A method of reducing loss of bone tissue, a method of treating osteoporosis and the use of connection

 

(57) Abstract:

The invention relates to medicine. A method for reducing or preventing loss of bone tissue caused by deficiency of estrogen, as well as a method of treatment of osteoporosis and the use of the compounds of formula

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for the treatment or prevention of loss of bone tissue caused by estrogen deficiency. The invention expands the Arsenal of tools specified destination. 3 C. to 20 C.p. f-crystals, 2 tab., 3 Il.

The renewal of bone tissue is a dynamic process in which the updating and maintenance of the mass and structure of the skeleton. The result is a balance between resorption and formation of bone. Osteoclasts and osteoblasts are the two key participants in the process of updating the bones. Osteoclast starts the update cycle, sucking them a cavity in the bone, which then is filled, due to the fact that the osteoblasts synthesize and lays into the cavity of new bone base. Activity osteoclast and osteoblasts is regulated by a complex interaction of systemic hormones and local production of growth factors and cytokines in the active sites of the updated dice.

Unstable restore bone vyzyvae is the group of skeletal mass, is one of the common diseases in post-menopausal women and often causes painful fractures of spine, hip and wrist.

Approximately 25% of women after menopause suffer from osteoporosis and generally recognized that the etiology of the disease involves reducing blood estrogen (Komm " et al. , Science 241, 84-84, 1988), Komm " et al. additionally report that the number of white women in the United States at risk of breaking a hip is 15%, which is 247000 of hip fractures per year in women older than 45 years. Osteoporosis is costly to both the individual and the whole society. In 1984 of 145,000 American women older than 65 years were treated for a fracture in stationary conditions and 107000 underwent arthroplasty and joint replacement of the hip. Among patients who lived alone prior to a hip fracture, 15% - 20% required long-term care, and even within one year after the fracture could not regain independence. The total financial cost of treatment of osteoporosis, including fractures, in the United States in 1986 amounted to $ 7-10 billion dollars (Peck et al., Am. J. Med. 84: 275 - 282, 1988).

Bone loss associated with osteoporosis, stop by the introduction of exogenous estrogens. To give effect, according Thorneycroff (Am. J. Obstet. Gynecol. 180: 1306 - 1310, 1989), therapy esigodini several different types of estrogen, the main estrogen, women in the period before menopause is 17-beta-estradiol, and this connection is often chosen for therapeutic use. However, at recommended doses, there is a serious side effect, the greatest nuisance is well-correlated effect between estrogen therapy and cancers of the uterus and breast. Cases of carcinoma also depend on dose and duration of treatment.

To avoid the risk of cancer, use of joint use of a progestogen to estrogen. This combination, however, is the return of menstruation, which is unacceptable for most women. An additional disadvantage is the fact that the long-term effects of a progestogen is not completely clear. Thus, most women will not require hormone therapy, so you can safely prevent the rapid bone loss that accompanies menopause.

Pandaman is a non-steroidal compound with known antiestrogenic activity. It is used in India as oral contraceptive (see, for example, Solmanet et al., Pat., USA N 4447622; Sinoh et al., Acta Endocrinol (Copenh) 126: 444-450, 1992; Grubb, Curr. Opin. Obstet. Gynecol. 3: 491 - 495, 1991; Sankarar et al., the youseo breast cancer (Misra et al., Int. J. Cancer 43: 781 - 783, 1989), but there are no studies of the impact pantherman loss of bone tissue.

There remains a need to create compositions and methods suitable for the reduction of bone loss, in particular, are associated with osteoporosis. In addition, require such compositions, which would not have had the side effect of estrogen. The present invention provides such compositions and methods, and offers other related advantages.

On the accompanying illustrations show -

in Fig. 1 - effect pantherman on bone loss in mice with remote ovaries,

in Fig. 2 - the impact of pandromeda on the volume of trabecular bone in the proximal areas of bone in mice with remote ovaries,

in Fig. 3 - effect pantherman loss of bone tissue (left) and on the weight of the uterus (right) in mice with remote ovaries.

The present invention is based in part on the discovery that the representative 3,4-diarylamino, pandaman (3,4-TRANS-2,2 - dimethyl-3-phenyl-4-[n-(pyrrolidinyloxy)phenyl] -7-methoxy - chroman), is a potent inhibitor of bone resorption in mice and rats with removed ovaries. In laboratory animals mimic the conditions of the period after menopause the novels suitable as therapeutic agents for reducing bone loss in a mammal, including primates, such as man.

According to the invention, the compounds of formula (I) or their pharmaceutically acceptable salts can be used to reduce the loss of bone tissue of the patient.

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In the formula (I) R1, R4and R5independently from each other are hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy or tert-amino-lower alkoxy, R2and R3independently from each other, represent hydrogen or lower alkyl. Used herein, the term "lower alkyl" means an unbranched or branched alkyl containing from 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl, etc., the Term "lower alkoxy" means an unbranched or branched alkoxy containing from 1 to 6 carbon atoms, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-amyloxy, sec-amyloxy, n-hexyloxy, 2-ethylbutane, 2,3-Dimethylbutane, etc., "Halogen" means chlorine, fluorine, bromine and iodine.

Tert-aminoadipyl can be dialkylamino, such as dimethyl diethyl-, dipropyl-, dibutil-, or polyethylenimine, such as piperidine, pyrrolidine, R - methyl is laksi; R2and R3means lower alkyl, especially methyl; R4= H and R5represents a tert - amino-lower alkoxy type polyethylenimine. Especially preferred are compounds in which R1located in the 7-position and represents lower alkoxy, especially methoxy; each of R2and R3means methyl, R4= H, R5is a 5-position and is a tert-amino-lower alkoxy radicals, such as pyrrolidinone.

Preferred is used compounds of the formula (I) in the TRANS configuration. These compounds can be used in the form of racemic mixtures or as individual d - or l-enantiomers.

A particularly preferred compound for use in this invention is centchroman (II):

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Although shown only one enantiomer, it is clear that the formula II used here to refer to the TRANS-configuration at the 3 - and 4 - phenyl, includes both the d and l enantiomers and racemic mixture.

3,4-Diarrhoea get by known methods such as described in U.S. Pat. USA N 3340276 Carney et al., Pat. CIF N 3822287 and Ray Bolger et al., J Med. Chem. 19: 276-279, 1976, which is included in the description by reference. In Pat. USA N 3822287 described preorasenesti active - d-and l - enantiomers can be prepared as described Salmn et al. in Pat. USA N 4447622 (included in the description by reference) through education optically active salt of the acid, which when alkaline hydrolysis produces the desired enantiomer.

According to the present invention 3,4-diarrhoea can be obtained in the form of pharmaceutically acceptable salts, especially salts with acids, including salts of organic and mineral acids. Examples of such salts are salts of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, salicylic acid and other similar acids. Suitable inorganic acid salts include salts of hydrochloric, Hydrobromic, sulfuric and phosphoric acids, and other similar salts. Acid salts can be obtained as direct products of synthesis. On the other hand, the free base can be dissolved in a suitable solvent containing the appropriate acid, and salts are distinguished by evaporation of solvent or by separation of the salt in the solvent.

3,4-diarylamino and their salts suitable as to mediclatina, for example, for the treatment of patients suffering from bone loss caused by osteoporosis (including osteoporosis in women after menopause and osteoporosis associated with glukokortikoidami), deforming acticom, hyperparathyroidism, increased content of calcium in the blood and other conditions characterized by excessive speed spilling bone and/or reduced rate of bone formation.

According to the invention 3,4-diarrhoea and their pharmaceutically acceptable salts are used in formulations with pharmaceutically acceptable carrier for medical preparations for parenteral, oral, nasal, rectal, subcutaneous or intradermal conventional methods. The dosage form may further include one or more diluents, fillers, emulsifiers, preservatives, buffer additives, excipients, etc., and be issued in such form, as a liquid form, powders, emulsions, suppositories, liposomes, transdermal leaves, subcutaneous implants with controlled-release tablets, etc. Working in this field can formulate the compound in an appropriate way in accordance with the usual practice, described in the book Remington's Pharmaccutical Sciences, Gennaro, ed.) - Rev. flax oral introduction. For him, the active compound suitable for use in oral administration form, such as tablets or capsules. Typically, the pharmaceutically acceptable salt of the compound is combined with a carrier and melted into the tablet. Suitable carriers are starch, sugar, calcium phosphate, calcium stearate, magnesium stearate, etc., Such compositions can optionally include one or more auxiliary substances such as wetting agents, emulsifiers, preservatives additives, stabilizers, colorants, etc.

The pharmaceutical composition is administered with daily - weekly intervals. "Effective amount" of such pharmaceutical compositions is an amount that provides a clinically significant inhibition of loss of bone tissue. The effective amount will depend, in particular, on the specific conditions of treatment, age, weight and General condition of the patient, and other factors, which is obvious by the previous work in this area. Typically the inhibition of bone loss is detected as statically significant difference between the volumes of spongy bone in the treated and control groups. This can be observed such as 5-10% or greater difference in weight to the x as mice or rats with removed ovaries, as models for osteoporosis, are typically used to calculate doses to humans in the same order. For example, therapeutic dose for the treatment of osteoporosis will vary generally from 0.01 - 50 mg/kg/day, preferably 0.05 to 10 mg/kg/day, more preferably 0.1 to 5.0 mg/kg/day. The use of CIS-isomers or racemic mixtures may cause a higher dose of the prescribed number.

The pharmaceutical compositions can be administered in the form of a single form daily - weekly. On the other hand, they can be executed as of the dosage form with controlled release of substances suitable for subcutaneous implants. Implants formulated to provide release of the active compounds within the required time period, which could be up to several years. Dosage forms with controlled release of substances are described, for example, Sanders et al., J. Pharm. Sci 73: 1924 - 1297, 1984, U.S. Pat. USA N 4489056, and U.S. Pat. USA N 4210644, which are included in the description by reference.

The following examples illustrate, but not limit the invention.

Example 1.

The ability centchroman to prevent osteopenia caused by estrogen deficiency, azenil) subjected to or operation of removal of the ovaries, or surgical simulate their removal to conduct a 4-week trials. When removal of the ovaries make a lateral incision on the skin of the mice and the peritoneum on each side, the ovaries are found, separated from the surrounding fat and connective tissue and cut out. During the simulation, the ovaries are, but then put in place. In all animals the peritoneum and the muscles and sew the incision on the skin closed with staples.

Centchroman dissolved in minimum amount of DMSO, is diluted in an oil medium to a concentration of 50 µg/100 µg. Mice treated twice a week for 4 weeks with subcutaneous injection centchroman or oil environment according to the following recipe: imitation/oil (SV): OVX/oil; OVX/50 mcg centchroman, 2 times a week. Each group consists of 8 animals.

After 4-week treatment centchroman anaesthetize mice ether and euthanized neck offset. Immediately after this, the hip removed, fixed in 70% ethyl alcohol (EtOH), dehydration in a series of solutions with increasing concentration of alcohol: 95% EtOH for 24 hours, and then the three treatments in 100% EtOH for 24 hours each. After the last incubation in 100% EtOH hips clear in two changes of xylene, then processing: 159 - 163, 1990) Frontal sections of the distal metaphases hips 5 μm thickness are cut on a rotary microtome Reichert-Jung 2050, equipped with a tungsten carbide knife. 5 µm sections placed on glass slide and stained with trichrome of Goldner.

Histomorphologically dimension of the distal metafit are using special programs Bioduant Bone Morphometry Program (Biometrics, Inc., Nashville, TN), light passing through the camera light an epifluorescent microscope (Scientific Instruments Inc., Redmons< WA).

Morphological measurements of trabecular bone volume (BV/TV) is performed on tissue space of more than 0.25 mm from the growth connection to exclude primary spongy tissue.

The data shown in Fig. 1, expressed as the mean values of SD for each group. Comparison of the volume of the trabecular bone of the outer thigh based on the analysis of variance using the statistical software Statview (Abacus Concets, Inc., Berkeley. CA).

The difference between the treatments received ANOVA were compared using the method of Lanet multiple comparisons.

Values of P less than 0.05 was considered significant.

In mice with remote ovaries and processed oil carrier was observed 50% reduction in volume of spongy the animal with remote ovaries, treated with 50 μm of centchroman twice a week, this bone loss was prevented.

Example 2

To assess the impact of centchroman on the loss of bone tissue and the mass of skeletons 54 female rats Sprague-Dawley previously noted during the following four weeks, labeled with tetracycline (3H-T; from Dupont NEN' Research Products, Bocton, MA). Animals were injected every 12 - 15 injection 15 μs, so that in General, it was about 3200 µs per animal. Three weeks after the last injection3H-T eight animals were scored as the main control, and then the remaining animals were treated with estrogen (E2) or centchroman (C) in the following groups:simulation /placebo; with remote ovaries (OVX) placebo; with remote ovaries/E2 (0.05 mg/kg/day); with remote ovaries /C (0.05 mg/kg/day); with remote ovaries /C (0.5 mg/kg/day); and remote ovaries / C (0.5 mg/kg/day). The processing of hormones was performed with subcutaneous injection implantant cellet containing cholesterol, lactose. Also determined the amount of local tissue femurs and vertebrae to document changes in the physical properties of bone, and to compare changes in the amounts of internal spongy bone of the tibia ispolzovatsya ether, euthanized neck offset, then immediately remove the uterus and record its weight; both the femur and three thoracic vertebra (T11-T13) were cut for analysis of bone resorption; one tibia and first lumbar vertebra collected to determine the physical properties of the bone; the second tibial bone cut out and spend histomorphometry. All fabrics are first fixed with 70% ethanol and dehydration a series of solutions with increasing concentrations of ethanol up to 100%. after the last dehydration 10% alcohol samples treated by the method below.

The study of bone resorption was based on the assessment of levels3H-T, preserved in labeled hip bones and vertebrae, basically as described by Klein and Tackman (Calcified Tissue Research 20: 275 - 290, 1976). Briefly, the samples were degreased three treatments chloroform for 24 hours each, dried 24 hours at 100oC, then recorded the weight. In order to extract 3H-T, femur and vertebrae were demineralization in 15 ml of 0.5 N hydrochloric acid (HCl), and formed at the top layer decantation and separated. For the quantitative determination of the levels of tritium 625 ál aliquots were collected by pipette into glass scintillation vials is coherent scintillation spectrometer (Beckma LS 1300).

After dehydration of the alcohol samples intended for measurement of bone mass, was degreased three treatments in chloroform for 24 hours each, were dried at 60oC during the night. The mass of bones was expressed in mg dry weight per gram of body weight.

After the last treatment, 100% alcohol tibial bone was cleaned twice a day treatment in xylene, treated without removing the calcium and pour polymethacrylates, as described by Bain et al., (Stain Technology 65: 159 - 163, 1990). Frontal sections of proximal tibia 5 µm thick were made with a rotary microtome Reichert - Jung 2050 Leica Instruments, Nuslock, Germany), with a tungsten carbide knife. 5 µm sections were placed on a glass slide and stained with trichrome of Goldner.

Histomorphometrical dimension of the proximal tibia was determined using a special program Bioguant Bone Morphometry (Biometrics, Inc. , Nasnville, TN), by allowing light through the camera light on /epifluorescent microscope Olympus BH-2 (Sientific Instruments, Inc., Redmond, WA).

Morphometric measurements of trabecular bone volume (BV/TV) are 3.0 mm2the tissue sample at 1.5 mm from the growth connection to exclude primary cancellous bone. Minimum four individual slice edit the tee and histomorphometry based on analysis of variance (ANOVA) using the statistical software Statview(Abacus Concets, Inc., Berkeley, CA). When statistical significance is shown A 110 A, the mean values of control and treatment are compared using the methods of multiple comparison Dunneft. Values of P less than 0.05 are considered significant.

In comparison with the group simulation/ base-treated animals removal of the ovaries in animals causes a significant decrease in wet weight of the label. Replacement of estrogen restores the weight of the uterus to the value observed in the simulation model, but when processed by centchroman not see a statistically significant effect, even at higher doses of 5.0 mg/day. Characterized by increased bone resorption, removal of the ovaries reduces skeletal retention3H-T in the hips and vertebrae (tables 1 and 2, respectively). As expected, treatment with estrogen increases the retention3H-T in the bones. Action centchroman mimics the effect of estrogen on the resorption of bone by a dose-dependent increase in skeletal retention3H-T these two parts of the skeleton (r2- value, equal to 0.96 and 0.92 for hip and vertebra, respectively).

The ability centchroman to inhibit the resorption of bone and prevent bone resorption confirmed smareeamargig rats with removed ovaries empty drug environment and centchroman shows a dose-dependent increase in trabecular bone of the proximal tibia (Fig. 2;2= 0,99). Like centchroman has a dose-dependent effect on the mass of the hip and vertebrae.

In conclusion, we can say that these data show that the ability centchroman to prevent bone resorption in rats with removed ovaries does not depend on the ability of the drug to reduce the weight of the uterus. This is clearly shown in Fig. 3 by combining the data on weight of the uterus and data when the resorption of bone from the hip, showing independent effects centchroman on these two tissues.

Although the preceding statement of invention is described in some detail by way of illustrations and examples, it is obvious that certain changes and modifications may be introduced into the region of the alleged claims.

1. The way to reduce or prevent loss of bone tissue in a patient, introducing a patient an effective amount of a composition containing an agent which inhibits bone resorption due to the deficiency of estrogen, in combination with a pharmaceutically acceptable carrier, characterized in that the said agent is a compound of the formula

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or its pharmacologically acceptable salt,

where R1and R4independently are hydrogen, hydroxy, nezavisimo are hydrogen or C1- C6-alkyl.

2. The method according to p. 1, wherein R1represents the lowest alkoxyl, R2and R3represent lower alkyl, and R4represents hydrogen.

3. The method according to p. 1, wherein R1is a methoxy group.

4. The method according to p. 1, wherein R2and R3represent methyl.

5. The method according to p. 1, wherein R4represents hydrogen.

6. The method according to p. 1, characterized in that the said connection is a dedicated d - or l-enantiomer.

7. The method according to p. 1, characterized in that the said compound is l-enantiomer.

8. The method according to p. 1, characterized in that the specified connection is

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9. The method according to p. 8, characterized in that the said connection is a dedicated d - or l-enantiomer.

10. The method according to p. 9, characterized in that the said compound is l-enantiomer.

11. The method according to p. 1, characterized in that said patient is a woman after menopause.

12. The method according to p. 1, characterized in that this composition represents a form suitable for oral administration.

13. The method according to p. 1, the Method according to p. 1, characterized in that the specified composition is administered with an interval from days to weeks.

15. The method according to p. 1, characterized in that the said composition is in the form of a subcutaneous implant.

16. A method of treating osteoporosis, characterized in that the patient is given a dedicated d - or l-enantiomer of a compound that inhibits bone resorption associated with estrogen deficiency, and those having the formula:

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or its pharmacologically acceptable salt,

where R1and R4independently are hydrogen, hydroxy, halogen, trifluoromethyl, C1- C6-alkyl or C1- C6-alkoxy;

R2and R3independently are hydrogen or C1- C6-alkyl,

sufficient for inhibition of bone resorption.

17. The method according to p. 16, wherein R1represents the lowest alkoxyl, R2and R3represent lower alkyl, and R4represents hydrogen.

18. The method according to p. 16, wherein R1is a methoxy group.

19. The method according to p. 16, wherein R2and R3represent methyl.

20. The method according to p. 16, wherein R4represents hydrogen.

23. The use of compounds of the following structure:

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or their pharmacologically acceptable salts,

where R1and R4independently are hydrogen, hydroxy, halogen, trifluoromethyl, C1- C6-alkyl or C1- C6-alkoxy;

R2and R3independently are hydrogen or C1- C6-alkyl,

as a means of treating or preventing loss of bone associated with estrogen deficiency.

 

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The invention relates to pharmacology

FIELD: organic chemistry, medicine, pharmacy.

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9 cl, 1 tbl, 3 sch, 94 ex

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2 ex

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1 tbl, 3 ex

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EFFECT: improved and enhanced effectiveness of method.

1 ex

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