US20200157100A1 - Novel salts and crystals - Google Patents

Novel salts and crystals Download PDF

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US20200157100A1
US20200157100A1 US16/714,139 US201916714139A US2020157100A1 US 20200157100 A1 US20200157100 A1 US 20200157100A1 US 201916714139 A US201916714139 A US 201916714139A US 2020157100 A1 US2020157100 A1 US 2020157100A1
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salt
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salt according
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free base
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Peng Li
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Intra Cellular Therapies Inc
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Assigned to INTRA-CELLULAR THERAPIES, INC. reassignment INTRA-CELLULAR THERAPIES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LI, PENG
Priority to US17/652,076 priority patent/US20220281867A1/en
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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/24—Antidepressants
    • 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 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 2A receptor, serotonin transporter (SERT), and/or dopamine D 1 /D 2 receptor signaling pathways.
  • SERT serotonin transporter
  • 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (sometimes referred to as 4-((6bR,10aS)-3 -methyl-2,3,6b,9,10, 10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3 -de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone, and also known as Lumateperone or as ITI-007), has the following structure:
  • ITI-007 is currently in clinical trials, e.g., for the treatment of schizophrenia, depression, and other psychological disorders. While ITI-007 is a promising drug, its production and formulation present challenges. In free base form, ITI-007 is an oily, sticky solid, with poor aqueous solubility. Making salts of the compound has proven to be unusually difficult.
  • a hydrochloride salt form of ITI-007 was disclosed in U.S. Pat. No. 7,183,282, but this particular salt form was hygroscopic and showed poor stability. It was obtained by precipitation from diethyl ether.
  • a toluenesulfonic acid addition salt (tosylate) of ITI-007 was finally identified and described in WO 2009/114181 and US 2011/0112105 (U.S. Pat. No. 8,648,077).
  • ITI-007 does not readily form salts with other common, pharmaceutically acceptable acids, despite the good solubility of the free base in a variety of organic solvents.
  • a toluenesulfonic acid addition salt tosylate
  • WO 2009/114181 and US 2011/0112105 a toluenesulfonic acid addition salt
  • a major salt screen was carried out, wherein the free base compound was studied in different solvent systems and under different conditions, and then systematically screened using a selection of over 100 acids under different conditions and with different solvent, co-solvent and anti-solvent systems, to identify new possible salt forms.
  • a new bis-tosylate salt polymorph was discovered. This new bistosylate salt form is crystalline and stable.
  • the present disclosure thus provides a new bis-tosylate salt form of ITI-007, which is especially advantageous for use in the preparation of galenic formulations, together with methods of making and using the same.
  • This disclosure shows that this new bis-tosylate salt form of ITI-007 can be prepared under various conditions, including from the free base form of ITI-007, as well as from the mono-tosylate salt form of ITI-007.
  • FIG. 1 depicts overlaid X-ray powder diffraction (XRPD) patterns for the ITI-007 bis-tosylate salt crystal obtained from Example 1 (from a 1:1 molar mixture of ITI-007 free base and toluenesulfonic acid) (upper curve), with reference to the known XRPD pattern for ITI-007 mono-tosylate salt crystal (lower curve).
  • XRPD X-ray powder diffraction
  • FIG. 2 depicts the TGA-DSC thermogram of the ITI-007 bis-tosylate salt crystal obtained from Example 1.
  • FIG. 3 depicts the 1H-NMR spectrum of the ITI-007 bis-tosylate salt crystal obtained from Example 1.
  • FIG. 4 depicts the FTIR spectrum of the ITI-007 bis-tosylate salt crystal obtained from Example 1.
  • FIG. 5 depicts overlaid X-ray powder diffraction (XRPD) patterns for the ITI-007 mono-tosylate salt crystal obtained from Example 2 (from a 2:1 molar mixture of ITI-007 free base and toluenesulfonic acid) (upper curve), with reference to the known XRPD pattern for ITI-007 mono-tosylate salt crystal (lower curve).
  • XRPD X-ray powder diffraction
  • FIG. 6 depicts the TGA-DSC thermogram of the ITI-007 bis-tosylate salt crystal obtained from Example 2.
  • FIG. 7 depicts the 1H-NMR spectrum of the ITI-007 bis-tosylate salt crystal obtained from Example 2.
  • the invention provides 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9, 10, 10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3 -de]quinoxalin-8-yl)-butan-1-one (ITI-007) in stable bis-tosylate salt form (Salt 1).
  • the invention further provides the following:
  • the invention provides a process (Process 1) for the production of Salt 1, comprising
  • reaction step (a) comprises dissolving or suspending the ITI-007 free base in an organic solvent, e.g., 2-butanone, and adding thereto the toluenesulfonic acid.
  • reaction step (a) comprises combining the ITI-007 free base with the toluenesulfonic acid and adding thereto an organic solvent, e.g., 2-butanone.
  • the process step (a) is carried out as a batch process, and in other embodiments the process step (a) is carried out as a continuous (flow) process.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Salt 1, or any of Salts 1.1-1.27, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Salt 1, or any of Salts 1.1-1.27, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, wherein the salt is predominantly, or is entirely or substantially entirely, in dry crystalline form.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Salt 1, or any of Salts 1.1-1.27, as active ingredient, in combination or association with a pharmaceutically acceptable diluent or carrier, wherein the composition is in the form of an injectable depot, e.g., to provide extended release of ITI-007.
  • composition 2 comprising:
  • the invention provides a method of making Composition 2 comprising the steps of:
  • the invention provides Salt 1, or any of Salts 1.1-1.27, or a pharmaceutical composition comprising Salt 1, or any of Salts 1.1-1.27, for use in treating a disease or abnormal condition involving or mediated by the 5-HT 2A receptor, serotonin transporter (SERT), and/or dopamine D 1 /D 2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorders, bipolar depression, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, and/or dementia.
  • a disorder selected from obesity, anorexia, bulimia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorders, bipolar depression, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, and/or dementia e.
  • 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 2A receptor, serotonin transporter (SERT), and/or dopamine D 1 /D 2 receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorders, bipolar depression, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, and/or dementia, the method comprising administering to a patient in need thereof a therapeutically effective amount of Salt 1, or any of Salts 1.1-1.27.
  • 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, 0.5 s/step, 0.010° /step, 3.0 mm 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 v1.4. 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/DSC1 Stare System, equipment #1547, auto-sampler equipped, using pin-holed Al-crucibles of 40 ⁇ l. Measurement conditions: 5 min 30.0° C., 30.0-350.0° C. with 10° C./min., N 2 flow of 40 ml/min.
  • the software used for instrument control and data analysis is STARe v12.10.
  • DSC Differential scanning calorimetry
  • FT-IR Fourier transform infrared spectroscopy
  • High performance liquid chromatography HPLC: The high performance liquid chromatography analyses are performed on an 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
  • XRPD analysis shows the obtained solid to be a crystalline solid.
  • the XRPD pattern is shown in FIG. 1 (upper curve) with reference to the XRPD pattern obtained from a previously made ITI-007 mono-tosylate salt crystal (lower curve).
  • the reference crystal was obtained from a 1:1 molar mixture of ITI-007 and toluenesulfonic acid using ethyl acetate or toluene as solvent.
  • the results show clear differences in the XPRD pattern between the solid obtained by Example 1 and the reference ITI-007 mono-tosylate salt.
  • One key distinguishing peak that is believed to signal formation of the bis-tosylate salt appears at an angle (2-theta) of about 10.45.
  • the peaks for the compound of Example 1 are identified in tabular form in table 1:
  • the DSC/TGA thermogram is shown in FIG. 2 .
  • DSC/TGA analysis shows one endothermic event at about 184° C., and one exothermic event at about 258° C.
  • the endothermic event is a melt, while the exothermic event is a recrystallization.
  • the TGA profile shows a mass loss of 1.7% from 40° C.
  • the recrystallization event occurs at a temperature about 25° C. lower than that previously observed for the reference ITI-007 mono-tosylate salt crystal.
  • Proton NMR is shown in FIG. 3 .
  • Proton NMR analysis shows that the compound is the bis-tosylate salt of ITI-007.
  • the proton NMR spectrum shows the presence of about two toluenesulfonic acid moieties per ITI-007 base moiety. This is demonstrated by the NMR protons at about 7.11 ppm, 7.36 ppm, 7.49 ppm and 8.03 ppm, which are present at an integral ratio of about 4:2:4:2.
  • the 7.11 and 7.49 ppm peaks represent protons from the aromatic tosylate ring of the toluene sulfonate moiety, while the 7.36 and 8.03 peaks represent protons from the aromatic 4-fluorophenyl ring of the ITI-007 moiety.
  • the remaining aromatic peaks between 6.4 and 7.0 ppm represent the aromatic protons of the quinoxaline core of ITI-007 and their integral is consistent with one molar unit of ITI-007 free base.
  • the alkyl peak at about 2.3 ppm represents the methyl group of the tosylate rings and its integral is also consistent with two molar units of toluenesulfonic acid.
  • the FTIR spectrum is shown in FIG. 4 , and it is also consistent with a bis-tosylate structure of the salt.
  • Dynamic vapor sorption (DVS) analysis shows a stepwise sorption with a total mass uptake at 95 RH % of 2%. This salt is thus slightly hygroscopic. Analysis results are summarized in Table 2 below.
  • the salt of Example 1 is a distinct crystalline salt form comprising a 1:2 molar ratio of ITI-007 free base to toluene sulfonic acid.
  • the lower solubility of ITI-007 free base in 2-butanone solvent compared to other solvents, result in the effective concentration of free base being lower, and the effective ratio of free base to toluenesulfonic acid being higher.
  • the bis-tosylate salt forms and unreacted free base remains in solution after filtration of the product.
  • XRPD analysis shows the obtained solid to be a crystalline solid.
  • the XRPD pattern is shown in FIG. 5 (upper curve) with reference to the XRPD pattern obtained from a previously made ITI-007 mono-tosylate salt crystal (lower curve).
  • the reference crystal was obtained from a 1:1 molar mixture of ITI-007 and toluenesulfonic acid using ethyl acetate or toluene as solvent.
  • the results show substantially the same XPRD pattern between the solid obtained by Example 2 and the reference ITI-007 mono-tosylate salt.
  • the peaks for the compound of Example 2 are identified in tabular form in table 3:
  • the DSC/TGA thermogram is shown in FIG. 6 .
  • DSC/TGA analysis shows one endothermic event at about 179° C., and one exothermic event at about 285° C.
  • the endothermic event is a melt, while the exothermic event is a recrystallization.
  • the TGA profile shows a mass loss of 0.4% from 40° C. to 220° C., and a mass loss of 9.4% from 220° C. to 290° C.
  • Proton NMR is shown in FIG. 7 .
  • Proton NMR analysis shows that the compound is the mono-tosylate salt of ITI-007.
  • the spectrum proton NMR spectrum shows the presence of one toluenesulfonic acid moiety per ITI-007 base moiety. This is demonstrated by the NMR protons at about 7.11 ppm, 7.36 ppm, 7.52 ppm and 8.05 ppm, which are present at an integral ratio of about 2:2:2:2.
  • the 7.11 and 7.52 ppm peaks represent protons from the aromatic tosylate ring, while the 7.36 and 8.05 peaks represent protons from the aromatic 4-fluorophenyl ring of the ITI-007 free base.
  • the remaining aromatic peaks between 6.4 and 7.0 ppm represent the aromatic protons of the quinoxaline core of ITI-007 and their integral is consistent with one molar unit of ITI-007 free base (integrals in a 1:1:1 ratio of clearly distinct peaks).
  • the alkyl peak at about 2.3 ppm represents the methyl group of the tosylate ring and its integral is also consistent with one molar unit of toluenesulfonic acid.

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11332469B2 (en) 2016-08-09 2022-05-17 Teva Pharmaceuticals International Gmbh Solid state forms of lumateperone ditosylate salt
EP4134101A1 (en) 2019-07-07 2023-02-15 Intra-Cellular Therapies, Inc. Deuterated lumateperone for the treatment of the bipolar ii disorder
US11690842B2 (en) 2018-08-31 2023-07-04 Intra-Cellular Therapies, Inc. Pharmaceutical capsule compositions comprising lumateperone mono-tosylate
US11753419B2 (en) 2019-12-11 2023-09-12 Intra-Cellular Therapies, Inc. 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)phenyl)butan-1-one for treating conditions of the central nervous system and cardiac disorders
US11957791B2 (en) 2018-08-31 2024-04-16 Intra-Cellular Therapies, Inc. Methods
US12122792B2 (en) 2023-08-31 2024-10-22 Intra-Cellular Therapies, Inc. Pharmaceutical compositions comprising 4-((6bR,10aS)-3-methyl2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin8(7H)-yl)-1-(4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)phenyl)butan-1-one for treating conditions of the central nervous system and cardiac disorders

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110072518B (zh) 2016-10-12 2021-10-26 细胞内治疗公司 无定形固体分散体
WO2019241278A1 (en) * 2018-06-11 2019-12-19 Intra-Cellular Therapies, Inc. Substituted heterocycle fused gamma-carbolines synthesis
EP4208434A4 (en) * 2020-09-04 2024-10-16 Intra Cellular Therapies Inc NEW SALTS, CRYSTALS AND CO-CRYSTALS
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

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7071186B2 (en) 1999-06-15 2006-07-04 Bristol-Myers Squibb Pharma Co. Substituted heterocycle fused gamma-carbolines
PL2262505T3 (pl) * 2008-03-12 2015-04-30 Intra Cellular Therapies Inc Podstawione heterocykliczne skondensowane gamma-karboliny w postaci stałej
PL3125893T3 (pl) * 2014-04-04 2024-02-12 Intra-Cellular Therapies, Inc. Deuterowane gamma-karboliny w fuzji z heterocyklami jako antagoniści receptorów 5-HT2A
RU2733975C2 (ru) 2016-03-25 2020-10-08 Интра-Селлулар Терапиз, Инк. Органические соединения
EP3436455A4 (en) * 2016-03-28 2019-09-04 Intra-Cellular Therapies, Inc. NOVEL SALTS AND CRYSTALS
ES2901375T3 (es) * 2016-08-09 2022-03-22 Teva Pharmaceuticals Int Gmbh Formas en estado sólido de sal de ditosilato de lumateperona
EP3717484A4 (en) * 2017-11-27 2021-08-04 Egis Gyógyszergyár Zrt. PROCESS FOR THE PRODUCTION OF LUMATEPERON AND ITS SALT

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11332469B2 (en) 2016-08-09 2022-05-17 Teva Pharmaceuticals International Gmbh Solid state forms of lumateperone ditosylate salt
US11760757B2 (en) 2016-08-09 2023-09-19 Teva Pharmaceuticals International Gmbh Solid state forms of lumateperone ditosylate salt
US11690842B2 (en) 2018-08-31 2023-07-04 Intra-Cellular Therapies, Inc. Pharmaceutical capsule compositions comprising lumateperone mono-tosylate
US11806348B2 (en) 2018-08-31 2023-11-07 Intra-Cellular Therapies, Inc. Methods of treatment using pharmaceutical capsule compositions comprising lumateperone mono-tosylate
US11957791B2 (en) 2018-08-31 2024-04-16 Intra-Cellular Therapies, Inc. Methods
US12070459B2 (en) 2018-08-31 2024-08-27 Intra-Cellular Therapies, Inc. Pharmaceutical capsule compositions comprising lumateperone mono-tosylate
EP4134101A1 (en) 2019-07-07 2023-02-15 Intra-Cellular Therapies, Inc. Deuterated lumateperone for the treatment of the bipolar ii disorder
US20240066030A1 (en) * 2019-07-07 2024-02-29 Intra-Cellular Therapies, Inc. Novel methods
US12090155B2 (en) * 2019-07-07 2024-09-17 Intra-Cellular Therapies, Inc. Methods
US11753419B2 (en) 2019-12-11 2023-09-12 Intra-Cellular Therapies, Inc. 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)phenyl)butan-1-one for treating conditions of the central nervous system and cardiac disorders
US12122792B2 (en) 2023-08-31 2024-10-22 Intra-Cellular Therapies, Inc. Pharmaceutical compositions comprising 4-((6bR,10aS)-3-methyl2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin8(7H)-yl)-1-(4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)phenyl)butan-1-one for treating conditions of the central nervous system and cardiac disorders
US12128043B2 (en) 2024-03-12 2024-10-29 Intra-Cellular Therapies, Inc. Pharmaceutical capsules comprising lumateperone mono-tosylate

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CN112384218B (zh) 2024-04-26
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