EA022828B1 - Method for producing salt of lorcaserin and phthalic acid, product of the method, pharmaceutical compositions for the treatment and/or prophylaxis of obesity-related disorders, the use of same, and methods for the treatment and/or prophylaxis of obesity-related disorders - Google Patents

Abstract

A method for producing salt of lorcaserin with phthalic acid is provided. The invention also relates to pharmaceutical compositions, comprising salt of lorcaserin with phthalic acid or salt of lorcaserin with phthalic acid and metformin, and the use thereof for the treatment and/or prevention of disorders related to excess weight and/or obesity, including in case of diabetes mellitus, and to methods for the prophylaxis or treatment of disorders related to excess weight and/or obesity, including in case of diabetes mellitus.

Description

FIELD OF THE INVENTION

The invention relates to medicine, in particular to a method for producing a salt of lorcaserin (1K) -8chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and phthalic acid, a product of the method and composition for treatment and / or preventing obesity, including lorcaserin and phthalic acid salt and metformin. The invention also relates to the use of a pharmaceutical composition 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 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 eating stereotype and exercise regimen | ТНе Ебпд Э15огбег5 / Еб. Wu Α.Τ Οίαηηίηί. Α.Ε. §1ab. - 8rgshdeg-Ueg1ad No. \ ν Wogk 1ps., 1993, ρ. 283; Κοζίη Ρ. That is, agbk a rgusodu o £ ίοοά with Noah. ΙηδΙίΙυΙ Iapope, 1998, p. 265]. However, using only a diet and correction of the physical activity regime, not all patients manage to achieve the target anthropometric indicators or keep them from increasing.

The main ways that the influence of modern drugs for the treatment of obesity are directed are two: a decrease in appetite and a decrease in the intake of excess calories into 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 the regulation of 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 5HT2C receptor plays an important role in the regulation of food intake and the effect of фен-fenfluramine against obesity. 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, a selective 5-HT2C receptor agonist may be more effective and safer against obesity. Thus, the 5-HT2C receptor is considered a well-suited receptor target for treating obesity and other disorders.

3-Benzazepines have been found to be 5-HT2C receptor agonists and have been shown to be effective in reducing obesity in animal models (e.g., US Patent Application Nos. 60/479280 and 10/410991).

Various routes have been reported for the synthesis of 3-benzazepines and their intermediates (U.S. Patent Application Nos. 60/479280 and 10/410991, Patents EP204349 and EP285919). Typically, a phenyl-containing starting material is used in the synthesis methods, on which an amine or amide-containing chain is built, which is capable of cyclization to form a condensed 7-membered ring of the benzazepine core. Various synthesis methods are described for (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (lorcaserin), its salts, crystalline forms, intermediates (No. O 2005/019179, No. O 2006/069363, No. O 2007/120517, No. O 2008/070111, No. O 2009/111004). In particular, a salt of hydrochloric acid and (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is described (patent EA 016485). Some salts, such as (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3benzazepine hydrochloride, and crystalline forms are presented in patent EA 017894.

A composition containing lorcaserin in combination with phentermine is described, and its use, in particular for the treatment of obesity (No. O 2006/071740).

Metformin is an oral hypoglycemic drug from the biguanide group. Metformin reduces hyperglycemia without leading to the development of hypoglycemia. Unlike sulfonylurea derivatives, 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 glucose utilization by cells, reduces liver glucose production by inhibiting gluconeogenesis and glycogenolysis, and delays the absorption of glucose in the intestine. Metformin stimulates glycogen synthesis by acting on glycogen synthetase. It increases the transport capacity of all types of membrane glucose transporters, in addition, it has a beneficial effect on lipid metabolism (reduces 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 mellitus b1e1 ίη 1ure 2 baBe1e8. E1aBe1e Me1aBo118che,

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1991, ν. 17, p. 213-17], allowed metmorphine to be considered the first choice drug for the hypoglycemic therapy of patients with overweight and obesity.

Due to the progressive nature of the development of type 2 diabetes mellitus, which is based on, on the one hand, insulin resistance and, on the other, a defect in insulin secretion by pancreatic β-cells, as well as restrictions on any glycosylated hemoglobin level classes of hypoglycemic drugs, it is believed that many patients need precisely combined hypoglycemic therapy.

Due to the growing demand for compounds for the treatment of disorders associated with the 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 drugs, including combination ones, to reduce weight 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 a method for producing a salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3benzazepine (lorcaserin) and phthalic acid, which may be useful as an agonist of the serotonin receptor (5- NT) for the treatment of conditions associated with overweight and obesity.

One aspect of the invention is a method for producing a salt of (1K) -8-chloro-1-methyl-2,3,4,5tetrahydro-1H-3-benzazepine and phthalic acid.

The proposed method for producing the salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and phthalic acid involves the interaction of a phenyl-containing compound with a reagent, cyclization, acid hydrolysis, separation of a mixture of optical isomers and characterized in that they react 2- (4-chlorophenyl) ethyl bromide with allylamine to obtain a compound of formula 1

for a period of time and under conditions suitable for the formation of said compound; cyclize the compounds of formula 1

under the action of cyclizing agents to form a compound of formula 2

representing a racemic mixture of stereoisomers of compound 2A and

compound 2b;

for a period of time and under conditions suitable for the formation of said compound; carry out the interaction of the compounds of formula 2

for a period of time and under conditions suitable for the formation of said compound; and sharing a mixture of optical isomers of a compound of formula 3

- 02282828 optically active resolving amine with the release of optically pure compounds of formula 3a

and formulas 3b

from diastereomeric salts, followed by regeneration of the optically active resolving amine.

Another aspect of the invention relates to a salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3benzazepine with phthalic acid.

Another aspect of the invention relates to a pharmaceutical composition containing, as an active component, a salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with phthalic acid.

Another aspect of the invention relates to a pharmaceutical composition containing, as active components, a 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.

The pharmaceutical composition for the treatment and / or prevention of disorders associated with overweight and / or obesity, including type II diabetes mellitus, contains the salt (1K) -8-chloro-1methyl-2,3,4,5-tetrahydro -1H-3-benzazepine with phthalic acid in an amount of from 5 to 30 mg; the rest is a pharmaceutically acceptable carrier.

A pharmaceutical composition for treating and / or preventing disorders associated with overweight and / or obesity, including type II diabetes mellitus, comprising (1K) -8-chloro-1-methyl-2,3 salt as active components , 4,5-tetrahydro-1H-3-benzazepine with phthalic acid and metformin, contains the salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with phthalic acid in an amount of 5 to 30 mg; metamorphine or a pharmaceutically acceptable salt thereof, from 500 to 2000 mg; and a pharmaceutically acceptable carrier (s).

Another aspect of the invention relates to the use of pharmaceutical compositions according to the invention for the prevention and / or treatment of disorders associated with overweight and / or obesity, including type II diabetes mellitus.

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, comprising administering to the patient the pharmaceutical compositions of the invention in a therapeutically effective amount.

List of figures

The drawing shows the pharmacokinetic profiles of lorcaserin hydrochloride and salts of lorcaserin with phthalic acid with a single oral dose of 10 mg / kg to male rats.

DETAILED DESCRIPTION OF THE INVENTION

The proposed method for producing salts of lorcaserin and phthalic acid provides for the preparation of a compound of formula 1

by reaction of 2- (4-chlorophenyl) ethyl bromide with a 2-100 fold, preferably 10-15 fold excess of allylamine, at a temperature of 20-100 C, preferably 50-60 C; preparing a compound of formula 2 by cyclization of a compound of formula 1

under the action of cyclizing agents (Lewis acids), such as, for example, A1C1 ₃ , A1Bg ₃ , polyphosphoric acid, etc. at a temperature of 100-200 ° C, preferably at 150 ° C, in the presence of solvents, such as di- and trichlorobenzenes, nitrobenzene, nitromethane, nitroethane, carbon disulfide, etc., or without solvents.

Purification and separation of the compounds of formula 2,

H ₃ representing a racemic mixture of stereoisomers, to optical isomers, comprises preparing a compound of formula 3

with phthalic anhydride in a suitable organic solvent, preferably substituted ketones at a temperature of 20-150 ° C, preferably at 110-130 ° C; crystallization of the compounds of formula 3

from a suitable organic solvent or a mixture of an organic solvent, preferably a lower aliphatic alcohol with water; separation of a mixture of optical isomers of a compound of formula 3

with optically active resolving amines, preferably such as (K) - (+) - alpha-methyl benzylamine, (8) - (-) - alpha-methyl benzylamine, (K) - (-) - 1,2,3, 4-tetrahydro-1-naphthylamine, (8) - (+) - 1,2,3,4tetrahydro-1-naphthylamine, (K) - (+) - (1-naphthyl) ethylamine, (8) - (- ) - (1-naphthyl) -ethylamine, and crystallization of the obtained salt from a suitable organic solvent or a mixture of organic solvents or a mixture of an organic solvent with water;

the selection of optically pure compounds of formula 3 a

or formula 3b

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by acidifying aqueous suspensions of diastereomeric salts to a pH of 0-5, preferably a pH of 23, and extracting an optically pure compound of formula 3a or formula 3b

a suitable organic, water-immiscible solvent, preferably ethyl acetate or chloroform; regeneration of the optically active separating amine by alkalizing the aqueous phase, which is an aqueous solution (or suspension) of the salt of the separating amine and the inorganic acid that has been acidified, to a pH of 8-14, preferably to a pH of 10-11; extraction of the optically active resolving amine with a suitable water-immiscible organic solvent, preferably methyl tert-butyl ether, distilling off the solvent and distilling the optically active resolving amine in vacuo; acid hydrolysis of a compound of formula 3 a or 3b

under the influence of an aqueous solution of a mineral acid, preferably hydrochloric, with a concentration of 10-50%, preferably 20-25%, followed by extraction of phthalic acid from the acidic reaction mass with a suitable organic solvent, preferably ethyl acetate, followed by evaporation of the organic solvent and recrystallization of phthalic acid from water by alkalizing the acid hydrolyzate to a pH of 8-14, preferably to a pH of 10-11, and extracting the compounds of formula 2a or 2b,

representing the optical isomers of lorcaserin, a suitable organic solvent, preferably diethyl ether or methyl tert-butyl ether, followed by evaporation of the organic solvent under vacuum; and obtaining salts of the compounds of formula 2a

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with phthalic acid in ratios of 1: 1 or 2: 1, followed by crystallization from a suitable solvent or dissolution of the resulting salt in water and subsequent lyophilization.

In one embodiment of the synthesis of lorcaserin, 4-chlorophenylacetic acid is used as a reagent for the synthesis of 2- (4-chlorophenyl) ethyl bromide. The synthesis of 2- (4-chlorophenyl) ethyl bromide is carried out by known methods of organic synthesis. 4-Chlorophenylacetic acid reacts with methyl alcohol under the action of thionyl chloride to give 4-chlorophenylacetic acid methyl ester, which is reduced by sodium borohydride to 2- (4-chlorophenyl) ethanol. From 2 (4-chlorophenyl) ethanol under the action of phosphorus tribromide, 2- (4-chlorophenyl) ethyl bromide is obtained, which in turn reacts with an excess of allylamine and X-allyl-2 (4-chlorophenyl) ethylamine is obtained as a result of the reaction. X-allyl-2- (4-chlorophenyl) -ethylamine under the action of aluminum chloride turns into (1 K8) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine.

In another embodiment of the synthesis of lorcaserin for the synthesis of 2- (4-chlorophenyl) ethylamine, 4-chlorophenylacetonitrile is used as a reagent. The synthesis of 2- (4-chlorophenyl) -ethylamine is carried out by known methods of organic synthesis. 4-chlorophenylacetonitrile is hydrogenated in hydrogen in the presence of Renney nickel, resulting in 2- (4-chlorophenyl) ethylamine, which reacts with allyl bromide. The reaction yields X-allyl-2- (4-chlorophenyl) ethylamine. X-allyl-2- (4-chlorophenyl) -ethylamine under the influence of aluminum chloride is converted into (1K8) -8-chloro-1-methyl2,3,4,5-tetrahydro-1H-3-benzazepine.

The advantages of the proposed method compared to previously known ones are cyclization of the allyl derivative instead of the 2-chloroethylamine derivative (using the allylamine derivative instead of the beta-chloroethylamine derivative for alkylation of the aromatic nucleus under the action of aluminum chloride), which allows avoiding the use of beta-chloroethylamine derivatives having an irritating, dermal bulk and carcinogenic properties, and the use of corrosive and toxic thionyl chloride; separation of optical isomers by reaction of racemic lorcaserin with phthalic anhydride instead of reaction with a separating optically active acid, followed by separation of a mixture of isomers with an optically active resolving amine, which, unlike an acid, can be regenerated; a simplified procedure for the purification of racemic lorcaserin in the form of a phthalic acid semiamide by simple recrystallization; as well as the possibility of obtaining lorcaserin substances in the form of its salt with phthalic acid, which, unlike lorcaserin hydrochloride, is characterized by a slower release of the active principle, which is shown in experiments by comparing the dissolution rate of a tablet based on lorcaserin hydrochloride and a tablet based on lorcaserin and phthalic salt acid (example 3), due to which the salt according to the invention have a reduced ability to cause side effects associated with the effects of lorcaserin on 5HT2A receptors with its rapid absorption (Ki1e5 apb KediaTsop5 Rebeg1 Keg181eg. 2013, ν. 78, Νο. 89).

So, when conducting experiments on rodents (see the drawing) with the oral administration of the salt of lorcaserin with phthalic acid, the maximum concentration in the blood plasma was reached after 24 minutes, with the introduction of lorcaserin hydrochloride - after 15 minutes. This effect allows to reduce peak fluctuations in the concentration of the active substance in blood plasma, to reduce the likelihood of side effects when taking a medicine, for example, such as neurological disorders.

The composition in accordance with the present invention, containing as active components the salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and phthalic acid and metformin, has a pronounced synergistic effect , which manifests itself in a significant increase in the effectiveness of the impact when combined in the composition of the composition of metformin and the salt of lorcaserin with phthalic acid with excess weight and / or obesity, in particular with type II diabetes mellitus. The discovered synergistic effect of the combined use of metformin and lorcaserin salt with phthalic acid can enhance their therapeutic effect and, thus, provide preventive protection and optimize the treatment of patients with overweight and / or obesity, including type II diabetes mellitus (example 2) .

Compositions in accordance with the present invention can be made in the form of tablets, capsules using pharmaceutically acceptable excipients and procedures traditional for the art, as well as in the form of an injection. In addition, the compositions may be in the form of drops or a solution for oral administration, or in the form of a nasal spray or nasal drops, a sublingual or oral aerosol, or in the form of a powder, or in the form of a lyophilisate for the preparation of a finished solution.

Enumeration of the form of pharmaceutical compositions is obtained by known methods. In accordance with the present invention, for patients in need of prophylaxis and / or treatment, the compositions are preferably prescribed for oral and / or parenteral use (e.g., intravenously, intramuscularly, subcutaneously).

Any pharmaceutically acceptable carriers or solvents are used to prepare the pharmaceutical compositions of the invention. For oral administration, the pharmaceutical compositions 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, glidants are often used, for example magnesium stearate, sodium lauryl sulfate, talc for tabletting or any other pharmaceutically acceptable glidants. 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, taste and odor enhancers, tinting agents, emulsifying agents and / or suspending agents, as well as solvents such as water, ethanol, propylene glycol, glycerin and their various combinations. For parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol can be used, 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 the treatment and / or prevention of disorders associated with overweight and / or obesity, including type II diabetes mellitus. 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, inefficiency of diet therapy and physical activity.

The proposed methods for the prevention or treatment of disorders associated with overweight and / or obesity, including type II diabetes mellitus, include the introduction of pharmaceutical compositions containing lorcaserin salt with phthalic acid, or lorcaserin salt with phthalic acid and metformin in a therapeutically effective amount . For example, a single dose of the active ingredients in a pharmaceutical composition may comprise a lorcaserin salt with phthalic acid of 5 to 30 mg;

metformin or a pharmaceutically acceptable salt thereof from 500 to 3000 mg.

When using a composition containing lorcaserin and phthalic acid, a single dose of lorcaserin and phthalic acid may be from 5 to 30 mg.

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 the most preferred embodiment, the daily dose of the active ingredients in the pharmaceutical composition is from 1000 to 2000 mg of metformin and 15-20 mg of lorcaserin salt with phthalic acid. Su-7 022828 the exact dose of the lorcaserin and phthalic acid salt when using a composition containing the lorcaserin and phthalic acid salt as the active ingredient is most preferably 15-20 mg.

The effect of lorcaserin salt with phthalic acid and a composition containing lorcaserin salt with phthalic acid and metformin on weight loss with increased nutrition was studied in a group of 3500 patients, women and men aged 32-60 years, showing signs of obesity with a body mass index more than 27 kg / m ² and signs of type II diabetes (example 2).

In the study, the advantage of combination therapy with lorcaserin salt with phthalic acid and metformin with respect to weight loss was reliably proven (Table 1).

The invention is illustrated by the following examples.

Example 1. Obtaining the compounds of formula 1 (Y-allyl-2- (4-chlorophenyl) -ethylamine).

(one)

To 130 g of boiling allylamine, to which 100 mg of hydroquinone was added (to inhibit polymerization) at a temperature of 55-58 ° C under nitrogen atmosphere, 50 g of 2- (4 chlorophenyl) ethyl bromide are added dropwise over 3 hours. The resulting mixture was boiled in a nitrogen atmosphere for 16 hours, the excess of allylamine was distilled off. The residue is dissolved in 300 ml of ethyl acetate, the ethyl acetate solution is washed with 100 ml of an aqueous solution of sodium carbonate, water, and a saturated solution of sodium chloride. The extract obtained is dried with magnesium sulfate, evaporated in vacuo at a residual pressure of 40 mbar and a temperature not exceeding 45 ° C. The resulting yellow oil (40 g) was used in the next step without purification.

Cyclization of the compound of formula 1 under the action of cyclizing agents into the compound of formula 2 in the form of a mixture of the optical isomers (1K8) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 2a and 2b.

To a suspension of A1C1 ₃ cooled to 0 ° C, 80.1 g (0.6 mol) in 100 ml of 1,2-dichlorobenzene was added dropwise with vigorous stirring a solution of 39.1 g of compound (1) in 50 ml of 1,2-dichlorobenzene . After passing through an exothermic reaction with the release of gaseous hydrogen chloride, the mixture is gently heated to a temperature of 145-155 ° C and maintained at this temperature for 14-18 hours. The reaction mass is cooled to 0 C and 15% hydrochloric acid (200 ml) is added to it, chilled to 0 ° C. The resulting mixture was stirred for 30 minutes, the lower aqueous layer was separated and it was extracted from impurities 2 times with 100 ml of cyclohexane.

Then the aqueous layer was alkalinized to pH 13 with 30% NaOH and the released amine was extracted 3 times with 150 ml of cyclohexane. The organic extract is washed with water, dried with magnesium sulfate and evaporated in vacuo at a temperature of 35-40 ° C and a residual pressure of 40 mbar. The resulting oil 32.7 g is used in the next step without purification.

The reaction of a compound of formula (2) with phthalic anhydride and the preparation of a compound of formula (3) (1K8) -2 - [(8-chloro-1,2,4,5-tetrahydro-1-methyl-3H-3-benzazepine-2- il) carbolyl] -benzoic acid as a mixture of optical isomers 3a and 3b

32.7 g of the oil obtained in the previous step are dissolved in 80 ml of methyl isobutyl ketone. 24.7 g of phthalic anhydride are added to the resulting solution and the resulting reaction mass is boiled for 2 hours. It is cooled to room temperature and stirred until crystallization of compound (3) begins. Stir at room temperature for 2 hours, then maintain the reaction mass at 4-8 ° C for 8 hours. The product is filtered and washed 2 times with 30 ml of methyl isobutyl ketone, cooled to 4-8 ° C. The resulting product is dried under vacuum at a temperature of 45 ° C and a residual pressure of 40 mbar. Obtain 52.3 g. For purification, the product is recrystallized from 100 ml of boiling ethyl alcohol, and 43.2 g of product (3) are obtained with a purity of more than 98% (HPLC).

The interaction of the compounds of formula (3) with an optically active resolving amine and the separation of the compounds of formula (4) 1-phenethylamine salt (1K8) - 2 - [(8-chloro-1,2,4,5-tetrahydro-1-methyl-3H3- benzazepin-2-yl) carbolyl] -benzoic acid to compounds (4a) and (4b) by crystallization.

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43.2 g of compound [3] are dissolved in 150 ml of hot methanol (60 ° C), 15.2 g of K (+) - alpha benzylamine are added to the resulting mixture. The resulting solution was slowly cooled to room temperature (within 2 hours), then stirred until crystallization began and another 4 hours. After that, the suspension was left for 8 hours at 4-8 ° C. The precipitated product (4a) is filtered, washed with 2 times 20 ml of methanol cooled to 4-8 ° С, dried under vacuum at a temperature of 35-40 ° С and a residual pressure of 40 mbar. We get 23.3 g of the product. After recrystallization from 30 ml of 50% ethyl alcohol, we obtain 19.1 g of product (4a) with an optical purity of more than 99%.

Then, the optically active compound (1K) -2 - [(8-chloro-1,2,4,5tetrahydro-1-methyl-3H-3-benzazepin-2-yl) carbolyl] -benzoic acid (3a) is isolated by dissolving or suspending salt (4a) in water, acidifying the solution to pH 2 and extracting compound (3a) with a suitable solvent (ethyl acetate, chloroform, etc.)

To a suspension of 19.2 g of compound (4a) in 60 ml of water and 60 ml of ethyl acetate was added 25% sulfuric acid to pH 2. After everything was dissolved and a transparent two-phase system was formed, the mixture was stirred for another 15 minutes. The ethyl acetate layer was separated, and the aqueous was extracted 2 more times with 20 ml of ethyl acetate. The combined organic extract was washed with 20 ml of water, dried over magnesium sulfate and evaporated to dryness. The obtained residue after evaporation (14 g) is transferred to the stage of acid hydrolysis.

The regeneration of the separating optically active amine, followed by extraction with a suitable organic solvent of the optically active amine in the form of a base.

The aqueous layer is adjusted to pH 12 with a 30% sodium hydroxide solution, the precipitated K (+) - alpha benzylamine is extracted with benzene (3 times 20 ml), the benzene extract is washed with 10 ml of water, dried with magnesium sulfate and distilled (first, we distilled off at atmospheric pressure benzene, amine distilled in vacuum).

The acid hydrolysis of compound (3 a) is carried out. Phthalic acid is isolated by extraction with a suitable organic solvent (ethyl acetate, chloroform, etc.) from the reaction mass after hydrolysis.

Isolation of compound (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2a) followed by extraction with a suitable organic solvent of compound (2a) as a base.

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To the residue after evaporation from the previous step (14 g), 50 ml of 25% hydrochloric acid are added and the mixture is boiled for 4 hours. After cooling to room temperature, the phthalic acid that has been extracted is extracted 3 times with 20 ml of ethyl acetate. The ethyl acetate extract was washed with 10 ml of water and evaporated to dryness. The residue is recrystallized from water.

The acidic aqueous layer was adjusted to pH 12 with 30% sodium hydroxide, the extracted amine was extracted with diethyl ether (3 times 20 ml), the ether extract was washed with 20 ml of water, dried with potassium carbonate and the ether was evaporated to constant weight under vacuum at a temperature of 35-40 ° C and a residual pressure of 40 mbar. Get compound (2A) in the form of a light yellow oil of 7.6 g

Obtaining a salt of a compound of formula 2a with phthalic acid by reacting compound 2a with phthalic acid in ratios of 1: 1 or 2: 1, followed by crystallization from a suitable solvent or dissolving the resulting salt in water and subsequent lyophilization.

When heated to 60 ° C, a mixture of 19.5 g of lorcaserin and 16.6 g of phthalic acid is dissolved in 100 ml of water. The resulting mixture was filtered while hot, cooled and lyophilized. 36.1 g of the acid salt of lorcaserin and phthalic acid are obtained in the form of a white crystalline powder. ¹ Hb (Cbb): 10.2 (bb, 1H); 9.8 (b3, 2H); 7.8 (ά, 2H,> 2Ηζ), 7.6 (ά, 2H,>2Ηζ); 7.15 (άά, 1H, 1 = 2.8); 7.1 (ά, 1H, 1 = 2Ηζ); 7.02 (ά, 1H, 1 = 8Sh); 3.6 (t, 2H); 3.5 (t, 2H); 2.8-3.0 (t, 3H); 1.55 (^ 3H, 1 = 7W).

L / MH: 1.39 min, 196 (Μ + 1) lorcaserin; 2.13 min., 165 (Μ-1) phthalic acid.

Example 2. The effect of a composition containing a salt of lorcaserin and phthalic acid, and a composition containing a salt of lorcaserin with phthalic acid and metformin, on weight loss.

The effect of lorcaserin and phthalic acid salts and the combined effect of metformin and lorcaserin and phthalic acid on weight loss with increased nutrition was studied in a group of 3500 patients, women and men aged 32-60, showing signs of obesity with a body mass index of more than 27 kg / m ² 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. A BMI equal to or greater than 28 corresponds to obesity, with a BMI of 28 to 35 indicating mild or moderate obesity, 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.

33.8% of patients participating in clinical trials had concomitant diseases: controlled hypertension - 12.6%, other cardiovascular diseases 7.2%, diabetes mellitus - 14%. The effectiveness of the drug was evaluated by the dynamics of weight loss.

To monitor the safety of the pharmaceutical compositions of the invention and their effect on the cardiovascular system, blood pressure and heart rate were regularly 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 monotherapy with lorcaserin and phthalic acid salt and combination therapy with metformin on body weight changes was studied with enhanced nutrition: men received 36004000 kcal per day, women - 2800-3200 kcal per day. Patients received pharmaceutical compositions in the form of a set of capsules or tablets.

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Table 1. The effect of lorcaserin salt with phthalic acid and combination therapy with lorcaserin salt. and phthalic acid and metformin for weight loss (M ± t) *

Substance (dose, mg / day) Number of patients Weight loss after 48 weeks of study,% Lorcaserin hydrochloride (20) 200 -5.9 ± 0.2 Salt of lorcaserin and phthalic acid (5) 200 -5.4 ± 0.25 Salt of lorcaserin and phthalic acid (20) 300 -6.1 ± 0.21 Salt of lorcaserin and phthalic acid (30) 300 6, 4 ± 0.33 Salt of lorcaserin and phthalic acid (5) Metformin (500) 500 -7.4 ± 0.45 Salt of lorcaserin and phthalic acid (10) Metformin (1000) 1000 -20.1 ± 0.62 Salt of lorcaserin and phthalic acid (20) Metformin (2000) 1000 -18.8 ± 0.55

* M - the average value of weight loss; t - deviation from the average; p <0.001.

From the data presented in the table, it follows that participants in the control group who took lorcaserin hydrochloride at a dose of 20 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 who took a dose of 20 mg of lorcaserin and phthalic acid for 48 weeks lost an average of 6.1%. Participants taking a composition containing 5 mg of lorcaserin and phthalic acid salt and 500 mg of metformin lost an average of 7.4%; and those who received the composition at a dose of 10 mg of lorcaserin and phthalic acid and 1000 mg of metformin or 20 mg of lorcaserin and phthalic acid and 2000 mg of metformin lost about 20%.

Thus, differences in weight loss when using a composition containing lorcaserin and phthalic acid salt and metformin and control after 48-week studies were observed at all doses (p <0.001), and the differences were significant when using the composition according to the invention in doses of 10 mg of lorcaserin and phthalic acid and 1000 mg of metformin, or 20 mg of lorcaserin and phthalic acid and 2000 mg of metformin.

Side effects of the compositions according to the invention were studied in healthy volunteers, and in contrast to the control (daily dose of lorcaserin hydrochloride 20 mg) with daily doses of lorcaserin and phthalic acid 20 mg and metformin 2000 mg, side effects such as insomnia, dry mouth, tachycardia, headache were observed in 6, 10.5, 0.84 and 14.7% of participants, respectively (Table 2).

When taking a lorcaserin salt with phthalic acid at a dose of 20 mg, side effects such as insomnia, dry mouth, tachycardia, headache were observed in 8.5, 15.8, 2.1, and 24.6% of participants, respectively (table . 2).

In the control, insomnia, dry mouth, tachycardia, and headache were observed in 10.7, 17.25, 2.6, and 30.3% of the participants, respectively (Table 2).

Table 2. Adverse reactions (M ± t) *

Unfavorable reactions Lorcaserin hydrochloride in the form of a tablet of 20 mg / day Βείνΐς®) N = 1905 Salt of lorcaserin with phthalic acid in the form of a table. 20 mg / day N = 215 Salt of lorcaserin with phthalic acid (20 mg / day) and metformin (2000 mg / day): composition in the form of a table. N = 218 Tachycardia% 2.6 2.1 0.84

Gastrointestinal Disorders%

Nausea 8.3 7.9 5.5 Diarrhea 6.5 6.05 5.96 Dry mouth Vomiting 17.25 3.8 15.8 3.72 10.5 2.75 Nervous System Disorders% Headache 30.3 24.6 14.7 Dizziness Insomnia thirteen 10, 7 eleven 8.5 8.5 6

* M - the average value of weight loss; t - deviation from the average; p <0.001; N is the number of patients.

Thus, as a result of the studies, a pronounced synergistic effect was reliably proved regarding weight loss and side effects in combination therapy with the composition according to the invention containing lorcaserin and phthalic acid salt in an amount of 5-11 022828 mg and metformin in an amount of 500-2000 mg, preferably 10 -15 mg salt of lorcaserin and phthalic acid and 1000-2000 mg of metformin, relative to monotherapy with lorcaserin hydrochloride or salt of lorcaserin and phthalic acid in a dose of 20 mg.

Based on studies of the efficacy and safety of the proposed composition, a preferred clinical dose range of 10 to 15 mg of lorcaserin and 1000-2000 mg of metformin was identified.

Example 3. Comparison of the dissolution rate and disintegration time of a tablet based on lorcaserin hydrochloride and tablets based on a salt of lorcaserin and phthalic acid.

In the table. 3 shows a comparison of differences in the disintegration time of tablets containing lorcaserin hydrochloride and tablets obtained using the method of the present invention.

Table 3

A drug The form introductions : Average weight Disintegration time Lokaserina hydrochloride Oral . 10 mg No more than 15 minutes Lorcaserin Salt and phthalic acid Oral 10 mg Not less than 20 minutes

When dissolved in water at 25 ° C, at least 75% of lorcaserin hydrochloride dissolves in 45 minutes, and not more than 55% of locaserin salt with phthalic acid.

Claims (19)

CLAIM 1. A method of producing a salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (lorcaserin) and phthalic acid, comprising reacting a phenyl-containing compound with a reagent, cyclization, acid hydrolysis separating a mixture of optical isomers, characterized in that 2- (4-chlorophenyl) ethyl bromide is reacted with allylamine to obtain a compound of formula 1, the compound of formula 1 is cyclized by cyclizing agents to form a compound of formula 2, compound 2b; interacting the compounds of formula 2 and separate the mixture of optical isomers of the compounds of formula 3 - 12 022828 from diastereomeric salts followed by regeneration of the optically active resolving amine. 2. The method according to claim 1, characterized in that the preparation of the compounds of formula 1 is carried out by reacting 2- (4-chlorophenyl) ethyl bromide with a 2-100-fold, preferably 10-15-fold, excess of allylamine at a temperature of 20-100 ° C preferably 50-60 ° C. 3. The method according to claim 1, characterized in that the separation of the mixture of optical isomers of the compounds of formula 3 with optically active separating amines, preferably such as (K) - (+) - alpha-methylbenzylamine, (8) - (-) - alpha-methylbenzylamine , (K) - (-) - 1,2,3,4-tetrahydro-1-naphthylamine, (8) - (+) 1,2,3,4-tetrahydro-1-naphthylamine, (K) - (+ ) - (1-naphthyl) ethylamine, (8) - (-) - (1-naphthyl) ethylamine. 4. The method according to claim 1, characterized in that the optically pure compounds of formula 2a and 2b are isolated. 5. The method according to claim 1, characterized in that receive salts of the compounds of formula 2A H ₃ C with phthalic acid by reacting a compound of formula 2a with phthalic acid in ratios of 1: 1 or 2: 1. - 13 022828 6. The product obtained by the method according to claim 1. 7. The salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and phthalic acid 8. A pharmaceutical composition for the treatment and / or prevention of disorders associated with overweight and / or obesity, containing as an active component the salt of lorcaserin with phthalic acid in the following amounts: salt of lorcaserin with phthalic acid from 5 to 30 mg; the rest is a pharmaceutically acceptable carrier. 9. A pharmaceutical composition for treating and / or preventing disorders associated with overweight and / or obesity, containing metformin or a pharmaceutically acceptable salt and lorcaserin salt with phthalic acid as active components in the following amounts: lorcaserin salt with phthalic acid from 5 to 30 mg; metformin or a pharmaceutically acceptable salt thereof from 500 to 3000 mg; and a pharmaceutically acceptable carrier. 10. The pharmaceutical composition of claim 8, made in oral form. 11. The pharmaceutical composition according to claim 9, made in oral form. 12. The use of the pharmaceutical composition of claim 8 for the treatment and / or prevention of disorders associated with overweight and / or obesity. 13. The use of the pharmaceutical composition of claim 8 for the treatment and / or prevention of disorders associated with overweight and / or obesity in type II diabetes mellitus. 14. The use of the pharmaceutical composition according to claim 9 for the treatment and / or prevention of disorders associated with overweight and / or obesity. 15. The use of the pharmaceutical composition according to claim 9 for the treatment and / or prevention of disorders associated with overweight and / or obesity in type II diabetes mellitus. 16. A method of treating and / or preventing disorders associated with overweight and / or obesity, comprising administering to the patient a composition of claim 8 in a therapeutically effective amount. 17. A method for the treatment and / or prevention of disorders associated with overweight and / or obesity in type II diabetes mellitus, comprising administering to the patient a composition of claim 8 in a therapeutically effective amount. 18. A method of treating and / or preventing disorders associated with overweight and / or obesity, comprising administering to the patient a composition according to claim 9 in a therapeutically effective amount. 19. A method of treating and / or preventing disorders associated with overweight and / or obesity in type II diabetes mellitus, comprising administering to the patient a composition according to claim 9 in a therapeutically effective amount.