The use of 2-phenyl-3-kolbenstvedt, their salts or solvate for inhibiting loss of bone tissue, the pharmaceutical composition comprising 2-phenyl-3 - kolbenstvedt, and their salts or solvate

 

(57) Abstract:

Method of inhibiting loss of bone tissue or resorbtive, including the introduction in need of treatment, the patient is the compounds of formula I:

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or its pharmaceutically acceptable salt, or its MES in small doses. In the scope of the invention included pharmaceutical components in unit dose forms containing a single dose low dose amount of this compound. 2 S. and 6 C.p. f-crystals, 1 table.

The invention relates to a method of inhibiting loss of bone tissue with the use of low doses (small amounts) of the particular compounds - 2-phenyl-3-koivistoinen.

Currently, the main disease or condition of the bones that attract attention include postmenopausal osteoporosis, problems of patients after oophorectomy, senile osteoporosis, problems of patients exposed to long-term treatment with corticosteroids, side effects of treatment with corticosteroids or steroids, problems of patients suffering from the syndrome Casings, gonadally the dysgenesis, periarticular erosions in rheumatoid arthritis, osteoarthritis, a disease Paget, disorder, osteomylitis what eidesmo. All these States are characterized by bone loss that occurs due to imbalance between degradation of bone (bone resorption) and the formation of new healthy bone tissue. This "cycle" of bone tissue usually continues throughout life and is the mechanism of regeneration of bones. However, these States shift the balance toward bone loss so that the number rezorbirovanny bone inadequately replaced by new bone tissue, which leads to loss of bone tissue.

One of the most common bone disease is postmenopausal osteoporosis. Usually after menopause, women observed increase speed "cycle" of bone tissue, which leads to loss of bone tissue by decreasing circulating estrogen. The rate of bone "cycle" is different for different bones, and is greatest at sites rich in trabecular bone, for example, in the spine and the femoral head. Possible bone loss in these areas immediately after menopause is 4-5% annually. The resulting loss of bone mass and increased bone porosity leads to an increased probability of the Xia huge number of people with detectivesyme fractures of the spine due to osteoporosis and fractures of the hip joints, which is associated with osteoporosis. With a broken hip due to 12% of deaths in the first two years, and 30% of patients after such fractures require follow-up home care. Therefore disease of bone characterized by a noticeable mortality, the decline in the quality of life of survivors and significant financial cost to their families.

It is essential that all the above listed condition favorable effect of treatment with agents that inhibit bone resorption. Bone resorption is due to the activity of specialized cells called osteoclasts. Osteoclasts are unique in their capacity to resorbtive as hydroxylapatite mineral and organic matrix of bone. They are identical recombinaison cells of the cartilage, which previously was called chondroblastoma. This is why potential inhibitors of resorbtive bone by osteoclasts should also inhibit carried out by cells degradation of cartilage that occurs in rheumatoid arthritis and osteoarthritis.

Therapeutic methods of treatment to inhibit loss of bone tissue include the use of estrogenos. As was clearly shown, extrogen preostane patients deteriorates due to related extragenomic side effects. These side effects include the resumption of menstruation, mastodynia, increasing the risk of uterine cancer and may increase the risk of breast cancer. Alternatively, for the treatment of patients with osteoporosis using calcitonin. It was shown that calcitonin salmon directly inhibits resorcinol activity of osteoclasts mammals, and it is widely used by doctors in Italy and Japan. However, calcitonin extremely expensive and not available to many, and, apparently, have a short-term impact. That is, the osteoclasts are able to "avoid" inhibition of calcitonin resorbtive with adjustable reducing the effectiveness of calcitonin receptors. Therefore, recent data from clinical trials suggest that long-term treatment with calcitonin may not be effective for a long time in terms of stopping the loss of bone tissue during the postmenopausal period.

In the invention, a method for inhibiting resorbtive of bone tissue and loss of bone tissue, which includes the introduction in need of such treatment the person of the compounds of formula:

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and its pharmaceutically acceptable salt or solvate, in quantity the military form, containing a dosage amount of from about 55 to about 150 mg of the compounds of formula I.

The invention includes the discovery of the fact that the compounds of formula suitable for inhibiting bone resorbtive and loss of bone in doses of from about 55 to about 150 mg/day. The methods proposed in the invention, we assume the introduction of the needy in the treatment of the human dose of the compounds of formula I, or its pharmaceutically acceptable salt, or MES in the amount of from about 55 to about 150 mg/day for inhibition of resorbtive or bone loss.

The term "inhibits" has its ordinary meaning, which includes prevention, prohibition, restriction, and slowing, stopping or reversing the progression or severity, and keep under control and/or treatment of existing characteristics. The method of the invention includes both medical therapeutic and/or prophylactic treatment depending on necessity.

Typically, the compound is used in combination with conventional excipients, diluents or carriers, and compressed into tablet form, or prepared in the form of elixirs or solutions for conventional oral administration, or administered intramuscularly or intravenously. Connection release, etc.

The method of the invention is suitable both for men and for women. Practical absence extragenic reactions should allow men to use the method of the invention without the response to the feminization of estrogen or agonists estrogen, such as gynecomastia. However, it is preferable to use the methods of the invention for women, and more preferably, for women with a lack of estrogen.

2-phenyl-3-kolbenstange compounds that are the active components in the method of the invention, were first developed and described as contraceptives in U.S. patent N 4133814, class C 07 D 333/157, 1979. It was found that some compounds in this group can be used to inhibit the growth of breast tumors.

In U.S. patent No. 4 418 068 class. C 07 D 333/52, 1983 describes a group of related compounds that can be used in an antiestrogen and antiandrogenna therapy, especially in the treatment of tumors of the breast and prostate. One of these compounds, hydrochloride compounds of formula I were tested in the clinic (short) for the treatment of breast cancer. This connection is called raloxifene (the former name of keoxifene).

In loxifene on biological markers of bone and lipid metabolism in healthy women in the postmenopausal age. Fourth international Symposium on osteoporosis. Hong Kong, March 29, 1993) discusses some of the positive characteristics of the use of raloxifene for inhibiting bone resorbtive and reducing serum cholesterol. The test dose was 200 and 600 mg/day. As follows from EPO publication EP-A-584952 published on March 2, 1994 (corresponding to patent application U.S. 07/920933, filed July 28, 1992 (X-7947)), the proposed interval is specified as 200-600 mg/day. Although this interval dosing of 200-600 mg/day, causes sufficient reaction and pharmaceutically acceptable, unexpectedly it was found that lower doses of raloxifene (from about mg/day to about 150 mg/day) provides equivalent benefits compared with higher doses.

It was shown that raloxifene binds to receptors on extrogen, and at first it was thought that it is a molecule that functions and pharmacology which as antiestrogen is that it blocks the ability of estrogen to activate the tissue of the uterus and dependent on estrogen cancers of the breast. Indeed, raloxifene inhibits the activity of estrogen in some cells, but other cell types raloxifene activates the same genes, copil, which demonstrates raloxifene, and which he differs from extrogen, is associated with a unique activation and/or suppression of various gene functions through raloxifene-estrogenove receptor complex, in contrast to the activation and/or suppression of genes extrogen-estrogenove receptor complex. Therefore, although raloxifene and estrogen use and compete for the same receptors, the pharmacological result of the genetic regulation of these two compounds it is not so easy to predict, and it is different from each of them.

Usually the compounds are used in combination with conventional excipients, diluents or carriers, and compressed into tablets or prepared in the form of elixirs or solutions for conventional oral administration, or administered intramuscularly or intravenously. Connection, you can enter through the skin or vaginally, and they can be prepared in dosage forms with delayed allocation.

The compounds used in the invention can be obtained in accordance with known procedures, for example by the method of U.S. patents NN 4133814, 4418068 and 4380635, which are included in the description by reference. In General, these methods come from benzo[b]thiophene and 6-hydroxyl groups of the comfort and removes the protection, receiving the compound of formula I. Examples of the preparation of such compounds are given in U.S. patents discussed earlier.

Used in the methods of the invention compounds can form pharmaceutically acceptable salt accession of acids and bases with a wide range of organic and inorganic acids and bases, including physiologically acceptable salts, which frequencies are used in pharmaceutical chemistry. Such salts also lead in the scope of the invention. Typical inorganic acids, which are used for such salts include hydrochloric, Hydrobromic, idiscovered, nitric, sulfuric, phosphoric, hypophosphorous, etc., Salts derived from organic acids such as aliphatic mono - and dicarboxylic acids, phenylsilane alcamovia acid, hydroxyalkanoate and hydroxyalkanoate acids, aromatic acids, aliphatic and aromatic sulfonic acids, can also be used. Such pharmaceutically acceptable salts include the acetate, phenyl acetate, triptorelin, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, acetoxybenzoic, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate-hydroxybutanoic, hippurate, lactate, malate, maleate, hydroxymet, malonate, mandelate, mesilate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, mono(acid)phosphate, di(acid)phosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, propionate, salicylate, sebacate, succinate subert, sulfate, bisulfate, persulfate, sulfite, bisulfite, sulfonate, benzene sulfonate, para-brabanthallen, chlorobenzenesulfonate, aconsultant, 2-hydroxyethanesulfonic, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluensulfonate, ecological, tartrate, etc., the Preferred salt is the hydrochloride.

Pharmaceutically acceptable salt accession acids are usually obtained, subjecting the interaction of a compound of formula I with an equimolar amount or an excess of acid. Typically, the reactants combine in such common solvents as diethyl ether or benzene. Usually salt is precipitated from the solution for a period of time from 1 h to 10 days, and it can be identified by filtration, or the solvent can evaporate in the usual way.

The grounds, which are usually used to produce salts include ammonium hydroxide and the hydroxides and carbonates of alkali and alkaline earth metals, and Tae suitable for obtaining salts of accession, include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, methylamine, diethylamine, Ethylenediamine and cyclohexylamine.

Pharmaceutically acceptable salts have a high solubility compared to the compounds from which they are derived, and therefore they are often more applicable to obtain compositions in the form of liquids or emulsions.

The pharmaceutical compositions can be obtained by methods known in the art. For example, compositions of the compounds can be obtained with conventional excipients, diluents or carriers and to prepare in the form of tablets, capsules, suspensions, powders, etc., Examples of fillers, diluents, and carriers that are suitable for such compositions include the following: fillers and agents that increase the volume, such as starch, sugars, mannitol, and derivatives of silicon; such binding agents, as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; such moisturizers like glycerin; leavening agents such as calcium carbonate and sodium bicarbonate; agents slow dissolution as paraffin; such accelerators resorbtive as a combination of Quaternary ammonium; such poverhnosot; and such moving as talc, calcium stearate and magnesium, and solid polyethylene glycols.

Compounds can also be prepared in compositions in the form of elixirs or solutions for convenient oral administration or as solutions for parenteral injection, such as intramuscular, subcutaneous or intravenous. In addition, the compounds suitable for the preparation of compositions in the form of dosage forms for delayed allocation, etc. of the Composition can also be prepared in such a way that they identified the active ingredient only or preferably in a certain area of the intestine and possibly within a certain period of time. You can use cover, a wafer and a protective matrix, for example, from polymeric materials or waxes.

The doses of the invention is from about 55 to about 150 mg/day, and preferably from 60 to 150 mg/day, and most preferably from 60 to 100 mg/day. Specific doses in the framework of the invention are 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145 and 150 mg/day.

Of the composition, preferably, create a standard dosage forms, each dosage contains from about 55 to about 150 mg, and more preferably, the example to the tablets or capsules, suitable for a single use, especially for a single daily administration, for humans and other mammals, each dose contains a predetermined quantity of active material calculated to produce the desired therapeutic effect, together with a suitable pharmaceutical excipient.

Duration of reception by the people of the dose from about 55 to about 150 mg/day will depend on the severity of the condition, the patient's health and related factors that must be assessed by the attending physician. It is assumed that the course of treatment should be at least six months, usually at least one year, and preferably, should not be interrupted.

Examples of compositions in dosage interval following:

Songs

Composition 1: Gelatin capsules.

Hard gelatin capsules get, using the following ingredients:

Ingredient Quantity (mg/capsule)

Raloxifene 55-150

Starch, NF 0-650

The starch in the form of presuposes powder 0-650

Silicone fluid, 350 CST 0-15

The ingredients are mixed, passed through a sieve of 45 mesh U.S. and filled into hard gelatin capsules.

Ingredient Quantity (mg/capsule)

Raloxifene 60

Starch, NF 112

Free presuposes powder starch 225,3

Silicone fluid, 350 CST 1,7

Composition 3: Raloxifene capsules.

Ingredients Quantity (mg/capsule)

Raloxifene 75

Starch, NF 108

Free presuposes powder starch 225,3

Silicone fluid, 350 CST 1,7

Track 4: Raloxifene capsules.

Ingredient Quantity (mg/capsule)

Raloxifene 100

Starch, NF 103

Free presuposes powder starch 225,3

Silicone fluid, 350 CST 1,7

Composition 5: Raloxifene capsules.

Ingredient Quantity (mg/capsule)

Raloxifene 125

Starch, NF 150

Free presuposes powder starch 397

Silicone fluid, 350 CST 3,0

Track 6: Raloxifene capsules.

Ingredient Quantity (mg/capsule)

Raloxifene 150

Starch, NF 150

Free presuposes powder starch 397

Silicone fluid, 350 CST 3,0

The above specific composition can be changed in accordance with reasonable options.

Companygreat Quantity (mg/tablet)

Raloxifene 60

Microcrystalline cellulose 0-650

Fine silica 0-650

Stearic acid 0-15

Song 8: Pills.

Ingredients Quantity (mg/tablet)

Raloxifene 75

Microcrystalline cellulose 0-650

Fine silica 0-650

Stearic acid 0-15

Composition 9: Pills.

Ingredient Quantity (mg/tablet)

Raloxifene 100

Microcrystalline cellulose 0-650

Fine silica 0-650

Stearic acid 0-15

Song 10: Pills.

Ingredient Quantity (mg/tablet)

Raloxifene 125

Microcrystalline cellulose 0-650

Fine silica 0-650

Stearic acid 0-15

Composition 11: Pills.

Ingredient Quantity (mg/tablet)

Raloxifene 125

Microcrystalline cellulose 0-650

Fine silica 0-650

Stearic acid 0-15

These components are mixed and pressed into tablets.

In another embodiment can be obtained tablets, each of which contains from 55 to 150 mg of the active ingredient, as follows:

Song 12: Tablets.Aya cellulose 35

Polyvinylpyrrolidone (as 10% solution in water) 4

The sodium carboxymethyl cellulose 4,5

Magnesium stearate 0.5 to

Talc 1

The sodium carboxymethyl cellulose 4,5

Magnesium stearate 0.5 to

Talc 1

Composition 13: Pills.

Ingredient Quantity (mg/tablet)

Raloxifene 75

Starch 45

Microcrystalline cellulose 35

Polyvinylpyrrolidone (in water 10% solution in water) 4

The sodium carboxymethyl cellulose 4,5

Magnesium stearate 0.5 to

Talc 1

Song 14: Pills.

Ingredient Quantity (mg/tablet)

Raloxifene 100

Starch 45

Microcrystalline cellulose 35

Polyvinylpyrrolidone (as 10% solution in water) 4

The sodium carboxymethyl cellulose 4,5

Magnesium stearate 0.5 to

Talc 1

Song 15: Pills.

Ingredient Quantity (mg/tablet)

Raloxifene 125

Starch 45

Microcrystalline cellulose 35

Polyvinylpyrrolidone (as 10% solution in water) 4

Song 16: Pills.

Ingredient Quantity (mg/tablet)

Raloxifene 150

Starch 45

Microcrystalline cellulose 35

Polyvinylpyrrolidone (as 10% solution t, starch and cellulose are passed through sieve No. 45 mesh U.S. and thoroughly mix. With the obtained powder mixed solution of polyvinylpyrrolidone and all this passed through sieve No. 14 mesh U.S. dollars. Thus obtained granules are dried at 50 60oC and passed through sieve No. 18 mesh U.S. dollars. Then the beads add previously passed through sieve # 60 mesh U.S. the sodium carboxymethyl cellulose, magnesium stearate and talc, and all this after stirring pressed into the device for the manufacture of tablets.

Suspensions, each of which contains 55 to 150 mg of drug per 5 ml dose, are prepared as follows:

Song 17: Suspension.

Ingredient Quantity (mg/5 ml)

Raloxifene 60

The sodium carboxymethyl cellulose 50

Syrup 1,25

A solution of benzoic acid 0,10

Corrigent q.v.

The dye q.v.

Purified water to 5

Song 18: Suspension.

Ingredient Quantity (mg/5 ml)

Raloxifene 75

The sodium carboxymethyl cellulose 50

Syrup 1,25

A solution of benzoic acid 0.10 ml

Corrigan q.v.

The dye q.v.

Purified water to 5 ml

Song 19: Suspension.

Ingredient Quantity (mg/5 ml)

Lorrigan q.v.

The dye q.v.

Purified water to 5 ml

Song 20: Suspension.

Ingredient Quantity (mg/5 ml)

Raloxifene 125

The sodium carboxymethyl cellulose 50

Syrup 1,25

A solution of benzoic acid 0.10 ml

Corrigent q.v.

The dye q.v.

Purified water to 5 ml

Composition 21: Suspension.

Ingredient Quantity (mg/5 ml)

Raloxifene 150

The sodium carboxymethyl cellulose 50

Syrup 1,25

A solution of benzoic acid 0.10 ml

Corrigent q.v.

The dye q.v.

Purified water to 5 ml

The medication is passed through sieve No. 45 mesh U.S. and mix with nitrocellulose and syrup to a smooth paste. A solution of benzoic acid, flavoring agent and the dye is diluted with a small amount of water and added with stirring. Then add the remaining water to the desired volume.

Example 1. 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl]benzo[b]thiophene.

Portion 4 g of the hydrochloride of 6-methansulfonate-2-(4-methanesulfonamido-3-[4-(2-piperidinoethyl)benzoyl]benzo[b]thiopheneacetic with 100 ml of denatured alcohol and 10 ml of 5N sodium hydroxide and stirred OSHA in vacuum, and the residue is dissolved in 200 ml of water and washed with 300 ml of diethyl ether. The aqueous layer was Tegaserod in vacuum, and then through it bubbled nitrogen to remove traces of ether. Then the resulting mixture was acidified with 1N hydrochloric acid, then alkalinized with excess sodium bicarbonate. The precipitate is collected by filtration and washed with cold water to obtain 2.4 g of the crude product. Its purified on a column of silica gel (h cm), elwira first 700 ml of 55% methanol in chloroform, and then 1 l of 10% methanol in chloroform. First out impurities and containing the product fractions are combined and evaporated in vacuo to obtain 1.78 g of yellow oil. This oil is dissolved in 6 ml of acetone, introducing a seed crystal and cooled in a refrigerator to obtain 1.2 g of the pure product, so pl. 143-147oC. the Identity of the product is confirmed as follows:

An NMR spectrum (100 Mghz, DMSO - d6) d 1.20-1.65 (6H, m, N/CH2CH2/2CH2); 2.30-2.45 (4H, m, N/CH2CH2/2CH2); 2.60 (2H, t, J 6 Hz, OCH2CH2N); 4.06 (2H, t, J 9 Hz, OCH2CH2N); 6.68 (2H, d, J 9 Hz, fragrance. to OH); 6.85 (1H, q, JH4-H59 Hz, JH5-H72 Hz, H5 benzothiophene ring), 6.90 (2H, d, J 9 Hz, aromatic. ring up OCH2CH2N); 7.18 (2H, d, J 9 Hz, tx2">

UV spectrum (in ethanol): nmax() 290 nm (34000).

Mass spectrum (bombardment by electrons) Mtwhen m/e 473.

Example 2. 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] benzo[b]thiophene.

A portion of 3.6 g of 6-methansulfonate-2-(4-methanesulfonylaminoethyl)-3-[4-(2-piperidinoethyl) benzoyl]benzo[b]thiophene are dissolved in 100 ml of tetrahydrofuran and 40 ml of methanol, and add 10 ml of 5N sodium hydroxide. The resulting mixture was stirred for 16 h at room temperature, and then treated according to the method of example 1 to obtain 3.5 g of a solid yellow product. This product was then purified through column chromatography with silica gel, elwira (with a gradient solvent of 5% methanol in chloroform to 30% methanol in chloroform. The fractions containing the product is evaporated to obtain 1.85 g of oily product, which is recrystallized from acetone and earn 1.25 g of the pure product. So pl. 141-144oC.

Example 3. Hydrochlor-6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidino - ethoxy)benzoyl]benzo[b]thiophene.

Under nitrogen atmosphere a mixture of 3 g of hydrochloro 4-(2-piperidinoethyl)benzoic acid, 2 drops of dimethylformamide, 2.5 ml of thionyl chloride and 40 ml Harb who I am. The remaining suspension is cooled to room temperature and to this was added 100 ml of dichloromethane, 2.7 g of 6-methoxy-2-(4-methoxyphenyl)benzo[b] thiophene and 10 g of aluminofluoride. The resulting solution was stirred for about 1 h, add 7.5 ml of ethanthiol and the resulting mixture was stirred for 45 min or more. Then add 40 ml of tetrahydrofuran, and then 15 ml of 20% hydrochloric acid with ectodermal to reflux. Add 50 ml of water and 25 ml saturated aqueous nitriloside. The resulting mixture is stirred and allowed to cool to room temperature. The precipitate is collected by filtration and washed successively with 30 ml water, 40 ml of 25% aqueous tetrahydrofuran and 35 ml of water. Then the hard part is dried at 40oC in a vacuum to obtain of 5.05 g of the product, which is identified according to NMR data:

1.7 (6H, m, N/CH2CH2/2CH2); 2.6-3.1 (2H, NCH2); 3.5-4.1 (4H, m, NCH2); 4.4 (2H, m, OCH2); 6.6-7.4 (9H, m, aromatics) 7.7 (2H, m, aromatics ortho to CO); 9.8 (2H, m, OH).

The results of the tests.

Spent 8 weeks parallel, double-blind, placebo research in 160 healthy women in postmenopausal period. Used doses of raloxifene in this study were 10, 50 and 200 mg Dose of 10 mg did not give noticeable is Askerov, apparently, you can take the dose of raloxifene 50 mg/day fully active when evaluating studies of greater duration.

1. The use of the compounds of formula I

< / BR>
or its pharmaceutically acceptable salt or MES 55 to 150 mg/day for inhibiting loss of bone tissue or bone resorbtive.

2. Application under item 1, characterized in that the connection is cleaners containing hydrochloride salt.

3. Application under item 1, characterized in that the number of connections 60 to 100 mg/day.

4. Application under item 1, characterized in that the number of connections 60 mg/day.

5. Pharmaceutical composition for inhibiting loss of bone tissue in the form of standard dosage forms comprising the active principle and the usual fillers, solvents or carriers, characterized in that the active principle is a compound of the formula I

< / BR>
or its pharmaceutically acceptable salt or MES 55 150 mg.

6. The composition according to p. 5, characterized in that the number of connections 60 to 100 mg.

7. The composition according to p. 5, characterized in that the number of connections 60 mg.

8. The composition according to p. 5, characterized in that provided in the

 

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