WO2017172784A1 - Novel salts and crystals - Google Patents

Novel salts and crystals Download PDF

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Publication number
WO2017172784A1
WO2017172784A1 PCT/US2017/024562 US2017024562W WO2017172784A1 WO 2017172784 A1 WO2017172784 A1 WO 2017172784A1 US 2017024562 W US2017024562 W US 2017024562W WO 2017172784 A1 WO2017172784 A1 WO 2017172784A1
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Prior art keywords
salt
iti
acid
diffraction pattern
crystal
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English (en)
French (fr)
Inventor
Lawrence P. Wennogle
Peng Li
Edwin Aret
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Intra Cellular Therapies Inc
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Intra Cellular Therapies Inc
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Priority to JP2018550823A priority Critical patent/JP2019513143A/ja
Priority to EP17776467.7A priority patent/EP3436455A4/en
Priority to US16/090,144 priority patent/US10654854B2/en
Publication of WO2017172784A1 publication Critical patent/WO2017172784A1/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This disclosure relates to certain novel salts and crystal forms of a substituted heterocycle fused gamma-carboline, the manufacture thereof, pharmaceutical compositions thereof, and use thereof, e.g., in the treatment of diseases or abnormal conditions involving or mediated by the 5- HT 2 A receptor, serotonin transporter (SERT), and/or dopamine Di/D 2 receptor signaling pathways.
  • SERT serotonin transporter
  • DA dopamine
  • SERT serotonin transporter
  • ⁇ -007 is currently in clinical trials, i.a., for treatment of schizophrenia. While ITI-007 is a promising drug, its production and formulation present challenges.
  • ITI-007 In free base form, ITI-007 is an oily, sticky solid, with poor solubility, not only in water but also in many organic solvents. Making salts of the compound has proven to be unusually difficult.
  • a hydrochloride salt form of ITI-007 was disclosed in US 7183282, but this salt is hygroscopic and shows poor stability.
  • a toluenesulfonic acid addition salt (tosylate) of ITI- 007 was finally identified and described in WO 2009/114181. [0005] There is a need for alternative stable and pharmaceutically acceptable salts and polymorphs of ⁇ -007.
  • the disclosure thus provides novel oxalate, 4-aminosalicylate, and cyclamate salt forms of ITI-007, and polymorphs thereof, which are especially advantageous for use in the preparation of galenic formulations, together with methods of making and using the same.
  • Figure 1 depicts an X-ray powder diffraction pattern for an ITI-007 oxalate salt crystal.
  • Figure 2 depicts an X-ray powder diffraction pattern for an ITI-007 4-aminosalicylate salt crystal.
  • Figure 3 depicts an X-ray powder diffraction pattern for an ITI-007 cyclamate salt crystal.
  • the invention provides l-(4-fluoro-phenyl)-4-((6bR,10aS)-3- methyl-2,3,6b,9,10,10a-hexahydro-lH,7H-pyrido[3 ',4':4,5]pyrrolo[l,2,3-de]quinoxalin-8-yl)- butan-l-one (ITI-007) in oxalate salt form (Salt 1).
  • the invention therefore provides the following:
  • Salt 1.2 in a homogeneous crystal form, free or substantially free of other forms, e.g., free or substantially free, e.g., less than 10 wt. %, preferably less than about 5 wt. %, more preferably less than about 2 wt. %, still preferably less than about 1 wt. %, still preferably less than about 0.1 %, most preferably less than about 0.01 wt. % of amorphous forms.
  • Salt 1 in crystalline form when crystallized from a mixture of oxalic acid and ITI-007, e.g. in an organic solvent, e.g., comprising toluene, ethyl acetate or mixtures thereof; e.g., wherein the oxalic acid and ITI-007 are in a molar ratio of about 1: 1, and the solvent is ethyl acetate.
  • an organic solvent e.g., comprising toluene, ethyl acetate or mixtures thereof; e.g., wherein the oxalic acid and ITI-007 are in a molar ratio of about 1: 1, and the solvent is ethyl acetate.
  • Salt 1 which is a solvate, e.g., an ethyl acetate solvate.
  • any foregoing form of Salt 1 in the form of a crystal having an X-ray powder diffraction pattern corresponding to the d-spacing and/or angle (2-theta) values of the following table, for example at least five, or at least six, or at least seven, or at least eight of said values, e.g., taking into account potential variations due to sample purity and instrument variation, for example 29 shifts due to variation in X-ray wavelength, e.g., wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer with a copper anode and a nickel filter, e.g., comprising at least those peaks having a relative intensity of at least 0.4, e.g., at least 0.5, e.g., at least 0.6, e.g., comprising peaks 1, 2, 6, 7, 8, and 9:
  • any foregoing form of Salt 1 in the form of a crystal having an X-ray powder diffraction pattern corresponding to Figure 1, e.g., taking into account potential variations due to sample purity and instrument variation, for example 2 # shifts due to variation in X- ray wavelength, e.g., an X-ray powder diffraction pattern corresponding to Figure 1 generated using an X-ray diffractometer with a copper anode and a nickel filter.
  • Salt 1 in the form of a crystal having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8, peaks having angle (2-theta) values and/or d-spacing values as provided in 1.13 and 1.14.
  • the invention provides a process (Process 1) for the production of Salt 1, comprising
  • the invention provides a method of purifying l-(4-fluoro-phenyl)- 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH,7H-pyrido[3',4':4,5]pyrrolo[l,2,3- de]quinoxalin-8-yl)-butan-l-one (ITI-007) in free or salt form, comprising reacting a crude solution of ITI-007 with oxalic acid, and recovering the oxalate salt thus formed, e.g., in accordance with Process 1, and optionally converting the oxalate salt back to ⁇ -007 free base or to another salt form.
  • the invention provides the use of oxalic acid in a method of isolating and/or purifying ⁇ -007.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Salt 1, e.g., any of Salt 1.1-1.18, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier.
  • the invention provides pharmaceutical composition
  • Salt 1 e.g., any of Salt 1.1-1.18, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, wherein the Salt 1 is predominantly, or is entirely or substantially entirely, in dry crystalline form.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Salt 1, e.g., any of Salt 1.1-1.18, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, in the form of an injectable depot form, to provide extended release of ITI-007.
  • the invention provides Salt 1, e.g., any of Salt 1.1-1.18, or a pharmaceutical composition comprising Salt 1, e.g., any of Salt 1.1-1.18, for use in treating a disease or abnormal condition involving or mediated by the 5-HT 2 A receptor, serotonin transporter (SERT), and/or dopamine Di/D 2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulemia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive- compulsive disorder, sexual disorders, depression, schizophrenia, migraine, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, sleep disorders, conditions associated with cephalic pain, social phobias, or dementia.
  • the invention provides a method for the prophylaxis or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT 2 A receptor, serotonin transporter (SERT), and/or dopamine Di/D 2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulemia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorders, depression, schizophrenia, migraine, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, sleep disorders, conditions associated with cephalic pain, social phobias, or dementia, comprising administering to a patient in need thereof a therapeutically effective amount of any of Salt 1, et seq.
  • the invention provides l-(4-fluoro-phenyl)-4-((6bR,10aS)-3- methyl-2,3,6b,9,10,10a-hexahydro-lH,7H-pyrido[3 ',4':4,5]pyrrolo[l,2,3-de]quinoxalin-8-yl)- butan-l-one (ITI-007) in 4-aminosalicylate salt form (Salt 2).
  • the invention therefore provides the following:
  • Any foregoing form of Salt 2 in crystalline form, when crystallized from a mixture of 4- aminosalicylic acid e.g.
  • an organic solvent e.g., comprising methanol; e.g., wherein the 4-aminosalicylic acid and ITI-007 are in a molar ratio of about 1: 1, the solvent is methanol, and dibutylether is added as an anti-solvent to precipitate the crystal.
  • Salt 2 which is a solvate, e.g., a methanol solvate.
  • Salt 2 which is a hydrate.
  • Salt 2 which is not a hydrate.
  • Salt 2 formed by combining free ITI-007 free base and 4- aminosalicylic acid in a 1 : 1 molar ratio.
  • any foregoing form of Salt 2 in the form of a crystal having an X-ray powder diffraction pattern corresponding to the d- spacing and/or angle (2-theta) values from the following table, for example at least five, or at least six, or at least seven, or at least eight of said values, e.g., taking into account potential variations due to sample purity and instrument variation, for example 29 shifts due to variation in X-ray wavelength, e.g., wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer with a copper anode and a nickel filter, e.g., comprising at least those peaks having a relative intensity of at least 0.4, e.g., at least 0.5, e.g., at least 0.6, e.g., comprising peaks 5, 6, and 19:
  • Any foregoing form of Salt 2 in the form of a crystal having an X-ray powder diffraction pattern corresponding to Figure 2, e.g., taking into account potential variations due to sample purity and instrument variation, for example 2 # shifts due to variation in X- ray wavelength, e.g., an X-ray powder diffraction pattern corresponding to Figure 3 generated using an X-ray diffractometer with a copper anode and a nickel filter. .
  • any foregoing form of Salt 2 in the form of a crystal having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8, peaks having angle (2-theta) values selected from the group consisting of about 6.74, 7.12, 8.37, 11.10, 12.25, 12.44, 13.22, 13.40, 14.85, 15.21, 16.12, 16.77, 17.70, 17.71, 18.19, 18.80, 18.97, 19.70, 20.18, 20.67, 21.49, 22.07, 22.47, 23.87, 24.29, 24.40, 24.94, 25.24, 25.99, 26.42, 27.29, 27.30, 28.05, 30.12, 33.53, 35.96, 36.21, and 36.07, taking into account potential variations due to sample purity and instrument variation, wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer with a copper anode and a nickel filter.
  • any foregoing form of Salt 2 in the form of a crystal having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8, peaks having d-spacing values selected from the group consisting of about 13.10, 12.41, 10.55, 7.96, 7.22, 7.11, 6.69, 6.60, 5.96, 5.82, 5.49, 5.28, 5.01, 5.00, 4.88, 4.72, 4.67, 4.50, 4.40, 4.29, 4.13, 4.02, 3.95, 3.73, 3.66, 3.65, 3.57, 3.53, 3.43, 3.37, 3.27, 3.26, 3.18, 2.96, 2.67, 2.50, 2.49, and 2.48, taking into account potential variations due to sample purity and instrument variation, wherein the X-ray powder diffraction pattern is generated using an X-ray diffractometer with a copper anode and a nickel filter.
  • Any foregoing form of Salt 2 in the form of a crystal having an X-ray powder diffraction pattern having at least 5, or at least 6, or at least 7, or at least 8, peaks having angle (2-theta) values and/or d-spacing values as provided in 2.13 and 2.14.
  • Any foregoing form of Salt 2 in the form of a crystal having an X-ray powder diffraction powder having relative angle (2-theta) values as provided in the table of embodiment 2.11, wherein the values are shifted by up to +/- 0.2 degrees, e.g., wherein the values are substantially uniformly shifted by up to +/- 0.2 degrees.
  • the invention provides a process for the production of Salt 2 (Process 2), comprising
  • the invention provides a method of purifying l-(4-fluoro-phenyl)- 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH,7H-pyrido[3',4':4,5]pyrrolo[l,2,3- de]quinoxalin-8-yl)-butan-l-one (ITI-007) in free or salt form, comprising reacting a crude solution of ⁇ -007 with 4-aminosalicylic acid, and recovering the 4-aminosalicylate salt thus formed, e.g., in accordance with Process 2, and optionally converting the 4-aminosalicylate salt back to ITI-007 free base or to another salt form.
  • the invention provides the use of 4-aminosalicylic acid in a method of isolating and/or purifying ITI-007.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Salt 2, e.g., any of Salt 2.1-2.18, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier.
  • the invention provides pharmaceutical composition comprising Salt 2, e.g., any of Salt 2.1-2.18, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, wherein the Salt 2 is predominantly, or is entirely or substantially entirely, in dry crystalline form.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Salt 2, e.g., any of Salt 2.1-2.18, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, in the form of an injectable depot form, to provide extended release of ITI-007.
  • the invention provides Salt 2, e.g., any of Salt 2.1-2.18, or a pharmaceutical composition comprising Salt 2, e.g., any of Salt 2.1-2.18, for use in treating a disease or abnormal condition involving or mediated by the 5-HT 2 A receptor, serotonin transporter (SERT), and/or dopamine Di/D 2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulemia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive- compulsive disorder, sexual disorders, depression, schizophrenia, migraine, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, sleep disorders, conditions associated with cephalic pain, social phobias, or dementia.
  • the invention provides a method for the prophylaxis or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT 2 A receptor, serotonin transporter (SERT), and/or dopamine Di/D 2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulemia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorders, depression, schizophrenia, migraine, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, sleep disorders, conditions associated with cephalic pain, social phobias, or dementia, comprising administering to a patient in need thereof a therapeutically effective amount of any of Salt 2, et seq.
  • the invention provides l-(4-fluoro-phenyl)-4-((6bR,10aS)-3- methyl-2,3,6b,9,10,10a-hexahydro-lH,7H-pyrido[3 ',4':4,5]pyrrolo[l,2,3-de]quinoxalin-8-yl)- butan-l-one (ITI-007) in cyclamate salt form (Salt 3).
  • the invention therefore provides the following:
  • Salt 3 or 2.1 in dry crystalline form Salt 3.2 in a homogeneous crystal form, free or substantially free of other forms, e.g., free or substantially free, e.g., less than 10 wt. %, preferably less than about 5 wt. %, more preferably less than about 2 wt. %, still preferably less than about 1 wt. %, still preferably less than about 0. 1 %, most preferably less than about 0.01 wt. % of amorphous forms. Any foregoing form of Salt 3 in crystalline form, when crystallized from a mixture of cyclamic acid, e.g.
  • salt 3 which is a solvate, e.g., an acetonitrile solvate.
  • Salt 3 which is a hydrate.
  • Salt 3 formed by combining free ITI-007 free base and cyclamic acid in a 1 : 1 molar ratio.
  • the invention provides a process for the production of Salt 3, comprising
  • the invention provides a method of purifying l-(4-fluoro-phenyl)- 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH,7H-pyrido[3',4':4,5]pyrrolo[l,2,3- de]quinoxalin-8-yl)-butan-l-one (ITI-007) in free or salt form, comprising reacting a crude solution of ⁇ -007 with 4-aminosalicylic acid, and recovering the 4-aminosalicylate salt thus formed, e.g., in accordance with Process 2, and optionally converting the 4-aminosalicylate salt back to ITI-007 free base or to another salt form.
  • the invention provides the use of 4-aminosalicylic acid in a method of isolating and/or purifying ITI-007.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Salt 3, e.g., any of Salt 3.1-3.18, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier.
  • the invention provides a pharmaceutical composition comprising Salt 3, e.g., any of Salt 3.1-3.18, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, wherein the Salt 3 is predominantly, or is entirely or substantially entirely, in dry crystalline form.
  • the invention provides a pharmaceutical composition comprising Salt 3, e.g., any of Salt 3.1-3.18, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, in the form of an injectable depot form, to provide extended release of ITI-007.
  • the invention provides Salt 3, e.g., any of Salt 3.1-3.18, or a pharmaceutical composition comprising Salt 3, e.g., any of Salt 3.1-3.18, for use in treating a disease or abnormal condition involving or mediated by the 5-HT 2 A receptor, serotonin transporter (SERT), and/or dopamine Di/D 2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulemia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive- compulsive disorder, sexual disorders, depression, schizophrenia, migraine, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, sleep disorders, conditions associated with cephalic pain, social phobias, or dementia.
  • the invention provides a method for the prophylaxis or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT 2 A receptor, serotonin transporter (SERT), and/or dopamine Di/D 2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulemia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorders, depression, schizophrenia, migraine, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, sleep disorders, conditions associated with cephalic pain, social phobias, or dementia, comprising administering to a patient in need thereof a therapeutically effective amount of any of Salt 3, et seq.
  • the standard sample holder (0.1 mm cavity in (510) silicon wafer) has a minimal contribution to the background signal. Measurement conditions: scan range 5 - 45° 2 ⁇ , sample rotation 5 rpm, 0.5s/step, 0.010°/step, 3.0mm detector slit; and all measuring conditions are logged in the instrument control file. As system suitability, corundum sample A26- B26-S (NIST standard) is measured daily.
  • the software used for data collection is Diffrac. Commander v2.0.26. Data analysis is done using Diffrac.Eva vl.4. No background correction or smoothing is applied to the patterns.
  • TGA thermogravimetry
  • DSC differential scanning calorimetry
  • TGA/DSC studies are performed using a Mettler Toledo TGA/DSC 1 Stare System, equipment #1547, auto-sampler equipped, using pin-holed Al- crucibles of 40 ⁇ . Measurement conditions: 5 min 30.0 °C, 30.0 - 350.0 °C with 10 °C/min., N2 flow of 40 ml/min.
  • the software used for instrument control and data analysis is STARe vl2.10.
  • DSC Differential scanning calorimetry
  • PLM Polarized light microscopy
  • the microscopy studies are performed using an AxioVert 35M, equipped with an AxioCamERc 5s, equipment #1612.
  • the microscope is equipped with four lenses: Zeiss A-Plan 5x/0.12, Zeiss A-Plan lOx/0.25, LD A-Plan 20x/0.30 and Achros TIGMAT 32x/0.40.
  • Data collection and evaluation is performed using Carl Zeiss Zen Axio Vision Blue Edition Lite 2011 vl.0.0.0 software. A small amount of sample is loaded on an object glass and carefully spread until a thin layer is obtained.
  • Dynamic Vapour Sorption The Dynamic Vapour Sorption studies are performed using a Surface Measurement Systems Ltd. DVS-1 No Video, equipment #2126. The sample is loaded into a balance pan, typically 20-30 mg, and equilibrated at 0% RH. After the material was dried, the RH is increased with 10% per step for 1 hour per increment, ending at 95% RH. After completion of the sorption cycle, the sample was dried using the same method.
  • the software used for data collection is DVSWin v3.01 No Video. Data analysis is performed using DVS Standard Analysis Suite v6.3.0 (Standard).
  • Capillary Melting Point The capillary melting point is determined on a Biichi Melting Point B-545, equipment #000011, conform USP guidelines.
  • X-ray fluorescence (XRF): The X-ray fluorescence studies are performed using a Bruker AXS S2 RANGER, equipment #2006. Using an end-window X-ray tube with Palladium anode and an ultra-thin Beryllium window (75 ⁇ ) for superior light element analysis. As detector the Xflash V5 detector with Cr, Ti, Al, Ta collimator (energy resolution ⁇ 129 eV FWHM at 100 000 cps Mnka) is used. The S2 Ranger is equipped with an autosampler with integrated 28 position X- Y automatic sample changer with exchangeable tray, which allows maximum sample diameter of 40 mm. Samples are mounted in steel rings of 51.5 mm diameter for automatic operation.
  • Measurement conditions disposable liquid cups (35 mm inner diameter, 40 mm outer diameter) with polypropylene foil 5 ⁇ . As system suitability check a copper disk is measured daily and a glass disk, containing several elements, is measured weekly.
  • the software used for data collection is S2 Ranger Control Software V4.1.0. Data analysis is performed using SPECTRA EDX V2.4.3 evaluation software. No background correction or smoothing is applied to the patterns.
  • FT-IR Fourier transform infrared spectroscopy
  • the off-gassing materials are directed through a transfer line to a gas cell, where the infrared light interacts with the gases.
  • the temperature ramp and first derivative weight loss information from the TGA is shown as a Gram-Schmidt (GS) profile; the GS profile essentially shows the total change in the IR signal relative to the initial state. In most cases, the GS and the derivative weight loss will be similar in shape, although the intensity of the two can differ. For this experiment are two devices coupled to each other.
  • the TGA studies are performed using a Mettler Toledo TGA/DSCl STARe System with a 34-position auto sampler, equipment #1547. The samples are made using Al crucibles (100 ⁇ ; pierced).
  • High performance liquid chromatography HPLC: The high performance liquid chromatography analyses are performed on LC-31, equipped with an Agilent 1100 series G1322A degasser equipment #1894, an Agilent 1100 series G1311A quaternary pump equipment #1895, an Agilent 1100 series G1313A ALS equipment #1896, an Agilent 1100 series G1318A column equipment #1897 and an Agilent 1100 series G1314A VWD equipment #1898 / LC-34, equipped with an Agilent 1200 series G1379B degasser equipment #2254, an Agilent 1100 series G1311A quaternary pump equipment #2255, Agilent 1100 series G1367A WPALS equipment #1656, an Agilent 1100 series G1316A column equipment #2257 and an Agilent 1100 series G1315B DAD equipment #2258.
  • HPLC High performance liquid chromatography
  • Solubility of free base in various solvents is evaluated, and based on the results of the solubility range, suitable solvents are selected for the salt screen.
  • the salt screen is divided into seven separate screens, using 90 different counter ions, six different solvents, and including four different crystallization methods, slurry experiments, cooling crystallization, evaporation and precipitation experiments.
  • the counterions are selected based upon availability and potential suitability to form pharmaceutically acceptable acid addition salts. They include the class I, II and III acids identified in Stahl P. H., Wermuch C.G. (editors), Handbook of Pharmaceutical Salts, IUPAC (2008).
  • An oxalate salt of ITI-007 is obtained in the course of salt screening from a slurry in ethyl acetate.
  • FT-IR of the ITI-007 oxylate salt formed in the experiments using oxalic acid shows 80% similarity with the FT-IR of the free base and -5-10% similarity with that of oxalic acid itself.
  • LC analysis shows no decomposition of the free base moiety of the formed salt, meaning an oxalate salt of ITI-007 has formed. This experiment is then repeated at gram scale and a concentration of lOOmg/mL of ITI-007 free base is used.
  • the oxalate salt is also analyzed by DSC/TGA, DVS, HPLC, ⁇ NMR and FT-IR.
  • Analysis of the HPLC data shows a purity of 91-area%.
  • Analysis of the ⁇ - ⁇ data shows some shifts compared to the free base, which confirms the salt formation.
  • FT-IR analysis confirms the chemical structure.
  • DVS analysis shows some stepwise sorption; the total mass uptake at 95 RH% is 5%, so the oxalate salt is moderately hygroscopic.
  • a 4-aminosalicylate salt is obtained in screening in a precipitation experiment using methanol. This experiment is repeated at a gram scale.
  • the ITI-007 free base and 4-aminosalicylic acid (ratio 1: 1) are dissolved in methanol (5 mL) and then dibutylether is added as an anti-solvent (lOmL).
  • the mixture is shaken at room temperature and a yellow solid is precipitated.
  • the yellow solid is filtered, dried and analyzed by XRPD.
  • XRPD analysis shows the 4-aminosalicilate salt to be crystalline.
  • the XRPD pattern is shown in Figure 2; the peaks are identified in tabular form in table 3:
  • the 4-aminosalicylate salt is also analyzed by DVS, DSC/TGA and HPLC, the results are summarized in table 4.
  • TGA shows three different mass losses, 1.8% in the temperature range of 40°C- 120°C, 10.8% in the temperature range 120°C-190°C and 13.8% in the temperature range of 190- 260°C.
  • the material decomposes above 260°C.
  • Analysis of the HPLC data shows a purity of 78- area%.
  • Analysis of the ⁇ - ⁇ data shows shift compared to the free base, both the free base and 4-aminosalicylic acid are present, which confirms the salt formation.
  • FT-IR analysis confirms the chemical structure.
  • Analysis of the DVS data shows a stepwise sorption with a total mass uptake of 5% (at 95 RH%), which indicates the 4-aminosalicylate is moderately hygroscopic.
  • a cyclamate salt of ITI-007 is obtained by screening in a slurry experiment in acetonitrile. This experiment is repeated at gram scale using a concentration of lOOmg/mL ITI- 007 free base. The free base and cyclamic acid are added in 1 : 1 ratio, and then acetonitrile is added and the mixture is slurried at 50°C for 2 hours. The mixture is allowed to cool down to room temperature, then filtered and dried to give an off white powder.
  • XRPD analysis shows the cyclamate to be a crystalline powder. The XRPD pattern is shown in Figure 3; the peaks are identified in tabular form in table 5:
  • the cyclamate salt of ITI-007 is also analyzed by DVS, DSC/TGA and HPLC. The results are summarized in table 20.
  • the third endothermic event represents decomposition of the compound, confirmed by the corresponding mass loss of 56.3%.
  • TGA shows another mass loss of 19.9% in the temperature range of 180°C- 260°C.
  • Analysis of the HPLC data shows a purity of 67 area%.
  • Analysis of the ⁇ - ⁇ data show some shifts compared to the free base, both the free base and cyclamic acid are present, which confirms the cyclamate salt formation.
  • FT-IR analysis confirms the chemical structure.
  • Analysis of the DVS data shows stepwise sorption with at total mass uptake of 8% at 95RH%, meaning the cyclamate salt is somewhat hygroscopic.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018189646A1 (en) 2017-04-10 2018-10-18 Dr. Reddy's Laboratories Limited AMORPHOUS FORM AND SOLID DISPERSIONS OF LUMATEPERONE p-TOSYLATE
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7183282B2 (en) * 1999-06-15 2007-02-27 Bristol-Myers Squibb Pharma Company Substituted heterocycle fused γ-carbolines
WO2009114181A2 (en) * 2008-03-12 2009-09-17 Intra-Cellular Therapies, Inc. Substituted heterocycle fused gamma-carbolines solid
US20140364609A1 (en) * 2007-03-12 2014-12-11 Intra-Cellular Therapies, Inc. Substituted heterocycle fused gamma-carbolines synthesis
US20150166540A1 (en) * 2010-04-22 2015-06-18 Intra-Cellular Therapies, Inc. Organic compounds
US20160030425A1 (en) * 2008-05-27 2016-02-04 Intra-Cellular Therapies, Inc. Methods and compositions for sleep disorders and other disorders

Family Cites Families (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2490813A (en) 1944-11-29 1949-12-13 Standard Oil Co Continuous process for making aryl amines
US3299078A (en) 1962-10-01 1967-01-17 Smith Kline French Lab Pyrido [3', 4': 4, 5] pyrrolo [3, 2, 1-hi] indoles and-[3, 2, 1-ij] quinolines
US3813392A (en) 1969-06-09 1974-05-28 J Sellstedt Pyrrolo(1,2,3-alpha epsilon)quinoxalin-2(3h)-ones and related compounds
US4115577A (en) 1972-06-19 1978-09-19 Endo Laboratories, Inc. Pyridopyrrolobenzheterocycles
US3914421A (en) 1972-06-19 1975-10-21 Endo Lab Pyridopyrrolobenzheterocycles for combatting depression
US4238607A (en) 1972-06-19 1980-12-09 Endo Laboratories Inc. Pyridopyrrolo benzheterocycles
US4183936A (en) 1972-06-19 1980-01-15 Endo Laboratories, Inc. Pyridopyrrolobenzheterocycles
US4219550A (en) 1978-11-09 1980-08-26 E. I. Du Pont De Nemours And Company Cis- and trans- octahydropyridopyrrolobenzheterocycles
US4522944A (en) 1982-12-23 1985-06-11 Erba Farmitalia Carboxamido-derivatives of 5H-1,3,4-thiadiazolo[3,2-a]pyrimidines, compositions and use
ZA871987B (en) 1986-03-19 1988-05-25 Kumiai Chemical Industry Co 5h-1,3,4-thiadiazole(3,2-a)pyrimidin-5-one derivatives and fungicidal compositions containing the same
ES2058069T3 (es) 1986-04-07 1994-11-01 Kumiai Chemical Industry Co Derivados de 5h-1,3,4-tiadiazolo-(3,2-a)-pirimidin-5-ona y nuevo compuesto fungicida agricola-horticola que contiene dicho derivado.
HU208484B (en) 1988-08-17 1993-11-29 Chinoin Gyogyszer Es Vegyeszet Process for producing pharmaceutical composition containing acid additional salt of selegilin as active component for treating schisofrenia
US5114976A (en) 1989-01-06 1992-05-19 Norden Michael J Method for treating certain psychiatric disorders and certain psychiatric symptoms
US5576460A (en) 1994-07-27 1996-11-19 Massachusetts Institute Of Technology Preparation of arylamines
US5648539A (en) 1996-02-29 1997-07-15 Xerox Corporation Low temperature arylamine processes
US5654482A (en) 1996-02-29 1997-08-05 Xerox Corporation Triarylamine processes
US5648542A (en) 1996-02-29 1997-07-15 Xerox Corporation Arylamine processes
US5847166A (en) 1996-10-10 1998-12-08 Massachusetts Institute Of Technology Synthesis of aryl ethers
US5723669A (en) 1997-01-30 1998-03-03 Xerox Corporation Arylamine processes
US5705697A (en) 1997-01-30 1998-01-06 Xerox Corporation Arylamine processes
US5723671A (en) 1997-01-30 1998-03-03 Xerox Corporation Arylamine processes
US6323366B1 (en) 1997-07-29 2001-11-27 Massachusetts Institute Of Technology Arylamine synthesis
GB2328686B (en) 1997-08-25 2001-09-26 Sankio Chemical Co Ltd Method for producing arylamine
US6395939B1 (en) 1997-10-06 2002-05-28 Massachusetts Institute Of Technology Diaryl ether condensation reactions
US6235936B1 (en) 1998-02-26 2001-05-22 Massachusetts Institute Of Technology Metal-catalyzed arylations of hydrazines, hydrazones, and related substrates
JP4647780B2 (ja) 1998-02-26 2011-03-09 マサチューセッツ インスティテュート オブ テクノロジー ヒドラジン、ヒドラゾン、ヒドロキシルアミンおよびオキシムの金属−触媒アリール化およびビニル化
US5902901A (en) 1998-05-07 1999-05-11 Xerox Corporation Arylamine processes
DE69935933T2 (de) 1998-07-10 2008-01-10 Massachusetts Institute Of Technology, Cambridge Liganden für Metalle und verbesserte Metall-katalysierte Verfahren, die darauf basieren
US6395916B1 (en) 1998-07-10 2002-05-28 Massachusetts Institute Of Technology Ligands for metals and improved metal-catalyzed processes based thereon
US6307087B1 (en) 1998-07-10 2001-10-23 Massachusetts Institute Of Technology Ligands for metals and improved metal-catalyzed processes based thereon
US7223879B2 (en) 1998-07-10 2007-05-29 Massachusetts Institute Of Technology Ligands for metals and improved metal-catalyzed processes based thereon
US20010008942A1 (en) 1998-12-08 2001-07-19 Buchwald Stephen L. Synthesis of aryl ethers
US6407092B1 (en) 1999-04-23 2002-06-18 Pharmacia & Upjohn Company Tetracyclic azepinoindole compounds
AR023574A1 (es) 1999-04-23 2002-09-04 Pharmacia & Upjohn Co Llc Compuestos de azepinindol tetraciclico,composiciones farmaceuticas y el uso de dichos compuestos para preparar un medicamento, e intermediarios
HK1043112A1 (zh) 1999-06-15 2002-09-06 Bristol-Myers Squibb Pharma Company 取代的稠杂环γ-咔啉
US6713471B1 (en) 1999-06-15 2004-03-30 Bristol-Myers Squibb Pharma Company Substituted heterocycle fused gamma-carbolines
US6541639B2 (en) 2000-07-26 2003-04-01 Bristol-Myers Squibb Pharma Company Efficient ligand-mediated Ullmann coupling of anilines and azoles
US6849619B2 (en) 2000-12-20 2005-02-01 Bristol-Myers Squibb Company Substituted pyridoindoles as serotonin agonists and antagonists
HUP0303432A3 (en) 2000-12-20 2012-09-28 Bristol Myers Squibb Co Substituted pyridoindoles as serotonin agonists and antagonists and pharmaceutical compositions containing the compounds and their use
EP1390340B1 (en) 2001-04-24 2017-03-01 Massachusetts Institute Of Technology Copper-catalyzed formation of carbon-heteroatom and carbon-carbon bonds
US6888032B2 (en) 2002-08-02 2005-05-03 Massachusetts Institute Of Technology Copper-catalyzed formation of carbon-heteroatom and carbon-carbon bonds
US7223870B2 (en) 2002-11-01 2007-05-29 Pfizer Inc. Methods for preparing N-arylated oxazolidinones via a copper catalyzed cross coupling reaction
ES2364046T3 (es) 2002-12-19 2011-08-23 Bristol-Myers Squibb Company Gamma-carbolinas tricíclicas sustituidas utilizadas como agonistas y antagonistas de los receptores de la serotonina.
CN1852893A (zh) 2003-07-21 2006-10-25 史密丝克莱恩比彻姆公司 (2S,4S)－4－氟－1－[4－氟－β－(4－氟苯基)－L－苯基丙氨酰基]－2－吡咯烷甲腈对甲苯磺酸盐及其无水晶体形式
US7109064B2 (en) 2003-12-08 2006-09-19 Semiconductor Components Industries, L.L.C. Method of forming a semiconductor package and leadframe therefor
JP2005259113A (ja) 2004-02-12 2005-09-22 Ricoh Co Ltd プロセス編集装置、プロセス管理装置、プロセス編集プログラム、プロセス管理プログラム、記録媒体、プロセス編集方法及びプロセス管理方法
US20050222209A1 (en) 2004-04-01 2005-10-06 Zeldis Jerome B Methods and compositions for the treatment, prevention or management of dysfunctional sleep and dysfunctional sleep associated with disease
US7592454B2 (en) 2004-04-14 2009-09-22 Bristol-Myers Squibb Company Substituted hexahydro-pyridoindole derivatives as serotonin receptor agonists and antagonists
MX2007006896A (es) 2004-12-15 2007-06-26 Hoffmann La Roche Fenil-metanonas bi- y triciclicas sustituidas como inhibidores del transportador 1 de glicina (glyt-1) para el tratamiento de la enfermedad de alzheimer.
KR20070099031A (ko) 2005-01-25 2007-10-08 셀진 코포레이션 4-아미노-2-(3-메틸-2,6-디옥소피페리딘-3-일)-이소인돌-1,3-디온을 사용한 방법 및 조성물
US20080194592A1 (en) 2005-08-23 2008-08-14 Intra-Cellular Therapies, Inc. Organic Compounds
JP2009523734A (ja) 2006-01-13 2009-06-25 ワイス ５−ヒドロキシトリプタミン受容体のためのリガンドとしてのスルホニル置換された１ｈ−インドール
US7998971B2 (en) 2006-09-08 2011-08-16 Braincells Inc. Combinations containing a 4-acylaminopyridine derivative
WO2009017836A1 (en) 2007-08-01 2009-02-05 Medivation Neurology, Inc. Methods and compositions for treating schizophrenia using antipsychotic combination therapy
KR101071877B1 (ko) * 2009-02-18 2011-10-10 동아제약주식회사 유데나필 산부가염, 그의 제조방법 및 이를 포함하는 약학적 조성물
AU2013245702A1 (en) 2012-04-14 2014-11-13 Intra-Cellular Therapies, Inc. Organic compounds
WO2014145192A1 (en) 2013-03-15 2014-09-18 Intra-Cellular Therapies, Inc. Organic compounds
WO2015085004A1 (en) 2013-12-03 2015-06-11 Intra-Cellular Therapies, Inc. Novel methods
US11014925B2 (en) * 2016-03-28 2021-05-25 Intra-Cellular Therapies, Inc. Co-crystals of 1-(4-fluoro-phenyl)-4-((6bR,1OaS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H- pyrido[3′,4′:4,51_pyrrolo [1,2,3-delqcuinoxalin-8-yl)-butan-1-one with nicotinamide or isonicotinamide

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7183282B2 (en) * 1999-06-15 2007-02-27 Bristol-Myers Squibb Pharma Company Substituted heterocycle fused γ-carbolines
US20140364609A1 (en) * 2007-03-12 2014-12-11 Intra-Cellular Therapies, Inc. Substituted heterocycle fused gamma-carbolines synthesis
WO2009114181A2 (en) * 2008-03-12 2009-09-17 Intra-Cellular Therapies, Inc. Substituted heterocycle fused gamma-carbolines solid
US20160030425A1 (en) * 2008-05-27 2016-02-04 Intra-Cellular Therapies, Inc. Methods and compositions for sleep disorders and other disorders
US20150166540A1 (en) * 2010-04-22 2015-06-18 Intra-Cellular Therapies, Inc. Organic compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LI ET AL.: "Discovery of a Tetracyclic Quinoxaline Derivative as a Potent and Orally Active Multifunctional Drug Candidate for the Treatment of Neuropsychiatric and Neurological Disorders", J. MED. CHEM., vol. 57, 2014, pages 2670 - 2682, XP008177111 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11760757B2 (en) 2016-08-09 2023-09-19 Teva Pharmaceuticals International Gmbh Solid state forms of lumateperone ditosylate salt
US11332469B2 (en) 2016-08-09 2022-05-17 Teva Pharmaceuticals International Gmbh Solid state forms of lumateperone ditosylate salt
US11052083B2 (en) 2017-03-24 2021-07-06 Intra-Cellular Therapies, Inc. Transmucosal methods for treating psychiatric and neurological conditions
US12336989B2 (en) 2017-03-24 2025-06-24 Intra-Cellular Therapies, Inc. Transmucosal methods for treating psychiatric and neurological conditions
US12268686B2 (en) 2017-03-24 2025-04-08 Intra-Cellular Therapies, Inc. Transmucosal methods for treating psychiatric and neurological conditions
US10716786B2 (en) 2017-03-24 2020-07-21 Intra-Cellular Therapies, Inc. Transmucosal and subcutaneous compositions
US11806347B2 (en) 2017-03-24 2023-11-07 Intra-Cellular Therapies, Inc. Transmucosal methods for treating psychiatric and neurological conditions
US11292793B2 (en) 2017-04-10 2022-04-05 Dr. Reddy's Laboratories Limited Solid dispersions of amorphous Lumateperone p-Tosylate
WO2018189646A1 (en) 2017-04-10 2018-10-18 Dr. Reddy's Laboratories Limited AMORPHOUS FORM AND SOLID DISPERSIONS OF LUMATEPERONE p-TOSYLATE
CN112384218A (zh) * 2018-06-06 2021-02-19 细胞内治疗公司 新的盐和晶体
CN112384218B (zh) * 2018-06-06 2024-04-26 细胞内治疗公司 盐和晶体
EP3609891A4 (en) * 2018-06-11 2021-04-14 Intra-Cellular Therapies, Inc. SUMMARY OF GAMMA-CARBOLINES MELTED WITH SUBSTITUTED HETEROCYCLES
JP2024073559A (ja) * 2018-08-31 2024-05-29 イントラ－セルラー・セラピーズ・インコーポレイテッド 新規方法
WO2020112941A3 (en) * 2018-11-27 2020-07-09 Teva Czech Industries S.R.O Solid state forms of lumateperone salts and processes for preparation of lumateperone and salts thereof
WO2020112941A2 (en) 2018-11-27 2020-06-04 Teva Czech Industries S.R.O Solid state forms of lumateperone salts and processes for preparation of lumateperone and salts thereof
WO2020182978A1 (en) 2019-03-13 2020-09-17 Sandoz Ag Crystalline salt of a 5-ht2a receptor antagonist
WO2022199708A1 (zh) * 2021-03-26 2022-09-29 上海博志研新药物技术有限公司 卢美哌隆药用盐、制备方法、含其的药物组合物及应用
CN115120593A (zh) * 2021-03-26 2022-09-30 上海博志研新药物技术有限公司 卢美哌隆药用盐、制备方法、含其的药物组合物及应用

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