WO2018115181A1 - Nouveau sel d'ivabradine et utilisations de ce dernier - Google Patents

Nouveau sel d'ivabradine et utilisations de ce dernier Download PDF

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WO2018115181A1
WO2018115181A1 PCT/EP2017/083919 EP2017083919W WO2018115181A1 WO 2018115181 A1 WO2018115181 A1 WO 2018115181A1 EP 2017083919 W EP2017083919 W EP 2017083919W WO 2018115181 A1 WO2018115181 A1 WO 2018115181A1
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formula
compound
composition
acid salt
solvent
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PCT/EP2017/083919
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English (en)
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Savvas IOANNOU
Christakis Sergides
Daphne PITTA
Andreas Pittas
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Biogena (A.P.I) Ltd
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Priority to EP17818573.2A priority Critical patent/EP3558948A1/fr
Publication of WO2018115181A1 publication Critical patent/WO2018115181A1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 novel salts and physical forms of ivabradine, methods for their formation, and uses thereof, such as in the treatment of myocardial ischemia and the like.
  • Ivabradine (Formula I), and in particular pharmaceutically acceptable acid salts thereof, have highly valuable pharmacological and therapeutic properties, especially for the treatment of bradycardia. These compounds are also useful in the treatment or prevention of myocardial ischemia, such as angina pectoris, myocardial infarct and associated rhythm disturbances, and in various pathologies relating to rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.
  • Ivabradine acts on the ⁇ f ion current, which is highly expressed in the sinoatrial node.
  • I f also known as the "funny current”
  • ⁇ f is a mixed Na + - K + inward current activated by hyperpolarisation and modulated by the autonomic nervous system.
  • ⁇ f is understood to be one of the most important ionic currents for regulating pacemaker activity in the sinoatrial node.
  • Ivabradine selectively inhibits the pacemaker ⁇ f current in a dose-dependent manner. Blocking this channel reduces cardiac pacemaker activity, selectively slowing the heart rate and allowing more time for blood to flow to the myocardium.
  • Ivabradine hydrochloride i.e. a compound of Formula I as a hydrochloric acid salt
  • EMEA European Medicines Agency
  • Ivabradine hydrochloride can be isolated in many crystalline polymorphic forms, the most well-known being the a-form, ⁇ -form, 3d- form, ⁇ -form, yd-form, ⁇ -form and 5d-form. Many other polymorphic forms are known, including form- ⁇ , form-l, form-ll, form-Ill, form-IV, form- ⁇ , form-K, form-X, form-Z and an amorphous form.
  • API active pharmaceutical ingredient
  • the particular polymorph of ivabradine hydrochloride formed may be dependent upon a number of factors, such as
  • polymorphs may be characterized as "pseudopolymorphs" due to their high sensitivity to humidity, which may be crystallised as a hemihydrate, monohydrate, tetrahydrate or mixtures thereof having different total hydration degrees.
  • polymorphic forms are characterised as “metastable” due to their ease of transformation from one polymorphic form to another, i.e. from 5- form to 5d-form and vice versa.
  • the ⁇ -form of ivabradine hydrochloride is a solvated form and may exist as either 51 or 52 dependent upon the solvent that co-exists in the crystal lattice.
  • Form-51 is acetonitrile solvated
  • form-52 is acetone solvated.
  • a further hydrated ⁇ -form is known, however, the form-51 , form-52, and 5-form may have identical X-ray powder diffraction (XRPD) patterns.
  • Drying 5-polymorphs of ivabradine hydrochloride can form an anhydrous 5d- form. This transformation is dependent upon the volatility of the solvated crystallised solvent. Conversely, an anhydrous 5d-form of ivabradine hydrochloride will readily convert to a ⁇ -hydrated form upon exposure to environmental humidity, ⁇ , 51 , or ⁇ 2 may form form- ⁇ of ivabradine hydrochloride upon exposure to an environment saturated with humidity. Form- ⁇ is ivabradine hydrochloride tetrahydrate and is generally understood to be the most stable polymorphic form of ivabradine hydrochloride.
  • Form-IV is referred as hemihydrate of ivabradine hydrochloride.
  • ivabradine hydrochloride may not be the most suitable choice of an ivabradine addition salt for use as a medicament.
  • WO 2011/104723 relates to acid addition salts of ivabradine and their use in pharmaceutical compositions and as medicines.
  • composition comprising a compound of Formula I as a p-toluenesulfonic acid salt, wherein the compound is in the form of an amorphous solid.
  • the p-toluenesulfonic acid salt of the compound of Formula I may be stable at room temperature, which can be an advantage over various polymorphic forms of ivabradine HCI. Further, the p-toluenesulfonic acid salt of the compound of Formula I may be characterised as having one solid form, with no polymorphic forms other than the amorphous form.
  • the compound of Formula I is the free base of ivabradine unless otherwise stated, such as when referred to the p-toluenesulfonic acid salt thereof.
  • the compound of Formula I as a p-toluenesulfonic acid salt may be referred to as ivabradine tosylate.
  • p- toluenesulfonic acid is para-toluenesulfonic acid, which may also be referred to as PTSA, pTsOH, or tosylic acid (TsOH).
  • compounds of Formula I may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism when in crystalline form. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of Formula I, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallisation techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).
  • composition may comprise the compound of Formula I in a variety of additional pharmaceutically acceptable acid salts in addition to the p- toluenesulfonic acid salt.
  • additional pharmaceutically acceptable acids include, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid; acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, oxalic acid, benzoic acid, methansulfonic acid, isethionic acid, or benzenesulfonic acid.
  • an "amorphous solid” is a material that does not have a periodical three-dimensional pattern, i.e. the material has no long-range intermolecular order.
  • An amorphous solid such as amorphous ivabradine tosylate, lacks crystallinity and can be identified as amorphous by XRPD as described herein.
  • An amorphous solid may be "X-ray amorphous" when the XRPD spectra contains no crystalline diffraction peaks.
  • a crystalline material comprises diffraction peaks that are relatively sharp in an XRPD spectra compared to peaks in an XRPD spectra of an amorphous solid, which are relatively broad peaks.
  • the composition comprises at least about 70 wt%, such as at least about 80 wt%, for instance at least about 90 wt%, preferably about 95 wt%, of the compound of Formula I in the form of an amorphous solid, based upon the total amount of the compound of Formula I in the composition. It may be advantageous that the composition comprises at least about 99 wt%, even more preferably at least about 99.9 wt%, of the compound of Formula I in the form of an amorphous solid, based upon the total amount of the compound of Formula I in the composition.
  • substantially all of the compound of Formula I is in the form of an amorphous solid, preferably all of the compound of Formula I is in the form of an amorphous solid.
  • the XRDP of the composition will comprise no sharp peaks, such as those that relate to crystalline forms of the compound of Formula I.
  • substantially all means all except for impurity levels of other compounds. Substantially all may therefore mean at least 95 wt%, such as at least 99 wt%, preferably 99.9 wt%, more preferably 99.99 wt% of the compound of Formula I is in the form of an amorphous solid.
  • the composition may comprise salts of ivabradine other than the p-toluenesulfonic acid salt.
  • salts are those formed from hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid; acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, oxalic acid, benzoic acid, methansulfonic acid, isethionic acid, benzenesulfonic acid, or combinations thereof.
  • Compounds of Formula I other than the p-toluenesulfonic acid salt of Formula I, may be present in the composition in any amount. However, it is preferred that compounds of Formula I other than the p-toluenesulfonic acid salt are present in only trace amounts.
  • trace amounts means that those compounds are present in an amount of less than about 1 wt%, such as less than about 0.5 wt%, preferably less than about 0.1 wt%, more preferably less than about 0.05 wt%, most preferably less than about 0.001 wt%, based upon the total weight of the composition.
  • the composition may consist essentially of, preferably consists of, the compound of Formula I as a p-toluenesulfonic acid salt. That is, the composition may contain only trace amounts of compounds other than the compound of Formula I as a p-toluenesulfonic acid salt.
  • the amount of impurities and compounds of Formula I other than the p- toluenesulfonic acid salt may be determined by any suitable method, such as by HPLC.
  • the amorphous solid, such as amorphous ivabradine tosylate, may be free flowing which may be particularly advantageous when processing, formulating and transporting the compound.
  • the composition may be a pharmaceutical composition comprising a compound of Formula I as a p-toluenesulfonic acid salt and a pharmaceutically-acceptable excipient.
  • the compound of Formula I as a p-toluenesulfonic acid salt should therefore be present in the composition in a therapeutically effective amount.
  • Suitable pharmaceutically-acceptable excipients are known to the skilled person, and include diluents (fillers), disintegrants, binders, lubricants, and glidants amongst others.
  • composition of the invention is provided for use as a medicament.
  • Such use may be in the treatment of myocardial ischemia, such as angina pectoris.
  • a method of treating myocardial ischemia comprising administering a composition of the invention comprising a therapeutically effective amount of a compound of Formula I as a p-toluenesulfonic acid salt to a subject in need thereof.
  • a process for the formation of a composition of the invention comprising the step of reacting a compound of Formula I (which may be referred to as the free base of ivabradine) with p-toluenesulfonic acid, in a first solvent, to form a compound of Formula I as a p-toluenesulfonic acid salt in the form of an amorphous solid.
  • a compound of Formula I which may be referred to as the free base of ivabradine
  • p-toluenesulfonic acid in a first solvent
  • the first solvent may be selected from the group consisting of saturated or unsaturated, cyclic or acyclic, C 5 to d 2 hydrocarbons, such as n-pentane, n- hexane, n-heptane, cyclohexane, and toluene; cyclic or acyclic C 2 to Ci 2 ethers, such as tetrahydrofuran, diethyl ether, diisopropyl ether, and dioxane; C 2 to Ci 2 esters, such as methyl acetate, and ethyl acetate; Ci to C 6 alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol; C 2 to C 8 sulfoxides, such as dimethyl sulfoxide; C 2 to Ci 2 amides, such as dimethylformamide, and dimethyl acet
  • the first solvent is a combination of ethyl acetate, acetone and diethyl ether, for example in a volume ratio of from about 15:1 :15 to about 25:1 :25, such as about 20:1 :20, respectively.
  • hydrocarbons are compounds formed from carbon and hydrogen atoms, such as those defined above.
  • the reaction may be carried out at temperatures typically from about 0 °C to about 80 °C. It is preferably that the reaction is carried out at a temperature from about 18 °C to about 30 °C.
  • the reaction may be performed for a period of from about 15 minutes to about 24 hours. Preferably the reaction is performed for about 3 to about 5 hours, more preferable about 4 hours.
  • a suitable amount of p-toluenesulfonic acid should be used to ensure that all of the compound of Formula I is converted into a compound of Formula I as a p- toluenesulfonic acid salt, preferably an excess of p-toluenesulfonic acid being present in the composition. It is preferred that the amount of p-toluenesulfonic acid used is from about 1 to about 1.3, preferably about 1.2, molar equivalents based upon the amount of compound of Formula I.
  • a compound of Formula I i.e. the free base of ivabradine
  • a solvent mixture of ethyl acetate and acetone such as in a volume ratio of 10:1 , respectively
  • stirring at a temperature of from about 18 °C to about 30 °C.
  • p- toluenesulfonic acid as the monohydrate
  • ethyl acetate for instance 10 volumes
  • the reaction mixture may be stirred for three hours at a temperature of from about 18 °C to about 30 °C. During this time a precipitate may be formed.
  • Diethyl ether (preferably a volume equal to that of ethyl acetate used to form the reaction mixture, for instance 20 volumes) may be added to the reaction mixture, and the reaction mixture may be stirred for one additional hour at a temperature of from about 18 °C to about 30 °C.
  • the precipitate may be collected by filtration and dried for a period of from about 10 to about 20 hours, preferably about 14 to about 16 hours, at a temperature of from about 35 °C to about 45 °C, preferably about 40 °C.
  • acetone in an amount of from about 2.5 vol% to about 5 vol% as a co-solvent. It may be preferable to use about 2.5 vol% of acetone as a co-solvent. This may delay precipitation and/or afford the compound of Formula I as a p-toluenesulfonic acid salt in higher purity.
  • diethyl ether may increase precipitation and/or assist in the recovery of the compound of Formula I as a p-toluenesulfonic acid salt.
  • the compound of Formula I as a p-toluenesulfonic acid salt as an amorphous solid may be washed with a second solvent.
  • This purification process may increase the purity of the solid by, for instance, removing impurities (such as those soluble in the second solvent) including other solvents.
  • the second solvent may be selected from the group consisting of saturated or unsaturated, cyclic or acyclic, C 5 to d 2 hydrocarbons, such as n-pentane, n- hexane, n-heptane, cyclohexane, and toluene; cyclic or acyclic C 2 to Ci 2 ethers, such as tetrahydrofuran, diethyl ether, diisopropyl ether, and dioxane; C 2 to Ci 2 esters, such as methyl acetate, and ethyl acetate; Ci to C 6 alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol; C 2 to C 8 sulfoxides, such as dimethyl sulfoxide; C 2 to Ci 2 amides, such as dimethylformamide, and dimethyl acet
  • the amorphous solid may be stirred in the second solvent for a period of from about 15 minutes to about 24 hours, such as from about 3 hours to about 5 hours, and preferably about 4 hours, at a temperature of from about 0 °C to about 80 °C. It is particularly preferred that the purification process is carried out by trituration at a temperature from about 18 °C to about 30 °C. When the second solvent comprises diethyl ether it is preferred that the temperature is below about 35 °C. Dependent on the second solvent used during the purification process the compound of Formula I as a p-toluenesulfonic acid salt may be partially or fully dissolved.
  • the amorphous solid may be partially or fully dissolved in the solvent, in particular at a temperature above about 65 °C.
  • the compound of Formula I as a p-toluenesulfonic acid salt which is dissolved in the second solvent may be recovered by methods known to the skilled person, such as by precipitation and filtration.
  • a particular feature of the third aspect of the invention comprises the step of reacting a compound of Formula I as a hydrochloric acid salt with a suitable base in a suitable third solvent to form the compound of Formula I.
  • the suitable base may be selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. It is preferred that the suitable base is sodium hydroxide.
  • the third solvent may be water, and in particular purified water.
  • the compound of Formula I (i.e. the free base of ivabradine) may be separated from the third solvent by any conventional means known to the skilled person, such as by extraction with an extraction solvent.
  • the extraction solvent may be ethyl acetate, which may be removed from the compound of Formula I by a suitable method, such as evaporation.
  • the compound of Formula I as the hydrochloric acid salt may be converted into the compound of Formula I (i.e. the free base of ivabradine) in the process of the invention as described above
  • the free base of ivabradine may be converted into the compound of Formula I as a hydrochloric acid salt as part of that process.
  • the conversion of ivabradine between the compound of Formula I (i.e. the free base) and the compound of Formula I as the hydrochloric acid salt may increase purity of the composition. For instance, it may be easier to remove impurities from the compound of Formula I as the hydrochloric acid salt when in a solid form, such as a crystalline form, (i.e. by washing and/or recrystallisation) compared to the removal of impurities from a compound of Formula I as the free base.
  • a solid compound of Formula I as the hydrochloric acid salt may be treated with an organic solvent, which is preferably acetonitrile, at a temperature from about 0 °C to 80 °C, preferably at about 70 °C to about 80 °C, for a period of from about 0.5 hours to about 24 hours, preferably about 2 hours, and subsequently and optional at a temperature of about 0 °C to about 5 °C, preferably at about 0 °C, for about 1 hour to about 24 hours, preferably about 18 hours.
  • the solid may be filtered at 0 °C to afford the compound of Formula I as the hydrochloric acid salt. This may produce a composition at a higher purity.
  • the process comprises the step of reacting a compound of Formula I (i.e. the free base of ivabradine) and hydrochloric acid in a suitable fourth solvent to form the compound of Formula I as the hydrochloric acid salt.
  • a compound of Formula I i.e. the free base of ivabradine
  • hydrochloric acid in a suitable fourth solvent
  • the fourth solvent may be selected from the group consisting of Ci to C 6 alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol; cyclic or acyclic C 2 to d 2 ethers, such as tetrahydrofuran, diethyl ether, diisopropyl ether, and dioxane; C 2 to C 8 sulfoxides, such as dimethyl sulfoxide; C 2 to Ci 2 amides, such as dimethylformamide, and dimethyl acetamide; acetonitrile; C3 to Ci 2 ketones, such as acetone; and a combination thereof.
  • Ci to C 6 alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol
  • the fourth solvent is a combination of acetonitrile and isopropanol.
  • the hydrochloric acid may be provided in isopropanol, preferably from about 5 to about 6 N HCI in isopropanol, which may be added to the compound of Formula I (i.e. the free base of ivabradine).
  • Ivabradine i.e. a compound of Formula I
  • a compound of Formula I may be purchased as its hydrochloric acid salt.
  • the compound of Formula I may be formed according to the following process.
  • (1 S)-4,5-Dimethoxy-1 -[(methylamino)methyl]benzocyclobutane hydrochloride (Formula II) may be reacted with 1 -bromo-3-chloropropane (Formula III) in the presence of a base (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, preferably potassium carbonate) in a solvent (e.g.
  • a base e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, preferably potassium carbonate
  • a solvent e.g.
  • a Ci to C 6 alcohol such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert- butanol; an ether, such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane; a sulfoxide, such as dimethyl sulfoxide; or an amide, such as dimethylformamide, dimethyl acetamide; acetonitrile or the like or mixtures thereof or under neat conditions, i.e.
  • a Ci to C 6 alcohol such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert- butanol
  • an ether such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane
  • a sulfoxide
  • the compound of Formula IV may be reacted with 7,8-dimethoxy-1 ,3,4,5- tetrahydro-2H-benzo[d]azepin-2-one (Formula V), preferably in the presence of a base (such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride or the like, preferably potassium tert-butoxide), in a suitable solvent (such as a Ci to C 6 alcohol, such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol; an ether, such as tetrahydrofuran, diethyl ether, diisopropyl ether; dioxane; a sulfoxide, such as dimethyl sulfoxide; an amide, such as dimethylformamide, dimethyl acetamide;
  • Figure 1 shows the XRPD spectra of six prepared samples of ivabradine tosylate i.e. a compound of Formula I as a p-toluenesulfonic acid salt, each being in the form of an amorphous solid. Each spectra shows only a broad peak which is indicative of an amorphous solid. The absence of sharp, defined peaks in the spectra shows that the samples lack any crystallinity.
  • ivabradine free base i.e. a compound of Formula (I) t-BuOK (13.05 g) was added to a stirred solution of 7,8-dimethoxy-1 ,3,4,5- tetrahydro-2H-benzo[d]azepin-2-one (Formula V) (23.39 g) in DMSO (234 mL) under nitrogen, at 25 °C. The reaction mixture was stirred for 1 hour at 25 °C.
  • Example 3 Formation of ivabradine hydrochloride, i.e. a compound of Formula I as a hydrochloric acid salt
  • a compound of Formula I (ivabradine free base) (48.4 g) was dissolved in acetonitrile (484 mL). The solution was cooled to 0 °C and stirred for 5 to 10 min. HCI solution in isopropanol (5-6 N; 24.8 mL) was added dropwise to the stirred solution. After formation of a white solid, the reaction mixture was stirred overnight at 0° ⁇ 5 °C. The solid was filtered and washed with acetonitrile. The solid was dried under vacuum at ambient temperature overnight affording 41.37 g (79%) of the compound of Formula (I) as a hydrochloric acid salt as white solid.
  • Example 4 Purification of ivabradine hydrochloride, i.e. a compound of Formula (I) as a hydrochloric acid salt
  • a compound of Formula (I) as a hydrochloric acid salt (ivabradine hydrochloride) (41.3 g) was stirred in acetonitrile (413 mL) at 80 °C for 2 hours. The mixture was cooled slowly to room temperature while stirring continued, and then stirred at ambient temperature for 1 hour and then at 0 °C for 18 hours. The solid was filtered and dried under vacuum at ambient temperature overnight affording 38.05g (92%) of the compound of Formula (I) as a hydrochloric acid salt as a colourless solid (purity: 99.6% by HPLC).
  • ivabradine free base i.e. a compound of Formula (I)
  • ivabradine hydrochloride i.e. a compound of Formula (I) as a hydrochloric acid salt
  • a compound of Formula (I) as a hydrochloric acid salt (ivabradine hydrochloride) (1.0 g) in deionized water (5 mL) was added NaOH (3M; 1 mL). The mixture was stirred for 10 minutes and ethyl acetate (5 mL) was added. The reaction was stirred for a further 10 minutes. The two layers were separated and the aqueous layer was extracted with EtOAc (3 x 5 mL). The organic phases were combined, dried (MgS0 4 ), and volatile organics were removed under reduced pressure affording 0.88 g (95%) of the compound of Formula (I) (ivabradine free base) as a viscous oil.
  • a compound of Formula (I) as a p-toluenesulfonic acid salt (ivabradine tosylate) was added in a flask containing diethyl ether (20 mL). The mixture was stirred at ambient temperature for 4 hours. The solid was filtered and washed with diethyl ether affording 0.95g (95%) of pure compound of Formula (I) as a p- toluenesulfonic acid salt (ivabradine tosylate) as a white solid (more than 99.8% by HPLC).
  • Stability of ivabradine hydrochloride and ivabradine tosylate Stability studies were conducted in which the stability of the 5d-form, ⁇ -form and 51 -form of ivabradine hydrochloride was compared to the stability of amorphous ivabradine tosylate of the present invention.
  • the amount of impurities in the test samples was established by HPLC using standard analytical techniques, such as calculating the relative area under UV peaks (expressed as a percentage in the table below). The samples were then stored for 30 days at a temperature of 40 °C ⁇ 2 °C and a relative humidity of 75% ⁇ 5%. The results are set out in the table below.
  • amorphous ivabradine tosylate is more stable under an inert atmosphere that the forms of ivabradine hydrochloride.
  • the 5d-form, 5- form and 51 -form of ivabradine hydrochloride are relatively unstable according to the data in terms of total impurities in the sample as measured by HPLC.

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Abstract

La présente invention concerne de nouveaux sels et formes physiques de l'ivabradine, des procédés pour leur formation, et leurs utilisations, comme dans le traitement de l'ischémie myocardique et similaire.
PCT/EP2017/083919 2016-12-20 2017-12-20 Nouveau sel d'ivabradine et utilisations de ce dernier WO2018115181A1 (fr)

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GB1621771.3 2016-12-20
GBGB1621771.3A GB201621771D0 (en) 2016-12-20 2016-12-20 New salts of compounds and uses thereof

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011104723A2 (fr) * 2010-02-23 2011-09-01 Ind-Swift Laboratories Limited Sels d'addition d'acide de l'ivabradine et leur préparation
EP2388248A1 (fr) * 2009-01-13 2011-11-23 Jiangsu Hengrui Medicine Co., Ltd. Procédés pour la préparation de sulfate d'ivabradine et de sa forme cristalline i
EP2471780A1 (fr) * 2007-05-30 2012-07-04 Ind-Swift Laboratories Limited Sels d'oxalate d'ivabridine cristallin et polymorphes correspondants
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