08-22 1995-08-21 자궁내막암의 억제 방법(methods of inhibiting endometrial cancer)
AU33700/95A AU688112B2 (en) 1994-08-22 1995-08-21 Methods of inhibiting endometrial cancer
JP8508265A JPH10504824A (ja) 1994-08-22 1995-08-21 子宮内膜癌を阻害する方法
EP95930243A EP0777476A4 (fr) 1994-08-22 1995-08-21 Procedes enrayant le cancer de l'uterus
MX9701327A MX9701327A (es) 1994-08-22 1995-08-21 Metodos para inhibir el cancer endometrial.
NO970783A NO970783L (no) 1994-08-22 1997-02-20 Fremgangsmåte for å hindre endometrialkreft
FI970717A FI970717L (fi) 1994-08-22 1997-02-20 Menetelmät kohtusyövän inhiboimiseksi

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US29385394A 1994-08-22 1994-08-22
US08/293,853 1994-08-22

Publications (1)

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WO1996005833A1 true WO1996005833A1 (fr) 1996-02-29

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EP (1) EP0777476A4 (fr)
JP (1) JPH10504824A (fr)
KR (1) KR970705387A (fr)
AU (1) AU688112B2 (fr)
CA (1) CA2198119A1 (fr)
CZ (1) CZ51897A3 (fr)
FI (1) FI970717L (fr)
HU (1) HUT76890A (fr)
IL (1) IL115022A (fr)
MX (1) MX9701327A (fr)
MY (1) MY113757A (fr)
NO (1) NO970783L (fr)
NZ (1) NZ292017A (fr)
RU (1) RU2161964C2 (fr)
TW (1) TW404834B (fr)
WO (1) WO1996005833A1 (fr)
ZA (1) ZA956994B (fr)

Cited By (4)

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US6030986A (en) * 1995-02-28 2000-02-29 Eli Lilly And Company Benzothiophene compounds, intermediates, compositions, and methods
US7429576B2 (en) 1998-06-11 2008-09-30 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US8389548B2 (en) 1998-06-11 2013-03-05 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
CN115825414A (zh) * 2023-01-09 2023-03-21 中国医学科学院北京协和医院 血液或尿液代谢标志物及其在子宫内膜癌早筛中的应用

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KR20160066490A (ko) * 2014-12-02 2016-06-10 주식회사 씨앤드씨신약연구소 헤테로사이클 유도체 및 그의 용도

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US4418068A (en) * 1981-04-03 1983-11-29 Eli Lilly And Company Antiestrogenic and antiandrugenic benzothiophenes
US5482949A (en) * 1993-03-19 1996-01-09 Eli Lilly And Company Sulfonate derivatives of 3-aroylbenzo[b]thiophenes
AU6556194A (en) * 1993-04-07 1994-10-24 Ligand Pharmaceuticals Incorporated Method for screening for receptor agonists
CN1108094A (zh) * 1993-10-15 1995-09-13 伊莱利利公司 治疗抗性瘤的方法
DK0771201T3 (da) * 1994-08-22 2001-05-07 Lilly Co Eli Anvendelse af 2-phenyl-3-aroylbenzothiophener til fremstilling af et medikament til inhibering af primær endometrisk hyperplasi
US5843964A (en) * 1994-09-22 1998-12-01 Eli Lilly And Company Methods of inhibiting endometrial mitoses

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Publication number Priority date Publication date Assignee Title
WO1993010113A1 (fr) * 1991-11-15 1993-05-27 Teikoku Hormone Mfg. Co., Ltd. Nouveau derive de benzothiophene

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6030986A (en) * 1995-02-28 2000-02-29 Eli Lilly And Company Benzothiophene compounds, intermediates, compositions, and methods
US7429576B2 (en) 1998-06-11 2008-09-30 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
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IL115022A0 (en) 1998-06-15
EP0777476A4 (fr) 1999-06-23
KR970705387A (ko) 1997-10-09
FI970717A0 (fi) 1997-02-20
HUT76890A (en) 1997-12-29
NO970783D0 (no) 1997-02-20
CA2198119A1 (fr) 1996-02-29
AU3370095A (en) 1996-03-14
AU688112B2 (en) 1998-03-05
RU2161964C2 (ru) 2001-01-20
FI970717L (fi) 1997-02-20
IL115022A (en) 2000-07-31
CZ51897A3 (en) 1997-06-11
ZA956994B (en) 1997-02-21
TW404834B (en) 2000-09-11
MY113757A (en) 2002-05-31
NZ292017A (en) 2000-07-28
NO970783L (no) 1997-02-20
JPH10504824A (ja) 1998-05-12
MX9701327A (es) 1997-05-31
EP0777476A1 (fr) 1997-06-11

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