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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to a process for synthesizing ivabradine of formula (I)
• Ivabradine as well as its addition salts with a pharmaceutically acceptable acid, and more particularly its hydrochloride, have very interesting pharmacological and therapeutic properties, especially bradycardic properties, which render these compounds useful in the treatment or prevention of different clinical situations of myocardial ischemia such as angina pectoris, myocardial infarction and associated rhythm disorders, as well as in various pathologies including rhythm disorders, especially supraventricular, and in heart failure.
• A is as defined above, in the presence of a base, in an organic solvent.
• the compound of formula (VII) is in optically active form, and more particularly of configuration (S).
• a pharmaceutically acceptable acid chosen from hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric acids. , ascorbic, oxalic, methanesulfonic, benzenesulphonic and camphoric, and its hydrates.
• a pharmaceutically acceptable acid chosen from hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric acids. , ascorbic, oxalic, methanesulfonic, benzenesulphonic and camphoric, and its hydrates.
• the compound of formula (VII) is in racemic form.
• the alkylation reaction of the racemic compound of formula (VII) with the compound of formula (VIII) is then followed by a step of optical resolution of the compound of formula (VI) obtained. - -
• a pharmaceutically acceptable acid chosen from hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric acids. , ascorbic, oxalic, methanesulfonic, benzenesulphonic and camphoric, and its hydrates.
• a pharmaceutically acceptable acid chosen from hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric acids. , ascorbic, oxalic, methanesulfonic, benzenesulphonic and camphoric, and its hydrates. -o-
• the base preferably used for carrying out the alkylation reaction of the compound of formula (VII) with the compound of formula (VIII) is potassium carbonate.
• the solvent preferentially used to carry out the alkylation reaction of the compound of formula (VII) with the compound of formula (VIII) is acetonitrile.
• the compounds of formula (VIIa) in their racemic or optically active form, in particular cases of the compounds of formula (VII) for which X represents a halogen atom or a mesylate group, are novel products which are useful as synthesis intermediates in the art. chemical or pharmaceutical industry, especially in the synthesis of ivabradine, its addition salts with a pharmaceutically acceptable acid and its hydrates, and are therefore an integral part of the present invention.
• This oil is purified by flash chromatography on 1.5 kg of silica (eluent: dichloromethane / ethanol / NH 4 OH: 80/20/2). 42 g of expected product are obtained in the form of a white solid.
• Step 1 tert-Butyl [3- (7,8-dimethoxy-2-oxo-1,2-dihydro-5-yl) benzazepin-3-yl) propyl] methyl carbamate
• Step 2 7,8-Dimethoxy-3 - [3 - (methylamino) propyl] -1,3-dihydro-2H-3-benzazepin-2-one
• IR (neat): ⁇ 3400, 1651, 1610, 1510, 856, 710 cm -1 .
• dichloromethane an exotherm of 20 ° C up to 28 ° C is observed.
• the mixture is stirred for 12 hours at room temperature.
• An insoluble material is filtered and then evaporated to dryness to obtain 15 g of a residue in the form of an oil.
• Example 5 2.1 g of the racemic compound obtained in Example 5 are separated on a 60 cm x 60 mm column packed with 2.1 kg of Chiralpak® AD phase (particle size 20 ⁇ m).
• the eluent used is an ethanol / acetonitrile / diethylamine mixture (10/90 / 0.1 by volume) at a flow rate of 50 mL / min.
• the associated ultraviolet detector is used at a wavelength of 280 nm.
• 0.95 g of enantiomer of configuration (R) is obtained in the form of white meringue and 0.95 g of enantiomer of configuration (S) also in the form of white meringue.
• IR (neat): ⁇ 1656, 1607, 1511, 1273, 1206, 1101, 836, 760 cm -1 .
• Example 7 1.4 g of the racemic compound obtained in Example 7 are separated on a 60 cm x 60 mm column packed with 3 kg of Chiralpak® T101 phase (particle size 20 ⁇ m).
• the eluent used is an ethanol / acetonitrile / diethylamine mixture (10/90 / 0.1 by volume) at a flow rate of 100 ml / min.
• the associated ultraviolet detector is used at a wavelength of 280 nm.
• 0.56 g of the enantiomer of configuration (R) is obtained in the form of a colorless oil and then 0.62 g of the enantiomer of configuration (S) also in the form of a colorless oil.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Cardiology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Heart & Thoracic Surgery (AREA)
• Urology & Nephrology (AREA)
• Vascular Medicine (AREA)
• Hospice & Palliative Care (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Other In-Based Heterocyclic Compounds (AREA)
• Saccharide Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 2009
  • 2009-02-04 FR FR0900457A patent/FR2941695B1/fr not_active Expired - Fee Related
• 2010
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  • 2010-02-03 CA CA2750089A patent/CA2750089C/fr not_active Expired - Fee Related
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  • 2010-02-03 AR ARP100100290A patent/AR075227A1/es not_active Application Discontinuation
  • 2010-02-03 CN CN2010800061486A patent/CN102300849A/zh active Pending
  • 2010-02-03 JP JP2011548741A patent/JP5563600B2/ja active Active
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  • 2010-02-03 WO PCT/FR2010/000080 patent/WO2010089475A1/fr active Application Filing
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  • 2010-02-03 MX MX2011007978A patent/MX2011007978A/es active IP Right Grant
  • 2010-02-03 EP EP10707068A patent/EP2393784A1/fr not_active Withdrawn
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  • 2010-02-03 US US13/138,333 patent/US8415468B2/en not_active Expired - Fee Related
  • 2010-02-03 AU AU2010210054A patent/AU2010210054B2/en not_active Ceased
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• 2011
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