MXPA97006520A - Methods to inhibit the ova cancer - Google Patents

Abstract

A method for inhibiting ovarian cancer which comprises administering to a human in need thereof an effective amount of a compound having the formula (I), wherein R 1 and R 3 are independently hydrogen, -CH 3, (a), or (b), wherein Ar is optionally substituted phenyl, R 2 is selected from the group consisting of pyrrolidine, hexamethyleneimide and piperidino, or a pharmaceutically acceptable salt or solvate thereof.

Description

METHODS TO INHIBIT OVARIAN CANCER DESCRIPTION OF THE TIGVENCIÓIT Ovarian cancer constitutes 18% of all gynecological neoplasms, occurs in women more frequently when they are in the fifth decade of their lives. Since the ovarian neoplasm usually remains hidden until it enlarges or grows long enough to produce symptoms, early detection is difficult; In 70 to 80% of patients, the disease is not diagnosed until it has become extensive inside or beyond the pelvis. Therefore, if the systematic examination of the pelvis shows an enlarged ovary > 5 cm in diameter, close monitoring is required. In young women, the detection of functional cysts is common; The re-examination after 6 weeks will show if spontaneous resolution has been presented. The size of the tumor may be the only criteria for surgery, and 1 of 4 ovarian tumors removed surgically is malignant. This proportion increases with the age of the patient. The ovaries in postmenopausal women are small and usually not palpable. Therefore, any ovarian enlargement in a postmenopausal woman would mean malignant cancer that requires immediate surgical excision. He REF: 25259 Serous cystadenocarcinoma is the most common type (found in 50% of cases) and occurs bilaterally in 30 to 50% of patients. Approximately 80% of malignant ovarian tumors arise from the epithelium of the ovary and are classified histologically as (1) serous cystadenocarcinomas, (2) mucinous cystadenocarcinomas, (3) endometroid tumors (similar to adenocarcinoma of the endometrium), (4) celioblastomas (tumors) de Brenner), (5) clear cell carcinomas and (6) unclassified carcinomas. Tumors that arise from germ or stromal cells that do not fall into this classification include tecagranulosa cell tumors, Sertoli-Leydig cell tumors, dysgerminomas, and malignant teratomas. Ovarian cancer tends to spread both by direct extension and by regional lymph nodes in the pelvis and in the para-aortic region. When the lymphatic system is involved, dissemination to the abdominal and pelvic peritoneum usually occurs. When the abdomen is involved, hematogenous spread can lead to the liver and lung. An ovary can grow to a considerable size before clinical symptoms occur. The earliest symptoms are a vague lower abdominal discomfort and moderate digestive discomforts. Bleeding is rare inappropriate endometial, probably a result of the secretion of hormones by the tumor. Abdominal swelling due to an enlarged ovary or accumulation of acytic fluid, pelvic pain, anemia and cachexia appear late in the course of the disease. Additional physical signs include functional tumoraleß effects (eg, hyperthyroidism, feminization, virilization), or more commonly, a fixed and lobulated solid mass associated with nodular implants in the cul-de-sac. A cervical smear from the vaginal fundus of pleural or peritoneal fluids may contain cells that allow the diagnosis of malignant disease of the ovary, X-rays may show distant metastasis in the lungs and bones. Although a pelvic mass and ascites usually signify a malignant ovarian tumor, a benign ovarian fibroma is associated with ascites and right hydrothorax (Meigs syndrome). Conventional therapeutic approaches are limited by the variety of types of histological tumors, by late discovery and by the prevalence of widely disseminated metastases, bilateral involvement and extension to the uterus and contiguous structures. Not all injuries require extensive or radical therapy. In a young patient with a unilateral low lesion Histological grade (such as a mucinous tumor), the reproductive capacity can be preserved by cutting only the tube and ovary involved. In an advanced state, total abdominal hysterectomy and bilateral salpingo-oophorectomy are applied with omentectomy for tumors that can be removed, but each case involves a considerable latitude. A careful surgical classification can be performed that includes biopsy of the diaphragm, parietal peritoneum, and retroperitoneal lymph nodes. Radical surgery with node dissections and excretions is not effective, but radiotherapy, and especially cheerapy, are becoming increasingly useful and are under continuous reassessment. When the fact of an involved tumor is presented which prevents a realistic hope of total excision, the initial laparotomy is carried out to diagnose, classify and remove as much tumor as possible. Subsequently, cheerapy or abdominal radiotherapy follows. The widely disseminated disease and stage IV tumors are treated with cheerapy after adequate surgical excision. Most oncologists agree that patients with tumors in advanced stages III and IV, a combination therapy with = 2 cytotoxic agents is preferable to treatment with a single agent.

For patients with common epithelial tumor, the 5-year total survival rate without evidence of recurrence is 15% to 45%. The prognosis for rare germ cells and stromal tumors varies considerably, based on the stage of diagnosis. For recurrent disease, the factor that correlates most strongly with survival is the time between diagnosis and the start of multiple agent therapy. With aggressive tumor-reducing surgery and a combination of chemotherapy, the long-term survival rate for all patients with ovarian cancer is improved (67% with stage III tumors in one series). However, the rate of death from ovarian cancer surpasses that of combined cervical and body cancer and is classified as the fifth cause of cancer mortality in women. This invention provides methods for inhibiting ovarian cancer which comprises administering to a human in need thereof an effective amount of a compound of formula I < D wherein R1 and R3 are independently hydrogen, -CH3, - o, (Ci-Ce alkyl) i. wherein Ar is optionally substituted -Ar phenyl; R2 is selected from the group consisting of pyrrolidino, hexamethyleneimino and piperidino; and pharmaceutically acceptable salts and solvates thereof. The present invention relates to the discovery that a select group of 2-phenyl-3-aroylbenzothiophenes (benzothiophenes), those of formula I are useful for inhibiting ovarian cancer. The methods of use provided by this invention are practiced by administering to a human in need thereof a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof which is effective to inhibit ovarian cancer. The term "inhibit" includes its generally accepted meaning which includes prohibiting, avoiding, restricting, diminishing, slowing or reversing. As such, the present method includes both medical therapeutic treatment and prophylactic administration, as appropriate. Raloxifene, a compound of this invention in which is the hydrochloride salt of a compound of formula I, R1 and R3 are hydrogen and R2 is 1-piperidinyl, is a nuclear regulatory molecule. It has been shown that raloxifene binds to the estrogen receptor and was originally considered to be a molecule whose function and pharmacology was to be an antiestrogen insofar as it blocked the ability of estrogen to activate uterine tissue and breast cancers estrogen-dependent Actually, raloxifene blocks the action of estrogen in some cells. However, in another cell type, raloxifene activates the same genes as estrogen and shows the same pharmacology, for example osteoporosis and hyperlipidemia. As a result, raloxifene has been mentioned as an antiestrogen with mixed agonist and antagonist properties. The profile The only one that shows haloxifene and that differs from estrogen is that it is not considered to be due to the activation and / or single deletion of various functions of the gene by the raloxifene-estrogen receptor complex as opposed to the activation and / or deletion of genes by the estrogen-estrogen receptor complex. Therefore, although raloxifene and estrogen use and compete for the same receptor, the pharmacological result of gene regulation in both can not be easily predicted and is unique to each. Generally, the compound is formulated with common excipients, diluents or carriers and compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered intramuscularly or intravenously. The compounds can be administered transdermally and can be formulated as sustained release dosage forms and the like. The methods used in the methods of the present invention can be made according to established procedures such as those described 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 begins with benzo [b] thiophene having a 6-hydroxyl group and a 2- (4-hydroxyphenyl) group. The initial compound is protected, it is acylated and deprotected to form the compounds of formula I. Examples of the preparation of such compounds are given in the North American patents described above. Optionally substituted phenyl includes phenyl and phenyl substituted once or twice with C 1 -C 6 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 or base addition salts with a wide variety of organic and inorganic acids and bases, and include physiologically acceptable salts, which are often used in pharmaceutical chemistry. Such salts also form 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 monocarboxylic and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkanedioic acids, aromatic acids, sulfonic, aliphatic and aromatic acids, may also be used. Such pharmaceutically acceptable salts, therefore, include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, il-benzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, J-hydroxybutyrate, butyn-l, 4-dioate, hexin-1,4-dioate, caprate, caprylate, chloride, cinnamate , citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxyalate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate , propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, c 1 or ob in c ens u 1 f ona to, et an su 1 f ona to, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naph alen-2-sulfonate, p-toluenesulfonate, xylene sulfonate, tartrate and the like. A preferred salt is the hydrochloride salt. The pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or excess acid amount. The reagents are generally combined in a mutual solvent such as diethyl ether or benzene. Salt is usually separated by precipitation from the solution between about 1 hour to 10 days and can be isolated by filtration or the solvent can be removed by distillation by conventional methods. Bases commonly used for the formation of salts include ammonium hydroxide and alkali metal and alkaline earth metal hydroxides, carbonates as well as aliphatic amines and primary, secondary and tertiary amines, aliphatic diamines. Bases especially useful in the preparation of addition salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylenediamine and cyclohexylamine. The pharmaceutically acceptable salts generally have characteristics of increased solubility as compared to the compound from which they are derived, and therefore, are often more susceptible to formulation as liquids or emulsions. The pharmaceutical formulations can be prepared by methods known in the art. For example, the compounds can be formulated with common excipients, diluents or carriers and formed into tablets, capsules, suspensions, powders and the like. Examples of excipients, diluents and carriers that are suitable for such formulations include the following: fillers and diluents such as starch, sugars, mannitol and silicic derivatives; binding agents such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatins and polyvinylpyrrolidone; wetting agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate, - detergent retarding agents such as paraffin, resorption accelerators such as quaternary ammonium compounds; surfactants such as cetyl alcohol, glycerol monostearate; absorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols. The compounds can also be formulated as elixirs or solutions for convenient oral administration or as solutions suitable for parenteral administration, for example, intramuscularly, subcutaneously or intravenously. Additionally, the compounds are suitable to be formulated as sustained release dosage forms and the like. The formulations can be constituted in such a way that they release the active ingredient only or preferably in a particular part of the intestinal tract, subsequently over a period of time. The coatings, envelopes and protective matrices can be manufactured, for example, from polymeric substances or waxes. The particular regimen and dosage of non-compound of formula I necessary to inhibit cancer of ovary according to this invention will depend on the severity of the condition, the route of administration and related factors that will be defined by the attending physician. Generally, accepted and effective daily doses will constitute from about 0.1 to about 1000 mg / day, more typically from about 50 to about 200 mg / day. Such dosages will be administered to a subject in need thereof from once to approximately three times a day, or more frequently as required, and for a sufficient time to effectively inhibit ovarian cancer. It is usually preferred to administer a compound of formula I in the form of an acid addition salt, as is usual in the administration of pharmaceutical substances having a basic group such as the piperidino ring. It is also advantageous to administer such compound orally. For such purposes, the following oral dosage forms are available.

EQRMULA? IQNES In the formulations that follow, "Active Ingredient" means a compound of formula I.

Formulation 1: Gelatin capsules Hard gelatin capsules are prepared using the following: The ingredients are mixed, passed through a No. 45 mesh US sieve and filled into hard gelatin capsules. Examples of formulations of raloxifene-specific capsules that have been used include those shown below: Formulation 2: Raloxifene capsules Formulation 3: Raloxifene capsule Formulation 4: Raloxifene capsule Formulation 5: Raloxifene capsule The specific formulations above can be changed in accordance with the reasonable variations that are provided. A tablet formulation is prepared using the ingredients below: Formulation 6: Tablets The compounds are mixed and compressed to form tablets. Alternatively, tablets are made as follows, each tablet contains 0.1-1000 mg of the active ingredient: Formulation 7: Tablets The active ingredient, starch and cellulose is passed through an American mesh screen No. 45 and mix carefully. The polyvinylpyrrolidone solution is mixed with the remaining powders which are then passed through a No. 14 mesh North American sieve. The granules produced in this way are dried at 50-60 ° C and passed through a US No. 18 mesh sieve. Sodium carboxymethylstarch, magnesium stearate and talcum are pre-filtered through a No. 60 American sieve and then added to the granules which, after mixing, are compressed into a tablet to provide tablets.

Suspensions are manufactured as follows, each containing 0.1 - 1000 mg of medication per 5 ml dose: Formulation 8: Suspensions The medicament is passed through a No. 45 mesh American sieve and mixed with the sodium carboxymethyl cellulose and the syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a little water and added with agitation. Subsequently, enough water is added to produce the required volume.

Cell culture assay Continuous cell lines of ovarian neoplasms are maintained in culture. A test is performed with raloxifene to determine its ability to inhibit the estrogen-induced effect that includes proliferation or up-regulation or down-regulation of genes regulated by estrogen. The effects of estrogen can be increased or altered by matching additions of appropriate cytokines, growth factors or growth hormones. The inhibition of estrogen-induced effects is evidence of activity in these cells.

Test 1 Between 3 and 20 women who have been diagnosed with ovarian cancer are used in this trial. The stage of cancer is noted, and women are given raloxifene in an amount between 50 and 600 mg / day. The administration period is 3 months. Women are observed during the administration period and three months after stopping the compound to determine effects on ovarian cancer.

Test 2 The same procedure as in Trial 1 is used, except that the administration period is 6 months.

Test 3 The same procedure as in Trial 1 is used, except that the administration period is 1 year. The activity in at least one of the above tests indicates that the compounds of the invention are of potential use in the treatment of ovarian cancer. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (3)

CLAIMS:

1. Use of a compound of formula (I) (I) characterized in that 1 and R3 are independently hydrogen, - CH3, or, -? - (C i-Ce alkyl) -i, wherein Ar is phenyl optionally -Ar replaced; R2 is selected from the group consisting of pyrrolidino, hexamethyleneimino and piperidino; or a pharmaceutically acceptable salt or solvate thereof to inhibit ovarian cancer in a human.

2. The use according to claim 1, characterized in that the compound is the hydrochloride salt thereof.

3. The use according to claim 1, characterized in that the compound is or its hydrochloride salt.