RU2232574C2 - "fluoglysine" medicinal preparation for treating different forms of depression - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: the suggested preparation is a molecular complex of free foundation of fluoxetine and glycyrrisinic acid at the following ratio of components: free foundation of fluoxetine : glycyrrisinic acid being 1 : (1 - 4).

EFFECT: higher efficiency.

2 dwg, 9 ex, 6 tbl

Description

The invention relates to medicine, namely to the development of new drugs with antidepressant effects.

Depression affects 3-5% of the population, approximately 200 million people in the world. Currently, in the world medical practice, in the treatment of various forms of depression or depressive states, selective type of action drugs, in particular, serotonin neuronal uptake inhibitors, such as fluoxetine, norfluoxetine, trazodone, are widely used. However, these drugs are characterized by a number of significant drawbacks: sufficiently large doses of drugs with a small breadth of the therapeutic index, a long elimination period, leading to damage to liver cells and an adverse effect on renal function.

Closest to the claimed agent is profluzac (international non-proprietary name - fluoxetine in the form of hydrochloride) with the chemical formula -N-methyl-3- (4 ^1- trifluoromethylphenoxy) -3-phenylpropylamine hydrochloride, a clinical study of which showed that the manifestation of the antidepressant effect is associated with its inhibition of neuronal uptake of serotonin in the central nervous system. Profluzac is a more potent serotonin uptake inhibitor than norepinephrine. Profluzac is much weaker than tricyclic antidepressants and antagonizes muscarinic, histamine and α-adrenergic receptors. Anticholinergic, sedative and cardiovascular properties are less pronounced. Proflusac is effective in eliminating depression, sleep disorders, and the anxiety subfactor in the treatment of older patients with depression [PU 3312DPP].

Profluzac has a fairly high toxicity (248 mg / kg for intragastric administration to mice and 452 mg / kg for rats) with a therapeutic daily dose of 20 to 60 mg.

Its toxicity and low therapeutic effect can be a serious drawback.

The problem to which the invention is directed, is to create an effective, low-toxic drug for the treatment of various forms of depression, as well as to expand the range of antidepressant drugs.

The problem is solved by using new compounds as antidepressants, which are molecular complexes of methyl 3- (4 ^1- trifluoromethylphenoxy) -3-phenylpropylamine (fluoxetine free base — SOF) with glycyrrhizic acid (HA) in the ratio 1: (1-4) .

The structure of the complex is presented in scheme 1.

Preliminary testing of the complex for antidepressant activity made it possible to select SOF: HA complex - 1: 4 (molar fractions) as the most promising drug. One weight part of the drug - complex 1: 4 in this case contains 0.0722 parts of SOF.

Acute toxicity of the drug - complex SOF: HA - 1: 4 was determined on white outbred mice weighing 20-22 g with a single intragastric route of administration according to the Kerber method.

It was shown that the drug - a complex of SOF: HA - 1: 4 is a low-toxic substance: LD _{50 is} more than 5000 mg / kg, i.e. 20 times lower than that of Profluzac (LD ₅₀ = 248 mg / kg) with a similar route of administration.

To study the antidepressant activity of the drug - a complex of SOF: HA - 1: (1-4), a set of standard methods was used: motor activity, forced swimming, interaction with hypnotic drug chloral hydrate, interaction with the precursor serotonin - 5-hydroxytryptophan; M-cholinomimetic - arecoline.

The studied drug, a 1: 1 and 1: 4 complex, was administered to mice in doses of 5, 10, 15 and 25 mg / kg intragastrically. The indicated doses of the drug - 1: 4 complex contain 0.36, 0.72, 1.08 and 1.42 mg / kg of SOF, respectively. Comparison standard - profluzak was introduced in a daily therapeutic dose of 25 mg / kg.

All obtained experimental data were processed using Student t-test.

The interaction of the drug-complex (in molecular ratios 1: 1 and 1: 4) with the hypnotic drug chloral hydrate was studied with their single intragastric administration in the above doses. The ability to change the duration of chloral hydrate sleep was judged by the time of loss and restoration of the inversion reflex of mice. The results presented in table. 1 and 2 indicate that, compared with profluzak, the drug - complex 1: 1 and 1: 4 in almost all doses reduced the duration of sleep in mice.

To clarify the manifestation of the degree of antagonism of the drug, a 1: 4 complex to muscarinic receptors, the standard arecoline tremor test was chosen. The drug - a 1: 4 complex was administered according to the above scheme. The effect was evaluated on a 5-point scale. The criterion of the effect was the strength and duration of tremor.

The results of the experiments are presented in table. 3. In this test, the drug - 1: 4 complex compared with control animals reduced the duration and intensity of arecoline tremor. The standard of comparison - profluzak showed antagonism.

In the “forced swimming” test, the drug administration scheme is a 1: 1 complex; 1: 4 and profluzaka was similar. The average duration of the stress state of immobilization (immobility) of mice for 20 minutes was taken into account.

Statistically processed results are presented in table. 4 and 5. A dose-dependent effect was established. The drug, a 1: 4 complex, increased the activity of mice at doses of 10 mg / kg by 30%, at a dose of 25 mg / kg by 25% and 15 mg / kg by 16%. At a dose of 5 mg / kg decreased the level of activity of mice and increased the time of immobilization by 29%.

One of the important tests that clarifies the effect of the drug, a 1: 4 complex on the serotonin structure, is its interaction with the serotonin precursor, 5-hydroxytryptophan. The drug was a 1: 4 complex in doses of 5, 10, 15, 25 mg / kg and the comparison standard was Profluzac at a dose of 25 mg / kg was administered once intragastrically.

A measure of effectiveness was the change in the number of acts of shaking the head within one hour. This effect is known to be caused by 5-hydroxytryptophan. The experimental data are presented in FIG. 2. In the course of studies, a dose-dependent effect was established. The most pronounced inhibitory effect on serotonin structures was observed in a 1: 4 complex drug at a dose of 25 mg / kg, completely eliminating the phenomenon of head shaking by the 52nd minute of the experiment. In the group of animals that were injected with the drug - complex 1: 4 at a dose of 5 mg / kg, an activating effect was observed throughout the experiment.

The effect of the drug - complex 1: 4 on the behavioral reactions of mice was studied with a single intragastric administration of the agent at a dose of 25 mg / kg on an open field model. The results presented in table. 6, indicate that the drug - complex 1: 4 reduces the activity of mice (in the number of general movements and jumps) compared with profluzak.

The invention is illustrated by the following examples.

Example 1. Obtaining a drug - a complex of N-methyl-3- (4 ^1- trifluoromethylphenoxy) -3-phenylpropylamine (SOF) with 3-O- (2 ¹ -O-β-D-glucuronopyranosyl) -β-D-glucuronopyranoside 3β-hydroxy-11-oxo-18βH-20-olean-12-en-30-oic acid (18 β-glycyrrhizic acid, β-HA), composition 1: 1

To a solution of 0.86 g (1 mmol) of β-HA (purity no lower than 98%) in 10 ml of 70% aqueous ethanol was added 0.31 g of SOF in 1 ml of acetone and heated in a boiling water bath for 2 hours, evaporated to dryness in vacuo yielded 1.17 g (100%) of the complex as a tan powder. UV spectrum λ $\genfrac{}{}{0ex}{}{\text{min}}{\text{max}}$ 252 nm (ε 13000).

¹³ C NMR spectrum (δ mg 22.63 MHz COC1 ₃ , TMS internal standard): glycyrrhizic acid fragment) 39.0 (C ¹ ), 27.2 (C ² ), 78.3 (C ³ ), 39.0 (C ⁴ ), 54.8 (C ⁵ ), 17.5 (С ⁶ ), 32.7 (С ⁷ ), 43.1 (С ⁸ ), 61.6 (С ⁹ ), 37.0 (С ¹⁰ ), 199.2 (С ¹¹ ), 128.1 (С ¹² ), 168.3 (С ¹³ ), 45.2 (C ¹⁴ ), 26.4 (C ¹⁵ ), 26.4 (C ¹⁶ ), 31.7 (C ¹⁷ ), 48.2 (C ¹⁸ ), 41.0 (C ¹⁹ ), 43.9 (C ²⁰ ), 31.1 (C ²¹ ), 37.7 ( C ²² ), 28.1 (C ²³ ), 15.6 (C ²⁴ ), 16.2 (C ²⁵ ), 18.6 (C ²⁶ ), 23.2 (C ²⁷ ), 28.1 (C ²⁸ ), 28.4 (C ²⁹ ), 176.1 (C ³⁰ ), 106.0 (C ^{1 '} ), 83.8 (C ^2' ), 77.75 (C ^{3 '} ), 72.8 (C ^4' ), 76.1 (C ^{5 '} ), 172.3 (C ^6' ), 105.1 (C ^{1 ''} ), 76.1 (C ^{2 ''),} 77.4 (C ^{3 '),} 72.7 (C ^4'), 77.1 (C ^{5 '),} 172.3 (C ^6''); (signals fragmenta_N-methyl-3- (4: ¹ -triftormetilfenoksi) -3-phenylpropylamine, SOF), 160.10 (C ^{4 '),} 139.5 (C ^1''), 46.32 (C ^3), 34.77, 33.15

Found%: C 62.58, H 48.56, N 1.28; F 5.20

Calculated%: C 62.60, H 8.66, N 1.23; F 5.04; C ₅₉ H ₈₀ NO ₁₇ F ₃

Example 2. Obtaining a drug - a complex of N-methyl-3- (4'-trifluoromethylphenoxy) -3-phenylpropylamine (SOF) with 3-O- (2 ¹ -O-β-D-glucuronopyranosyl) -β-D-glucuronopyranoside 3β-hydroxy-11-oxo-18βH-20-olean-12-en-30-oic acid (18 β-glycyrrhizic acid, β-HA), composition 1: 4.

To a solution of 3.40 g (4 mmol) of β-HA (purity no lower than 98%) in 30 ml of 70% aqueous ethanol was added a solution of 0.31 g (1 mmol) of SOF in 1 ml of acetone and heated in a boiling water bath for 2 h , evaporated in vacuo (0.1 mm Hg) at 40 ° C to dryness for 5 hours, 3.71 g (100%) of a complex of SOF: β-HA with a composition of 1: 4 were obtained

UV spectrum λ $\genfrac{}{}{0ex}{}{\text{min}}{\text{max}}$ 252 nm (ε 13000)

The ¹³ C NMR spectrum is basically identical to the ¹³ C NMR spectrum shown for the SOF: β-HA complex of 1: 1 composition (see Example 1).

Molecular mass measured by ITEC 3450 ± 200

Found%: C 61.76, H 7.42, N 0.36; F 1.56

Calculated%: C 61.72, H 7.39, N 0.39; F 1.58; C ₁₈₅ H ₃₃₈ NO ₆₅ F ₃

Example 3. The study of the antidepressant effect of the drug - complex 1: 4 on the test “chloral hydrate sleep”

An intragastric hypnotic drug, chloral hydrate, at a dose of 325 mg / kg was administered to vigorous outbred mice weighing 20-22 g [1].

The drug was a 1: 4 complex at doses of 5, 25 mg / kg and proflacac at a dose of 25 mg / kg was administered intragastrically one hour before the experimental model was reproduced.

The criterion of the effect was the time of loss and restoration of the reflex of turning the mice from a lateral position.

It was established that the drug - complex 1: 4 potentiates the effect of sleeping pills to a greater extent at a dose of 5 mg / kg than at a dose of 25 mg / kg compared with the control group. Whereas profluzac increases the time for the hypnotic effect of chloral hydrate by 4 times. The results are presented in table. 1.

Example 4. The study of the antidepressant effect of the drug is a 1: 1 complex on the test “chloral hydrate sleep”

An intragastric hypnotic drug, chloral hydrate, at a dose of 325 mg / kg was administered to vigorous outbred mice weighing 20-22 g [1].

The drug was a 1: 1 complex in doses of 5, 25 mg / kg and profluzac at a dose of 25 mg / kg was administered intragastrically one hour before the experimental model was reproduced.

The criterion of the effect was the time of loss and restoration of the reflex of turning the mice from a lateral position.

The results presented in table. 2, indicate that the drug - complex 1: 1 in all doses potentiates the effect of sleeping pills in comparison with the control group 2 times, while profluzac increases the time for sleeping pills of chloral hydrate by 4 times.

Example 5. The study of the antidepressant effect of the drug complex 1: 4 on a model of arecoline tremor

To reproduce the excitation model of central M-cholinergic receptors, arecolin was administered intraperitoneally at a dose of 15 mg / kg an hour before the introduction of the 1: 4 complex [2]. The drug was a 1: 4 complex at doses of 5, 25 mg / kg and the comparison standard was Profluzac at a dose of 25 mg / kg was administered once intragastrically.

As a result of studies, it was shown that the drug - complex 1: 4 in doses of 5 and 25 mg / kg increased the intensity of tremor in mice without increasing the duration. Profluzac showed pronounced antagonism at a dose of 25 mg / kg. The results in the table. 3.

Example 6. The study of the antidepressant effect of the drug - complex 1: 4 on the model of "forced swimming"

The drug was a 1: 4 complex at doses of 5, 10, 15, 25 mg / kg and profluzac at a dose of 25 mg / kg was administered once intragastrically one hour before the “forced swimming” test was reproduced [3]. Antidepressant effect was evaluated by the time of immobilization of mice.

A dose-dependent effect was established. The drug, a 1: 4 complex, increased the activity of mice at doses of 10 mg / kg by 30%, at a dose of 25 mg / kg by 25% and 15 mg / kg by 16%. At a dose of 5 mg / kg decreased the level of activity of mice and increased the time of immobilization by 29%. The research results are presented in table. 3.

Example 7. The study of the antidepressant effect of the drug - complex 1: 1 on the model of "forced swimming"

The drug was a 1: 1 complex in doses of 5, 10, 15, 25 mg / kg and profluzac at a dose of 25 mg / kg was administered once intragastrically one hour before the “forced swimming” test was reproduced [3]. Antidepressant effect was evaluated by the time of immobilization of mice.

A dose-dependent effect was established. The drug, a 1: 1 complex, increased the activity of mice at doses of 10 mg / kg by 30%, at a dose of 25 mg / kg by 25% and 15 mg / kg by 16%. At a dose of 5 mg / kg decreased the level of activity of mice and increased the time of immobilization by 29%. The research results are presented in table. 4.

Example 8. The study of the antidepressant effect of the drug is a 1: 4 complex on the model of 5-oxytryptophan head shaking phenomenon (“wet dog shake test”) in mice

Serotonin precursor 5-hydroxytryptophan (an ICN substance) was administered to mice intraperitoneally at a dose of 300 mg / kg [8]. The drug, a 1: 4 complex, was administered once intragastrically at doses of 5, 10, 15, 25 mg / kg, and the reference standard was profluzac at a dose of 25 mg / kg. The number of acts of shaking the head was counted every 6.5 minutes for 60 minutes. In the course of studies, a dose-dependent effect was established. The most pronounced inhibitory effect on serotonin structures was observed in a 1: 4 complex drug at a dose of 25 mg / kg, completely eliminating the phenomenon of head shaking by the 52nd minute of the experiment. In the group of animals that were injected with the drug - complex 1: 4 at a dose of 5 mg / kg, an activating effect was observed throughout the experiment. The research results are presented in FIG. 2.

Example 9. The study of the antidepressant effect of the drug - complex 1: 4 on the model of “open field”

The drug was a 1: 4 complex in doses of 5, 10, 15, 25 mg / kg and the reference standard was Profluzac at a dose of 25 mg / kg was administered once intragastrically an hour before placing the animals in an “open field”.

The effect was evaluated by changing the number of different types of movements and the general emotional state of the animals on a Tru Scan device (USA). The results are presented in table. 6.

Thus, it was shown that the drug, a complex of SOF with GK-1: 4, exhibits an antidepressant effect similar to profluzac, at a dose of the active pharmacone, about 18 times smaller.

This means that the drug - complex 1: 4 in activity exceeds the serotonin reuptake blocker profluzac by more than an order of magnitude.

The drug - a 1: 4 complex is 20 times less toxic than profluzac. The use of a drug - a complex of SOF: GK-1: 4 instead of Proflozac will reduce the dose of expensive SOF by about 18 times. Glycyrrhizic acid has antiulcer, anti-inflammatory, hepatotropic and immunostimulating activities, which is also an important complementing factor for a long-term drug [4-10].

Literature

1. Mashkovsky M.D., Andreeva N.I., Polezhaeva A.I. Pharmacology of antidepressants. - M .: Medicine, 1983, p.194.

2. Uskova N.V., Antelova N.A. A comparison of aceclidine tremor with arecoline and nicotine in rats of different ages // Farm. and toxicol., 1977, v.40, No. 5, p. 517-521.

3. Porsolt D.R., Anton G., Blavet N. Comparison of antidepressants in swimming test // Nature, 1978, v. 47, p.379-391.

4. Tolstikov G.A., Schulz E.E., Baptina L.A., Tolstikova T.G. Licorice. Unused opportunities of healthcare of Russia. / Chemistry in the interests of sustainable development, 1997, No. 5, p. 57-73.

5. Tolstikov G.A., Baltina L.A., Schulz E.E., Pokrovsky A.G. Glycyrrhizic acid // Biorgan. Chem., 1997, v.23, No. 9, p.679.

6. Baltina L.A., Davydova V.A., Tolstikova T.G. and others. Trisubstituted salts of β-glycyrrhizic acid with anti-inflammatory and antiulcer activity // Chemical Pharmacist. J., 1991, No. 3, pp. 45-48.

7. Davydova V.A., Tolstikova T.G., Baltina L.A. et al. Salts of β-glycyrrhizic acid - stimulating the reparative regeneration of the skin // Chem.-pharmacist. J., 1991, No. 5, pp. 39-43.

8. Tolstikov G.A., Baltiina L.A., Tolstikova T.G. et al. Complexes of β-glycyrrhizic acid with non-steroidal anti-inflammatory drugs as new transport forms // Chem.-pharmacist. J., 1991, v. 25, No. 2, pp. 29-32.

9. Mizoguchi J., Ikemoto J., Arai T. Effect of glycyrrhizin on the antibody production of pokeweed mitogen stimulated lymphocytes in vitro // Arerugi, 1984, v. 33, No. 6, p. 328-335.

10. Hirabayashi K., Ywaba S., Matsumoto H. Antiviral activities of glycyrrhizin and its modified compounds aganist human immunodeficiency virus type I (HIV-I) and herpes gimplex virus type I (HSV-I) in vitro // Chem. Pharm. Bull., 1991, v. 39, No. 1, p. 112-115.

Claims (1)

A drug for the treatment of various forms of depression, including the molecular complex of the free base of fluoxetine with glycyrrhizic acid with a molar ratio of free base of fluoxetine: glycyrrhizic acid 1: (1-4).

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