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WO2015185990A1 - Procédé de production de sels doubles de lorcasérine (et variantes), produits du procédé, sels doubles, compositions pharmaceutiques pour le traitement et/ou la prévention des troubles liés à l'obésité, leur utilisation et méthode de prévention et de traitement des troubles liés à l'obésité - Google Patents

Procédé de production de sels doubles de lorcasérine (et variantes), produits du procédé, sels doubles, compositions pharmaceutiques pour le traitement et/ou la prévention des troubles liés à l'obésité, leur utilisation et méthode de prévention et de traitement des troubles liés à l'obésité Download PDF

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Publication number
WO2015185990A1
WO2015185990A1 PCT/IB2015/001000 IB2015001000W WO2015185990A1 WO 2015185990 A1 WO2015185990 A1 WO 2015185990A1 IB 2015001000 W IB2015001000 W IB 2015001000W WO 2015185990 A1 WO2015185990 A1 WO 2015185990A1
Authority
WO
WIPO (PCT)
Prior art keywords
phthalic acid
benzazepine
chloro
tetrahydro
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2015/001000
Other languages
English (en)
Russian (ru)
Inventor
Евгений Юрьевич БЕЛОВ
Евгений Александрович ЧЕРТОРИЖСКИЙ
Пётр Александрович БЕЛЫЙ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Delcroston Management Ltd
Original Assignee
Delcroston Management Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Delcroston Management Ltd filed Critical Delcroston Management Ltd
Publication of WO2015185990A1 publication Critical patent/WO2015185990A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • 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
  • the invention also relates to the use of said
  • 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.
  • drugs for the treatment of obesity 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.
  • 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.
  • 5-HT serotonin
  • 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
  • composition comprising lorcaserin is described in combination with
  • 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
  • lipid metabolism lowers total cholesterol, LDL and TG.
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • disorders associated with overweight and / or obesity 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).
  • 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.
  • 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.
  • a double salt of (1K) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with phthalic acid and metformin 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
  • diabetes mellitus type P 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.
  • 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
  • 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,
  • 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.
  • compositions are prepared by known methods.
  • the composition is preferably prescribed for oral and / or parenteral administration (e.g., intravenously, intramuscularly, subcutaneously).
  • 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
  • moving agents are often used, for example, magnesium stearate, sodium lauryl sulfate, talc for tabletting or any other
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a single dose of the active components in the composition is a single dose of the active components in the composition.
  • the pharmaceutical composition may comprise:
  • the rest is a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may comprise:
  • 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 .
  • 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.
  • 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.
  • 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
  • the resulting mixture is filtered while hot, cooled and
  • 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 ⁇ - ⁇ -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.
  • Example 3 The effect of the pharmaceutical compositions according to the invention on weight loss
  • Body mass index is defined as the weight of a person (in kilograms) divided by his height (in meters) squared. BMI equal to or greater than
  • BMI 28 to 35 indicates obesity of mild or moderate severity
  • BMI of 35 to 40 corresponds to severe obesity
  • n 190 Double salt of lorcaserin, phthalic acid i
  • n 320
  • Double salt of lorcaserin, phthalic acid Double salt of lorcaserin, phthalic acid:
  • 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.
  • 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.
  • insomnia In control, insomnia, dry mouth, tachycardia, and headache were observed in 1 1.5%, 19%, 2.9%, and 34.1% of participants, respectively.
  • metformin hydrochloride and monosodium salt with phthalic acid in the ratio 1: 1: 1
  • a pharmaceutical composition for treating and / or preventing disorders associated with overweight and / or obesity 8.
  • a pharmaceutical composition for treating and / or preventing disorders associated with overweight and / or obesity is provided.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Child & Adolescent Psychology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne la médecine et notamment des procédés pour produire des sels doubles de (1R)-8-chloro-1-méthyl-2,3,4,5-tétrahydro-1N-3- benzoazépine (lorcasérine), des produits, procédés et compositions pou traiter et/ou prévenir l'obésité comprenant des sels doubles de lorcasérine, d'acide phtalique et de metformine ou de lorcasérine, d'acide phtalique et d'acide aminé de base. L'invention concerne aussi l'utilisation de ces compositions pharmaceutiques pour la prévention et/ou le traitement des troubles liés à un poids excessif et/ou à l'obésité, y compris en cas de diabète sucré, et des méthodes de prévention et de traitement des troubles liés à un poids excessif et/ou à l'obésité, y compris en cas de diabète sucré.
PCT/IB2015/001000 2014-06-02 2015-04-27 Procédé de production de sels doubles de lorcasérine (et variantes), produits du procédé, sels doubles, compositions pharmaceutiques pour le traitement et/ou la prévention des troubles liés à l'obésité, leur utilisation et méthode de prévention et de traitement des troubles liés à l'obésité Ceased WO2015185990A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EA201400536A EA022748B1 (ru) 2014-06-02 2014-06-02 Способы получения двойных солей лоркасерина (варианты), продукты способов, двойные соли, фармацевтические композиции для лечения и/или профилактики нарушений, связанных с ожирением, их применение и способ лечения и/или профилактики нарушений, связанных с ожирением
EA201400536 2014-06-02

Publications (1)

Publication Number Publication Date
WO2015185990A1 true WO2015185990A1 (fr) 2015-12-10

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PCT/IB2015/001000 Ceased WO2015185990A1 (fr) 2014-06-02 2015-04-27 Procédé de production de sels doubles de lorcasérine (et variantes), produits du procédé, sels doubles, compositions pharmaceutiques pour le traitement et/ou la prévention des troubles liés à l'obésité, leur utilisation et méthode de prévention et de traitement des troubles liés à l'obésité

Country Status (2)

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EA (1) EA022748B1 (fr)
WO (1) WO2015185990A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009051747A1 (fr) * 2007-10-15 2009-04-23 Concert Pharmaceuticals, Inc. Lorcasérine deutérée
WO2012030938A1 (fr) * 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Sels de lorcasérine dotés d'acides optiquement actifs
WO2012030927A2 (fr) * 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Formes galéniques à libération modifiée d'agonistes de 5-ht2c, utiles pour la gestion du poids

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0411470A (pt) * 2003-06-17 2006-07-11 Arena Pharm Inc derivados de benzazepina úteis para o tratamento de doenças associadas com o receptor de 5ht2c

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009051747A1 (fr) * 2007-10-15 2009-04-23 Concert Pharmaceuticals, Inc. Lorcasérine deutérée
WO2012030938A1 (fr) * 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Sels de lorcasérine dotés d'acides optiquement actifs
WO2012030927A2 (fr) * 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Formes galéniques à libération modifiée d'agonistes de 5-ht2c, utiles pour la gestion du poids

Also Published As

Publication number Publication date
EA201400536A1 (ru) 2015-08-31
EA022748B1 (ru) 2016-02-29

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