WO2015185990A1

WO2015185990A1 - Methods for producing double salts of lorcaserin (variants), products of said methods, double salts, pharmaceutical compositions for the treatment and/or prophylaxis of obesity-related disorders, the use of same, and method for the treatment and/or prophylaxis of obesity-related disorders

Info

Publication number: WO2015185990A1
Application number: PCT/IB2015/001000
Authority: WO
Inventors: Евгений Юрьевич БЕЛОВ; Евгений Александрович ЧЕРТОРИЖСКИЙ; Пётр Александрович БЕЛЫЙ
Original assignee: Делкростон Менеджмент Лимитед
Priority date: 2014-06-02
Filing date: 2015-04-27
Publication date: 2015-12-10
Also published as: EA022748B1; EA201400536A1

Abstract

This invention relates to medicine, and more particularly to methods for producing double salts of (1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1Н-3-benzazepine (lorcaserin), the products of said methods and compositions for the treatment and/or prevention of obesity comprising double salts of lorcaserin, phthalic acid and metformin or lorcaserin, phthalic acid and an essential amino acid. The invention also relates to the use of the aforesaid pharmaceutical compositions for the treatment and/or prevention of disorders related to excess weight and/or obesity, including in the case of diabetes mellitus, and to methods for the prophylaxis or treatment of disorders related to excess weight and/or obesity, including in the case of diabetes mellitus.

Description

Methods for producing double salts of lorcaserin (options), products of the methods, double salts, pharmaceutical compositions for treating and / or preventing disorders associated with obesity, their use and method for treating and / or preventing disorders related to obesity.

The technical field to which the invention relates.

The invention relates to medicine, in particular to methods for producing double salts of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

(lorcaserin), products of methods and compositions for treatment and / or

prevention of obesity, including double salts of lorcaserin, phthalic acid and metformin or lorcaserin, phthalic acid and basic amino acids. The invention also relates to the use of said

pharmaceutical compositions for treating and / or preventing disorders associated with overweight and / or obesity, including diabetes mellitus, and to methods for preventing or treating disorders associated with overweight and / or obesity, including sugar diabetes.

State of the art

The attention to the problem of obesity among researchers around the world in recent years is associated with the leading role of this pathology as a risk factor for numerous serious diseases, primarily cardiovascular.

Many researchers emphasize the importance and priority of fundamental changes in the lifestyle of a patient with obesity, his nutritional

stereotype and exercise regimen [The Eating Disorders / Ed. By A.J.

Giannini, A.E. Slaby.— Springer-Verlag New York Inc., 1993, p. 283; Rozin P.

Towards a Psycology of food choice. Institut Danone, 1998, p. 265]. However, using only diet and exercise correction By far, not all patients manage to achieve anthropometric indicators or keep them from increasing.

The main ways that the influence of modern

There are two drugs for the treatment of obesity: a decrease in appetite and a decrease in the intake of "extra" calories in the patient's body, in particular with fats. For the purpose of anorexigenic effect, drugs are used today that affect the formation of a feeling of fullness in the brain by increasing the level of biogenic amines (serotonin, norepinephrine), in particular sibutramine.

Neurotransmission of serotonin (5-HT) plays an important role in numerous physiological processes. So, for example, 5-HT is involved in regulation

eating behavior. 5-HT is thought to have an effect, causing a feeling of fullness or fullness, so that food absorption stops earlier and fewer calories are consumed. It was shown that the stimulating effect of 5-HT on the 5-HT2C receptor plays an important role in the regulation of food intake and the anti-obesity effect of D-fenfluramine. Since the 5-HT2C receptor is expressed at a high level in the brain (especially in the limbic structures, extrapyramidal pathways, the thalamus and hypothalamus, and mainly in the choroid plexus) and is expressed at a low level or is absent in peripheral tissues, the 5-HT2C receptor selective agonist may be a more effective and safer anti-obesity drug. Thus, the 5-HT2C receptor is considered well

a suitable receptor target for the treatment of obesity and other disorders.

3-benzazepines found to be receptor agonists

5-HT2C and are effective in reducing obesity in animal models; various routes for the synthesis of 3-benzazepines and their intermediates have been reported (patents EP204349 and EP285919). Usually in synthesis methods use a phenyl-containing starting material on which an amine- or amide-containing chain is built, which is capable of cyclization to form

condensed 7-membered ring of the benzazepine nucleus. Are described

various methods for the synthesis of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, representing lorcaserin, its salts, crystalline forms, intermediates (WO 2005/019179, WO 2006 / 069363, WO 2007/120517, WO 2008/0701 1 1, WO 2009/1 1 1004). In particular, a salt of hydrochloric acid and (H) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is described (patent EA 016485). Some salts, such as (1) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, and crystalline forms

presented in patent EA 017894.

A composition comprising lorcaserin is described in combination with

phentermine, and its use, in particular for the treatment of obesity (WO

2006/071740).

Metformin is an oral hypoglycemic drug from the big anide group. Metformin reduces hyperglycemia without leading to the development of hypoglycemia. Unlike derivatives with lphonylurea, it does not stimulate insulin secretion and does not have a hypoglycemic effect in healthy individuals; increases the sensitivity of peripheral receptors to insulin and

utilization of glucose by cells, reduces the production of glucose by the liver by inhibiting gluconeogenesis and glycogenolysis, delays the absorption of glucose in the intestine. Metformin stimulates glycogen synthesis by acting on glycogen synthetase. Increases the transport capacity of all types of membrane glucose transporters, in addition, has a beneficial effect on

lipid metabolism (lowers total cholesterol, LDL and TG). While taking metformin, the patient's body weight either remains stable or decreases moderately. The effectiveness of weight loss using metformin as a supplement to the diet in individuals with obesity and type 2 diabetes [Teire B., Bergis K. Prospective randomized two years clinical study comparing additional metformin treatment with reducing diet in type 2 diabetes. Diabete Metabolisme, 1991, v. 17, pp 213-17], allowed metmorphine to be considered the drug of first choice for sugar-lowering therapy for patients with overweight and obesity.

Due to the growing demand for compounds for the treatment of disorders associated with 5-HT2C receptor, and given that obesity is a risk factor for numerous serious diseases, including type 2 diabetes mellitus, there is a need to create effective agents for weight loss and control blood glucose, as well as the need for new and more effective methods for producing 3-benzazepines.

SUMMARY OF THE INVENTION

The invention relates to methods for producing double salts of (1H) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (lorcaserin), which may be applicable as serotonin receptor agonists (5- NT) for the treatment of conditions, in particular those associated with overweight and obesity.

One aspect of the invention is a method for producing double salts of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (lorcaserin), phthalic acid and basic amino acids, in particular L- arginine, L-lysine or L-histidine. Another aspect of the invention is a method for producing double salts of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, phthalic acid and metformin.

In one embodiment of the process, double salts of the compound of lorcaserin and basic amino acids, in particular L-arginine, L-lysine or L-, are obtained histidine, with phthalic acid by reacting (1K) -8-chloro-1- 2,3,4,5-tet agidro-SH-3-benzazepine of the formula I

(I)

and a basic amino acid with phthalic acid for a period of time and under conditions suitable for the formation of double salts of said compound.

According to another variant of the method, double salts of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, metformin and phthalic acid are obtained by the reaction of (1 R) - 8-chloro - 1-methyl l-2, 3,4,5-tetrahydro-1 H-3-benzazepine of the formula I

(I)

and metformin hydrochloride with monosodium salt of phthalic acid for a period of time and under conditions suitable for the formation of double salts of said compound.

Another aspect of the invention relates to pharmaceutical compositions containing, as active components, a double salt of (1R) - 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with phthalic acid and basic amino acids, in in particular, L-arginine, L-lysine or L-histidine or a double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with phthalic acid and metformin. The pharmaceutical compositions proposed in accordance with the present invention are an effective tool for weight loss and are useful in the treatment of disorders associated with overweight and / or obesity, including type II diabetes mellitus.

Pharmaceutical composition for the treatment and / or prevention

disorders associated with overweight and / or obesity, including type II diabetes mellitus, contain as active substance the double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro Sh-3-benzazepine with phthalic acid and basic amino acids, in particular L-arginine, L-lysine or L-histidine and a pharmaceutically acceptable excipient (s).

Preferably the content of the double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with phthalic acid L-arginine or L-lysine, or L-histidine in the composition is from 5 mg to 50 mg, the rest is a pharmaceutically acceptable excipient / s.

In another embodiment, the pharmaceutical composition contains, as an acrylic substance, a double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with phthalic acid and metformin. Preferably the content of the double salt of (1H) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with phthalic acid and metformin in the composition is from 5 mg to 50 mg, the rest is pharmaceutically acceptable excipient / s.

Another aspect of the invention relates to the use of pharmaceutical compositions according to the invention for the prevention and / or treatment

disorders associated with overweight and / or obesity, including diabetes mellitus type P.

Another aspect of the invention relates to methods for the prevention and / or treatment of disorders associated with overweight and / or obesity, including type II diabetes mellitus, including administration to a patient pharmaceutical compositions according to the invention in a therapeutically effective amount.

DETAILED DESCRIPTION OF THE INVENTION

According to the variants of the proposed method receive double salts of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and metformin, or the basic amino acid, for example, L-arginine, L-lysine, L-histidine with phthalic acid by reacting (1) -8-chloro-1-methyl-2,3,4,5-tet agidro-W-3-benzazepine of formula I

(I)

and a basic amino acid or metformin with phthalic acid in 1: 1: 1 ratios, followed by crystallization from a suitable solvent, or dissolving the resulting salt in water and subsequent lyophilization.

Compositions in accordance with the present invention can be made in the form of tablets or capsules using pharmaceutically acceptable excipients and procedures traditional in the art, as well as in the form of an injection. Besides,

the composition may be in the form of drops or a solution for oral administration, or in the form of a nasal spray or nasal drops, an aerosol

sublingual or oral, or in the form of a powder, or in the form of a lyophilisate for the preparation of a ready-made solution.

The listed forms of pharmaceutical compositions are prepared by known methods. In accordance with the present invention, for patients in need of prevention and / or treatment, the composition is preferably prescribed for oral and / or parenteral administration (e.g., intravenously, intramuscularly, subcutaneously).

Any pharmaceutically acceptable excipients or

solvents. For oral administration, the pharmaceutical composition may take the form of solutions, suspensions, tablets, pills, capsules, powders. Tablets containing various excipients, for example sodium citrate, calcium carbonate and calcium phosphate, or any other pharmaceutically acceptable excipients, may also include various disintegrants, for example starch, preferably potato starch or tapioca, complex silicates or any other pharmaceutically acceptable

disintegrants, together with binders, for example,

polyvinylpyrrolidone, sucrose, gelatin, gum arabic and any other pharmaceutically acceptable binders. In addition, moving agents are often used, for example, magnesium stearate, sodium lauryl sulfate, talc for tabletting or any other

pharmaceutically acceptable lubricants. The compositions of the invention may also be soft or hard filled gelatin capsules; preferred capsules in this case include, for example, lactose or milk sugar, as well as high molecular weight polyethylene glycols. If aqueous suspensions and / or elixirs are desired for oral administration, the claimed compositions may be combined with

various sweeteners to improve taste and smell, tinting agents, emulsifying agents and / or

suspending agents, as well as solvents such as water, ethanol, propylene glycol, glycerin and various combinations thereof. For

parenteral administration solutions in sesame or peanut butter or in aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions may be suitably buffered, if necessary, and the aqueous solvent is first isotonized with a sufficient amount of a salt or glucose solution. These aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.

The invention also relates to the use of the above.

compositions for treating and / or preventing disorders associated with overweight and / or obesity, including type P diabetes. These disorders include overweight, obesity, repeated

weight gain after a previous decrease, for example, after a diet, a change in body composition, including type II diabetes mellitus, including obesity with a body mass index of 27 kg / m ² or more, with ineffective diet therapy and physical activity.

The proposed method for the prevention or treatment of disorders associated with overweight and / or obesity, including type II diabetes mellitus, involves the introduction of the compositions according to the invention in a therapeutically effective amount.

In one embodiment, a single dose of the active components in the composition

The pharmaceutical composition may comprise:

double salt of (1 I) -8-chloro-1-methyl-2,3, 4, 5-tetrahydro-1 H-3-benzazepine, phthalic acid and basic amino acids - from 5 mg to 50 mg;

the rest is a pharmaceutically acceptable excipient.

In another embodiment, a single dose of the active components in the composition

The pharmaceutical composition may comprise:

double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-Ш-3-benzazepine, phthalic acid and metformin - from 5 mg to 50 mg; the rest is a pharmaceutically acceptable excipient.

The daily dose depends on the severity of the disease, the weight of the patient and the desired effect. The dose is set individually, depending on tolerability and clinical efficacy. In a most preferred embodiment, the daily dose is from 10 to 30 mg of the double salt of (11) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, phthalic acid and metformin. In another most preferred embodiment, the daily dose is from 10 to 30 mg of the double salt of (1 I) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1 N-Z-benzazepine, phthalic acid and the main amino acid .

The effect of the double salt of (11) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, phthalic acid and metformin and the double salt of (P) -8-chloro-1-methyl- 2,3,4,5-tetrahydro-1 H-3-benzazepine, phthalic acid and the main amino acid in the pharmaceutical compositions according to the invention for weight loss with enhanced nutrition was studied in a group of 1,100 and 900 patients, respectively, aged 32-60 years old, showing signs of obesity with a body mass index of more than 27kg / m2 and signs of type II diabetes (example 3).

The invention is illustrated by the following examples.

Example 1. Obtaining double salts of (P) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1 N-Z-benzazepine, phthalic acid and basic amino acids.

These salts are obtained by reacting (11) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine (lorcaserin), the basic amino acid and phthalic acid in 1: 1: 1 ratios at mixing and dissolving the resulting mixture in water, followed by lyophilization.

The double salt of lorcaserin, L-arginine and phthalic acid get

dissolving in 200 ml of water while heating to 60 degrees. With a mixture of 19.5 grams of lorcaserin, 16.6 grams of phthalic acid and 17.4 grams of L-arginine. The resulting mixture is filtered while hot, cooled and

lyo filiziruyut. Obtain 53.5 grams of a double salt of lorcaserin, L-arginine and phthalic acid of the following structure:

Lo acerin phthalic acid L-arginine

The resulting product has the following characteristics:

1H NMR (DMSO-d6 + D2O): 7.9 (d, 2H); 7.5 (d, 2H); 7.1 (d, 3H); 4.1 (s, lH); 3.5 (t, lH); 3.1-3.3 (m, 3H); 2.8-3.1 (m, 6H); 1.8 (m, 2H); 1.5 (m, 2H); 1.25 (d, 3H)

LCMS: 1.85 min, 175 M + H ⁺ ; 3.45 min, 232 M + H ⁺ ; 5.2 min, 165 MH ⁺

A double salt of lorcaserin, L-lysine and phthalic acid is obtained by dissolving in 200 ml of water while heating to 60 ° C a mixture of 19.5 grams of lorcaserin and 16.6 grams of phthalic acid and 14.6 grams of L-lysine.

The resulting mixture is filtered while hot, cooled and

lyophilized. Obtain 51 grams of the double salt of lorcaserin, L-lysine and phthalic acid of the following structure:

lorcaserin phthalic acid L-lysine

The resulting product has the following characteristics:

1H NMR (DMSO-d6 + D2O): 7.9 (d, 2H); 7.5 (d, 2H); 7.1 (d, 3H); 4.3 (s, lH); 3.5 (t, lH); 3.1-3.3 (m, 3H); 2.8-3.1 (m, 6H); 1.8 (m, 2H); 1.5 (m, 2H); 1.2-1.4 (m, 2H); 1.2 (d, 3H) LCMS: 1.94 min, 147 M + H ⁺ ; 3.45 min, 232 M + H ⁺ ; 5.2 min, 165 MH ⁺ A double salt of lorcaserin, L-histidine and phthalic acid is obtained by dissolving a mixture of 19.5 grams in 200 ml of water while heating to 60 ° C.

lorcaserin, 16.6 grams of phthalic acid and 15.5 grams of L-histidine.

The resulting mixture is filtered while hot, cooled and

lyophilized. Obtain 51.9 grams of the double salt of lorcaserin, L-histidine and phthalic acid of the following structure:

lo caserin phthalic acid L-histidine

The resulting product has the following characteristics:

W NMR (DMSO-d6 + D2O): 8.4 (s, lH); 7.9 (d, 2H); 7.5 (d, 2H); 7.2 (s, lH); 7.1 (d, 3H);

4.2 (s, lH); 3.75 (t, lH); 2.7-3.3 (m, 9H); 1.25 (d, 3H)

LCMS: 2.12 min, 156 M + H ⁺ ; 3.45 min, 232 M + H ⁺ ; 5.2 min, 165 MH ⁺

Example 2. Obtaining a double salt of (11) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and metformin with phthalic acid.

The double salt of (1 I) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine (lorcaserin) and metformin with phthalic acid is obtained by the interaction of (1 I) -8-chloro - 1-methyl-2,3,4,5-tetrahydro-1 Н-З-benzazepine, metformin hydrochloride and monosodium salt with phthalic acid in 1: 1: 1 ratios in ethyl alcohol, followed by filtration of the resulting reaction mass from the separated sodium chloride by evaporation of the filtrate and crystallization of the obtained salt from a suitable solvent, or dissolution of the obtained salt in water and subsequent lyophilization her.

Reaction Scheme: lorcaserin monosodium salt of phthalic acid metformin hydrochloride

lorcaserin phthalic acid metformin

To obtain a double salt of lorcaserin, metformin and phthalic acid when heated to 60 degrees. C is dissolved in 300 ml of 95% ethyl alcohol, a mixture consisting of 19.5 grams of lorcaserin, 18.8 grams of monosodium salt of phthalic acid and 16.6 grams of metformin hydrochloride. The reaction mass is stirred at this temperature for 30 minutes, cooled to room temperature. The resulting mixture was filtered from the precipitated sodium chloride, the precipitate of sodium chloride was washed 2 times with 25 ml of 95% ethyl alcohol. The filtrate was evaporated and the residue was dissolved in 180 ml. water at a temperature of 60-70 degrees. C, filtered hot. The filtrate is cooled and lyophilized. Obtain 49 grams of a double salt of lorcaserin, metformin and phthalic acid of the following structure:

lorcaserin phthalic acid metformin

The resulting product has the following characteristics:

1H NMR (DMSO-d6 + D2O): 7.9 (d, 2H); 7.5 (d, 2H); 7.1 (d, 3H); 4.3 (s, lH); 3.1-

3.3 (m, 3H); 2.8-3.1 (m, 10H); 1.25 (d, 3H)

LCMS: 1, 12 min, 130 M + H ⁺ ; 3.45 min, 232 M + S; 5.2 min, 165 MH ⁺

Example 3. The effect of the pharmaceutical compositions according to the invention on weight loss

The effect of the double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-Ш-3-benzazepine, metformin and phthalic acid and the double salt of (1) -8-chloro-1-methyl- 2,3,4,5-tetrahydro-1H-3-benzazepine, phthalic acid and the basic amino acid in the pharmaceutical compositions according to

invention for weight loss with enhanced nutrition was

investigated on a group of patients aged 32-60 years, showing

signs of obesity with a body mass index of more than 27kg / m2 and signs of type II diabetes.

Body mass index (BMI) is defined as the weight of a person (in kilograms) divided by his height (in meters) squared. BMI equal to or greater than

28, corresponds to obesity, and a BMI of 28 to 35 indicates obesity of mild or moderate severity, and a BMI of 35 to 40 corresponds to severe obesity.

Baseline patient characteristics:

BMI 34.2 ± 6.2;

body weight 106.70 ± 16.5 kg;

waist circumference 102.95 ± 14.1 cm.

47% of patients participating in clinical trials had concomitant diseases: controlled hypertension - 19.5%, other cardiovascular diseases - 12%, diabetes mellitus - 16%.

The effectiveness of the drugs was evaluated by the dynamics of weight loss. To monitor the safety of the pharmaceutical composition according to the invention and its effect on the cardiovascular system regularly

blood pressure and heart rate were measured.

In the statistical processing of the obtained data, the assessment of the relative changes in laboratory parameters was carried out using

a parametric approach - Student's criterion. All data are presented as arithmetic mean ± standard deviation.

The effect of pharmaceutical compositions on changes in body weight was studied with enhanced nutrition: men received 3600-4000 kcal per day, women - 2800-3200 kcal per day. Patients received the pharmaceutical composition in the form of a set of capsules or tablets (the amount of lorcaserin hydrochloride of 10 mg is equivalent to 22 mg of the double salt according to the invention in terms of lorcaserin).

Table 1. The effect of the pharmaceutical composition containing the double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

(lorcaserin), phthalic acid and L-arginine to reduce body weight (M + t) *

Substance

(dose, mg / day)

48 weeks

Lorcaserin hydrochloride (10) -5.9 ± 0.2

n = 190 Double salt of lorcaserin, phthalic acid i

L-arginine (1 1) -4.5 ± 0.24

n = 320

Double salt of lorcaserin, phthalic acid

L-Arginine (22) -6.55 + 0.32

n = 400

Double salt of lorcaserin, phthalic acid:

L-Arginine (45)

-7.9 + 0.3

p-370

* M - the average value of weight loss;

t - deviation from the average;

p <0.001;

n - number of participants

Table 2. The effect of the pharmaceutical composition containing the double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (lorcaserin), phthalic acid and metformin on weight loss (M + t) *.

Substance (dose, mg / day) Number of patients Weight loss after 48 weeks of study,%

Lorcaserin hydrochloride (10) 390 -5.5 + 0.2

Lorcaserin double salt, 400 -4.2 + 0.27

phthalic acid and

metformin (1 1) Lorcaserin double salt, 590

phthalic acid and -6.23 ± 0.3

metformin (22)

Double salt of lorcaserin, 450

phthalic acid and -8.1 + 0.35

metformin (45)

* M - the average value of weight loss;

t - deviation from the average;

p <0.001

From the data presented in the tables it follows that the participants in the control group who took lorcaserin hydrochloride at a dose of 10 mg for 48 weeks lost an average of 5.9% weight loss, of which about 42% lost more than 5% of their weight, and about 19 % lost more than 10% of the weight. Participants taking a composition containing 22 mg of the double salt of lorcaserin, phthalic acid and metformin, or 22 mg of the double salt of lorcaserin, phthalic acid and L-arginine, lost an average of 6.55 and 6, 23%, respectively; and those who received the composition at a dose of 45 mg of the double salt of lorcaserin, phthalic acid and metformin, or 45 mg of the double salt of lorcaserin, phthalic acid and L-arginine, lost about 7.9 and 8.1%, respectively.

Compositions containing a double salt of lorcaserin, phthalic acid and metformin or a double salt of lorcaserin, phthalic acid and L-arginine have a more pronounced effect of weight loss with overweight and / or obesity, in particular, with type II diabetes mellitus, compared with lorcaserin hydrochloride , which allows you to enhance the therapeutic effect of lorcaserin, and thereby provide preventive protection and optimize the treatment of patients with overweight and / or obesity, including type I diabetes.

Side effects of the proposed composition were investigated in healthy volunteers, and, in contrast to control, with doses of salt

lorcaserin, phthalic acid and metformin or a salt of lorcaserin, phthalic acid and L-arginine from 10 to 30 mg, side effects such as insomnia, dry mouth, tachycardia and headache were observed in 1.0%, 2.4%, 0.4 % and 3.5% of participants, respectively.

In control, insomnia, dry mouth, tachycardia, and headache were observed in 1 1.5%, 19%, 2.9%, and 34.1% of participants, respectively.

Based on studies of efficacy and safety

of the proposed compositions, a preferred

clinical dose range of 10 to 30 mg of the double salt of (lR) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, phthalic acid and metformin or the double salt of the salt (1 ) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, phthalic acid and basic amino acids.

Claim

1. A method of producing a double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with phthalic acid and a basic amino acid by reacting (1K) -8-chloro-1 methyl-2,3,4,5-tetrahydro-1H-3-benzazepine of the formula I

, the main amino acid and phthalic acid in ratios of 1: 1: 1.

2. The method of producing a double salt (1K.) - 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with phthalic acid and metformin

interactions of () -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine of formula I

, metformin hydrochloride and monosodium salt with phthalic acid in the ratio 1: 1: 1

3. The double salt obtained by the method according to p. 1.

4. The double salt obtained by the method according to p. 2.

5. Double salt of () -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, phthalic acid and the basic amino acid.

6. The double salt of (G) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, phthalic acid and L-lysine, having the following structure

7. Double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, phthalic acid and L-arginine, having the following structure

8. The double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, phthalic acid and L-histidine, having the following structure

9. The double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, phthalic acid and metformin, having the following structure

8. A pharmaceutical composition for treating and / or preventing disorders associated with overweight and / or obesity,

containing as active component a double salt of (lR) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with phthalic acid and a basic amino acid; and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition for treating and / or preventing disorders associated with overweight and / or obesity,

containing as active component a double salt of (G) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with phthalic acid and metformin, and a pharmaceutically acceptable carrier

10. The pharmaceutical composition according to any one of paragraphs. 8-9, made in oral form.

1 1. The use of the pharmaceutical composition according to any one of paragraphs. 8-9 for the treatment and / or prevention of disorders associated with overweight and / or obesity.

12. A method for the treatment and / or prevention of disorders associated with overweight and / or obesity, comprising administering to the patient a composition according to any one of paragraphs. 8-9 in a therapeutically effective amount.

Claims

Claim

1. A method of producing a double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with phthalic acid and a basic amino acid by

the interaction of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine of the formula I

, the main amino acid and phthalic acid in ratios of 1: 1: 1.

2. A method of producing a double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with phthalic acid and metformin by

interactions of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine of the formula I

3. The double salt obtained by the method according to p. 1.

4. The double salt obtained by the method according to p. 2.

5. Double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, phthalic acid and the main amino acid.

6. A double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, phthalic acid and L-lysine, having the following structure

SUBSTITUTE SHEET (RULE 26)

10. A pharmaceutical composition for the treatment and / or prevention of disorders associated with overweight and / or obesity, containing as an active component a double salt of (11) -8-chloro-1-methyl-2,3,4,5-tetrahydro 1H-3-benzazepine with phthalic acid and basic

amino acid and a pharmaceutically acceptable carrier.

1 1. A pharmaceutical composition for treating and / or preventing disorders associated with overweight and / or obesity, containing, as an active component, a double salt of (11) -8-chloro-1-methyl-2,3,4,5-

SUBSTITUTE SHEET (RULE 26) tetrahydro-1H-3-benzazepine with phthalic acid and metformin and a pharmaceutically acceptable carrier

12. The pharmaceutical composition according to any one of paragraphs. 10-1 1, made in oral form.

13. The use of the pharmaceutical composition according to any one of paragraphs. 10-1 1 for the treatment and / or prevention of disorders associated with overweight and / or obesity.

14. A method for the treatment and / or prevention of disorders associated with

overweight and / or obesity, including the appointment to the patient of a composition according to any one of paragraphs. 10-1 1 in a therapeutically effective amount.

SUBSTITUTE SHEET (RULE 26)