Means for inhibiting pathological conditions of the mammary glands

 

(57) Abstract:

The invention relates to medicine, specifically to gynecology. A new tool for the suppression of pathological conditions of the breast: gynecomastia, galaktorei, defibrase non-cancer mastodynia and mastitis. Such a proposed compound of the formula I

< / BR>
where R1and R3independently represent hydrogen, -CH3, (C1-C6-alkyl) or where Ar is optionally substituted phenyl, and R2selected from the following groups: pyrrolidino, hexamethyleneimino and piperidino, or its pharmaceutically acceptable salt or MES. The invention expands the Arsenal of tools for the treatment of these diseases. 3 C.p. f-crystals.

In the United States every fourth woman needs medical treatment for certain diseases of the breast. Diseases of the mammary glands, though much less common, are also found in men. Such diseases are galactorrhea, gynecomastia, hypertrophy, politely, mastodinia/mastalgia, hyperprolactinemia and mastitis, which, in General, are not cystic fibrosis or cancer origin.

Pain in the breast to represent the deposits of discomfort is usually classified as follows:

(1) cyclic mastalgia or mastodinia observed in women before menstruation;

(2) changes in the breast such as ectasia ducts and fibroadenomatosis;

(3) reflected the pain associated with rib chondrite.

Gynecomastia is the enlargement of breast in men (women similar condition called hypertrophy. This increase is localized mainly in the area of the nipple and may be unilateral, but is most often bilateral. The indicated deviation is usually benign in nature; however, it may be a source of serious psychological disorders in a patient. Most often, gynecomastia is seen in men at puberty, but can occur at any age.

Gynecomastia can be caused by many reasons, such as the syndrome of Kleinfelter (chromosomal defect XXV), liver disease, oestrogens therapy regarding carcinoma of the prostate, tumors of the endocrine system, and some medications (digitalis and Dilantin). The common factor underlying all of these reasons and induced them gyno is producing anomalously therapy:

(1) identifying and eliminating the cause of disease;

(2) surgical removal of the breast tissue;

(3) treatment diethylstilbestrol and radiation therapy.

However, the identification and elimination of causes of gynecomastia, it is not always possible. Surgical intervention and treatment diethylstilbestrol and exposure often do not give the desired effect, are too expensive and entail the risk of side effects. In line with this, it is obvious that it would be desirable to find a more effective and safe treatment of gynecomastia.

Galactorrhea is a pathological expiration of milk from the mammary glands of men or women, are not directly related to pregnancy. In men, this phenomenon is quite rare and is accompanied by severe psychological disorders. The reason galaktorei is, obviously, excessive production of estrogen and prolactin.

In this case, if the reason that causes the specified pathology, cannot be found or corrected, usually carried out surgical treatment. Here, clearly, there is a problem developing safer ways of treating diseases of the mammary glands, namely, that a person in need of such treatment is administered an effective amount of the compounds of formula I

< / BR>
where R1and R3independently represent hydrogen, -CH3, (C1-C6alkyl), or where Ar is optionally unsubstituted phenyl;

R2choose from the following groups: pyrrolidino, hexamethyleneimino and piperidino;

or its pharmaceutically acceptable salt or MES.

In this application it is shown that the selected group of compounds 2-phenyl-3-koivistoinen (benzothiophene), i.e. the compounds of formula I, can be used to suppress or eliminate breast pathologies.

These methods of treatment of diseases of mammary glands disclosed in this application are that the person in need of such treatment, introducing a compound of the formula I or its pharmaceutically acceptable salt or MES in a dose which is effective for suppressing pathologies of the breast. Such pathologies are hyperprolactinemia, politely, gynecomastia, galactorrhea, and mastodinia and breast, not having fibrocystic or cancer origin.

In the present description, the term "who's pathology of the breast, as well as slowing the development and/or treatment of existing pathologies. The method of the present invention provides a conservative therapeutic treatment and/or preventive treatment of the above disorders.

The purposes of the present application connection Raloxifene (cleaners containing hydrochloride salt of the compounds of formula I, where R1and R3are hydrogen, a R2is 1-piperidine) is a nuclear regulatory molecule.

It was found that raloxifene is associated with the estrogen receptor and its functions and pharmacological properties is, as originally intended, an antagonist of estrogen, that is, it blocks the ability of estrogen to activate the tissue of the uterus and inhibits the emergence of estrogenzawisimy breast cancer. Indeed, raloxifene blocks the effects of estrogen in some cells; however, in some types of cells raloxifene activates the same genes as estrogen, and therefore detects the same pharmacological properties, i.e., causes osteoporosis and hyperlipidemia.

In accordance with that raloxifene has been classified as an antagonist of estrogen with mixed agonistic and antagonistic ICUMSA from the profile of the estrogen, he, as expected, due to the unique ability of raloxifene to activate and/or repress the function of various genes through raloxifene-oestrogens receptor complex in contrast to the estrogen-estrogen receptor complex.

Therefore, although raloxifene and estrogen are associated with the same receptor and are competing for this receptor, however, pharmacological action, stipulated by the regulation of genes of these two compounds, specific for each connection and is not easily predictable.

Basically, the connection of the present invention may be introduced in combination with standard fillers, diluents or carriers in the form of tablets or in the form of elixirs or solutions for oral administration; or it can be given intramuscularly or intravenously. These compounds may be introduced percutaneously and, in addition, they can be included in a pharmaceutical form prolonged release, etc.

The compounds used in the methods of the present invention can be obtained in accordance with known procedures described in the U.S. patents NN 4133814, 4418068 and 4380635, catasetinae use benzo[b]thiophene, with the 6-hydroxyl group and 2-(4-hydroxyphenyl) group. This is the initial connection is subjected to blocking, acylation, and then unblocking, resulting in a gain of compounds of formula I.

Examples for such compounds are described in the above U.S. patents. Substituted phenyl is phenyl, mono - or disubstituted by C1-C6-alkyl, C1-C4-alkoxy, hydroxy, nitro, chloro, fluorescent, or trichloro - or formation.

The compounds used in the methods of the present invention can form pharmaceutically acceptable acidic or basic additive salts with a wide range of organic and inorganic acids and bases, including pharmaceutically acceptable salts, commonly used in pharmaceutical practice.

These salts are also part of the present invention. Examples of inorganic acids that can be used to obtain the above-mentioned salts are chloride-hydrogen (salt), Hydrobromic, Modesto-hydrogen, nitrogen, sulfur, phosphorus, fosforova acid, etc.

Can also be used salts derived from organic acids, such as aliphatic moslty, aromatic acids, aliphatic and aromatic sulfonic acids.

Examples of such pharmaceutically acceptable salts are the acetate, phenyl acetate, triptorelin, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoic, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, - hydroxybutyrate, Butin-1,4 - diet, hexyne-1,4-diet, capret, kaprilat, chloride, cinnamate, citrate, format, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxymet, malonate, mandelate, mesilate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate, monolithicflat, debivort, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, persulfate, sulfite, bisulfite, sulfonate, benzene sulfonate, p-bromophenylacetate, chlorobenzenesulfonate, aconsultant, 2-hydroxyethanesulfonic, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluensulfonate, ecological, tartrate, etc., is Preferable cleaners containing hydrochloride salt.

Pharmaceutically acceptable acid salt additive can be obtained by reaction seinorama solvent, such as diethyl ether or benzene. Usually salt is precipitated from the solution for a period of from 1 hour to 10 days, after which it can be isolated by filtration or by distillation of the solvent by standard methods.

Bases are usually used to obtain the salts are ammonium hydroxide, hydroxides of alkali and alkaline-earth metals, carbonates, aliphatic, primary, secondary and tertiary amines, and aliphatic diamines. Particularly preferred bases that can be used to obtain additive salts are ammonium hydroxide, potassium carbonate, methylamine, diethylamine, Ethylenediamine and cyclohexylamine.

Pharmaceutically acceptable salts usually have higher solubility characteristics than the connection from which they were obtained, and therefore they are often used to obtain liquids or emulsions.

The pharmaceutical preparations can be obtained using traditional techniques. For example, the active compounds in combination with commonly used excipients, diluents or carriers can be manufactured in the form of tablets, capsules, suspensions, powders, etc.

Podhodjashaja, and siliculose derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; wetting agents such as glycerol; dezintegriruetsja agents, such as calcium carbonate and sodium bicarbonate; additives that slow down the process of dissolution such as paraffin; accelerators resorbtive, such as Quaternary ammonium base; surfactants, such as cetyl alcohol and glycerol monostearate; media-adsorbents, such as kaolin and bentonite; and oiling agents, such as talc, calcium stearate, magnesium stearate, and solid polietilenglikoli.

Active compounds may also be included in elixirs and solutions for oral administration or as solutions for parenteral administration, for example, intramuscular, subcutaneous or intravenous injection. In addition, these compounds may be introduced into the dosage form extended release and other drugs.

These drugs can be manufactured in such a way that the active ingredient will be released only (or preferentially) in a certain part of the intestinal tract and, possibly, at some period of kernich materials and waxes.

In accordance with the present invention, a specific dose of a compound of formula I required to inhibit disease of the breast depends on the severity of the disease, the route of administration and other factors that should be considered by the attending physician. Basically, acceptable and effective daily dose is from about 0.1 to about 1000 mg/day, and preferably, from about 50 to about 200 mg/day. The dose can be administered to the patient in need of appropriate treatment, from one to three times a day or more often if necessary for the effective treatment of pathologies.

Usually, it is preferred to introduce the compound of formula I in the form of an acid additive salt, as is commonly the case when using pharmaceuticals, having a basic group, such as piperidino ring. In addition, the compound is preferably administered orally. For this purpose suitable are oral medications that are described below.

Drugs

The following examples of the preparation of drugs the term "active ingredient" means a compound of formula I.

Preparation 1. Gelatin capsules.

Hard gelatin capsules is ngredient - 0,1-1000

Starch, NF 0-650

Flowable powder of starch - 0-650

Silicone fluid, 350 CST - 0-15

The above ingredients were mixed, passed through a sieve No. 45 mesh (U.S.) and the resulting mixture was filled in hard gelatin capsules.

Below are examples of specifically manufactured capsules containing raloxifene:

The drug 2. Capsule containing raloxifene.

The ingredient Quantity (mg/capsule)

Raloxifene - 1

Starch, NF - 112

Flowable powder of starch - 225,3

Silicone fluid, 350 CST - 1,7

Preparation 3 . Capsule containing raloxifene.

The ingredient Quantity (mg/capsule)

Raloxifene - 5

Starch, NF - 108

Flowable powder of starch - 225,3

Silicone fluid, 350 CST - 1,7

Preparation 4. Capsule containing raloxifene.

The ingredient Quantity (mg/capsule)

Raloxifene - 10

Starch, NF - 103

Flowable powder of starch - 225,3

Silicone fluid, 350 CST - 1,7

The drug 5. Capsule containing raloxifene.

The ingredient Quantity (mg/capsule)

Raloxifene - 50

Starch, NF - 150

Flowable powder of starch - 397

ut to be some changes within, not beyond the scope of the present invention.

Preparations in the form of tablets was obtained using the following ingredients:

Preparation 6. Tablets.

The ingredient Quantity (mg/tablet)

The active ingredient is 0.1-1000

Microcrystalline cellulose - 0-650

Colloidal silicon dioxide is 0-650

Stearic acid - 0-15

These components were mixed and compressed into tablets.

Alternatively, tablets, each containing 0.1 to 1000 mg of active ingredient, can be manufactured as described below:

Preparation 7. Tablets.

The ingredient Quantity (mg/tablet)

The active ingredient is 0.1-1000

Starch - 45

Microcrystalline cellulose - 35

Polyvinylpyrrolidone (10% solution in water) - 4

Sodium carboxymethylcellulose is 4.5

Magnesium stearate and 0.5

Talc - 1

The active ingredient, starch and cellulose was passed through sieve No. 45 mesh (U.S.) and thoroughly mixed. The resulting powder was mixed with a solution of polyvinylpyrrolidone, and then was passed through sieve No. 14 mesh U.S. dollars. Thus obtained pellets were dried at 50-60oC and passed through a sieve No. 18 mesh U.S. dollars. Then these granules daubeny through sieve # 60 mesh U.S. and the resulting mixture after mixing was compressed into tablets on teletrauma machine.

Suspensions, each of which contained 0.1 to 1000 mg of a drug in a dose of 5 ml, was prepared as follows:

Preparation 8. Suspension.

The ingredient Quantity (mg/5ml)

The active ingredient is 0.1-1000 mg

Sodium carboxymethyl cellulose 50 mg

The syrup 1.25 mg

A solution of benzoic acid 0.10 mg

Flavor - Hon. No.

Dye - effectiveness. No.

Purified water to 5 ml

The drug was passed through sieve No. 45 mesh U.S. and was mixed with the sodium carboxymethyl cellulose and syrup to form a homogeneous paste. After that, stirring, was added a solution of benzoic acid, flavouring and colouring agents, which were diluted with some water. Then add sufficient water to obtain the desired volume.

Test procedures.

Analysis 1. Clinical trials were selected 5-50 women. In the histories of these women were recorded pathological conditions of the breast, described in this application, but otherwise these women had good health. Since the), that is, all women were divided into two groups, one of which received the active compound of the present invention, and the other a placebo.

Women in the test group was orally administered from 50 to 200 mg of drug per day. Duration of therapy was 3-12 months. Specific regimen at the level of the pathology of the mammary glands for both groups. At the end of the research the results compare. Moreover, the obtained results were compared between the members of each group and, in addition, the results obtained for each patient were compared with the symptoms of this patient, registered before the start of the research.

Studies have shown that the compounds of the present invention have a beneficial effect on the disease of breast cancer or its symptoms.

Analysis 2. For analysis were taken 3-20 men suffering from gynecomastia or galactorrhea. Prior studies have carried out measurements of the size of the mammary glands and recorded the presence of lactation. These patients received oral 30-100 mg of active compound per day in single or divided doses. Duration of treatment was 3 to 12 months. Through defined is S="ptx2">

Studies have shown that the compounds of the present invention have a beneficial effect on the disease of breast cancer or its symptoms.

1. The use of the compounds of formula

< / BR>
in which R1and R3independently represent hydrogen, -CH3, (C1- C6-alkyl) or where Ar represents optionally substituted phenyl;

R2is selected from the group consisting of pyrrolidino and piperidino, or its pharmaceutically acceptable salt or MES for inhibition of such pathological conditions of the breast, gynecomastia, galactorrhea, Nebraska non-cancer mastodinia and breast.

2. Application under item 1, in which the connection is its cleaners containing hydrochloride salt.

3. Application under item 1, in which the connection is prescribed for prophylaxis.

4. Application under item 1, in which the connection is

< / BR>
or cleaners containing hydrochloride salt.

 

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