RU2328285C2 - Means and method of conditions treatment implying androgen action decrease is considered to be favourable, and method of androgen-dependent tissue sensitivity itensifying using 9-oxoacridine-10-acetic acid - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention describes application of 9-oxoacridine-10-acetic acid, it pharmaceutically acceptable salts and its ethers as additional means for treatment of conditions implying androgen action decrease is considered to be favourable, and method of condition treatment implying that androgen action decrease is considered to be favourable, and needy patient in introduced with effective amount of 9-oxoacridine-10-acetic acid it pharmaceutically acceptable salts and its ethers combined with hormonotherapy directed on androgen action decrease. Besides, method implies androgen-dependent tissue sensibility intensifying to antiandrogen hormonotherapy directed on androgen action decrease.

EFFECT: increased efficiency of antiandrogen hormonotherapy.

30 cl, 5 tbl, 9 ex

Description

The invention is intended for use in medicine and relates to agents for treating conditions in which the androgen reduction is therapeutically beneficial, in particular for the treatment of androgenetic alopecia, prostate adenoma, prostate cancer, and the prevention of prostate cancer recurrence.

Androgens are a group of male sex hormones that include, but are not limited to, testosterone, dehydroepiandrosterone, and androstenediol. Androgens are synthesized in the testes, ovaries and adrenal cortex. The production and entry into the blood of androgens is regulated by the pituitary gland.

It was found that androgens are involved in the etiopathogenesis of a number of diseases, which include, in particular, alopecia, adenoma and prostate cancer.

Androgenic alopecia is one of the known aspects of the use of antiandrogen hormone therapy. Androgenic alopecia, due to the high sensitivity of hair follicle cells to androgens, especially to dihydrotestosterone, formed under the influence of 5-alpha reductase from testosterone. In order to treat this disease, 5-alpha reductase blockers are most often used, for example finasteride, which is a synthetic 4-azasteroid compound N- (2-methyl-2-propyl) -3-oxo-4-aza-5-α-androst -1-ene-17-β-carboxamide.

Benign prostatic hyperplasia (adenoma) is the most common benign disease in men. In the pathogenesis of prostate adenoma, the conversion of testosterone to dihydrotestosterone (DHT) in the tissues of the prostate gland plays a significant role. Therefore, in its treatment, the use of competitive inhibitors of 5-alpha-reductase type II is considered effective. Such preparations include, for example, the aforementioned finasteride. Finasteride significantly reduces the level of both circulating in the blood and intraprostatic year of hydrotestosterone.

The hormonal dependence of prostate cancer was also discovered more than half a century ago. Since then, hormone therapy has remained the leading treatment for common forms of this tumor.

In all cases of using hormone therapy for prostate tumors, its main goal is to reduce or completely stop the influence of the patient’s own (endogenous) male sex hormones (androgens) on the tumor cells. For this purpose, hormones, their analogues, agonists or antagonists, as well as stimulators or inhibitors of the synthesis of hormones are used.

Any antiandrogenic effect causes an organism’s response aimed at compensating for such an effect, since the level of testosterone in the body is regulated by the feedback principle. Therefore, it would be useful to have a means that impedes such a compensatory response.

The authors of this invention are not aware that at the moment such special agents have been proposed that would increase the effectiveness of antiandrogen therapy. However, it is known that some adjuvants are used in the treatment of prostate cancer.

For example, it has been proposed to use 1α, 25-dihydroxycholecalciferol (calcitriol), which is a biologically active form of vitamin D ₃ (publication WO 2004/087190 of October 14, 2004, Applicant GENIX THERAPEUTICS INC., As a means to increase the effectiveness of antiandrogen therapy in the treatment of prostate cancer). ) Calcitriol enhances the action of the release hormone luteinizing hormone agonist, which has androgen-suppressing properties, being an inhibitor of gonadotropin secretion (inhibition of gonadotropin secretion leads to inhibition of testosterone production by the testes). From the same publication (WO 2004/087190), there is also known a method for treating prostate cancer in which a LHRH analogue and calcitriol are administered to a patient. This publication does not provide any evidence of the effectiveness of such a tool and method.

As the closest analogue of the present invention, there can be mentioned a combination for the treatment of prostate cancer, which increases the effectiveness of antiandrogen therapy in the treatment of prostate cancer, comprising at least one compound having antiandrogenic activity and β-interferon (see DE 19536818, SCHERING AG , 03/27/1997).

The objective of the invention is to increase the effectiveness of the treatment of conditions in which the therapeutically beneficial is to reduce the action of androgens, as well as to provide a means for this increase and to create a more effective way to treat such conditions.

This problem is solved by the fact that as a means for treating conditions in which the decrease in the action of androgens is therapeutically favorable, 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and its esters are proposed. These substances are proposed to be used in combination with antiandrogen hormone therapy. They are used to increase the effectiveness of antiandrogen hormone therapy. Thus, 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and esters can be used in combination therapy of conditions in which the decrease in the action of androgens is therapeutically favorable, as a means of increasing the effectiveness of antiandrogen hormone therapy, which is aimed at reducing the effect androgen.

9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and esters are proposed for use in the manufacture of a medicament for the treatment of conditions in which the decrease in the effect of androgens is therapeutically beneficial, that is, in the manufacture of an agent for increasing the effectiveness of antiandrogenic effects (antiandrogen hormone therapy) in the treatment of conditions in which the androgen reduction is therapeutically beneficial.

Also according to this invention, the following is proposed:

- a combination for decreasing the action of androgens, containing a compound selected from the group consisting of 9-oxoacridine-10-acetic quota, its pharmaceutically acceptable salts and its esters, and at least one agent that reduces the effect of androgens;

- a pharmaceutical composition that reduces the effect of androgens, containing effective amounts of a compound selected from the group consisting of 9-oxoacridine-10-acetic quota, its pharmaceutically acceptable salts and its esters, and at least one agent that reduces the effect of androgens, and a pharmaceutically acceptable excipient; and

- a kit for reducing the action of androgens containing a compound selected from the group consisting of 9-oxoacridine-10-acetic quota, its pharmaceutically acceptable salts and its esters, in a separate dosage form and at least one agent that reduces the effect androgen in a separate dosage form.

The present invention also provides a method for treating conditions in which the androgen action is therapeutically beneficial, in which an effective amount of a compound selected from the group consisting of 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and esters, and carry out hormone therapy, aimed at reducing the effects of androgens.

A method is also proposed to enhance the sensitivity of androgen-dependent tissues to hormone therapy aimed at decreasing the action of androgens, in which an effective amount of a compound selected from the group consisting of 9-oxoacridine-10-acetic quota, its pharmaceutically acceptable salts and esters is administered.

According to this invention, preferred salts of 9-oxoacridine-10-acetic acid are selected from the group consisting of sodium, meglumine, eglumine salts, and a salt with 3-O- (N, N-dimethylamino-n-propyl) -1.2: 5,6-di-O-isopropylidene-α, D-glucofuranose.

According to the present invention, preferred 9-oxoacridine-10-acetic acid esters are selected from the group consisting of ethyl, propyl, butyl, isopropyl, and amyl esters.

The present invention suggests that, in a preferred case, conditions in which the decrease in the action of androgens is therapeutically favorable, a group is selected including alopecia, prostate adenoma, prostate cancer and the possibility of recurrence of prostate cancer.

According to the present invention, the androgen reducing agent is preferably one selected from the group consisting of simple or steroidal antiandrogens, steroid synthesis inhibitors, androgen synthesis inhibitors, 5-alpha reductase inhibitors, glucocorticoids, estrogens, agonists (analogues) releasing luteinizing hormone hormone (LHRH) and LHRH antagonists.

More preferably, the androgen reducing agent is a finasteride 5-alpha reductase inhibitor or creeping palm fruit extract (Serenoa Repens).

When implementing the method of treatment, 9-oxoacridine-10-acetic acid, its salt or its ester can be administered by the course before the start of hormone therapy, or by the course simultaneously with the hormone therapy, or start its administration before the start of the hormone therapy and continue during the hormone therapy.

9-oxoacridine-10-acetic acid is a substance having the structural formula

According to another nomenclature, it can also be called 10- (carboxymethyl) -9 (10H) acridone, in the CAS database it has the number 38609-97-1, the international non-proprietary name is cridanimod.

Derivatives of 9-oxoacridine-10-acetic acid were proposed in 1971 by Hoffman La Roche Inc. as powerful antiviral agents (US Pat. No. 3,3681,360).

Currently, preparations based on 9-oxoacridine-10-acetic acid and its pharmaceutically acceptable salts are offered for the treatment and prevention of a wide range of diseases. In particular, its properties are known as immunomodulating, interferonogenic, antibacterial, antipromotor and radioprotective.

The authors of this invention unexpectedly found that the use of preparations of 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and esters allows to increase the effectiveness of therapy aimed at reducing androgenic effects on the body.

Conditions in which a decrease in the effect of androgens is required, in particular, as indicated above, are alopecia, prostate adenoma, prostate cancer and the possibility of recurrence of prostate cancer.

Therapy aimed at reducing androgenic effects on the body may be the introduction of one or more than one agent selected from the group consisting of simple or steroidal antiandrogens, steroid synthesis inhibitors, in particular androgen synthesis inhibitors, in particular 5-alpha reductase inhibitors , glucocorticoids, estrogens, agonists (analogues) of the releasing hormone luteinizing hormone (LHRH) and LHRH antagonists. The introduction of any of these substances, or a combination thereof, in the context of the present invention is considered to be a “hormone therapy aimed at reducing the action of androgens”.

The mechanism by which 9-oxoacridine-10-acetic acid and its pharmaceutically acceptable salts and esters increase the effectiveness of antiandrogen agents is not fully understood. There is an assumption that the anion of 9-oxoacridine-10-acetic acid interferes with the expression of additional receptors on androgen-sensitive cells, which occurs in response to a decrease in androgen stimulation. The expression of additional receptors serves to compensate for the decrease in androgen stimulation and reduces the effect of aniandrogen therapy. 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and esters that interfere with such expression, thus increase the effectiveness of antiandrogenic effects.

The use of an agent that increases the effectiveness of antiandrogen therapy, namely, 9-oxoacridine-10-acetic acid and its pharmaceutically acceptable salts and its esters, proposed according to this invention, can reduce the dose and / or duration of use of the main antiandrogen agent in the treatment of these states.

9-oxoacridine-10-acetic acid and its pharmaceutically acceptable salts and its esters can be used simultaneously with the antiandrogen hormone effect or before it begins. It has been established that if the course of administration of 9-oxoacridine-10-acetic acid or its pharmaceutically acceptable salt or ester was carried out before the start of antiandrogen hormone therapy, then, during subsequent antiandrogen hormone therapy, the effect is comparable to that observed with the simultaneous start of administration 9 -oxoacridine-10-acetic acid or its pharmaceutically acceptable salt or its ester and the same antiandrogen hormone therapy. If 9-oxoacridine-10-acetic acid or its pharmaceutically acceptable salt or its ester begins to be used before the start of the antiandrogen hormone effect and continues to be used during this exposure, the effect of their administration is even more pronounced.

It is known that the immunomodulating effect of 9-oxoacridine-10-acetic acid and its pharmaceutically acceptable salts depends on the dose only in the range of 0-10 mg / kg, however, according to this invention, the enhancement of the effect of antiandrogen therapy is dose-dependent and at doses above 10 mg / kg body, which indicates that the authors discovered new properties of 9-oxoacridine-10-acetic acid.

According to studies by the authors of this invention, as an adjuvant in antiandrogen therapy, 9-oxoacridine-10-acetic acid and its pharmaceutically acceptable salts and its esters do not act through immunostimulation (induction of interferon), but by a completely different mechanism, which effective in combination with antiandrogenic exposure.

The proof of this position is, in particular, the fact that the combination of antiandrogenic exposure with the introduction of interferon gives a lesser effect than the combination of antiandrogenic exposure with the introduction of 9-oxoacridine-10-acetic acid.

It should be noted that in the context of this description, when 9-oxoacridine-10-acetic acid is mentioned, its pharmaceutically acceptable salts and its esters are also meant.

The term "pharmaceutically acceptable salt" refers to salts that retain the above-described properties of 9-oxoacridine-10-acetic acid, and which are not biologically or in any other way unacceptable. Pharmaceutically acceptable salts obtained by addition of bases can be obtained with inorganic or organic bases.

Inorganic base salts include, for example, sodium, potassium, lithium, ammonium, calcium and magnesium salts.

Salts with organic bases include, but are not limited to, salts of primary, secondary, tertiary and quaternary amines, such as alkyl amines, diaclylamines, trialkyl amines, substituted alkyl amines, di (substituted alkyl) amines, tri (substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenylamines, substituted alkenylamines, di (substituted alkenyl) amines, tri (substituted alkenyl) amines, cycloalkylamines, di (cycloalkyl) amines, tri (cycloalkyl) amines, substituted cycloalkylamines, di (substituted cycloalkyl) amines, three (substituted cycloalkyl) a mines, cycloalkenylamines, di (cycloalkenyl) amines, tri (cycloalkenyl) amines, substituted cycloalkenylamines, di (substituted cycloalkenyl) amines, tri (substituted cycloalkenyl) amines, arylamines, diarylamines, triarylamines, diheteroarylaryl arylamines mixed di- and triamines, where at least one of the substituents on the amine is different and selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclyl and the like. This also includes amines in which two or three substituents, together with the nitrogen atom to which they are attached, form heterocyclyl or heteroaryl.

Specific examples of suitable amines include, in particular, isopropylamine, trimethylamine, diethylamine, tri (isopropyl) amine, tri (n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine , ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine and the like.

An example of an alkali metal salt of 9-oxoacridine-10-acetic acid is the sodium salt:

An example of a salt with an amino compound is the salt of 1-deoxy-1- (methylamino) -D-glucitol (i.e. meglumine):

Other examples of salts with various complex quaternary ammonium bases are salts with amino-substituted carbohydrates, for example with 2-deoxy-2-amino (or 2-alkylamino -) - D-glucose, where R represents H or lower alkyl:

with 1-deoxy-1-methylamino-D-glucose:

as well as salts with various esters of carbohydrates and aliphatic amino alcohols, for example

where R ₁ , R ₂ represents alkyl, aryl, heteryl.

Examples of suitable cations are also, in particular, 3-O- (N, N-dimethylamino-n-propyl) -1,2 cations: 5,6-di-O-isopropylidene-α, D-glucofuranoses,

1-deoxy-1- (ethylamino) -D-glucitol (i.e. egglumina),

1-deoxy-1- (propylamino) -D-glucitol,

1-deoxy-1- (butylamino) -D-glucitol,

1-deoxy-1- (methylamino) -L-glucitol,

1-deoxy-1- (ethylamino) -L-glucitol,

1-deoxy-1- (propylamino) -L-glucitol and

1-deoxy-1- (butylamino) -L-glucitol.

Under the esters of 9-oxoacridine-10-acetic acid are meant compounds in which the hydrogen atom in the HO group is replaced by an organic group R.

Examples of suitable esters are 9-oxoacridine-10-acetic acid esters with lower alkyls (namely, (C ₁ -C ₁₂ ) alkyls, in particular ethyl, propyl, isopropyl, butyl and amyl esters), as well as choline and other lipophilic alcohols.

After rapid penetration through biological membranes, these compounds are then readily hydrolyzed "in vivo" to free 9-oxoacridine-10-acetic acid.

The term “antiandrogens” or “antiandrogenic agents” in the literature is used in the broadest sense to mean all substances that can suppress the biosynthesis, secretion and transport of androgens or weaken their effect. In this sense, in the framework of this description, the term “antiandrogen therapy” can be used instead of the term “therapy aimed at reducing androgenic effects on the body”.

As used herein, the terms “antiandrogenic hormone therapy”, “hormone therapy”, and “antiandrogenic therapy” are used interchangeably.

In pharmacology, in the narrow sense, it is customary to classify antiandrogens as a number of compounds of steroidal and nonsteroidal structures capable of suppressing the physiological activity of endogenous androgens. The action of such substances is associated with competitive blocking of androgen receptors in target tissues; they do not interfere with the biosynthesis and secretion of androgens.

Steroidal antiandrogens include, for example, cyproterone.

Non-steroidal antiandrogens include, for example, flutamide, bicalutamide and nilutamide.

To some extent, antiandrogenic activity is characteristic of a number of endogenous steroid compounds, including progestins and estrogens. Anti-androgenic activity is possessed by their synthetic derivatives, as well as some derivatives of androgens.

Inhibitors of steroid synthesis include substances that inhibit the production of steroids, including androgens, by affecting the activity of steroidogenic enzymes, such as aminoglutethimide and ketoconazole.

Compounds that inhibit 5α-reductase and, accordingly, the conversion of testosterone to dihydrotestosterone, have a special type of antiandrogenic activity. They do not bind to androgen receptors, but they are often also classified in the pharmacology class as antiandrogens.

5-alpha reductase inhibitors include, in particular, finasteride (Proscar) or creeping palm fruit extract (Serenoa Repens) (Permixon).

Glucocorticosteroid drugs (glucocorticoids) can be selected from the group including hydrocortisone, prednisolone, dexamethasone.

Estrogens (estrogen preparations) include, in particular, ethinyl estradiol, diethylstilbestrol and hexestrol.

Hypothalamic factors (“releasing factors”) releasing pituitary hormones (gonadorelin analogues), namely luteinizing hormone releasing hormone (LHRH) agonists that inhibit androgen synthesis, are, in particular, triptorelin, buserelin, leuprolide (leupralin) goserelin. Abarelix can be used as an antagonist of the releasing hormone luteinizing hormone.

In the treatment of benign prostatic hyperplasia, hormone therapy may include, for example, 5-alpha reductase inhibitors, in particular finasteride, its analogues and derivatives, or, for example, an extract from the Serenoa Repens plant, for example Permixon, as well as various combinations thereof. Additionally, together with 5-alpha-reductase inhibitors, it is possible to use drugs of the alpha-adrenergic blocking group (alpha-adrenergic receptor blockers), which are often used for benign prostatic hyperplasia to reduce the tone of the smooth muscles of the prostate gland, for example terazosin, doxazosin, tamsulosin or their analogues.

For use in the treatment of benign prostatic hyperplasia, 9-oxoacridine-10-acetic acid or its pharmaceutically acceptable salts and its esters are conveniently used topically, for example, in the form of suppositories.

Pharmaceutical salts of 9-oxoacridine-10-acetic acid used according to the present invention can be used in a single dose (in terms of the remainder of 9-oxoacridine-10-acetic acid) from 0.5 to 100 mg / kg body weight, preferably from 4 to 20 mg / kg body weight. In this case, the daily dose may vary from 2 to 1000 mg / kg, preferably from 2 to 200 mg / kg. The specific dose of the drug can be calculated by a specialist based on the description of the invention and the examples given.

It is understood that the amounts used of 9-oxoacridine-10-acetic acid or a pharmaceutically acceptable salt thereof or its ester and antiandrogen agent are synergistically effective.

In general, all agents of the invention may alternatively include, consist of or substantially consist of any suitable components disclosed herein, and such agents, including the composition, kit and combination, of the invention may additionally or alternatively be prepared by such in such a way that any component, material, ingredient or object that was used in a preparation known from the prior art or which is not necessary to achieve the technical result of this and gaining.

The same applies to the methods of the invention, which alternatively may include, consist of or essentially consist of any suitable steps disclosed herein, and such methods of the invention may additionally or alternatively exclude any stage or object that used in a method known from the prior art, or which is not necessary to achieve the technical result of the present invention.

The invention is further illustrated by specific examples.

To denote 9-oxoacridine-10-acetic acid, the abbreviation CMA will be used below.

The experiments and clinical trials conducted by the authors used, inter alia, commercial preparations of CMA salts available on the market, for example, CMA sodium salt (Neovir, Farmsintez, Russia), CMA meglumine salt (Cycloferon, NTFF Polisan, Russia), as well as commercially available CMA (Sigma, USA, cat. No. 17927, 2005 catalog).

Esters and some other salts of SMA were synthesized by known, relatively simple methods (see for example: Inglot, AD et al., Archivum Immunologiae et Therapiae Experimentalis, 1985, vol. 33, pp. 275-285; RF patent No. 2135474; patent RF №2036198; RF patent №2033413). In some cases, for example, suppositories containing SMA and its pharmaceutically acceptable salts and its esters based on suppository materials widely used for these purposes, such as Vitepsol (Witepsol W 35, E 75), were prepared for the administration of per rectum in a clinic, as illustrated by examples.

EXAMPLE 1. Preparation of a medicinal product for local (rectal) use containing non-ionized SMA as an active substance

250 g of finely crystalline SMA was mixed when heated to 60 degrees Celsius with a candle base consisting of the widely used candle base Witepsol W 35 and Tween 80 emulsifier, the mixture was homogenized in a stirrer to obtain a suppository mass with a total weight of 1.5 kg and 970 suppositories were molded each weighing 1.5 g of the following composition: SMA - 0.250 g; Tween 80 - 0.05 g; Witepsol W 35 - 1.2 g. The yield was 97%.

EXAMPLE 2. Preparation of a medicinal product for local (rectal) use containing SMA ester as an active substance

280 g of CMA ethyl ester was mixed, when heated to 60 degrees Celsius, with a candle base consisting of the widely used candle base Witepsol W 35 and Tween 80 emulsifier. The mixture was homogenized in a mixer to obtain a suppository mass with a total weight of 1.5 kg and molded 970 suppositories, each weighing 1.5 g of the following composition: SMA - 0.280 g; Tween 80 - 0.05 g; Witepsol W 35 - 1.17 g. The yield was 97%.

EXAMPLE 3. A pharmaceutical composition containing SMA and finasteride

500 g of crystalline CMA (CAS 38609-97, Fluka, # 17927) was mixed with 5 g of finasteride, i.e., N- (2-methyl-2-propyl) -3-oxo-4-aza-5-α-androst-1 non-17-β-carboxamide, CAS 98319-26-7 (Sigma, # F1293). After thoroughly mixing in a drum grinder, the mixture was capsulated in hard gelatin capsules to obtain 980 capsules. Each capsule contained 500 mg of MCA and 5 mg of finasteride. The yield was 98%.

EXAMPLE 4. Strengthening with the help of SMA and its pharmaceutically acceptable salts and its esters of the inhibitory effect of the inhibitor of 5-alpha-reductase finasteride on testosterone-stimulated prostate growth.

We used the classic model of stimulation of prostate growth in pre-orchiectomized animals with testosterone preparations. In the experiment used 12 groups of animals of 10 rats each. Sprey-Dawley rats were used, weighing 220-230 g. All animals were castrated under ketamine anesthesia. Three days after castration, testosterone enanthate (Testoviron Depot, Schering, Germany) at a dose of 30 mg / kg once a week for 2 weeks was started to be administered to animals (groups No. 1-12). Animals of the first group served as a negative control, and they were orally administered a "blank" carrier - starch gel. Other groups of animals were injected daily 5 days of the first week after castration and 4 days of the next week, the corresponding preparations as follows.

Groups 2, 3, 4, 5, 6, and 7: finasteride (Proscar, Merck Sharp, and Dome B.V.) at a dose of 10 mg / kg orally in starch gel.

In addition to the administration of finasteride in groups 3-7, respectively, were administered:

- group 3: interferon beta-1a (Avonex, Biogen B.V., Netherlands) at a dose of 1 × 10 ⁵ IU / kg subcutaneously;

- group 4: received subcutaneously in physiological saline a sodium salt of MCA at a dose of 5 mg / kg, which corresponded to an equimolar dose of 4.6 mg / kg of MCA;

- group 5: received subcutaneously in physiological solution meglumine salt CMA at a dose of 8.2 mg / kg, which also corresponded to an equimolar dose of 4.6 mg / kg CMA;

- group 6: received MCA subcutaneously in the form of a fine suspension in physiological saline at a dose of 4.6 mg / kg;

- group 7: received CMA ethyl ester subcutaneously in the form of a fine suspension in physiological saline at a dose of 5.1 mg / kg, which corresponded to an equimolar dose of 4.6 mg / kg CMA.

Groups 8, 9, 10, 11, and 12 did not receive finasteride, but received, respectively, interferon beta-1a, sodium salt of CMA, meglumine salt of CMA, unsolubilized CMA and ethyl ester of CMA in doses, modes and routes of administration to similar groups 3, 4 , 5, 6 and 7.

On the 11th day from the start of drug administration (that is, a day after the last injection), the animals were killed by ether anesthesia, the ventral prostate was excised and weighed; the average weight of the ventral prostate in each group was determined, then the relative mass (in%) of the ventral prostate in the group (relative to the average weight of the ventral prostate in group 2, that is, the negative control group) was calculated.

The results of this series of experiments are shown in table 1.

Table 1 Strengthening with the help of SMA and its pharmaceutically acceptable salts and esters of the inhibitory effect of the inhibitor of 5-alpha reductase finasteride on testosterone-stimulated prostate growth. Group of animals (the number of animals in each group is 10) Relative average mass of the ventral prostate (relative to group 1) one Negative control = solvent one hundred% 2 Finasteride 57% 3 Finasteride Plus Interferon Beta-1A 48% four Finasteride plus SMA (as sodium salt) 24% 5 Finasteride plus SMA (as meglumine salt) 26% 6 Finasteride Plus SMA 25% 7 Finasteride plus CMA ethyl ester 34% 8 Interferon Beta-1A 97% 9 SMA (as sodium salt) one hundred% 10 SMA (as meglumine salt) 101% eleven SMA (unsolubilized) 96% 12 CMA ethyl ether 99%

According to the results presented in table 1, 9-oxoacridine-10-acetic acid (CMA) itself, its sodium and meglumine salts and its ethyl ether, as well as interferon beta-1a had practically no effect on the parameter being determined, which reflects the level of androgen suppression stimulation. Moreover, the combination of finasteride with SMA, as well as its sodium and meglumine salts and its ethyl ether, clearly enhances the result, and more than the combination with interferon.

In other series of experiments on a similar design, other CMA compounds were investigated. We investigated, in particular, other CMA esters, including butyl ether, as well as other salts of CMA. These included, for example, salts formed by CMA and cyclic amino sugars and their esters, in particular a salt formed by CMA and 3-O- (N, N-dimethylamino-n-propyl) -1,2: 5,6-di- O-isopropylidene-α, D-glucofuranose. This salt is described in RF patent No. 2197248 (Anandin preparation).

All investigated salts and pharmaceutically acceptable salts and its esters of SMA showed similar activity with respect to enhancing the effect of antiandrogenic effects on rat prostate weight. CMA esters in the same mass doses acted, although more pronounced than interferon, but, as a rule, are slightly weaker (10-15%) than the salts of CMA. Both in the experiment illustrated in Table 1, and in other experiments conducted by the authors, the ability of SMA and its pharmaceutically acceptable salts and its esters to independently influence the growth parameters of normal, hyperplastic and malignant androgen-dependent tissues outside hormonal exposure was separately studied. However, such an independent effect of SMA and its pharmaceutically acceptable salts and its esters was not found. Thus, SMA itself and its pharmaceutically acceptable salts and its esters do not have independent hormonal and / or antitumor activity against both androgen-dependent tissues (including hyperplastic) and tumors originating from them.

EXAMPLE 5. The ability of the sodium salt of SMA to enhance the effect of antiandrogen therapy on a hormone-sensitive variant of prostate adenocarcinoma in rats.

We used male Copenhagen rats weighing 200-230 g. To model the tumor process under ketamine anesthesia, tumor pieces of the androgen-sensitive variant (H variant) of rat prostate adenocarcinoma R3327 Dunning (Dunning R3327-H) volume were transplanted under the skin of the right side 5 mm ³ . Hormone treatment was started after 2.5 months, when the tumor volume reached 0.5-1.5 cm.

The exposure to SMA in the form of sodium salt (NaCMA) or interferon beta-1a was carried out in the preliminary sensitization mode (ie, “presensitization”) or in the treatment regimen (in parallel with the course of hormone therapy). In the first case (Mode I) effect started for 2-2 _^1/2 weeks before hormone therapy and completed before the start of hormone therapy. In the second case (regimen II), exposure began simultaneously with the start of hormone therapy and continued until the end of the experiment. Also, in one of a series of experiments, animals began to receive NaCMA or interferon beta-1a, respectively, before the start of hormone therapy and continued to receive them during hormone therapy (regimen III). In all modes of administration (I, II or III), CMA (in the form of sodium salt) was administered at a dose of 10 mg / kg of animal weight daily, and interferon beta-1a was administered at a dose of 1 × 10 ⁵ / kg of animal weight daily.

Immediately before the start of hormonal treatment and then once every two weeks, the size of the tumor was measured, its volume was calculated. The effectiveness of the exposure was determined by the index of inhibition of tumor growth (SRW). SRW was defined as the ratio of the difference between the average tumor volumes in the negative control group (untreated group) and the corresponding group exposed to this effect to the average tumor volume in the negative control group. SRW was expressed as a percentage.

The experiments used antiandrogen flutamide (Flucin, Schering Plow, USA), which was administered orally in starch gel at 15 mg / kg daily.

Also, the LHRH analog of leuprolide acetate (leuprorelin) (Lucrin-Depot, Abbot Laboratories Ltd., USA) was used, which was administered subcutaneously at a dose of 0.1 mg / kg once every 4 weeks.

To assess the effect of CMA regarding the possibility of changing the sensitivity to chemo-hormone therapy, an agent with a double action was used: estrogenic and direct cytotoxic. For this purpose, estramustine was used (Estracite, Pharmacy and Upjon, USA). Estramustine was administered intraperitoneally at 100 mg / kg 3 times a week for 4 weeks.

Another option for hormonal treatment was castration.

Options for hormonal effects and treatment regimens, as well as experimental results, are illustrated in Table 2.

Table 2. The ability of SMA sodium salt to enhance the effect of antiandrogen therapy on a hormone-sensitive variant of prostate adenocarcinoma in rats Group No. / Hormone Exposure Impact Therapy mode * SRW,% 2nd week from the start of hormone therapy 12 weeks from the start of hormone therapy one. No (negative control) - - - - 2 Flutamide - - 65 40 NaCMA I 79 57 interferon beta-1a 63 42 NaCMA II 85 63 Interferon Beta-1A 62 38 NaCMA III 89 73 Interferon Beta-1A 72 49 3 Leuprolide - - 57 69 NaCMA I 63 85 Interferon Beta-1A 58 70 NaCMA II 77 94 Interferon Beta-1A fifty 71 NaCMA III 76 90 Interferon Beta-1A 60 72 four Estramustine - - 25 60 NaCMA I 38 89 Interferon Beta-1A 23 61 NaCMA II 46 87 Interferon Beta-1A 34 69 NaCMA III 57 89 Interferon Beta-1A 29th 72 5 Castration - 52 74 NaCMA I 66 83 Interferon beta-1a 53 72 NaCMA II 75 90 Interferon beta-1a 54 73 NaCMA III 77 93 Interferon beta-1a 62 75 * See explanations in the text.

The higher the TPO index, the more effective is the inhibition of tumor growth and, therefore, the combination and treatment regimen used are more effective.

From the presented data it can be seen that NaCMA is very effective in enhancing hormone sensitivity of hormone-sensitive prostate cancer. Its effectiveness exceeds the effectiveness of interferon beta-1a, since in all experiments the index for the combination in which NaCMA is included is higher than in the experiment without the use of CMA or for combination with interferon beta-1a.

In addition, NaCMA, in contrast to interferon beta-1a, was able to “presensitize” the tumor to subsequent hormonal or chemo-hormonal effects (Mode I).

The greatest effect was manifested in that variant of the administration regimen, when NaCMA was administered before the start of hormonal exposure and continued to be further administered during the course of hormone therapy or chemo-hormone therapy (regimen III).

EXAMPLE 6. The ability of the MCA meglumine salt to enhance the effect of antiandrogen therapy on a hormone-sensitive variant of prostate adenocarcinoma in rats.

The experiments were carried out according to the protocol described in example 5, however, instead of flutamide, nilutamide was used instead of flutamide, which was administered orally in starch gel at 7 mg / kg / day (Anandron, Rousel Uclaf, France), and buserelin at 0 instead of leuprolide. 1 mg / kg once every 4 weeks (Buserelin-depot, Pharm-Sintez, Russia), and the meglumine salt acted as the pharmaceutical salt of the MCA.

The experimental results are illustrated in table 3.

Table 3 The ability of meglumine salt SMA to enhance the effect of antiandrogen therapy on a model of hormone-sensitive variant prostate adenocarcinoma in rats Group No. / Hormone Exposure Impact Therapy mode * SRW,% 2 I am a week from the start of hormone therapy 12 weeks from the start of hormone therapy one. No (negative control) - - - - 2 Nilyutamide - - 68 36 Meglumine salt СМА I 65 54 interferon beta-1a 67 42 Meglumine salt СМА II 88 62 Interferon Beta-1A 64 37 Meglumine salt СМА III 90 71 Interferon Beta-1A 70 51 3 Buserelin - - 55 67 Meglumine salt СМА I 65 84 Interferon Beta-1A 56 68 Meglumine salt СМА II 79 95 Interferon Beta-1A 49 70 Meglumine salt СМА III 75 89 Interferon Beta-1A 61 73

From the presented data it can be seen that the effect of the meglumine salt CMA is similar to the effect of the sodium salt CMA (see example 5).

EXAMPLE 7. Treatment of benign prostatic hyperplasia (adenoma).

The therapeutic effect of the treatment method according to the invention was studied in patients with benign prostatic hyperplasia (adenoma). The age of the patients ranged from 50 to 72 years, the diagnosis of benign prostatic hyperplasia was based on anamnesis, digital rectal examination, dopplerography, determination of the volume of residual urine, determination of the level of prostate-specific antigen (PSA) in blood serum. Patients were randomly divided into four groups.

Two groups received treatment with variants of the method according to the invention as follows.

The first group received a 5-alpha reductase inhibitor finasteride (5 mg per day at night) and CMA in the form of meglumine salt (Cycloferon, NTFF Polisan, Russia) in the form of tablets at a dose of 600 mg (counting for CMA), orally 2 times a week .

The second group received a preparation of Serenoa Repens extract, which also has inhibitory activity against 5-alpha reductase (Permixon, Pierre Fabre Medicament) at 160 mg 2 times a day. The second group of patients also received intra suppository 1 twice a week suppositories containing 250 mg of CMA, and made as described in Example 1. In this case, suppositories with CMA began to be used 2 weeks before the appointment of a plant inhibitor of 5-alpha-reductase ( Permikson).

The third and fourth groups received the same therapy, respectively, except that instead of CMA preparations, patients received 3 million units of recombinant interferon beta-1a (Avonex, Biogen B.V., the Netherlands) also 2 times a week, subcutaneously.

The effect of therapy was evaluated after 12 weeks of treatment. Changes were evaluated (compared with the initial values before hormonal treatment was prescribed) of the following indicators: prostate volume, number of points on the IPSS scale, maximum urine flow rate, and the amount of residual urine. The frequency of side effects was also determined. All 4 groups were comparable in age and severity of manifestations of benign prostatic hyperplasia (adenoma). The results are presented in table 4.

Table 4 Treatment of benign prostatic hyperplasia (adenomas) Hormone therapy Finasteride Permixon Meglumine salt СМА interferon beta-1a SMA interferon beta-1a Groups, number of patients 1 (N = 9) 2 (N = 8) 3 (N = 7) 4 (N = 8) The change in prostate volume (%) -26.4 -15.1 -21.2 -10.3 Change IPSS Scores -12.3 -9.2 -7.2 -6.3 Change in maximum urine flow rate ml / sec +15.2 + 12.3 +10.4 +8.70 The change in the volume of residual urine (ml) -14.3 -10.2 -9.1 -7.4 Side effects, % 22.2 50,0 12,2 25.0

From the table it follows that the use of SMA and its pharmaceutically acceptable salts and its esters significantly reduces the clinical manifestations of benign prostatic hyperplasia (adenoma) with antiandrogenic exposure. Moreover, more than interferon beta-1a and with fewer side effects.

Side effects of therapy included:

- in patients receiving finasteride: ejaculation disorders, decreased libido, impotence;

- in patients receiving the preparation of Creeping Palm Extract (Serenoa Repens): nausea, heartburn, stomach pain;

- in patients also receiving interferon beta-1a: nausea, vomiting, chills.

There were no specific side effects due to SMA.

EXAMPLE 8. Treatment of benign prostatic hyperplasia (adenomas).

Two groups of patients were treated using the preparation of creeping palm extract (Serenoa Repens), which has inhibitory activity against 5-alpha reductase (Permikson, Pierre Fabre Medication) - 160 mg 2 times a day.

The first group additionally received 3 million units of recombinant interferon beta-1a (Avonex, Biogen B.V., Netherlands) 2 times a week, subcutaneously.

The second group of patients also received additionally twice a week rectally 1 suppository containing 280 mg of CMA ethyl ester and made as described in Example 2. In this case, suppositories were started to be used simultaneously with the administration of a plant inhibitor of 5-alpha reductase ( Permikson).

The results are presented in Table 5.

Table 5 Treatment of benign prostatic hyperplasia (adenomas) Type of additional exposure SMA ester interferon beta-1a Groups, number of patients 1 group (N = 5) 2 group (N = 5) The change in prostate volume (%) -18.4 -10.3 Change IPSS Scores -9.4 -6.3

From the table it follows that the use of SMA and its pharmaceutically acceptable salts and its esters significantly reduces the clinical manifestations of benign prostatic hyperplasia (adenoma) with antiandrogenic exposure.

EXAMPLE 9. Prevention of recurrence of prostate cancer.

Patient P., 69 years old, was diagnosed with prostate cancer 5 years ago (based on a digital examination of the prostate, biopsy, and tomographic examination of the pelvic organs). Gleason score 8, PSA before surgery 45 ng / ml, distant and regional metastases are absent, prostate volume 45 cm 3. The patient underwent radical prostatectomy with dissection of the pelvic lymph nodes. A histological examination of the surgical material revealed lesions of the lymph nodes. The postoperative PSA level was 0.1 ng / ml.

After surgery, to reduce the risk of recurrence of RP, the patient was prescribed prevention of recurrence of RP: antiandrogen flutamide (750 mg per day orally, divided into three doses) and sodium salt of SMA (12.5% sterile injection for 4 ml 2 times a week) .

Over the next period (5 years), serum PSA remained at an undetectable level; no signs of tumor recurrence were observed. Thus, the proposed method is highly effective for the prevention of recurrence of prostate cancer.

Claims (30)

1. The use of 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and its esters as an additional agent for the treatment of conditions in which the androgen reduction is therapeutically beneficial. 2. The use according to claim 1 in combination with antiandrogen hormone therapy to increase its effectiveness. 3. The use according to claim 1, where the salts of 9-oxoacridine-10-acetic acid are selected from the group comprising sodium, meglumine, egglumine salts, and a salt with 3-O- (N, N-dimethylamino-n-propyl) -1 , 2: 5,6-di-O-isopropylidene-α, D-glucofuranose, and the ester is 9-oxoacridine-10-acetic acid ethyl ester. 4. The use according to claim 1, where the conditions in which the decrease in the action of androgens is therapeutically favorable are selected from the group consisting of androgenetic alopecia, prostate adenoma, prostate cancer and the possibility of recurrence of prostate cancer. 5. A tool for increasing the effectiveness of antiandrogen hormone therapy, which is 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salt or its ester in the form of a single dose, which is from about 0.5 to 100 mg per kg of body weight. 6. The tool according to claim 5 for use in combination therapy of conditions in which the decrease in the action of androgens is therapeutically favorable. 7. The tool according to claim 5, characterized in that the salts of 9-oxoacridine-10-acetic acid are selected from the group comprising sodium, meglumine, egglumine salts, and a salt with 3-O- (N, N-dimethylamino-n-propyl ) -1.2: 5,6-di-O-isopropylidene-α, D-glucofuranose, and the ester is 9-oxoacridine-10-acetic acid ethyl ester. 8. The tool according to claim 5, characterized in that the conditions in which the decrease in the action of androgens is therapeutically favorable are selected from the group including androgenic alopecia, prostate adenoma, prostate cancer and the possibility of recurrence of prostate cancer. 9. A combination for the treatment of conditions in which the androgen reduction is effective, containing an effective amount of 9-oxoacridine-10-acetic acid, a pharmaceutically acceptable salt or ester thereof, and at least one androgen reducing agent. 10. The combination according to claim 9, characterized in that the androgen reducing agent is an agent selected from the group consisting of simple or steroidal antiandrogens, steroid synthesis inhibitors, androgen synthesis inhibitors, 5-alpha reductase inhibitors, glucocorticoids , estrogens, agonists (analogues) of the releasing hormone luteinizing hormone (LHRH) and antagonists of LHRH. 11. The combination according to claim 9, characterized in that the androgen reducing agent is a finasteride 5-alpha reductase inhibitor or creeping palm fruit extract (Serenoa Repens). 12. The combination according to claim 9, characterized in that the salts of 9-oxoacridine-10-acetic acid are selected from the group consisting of sodium, meglumine, egglumine salts, and a salt with 3-O- (N, N-dimethylamino-n-propyl ) -1.2: 5,6-di-O-isopropylidene-α, D-glucofuranose, and the ester is 9-oxoacridine-10-acetic acid ethyl ester. 13. A pharmaceutical composition for treating conditions in which the androgen reduction is therapeutically beneficial, comprising an effective amount of 9-oxoacridine-10-acetic acid, a pharmaceutically acceptable salt or ester thereof, and at least one androgen reducing agent, and also a pharmaceutically acceptable excipient. 14. The composition according to p. 13, characterized in that the androgen reducing agent is an agent selected from the group consisting of simple or steroidal antiandrogens, steroid synthesis inhibitors, androgen synthesis inhibitors, 5-alpha reductase inhibitors, glucocorticoids , estrogens, agonists (analogues) of the releasing hormone luteinizing hormone (LHRH) and antagonists of LHRH. 15. The composition according to p. 13, characterized in that the androgen-reducing agent is a finasteride 5-alpha reductase inhibitor or creeping palm fruit extract (Serenoa Repens). 16. The composition according to p. 13, characterized in that the salts of 9-oxoacridine-10-acetic acid are selected from the group consisting of sodium, meglumine, egglumine salts and a salt with 3-O- (N, N-dimethylamino-n-propyl ) -1.2: 5,6-di-O-isopropylidene-α, D-glucofuranose, and the ester is 9-oxoacridine-10-acetic acid ethyl ester. 17. A kit for treating conditions in which the decrease in the action of androgens containing 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salt or its ester in a separate dosage form and at least one androgen reducing agent is therapeutically beneficial in separate dosage form. 18. The kit according to claim 17, wherein the androgen reducing agent is an agent selected from the group consisting of simple or steroidal antiandrogens, steroid synthesis inhibitors, androgen synthesis inhibitors, 5-alpha reductase inhibitors, glucocorticoids, estrogens agonists (analogues) of the releasing hormone luteinizing hormone (LHRH) and antagonists of LHRH. 19. The kit according to claim 17, wherein the androgen reducing agent is a finasteride 5-alpha reductase inhibitor or creeping palm fruit extract (Serenoa Repens). 20. The kit according to 17, characterized in that the salts of 9-oxoacridine-10-acetic acid are selected from the group comprising sodium, meglumine, egglumine salts, and a salt with 3-O- (N, N-dimethylamino-n-propyl ) -1.2: 5,6-di-O-isopropylidene-α, D-glucofuranose, and the ester is 9-oxoacridine-10-acetic acid ethyl ester. 21. A method of treating conditions in which the decrease in the effect of androgens is therapeutically favorable, in which an effective amount of 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salt or its ester is administered to a patient in need thereof, and a hormone therapeutic effect is performed to reduce action of androgens. 22. The method according to item 21, wherein the salts of 9-oxoacridine-10-acetic acid are selected from the group consisting of sodium, meglumine, egglumine salts and a salt with 3-O- (N, N-dimethylamino-n-propyl ) -1.2: 5,6-di-O-isopropylidene-α, D-glucofuranose, and the ester is 9-oxoacridine-10-acetic acid ethyl ester. 23. The method according to item 21, wherein the conditions in which the decrease in the effect of androgens is therapeutically favorable is selected from the group consisting of androgenetic alopecia, prostate adenoma, prostate cancer and the possibility of recurrence of prostate cancer. 24. The method according to item 21, wherein the hormone therapeutic effect aimed at reducing the action of androgens is the introduction of one or more than one agent selected from the group including simple or steroidal antiandrogens, steroid synthesis inhibitors, androgen synthesis inhibitors , 5-alpha reductase inhibitors, glucocorticoids, estrogens, agonists (analogues) of the releasing hormone luteinizing hormone (LHRH) and LHRH antagonists. 25. The method according to paragraph 24, wherein the 5-alpha reductase inhibitor is finasteride or creeping palm fruit extract (Serenoa Repens). 26. The method according to item 21, wherein the 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salt or its ester is administered before the start of hormone therapy. 27. The method according to item 21, wherein the 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salt or its ester is administered simultaneously with hormone therapy. 28. The method according to item 21, wherein the introduction of 9-oxoacridine-10-acetic acid, a pharmaceutically acceptable salt or ester thereof, is started before the start of the monotherapy and continued during the monotherapy. 29. A method of enhancing the sensitivity of androgen-dependent tissues to antiandrogen hormone therapy aimed at reducing the effect of androgens, wherein an effective amount of a compound selected from the group consisting of 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and its esters is administered. 30. The method according to clause 29, wherein the salts of 9-oxoacridine-10-acetic acid are selected from the group comprising sodium, meglumine, egglumine salts and a salt with 3-O- (N, N-dimethylamino-n-propyl ) -1.2: 5,6-di-O-isopropylidene-α, D-glucofuranose, and the 9-oxoacridine-10-acetic acid ester is ethyl ester.