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WO2011063773A2 - Formes cristalline et amorphe d'almorexant et leur procédé de préparation - Google Patents

Formes cristalline et amorphe d'almorexant et leur procédé de préparation Download PDF

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Publication number
WO2011063773A2
WO2011063773A2 PCT/CZ2010/000119 CZ2010000119W WO2011063773A2 WO 2011063773 A2 WO2011063773 A2 WO 2011063773A2 CZ 2010000119 W CZ2010000119 W CZ 2010000119W WO 2011063773 A2 WO2011063773 A2 WO 2011063773A2
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WO
WIPO (PCT)
Prior art keywords
almorexant
hydrochloride
acetate
amorphous
polymorphous
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/CZ2010/000119
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English (en)
Other versions
WO2011063773A3 (fr
Inventor
Stanislav Radl
Josef Cerny
Hana Brusova
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.)
Zentiva KS
Original Assignee
Zentiva KS
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 Zentiva KS filed Critical Zentiva KS
Publication of WO2011063773A2 publication Critical patent/WO2011063773A2/fr
Publication of WO2011063773A3 publication Critical patent/WO2011063773A3/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
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the invention relates to crystalline and amorphous forms of (2R)-2- ⁇ (15)-6,7-dimethoxy-l-[2- (4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-lH-isoquinolm-2-yl ⁇ -N-methyl-2-phenyl- acetamide hydrochloride (I) (almorexant) and a method of their preparation.
  • the compound of formula (I) acts as a selective antagonist of the 0X1 and 0X2 orexetin receptors and is effective in treatment of sleep disorders.
  • Almorexant is currently in the phase III of clinical tests (RESTORA 1).
  • the project is being developed by the Actelion Company in cooperation with the GlaxoSmitliKline Company.
  • the invention provides crystalline and amorphous forms of (2R)-2- ⁇ (l 1 S)-6,7-dimethoxy-l-[2- (4-trifluoiOmethyl-phenyl)-ethyl] -3 ,4-dihydro- lH-isoquinolin-2-yl ⁇ -N-methyl-2-phenyl- acetamide hydrochloride (almorexant) (I) and a method of their preparation.
  • the thus obtained Form A has the advantage of an easy method of preparation consisting in crystallization from suitable solvents or mixtures of solvents.
  • the form obtained in this manner exhibits high stability, high chemical as well as polymorphous purity, and low contents of residual solvents.
  • the amorphous form has the advantage of very good solubility, which is suitable for the manufacture of medical dosage forms.
  • almorexant hydrochloride (almorexant) (I) we tried to develop suitable forms, which could be used for the formulation of solid dosage forms. As a result we have obtained two suitable forms of almorexant hydrochloride (I), namely the crystalline form A and an amorphous form.
  • the preparation method of almorexant hydrochloride (I) of form A developed by us consists in dissolving the almorexant base in an organic solvent, such as ethers, e.g. diethyl ether, methyl-i-butyl ether, tetrahydrofuran, or dioxane, chlorinated solvents, e.g. dichloromethane, dichloro ethane, chloroform, or tetrachloromethane, aromatic hydrocarbons, e.g.
  • organic solvent such as ethers, e.g. diethyl ether, methyl-i-butyl ether, tetrahydrofuran, or dioxane
  • chlorinated solvents e.g. dichloromethane, dichloro ethane, chloroform, or tetrachloromethane
  • aromatic hydrocarbons e.g.
  • benzene, toluene, or xylene or in solvents such as acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide, hydrocarbons, e.g. heptane, cyclohexane, methylcyclohexane, or (Ci-C 6 ) alcohols, e.g.
  • methanol, ethanol, 2-propanol, 1- propanol, 1-butariol, 2-butanol either in anhydrous solvents or their mixtures, or in solvents or their mixtures with addition of water.
  • an anhydrous solution of hydrogen chloride gas in an organic solvent such as (Ci-C 6 ) alcohols, e.g. methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, 2-butanol, ethers, e.g.
  • almorexant hydrochloride (I) is also possible to add aqueous hydrochloric acid, preferably with a concentration of 1 to 37% (by weight), to the prepared solution of almorexant base (I) to obtain almorexant hydrochloride (I).
  • a very suitable method of preparation of almorexant hydrochloride of form A is also represented by crystallization of other forms (amorphous form as well) from (Ci-Ce) alcohols, e.g. methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, 2-butanol or their mixtures both in anhydrous solvents and in solvents containing water, which may be at a concentration from 0.01% to 15%) by weight.
  • Si-Ce methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, 2-butanol or their mixtures both in anhydrous solvents and in solvents containing water, which may be at a concentration from 0.01% to 15%) by weight.
  • Form A prepared in this manner contains less than 5% by weight of other polymorphous forms, usually less than 1% of other polymorphous forms.
  • Crystalline form A manifests in an X-ray powder pattern characteristic peaks in the following positions: 4.69; 9.40; 9.81; 14.50; 15.01 ; 16.26; 18.89; 22.22; 22.51; 23.18; 25.24; 26.05; 29.41; 29.83; 38.85 ° 20 ⁇ 0.1° 2 ⁇ , which corresponds to the X-ray pattern (figure 1).
  • the main peaks were observed at 4.69; 9.40; 15.01 ; 16.26; 18.89; 25.24° 2 ⁇ ⁇ 0.1° 2 ⁇ .
  • DSC was measured for form A.
  • the temperature programme used was 50-250 °C, the heat-up rate 10 °C/min in a nitrogen atmosphere.
  • the obtained thermogram has one significant endotherm, corresponding to melting of the substance.
  • the endothemi is characterized by the values of onset 206 °C and peak 213 °C (average values obtained from more measurements), which corresponds to the record (figure 3).
  • Form A exhibits high stability, decomposition does not occur even at a relatively high temperature (90 °C) and is also stable in the light. Good physical characteristics of form A also represent a great advantage. It is very easy to filter, wash and dry. After drying in a vacuum drier at 30 °C for 6 hours the contents of residual solvents are within the admissible limits.
  • almorexant hydrochloride is represented by the amorphous form.
  • the preparation method of amorphous almorexant hydrochloride (I) developed by us consists in dissolving almorexant hydrochloride in a suitable solvent, such as ethers, e.g. diethyl ether, methyl-r-butyl ether, tetrahydrofuran, or dioxane, chlorinated solvents, e.g. dichloromethane, dichloro ethane, chloroform, or tetrachloromethane, aromatic hydrocarbons, e.g.
  • a suitable solvent such as ethers, e.g. diethyl ether, methyl-r-butyl ether, tetrahydrofuran, or dioxane
  • chlorinated solvents e.g. dichloromethane, dichloro ethane, chloroform, or tetrachloromethane
  • aromatic hydrocarbons
  • benzene, toluene, or xylene or in solvents such as acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, acetonitnle, (Ci-C 6 ) alcohols, e.g. methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, 2-butanol, or their mixtures, and spraying the solution prepared in this manlier into the hot stream of an inert gas, followed by settling and isolating (spray drying) of the amorphous particles.
  • solvents such as acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, acetonitnle, (Ci-C 6
  • amorphous almorexant hydrochloride consists in dissolving almorexant hydrochloride in a suitable solvent, such as chlorinated solvents, e.g. dichloromethane, dichloroethane, chloroform, or tetrachloromethane, ethers, e.g. diethyl ether, methy -butyl ether, tetrahydrofuran, or dioxane, aromatic hydrocarbons, e.g.
  • chlorinated solvents e.g. dichloromethane, dichloroethane, chloroform, or tetrachloromethane
  • ethers e.g. diethyl ether, methy -butyl ether, tetrahydrofuran, or dioxane
  • aromatic hydrocarbons e.g.
  • Amorphous almorexant hydrochloride can also be prepared by dissolving almorexant hydrochloride in a suitable solvent, such as chlorinated solvents, e.g. dichloromethane, dichloroethane, chloroform, or tetrachloromethane, ethers, e.g.
  • diethyl ether diethyl ether, methyl-i-butyl ether, tetrahydrofuran, or dioxane, or in solvents such as acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, acetonitnle, or their mixtures, and precipitating by addition of another solvent to the solution.
  • solvents such as acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, acetonitnle, or their mixtures, and precipitating by addition of another solvent to the solution.
  • Suitable solvents for the precipitation mainly include C5-C16 aliphatic or alicyclic hydrocarbons such as pentane, hexane, heptane, cyclohexane, methylcyclohexane, decalin, and the like, or mixtures thereof such as petroleum ether, petrol, petroleum, and the like.
  • the amorphous product prepared using this method contains less than 5% by weight of the other polymorphous forms, usually less than 1% by weight of other polymorphous forms.
  • An X-ray patterns confirms that it is an amorphous form of almorexant hydrochloride (figure 2). Further, DSC was measured for the amorphous form.
  • the temperature programme employed was 50 -250 °C, heat-up rate 10 °C/min in a nitrogen atmosphere.
  • the obtained thermogram has one significant exotherm and one significant endotherm.
  • the exotherm is characterized by the values of onset 153 °C and peak 160 °C and the endotherm is characterized by the values of onset 212 °C and peak 215 °C (average values obtained from more measurements), which corresponds to the record (figure 4).
  • Tg glass transition
  • Amorphous almorexant hydrochloride exhibits very good solubility and it is known from earlier published papers (Konno T., Chem. Pharm. Bull. 1990, 38, 2003-2007) that amorphous forms exhibit high bioavailability, which makes it suitable for pharmaceutical formulations.
  • Almorexant hydrochloride (50 g) was dissolved in 400 ml of isopropyl alcohol under boiling. Being intensively stirred the solution was cooled down to 60 °C. After inoculation with 0.5 g of form A the product starts to precipitate. Under stirring the suspension was cooled down to 0 °C and stirred for 1 hour. Then, the product was aspirated, washed with 50 ml of ice-cold isopropyl alcohol and dried in a vacuum drier at 30 °C. 45 g (90%) of almorexant hydrochloride, form A, were obtained (confirmed by an XRPD analysis).
  • Almorexant hydrochloride (5 g) was dissolved in a mixture of 20 ml of isopropyl alcohol and 5 ml of ethanol under boiling. Being intensively stirred the solution was cooled down to 60 °C. After inoculation with 0.1 g of form A the product starts to precipitate. Being stirred the suspension was cooled down to 0 °C and stirred for 1 hour. Then, the product was aspirated, washed with 5 ml of ice-cold isopropyl alcohol and dried in a vacuum drier at 30 °C. 4.3 g (86%) of almorexant hydrochloride, form A, were obtained (confirmed with an XRPD analysis).
  • Almorexant hydrochloride (3 g) was dissolved in 20 ml of acetone. Being intensively stirred the solution was cooled down to 60 °C. After inoculation with 0.1 g of form A the product starts to precipitate. Being stirred the suspension was cooled down to 0°C and stirred for 1 hour. Then, the product was aspirated, washed with 3 ml of ice-cold acetone and dried in a vacuum drier at 30 °C. 2.5 g (82%) of almorexant hydrochloride, form A were obtained (confirmed with an XRPD analysis)
  • Almorexant hydrochloride 50 g was dissolved in 300 ml of dichloromethane. The solution was sprayed into the stream of a hot inert gas, whereupon the amorphous particles were settled and isolated (spray drying). 48 g (96%) of amorphous almorexant hydrochloride were obtained (confirmed with an XRPD analysis).
  • Almorexant hydrochloride (3 g) was dissolved in 10 ml of dichloromethane. The solution was sprayed into intensively stirred pentane (100 ml). The precipitate was aspirated, washed with 10 ml of pentane and dried in a vacuum drier. 2.6 g (86%) of amorphous almorexant hydrochloride were obtained (confirmed with an XRPD analysis).
  • DSC analysis the thermogram was obtained with a Pyris 1 DSC Perkin Elmer device. The sample was measured in the temperature range of from 50 to 300 °C with the heat-up rate of 10 °C/min in a nitrogen stream. The measurement was performed in standard Al pans.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Anesthesiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention porte sur des formes cristalline et amorphe du chlorhydrate de (2R)-2-{(1S)-6,7-diméthoxy-1-[2-(4-trifluorométhylphényl)éthyl]-3,4-dihydro-1H-isoquinolin-2-yl}-N-méthyl-2-phénylacétamide (I) (almorexant) et sur leur procédé de préparation.
PCT/CZ2010/000119 2009-11-25 2010-11-24 Formes cristalline et amorphe d'almorexant et leur procédé de préparation Ceased WO2011063773A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ20090791A CZ2009791A3 (cs) 2009-11-25 2009-11-25 Krystalická a amorfní forma hydrochloridu (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-fenyl)-ethyl]-3,4-dihydro-1H-isochinolin-2-yl}-N-methyl-2-fenyl-acetamidu (almorexantu) a zpusob jejich prípravy
CZPV2009-791 2009-11-25

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WO2011063773A2 true WO2011063773A2 (fr) 2011-06-03
WO2011063773A3 WO2011063773A3 (fr) 2012-02-02

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111650330A (zh) * 2020-06-17 2020-09-11 山东非金属材料研究所 一种测定丙烯腈-衣康酸共聚物共聚比的非水滴定法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005118548A1 (fr) 2004-03-01 2005-12-15 Actelion Pharmaceuticals Ltd Derives de 1,2,3,4-tétrahydroisoquinoléine substitués
WO2009083899A2 (fr) 2007-12-28 2009-07-09 Actelion Pharmaceuticals Ltd Procédé de préparation d'un dérivé énantiomère trisubstitué de 3,4-dihydro-isoquinoléine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005118548A1 (fr) 2004-03-01 2005-12-15 Actelion Pharmaceuticals Ltd Derives de 1,2,3,4-tétrahydroisoquinoléine substitués
WO2009083899A2 (fr) 2007-12-28 2009-07-09 Actelion Pharmaceuticals Ltd Procédé de préparation d'un dérivé énantiomère trisubstitué de 3,4-dihydro-isoquinoléine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KONNO T., CHEM. PHARM. BULL., vol. 38, 1990, pages 2003 - 2007

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111650330A (zh) * 2020-06-17 2020-09-11 山东非金属材料研究所 一种测定丙烯腈-衣康酸共聚物共聚比的非水滴定法

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WO2011063773A3 (fr) 2012-02-02

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