WO2010095106A1 - Solid forms of ( 2r) -2- { ( is ) -6, 7 -dimethoxy- 1- [2- (4-triflu0r0methyl-phenyl) -ethyl] -3, 4-dihydr0-1h -isoquinolin-2-yl} -n-methyl-2-phenyl-acetamide hydrochloride - Google Patents

Solid forms of ( 2r) -2- { ( is ) -6, 7 -dimethoxy- 1- [2- (4-triflu0r0methyl-phenyl) -ethyl] -3, 4-dihydr0-1h -isoquinolin-2-yl} -n-methyl-2-phenyl-acetamide hydrochloride Download PDF

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WO2010095106A1
WO2010095106A1 PCT/IB2010/050722 IB2010050722W WO2010095106A1 WO 2010095106 A1 WO2010095106 A1 WO 2010095106A1 IB 2010050722 W IB2010050722 W IB 2010050722W WO 2010095106 A1 WO2010095106 A1 WO 2010095106A1
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crystalline form
phenyl
compound
powder diffraction
ray powder
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PCT/IB2010/050722
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French (fr)
Inventor
Stephan Buchmann
Christoph Imboden
Bernd Siebenhaar
Martin Szelagiewicz
Markus Von Raumer
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Actelion Pharmaceuticals Ltd
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Publication of WO2010095106A1 publication Critical patent/WO2010095106A1/en

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    • 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
    • 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 hydrated crystalline forms of (2R)-2- ⁇ (1 S)-6,7-dimethoxy-1 - 5 [2-(4-thfluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl ⁇ - ⁇ /-methyl-2- phenyl-acetamide hydrochloride (hereinafter also referred to as "COMPOUND”), to the amorphous form of this compound, and to further crystalline forms of this compound, to processes for the preparation thereof, pharmaceutical compositions containing said crystalline forms or said amorphous form, and their use as orexin0 receptor antagonists.
  • 2R -2- ⁇ (1 S)-6,7-dimethoxy-1 - 5 [2-(4-thfluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl ⁇ - ⁇ /-methyl-2- phenyl-acetamide hydrochloride (hereinafter
  • the compound has been shown for example to cross the blood-brain barrier; to show a good systemic bioavailablility; to decrease alertness, characterized by decreases in both active wake and locomotion; and to dose-dependently increase the time spent in both REM and NREM sleep (F.
  • Such advantages may include lower solubility, better thermodynamic stability, defined morphology and better long term stability in high water activity environments, such as pharmaceutical compositions containing a high amount of water such as an aqueous suspension; or also a suspoemulsion, an ointment, a gel, or a cream.
  • a further crystalline form of the COMPOUND obtainable by crystallisation from methanol, was also found. This form is thought to be an advantageous solid for the crystallization process due to its lower solubility in methanol and the respective associated yield increase.
  • the use of methanol as process solvent may in addition have the advantage of increasing the chemical purity.
  • the amorphous form of COMPOUND was also prepared. Advantages of such an amorphous form may include a high solubility or a fast dissolution rate. It may advantageously be used in pharmaceutical compositions in the form of dispersible tablets, i.e. tablets designed to dissolve or disintegrate in water over a very short period of time (e.g. 30 seconds or 1 or 2 minutes).
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensities given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-30° 2theta with relative intensity larger then 10% are reported): 4.67° (28%), 9.38° (100%), 9.81 ° (45%), 11.72° (12%), 11.98° (19.0%), 14.12° (43%), 14.50° (71 %), 14.73° (37.0%), 15.00° (78%), 15.27° (65%), 16.29° (92.0%), 17.97° (27.0%), 18.67° (26%), 18.89° (93%), 19.73° (22.0%), 22.21 ° (91 %), 22
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-30° 2theta with relative intensity larger then 10% are reported): 8.44° (83%), 10.39° (21 %), 11.05° (32%), 11.34° (18%), 13.19° (79%), 14.57° (27%), 15.08° (19%), 15.28° (13%), 16.27° (45%), 16.68° (33%), 17.03° (87%), 19.11 ° (24%), 19.57° (60%), 20.49° (14%), 20.92° (44%), 22.17° (16%), 22.66
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-30° 2theta with relative intensity larger then 10% are reported): 6.29° (22%), 7.68° (20%), 9.14° (28%), 10.68° (25%), 11.66° (15%), 12.10° (31 %), 12.57° (100%), 15.42° (21 %), 16.69° (42%), 18.30° (27%), 18.82° (14%), 18.96° (23%), 19.54° (23%), 21.41 ° (40%), 21.64° (36%), 21.89° (18%), 22.11
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-30° 2theta with relative intensity larger then 10% are reported): 6.85° (49%), 8.97° (32%), 11.68° (18%), 12.42° (48%), 13.31 ° (100%), 13.74° (66%), 14.63° (22%), 15.57° (60%), 16.69° (20%), 17.24° (21 %), 17.95° (65%), 18.89° (21 %), 19.66° (37%), 20.59° (53%), 21.60° (44%), 21.93° (88%), 22.55
  • Figure 5 shows the X-ray powder diffraction diagram of the COMPOUND in a X-ray amorphous Form 5 as obtained from Example 4.
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-30° 2theta with relative intensity larger then 10% are reported): 6.81 ° (16%), 7.54° (32%), 10.60° (28%), 11.41 ° (43%), 12.00° (34%), 12.63° (34%), 13.60° (35%), 15.04° (21 %), 16.06° (100%), 16.84° (24%), 17.42° (24%), 18.06° (11 %), 18.62° (20%), 18.90° (48%), 19.72° (18%), 19.86° (19%), 20.07° (5
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-30° 2theta with relative intensity larger then 10% are reported): 6.4° (16%), 7.3° (15%),
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-20°
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-25° 2theta with relative intensity larger then 10% are reported): 4.6° (62%), 9.2° (100%), 13.8° (28%), 14.4° (25%), 14.6° (18%), 17.7° (13%), 18.4° (12%), and 22.2° (26%).
  • the angle of refraction 2theta (2 ⁇ ) is plotted on the horizontal axis and the counts on the vertical axis.
  • FIG 10 shows the isotherm plot of the gravimetric vapour sorption analysis (GVS) of COMPOUND in anhydrous crystalline Form 1 at 25°C. At 95% RH, the GVS shows a sorption of about 0.3% of moisture after equilibration for 3 hours.
  • VVS gravimetric vapour sorption analysis
  • the present invention relates to a hydrated crystalline form, especially to an essentially pure hydrated crystalline form, of the COMPOUND containing from 0.5 to 5 equivalents of water per equivalent of COMPOUND. ii) In another embodiment, the present invention relates to a hydrated crystalline form according to embodiment i) containing from 1 to 3.5 equivalents of water per equivalent of COMPOUND. iii) In another embodiment, the present invention relates to a hydrated crystalline form according to embodiments i) or ii) containing from 2.5 to 3.5 equivalents of water per equivalent of COMPOUND.
  • the present invention relates to a hydrated crystalline form according to any one of embodiments i) to iii) containing 3 equivalents of water per equivalent of COMPOUND.
  • the present invention relates to a hydrated crystalline form according to any one of embodiments i) to iii), v) or vi), which essentially shows the X-ray diffraction pattern as depicted in Figure 2.
  • the present invention relates to the hydrated crystalline form according to any one of embodiments i) to iii), v), vi) or vii) obtainable by: i) suspending COMPOUND in the anhydrous crystalline Form 1 (1.2 g) in water (4 ml_) at room temperature; ii) sonicating the sample for 2 minutes in a standard sonication bath and stirring with a mechanical stirrer at room temperature for 16 hours, sonicating the sample for 1 minute, stirring with a mechanical stirrer at room temperature for 3 days, and sonicating the sample for 1 minute; iii) filtering off the solid by centhfugation and storing the solid at 92% relative humidity and room temperature.
  • a further object of this invention relates to a pharmaceutical composition containing, as active principle, the COMPOUND in the crystalline form defined in one of embodiments i) to viii), as well as at least one pharmaceutically acceptable excipient.
  • Another embodiment of this invention provides the COMPOUND in a further crystalline form obtainable by crystallisation from methanol.
  • the crystalline form according to embodiment x) will especially be a form essentially showing the X-ray diffraction pattern as depicted in Figure 3.
  • a further object of this invention relates to a pharmaceutical composition containing, as active principle, the COMPOUND in the crystalline form defined in one of embodiments x) to xiii), as well as at least one pharmaceutically acceptable excipient.
  • xv) Another embodiment of this invention provides the COMPOUND in a further crystalline form obtainable by crystallisation from 1 -butanol.
  • the crystalline form according to embodiment xv) will especially be a form essentially showing the X-ray diffraction pattern as depicted in Figure 6.
  • a further object of this invention relates to a pharmaceutical composition containing, as active principle, the COMPOUND in the crystalline form defined in one of embodiments xv) to xviii), as well as at least one pharmaceutically acceptable excipient.
  • Another embodiment of this invention provides the COMPOUND in a further crystalline form obtainable by crystallisation from ethanol.
  • the crystalline form according to embodiment xx) will especially be a form essentially showing the X-ray diffraction pattern as depicted in Figure 8.
  • a further object of this invention relates to a pharmaceutical composition containing, as active principle, the COMPOUND in the crystalline form defined in one of embodiments xx) to xxiii), as well as at least one pharmaceutically acceptable excipient.
  • xxv) Another embodiment of this invention provides the COMPOUND in a further crystalline form obtainable by crystallisation from 1 -propanol.
  • the crystalline form according to embodiment xxv) will especially be a form essentially showing the X-ray diffraction pattern as depicted in Figure 7.
  • a further object of this invention relates to a pharmaceutical composition containing, as active principle, the COMPOUND in the crystalline form defined in one of embodiments xxv) to xxiii), as well as at least one pharmaceutically acceptable excipient.
  • xxx) Yet another embodiment of this invention relates to the COMPOUND in amorphous form.
  • xxxi) A further object of this invention relates to a pharmaceutical composition containing, as active principle, the COMPOUND in the amorphous form defined in embodiment xxx), as well as at least one pharmaceutically acceptable excipient.
  • essentially pure is understood in the context of the present invention to mean especially that at least 90, preferably at least 95, and most preferably at least 99 per cent by weight of the crystals of a COMPOUND are present in a crystalline form according to the present invention, especially in a single crystalline form of the present invention.
  • the term "essentially” means that at least the major peaks of the diagram depicted in said figures, i.e. those having a relative intensity of more than 10%, especially more than 20%, as compared to the most intense peak in the diagram, have to be present.
  • the person skilled in the art of X-ray powder diffraction will recognize that relative intensities in X-ray powder diffraction diagrams may be subject to strong intensity variations due to preferred orientation effects.
  • the term "about” placed before a temperature "Y” refers in the current application to an interval extending from the temperature Y minus 1 O 0 C to Y plus 1 O 0 C, and preferably to an interval extending from Y minus 5 0 C to Y plus 5 0 C.
  • Room temperature means a temperature of about 25 0 C.
  • the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) can be used as medicament, e.g. in the form of a pharmaceutical composition for enteral or parenteral administration.
  • the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) can be used in the form of a pharmaceutical composition comprising the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) and a pharmaceutically acceptable excipient.
  • Such pharmaceutical composition according to embodiment ix) preferably contains a high amount of water.
  • Such pharmaceutical compositions containing a high amount of water are especially an aqueous suspension; or also a suspoemulsion, an ointment, a gel, or a cream.
  • such such pharmaceutical compositions containing a high amount of water, especially aqueous suspensions can be used for a pediatric formulation of the COMPOUND.
  • a drug product in the form of a pharmaceutical composition containing a high amount of water, especially in the form of an aqueous suspension will be more children-friendly.
  • a system containing a high amount of water may be defined as a system containing a sufficient amount of water to result in a high water activity environment.
  • the water activity may be defined as the ratio of the vapour pressure of water in a material, such as a pharmaceutical composition as mentioned before, to the vapour pressure of pure water at the same temperature (in general at a temperature between 0 0 C and 45°C, notably at room temperatur).
  • the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) is especially suitable for the prevention or treatment of a disease or disorder mentioned herein, notably in a pediatric patient population, wherein the COMPOUND is in the form of a pharmaceutical composition containing a high amount of water, especially in the form of an aqueous suspension.
  • the COMPOUND according to any one of embodiments xx) to xxiii); xxv) to xxviii); or according to embodiment xxx) can be used as medicament, e.g. in the form of a pharmaceutical composition for enteral or parenteral administration.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21 st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the crystalline forms of the present invention, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the hydrated crystalline forms of COMPOUND may be used as single component or as mixtures with other crystalline forms or the amorphous form of COMPOUND.
  • Such diseases or disorders which can be treated and/or prevented with the crystalline hydrate forms of the present invention are described for example in WO2005/118548, WO2007/105177 and WO2009/0047723.
  • Particularly preferred diseases or disorders to be treated and/or prevented with the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) are selected from the group consisting of all types of sleep disorders, of stress- related syndromes, of psychoactive substance use, abuse, seeking and reinstatement, of cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders, of eating or drinking disorders.
  • Eating disorders may be defined as comprising metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa.
  • Eating disorders i.e. pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs. expenditure); disturbed perception of food quality (high fat or carbohydrates, high palatability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance.
  • Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake.
  • Sleep disorders include all types of parasomnias, insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
  • Insomnias are defined as comprising sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness.
  • Insomnia also include stress-related syndromes including post-traumatic stress disorders as well as other types and subtypes of anxiety disorders such as generalized anxiety, obsessive compulsive disorder, panic attacks and all types of phobic anxiety and avoidance.
  • Cognitive dysfunctions include deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders.
  • particularly preferred diseases or disorders to be treated and/or prevented with the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) are selected from the group consisting of sleep disorders that comprises all types of insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias, restless leg syndrome, sleep apneas, jet-lag syndrome, shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
  • particularly preferred diseases or disorders to be treated and/or prevented with the COMPOUND in hydrated crystalline form are selected from the group consisting of cognitive dysfunctions that comprise deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders.
  • particularly preferred diseases or disorders to be treated and/or prevented with the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) are selected from the group consisting of eating disorders that comprise metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa.
  • particularly preferred diseases or disorders to be treated and/or prevented with the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) are selected from the group consisting of psychoactive substance use, abuse, seeking and reinstatement that comprise all types of psychological or physical addictions and their related tolerance and dependence components.
  • the present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii).
  • (2R)-2- ⁇ (1 S)-6,7-dimethoxy-1 -[2-(4-thfluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H- isoquinolin-2-yl ⁇ - ⁇ /-methyl-2-phenyl-acetamide hydrochloride in the anhydrous crystalline Form 1 can be prepared for example as described in the published PCT application WO2005/118548 (see in particular Example 2 c), Procedure III).
  • (2R)-2- ⁇ (1 S)-6,7-dimethoxy-1 -[2-(4-thfluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H- isoquinolin-2-yl ⁇ - ⁇ /-methyl-2-phenyl-acetamide free base in the amorphous form can be prepared for example as described in the published PCT application WO2005/118548 (see in particular Example 2 a) or b), Procedure I or II).
  • Method A X-ray powder diffraction patterns were collected on a Bruker D8 Advance X-ray diffractometer equipped with a VANTEC-1 detector using 360 ⁇ 10 active channels operated with CuK a -radiation in reflection mode. Typically, the X-ray tube was run at of 35kV/45mA. A step size of 0.017° (2 ⁇ ) and a step time of 105 ⁇ 5 sec over a scanning range of 2 - 50° in 2 ⁇ were applied. The divergence slit was set to variable V12. The powder was slightly pressed into a silicon single crystal sample holder with depth of 0.1 mm or 1 mm and samples were rotated in their own plane during the measurement. Selected samples were covered with Kapton foil.
  • the background signal has been removed using the instrument evaluation software (EVA), for samples that were covered by Kapton during data acquisition.
  • the accuracy of the 2 ⁇ values as provided herein is in the range of +/- 0.1 -0.2° as it is generally the case for conventionally recorded X-ray powder diffraction patterns.
  • Method B X-ray powder diffraction patterns of Figures 7, 8, and 9 and of samples described in reference examples 11 , 12, 13, 14, and 15 were recorded on a
  • Panalytical Xpert Pro diffractometer equipped with a X'celerator detector operated with CuK ⁇ -radiation in reflection mode. Typically, the X-ray tube was run at
  • a step size of 0.017° (2 ⁇ ) and a step time of 20 sec over a scanning range of 2 - 40° in 2 ⁇ were applied.
  • the powder was slightly pressed into a silicon single crystal sample holder with depth of 0.1 mm or 1 mm and samples were rotated in their own plane during the measurement. Selected samples were covered with
  • Measurements were performed in dynamic mode on a DVS-1 (Surface Measurement System Ltd). The sample was allowed to equilibrate at 50% RH before starting a predefined humidity program (50-0-95-50% RH, scanning with 5% ⁇ RH hour "1 and with 3 hours equilibration periods at 0% and 95% RH.
  • a predefined humidity program 50-0-95-50% RH, scanning with 5% ⁇ RH hour "1 and with 3 hours equilibration periods at 0% and 95% RH.
  • a defined amount of solid was placed in a vial and the solubility was determined by addition of defined aliquots (about 0,1 ml_ or less) of demineralized water until a maximum volume or until all dissolved. In between addition of aliquots the sample was allowed to equilibrate at 25°C and shaking (450 rpm).
  • COMPOUND in crystalline Form 1 is obtained according to the procedure given in Example 2 c), Procedure III, of WO2005/118548. Characterization data for anhydrous crystalline Form 1 are presented in Tables 1 and 2. Table 1 : Characterization data for COMPOUND in anhydrous crystalline Form 1
  • Table 4 Solubility data for COMPOUND in hydrated crystalline Form 2
  • COMPOUND in anhydrous crystalline Form 1 (0.2 g) was suspended in 0.1 ml_ methanol (dried using molecular sieve 3A) at room temperature and the suspension was sonicated for 1 minute at room temperature to yield a very viscous suspension. Additional 0.1 ml_ methanol (dried using molecular sieve 3A) was added and the suspension was stirred at room temperature for 3 days. The paste-like sample was analyzed XRPD without drying of the sample. The XRPD sample holder was covered with a Kapton foil during measurement. The product was COMPOUND in crystalline Form 3.
  • COMPOUND in crystalline Form 3 was stored for 2 days at 20mbar and room temperature and the so obtained solid was COMPOUND in crystalline Form 4.
  • COMPOUND in anhydrous crystalline Form 1 (0.09 g) was dissolved in 5.0 ml_ of a dichloromethane:heptane 1 :1 v/v mixture at room temperature. The solution was filtered and the solution was evaporated overnight to dryness at room temperature in a dry nitrogen flow. The solid residue was COMPOUND in Form 5.
  • Form 5 is X-ray amorphous. ( Figure 5).
  • COMPOUND in anhydrous crystalline Form 1 (0.200 g) was suspended in 1 - propanol/nitromethane (4:1 , 4ml), stirred at 25°C for four hours and then filtered to obtain a clear solution. The solvent was allowed to evaporate in a centrifugal evaporator until most of the solvent was removed. The so obtained solid was COMPOUND in crystalline Form 6.
  • COMPOUND in crystalline Form 6 may be generated as follows:
  • COMPOUND in anhydrous crystalline Form 1 (0.196 g) was dissolved in 1.4 ml_ 1 - propanol (dried using molecular sieve 3A) at 50 0 C. The solution and was cooled to 0 0 C by placing the container in an ice bath. The mixture was stirred during the whole operation. After a total of 23 minutes the solid material was isolated by filtration and was air dried for ca. 10 minutes. The so obtained solid was COMPOUND a mixture of anhydrous crystalline Form 1 and crystalline Form 6.
  • COMPOUND in anhydrous crystalline Form 1 (0.100 g) was suspended in ethanol (1 ml), stirred at room temperature overnight and then filtered to obtain a clear solution. The solvent was allowed to evaporate until almost all evaporated at ambient while magnetic bar stirring. The so obtained solid in the residual solvent was COMPOUND in crystalline Form 10.
  • COMPOUND in hydrated crystalline Form 2 was submitted to a varying RH experiment at 25°C. After equilibration at 95% RH the relative humidity was decreased at a rate of 5%RH per hour until 0% RH, keeping the sample at 0%RH for 5 hours and scanning the humidity at the same rate back to 95%RH, staying there for 10 hours and scanning the RH at the same rate back down to 50%RH.
  • the so obtained solid was COMPOUND a mixture of anhydrous crystalline Form 1 and crystalline Form 7.
  • COMPOUND in anhydrous crystalline Form 1 (0.1 g) was dissolved in 3.0 ml_ 1 - propanol at room temperature. The solvent was evaporated within 60 minutes at 50°C and ca. 50 mbar. The so obtained solid was COMPOUND in a mixture of anhydrous crystalline Form 1 and crystalline Form 8.
  • COMPOUND in anhydrous crystalline Form 1 (0.264 g) was weighed into a 20-mL vial. P-xylene (2.OmL) was added, and the mixture was stirred and thermocycled between 5°C-40°C (in four hour cycles) for two days. The resulting wet-cake was rapidly isolated using only a two minute vacuum filtration on a B ⁇ chner funnel. The so obtained solid was COMPOUND crystalline Form 12.
  • COMPOUND in anhydrous crystalline Form 1 (6.1 g) was weighed into a 250-mL round bottom flask, methyl acetate (122.OmL) was added and the mixture was vortexed for one minute to disperse the particles. The slurry was stirred at 25°C for two days. The resulting white solid was isolated by filtration on a B ⁇ chner funnel. The wet cake consists of COMPOUND in crystalline Form 14.
  • COMPOUND in its amorphous form (0.2g) was suspended in 1 ,4-dioxane/carbon disulfide mixture (1 :4, 3ml) and stirred at 5°C for 1 day. The solid was quickly isolated by vacuum filtration.. The wet cake was COMPOUND in crystalline Form 15.
  • COMPOUND in anhydrous crystalline Form 1 (0.1 g) was suspended in tetrahydrofuran (1 ml) at room temperature overnight. The suspension was filtered to obtain a clear solution. The solution was then allowed to evaporate while being stirred. The so obtained wet solid was COMPOUND in crystalline Form 16.

Abstract

The invention relates to hydrated crystalline forms of (2R)-2-{(1 S)-6,7-dimethoxy-1 - [2-(4-thfluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2- phenyl-acetamide hydrochloride, to the amorphous form of this compound, and to further crystalline forms of this compound, to processes for the preparation thereof, pharmaceutical compositions containing said crystalline forms or said amorphous form, and their use as orexin receptor antagonists.

Description

SOLID FORMS OF
( 2R) -2- { ( IS ) -6 , 7 -DIMETHOXY- 1- [2- U-TRIFLUOROMETHYL-PHENYL) -ETHYL] -3 , 4-DIHYDRO-1H -ISOQUINOLIN-2-YL} -N-METHYL-2-PHENYL-ACETAMIDE HYDROCHLORIDE
The invention relates to hydrated crystalline forms of (2R)-2-{(1 S)-6,7-dimethoxy-1 - 5 [2-(4-thfluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2- phenyl-acetamide hydrochloride (hereinafter also referred to as "COMPOUND"), to the amorphous form of this compound, and to further crystalline forms of this compound, to processes for the preparation thereof, pharmaceutical compositions containing said crystalline forms or said amorphous form, and their use as orexin0 receptor antagonists.
Background of the Invention
The preparation of (2R)-2-{(1 S)-6,7-dimethoxy-1 -[2-(4-thfluoromethyl-phenyl)-ethyl]- 3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2-phenyl-acetamide, its hydrochloride (COMPOUND in anhydrous crystalline Form 1 ), and the medicinal use thereof, is5 described in WO2005/118548, WO2007/105177 and WO2009/0047723. In the rat, the compound has been shown for example to cross the blood-brain barrier; to show a good systemic bioavailablility; to decrease alertness, characterized by decreases in both active wake and locomotion; and to dose-dependently increase the time spent in both REM and NREM sleep (F. Jenck et al., Nature Medicine 2007, 13, 150-155).0 It has now been surprisingly found that hydrated crystalline forms of (2R)-2-{(1S)-6,7- dimethoxy-1 -[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-/V- methyl-2-phenyl-acetamide hydrochloride may under certain conditions be found, said hydrated crystalline forms having advantageous properties, especially compared to the anhydrous crystalline Form 1 of COMPOUND as disclosed in5 WO2005/118548. Such advantages may include lower solubility, better thermodynamic stability, defined morphology and better long term stability in high water activity environments, such as pharmaceutical compositions containing a high amount of water such as an aqueous suspension; or also a suspoemulsion, an ointment, a gel, or a cream. 0 Besides, a further crystalline form of the COMPOUND, obtainable by crystallisation from methanol, was also found. This form is thought to be an advantageous solid for the crystallization process due to its lower solubility in methanol and the respective associated yield increase. Besides, the use of methanol as process solvent may in addition have the advantage of increasing the chemical purity.
Besides, a further crystalline form of the COMPOUND, obtainable by crystallisation from ethanol, was also found. This form is thought to be an advantageous solid for the crystallization process due to its lower solubility in ethanol and the respective associated yield increase. Besides, the use of ethanol as process solvent may in addition have the advantage of increasing the chemical purity. The form may also be advantageous for certain specific formulations where the presence of an aliphatic aclohol is beneficial. Besides, a further crystalline form of the COMPOUND, obtainable by crystallisation from 1 -propanol, was also found. This form is thought to be an advantageous solid for the crystallization process due to its lower solubility in 1-propanol and the respective associated yield increase. Besides, the use of 1 -propanol as process solvent may in addition have the advantage of increasing the chemical purity. The form may also be advantageous for certain specific formulations where the presence of an aliphatic aclohol is beneficial.
Besides, a further crystalline form of the COMPOUND, obtainable by crystallisation from 1 -butanol, was also found. This form is thought to be an advantageous solid for the crystallization process due to its lower solubility in 1 -butanol and the respective associated yield increase. Besides, the use of 1 -butanol as process solvent may in addition have the advantage of increasing the chemical purity.
Furthermore, the amorphous form of COMPOUND was also prepared. Advantages of such an amorphous form may include a high solubility or a fast dissolution rate. It may advantageously be used in pharmaceutical compositions in the form of dispersible tablets, i.e. tablets designed to dissolve or disintegrate in water over a very short period of time (e.g. 30 seconds or 1 or 2 minutes).
Description of the Figures
Figure 1 shows the X-ray powder diffraction diagram of the COMPOUND in the anhydrous crystalline Form 1 , wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). The X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensities given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-30° 2theta with relative intensity larger then 10% are reported): 4.67° (28%), 9.38° (100%), 9.81 ° (45%), 11.72° (12%), 11.98° (19.0%), 14.12° (43%), 14.50° (71 %), 14.73° (37.0%), 15.00° (78%), 15.27° (65%), 16.29° (92.0%), 17.97° (27.0%), 18.67° (26%), 18.89° (93%), 19.73° (22.0%), 22.21 ° (91 %), 22.64° (61 %), 23.20° (68%), 23.60° (20%), 23.94° (12%), 24.30° (45%), 25.26° (67%), 25.77° (19%), 26.07° (30%), 26.44° (14%), 27.98° (12%), 29.46° (20%), and 29.88° (26%).
Figure 2 shows the X-ray powder diffraction diagram of the COMPOUND in hydrated crystalline Form 2 as obtained from Example 1 , wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). The X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-30° 2theta with relative intensity larger then 10% are reported): 8.44° (83%), 10.39° (21 %), 11.05° (32%), 11.34° (18%), 13.19° (79%), 14.57° (27%), 15.08° (19%), 15.28° (13%), 16.27° (45%), 16.68° (33%), 17.03° (87%), 19.11 ° (24%), 19.57° (60%), 20.49° (14%), 20.92° (44%), 22.17° (16%), 22.66° (94%), 23.27° (100%), 23.52° (95%), 24.67° (71 %), 25.03° (96%), 26.11 ° (28%), 26.50° (28%), 26.91 ° (11 %), 28.44° (12%) and 29.38° (39%). Figure 3 shows the X-ray powder diffraction diagram of the COMPOUND in a crystalline Form 3 as obtained from Example 2, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). The X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-30° 2theta with relative intensity larger then 10% are reported): 6.29° (22%), 7.68° (20%), 9.14° (28%), 10.68° (25%), 11.66° (15%), 12.10° (31 %), 12.57° (100%), 15.42° (21 %), 16.69° (42%), 18.30° (27%), 18.82° (14%), 18.96° (23%), 19.54° (23%), 21.41 ° (40%), 21.64° (36%), 21.89° (18%), 22.11 ° (12%), 22.83° (34%), 23.02° (18%), 24.12° (32%), 24.34° (37%), 24.99° (13%), 25.28° (91 %), 25.48° (38%),and 29.99° (12%).
Figure 4 shows the X-ray powder diffraction diagram of the COMPOUND in a crystalline Form 4 as obtained from Example 3, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). The X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-30° 2theta with relative intensity larger then 10% are reported): 6.85° (49%), 8.97° (32%), 11.68° (18%), 12.42° (48%), 13.31 ° (100%), 13.74° (66%), 14.63° (22%), 15.57° (60%), 16.69° (20%), 17.24° (21 %), 17.95° (65%), 18.89° (21 %), 19.66° (37%), 20.59° (53%), 21.60° (44%), 21.93° (88%), 22.55° (40%), 23.89° (37%), 24.99° (24%), 25.50° (29%), 26.68° (32%), 27.45° (35%), and 28.68° (15%).
Figure 5 shows the X-ray powder diffraction diagram of the COMPOUND in a X-ray amorphous Form 5 as obtained from Example 4.
Figure 6 shows the X-ray powder diffraction diagram of the COMPOUND in a crystalline Form 9 as obtained from Example 5, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). The X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-30° 2theta with relative intensity larger then 10% are reported): 6.81 ° (16%), 7.54° (32%), 10.60° (28%), 11.41 ° (43%), 12.00° (34%), 12.63° (34%), 13.60° (35%), 15.04° (21 %), 16.06° (100%), 16.84° (24%), 17.42° (24%), 18.06° (11 %), 18.62° (20%), 18.90° (48%), 19.72° (18%), 19.86° (19%), 20.07° (56%), 20.46° (26%), 21 .02° (66%), 21.35° (54%), 22.07° (62%), 22.75° (68%), 23.60° (51 %), 24.16° (56%), 24.86° (79%), 25.14° (31 %), 25.44° (14%), 25.63° (15%), 25.98° (35%), 27.36° (56%), and 28.65° (16%).
Figure 7 shows the X-ray powder diffraction diagram of the COMPOUND in a crystalline Form 6 as obtained from Example 6, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). The X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-30° 2theta with relative intensity larger then 10% are reported): 6.4° (16%), 7.3° (15%),
9.1 ° (16%), 1 1.3° (63%), 12.0° (42%), 12.2° (32%), 12.5° (23%), 12.9° (81 %), 16.3°
(92%), 16.8° (40%), 18.2° (34%), 18.8° (34%), 19.7° (79%), 20.7° (41 %), 21 .8° (66%), 22.3° (93%), 24.8° (50%), 25.2° (100%), 26.1 ° (52%), 26.5° (58%), and 26.9° (34%).
Figure 8 shows the X-ray powder diffraction diagram of the COMPOUND in a crystalline Form 10 as obtained from Example 7, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). The X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-20°
2theta with relative intensity larger then 10% are reported): 6.4° (46%), 7.3° (22%), 9.0° (30%), 1 1 .2° (28%), 1 1.4° (30%), 12.8° (100%), 13.0° (74%), 16.4° (43%), 18.1 °
(33%), and 18.3° (40%).
Figure 9 shows the X-ray powder diffraction diagram of the COMPOUND in a crystalline Form 11 as obtained from Example 8, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). The X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (peaks from the range 2-25° 2theta with relative intensity larger then 10% are reported): 4.6° (62%), 9.2° (100%), 13.8° (28%), 14.4° (25%), 14.6° (18%), 17.7° (13%), 18.4° (12%), and 22.2° (26%). In the X-ray diffraction diagrams of Figures 1 to 9 the angle of refraction 2theta (2Θ) is plotted on the horizontal axis and the counts on the vertical axis.
Figure 10 shows the isotherm plot of the gravimetric vapour sorption analysis (GVS) of COMPOUND in anhydrous crystalline Form 1 at 25°C. At 95% RH, the GVS shows a sorption of about 0.3% of moisture after equilibration for 3 hours.
Detailed Description of the Invention i) The present invention relates to a hydrated crystalline form, especially to an essentially pure hydrated crystalline form, of the COMPOUND containing from 0.5 to 5 equivalents of water per equivalent of COMPOUND. ii) In another embodiment, the present invention relates to a hydrated crystalline form according to embodiment i) containing from 1 to 3.5 equivalents of water per equivalent of COMPOUND. iii) In another embodiment, the present invention relates to a hydrated crystalline form according to embodiments i) or ii) containing from 2.5 to 3.5 equivalents of water per equivalent of COMPOUND. iv) In another embodiment, the present invention relates to a hydrated crystalline form according to any one of embodiments i) to iii) containing 3 equivalents of water per equivalent of COMPOUND. v) In another embodiment, the present invention relates to a hydrated crystalline form according to any one of embodiments i) to iv), characterized by the presence of a peak in the X-ray diffraction diagram at an angle of refraction 2theta of 8.4°, 13.2°, and 17.0°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). vi) In another embodiment, the present invention relates to a hydrated crystalline form according to any one of embodiments i) to iv) characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 8.4°, 10.4°, 11.1 °, 11.3°, 13.2°, 16.3°, 16.7°, 17.0°, and 19.6°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). vii) In another embodiment, the present invention relates to a hydrated crystalline form according to any one of embodiments i) to iii), v) or vi), which essentially shows the X-ray diffraction pattern as depicted in Figure 2. viii) In another embodiment the present invention relates to the hydrated crystalline form according to any one of embodiments i) to iii), v), vi) or vii) obtainable by: i) suspending COMPOUND in the anhydrous crystalline Form 1 (1.2 g) in water (4 ml_) at room temperature; ii) sonicating the sample for 2 minutes in a standard sonication bath and stirring with a mechanical stirrer at room temperature for 16 hours, sonicating the sample for 1 minute, stirring with a mechanical stirrer at room temperature for 3 days, and sonicating the sample for 1 minute; iii) filtering off the solid by centhfugation and storing the solid at 92% relative humidity and room temperature. ix) A further object of this invention relates to a pharmaceutical composition containing, as active principle, the COMPOUND in the crystalline form defined in one of embodiments i) to viii), as well as at least one pharmaceutically acceptable excipient. x) Another embodiment of this invention provides the COMPOUND in a further crystalline form obtainable by crystallisation from methanol. xi) In particular, the crystalline form according to embodiment x) will be characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 6.3°, 7.7°, and 10.7°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). xii) More particularly, the crystalline form according to embodiment x) will be characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 6.3°, 7.7°, 10.7°, 12.1 °, 12.6, 16.7°, 21.4°, and 25.3°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). xiii) The crystalline form according to embodiment x) will especially be a form essentially showing the X-ray diffraction pattern as depicted in Figure 3. xiv) A further object of this invention relates to a pharmaceutical composition containing, as active principle, the COMPOUND in the crystalline form defined in one of embodiments x) to xiii), as well as at least one pharmaceutically acceptable excipient. xv) Another embodiment of this invention provides the COMPOUND in a further crystalline form obtainable by crystallisation from 1 -butanol. xvi) In particular, the crystalline form according to embodiment xv) will be characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 7.5°, 16.1 °, and 27.4°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). xvii) More particularly, the crystalline form according to embodiment xv) will be characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 7.5°, 11 ,4°, 13.6°, 16.1 °, 22.1 °, and 27.4°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). xviii) The crystalline form according to embodiment xv) will especially be a form essentially showing the X-ray diffraction pattern as depicted in Figure 6. xix) A further object of this invention relates to a pharmaceutical composition containing, as active principle, the COMPOUND in the crystalline form defined in one of embodiments xv) to xviii), as well as at least one pharmaceutically acceptable excipient. xx) Another embodiment of this invention provides the COMPOUND in a further crystalline form obtainable by crystallisation from ethanol. xxi) In particular, the crystalline form according to embodiment xx) will be characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 6.4°, 12.8°, and 13.0°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). xxii) More particularly, the crystalline form according to embodiment xx) will be characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 6.4°, 7.3°, 9.0°, 12.8°, 13.0, 16.4°, 18.1 °, and 18.3°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). xxiii) The crystalline form according to embodiment xx) will especially be a form essentially showing the X-ray diffraction pattern as depicted in Figure 8. xxiv) A further object of this invention relates to a pharmaceutical composition containing, as active principle, the COMPOUND in the crystalline form defined in one of embodiments xx) to xxiii), as well as at least one pharmaceutically acceptable excipient. xxv) Another embodiment of this invention provides the COMPOUND in a further crystalline form obtainable by crystallisation from 1 -propanol. xxvi) In particular, the crystalline form according to embodiment xxv) will be characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 9.1 °, 11.3°, and 12.9°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). xxvii) More particularly, the crystalline form according to embodiment xxv) will be characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 6.4°, 7.3°, 9.1 °, 11.3°, 12.9°, 16.3°, 19.7°, and 25.2°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). xxviii) The crystalline form according to embodiment xxv) will especially be a form essentially showing the X-ray diffraction pattern as depicted in Figure 7. xxix) A further object of this invention relates to a pharmaceutical composition containing, as active principle, the COMPOUND in the crystalline form defined in one of embodiments xxv) to xxiii), as well as at least one pharmaceutically acceptable excipient. xxx) Yet another embodiment of this invention relates to the COMPOUND in amorphous form. xxxi) A further object of this invention relates to a pharmaceutical composition containing, as active principle, the COMPOUND in the amorphous form defined in embodiment xxx), as well as at least one pharmaceutically acceptable excipient. The term "essentially pure" is understood in the context of the present invention to mean especially that at least 90, preferably at least 95, and most preferably at least 99 per cent by weight of the crystals of a COMPOUND are present in a crystalline form according to the present invention, especially in a single crystalline form of the present invention. When defining the presence of peak in e.g. an X-ray powder diffraction diagram, a common approach is to do this in terms of the S/N ratio (S = signal, N = noise). According to this definition, when stating that a peak has to be present in an X-ray powder diffraction diagram, it is understood that the peak in the X-ray powder diffraction diagram is defined by having an S/N ratio (S = signal, N = noise) of greater than x (x being a numerical value greater than 1 ), usually greater than 2, especially greater than 3.
In the context with stating that the crystalline form essentially shows an X-ray powder diffraction pattern as depicted in Figure 1 and Figure 2, respectively, the term "essentially" means that at least the major peaks of the diagram depicted in said figures, i.e. those having a relative intensity of more than 10%, especially more than 20%, as compared to the most intense peak in the diagram, have to be present. However, the person skilled in the art of X-ray powder diffraction will recognize that relative intensities in X-ray powder diffraction diagrams may be subject to strong intensity variations due to preferred orientation effects. When specifying an angle of refraction 2theta (2Θ) for a peak in the invention embodiments and the claims, it should be understood that the value given is to be understood as an interval from said value minus 0.2° to said value plus 0.2°, and preferably from said value minus 0.1 ° to said value plus 0.1 °. Unless used regarding temperatures, the term "about" placed before a numerical value "X" refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term "about" placed before a temperature "Y" refers in the current application to an interval extending from the temperature Y minus 1 O 0C to Y plus 1 O 0C, and preferably to an interval extending from Y minus 5 0C to Y plus 5 0C. Room temperature means a temperature of about 25 0C.
The COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) can be used as medicament, e.g. in the form of a pharmaceutical composition for enteral or parenteral administration.
Especially, the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) can be used in the form of a pharmaceutical composition comprising the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) and a pharmaceutically acceptable excipient. Such pharmaceutical composition according to embodiment ix) preferably contains a high amount of water. Examples of such pharmaceutical compositions containing a high amount of water are especially an aqueous suspension; or also a suspoemulsion, an ointment, a gel, or a cream. Notably, such such pharmaceutical compositions containing a high amount of water, especially aqueous suspensions, can be used for a pediatric formulation of the COMPOUND. Children have difficulties in taking tablets, thus a standard tablet formulation is not convenient for administration to children. A drug product in the form of a pharmaceutical composition containing a high amount of water, especially in the form of an aqueous suspension will be more children-friendly. A system containing a high amount of water may be defined as a system containing a sufficient amount of water to result in a high water activity environment. The water activity may be defined as the ratio of the vapour pressure of water in a material, such as a pharmaceutical composition as mentioned before, to the vapour pressure of pure water at the same temperature (in general at a temperature between 00C and 45°C, notably at room temperatur). Within the scope of this invention, systems having a water activity of at least 0.8, notably of at least 0.9, are considered as high water activity environments (it being understood that said ratio may not be greater than 1 ). Thus, the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) is especially suitable for the prevention or treatment of a disease or disorder mentioned herein, notably in a pediatric patient population, wherein the COMPOUND is in the form of a pharmaceutical composition containing a high amount of water, especially in the form of an aqueous suspension.
In another embodiment, the COMPOUND according to any one of embodiments xx) to xxiii); xxv) to xxviii); or according to embodiment xxx) can be used as medicament, e.g. in the form of a pharmaceutical composition for enteral or parenteral administration. The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21 st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by bringing the crystalline forms of the present invention, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
The hydrated crystalline forms of COMPOUND may be used as single component or as mixtures with other crystalline forms or the amorphous form of COMPOUND. Such diseases or disorders which can be treated and/or prevented with the crystalline hydrate forms of the present invention are described for example in WO2005/118548, WO2007/105177 and WO2009/0047723.
Particularly preferred diseases or disorders to be treated and/or prevented with the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) are selected from the group consisting of all types of sleep disorders, of stress- related syndromes, of psychoactive substance use, abuse, seeking and reinstatement, of cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders, of eating or drinking disorders.
Eating disorders may be defined as comprising metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa. Eating disorders, i.e. pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs. expenditure); disturbed perception of food quality (high fat or carbohydrates, high palatability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance. Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake. Sleep disorders include all types of parasomnias, insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders. Insomnias are defined as comprising sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness. Insomnia also include stress-related syndromes including post-traumatic stress disorders as well as other types and subtypes of anxiety disorders such as generalized anxiety, obsessive compulsive disorder, panic attacks and all types of phobic anxiety and avoidance. Psychoactive substance use, abuse, seeking and reinstatement are defined as all types of psychological or physical addictions and their related tolerance and dependence components. Cognitive dysfunctions include deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders. In another embodiment, particularly preferred diseases or disorders to be treated and/or prevented with the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) are selected from the group consisting of sleep disorders that comprises all types of insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias, restless leg syndrome, sleep apneas, jet-lag syndrome, shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
In another embodiment, particularly preferred diseases or disorders to be treated and/or prevented with the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) are selected from the group consisting of cognitive dysfunctions that comprise deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders. In another embodiment, particularly preferred diseases or disorders to be treated and/or prevented with the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) are selected from the group consisting of eating disorders that comprise metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa.
In another embodiment, particularly preferred diseases or disorders to be treated and/or prevented with the COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii) are selected from the group consisting of psychoactive substance use, abuse, seeking and reinstatement that comprise all types of psychological or physical addictions and their related tolerance and dependence components.
The present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of COMPOUND in hydrated crystalline form according to any one of embodiments i) to viii).
(2R)-2-{(1 S)-6,7-dimethoxy-1 -[2-(4-thfluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H- isoquinolin-2-yl}-Λ/-methyl-2-phenyl-acetamide hydrochloride in the anhydrous crystalline Form 1 can be prepared for example as described in the published PCT application WO2005/118548 (see in particular Example 2 c), Procedure III). (2R)-2-{(1 S)-6,7-dimethoxy-1 -[2-(4-thfluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H- isoquinolin-2-yl}-Λ/-methyl-2-phenyl-acetamide free base in the amorphous form can be prepared for example as described in the published PCT application WO2005/118548 (see in particular Example 2 a) or b), Procedure I or II).
Experimental Part
The following Examples illustrate the invention in more detail. Temperatures are given in degrees Celsius. If not stated otherwise percentages are given by weight.
Abbreviations as used herein: ca. about GVS Gravimetric vapour sorption
1H-NMR hydrogen-1 nuclear magnetic resonance
RH relative humidity rt room temperature rpm rotations per minute
XRPD X-ray powder diffraction
X-rav powder diffraction analysis
Method A: X-ray powder diffraction patterns were collected on a Bruker D8 Advance X-ray diffractometer equipped with a VANTEC-1 detector using 360±10 active channels operated with CuKa-radiation in reflection mode. Typically, the X-ray tube was run at of 35kV/45mA. A step size of 0.017° (2Θ) and a step time of 105±5 sec over a scanning range of 2 - 50° in 2Θ were applied. The divergence slit was set to variable V12. The powder was slightly pressed into a silicon single crystal sample holder with depth of 0.1 mm or 1 mm and samples were rotated in their own plane during the measurement. Selected samples were covered with Kapton foil. Diffraction data are reported using Cu Kα1 (wavelength λ = 1.5406 A), after the Kα2 component has been stripped using the instrument evaluation software (EVA). In addition, the background signal has been removed using the instrument evaluation software (EVA), for samples that were covered by Kapton during data acquisition. The accuracy of the 2Θ values as provided herein is in the range of +/- 0.1 -0.2° as it is generally the case for conventionally recorded X-ray powder diffraction patterns.
If not indicated explicitly XRPDs are recorded using Method A.
Method B: X-ray powder diffraction patterns of Figures 7, 8, and 9 and of samples described in reference examples 11 , 12, 13, 14, and 15 were recorded on a
Panalytical Xpert Pro diffractometer equipped with a X'celerator detector operated with CuKα-radiation in reflection mode. Typically, the X-ray tube was run at
45kV/40mA. A step size of 0.017° (2Θ) and a step time of 20 sec over a scanning range of 2 - 40° in 2Θ were applied. The powder was slightly pressed into a silicon single crystal sample holder with depth of 0.1 mm or 1 mm and samples were rotated in their own plane during the measurement. Selected samples were covered with
Kapton foil. Diffraction data are reported using Cu Kα1 (wavelength λ = 1.5406 A) without background correction. The accuracy of the 2Θ values as provided herein is in the range of +/- 0.1 -0.2° as it is generally the case for conventionally recorded X-ray powder diffraction patterns. Gravimetric vapour sorption analysis
Measurements were performed in dynamic mode on a DVS-1 (Surface Measurement System Ltd). The sample was allowed to equilibrate at 50% RH before starting a predefined humidity program (50-0-95-50% RH, scanning with 5% ΔRH hour"1 and with 3 hours equilibration periods at 0% and 95% RH.
Aqueous solubility
A defined amount of solid was placed in a vial and the solubility was determined by addition of defined aliquots (about 0,1 ml_ or less) of demineralized water until a maximum volume or until all dissolved. In between addition of aliquots the sample was allowed to equilibrate at 25°C and shaking (450 rpm).
Characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)- ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-/V-methyl-2-phenyl-acetamide hydrochloride in the anhydrous crystalline Form 1
COMPOUND in crystalline Form 1 is obtained according to the procedure given in Example 2 c), Procedure III, of WO2005/118548. Characterization data for anhydrous crystalline Form 1 are presented in Tables 1 and 2. Table 1 : Characterization data for COMPOUND in anhydrous crystalline Form 1
Figure imgf000016_0001
Table 2: Solubility data for COMPOUND in anhydrous crystalline Form 1
Figure imgf000016_0002
Example 1 :
Generation and characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2- phenyl-acetamide hydrochloride in hydrated crystalline Form 2 COMPOUND in anhydrous crystalline Form 1 (1.2 g) was suspended in 4.0 ml_ water at room temperature, sonicated for 2 minutes in a standard sonication bath and stirred for 16 hours at room temperature. The easily stirrable suspension was again sonicated for 1 minute, stirred for 3 days at room temperature, sonicated for 1 minute and isolated by filter centrifugation. The product is stored at 92% relative humidity and room temperature. A sample of the solid product was analysed by XRPD. The product was COMPOUND in hydrated crystalline Form 2. Characterization data for COMPOUND in hydrated crystalline Form 2 are presented in Tables 3 and 4.
Table 3: Characterization data for COMPOUND in hydrated crystalline Form 2
Figure imgf000017_0001
Form 2 is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 8.44°, 10.39°, 11.05°, 11.34°, 13.19°, 16.27°, 16.68°, 17.03°, and 19.57° and in particular by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 8.44°, 13.19°, and 17.03°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). (Figure 2). Table 4: Solubility data for COMPOUND in hydrated crystalline Form 2
Figure imgf000017_0002
Example 2: Generation and characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2- phenyl-acetamide hydrochloride in crystalline Form 3
COMPOUND in anhydrous crystalline Form 1 (0.2 g) was suspended in 0.1 ml_ methanol (dried using molecular sieve 3A) at room temperature and the suspension was sonicated for 1 minute at room temperature to yield a very viscous suspension. Additional 0.1 ml_ methanol (dried using molecular sieve 3A) was added and the suspension was stirred at room temperature for 3 days. The paste-like sample was analyzed XRPD without drying of the sample. The XRPD sample holder was covered with a Kapton foil during measurement. The product was COMPOUND in crystalline Form 3. Form 3 is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 6.29°, 7.68°, 10.68°, 12.10°, 12.57, 16.69°, 21.41 °, and 25.28°, and in particular by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 6.29°, 7.68°, and 10.68°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). (Figure 3).
Example 3:
Generation and characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2- phenyl-acetamide hydrochloride in crystalline Form 4
COMPOUND in crystalline Form 3 was stored for 2 days at 20mbar and room temperature and the so obtained solid was COMPOUND in crystalline Form 4. Form 4 is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 6.85°, 8.97°, 13.31 °, 13.74°, 15.57°, and 21.93°, and more preferred by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 6.85°, 13.74°, and 15.57°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). (Figure 4).
Example 4: Generation and characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2- phenyl-acetamide hydrochloride in Form 5
COMPOUND in anhydrous crystalline Form 1 (0.09 g) was dissolved in 5.0 ml_ of a dichloromethane:heptane 1 :1 v/v mixture at room temperature. The solution was filtered and the solution was evaporated overnight to dryness at room temperature in a dry nitrogen flow. The solid residue was COMPOUND in Form 5. Form 5 is X-ray amorphous. (Figure 5).
Example 5: Generation and characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2- phenyl-acetamide hydrochloride in crystalline Form 9
(2R)-2-{(1 S)-6,7-dimethoxy-1 -[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H- isoquinolin-2-yl}-/V-methyl-2-phenyl-acetamide in amorphous form is obtained according to the procedure given in Example 2 a) , Procedure I or Example 2 b), Procedure II, of WO2005/118548. 311 mg of (2R)-2-{(1 S)-6,7-dimethoxy-1 -[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2-phenyl- acetamide as amorphous free base were dissolved in 3.0 ml acetonitrile (dried) and 0.223 ml HCI (in 1 -butanol, approx. 3M) was added and the solvent was evaporated in 17 hours at room temperature using dry nitrogen flow. 35 mg of solid material was obtained and 125 mg of COMPOUND in Form 1 were then suspended in 0.7 ml 1- butanol (dried), sonicated for approx. 1 minute and stirred for 10 minutes at room temperature. An additional 0.2 ml 1 -butanol was added, sonicated for approx. 1 minute, stirred for 21 hours at room temperature and centrifuged. 72 mg of the sample were vacuum dried for 3 hours starting at approx. minus 500C and rising to room temperature. The product was COMPOUND in crystalline Form 9. Form 9 is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 7.54°, 11 ,41 °, 13.60°, 16.06°, 22.07°, and 27.36°, and in particular by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 7.54°, 16.06°, and 27.36°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). (Figure 6).
Example 6: Generation and characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-/V-methyl-2- phenyl-acetamide hydrochloride in crystalline Form 6
COMPOUND in anhydrous crystalline Form 1 (0.200 g) was suspended in 1 - propanol/nitromethane (4:1 , 4ml), stirred at 25°C for four hours and then filtered to obtain a clear solution. The solvent was allowed to evaporate in a centrifugal evaporator until most of the solvent was removed. The so obtained solid was COMPOUND in crystalline Form 6. Form 6 is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 6.4°, 7.3°, 9.1 °, 11.3°, 12.9°, 16.3°, 19.7°, and 25.2°, and more preferred by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 9.1 °, 11.3°, and 12.9° wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). (Figure 7, Method B). Alternatively, COMPOUND in crystalline Form 6 may be generated as follows:
COMPOUND in anhydrous crystalline Form 1 (0.196 g) was dissolved in 1.4 ml_ 1 - propanol (dried using molecular sieve 3A) at 500C. The solution and was cooled to 00C by placing the container in an ice bath. The mixture was stirred during the whole operation. After a total of 23 minutes the solid material was isolated by filtration and was air dried for ca. 10 minutes. The so obtained solid was COMPOUND a mixture of anhydrous crystalline Form 1 and crystalline Form 6.
Example 7:
Generation and characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-/V-methyl-2- phenyl-acetamide hydrochloride in crystalline Form 10
COMPOUND in anhydrous crystalline Form 1 (0.100 g) was suspended in ethanol (1 ml), stirred at room temperature overnight and then filtered to obtain a clear solution. The solvent was allowed to evaporate until almost all evaporated at ambient while magnetic bar stirring. The so obtained solid in the residual solvent was COMPOUND in crystalline Form 10. Form 10 is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 6.4°, 7.3°, 9.0°, 12.8°, 13.0, 16.4°, 18.1 °, and 18.3°, and more preferred by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 6.4°, 12.8°, and 13.0° wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). (Figure 8, Method B).
Example 8:
Generation and characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2- phenyl-acetamide hydrochloride in crystalline Form 11 COMPOUND in anhydrous crystalline Form 1 (6.1 g) was weighed into a 250-mL round bottom flask. Methyl acetate (122.OmL) was added and the mixture was vortexed for one minute to disperse the particles. The slurry was stirred at 25°C for two days. The resulting white solid was isolated by filtration on a Bϋchner funnel. The wet cake was dried at 500C under vacuum for five hours and yielded COMPOUND in crystalline Form 11. Form 11 is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 4.6°, 9.2°, 13.8°, 17.7°, 18.4°, and 22.2°, and more preferred by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 4.6°, 9.2°, and 13.8°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A). (Figure 9, Method B).
The following reference Examples 9 to 15, describe ways of obtaining further crystalline Forms (Forms 7, 8, and 12 to 16) of COMPOUND: Example 9:
Generation and characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2- phenyl-acetamide hydrochloride in crystalline Form 7
COMPOUND in hydrated crystalline Form 2 was submitted to a varying RH experiment at 25°C. After equilibration at 95% RH the relative humidity was decreased at a rate of 5%RH per hour until 0% RH, keeping the sample at 0%RH for 5 hours and scanning the humidity at the same rate back to 95%RH, staying there for 10 hours and scanning the RH at the same rate back down to 50%RH. The so obtained solid was COMPOUND a mixture of anhydrous crystalline Form 1 and crystalline Form 7. Form 7 is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 10.61 °, 15.79°, and 18.31 °, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A).
Example 10: Generation and characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-/V-methyl-2- phenyl-acetamide hydrochloride in crystalline Form 8
COMPOUND in anhydrous crystalline Form 1 (0.1 g) was dissolved in 3.0 ml_ 1 - propanol at room temperature. The solvent was evaporated within 60 minutes at 50°C and ca. 50 mbar. The so obtained solid was COMPOUND in a mixture of anhydrous crystalline Form 1 and crystalline Form 8. Form 8 is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 7.33°, 15.69°, 20.45°, 24.71 °, and 31.64°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A).
Example 11 :
Generation and characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2- phenyl-acetamide hydrochloride in crystalline Form 12
COMPOUND in anhydrous crystalline Form 1 (0.264 g) was weighed into a 20-mL vial. P-xylene (2.OmL) was added, and the mixture was stirred and thermocycled between 5°C-40°C (in four hour cycles) for two days. The resulting wet-cake was rapidly isolated using only a two minute vacuum filtration on a Bϋchner funnel. The so obtained solid was COMPOUND crystalline Form 12. Form 12 is characterized by the presence of peaks in the X-ray powder diffraction diagram (Method B) at the following angles of refraction 2Θ: 4.2°, 9.5°, 12.6°, 15.6°, 16.8°, 21.1 °, and 27.5°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A).
Example 12:
Generation and characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-/V-methyl-2- phenyl-acetamide hydrochloride in crystalline Form 13 COMPOUND in anhydrous crystalline Form 1 (0.76 g) and dichloromethane (1.2ml) was mixed in a 2-ml HPLC vial. The mixture was allowed to incubate at 25°C overnight. The solid in suspension was COMPOUND crystalline Form 13. Form 13 is characterized by the presence of peaks in the X-ray powder diffraction diagram (Method B) at the following angles of refraction 2Θ: 8.7°, 13.0°, 13.8°, 14.0°, 14.4°, 15.5°, 21.7°, and 23.4°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A).
Example 13:
Generation and characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2- phenyl-acetamide hydrochloride in crystalline Form 14
COMPOUND in anhydrous crystalline Form 1 (6.1 g) was weighed into a 250-mL round bottom flask, methyl acetate (122.OmL) was added and the mixture was vortexed for one minute to disperse the particles. The slurry was stirred at 25°C for two days. The resulting white solid was isolated by filtration on a Bϋchner funnel. The wet cake consists of COMPOUND in crystalline Form 14. Form 14 is characterized by the presence of peaks in the X-ray powder diffraction diagram (Method B) at the following angles of refraction 2Θ: 9.3°, 12.4°, 12.6°, 15.6°, 18.5°, 18.8°, 21.2°, 22.4° and 29.0°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A).
Example 14:
Generation and characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-/V-methyl-2- phenyl-acetamide hydrochloride in crystalline Form 15
COMPOUND in its amorphous form (0.2g) was suspended in 1 ,4-dioxane/carbon disulfide mixture (1 :4, 3ml) and stirred at 5°C for 1 day. The solid was quickly isolated by vacuum filtration.. The wet cake was COMPOUND in crystalline Form 15. Form 15 is characterized by the presence of peaks in the X-ray powder diffraction diagram (Method B) at the following angles of refraction 2Θ: 4.2°, 4.5°, 8.5°, 9.2°, 9.6, 12.7, 13.8, and 15.8°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A).
Example 15:
Generation and characterization of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2- phenyl-acetamide hydrochloride in crystalline Form 16
COMPOUND in anhydrous crystalline Form 1 (0.1 g) was suspended in tetrahydrofuran (1 ml) at room temperature overnight. The suspension was filtered to obtain a clear solution. The solution was then allowed to evaporate while being stirred. The so obtained wet solid was COMPOUND in crystalline Form 16. Form 16 is characterized by the presence of peaks in the X-ray powder diffraction diagram (Method B) at the following angles of refraction 2Θ: 4.2°, 4.6°, 8.4°, 9.4°, 9.8°, 12.7°, 14.1 °, 15.0°, 18.9°, and 23.2°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A).

Claims

Claims
1. A hydrated crystalline form of the compound (2R)-2-{(1 S)-6,7-dimethoxy-1 -[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2-phenyl- acetamide hydrochloride containing from 0.5 to 5 equivalents of H2O per equivalent of (2R)-2-{(1S)-6,7-dimethoxy-1 -[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H- isoquinolin-2-yl}-Λ/-methyl-2-phenyl-acetamide hydrochloride.
2. A hydrated crystalline form according to claim 1 , which contains from 1 to 3.5 equivalents of H2O per equivalent of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2-phenyl- acetamide hydrochloride.
3. A hydrated crystalline form according to claim 1 , which contains from 2.5 to 3.5 equivalents of H2O per equivalent of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4- trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}-Λ/-methyl-2-phenyl- acetamide hydrochloride. 4. A hydrated crystalline form according to any one of claims 1 to 3, characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 8.
4°, 13.2°, and 17.0°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A).
5. A hydrated crystalline form according to any one of claims 1 to 3, characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2Θ: 8.4°, 10.4°, 11.1 °, 11.3°, 13.2°, 16.3°, 16.7°, 17.0°, and 19.6°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ = 1.5406 A).
6. A hydrated crystalline form according to any one of claims 1 to 5, obtainable by: i) suspending COMPOUND in the anhydrous crystalline Form 1 (1.2 g) in water (4 ml_) at room temperature; ii) sonicating the sample for 2 minutes in a standard sonication bath and stirring with a mechanical stirrer at room temperature for 16 hours, sonicating the sample for 1 minute, stirring with a mechanical stirrer at room temperature for 3 days, and sonicating the sample for 1 minute; iii) filtering off the solid by centhfugation and storing the solid at 92% relative humidity and room temperature.
7. A pharmaceutical composition comprising a hydrated crystalline form according to any one of claims 1 to 6 and a pharmaceutically acceptable excipient.
8. A pharmaceutical composition according to claim 7, wherein said pharmaceutical composition contains a high amount of water, wherein said high amount of water is defined by the ratio of
• the vapour pressure of water in said pharmaceutical composition to
• the vapour pressure of pure water at the same temperature, wherein said ratio is at least 0.8.
9. A hydrated crystalline form according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 7 or 8, for use as a medicament.
10. Use of a hydrated crystalline form according to any one of claims 1 to 6 for the preparation of a pharmaceutical composition for the prevention or treatment of diseases or disorders selected from the group consisting of all types of sleep disorders, of stress-related syndromes, of psychoactive substance use, abuse, seeking and reinstatement, of cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders, of eating or drinking disorders.
11. Use of a hydrated crystalline form according to any one of claims 1 to 6 for the preparation of a pharmaceutical composition for the prevention or treatment of diseases or disorders selected from the group consisting of all types of insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias, restless leg syndrome, sleep apneas, jet-lag syndrome, shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
12. A hydrated crystalline form according to any one of claims 1 to 6 for the prevention or treatment of diseases or disorders selected from the group consisting of all types of insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias, restless leg syndrome, sleep apneas, jet-lag syndrome, shiftwork syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
PCT/IB2010/050722 2009-02-20 2010-02-18 Solid forms of ( 2r) -2- { ( is ) -6, 7 -dimethoxy- 1- [2- (4-triflu0r0methyl-phenyl) -ethyl] -3, 4-dihydr0-1h -isoquinolin-2-yl} -n-methyl-2-phenyl-acetamide hydrochloride WO2010095106A1 (en)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2005118548A1 (en) 2004-03-01 2005-12-15 Actelion Pharmaceuticals Ltd Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
WO2007105177A1 (en) 2006-03-15 2007-09-20 Actelion Pharmaceuticals Ltd Tetrahydroisoquinoline derivatives to enhance memory function
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WO2005118548A1 (en) 2004-03-01 2005-12-15 Actelion Pharmaceuticals Ltd Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
WO2007105177A1 (en) 2006-03-15 2007-09-20 Actelion Pharmaceuticals Ltd Tetrahydroisoquinoline derivatives to enhance memory function
WO2009004772A1 (en) 2007-07-05 2009-01-08 Panasonic Corporation Robot arm control device and control method, robot and control program
WO2009083899A2 (en) * 2007-12-28 2009-07-09 Actelion Pharmaceuticals Ltd Process for the preparation of an enantiomeric trisubstituted 3,4-dihydro-isoquinoline derivative
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